MECHANISTIC VIEWS OF INTRAMOLECULAR …bolivianchemistryjournal.org/QUIMICA 2013...

REVISTA BOLIVIANA DE QUÍMICA Vol. 30, No.1, pp. 24-41, Ene./Jun. 2013

Bolivian Journal of Chemistry 30(1) 24-41, Jan./Jun. 2013

Received 21 07 2013 Published 20 09 2013

Downloadable from: Revista Boliviana de Química. Volumen 30 Nº1. Año 2013

http://www.bolivianchemistryjournal.org, http://www.scribd.com/bolivianjournalofchemistry

24

MECHANISTIC VIEWS OF

INTRAMOLECULAR HYDROXYCYCLOPROPANATION OF

ωωωω-VINYL CARBOXYLIC ESTERS

José A . B ravo,* P atricia M ollinedo, J. M auricio P eñarrieta, José L . V ila

Department of Chemistry, Universidad Mayor de San Andrés, P.O. Box 303, La Paz, Bolivia

Keywords: Organic Chemistry, Addition Reactions, Alkenes, Esters, Grignard Reagents, Mechanisms of Reactions,

Natural Products, Organometallics, Kulinkovich, cyclopropanation, Jin Kun Cha.

ABSTRACT

The overwhelming presentation of plenty of synthetic steps in a verbally reduced or succinct form as appearing in any

paper is here focused in an extensive and particularly graphical manner; just to extend the screen when the reader is

boarding a published series of synthesis. The Intramolecular Hydroxycyclopropanation of ω-Vinyl Carboxylic Esters

appeared to us to be a fascinating synthesis thematic and served us as an example to propose didactical and

mechanistic views.

*Corresponding author: [email protected]

ANALYSIS AND MECHANISTIC PROPOSALS

As academics we are highly concerned with the didactical importance of covering the needs of debutant students in

organic synthesis. This article presents an analytical and didactical approach to synthetic works by Jin Kun Cha and

col. by means of reactions’ theoretical mechanisms. We are continuing the previously published: “A Theoretical

Mechanistic Approach to Diasteroselective Synthesis of cis-1,2-dialkenylcyclopropanols and Subsequent Oxy-Cope

Rearrangement ” (1) presenting now another synthesis by Cha and coworkers concerning Grignard reagents in the

presence of transition metals (2). Cha worked with organotitanium compounds to effect cyclopropane-mediated

natural product synthesis. Prof. Cha group became interested in the Kulinkovich hydroxycyclopropanation (3). They

published first the treatment of a carboxylic ester with an excess (3 equiv) of Grignard reagent in the presence of

Ti(Oi-Pr)4 (1 equiv) affording cis-1,2-dialkylcyclopropan-1-ols (4). We already proposed a mechanistic approach (1)

about such article. The second related article by Cha and col. (2) reports an intramolecular version of the

Kulinkovich hydroxycyclopropanation (4) and imposes the treatment of ω-vinyl carboxylates with n-BuMgCl in the

presence of Ti(Oi-Pr)4 or ClTi(Oi-Pr)3. The Kulinkovich hydroxycyclopropanation’s scheme 1 (2) is reproduced

here in Scheme 1 and it can be depicted through the next mechanistic proposal which has already been graphically

and verbally described (1) and it is re-explained here.

H

O

R'

R

XMg

2

(i_PrO)4Ti (R1O)2Ti

R'

R'3

R'CH2CH3

R'CH2CH2MgX2

Grignard

Transition metal

Ti

R'

(i-PrO)2

4

RCO2R"

1

Ti

O

H

Ri_PrO

R'

OR''i_PrO

5

H

O

R'

R

(i_PrO)2Ti

OR'' 6R'CH2CH2MgX2

Carboxylic ester

Scheme 1. Kulinkovich’s Hydroxycyclopropanation virtual loop (2)






25

To depict this Kulinkovich hydroxycyclopropanation scheme we start with our 2 equiv of Grignard reagent or 2

R’CH2CH2MgX or 2 R’CH2CH2-+

MgX. A first interaction occurs between Grignard reagent and the titanium

tetraisopropoxy derivative. Titanium is linked to the four alkoxy substituents. The reaction provokes the expulsion

of two alkoxy residues to leave a Ti 2+(IV)

(OiPr)2 species. The metal di-cationic charge is used by two carbanions

each from 1 equiv of the Grignard reagent, to obtain a dialkoxy-dialkyl titanium derivative 3. (Figure 1).

-OiPr+2R'CH2CH2:

- +Ti

+2(IV)

OiPr

OiPr

OiPrTi

OiPr

OiPrOiPr

+ R'CH2CH2:-

+MgX2 2 Ti

OiPrOiPr

R'R'R'CH2CH2Ti

CH2CH2R'

OiPrOiPr

(iOPr)2Ti

R'

R'

+ iPrO-Mg

+2

3

Figure 1. Obtaining of dialkoxy-dialkyl titanium derivative 3

Titanium receives temporarily an extra electron from an alkyl methylene to afford the Ti-1(IV)

(iPrO)2(CH2CH2R’)

species and the carbonium ion R’CH2CH2+. A reductive nucleophilic attack by the anionic titanium leads to the

apparition of the Ti 3-membered ring intermediate 4 (or a titanocyclopropanoid or titanacyclopropane (2)). (Figure

2).

(iOPr)2Ti:-

R'H

H

H-

+R'

3

(iOPr)2Ti

H

R'+ CH3CH2R'

4

Figure 2. Formation of Titanacyclopropane, 4

The next step in this pathway consists of the condensation of intermediate 4 with a carboxylic ester RCO2R”. The

carbonyl group of this ester drives the reaction by interacting with the Titanacyclopropane in a transition state that

implies a co-planarity of both species. A nucleophilic attack by the nucleophile carbonyl oxygen over titanium

dispatches the two electrons of the bond Ti-CH(R’)(CH2) over that carbon. Hence the Titanacyclopropane splits to

afford a carbanion and a cationic oxygen over the same molecule. A nucleophilic attack over the carbonyl carbon

(with an exacerbated electrophilic character) leads to the formation of a titanium furanoid ring (Figure 3)

4

CH3CH2R'+(iOPr)2Ti

H

R'

R

O

O R''

(iPrO)2TiC:

H

R'R

O+

OR"

- -

(iPrO)2TiC:

H

R'R

O+

O

R"

Ti

H

R'

R

OOR"

iPrO

iPrO

65

Figure 3. Formation of a titanium furanoid ring, 5

An intramolecular nucleophilic attack by the ethereal oxygen of the “α-O-R” substituent group over the electrophilic

titanium dispatches the two electrons of the Ti-CH2- bond on intermediate 5 to afford the corresponding splat species

bearing a carbanion and a cationic oxygen, which in turn recovers neutrality by splitting the four-membered, di-

oxygenated (oxirane-type) ring. The result is the dipolar (a carbanion and carbonium ion) species that neutralizes the

charged extremes into a substituted cyclopropane or intermediate 6 (Figure 4).

5

Ti

R'

H

O

R

OR''

iPrO

iPrO

..Ti

H2C- H

R'

R

O+OR"

iPrO

iPrO

¨

Ti

H2C- H

R'

RC

+

O

iPrO

iPrO

OR"¨

OiPr R'

Ti

H

R'

RO

iPrO

iPrO

OR"

R

O Ti

OR"

OiPrOiPr

H

R'

6

H

O

R'

R

(iPrO)2Ti

OR''

Figure 4. Formation of a substituted cyclopropane 6 from a titanium furanoid ring, 5






26

It is now time for two more equiv of Grignard reagent and for intermediate 6 to interact to afford species 2, closing

thus our looping cycle. This meeting takes place by means of cationic interchange, or the cationic moiety of Grignard

MgX+ that replaces cationic Ti

+(OiPr)2(OR”) through the temporary apparition of an anionic oxygen. The remaining

Ti2+

(OiPr)2 species neutralizes the two anionic moieties liberated by the 2 equiv of Grignard reagent to form two new

equiv of the species 3 to continue the cycle (Figure 5).

R

O-H

R'

+Ti

OR"

OiPrOiPr

+MgX

R'CH2CH2-

+MgX

+

+ R'CH2CH2-

R

OH

R'

MgX+

R'H

O

R

XMg

8R'

R"OMgX2+Ti

OiPrOiPr

R'CH2CH2-

+ 2 +(iOPr)2Ti

R'

R'3

2

Figure 5. Generation of Ti(IV) (iPrO)2(CH2CH2R’) 3, in the virtual cycle

This synthetic pathway (Scheme 1) was largely applied by Cha and coworkers to produce a number of azulene

sesquiterpene derivatives as published by these authors. Cyclisation (Scheme 1) goes on under stoichiometric or

catalytic conditions involving the double alkylation of the tiatanacyclopropane intermediate 4, itself formed by the

reaction of Ti(Oi-Pr)4 or ClTi(Oi-Pr)3 and a Grignard reagent followed by elimination of the corresponding alkane

(R’CH2CH3). The thesis that the putative intermediate 4 or the Titanacyclopropane intermediate could undergo a

reversible exchange with an alkene has been thought. If a carboxylic ester is chained to the alkene moiety, then an

intramolecular hydroxycyclopropanation is feasible. And this is the method currently under discussion. The

numerous results afforded by Cha and coworkers include, structurally, two-fused cycles compounds all of them

showing the cyclopropane feature, characteristic of the Kulinkovich synthesis. The second fused cycle comprises

many models depending on the alkene used to be condensed to the Kulinkovich’s intermediate substrate. The

following mechanisms correspond to entries 1 to 15 in table 1, page 292, (2).

Entry 1.

It regards the first intramolecular hydroxycyclopropanation achieved by the original paper authors. Methyl 5-

hexenoate with 3 or 5 equiv of Grignard’s n-BuMgCl in the presence of 0.5 equiv of ClTi(OiPr)3 afforded the first

intramolecular hydroxycyclopropanation product or cyclopropanol 8 (Scheme 2).

CO2Me

n-4

substrate products

OH

H

n-4

7: n=5 8: n=5

Entry 1

CO2Me

7

α

β

γ

ω

n-BuMgCl (5 equiv)

ClTi(O-iPr)3 (0.5 equiv)

THF or ether

OH

(55%)

8

+

Ti(OiPr)2 + CO2Me

Ti(OiPr)2

δ

Scheme 2. Intramolecular hydroxycyclopropanation: cyclopropanol 8 (2)

To explicitly understand this reaction we must follow the mechanism exposed above as a model; however some

different explanations must be given in order to achieve the reported results (4). This implies a modification of the

section comporting the intermolecular interaction between the Titanacyclopropane derivative 4 and the carboxylic

ester for now we must explain the apparition of the intramolecular process product. Thus, once generated

intermediate 4 as shown mechanistically above what is provoked now contrasting with the intermolecular version is

that before proceeding to a coplanar interaction between the Titanacyclopropane and the carboxylic ester, a splitting

of 4 happens in order to generate the 1-butene residue (Figure 6) .

H

+ ..-(OiPr)2Ti+

Figure 6. Splitting of 4 (Titanacyclopropane) into the 1-butene residue

R O

O R ' ' ( O i P r ) 2 T i

H R ' + C H 3 C H 2 R '

( O i P r ) 2 T i H

Instead ( O i P r ) 2 T i + : H -






27

Titanium liberates one electron splitting so the bonding with its neighboring methylene which in turn receives the

two bonding electrons acquiring an anionic character. Indeed, titanium becomes a cationic nucleus. Neutrality returns

to the Ti nucleus by means of receiving an electron coming from the splitting of its bonding to the protoalkene. The

alkene appears due to the driving force derived from the re-accommodation of the electronic excess over the

carbanion into a π bond. Titanium is now a neutralized nucleus; however there should be an electronic re-

accommodation in different atomic orbitals generating so a dipolar situation giving titanium a nucleophilic character.

This nucleophile will attack the terminal alkene of the ω-vinyl carboxylic ester. This fact collapses finally in the

tricycle titanium derivative, some kind of eptitanium (like epoxy) or a Titanacyclopropane appearing after addition

over the double bond of the ω-vinyl ester (Figure 7).

..-(OiPr)2Ti+

CO2Me

..-CO2Me(OiPr)2Ti

+Ti(OiPr)2

CO2Me O

OH

H

H

..-(OiPr)2Ti+

.

O

OH

(OiPr)2Ti+

HH

.

.-O

O

H

(OiPr)2Ti+

HH

..-

O

O

(OiPr)2Ti+

HH

H

..

(OiPr)2Ti

OMe

O

H180º

Toward Transition State

(OiPr)2Ti

H

OOMe

Figure 7. Apparition of eptitanium after addition of (OiPr)2Ti+:- over the double bond of the ω-vinyl ester

The intramolecular nucleophilic attack by the carbonyl oxygen in the methyl ester moiety occurs to produce a

dipolar transition state. This nucleophilic attack exscinds heterolytically the bond Ti-C(H)(CH2)[(CH2)3CO2Me] and

establishes a new link between oxygen an titanium. Stereochemistry in these mechanisms has a speculative character.

A supraplanar attack over carbonyl electrophilic center (Cδ+

=Oδ−

) itself contained in a parallel plan to that containing

the titanium derivative occurs placing the methoxy group upwards, adopting thus an axial position in the fusion

bridge of the newest fused cycles compound. An isomerization towards a more comfortable conformer occurs

changing all axial into equatorial bonds. The new conformer is particularly benefited by the absence of the previous

through-space Van der Waals radii interaction of the axial methoxy and the axial isopropoxy substituents, all

according to framework molecular models (Figure 8). All these steps conduct to the formation of the fused rings

according to the reported reaction products (2). The polar attraction manifested by oxygen and titanium establishes a

bridge for a much tensed four-side cycle including a highly stressing double oxy function. This tension incites the

carbanion next to the stressed di-oxy ring to attack establishing a less tensed cycle a` trois. This enterprise generates

the stable enough 3/5 fused rings compound, which is analog to intermediate 6 in the Scheme 1 of the present paper.

Ti

H

O+

OMe

iPrO

iPrO

..-

Transition State

Ti

OiPrO

OiPrOMe H

isomerization to

more confortable conformer

ax

eqax ax

eqeq

eq

ax ax+

-

Ti

O

iPrO

OiPr

OMeH

Ti

O

iPrO

OiPr

OMe

H

Ti O

iPrO

OiPr

OMe

Hax

Nucleophilic attack

with configuration

inversion

Figure 8. Formation of a 3/5 fused cycles compound






28

We return now to Scheme 1 to observe that intermediate 6 will interact with the Grignard reagent that for entry 1

corresponds to nBu-+

MgCl. This happens first by means of exscinding the Ti-O-Cycles bond to generate an alcoxy

function which in turn is neutralized by the Lewis acid from Grignard r. namely +MgCl giving rise to the intermediate

to element 2 in the scheme. This Grignard adduct is finally destroyed in a protic medium to afford alcohol 8 (Figure

9).

+(iPrO)2Ti

OMe

nBu

nBu- +MgCl+

6ax

Ti O

iPrO

OiPr

OMe

Hax

Ti+

iPrO

OiPr

OMe

HO-

HClMgO

OH

8

H+

HClMgO

HHO

Figure 9. Generation of compound 8 (entry 1, (2))

What follows next is the different interactions for cation +Ti(OiPr)2(OMe). This is first neutralized by the basic

moiety of the Grignard reagent or the nBu- carbanion (Figure 9). Next the basic

–OMe is separated from titanium due

to a better interaction with Lewis acid +MgCl from a second equiv of Grignard r. The just formed Ti cation reacts

with the basic moiety left by the second Grignard equiv to generate intermediate 3 (Figure 10) in Scheme 1 thus

giving continuity to the virtual reacting loop.

+ nBu- +MgCl-

OMe+ (iPrO)2Ti+

nBu

(iPrO)2Ti

OMe

nBu

ClMgOMe+Ti

iPrO

iPrO3

(iPrO)2Ti

nBu

nBu

+

Figure 10. Interactions for cation +Ti(OiPr)2(OMe).

Entry 2.

Under the standard conditions (5 equiv of nBuMgCl, 0.5 equiv of ClTi(OiPr)3, ether, room temperature) the authors

achieved the synthesis of bicyclic 10 out of the homologue 9. The mechanism is the same as the previously

presented. This demarche is graphically described as follows in Figure 11.

CO2Me

n-4

substrate products

OH

H

n-4

9: n=6 10: n=6

Entry 2

iPrO

Ti

iPrOOiPr

Cl+ MgCl2

iPrO

Ti+2

iPrO

+ -OiPr + Cl

-+

-:

+ MgCl+

2 2

iPrO

Ti

iPrO

iPrO

Ti-:

iPrO

H

H

+

+

iPrO

Ti

iPrO

H

+

4 4

iPrO

Ti+

iPrO

-: H

iPrO

Ti+

iPrO

H

+:-

+

CO2Me9

CO2MeTi

+

iPrO

iPrO

:-

CO2MeiPrO

iPrO

Ti H

1 80 º

O

H

(OiP r)2 Ti

OMe

OOMe

H

(OiPr)2Ti

Transition State

..-Ti

H

O+

OMe

iPrO

iPrO


ax

eq

eqeq

axaxeq

ax

isomerization to

more confortable

conformer

Ti

OiPrO

OiPrOMe

H

Ti

O

iPrO

OiPr

OMe

H Nucleophilic attack

with configuration

inversion

ax

Ti O

iPrO

OiPr

OMe

H

Ti

O

iPrO

OiPr

OMeH

-

+ ax

H

ClMgO

-HOTi

+

iPrO

OiPr

OMe

axT i O

iPrO

OiPr

OM e

Hax6

+ nBu- +MgCl

(iPrO)2T i

OMe

nBu

+

HHO

HClMgO

H+

10

OH







29

Entry 3.

According to Cha and coworkers (2) a precipitous decrease in yield was observed for the intramolecular

hydroxycyclopropanation of 11 to afford bicyclo[5.1.0]octan-1-ol 12 in a 11% yield. Now we start our discussion

from the apparition of the transition state (Figure 12).

CO2Me

n-4

substrate products

OH

H

n-4

11: n=7 12: n=7

Entry 3

CO2Me+:

-+

HiPrO

Ti+

iPrO

iPrO

Ti+

iPrO

-: H

4

iPrO

Ti

iPrO

H

11

iPrO

iPrO

Ti H

CO2Me

:-

Ti+

iPrO

iPrO

CO2Me

Toward Transition State H

(OiPr)2Ti

OMeO

Ti

H

O+

OMe

iPrO

iPrO

..-Transition State

Ti

O

iPrO

OiPr

OMe

H

Ti

OiPrO

OiPrOMe

H

isomerization to more confortable

conformer ax

eqax ax

eq eq

eq

ax +

-

Ti

O

iPrO

OiPr

OMe H

Nucleophilic attackwith configuration

inversion

Ti O

iPrO

OiPr

OMe

H

+(iPrO)2Ti

OMe

nBu

nBu- +MgCl+

6

Ti O

iPrO

OiPr

OMe

HTi

+

iPrO

OiPr

OMe

HO-

HClMgO

12

H+

HClMgO

HHO

OH


As observed in the above graphics and after framework molecular models construction, the sp3 carbons of the fusion

bridge become very deformed from the tetrahedral geometry. It means that the instability of compound 12 is

increased regarding that of compound 10. This could be a reason to explain the lower yield for compound 12 with

respect to the yield of 10 and 8.

Entries 4 and 5

The original paper’s authors (2) mentioned that further extension to methyl 8-nonenoate and methyl 4-pentenoate

failed to produce the corresponding bicyclic cyclopropanols 14 and 16 (0% yield for both). See Figure 13.

CO2Me

n-4

substrate products

OH

H

n-4

13: n=8 14: n=8

Entry 4

CO2Me

n-4

substrate products

OH

H

n-4

15: n=9 16: n=9

Entry 5

Figure 13. Entries 4 and 5 (2)

Entries 6 and 7

According to Cha and coworkers, as a rule, the intramolecular hydroxycyclopropanations are not much influenced as

a result of the presence of different substituents in the chain (entries 6-13, (2)). We start this reaction graphic

description from the nucleophilic attack over the terminal vinyl of the methyl carboxylate 17. This compound is

actually being substituted at positions α and γ from carbonyl (Figure 14).






30

CO2Me

R4 R2 R3

R3R2 OH

HR4

substrate productsEntry 6

17: R2=OTIPS

R3=R4=H

18: R2=OTIPS

R3=R4=H

CO2Me

R4 R2 R3

R3R2 OH

HR4


19: R4=OTIPS

R2=R3=Me

20: R4=OTIPS

R2=R3=Me

17

iPrO

Ti+

iPrO

H

+:-

+CO2Me

R4 R2 R3

R2=OTIPSCO2Me

Ti+

iPrO

iPrO

R4 R2 R3:-

CO2MeiPrO

iPrO

Ti H R4 R2 R3

R3=R4=H

Figure 14. Nucleophilic attack over vinyl 17 toward the formation of 18 (entry 6, (2))

In order to better propose the corresponding theoretical mechanism, we will imagine stereochemistry for the two

chiral centers under a speculative scope (Figure 15).

CO2MeiPrO

iPrO

TiH R4 R2 R3HO

(OiPr)2Ti+

HH

H

O

R3R4

R2H

..

H

(OiP r)2Ti

O

O

R2HR3

R4

180º

H

(OiPr)2Ti

O

O

R3

R4R2

H

HH

H

(OiPr)2Ti

H

H

H

R2

R4

R3

O

O

H

(OiPr)2Ti H

OMe

H

R2

R4

R3O

H

H

(OiPr)2Ti H

R4H

H

O

O

R3

R2

H

(OiPr)2Ti H

R4

H

H

O

O

R3

R2

HH

H

(OiPr)2Ti H

R4

H

H

H

HR2R3

O

O

H

(OiPr)2Ti H

R4

H

H

H H

R2R3

O

O

H

(OiPr)2Ti H

R4

H

H

H H

R3

R2O

OH

(OiPr)2TiH

R4

H

H

H H

R3

R2O

O

H

(OiPr)2TiH

R4

H

H

H H

R3

R2

OO

H

(OiPr)2TiH

R4

H

H

H HR3

R2

OO+

-:

H

(OiPr)2TiH

R4

H

H

H HR3

R2

MeO

O

H

Ti

HH

R3 R2

MeO

O

H

R4

iPrO

OiPr ax eq

eq

Transition state

Ti

O

iPrO

OiPr

OMe R4

R3

R2

H

isomerization to

more confortable

conformerax

eq

eq ax+

-

Ti

O

iPrO

OiPr

OMeH

R3R2

Ti O

iPrO

OiPr

OMe

H

R3R2

R4

H

Nucleophilic attack

with configuration

inversion

Hax

nBu- +MgCl+Ti O

iPrO

OiPr

OMe

H

R4

H

R2

R3

Ti+

iPrO

OiPr

OMe

--O H

R4

H

R2

R3

+(iPrO)2Ti

OMe

nBu

ClM gO

H

R4

H

R2

R3

OH

H

R3 R2

R4H

+ClM gO

H

R4

H

R2

R3

HO

H

R4

H

R2

R3or as seen on Cha`s article

OH

H

R3 R2

R4

18 and 20 18 and 20

Figure 15. Generation of compounds 18 and 20 (entries 6 and 7, (2))






31

Entry 8 and entry 9

Contrasting to entries six and seven, the intramolecular hydroxycyclopropanation in entries 8 and 9 becomes

influenced by the presence of substituents at the allylic position in the side chain. This can be translated as a dramatic

diminution in yields (14% for product 22, entry 8, and 0% for the expected 24a, entry 9). This entry is graphically

described as follow in Figures 16, 17 and 18.

CO2Me

OTIPS


OH

H

OTIPS21 22


CO2Me

Me Me

OH

HMe Me

23 24a

Me Me HO

Me

;

24b

(OiPr)2Ti+..-+

H-

(OiPr)2Ti+

: H

(OiPr)2Ti

H

..-CO2Me(OiPr)2Ti

+

OTIPS

CO2Me

OTIPS

..-(OiPr)2Ti

+

CO2MeH

OTIPS

(iPrO)2Ti (iPrO)2Ti

CO2MeH

OTIPS180º

(OiPr)2Ti

H

O

OMeOTIPSH

(OiPr)2Ti

H

OMe

O

OTIPSH


Figure 16. Nucleophilic attack over vinyl 21 toward the formation of 22 (entry 8, (2))

At this point a competitive elimination of the HOTIPS group takes place to give the corresponding tricycle alkene.

This fact is responsible for the low yield in the intramolecular product 22 (Figure 17).

For entry 8:

(OiPr)2Ti

H

OMe

O

TIPSOH

Competing Elimination Reaction

H

OMeO

+ HOTIPS

(OiPr)2Ti

H

OMe

O

TIPSOH

(OiPr)2Ti

H

H

OTIPS

OMe

O

(OiPr)2Ti

H

H

OTIPS

OMe

O

H

H

HH

(OiPr)2Ti

H

H

OTIPS

HH

O

MeO

(OiPr)2Ti

H

H

OTIPS

HH

O

MeO(OiPr)2Ti

H

H

OTIPSHH

O

MeO

(OiPr)2Ti

H

H

OTIPSHH

O

MeO

-:

+

Nucleophilic attack

with configuration

inversion

Ti

O

iPrO

OiPr

OMe

H

H

OTIPSTi

O

iPrO

OiPr

OMeH

H

OTIPS

-

+ axax

eq

eqeq

axaxeq

ax

isomerization to

more confortable

conformer

Ti

OiPrO

OiPrOMe H

H

OTIPSax

eqeq

ax

Transition State

ax

Ti O

iPrO

OiPr

OMe

H

H

OTIPS

HClMgO

H

OTIPS

-HO

H

OTIPS

Ti+

iPrO

OiPr

OMe

axTi O

iPrO

OiPr

OMe

H

H

OTIPS

ax

+ nBu- +MgCl

(iPrO)2Ti

OMe

nBu

+

HHO

H

OTIPS

HClMgO

H

OTIPS

H+

OH

OTIPSH

22

Figure 17. Generation of 22 (entry 8, (2))

For entry 9:

The expected intramolecular product 24a did not appear giving no yield. Instead product 24b (Figure 18) appeared

as a result of a known intermolecular mechanism, it was yielded in a 61%. This result clearly shows that under the






32

given conditions, and with respect to eventual substituent groups present at the allyl position of the alkene, both

mechanisms, have a competitive character.

Ti(OiPr)2

+ CO2Me

OH

24a 0%

(iPrO)2Ti

H

O

OMe

O

OMe

H

(iPrO)2Ti

+

-:

-:

+ O

OMe

H

(iPrO)2Ti

OH

Ti

OiPr

iPrO

OMe

O

H

TiOiPr

iPrO

MeO

-:

OMeiPrO

OiPr

TiHO

MeO

iPrO

OiPrTi

H

O

+ Configuration inversion

nBuMgCl

OMeiPrO

OiPr

Ti

HO

HO

-

iPrO

OiPr

Ti+

OMe

HOMgCl

H+

HOH OH

H

OH

H

24b

Figure 18. Generation of 24b (entry 9, (2))

Entry 10

Mechanism for entry 10 is the same as that proposed for entries 6, 7 and 8. As a practice for the novel, it should be

done apart using entry 8 as a guide. However the apparition of a mixture of epimers as resulting products encourages

us to develop graphically one of such reactions (Figure 19).

CO2Me

MeTIPSO


OH

H

TIPSO

Me

OH

H

Me

TIPSO

25 26a 26b

+:-

H

Ti+

iPrO

iPrO

-:

Ti+

iPrO

iPrO

HTi

iPrO

iPrO

H

(OiPr)2Ti+

..-CO2Me

Me OTIPS

CO2Me(OiPr)2Ti+

Me OTIPS

..-

(iPrO)2Ti

CO2M eH

M e OT IPS (OiPr)2Ti

H

O

OMe

MeOTIPS

180º

(OiPr)2Ti

H

H

H

OMe

O

MeTIPSO

(OiPr)2Ti

H

OMe

OOTIPSMe

HH

(OiPr)2Ti

H

H

H

OTIPSMe

O

MeO(OiPr)2Ti

H

H

H

OMe

OMe

H

TIPSO

H

to a more stable

conformer

eq

eq

axax

Ti

H

H

H

OTIP S

Me

O

OMeOiPr

iPrO+

-:(OiPr)2Ti

H

H

HOTIPSMe

O

MeO

(OiPr)2Ti

H

H

HOTIPSMe

O

MeO

(OiPr)2Ti

H

H

H

OTIPSMe

O

MeO

ax

eq

eqax +

-

Ti

O

iPrO

OiPr

OMe H

OTIPS

Me

Ti

O

iPrO

OiPr

OMe

H

OTIPS

Me

Nucleophilic attackwith configurationinversion

eq

ax

Ti O

iPrO

OiPr

OMe

H

OTIPS

Me

+(iPrO)2Ti

OMe

nBu

nBu- +MgCl+Ti

+

iPrO

OiPr

OMe

HO

OTIPS

Me- HClMgO

OTIPS

Me

OH

TIPSO

Me

H+

HClMgOOTIPS

Me HHO

H

OTIPS

Me

OTIPS

26a

Figure 19. Generation of 26a (entry 10, (2))






33

This same mechanistic demarche gives rise to epimer 26b with the only fact of departing from at the β-of-carbonyl

inverted configuration position in the methyl ester compound.

Entry 11

Entry eleven presents new structural features and consequently new challenges in proposing a theoretical reaction

mechanism. Now the side chain includes a substituted cyclohexane (Figure 20).

CO2MeH

OTBS


H

OTBS

OH

H

27 28a 28b

H

OTBS

OH

H+

:-

H

Ti+

iPrO

iPrO

-:

Ti+

iPrO

iPrO

HTi

iPrO

iPrO

H+

H

OTBS

CO2Me

OTBS

H

CO2Me

H

H

H

Ti+

iPrO iPrO

:-

Ti+

iPrO iPrO

CO2Me

HH

H

OTBS

H

:-

CO2Me

HH

H

OTBS

H

Ti(OiPr)2

CO2Me

H

H

H

OTBS

H(iPrO)2Ti

TiH

H H

OTBS

H

MeO2C

OiPr

OiPr

Ti

iPrO

iPrO

H

H

H

OTBS

CO2Me

H

H

H

H

iPrO

iPrO

Ti

OTBS

CO2Me

H

H

H

H

iPrO

iPrO

Ti+

OTBSH

OMeO :- :

-

iPrO

iPrO

Ti

HOTBS

H

H

H

O+

MeO

iPrO

iPrO

Ti

HOTBS

H

H

HO

+MeO

:-

iPrO

iPrO

Ti

HOTBS

H

HOMeO

H

Transition State

iPrO

iPrO

Ti

HOTBS

OMeO H

..-

+

iPrO

iPrO

Ti

HOTBS

OMe

O H OTBS

HOTi(OiPr)2OMe

H

OTBS

HO

H

Ti(OiPr)2OMe

OTBS

HO

- Ti

+(OiPr)2OMe

H

+ nBuMgCl

OTBS

HO

-

+MgCl

H

+ nBuTi(OiPr)2OMe

OTBS

HOH

H

H+

28b

Figure 20. Obtention of 28b (entry 11, (2))

In order to obtain the isomer 28a (Figure 21), we must follow the mechanism below. We observe here that the

stereochemical definition for one or the other isomer comes out just before establishing one or the other transition

state. At that stage the free rotation about the sigma bond of the methyl ester group and the way for it to face the

Lewis acid-base interaction between the carbonyl oxygen and the cationic titanium provokes a beta or alpha

orientation for the tricycle. It is obvious that the most favored diasteroisomer in yielding was 28a due to an easier

nucleophilic attack from the carbonyl oxygen to titanium in comparison to 28b (2:1).

H

H

H

iPrO

iPrO

Ti+

OTBSH

OMeO :- :

-

iPrO

iPrO

Ti

HOTBS

H

H

HOMeO

+iPrO

iPrO

Ti

HOTBS

H

H

HOMeO

+

:-

iPrO iPrO

Ti

HOTBS

OH

Transition State

MeOOTBS

HOTi(OiPr)2OMe

H

M eOO H

OTBSH

TiiPrOiPrO

+ ..-

O H

OTBSH

TiiPrOiPrO

MeO

OTBS

HO

H

Ti(OiPr)2OMe

OTBS

HO

- Ti

+(OiPr)2OMe

H

+ nBuMgCl

OTBS

HO

-

+MgCl

H

+ nBuTi(OiPr)2OMe

OTBS

HOH

H

H+

28a

Figure 21. Obtention of 28a (entry 11, (2))

Entry 12






34

The prodigious synthetic work by Cha and coworkers also permitted these authors to afford the trans-ring junction

diasteroisomers 30a and 30b besides the cis-ring junction diasteroisomers 28a and 28b exposed in entry 11. The

trans isomers resulted less favored in yielding due to the additional associated strain, all according to the original

paper authors (2). No immediate references are given regarding the experimental conditions applicable in order to

obtain cis or trans diateroisomers. As expected the mechanistic proposal regards a close similarity to the ones

expressed in entry 11 (Figure 22).

CO2MeH

OTBS


H

OTBS

OH

H

29 30a 30b

H

OTBS

OH

H

+:-

H

Ti+

iPrO

iPrO

-:

Ti+

iPrO

iPrO

HTi

iPrO

iPrO

H+

H

OTBS

CO2Me

OTBS

CO2Me

HH

H

H

Ti+

iPrO iPrO

:-

Ti+

iPrO iPrO

H

CO2MeH

H

OTBS

H

:-

H

CO2MeH

H

OTBS

H

Ti(OiPr)2

H

CO2Me

H

H

OTBS

H(iPrO)2Ti

TiH

H H

OTBS

H

MeO2C

OiPr

OiPr

Ti

iPrO

iPrO

H

H

H

OTBS

H

MeO2C

H

H

H

iPrO

iPrO

Ti

OTBS

H

O

OMeH

H

H

H

H

iPrO

iPrO

Ti

OTBS

H

O

OMeH

H

H

H

H

iPrO

iPrO

Ti

OTBS

H

O

OMeH

H

Free rotation

Figure 22. Toward the obtention of the trans-ring junction diasteroisomers 30a and 30b

At this point, the mechanism goes toward provoking an interaction between the ester moiety and titanium (Figure

23). To achieve such relationship an appropriate approaching of the ester function to titanium is necessary. Thus

there must be a sigma bond free rotation of the tripod conformed by the cyclohexane and –OTBS as shown above in

Figure 22.

TBSO

HH

H

iPrO

iPrO

Ti

H

HHO OMe

TBSO

HH

H

iPrO

iPrO

Ti+

H

HHO OMe

:-

:-

TBSO

HH

H

iPrO

iPrO

Ti

H

HHO

+ OMe

Figure 23. Interaction between the ester moiety and titanium (toward 30a)

Model A






35

Once established the Ti-O link, the formation of a 5 membered cycle comes out from a nucleophilic attack from the

carbanion faced to the carbonyl carbon avid itself of electronic charge (Figure 22). The result is apparent in the

three-fused-cycles non-ionic intermediate in Figure 24. The proximity of an oxygen atom from a methoxy group to

the titanium nucleus in such intermediate makes possible the continuation of the reaction by means of a nucleophilic

attack over Ti. This splits the furanoid ring to give a highly instable 4-membered dioxy-titanium cycle and a

methylene carbanion (Figure 25).

TBSO

HH

H

iPrO

iPrO

Ti

H

HHO

OMe

TBSO

HH

H

iPrO

iPrO

Ti

H

HHO

OMe

TBSO

H

iPrO

iPrO

Ti

H

HHO

O+Me

:-

Being the 4-membered dioxy-titanium cycle besides an electronic deficient charged species, this reacts by splitting

the 4-membered cycle by the attack of the nucleophile basic methylene. An important feature of the electronic

movement at this stage of the intramolecular interactions is that the nucleophilic attack taking place between the

already mentioned nucleophilic carbanion (:CH2-) and the dioxygenated carbon at the just formed 4-membered

dioxytitano cycle, implies as a result the apparition of the fused tricycle in an α orientation all through the inversion

of the configuration of this chiral carbon [(iPrO)2TiO(MeO+)C] (Figure 26). The complementing mechanism to

obtain the alcohol derivative form out fro the titanium intermediate is shown in Figure 27.

TBSO

H

iPrO

iPrO

Ti

H

HHO

O+Me

:-

TBSO

H

iPrO

iPrO

Ti

H

HHO

OMe

Figure 26. Apparition of the fused tricycle in an α orientation all through configuration inversion of the chiral carbon

[(iPrO)2TiO(MeO+)C], (toward 30a)

OTBS

HO

H

Ti(OiPr)2OMe

OTBS

HO

- Ti

+(OiPr)2OMe

H

+ nBuMgCl

OTBS

HO

-

+MgCl

H

+ nBuTi(OiPr)2OMe

OTBS

HOH

H

H+

30a

Figure 27. Obtaining of alcohol form derivative out from the titanium intermediate, or final product 30 a

Figure 24. A three-fused-cycles non-ionic

Intermediate (toward 30a)

Figure 25. Splitting of the furanoid ring,

apparition of the instable 4-membered dioxy-

titanium cycle (toward 30a)






36

In order to propose a mechanistic explanation for product 30b we must observe at model A (Figures 23 and 28) that

the two electrons are in the inner position, ready for a nucleophilic attack over the electrophilic carbon of carbonyl in

the ester moiety actually linked to titanium through the carbonyl oxygen. To achieve the attended inverted (relative

to the α position of the tricycle in 30a) stereochemistry for the 3-membered cycle as shown in 30b (2), we locate

temporarily the two electrons in the outer position just as shown in Model B (Figure 28). Afterwards there must be

an accommodation of the two electrons on that carbanion, currently at a sp2 hybrid state, in order to be located (the 2

e-) again in the inner position. So, model B must be turned for the 2 e

- to regain the inner position being thus ready

again for the nucleophilic attack over the carbonyl carbon. The result of turning atoms through bonds is shown below

on model C (Figure 28).

TBSO

HH

H

iPrO

iPrO

Ti

H

HHO

+OMe

:-

:-

TBSO

HH

HiPrO

iPrO

Ti

H

HHO

+OMe

This conformer (Model C, Figure 28) presents already the hydrogen of this carbanion (sp2) in an alpha position

differing from the same cycle junction hydrogen in diasteroisomer 30a, where it appears in the beta position.

TBSO

HH

HiPrO

iPrO

Ti

H

HHO

+OMe

:-

TBSO

H

Ti

H

HH

OMeO

OiPr

OiPr

TBSO

H

Ti

H

HH

O

MeO+

OiPrOiPr

:-

Figure 29. The nucleophilic attack by the electrons from the inner position in Model C to drive reaction to the obtention of

compound 30b

TB S O

H H

H

i P r O

i P r O T i

H H H

O + O M e : -

Model A Model B

Model C

Figure 28. Positioning demarche of 2 electrons of one cyclic carbanion methyne to obtain product 30b

Let us proceed now to the nucleophilic

attack by the electrons from the inner

position into the carbonyl carbon. This

provokes indeed the displacement of

the π electrons of carbonyl to

compensate the cationic charge over

oxygen

deriving thus in

an ether cyclic

ether function

(Figure 29).






37

The remaining operations regards the replacement of the titanium moiety by the Grignard’s cation and the final

alcoholic water residue to afford 30b (Figure 30). This intramolecular nucleophilic attack driving to the apparition of

the β−oriented-three-membered cycle characterizing compound 30b, happens with inversion of configuration at the

chiral centre supporting the +OMe and OTi residues.

TBSO

H

Ti

H

HH

O

OiPrOiPr

OMe

OTBS

HO

H

Ti(OiPr)2OMe

30b

H+

OTBS

HOH

H

nBuTi(OiPr)2OMe+

OTBS

HO

-

+MgCl

H

nBuMgCl+

OTBS

HO

- Ti

+(OiPr)2OMe

H

Figure 30. Successive replacement of the titanium moiety by the Grignard’s cation and of this by H+ to afford 30b

Entry 13

Even though the failure to accomplish derivative 32 (0% yielding (2)) we propose with a didactical purpose how

such reaction should happen from a strictly theoretical stand point (Figure 31).

CO2Me

substrate products

Entry 13

OH

H

31 32

O

OMe

H

H

H

Ti+

iPrO iPrO

:-

Ti+

iPrO iPrO

H

H

H

:-

O

OMe

H

H

H

Ti(OiPr)2

O

OMe

H

H

H

O

OMe

(iPrO)2Ti

TiH

H H

OiPr

OiPr

OMe

O Ti

iPrO

iPrO

H

H

H

OMe

O

H

H

H

iPrO

iPrO

Ti

H

H

O

OMe:-

H

H

H

iPrO

iPrO

Ti+

HH

O

OMe

:- :

-

HO

MeO

HH

Ti+

OiPr

OiPrH

H

H

O

MeO

H

H

Ti+

OiPr

OiPr

H

H

:-

H

O

MeO

HH

Ti+

OiPrOiPr

HH

:-

Figure 31. Speculative mechanism to obtain 32 (entry 13, (2))






38

The constructed model at this stage shows partially our molecule, particularly the conjugated C=C and C=O(OCH3)

systems. We do also identify the methine carbanion as well as the Ti+(OiPr)2 cation. The next electronic movement

comports the nucleophilic attack C=O→Ti+ (Figure 31). This gives rise to an eight-membered cycle which according

to the constructed model exhibits annular tension because of failing to reach the previous and normally expected co-

planarity of both π conjugated systems (Figure 32). Isn’t this the cause for the reaction failure? However still

theorizing we can suppose from there on another nucleophilic intramolecular attack from the methine carbanion to

the electrophilic carbonyl carbon. As a result we’ve got a three fused cycles system 6-5-5 (Figure 31).

:-

H

O+

MeO

H

H

Ti

H

H

TS

H

OMeO

H

H

H

H

Ti

Figure 32. Speculative mechanism to obtain 32: non-coplanarity of π conjugated systems. Formation of 6-5-5 fused tricycle

(entry 13, (2))

We can describe these steps inverting the order of the nucleophilic attacks episodes (Figure 33): we first propose an

CH:- attack on C=O and then, once free from the contracting non-planarity of the π conjugated systems (now existing

only the C=C system), the second nucleophilic attack of C-O- to the Ti

+(OiPr)2 cation. Anyway the first attack may

never happen because of the currently absence of the Lewis acid catalytic action of Ti+(OiPr)2, once linked to C=O

as it was our first option. The problem arising from these mechanistic proposals is the trans disposition reached by

the 1,2-trans-H-OMe group at the ring junction after the methine attack on the carbonyl carbon of the ester moiety.

This does not conduct to the expected stereochemistry at the ring junction of the final structure comporting the 5-

and 3-membered fused rings. The good structure (2) 32 (Figure 31) presents a cis disposition for the just mentioned

groups. It forces to another pre-disposition of the methine before attack on the C=O. For solving this we will only

consider the case of a first nucleophilic attack on titanium by the carbonyl oxygen and then a second by the

carbanion methine on the carbonyl carbon of the ester moiety. The transition state has already been described as we

can see in Figure 34.

:-

H

O

MeO

HH

Ti+

OiPrOiPr

HH

H

O-

MeO

HH

Ti+

OiPrOiPr

HH

H

OMeO

H

H

H

H

Ti

Figure 33. Speculative mechanism to obtain 32: Inverting the order of the nucleophilic attacks episodes






39

H

O

MeO

HH

Ti+

OiPrOiPr

HH

:-

:-

H

O+MeO

H

H

Ti

H

H

TS

Figure 34. Speculative mechanism to obtain 32: Transition state, the case of a first nucleophilic attack on titanium by the

carbonyl oxygen and then a second by the carbanion methine on the carbonyl carbon of the ester moiety

Nevertheless, the intramolecular carbanion attack on C=O as just described, proved to give rise to the 1,2-trans-H-

OMe isomer. This TS shows the methine hydrogen in an outer position regarding the 8-membered ring. Thus it

becomes necessary to employ the opposite position for that methine hydrogen before the carbanion attack, or the

inner hydrogen position on the carbanion. For that purpose the 8-sided cycle must be re-accommodated throughout

restricted sigma bonding rotation. The result can be drawn and constructed as follows (Figure 35):

TS

H

O+MeO

H

H

Ti

H

H

:-

Restricted bond rotation and restablishment of co-

planarity of C=C and C=O

H

O+

MeO

H

HTi

H

H

:-

Figure 35. Speculative mechanism to obtain 32: Re-accommodation of the 8-sided cycle throughout restricted sigma bonding

rotation, recovery of co-planarity in the conjugated π-systems (cf. Figure 34)

This TS shows after rotation the inner hydrogen which means the electron pair placed in an outer position. It

signifies that there is no spatial disposition for the nucleophilic intramolecular action of the Lewis base (CH:-). This

TS needs anyway the electron pair in an inner or well disposed situation. In order to place the electron par inside the

8-sided cycle, the sp3 carbon (CH:

-) hybridize to sp

2 and then to sp

3 state again resulting all in a configuration

inversion of the chiral centre and thus the electron pair placed inside the ring ready for a nucleophilic attack (Figure

36).

Restricted bond rotation

H

O+

MeO

H

HTi

H

H

:-

H

O+

MeO

H

TiH

H

H

..

- :-

H

O+

MeO

H

H

TiH

H

Figure 36. Speculative mechanism

to obtain 32: Hybridization of the

sp3 carbon (CH:-) to sp2 and then

to sp3 inside the 8-sided cycle to

place the electron par again

resulting all in a configuration

inversion of the chiral centre to

make possible a nucleophilic attack






40

The next steps would involve the formation of the highly tensioned dioxotitano 4 membered ring and the formation

of the three membered fused ring by the carbanion attack over the elctrophilic carbon supporting the MeO+ function.

All this is followed by the known steps leading to the final alcohol form of the hypothetic product 32 (Figure 37).

OTi

H

H

HH

O:

MeH

O Ti

MeO+

H

HH

H..

-

H

H

H

MeO(OiPr)2TiO

H

OTi(OiPr)2OMe H

OTi(OiPr)2OMe

32 0%

O- Ti

+(OiPr)2OMe

H

+ nBuMgCl

O-

+MgCl

H

+ nBuTi(OiPr)2OMe

OH

H

H+

Figure 37. Speculative mechanism to obtain 32: final steps

Entries 14 and 15

According to Cha and col. esters of ω-alken-1-ols, particularly 3-buten-ols, seem to be amenable to intramolecular

hydroxycyclopropanations. Thus, Cha and col. also effected the reaction of benzoate 33 to give a 7:1 mixture of the

cyclopropanols 34a and 34b. A further extension to the homologue 35, lacked of good yield. These reaction entries

can be mechanistically envisaged as follow (Figure 38).

O Ph

O

n

Entry 14: n=1 33 34a: α-H 34b: β-H (7:1, 78%)

Entry 15: n=2 35 36a: α-H 36b: β-H (15%)

OH

OHPh

H n

For entry 14:

+Ti

iPrO

iPrO

Ti+

iPrO

iPrO

-:

Ti+

iPrO

iPrO:-

+ O Ph

OO

HH

H

O

iPrO OiPr

Ti+:-

TS1

O

H H

H

O

iPrO OiPr

Ti

H

(OiPr)2Ti

O

Ph

H

H O

Ti

OiPr

OiPr

H

H H

OPh

O

O

Ph

O

H

H

(OiPr)2Ti

H

H

H

OO

Ph

H

H

(OiPr)2Ti

H

H

H

O

+O

Ph H

H

(OiPr)2Ti

H

H

H

:-

Figure 38. Views of the synthesis of 34a and 34b (entry 14 (2))






41

(OiPr)2

:-

(OiPr)2Ti+

O

Ph H

O:O

H

O

Ti

PhO

Ph

O

H

Ti+(OiPr)2

:-

:-

O+

Ph

O

H

Ti(OiPr)2

OO

H

Ti(OiPr)2

Ph

O-

O

H

+Ti(OiPr)2

Ph

nBu- Mg

+Cl+ OMgCl

O

H

Ti(OiPr)2nBu

Ph

OH

OHPh

H

OMgCl

HPh

O- +

Ti(OiPr)2nBu + nBuMgCl+Ti(OiPr)2nBu2

OMgCl

HPh

OMgCl

2H+ OH

HPh

OH34a

TS2

iPrO OiPr

Ti+

O

H

HH

O

:-

Ti

OiPr

OiPr

H

H

H

O

Ph

O

H

(OiPr)2Ti

H

H

O

Ph

OO

Ph

O

H

H

(OiPr)2Ti

H

+O

Ph

O

Ti

HOiPriPrO

:-

According to

Fram ework

molecular

models

Ti O

O

Ph

iPrO

iPrOH

Ti+

O

O

Ph

iPrO

iPrOH

:-

.

:-

+Ti

O

O

Ph

H

OiPr

OiPr

TiO

O+

Ph

H

OiPr

OiPr

:-

:-

Ti

+

OO

Ph

H

OiPr

OiPrTiO

O

Ph

H

OiPr

OiPrO

-OTi

+(OiPr)2

Ph

H

.

nBu- Mg

+Cl+

OMgClO Ti(OiPr)2nBu

Ph

H

O-

Ph

OMgClH

+Ti(OiPr)2nBu+

nBuMgCl+

OMgClPh

OMgClH

Ti(OiPr)2nBu2+2H +

OHPh

OHH 34bOH

OHPh

H

Figure 38(Cont.). Views of the synthesis of 34a and 34b (entry 14 (2))

For entry 15: The mechanistic approach for the 33-homologue 35 is the same as for 33 (see entry 14 mechanistic

approach for details).

REFERENCES

1. Bravo, J. Bol. J. of Chem. 2005, 23, 1-10. (http://www.bolivianchemistryjournal.org, 2005)

2. Lee, J.; Kang, C. H.; Kim, H.; Cha, J. K. J. Am. Chem. Soc. 1996, 118, 291-292

3. Kulinkovich, O. G.; Sviridov, S. V; Vaasilevskii, D. A. ;. Pritytskaya, T. S. Zh. Org. Khim. 1989, 25, 2244.

4. Lee, J.; Kim, H.; Cha, J. K. J. Am. Chem. Soc, 1995, 117, 9919

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