The Rhodium (II)-Catalyzed Intramolecular

Tertiary C-H Insertion of Diazoacetates: Application

in the Total Synthesis of Alkaloids

Possessing A Chiral Quaternary Carbon Center

A Thesis

Submitted to the Faculty of Graduate Studies #and Research

In Partial Fulfillment of the Requirements

for the Degree of Doctor of Philosophy in Chemistry

University of Regina

BY

Qing Yu

Regina, Saskatchewan

December, 2000

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Abstract

The rhodium(1)-catalyzed teniary C-H insertion of a senes of a-substituted ac

diazoacetate derivatives wüs investigated as a methodology for the formation of 4,4-

disubstituted yrlactones. The initial studies used mode1 systern 3-(3-ethyl-2-methy1)pentyl

a-diazoacetate 69a-c possessing an acetyl. a carbomethoxy or a carbotrifluoroethoxy as cc

substituent. The result showed that the regioselectivity of the reaction was controlled by

the nature of the ligands on the dirhodium(II) catalysts: rhodium([D acetarnidate favored

tertiary C-H insertion and rhodium (II) perîluorobutyrate favored secondary C-H

insertion. It was also found that a-substituents on the carbenoid center affected y-lactones

distribution. The a-acetyl group promoted secondary C-H insertion and Pester group

hvored tertiary C-H insertion. Studies extended to more complex fi'-substituted cc-diazo

esters systems such as 5-(?-et hyl- I -pentenyl)-a-(carbornethoxy)-a-diazoacette 7?a and

5-(5-ethyl- 1 -hexenyl)-a-(carbomethoxy)-adocette 83, it was found that the

cyclopropanation was competi ti ve wi th tertiary C-H insertion. The rhodium(@ acerate

favored teniary C-H insertion and rhodium(lI) pefluorobutynte promoted

cyclopropanation. In contrast. the Rh(II)-catalyzed reaction of methyl 2-diazo-6-ethyl-3-

0x0-8-nonenoate 92 (bbcarbon" analog of 77a) resulted mainly in the cyclopentanone

derivative, and no cyclopropanation product was detected. This result suggests that the

ester oxygen in compound 77a and 83 play an important role in determining the regio-

and chemo-selectivities of their reactions.

The Rhz(OAc)4-catalyzed tertiary C-H reaction of [5-(t-butyldiphenylsilyloxy)-2-

ethylpentyll-a-diazo-a-(methoxycarbony) acetate 147 provided easy access to 4.4-

disubstituted ylactone 4-[3-(t-butyldiphenyIsilyloxypropyl)4ethyl~hy&o-2(3~-

furanone 152 which was used as a common key intermediate for the formai synthesis of

(+)-quebrachamine (+)-quebrachamine and total synthesis of (-)-eburnamonine and epi-

eburnarnonine.

The cornpound 152 was convened to ii Cs unit 4-ethyl-4-[2-

hydroxycarbonyl)ethy[]-2-methoxytetnhydrofuran 155. The Pictet-Spengler condensation

of tryptamine with 155 was the key step in the formal total synthesis of (k)-

quebrachamine. (S)4-[3-(r-buty~diphenylsilyloxypropyl)-.l-ethyldihydro-2(3H)-funnone

152 was converted to (3S)-6-(t-butyIdiphenylsilyl)oxy-3-ethyl-3-

[(methylsulfonyl)oxy~ethyl- 1-hexanal 201. The Pictet-Spengler condensation of

tryptamine with 201 was the key step in the formal total synthesis of (+)-quebracharnine.

The (S)- 152 w u also convened to another Co unit (49-N-[2-(3-indoly1)-ethylw-ethyl-l-

(2-r-butyldiphenylsiloxy-ethyl)-5-0x0-pente 253~ . The Pictet-Spengler condensation

of tryptamine with 253c was the key step in the total synthesis of (-)-ebumarnonine and

epi-eburnarnonine.

An approach toward the enantioselective synthesis of (-)-mesembrine is dso

described. The creation of chiral quaternary carbon canter was realized by Rhz(OAc)4-

catalyzed tertiary C-H insertion reaction of methyl (2R)-2-(3,4-dimethoxypheny1)-5-

hexen-1-y[ diazopropanedioate (97b). Next. the f o h c acid catdyzed acyliminium ion

cyclization of N-benzyl (4S)4(3-buten- 1 -yl)4-(3,4-dimethox ypheny1)-5-hydroxy-y-

lactam 316 was used as key step toward total synthesis of (-)-mesembrine.

Acknowledgments

The author would like to thank his research supervisor Dr. Andrew G.H. Wee for

his guidance and supervision throughout the research leading to this thesis.

Thanks are also extended to Mr. Henry Yee and his colleague Dr. B. Liu for their

understanding, encouragement and useful discussions.

Financial assistance from the Faculty of Graduate Studies and Reaserch. teaching

assistantshi ps from the Depanment of Chemistry and research rissistantshi ps through the

NSERC reseÿrch gant of Dr. Wee are ptefully acknowledged.

Finally, the author would like to express his hearty thanks to his wife who

sacrificed her own career drearn to support the family for such a long time. Special thanks

are given to his loving and understanding son. William. who brought him great joy and

responsibility and who has made a lot of sacrifices in order for the completion of this

tfiesis.

Table of Contents

.......................................................................................................... A bstract

........................................................................................... Acknowledgments

........................................................................................... Table of Contents

..................................................................................... List of A bbreviations

List of Figures ................................................................................................

List of Tables .................................................................................................

I

... 111

iv

i x

xii

... XI11

1 . Introduction .......................m....m..m....m...........m............m...................m....m..m....................m...m 1

1 . 1 Intramolecular Rh(ii)-Catalyzed Transformation of Diazo Carbonyl Compounds ....... 2

1.2 Rh(@-Cataiyzed Intnmolecular C-H Insertion of Diazo Carbonyl Compounds ......... 4

. . 1.2.1 Regioselectiv~ty of the Reaction ....................................................................... 5

1.2.2 Chemoselectivity of the Reaction ......................................................................... 13

.......................................... 1.3 Construction of Asymmetnc Quatemary Carbon Centen 14

......................................................................... 1.3.1 As ymmetnc Aldol Condensation 15

1.3.2 Asymmetric Alkylation Reaction .................................................................... 15

....................................................................... 1.3.3 Asymmetric Dieis-Alder Reaction 17

.................................................................................. 1.3 -4 As ymmetnc Hec k Reaction 18

............................................................ 1.3.5 Rh(II)-Catalyzed C-H Insertion Reaction 18

1.4 The Objectives of this Study ....................................................................................... 20

................................................................................................ 2 . Results and Discussion 22

77 ............................................ 2.1 Rh(II)-Catalyzed Tertiary C-H Insertion of Diazoacetates

2.1.1 Regioselectivity in Rh(I1)-Catalyzed Tertiary C-H Insertion of Diazo Ester

79 ..................................................................................................................... Compounds

2.1.1.1 Preparation of Diazo Esten 61a-c ............................................................... 25

2.1.1.2 Rh(II)-Catalyzcd Tertiary C-H Insertion of Diazo Esten 61a-c ................... 26

2.1.1.3 Summas, ....................................................................................................... 31

2.1.2 Chemoselectivity in the Rh(I1)-Catalyzed Reaction of Diazo Esters ................... 32

1.1.2.1 The Cornpetition Between Tertiary C-H Insertion and Cyclopropanation .... 32

2.1.2.2 The Effect of Remote Double Bond of Diazo Ester 75 ................................. 38

2.1.2.3 The Effect of Ketone Functionality vs Ester Functionality ........................... 41

2.1.2.4 The Effect of Benzylic Tertiary C-H ............................................................. 44

1.2 Applications in The Total Synthesis of Alkaloids Possessing a Quatemary Carbon

Centre ................................................................................................................................ 50

22.1 Total S ynthesis of Quebnchamine ................................................................... 51

2.2.1.1 Litenture Routes For The Synthesis of Quebrachamine: A Brief Survey .... 51

2.2.1.2 Rh(II) Carbenoid C-H Insertion Approach to (f )-Quebrachamine ............... 59

2.2. L . 3 An Approach to (+)-Quebrachmine Via Rh (II)-Cataiyzed C-H Insertion

............................................ h o a Configuntionally Defined Tertiary Stereocenter 76

................................................................... 2.22 Total S ynthesis of (-)-Eburnamonine 86

........................................................................................ 2.2.2.1 Retrosynthetic Plan 92

2.2.2.2 Preparation of Diol 234 ............................................................................... 93

2.2.2.3 Selective Formation of Monosilyl Ether 237 ................................................ 95

7.2.2.4 The Preparation of Pivotai Aldehyde 239b-c ............................................... 97

2.2.2.5 The Preparation of the Tetracyclic Amide Alcohol 243 ............................... 99

2.2.3 Approach to the Totd Synthesis of (-)-Mesembnne .......................................... 104

...................................................................................... 2.2.3.1 Retrosynthetic Plan 112

.......................................... 2.2.3.2 The hepration of Chiral Alcohol (R)-(-)- 87b 113

2.2.3.3 The Formation of y-Lactone (-)-298 ........................................................... 120

2.1.3.4 The Preparation of Pivota1 Intermediate 300 .............................................. 111

2.7.3.5 The Cyclization of 300 and Subsequent Reaction ....................................... 127

. .............................***..*..*............................*.................*.............................. 3 Surnmary 126

4 . Future Work .............................................................................................................. 130

5 . Experimental Section .................... .... .......... .....~~........~~.........~.~..............~..~~....~. 129

5.1 Genenl Procedure for Preparation of Maionates ...................................................... 130

5.2 General Procedure for Diazotization Reaction ........................................................ 130

5.3 General Procedure for Prepantion of a-Diazo-fi-Keto Esters .................................. 13L

5.4 Generd Procedure for Rh(II)-Catalyzed Reaction .................................................... 131

5.5 Generd Procedure for Alkylation of the Dianion of a Carboxylic Acid ................... 132

5.6 Generai Procedure for Decarboxylation Reaction .................................................... 133

............................... 5.7 Prepamtion of Diazo Compounds 61a-c and Their Reactions 133

5.8 Preparation of Diazo Compounds 69a-c and Their Reactions .................................. 140

5.9 Prepmtion of Diazo Compounds 75 and Its Reaction ............................................. 144

5-10 Prepantion of Diazo Compound 84 and Its Reaction ............................................ 147

.............................. 5.1 1 Preparation of Diazo Compounds 89a-e and Their Reactions 150

................................................................... 5.12 Total Synthesis of (f )-Quebrachamine 157

5.12. L The Preparation of a-Diazoacetate 138 ........................................................... 157

..................................................................... 5.11.2 The Formation of ~Lactone 139 159

................................................... 5.12.3 The Preparation of Pivotal Intermediate 116 161

5.12.4 The Preparation of the Tetncyclic Amino Alcohol 152 .................................. 164

.......................................... 5.12.5 The Reactions Related to the Mechanistic Studies 167

5.13 Total Synthesis of (+)-Quebracharnine ................................................................... 169

5.13.1 The Preparation of Chiral Alcohol S-(+)-MO .................................................. 169

..................................................... 5.13.1.1 Formation of Imide 175 via Alkylation 169

.................... 5.13.1.2 Formation of Imide 175 via Aldol Reaction-Deoxygenation 171

............................ 5.13.1.3 Conversion of h i d e 175 to Chiral Alcohol S-(+)-Ill0 173

5.13.2 The Formation of ~Lactone (-)-Id3 .............................................................. 176

5.13.3 The Prepantion of Aldehyde 187 ..................................................................... 180

.................................. 5.13.4 The Preparation of the Tetracyclic Arnino Alcohol 191 183

...................................................................... 5.14 Total S ynthesis of (-)-Eburnamonine 184

5.15 Approach to Total Synthesis of (-)-Mesembrine ................................................ 192

......................... 5.15.1 The Prepantion of Chiral Alcohol (R)-(-)- 87b .... .......... 192

5.15.1.1 The Reparation of Allyl Haiides 295 a-b ................................................ 192

..................................................................... 5.15.1.2 The Formation of h i d e 292 196

5.15.1.3 The Formation of the Chiral Alcohol (R)-(-)- 87b ................................... 199

5.15.2 The Formation of ~Lactone (-)-298 .............................................................. 200

515.3 The Preparation of Pivotal Intermediate 300 ................................................... 701

5.15.1 The Cyclization of J00 and Subsequent Reaction ............................................ 20.)

6 l References m m m m ~ m m m m m m m m m m m m m m m m m m m a m a m m m m m a m m m m m m m m ~ ~ ~ m m m ~ m m m m ~ m ~ m a ~ m m m m m m m m m m m a ~ ~ m ~ m a m m ~ ~ ~ e o e m m m m m m 208

7 . Appendices ....m.mm. m e m m m m m m m m ~ m m m m m ~ m m m m m m m m ~ ~ ~ ~ ~ o m m e m o o m m ~ m ~ m ~ ~ m ~ m m ~ m m o m o m ~ m ~ m m m m m m o m m ~ m ~ m ~ ~ m m ~ 2 ~ 8

Appendix A: Recent Reviews on Rh(@ Catalyzed Reactions of Diazo Carbonyl

..................................................................... Compounds 218

Appendir B: Recent Publications For the Total Synthesis of Mesembrine .............. 219

Appendix C : Recent Publications For the Total Synthesis of Eburnamonine ............ 219

List of Abbreviations

acam

AIBN

anal

cap

COSY

DBU

DCC

DEPT

DIBAL-H

DMAP

DMF

DMSO

acetyl

acetamidrite

2'2'-azobisisobutyrinitrile

anal ysis

aqueous

2,2'-bisdiphenylphosphino- 1 . 1 '-binaphthyl

benzy l

boiling point

benzoyl

calculated

caprolac tamate

correlation spec troscopy

1,8-diazabicycl0[5.4.0]undec-7-ene

dicyclohexylcarbodiimide

distortionless enhancernent polarization tnnsfer

diisobutylalurniniurn hydnde

4-(N'hi-dirnethy1amino)pyridine

dimeth y lformarnide

dimethylsulfoxide

ee

=q

W A

HRMS

IR

J

LAH

LDA

='p

Ms

NBS

NMR

NOE

Oct

PCC

PDC

PE

pftpa

Pi v

PY

TBDMS

enantiomeric excess

equivalent

hexamethylphosphoric triamide

high resolution mass spectra

infrued

coupling constant

lithium aluminum hydnde

lithium diisopropylarnide

melting point

methanesulfonyl

N-bromosuccinimide

nuclear magnetic resonance

nuclear Overhauser enhancernent

oc t anoate

pyridinium chlorochrornate

pyridinium dichromate

petroleum Ether

Peffluorobutynte

pefluorotriphenylacetate

pivalate

p yridi ne

ren-butyldimethylsilyl

TBDPS

t-BU

Tf

TFA

THF

tes

Ts

tert-butyldiphenylsilyl

ten-butyl

tri fluoromethanesul fonyl (tri fl yl)

tri fluoroacetic acid

tetrah yclrofuran

viphenylacetate

p-toluenesulfonyl (tosyl)

List of Figures

Figure I . The Objectives of this Study ..................................................................

Figure 2 . Litenture Approaches Toward Total S ynthesis of Quebracharnine ...........

Figure 3 . Retrosynthetic Plan for the Total Synthesis of

........................................................................... (*)-Que brachmine 144

......... Figure 4 . The Mechanistic Rationalization for the Formation of Diacetal 156

Figure 5 . A Proposed Mechanistic Rationalization for the Cyclization ....................

Figure 6 . Literature Results Related to Pictet-Spengler Cyclization .........................

Figure 7 . Retrosynthetic Plan for the Total Synthesis of (+)-Quebrachamine ..........

Figure 8 . Mechanistic Rationalization for the Formation of 201 ..............................

Figure 9 . Literature Approaches Toward Total Spthesis of Ebumamonine ............

Figure 10 . Spthetic Plan for the Total Synthesis of (-)-Eburnarnonine 246 ............

Figure 1 1 . Literature Approaches Toward Total Synthesis of Mesembrine ..............

Figure 12 . Synthetic Plan for The Total Synthesis of (-)-Mesembrine .....................

Figure 13 . The Rationalization for the Isomerization of Allylic Halide 3llb-Br ......

Figure 14 . Mechanism for the Hydrogenolysis of Allylic Compound .......................

Figure 15 . The Explanation for the Distereoselectivity of the Cyclization ................

Figure 16 . The Conformation of Compounds 320a and 320b .................................

nii

Table 1 . Rh(II) Catalyzed Reaction of 61 ........................................................................... 26

. ...................................................*.........*................. Table 2 Rh(II) Catalyzed Reaction of 69a 34

Table 3 . Rh(II) Catalyzed Reaction of 75 ................................................................................. 40

. .................................... Table 4 Rh(II) Catalyzed Reaction of 89b as a Function of Catalysts 47

Table 5 . Rh(II) Catalyzed Reaction of Diazoester 138 .......................................................... 63

Table 6 . NOE Data for Cornpound lS1a ................................................................................ 68

.................................. Table 7 . The Selectivity in the Fonation of Mono-protected Di01 234 96

Table 8 . Different Conditions for the Pictet-Spengler Cyclization of 23% and 24ûc ........... 100

Table 9 . NOE Experiment for Compound 2428 .................................................................. 101

Tabie 10 . The Formation of Allyl Halides 295a-b ................................................................. 116

... X l l l

1. Introduction

The decomposition of diazo compounds (Scheme 1) is one of the most important

methods for the generation of free carbenes.' The free carbenes are very reactive and their

reactions are non-selective. Therefore. this method has not been extensively used in

organic synthesis.

Scheme 1

9 R,C :-

\ Q @ MLn R, C-NGN C=ML~- 9 e e

R' -Na R' R,C-MLn

During the early studies on diazo chemistry. it was discovered that the problems

of low selectivity and high reactivity could be significantly reduced by employing

uansition metais for their de~om~osition.~ By binding itself with the transition metal to

lorm a cornplex. the carbene increases its stability which, in tum, reduces its reactivity.

This metal-carbene cornplex is called a metallocarbenoid.

Copper complexes were the fint class of catalysts to be used in this area.' Other

transition met& such as palladium" and cobalt5 had also been utiiized. However. i t was

not until 1973 when Teyssie and coworkers discovered that rhodium(II) complexes

facilitate nitrogen Ioss from diazo cornpounds that the use of rhodium(Q catalysts

became increasingl y popular.6 Among them, rhodium(II) carbox y lates had recei ved the

most attention. In particular. rhodium(~ acetate was the most comrnon and extensively

used catdysts.'

1.1 Intramolecular Rh(I1)-Catalyzed Transformation of Diazo Carbonyl

Compounds

The rhodium(II)-carSenoid mediated reaction cm involve either intermolecular or

intramolecular processes. However, from the synthetic point of view. an intermolecular

process is not generally useful because of the low regio- and cherno-selectivity. On the

other hand. an intramolecular process is synthetically more useful because of the high

regio- and cherno- selectivity and is well suited for ring forming reactions.

The most common intramolecular Rh(ii) catalyzed reactions of diazocarbonyl

compounds are: carbon-hydrogen insertion.heteroatom-hydrogen insertion.'

cyclopropanation.'O y lide formation and subsequent reaction.' ' These advances have been exploited in organic synthesis and are enemplified by

the selected exmples shown in Schemes 2-5.

Scheme 2

(+)- i s o c ~ a c y c h

The example shown in Scheme 2 involves a Rh(II)-carbenoid inuamolecular C-H

insertion as the key step for the total synthesis of (+)-isocarbacyclin, one of the most

promising therapeutic agents for cardiovascular and circulatory disordem8 Here. the

Rh(II)-carbenoid inserts into an inactivated C-H bond to form a cis-fused bicyclic ring

compound. There is a possibility for the carbenoid to form four andor six membered

rings. However, only the five membered ring product was observed.

Scheme 3

The example shown in Scheme 3 represents the Merck synthesis of the antibiotic

thienmycin.' Here the key step is the inrramolecular N-H insertion of carbenoid to form

the 5-mernbered ring.

Scheme 4

_I_t - OH OH

Prosuglandin Ez methyl ester

in the example shown in Scheme 4, the Rh(@ catalyzed cyclopropanation reaction

gave the key intemediate which was then converted to prostaglandin Er methyl ester.''

Again, there is a possibility for carbenoid adding to the double bond to form u bicyclo

[S. 1 .O] ring system. However, only the bicyclo [3.1 .O] ring formation was observed.

Scheme 5

The example shown in Scheme 5 represents the synthetic route for (+)-acorenone

B." The carbenoid hnt reacted with sulfide to form a sulfonium ylide which then

underwent a [2,3]-sigmatropic remangement to fom the spiro carbocyclic compound. a

key intermediate used in the synthesis of (+)-acorenone B.

1.2 Rh(I1)-Catalyzed lntramolecular C-H Insertion of Diazo Carbonyi Compounds

In 1982. ~enke r t " first demonsmted the effectiveness of Rh2(OAc)4 for

catal yzing the intramolecular reaction of diazoketones. Since then. the intnmolecular

Rh(ü)-carbenoid C-H insertion has assumed strategic importance in carbon-carbon bond

forming reactions in organic ~~nthes i s . '~ The rnechanism for the intnmolecular C-H

insertion proposed by aber""^ and ~ o ~ ~ e ~ ~ is show in Scheme 6. Initial attack of the

diazo carbon at dirhodium followed by loss of dinitrogen gives the Rh(lI) carbenoid. The

vacant p orbital of the carbene carbon ovedaps with the o orbital of the reacting C-H

bond. The C-C bond and C-H bond formation takes place concertedly as the Rh(@-

Scheme 6

L

R = C(0)XCH2CH3

carbenoid dissociates. Since the Rh(II)-carbenoid is electrophilic in characier. resembling

these of a metai-stabilized cÿrbocation, the regioselectivity which leads to the control of

the ring size is strongly influenced by electronicl" factors derived both from the carbenoid

(such as ligand. u-substituents) and from reacting C-H bond. As well. the steric's and

16 conformational factors derived both from the carbenoid and from reacting C-H bond

will also affect the regioselecrivity of the reaction.

1.2.1 Regiosefectivity of the Reaction

There is a genenl agreement that inuamolecular C-H insertion prefen five

membered ring formation than four and six membered ring fomation.17 However. four

and six membered ring formation is dso possible.1L16

For reactions involving five membered ring formation. the reactivity of the C-H

bond controlled the regioselectivity. A tertiary C-H bond is more reactive than a

secondary C-H bond which, in turn, is more reactive than a primary C-H bond. Therefore

insertion into a te r t iq C-H bond is favored over a secondary C-H bond, and a primary C-

18 H bond is the least favored. Normaily, the ntio of the products derived from carbenoid

insertion into methine or methylene C-H bonds to that derived from carbenoid insertion

into a prirnary CC- bond is large. In fact, products arising only from insertion into

methine and methylene C-H bonds are ais0 sometimes obtained. However. the ntio of the

producrs derived from carbenoid insertion into a methine C-H bond to the products

derived from carbenoid insertion into a methylene C-H bond is much smaller. sornetimes

there is no selectivity at dl . This is because metallocarbenoid insertion into methine C-H

bond is sterically more demanding when compared with insertion into a methylene C-H

bond.

Scheme 7

I 2 3

ratio > 99 1

It has been shown that lunctional groups adjacent to the C-H bond were able to

influence the reactivity of the C-H bond and therefore also affect the regioselectivity of

the reaction. For exarnple. ~ d a r n s ' ~ round that in systems exemplified by 1 (Scheme 7).

where steric and conformational effects were minirnized. the electron donating goup

(OMe) activates the adjacent CrH bond by increasing the elecuon density of this bond.

Rh(m carbenoid insertion was found to occour preferentidly at CrH bond over the C5-H

bond to give bicyclic ketone 2 and 3, respectively. The ntio of 2 : 3 was 99 : 1.

Scheme 8

O

Stork and CO-worke~?~ discovered that an electron withdnwing group. such as an

ester function. deactivates adjacent C-H bond by decreasing the electron density of the C-

H bond. By replacing one of the rnethyl groups with a methoxycarbonyl group (othenvise

it is a symmetric system). they found that (Scheme 8) the ester group directed the

carbenoid away from insertion into the a-methylene hydrogens although this would also

lead to the formation of a five membered ring. As a result. insertion into the aliphatic side

chain becme favorable.

The substituent a to the diazo carbon is also very important because it modifies

the electrophilicity of the carbenoid center. ""16 The metallocarbenoid carrying an acetyl

group is more electrophilic than an ester-substituted one which, in tum, is more

electrophilic than an unsubstituted one. For example (Scheme 9). the acetyl substituted

compound 6 produced 7 as the sole product in 85% yield."' Ester substituted compound

8, on the other hand, afforded Flactone 9 as well as plactone 10 (7/8 = 112.1).'~

However. unsubstituted compound 11 provided no C-H insertion product. 17' Fumarate

and maleate esters that resulted from dimenzation of the Rh(II) carbenoid intermediate

were the major products obtained.

Scheme 9

In addition. the nature of the ligand in the dirhodium(m catalyst modifies the

electrophiiicity of the cmbenoid therefore aiso influences the regioselectivity of the

reaction. Doyle and CO-workerd7 have shown (Scheme 10) that Rh,(OAc), - resulted in the

formation of the mixture of y-lactones 13 and 14. While Rh,(ptb), - afforded nearly equal

amounts of iactones 13 and 14, the use of the catdyst Rh,(acam), - led to the exclusive

formation of lactone 13.

Scheme 10

ratio (13 / 14) statisticall y corrected ratio

Rhr (OAc)+ 53 : 47 1.7 : 1 R h (pfb)a 37 : 68 1 : 1.4 Rh? (acam)a 99 : 1 149: 1

Here. varying the ligands on rhodium(U) metal permits control of the

electrophilicity of the metal carbene. From Rh,(pfb), - to Rh,(acam),, - the electron

withdrawing ability of the ligand decreases which. in tum. lowen the reactivity but

increases the selectivity of the metallocarbenoid.

Scheme 11

Steric factors frorn both the Rh(JI) catalyst and the substrate also play important

roles in determining the stereoselectivity of the reaction. For example. treatment of

compound 15" with Rh2(OAcb led to a 3 : 1 mixture of the tram and cis insertion

products 16 and 17 , respectively (Scheme 11). In contrast, when compound 18 was used,

only cis product 19 was obtained. Here, the angular methyl group blocks the approach of

the Rh@)-carbenoid to the equatorial hydrogen. which is responsible for the formation of

the cis product.

Scheme 12

The steric size of the catalyst plays a role, too. It was reponed by Ikegami et al.

(Scheme L2) chat rhodium@) triphenylacetate.?' Rh?(t~a)~, which features a bulky

bridginz ligand on the rhodium(II) metal. exhibits high selectivity for insertion into a

methylene C-H bond nther than into a methine C-H bond. Thus treatrnent of compound

20 with R ~ ? ( O A C ) ~ resulted in a 37 : 63 mixture of 21 and 22 whereas the use of

Rh? ( t~a )~ increased the ratio to 96 : 4. More than likely, the distribution of products in this

system is related to steric factors. The bulkiness of the ligand prevents the carbenoid frorn

approaching the teniary C-H which was already shielded by the neighbouring group. As a

result, insertion into the secondary C-H became favorable.

Scheme 13

Conformational factors also govern the regioselectivity of the reaction. Lee and

coworkent6 demonstrated that (Scheme 13) formation of the Flactone 24 is preferred

over the plactone 25 (p : y = JO : 13) when both /% and y teniary C-H bonds are

available.

Scheme 14

As shown in Scheme 14. the conformation of the rnetallocarbenoid species fomed

from the a-diazomalonate suggests that because of the shorter C-O bond than C-C bond.

the carbenoid positioned itself doser to /% than to p tertiary C-H bonds.

Scheme 15

The same conclusion was also reached by Doyle's g r ~ u ~ . ' ~ For exmple.

decomposition of 26 (Scheme 15) in refluxing benzene. catalyzed by rhodium(II) acetate.

Scheme 16

fomed Flactam 27, soleiy as the trcins isomer, in nearly quantitative yield. The success

of the reaction was attributed to conformational preference about the amide unit. which

placed the reacting C-H bond in close proximity to the carbenoid center (Scheme 16).

1.2.2 C hemoselectivity of the Reaction

The chemoselectivity of the reaction is usually much more important than the

regioselectivity of the reaction because it involves competitive Rh(m carbenoid mediated

reactions. However, the rationalization for chemoselectivity of the reaction is more

complicated. The cornpetitions between C-H insertion and cyclopropanation, aromatic

substitution and aromatic addition are affected by electronic as well as steric factors.

For reactions involving the competition between C-H insertion and

cyclopropanation. the ligands attached to the dirhodium (II) core affect the

c hemoselectivi ty of the reaction. B y studying the competition between cyclopropanation

and teniary C-H insertion for the formation of five-membered ring (Scheme 17), Padwa

Scheme 17

and ~ o ~ l e " found that the R h ? ( ~ f b ) ~ catalyst favon C-H insertion and R h ? ( c a ~ ) ~ favors

cyclopropanation. These results are explained by the electrophilicity of the metal carbene.

Rh?(pfb), increases the electrophi lici ty of the carbene and, there fore. favours C-H

insertion over cyclopropanation.

Scheme 18

Furthemore, the a-substituent in the rhodium(II) carbenoid carbon was also

found to influence the regioselectivity of the insertion reaction. By compuing the

25 reactivity of a-diüzo ketones and M i v o Fketo esters (Scheme 18). Ceccherelli found

that the a-diazo ketone 31a reacted only with a carbon-carbon double bond whereas a-

diazo b-keto ester 31b insened into the allylic C-H bond. The ester group increases the

electrophilicity of metal carbene and. therefore, favoun C-H insertion.

1.3 Construction of Asymmetric Quaternary Carbon Centers

The creation of quatemary carbon center, a carbon center with four different non-

hydrogen substituents. is one of the chdlengs in the spthesis of biologicaily important

natunl products such as terpenoids. steroids and aikaloids. The asymmeuic construction

of dl-carbon-substituted quaternary centen is particularly demanding and much interest

14

has been directed toward the development of new strategies for their preparation.'6 Select

representative strategies are shown here.

1.3.1 Asymmetric Aldol Condensation

As early as 197 1, the enantioselecûve version of the classicd Robinson annulation

reaction was realized by using an ÿmino acid as catalyst and this strategy was applied for

the synthesis of opticaliy active diketones." Thus the treatment of 34 with (SI-proline

afforded (3-35 in 84% ee (Scheme 19).

Scheme 19

1.3.2 Asymmetric Alkylation Reaction

Alkylation of chiral enolates" and enamines" is very useful methods for C-C

bond formation.

Scheme 20

Condensation of (9-valinol 36 with 37 afforded a single diastereomer 3g30 which

was alkylated to give the endo isomer 39 predominantly while the exo position was

shielded by an isopropyl group as well as a phenyl group. The mixture of 39 underwent a

second alkylation attacking from endo position to give JO in 50-90% yield. The acid

hydrolysis yieided the au-disubstituted keto acid 41 with >95% ee (Scheme 20).

Scheme 21

An enamine 14" derived from keto ester 42 and 43 was treated with LDA to give

a lithiated species 15 which was then dkyiated to give 16 in 99% ee (Scheme 21). Only

Bdicarbony 1 compounds provided good results.

1.3.3 Asyrnmetric Diels-Alder Reaction

The use of chiral catalysts for the Diels-AIder reaction provides effective methods

for the asymmetric C-C bond fornation. For example. cycloaddition of cyclopentridiene

with 2-methylacrolein using 18 as a catalyst gave (R)-adduct 47 in 96% ee with e.ro/endo

ratio of 9 : 1'' (Scheme 12) .

Scheme 22

1.3.4 Asymmetric Heck Reaction

The Heck reaction is also an excellent choice for the formation of quatemary

carbon centen." The palladium-catalyzed cyclization of 19 in the presence of (R)-BINAP

gave the regio- and face -seleciive product 50 (Scheme 73). Only the intnmolecular

process was investigated.

Scheme 23

1.35 Rh(I1)-Catalyzed C-H Insertion Reaction

Taber's group33 discovered that the treatment of optical 1 y pure a-diazo-8-keio

ester 51 with R~?(OAC)~ afforded cyclopentanone 52 with retention of configuration.

Funher functional goup manipulation provided (+)-a-cuparenone 53 in 96% optical

purity (Scheme 24).

Scheme 24

O

Since the construction of teniary chiral centers" is much easier. the stereospecific

C-H insertion into a chiral teniary C-H bond provided a general methodology for the

formation of chiral quatemary center.

1.4 The Objectives of This Study

At the time when we stiuted our studies. most examples in Rh(m carbenoid

chemistry dealt primarily with diazo ketone compounds. However, the studies on the

reaction of diazo ester compounds were limited. Limited exmples showed that formation

of y-lactone was preferred.17'.'6.35 but 6lact0ne'~ and p-lactone16 formation were also

possible.

It 1s clear that with mode1 systems, product yields were high and significant regio-

and chemo- control could be achieved. However. the use of these results for targeted

outcornes in cornplex systems capable of more than one carbenoid transformation was

limited by the lack of information on regio- and chemo- selectivities.

To the best of out knowledge. a study of the competition between

cyclopropanation and tertiary C-H insertion has never been investigated for the diazo

maIonate ester system. The competition between C-H insertion and cyclopropanation in

diazo esters, if analogous to that of diazo ketones, should provide a convenient method

for the synthesis of 4.4-disubstituted y-lactones or highly substituted bicyclic lactones.

On the other hand, the stereospecific C-H insertion reaction has never been

investigated as n methodology for the formation of chiral 4.4-disubstituted y-lactones.

The objectives of this research were:

1) To investigate the Rh(I1) carbenoid mediated tertiary C-H insertion of diazo

esters as a rnethod for the construction of 4.4-disubstituted y-Iactones. The selectivity

between tertiary and secondary C-H insertion as well as the selectivity between reniary C-

H insertion and cycloaddition reaction was investigated. The scope and limitation of these

reactions were exrtmined.

2) To develop a genernl stntegy for the use of 4.4-disubstituted y-lactones in the

total synthesis of alkaloids possessing quatemxy carbon centers. such as (+)-

quebrachamine. (-)-mesembnne and (-)-ebumarnonine.

OMe

(+)-Que brac hamine (-)-Mesembrine (-)-Ebumarnonine

Figure 1. The Objectives of This Study

2. Results and Discussion

2.1 Rh(I1)-Catalyzed Tertiary C-H Insertion of Diazoacetates

2.1.1 Regioselectivity in Rh(I1)-Catalyzed Tertiary C-H Insertion o f Diam Ester

Compounds

In 1993. ~ o ~ l e ~ ~ reponed that electronic factors from ligands and reacting C-H

bond govem the regioselectivity in the Rh(U) catalyzed reaction of 54 (competition

between tenixy and primary C-H) (Scheme 25) and 57 (competition between secondary

and primary C-H) (Scheme 26). and it was found that insertion into an electron-rich C-H

bond was prefemd.

Scheme 25

55 56

Scheme 26

On the other hand, the regioselectivity in the reaction of 60 (cornpetition between

t e n i q and secondary C-H) (Scheme 27) and 63 (competition between secondary

benzylic and prirnary C-H) (Scheme 28) does not follow the same trend and the outcome

was due to conformational factors. Product distributions from C-H insertion are invariant

with the dirhodium(I1) ligands in each of the reactions; insertion into a secondary C-H

bond is hvored over tertiary C-H insertion with 60 (62 : 61 = 95 : 5) and insertion into a

primary C-H bond is preferred to a secondary benzylic C-H bond with 63 (65 : 64 = 70 :

30).

Scheme 27

60 61 62 ratio 5 95

statistically corrected ratio 5 95

Scheme 28

63 64 65 ratio 30 70

statisticall y corrected ratio 1.3 1

We reasoned that the results from the reaction of 60 and 63 rnight not be

attributed solely to confomationd preferences. but that electronic and steric factors also

play important roles. In other words, the acetyl substinited carbenoid may be too reactive

so that its ability to distinguish between tertiary and secondary C-H bonds is decreased.

For compound 63, the secondary C-H bond may be deactivated by phenyl group. The

reactivi ty between pnmary and secondary C-H may become similar. therefore no

regioselectivity at al1 (statistically corrected ratio for 65 : 64 = 1.3: 1). Replacing phenyl

group with electron donating group like dkyl group should improve the regioselectivity

for secondary C-H inseriion. That is exactly the case when compound 57 was used. For

compound 60. the tertiüry C-H bond rnay be too hindered to be reached by the carbenoid

so that insertion into secondary C-H becarne favorable. As we know. a-substituent to

diazo carbon influences the electrophilicity of the carbenoid. It is expected that chiinging

u-substituent from electron-withdrawing acetyl to less electron-withdnwing

methoxycarbonyl group should increase the regioselectivity for teniary C-H insertion. In

order ro test this hypothesis. compounds 69a-c where the cornpetition was still between

teniary and secondary C-H insertion were prepared and subjected to different Rh(iI)

catalysts to ascenain the regioselectivity of the reaction.

Here compound 69a was designed wherein steric effects were minirnized by

replacing one of the isopropyl groups in 60 (Scherne 27) with an ethyl group. Compound

6% was designed to decrease carbenoid reactivity by replacing the acetyl goup in 69a

with less electron-withdnwing methoxycarbonyl group. Compound 6% was designed to

test the inductive effect of the trifluoroethyl group in the ester moiety.

2.1.1.1 Preparation of Diazo Esters 69a-c

The prepantion of diazo esters 69a-c follows the route as sumrnarized in Scheme

29. The teniary alcohol67 was prepared by the reaction of isopropyl magnesium chloride,

in the presence of anhydrous CeC1-j. with 3-pentanone. The use of Ceci3 was essential

because. in its absence. the aldol reaction product was obtnined. The esters 6th-c were

prepared via acylation [a-(rnethoxycarbony1)acetic acid. a-(2.2.2.-

trifluoroethoxycarbony1)acetic acid. D C C ' ~ ~ or diketene, E ~ ~ N " ~ ] and then followed by

di~otization'~ of the corresponding malonate 69b-c (MsN3, DBU") or P-keto ester 69a

(MsN3, Et3N, H~O-CH~CN") to give diaro esters 69a-c.

Scheme 29

2.1.1.2 Rh(II)-Catalyzed Tertiary C-H Insertion of Diazo Esten 69a-c

The Rh(I1)-catalyzed reaction of 69a-c (Scheme 3 1 ) was conducted under reaction

conditions identical to those reported by Doyle, i.e.. 12h in refluxing benzene. The results

are shown in Table 1.

Scheme 30

Table 1. Rh(Ii) Catalyzed Reaction of 69

y-lactones 70 : 71 diazo statistically

substrrite catalyst yield(%) retative ratio comected ratio 69a Rhz (pfb), 3 1 1 0 0 : O L O

In contrat to Doyle's results for 60 (Scheme 27) where the regioselectivity was

govemed only by conformational preferences in the compound. the regioselectivity in the

present study was found to depend on the nature of the dirhodium(II) catalysts,meaning

the regioselectivity of the reaction was affected by the electronic/stenc factors.

The y-lactones 70b and 71b as well as 7 k and 71c are easily separable. y-

Lactones 70a and 7la were obtained as an insepanble mixture. The ratio 70a : 71a was

based on the integration of the MeCH multiplet (6 3.06-3.15. 1H) in 70a and the

AcCHC(0) singlet (6 3.30-3.50. 1H) in 71a.

Scheme 31

O

1). CH3C(O)Cl pyridine

w 2). 03.CH2C12

-78%. PPh3

OAc HO - O 3). PhC(0)Cl

pyridine. DMAP 0°C

For further structural confirmation (Scheme 31). the mixture was acetylated CO

give an insepanble mixture of four en01 acetates. The mixture was ozonized (CH2CI2, -

7 8 T . Jh) and then reduced to afford the crystalline a-tetronic acid 72 and unoxidized.

starting enol acetate 73 (contamînated by a small amount of an unidentified impurity).

The resistance of 73 to ozonolysis was unexpected and may be due to the steric shielding

of the double bond in 73 by the vicinai gem-dimethyl groups which makes the double

bond less accessible by ozone. Subsequent ueatment of 73 with NaB& followed by

benzoylation of the crude alcohol gave the benzoate denvative 74 as a single

diastereomer ("c NMR showed 19 lines). The salient signals in the 'HNMR of 74 are the

doublet due to H-3 which is centered at 6 2.96 (J3.i. = 9.8 Hz) and a double quartet due to

the H-1' which is crntered at 6 5.45 (JI+. J = 9.8 Hz and = 5.6 Hz).

It is clear that for u-acetyl diamester 69a. the y-lactone 70s (secondary C-H

insertion) was the only product formed when Rh?(pfb), was used as the catalyst. This

result is similar to that obtained in 60 (Scheme 27). However. with Rh2(OAc),, insertion

into a teniary C-H bond to give 71a was competitive but the rnodest preference for the

formation of secondary C-H insertion product 70a was observed (70a : 71a = 1.8 : 1).

With Rh2(acam),, the formation of a statistically 1 : 1 mixture of 70a and 71a was

obtained. By changing catalysts from electron-withdrawing Rh2(pfb), to less electron-

36 withdrawing Rhz(OAc), and Rhp(acam),. the preference secondary C-H insertion

decrease.

Different trends were observed when compounds 69b and 69c were treated with

different catalysts. Even with Rh,(pfb),, insertion into a secondary C-H to give 70b and

7 k was only slightly favoured (70b : 7lb = 1.5 : 1). With Rh?(OAc),, there was an

increase in preference for tertiary C-H insertion product 71b and 7lc (70b : 71b = 1 :

1.7). The highest preference for tertiary C-H insertion product 71b and 71c was reaiized

by using Rh2(acam), as the catdyst (70b : 7lb = 1 : 5.5). We also found that the

electron-withdnwing, inductive effect of the trifluoroethyl group in the ester moiety in

69c had little influence on the reactivity of the metallocarbenoid; a ratio of products. 70c :

71c. similar to that obtained for 69b was obtained.

These results suggest that by reducing steric facton in these systems, electronic

effects transmitted to the metallocarbenoid site from the ligands in the Rh@) catalyst as

well 3s from the cl-substituent on the carbenoid carbon govem the regioselectivity of the

reaction. By changing to ei ther a more electron-withdnwing a-substi tuent or a more

electron-withdnwing catalyst, the selectivity for secondary C-H insertion increases.

As mentioned before. the reactivity of the metalloîarbenoid increases when either

a more electron-withdrawing a-substituent or a more electron-withdnwing Rh(U) catalyst

is uied. However, i t is unusual that increasing the reactivity of the rnetallo-carbenoid

increases its selectivity for secondary C-H insertion. This result cannot be explained by

considering only the reactivity of the carbenoid. As a genenl rule. if the carbenoid is

highly reactive (analogous to a free carbene) it would result in the statistical distribution

of products. This result cannot be explained by considering only the electronic factors. If

electronic facton govem the reaction pathway, insertion into a teniary C-H bond would

be preferred since a tertiary C-H bond is more reactive than a secondary C-H. Finally. this

result cannot be explained by considenng only the confomational preference. If

confomational preferences govem the reaction pathway, insertion into a secondary C-H

bond would predorninate no matter what kind of cataiysts are used."

Taken together. these results indicate that the substituent on the carbenoid carbon

exerts an important although subtle influence on the electrophiliciry of the

metallocarbenoid site. The acetyl substituent is a stronger electron-withdrawing group

than the ester group; hence, the acetyl-substituted metallocarbenoid is more electrophilic

and more reactive. We know that if the carbenoid is more reactive it is less discriminating

between secondary and tertiary C-H bonds electronically. Therefore. the regioselectivity

of the reaction will depend on the steric factors of the substrates and insertion into the Iess

hindered site is expected. This fact is supported by our observation that ûcetyl-substituted

69a gave more secondary C-H insertion product than ester-substituted 69b and 6%. As

mentioned before varying the ligands on the rhodium(@ metd also changes the

electrophilicity of the metûllocarbenoid. Thus. the carbenoid derived from Rh,(@%), is -

more reactive than the carbenoid derived from Rh,(OAc), - or Rh,(acam),. - By changing

the catalyst from the strongly electron-withdrawing Rh,(ptb), to the electron-donating -

Rh,(acam),, - the tendency for insertion into secondq C-H bond decreases. It is also

interesting to compare the results from 69a with that from 60 where the only difference

between these two substrates is stenc in nature (Scheme 17). The dependence of

regioselection of 69a on the dirhodium(lI) catalyst suggests that stenc factors are as

important as confornational factors in controlling the regioselectivity of the reaction.

Clearly the regioselectivity of the insertion reaction is govemed by steric,

electronic and conformational factors. By modifying the electronic demand. steric

requirement. appropriate substitution on the diazocarbon and using a suitable

dirhodium(II) catalyst it should be possible to promote a specific kind of C-H insertion

reaction. So if preferential insertion înto a tertiary C-H bond versus a secondary C-H

bond is needed it is suggested to use secondary C-H bonds that are deactivated (using a

Ph or carbonyl group), increased steric shielding of the secondary C-H bonds. C0,Me -

nther than C(0)Me as the substituent on the diazocarbon and Rh(m catalysts with

electron-donating ligands. Conversely if preferential insertion into a secondary C-H bond

versus a tertiary C-H is needed it is suggested to use tertiary C-H bonds that are

deactivated (using a Ph or carbonyl group). increased steric shielding of the tertiary C-H

bonds, C(0)Me rather than C0,Me as the substituent on the diazocarbon and Rh(Il) ..

catalysts with electron-withdnwing ligands andor with bulky ligands. Finally, modifying

the steric size of the ligands on Rh (II) mmay also affect the result of the reaction. For

example. if we prepare Rh-(pf~pa)~ where pftpa = perfluorotriphenylacetate we form a

catalyst which is electron withdrawing as well as bulky. Applying this catalyst to

cornpound 54 and 57. we would expect the preferential insertion into the primary C-H.

2.1.1.3 Summary

The above results indicate that a balance between the effect of the u-substituent

and the nature of the Rh (U) catalysts provides control in the regioselectivity of the

reaction. The electronic effects transmitted to the metallocarbenoid site from the a-

substituent on the carbenoid carbon govern the regioselectivity of the reaction. An a-

acetyl substituent increases selectivity for secondary C-H insertion. An cr-ester substituent

increases selectivity for tertiary C-H insertion. It is also interesting to note that the

electron-withdmwing, inductive effect of the uifluoroethyl group in the ester moiety in

6% had little influence on the reactivity of the metallocarbenoid. The ester-substituted

Rh(II) carbenoids are responsive to the electronic nature of the ligand on the dirhodium

(iI) metal. Rh2(pfb), promoted secondary C-H insertion and Rh2(acam), favored tertiary

C-H insertion.

2.1.2 Chemoselectivity in the Rh(I1)-Caîalyzed Reaction of Diazo Esters

Having ascenained that the reactivity of the carbenoids cm be moduiated by the

nature of the ligand on the dirhodiurn(II) metal center and that ester substituted Rh(II)

carbenoids provide more tertiary C-H insertion products. we tumed Our attention to the

Rh(iI) catalyzed tertiary C-H insertion reaction of compounds 77. Compounds 77 have

two side chains, an ethyl group and an olefin group. which will enable the study of the

cornpetition between C-H insertion and cyclopropanation. If the reaction for the

formation of y-lactone is successful. the olefinic double bond moiety should provide an

extra handle for funher functional group modification.

2.1.2.1 The Cornpetition Between Tertiary C-H Insertion and Cyclopropanation

2.1.2.1.1 Preparation of Diazo Esters 77 a-c

The required alcohol 75 was readily prepared via the alkylation of the dianion

denved from 4pentenoic acid with ethyl iodide? followed by reduction with M.

Acylaùon of the primary alcohol 75 with a-(rnethoxycarbonyl)acetic acid or diketene.

EttN provided the rnaionate ester 76a or keto ester 76b. Diazotization under standard

39 conditions furnished the diazo compounds 77a-b. The diazo acetate 77c was prepared

by deacylation of 77b with pyrrolidineM (Scheme 32).

Scheme 32

MsN3, DBU - A.8 R 9 H

or MsN3, Et3N CH3CN. rt O O

2.1.2.1.2 Optimization Studies Using Diazo Ester 77a

Our fint aim was to delineate the effect of solvent polarity and reaction

temperature on the regio- and chemo- selectivities using compound 773 as the test

substrate and Rh,(OAc), - as the catalyst (Scheme 33). The reactions were conducted in

either dry CH2C12 or benzene as solvent. The resulü are show in Table 2.

Scheme 33

Table 2. Rh(II) Cataiyzed Reaction of 77a - - - --

relative yieldsC

entry catalyst solvent T OC yield(8)' 78a 79a 80a

11 R h , ( a ~ m ) ~ 'tiH6 a rt 62 ndd 34 66

a) Method A: Compound 77a (0.01M) b) Method B: Slow addition. The final concentration of 77a was O.OIM. C) Cornbined yield. d) Not detected e) Relative yietds rire based on isolated products

It is evident that solvent polarity affected the regio- and chemo- selectivities of the

reaction. The use of the more polar CYCI, - - resulted in a higher preference for the

formation of y-lactone 79a over p-iactone 78a (entries I and 3). However. the second

most abundant product. the cyclopropanated lactone 80a. was also obtained even though

it is a seven-membered ring product. Although the reaction conducied in benzene showed

good regioselectivity similar to that observed in CH,CI, - - the chemoselectivity of the

reaction was reversed: the cyclopropanated lactone 80a was preferentially formed and

there was a marked decrease in the yield of 79a (compare entries 1 and 3). The reaction

temperature had no effect on the regio- and chemo- selectivities of the reaction (compare

entries 1 and 1: 3 and 4). Surpnsingly. the yield of fhctones remained fairly constant in

most of the reactions. Slow addition of a solution of 77a in dry benzene to Rh,(OAc), - in

refluxing benzene did not irnprove the yield of the y-lactone 79a; the ratio of the products

was similar to that obtained under the usual conditions (compare entries 4 and 5) .

2.1.2.1.3 Effort of bridging ligands

Next, the influence of bridging ligands on the metallocarbenoid mediated reaction

in 77a was investigated. The reactions were conducted in CH,CI, at n since the * -

aforementioned studies indicated that the use of CH,CI, favored formation of the y- - -

lactone 79a. The results (Table 2, entries 6-9) show that the cyclopropanated lacione 80a

was preferentidly formed with the next most abundant product k ing 79a. 8-Lactone 78a

was obtained as a minor product. In particular, 78a was not detected (entry 8) in the

Rh,(acarn), - catalyzed reaction.

The use of Rh,(Oct), and Rh,(Piv), - (entries 6 and 7) resulted in a marked decrease

in the yield of 791 but a panllel increase in the yield of 80a. We were surprised to find

that the predominant product in the Rh,(pfb),-catalyzed - reaction was the cyclopropanated

product 80a instead of the C-H insertion product. The use of the less reactive and more

selective Rh,(acm), - led to 80a as the major product. It was noted that the reaction of 771

with Rh,(OAc), - in benzene at n resulted in a good yield of cyclopropanated lactone 80a

(entry 3). Seemingly, the formation of 80a was favored when the more soluble Rh,(Piv), -

and Rh,(acam), - catalysts were used (entries 7 and 8). Therefore. we investigated the

Rh,(Piv),- - and Rh,(acam),-catdyzed - reactions of 77a in benzene to see if a higher yield

of 80a could be realized. Disappointingly, these modified conditions did not lead to any

impmvement in the yield of 80a (compare entries 7 and 10.8 and 1 1 ).

It is interesting to compare the results from the Rh(ii) carbox ylate-catai yzed

reaction in 77a (entries 1. 6 and 7). The highest yield recorded for the formation of y-

lactone 799 was in the Rh,(OAc),catalyzed - reaction. The Rh,(Oct), - and Rh,(Piv),- -

mediated reactions resulted in a marked decrease in the yield of 79a but a parallei

increase in the yield of 80a. We attributed the decrease in the yield of y-lactone 79a from

Rh,(OAc), - to Rh,(Oct), - to RhJPiv), - to the increase in steric size of the metallocarbenoid.

which rnakes tertiary C-H insertion more ciifficuit. As a result, the metallocarbenoid

reacts via the next least energetically demanding pathway, namely, cyclopropanation to

give 80a.

The formation of the cyclopropmated lactone 8th is unusuai. The dirhodium(II)

carbenoid in~amoleculu cyclopropanation reaction generally favon formation of

bicyclo[3.1 .O]hexane and bicyclo[4.1 .O]heptane ring systems. The formation of lower or

higher homologs of these ring systems is uncornmon." It is unusual that the Rh,(ptb), -

carbenoid also promotes cycloaddition. It was reported by Padwa and Doyle (Scheme 17.

'3 pg 13) that Rh,(pfb), - favored ter t iq C-H insertion even though there was the

possibility for cycloaddition to form the bicyclo[3.1.0]hexane ring. A possible

explanation for the formation of the cyclopropanated lactone 80a is that because of the

shoner C-O bond compared to C-C bond. the double bond may be closer to the

metallocarbenoid (see pg 1 L for a similar transition state) which would facilitste the

cyclopropanation reaction. It is also possible that the electrophilic metallocarbenoid may

form a nîomplex wi th the C=C double bond which will result in an ordered mangement

wherein the metallocarbenoid and the double bond are in close proximity. This will make

the cyclopropanation reaction an entropically favoured process."

Next. the a-substituent effect was studied. It was expected that the use of

compound 77b with a more electron withdrawing acetyl group should increase the yield

for the formation of y-lactone 79a. However. when 77b was subjected to different

rhodiumo catalysts, there was no selectivity for the formation of 79a. A very complex

mixture was obtained. The infra-red spectrum of the crude mixture suggests the presence

of lactone products; for example, the presence of u,, (C=O) at 1880 cm" indicates a p-

lactone carbonyl absorption and um, (C=O) at 1784 cm-' indicates a y-lactone carbonyl

absorption. The chrornatographic sepantion of the mixture was unsuccessful.

Unlike ~adwa's" results (Scheme 17). the Rh,(OAc), catalyzed decomposition of

unsubstituted compound 7% gave a very complex mixture. A similiar result was obtained

when Rh,(Oct),, Rh,(Piv),, Rh,(acam), and Rh,(pfb), were employed as cütalysts.

The infra-red spectrum of the crude mixture obtained from the Rh,(OAc),

catalyzed reaction showed carbonyl absorption peaks at u,, 1732 and 1664 cm". The

charactenstic carbonyl absorption (1784 cm'') for a y-lactone was not observed. This

result suggests that the formation of y-lactone is not a preferred pathway in the reaction.

The chrornatographic sepantion using pdient elution technique was attempted in vain.

These results suggest rhat the electronic effect of the u-substituent on the

carbenoid carbon exens an important influence on the reactivity of the metallocarbenoid

which controls the selectivity of the reaction.

2.L2.2 The Effect of Remote Double Bond of Diazo Ester 83

We then investigated the Rho-catalyzed reaction of 83 (a homolog of 77a). We

reasoned that by moving the double bond one additional carbon farther from the

metailocarbenoid center would make the cyclopropanation pathway less likely based on

enthdpic and entropic considerations. This, in tum, would result in a higher preference of

the metallocarbenoid for tertiary C-H insertion.

2.1.2.2.1 Preparation of Diam Ester 83

A similar protocol for the preparation of compound 77a was used to prepare

compound 83. The primary alcohol 81 was acylated with a-(methoxycarbonyl)acetic acid

which was followed by diazotization under standard conditions3' to afford the diruo

compound 83 (Scheme 34).

Scheme 34

2.1.2.2.2 Rh(I1)-Catalyzed Reaction of Diam Ester 83

With compound 83 in hand, the initial study of its Rh(@-catalyzed reaction

(Scheme 35) was carried out by using the same reaction conditions (in CH$[, - - at rt) for

77a and Rh,(OAc), - as catalysr. The initial resuit was very disappointing. The yeld

Scheme 35

for the y-lactone formation did not irnprove. The water insertion product and dimer

formation were the other two major by-products. Changing catalysts from Rh,(OAc), - to

Rh,(acam), - to Rh,(Piv), - did not improve the result. After optimizing reaction conditions.

we found that the reaction was best perfomed by the slow addition of a CH&& solution

of 83. using a synnge pump, to the R h ( m catalyst in refluxing CH2CII. The change in

procedure avoided the formation of dimeric products and gave good overall yields of

products. The results are summarized in Table 3.

Table 3. Rh(Q Catalyzed Reaction of 83

relative vields"

entry catalyst solvent T OC yield(%)' 84 85 86 b

1 Rh2(OAc), C%C12 40 87 11 83 6.0

b) Methoci B: Slow addition of 83 in C-L, to a suspension of the Rh(ii) catdyst in reflïxing CKCl.. The final concentration of 83 was 0.0 LM.

C) Combined yi&ld: d) Relative yields are based on isolated products

Among the four Rh@) catalysts exarnined, the use of Rh,(p€b), - resulted in the

highest yield of the cyclopropanated lactone 86. This result is similar to the result

obtained for 77a but the selectivity for cyclopropanation is much lower (entry 1). We

observed that the yield for the formation of y-lactone 85 increased for ail the catalysts

exarnined. The best yield of the y-lactone 85 was obtained with Rh,(OAc), - as the catalyst

(entry 1) which is in agreement with the result obtained for 77a. However. the selectivity

for the formation of the y-lactone increased significantly. As expected. the use of the

"bulky" Rh,(Piv), - resulted in a lower yield of 85 (entry 2). With Rh,(acam), - the

chernoselectivity of the reaction revened and a good yield of y-lactone 85 was obtained

(entry 3).

In conclusion. it is evident that moving the C-C double bond farther away

minimized cyclopropane formation. Also. the chemoselectivity of the reaction was

significantly revened.

2.123 The Effect of Ketone Functionality vs Ester Functionality

As stated before, the dirhodium(Il) carbenoid-mediated intrzimolecular

cyclopropanation reaction generaily favors formation of bicyclo[3.1.O.]hex;uie and

bicyclo[J. l .O.]heptane ring systerns. The formation of the 3-oxabicyclo[S. 1 .O.] and 3-

oxabicyclo(6.1.0.] lactones, 80a and 86, was unexpected which suggests that their

formation may be entmpically favored. This result cannot be simply explaïned by

considering only the effect of a shorter C-O bond. The ester O oxygen may have an

influence on the outcome of the reaction. Therefore, the a-diazo-B-keto ester 92 (the

"carbon" andog of 77a) was prepared and its Rh(Il)-catalyzed reaction was investigated

(Scheme 37). We were interested to see if the simple replacement of oxygen with carbon

would change the regio- and chemo- selectivities of the reaction.

2.123.1 Reparation of Diazo Keto Ester 92

The requisite u-diazo P-keto ester 92 was prepared following the sequence show

in Scheme 36. The brornide 87 was obtüined in two steps starting from alcohol 75 via

Scheme 36

LiBr /DMF CH(COOMe)2

50% for three steps

formation of tosylate which was then followed by halogen exchange. The malonate

carbanion wûs alkylated by bromide 87 followed by decarboxylation and hydrolysis to

afford acid 90 in 50% yield over three steps. Activation of the carboxylic acid group as an

imidazolide followed by reac tion with magnesium salt of a-(methox ycarbony1)acetic acid

afford the Fketo ester 91U which upon dia~otization~~ furnished 92.

2.1.2.3.2 Rh(11)-Catalyzed Reaction of Diazo Keto Ester 92

Compound 92 was subjected to different catalysts under the same reaction

conditions for 77a (CH,Cl, at n). Both the Rh,(OAc), and Rh,(pfb), catalyzed reaction - - - -

furnished a mixture that was comprised of a less polar ( Rr = 0.50.7 : 1 PE : EtzO) and a

Scheme 37

more polar ( Rr = 0.28, 7 : 1 PE : Et20) component. The reaction with Rh,(acam), - provided only the less polar component. The less polar component was identified as the

substituted cyclopentanone 93 which resulted from insertion into the tertiary C-H bond

and existed as a mixture of keto and en01 tautomers. For further corroboration of the

structure, 93 was acetylated to afford the enol acetate 94.

As expected. Rh,(OAc), - prornoted insertion into the tertiary C-H bond and a good

yield (83%) of 93 was obtained. Rh,(pfb), - resulted in the lowest yield (30%) of 93. The

byproduct obtained from these two reactions showed a very complex 'H NMR spectrum

which harnpered funher structural characterization. Nevenheless. the presence of double

bond resonances indicated that cyciopropanation was not a favoured pathway in the

reaction of 92. More importantly. in comparing the results of 77a and 92. it is clear that

the ester oxygen atom in 77a plays a role in infiuencing the regio- and chemo-

selectivities of the reaction. We do not have a satisfactory explanation at the present time

for this effect.

2.1.2.4 The Effect of Benzylic Tertiary C-H

In continuation of our efforts to develop a genenl methodology for the

construction of quaternary carbon centen, we noticed that some naturd products such as

mesembrine have a substituted aryl group at the quaternary carbon center. Therefore. it

would be useful to investigate whether the preceding approach would work for these

systems. Hence, we investigated the Rh(lI)-cataiyzed reaction of diazo compounds 97a-e

1 ail (Scheme 40). We chose the dirnethoxyphenyl goup because Taber and CO-worken

have shown that the phenyl unit is an inductively elecuon-withdrawing group which

deactivates the benzylic position. We reasoned that the two methoxy substituents in the

ring would make the phenyl ring electron-rich through their combined +-electromenc

effect. It was expected that the replacement of the ethyl group with the aryl group would

not alter the outcome of the reaction because the potential aromatic cycloaddition reaction

would fomi a disfavored bicyclo~.4.0]undeca~eneone.24

We were interested in determining whether a simple replacement of the ethyl

rnoiety in 77a and 83 by an aryl group would result in a predictable outcome in the

distribution of products.

2.1.2.4.1 Preparation of Diazo Esters 97a-e

Scheme 38

HO-CCHKO-Me. DCC, or P h S ~ C H g O $ L DCC

O . EoN -&OirR O

O

I MsN3, DBU

or MsN3. GjN

The required alcohols 95a-b were readily prepared via the aikylation of the

dianion of 3,4-dimethoxyphenyl acetic acid with allyl bromide or 3-butenyl bromide,"

followed by reduction with LAH. Acylation of the primary alcohols 95a-b with a-

(methoxycarbonyl)acetic acid or u-phenylsulfonylacetic acid or diketene provided

malonate esters 96a-b or phenylsulfonyl acetate 96d or keto ester 96c. Diazotization

39 under standard conditions furnished the diazo compounds 97a-d. Compound 95b when

treated with cc-(p-toluenesulfony1hydnzone)acetyl ~hloride''~ in the presence of Et3N

provided diazo acetate 97e (Scheme 38).

2.1.2.1.2 Rh(I1) Catalyzod Reaction of Diau, Esters 97a-e

We first investigated Rh(I1)-catalyzed reaction of 97b (Scheme 40). which is an

aryi substituted analog of 83. using reaction conditions (CH,CI2. slow addition)

previously developed for compound 83. Table 4 sumrnuizes the results.

Scheme 39

Table 4. Rh@) Cataiyzed Reaction of 97b as a Function of Cataiysts

relative yields"

entry catdyst isolatedyield(96) 98b 99b lOOb lOlb others

a) Relative yields are based on isolated products

Unexpectedly and somewhat disappointingly. a mixture of the lactones 98b. 99b.

lOOb and lOlb was obtained dong with some other uncharacterizable. inseparable

products. It is clear that the reaction catalyzed by Rh,(OAc), gave the best yield of y- - lactone 99b. Comparatively. the Iess electrophilic Rh,(acam), - catalyst gave half the yield

of y-lactone 99b. The use of Rh,(pfb), resulted in the highest yield of the eight-membered -

lactone lOlb which is in agreement with the result obtained for 83. In this case the y-

lactone 99b was not detected at d l .

As expected fi-lactones were formed as minor products in dl the Rh(iI)-catalyzed

reactions. It should also be noted that aromatic cycloaddition products were not detected.

The formation of the benzoxepinone derivative lOOb that had resuited from

electrophilic ammatic substitution was unexpected especially for the Rh,(;icarn), -

catdyzed reaction. This outcome is in contrast to the results obtained by Padwa and

~o~le." 'The formation of the seven membered ring aromatic substitution product w u not

detected in Rh(II)-catdyzed reaction of compound M. It is dso true that

102

Rh,(acam), did not promote luornatic substitution. So it is possible. in our case. that the -

presence of two electron donating methoxy groups in the benzene ring may have

facilitated the electrophilic aromatic substitution.

It is ülso useful to compare the present result with that from compound 83 (Table

3. pg 40). We see that the yield for the formation of the y-lactone dropped dramaticdly. It

is possible that the replacement of the ethyl group with the aryl group may have

deactivated the teniary C-H position despite the presence of electron donating groups.

Next. we investigated the Rh(JI)-catalyzed reaction of 97a. A very complex

mixture of products was obtained for d l the catalysts examined so no further purification

wûs attempted.

On the basis of our previous observation of the influence that the a-substituent

had on the reactivity and selectivity of the Rh(I1) carbenoid. we then studied the reaction

of diazo ester of type 9%-e. where R = CH3C(0), PhSOL and H respectively.

Disappointingly, for 97c and 97e, the reactions only gave complex mixtures of products

and no funher attempts were made to separate andfor chmcterize the products. For 97d,

we were surprised to find that there was no reaction at dl. The use of higher reaction

temperature only resulted in the decomposition of 97d.

Once again, the results suggested that the electronic effect of the substituent on

the carbenoid carbon exerts an important influence on the reactivity of carbenoid which

controls the selectivity of the reaction.

The regio- andlor chemo-selectivities for the Rh(Ii)-cataiyzed reaction of diazo

compounck 77. 83, 92 and 97 were exümined. It was found that the a-substituents on the

carbenoid carbon exert an important influence on the reactivity of the Rh(U)-carbenoid

which. in tum. controls the selectivity of the reaction. The nature of the Rh(II) catalysts

provides control for the regio- and chemo-selectivi ty of the reaction. For reactions w here

the cornpetition between tertiary C-H insertion and cyclopropanation exists. Rh,(OAc), -

favoured tertiary C-H insertion. The polarity of the solvent influences the regio- and

chemo-selectivity of the reaction. For reactions involving the competition between

tertiary C-H insertion and cyclopropanation. the use of CYCI, - - promoted teniary C-H

insertion. The aryl group in 97 was found to be a deactivating group which Ied to the low

yeld of the y-laciones. In addition, although it is still not well understood why Rh,(ptb), -

led to mainly cycloaddition products, the Rh,(pfb), - catalyzed reaction does provide a

good rnethod for the prepantion of bicyclo [5.1 .O] and bicyclo r6.1 .O] lactones.

2.2 Total Synthesis of Alkaloids Possessing a Quaternary Carbon Centre

Having established a method for the formation of 4.1-disu bstituted y-lactones. we

then tumed Our attention to developing a genenl strategy for the use of 44-disubstituted

y-Iactones in the total synthesis of alkaloids possessing a quatemary carbon center.

Geminally disubstituted y-lactones are useful intemediates in the synthesis of

natural products possessing a quatemary carbon center and much interest has been

directed toward the development of new methods for their preparation.26 In particular, C-

3 disubstituted y-lactones have received the most attention and have been effectively

utilized for the synthesis of alkaioids possessing a quatemq carbon tenter? In contnst.

C-4 disubstituted y-lactones have not received the same attention and one reason for this

could be the lack of general methods for their preparation.

tndole alkaloids. because of their high biologcal activities and unique structures.

have remained attractive targets for total synthesis. *a. b. 17 To demonstnte the utility of

Our method in natural product synthesis, we have chosen (+)-quebracharnine, (-)-

rnesembrine and (-)-eburnamonine as our target rnolecules.

2.2.1 Total Synthesis of Quebrachamine

2.2.1.1 Literature Routes For The Synthesis of Quebrachamine: A Brief Survey

Several strategies for the synthesis of quebnchamine 144 have been developed.~'

Three main approaches, A-C. are listed in Figure 3.

205 166

Figure 2. Litenture Approaches Toward Total S ynihesis of Quebrac hvnine

Approach A

In this approac h. the reduc tive cleavage of 1.2-deh ydroûspidospermidine

derivative 108 with potassium borohydride is the key step in the synthesis of

quebracharnine. Different methods have been developed for its prepantion.4s

For example (Scheme 40), 2-hydroxytryptamine 103 was treated with excess

dimethyl 4-ethyliCformylpimelate 104 (with the well defined quatemary carbon center)

to give lactam 105. Laciam 105 was cyclized followed by decarboxylation to give 106.

Lactam 106 was converted to thiolactam 107 which was reduced to give 1 2 -

deh ydroaspidospermidine 108.

Scheme 40

A second route (Scheme 41) developed for the spthesis of 108 involves reaction

of cyclohexenone 109 (prepared from butynldehyde in seven steps) with aqueous

arnmonia to give bicyclic keto lactarn 110. The carbonyl group of 110 was protected and

the amide was reduced to afford keto amine 111. Acylation of 111 with chloroacetyl

chioride followed by cyclization using potassium t-butoxide led to the formation of

tricyclic keto lactarn 112 which was converted into keto amine 113 via ketalization.

reduction and regeneration of the ketonic function. Next. Fischer indole cyclization of the

phenylhydnzone of 113 in acetic acid afforded 1.2-dehydroaspidospermidine 108.

Scheme 41

112

Approach B

LiAl H PhNHNH2 ___)

AcOH

In this approach. the photoisornerîzation of 1-acylindoles to 3-acylindoles was

exploited as the key step in the formation of 117. The key intermediate 117 was then

convened into quebracharnine by well known procedures"9 (Scheme 42). So compound

114 (prepared from 4-carûomethoxybutyryl chioride in six steps) was inadiated with a

high pressure mercury lamp to give the nine-rnembered lactarn 117 presumably through

the 1,3-isomerization to afford 115 followed by an intramolecular condensation which led

to the ring expansion to give the final product. After protecting the indole nitrogen with

dihydropyran, compound 117 was treated with 1-chloro-3-iodopropane to give the

tetracyclic lactam 118. Further alkylation with ethyl iodide followed by reduction with

LAH and deprotection afforded the quebrachamine 144.

Scheme 42

Approach C

The prepantion of appropriately functionalized tetrahydro-fkarboline

derivatives. such as 166 and 205. was the key step in this approach. This was achieved by

either Pictet-Spengler or Bischler-Napieralski condensation of tryptarnine with a Cs-

aldehyde that dready had a quatemary carbon center. Subsequent intramolecular

alkylation of the Np nitrogen and following Birch reduction of the quatemary ammonium

sdt provided quebrachamine. This latter strategy provided a facile access to the

quebrachamine ring system and therefore was frequently adopted in synthetic planning.&3.

'O This approach was also used in the enantioselective synthesis of (+)-quebrachmine.

The key part of the synthesis was to make the CI>-aldehyde readily available.

Therefore. much of the effort was directed at devising methods for the preparation of the

Co unit wherein three of the four groups in the quaternary center were chemo-

differentiated. In this Cs-aldehyde. one of the C-2 subunits was ethyl group and the other

C-2 subunit hüd to be an aldehyde or its masked form. So variation at the C-l and C-3

subunits as well as the C-2 aldehyde unit in different masked forms provided various

entries to the preparation of the Cg aldehyde.

For example. ethyl 2-(3-benzyloxypropyl) butynte 119 (prepared in seven steps

from propane-1.3-diol) was converted to the allyl ester 120 which was then treated with

osmium tetraoxide-sodium periodate to afford Cq-aldehyde 121S1(~cheme 43). Pictet-

Spengler condensation of 121 with tryptamine in acetic acid led to the formation of the

key intermediate 205.

Scheme 43

The a-diketone monothioketal 123 (prepared from 4-ethoxycarbonyl-

cyclohexanone 122 in four steps) was treated with sodium hydnde in t-butyi alcohol

containing three equivalents of water to give the h d f ester 124 (a Cs-ddehyde denvative).

The coupling of 124 with tryptamine gave the amide 125 which upon treatment with

excess methyl iodide in aqueous acetonitrile afforded the lactam 126. Lithium alurninurn

h ydride reduction gave the tetrac yclic amino alcohol 166~' (Scheme 44).

Scheme 44

LAH -

On the other hand, the C unit also came in the form of 3.3-disubstituted y-

lactones. j3 Takano and CO-workenflb reported that 2.7-diallylbutyric acid 127

(prepared from butyronitrile in two steps) was treated with iodine and potassium iodide in

aqueous sodium bicarbonate to give the intermediate iodo alcohol which was cyciized to

afford iodo-lactone 128. Lactone 12% was hydrolyzed in aqueous potassium hydroxide to

give the di01 followed by the oxidation with sodium metaperiodate to give the

hydroxylactone 129, a Cg-aldehyde derivative. Pictet-Spengler condensation of 129 with

tryptamine in acetic acid gave the lactarn 130 which was converted to the amino alcohol

131 via hydrobontion. Further reduction of 131 afforded 205 (Scheme 15).

Scheme 45

The preparation of hydroxylactone 129 in its optically pure form was also realized

by Takano and co- workers in their effort to s ynthesize (+)-que bra~harnine. '~ The

alkylation of chiral lactone 132 (denved from L-glutamic acid) with allyl bromide

Scheme 46

W C ?

followed by the alkylation with ethyl iodide gave the 3.3-disubsti tuted y- lactone 133 with

3s configuration. Compound 133 was then converted to the hydroxyiactone 129 via

deüitylation. hydrolysis and oxidation (Scheme 46). Conversion of 129 to (+)-

quebrachamine followed the same procedure as described for its racemic synthesis.

On the other hand, the chiral nitro enamine 134 (prepared from l-morpholino-2-

nitro olefin and /S)-2-(methoxyrnethy1)pyrrolidine) reacted with the enoiate 135 to yield

Scheme 47

the a: a-disubsti tuted Glactone 136 with 3s configuration through an addition-elimination

process. Compound 136 was treated with TiC13 in aqueous methanol to give an rldehyde

intemediate followed by ring rearrangernent to provide methyl acetal 137, a Cs-aldehyde

deri~ative~~' (Scheme 47). The Pictet-Spengler condensation of 137 with t-ptamine

provided the arnino alcohol205.

Scheme 48

AcOH -

Major Minor 138 139 143

In addition, a unique strategy for the formation of Cg unit where the quatemary

carbon center was created by cycloaddition instead of alkylation was deveioped by

wenkert5! So the cyclic en01 ether 138 was treated with a-diazoacetate in the presence of

Cu(D catalyst to give the oxycyclopropane denvative 139. The acid-induced ring cleavage

of 139 gave the lactone 140 which was rhen reduced with DIBAL-H to yield compound

141, a Cs-aldehyde derivative. The Pictet-Spengler condensation of 141 with tryptamine

resulted in the formation of 142 which was then reduced with sodium cyanoborohydride

to gwe the arnino alcohol205 (Scheme 48).

Recently, an asymmetric version of this strategy was developed by Andersson and

CO- ork ken.''^ The enantiomerically pure oxycycIopropane derivative 139 was obtained

when the cyclopropanation reaction was catalyzed by Cu(I)OTf in the presence of

Evans's chiral bisoxüzoline ligand 143. Conversion of 139 to (+)-quebracharnine

followed the same procedure as described by Wenken.

2.2.1.2 Rh(I1) Carbenoid C-H Insertion Approach to (k)-Quebrachamine

Our smtegy toward this synthesis is based on the Rh(@ catalyzed teniary C-H

insertion reaction of a-diazo esters. We have shown that the Rhz(OAc)tcataiyzed

reaction of p'-substituted u-diazo esters is a useful method for the synthesis of 4.4-

disubstituted y-Iactones (see section: 2.1.1). In principle, this should lead to the easy

access of 4,ctdisubstituted y-lactones. in addition, if chiral dcohols are used, the

fomation of c h i d non-racirnic C 1 disubstituted y-lactones is possible.

The use of 4,4-disubstituted y-lactones in alkaloid synthesis has not ken

extensively investigated. To demonstrate the utility of Our method in natural product

synthesis, we have chosen quebracharnine as a target molecule.

2.2.1.2. 1 Retrosynthetic Analysis

Our initial efforts were directed at the synthesis of (I)-quebrachamine. The

retrosynthetic andysis is outlined in Figure 3. We envisaged that quebrachamine 1 4 is to

be derived from the known tetracyclic amino alcohol 166. Compound 166 should be

available through the condensation of tryptamine and the key intermediate 155 which is

derived from plactone 152. ~Lactone 152 is prepared via the Rh(IT)-catalyzed teniary C-

H insertion reaction of a-diazoacetate 147 followed by decarboxylation of the product.

155

Figure 3. Retrosynthetic Plan for the Total Synthesis of (k)-Quebrachamine

2.2.1.2.2 The Preparation of sDiazoacetate 147

The a-diazoacetate 147 was prepared as shown in Scheme 19. The double bond

moiety in the known P-keto ester 76a was hydrateds5 using disiamylborane followed by

oxidation with alkaline hydrogen peroxide to give a good yield of the primary alcohol

145. Reaction of 145 with r-BuPh?SiCI proceeded efficiently to afford the silyl ether 146,

which was dia~otized.'~ with mesyl a ~ i d e ' ~ to give the diazo cornpound 147.

Scheme 49

Reagents: a) (Sia)?BH, THF. O OC; H201. NaOH. 708 b) t-BuPhzSiCI, pyndine.8956 c) MsN3, Et3N, MeCN, 88%

The reason the hydroxy goup was introduced before Rh@)-catalyzed teniary C-H

insertion was that we had shown that the Rh(II)-carbenoid cycloaddition to the double

bond was cornpetitive with teniary C-H insertion. This modification should suongly

favour teniary C-H insertion. in addition, it was enpected that the Rhz(acam)a-denved

carùenoid would favor insertion into the more electron-rich methine C-H over the less

electron-rich methylene C-H bond resulting in an increased preference for the formation

of y-lactone (see section: 7.1.1).

2.2.1 J.3 Formation of y-Lactone 148

The Rh@)-catalyzed reaction of a-diazoester 147 under different reaction

conditions was then investigated (Scheme 50). The results were shown in Table 5. [t

tumed out that when we carried out the Rh(1I)tatalyzed reactions using Method A

(CH2C12, 0.01M. Section 2.1.2.1.2, page 33), the 8-Iactone 149 was obtained as usual.

However. the chernical yield of the desired 148 was nther low: 39% and 24% with

Rh2(OAc)a and Rhr(acÿm)4, resprctively. The water insertion product 150 and dimer 151

were also obiained in significant amounts. In Method B (CH?Cl2, slow addition. final

Scheme 50

Table 5. Rh(Q Catalyzed Reaction of Diazoester 147

entry cataf yst me thod i48(%") 149 t50+ 151

(ratio 1501 151)

Method A: CHg12, 0.01M; Method B: CH2C12, 0.0 LM, slow addition; Method C: same as Method B but use flarnedried reaction apparatus. il) isolûted yield for 148.

concentration 0.OLM). there was a substantiai decrease in the amount of byproducts that

were formed and a marked increase in the yeld of 148 when Rhz(OAcl4 was used as the

catnlyst (compare entries L and 2). This was not the case with Rhz(acam)d wherein

byproduct 150 and dimer 151 were still produced as main products and only a slight

improvement in the yield of 1 1 was realized (compare entries 4 and 5). The best results

for the formation of 148 were obtained when Method C (same as Method B but use

flame-dried reaction apparatus) was used (entries 3 and 6). In particular, the mount of

byproducts formed in the Rh2(acamk-catalyzed reaction was dnstically cunailed

(compare entries 5 and 6).

These composite results indicated that insertion into stericaily hindered tertiary C-

H bond was slow. Because there were no other active sites availabte such as a double

bond. the intermolecular water insertion became cornpetitive with tertiary C-H insertion.

It is be~ieved~~ that the Rhr(acûm)~-catalyzed C-H insertion reaction proceeded through a

Iate transition state which meant that the carbenoid had to react with the C-H bond at a

closer distance. The steric interference of the substituent around the tertiary carbon with

the approaching Rh(II)-carbenoid would hinder the teniary C-H insertion reaction. That

was why the yield for the formation of y-lactone 148 was lower when Rh2(acmk was

used as catalyst. However. increasing the reactivity of carbenoid by using stronger

electron withdrawing catalyst should enable the cvbenoid to react with the tertiary C-H

bond from a greater distance (early transition state) which in tum should tavour y-lactone

148 formation. That was why the use of Rh?(OAck increased the yield for the formation

of y-lactone 148 instead of the rlectron-donating ~h? (aca rn )+~~ On the other hand. the

reaction rate for intermolecular process is concentration dependent which means

decreasing the concentration of the carbenoid or concentration of water should dso

increase the yield for the y-lactone 148 formation. That was why formation of y-lactone

148 becarne predominant by using Method B where the concentration of carbenoid was

minimized or Method C where both the concentration of carbenoid and that of water were

minimized.

2.2.1.2.4 The Preparation of Pivotal Intermediate 155

The y-lactone 148 was then decarboxylated by using a modified litenture

condition (wet DMSO containing NaCI at 1 1 0 " ~ ) ~ ' to give a 84% of 152 (Scheme 51).

The recommended conditions for decarboxylation ( l6O0C) resulted in an unexpected loss

of the t-BuPhSi group. The compound 152 was efficientiy desilylated with BuJW in

THF to give 153 which was subjected to Jones' oxidationSob to yield the carboxylic acid

154 in 98% yieid.

Scheme 51

148; R = SiPh2Bu-t 152; R = TBDPS

Reagents: a). DMSO-HrO. NaCI. L LO°C, 84% b). BuJW. THF, 0°C. 93% c). Cr03, H2S04, H'O, 98%

Next we investigated the preparation of 155 (Scheme 52) via selective reduction

of the lactone carbonyl in 154 with DiBAL-H using the method developed by Fuji and

coworker~.~~~ This led to a 65% isolated yield of the desired compound 155. However,

Scheme 52

1 ). DIBAL-H

O 2). MeOH, TsOH Meo

three other minor products, identified as the diacetal 156. the acetal ester 157 and the

acetal aicohol 158 were also isolated. The ratio of 155:156:157: 158 is 722 1:4:3.

The formation of the acetal ester 157 under the reaction conditions was expected.

However, the formation of the diaceta1 156 and the acetd alcohol 158 were unusual,

because under normal conditions. the acid functional group is not reactive toward

DIBAL-H reduction. The mechanistic rationale for the formation of diacetal 156 and the

acetd alcohol 158 is shown in Figure 4. Compound 154 was reduced by DIBAL-H to

DIBAL-H (C H&COOAI R2-

DiBAL-H OH- - O DIBAL-H t OH

161 162 163

Figure 1. The Mechanistic Rationalization for the Formation of Diacetal 156

give the cycIic hemiacetal 151 which Ied to the desired product 155 when treated with

MeOH. The aluminurn salt in 151 may catalyze the cyclization process to give the

bicyclic lactone 152. Lactone 152 cauld be reduced again to give bicyclic hemiacetal 153

which was in equilibrium with its aldehyde form 154. Aldehyde 154 would provide

diacetal 156 when reacted with MeOH. Aldehyde 154 could also be funher reduced to

alcohoI 155 which would result in the formation of the acetal alcohol 158 when MeOH

was applied.

2.2.1.2.5 The Preparation of the Known Tetracycüc AMno Alcohol166

With 155 in hand. we investigated its condensation with tryptamine under Pictet-

~~en~le&eaction conditions. Thus treatment of 155 (Scheme 53) with three equivalents

Scheme 53

Reagents: a). Tryptamine, glacial AcOH-PhMe (2: 1 vlv), 80 and then 1 lOaC, 57% b). LAI&, THF, reflux, 95% c). Ref. 59.

of tryptamine in refiuxing toluene-acetic acid (12 vlv) led to a 1.3: 1 mixture of separable

diastereomen, Fethyl isorner 165a and a-ethyl isomer lMb, in a cornbined yield of

57%. Their structures were in full accord with their 'H NMR and 13c NMR (including

COSY and HETCOR) as well as high resolution mass spectral data. The relative

stereochemistry between the C( 13b)-H and the ethyl and CH20Ac group was assigned on

the basis of NOE experiments (Table 6).

Table 6. NOE Data for Compound 165a

For example. irradiation of the low field doublet of the CHrOAc group Hb in 165a

centred at S 4.99 resulted in a 4.8% enhancement in the C(l3b)-H doublet centred at 6

5.20 which established their syn relative stereochemistry. No enhancement, however. was

observed when the high fieid doublet H, at 6 3.80 was irradiated. On the other hand,

irndiation of either Ha or Hb of the CH20Ac group in 165b resulted in no signal

enhancernent for H13b which supported their tram relative stereoc hemistry.

It was notewonhy that by reducing the arnount of tryptamine, the yield of the

product droped dramaticdly. For example, when 1. Leq of tryptamine (instead of 3eq) was

used, the yield of 165 decreased to 341. The other product isolated frorn the reaction

mixture was Nb-acetyl tryptmine which suggested that an unanticipated Nb-acylation

pathway was competitive with the desired Pictet-Spengler reaction pathway. Replacement

of acetic acid with the more hindered pivalic acid did not suppress the undesired Nb-

acylation pathway; in fact Nb-pivdyltryptarnine was the only product isolated and the

desired product 165 was not detected at all. This result suggested that the acidity of the

reaction may be important to the success of the reaction and acid itself may be involved in

the process of the cyclization which led to the formation of the desired product 165. This

result will be addressed in the next section.

Standard reduction of 165a and 165b with L M & in refluxing THF fumished the

known key tetracyclic amino alcohol 166a (mp. 115-216°C. lit.j9 119-221°C) and 166b

(mp. 230232°C. lit. 232-135'C). Since Takano and coworkenS9 had converted 166 to

(t)-quebrachamine 144. this constituted a formal synthesis of

2.2.1.2.6 A Mechanistic Rationalization For The Cyclization of 155

Cyclic acetal compounds possessing a carboxylic acid side chain have been used

in Pic tet-Spengler type condensations by several gououps. Job.50b.6 1 Although the mechanism

of the Pictet-Spengler reaction is known, the mechanism of the reaction involving cyclic

acetal compounds possessing a carboxylic acid side chain is not clearly defined. Some

possible explanations for the cyclization are listed in Figure 5.

172 165 Fipre 5. A Proposed Mechanistic Rationalization for the Cyclization

According to the mechanism of the Pictet-Spengler reaction, tryptamine reacts

with an ddehyde to form an iminium ion intermediate which was then cyclized to form

the product. So the intermediate 170 andfor 171 should be involved in the process of the

reaction.

There are three possible pathways A, B and C to fom the product. The path A

involved the initial formation of intermediate 168 which was in equilibrium with irnine

170. The attack of the indole moiety in 170 on the irnine or iminium ion intermediate

would lead to the intermediate 172 which underwent latamization to give 165.

If the reaction did proceed through intermediate 172, the lack of the carboxylic

acid side chain should not affect the cyclization of the reaction. in order to test this

assumption, compound 173. prepared from lactone 152 via DIBAL-H reduction, was

treated with Nb-benzyl tryptamine under the same conditions used for cyclization

(Scheme 54). Disappointedly. the only component isolated from the very complex

product mixture was cornpound 174.

Scheme 54

This result suggested that the equilibrium between mixed acetai 174 and iminium

ion generated from it may be in favor of the more stable five membered mixed acetal. As

a result. there was no cyclization during the reaction. This result clearly indicated that the

five-membered cyclic acetd without carboxylic acid side chain such as 173 was not

suitable to be used in Pictet-Spengler type condensations.

Scheme 55

M e 0 fi"-fl& / H I - no product

179

Further evidence could be found (Scheme 55) when five-membered cyciic acetal

176 (prepared from alcohol 153 in three steps) was used in an attempted Pictet-Spengler

cyclization. Again, there was no cyclized product isolated at d l .

These observations were in accord with litenture precedents. For example, five-

membered carboxylate herni-acetal 177~'' (where the carboxylate group was a good

Ieaving gmup) only provided bicyclic lactone 178. A high temperature was needed

(250°C) for further cyclization. On the other hand. the six-mernbered &lactol 179~~

proved to be a good masked aldehyde for the cyclization.

These combined results clearly indicated that there was a strong tendency for a

five-mernbered cyclic acetal to stay in its cyclic fom. Therefore. the five-membered

cyclic acetals without carboxylic acid side chain were not suitable to be used in Pictet-

Spengler type condensations. In other words, the intemediate 172 was not involved in the

formation of product. Path A is not followed.

The path B involved the initial formation of amide 167. The attack of the amide

group from 167 on the acetal carbon afforded bicyclic lactam 169. The acyliminium ion

intermediate 171. generated from 169 or directly from amide 167 should undergo Pictet-

Spengler cyclization to form 165.

The formation of bicyclic Iactam 169 was supponed by literature precedents.

However. based on literature results. the conversion of bicyclic lactarn 169 to

acyliminium ion intermediate 171 w u not likely. For exiimple (Figure 6). compound

180.'Ob a cyclic acetal compound possessing a carboxylic acid side chain. gave good yield

of cyclization product 181. However. the preforrned amide 1 8 2 ~ ' ~ (derived from 180)

gave 181 as well as bicyclic Iactam 183. interestingly. 183 was not convened to 181 even

after prolonged heating. More interestingly, amide 184 with a substituent on the five-

rnembered cyclic acetal provided only the bicyclic Iactm 185 which cannot be converted

to the cyclization product. It was possible that the already suong propensity of y-lactol

(e.g. 182 and 184 ) to exist and react in the cyclic hemiacetal form was intensified by ring

substitution. These results clearly indicated that the formation of the mixed amide-acetd

like 169 was possible. However. formation of acyliminium ion intermediate 171 from 169

was not possible.

184 185

Figure 6. Literiture Results Related to Pictet-Spengler Cyclization.

Evidence that the fomation of amide 167 was not the initial step in the actual

process was funher provided by the reaction of preformed amide 167 that was prepared

by the reaction of 155 with tryptarnine @CC, DMAP). Subjecting 167 to the same

cyclization reaction conditions did not result in the formation of 165. It was possible

either initially formed 169 was unstable or fomation of the acyliminium ion intermediate

171 frorn 167 or 169 was not a feasible pathway because of the stability of the five-

membered ring. The path B is not followed.

Reaction path C depends on the intermediacy of a putative acyliminium ion

structure 171. Thus. the initially formed imine 170 or iminium ion may undergo

competing intermolecular attack by excess carboxylate anion (as suggested by

ane es si an^') to give a transient a-acyloxy amine which spontaneously cyclized with the

carboxylic acid side chain to give the intermediate 171. The resulting extended

conjugated acyliminium ion lactam system 171 should facilitate the cyclization to give

the product 165.

As mentioned before, acetic acid prornoted cyclization. Pivalic acid. on the other

hand, favored formation of Nb-pivalyltryptamine. This mechanistic ntionale provided

explanation for the d e of the different ciirboxylic acid. The use of acetic acid facilitated

the attack of the carboxylate anion on the imine 170 or iminium ion to form transient a-

acyloxy amine which. therefore, favored the formation of intermediate 171. The use of

bulky pivalic acid may prevent attack of the carboxylate to the imine 170 or irniniurn ion

which, therefore, disfavored the formation of intermediate 171. As a result, there was no

cyclization when pivalic acid was used as catalyst. As we know, the acid used may also

serve severd other purposes. It may tnp the hydroxy group genented frorn formation of

imine 170 to Fom an ester therefore moving forward the equilibrium of the reaction. It

may also activate the carboxylic acid side chain by formation of mixed anhydride

intermediate which should promote formation of intermediate 171. The use of bulky

pivalic acid instead of acetic acid disfavored either process. That is why the use of acetic

acid provided the best result.

Frorn this studies, it is clear that the five membered cyclic caetal compounds

without carboxylic acid side chain cm not be used in Pictet-Spengler type cyclization. For

cyclic caetal compounds with carboxylic acid side chain. it is very likely that the Pictet-

Spengler cyclization proceeds through Path C (see pg 70). The type of acid cataiyst plays

key role this cyclization.

2.2.1.3 An Approach to (+)-Quebrachamine Via Rh (11)-Catalyzed C-H Insertion

Into a Confiprationaily Defined Tertiary Stereocenter

2.2.1.3.1 Retrosynthetic Plan

Next. we tumed Our attention to the asymrnetric spthesis of (+)-quebrachamine

1.14. Our synthetic plan is outlined in Figure 7. Compound 144 is denved from the known

tetracyclic amino alcohol 205 w hich should be avliilable through the condensation of

tryptamine and the key intermediate 201. One of the C-2 units of 201 has to be an

aldehyde; the C-l unit of 201 could be either a carboxylic group or n hydroxymethyl

group in its protected form. Compound (9-201 may be prepared from the plactone (a-(-

)-152 via standard functional group modification. yhctone 152 is prepared via the

Rh@)-catalyzed tertiary C-H insertion reaction of a-diazo ester (3-(+)-147 followed by

decarboxylation of the product. As mentioned before (see section: 1.3.5). the Rh (II)-

cataiyzed C-H insertion reaction is stereospecific and proceeded with retention of the

configuration. The ~iactone 152 should also have the S configuration. The u-diazo ester

(3-(+)-Id7 is derived from c h i d aIcohol (S)-(+)-194.

Figure 7. Retrosynthetic Plan for the Total Synthesis of (+)-Quebrachamine

2.2.1.3.2 The Preparation of Chiral Alcohol (S)-(+)- 194

The preparation of chiral alcohol (S)-(+)-194 was accomplished by the f'ollowing

sequences. based on two different methods developed by ~ v a n s . ~ ~ in order to find the best

method which provided the product of highest optical purity.

Scbeme 56

Reagent: a) n-BuLi; butanoyl chloride, -78OC: b) NaN(SiMe&; dlyl bromide, -78OC.

Treatment of oxazolidinone 187 with butyllithium (Scheme 56) and followed by

acylation with butanoyl chloride afforded the imide 188. Deprotonation of 188 with

sodium bis(trimethylsily1)amide followed by with allyl brornide gave

olefinic imide 189 ( [alBo = +26.l. CHCI,).

Altematively (Scheme 57). imide 190. prepared by acylation of the same

oxazolidinone 187 with 4-pentenoyl chloride, could undergo an aldol reactionM with

acetaldehyde to give 191 as a mixture of two dia~tereoisomen.~~ The stereochemistry of

the carbinol center in the ddol product 191 is of no consequence because it is to be

deoxygenated. Next. the thiocarbonate deoxygenation reaction was used to convert 191 to

189. Thus treatment of 191 with phenyl chlorothiocarbonate (Robins' p ~ c e d u r e ) ~ ~ * ~ '

followed by radical deoxygenation with tributyltin hydnde resulted in the same imide 189

( [ u ] ' ~ ~ = +16.8. CHCI,).

Scheme 57

Reagents a) n-BuLi. Cpentenoyl chloride. -7VC. 84%; b) TQBBu2, Et3N; CHEHO. -78°C. 52%; c) PhOC(=S)Cl. Py. DMAP. it, 92%; d) Bu3SnH. AIBN. 75OC. 76%

The results clearly indicated that both methods provided similar distereoselectivity

based on the almost identical value.

Reaction of 189 with lithium hydroxide (Scheme 58) and hydrogen peroxide gave

recoverd oxazolidinone 187 and the acid 193 as a colorless Iiquid which was reduced

with lithium aluminum hydride to produce (3-(+)-alcohol 194 in 50% yield.68 The low

yield of 194 is due to its volatility. The absolute configuration and optical punty were

confirmed by conversion of 194 into known compound 195 and by cornpuison of [alD

values.

Scheme 58

Reagents: a) LiOH-H202, THF-H20. O°C. 99% ; b) L i A l h , O°C + n, 50%: c ) NaH; 4-Methoxybenzyl bromide. THF-DMF

We also uied to reduce 189 to (S)-(+)-194 in one step using LAI& (Scheme 59)

as suggested by Evans. The results were rather disappointing. A mixture of aicohol (9-

(+)-194, oxazolidinone 187 ancilor compound 1% as well as amino dcohol 197 were

obtained under d l the conditions tested. The formation of 1% or 197 was dependent on

the reaction conditions. For example, when the reduction was conducted at -78°C

compound 196 was the major byproduct. When the reaction was done at -5°C. both 1%

and 197 were found in the reaction mixture. When the reaction was done at 67°C

(refluxing THF), only 197 was formed as byproduct.

Scheme 59

2.2.1.3.3 The Formation of y-Lactone (S)-(-)- lSL

With 194 in hand, (-)-152 was easily prepared (Scheme 60) following the

sequences described previously in Scheme 32 and Scheme 49. Thus the double bond

moiety in the known B-keto ester (-)-77a prepared via the reaction of alcohol (+)-194

with (rnethoxycarbonyl)acetic acid was hydnted using disiarnylbonne followed by

oxidation with aikaline hydrogen peroxide to give a pood yield of the pnmary dcohol(-)-

145. Reaction of 145 with t-BuPhzSiCl proceeded efficiently to afford the silyl ether (+)-

146. which was diazotized with mesyl mide to give the diazo compound (+)-147.

R~?(OAC)~ cataiyzed decomposion of (+)-147 under optimized conditions provided the

teniary C-H insertion product y-Iactone (-)-148 which was then decarboxylated by using

modified reaction conditions (wet DMSO containing NaCl at 1 LO°C) to give (-)-152 in

84%.

Scheme 60

(CH2 $OTB DPS (CH&OTBDPS C d

____I)

Et A o v C O~MB - Et / C o p C Q M e O O

(+)-146 (+)-la7

Reagents: a) H02CCH2C02Me. DCC, DMAP, 91%; b) (Sia)?BH. THF. O OC; H202, NaOH, 70%; c) t-BuPhzSiCI. pyridine,89%; d) MsN3, Et3N, MeCN. 88%; e) Rhr(OAc)t, 90%; f) DMSO-Hfl, NKI, 1 lO0C, 84%.

2213.4 The Preparation of Key Intermediate 201

y-Lactone (-)-152 was easily convened to y-lactol 198 via DIBAL-H reduction.

However. as demonstnted before (Scheme 54). y-lactol 198 was not suitable for the

Pictet-Spengler type condensation because of the stability of the five-membered ring. It

was necessÿry to conven 198 into another rnasked hydroxy aldehyde. We had two

choices: the aldehyde 201 or carboxylic acid 202. Either compound can be used in the

Pictet-Spengler reaction. Both the aldehyde 201 and carboxylic acid 202 were derived

from 1,3-di thiane 199.

The formation of 1.3-dithiane 199 was not straightforward. The conventional

rnethods for thioacetalization such as concd. aq. HCI. BF3 EtzO. AI CI^.^^ ~ ~ ( 0 ~ 0 ~ and

Zn(OTf12 'Owere not suitable in this case because compound 198 is not only sensitive to

acidic condition but also recalcitrant to ring opening7' The best rnethod was found when

(Scheme 61) compound 198 was reacted with 1.3-propanedithiol in the presence of

titanium tetrachloride." The 1.3-dithiane 199 was obtained in good yeld.

in order to form the aldehyde 201. the hydroxy group in 1,3-di thiane 199 had to be

protected. However w hen one equivalent of t-butyldimeth ylsil yl chloride or TsCl were

used, there was no reaction at dl. Even when one equivalent of MsCl was used, the yield

was very low. The best result was obtained when five equivalents of MsCl were used. It is

probabiy that the dithiane sulfur atom acted as a nuclophile and formed a temporary

complex with MsCI. There was anotiier advantage in forming the mesylate (see below).

Deprotection of the dithiane group in 200 to obtain 201 was accomplished by using

Hg(C1O4)?-3H20 in a mixture of P A . CHC13 and HrO (3/6/1) at ambient temperature?

Other methods for deprotection. such as the use of MeVHtO/NarCOi; NBS/HD

l~tidine;'~ ~ b o ~ / B ~ ~ . e t h e ? were found to be inefficient.

Scheme 61

152; R = TBDPS 198 199

c ""'u(CH~ OR - d OMS -

O OMS

Reagents: a) DIBAL-H, PhMe-EtrO, -7S°C. 95%; b) HS(CH2)3SH. TiC14. CHrCL2, - 20°C, 99%; C) MsCl. Py, DMAP. O°C, 85%; d) Hg(C104)t-3Hz0, [PAlHtOICHC13, 72%.

The formation of carboxylic acid 202 was dso investigated. However, the

oxidation of 1,3-dithiane 199 with pyridinium di~hromate"~ (7eq PDC) in dry DMF

failed to provide 202. The reaction was not clean. After column purification one

component. tentatively assigned as aldehyde 203 based on IR and NMR spectra, was

obtained. It was clear that the dithime group was not tolerated under the reaction

conditions.

2.2.1.3.5 The Preparation of the Known Tetracyclic Amino AIcohol205

When 201 was subjected to the Pictet-Spengler reaction (Scheme 62) with

tryptamine in refiuxing toluene. an excellent yield of 204 as an 1: 1 epimeric mixture at C-

l lb was obtained. This l : l ratio was determined by 'H NMR and was based on the

integration of two methyl signals centered at 6 0.72 and 0.85. respectively.

Scheme 62

dcud30R - a OH

O OMS =/

R = t-BuPhzSi R = t-BuPhlSi

201 204 205

Reagents: a) Tryptamine. toluene. 1 LO0C, 908; b) B W , THF, 0°C

However. it was found that compound 204 was unstable in solution. The

deuterochloroform solution of 204 tumed dark brown on standing. It was decided to

desilylate 204 to obtain the known amino aicohol 205. Thus, desilylation of 204

proceeded uneventfully. but the subsequent chromotopnphic purification of amino

alcohol 205 proved difficult; an impunty was found to CO-elute with 205. Future work in

this part by using other desilylation reagents should provide pure known tetracyclic amino

alcohol 205.~~" Nevenhless. this approach Ieading to the synthesis of the advanced

intermediate 205 consti tutes a formal synthesis of (+)-que brac hamine.

The formation of cyclization product 204 was very interesting. The following

pathway (Figure 8) was suggested: the tryptmine was alkylated by 201 to form the

secondary amine 206 which reacted with the aldehyde unit to form an iminium ion

intermediate 207. The attack of the indole moiety on the irninium ion resulted in the

formation of 204. So the use of mesylate finished the cyclization and the founh ring

formation at the same time.

207 204

Figure 8. Mechanistic Rationalization for the Formation of 204

2.2.2 T o u Synthesis of (-)-Eburnamonine

Having successfully applied Our strategy for the formation of 44-disubstituted y-

lactones to the total synthesis of quebrachamine. we then tumed our attention to another

indole dkaioid (-)-ebumamonine w here the construction of the pentacyclic skeleton wi th

a quaternary carbon centre is very challenging to the s ynthetic organic chemists.

Figure 9. Literature Approaches Toward Total Synthesis of Eburnamonine

Over the years many conceptually different routes to eburnamonine have k e n

46a.75 developed. With few the vast majority of the routes utilizes either

J6a.b.54i1.77.78 Pictet-Spengler or Bischler-Napiedski ~ ~ c l i z a t i o n ~ ~ . ~ ~ with an uppropriately

functiondized Cs unit as the key step for the construction of C(1) and C(3) carbon carbon

bond. Therefore how to construct the Cs unit with a quartemary carbon center and how to

introduce this Cs unit into the system is very crucial for the success of any approach. Four

main approaches A-D are listed in Figure 9.

Scheme 63

Reagents: a. 1) PTSA. 80°C; 2) Oxalyl chlonde; 3) LIH. b. LDA, BrCH2COOEt. -78OC; c. POC13, LiCI04; d, Hi, PdK; e, NaOMe

The most direct approach for the total synthesis of eburnarnonine is approach A. 'O

The key intermediate 21 1 was prepared from l a c t a 210, which in turn was constructed

from tryptarnine and the bromo ester 209 (Scheme 63). Bischler-Napierals ki c yciization

of Iactam 211 using POC13 afforded the cyclic iminium chloride that was convened to the

perchlorate sait 212. Hydride reduction of 212 provided the amine 213 which was then

cyclized to yield (t)-ebummonine 246.

Scheme 64

216 217 246

Reagents: a. BH3; b, tryptamine: c. POC13. LiC!04; d. LAH; e. 1) Me[. &O; 2 ) PDC

Approach B w here the bisch fer-Napieraislu cyc lization of amide 215 also served

as the key step for the synthesis of (+)-ebumamonine was originally deveioped by Takano

and CO-worken (Scheme 6 ~ ) . ' ~ The intermediate 214 was realized as the key Cs unit

equivalent which was prepmd from the half ester 124 (preparation shown in Scheme 44).

A similar route based on the key intermediate 214 was used for the asymmetric

synthesis of (-)-eburnamonine. So various methodologies were directed at the asymmetric

synthesis of lactone 214. For example. the 3,3-disubstituted lactone 133 (prepared as

shown in Scheme 16) was ueated with dicyclohexylborane to yield primary alcohol which

was detntylated to give di01 218. Basic hydrolysis followed by treatment with sodium

penodate afforded aldehyde 220 which spontaneously cyclized to give the bicyclic

lactone 221. Compound 221 was then treated with propane-1.3-dithiol to give

enantiomericdl y enriched Iactone 214 (Scheme 65).

Scheme 65

Reagents: a. Dicyclohexylbonne, H202; b, KOH; c. NaIQ; d. HS(CH2)$3H

The lactone 221 was also prepared by Meyers' groups as a useful building block

for the asymmetric synthesis of (-)-ebumamonine. For exampie. chiral lactam 322 was

Scheme 66

- 9-BBN - Eti Allyl bromide

Et O O

alkylated with ethyl iodide to give compound 223 as a 1: 1 epimenc mixture which was

alkylated again with allyl bromide to give a dialkylated product 224 as a 4.6:l mixture

favoring the endo allyl epimer. The mixture was converted to aicohol 225 which was

easily sepmted by column chromatognphy to give enantiorneric pure 225. Heating the

alcohol 225 with HCI generated aldehyde 226 which spontaneously cyclized to give the

bicyclic lactone 221 (Scheme 66).

Scheme 67

Jones ragent Tic11 b~oaOH N f i G a O H -

3/ z/ DIBAL-H MeOH

A similar 3.3-disubstituted y-lactone 235 was also prepared by Schultz and CO-

workersasb employng an asymmetric Birch reduction - alkylation protocol. The role of

the Me3Si group was to (a) direct Baeyer-Viiligr oxidation to give lactone 234

regioselectively; and (b) facilitate the olefin formation to yield key intermediate 237. The

double bond here provided a potential hydroxy group for 239. It also accounted for the

hi@ diastereoselectivity observed dunng the acid-catalped cyclization with tryptamine

to form tetracyclic amide 238 (Scheme 68).

Scheme 68

Reqents: a, K. NH3. un-BuOH, -7S°C; LiBr; piperylene: Eti, -7g0C; b. PDC. Celite: c. H2, PdIC; d. ni-CPBA; e. TsOH; f, tryptamine; g, 1) LiBb; 1) KH. THF: 3) TPAP. NMO; h, CF3COOH. -SS°C; i, BH3THF; H2O2.

On the other hand. wenken7' developed a unique stntegy shown as approach D

which involved the amino-lactone 244 as the key intemediate. The 3-acetyl-2-piperidine

240 prepared via hydrogenation of fi-acetylpyridine was treated with propane- 13-dithiol

followed by desulfurization with Raney nickel to give enamîde 242. Compound 242 was

ueated with diazoacetate in the presence of catalytic amount of copper to give

cyclopropanecarboxylate 243 which was hydrolyzed with base to afford the key arnino-

lactone 244. Alkylation of 244 with uyptophyl bromide gave compound 245 whose

exposure to acetic acid Ied to (k)-ebumarnonine (Scheme 69).

Scheme 69

2.2.2.1 Retrosynthetic Plan

As shown in Figure 10. Our strategy is also based on the Pictet-Spengler

cyclization of tryptamine with a Co unit. [t is clear the aldehyde 253' (similar to the Cs-

unit 229 used by Fuji) is needed for the preparation of key intermediate 257b. The

aldehyde 253' is denved from y-lactone S-(-)-152 (Section 2.2.1.3.3 ) via translocation of

the aldehyde center. [t is interesting to compare the aldehyde 253' (for ebumamonine)

with 201 (for quebracharnine); both are derived from the sarne intermediate y-lactone S(-

)-152. It is worth mentioning that except for the ethyl group, each carbon unit of the chiral

quatemary centre in 253' has a different oxidation stage from 201. So further

manipulation of y-lactone S-(-)-152 is needed.

Figure 10. Synthetir Plan for the Total Synthesis of (-)-€bumanonine 216

2.2.2.2 Preparation of Di01 218

First lactone S-(-)-152 was converted to amide 247. This was done by desilylation

of S-(-)-152 using n - B u (Scheme 70) and then oxidation with Jones reagent to give acid

(5')-154 which was then coupled with tryptamine to fom amide 217.

Scheme 70

Reagents: a) BuSr\CF/THF. 93%; b) Cr03, H2S04. 95%; c) tryptarnine. DCC. CH2C12, 67%; d) LiBH>, THF-MeOH. 93%

With compound 247 in hand, the selective reduction of lacione carbonyl group in

the presence of the amide goup was investigated in order to translate the aldehyde

function. First. compound 247 was treated with DIBAL-H followed by N d & reduction

which provided the desired di01 248, albeit in a disappointingly low yield (36%). Another

component. tentatively assigned ('HNMR spectrum indicated the absence of the amide N-

H signal around 6 5.9) the structure 250 was also obtained in small amount. However. an

excellent yield (92%) of diof 248 was obtained when compound 247 was reduced with

LiBK in T K F - M ~ o H . ~ ~ No formation of 250 was observed in this case.

Scheme 71

It is likely that the initially fomed hemi-acetal 249 was intercepted by the amide

WH group to form cornpound 250 (Scheme 7 1). On the other hand. the nte difference in

the reduction between LiBK and N a B h may be responsible for the exclusive formation

of diol 248 in the former case.

2.2.2.3 Selective Formation of Monosilyl Ether 251

We next investigated the preparation of the monosilyl ether 251 (Scheme 72). It is

reasoned that the reactivity of the hydroxyl unit in the two primary dcohol groups is

sufficiently different because one of them is neopentylic in structure.

Scheme 72

Table 7. The Selectivity in the Formation of Mono-protected Diol 248

Reagen t Condition Result 251 : 252

PhCOCI P yndi ne No reliction

Py/CHCld(i-Pr)?NEt No selectivity a ; 1 1

t-BuMezSiCl Py/CHCld(i-Pr)?NEt No reaction

Irnidazole/DMF

t-BuPh2SiCI Pyridine No reaction

Py/CHC13/(i-Pr)2NEt No reaction

The formation of benzoate and t-buiyldimethylsilyl ether as well as t-

butyldiphenylsilyl ether from 248 was investigated under various conditions and the

results are shown in TabIe 7.

It was surprising to find that there was no benzoate formation when the reaction

was carried out in pyridine. The starting material 248 was recovered. The addition of

N,N-diisopropylethylamine did result in ester formation but there was no selectivity

between 251a : 25%. Then the formation of t-butyl dimethylsilyl ether was investigated.

While the use of N,N-diisopropylethylamine proved to be ineffective, the use of

imidazole in DMF gave the desired mono-silyl ether 251b as well as the disubstituted

silyl ether 252b in a ratio 1.7 : 1. The best yeld and selectivity was achieved when t-

butyldiphenylsilyl chloride was used in the presence of imidazole as b u e and c a t û ~ ~ s t . ~ ~

The ratio of 251c : 252c is L.1: 1 with 93% isolated yield for the formation of 251~. When

pyridine or N.N-diisopropylethyiamine was used as the base, no reaction was observed

and di01 218 was recovered.

2.2.2.1 The Prepamtion of Pivotal Aldehyde 253b-c

Next. oxidation of alcohols 25lb-c ro aldehydes 253b-c was investigated. It was

reported by ~ c h u l t z ' ~ ~ that the use of N-methyl morpholine N-oxide (NMO) in the

presence of catalytic mount of tet~propylarnmonium pemthenate (TPAP)" did not

affect the indole nucleus. So we applied this condition and the aldehyde 253 was obtained

in 34% yield. Some starting alcohol 251b-c was recovered dong with hydroxyarnide 254

(Scheme 73) which were not sepanble from each other.

Scheme 73

/O\

In an attempt to drive the reaction to completion by increasing the amount of

onidant ( M O ) to 7eq. from 1.3eq.. the alcohol 251 b-c was consumed and a mixture of

aldehyde 253 and hydroxyamide 254 as well as overoxidation product 255 was obtained.

Changing the solvent to acetonitrile led to an increase in the rate of oxidation and a

paralleled increase in the yield of 255. The best yield for the formation of aldehyde 253

using this rnethod was around 50%.

Next. the reaction of 25lc with sulfur trioxide pyridine cornplex (S03Py) in

DMSO, anoiher mild method used in indole types rextion, was in~esti~ated. '~ When

251c was treated with seven equivalents of Soi Py in DMSO followed by Et3N. the

aldehyde 2% as well as 254c were obtained in a total yield of 95% and the ratio between

25% : 254c is 1 : 1.7. It was pleasing to note that there was no overoxidation product 255

formed under the reaction conditions (Scheme 74).

Scheme 74

& -=/ TBDPSO '/

TBDPSO TBDPSO

2.2.2.5 The Preparation of the Tetracyclic Amide Alcohol257

Scheme 75

& TBDPSO

H& TBDPSO \

O-Go * t

TBDPSO -

The Pictet-Spengler cyclization of compound 25k and 254c was then

investigated (Scheme 75). As we k n o ~ ? ~ the diastereoselectivity of the reaction was

controled by reaction conditions. Therefore. different conditions were examined to find

out the optimized conditions for cyclization and the results are listed in Table 8.

Table 8. Different Conditions for the Pictet-Spengler Cyclization of 253c and 254c

Condition Temp.('C) Time (h) Compd. Yield (%) 2568 : 256a

AcOH

toluene 110 72 253c

254c

72 25%

254c

48 25%

254c

CF3COOH - 42 to ït 16 253c

254c

No reaction

57% conversion

-- 2 : 1

-- 2 : 1

-- 3 : 1

88 2 : 1

95 3 : 1

96 3 : l

The compound 25k was fint heated under refluxing toluene for three days.

However. there was no product formation at all. On the other hand, the use of compound

254c under the same conditions did provide cyclization product but the reaction is very

slow. The cyclization was finally realized when acetic acid was added into reaction

mixture and a 1: 2 mixture of 256a and its C-l lb b-epimer 2566 was obtained. These

results clearly suggested thüt the hydroxyamide 254c was the active species for the

cyclization and acid was essential not only for conversion of 25k to 254c but dso for the

cyclization.

Since the undesired p-epimer 2568 was the major product when acetic acid was

used as the critalyst. different acids were then investigated in an effort to improve the

diastereoselectivity of the reaction. However. the use of Nafion-H in renuxing toluene did

not improve on the results and sarne product distribution was obtained. We dso examined

the reaction conditions employed by Schultz and CO-workers: tnfluoroacetic acid at 42'C

to rt for 16h. It provided the best yield of product but the ratio between 2566 and 256a

increased to 3 : 1. This result indicated that 2568 was the kineticaliy favored product

under reaction conditions.

The use of 25&, on the other hand, gave the same results as 253c under al1 the

acidic conditions examined which suggested that the formation of hydroxyamide 254c

from 25k was fast and cyclization was the rate-determining step.

Table 9. NOE Experiment for Cornpound 2568

The stereochemistry of 2566 was established based on the NOE experiment and

the resuits are shown in Table 9. For exampie, irradiation at HIZb resulted in no signal

enhancernent for the CH2 unit of the ethyl group but signal enhancements were observed

for H, and Hb in the silyloxy ethyl group. These results suggested that the relative

stereochemistry between HIZb and the ethyl group was vans. It w u also interesting to see

that H-2' was located quite close to and Hb was very close to indole N-H bond.

These results further indicated a preferred conformation where the silyloxy group pointed

away from ring structure.

The compound 256u was then desilylated with trimethylsilyl chloride in methanol

ail to gave amide alcohol 2 5 7 ~ [m-p. 185-286 OC (decompose), Lit. m.p. 263-265°C:

-197.3 (c 0.13. MeOH). Lit. [alZao 495.5 (c 0.16, MeOH)] in excellent field

(Scheme 76).

Scheme 76

In order to produce more of 257% the epimerization of cornpound 2568 to 2 5 7 ~

was also investigated (Scheme 77). Fuji and CO-workers have examined the boron

trifluoride ethente mediated epimerizatîon of 2578 to 257a under equilibnting

conditions and have found that. at best. a 1 : 1 ratio of 2578 : 257a was obtained. Since

desilylation of 2566 to 2578 can be effected under the conditions. Fuji's conditions were

applied here in an effort to desilylûte 2568 and epimerize the resulting arnide alcohol

2578 to give 257a.

Scheme 77

It was observed that the disappearance of silyl compound 2568 was fast and there

was formation of amide alcohol 2578 and 257a. However. prolonged heating of the

reaction mixture did not conven more of the amide alcohol 2578 to 2 5 7 ~ ~ . Another new

unidentified compound was formed during the pmcess. In Our hands. under the optirnized

reaction conditions (l0h. 35-40 OC). only amide alcohols 2578 and 257a were obiained

but in a ratio 4: 1. So in principle. the amide alcohol 257p can also be used as a key

intermediate in the total synthesis of (-)-eburnarnonine.

Compound 257a was then convened to (-)-ebumarnonine {[a]"D -77 (c 0.13,

CHC13). Lit. [ajxo -88 (c 0.09. CHC13) J following the procedure described by Fuji and

CO-worken "".

2.2.3 Approach to the Total Synthesis of(-)-Membtine

Sceletirtm alkaloid (-)-mesembnne 305. characterized by the benzylic quaternary

carbon center and a cis- fused oc tahydroindole nucleus.B4 has always been an interesting

cornpound for total synthesis. Because of its being convenient testing target for new

synthetic rnethodologies as well as its close structurai relationship with the more cornplex

Amnryllidacear alkaloids such as crinine, martidine and pretazettine which are

biologically active and structurally interesting cornpounds," a number of different

strategies have been developed for the construction of mesembrine. Five main stntegies

from the litenture are shown in Figure 11.

Figure 11. Literature Approaches Toward Total S ynthesis of Mesembrine

In path A. the annulation of 3-aryl-2-pyrrolines 260 with vinyl methyl ketone

serves as the key step. 84b. 86 It is one of the most efficient strategies available for the

synthesis of mesembrine. However. this strategy is not adaptable for the asymmetric

synthesis of mesembnne. For example, starting from N-methylpyrrolidinone, Pinnick and

coworkers prepared mesembrine in three steps as shown in Scheme 78.Mb The N-

methyipyrrolidinone 258 was arylated with bromoveratrole to give lactam 259 which was

then reduced with DEAL-H in h e x a n e m to give the corresponding enarnine 260.

Annulation with methyl vinyl ketone completed the total synthesis of (t)-mesembrine.

Scheme 78

The strategy outlined in Path B is one that has been adopted by many researchen

for the synthesis of mesembrine. The key step in this approach was an intramolecular

conjugate addition of an amine or amide to 2-~~clohexenones.~~ The preparation of 4.4-

disubstituted 2-cyclohexenones 271 was therefore crucial for the success of this approach.

Several synthetic routes to the 4.4-disubstituted kyclohexenones 274 have been

reported one of which applied the amide acetd Claisen reamgement to construct the

quaternary carbon centre.87' In spite of the presence of a chiral auxiliary group on N atom,

there was no diastereoselection observed. For example (Scheme 79). (+)-allylic aicohol

261 was heated in toluene with chinl amide acetal 262 to yield a I:1 diastereoisomenc

mixture of thioacetal amide 265 via intermediate 263. Further manipulation of 265b

provided alcohol 266. which was oxidized with activated MnOl in benzene to afford (-)-

mesembrine.

Scheme 79

Reagents: i). 1. HgCl2/Hg0/MeOH; 2. Na&: ii). 1. Nam3; 2. LAH

The prepantion of 4.4-disubstituted 2-cyclohexenones 274 in optically pure form

was investigated by Meyen and CO-~orkers.~'' Treatment of (f)-267 with (3-valinol in

toluene produced the bicyclic lactam 269a,b as a mixture of two diastereomen.

Scheme 80

OHC O O

Mc

271 272 273 274

The mixture was then deprotonated (which generated the same enolate) and treated with

allyl bromide to give the alkylated product 270 with > 99% distereoselectivity. Next. the

allyl group in 270 was transformed into the arninoethyl group. Funher manipulation of

271 afforded chiral 4,Cdisubstituted 2-cyclohexenones 274 w hic h spontaneousl y cyclized

to give (+)-mesembrine under the reaction conditions (Scheme 80).

In path C (plO4). the intramolecular annulation of allylic amine under different

conditions was the key step for the formation of the cis-3a-aryloctahydroindole nucle~s.'~

For exarnple (Scheme 81). when allyl carbonate 275 and N-tosylallylamine 276 were

heated in the presence of Pd2dba3 as catalyst and (3-BINAP as a chiral ligand. the desired

allyl amine 277 was obtained with 70% ee. The tosyl group of 277 was replaced with

diphenylmethyl group which was then cyclized in the presence of 3 zirconium catalyst

and then reacted with O2 to give compound 278. Next, allylic oxidation of 278 followed

by hydrogenation. N-protection and ketalization dforded compound 279. The

hydroxymethyl goup of 279 was then removed via deformylation of aldehyde derived

from 279 with RhCl(PPh&. Finally the tosyl group of 280 was replaced with methyl

group to give (-)-mesembnne 305.

Scheme 81

Path D (pg 104)which was developed by Takano in 198 1 involved bicyclic enone

286 as a key intermediate. The enone 286 was derived from chiral 3.3-disubstituted y-

lactones. Much effort in this area was focused on the preparation of chinl 3.3-

disubstituted Y-lactones.J9 or example (Scheme 82). (5')-benzyl-2.3-epoxypropyi ether

281 prepared from D-mannitol was treated with anion of 3,4-dirnethoxybenzyl cyanide to

give the epimeric y-lactone 282 after alkaline hydrolysis. Alkylation of the enolate of y-

lactone 282 with crotyl brornide afforded 3.3-disubstituted y-lactone 283 which h d

resulted from alkylation lrom the less hinded side of the enolate. HCI catalyzed

debenzylation of 283 followed by sequential saponification. periodate cieavage and

reduction gave the desired 3.3-disubstituted y-Iactone 284. Wacker oxidition of the

double bond led to the regioselective formation of carbonyl goup to give the desired

methyl ketone 285 which was then cyclized under basic conditions to give chiral bicyclic

enone 286. Compound 286, when heated with MeNHz in a seded flask. converted to (-)-

mesembrine. In this approach. the stereocenter in 281 was used to control the formation

of a second stereocenter in y-lactone 283 only.

Scheme 82

___)

a). KOH. NrilOa P K E O b). NaBk

On the other hand. Fukumoto and coworkers (Scheme 83) recently reported the

constmction of 3.3-disubstituted y-lactone 285 from geminally-substituted chinl

cyclobutanone 289 which was denved from the enantiospecific ring expansion of chiral

spiroepoxide 288. The chiral spiroepoxide 288 was produced in situ via the Katsuki-

Sharpless asymmeuic epoxidation of 2-aryl-2-cycIopropylideneethanol 287. Funher

manipulation of 289 provided sulfone 290 which was alkylated with ailyl bromide to

give olefin 291. Next. reductive elimination of phenylsulfonyl group in 291 gave

cyclobutanone 292 which was then converted into chiral 3,3-disubstituted y-lactone 285

via chssicd procedure.87

Scheme 83

-

OMe TMSOTf OMe

In path E (pg 104) the iminium or acyliminium ion was realized as the key

intermediate for the total synthesis of rne~ernbrine."~ For example (Scheme 84). amine

293. prepared from veratrole in three steps was treated with chloro enone to give

vinylogous amide 295. Irradiation of 295 using a medium-pressure mercury lamp gave

the unstabie photocycloaddition product 2% which suffered a retro-Mannich reaction to

give imine 297. Methylation of 297 followed by treatment with DMAP in refiuxing

acetonitrile produced (t)-mesembrine 305.

Scheme U

Another approach employs acyliminium ions as reactive intermediates.

Intrmolecular interception of a cyclic acylirninium ion can be used for ring construction.

For example, regioselective alkylation of succinimide 299 with 4-iodobut-1-yne gave

disubstitured succinimide 300. Regioselective reduction of 300 with N d & afforded

hydroxyarnide 301 as the major product. HCOOH cyclization of Ml provided the desired

bicyclic compound 302 in excellent yeld. Next, compound 302 was converted into

mesembrine in three sreps via protection of the ketone group. reduction of the lactam and

deprotection of the carbonyl group (Scheme 85). Only (+)-mesembrine has been prepared

based on this approach.

Scheme 85

From rhis brief survey. it is apparent that many different approaches to the total

synthesis of mesembrine have been developed. As the construction of a configurationally

defined quatemary carbon center is always the key to the success of any approach. the

development of new and general methods for the creation of quatemary carbon center.

especially in irs optically pure fom, is still an area of intense re~earch.'~

Our approach toward total synthesis of (-)-mesembrine is based on the Rh(II)

catalyzed teniary C-H insertion reaction coupled with the use acyliminium ion cyclitation

technology.

2.2.3.1 Retrosynthetic Plan

The retrosynthetic andysis of (-)-mesembrine is shown in Figure 11. (-)-

Mesembrine is to be derived from mesembranol which may be obtained from 319 via

functional group modification. Disconnection between C-7 and C-7a leads to 316; in the

fonvard synthesis, this manipulation corresponds to the formic acid catalyzed cyclic CI-

acylimminium ion cyclization reaction. Compound 316 is derived from y-lactone 314

which, in principle. is accessible from the Rh(@ catalyzed tertiary C-H insertion of

(R)-Wb

Figure 12. Synthetic Plan for The Total Synthesis of (-)-Mesembrine

2.2.3.2 The Preparation of Chiral Alcohol (R)-(-)- 95b

The fint goal of the project was to prepare the chiral alcohol (R)-(-)- 95b. This

was accomplished by the following sequences where the Evans' oxazolidinone was used

to control the diastereoselectivity of the reaction.

2.2.3.2.1 The Formation of lmide 307

Scheme 86

Acid 306 which was activated via formation of rnixed anhydride with pivdoyl

chlonde was treated with oxazolidinone anion to give imide 307 (Scheme 86). Attempts

at preparing 308 via direct alkylation of the enolate denved from M7 with 4-bromo-

butene did not provide any of the desired product. Only starting 3(n was recovered

quanûtatively. This outcome is not entirely unexpected because ~ v a n s ~ ~ had found that

enolates derived from imide like 307 only reacts with activated halides such as dlyl or

benzyl hdides.

It was decided to develop a more reactive equivalent of 4-bromo-butene. The

allylic hdides 311 a-b were chosen for this purpose. It is expected that the alkylation with

311 a-b will be efficient and the allylic ester cm be converted to a terminal olefin using

Tsuji's method.13

2.2.3.2.2 The Preparation of AUylic Halides 31 1 a-b

Two kinds of esters 311 a-b (a; R = benzoyl, b; R= acetyl) were prepared. It was

expected that the benzoyl ester should increase the stability of the substrates. However.

there were no litenture reports on the conversion of allylic benzoates io terminal olefins

under Tsuj i ' s conditions. It was therefore unclear w hether the reac tion would proceed

The alcohol monoester 310a-b. prepared from commercially available di01 309.

was convened to the corresponding dlylic halides under different conditions (Scheme 87)

and the results are surnmarized in Table 10.

Scheme 87

reagents

35% X = 1. Br.Cl

309 310a; R=COPh 311a; R=COPh b: R = COMe b; R = COMe

Table 10. The Formation of Allyl Halides 311a-b

Entry Reagents Conditions Yield Produc t (W

1 Ph3P& Pyltoluene, O°C-rt 54 31 l a4 (cis)

2 NBS/MetS CHg12, -20 - O°C 55 31 la-Br (cis)

4 Ph3P/CBrJ CH2ClI, 0°C 90 31 la-Br (cis)

5 Ph3P/CBr4 CH2C12, 0°C 38 31 1 b-Br (cis)

6 TsC1 Py/DMAP/ CH2Ci2, 0°C ND 31 la-Cl (cis)

7 TsCl PyIDMAPI CHrCII, O°C ND 311b-CI (cis)

8 31 1 b-Cl/ Na1 acetone. reflux ND 31 1 b-1 (tram)

ND: not determined

When alcohol 310a was treated with NBS/Me2S 91 or Ph3PI12. the corresponding

halides 311a-I and 3lla-Br were obtained although in rnodest yield (entry 1 and 2).

Better results was achieved when Ph3P/CBr4 was used as reqent;" the yield as high as 90

% was obtained (entry 4).

When alcohol 310b wcis treated with NBS/Me2S. the bromide 3llb-Br was

obtained in 72 % yield (entry 3). However, both cis and tram isomen were present in a

ratio of 1: 1. in contrast to previous result, when Ph3P/CBt was used. the yield droped CO

38 % and cis isomer was obtained (entry 5).

On the other hand. when dcohol 31Oa-b were treated with TsCI. only the

chlorides 311a-CI and 311b-CI were obtaïned (entry 6 and 7). It is clear that the initially

fomed allylic tosylate was so highly reactive that it undenvent nucleophilic attack by

chloride anion under the reaction conditions.

When chloride 311b-Cl was treated with sodium iodide in acetone under

refluxing, the iodide 3llb-I was obtained but as the truns isomer (entry 8).

OH NBS pGy

Figure 13. The Rationalization for the Isomerization of Allylic Halide 3llb-Br

It was clear from the results that there was a significant difference between the

reactivity of alcohol 3lOa and 310b. These results cm be explained by considering the

participation of ester goup during the reaction. A plausible mechanistic pathway was

shown in Figure 13.

The alcohol 3lOb was treated with, for example, NBSIMe2S. The hydroxy group

was activated by Me2S to produce the intemediate A which rearranges to intermediate B.

Intermediate B is in equilibnum with B'. Nucleophilic attack by bromide anion affords

both cis and tram 3llb-Br. When R is the phenyl group as in 310a. the formation of

intemediate B is Iess favoured because of the loss of conjugation between the carbonyl

group and the phenyl ring. Consequently, for 310a, the stereochemistry of the double

bond is preserved. Only the SN? displacement product was observed.

2.2.3.2.3 The Formation of the Chiral Alcohol (R)-(-)O 95b

Next. the alkylation of irnide 307 with ailyiic halide 311a or 311b was

investigated. The enolate derived from 307 was treated with iodide 311a-1 or 311b-1 to

give 312a in excellent yield (Scheme 88). The use of brornide 3lla-Br or 3llb-Br.

however. resulted in slow formation of product and the reaction is incomplete.

Scheme 88

The stage is set for the conversion of the allylic esters side chain in 312a and 312b

to the terminal butenyl group. It was reported by Tsuji and c o - ~ o r k e r s ~ ~ that allylic

acetate when treated with palladium (O) in the presence of formic acid-triethylamine gave

the terminal olefin in good yields. Here the palladium (O) reacted with allylic compound

to form the (n-aliy1)palIadium intermediate which was then reduced by hydride genented

from ammonium

(Figure 14).

Figure

formate by decarboxylation to give the terminal olefin compound

14. Mechanism for the Hydrogenolysis of Allylic Compound

Compound 312b was used fint and the desired product 308 was obtained in good

yield as expected. Encourged by the results from the reduction of 312b. we then subjected

312a to reduction under the same reaction conditions. Again. a good yield of terminai

olefin JO8 was obtained. This result clearly indicates that the benzoyl ester csn also be

used in this type of reaction.

Next, olefm 308 was reduced by LAH to give the chiral alcohol (R) - ( - ) - 95b and

chiral oxazolidinone was recovered (Scheme 88). The alcohol was converted into Mosher

ester 313 and the optical punty was determined by '%? NMR a ~ ~ a l ~ s i s . ~ ~ The ' 9 ~ NMR

spectnim showed two peaks at 6 -7 1.99 and -72.14 respectively with an inteption ntio

of 1.0 : 10.5. So the optical purity of the product is 83% ee.

2.2.3.3 The Formation of pLactone (-)-314

With alcohoi (R)-(-)-95b in hand, diazoacetate (R)-97b was easily prepared

following the sequence we used in Scheme 38 (Section 2.1.2.4.1, pg 45). Rht(OAc)a

catalyzed decomposion of (R)-97b under optimized conditions (CH2C12, refluxing) (

Scheme 39, pg 46) provided teniary C-H insertion product y-lactone 99b ( yield 38%)

which was then decarboxylated (wet DMSO containing NaCl üt 160 O C ) to give a 84% of

(S)-(-)-314 (Scheme 89).

Scheme 89

Reagents: a) HOICCH2COtMe. DCC. DMAP/CH2C12, 94%; b) MeS02N3, DBU. CHiCN, 98%: C) Rh2(OAc)4, CH2C12, d) DMSO-H20. 16O0C. 84%

2.2m3m4 The Preparation of Pivotal Intermeàiate 316

Next, the preparation of h ydrox yûmide 316 from y-lactone (-)-314 was

investigated (Scheme 90). First, y-lactone (-)-314 was treated with benzyl amine.

However. there was no amide formation at dl. The use of reagent prepared95 from LiAIK

and benzyl amine was also ineffective. A good yield of amide 315 was obtained when y-

lactone (-)-314 was treated with benzyl amine in the presence of diethyl aluminum

~h lo r ide .~~ Oxidation of the primary alcohol unit in 315 was accomplished by using sulfur

trioxide as ~xidant.'~ It was found that the reaction was very slow when only three

equivalents of oxidant were used. The oxidation proceeded efficiently when six

equivdents of oxidant were used. The aldehyde was obtained as its cyclic tautorner 316.

No over-oxidation product 317 was detected. The 'H NMR analysis showed that 316 is a

mixture of epimers (ratio 3.3 : 1) and no attempts were made to determine the

stereochemistry of the hydroxyl group.

It should be noted that other oxidation methods were also studied. For example.

Swern oxidation 97 of 315 was unsuccessful and starting material was recovered. The use

of PDC or PCC~' as oxidmts oniy gave the overoxidation product 317.

2.2.3.5 The Cyclization of 316 and Subsequent Reaction

Scheme 91

OMe S)Mc OMe 1

OCH

C W h

Since ncemic 316, where the N-benzyl goup was replaced by the N-methyl

group was used by Speckarnp and co-worker~~~ for the total synthesis of (k)-mesembrine.

the same strategy was applied here to conven chiral 316 to the (-)-mesembrine. So the

formic acid catdyzed cyclization of 316 gave cis-fused octahydroindole ring compound

318 (Scheme 91). Without purification, LAH reduction of compound 318 followed by

reaction with benzoyl chloride gave 319 as a 4:l mixture of two distereomers. The

explmation for the selectivity is shown in Figure 15. The cyclization proceeds via a six

membered chair-like transition state. The rather Rat 5-membered lactam-ring excluded

possessing axial and equatorial aryl goup are possible. For steric reasons. the solvent

approaches the double bond via the preferred equatorial position. That's why 319a' was

obtained as the major stereoisomer.

Figure 15. The Explanation for the Distereoselectivity of the Cyclization

Scheme 92

Nd. Acemre

D &

IAH OR 1 1. Hz. Pd/MeOH 0-

2). Cl$OEr. N d C a II

OCPh O A H

O on

With compound 319 in hand. the next step was to replace the N-benzyl group with

the N-methyl group (Scheme 92). Two different methods were investigated. Fint.

compound 319 was treated with ethyi chloroformate in the presence of sodium iodide to

give 320 and released benzyl iodide.loO Altematively, compound 319 was hydrogenated to

give the secondary amine which was then reacted with chloro formate to afford the s m e

compound 320. The compound 32Oa and 320b were separated by column

chromatograph y.

It was interesting to note that the 'H NMR and I3c NMR spectn of 320a showed

that r 1: 1 ratio of rotamen were obtained which suggested that there wüs some restriction

about rotating the N-carbonyl bond in the diastereomer 32Oa. On the other hand. the

epirner 32Ob was a single compound as indicated by 'H NMR and "C NMR spectra. It

was possible that the interaction between carbonyl group and hydrogen atom in 320a may

prevent the carbamate from tiee rotation about the C-N bond. In compound 320b,

carbonyl group was far away from hydrogen. therefore there was no interaction between

them (Figure 16).

Figure 16. The Conformation of Compounds 32Oa and 320b

Since there was not enough material left, the combined 32Oa and 320b was treated

with LAH to afford the known mino alcohol 321 as a mixture of two very closely

moving distereornen. No chromatognphic sepantion was attempted. The IR spectrum of

the mixture indicated the disappemce of both ester and urethane carbonyl absorbtions

(1737 and 17 17 cm*') and 'HNMR spectrurn showed the absence of the benzoyl group as

well as ethoxy group. The mixture of amino alcohol 321 was then oxidized with S03.Py

cornplex in DMSO and PDC in DMF respectively. Surprisingly. both oxidation reactions

proceeded very slowly and were incornplete. Due CO the consumption of starting material

at the oxidation reaction step and the difficulty in recovenng unreacted amino alcohol

321. the synthesis of (-)-mesembrine was not punued funher.

To finish this project. more mino dcohol 321 is needed. And for the last

oxidation step. the use of Jones reagent, which is a knowo procedure for this

transformation, should provide an alternative oxidation method to the final product (-1-

mesembrine. Io'

in summary. the study began with the evaluation of the regio- and chemo-

selectivi ties in the reaction of cc-substituted a-diazomalonates 69a-c, 77a-c, 83 and 97a-e.

The results indicated that regio- and chemo-selectivities are controlled by both the

carbenoid a-substituenis as well as the ligands on the dirhodium (II) catalysts.

Cyclopropanation was competitive with tertiary C-H insertion. For the systerns examined.

the Rhz(OAc)4 was found to be the best catalyst for effecting tertiary C-H insertion. The

strongly electron-withdrawing Rh2(pfb)4 was the catalyst of choice for causing

cyclopropanation of alkene double bond. The results also suggest that the ester oxygen in

compounds of type 77. 83 and 97 plays an important role in determining the regio- and

chemo-selectivities of their reactions.

The method developed in this study is useful for the preparation of 4.4-

disubstituted y-lactones which have not been extensively used in total synthesis because

of the lack of genenl methods for their preparation.

The use of 4,4-disübstituted y-lactones as building blocks in natunl product

synthesis, especially in alkaloid synthesis was demonstrated by the total synthesis of three

target alkaloids: quebnchamine, ebumamonine and mesembrine.

The Pictet-Spengler cyclization of tryptarnine with a Cs unit 155 or (5')-201 was

used as the key step for the total synthesis of quebnchamine. The Pictet-Spengler

cyclization of tryptamine with another Cs unit 253c was also the key step in the synthesis

of (-)-ebumamonine 246. Al1 of these three C9 compounds were derived from the 4,4-

disubstituted y-lactone 152.

In addition. 4,J-disubstituted y-lactone (-)-SI4 was found to be useful as a key

intermediate for the synthesis of (-)-mesembrine.

4. Future Work

It is clear from the synthetic approaches outlined in this study. the

distereoselective alkylation followed by stereospecific C-H insertion to form 4.4-

disubstituted y-lactones represents a general strategy for the synthesis of natural products

containing a chiral quatemary carbon center.

This stntegy also gives access to a number of Aspidospernia and Vincarnine

alkaloids since the quarternary ammonium salt 186 has previously been transformed into

these indole al kaloids. 1°'

Further application of 4.4-disubstituted y-lactones. the versatile chiml building

blocks should provide more access to the opticall y active natunl products possessing

quatemary carbon center.

Here is a proposed efficient enantioselective synthesis of (+)-apovincamine

(Scheme 93).

(+)-Apovincarnine is one of the most important vincane-type dkaioids which has

k e n used for the treatment of cognitive and behaviord symptoms associated with

vascular and degenentive disorder of the centrai nervous system and has been reponed to

have beneficial effects in the treament of cerebrai ischerni~. '~~

Scheme 93

"(C H5)2C0 -H d- o o

Reagents: a) Tryptamine. DCC. DMAP: b) MeMgBr: c) NaBi&; d) S 0 3 Py. DMSO e) CF3COOH. CHrCI2; f) LAH. EtrO.

The acid (S)-154 derived from 4.4-disubstituted y-lactone 152 could be used as

starting material for this total synthesis. Once coupled with tryptamine. amide 247 could

be converted to di01 322 by treatment with MeMgBr followed by reduction with NaBHi.

Next, different oxidation reagents could be tried to convert the di01 322 to keto aldehyde

323. As we know, the desired tricyclization of keto aldehyde 323 could be effected by

different acid catalysts, various acids such as CF3COOH, AcOH would be investigated

for this transformation. Subsequent LAH reduction should afford the known pentacyclic

amine 325. Since compound 325 has k e n converted to (+)-apovincamine 326,Iw this

would finish our synthesis of (+)-apovincarnine 326.

5. Experimental Section

Ceneral. Infnred spectra were recorded using a Perkin-Elmer 1600 Fï infrared

spectrophotometer. NMR spectra were obtained at 200.00 MHz on a Bruker AC 200

QNP at University of Regina; chernical shifts are reported in parts per million (6) relative

I to the appropriate reference signals. HNMR (200 M H z ) were recorded in

deuteriochlorofonn (CDCI:) using tetramethylsilane (6H0.0) or residual chIorofonn (8H

7.74) as reference; multiplicities of signals are given as S. singlet; d. doublet; t, triplet; q,

quartet; m, multiplet; br. broad, and coupling constants are given in Hz. "C and "C

DEPT-135 NMR (50.33 MHz) were recorded in CDC13 using the CDC13 triplet centred at

105 6 77.0 as reference. The "C Dm-135 pulse sequence inverted only the CH2s

(designated -); the CHs and CH3s rernained upnght. Quatemary carbons are not seen.

Low and high resolution electron-impact (70 ev) m a s spectra were recorded at the

University of Saskatchewan on an VG-MS- 11 spectrometer. Reaction progress was

monitored by thin-iayer chrornatography on Merck silica gel 60,, precoated (0.15 mm)

on aluminum-backed sheets. Al1 reactions were conducted under a static pressure of

argon.

5.1 Geneml Procedure for Preparation of Malonates.

Alcohol (2.1 mmol) was dissolved in dry CHzClt (30 mL) at O OC. Then a-

(rnethoxycarbonyl)acetic acid (2.3 mmol) was added followed by DMAP (0.21 mmol)

and DCC (2.3 mmol). The reaction mixture was stirred at O OC for 1 h. then I M aq. HCl

(15 mL) was ridded and the mixture was stirred at rt for 30 min. The reaction mixture was

diluted with CH2C12 (30 mL) and washed with HzO (20 mL). Aqueous layer was

extracted with CHzClr (20 mL). The combined organic extracts were washed successiveIy

with 5 % NaHC03. brine. dried. filtered and concentrated. The pure product was obtained

by flash chromatography.

5.2 General Procedure for Diazotization Reaction,

Malonate (0.87 mmol) was dissolved in anhydrous CH3CN (15 mL) at O O C . and

methanesulfonyl azide (1.8 mmol) was added followed by addition of DBU (1.8 mmol).

The reaction mixture was stirred at O OC for 30 min. and rt for 3 h. The mixture was

diluted with CHzCll (30 mL), washed with 10 % NaOH solution(l0 rnL) and the aqueous

layer was re-extncted with CHICll (20 mL). The combined organic extncts were washed

with H20, dried, filtered and concentrated. The diazo product was obtained by flash

chromatopph y.

5.3 General Procedure for Preparation of cr-Diazo-PKeto Esters.

Diketene (0.48 mL, 6.0 mmol) was added neat over a period of 5 min. to a

solution of alcohol (4.0 mmol) and Et3N (0.56 mL, 4.0 mmol) in dry CH2C12 (20 rnL) at

O O C . The reaction mixture was stirred for 3 h at O O C and 1 h at rt. Solvent and excess

diketene were removed under reduced pressure, and the resulting liquid was immediately

dissolved CHFN (20 mL). To this solution were added Et3N (0.56 mL. 1.0 mmol). Y0 -

(0.080 mL. 4.0 mmol) and MsN3 (0.48 rnL. 5.2 rnmol) and the reaction was stirred at n

for 12 h. Most of the solvent was removed by rotary evaporation. and the resulting oil was

dissolved in EtzO (80 mL) and washed successively with 1 M NaOH (4x20 mL) and

bnne (10 mL). dried. filtered, and concentrated to give a yellow oil. The diazo product

was obtained by flash chrornato~pphy.

5.4 General Procedure for Rh(I1)-Catalyzed Reaction

Method A. To a mixture of diazo compound (0.50 mmol) in CH2C12 or benzene (50 mL)

was added the appropriate dirhodium(U) catalyst (2 mol 9%). The reaction mixture was

stirred at rt or at reflux for 12 h . The mixture was filtered when cooIed to rt and the

solvent was rernoved under reduced pressure. Separation of the reaction mixture was

achieved by flash chromatography.

Method B. The diazo compound (0.50 mmol) was dissolved in either dry CH2Cl2 or

benzene (10 mL), and the solution was added dropwise, using a synnge pump. over a

period of 6 h to the Rh(U) catalyst (2 mol %) in the appmpriate solvent (20 mL) at reflux.

After addition was complete. the mixture was stirred at reflux for 20 h. The mixture was

cooled to rt. filtered. concentrated and purified by flash chromatography to give the

products.

5.5 General Procedure for Alkylation of the Dianion of a Carboxylic Acid

The appropriate acid (10 mmol) was added at O O C to a solution of LDA [prepared

from diisopropylarnine (3.1 rnL, 21 mmol) and n-BuLi (9.2 rnL. 27 mmol, 2.4 hl in

hexane)] in THF (20 mL) followed by addition of HMPA (1.9 mL, 11 mmol). The

mixture was stirred at n for 30 min then cooled to O OC and the appropriate alkyl halide

(1 1 mmol) was added. The mixture was stirred at n for Ih. then 10 % aq HCI (30 rnL)

was added and the mixture was extracted with Et20 (3 x 30 mL). The combined organic

layers were washed with water, brine. dned and concentrated to give the crude product

which, without purification, was dissolved in dry Et10 (150 rnL) and treated with WH

(0.74 g, 19 mmol) at O O C . The mixture was heated at reflux for 1 h, cooled to O OC, and

water (3 mL) was added slowly followed by addition of 10 % aq. NaOH (20 mL). The

ether Iayer was separated and aqueous Iayer was re-extracted again with Et@ (3 x 15

mL). The cornbined organic layers were dried, filtered, and concentrated to give the crude

produc t which was puri fied by flash chromatography.

5.6 Ceneral Procedure for Decarboxylation Reaction

The appropriate lactone (0.35 mmol) was dissolved in a mixture of DMSO (1.0

mL) and H 2 0 (0.0 12 rnL) containing powdered NaCl (10 mg, 0.35 mrnol). The mixture

was heated at 160 O C for 12 h and then cooled to rt. Water (1.0 rnL) was added, the

mixture was extracted thoroughly with EtrO (3 x 10 r d ) , and the ethered extracts were

washed with brine (10 mL), dried, filtered, concentrated and the residual product was

purified by flash chromatographed.

5.7 Preparation of Diazo Compounds 69a-c and Their Reactions.

Methyl 3-ethyl-2-methyl-3-pentyl malonate (68b): Prepared according to the

procedure described in Section 5.1. Yield 42 % from dcoholJ9 (0.26 g, 7.0 m o l ) . (30: 1

and 4:l Petroleum ether/Et20) Colorless liquid: IR umm. (neat): 1754, 173 L cm". 'H

NMR: 6 0.91 (t, 6H. J = 7.4 Hz. 2xMe), 0.94 (d, 6H, J = 6.6 Hz, CHMe,), 1.91 (q, 2H, J

= 7.4 Hz, CHzMe), 1.92 (q, 2H, J = 7.4 Hz, CHiMe). 2.37 (sept, 1H, J = 6.6 Hz, =e2),

3.35 (s, 7H, CH2C=O). 3.74 (s, 3H, OMe). "C NMR: 6 8.7, 17.6. 16.9 (-), 33.8.12.7 (-1,

52.2.92.3. 165.4, 167.4. Anal. Calcd for C12H2QJ : C, 62.58; H, 9.63. Found: C, 62.38;

H, 9.39.

2,2,2-Trifluoroethyl 3-ethyI-2-methyi-3-pcntyl malonate (6&): Prepared

according to the procedure described in Section 5.1. yield 64 % from alcohol 59 (0.16 g,

2.0 rnrnol). (30: 1 and 4: 1 Petroleurn etherEt~0) Coiorless liquid: IR um, (neat): 1770,

- 1 1 1732 cm . H NMR: 6 0.90 (t. 6H.k 7.3 Hz. 2 x Me), 0.94 (d, 6H. J = 6.9 Hz, CHMe,), -a

1.92 (q. IH. 3 = 7.0 Hz. CHMe). 1.93 (q, 2H. J = 7.0 Hz. CH7Me). 2.36 (sept. 1H. J =

l j 7.0 HZ. CHMe?). 3.43 (S. IH. CH2C=O). 4.50 (q. 2H. J = 8.0 HZ. CHKFj). C NMR: 6

8.7. 17.6.16.8 (-), 33.8.42.1 (-), 60.9(-) (q), 93.1. 164.3. Anal. Calcd for C,,H21Fj0, : C.

52.34; H, 7.10. Found: C, 52.09; H, 6.91.

3-Ethyl-2-methyl-3-pentyl a-diazoacetoacetate (698). Prepared according to the

procedure described in Section 5.3.(silica gel 20: 1 and 7: 1 Peuoleum ether/Et,O). - 75.4 96

from alcohol 59 (0.52 g, 4.0 rnrnol). Pale yellow oil: IR u,, (neat): 2128, 1711, 1660

- 1 1 cm . H NMR: 50.91 (t, 6H. J = 7.4 Hz, 2 x Me), 0.94 (d, 6H, J = 6.8 Hz. CHMe:), 1.93

(q, 2H. J = 7.4 Hz. -Me), 1.94 (q, 2H, J = 7.4 Hz, CH7Me). 2.39 (sept, L H. 1 = 6.8 Hz.

CHMe-), 2.33 (s, -

190. Anal. Calcd

8.22; N, 1 1.46.

t3 3H, CH;C=O). C NMR: S 8.9, 17.7, 27.3 (-), 28.1. 34.4. 93.5. 160.

for C,,$,N,O, : C, 39.98; H, 8.39; N. 11.66. Found: C, 59.74: H,

Methyl 3-ethyi-2-methyl-3-pentyl a-diazornalonate (69b): Prepared according

to the procedure described in Section 5.2. 92.4 % ( 20: 1 and 7: 1 Petroleum etherIEtz0)

from 68b (0.20 g, 0.87 m o l ) . Paie yellow oil: IR u,, (neat): 2134, 1765,1742, 1687

- 1 1 cm . H NMR: 6 0.90 (t, 6H. J = 8.0 Hz, 2 x Me), 0.93 (d. 6H, J = 6.9 Hz, CHMez), 1.92

(q. 2H. J = 8.0 Hz, -.Me), 1.93 (q, 2H. J = 8.0 Hz. CH-Me), 1.38 (sept, LH. J = 6.9 Hz,

13 wed. 3.81 (s, 3H. OMe). C NMR: S 8.9. 17.7. 27.3 (-). 34.2, 52.4. 93.1. 159.5,

164.2. Anal. Calcd for C,,H,N,O, : C, 56.23; H. 7.87; N. 10.93. Found: C. 56.10: H. - -

2 3 f -Trifluoroethyl3sthyl-2-methyl-J-pentyl a-diazomalonate 69c: Prepared

according ro the procedure described in Section 5.2- 59 % ( 20:l and 7:l Petroleurn

ether/Et,O) - from 6ûc (0.36 g, 1.2 rnrnol). Paie yellow oil: IR u,, (neat): 2142, 1766,.

- 1 I 1690 cm . H L M : 60.93 (t, 6H. J = 7.6 Hz. 2 x Me), 0.96 (d, 6H. J = 6.6 Hz. CHMe,),

1.95 (q, 2H. 3 = 8.0 Hz, CHTM~), 1.96 (q, 1H. J = 8.0 Hz, CH-Me). 2.42 (sept. 1H. J =

60.46) (q), 94.3. 158.7, 159.5. Anal. Calcd for C,,H,,F,N,O, : C. 48.14; H. 5.90: N,

8.64. Found: C, 48.05; H, 5.83; N. 8.58.

Decomposition of Diazo Compounds 69. The Rh@) catalyzed C-H insertion

reaction of was cmied out as described in Section 5.4. Method A: benzene, reflux

Following the general procedure descnbed in Section 5.4. Method A, diazo compound

69a (0.10 g, 0.47 mmol) was treated with Rh?(~fb)~ (8.3 mg, 0.008 mmol) in dry benzene

(40 mL) at reflux. The crude pmduct was purified by flash chromarography (7: 1 and 4: 1

Petroleum etherlEt,O) - to give 70a (28 mg, 31 8 yield) as a mixture of diastereomen

(ratio 1 : 1) based on integration between 3.38 (d, J = 11.6 Hz) and 3.47 (d. J = 11.8 Hz)

- 1 t (1H). Colorless liquid: IR u,, (neat): 1744 cm . H NMR: S 0.85- 1-25 (m. EH. 4 x

Me). 1 .jO-2.35 (m. 3H. CHMe2, CH?Me), 1.33 and 2.42 (s, 3H, m C = O ) , 3.06-3.15 (m.

IH. CHMe), 3.38 (d, J = 11.6 Hz) and 3.47 (d, J = 11.8 Hz) (IH). Anal. Calcd for

C,2H200, : C, 67.89; H, 9.50: Found: C, 67.75; H. 9.5 1.

3-Acetyl-5,5-dkthyl-4,4-dimethyl dihydro-2(3H)-Puranone (71a): The same

reaction was repeated by using different catalysts R~?(OAC)~ and Rh2(acam)4 to afford a

l mixture of 70a and 71a. However. 71a was coeluted with 708 and was evident in the H

NMR spectrurn of reaction mixture only by integration at 6 3.30-3.50 which included (S.

1H. CH3COaCO ) of 71a and 3.38 (d. J = 1 1.6 Hz) and 3.47 (d. J = 1 1.8 Hz) (1H.

CH3COCI-JCO) of 70a. The ratio was determined by cornparison of integration between 6

36 3.06-3.15 (m. lH, (3ICH3,IOa) and 3.30-3.50 (xH. CH3COçf[CO, 70a and 71a).

The data are collected in

Table 1 (pg. 26).

Characterization of 70a and 71a

The mixture of 70a and 71a (0.17 g. 0.81 mmol) was dissolved in dry pyridine

(4.0 mL) and was treated with acetyl chionde (0.090 mL, 1.2 mmol) to give an

inseparable mixture of the corresponding en01 acetates (0.14 g, 69 %). Without further

processing, thc en01 acetates was dissolved in dry CH2Clr (10 mL) and cooled to -78 O C .

Ozone was bubbled into the solution for 4 h and then argon was bubbled into the solution

to drive off excess ozone. PhlP (10 mg, 0.60 mmol) was added, and the mixture was

stirred at rt ovemight. CHzCIz wûs evaporated, and the residue oil was chromatognphed

to fumish the u-tetronic acid 72 (27 mg). Unoxidized en01 acetate 73 was also recovered,

but was contaminated by small ümount of an unidentified component.

- 1 I a-Tetronic acid 72. IR um, (neat): 3525-3 100. 1735. 1708 cm . H NMR: 6

0.70 (t, 3H. J = 7 . 4 Hz, Me). 0.78 (d, 3H. J = 6 . 8 Hz, CKMe). 1.05 (d, 3H. J = 6.8 Hz.

CHMe). 1.55-1.75 (m. lH.CH,Me), 1.82 (s, 3H, &CH=), 1.90-2.04 (m. 1H. m e r ) ,

91.7, 133.2. 138.0, 170.7. Anal. Calcd for C,,H,,O, : C, 65.19: H, 8.75; Found: C,

- 1 I Recovered En01 acetate 73. IR u,, (neat): 1760, 1748. 168 1 cm . H NMR: 6

0.95 (t, 3H. J = 7.1 Hz. Me), 0.97 (t. 3H. J = 7.4 Hz, Me). 1.23 (s, 3H, Me), 1.26 (S. 3H.

13 Me), 1.62-1.80 (m, 4H, 2 xCH2), 2.20 (s, 3H, Mec=), 2.18 (S. 3H. C(0)Me). C NMR: 6

Conversion of 73 to 74. compound 73 (17 mg) was dissolved in 95 5% ethanol

(1.0 mL), cooled to O OC, and treated with NaB& (17 mg). After 4 h, glacial AcOH (2

drops) was added to destroy excess reductant. The mixture was concentnted, and bnne

was added. The mixture was extracted with EtOAc (2 x4 mL), and the combined organic

layers were dried. filtered, and concentrated. The residue was taken into dry pyndine (1

mL) containing DMAP (two crystals) and treated with benzoyl chloride (0.010 jL). after

20 h, the mixture was diluted with EtOAc (5 mt) and washed with 1 M H$OJ (2 x 3

mL), water (4 mL), and then saturated NaHCO, (4 rrL).the organic layer w u dried.

filtered, and evaporated. The cmde product was chromatognphed (pipette) using 10 : 1

PE : Et?O as eluent to give the benzoate derivative 74 (8.0 mg). IR u,, (neat): 1760,

- 1 1 1715, 1602, 1584 cm . H NMR: 6 0.92 (t, 3H. J = 7.0 Hz, Me). 1.00 (t, 3H. J = 7.0 Hz,

Me), 1.05 (S. 3H, Me), 1 .Y (s, 3H. Me), 1.65(d, 3H, J = 3.6 Hz, CHMe), - 1.70-2.00 (m.

13 4H. 3xCH2),2.96(d, lH, J = 9 . 8 Hz.CHC=O), 5.45 (dq, 1H. J = 9 . 8 . 5.6Hz.ClJO). C

LW: 6 8.04. 8.83, 19.27, 19.83. 34.19 (-), 24.26 (-), 45.54, %Ji, 69.1 1, 90.16, 128.47,

129.63, 130.02, 130.07, l33.IJ. 137.70, 149.40, 16523. 173.98. (Ni3) m/z (relative

intensity): 3 19.2 (M + 1. LOO), 197 (M -PhCOO. 52). CI-HRMS Calcd for C,,H2,0J

3 19.1909, found 3 19.1908.

Methyl tetrahydro-5sthyl-5-isopropyC4-methy1-2-0~0-3-fumncarboxy1ate

(70b) and Meth y l tetrahydro-5,5-diethyl-4,4-dimethyl~2-0~0-3-fu~carboxyIate

(71b). Following the general procedure described in Section 5.4. Method A, diazo

compound 69b (0.10 g, 0.39 mrnol) was treated with Rhr(pfb)4 (8.3 mg, 0.008 m o l ) in

dry benzene (40 mL) at reflux. The crude product was purified by flash chromatography

(7: 1 and 4: 1 Peuoleum ether/Et,O) - to give 70b (66 mg, 74 7% yield) and 71b (1 1 mg, 12

%). 70b: Mixture of diastereomen (ratio 1 : 1) based on integration between 1.17 and

- 1 1 1.23 (d, 3H. J = 7.2 Hz, CHMM). Coloriess liquid: IR u,, (neat): 1774, 1740 cm . H

NMR: 8 0.90- 1 .O5 (m. 9H, CHMer, Me), 1.17 and 1 .23 (d, 3H, J = 7.2 Hz. CHMM), 1 S O -

2.30 (m. 3H. CHMe?, CHzMe), 7.90-3.10 (m, IH, me), 3.36 (d. I= 13.0 Hz) and 3.15

(d. J = 12.6 Hz) ( 1 H. CHC=O), 3.82 and 3.84 (S. 3H. OMe). Anal. Calcd for C , - ,H, ,O O 4 - .

C, 63.13; H. 8.83; Found: C, 63.09: H. 8.98. 71b: Colorless liquid: IR um, (neat):

- 1 1 1780, 1735 cm . H NMR: 8 0.92 (t, 3H. J = 7.1 Hz, Me), 0.96 (t, 3H, J = 7.4 Hz, Me),

1.09 (S. 3H. Me), 1.27 (S. 3H, Me), 1.50-2.00 (m. 4H. 2 x CH?), 3.55 (s, lH, CHC=O),

3.77 (S. 3H. OMe). I3c M: 6 8.0, 8.6. 20.9. 23.6. 24.3 (-), 25.0 (-). 45.7, 52.4. 58.0.

91.6. 167.5. 170.6. Anal. Calcd for C,2Hzo0, : C. 63.13; H. 8.83: Found: C. 63.09: H,

9.02.

The same reaction was repeated by using different catalysts Rhz(OAck and

Rh2(acamk. The data are coilected in

Table 1 (pg. 26).

2,2,2-Trifluorwthyl tetrahydro-5-ethyl-5-isopropyl-4-methyl.29~0-3-

furancarboxylate (7k) and 2,2,2-Trifluorwthyl tetrahedro-5,s-diethyl+dimethyl-

2-0x0-3-furancarboxylate (71c). Following the general procedure described in Section

5.4. Method A, diazo compound 6% (0.064 g, 0.20 mmol) was treated with Rh?(~fb)~

(4.3 mg, 0.004 rnmol) in dry benzene (JO mL) at reflux. The crude product was purified

by flash chromatopphy (7: 1 and 4: 1 Petroleum ether/Et,O) to give 70e (39 mg, 66 % -

yield) and 71c (6.4 mg, 11%). 7k : Mixture of diastereomen (ratio 1 : 1) based on

integration between 1.19 and 1.24 (d. 3H. J = 6.3 Hz, CHAM. Colorless liquid: IR um,

-1 1 (neat): 1778, 1754 cm . H NMR: 6 0.90-1.04 (m. 9H. CHAM 2, Me), 1.19 and 1.24 (d,

3H. J = 6.3 Hz. Cm>, 1.50-2.32 (m. 3H. CllJMer, CH2Me), 2.90-3.10 (m. 1H. CHMe).

3.45 (d, J = 12.0 Hz) and 3.55 (d, J = 12.0 Hz) (LH, CHC=O), 1.40-4.76 (m. 2H.

CH2CF3). Anal. Calcd for C,,H,,F,O, : C. 52.70: H. 6.16; Found: C. 52.71: H, 6.36.

- 1 I 71c: Colorless liquid: IR u,, (neat): 1790, 1750 cm . H NMR: 6 0.95 (t. 3H. J = 7.4

Hz, Me), 1.00 (t, 3H. J = 7.4 Hz, Me), 1.13 (s, 3H, Me), 1.31 (S. 3H, Me), 1.50-3.10 (m.

4H. 2 x CH?), 3.68 (s, 1 FI. CHC=O), 4.30450 (m. lH, CHCF3), 4.604.80 (m. 1H.

CHCF3). 13c NMR: 6 8.0. 8.6, 20.7. 23.3. 21.2 (-). 25.0 (-). 46.0. 57.6.61.1 (-) (9). 91.9.

119.9. 125.9, 167.5. 170.6. Anal. Cûlcd for C,,H,,F,O, : C. 51.70; H. 6.46; Found: C.

The same reaction was repeated by using different catalysts R ~ ? ( O A C ) ~ and

Rhz(acam)4. The data are collected in

Table 1 (pg. 16).

5.8 Preparation of Diazo Compounds 77a-c and Their Reactions.

2-EthyC4pentenol 75: Pcepared from 4-pentenoic acid (2.0 g, 2.0 mmol) and

ethyl iodide (1.9 mL, 2.4 mrnol) according to the procedure described in Section 5.5. 49

% for two steps after chromatognphy separation (7 : L and 4 : 1 Petroleum ether/Et,O). -

- 1 1 IR um, (neat): 3360, 3077. 164û cm . H NMR: 6 0.89 (t, 3H. J = 7.4 Hz. Me). 1.20-

1.41 (m, 2H. J = 6.8 Hz. CH?), 1.51 (br sept. 1H. J = 6.3 Hz. rnt), 1.67, (S. LH, OH).

2.09 (br t. 2H. J = 6.9 HZ. CH2C=). 3.54 (d. 2H. J = 6.3 Hz, CHrO). 4.96-5.12, (m. 2H.

CH2=), 5.70-5.92 (rn, 1 M, CH=).

Methyl t e t h yl-4-penten yl malonate (76a): Repared according to the procedure

described in Section 5.1. 86 % yield ( 7 : 1 and 4 : 1 Petroleum ether/Et,O) from 75 (0.63 - - 1 1

g, 5.5 mmol). Colorless liquid: IR um, (neat): 3077. 1738. 1640 cm . H NMR: 8 0.93

(t. 3H. J = 7.1 Hz. Me), 1.38 (quint. 2H. J = 6.8 Hz, CH?), 1.71 (br sept. 1H. J = 6.0 Hz,

CHEt). 2.10 (br t. 1H. J = 6.6 Hz. CH2C=), 3.41 (S. 2H, CHrC=O). 3.78 (S. 3H. OMe).

4.08 (d, 2H. J = 5.7 Hz. CH20), 5.04. (br d, 2H. J = L 2.4 Hz. CH2=), 5.65-5.86 (m. 1 H,

Methyl 2-ethyl-4-pentenyl a-diazomalonate (77a): Prepared according to the

procedure described in Section 5.2.90 Q yield (7 : 1 Peuoleum ether/Et,O) - frorn 76a (1.0

- 1 1 g. 4.8 m o l ) . Paie yellow liquid: IR u,, (neat): 2136, 1766, 1738, 1698 cm . H NMR:

6 0.94 (t. 3H. J = 7.4 Hz, Me), 1.38 (quint, 1H. J = 6.9 Hz. CH?), 1.73 (sept, LH, J = 6.3

Hz, CH), 2.12 (t, 1H. J = 6.3 Hz. CHrC=), 3.86 (S. 3H. OMe), 4.18 (d, 2H. J = 5.1 Hz.

13 OCHt). QJ8-5.lO (m. 2H, CHt=). 5.67-5.87 (m, 1 H. CH=). C NMR: 6 1 1.1, 13.4(-),

35.1(-), 36.8. 52.5. 67.3(-). 116.7(-), 135.9. 160.9, 161.6. Anal. Calcd for C,,H,,N20, :

C, 54.99; H, 6.7 1; N, 11.66. Found: C, 54.73; H, 6.46; N, 11.69.

2-Ethyl-4-pentenyl a-diazoacetoacetate 77b. Prepüred according to the

procedure described in Section 5.3. 53 96 (7 : 1 Petroleum ether/Et,O) - from alcohol 75

- t I (0.27 g, 1.3 mmol). Pale yellow liquid: IR Umax (neat): 2140. 1720. 1661 cm . H NMR:

6 0.95 (t, 3H. J = 7.4 Hz, Me). 1.39 (quint. ZH. J = 6.9 Hz, CH?). 1.74 (sept, 1H. J = 6.3

Hz. CH), 2.1 1 (t. 2H. J = 6.3 Hz. CH2C=), 1.48 (S. 3H. MeC=O), 1.18 (d. 2H. J = 6.3 Hz.

13 WH-), 5.05 (bd. ZH. J = 6.3 Hz, CH2=), 5.65-5.89 (m, 1 H, CH=). C NMR: 6 1 1.1,

2-Ethyl-Cpentenyl u-diazoaceâate 77c. Compound 77b (2.0 mrnol) was

dissolved in dry C H F N (5 mL), pyrrolidine (0.17 mL, 3.0 mrnol) was added. and the

mixture was stirred at n for 24 h. Then the solvent was evaporated, the residue was

treated with 20 mL of LM NaOH and extracted with EtOAc (2 x 20 mL). The combined

extracts were washed with bnne ( 10 mL), dried. and concentnted. Flash chromatography

(7: 1 Petroleum ether/Et,O) - provided 77c ( Yield 90 %) as a pale yellow liquid: IR um,

- 1 1 (neat): 2114. 1700. 164) cm . H NMR: 60.90 (t, 3H.J= 7.4 Hz. Me). 1.36 (quint. ZH. J

= 6.9 HZ. CH2), 1.69 (sept. 1 H. J = 6.3 Hz. CH), 2.08 (t. 2H. 1 = 6.3 Hz, CHrC=C), 4.08

(d. 2H, / = 5- 1 Hz, 0CH2), 4.73 (S. lHT CH=&), 4.96-5.09 (m. 2H, CHt=), 5.64-5.86 (m.

Met hy 1 2-(1-et hy l-3- buteny l)-4-0x0-3-oxenarolate (78a) and Met hy l

tetrahydro-4-ethyl4(2-propenyl)-2-0~o13~f~r~n~arb0xyIate (79a) and Methyl 5-

ethyl-24x0-3sxabicyclo [5.1.0] octanecarboxylate (80a). Following the general

procedure described in Section 5.4 Method A. diazo compound 77a (0.12 g. 0.50 mmol)

was treated with R ~ ( O A C ) ~ (5.5 mg, 0.010 mmol) in dry CHrCll(50 rnL) at n. The cnide

pmduct was purified by flash chromatognphy (7: 1 and 4: 1 Petroleum etherlEt,O) - to give

78a (10 mg, 10 % yield) and 79a (52 mg, 5 1 %) as well as 8Oa (38 mg, 3 1 %). 78a: Rr =

0.40 ( 4 : 1 PE : Et?O). Mixture of diastereomers ( L : I ) based on integration between

- 1 I 3.81 and 3.82 (S. 3H. OMe). Colorless liquid: R um, (neat): 1835, 1748 cm . H

NMR: 8 0.98 (t, 3H. J = 8.6 Hz, Me). 1.33-7.33 (m, 5H. CH2, CH, CH2C=), 3.8 1 and 3.82

(S. 3H. OMe). 1.21 (d. 1H. J = 4 . 6 Hz. CHC=O), 1.60470 (m. 1H. CHO), 5.00-5.18 (m.

2H, CH2=), 5.62-5.89 (m. lH, CH=). Anal. Calcd for C, ,H,,O, : C. 62.35; H. 7.60:

Found: C. 62.49; H. 7.66. 79a: Rf = O.? 1 ( 4 : 1 PE : Et,O). Mixture of diastereomen ( 1 : -

1) based on integration between 3.72 and 3.73 (S. 3H. OMe). Colorless liquid: iR u,,

- 1 1 (neat): 1788. 1732 cm . H NMR: 60.91 and0.93 (t. 3H, J=7 .4 Hz. Me). 1.33-1.65 (m.

2H, CHt), 2.13 and 2.31 (dd, W. J = 6.9 and 13.7 Hz, CHIC=), 3.30 and 3.33 (s, IH,

CHC=O), 3.72 and 3.73 (s, 3H, OMe), 4.02 and 4.10; 4.18 and 4.24 (d, 2H, J = 8.8 Hz,

CH2O). 5.05-5 .X (m. 2H, CH2=), 5.56-5.82 (m, 1 H, CH=). Anal. Cdcd for C, , H,,O, :

C, 62.25; H, 7.60; Found: C. 62.25; H, 7.45.80a: Rr = 0.13 ( 4 : 1 PE : ELO). - Coloriess

- i 1 liquid: IR u,, (neat): 1740 cm . H NMR: 6 0.40-0.60 (m. 0.5H. 8-H), 0.82-1 -55 (m.

6.5H. CHzMe, 8-H), 1.60-2.50 (m. 4H. CHCH2CH), 3,80 (s, 3H, OMe), 4.00435 (m)

and 4.55 (dd. 2H, J = 12.6 and 5.7 Hz. CH20). Anal. Calcd for C, , H,,O, : C, 67.25; H.

7.60; Found: C, 62.19: H, 7.5 1.

The same reaction was repeated under di Fferent reaction conditions (solvent and

temperature) and using different Rh@) catalysts. The data are collected in Table 2 (pg. 34

)

The structure of y-lactone 79a (74 mg, 0.35 mmol) was funher confirmed by

decarboxylation following the general procedure described in Section 5.6 to 4-EthyI-4-(2-

- 1 I propeny1)-y-lactone (39 mg. 72 '70). Colorless liquid: IR u,, (neat): 1778 cm . H

NMR: 6 0.92 (t. 3H. J = 8.0 Hz. Me). 1.52 (q, 2H. J = 8.0 Hz. CHzMe), 2.11 ( br d, 2H. J

= 8.0 Hz, CHzC=), 2.28 and 2.39 ( cf, 2H. J = 18.1 Hz, CH2CO), 3.99 and 4.09 (d, 2H. J =

5.9 Preparation of Diazo Compounds 83 and Its Reaction.

2-Ethyl-5hexenol81: prepared from 5-hexenioc acid (2.3 g, 20 mmol) and ethyl

iodide (1.9 rnL, 24 mmol) according to the procedure described in Section S.S. ( 45 % for

- 1 1 two steps). IR u,, (neat): 3340, 3076, 1641 cm . H NMR: 6 0.92 (t, 3H. J = 6.9 Hz,

Me), 1.33 (S. 1 H, OH), 1.35-1.53 (m. 5H. CH, 2 x CIE), 1.08 (q, 2H, CH2C=), 3.57 (d.

2H, J = 5.1 Hz, CH20), 4.90-5.10. (m. 2H. CHi=), 5.7 1-5.93 (m. 1 H. CH=).

Methyl 2-ethyl-5-hexenylmalonate (82): Prepared accordmg to the procedure

described in Section 4.1. 94 % after column purification ( 20:l and 7:i Petroleurn

ether/Et,O) - from alcohol 81 (0.38 g. 3.0 mmol). Colorless liquid: IR um, (neat): 3077.

- 1 1 1737, 1640 cm . H NMR: 8 0.88 (t. 3H. J = 6.9 Hz, Me), 1.38-1.45 (m. JH. 2 x CH2).

1.62 (br sept, 1 H. J = 5.8 Hz, CH), 1.98-2.11 (m. ZH. CH2C=), 3.38 (S. 2H. CH2CO), 3.72

(S. 3H, OMe), 4.06 (d, 2H. J = 5.7 Hz, CH20), 4.89-5.05. (m, 2H. CHz=), 5.65-5.88 (m,

), 138.6, 166.6. 167.0. HRMS Calcd for C,,H, - ,O O J + H+ 229.1440, Found 229.145 1:

C,zH,,O,-OMe 197.1178,Found 197.1183.

Methyl 2-ethyl-Shexenyl diazopropanedioate (83): Prepared according to the

procedure described in Section 5.2. 86 % ( 20: 1 and 7: 1 Peuoleum etherlEt,O) from 82 - - 1 I

(0.62 g, 1.7 mmol). Pale yellow liquid: [R u,, (neat):Z 136, 1764, 1738, 1698 cm . H

NMR: 6 0.91 (t, 3H, J = 7.4 Hz. Me), 1.31-1.50 (m, 4HT 7 x CH?). 1.68 (sept. LH, J = 6.7

HzT CH), 2.08 (br q, 2H, J = 8.0 Hz, CH2C=), 3.83 (S. 3H, OMe). 4.18 (d, 2H. I = 5.7 Hz,

13 CHO2). 4.9 1-5.09 (m ZH, CH2=), 5.69-5.90 (m, LH, CH=). C NMR: 6 10.9, 23.6(-),

29.9(-). 30.9(-), 38.2, 52.5, 67.5(-), 114.7(-), 138.5, 160.9, 161.6. HRMS Calcd for

C I, ,H 18 N z O 4 + H+ 255.1345, Found 255.1336: . C,2Hl,N,0,- OMe 223.1083, Found

Methyl 2-(L-ethyl-4-pentenyl)-4-0xo-3-0xetanecarboxyIate (84) and Methyl

tetrahydro-4-ethyl-l-(3-butenyl)-2-oxo.j (85) and Methyl S-ethyl-

2-0x0-3-oxabicyclo [6.1.0] nonanecarboxylate (86). Following the genenl procedure

described in Section 5.4 Method B. diazo compound 83 (0.10 g, 0.39 rnmol) was treated

with Rh2(OAc)a (4.1 mg, 0.008 mmol) in dry CH2C12 (50 mL) at reflux via slow addition.

The crude product was purified by flash chrornatognphy (7: 1 and 4: 1 Petroleurn

ether/Et,O) to give 84 (8.3 mg, 9.4 %) and 85 (65 mg, 73 %) as well as 86 (1.8 mg, 5.1 -

%). 84: Rt = 0.30 ( 4 : 1 PE : Et,O. Mixture of diastereorners ( 1 : 1) based on integrrition -

between 0.96 and 0.97 (t. 3H. J = 7.1 Hz. Me). Colorless liquid: CR u,, (neat): 1834.

- 1 1 1742 cm . H NMR: 6 0.96 and 0.97 (t. 3H. J = 7.4 Hz. Me), 1.37-1.85 (m, 5H, 2 x CHr,

CH). 2.00-2.22 (m. 2H. CH2C=), 3.86 (S. 3H, OMe), 4.19 (d, lH, J = 4.6 Hz, CKC=O),

4.69 (dd, IH, J = 4.6 and 9.2 Hz, CHO), 4.97-5.13 (m, 2H, CH2=), 5.68-5.92 (m. 1H.

CH=). HRMS Calcd for C,2H,,0, 0 Z6.EO5; Found: 226.EOO. 85: Rr = 0.17 ( 4 :

1 PE : Et,O. Mixture of diastereornen (1 : 1) based on integntion between 3.30 and 3.33 - - 1 1

(s, lH, CHC=û). Colorless liquid: IR um, (neat): 1784. 1733 cm . H NMR: 6 0.89

and 0.93 (t, 3H. J = 7.4 HZ, Me), 1.33-1.70 (m. 4H. , 2 x CH:), 1.95-2.12 (m, 2H.

CH2C=), 3.30 and 3.33 (S. 1H. CHC=O), 3.78 (s, 3H, OMe), 4.10 and 4.22 (d, 2H, J = 8.6

Hz, CH20), 4.93-5.12 (m. W, CH-), 5.62-5.90 (m. 1 H, CH=). H R M S Calcd for

c,~H,,o, ( ~ 3 226.1205; Found: 226.1207.86: Rr = 0.09 ( 4 : 1 PE : Et,O. - Mixture of

diastereomers (1 : 1) based on integraiion between 3,77 and 3.78 (s, 3H, OMe). Colorless

-1 1 liquid: IR u,, (neat): 1732 cm . H NMR: S 0.82-2.40 (m, 13H). 3.77 and 3.78 (s, 3H,

OMe), 4.104.40 (m) and 1.60 (d, J = 12.7 Hz) (2H, CH?O). HRMS Calcd for C,,H,,O, -

(M+) 226.1205; Found: 226.1 198.

The same reaction was repeated using different Rh(@ catalysts. The data are

collected in Table 3 (pg. 40).

5.10 Pteparation of Diazo Compound 92 and Its Reaction.

4-Ethyl-Gheptenoic acid 90. To a suspension of NaH (53 mg. 1.1 mmol, 50 % in

minerai oil) in dry DMF (5.0 mL) was added dimethyl malonate (145 mg, 1.1 mmol) in

DMF (1.0 mL) at O O C and then stirred at n for 30 min. A solution of 5-bromo-4-ethyl-1-

pentene (176 mg, 1.0 mmol) in DMF was added dropwise. The resulting mixture was

heated at 80 O C for 12 h, cooled to rt and pour into 10 mL of ice-water. Extracted with

petroleurn ether (2 x 20 rnL), the combined organic layers were dried. and evaporated to

give an oil. Without purification. the crude oil was dissolved in 3 mL of DMF. LiBr (418

mg, 4.9 mmol) was added and then the mixture was heated at 130 O C for 12 h. The same

work up as described above provided 89 which was treated with 2 mL of 10% NaOH at n

for 12 h. The basic mixture was cooled to O OC. acidified using 10 % aqueous HCI and

exuücted with EtrO (10 rnL x 2). The combined organic layer was dried, filtered and

concentrated to give pure 90 in 74 mg (50 % yield for three steps). IR u,, (neat): 3076,

- 1 1 1749. 1719, 1640cm . H M : 60.88 (t, 3H. J = 7 . 1 Hz. Me), 1.25-1.50(m, 3H.CH.

CH?), 1.56-1.70 (m. 2HT CH2), 2.04 (t, 2H, J = 6.4 Hz, CHIC=), 2.38 (t, 2H, J = 8.0 Hz.

CHrC=O), 4.95-5.1 1 (m. 2H. CH$=), 5.65-5.98 (m. 1 H, CH=), 10- 1 1 (br 1 H, COOH).

Methyl 6-ethyl-3-0x0-8-nonenoate 91. Compound 90 (0.66 g, 4.2 mmol) was

dissolved in dry THF (20 mL) and N.N'-cxbonyldiimidazde (0.82 g, 5.0 rnmol) was

added. The reaction mixture was stirred at rt for 12 h.

Isopropyl magnesium brornide (8.5 rnL, 16.9 rnmol, 2 M in ?MF) was added

dropwise to a solution of U-(methoxycarbony1)acetic acid (1.0 g, 8.5 mmol) in THF (10

mL) at O OC, stirred for 0.5 h rit O OC then at rt for 0.5 h and 40 OC for another 0.5 h. The

reaction mixture was cooled to O OC and to this was added the imidazolide solution

(prepared above) via cannula. The mixture was stirred at O O C to rt over a period of 4 h.

then 1 M H3P04 (20 mL) was added and the mixture was extracted with Et20 (3 x 20

mL). The combined organic layen were washed with NaHC03 (10 mL), bnne, chied. and

evaporated. Chromatopphic sepantion ( 7 : 1 PE : Et2O) gave pure 91 (0.38 g, yield 43

%) as a mixture of keto and en01 tautomers as shown in NMR at 3.41 (s, 2H, CH2C=O)

- 1 1 and 12.0 (s, E=COH). iR u,, (neat): 3076. 1749. 1719, 1640 cm . H NMR: 8 0.82

(t, 3H, J = 6.4 Hz, Me), 1.16-1.62 (m, 5H, CH, 2 x CH2), 1.98 (br s, 2H, CH-=), 1.48 (t,

2H, J = 6.4 Hz, CH2C=O), 3.41 (s, 2H, CHK=O), 3.70 (s, SH, OMe), 4.90-5.05 (m, 2H.

CH2=), 5.58-5.83 (m. 1 H, CH=), 12.0 (s, =OH).

Methyl 2-diazo-6-ethyl-3-0x0-8-nonenoate 92. Prepared according to the

procedure described in Section 5.2. (84.0 %) ( 20: 1 and 7: 1 Petroleum ether/Et,O) - from

- 1 1 91 (0.30 g, 1.5 mmol). Pale yellow liquid: [R u,, (neat): 2135, 1717, 1659 cm . H

NMR: 8 0.88 (t, 3H. J = 7.1 Hz, Me), 1.21-1.50 (m, 3H, CH, CH2), 1.55-1.68 (m, 2H.

CHd, 1.05 (t, 2H, J = 6.4 HZ, CH+), 1.85 (bt. IH, J = 7.8Hz. CH2C=O), 3.84 (s, 3H,

13 OMe), 4.95-5.08 (m, 2H, CH2=). 5.65-5.89 (m. 1 H, CH=). C NMR: 6 10.79, 25.48(-),

27.39 (4, 37.54(-), 37.7, 38.5, 52.1, 115.9(-), 137.0, 161.8. 193.1.

3-Ethyl-2-(methoxycarbonyl)-3-(2-propeny~none 93. Follow ing the

genenl procedure described in Section 5.4 Method A. diazo compound 92 (90 mg, 0.38

mmol) was treated with Rh?(OAck (4.0 mg, 0.008 mmol) in dry CHrClz (50 mL) at n.

The crude product was purified by flash chromatopphy (7:l and 4 1 Petroleum

etherlEt,O) to give a mixture of keto and en01 tautomers 66 mg. 83 %: IR u,, (neat): - - 1 1

3075, 1756. 1656, 1611 cm . H NMR: 6 0.78 (t, J = 7.7 Hz), 0.91 and 0.93 (t, J = 7.7

Hz) (3H. Me), 1.35-2.50 (m. 8H, 4 xCH2), 3.05 and 3.09 (s, O.JH, CHC=O), 3.70, 3.72

and 3.77 (S. 3H, OMe), 4.92-5.20 (m, 2H, CH2=), 5.59-5.89 (m. 1H. CH=). 10.95 (S.

O.6H. C=COH).

The sarne reaction was repeated using different Rh(Q catdysts. The data are

collected in Scheme 37 (pg. 41)

The structure of 93 was further coafirmed by acylation reaction.

Compound 93 (22 mg) was dissolved in dry CH2C12 at O O C . Pyridine (0.5 mL)

was added and the mixture was stirred at O OC for 20 min. Acetyl chlonde (12 pL. 0.17

mmol) was added slowly. and the mixrure was stirred at O O C for 30 min and ür rc

ovemight. The mixture was diluted with CH2C12, washed with water, satunted aqueous

CuSOJ and water again. The solution was then dried, filtered and evaporated. The residue

was chrornatognphed (20 : 1 PE :EtlO) to give 94 (2 1 mg, 75 %). CR u,, (neat): 1775.

- 1 I 1713 1649 cm . H LW: 8 0.83 (t. J = 7.7 Hz, 3H, Me), 1.40-2.60 (m, 8H, 4 xCH2),

5.11 Preparation of Diuo Compounds 97as and Their Reactions.

2-(3&Dimethoxyphenyl)-Epenten-1-01 9% Prepared from 3.1-

Dimethoxyphenyl acetic acid (2.0 g, 10 mmol) and d l y l bromide (1.3 g, 1 1 mmol)

according to the procedure described in Section 5.5. Yield 5 1 % for two steps. IR u,,

-I t (neat): 3494. 3074, cm . H NMR: 6 1.5 1, (s, lH, OH), 2.25-2.53 (m. 2H. CHIC=). 2.82

(quint, iH, /=6.9 Hz, Cm), 3.61-3.83 (rn, 2H, CH20), 3.86 (s, 3H, OMe), 3.88 (s, 3K

OMe), 4.92-5-10 (m, 1H, CHc), 5.70-5.90 (m, 1 H, CH=), 6.70-6.86 (m, 3H, ArH).

Meth y l 2-(3Pdimet hoxyphenyI)+en ten y Imalonate 96a. Pre pared from 95a

(1.2 g. 5.2 mrnol) according to the procedure described in Section 5. L .( 85 %), ( 4: 1 and

- 1 1 3:l PUEtOAc). Colorless liquid: IR u,, (neat): 3075, 1750. 1738 cm . H NMR: 6

2.29-2.60 (m. 1H. CH?C=), 1.98 (quint, LH. J =6.9 Hz, CHAr). 3.35 (S. 3H. CH2C=O),

3.71 (S. 3H. OMe). 3.84 (S. 3H. OMe), 3.86 (s, 3H, OMe). ), 4.28 (d, ZH. J = 7.4 Hz.

13 CH20). 4.93-5.09 (m, 2H. CH2=). 5.57-5.80 (m. 1H. CH=). 6.70-6.85 (m. 3H. ArH). C

NMR: 6 36.8(-). 41.3-). 4 .0 . 52.5. 55.8, 68.8.(-), 11 1.1. 116.9(-), 119.7, 133.5, 135.6.

Methyl 2-(3,4dimethoxyphenyl)- 4-pentenyl diazopropanedioate 97a.

Prepared according to the procedure descnbed in Section 5.2. 83 9% from %a (1.4 g. 4.4

mmoi) (4:l and 3:l PE EtOAc). Pale yellow iiquid: IR u,, (neat): 2140. 1760. 1732.

- 1 1 1694 cm . H NMR: 6 2.32-1.60 (m. 1H. CH2C=). 3.01 (quint. 1H. J = 7.3 Hz, CHAr).

3.83 (s, 3H. OMe), 3.88 (S. 3H. OMe), 3.90 (S. 3H. OMe), ), 4.33 (d. ZH, / = 7.7 Hz.

13 CH.0). 4.92-5.10 (m. 1H, CH2=), 5.57-5.80 (m. IH, CH=), 6.68-6.87 (m. 3H, ArH). C

2-(3,4-dimethoxypheny1)-5-hexen-1-01 95b. Prepared from 3.4-

Dimethoxyphenyi acetic acid (2.0 g, 10 mmol) and Cbromo butene (1.L mL. 11 rnmol)

accoreding to the procedure described in Section 5.5. Yieid 62 % for two steps. IR u,,

-1 1 (neat): 3492 cm . H NMR: 6 1.3 1 (bs. 1H OH). 1.56 -2.10 (m, 4H. CHXHK=), 2.69-

3.87 (m, 1 H, CHAr), 3.60-3.83 (m, 2H, CH,O). 3.88 (s, 6H, 2 x OMe), 4.90-5.05 (m, 2H,

13 CH?=). 5.77-5.90 (m. 1H. CH=) 6.68-6.88 (m. 3H, ArH). C NMR: 6 3 1.3(-), 3 1.4(-).

Methyl2-(3,4-dirnethoxypheny1)-5-hexenylmalonate (%b): Prepared according

to the procedure described in Section 5.1. 83 % ( 4: 1 and 3: 1 PE/EtOAc) from 95b (340

- 1 I mg. 1.4 mmol). Colorless liquid: W u,, (neat): 3075. 1736, 1640 cm . H NMR: 5

1.50-2.10 (m. 4H. CH,CH?C=). 2.85-3.00 (m. LH. CHAr), 3.35 (S. IH, CH2C=O), 3.70

(s, 3H. OMe), 3.87 (s, 3H. OMe), 3.88 (S. 3H, OMe), 4.26 (d, ZH, J = 6.5 Hz, CH20),

13 4.90-5.00 (m. 1H, CH?=), 5.70-5.90 (m, L H, CH=) 6.65-6.90 (m. 3H. ArH). C NMR: S

138.1. 147.8, 148.9 166.4, 166.8. H R M S Calcd for C,,H&O, : 336.1573: Found :

Meth y l 2-(3,l-dimet hoxypheny1)-S-hexen y l diazop ropanedioa te (Wb):

Prepared according to the procedure described in Section 5.2. (83 9%) (4: 1 and 3: 1

PEEtOAc) from %b (57 mg, O. 17 mmol) Colorless liquid: IR u,, (neat): 2 137, 1759.

- 1 1 1736, 1692 cm . H NMR: 6 1.50-2.00 (m, JH, CHKH2C=), 2.82-3.00 (m. lH, Cm),

3-80 (s, 3H, OMe), 3.84 (s, 3H, OMe), 3.86 (S. 3H, OMe), 4.30 (d, 2H. J = 6.8 Hz,

13 CHB), 4.87-5.00 (m, 2H, CH2=), 5.63-5.85 (m, lH, CH=) 6.67-6.83 (m, 3H, ArH). C

NMR: 6 31.1(-), 43.8, 52.5. 55.8, 69.4,(-), 11 1.0, 11 1.2, 115.0(-), 119.8, 133.6, 138.0,

147.8. 148.9 160.7, 161.4. And. Calcd for C,,H.,,N,O, - - : C, 59.66; H, 6.12; N, 7.73.

Found: C, 59.58; H, 624; N, 7.73.

2-(3,4-Dimethoxy phen yl)-5-hexen yl diazoacetylacetate (97c): Prepared

according to the procedure descnbed in Section 5.3. 73% ( 1: 1 and 3: 1 PEEtOAc ) from

- 1 I colorless liquid: IR u,, (neat): 3076. 2 142. 17 14.1659 cm . H NMR: 6 1.66-2.17 (m.

4H. CHICH:C=), 2.41 (S. 3H. MeC=O), 2.89-3.04 (m, 1H. CHAr), 3.90 (S. 6H, 2 x

OMe), 4264.45 (m, 2H, CH20), 4.90-5.07 (m, 2H, CH2=), 5.69-5.90 (m, lH, CH=)

6.67-6.83 (m, 3H, ArH).

2-(3,4-Dimethoxyphenyl)-5-hexenyl-cl-(phenylsulfonyl)acete (96d): Prepared

from phenylsulfonyl acetic acid (0.12 g, 1.1 mmol) and alcohol 95b (0.24 g. 1 .O mmol)

I according to the procedure described in Section 5.1.(80 470). ( 4: 1 and 3: 1 PEEtOAc). H

NMR: 6 1.54-2.02 (m. 4H, CHKH2C=), 1.76-2.92 (m. LH, CHAr), 3.90 (s, 6H, 2 x

OMe), 4.10 (s, 2H. CH2C=O), 4.20 (d, 2H. J = 6.3 Hz, CH@), 4.85-5.04 (rn, 2H, CH2=),

5.63-5.86 (m, 1H, CH=) 6.65-6.83 (m, 3H, ArH), 7.48-7.72 (m, 3H, PhH), 7.81-7.92 (m,

2H, PhH).

2-(3,4-DimethoxyphenyI)-5-hexenyl-a-dia~o-~~-(phenyI~uLfonyI)acetate 97d.

Prepared according to the procedure described in Section 5.2. (83 %) ( 4:l and 3:l

PEEtOAc) from 96d (0.34 g, 0.8 mrnol). Colorless liquid: IR II,, (neat): 3063. 2127.

- 1 1 L7 18, 1640 cm . H NMR: 6 1.63-2.02 (m, 4H. CHXH-C=), 2.80-2.97 (m. IH. CHAr),

3.85 (s, 3H. OMe), 3.87 (S. 3H. OMe), 1.08435 (m. ZH, CHIO), 4.88-5.00 (m, 2H.

CHt=), 5.62-5.82 (m, 1H. CH=) 6.62-6.83 (m. 3H. ArH). 7.45-7.70 (m. 3H. PMI), 7.85-

7.93 (m. 2H, PhH).

2-(3,4-Dimethoxypheny1)-5-hexenyl-~x-diammdak 97e. p-Toluenesul fon y 1

hydrazone acid chlonde (0.30 g, 1.14 mmol) prepared from p-toluenesul fon y l hydrazone

and SOCl? was dissolved in CH2C12 (3 d) at O O C . Alcohol 95b (0.27 g, 1.14 mmol) in

CHzCll was added to the mixture via cannula. A solution of EtjN (0.32 rnL, 2.3 rnmol) in

CH2C12 ( 1 rnL) was then added dropwise via cannula over a penod of 5 min and the

reaction mixture stirred for 2 h. The solvent was evaporated and the residue was

dissolved in water (5 mL) and exuacted with EtrO (2 xlO mL). The combined organic

layen were washed with LM NaOH. brine. dried and concenuated. Chromatographie

purification (5 : 1 PEIEtOAc) yielded We (0.24 g. 68 % yield) as a pale yeilow Iiquid: IR

- 1 1 u,, (neat): 3080,2127, 1736, 1692 cm . H NMR: 6 1.65-2.08 (m. 4H, m 2 C = ) ,

2.80-3.00 (m, lH, CHAr), 3.85 (s, 6H, 2 x OMe), 1.37 (d, 2H, J = 6.3 Hz, CH20), 4.88-

5.02 (m, 2H, CH2=), 5.68-5.88 (m, LH, CH=) 6.55-6.85 (m. 3H. ArH).

Methyl 2-(l-(3,4-dimethoxyphenyl)-;Ipentenyl)-4-0~0-3-oxebn~arb~late

(98b) and Methyl t e t r a h e d r o - 4 - ( 3 , 4 - d i r n e t h o ~ y p h e n y l ) 4 ( 3 - b ~ ~

fumcarboxylate (99b) and Methyl 5-(3-butenyl)-7,8-dirnethoxy-4,5-dihydro-2-0~0-

J-boazoxepin-1-carboxylate (100b) and Methyl 5-(3,4-dimethoxyphenyI)-24x0-3-

oxabicycto [6.1.0] nonanecarboxylate (101b): Following the generai procedure

described in Section 5.4 Method A, diazo compound 97b (0.20 g, 0.55 rnmol) was treated

with Ri1~(0Ac)~ (6.0 mg, 0.01 mmol) in dry CH2C12 (40 mL) at rt. The cmde product was

purified by flash chromatography (6: 1 and 3: 1 PE/Et,O) - to give 98b (21 mg, 12 %) and

99b (71 mg, 38 %) as well as lOOb (21 mg, 13 %). (98b): l:! mixture of two

diastereoisomers based on integration between 3.68 and 3.78 (S. 3H. OMe),. colorless

- 1 1 Iiquid: IR u,, (neat): 1834, 1743 cm . H NMR: 8 1.70-2.10 (m. lH1 CH2CH2C=),

2.80-3.00 (m, IH, CHAr), 3.68 and 3.78 (s, 3H, OMe), 3.85 (s, 6H, OMe x 3, 3.98 and

3.99 (d. 1H. J = 1.6 Hz, CHC=O), 4.90-5.04 (m,

(m, 3H1 AtH). HRMS Calcd for

Colorless liquid: IR u,, (neat):

3H, CHi=, m), 5.65-5.8 1 (m. lH,

C,&,O, -- (hl+) 334.1416; Found:

- 1 1 1783, 1735 cm . H NMR: S 1.70-

2.20 (m. lH1 CH?CHrC=), 3.40-3.90 (m. IOH, OMe x 3. CHC=O), 4.50-5.05 (m, JH,

CH2=, CHzO), 5.50-5.70 (m, l f f , CH=), 6.48-6.60 (m, 1H, ArH), 6.73-6.85 (m. 3H.

ArH). H R M S Calcd for C,,H,,O, -- (M+) 334.1416: Found: 334.1427. (100b): Mixture

of diasteremen ( 1 : 1) based on inte,ption between 3.79 and 3.83 (S. 3H. OMe).

-1 1 Colorless Iiquid: iR um, (neat): 1738 cm . H NMR: 6 1.60-2.40 (m, 1H.

-$=), 2.85-3.00 (m, IH. CHAr), 3.79 and 3.83 (s, 3H, OMe), 3.83 (S. 3H, OMe),

3.86 (s, 3H, m e ) , 3.153.38 (m) ruid 4.40 (dd, J = 3.5 and 13.7 Hz) and 4.58 (d, J = 13.7

Hz) (2H, CH@), 4.78 and 4.88 (s, lH, CHC=O), 4.95-5.15 (m, 2H, CHL), 5.70-5.90 (m,

IH, CH=), 6.55 and 6.56 (s) 6.57 and 6.70 (s) (2H, ArH). HRMS Caicd for C,,H,,O, --

0 334.1416; Found: 334.1410. (IOlb): Colorless Iiquid: IR u,, (neat): 1730 cm

I l . H NMR: 6 1.40 (dd. 1 H, J = 7.2 and 4.3 Hz, H-9). 1 AS- 1.70 (m, 7H. CH?), 1.82-2.30

(rn,4H, H-8, H-9, CH?), 3.00-3.15 (rn, lH,CHAr), 3.75 (s, 3H, OMe), 3.82 (s, 3H,

OMe), 3.84 (s, 3H, OMe), 4.36 (dd, IH, J = 5.3 and 12.3 Hz, CHO), 4.85 (dd, lH, J = 2.3

and 12.3 Hz, CH0),6.79 (S. 3H. ArH).HRMS Calcd for C,,H,,O, -- (M? 334.1416:

Found: 334.14 19.

The sarne reaction was repeated using different Rh(II) catdysts. The data are

collected in Table 4 (pg. 47).

The structure of 99b was further was funher confirmed by decarboxylation

following the general procedure descri bed in Section 5 $6 to 4-(3.4-dimethoxyphenyi)4-

- 1 1 (3-buteny1)-y-lactone: Colorless liquid: IR um, (neat): 1790 cm . H NMR: 6 1.73- 1 .go

(m. 1H. CH2CH:C=), 2.73 and 2.87 (cf. IH. J = 16.9 Hz. CH2C=O), 3.85 (s, 6H. 2 x OMe

), 4.39 and 4.48 (d. 2H. J = 9.4 Hz, CHIO), 4.80-5.M) (m, 2H, CH2=), 5.50-5.65 (m. 1H.

13 CH=),6.50-6.85(m93H.ArH). CNMR:628.7(-).39.4(-),39.9(-),13.7(-),47.4,55.8.

55.9, 109.1, 11 1.1, 115.1 (-), 118.0, 134.8, 137.2, 148.0, 149.1, 176.0. HRMS Cdcd for

The structure of lOOb was further confirmed by decarboxylation following the

general procedure descrïbed in Section 5.6 to 5-(3-buteny1)-7-8-dimeth0xy-4~5-dihydro-3-

- 1 1 benzoxepin-2-( im-one: Colorless liquid: IR II,, (neat): 1745 cm . H NMR: 6 1.60-

2.00 (m, 2H, CH2), 2.00-2.33 (m, 2H, CHIC=), 3.00-3.15 (m, lH, CM), 3.87 (s, 3H,

OMe), 3.88 (s, 3H, OMe), 3.78 and 4.05 (d, 2H, J = 15.3 Hz, CH2C=O), 4.45 (dd, lH, J =

6.0 and 13.2 Hz, CHO), 4.65 (dd, lH, J = 2.6 and 13.2 Hz, CHO), 4.90-5.10 (m, 2H,

13 CH?=), 5.70-5.90 (m. LH, CH=), 6.53 (S. lH, ArH), 6.60 ( s, lH, ArH). CNMR: 6 30.9

147.7, 148.5, 172.6. HRMS Calcd forC, ,H ,O, (~3 276.1361, Found 276.1354.

5.12 Total Synthesis of (+)-Quebrachamine

5.12.1 The Preparation of GDiazoacetate 117

(2-Ethyl-5-hydroxypenty1)-cr-(methoxycarb (145) Compound 7th

(0.21 g, 1 mmol) in dry TH' was added dropwise to a mixture of disiarnylborane

(prepared in situ using 1.7 mL of 1 M BH3 in THF and 1.2 mL 2 M 2-methyl-2-butene in

T m at O OC. After stimng for 30 min at O O C and 30 min at n, the solution was recooled

to O O C . Water (0.1 rnL), 30 % H202 (0.5 mL, 4.2 mmol) and 1 M aqueous NaOH (0.13

mL. 0.43 mmol) were added sequentially. The mixture was stirred for 20 min at 10-20 O C

and then ether (2 mL) was added and the layen sepyated. The aqueous layer was

extracted twice with ether (5 mL) and the combined ethereal layen were washed with

satunted NaHS03, dned. fi ltered and concentrated to gve an oi l. Chromatographie

purification (2 : 1 pet.ether : EtOAc) gave 0.17 g (74 %) of 145. IR u,, (neat): 3418,

-1 1 1756, 1733, cm . H NMR: 6 0.88 (t. 3H, J = 8 Hz, Me), 1.26-1.43 (m. 4H, CHs, 1.46-

13 3.71 (S. 3H, OMe), 4.60 (d, 1H. J = 5.7 Hz, 0 0 , 4.70 (d, IH, J = 5.7 HZ, OCH). c

167.1. Anal. Calcd forC,,H,,05 : C. 56.88; H.8.68. Found: C, 56.73; H. 8.78.

[5-(t-Butyldiphenylsilyloxy)-2-ethy~~ntyl-a-(methocarnyi)acete (146) t-

Butyldiphenylsilyl chlonde (4 mL. 15 mmol) was added to a mixture of alcohol 145 (3.5

g. 15 mmol) in dry pyridine (35 mL) at O O C . The mixture was stimd at 0' C to n over a

period of 1 1 h. Water (50 mL) and EtOAc (50 rnL) were added and the organic layer was

separated. The aqueous phase was reextncted with EtOAc (30 mL) and the combined

organic layers were washed with satunted CUSOJ. water, brine and dried. The filtered

solution was evaporated to give a cmde oil which was purilied by chromatography (7 : L

and then 2 : 1 PE : Et20) to afford 146 as a thick oil. Yield was 6.4 g, 89 W . IR umm

- 1 I (film): 1754. 1738 cm

1.27- i .70 (m, 7H, CH<

CH20Si), 3.72 (s, 3H,

. H NMR: 6 0.88 (t, 3H. J = 7.4 Hz, Me). 1.05 (s, 9H. t-Bu),

(CH2)+, CH-Me), 3.38 (s, 2H, CHZC=O), 3.65 (t, 2H, J = 6.3 Hz,

OMe), 4.06 (d, 2H, J = 5.7 Hz, 0CH2), 7.32-7.40 (m, 6H, PhH),

13 7.60-7.73 (m, 3H, PW. C NMR: 6 10.8, 19.2, 23.5 (-), 16.7 (-), 26.8, 29.6 (-). 38.4.

41.4 (-), 52.4,64.0 (-), 67.8 (-), 127.6, 129.5, 134.0, 135.5, 166.6, 167.0. And. Caicd for

C,,.E$,05Si - : C. 68.90; H,8.14. Found: C, 69.19; H, 7.89.

(147). Compound 146 (4.3 g, 9.1 mmol) was dissolved in dry MeCN (30 mL) and the

solution was cooled to O OC. Mesyl azide (1.3 mL, 14 mrnol) was added followed by dry

Et3N (2.5 mL, 18 mrnol). The mixture was stirred ac O "C for 30 min and then at fi for 10

h. The mixture was diluted with CH2C12 (LOO mL) and washed with 10 % aqueous NaOH

(20 mL) and water (30 mL). The aqueous layer was reextncted with more CH2C12 (2x30

mL). The cornbined organic layers were dried. filtered and evaporated. Column

chromatognphy (7 : 1 and then 2 : 1 PE : Et20) of the crude product gave 5.9 g (88 9%) of

- 1 1 the diazo product 147. IR u,, (neat): 2 135, 176 1, 1737, 1695 cm . H NMR: 6 0.89 (t,

3H, J = 7.2 Hz, Me), 1.05 (S. 9H, t-Bu), 1-27-1.70 (m, 7H, CH, CH2Me), 3.64 (t,

2H, J = 6.0 Hz. CH20Si), 3.83 (S. 3H, OMe), 4.15 (d, 1H, J = 5.8 Hz, OCHI). 7.30-7.40

13 (m. 6H, PhH), 7.60-7.75 (m, 4H. PhH). C NMR: 6 10.9, 19.2. 23.6 (-), 26.7 (-), 26.8.

29.6 (-), 38.6, 52.5, 63.9 (-), 67.7 (-), 127.6, 129.5, 133.9, 135.5, 160.9, 161.6. Anal.

Calcd for C27H3tjN205Si : C. 65.19; H,7.3 1; NT 5.64. Found: C, 65.34; H, 7.29: N. 5.54.

5.12.2 The Formation OP pLactone 148

Rh(@-catalyzed reaction of 147 was performed in CH2C12 using 1 mol % of the

catalyst. Method A and B are basically those described in Section 5.4, but differ only in

total reaction times: For Method A, the total reaction time was 4 h; For Method B. the

total reaction time was 10 h. Method C is sirnilar to Method B except that the reaction

apparatus was flarne dned under vacuum before use.

Methyl tetrahydro-4-[3-(t-Butyldip h e n y l s i l y l o i 3 -

furancarboxyloie (148) Obtained as a 1 : 1 mixture of diastereorners based on the

-1 1 integration of the ester methoxy singlets. IR u,, (neat): 1787, 1737 cm . H NMR: 6

0.90 and 0.91 (t, 3H, J = 7.2 Hz, Me), 1.04 (s, 9H, t-Bu), 1.31-1.70 (m, 6H, (CH?),,

CH?Me), 3.27 and 3.18 (s, 1 H , H-3), 3.55-3.70 (m, 1H. CHaSi) , 3.7 1 and 3.76 (S. 3H.

OMe), 4.03 and 4.07 (d, lH, J = 8.6 Hz, H-5), 4.19 (d, lH, J = 8.6 Hz, H-57, 7.35-7.45

(m. 6H, PhH), 7.60-7.70 (m, JH, PhH). And. Calcd for C27H3005Si : C. 69.20; H,7.74.

Found: C, 69.00; H, 7.92.

l-(l-(f-ButyldiphenyIsilyloxy)-l-ethylbutyl]-3-(methoxycarbonyl)-2-ox~xe~ne

(149). Obtained as a 2.2 : i mixture of major diastereomen on the basis of the

intergration of the methoxy singlet of the C02Me moiety. IR u,, (neat): 1834. 1744

- 1 1

cm . H NMR: 6 0.94 (t. 3H. J = 7.4 Hz. Me), 1.08 (S. 9H, t-Bu), 1.30-1.80 (m, 7H. CH.

( C H h CH?Me), 3.60-3.73 (m. 2H, CH20Si), 3.76 and 3.80 (s, 3H, OMe), 4.07 ( J = 5.7

Hz) and 4.15 ( J = 5.1 Hz) (d, lH, H-3). 4.62 (dd, LH, J = 8.6,5.1 Hz, H-4), 7.30-7.60 (m.

6H, PhH), 7.6 1-7-75 (m. JH, PhH). Anal. Calcd for CXH3&Si : C, 69.20; H.7.74.

Found: C, 68.99; H, 7.9 1

- t 1 (150) Obtained as one diastereomer. IR u,, (neat): 3575-3225, 1760, 1743 cm . H

NMR: 6 0.90 (t, 3H, J = 7.3 Hz. Me), 1.05 (s, 9H, t-Bu), 1.23-1.70 (m. 7H. CH, (CH2),,

m , M e ) , 3.39 (br s, lH, OH), 3.62 (t, 2H, J = 5.8 Hz, CH20Si), 3.79 (s, 3H, OMe), 4.02-

4.2 1 (m, 2H, OCUt), 4.70 (br s, lH, a O H ) , 7.30-7.45 (m, 6H. PhH), 7.60-7.75 (m, 4H,

71.4, 127.6, l19.6, 134.0, 135.6, 168.6, 169.0. And. Cdcd for Ct7H3806Si : C, 66.63;

H,7.87. Found: C, 66.60; FI, 7.98.

Dimer (151). Obtained as a 1 : 1 mixture of diastereomer on the basis of the integration of

- 1 i the C (a)-H singlers. IR umax (nent): 1770, 1743 cm . H NMR: 8 0.88 (t. 6H. J = 7.1

Hz, 2 x Me), 1.05 (S. 18H. 2 x t-Bu), 1.21-1.70 (m, 14H, 2 x [CH, (CH?)?, CH2Me] ),

3.63 (t, JH, J = 6.6 Hz. 2 x CH20Si), 3.74 (S. 6H, 2 x OMe), 4.0042 (m, 4H. 2 x

OCH?), 3.92 (s, lH, C(u)-H) and 4.94 (s, 1 H, C(U)-H). 7.30-7.58 (m. EH. 2 x PhH),

7.60-7.70 (m. 8H, 1 x PhH). Anal. Calcd for CS&JOt ,SiS : C, 67.89; H.7.80. Found: C,

67.95; Fi, 8.01.

5.123 The Preparation of Pivotal Intermediate 155

4-[3-(t-ButyldiphenyIsilyloxypropyl)4ethyldihydro-2(3furanone (152). y-Lactone

148 (0.72 g, 1.53 mmol) was dissolved in DMSO (2 mL) containing NaCl (90 mg, 1.53

mmol). Water (60 pL, 3.1 mmol) was added and the mixture was heated at 1 10 O C for 12

h. The mixture was cooled to n and water (2 rnL) was added. The aqueous layer was

extracted with Et.0 (3 x 20 mL). The combined organic Iayers were washed with brine

(20 rnL) and then dried. The filtered solution was evaponted and the crude product was

purified by chromatography (4 : 1 and then 2 : 1 PE : EtzO) to give 152 (0.53 g, 84 9%). IR

- 1 1 u,, (neat): 1778 cm . H NMR: 6 0.87 (t, 3H, J = 7.2 Hz, Me), 1.05 (S. 9H, t-Bu),

1.42- 1.58 (m, 6H. (CHz)?, CHrMe), 2.3 1(s, 2H. H-3). 3.65 (t, 2H. J = 5.1 Hz. CH?OSi).

3.96 (d, lH, J = 8.6 Hz. H-5). 4.03 (d, 1H. J = 8.6 Hz. H-5'). 7.35-7.40 (m. 6H. PM),

42.5.63.7(-), 77. 1(-). 127.7. 129.7. 133.7, 135.5, 177.1. Anal. Calcd for C3H3JOjSi : C,

73.13; H, 8.35. Found: C, 73.08; H, 8.49.

4-Ethyl-J-(3-hydmxypn>pyl)dihydro-2(3H)~none (153). Compound 152 (0.40 g.

1 .O mrnol) was dissolved in THF (5 mL) and the solution was cooled to O OC. BuJW

(0.5 1 mL, 0.5 1 m o l . 1 M in THF) was added dropwise and the mixture was stirred at n

for 40 min. Water (1 rnL) was added and TKF was evaporated. The residual oii was

chromatographed (1 : 1 PE : EtOAc) to give 0.16 g (93 %) of 153. iR u,, (neat): 3600-

t I 3 125. 1770 cm- . H NMR: 6 0.88 (t, 3H. J = 7.7 Hz. Me), LAO- 1.60 (m. 6H. (CH+,

CH2Me). 1.60- 1.88 (br hump. 1 H. OH), 2.35(s. 2H. H-3). 3.66 (br S. IH, CH20H), 4.03

177. L . Anal. Calcd for CsHi [O3 : C. 62.77; H, 9.36. Found: C, 62.57; H. 9.16.

4 - E t h y l - 4 - [ 2 - h y d r o x y c a c b o n y l ) e t h y l ] d i h y d ~ (154). Jones' reagnt

was added dropwise to a solution of 153 (0.62 g, 3.6 mrnol) in acetone (40 rnL) at O O C

until the organge color of the oxidant persisted. A few drops of ?-propanol was added and

then followed by water (1 m . ) . The mixture was evaporated and the resulting mixture

was mixed with saturated NaCI. The mixture was extracted with EtOAc (2 x 20 cd). The

organic layen were washed with brine, dned, filtered and evaponted to give a colorless

- 1 1 solid 154 (0.66 g, 98 %). Mp 65-67 O C . IR u,, (neat): 3500-2500. 1770, 1710 cm . H

NMR: 8 0.90 (t, 3H. J = 7.4 Hz. Me), 1.52 (q, 7H. J = 7.4 HZ, CH?), 1.78-1.88 (m. 2H,

CH?, 2.20-2.39(m, JH, 3 x CHIC=O), 4.00 (d, IH, J = 9.2 Hz, CHO), 4.06 00 (d, lH, J =

13 9.2 Hz. CHO). C NMR: 6 8.4, 28.8(-). 29.1 (-), 30.6(-). 39.6 (-), 42.4, 76.5(-), 176.5.

4-Ethyl-l-[2-hydroxycarbonyl)ethyl~methoxytet~ydrofumne (155). The acid 154

(0.30 g, 1.6 mmol) wûs dissolved in dry Et20 (20 mL) and the solution was cooled to -78

OC. DIBAL-H (3.3 mL. 3.3 rnmol. 1 M in toluene) was added dropwise to the cold

solution. After stirring at -78 O C for 1 h. dry MeOH ( 10 mL) and p-TsOjHH20 (1. Lg. 5.5

mmol) were added and the mixture was wamed slowly to rt and then was refluxed for 40

min. The solvent was evaporated and woter (2 mL) was added and the mixture was

extracted twice with EtOAc (20 mL). The organic layen were washed with brine, dried.

filtered and evaporated to give an oil. Chromatographie separation (1 : 1 PE : EtOAc)

afforded the desired 155 (O.? g) as well as the diacetal 156 (60 mg), the aced ester 157

(10 mg) and the acetal alcohol 158 (8 mg). Al1 four compounds were obtained as 1 : 1

mixture of diastereomers on the bais of the inteption of the methyl triplet of the ethyl

moiety.

-1 1 Compound 155. iR um, (neat): 3500-2500,17 12 cm . H NMR: 6 0.83 and 0.84 (t. 3H.

J = 7.4 Hz. Me), 1.3 1- 1-96 (m, 6H, CHr C(3)Hz CH2Me), 2.1 l -X6(m, 2H, CHtC=O),

3.32 (S. 3H, OMe), 3.58 (d, 1 H, J = 9.1 Hz, C(5)H). 4.06 00 (d, IH, J = 9.2 Hz. C(5)H).

1.97-5.03 (m, lH, C(2)H. Anai. Calcd for Cl&Iis04 : C, 59.39; H, 8.97. Found: C.

-1 1 Compound 156. IR u,, (neat): 1125, 1101,1054 cm . H NMR: 6 0.84 and 0.85 (t. 3H.

J = 7.7 Hz, Me), 1 .X- 1.68 (m. 7H, (CH2); CH2Me, C(3)H), 1.9 1 and 1.93 (dd, lH, J =

13.7, 2.9 Hz.C(3)H). 3.32 (S. 6H,OMe), 3.33 (s, 3H,OMe), 3.60(s, 2H.C(5)H2).4.33 (t.

1H. 3 = 5.1 Hz, CH(OMe)?), 4.97-5.03 (m. LH, C(2)H. Anal. Calcd for CIIH30J : C,

62.M; H, 10.41. Found: C, 62.33; H, 10.43.

Compound 157. Infrared spectrum showed the absence of the broad absorption in the

range 3500-1500 cm " and the absorption at 1712 cm -' that are chiuacteristic of a COzH

group and the presence of an ester carbonyl absonion at 1741 cm". Its 'H NMR spectnim

is identicai to that of 155 with the exception of the methoxy singlet of the ester group st 6

3.37. Base hydrolysis (K2C03. MeOH) of 157 gave 155.

- 1 1 Compound 158. IR u,, (neat): 3424, 1101. LOS4 cm . H NMR: 6 0.83 and 0.85 (t. 3H,

J = 7.4 Hz. Me), 1.33-1.85 (m, 8H, (CH2)?. CHtMe, C(3)H, OH), 1.92 (dd, IH. J = 13.7

Hz. C(3)H). 3.32 (S. 3H. OMe), 3.56-3.7 1 (m. 4H, C(5)Hz, CH20H). 4.99-5.0 1 (m. 1 H,

5.12.4 The Preparation of the Tetracyclic Amino Alcohol 166

2-(Acetoxymethy1)-2-~hy~,4,5,7,8,13,13b-0~tahydr0-5~x0-1H-

azepino[l'2':1 J]pyrido[3,4-blindole (165). A mixture of 155 (0.14 g, 0.7 mrnol) and

tryptamine (0.4 g. 2.1 mmol) were dissolved in a mixture of toluene (4 mL) and acetic

acid (8 mL). The solution was stirred at 80 OC for 24 h and then at reflux for another 24 h.

The solution was evaporated and then a mixture of 10 % aqueous NaOH (10 rnL) and ice-

water (10 mL) were added. The aqueous mixture was extracted with CH2C12 (2x20 mL).

The organic phases were washed with brine. dried. filtered and evaporated. The crude

product was purified by chromatography (2 : I PE : EtOAc) to afford 80 mg of 165a and

- 1 I 60 mg of 165b. Compound 165a: IR um, (film): 3384. 1732, 1634 cm . H NMR: 6

0.90 (t, 3H, J = 7.5 Hz, Me). 1.30-1.95 (m, 6H, CH2Me, C(3)Hz, C(1)H2). 3.35 (S. 3H.

MeC=O). 1.46 (dd, IH, / = 14.6, 7.3 Hz. C(4)H). 2.65-2.95 (m. 3H. C(4)H7, C(8)H2).

3.10 (dq. 1H. J = 13.4. 10.9.5.5 HzT C(7)H), 3.80 (d. lH, J = 12.2 Hz. CHOAc). 4.78 (dq,

LH, J = 13.4, 10.9, 5.5 Hz, C(7)H'). 1.99 (d, LH, J = 12.2 Hz, CHOAc), 5.20 (d, IH, J =

9.6 Hz. C(l3b)H). 7.01-7.25 (m. 2H. C(lO)H, C(ll)H), 7.30 (br d. lH, I = 7.2 Hz,

13 C(17)H). 7.49 (br d. 1H. J = 7.2 Hz. C(9)H). 8.75 (br s, 1H. NH). C NMR: 6 7.420.7 (-

118.2, 119.5, 121.9. 126.4, 132.7,, 136.4, 173.9, 174.8. HRMS Calcd. for CI1HwN2O3:

354.1943. Found: 354.1940.

- 1 1 Cornpound 165b: IR u,, (film): 3457. 1732, 1632 cm . H NMR: 6 0.99 (t, 3H, J = 7.5

Hz, Me), 1.42-1.95 (m, 6H, CH?Me, C(3)Hr, C(l)H2). 2.05 (S. 3H. MeC=O), 2.48 (dd.

lH, J = 13.8.6.9 Hz, C(4)H). 2.62-2.93 (m. 3H, C(4)H9, C(8)Hz), 3.04 (dq, lH, J = 12.6.

10.3, 4.3 Hz, C(7)H), 3.81 (d, lH, J = 11.5 Hz, CHOAc), 3.87 (d, IH. J = 11.5 Hz.

7.02-7.26 (m. 2H. C(1O)H. C(lI)H), 7.30 (br d, lH, J = 7.2 Hz, C(12)H). 7.48 (br d. LH,

31.2 (-), 37.7 (-), 38.0, 40.1 (-). 48.7, 70.5 (-), 100.7. 110.8. 118.3, 119.7, 122.2, 116.5,

132.1 .. 136.4, 170.9, 174.9. HRMS Calcd. for C2iHi&203: 354.1943. Found: 354.1945.

2-Ethyl-2-(hydroxymethyl)-2,3,4,5,7,8,13,13b-0~tahydro-l H-

azepino[l'2':1,2]pyrido[3,4-blindoie (166). The acetate 165a (40 mg, O. l l mmol) was

dissolved in dry THF (10 rnL) at n and LiAlH4 (40 mg, 0.1 1 mmol) was added. The

mixture was stirred at rt for 30 min and then was refluxed for 20 h. The reaction mixture

was cooled to n and 10 % üqueous KOH (50 pl) was added and the mixture was stirred

for 30 min. The mixture was filtered rhrough a bed of celite and the solid residue was

washed with CH2C12 (3x 10 r d ) . The combined filtrates were dried. filtered and

evaporated to leave a semi-solid thot was chromatographed (10 : 1 CH:C12 : MeOH ) to

give the known 16th (30 mg. 95 %). 166a. mp. 215-216 O C (lit." 219-221 OC). IR grnm

- 1 1 (film): 331 1 cm . H NMR: 6 0.87 (t, 3H, J = 8.0 Hz. Me), 1.33 (q. 2H, CH2Me). 1.18 (br

t. 2H. J = 5.7 Hz, C(3)Hr), 1.76 (dd. IH, J = 14.9, 3.9 Hz, C(1)H). 1.73-1.96 (m. ZH.

C(4)Hd.). 2.12 (dd, 1H. J = 14.9. 2.9 Hz. C(1)H). 2.53-3. M(m. 7H, C(5)H2, C(7)Hz.

C(8)Hz, OH). 3.6 1 (S. 2H, CH20H), 4.00 (br d, IH, J = 9.2 Hz, C( 13b)H), 7.02-7.30 (m,

13 2H. ArH), 722-7.31 (m. 1H. ArH). 7.11-7.50 (m. lH, ArH). 8.10 (brs. 1H. NH). C

166b was obtained in 96 % yield using the same procedure described above. mp. 130-232

-1 1 O C ( lit. 232-235 OC). IR u,, (film): 3432 cm . H NMR: 6 0.94 (t. 3H. J = 7.8 Hz,

Me), 1.40-1.94 (m, 7H, C(l)H, CH2Me,C(3)Hz, C(4)&), 2.09(dd, lH, J = 15.4, 2.3 Hz,

3.22(d, 1H. J = 10.5 Hz,CHOH),),3.33 (d, 1H, J = 10.5Hz,CHOH),3.75 (brd, 1H. J =

9.2 Hz, C(l3b)H). 6.91-7.10 (m, 2H, ArH), 7.23-7.41 (m, 1H, ArH), 9.83 (s, lH, NH).

13 C NMR: 6 7.0. 19.9 (-), 23.6 (-), 27.7 (-), 32.8 (-), 40.4. 40.8 (-), 51.8(-), 54.7, 5 8 3 - ) .

5.12.5 The Reactions Reiated to the Mechanistic Studies

Amide 167. Compound 167 (15 mg, 54 % yield) was prepared from 155 (16 mg. 0.08

rnmol) according to the procedure described for compound 247. IR u,, (neat): 3428.

- 1 I

3308,3053, 1654 cm . H NMR: 6 0.83 and 0.84 (t, 3H, J = 7.4 Hz, Me), 1.20- 1.98 (m.

6H, 3 x CH2), L.99-2.l3 (m. ZH, CHIC(0)N), 2.97 (t, 2H, J = 6.6 Hz, CH&), 3.3 1 (S.

3H, OMe), 3 .jO-3.70 (m, 4H, CH2N, CH@), 4.90-5.03 (m. 1 H, OCHO), 5.60 (bs. 1H,

W = O ) , 7.04 (S. 1 H, ArH), 7.08-7.29 (m. 2H, ArH), 7.40-7.60 (rn, 2H, ArH), 8.30 (S. -

lH, NH).

4-[3-(t-ButyldiphenyIsilyloxypropyi)4ethyI-2-hydr01rytetrahydrofumne 173 y-

Lactone 152 (0.08 g, O. 19 mmol) was dissolved in dry EtzO (5 mL) at -78 OC. DIBAL-H

(0.21 rnL, 0.21 mmol, 1 M in toluene) was added dropwise to the cold solution. After

stimng at -78°C for 1 h, dry MeOH (0.1 mL) was added and the mixture was w m e d

slowly to rt. The solvent was evaporated and water (2 mL) was added and the mixture

was extracted twice with EtOAc (10 mL). The organic layers were washed with brine,

dried. filtered and evaporated to give an oil. Chromatographie separation (1 : 1 PE :

EtOAc) afforded the desired 173 (0.08 g, 95 % yeld) as 1 : L mixture of diastereorner on

the basis of the integration of the rnethyl triplet of the ethyl moiety. iR u,, (neat): 3408,

1 1 3070. 3û48 cm- . H NMR: 8 0.8 1 and 0.82 (t. 3H. J = 7.2 Hz. Me). 1 .O5 (S. 9H. PB@.

1.31-1.69 (m. 7H. (CHr)2, CH?Me. OH). 1.95 (quent, LH. J = 6.9 Hz. H-3). 2.55 (t, IH. J

= 4.3 Hz. H-3), 3.56-3.78 (m. JH, CH?OSi, CHrO), 5.47-5.56(m. 1H. OC-), 7.3 1-7.49

(m. 6H. PhH). 7.60-7.70 (m, 4H. PhH).

CEthyl-4-(3-bromopropyl~dihydr0-2(3H)-f ranone 175. Compound 153 (O. 1 O g. 0.57

mmol) was dissolved in CH?Cl? (10 mL) at O O C . Ph3P (0.22 g. 0.85 mmol) and CBr4

(0.28 g. 0.85 mmol) was added slowly and then the reaction mixture was stirred at rt for 1

h. Water (10 rnL) was added and exmcted with CH2C12 (20 mL). The organic layer was

dried. evaporated and the crude product was purified by chromatopphy (7 : 1 PE : Et20)

- 1 I to pive 175 (0.12 g, 88 % yield). IR u,, (neat): 1778 cm . H NMR: 6 0.88 (t, 3H. J =

7.4 Hz, Me), 1.51, (q, 2H. J = 7.4 Hz, CHrMe), 1.55-1.68 (m. 2H. CH?). 1.71-1.88(m,

1H. CH?), 2.33(s. ZH, R3). 3.38 (t. 2H, J = 6.3 Hz. CH2Br), 3.98 (d, 1H. J = 9.1 Hz, H-

13 5). 4.04 (d. 1H. J z 9 . 2 HZ. H-5). C NMR: 6 8.5. 27.6 (-). 79.1 (-), 33.4 (-). 34.7 (-).

4-Ethyl4[3-bromopropyl]-2-methoxytetrabydrofue 176. Compound 175 (0.11 g,

0.47 mmol) was dissolved in dry EtrO (10 mL) and the solution was cooled to -78 OC.

DBAL-H (0.5 mL. 0.5 mmol, 1 M in toluene) wûs added dropwise to the cold solution.

After stimng ai -78 OC for 1 h, dry MeOH (3 mL) and p-Ts03H H20 (0.16 g, 0.83 mmol)

were added, the mixture was warmed slowly to rt and then was refluxed for 40 min. The

solvent was evaporated. water (10 mL) was added and the mixture was extracted twice

with EtOAc (IO mL). The combined organic layen were washed with brine. dried,

filtered and evaporated to give an oil. Chromatognphic sepmtion (7 : 1 PE : Et20)

afforded the desired 176 (0.10 g, yield 89 %) as a 1 : 1 mixture of diastereomen based on

- 1 1

the integration of the methyl triplets. IR u,, (neat): 1459. 1102, 1050 cm . H NMR: 6

0.85-0.87 (t, 3H. J = 7.4 Hz. Me), 1.36-2.0 (m. 8H, CH2Me, 4 x CH?), 3.33 (s, 3H, OMe),

3.38 and 3.39 (t , 2H, J = 6.9 Hz, CHIBr), 3.60 (s,lH, CH20), 4.97-5.05 (m. 1 H, OCHO).

5.13 Total Synthesis of (+)-Quebrachamine

5.13.1 The Preparation of Chiral Alcohol S-(+)ml94

5.13.1.1 Formation of Imide 189 via Alkylation

(JR,5S)-3-(Butanoyl-CmethyClphenyl-2m~xaz~iidinone 188. Compound 187

(1.3 g, 7.3 rnmol) was dissolved in THF (10 mL). A few crystds of bipyridine were added

followed by addition of n-BuLi (2.0 M in hexane) at -78 O C until the color of the mixture

turned brick-red. After stimng for 30 min, butyryl chlokde (0.80 mL, 7.3 mmol) was

added dropwise and then the mixture was stirred at -78 "C for another 30 min. Then

satunted aqueous W C 1 ( 10 rnL) was added and the mixture was then stirred ar rt. The

mixture was exvacted with EtOAc (2 x 10 mL) and the combined organic layen were

washed with 5 % NaHC03. brine. dried and concentrated. Chrornatographic separation (7

: 1 PE : Et.0) gave 188 as a coloriess soiid ( 1.6 g. 88 %). m.p. 57-59 OC.'" IR umax

- 1 1 (film): 1790, 1704 cm . H NMR: 6 0.90 (d, 3H. J = 6.3 Hz, CHM), 1.01 (t. 3H. J = 7.1

Hz, Me), 1.63- 1.82 (m, 2H, CH?), 2,79-3.07 (m. 2H, CH2C=O), 4.7 14.83 (m, IH, CHN),

13 5.66 (d. IH. J = 7.4 Hz. CHO). 7.12-7.50 (m. 5H, PhH). C NMR: 6 13.6, 14.6. 17.3 (-),

= +40.2. (C 0.6. CH2Clr). Lit 40.2, (CH~CI?).'~'

(ilR,SS)-3-[(2S)- 2-Ethyl- li>xo-J-pntenyl]-4-m41hyl-3-phenyl-2-

oxazolidinone 189. Ni~N(sitMe~)~ (6.4 mL, 6.4 rnmol. 1M solution in T m was added

dropwise to the imide 188 (1.4 g. 5.7 rnmol) in THF (15 rnL) at -78 O C . The mixture was

stirred at -78 "C for 2 h, allyl brornide (1.5 mL. 29 mmol) was then added via Syringe and

the mixture wss stirred for another 3 h at -40 O C . The reaction was quenched with

aqueous W C 1 (10 rnL) at -78 O C and then w m e d slowly to rt. The mixture was

exuacted with EtOAc (2 x 20 rnL) and the cornbined organic layen were washed with 5

O/o N;iHC03, brine, dried and concentrated. Chrornatographic separaùon (7 : 1 PE : Et20)

- 1 1

gave 189(1.4g, 88 %). IRu,, (neat): 1790, 1698. 1641 cm . H NMR: 60.87(d, 3H.

J = 6.9 Hz, CHMe), 0.95 (t, 3H, J = 7.2 Hz. Me), 1.48-1.87 (m. 2H. CH2}, 2,22253 (m.

2H, CH2C=), 3.80-3.93 (m, LH, CHC=O), 4.73-4.88 (m, lH, CHN), 4.96-5.1 l(m, 2H,

C h = ) , 5.65 (d, 1 H, J = 7.4 Hz, CHO), 5.70- 5.92 (m, LH, CH=), 7.25-7.50 (m, SH, PhH).

5.13.1.2 Formation of lrnide 189 via Aldol Reaction-Ikoxygenation

(4R,5S)-3-[(2R)- 2-(1-Hydroxyethy1)- 1-0x0-4-pentenyll-4-methyl-5-phenyu

oxazolidinone 191. Imide 190 (1.7 g, 6.5 mmol) was dissoived in CH2C12 (10 mL) at O

OC. T,0BBu2 (7.2 mL, 7.1 mmol. 1 M solution in CH2C12) was added foilowed by EtjN

(1.1 rnL) and the mixture was stirred at O O C for 30 min. The boron enolate solution was

cooled to -78 "C, acetaldehyde (3.6 mL. 7.1 mmol. 2 M in CH2CII) was added dropwise

via cannula and the reaction mixture was stirred for 30 min at -78 OC. The reaction

mixture was stirred nt n for 12 h. then phosphate buffer solution (7.2 mL, PH = 7.0) was

added at O OC followed by 30 % HzOz (6.3 mL) and methanol (18 mL). The mixture was

stirred for I h, NazSOs (38 mL, 1.5 M) was added and stimng was continued for L h. The

organic layer was separated and the aqueous layer was reextracted with CHFI? (2 x 30

mL). The combined organic layers were washed with aqueous Na2S03, brine, dried and

concentnted. The residual oil was purified by column chromatopphy (3 : 1 and 1 : L PE

: Et20 ) to give 191 (0.82 g, yield 52 %). IR Umm (film): 3496,3073, 1773. 1699, 16.11

- 1 1

cm H NMR: 6 0.86 (d, 3H, J = 6.9 Hz, NCHMe), 1.26 (d, 3H, J = 6.0 Hz, OCHAM,

2,38272 (m, 3H, OH, CH2C=), 4.06-4.23 (m, 2H, CHOH, CHC*), 4.83 (quint, IH, J =

6.9 Hz, C m , 4.94-5.13 (m. 2H, CH-), 5.67 (d. 1 H, J = 6.9 Hz, CHPh), 5.72- 5.96 (m,

1 H, CH=), 7.20-7.50 (m, 5H. PhH).

(4R95S)-3-[(ZR)-1-0x0-2-(1-p henoxyt hiocarbonyloxy)ethy~-4pen tenyî]-4-

rnethyl-5-phenyl-2-oxazolidinone 192. The alcohol 191 (1.3 g, 4.4 m o l ) was dissolved

in CH2C12 (30 mL) at n. Pyndine (1.1 mL, 15 mmol) and DMAP (0.050 g, 0.40 mmol)

was added followed by addition of phenyl chlorothionoforrnate (0.70 mL. 1.8 mmol).

After stimng the mixture for 3 h at n. the solvent was evaporated and the residue was

dissolved in EtOAc (30 rnL). The organic layer was washed with saturated aqueous

CuS04 (20 mL), brine. dried and concentrated. Chromatographie separation (7: 1 and 3: 1

- 1 1 PE : EtzO) gave 192 (1.9 g. 92 %). IR u,, (film): 3069. 1788, 1736, 1697 cm . H

NNEk60.88 (d, 3H, J = 6 . 9 Hz. NCH&@, lSO(d.3H. k 6 . 3 Hz.OCHMM), 2.36-2.77

(m. 2H, CH?C=), 4.53 (quint, IH, J = 4.6 W. CHC=O), 1.77 (quint. 1H. J = 6.9 Hz.

Cm), 4.98-5.18 (m. 2H. CH2=), 5.67 (d, IH. J = 6.9 Hz, CHPh), 5.71- 5.93 (m. ZH,

CHO, CH=), 7.10-7.50 (m, 5H, PhH).

(4R95S)-3-[(2S)- 1-0xo-2-ethyl;l-pentenyl]-4-methy1-5-phenyl-2~oxazolidinone

189. Bu3SnH (10 mL, 37 mmol) was added to a mixture of thionoformate 192 (6.6 g, 15

mmol), AIBN ( 0.48 g, 3.0 mmol) in toluene (220 rnL) at n. The mixture was heated at 75

O C for 12 h. then cooled to n and aqueous 10 % KF (100 mL) was added. After stirring at

n for L h, the mixture was extracted with EtOAc (2 x 100 mL). The cornbined organic

layers were washed with brine and then treated with activated carbon. After stimng for a

while, the mixture was filtered and concentrated. Chromatographie sepantion (7:l PE :

Et2O) gave 189 (3.3 g. yield 76 %). +26.8, (c 1.8, CHCI,). IR u,, (neat): 1790.

- 1 1 1698, 1641 cm . H NMR: 6 0.87 (d, 3H, J = 6.9 Hz, CH&&), 0.95 (t, 3H. J = 7.2 Hz,

Me), 1 .W 1.87 (m. 2H. CHZ), 222-2.53 (m, 2H, CH2C=), 3.80-3.93 (m, 1H. CHC=O),

4.73488 (m. LU, Cm), 4.96-S.Ll(m, 2H, CHi=), 5.65 (d. IH, J = 7.3 Hz, CHO), 5.70-

13 5.92 (m. 1H. CH=), 7.25-7.50 (m, jH, PW). C NMR: 6 11.6, 14.6. 24.6 (-). 36.3 (-),

5.13.1.3 Conversion of Imide 189 to Chiral Alcohol S-(+)-194

(2S)-2-Ethyl-.l-pentenok acid 193. A 30 % aqueous h ydrogen peroxide solution

(0.18 mL, 1.5 mrnol) and a solution of LiOH (0.0 18 g, 0.77 mmol) in water (0.24 rnL)

was added to ü solution of imide 189 (0.11 g, 0.38 rnmol) in 2 mL of TKF-HP (3 : 1) at

O O C . After 1 h. 1. I mL of 1.5 M NaS03 (1.6 rnmol) was added to quench the excess

Hz02, and THF was removed in vaccum. The aqueous mixture (pH = 13) was extracted

with CH2Clz (3 x10 mL) which after evaporated solvent gave oxazolidinone 187 (0.060

g). The aqueous layer was acidified (1 M HCI, pH = 1) and extracted with Et20 (3 xlO C

rnL). The organic layer was dried. and evaporated to give acid 193 (0.05 g. 100 96).

- 1 1 [a]"~ -2.5. (c 7.0 CHCls) IR Umax (neat): 3600-2500, 1768, 1643 cm . H NMR: 6 0.95

(t, 3H, J = 7.7 Hz, Me), 1.50-1.80 (m, 2H. CHrMe). 7.20-2.50 (m, 3H. CH, CH2C=), 5.0-

5.15 (m, CHt=), 5.68-5.89 (m, 1 H, CH=).

(ZS)-2-Ethyl-4-penten-ls1194. Acid 193 (0.050 g, 0.40 mmol) was dissolved in

Et10 (10 mL) and cooled to O OC. LAH (0.036 g, 0.90 rnmol) was added and the mixture

was stirred for 30 min at O O C then at n for 12 h. Water (0.04 mL). aqueous 15 % NaOH

(0.04 mL) and water (0.12 mL) was added sequentially to quench the excess L M .

Anhydrous NarS04 was added and the mixture was stirred at rt for 1 h, then filtered

through Celite and the residue was washed with Et20 (2 xlO rnL). The filtrate was

concentrated by distillation at atmosphenc pressure (Vigreaux column) to give the crude

alcohol 194 as a cleu liquid (0.023 g. 50 55). [a]% +1.8, (c 1 A. CHC13). IR u,,

- 1 I (neat): 3360. 3077, 1640 cm . H NMR: 8 0.89 (t. 3H. J = 7.4 Hz. Me), 1 .zO- 1-41 (m.

2H. J = 6 . 8 Hz,CH2). 1.51 (br sept, 1H. J = 6 . 3 Hz,-t), 1.67, (S. 1H. OH). 1.09 (brt.

2H, J = 6.9 Hz, CHIC=), 3.54 (d, 2H, J = 6.3 Hz, CHfl), 4.96-5.12, (m. 2H. CH2=),

5.70-5-92 (m. 1 H, CH=).

(4s)-44 @-methoxyphenyl)methoxyJmethyl]-1-hexene 195. Alcohol 194

(0.020 g, 0.18 mmol) was added to NaH (0.028 g. 0.60 mmol. 50 % in oïl) suspended in a

mixture of THFIDMF ( 1 : 1) ( 1 .O mL) at O OC. After 15 min. 4-rnethoxybenzyl bromide (

0.041 mL. 0.30 mm01 ) was added dropwise and the mixture was stirred at rt for 20 h.

The mixture was recooled to O OC, water was added followed by diethylarnine and then it

was stirred for L h. The mixture was diluted with EtzO (10 rnL) and washed successively

with water (2 mL), aqueous CuS04 and water. The organic layer was dried, filtered,

evaponted and the residue was purified by chromatography (30 : 1 PE : Et20) to give

(4s)-195 (0.036 g, 88 8). [a lU~ -2.8, (c 1.8, CHC13) Lit. Compound (4R)- 195 [a]%

- 1 1 + 1.9, (C 2.01, CHCI3). IR Umm (neat): 3074, 1640, 1613, 1586 cm . H NMR: 6 0.88 (t,

3H. J = 7.1 Hz. Me), 1.28-1.4 (m. 2H. CH2Me), 1.63 (hept, LH, J = 6.6 Hz, CH), 2.20-

3.50 (m, 2H. CHzC=). 3.33 (d. 2H, J = 5.8 Hz. CH20), 3.81 (s, 3H, OMe). 4.43 (s, 2H,

CH2Ph). 4.93-5.07 (m, CH2=). 5.66-5.88 (m, lH, CH=). 6.88 (d, 2H, J = 9.2 Hz, PhH),

Compound 196 and Amino Alcohol 197. The irnide 189 (120 mg, 0.43 m o l )

wûs treated with LAH (50 mg. 1.3 mmol) in THF (10 mL) at -5 OC (following the

procedure described for the reduction of acid 193) gave alcohol 194 (24 mg. 50 %),

oxazolidinone 173 (JI mg, 54 %), cornpound 196 (1 1 mg, 9.2 %) and amino Alcohol 1W

- 1 1 (1 1 mg, 10 %). Compound 196: [R um, (neat): 3466,3350,3055, 1642 cm . H NMR:

6 0.92 (t. 3H, J = 7.4 Hz. Me), 0.99 (d , 3H, J = 6.9 Hz. C m ) , 1.374.76 (m. ZH. CH2

Me), 1.90-2.08 (m. LH, CHC=O). 2.08-3.42 (m. 2H, CHIC=), 3.80 (bs, 1H. OH). 4.15-

4.40 (m, lH, Cm), 4.81 (d, 1H, J = 1.9 Hz, CHO), 4.85-5.10 (m. 2H. CH2=), 5.53- 5.82

(m. ZH, -OH, CH=), 7.11-7.41 (m, 5H. PhH). Amino Alcohol 197 : IR um, (neat):

- 1 1

3413, 3063, 3030, 1639 cm . H NMR: 6 0.86 (t, 3H, J = 7.4 Hz, Me). 0.88 (d, 3H. J =

6.9 Hz, C m ) , 1.15-1.44 (m, 2H, CH2Me), 1.44-1.67 (m, IH, =t), 1.91-2.12 (m. 2H,

CH2C=), 2.18 (s, 3H, M e ) , 2.25-2.43 (m, 2H, NCH?), 2.68-2.83 (m. 1H. CHN), 3.10-

3.60 (bs, LH, OH), 4.79 (d, lH, J = 4.6 Hz, CHO), 4.95-5.09 (m, 1H. CH2=), 5.63- 5.88

13 (m, 1H. CH=), 7.18-7.40 (m. 5H. PtiH). C NMR: 6 9.9, 10.7, 24.0 (-), 35.8 (-), 37.3,

38.6,59.4 (-), 64.5,73.4, L 15.9 (-), 126.1, 126.8, 127.9, 137.1, 142.5.

When the same reaction was done at -78 O C from imide 189 (0.13 g. 0.45 rnrnol),

a mixture of dcohol 194 (12 mg, 25 %), oxazolidinone 173 (61 mg, 76 %). compound

1% (16 mg, 12 %) was obtained.

When the same reaction was done at 67 OC, the only byproduct detected was

amino Alcohol1W.

5.13.2 The Formation of pLactone (-)-152

( 2s )-Methyl 2-ethyl-4-pentenylmalonate (76a): Prepared from chiral alcohol

S-(+)-194 (0.63 g, 5.5 mmol) according to the procedure described in Section 5.1. (Log,

86 %), ( 7:l and 4 1 PE/Et?O). Colorless liquid: (alD -1.9 (c 1.3, CHCli). IR umûx

- 1 1 (neat): 3077. 1738. 1640 cm . H NMR: 6 0.93 (t, 3H. J = 7.4 Hz, Me). 1.38 (quint, ZH, J

= 6.8 Hz, CH2). 1.71 (br sept, LH. J = 6.0 Hz, CHEt), 3.10 (br t, ZH, J = 6.6 Hz, CH2C=),

3.41 (S. IH. CHK=O), 3.78 (s, 3H, OMe), 4.08 (d, 2H, J = 5.7 Hz, CHIO), 5.04, (bt d,

1 5 îH, J = 12.4 Hz, CH-), 5.65-5.86 (m. 1H. CH=). C NMR: 6 11.0, 23.3(-). 35.0(-).

38.6. 11.1(-), 52.5. 674-), 116.7(-), 135.9. 166.6, 167.0. HRMS Calcd for C1,H1,O, -

OMe 183.1019, Found l83.lOX

(2S)-(2-EthyI-5-hyd~oxypentyl)-a-(metboxycatyl)acete (145). Compound

S-(-)-76a (0.31 g. 1 mmol) in dry THF was added dropwise to a mixture of

disiarnylborane (prepared in situ using 1.2 mL of 1 M BH3 in THF and 1.2 mL 2 M 2-

methyl-?-butene in THF) at O OC. After stimng for 30 min at O O C and 30 min at n, the

solution was recooled to O OC. Water (O. 1 mL). 30 % Hz02 (0.5 rnL. 3.2 mmol) and 1 M

aqueous NaOH (0.13 mL, 0.43 mmol) were added sequentially. The mixture was stirred

for 20 min üt 10-20 O C and then ether (2 mL) was added and the layen separated. The

aqueous layer was extracted twice with ether (5 mL) and the combined ethereal layen

were washed with saturated NaHS03, dried. fiitered and concentrated to give an oil.

Chromatographie purification (2 : 1 pet.ether : EtOAc) gave 0.17 g (74 %) of (S)-(-)-145.

1 t [ulD -2.1 (C 1.0. CHC13). IR Umm (neat): 3418, 1756, 1737 cm- . H NMR: 6 0.88 (t. 3H.

J = 8 fi, Me), 1.26- 1.43 (m, JH, CH?, 1.46- 1.70 (m. 4H, CH, CH2, OH), 3.37 (s, 3H.

C&C=O), 3.62(t, 2H. J = 6.9 Hz, CH20H). 3.7 1 (S. 3H, OMe), 4.60 (d, 1 H, J = 5.7 Hz,

13 OCH), J.70(d, lH./=5.7 HZ. OCH). C NMR: 6 10.9. 23.6(-), 16.7 (-), 29.7 (-). 38.5.

41.4 (-). 52.5. 63.0 (-). 67.6 (-). 166.6, 167.1. Anal. Calcd for C,,H,05 : C. 56.88;

H,8+68. Found: C, 56.73; H, 8.78.

(2S)-[5-(t-Butyldiphenylsilyloxy)-2-ethylpentyl-a-(methocarnyl)acete (146). t-

Butyldiphenylsilyl chloride (4 mL, L5 mmol) was added to the mixture of alcohol (S)-(-)-

145 (3.5 g, 15 mrnol) in dry pyridine (35 mL) at O OC. The mixture was stirred at O "C to

n over a period of 12 h. Water (50 mL) and EtOAc (50 mL) were added and the organic

layer was separated. The aqueous phase was reextracted with EtOAc (30 mL) and the

combined organic layers were washed with saturated CuS04, water, brine and dned. The

filtered solution was evaponted to give a cnide oil which was purified by

chromatography (7 : 1 and then 2 : 1 PE : Et20) to afford (S)-(+)-146 as a thick oil. Yield

- t 1 was 6.4 g, 89 %. [alD +2.5 (c 1.0, CHC13). IR u,, (film): 1754, 1738 cm . H NMR: 6

0.88 (t, 3H. J = 7.4 Hz, Me), 1.05 (S. 9H. t-Bu), 1.27-1.70 (m, 7H, CH. (CHt)?, CH2Me),

3.38 (s, ZH. CH2C-O). 3.65 (t, 7H, J = 6.3 Hz, CHQSi), 3.72 (S. 3H, OMe), 4.06 (d. 2H,

15 J = 5.7 Hz, OCH?). 7.32-7.40 (m, 6H, PhH), 7.60-7.73 (m, 4H, PhH). C NMR: S 10.8,

134.0, 135.5, 166.6. 167.0. Anal. Calcd for C,&,05Si - : C, 68.90: H.8.14. Found: C,

(ZS)-[S-(t-Butyldiphenylsilyloxy)-2-ethy1pen tyl] a-diazo-a - (methoxycarbonyl)acetate (147). Compound (S)-(+)- 146 (1.3 g, 9.1 mmol) was

dissolved in dry MeCN (30 mL) and the solution was cooled to O OC. Mesyl azide (1.3

mL, 14 mmol) was added followed by dry EtiN (1.5 mL. 18 mmol). The mixture was

stirred at O "C for 30 min and then at n for 10 h. The mixture was diluted with CH2C12

(LOO rnL) and washed with 10 % aqueous NaOH (20 mL) and water (30 mL). The

aqueous layer was reextracted with more CH2C12 (2x30 mL). The combined organic

layen were dried. filtered and evaporated Chromatographie purification (7 : I and then 2

: i pet-ether : Et2O) of the cmde pmduct gave 5.9 g (88 %) of the diazo product (S)-(+)-

-1 1 147. [alD t3.3 (c 1.5. CHCl3). IR u,, (neat): 2135, 1761, 1737, 1695 cm . H NMR: 6

0.89 (t, 3H. J = 7.2 Hz. Me), 1.05 (S. 9H, t-Bu), 1.27- 1 J O (m, 7H. CH. (CHr)t, CH2Me),

3.64 0, 2H, J = 6.0 Hz, CHPSi), 3.83 (s, 3H, OMe), 4.15 (d, 3H. J = 5.8 HZ, OCH?),

13 7.30-7.40 (m. 6H, PhH), 7.60-7.75 (m. JH, PhH). C NMR: 6 10.9, 19.2, 23.6 (-), 26.7 (-

). 26.8, 29.6 (-). 38.6. 52.5, 63.9 (-). 67.7 (-), 127.6, 129.5, 133.9, 135.5, 160.9, 161.6.

Anal. Calcd for CpH3&I2OjSi : C, 65.29; H.7.31; N, 5.64. Found: C, 65.34; H, 7.29; hi,

5.54.

2(3H)-furanone (118). Rh2(OAc)4-catalyzed reaction of 147 (5.9 g, 12 mmol) was

performed in CHzC12 using 2 mol % of the catalyst. Method C as descnbed in Section 5.4.

The product was obtained as a i : 1 mixture of diastereomen based on the integration of

the ester methoxy singlers. Yield 4.9 g, 87 8. [all, -4.7 (c 1.6. CHCI,). IR u,, (neat):

- 1 1 1787, 1737 cm . H NMR: 6 0.90 and 0.9 1 (t, 3H. I = 7.2 Hz, Me). 1.04 (S. 9H, t-Bu),

1-3 1-1.70 (m, 6H, (CH&, CHIMe), 3.27 and 3.28 (s, LH, H-3), 3.55-3.70 (m, 2H.

CH?OSi), 3.71 and 3.76 (S. 3H, OMe), 4.03 and 4.07 (d, lH, J = 8.6 Hz, H-S), 4.19 (d,

1H. J = 8.6 Hz, H-57, 7.35-7.45 (m, 6H, PhH), 7.60-7.70 (m, 4H. PhH). Anal. Calcd for

C Z ~ H ~ ~ O ~ S ~ : C* 69.20; H-7.74 Found: C, 69.00; H, 7.92.

( 4 S ) - 4 - [ 3 - ( t - B u t y l d i p h e n y l s i l y l o x y p r o p y l ) ~ e (152). y-

Lactone (S)-(-)-la (0.72 g, 1.53 mmol) was dissolved in DMSO (1 rnL) containing NaCl

(90 mg, 1.53 rnmol). Water (60 a, 3.1 mmol) was added and the mixture was heated at

110 O C for 12 h. The mixture was cooled to n and water (2 mL) was added. The aqueous

layer was extracted with EtzO (3 Y. 20 mL). The combined organic layers were washed

with brine (20 mL) and then dried. The filtered solution was evaponted and the crude

product was purified by chromatognphy (4 : 1 and then 1 : 1 PE : EtzO) to give (S)-(-)-

- 1 I 152 (0.53 g. 84 %). [alo -3.3 (c 1.5. CHC13). IR u,= (neat): 1778 cm . H NMR: 6 0.87

(t. 3H. J = 7.2 Hz. Me), 1.05 (S. 9H. t-Bu). 1.41-1.58 (m. 6H. (CH&, CH2Me). 2.31(s.

2H, H-3). 3.65 (t. 2H. 1 = 5.1 Hz, CH20Si), 3.96 (d, LH. J = 8.6 Hz, H-5). 4.03 (d. 1H. J

13 = 8.6 Hz, H-5'). 7.35-7.40 (m. 6H. PhH), 7.60-7.70 (m. 4H. PhH). C NMR: 6 8.4. 19.2.

177.1. Anal. Calcd for CaHs403Si : C. 73.13; H. 8.35. Found: C. 73.08; H, 8.49.

5m13m3 The Preparation of Aldehyde 201

(4S)-4-[3-(t-Butyldiphenylsilyloxypropyl)~4-ethyl-2-hydro~tetrahydrofumne 198. y-

lactone (S)-(-)-152 (0.080 g. 0.19 mrnol) was dissolved in dry Et20 (5 rnL) at -78 OC.

DIBAL-H (0.21 mL. 0.21 mmol. 1 M in toluene) was added dropwise to the cold

solution. After stimng at -78'C for 1 h. dry MeOH (0.1 mL) was added and the mixture

was watmed slowly to rt. The solvent was evaponted and water (2 rnL) was added and

the mixture w s extracted twice with EtOAc (IO mL). The organic layen were washed

with brine, dried, filtered and evaponted to give an oil. Chromatographie sepantion (1 : 1

PE : EtOAc) afforded the desired 198 (0.080 g, 95 % yield) as 1 : 1 mixture of

divtereorner on the buis of the integration of the methyl tripiet of the ethyl moiety. iR

-1 1 u,, (neat): 3N8 , 3070. 3038 cm . H NMR: 6 0.81 and 0.81 (t. 3H. J = 7.2 Hz. Me),

1 .O5 (S. 9H. t-Bu), 1.3 1- 1.69 (m. 7H. (CH&, CHrMe, OH). 1.95 (quent, 1 H, J = 6.9 Hz.

H-3). 2.55 (t, 1 H, J = 4.3 Hz, H-3), 3.56-3.78 (m, 4H, CHiOSi, CH-O), 5.47-5.56(m, 1H.

OCHO), 7.3 1-7.49 (m. 6H, PM), 7.60-7.70 (m. 4H. PhH).

S - 8 (0.19 g, 0.44 mmol) was dissolved in CHIClz (10 mL), 1.3-propanedithiol

(0.065 mL, 0.65 mmol) was then added and the mixture was cooIed to 4 0 OC. Titanium

terrachloride (0.28 mL. 0.28 mmol, 1 M in CH2Clr) was added dropwise and stirring was

continued for 2h. Water ( 5 mL) was added and extracted with CH2CI7 ( 2 x10 mL), The

organic layer was washed with water. bnne. dned and concentrated. Cnide mixture was

purified by column chromatography (4 : 1 PE : EtzO) to give (S) - 199 ( 0.13 g. 99 %). IR

- 1 I um, (neat): 3442 cm . H NMR: 6 0.81 (t, 3H. J = 8.0 Hz, Me). 1.06 (S. 9H. t-Bu).

OH, CHd, 2.73-3.0 (m. IH. 2 x CH2S), 3.43 (d. 2H. J = 6.9 Hz. -OH), 3.65 (t, 1H. J =

6.9 Hz, CH20Si), 4.05 (t, lH, J = 5.1 Hz, SCHS), 7.33-7.49 (m, 6H, PhH), 7.6 1-7.72 (m,

42.2,64.4(-), 66.3 (-). 127.6. 129.5. 133.9. 135.6. HRMS Calcd for C,,H,I0,S2Si 502.85. - Found 502.2394.

(2S)-5-(t-Butyldiphenylsilyl)oxy-l-(lJ-dithian-2-yl)methyl-2-ethyl- 1-

methylsulfonyloxypentane LOO. (S)- 199 ( O. L 1 g, 0.2 mrnol) was dissolved in pyridine

(10 mL) and MsCl(0.07 mL, 0.91 mmol) was added at O OC. The mixture was stimd at rt

for 12 h. Water was added and evaporated solvent. The residue was dissolve in CH2C12

(20 mL) and washed with 10 rnL of 1 M HCI, NaHC03, brine. Organic layer was dned,

filtered and concentrated. Chromatography sepmtion (4: 1 Pet : Et20) afforded pure (S)-

- 1 (+)-200 (0.1 1 g, 85 % yield). [a]"D + 0.97 (c 5.2, CHCls). IR um, (neat): 3073 cm .

1 H NMR: 6 0.85 (1. 3H. 5 = 7.4 Hz. Me). 1.10 (S. 9H. t-Bu), 1.36-1.65 (m. 6H. (CH?)?,

CH2Me. ). 1.7 1 (d, ZH. J = 5.7 Hz. CHCH,), 1.74- 1.92 (rn, 1 H, CH), 1.98-2.ll(m. 1 H.

CH), 2.68-3.0 (m. W. 2 x CH2S), 3.02 (S. 3H, MeS03). 3.68 (t, 1H. J = 5.1 Hz, CH20Si).

1.0-4.14 (m. 1H. SCHS). 4.08 (S. 2H. CH20), 7.32-7.18 (m, 6H. PM), 7.61-7.71 (m, 4H,

13 PhH). C NMR: 6 7.3. 19.3. 25.2 (-). 25.9 (-), 26.3 (-), 16.9. 29.2 (-). 31.2(-), 37.3. 39.7.

40.0 (-), 42.2,64.0(-). 72.5 (-). 127.7. 179.6. 133.9, 135.6.

201. Hg(CIOr)2.3Hz0 (0.028 g, 0.062 mmol) was added to the mixture of (S)-(+)-200

(O. 18 g, 0.03 1 mmol) in 1 rnL of isopropan0VCHC1~~0 (3:6: 1). The mixture was stirred

at n for 1 h, the mixture was filtered and the filtrate was washed with CHC13 (10 rnL).

The organic layer was washed with 5 mL each of NaHCOs, brine, dned and concentrated.

Chromatographie sepantion (2: 1 PE : Et?O) afforded pure (S)-201 (0.0 1 1 g. 72 % yield).

-1 1 IR u,, (neat): 3070,1740. 1720 cm . H NMR: 6 0.87 (t, 3H, J = 7.4 Hz, Me), 1.06 (S.

9H. t-Bu), 1.33-1.60 (m. 6H. (CH?)?, CH2Me, ), 2.40 (s,lH, CHC=O), 1.42 (S. IH,

CHCS) , 2.97 (s, 3H, MeSOi), 3.6 1 (bt, 2H. J = 5.1 Hz, CH20Si), 4.09 (s, 2H. CHIO),

13 7.28-7.49 (m. 6H, PhH), 7.50-7.69 (m, 4H, PhH). C NMR: 6 7.3, L9.2,26.0 (-1, 26.4 (-),

5.13.4 The Preparation of the Tetracyclic Amino Akohol205

indolo[2,3-alindolizine 204. Tryptamine (7.3 mg, 0.045 mmol) was added to the

mixture of (S)-201 (20 mg, 0.041 mmol) in toluene (15 mL). The mixture was then

heated ai reflux for 18 h. After this period, toluene was evaporated and the residue was

purified by column chromatography (4: 1 and 1: 1 PE : EtOAc) to give 204 (72 mg, 98%

yield) as an 1: 1 mixture of epirner based on the inteption of two methyl signals centered

at 6 0.72 and 0.85 respectively. p-epimer 204a. [a]"() +33.3 . (c 0.3, CHCI3). IR u,,

- 1 1 (film): 3460. 3053 cm . H NMR: 6 0.72 (t. 3H. J = 7.4 Hz, Me), 1.07. (S. 9H. CMe3).

1.18-1.34 (m, 2H, CH2Me), 1.52 (bs, 4H. 2 x CH?), 1.61 (dd, 1H. J = 5.7, 12.3 Hz, H-1).

2.02 (dd, lH, J = 8.0, 12.4 Hz. H-l), 2.55 (d. LH, J = 9.2 Hz. H-3). 2.6-2.71 (m. lH, H-6).

1.74 (d, lH, J = 9.2 Hz. H-3). 2.83-3.05 (m, 1H. H-5, H-6). 3.16-3.38 (m. lH, H-5). 3.68

(bs, 2H. CH20), 4.13 (bt, lH, J = 6.9 Hz, CHAr), 7.05-7.19 (m, 1H. ArH), 7.71-7.53 (m.

13 RH, ArH, PhH), 7.58-7.73 (m. 4H, PhH). 7.75 (bs, 1H. NH). CNMR: 6 9.1, 17.9 (-),

1 u-Epimer 204b [a]'"D -36.5, (c 0.48. CHC13). H NMR: 6 0.85 (t. 3H. J = 8.0 Hz, Me),

0.98, (S. 9H, CMe3), 1-17-1.3 1 (m. 3H. CH2-3', CH4'), 1.33-1.47 (m, lH, CHI ' ) , 1 .J8-

1.64 (3H. CH2Me. CRI) , 2.04 (dd, lH, J = 8.0. 12.6 Hz, H-1). 2.57 (d. lH, J = 9.2 Hz,

H-3), 2.58-2.68 (m, 1 H, H-6). 2.69 (d, 1 H, J = 9.1 Hz, H-3), 2.80-3 .O5 (m. ZR H-5, H-6).

3.16-3.33 (m. 1H. H-5), 3.51 (bs, 2H. CH?O), 4.15 (bt. 1H. J = 6.3 Hz, CtWr), 7.03-7.18

(m, 2H. ArH), 7.20-7.42 (m, 8H, ArH. PhH), 7.43-7.66 (m. 4H, PhH), 7.70 (bs, LH, NH).

13 CNMR 6 8.9, 17.9 (-), 19.1, 36.8, 28.1 (-). 30.6 (-), 34.2 (-), 41.8 (-), 14.3, 16.3 (-),

56.9. 60.7 (-), 64.1 (-). 107.4. 110.7. 118.1, 119.3. 121.3. 127.5. 129.5, 134.0. 135.5,

135.9.

5.14 Total Synthesis of (-)-Eburnamonine

(JS)-4-Ethyl4-(3-hydroxypropyl)dihydro.2ranone (153). Compound (4s)-152

(0.40 g. 1 mmol) was dissolved in THF (5 mL) and the solution was cooled to O O C .

B W (0.51 ML, 0.5 1 mmol. 1 M in THF) was added dropwise and the mixture was

s h e d at rt for JO min. Water (1 mL) was added and THF was evaponted and the

residual oil was chromatographed ( 1 : 1 PE : EtOAc) to give O. 16 g (93 %) of 153. [~ t } ' ' '~

- 1 1 4 .5 (c 1.7, CHCI;) IR u,, (neat): 3600-3123. 1770 cm . H NMR: 8 0.88 (t. 3H. J =

7.7 Hz. Me), 1 .N- 1.60 (m. 6H. (CH2)?, CH2Me), 1.60- 1.88 (br hump. 1 H. OH). 1.35(s.

13 2H, H-3). 3.66 (br S. ZHT CHIOH). 403 (s, 1H. H-5). C NMR: 6 8.4. 27.2(-), 29.0 (-).

32.2(-), 39.8 (-). 42.5. 62.6(-). 77.0(-). 177.1. Anal. Calcd for CqHI IO3 : C. 62.77: H.

9.36. Found: C, 62.57; H, 9.16.

(4s)4-Ethyl4-[2-hydroxycarbonyl)ethyl]dihydro2(3-€unone (154). Jones

reagent was added dropwise to a solution of (49-153 (0.61 g, 3.6 mmol) in acetone (40

mL) at O OC until the orange color of the oxidant persisted. A few drops of ?-propanol

was added and then followed by water (1 mL). The mixture was evaporated and the

resulting mixture was mixed with saturated NaCI. The mixture was extracted with EtOAc

(2 x 20 mL). The organic layers were washed with brine, dried, filtered and evaporated to

- 1 1 3500-2500, 1770, 1710 cm . H NMR: 6 0.90 (t, 3H, J = 7.4 Hz. Me), 1.52 (q, 2H, J =

7.4 Hz. CH?). 1.78-1.88 (m, 2H, CH?), 2.20-2.39 (m. 4H. 2 x CH?C=O), 4.00 (d, IH, J =

13 9.2 HZ, CHO), 4.06 (d, 1 H, J = 9.1 HZ, CHO). C NMR: 6 8.4, 28.8(-), 29.1 (-), 30.6(-),

39.6 (-), 42.4. 76.3-), 176.5, 178.4. Anal. Calcd for CqHi404 : C. 58.05; H. 7.58. Found:

Amide 247. Acid (SI-154 (0.076 g, 0.41 rnmol) was dissolved in CH2CI2 (10 r d ) at O OC

and DCC (0.10 g, 0.5 rnmol) was added. Alter for lh. tryptarnine (0.080 g, 0.5 rnmol)

was added and the mixture was stirred for 15 h at n. The precipitate was removed by

filtration and the residue was washed with CHCI? (10 mL). The fiItrate was washed with

5 % HCI, water, saturated NaHC03, brine, dried and concentrated. Chromatographie

sepantion ( 1: 1 and 1 2 PE : EtOAc) gave amide 247 (0.090 g, 67 % yield). [a}'$) -2.9 (c

-1 1 0.9. CHC13) iR u,, (neat): 33 14, 1770, 1650 cm . H NMR: 6 0.83 (t, 3H, J = 7.7 Hz,

Me), 1.4) (q, 1H. J = 7.7 Hz, CH?), 1.674.78 (m. 2H, CH2), 1.93-2.05 (m. ?H,

CHzC(0)N). 2.20 (S. CH?C=O), 2.94 (t, 2H, J = 6.6 HZ, CH2Ar), 3.56 (dt. 2H, J = 6.8,

6.3 Iiz,CH2N), 3.88 (d. LH, J = 8.4Hz,CHO), 3.94 (d. 1H. J=8.4 Hz, CHO). 5.93 (bt.

13 lH, J = 5 . 7 Hz, mC=O). 6.95-7.6 (m, SH, ArH), 8.68 (bs. lH, NH). C NMR: 6 8.5,

119.4, 122.1, 122.3, 127.4. 136.5. 172.1, 177.3. HRMS Calcd for C19H2fl2O3 :

328.1787. Found: 328.1787.

(4S)-N-[2-(indoie-3-yI)-ethyl)]-4-ethyl-4-hydroxymet h y l-6- h yd rox y hexamide 248 To

a solution of amide 247 (0.054 g, 0.16 mmol) in THF (1 mL)-MeOH (0.2 mL) at O O C

was added LiB& solution (0.4 mL, 0.8 mmol. 2. M in THF). The mixture was stirred at rt

for 48 h, cooled to O OC and quenched with satunted NbCI solution (0.5 mL). The

aqueous layer was extracted with CH2C12 (10 mL) and the combined organic layers were

dried and comcentnted. Chrornatographic separation (?O : 1 CH2CIZ : MeOH) gave diol

- I 248 (0.050 g. 92 % yield). [u}"'~ +1.3 (c 1.0. MeOH) [R u,, (film): 3328, 1633 cm .

1 H NMR: 6 0.77 (t. 3H. / = 7.7 Hz, Me). 1.16 (q, 7H. J = 7.1 Hz. CH:Me), 1.32-1.55 (m.

3H, CHz-3, CH-5). 1.68- 1.86 (m. LH. CH-5). 2.06 (t. 2H. J = 6.9 Hz. CHICa). 2.97 (t,

2H. J = 6.3 Hz. CH?Ar), 3.27 (bs. 2H. CH20), 3.53-3.74 (m. SH. CHrN, CH@-6, OH),

4.48 (bs, LH. OH), 5.81 (bt, 1H. J = 5.6 Hz, N C = O ) , 7.0-7.66 (m. 5H. ArH), 8.35 (bs.

(4S)-N-[2-(3-Indolyl)sthyl)]-4oethyl4hydro~methyl-6-t-butyldipheny IsiIoxy-

hexamide 251c and (#S)-N-[2-(3-indoIyi)-ethyl)~et hyl4J-

butyldiphenylsiloxymethyl-6-t-buty ldipve 252c To a solution of

di01 248 (0.23 g, 0.69 mmol) in DMF (5 mL) was added t-butyldiphenylsilyl chloride

(0.21 g, 0.76 mrnol) foliowed by addition of imidazole (0.12 g, 1.7 mmol). The mixture

was stirred at -20 OC for 4 h and then 12 h at n. The reaction was quenched with

saturated NaCl (5 mL) and extracted with CH2C12 (2 x 10 mL). The organic layer was

washed with brine, dx-ied, filtered and concentrated. Chromatographic separaiion (1: 1 PE

: Et?O and 1: 1 PE : EtOAc) gave rnonosilyl ether 251c (0.36 g, 92 % yield) and 252c

(0.038 g. 6 8 yield). 251c -6.9 (c 0.4, CHClù. IR u,, (film): 3414, 3304, 3048,

- t 1

1650 cm . H NMR: 6 0.75 (t, 3H. J = 7.4 Hz, Me), 1.04 (S. 9H, Me3C), 1.1 1- 1.3 1 (m.

2H. CH2Me), 1.39- 1.60 (m. 4H. CH?-3. CHr-5). 1.87-2.12 (m. 2H. CH?C=O), 2.95 (t.

1H, J = 6.9 Hz, CH2Ar), 3.29 (S. 2H, CFLOH), 3.50-3.75 (m. 5H. CH2N, CH20-6, OH).

5.53 (bt, lH, J = 5.6 Hz, m C = O ) , 7.0 (d, 1H. J = 2.2 Hz, ArH). 7.06-7.25 ( m. 2H.

13 ArH), 7.3-7.50 (m, 7H, ArH, P M ) , 7.50-7.70 (m, 5H, ArH, PhH), 8.10 (bs, lH, NH). C

136.3, 173.7. HRMS Calcd for C a b N 2 0 3 S i : 570.3278. Found: 570.3274. 252c [ ~ t ) ' ~ ~

- 1 L -2.6 (c 1.9. CHC13). iR um, (neat): 3428. 3294. 3070, 1638 cm . H NMR: S 0.67 (t,

3H, J = 7.4 HZ, Me), 1.00 (S. 9H, Me3C), 1.03 (s, 9H, Me3C), 1.15-1.30 (m. 2H.

CHrMe), 1.38- 1.60 (m, 4H. CHz-3. CHz-5), 1.64-1.77 (m, 2H. CH2C=O), -. 7 87 (t, 7H. - J

= 6.9 Hz, CH&), 3.26 (S. 2H. CHTO), 3.46 (q, 2H. J = 6.9 Hz, CH2N), 3 '63 (t. 2H. J =

7.4 HZ, CHIO-6), 5.02 (bt, lH, J = 5.7 HZ, ==O), 6.83 (d, 1H. J = 2.3 Hz, ArH), 7.04-

7.22 ( m, 2H, ArH). 7.24-7.43 (m, 7H, ArH, PtiH), 7.52-7.67 (m. 5H, ArH, PhH), 7.79

13 (bs, LH, NH). C NMR: 67.5, 19.1, 19.4. 25.3 (-), 26.5 (-), 26.9, 27.0, 29.9 (-), 30.9 -,

134.0, 135.6. 135.8, 136.4, 173.2. HRMS Cdcd for CsiH&?Ofiiz : 808.1456. Found:

808.4459.

(4S)-N-[2-(3-indolyi).ethyl)~ethyl-J-ethyl)-5-0~0-

pentamide 253c and (5S)-N-[2-(34ndolyl)-ethyl)]-5sthyW (2-t-butyldiphenylsiloxy.

ethyl)-6-hydroxy-64actam 254c Monosilyl ether 251c (0.24 g, 0.42 m o l ) was

dissolved in DMSO ( 5 rnL) at n and Et3N (1.1 mL, 7.4 mrnol) was added followed by

addition of SO3.Py complex (0.48 g, 3.0 mmol) in DMSO (2 mL). The mixture was

stirred at n for 60 h and then 1 M NaOH (5 mL) was added. The mixture was stirred for

another 15 min and then was extrxted with EtOAc (2 x 10 mL). The combined organic

layers were washed with brine. dried,filtered and concentrated. Chromatographie

sepantion (1: 1 PE : Et20 and 1: 1 PE : EtOAc) gave 25k (0.083 g, 35 % yield) and

254c (O. 14 g, 60 5% yield). 253c IR u,, (neat): 3401,3396, 3053,1710. L721. 1653 cm

1 1 . H NMR: 6 0.73 (t. 3H. J = 7.4 Hz. Me). 1.02 (S. 9H, Me3C), 1.50 (q. 1H. J = 7.4 Hz.

CHMe), 1.51 (q, 1H. J = 7.7 Hz, me), 1.63-1.90 (m. 6H, C H 9 . CHr-3. CH2-5), 2.93 -

(t. 2H. J = 6.6 Hz, CH?Ar), 3.47-3.64 (m, 4H. CH2N, CHrO), 5.35 (m. lH, - NHC=O),

6.97 (d, 1 H, 1 = 2.2 Hz. ArH). 7.07-7.74 ( m. 3H. ArH), 7.29-7.45 (m. 7H, ArH, PhH).

13 7.55-7.68 (m. 5HT ArH.PW, 8.02 (bs, 1H. NH),9.42 (S. lH, CH=O). C NMR: 87.6,

19.1, 23.7 (-), 25.3 (-), 26.7. 26.9 (-), 30.7 (-), 35.0 (-), 39.7 (-), 50.3. 59.7 (-). llL.3,

112.9. L 15.6, 118.7. 119.5. 123.1, 122.3. 127.8. 129.8, 133.4, 135.6, 136.4. 172.2. 105.7.

HRMS Calcd for CjsH.&J2O3Si : 568.3121. Found: 568.3121. 254c ;Mixture of two

diastereomen (1 : 1 ) based on integration at 6 0.63 & 0.68 (t. 3H. J = 7.4 Hz, Me).

-1 1 [a l% +13.9 (c 0.9, CHC13) IR u,, (film): 3420. 3300. 3050, 1625 cm . H mlR: 6

0.63 & 0.68 (t, 3H. J = 7.4 Hz, Me), 1.05 & 1 .O8 (s, 9H, Me3C), 1.16-2.07 (m. 6H.

CHMe. 1 x CHZ), 2.18-2.50 (m, 2H, CH$=O), 2.76 (d, OSH, J = 5.7 Hz, OH), 3.00- -m

3.20 (m. 2H, CH2h) , 3.46-3.73 (m, 3H. CH2N, CHOSi), 3,77409 (m, lH, CHOSI),

4.36 (d, O.SH, J = 3 . 4 Hz, OH), 4.56 (d, 0.5H, J = 5.7 Hz, OCHO), 4.71 (d, 0.5H. J = 2.9

Hz, OCHO), 6.98-7.33 ( m, 3H. ArH), 7.30-7.55 (m, 7H, ArH, PhH), 7.60-7.78 (m, 5H,

ArH. PhH), 7.95 & 8.02 (bs. 1H. NH). KRMS Cdcd for C3&N203Si : 568.3121.

Found: 568.3 1 L 8.

- 1 255. IR u,, (film): 3420. 3074, 1727. 1660 cm . 'H NMR: 6 0.78 (t, 3H. , Me), 1 .O3

(S. 9H. Me3C), 1.5-1.09 (m, 6H. CH,Me, 2 x CH?). 2.63 (t, 1H, J = 6.9 Hz. CH2C=O).

2-91 (t, 2H. J = 8.0 Hz. CH2Ar), 3.53-3.77 (m, 1H, CHIN), 4.02 (t, 3H. CH20Si), 7.00 (

d, lH, J = 3.0 Hz, ArH), 7.09-7.27 (rn, ?H, ArH), 7.23-7.32 (m, lH, ArH), 7.33-7.50 (m.

CH, PhH), 7.53-7.78 (m, 5H, ArH, PhH), 7.83 (bs, iH, NH).

(lS, 12bR)- 1-Ethyl- 1-(2-t-butyldiphenylsi lyloxyethy 1,2,3,+6,7,12,12b-

octahydro-indole [2,3-a] quinolizine 256B and (lS,12bS)-1-Ethyl-1-(2-t-

butyldiphenylsilyI0xyethy~)-4-oxo-1~J,4,6,7,12,12b-0~tahydr0-ind01e 1293-a]

quinolizine 256u Aldehyde 253c (0.073 g, 0.13 mmol) was dissolved in dry CH2C12 (10

mL) at 4 2 OC and trifluoroacetic acid (0.065 mL, 0.78 mmol) was added dropwise. The

mixture was Stirred at -42 'C and then allowed to warm slowly to n for 16 h. The

reaction was quenched with saturated NaHC03 and extracted with CH2C12 (2 x 10 mL).

The organic layer was dned and conceninted. Chromatognphic purification (1 : 1 PE :

EtOAc) gave 256 (0.068 g, 95 % yield) as a mixture of two diastereomers in a ratio 2560

: 256a 3 : 1. Amide 2S@: [alBD +85 (c 0.5, CHC13) IR u,, (film): 3347, 3052, 1644

- 1 I cm . H NMR: 6 0.68 (t, 3H, J = 7.4 Hz, Me), 0.8-1.11 (m. IH. CHMe), 1.02 (s, 9H.

Me3C), 1.38- 1.60 (m, 2H, m e , H-2), 1.65- 1.86 (m. 2H, H-2, BCH2O), 2.36-2.50 (m,

3H, CH?-3. CHCH-O), 2.65-2.90 (m, 3H, CH2Ar, H-6), 4.0 1 (bt, 2H, J = 4.0 Hz, CH20),

5.1 1-5.23 (m. 2H, H-6, H- 12b), 7.06-7.22 ( m, SH, ArH), 7.37-7.58 (m, 8H, ArH. PhH),

for C3s&2N202Si : 550.3016. Found: 550.3018. 256a : -50 (c 0.1. CHC13) iR

- 1 1 u,, (film): 3487, 3052, 1632 cm . H NMR: 6 0.98 (S. 9H, Me3C), 1-12 (t. 3H. J = 7.4

Hz, Me). 1.70- 1.37 (m. 1H. mCH2O,), 1.66-1.98 (m. SH, CHzMe. CH2-2, CkJCH20),

2.43-2.55 (m, 2H, CH2-3,), 2.63-2.83 (m, 3H, CH2&, H-6), 3.59 (t, ZH. J = 6.9 Hz,

CHIO), 4.76 (S. 1 H, H- 12b), 5.10-5.22 (m. 1 H, H-6), 7.09-7.23 ( m, 2H, ArH), 7.247.46

13 (m, 8H, ArH, PhH), 7.48-7.58 (m, 4H, PhH), 7.87 (bs, lH, NH). C NMR: 6 8.3, 19.0.

Under the reaction conditions, compound 254e (0.13 g, 0.23 mmol) was treated under

sarne reaction conditions to give 256 (0.13g, 100 % yield) as a mixture of two

diastereorners in a ratio 256b : 256a 3 : 1.

(1s. 12bS)- l-Ethyl-l-(2-hydro~ethyl)4oxo-l,4,6,7,12,12b-hydro-indole [2,3-

a] quinolizine 257a. Compound 256a (0.020 g, 0.036 mmol) was dissolved in MeOH (1

mL), cooled to O O C followed by dropwise addition of trimethylsilyl chloride (0.016 g,

0.14 mmol). The mixture was stirred at O O C for 1 h then rt for 2 h. MeOH was

evaponted, the residue was treated with N;IHC03 and the mixture was extricted with

CH2C12 (2 x 10 mL). The combined organic layer were washed with brine. dried, filiered

and concentrated. Chromütographic purification (8 : 1 and 4 : 1 CH2C12 : acetone) gave

pure 257u (10.8 mg, 96 % yield). m.p. 285-286 "C (decompose). [ulL4~ -191.3 (c 0.13.

- 1 1 MeOH). iR um, (KBr): 3272. 3054, 16W cm . H NMR (DMSO-4): 1.07 (t. 3H. J =

7.4 Hz, Me). 1 .M- 1.64 (m. 1H, =e, H-2), 1.65-2.12 (m. 3H, W e , H-2, Cl-JCH20).

2.30-2.43 (m, 2H, CH2-3,), 1.49-2.90 (m, 3H, CH2Ar, s H 2 0 ), 3.11-3.50 (m. 3H,

CH20, H-6), 1.18 (t, lH, J = 5.2 Hz, OH), 4.83 (S. LW, H-12b), 1.86-5.02 (m. 1H. H-6),

6.91-7.12 ( m, 1H, ArH), 7.34-7.51 (m. 3H, AH) . 10.23 (bs, IH, NH).

(ISJ2bR)- 1-Ethyl- 1-(2-hydroxyethy1)-4-0x0-1,2,3,4,6,7,12,12 b-octahydro-indole

[2,3-a] quinolizine 2578 Compound 2568 (0.050 g, 0.091 mrnol) was dissolved in

BF3'0Et2 (1.3 rnL) and heated at 3540 O C for 10 h. The mixture was cooled to O "C and

NaHCO, (5 mL) was added. The organic layer was separated and the aqueous layer was

re-extmcted with CH2Clt (2 x 20 mL). The combined organic layen were dned, filtered

and concentrated. Chromatographie purification (8 : 1 and 4 : 1 CHtC12 : acetone) gave

pure 257p 0.02 1 g and 257a 0.005 g. 257B m.p. 1 10- 1 13 O C . [Lit. 46b m.p. 106- 108 O C ] .

+111 (c 0.54. MeOH). Lit. +98.7 (c 0.2, MeOH). R II,, (film): 3337, 3052.

- 1 I 1630 cm . H NMR: 60.70 (t, 3H. J = 7.8 Hz, Me), 0.8-1.03 (m. IH, CHMe), 1.37-1.65

(m, 2H, m e , H-2), 1.70-2.10 (m. 2H, H-2, W H O ) , 2.1 1-2.33 (m, 1 H, mCH2O),

2.42-258 (m, 2H, CH2-3). 2.59-2.80 (m, 3H, CHIAr, H-6)- 3.12 (S. 1 H, OH), 3.95-4.19

(m, 2H. CH70), 5.03-5.23 (m, 2H, H-6, H- 12b). 7.03-7.22 ( m. 2H, ArH), 7.36 (d, lH, J

13 = 7.2 Hz, ArH), 7.48 (d, lH, J = 7.3 Hz. ArH), 9.74 (S. 1H. NH). C NMR: 6 7.1. 21.2 (-

5.15 hpproach to Total Synthesis of (-)-Mesembrine

5.15.1 The Preparation of Chiral Alcohol (R)-(0)- 95b

5.15.1.1 The Preparation of Allyl Hdides 31 1 a-b

5.15.1.1.1 The Preparation of AUyl Aalides 311a

(Z)4.Benzoyl-l-iodo-2-butene 3110-1. Ph3P (5.0 g, 19 mmol) was dissolved in toluene

(40 rnL) and Iz (4.8 g, 19 mmol) was added slowly at O OC. The resulting mixture was

stirred at n for 13 h. then cooled to O OC and a solution of alcohol310a (3.3 g. 17 mmol)

and pyridine (2.1 mL. 32 rnrnol) in toluene (40 mL) was added dropwise. The mixture

was stirred for 2 h at O O C and at n for 2 h. The mixture was filtered and concentrated.

Petroleum ether (200 rnL) was added to the residue, the mixture wsis stirred for 10 min

and then filtered. The filtrate was evaporated and the residue was purified by column

chromatograph (20 : 1 PE : Et20) to give 3lla-1 (3.8 g, 54 % yield). IR u,, (film):

- 1 f 3062. 1720 cm . H NMR: 8 4.0 (d, 2H. J = 6.0 Hz. CH21). 4.93 (d. IH, J = 7.2 Hz.

CHIO), 5.62-5.79 (m, 1 H. CH=), 5.95-6.19 (m. LH, CH=), 7.38-7.67 (m. 3H, ArH), 8.W

(d, 2H, J = 7.8 Hz, ArH).

(Z)-4-Benzoyl-l-brom0-2-butene 3lla-Br. Method A ~ ' : Dirnethyl sulfide (0.16 mL. 3.6

mrnol) was added dropwise to the mixture of NBS (0.54 g. 3 mrnol) in CH2CI2 (10 mL) at

O OC. The mixture was cooled to -10 O C and alcohol310a (0.38 g, 2 mmol) in CH2C12 (10

mL) was added dropwise. The resulting mixture was w m e d to O O C and stirred for 3 h.

It was then diluted with hexane (100 mL) and the mixture was poured into 15 rnL of ice-

water mixture. The organic layer was washed with coid brine. dried, filtered and

concenmted. Column chromatographic sepantion ( 10 : 1 PE : Et?O) gave bromide 31 1a-

- 1 1 Br (0.28 g, 55 7% yield). IR u,, (film): 3062,3035, 1720. 1601. 1584 cm . H NMR: 6

4.11 (d, ZH, J = 8.9 Hz, CH2Br), 4.95 (d, ZH. J = 6.6 Hz, CH20), 5.75-6.10 (m. ZH,

CH=), 7.39-7.66 (m. 3H, ArH), 8.05 (d. 2H, J = 6.2 Hz, ArH).

Method B~': Alcohol 3lOa (0.38 g, 2.0 m o l ) was dissolved in CHzClz (70 mL) at O OC

and Ph3P (0.79 g. 3.0 mmol) and CBfi (1.0 g, 3.0 rnmol) were added slowly. The

resulting mixture was stirred for 2 h at O OC and then water (10 rnL) and CH2Clr (20 mL)

was added. The aqueous layer was re-extracted with CH2C12 (20 mL). The combined

organic layen were dried. filtered and concentrated. The residue was added Petroleum

ether (50 rnL) and solid was filtered. The filtrate was concentnted and purilied by

column chromatography to afford 311~-Br (0.46 g. 90 % yield).

(Z);I-Benzoyl-1-chloro-2-butene 311a-Cl. Alcohol 310a (0.43 g, 2.5 mmol) was

dissolved in CHzC12 (10 mL) at O OC and pyndine (0.6 mL. 10 mmol) was added followed

by DMAP (0.06 g, 0.5 mmol). Then TsCl (0.63 g, 6.8 mmol) was added and the mixture

was stirred at O O C for 12 h. Water (10 mL) and CHICll (20 mL) was added to the

reaction mixture. The aqueous layer was re-extncted with CH2C12 (?O mL). The

combined oganic layen were washed with satunted CuSOa (15 rnL). water, dned.

filtered and concentrated. Column chromatographie sepantion (20 : 1 PE : EtrO) gave

1 chloride 3lla-Cl (O. 18 g, 34 % yield). H NMR: 6 4.22 (d, 2H, J = 6.0 Hz. CHICI), 5.91

(d, 2H. J = 4.8 Hz, CHP) , 5.68-6.09 (m. 2H. CH=), 7.17-7.62 (m. 3H, ArH), 7.76-8.15

(m, ZH, ArH).

5.15.1.1.2 The Preparation of Allyl Haiides 3 l l b

(2)-4-Acetoxy- 1-bromo-2- butene 31 1 b-Br. Alcohol31Ob (0.4 g, 3.1 mmol) was treated

with Ph3P and CBo according CO the procedure described for 3lla-Br to give bromide

- 1 1 3llb-Br (0.23 g, 38 % yeld). IR u,, (film): 3030. 1741 cm . H NMR: 6 2.10 (S. 3H.

Me). 4.02 (d. 2H. J = 8.6 Hz. CA2Br), 4.70 (d, 1H. J = 6.9 Hz. CH?O), 5.63-5.77 (m. 1H.

CH=), 5.85-6.03 (m, 1H. CH=).

1 (E)QAcetoxy-1-bromo-2-butene 3llb-Br H NMR: 6 2.10 (s, 3H. Me), 3.97 (d. 2H. /

= 6.0 Hz. CH2Br). 4.60 (d. 2H. J = 5.0 Hz. CH20), 5.70 -6.09 (m. 2H. CH=).

(2)-4-Acetoxy- 1-chloro-2-butene 31 1b-CI Alcohol3lOb ( 1.86 g. 14 mmol) was treated

with TsCl according to the procedure described for 31la-CI to give 3llb-CI (0.99 g, 47

1 % yield). H NMR: 6 1.10 (S. 3H. Me). 4.13 (d. 2H. J = 6.2 Hz. CH2Br). 4.68 (d. 1H. J =

6.2 Hz, CH20), 5.68 -5.94 (m, 2H. CH=).

(E)-l-Acetoxy-1-iodo-2-butene 311b-1. Chloride 3llb-Cl (0.99 g, 6.7 mmol) was

dissolved in acetone (80 mL) followed by addition of sodium iodide (10 g, 67 mmol). The

mixture was then heated at reflux for 12 h. Acetone was evaporated and water (10 mL)

was added and the mixture was extncted with E t 0 (2 x 30 mL). The combined organic

layers were washed with waier, Na2Sr03, brine, dried, filtered and concentmted. Column

chromatopphic sepadon ( 10 : I PE : EtzO) gave iodide 311b-1 ( 1.0 g, 64 % yield). IR

- t 1

u,, (film): 3014. 1739 cm . H NMR: 6 2.09 (S. 3H, Me), 3.89 (d, 2H. J = 7.7 Hz.

CHzI). 4.56 (d, 2H, J = 5.8 Hz. CHrO). 5.70 -5.89 (m, 1 H, CH=). 5.92-6.12 (m. IH,

CH=).

5.15.1.2 The Formation of Imide 308

( 4 R , S S ) - 3 - ( 3 , 4 - D i m e t h o x y p h e n y l ) a c e t y l ~ 307. Acid

306 (5.0 g, 26 mmol) was dissolved in THF-EtrO (180 mL, 1: 1) followed by addition of

Et3N (3.8 rnL, 28 mmol). The mixture was cooled to O OC and pivaloyl chlonde (3.3 mL.

26 mmol) was added dropwise and stirred at n for 30 min. The mixture was filtered under

Ar to give the crude mixed anhydride which was used without any funher purification.

Oxazolidinone (5.1 g, 28 mmol) and few crystals of bipyridine were dissolved in THF (40

rnL) then cooled ro -78 OC. n-BuLi was added dropwise until the mixture turned to brick-

red. After 30 min at -78 O C , the rnixed anhydride prepared above, was added dropwise

via cannula. After 30 min, the reaction was quenched by addition of aqueous NI&Cl

solution (10 mL). The reaction mixture was diluted with water (30 mL) and EtOAc (LOO

CL). The organic phase was separated and the aqueous layer was re-extncted with

EtOAc (2 x 100 mL). The combined organic layen were washed with 5 % aqueous

NaHC03, bnne. dried. filtered and concentrated. Chrornatographic separation (4 : 1 PE :

EtOAc) gave pure imide 307 (7.3 g, 80 96 yield). m.p. 94-96 OC. +11.6 (c 3.6.

-1 I CHCI$. IR um, (film): 1780. 170 1 cm . H NMR: 6 0.89 (d, 3H. J = 6.2 Hz. C m .

3.87 (s, 3H, OMe), 3.88 (s, 3H. OMe), 4.15 (S. 2H, CH2C=O), 4.76 (quint, 1H. J = 7.0

K. C m , 5.66 (d. lHT J = 7.3 Hz. CHO). 6.79-6.93 (m, 3H, ArH), 7.24-7.33 (m, 2H,

13 PW,7.35-7.47(m,3H.PhH). CNMR:S 14.4, 41.1 (-),55.0,55.8,78.9, 111.1, 112.8.

121.8. 125.6, 125.9, 128.7, 128.8, 133.1, 148.2, 148.8, 153.0, 171.1. Anal. Calcd for

C2,H,,N0, - : C. 67.59: H. 5.96; N. 3.94. Found: C, 67.37; H, 5.83; N, 4.01.

(4R,5S)-3-[(2R)-(4Z)-2-(3,1-Dimet hoxy p heny1)-6-benzox y - 1-0x0-4- hexen y l-1-4-

methyl-5-phenyl-2-oxazolidinone 312a NaN(SiMe& ( 12 mL. 12 mmol. 1 M in THF)

was added dropwise to a solution of 307 (2.8 g, 7.8 mmol) in THF (150 mL) at -78 OC.

After stirred for 30 min. the iodide 3lla-1 (4.7 g, 16 mmol) was added slowly. After

stimng for another 5 h at -78 OC. the reaction was quenched by aqueous NKCl (10 rnL)

The reaction mixture was diluted with water (30 rnL) and EtOAc (100 mL). The two

layers were separateci and the aqueous hyer was re-extracted with EtOAc (2 x 100 mL).

The combined organic layen were washed with 5 % aqueous NaHC03, brine. dried,

filtered and concentnted. Chrornat~~nphic purification (4 : 1 PE : EtOAc) gave pure

3l2a (3.8 g, 91 '7c yield). [ u ) ' ~ ~ -18.1 (c 2.0, CHC13) IR u,, (film): 3064, 1770. 1696

- 1 I cm . H NMR: 6 0.92 (d. 3H. J = 6.0 Hz. CHMM. 2.59-3.78 (m. lH, CHC=), 2.89-3.10

(m, 1H. CHC=). 3.88 (s, 3H. OMe). 3.89 (S. 3H, OMe), 4.69 (quint, 1H. 3 = 6.0 Hz.

Cm), 4.84 (d, 2H. J = 4.8 Hz, CH20). 5.12 (t, 1 H. J = 6.0 Hz. CHGO). 5.52 (d, 1 H. J =

7.3 Hz, CHO), 5.58-5.79 (m, 2H, CH=), 6.78-7.0 (m, 3H. ArH), 7.13-7.60 (m. 8H, PhH),

13 8.04 (d, 2H, Jz7 .2 HZ, PhH). C NMR: 6 14.5. 31.1 (-),47.8,55.3,55.8,60.7 (-), 78.6,

methyl-5-phenyi-2-oxazolidinone 312b The iodide 3 l l b-1 ( 1 .O g. 4.3 rnmol) was

treated with 3û7. according to the procedure described for 312a, to give 312b (0.82 g, 82

- 1 1 % yield). IR u,, (film): 1779, 1734. 1696 cm . H NMR: 6 0.94 (d. 3H. J = 6.9 Hz.

CH>), 2.0.1 (s, 3H. Mec-O), 2.50-2.68 (m, lH, CHC=), 2.8 1-3.03 (m. 1H. CHC=),

3.86 (S. 3H. OMe), 3.90 (s, 3H. OMe). 4.59 (d. 2H. 1 = 5.5 k, CH20), 4.68 (m. 1 ~ ,

CHN.). 5.07 (t. 1H. J = 7.1 Hz. CHC=O), 5.48-5.72 (m. 3H, CHO, 2 x CH=). 6.78-7.0

13 (rn.3H. ArH).7.29-7.48(m. 5H. PhH). C NMR: 6 14.5. 20.9.32.1 (-),47.6. 55.3.55.8.

(4R95S)-3-[(ZR)-2-(3,;I-Dimet hoxypheny1)- 1-0x0-5-hexen- 1-YI]-4-methyl-5-phenyl-2-

oxazolidinone 308. Bu3P (0.19 mL, 0.78 mmol) w s added to the mixture of Pd(OAc)?

(0.080 g, 0.38 mmol) in THF (JO mL) at n. The solution of Et3N (5.3 mL. 38 mmol) and

HCOOH (1.5 mL. 38 mmol) in THF (40 m . ) was added followed by addition of 312a

(4.1 g, 7.8 mrnol) in THF (10 rnL). The resulting mixture was heated at reflux for 2 h,

cooled to rt and then water ( JO mL) and EtzO (100 mL) were added. The aqueous layer

was re-extracted with Et20 (2 x 50 mL). The combined organic layers were washed with

brine. dried. filtered and evaponted. The residue was purified by column chromatopphy

(4 : 1 PE : EtOAc) to give 308 (1.9 g. 93 % yeld). [allaD -32.5 (c 1.4, CHC13) IR u,,

- 1 1 (film): 3074, 1780, 1697 cm - H NMR: 6 0.94 (d. 3H, / = 6.3 Hz, CHMA, 1.79-2.31 (m,

4H. -.C=), 3.88 (S. 3H. OMe), 3.89 (s, 3H, OMe). 4.68 (quint. IH. J = 6.9 Hz.

Cm). 4.91-5.12 (m, 3H, CH2=. CHC=û), 5.51 (d, LH, J = 6.1 Hz. CHO), 5.60-5.92 (m,

13 IH, CH=), 6.79-7.0 (m. 3H. ArH), 7.71-7.47 (m. 5H. P W . C NMR: 6 14.5, 31.5 (-),

5.15.1.3 The Formation of the Chiral Alcohol IR)-(0)- 95b

(ZR)-2-(3,1-Dirnethoxyphenyl)-J-hexen-1-01 95b A solution of imide 3û8 ( 1.3 g. 3.1

mmol) in T W (30 mL) was added dropwise to a suspension of LAH (0.36 p. 9.5 mmol)

in THF (50 mL) at -20 O C . After 2.5 h at -20 OC, the reaction was quenched by addition

of water (0.5 mL), 10 % NaOH (30 mL) and EtzO (80 mL). The aquious layer was re-

exuacted with EtzO (2 x 50 mL). The combined ethereal layes were washed with N&CI

(20 mL), bine. dried, filtered and concentnted. The residue was purified by column

chromatography (1 : 1 PE : EtOAc) to give alcohol 95b (0.63 g, 85 % yield). IR u,,

- 1 I

(neat): 3492 cm . H NMR: 6 1.3 1 (bs, 1H OH). 1.56 -2.10 (m. 1H, CH,CH2C=), 2.69-

3.87 (m. 1H. CHAr), 3.60-3.83 (m, 2H, CH20), 3.88 (s, 6H, 2 x OMe), 4.90-5.05 (m. 3H.

13 CH,=), 5.77-5.90 (m, lH, CH=) 6.68-6.88 (m, 3H. ArH). C NMR: 6 3 1.3(-), 3 LA(-),

(c 2.7, CHC13) and recovered oxazolidinone (0.39 g. 70 96 yield).

19 Mosher ester 313. F NMR (CFC13): 6 -71.99 (1 .O), 72-14 (10.5).

5.15.2 The Formation of y Lactone (-)-314

Methyl (ZR)-2-(3,4-DimethoxyphenyI)-5-hexen-I-yl malonate (96b): Prepared

according to the procedure described in Section 5.1.( 83 %), ( 4: 1 and 3: 1 PU EtOAc)

- 1 1 colorless liquid: [a}'"~, -6.9 (c 3.3, CHC13) IR u,, (neût): 3075, 1736, 1640 cm . H

NMR: 6 1.50-2.10 (m. 4H. CHCHC=), 2.85-3.00 (m. 1H. CHAr), 3.35 (s, 2H,

CH2C=O), 3.70 (s, 3H, OMe), 3.87 (s, 3H, OMe), 3.88 (s, 3H, OMe), 4.26 (d, IH, J = 6.5

Hz, CHIO), 4.90-5.00 (m, 2H, CH-), 5.70-5.90 (m, LH, CH=) 6.65-6.90 (m, 3H, ArH).

13 C NMR: 6 3 1.1(-). 31.4(-), 41.3(-), 43.7, 52.4, 55.8, 69.4,(-), I l 1.0. 11 1.2, 115.0(-),

119.8. 133.6, 138.1, 147.8. 148.9 166.4, 166.8. HRMS Calcd for C,,H,,O, : 336.1573;

Found : 336.1574.

Methyl (ZR)-2-(3,4-Dimethoxyphenyl)-5-hexen-I-yl diazopropandioate

(97b): Prepared according to the procedure described in Section 5.1. (83 %). ( 4: 1 and 3: 1

PUEtOAc ) colorless liquid: -12.9 (C 1.4, CHClj) IR u,, (neat): 1137. 1759.

- 1 I 1736, 1692 cm . H NMR: 6 1.50-2.00 (m. 4H, CHXH2C=), 2.82-3.00 (m. 1H. CHAr),

3.80 (s, 3H, OMe), 3.84 (s, 3H, OMe), 3.86 (s, 3H, OMe), 4.30 (d. 2H, J = 6.8 HZ,

13 CHtO), 4.87-5.00 (m, 2H, CH-), 5.63-5.85 (m, lH, CH=) 6.67-6.83 (m, 3H, ArH). C

147.8, 118.9 160.7. 161.1. And. Calcd for C,,H,,N,O, - - : C, 59.66; H, 6.12; N, 7.73.

Found: C, 59.58; H, 6.24; N, 7.73.

Met hy 1 (4S)-Tetrahydro-4-(3,4-dimethoxyphenyl)~n-l-yl)-2-oxo-3-

hrancarboxylate (99b): Prepared according to the procedure described in section 5.11

-1 1 for recimic 99b. Yield 38 % Colorless liquid: IR umax (neat): 1783. 1735 cm . H

NMR: 6 1.70-2.20 (m. 4H. BI2C=), 3.40-3.90 (m, 1OH. OMe x 3, CHC=O), 4.50-

5.05 (m. 4H. CH2=, CHzO). 5.50-5.70 (m. 1 H. CH=), 6.48-6.60 (m. IH, ArH), 6.73-6.85

(m. ZH. ArH). HRMS Calcd for C,,H,,O, -- (M+) 334.14 16: Found: 334.1427.

(4s)-4-(3,4-Dimethoxypheny1)-4-(3- buten- 1-YI)-y-lactone 3 14: Prepared

according to the procedure described in section 5.1 1 for recimic 311. yield 84 %.

- t 1 Colorless liquid: [ajBD -0.96 (c 2.6. CHC13) IR u,, (near): 1790 cm . H NMR: S

1.73-1.90 (rn, JH. CHKHC=), 2.73 and 2.87 (d, 2H. J = 16.9 Hz. CH2C=O), 3.85 (S.

6H. 2 x OMe ). 4.39 and 4.48 (d, 2H, J = 9.4 Hz, CH@), 4.80-5.00 (m. 2H. CH2=), 5.50-

5.65 (m. IH, CH=). 6.50-6.85 (m, 3H, ArH). ' 3 ~ ~ ~ ~ : 6 28.7 (-), 39.4 (-), 39.9 (-). 43.7

(-). 47.4, 55.8, 55.9. 109.1, 11 1.1. 115.1 (-), 118.0, 134.8, 137.2. 148.0. 149.1. 176.0.

H R M S Caicd for C,,HZoO, (M? 276.1362, Found 276.1358.

5.153 The Reparation of Pivotal Intermediate 316

N-ben y l (3S)-3-(3,4-Dimetho~yphenyl).+hydroxymethy h e p t e n a d e 315. To a

solution of benzylarnine (0.32 mL. 2.8 mmol) in CH2Clr (25 mL) was added Et2AICI (2.8

mL, 2.8 rnmol, 1 M in hexane) at n. The mixture was stirred for 30 min then cooled to O

O C . y-Lactone 314 (0.16 g, 0.60 mmol) was added dropwise as a solution in CHICI? and

the mixture was stirred at n for 12 h, Water (10 mL) was added and the mixture was

extracted with Et10 (2 x 10 mL). The cornbined organic layers were washed with 1 M

HCI. NaHC03, brine. dned. filtered and concentrated to give a oil which was purified by

colurnn chrornatography (1 : 1 PE : Ei2Ac) to give amide 315 (0.18 g. yield 83 %). [a)"'~

- 1 1 -7.6 (c 1.6, CHCI3) il3 u,, (neat): 3319, 3018, 1640 cm . H W: 6 1.62-1.95 (m.

4H. CHICH@), 1.62 and 2.73 (d. 2H. J = 13.7 Hz, CH?C=O), 3.83 (s, 3H, OMe ), 3.84

(s, 3H. OMe). 3.854.13 (m. 2H, CH2Ph), 4204.49 (m, 2H, CH20), 4.82-5.00 (m, 2H,

CHI=), 5.60-5.82 (m. 1 H, CH=), 5.99 (bs, NH), 6.70-6.90 (m, 3H, ArH), 7.00-7.13 (m,

2H, PhH), 7.19-7.35 (m. 3H, PhH). ' 3 ~ ~ ~ ~ : 6 28.1 (-), 37. L (-), 43.6 (-). 45.6. 45.7 (-).

55.7, 55.9, 67.6 (-), 109.9. 111.1, 114.4 (-), 118.6. i17.5, 127.6, 128.6, 135.9, L37.7,

138.1. 147.5. 148.9. 171.7. HRMS Calcd for C2,H2,N0, (M+) 383.2097. Found.

383 -30%.

N-Benzyl (4S)-4-(3-buten-l-yl)-J-(3,4-dimethoxyphenyl)5-hydroxy-y-lacm 316. A

solution of compound 315 (0.15 g, 0.42 m o l ) in DMSO ( 1.1 rnL) containing Et3N (1. 1

mL, 7.6 mmol) was treated with a solution of P y S 0 3 (0.44 g. 2.7 mmol) in DMSO (2.2

mL) at n. The mixture was s h e d at rt for 12 h. Aqueous 1M NaOH (1 mL) was added

and the mixture was stirred for 10 min then extncted with EtOAc (2 xIO mL). The

combined ongnic layen were washed with brine (5 a), dried, filtered and concenmted

to give hydroxyamide 316 as a mixture of two diastereomers. Chromatognpgy sepantion

(1 : 1 and 2 : 1 EtOAc : PE) provided compound 314a @-OH) (O. 11 g, 71 % yield) and

316b (0.032 g. 21 % yield). 316a m.p. 94-96 OC. [a}"D -3.0 (c 2.5, CHC13). iR u,,

- 1 1 (film): 3336, 3066, 3006. 1666 cm . H NMR: 6 1.65-2.15 (m, jH, CHKH?C=. OH),

2.73 and 2.92 (d, 2H, J = 16.5 Hz, CHg=O), 3.76 (s, 3H, OMe ), 3.88 (s, 3H, OMe ),

4.10 (d, 1 H, J = 15 Hz, CHPh). 1.73-5.07 (m. 4H, CHPh, CH2=, CHO), 5.6 1-5.83 (m, 1 H,

CH=), 6.62-6.85 (m, 3H, AM), 6.85-6.98 (m, 2H, PhH), 7.02-7.22 (m, 3H, PhH).

13 CNMR: 6 29.0 (-), 34.8 (-), 39.8 -. 13.1 (-), 19.0. 55.9, 89.8, 109.9. 110.9, 111.7 (-),

118.6, 127.4, 127.8, 128.0, 128.4, 135.4, 136.0, 138.2, 147.9, 149.0, 174.0. HRMS Calcd

for C,,H,NO, (M? 38 1.lgJl. Found. 38 1.1937.Compound 316b (0.031 g, 21 %

yield). m.p. 130- 132 OC. +34.6 (c 1.6. CHCI3). IR u,, (film): 3340, 30 12. 1674

- 1 1 cm . H NMR: 6 L .J6- L .92 (m. JH, &bCH2C=), 2.39 (d, 1 H, 3 = 6.1 Hz. OH). 2.60 and

3.01 (d, 2H, J = 16.0 Hz, CHzC=O), 3.83 (s, 6H, OMe ), 1.12 (d, lH, J = 14.7 Hz,

CHPh), 4.73-5.05 (m, 4H, CHPh, CH2=, CHO), 5.45-5.70 (rn, IH, CH=), 6.53-6.90 (m.

3H. ArH), 7.22-7.43 (m. 5K PhH). ' 3 ~ ~ ~ ~ : 6 28.6 (-), 38.3 (-), 38.7 (-). 44.0 (-). 49.8,

55.8, 56.0, 88.7. 110.7, 11 1.1, 114.8 (-), 119.9, 127.7, 128.5, 128.7, 130.0, 132.0, 136.5,

137.5, 148.1, 149.1, 173.6.

- 1 1 (film): 1774, 1704 cm . H NMR: 8 1.75-2.10 (m. 4H. CHCH?C=), 2.93 and 3.13 (d,

2H, J = 19.2 Hz, CH$C=O), 3.8 I (s, 3H, OMe ), 3.89 (s, 3H, OMe ). 4.71 (s, 2H, CH2Ph),

4.88-5.02 (m, 2H, CH-), 5.60-5.82 (m, lH, CH=). 6.78-6.95 (m, 3H, ArW), 7.21-7.42

5.15.4 The Cyclization of 316 and Subsequent Reaction

(3aS,7aS)- 1-Benzyl-3a-(3,J-dimethoxyp heny I)-octahydro-6-(p henylcarbony1)oxy-

indole 319. Hydroxy amide 316 (0.16 g, 0.42 mmol) was dissolved in HCOOH (13 mL)

and stirred at n for 60 h. Then HCOOH was evaporated and the residue was dissolved in

CHCI3 (10 mL) and washed with saturated NûHCOj (5 d). The organic layer was dned,

filtered and concenrated to give a solid (0.17 3). After column chromatographic

sepantion (1: 1 and 7: 1 EtOAc : PE), compound 318 was obtained as a mixture of two

diastereomen and the ratio is 1 : 4 based on inteption at 7.99 and 8.00 (S. lH, C(0)H).

- 1 1 iR v,, (film): 1719, 1679cm . HNMR:6 1.65-2.40 (m, 6H. 3 x u ) , 2.64 and2.71

(d. 2H, J = Hz. CHIC=O), 3.78, 3.83 and 3.87 (s, 6H. OMe ), 3.70-4.3 1 (m, 2H. CHO.

CHPh), 4.73-5.3 L (m, 2H, CHPh, Cm), 6.60-6.90 (m, 3H. ArH), 6.93-7.08 (m. LH,

PhH), 7.14-7.40 (m. 4H. PhH), 7.99 and 8.00 (S. lH, C(0)H). The cornpounds are slightly

unstable and were used without funher purification. The diastereomenc mixture was

dissolved in THF (25 mL) and LAH (O. 12 g, 3.0 mmol) was added. The mixture was then

heated at reflux for 24 h and then cooled to O OC. Water (0.5 mL) was added and the

mixture was stirred for 30 min. The inorganic solids were filtered off and the residue was

washed with THF (3 xlO mL). The cornbined filtrates were dried over N&03 and

evaponted to give a liquid (0.17 g). The crude oil was dissolved in CH2C12 (10 mL)

containing pyridine (0.4 rnL) and cooled to O OC. Benzoyl chloride (0.15 mL) was added

and the mixture was stired at O "C and allowed to warm slowly to r t overnight (13 h).

water (5 rnL) and CH2C12 (5 rnL) were added. The organic layer was washed with water,

saturated CuS04 solution. water. brine, dried, filtered and concentrated. The residue was

purified by column chromatography (6: 1 and 4: 1 PE : EtOAc) to give 319 (0.14 g, 69 %

yield for three steps) as a mixture of two distereomea. Pure sample 319a and 319b can be

- 1 I obtained by second column chromatogaphy. 319a IR u,, (film): 17 11 cm . H NMR:

8 1.66-2.52 (m, 9H. CH-?. 4 x CH?), 2.87-3.06 (m, 1H, CH-2), 3.19 (t, LH. J = 4.5 Hz.

H7a). 3.30 (d, LH, I = 13.2 HZ. CHPh), 3.90 (S. 6H. OMe ). 4.01 (d, 1H. J = 13.2 Hz,

CHPh). 5.05-5.1 1 (m. 1H. CHO). 6.70-7.0 1 (m. 3H. ArH), 7.02-7.30 (m. 5H, PhH). 7.31-

7.66 (m. 3H, PhH). 7.97-8.18 (m. 2H. PhH). ' 3 ~ ~ ~ ~ : 6 27.2 (-), 78.3 (-), 3 1.7 (-), 37.8 (-

). 47.5 50.6 (-). 55.8, 56.0. 57.5 (-). 64.4. 70.4. 110.1, 110.7, 118.2, 126.5. 127.9. 128.2,

128.5, 129.8. 131.0. 132.7. 139.5. 140.5. 147.1. 148.5, 166.8.319b IR um, (film): 1713

- 1 1 cm . H NMR: 6 1.40-2.52 (m. 9H. CH-2.4 x m), 2.99-3.19 (m. 2H. CH-2. H7.), 3.20

(d. LH. J = 11.9 Hz. CHPh). 3.90 and 3.91 (S. 6H. OMe ), 4.31 (d, IH, I = 12.9 Hz,

CHPh), 5.41-5.61 (m. IH. CHO). 6.80-7.02 (m. 3H, ArH), 7.70-7.59 (m. 8H. PhH), 8.00

(d, 2H, J = 7.1 Hz, PhH).

(3aS,7aS)- 1 -E thoxy car bonyl-3a-(3,1-dimethoxyp heny1)-octah yd ro-6-

(phenylcarbonyl) oxy-indole 320 Method A: A solution of compound 319 (0.042 g,

0.086 mmol) in acetone (2 mL) was added Na1 (0.076 g. 0.52 mmol) followed by addition

of ethyl chloroformate (0.032 mL. 0.34 mmol) at O O C . The mixture was heated at reflux

for 12 h. Cooled to O OC and 1 M NaOH (2 mL) was added. The aqueous mixture was

extracted with EtOAc (2 xlO mL). The combined organic layen were washed with brine,

dried, filtered and evaporated. Chromatopphic sepmtion (2 : 1 PE : EtOAc) gave 320 (

0.028 g. 73 % yield) as a mixture of two diastereomea. Pure sample 320a and 320b c m

be obtained by second column chromatography. 320a [c& -15.8 (c 0.95, CHC13). IR

-1 1 u,, (film): 3061. 1737. 1713. 1694crn . HNMR: 6 1.18 and 1.26 (t, 3H. J=7.9 Hz,

Me). 1.60-2.68 (m. 8H. 4 x CH& 3.21 (q. 1H. J = 8.6 Hz. CH-2), 3.49 (t, l u , j = 7.9 m.

Hd. 3.89 (S. 6H. OMe ). 3.974.28 (m. IH. CHfl). 4.361.60 (m, 1H. H-2). 5.07 (bs,

1H. CHO), 6.76-6.98 (rn, 3H, ArH), 7.31-7.69 (m. 3H. PhH). 8.04 (d, 2H. J = 4 Hz. PhH).

- 1 1 -63.4 (c 0.67. CHClî). IR u,, (Film): 3056, 1713, 1713, 1690 cm . H NMR: 6

1.23 (t, 3H, I = 6.9 Hz, Me), 1.80-2.56 (m. 8H. 4 x CH2). 3.20-3.58 (m. 2H. CH-2. Kt,),

3.88 (s, 6H. OMe ), 4.01428 (m, 2H. CH20), 1.404.70 (m. 1H. H-2). 5.33 (bs, lH,

CHO), 6.78-7.01 (m. 3H. ArH). 7.32-7.63 (m, 3H. PhH). 8.02 (d, 2H. J = 7.4 Hz, PhH).

13 CNMR: 6 14.8. 16.3 (-), 29.7 (-), 30.7 (-), 31.8 (4, 43.8 (-), 47.1. 55.9. 58.1, 60.9 (-).

69.8. 109.3. 11 1.0. 117.7. 128.4. 129.5, 130.6. 32.9. 138.5. 147.5, 143.9. 155.1, 165.8.

Method B. Compound 319 (0.031 g, 0.064 -01) was dissolved in MeOH (10 mL) and

palladium hydroxide on carbon (0.014 g, 0.013 mol) was added. The mixture was

hydrogenated (1 atm, bailoon) at n for 15 h. The catalyst was filtered off and MeOH was

evaporated to leave a yellow solid. The solid was dissolved in CHzClt (1 mL) and a

solution of NaHC03 (0.030 g. 0.39 mrnol) in water (0.8 mL) was added followed by

addition of ethyl chloroformate (0.036 rnL, 0.39 mrnol). After refluxing for 2 h, the

mixture was cooled to rt, the organic layer was sepanted and the aqueous phase was re-

extracted with CH2C12 (2 x 5 mL). The combined organic layen were washed with brine.

dried. filtered and concentrated to give 320 ( 0.019 g, 66 % yield) as a mixture of two

diastereomers.

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7. Appendices

Appeadix A: Recent reviews on R h 0 caîaiyzed reactions of diam carbonyl compounds

1. Timons, D. J.; Doyle, M . P., J. Organomet. Chem. 2001,617-618.98.

2. Davies. H. M. L.; Antoulinakis, E. G. J. Organomet. Chem. 2ûû1.617-618.47.

3. Padwa. A.. J- Organomet. Chem. 2001.617-618,3.

4. Cohcot, T. J., froc, - Indian Acad. Sci., Chem. Sci. 2000,112, 197.

5. Davies, H. M. L.; Panaro, S . A. Tetrahedron 2000, 56, 487 1.

6. Doyle, M . P . Ennntiomer 1999, 4 , 621.

7. Lydon, K. M.; McKervey, M. A. Cornpr. Asymmetric Catal. 1-11! 1999. ? 539.

8. Padwa, A; Stmub, C. S.Adv. Cycloaddit. 1999.6. 55.

9. Taber, D. F.; Stiriba, S-E. Chem.--Ezu. J. 1998,4,99û.

10. Doyle, M. P.; Protopopova, M. N. Tetrahedron 1998, 54, 7919.

11. Doyle, M. P. Pure Appl. Chem. 1998,70, 1123.

12. Ene, D. G.; Doyle. M. P. Chim. Oggi 1998, 16, 37.

13. Davies, H. M. L. Ciirr. Org. Chem. 1998, 2. 463.

Appendix B: Recent publications for the total synthesis of mesembrine

LTaber, D. F.; Neuben,T. D.J. Org. Chem. 2001.66, 143.

2. Rigby, J. H.; Dong, W., Org. Lett. 200û. 2, 1673.

3. Iwamatsu. S.; Matsubara. K.; Nagashima, H., I. Org. Chem. 1999,64,9625.

4. Dalko, P. 1.; Brun. V.; Langlois. Y., Tetrahedron en. 1998,39,8979.

5. Ymada, O.; Ogasawan, K., Tetrahedron Lett. 1998,39,7747.

6. Kamikubo. T.; Ogasawan, K., Chem. Commrm. (Cambridge) 1998. 7,783.

7. Cassayre. J.; Quiclet-Sire. B.; Saunier, J.; Zard, S. 2. Tetrahedron 1998, 51, 1029.

Appendix C : Recent publications for the total synthesis of eburnamonine

1. Ghosh. A. K.; Kawahama, R. J. Org. Chem. 2ûûû, 65,5433.

2. Grieco, P. A.; Kaufman, M. D. I. Org. Chem. 1999,64,7586.