Phosphoramidites in synthesis - University of...

Phosphoramidites in synthesis

Robert Straker Literature Review – July 2014

2

Introduction •  History •  Structure •  Synthesis

Application – 1,4-Addition of organometallic nucleophiles •  Copper-catalyzed asymmetric conjugate addition of dialkylzinc reagents •  Zinc enolate trapping •  In situ generation of organometallic nucleophiles •  Generation of chiral all-carbon-quarternary centres

Application – Cycloaddition reactions •  Gold-catalyzed [2+2] cycloadditions •  Metal-mediated [2+2+1] Pauson Khand cycloadditions •  Palladium-catalyzed intermolecular [3+2] cycloaddition •  Metal-catalyzed intermolecular [4+2] Diels-Alder cycloaddition •  Metal-catalyzed intramolecular [4+3] cycloaddition •  Rhodium-catalyzed intramolecular [5+2] cycloaddition •  Metal-mediated [6+2] and [6+3] cycloadditions

Miscellaneous •  Palladium-catalyzed cross-coupling reactions

References

Slide

4 6 9

12 15 19 20

23 26 27 28 29 30 32

34

39

Phosphoramidites in synthesis Content

Introduction


4 1. Teichert, J. F.; Feringa, B. L., Angew. Chem. Int. Ed. 2010, 49, 2486-2528

Phosphoramidites in synthesis Introduction – History: Privileged Ligands1

O

OP N

Ph

Ph

M cat.

O

Et

Ph

OH

NTsPh

H

Ph

SiCl3

1,4-Addition

Hydrosilylation Allylic substitution

Hydrovinylation

Cycloisomerization

NH

Asymmetric Hydrogenation

O

BnN

C-H Activation

Ph

OH

Allylation

5

Phosphoramidites in synthesis Introduction – History

Ben L. Feringa

•  Obtained his PhD in 1978 at the University of Groningen under the guidance of Prof. Hans Wynberg

•  Appointed full professor in 1988 at the University of Groningen.

•  Knighted in 2008 by Her Majesty the Queen of the Netherlands.

•  First introduced phosphoramidites in 1994, describing them as “interesting chiral ligands”.2

2. Hulst, R.; de Vries, N. K.; Feringa, B. L., Tetrahedron: Asymmetry 1994, 5, 699-708

Trivalent Phosphorous •  Phosphoramidites are one of a family of amides of trivalent phosphorous acid H3PO3.

•  Distinct from other trivalent phosphorous ligands as they contain one P-N bond and two P-O bonds.

•  Both phosphorous and nitrogen possess unshared lone pairs, which can act as metal binding sites


Phosphoramidites in synthesis Introduction – Structure

P RR

RP OR

RO

ROP R

RO

ROP OR

R

RP NR2

R

R

P ORR2N

R2NP NR2

RO

ROP NR2

R2N

R2N

phosphine phosphite phosphonate phosphinite aminophosphinite

phosphordiamide phosphoramidite phosphortriamide

7 3. Holscher, M.; Francio, G.; Leitner, W., Organometallics, 2004, 23, 5606-5617


Modular Framework •  Stereodescrimination can originate from either the diol or amine component – matched/mismatched. •  Possible to tune the steric and electronic properties with a variety of readily available building blocks. •  Phosphrous has a pseudotetrahedral geometry, whilst nitrogen is usually trigonal planar.3

X-Ray crystal structure of (S,R,R)-L2

O

OP N

Ph

Ph

(S,R,R)-L2

O

OP N

Ph

Ph

(R,S,S)-ent-L2

O

OP N

Ph

Ph

(R,R,R)-ent-L2b

O

OP N

Ph

Ph

(S,S,S)-L2b



O

OP N

Ph

PhO

OP N

chiral BINOL, achiral amine(S)-L1 (MonoPhos)

chiral BINOL, chiral amine(S,R,R)-L2

O

OP N

Ph

Ph

flexible biphenol(R,R)-L4

O

OP N

Ph

Ph

dibridged biphenylcis-(S,S,aR,S,S)-L5

O

OPN

Ph

PhOO

P N

spirobiindanediol(R)-L6

O

OP N

Ph

Ph

chiral pyrrolidine(S,S,S)-L7

OP

ON

ArAr

Ar Ar

O

O

Ph

TADDOL backbone(S,S,R)-L8

O

OP N

Ph

Ph

3,5-disubstituted BINOL(S,S,S)-L3

Ar

Ar

Commonly used classes of phosphoramidite ligand1

Three main routes to phosphoramidite ligands have been established: •  A is the most commonly adopted.4

•  B is preferred for more sterically encumbered amines.5

•  C represents an efficient synthesis of MonoPhos, which can undergo subsequent amine exchange.2

9

O

OP N

R

R

OH

OH

O

OP Cl

O

OP N

P NR

RCl

ClHN

R

R

OH

OH

PCl3Et3N

HNR2Et3N

P(NMe2)3

BINOLcat. tetrazole

PCl3Et3N

BINOLbase

A

B

C

Phosphoramidites in synthesis Introduction – Synthesis

4. de Vries, A. H.; Meetsma, A.; Feringa, B. L., Angew. Chem. Int. Ed. 1996, 35, 2374-2376 5. Alexakis, A.; Polet, D.; Rosset, S.; March, S., J. Org. Chem. 2004, 69, 5660-5667

2. Hulst, R.; de Vries, N. K.; Feringa, B. L., Tetrahedron: Asymmetry 1994, 5, 699-708

Fully automated parallel synthesis and in situ screening of ligand libraries6

•  Modular nature of phosphoramidites makes them ideally suited to parallel synthesis approach.

•  Particularly useful for highly substrate dependant reactions as ligand libraries can be stored and reused.

10

Phosphoramidites in synthesis Introduction – Synthesis

6. Lefort, L.; Boogers, J. A. F.; de Vries, A. H. M.; de Vries, J. G., Org. Lett. 2004, 6, 1733-1735

OP

OCl

RN

R'

H

ParallelSynthesizer

Ligand Libraryone vessel, one compound

Hits

AnalysisParallel

Reactors

metalprecursor

prochiralsubstrates

1,4-Addition of organometallic nucleophiles


12 4. de Vries, A. H.; Meetsma, A.; Feringa, B. L., Angew. Chem. Int. Ed. 1996, 35, 2374-2376 7. Feringa, B. L.; Pineschi, M.; Arnold, L. A.; Imbos, R.; de Vries, A. H. M., Angew. Chem. Int. Ed. 1997, 36, 2620-2623

Copper-catalyzed asymmetric conjugate addition with dialkyl zinc reagents4

•  Demonstrated by Feringa et al., high chemo- and enantioselectivity with cyclic and acyclic enones.

Phosphoramidites in synthesis Application – 1,4-Addition of organometallic nucleophiles

2 mol% Cu(OTf)24 mol% L1

1.5 eq. ZnEt2 Ph

Ph

O

Ettoluene– 50 °C

84%, 90% ee

Ph

O

Ph O

OP N (S)-L1

•  Further explored ligand substituents and discovered additional chiral centres were beneficial.7


1.5 eq. ZnEt2O O

Ettoluene– 30 °C

95%, 98% ee

O

OP N

Ph

Ph

(S,R,R)-L2

13 8. Zhang, H.; Gschwind, R. M., Chem. Eur. J. 2007, 13, 6691-6700 9. Schober, K.; Zhang, H.; Gschwind, R. M., J. Am. Chem. Soc. 2008, 130, 12310-12317

Catalytic Cycle – Gschwind et al.8,9

I – Alkyl transfer of dialkyl zinc reagent to dimeric copper(I) precatalyst.

II – π coordination of CuI centre to alkene moiety of Michael acceptor. Zinc(II) acts as a Lewis acid, binding to the carbonyl group.

III – Oxidative 1,4-addition of CuI to activated enone.

IV – Reductive elimination, releasing zinc enoate and copper(I) complex, rate determining step.

O

L CuIX

XCuI

L

L

CuIL

L

XZn

R

CuI X

L

R

O

CuI

L

X

R

CuIL

LXZn

R

O

CuIII

L

X

R

CuIL

L

XZn

R

O

R

ZnR

ZnR2

I

IIIII

IV


14 10. Naasz, R.; Arnold, L. A.; Minaard, A. J.; Feringa, B. L., Angew. Chem. Int. Ed. 2001, 40, 927-930 11. Bertozzi, F.; Crotti, P.; Macchia, F.; Pineschi, M.; Feringa, B. L., Angew. Chem. Int. Ed. 2001, 40, 930-932

Kinetic Resolution Reactions •  Selective conversion of one enantiomer of starting material to conjugate addition product.10


0.8 eq. ZnEt2O O

toluene– 30 °C, 20 min

33%, 99% ee

O

Et O

OP N

Ph

Ph

(S,R,R)-L2

•  Ligand delivers nucleophile in SN2’ fashion to one enantiomer and SN2 to the other.11


O

OP N

Ph

Ph

(R,R,R)-ent-L2b

1.5 mol% Cu(OTf)23 mol% L2b

1.5 eq. ZnMe2

toluene– 10 °C, 3 h

OOH OH

49%, 96% ee 51%, 92% ee

15 12. Rathgeb, X.; March, S.; Alexakis, A., J. Org. Chem. 2006, 71, 5737-5742 13. Li, K.; Alexakis, A., Tetrahedron Lett. 2005, 46, 8019-8022

Intermolecular trapping of zinc enolates with electrophiles •  Alexakis demonstrated highly diastereoselective trapping of zinc enolate intermediates.12

Intramolecular Michael reaction •  Chemoselective conjugate addition, followed by trapping with tethered electrophile.13


72%19:1 dr, 99% ee

1 mol% [Cu(TC)]2 mol% L4

1.2 eq. ZnEt2O

EtEt2O– 30 °C, 2 h

O

OP N

Ph

Ph

(R,R)-L4

rt, 6 h

O

Et

NO2Br

OZnEtNO2

Ph

O

OMe

O

2 mol% [Cu(TC)]4 mol% ent-L41.5 eq. ZnEt2

Et2O– 30 °C - rt, 2 h

Et

Ph

OCO2Me

99%9:1 dr, 92% ee

16 14. van Summeren, R. P.; Reijmer, S. J. W.; Feringa, B. L.; Minaard, A. J., Chem. Comm. 2005, 1387-1389

Construction of 1,5-dimethyl arrays – Application to Natural Products14

•  Judicious choice of catalyst allows construction of all four diastereomers of isoprenoid building blocks.

•  Selective oxidative ring opening of the corresponding silyl enol ether prevents racemization.

2.5 mol% Cu(OTf)25 mol% L

1.5 eq. ZnMe2

5 mol% Cu(OTf)210 mol% ent-L2

5 eq. ZnMe2


O O

OZnMe

OZnMetoluene

– 25 °C, 12 h

L2

ent-L2

85%, 99% ee

98% de, 99% ee

98% de, 99% ee

O

OP N

Ph

Ph

(S,R,R)-L2

C4H9

C4H9

Insect pheramones(Lyonetia prunifoliella)


17 15. Zhang, H.; Fang, F.; Xie, F.; Yang, G.; Zhang, W., Tetrahedron Lett. 2010, 51, 3119-3122 16. Yu, H.; Xie, F.; Ma, Z.; Liu, Y.; Zhang, W., Adv. Synth. Catal. 2012, 354, 1941-1947

Reversal of stereoselectivity: Substituent Effect – Zhang et al.15,16

•  Backbone substituents in D2-symmetric ligands can switch enantioselectivity absolutely.

•  Matched and mismatched cases with cis- and trans-dibridged phosphoramidites.


1 mol% Cu(Ac)22 mol% cis-L5a

1.2 eq. AlEt3

Et2O– 50 °C, 8 h

89%, >99% ee

Ar

O

Ar Ar

O

Ar

Et

1 mol% Cu(OAc)22 mol% trans-L5b

1.2 eq. AlEt3

Et2O– 50 °C, 8 h

Ar

O

Ar

Et

90%, >99% ee Ar = p-MeOC6H4

O

OP N

Ph

Ph

cis-(S,S,aR,S,S)-L5xx = a, R = H; x = b, R = Me

RR

RR

O

OPN

Ph

PhO

OP N

Ph

Ph

trans-(S,S,aR,S,S)-L5xx = a, R = H; x = b, R = Me

RR

RR

O

OPN

Ph

Ph

18

Reversal of stereoselectivity: Substituent Effect – Zhang et al.15,16

•  Unfavourable steric interaction of the amine substituent with the substrate in L5a-TS2.

•  Overriding steric interaction of backbone substituent with substrate in L5b-TS1.

OO

O

O PP

N

N Me Ph

Ph

Me

Ph MePh

MeCu

PEt

Ar

Ar

OAl

OO

O

O PP

N

N Me Ph

Ph

Me

Ph MePh

MeCu

PEt

OO

O

O PP

N

N Me Ph

Ph

Me

Ph MePh

MeCu

PEt

OO

O

O PP

N

N Me Ph

Ph

Me

Ph MePh

MeCu

PEt

Me

Me

Me

Me

L1-TS2 L1-TS1

L2-TS1 L2-TS2

S product

Ar

O

Ar

Et

R product

Ar

O

Ar

Et

Ar Ar

OAl

Ar

Ar

OAl

Ar Ar

OAl


15. Zhang, H.; Fang, F.; Xie, F.; Yang, G.; Zhang, W., Tetrahedron Lett. 2010, 51, 3119-3122 16. Yu, H.; Xie, F.; Ma, Z.; Liu, Y.; Zhang, W., Adv. Synth. Catal. 2012, 354, 1941-1947

19 17. Maksymowicz, R. M.; Roth, P. M. C.; Fletcher, S. P., Nat. Chem. 2012, 4, 649-654

In situ generation of organometallic nucleophiles – Fletcher et al.17

•  Hydro-zirconation of alkene allows preparation of a variety of previously inaccessible nucleophiles.

O O

Et2Ort

65%, 84% ee

R

Cp2ZrHClCu(OTf)⋅PhH

L2

R O

OP N

Ph

Ph

(S,R,R)-L2

O

O OO

Ph

O

49%, 94% ee 66%, 76% ee

Br

62%, 72% ee

60%, 87% ee

O

TMS

53%, 96% ee

OTBS

O

52%, 71% ee

O

71%, 78% ee


20 18. d' Augustin, M.; Palais, L.; Alexakis, A., Angew. Chem. Int. Ed. 2005, 44, 1376-1378 19. Sidera, M.; Roth, P. M.; Maksymowicz, R. M.; Fletcher, S. P., Angew. Chem. Int. Ed. 2013, 52, 7995-7999

Generation of chiral all-carbon-quarternary centres •  Alexakis et al. addressed the issue of sterically encumbered Michael acceptors with stronger lewis acids.18

•  The Fletcher group applied their hydro-metallation approach to broaden the scope of available substituents.19


O O

Et2O– 30 °C, 18 h

2 mol% CuTC2 eq. AlMe34 mol% L9

O

OP N

Ph

PhEt

78%, 94% ee

(S,S)-L9

O O

t-BuOMe– 30 °C, 18 h

82%, 95% ee

TMS

Cp2ZnHCl10 mol% CuCl

15 mol% AgNTf210 mol% L10

O

OP N

PhPh

(R)-L10

Cycloaddition reactions


23 20. Pantiga, S. S.; Diaz, C. H.; Rubio, E.; Gonzalez, J. M., Angew. Chem. Int. Ed. 2012, 51, 11552-11555

Gold-catalyzed intermolecular [2+2] cycloaddition20

Phosphoramidites in synthesis Application – Cycloaddition reactions

CH2Cl2– 70 °C, 12 h

•TsPhN

R(R,R,R)-L11

5 mol% AuCl5 mol% L11

0.4 mol% AgNTf2 TsPhNR

99%, 84% ee

TsPhN

OMe

77%, 95% ee

NsPhN

OMe

69%, 86% ee

TsPhN

79%, 87% ee

TsPhN

F

O

OP

Ph

Ph

PhPh

R'

R'

95%, 72% ee

TsPhN TsPhN

78%, 90% ee

TsPhN

OMe

Me

52%, 90% ee

24 21. Gonzalez, A. Z.; Benitez, D.; Tkatchouk, E.; Goddard, W. A.; Toste, F. D., J. Am. Chem. Soc. 2011, 133, 5500-5507

Gold-catalyzed intramolecular [2+2] cycloaddition21

•  Formation of 3,4-substituted pyrollidines from allenenes – synthesis of Natural Product.

•  Choice of ligand and nucleophile favours formation of either cis- or trans-substituted products.

O

OP N

Ph

Ph

Ar

Ar

(R)-L

OOP N

(S,S,S)-L

MeN

OH

H

HO

NMeN

Ph

(-)-isocynometrine

CF3

CF3

Ar

CH3NO225 °C

TsN•

CH2Cl225 °C

5 mol% AuCl5 mol% L

5 mol% AgBF4

TsN

Ph

H

HPh

TsN

OMe

Ph

H

H

5 mol% AuCl5 mol% L

5 mol% AgBF49 eq. MeOH

86%, 92% ee86%, 94% ee


612

6 12

25 21. Gonzalez, A. Z.; Benitez, D.; Tkatchouk, E.; Goddard, W. A.; Toste, F. D., J. Am. Chem. Soc. 2011, 133, 5500-5507


I – Coordination of chiral Gold complex to allene moiety.

II – Reversible cis- or trans-insertion of alkene into activated allene – SD. III – Nucleophilic trapping of carbocation with intramolecular migration or exogenous nucleophile – SD.

TsN

D

AuL

Ph

TsN

D

TsN

D

AuL

Ph

H

Ph

TsN D

•

Ph

TsN D

•

Ph

LAu

LAu+

MeOHTsN

D

H

Ph

MeOH

OMe

LAu+

trans-II

cis-II

I

trans-III

cis-III

H

HH


cis-III trans-II

cis-II

trans-III

26 22. Konya, D.; Robert, F.; Gimbert, Y.; Greene, A. E., Tetrahedron Lett. 2004, 45, 6975-6978 23. Fan, B. M.; Xie, J. H.; Li, S.; Tu, Y. Q.; Zhou, Q. L., Adv. Synth. Catal. 2005, 347, 759-762

Cobalt-mediated intermolecular [2+2+1] Pauson-Khand cycloaddition22

•  First use of phosphoramidite ligands in intermolecular cycloaddition, reaction of alkyne and norbornene.

Rhodium-catalyzed intramolecular [2+2+1] Pauson-Khand cycloaddition23

•  Formation of bicyclic products from 1,6-enynes under carbon monoxide atmosphere.


toluene80 °C, 12 h

70%, 38% ee

(S)-L13O

Ph

Co2(CO)8L13

Ph

O

OP N

DCE90 °C, 3 h

56%, 84% ee

∗∗

O O

Ph

HO

Ph

3 mol% [Rh(CO)2Cl]213 mol% L6

12 mol% AgSbF61 atm CO

(R)-L6OO

P N

27


24. Trost, B. M.; Silverman, S. M.; Stambuli, J. P., J. Am. Chem. Soc. 2011, 133, 19483-19497 25. Trost, B. M.; Stambuli, J. P.; Silverman, S. M.; Schworer, U., J. Am. Chem. Soc. 2006, 128, 13329-13329

26. Trost, B. M.; Cramer, N.; Silverman, S. M., J. Am. Chem. Soc. 2007, 129, 12396-12397

Palladium-catalyzed intermolecular [3+2] cycloaddition – Trost et al.24

•  Cycloaddition of trimethylene unit, a useful transformation to provide 5-membered carbocycles.25

•  Modification of ligand substituent allows application to oxindoles in the generation of spirocycles.26


63%, 82% ee

(S,S,S)-L7O

OP N

Ph

Ph

TMS OAcPh

5 mol% Pd(dba)210 mol% L7

O

O

Ph

toluene0 °C, 12 h

99%19:1 dr, 82% ee

(R,R,R)-L14O

OP NTMS OAc

2.5 mol% Pd(dba)210 mol% L14

NE

ONE

O

CN

Cl ClCN


28 27. Faller, J. W.; Fontaine, P. P., Organometallics 2005, 24, 4132-4138 28. Liu, B.; Li, K. N.; Luo, S. W.; Huang, J. Z.; Pang, H.; Gong, L. Z., J. Am. Chem. Soc. 2013, 135, 3323-3326

Ruthenium-catalyzed intermolecular [4+2] Diels-Alder cycloaddition27

•  Preformed chiral Ru complex acts as a Lewis acid, high regioselectivity and moderate enantioselectivity.

Gold-catalyzed intermolecular [4+2] azo hetero-Diels-Alder28

•  Diazene dienophiles provide multifunctional heterocycles – Natural Products.

99%>20:1 dr, 97% ee

TBSO

toluene– 78 °C

5 mol% AuNTf25 mol% L15

NNBoc

O

NHArNBocN NHAr

O

TBSO

O

OP N

Ph

Ph

9-anthracene

9-anthracene

(R,S,S)-L15

CH2Cl2– 25 °C

O

CHORu

NMe2

PPh2

ClL

10 mol% ML110 mol% AgBF4

O

OP N

(S)-L1 ML1

+ SbF6-

93:7 dr, 70% ee

29 29. Gulias, M.; Duran, J.; Lopez, F.; Castedo, L.; Mascarenas, J. L., J. Am. Chem. Soc. 2007, 129, 11026-11027 30. Alonso, I.; Faustino, H.; Lopez, F.; Mascarenas, J. L., Angew. Chem. Int. Ed. 2011, 50, 11496-11500

Palladium-catalyzed intramolecular [4+3] cycloaddition29

•  First example of metal-catalyzed intramolecular [4+3], diene-tethered alkylidenecyclopropanes.


•  Highly diastereo- and enantioselective cycloaddition of allenedienes.


dioxane101 °C, 2 h

73%, 47% ee

EE

EECO2Et

CO2Et

H

H

6 mol% Pd2(dba)324 mol% L16

O

OP N

Ph

Ph

(R,R)-L16

CH2Cl2rt, 36 h

TsN•

TsN

74%, 95% ee

H

H

5 mol% Au*5 mol% AgNTf2

PhPh

O

OP N

Ph

Ph

9-anthracene

9-anthracene

(R,R,R)-Au*AuClH

30 31. Shintani, R.; Nakatsu, H.; Takatsu, K.; Hayashi, T., Chem. Eur. J. 2009, 15, 8692-8694 32. Straker, R. N.; Anderson, E. A., unpublished results

Rhodium-catalyzed intramolecular [5+2] cycloaddition •  Reaction of alkyne-tethered vinylcyclopropanes gave bicyclic products with high enantioselectivity.31

•  Reaction of ynamide-vinylcyclopropanes, improved rate of reaction with Fluoride-substituted ligand.32


CH2Cl2rt, 15 min

99%, 98% ee

5 mol% [RhCl(C2H4)2]26 mol% L17

6 mol% NaBArF4

NTs

Ph

H

TsN

Ph

O

OP N

F

F

(S,R,R)-L17

CH2Cl230 °C, 2 h

90%, 95% ee

5 mol% [RhCl(C2H4)2]26 mol% L2

6 mol% NaBArF4

O

HO

Ph

O

OP N

Ph

Ph

(S,R,R)-L2

Ph

31

Rhodium-catalyzed intramolecular [5+2] cycloaddition31

•  Unfavourable interaction of substrate cyclopropane moiety with ligand BINOL backbone in TS1’.

•  Coordination of Rh to substrate in TS1 is followed by oxidative cyclopropane cleavage and insertion of alkyne to give the metallocycle in TS2.

•  Reductive elimination gives the R product.

O

ON

MeMe

PO

ON

MeMe

P

Ph

TsN

RhO

ON

MeMe

PRh

TS1 TS2

NTsPh

HPh

TsN

O

ON

MeMe

P

Ph

TsN

Rh

TS1'

TsN

RhPh

H

R Product

31. Shintani, R.; Nakatsu, H.; Takatsu, K.; Hayashi, T., Chem. Eur. J. 2009, 15, 8692-8694


32

Cobalt-catalyzed intermolecular [6+2] cycloaddition33

•  Formation of bicyclo[4.2.1]nonatrienes, confirmed by vibrational circular dichroism (VCD) experiments.

33. Toselli, N.; Martin, D.; Achard, M.; Tenaglia, T. B.; Buono, G., Adv. Synth. Catal. 2008, 350, 280-286 34. Trost, B. M.; McDougall, P. J.; Hartmann, O.; Wathen, P. T., J. Am. Chem. Soc. 2008, 130, 14960-14961


O

OP N (R)-L18

DCE40 °C, 20 h

Ph H

1-naphthyl

1-naphthylPh

5 mol% CoI210 mol% L1810 mol% ZnI215 mol% Zn

93%, 90% ee

Palladium-catalyzed intermolecular [6+3] cycloaddition34

•  Reaction of trimethylenemethane with tropones to give bicyclo[4.3.1] and [3.3.2]decadienes.

O

OP N

(R,R,R)-L19

toluene0 °C

O

93%, 90% ee

Ph

Ph

O

TMSCN

OAc

5 mol% Pd(dba)210 mol% L19

CNtoluene170 °C

O

NC

89%6:1 dr, 99% ee

microwave

Miscellaneous Reactions


34

Palladium-catalyzed Heck reactions •  Highly E selective arylation of styrene, with only trace amounts of diphenylethylene observed.35

35. Strijdonck, G. P. F.; Boele, M. D. K.; Kamer, P. C. J.; de Vries, J. G.; van Leeuwen, P. W. N. M., Eur. J. Inorg. Chem. 1999, 1073-1076 36. Imbos, R.; Minaard, A. J.; Feringa, B. L., J. Am. Chem. Soc. 2002, 124, 184-185

Phosphoramidites in synthesis Miscellaneous Reactions

MeCN80 °C

1 mol% Pd(dba)22 mol% L201 eq. Et3N

I

E/Z 90:1

OO

P N

t-BuMeO

t-BuMeO

L20

•  Asymmetric intramolecular cross-coupling reaction using TADDOL-derivative phosphoramidites.36

CHCl361 °C

100%, 96% ee

(S,S)-L21O

PO

N

PhPh

Ph Ph

O

O

6 mol% Pd(OAc)212 mol% L214 eq. Cy2NMe

O

OMeO I∗∗

O

OMeO

35

Palladium–catalyzed allylic substitution reactions •  Asymmetric allylic alkylation (AAA) reaction using TADDOL-phosphoramidites.37

37. Boele, M. D. K.; Kamer, P. C. J.; Lutz, M.; de Vries, J. G.; van Leeuwen, P. W. N. M.; van Strijdonck, G. P. F., Chem. Eur. J. 2004, 10, 6232-6246

38. Zeng, B. S.; Yu, X.; Siu, P. W.; Scheidt, K. A., Chem. Sci. 2014, 5, 2277-2281


•  Synthesis of biologically active chromenes via 6-endo-trig cyclization reaction.38

Ph Ph

OAc

CH2Cl2rt

Ph∗∗

Ph

CH(CO2Me)2

98%, 93% ee

(S,S,R)-L8O

PO

N

ArAr

Ar Ar

O

O

Ar = 3,5-Me-C6H3

Ph

1 mol% [Pd(allyl)(OAc)2]2 mol% L8

1.5 eq. CH2(CO2Me)21.5 eq. BSA

(S,S)-L22

OAc OAc

MeOH:H2O (1:1)rt, 20 h

O

72%, 94% ee

F

F

2 mol% Pd(dba)28 mol% L221 eq. K2CO3

OP

ON

ArAr

Ar Ar

O

O

Ar = 3,5-Et-C6H3

36

Palladium-catalyzed deracemization reactions •  Asymmetric allylic alkylation (AAA) reaction of strained lactones.39

39. Luparia, M.; Oliveira, M. T.; Audisio, D.; Frebault, F.; Goddard, R.; Maulide, N., Angew. Chem. Int. Ed. 2011, 50, 12631-12635 40. Misale, A.; Niyomchon, S.; Luparia, M.; Maulide, N., Angew. Chem. Int. Ed. 2014, 53, 7068-7073


•  Overriding natural “umpolung” chemistry with unsual ligand effect.40

CO2MeAcO CO2MeTHF– 60 °C

5 mol% [Pd(allyl)Cl]215 mol% L242.4 eq. Et2Zn

78%99:1 dr, 88% ee

OP

ON

ArAr

Ar Ar

O

O

Ph

Ph

(S,S,S,S)-L24

Ar = (4-t-Bu)-C6H4

THF0 °C, 1 h

OH

H O

MeO

O O

OMe

COOH

CO2MeCO2Me2.5 mol% [Pd(allyl)Cl]2

7.5 mol% L23

OP

ON

ArAr

Ar Ar

O

O

Ph

Ph

(R,R,R,R)-L23

61%95:5 dr, 96% ee Ar = (3,5-t-Bu-4-OMe)-C6H2

O

OP N

Ph

Ph

M cat.

O

Et

Ph

OH

NTsPh

H

Ph

SiCl3

1,4-Addition

Hydrosilylation Allylic substitution

Hydrovinylation

Cycloisomerization

NH

Asymmetric Hydrogenation

O

BnN

C-H Activation

Ph

OH

Allylation

37

Phosphoramidites in synthesis Summary

Questions?


40

Phosphoramidites in synthesis References

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16. Yu, H.; Xie, F.; Ma, Z.; Liu, Y.; Zhang, W., Adv. Synth. Catal. 2012, 354, 1941-1947

17. Maksymowicz, R. M.; Roth, P. M. C.; Fletcher, S. P., Nat. Chem. 2012, 4, 649-654

18. d' Augustin, M.; Palais, L.; Alexakis, A., Angew. Chem. Int. Ed. 2005, 44, 1376-137818.

19. Sidera, M.; Roth, P. M.; Maksymowicz, R. M.; Fletcher, S. P., Angew. Chem. Int. Ed. 2013, 52, 7995-7999

20. Pantiga, S. S.; Diaz, C. H.; Rubio, E.; Gonzalez, J. M., Angew. Chem. Int. Ed. 2012, 51, 11552-11555

41

Phosphoramidites in synthesis References

21. Gonzalez, A. Z.; Benitez, D.; Tkatchouk, E.; Goddard, W. A.; Toste, F. D., J. Am. Chem. Soc. 2011, 133, 5500-5507

22. Konya, D.; Robert, F.; Gimbert, Y.; Greene, A. E., Tetrahedron Lett. 2004, 45, 6975-6978

23. Fan, B. M.; Xie, J. H.; Li, S.; Tu, Y. Q.; Zhou, Q. L., Adv. Synth. Catal. 2005, 347, 759-762

24. Trost, B. M.; Silverman, S. M.; Stambuli, J. P., J. Am. Chem. Soc. 2011, 133, 19483-19497

25. Trost, B. M.; Stambuli, J. P.; Silverman, S. M.; Schworer, U., J. Am. Chem. Soc. 2006, 128, 13329-13329

26. Trost, B. M.; Cramer, N.; Silverman, S. M., J. Am. Chem. Soc. 2007, 129, 12396-12397

27. Faller, J. W.; Fontaine, P. P., Organometallics 2005, 24, 4132-4138

28. Liu, B.; Li, K. N.; Luo, S. W.; Huang, J. Z.; Pang, H.; Gong, L. Z., J. Am. Chem. Soc. 2013, 135, 3323-3326

29. Gulias, M.; Duran, J.; Lopez, F.; Castedo, L.; Mascarenas, J. L., J. Am. Chem. Soc. 2007, 129, 11026-11027

30. Alonso, I.; Faustino, H.; Lopez, F.; Mascarenas, J. L., Angew. Chem. Int. Ed. 2011, 50, 11496-11500

31. Shintani, R.; Nakatsu, H.; Takatsu, K.; Hayashi, T., Chem. Eur. J. 2009, 15, 8692-8694

32. Straker, R. N.; Anderson, E. A., unpublished results

33. Toselli, N.; Martin, D.; Achard, M.; Tenaglia, T. B.; Buono, G., Adv. Synth. Catal. 2008, 350, 280-286

34. Trost, B. M.; McDougall, P. J.; Hartmann, O.; Wathen, P. T., J. Am. Chem. Soc. 2008, 130, 14960-14961

35. Strijdonck, G. P. F.; Boele, M. D. K.; Kamer, P. C. J.; de Vries, J. G.; van Leeuwen, P. W. N. M., Eur. J. Inorg. Chem. 1999, 1073-1076

36. Imbos, R.; Minaard, A. J.; Feringa, B. L., J. Am. Chem. Soc. 2002, 124, 184-185

37. Boele, M. D. K.; Kamer, P. C. J.; Lutz, M.; de Vries, J. G.; van Leeuwen, P. W. N. M.; van Strijdonck, G. P. F., Chem. Eur. J. 2004, 10, 6232-6246

38. Zeng, B. S.; Yu, X.; Siu, P. W.; Scheidt, K. A., Chem. Sci. 2014, 5, 2277-2281

39.  Luparia, M.; Oliveira, M. T.; Audisio, D.; Frebault, F.; Goddard, R.; Maulide, N., Angew. Chem. Int. Ed. 2011, 50, 12631-12635

40 Misale, A.; Niyomchon, S.; Luparia, M.; Maulide, N., Angew. Chem. Int. Ed. 2014, 53, 7068-7073

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