Applications of Mukaiyama

Aldol Reaction

Presented By :

Gurudutt DubeyM.Tech. (Pharm.) I Semester

Department of Pharmaceutical Technology (Process Chemistry)National Institute of Pharmaceutical Education and Research, Mohali, Punjab (India)

1

INTRODUCTION

Mukaiyama Aldol Reactions :

O-Hydro-C-(α-acylalkyl)-addition

2

Trimethylsilyl enol ether acts as an enolate in Lewis acid catalysed reaction.

It is considered as hydrogen equivalent which attacks on aldol hydroxyl group.

March J. et al. Advance Organic Chemistry 6th edition, 2007, 1351

R1R2Me3SiO

O

R3 R4Lewis Acid

CH2Cl2

OR2

R1

R3

R4

R1

OR2

R4

OSiMe3R3

H2O

OH

3

Applications in Synthesis of Various Analogs

4Org. Lett. 2012, 14, 1168-1171

Direct Use of Esters in the Mukaiyama Aldol Reaction Esters can be efficiently used in place of aldehyde

R OMe

O

OMe

OSiMe3

R OMe

OOH5 mol% InI3HSiMe2Ph

DCM, r.t., 2-12 h

R: Alkyl, Benzyl

5

Synthesis of Functionalized Diazoacetoacetates from Diazoacetates

via Mukaiyama Reaction

Me3SiO

C2H5OAr

H ArN2

O

O OO

N2C2H5O

OH

3 mol% Sc(OTf)3

60-80%

DCM, rt

Diazo Decomposition of Mukaiyama-aldol Adduct

Org. Lett 2008, 10(8), 1605-1608

Ar

OO

N2

C2H5O

OTBS

1 mol% Rh2(OAc)3

DCM, reflux

OO

H OTBSR OTBS

R COOC2H5H COOC2H5

6

Enantioselective catalytic Mukaiyama reaction in aqueous media

Org. Biomol. Chem. 2004, 2, 3401-3407

PhMe

OTMS

PhCOPh

OH

Me

PhCHO

Ga(OTf)3 + L*(20 mol%)

Triton X-100 (3 mol%)

H2O, 0 0C, 72 h

41% yield, 84% ee

N N

But

OH

Ph

HOPh

Ph

OHPh

L* =

7

VINYLOGOUS MUKAIYAMA ALDOL REACTION

Org. Lett. 2007, 9(26), 5667-5639

R

O

OMe

OTBS

NH

O

NB

O

Ph

Ts OMe

O

R

OH

iPrOH

R= Alkyl, Aryl 99% ee

• For one step synthesis of δ-Hydroxy-α,β-unsaturated carbonyl compounds.

• Catalyst: Tryptophane-based B-phenyloxazaborolidinone

• Isopropyl alchol is used to improve the yield of enantioselective product.

Vinylogous Mukaiyama Aldol Reaction to Natural Product Synthesis

Intermediate formation in synthesis of Khafrefungin, an antifungal agent

8Org. Lett. 2007, 9(5), 849-852

N O N O

O OO

Me

R2

OH

Me

N O

OO

Me

R2

OH OTBS

Me

R1

R1=H

R2CHOTiCl4

R1=Me

R2CHOTiCl4

1,6,7- Remote Asymmetric Induction1,7- Remote Asymmetric Induction

Vinylogous Mukaiyama Aldol Reaction to Natural Product Synthesis

Intermediate formation in synthesis of Khafrefungin, an antifungal agent

9

H3C(H2C)9O

Me

OH

Me Me Me

O

Me Me

OOH

OH

OH

O

HO

Org. Lett. 2007, 9(5), 849-852

Khafrefungin

N O N O

O OO

Me

R2

OH

Me

N O

OO

Me

R2

OH OTBS

Me

R1

R1=H

R2CHOTiCl4

R1=Me

R2CHOTiCl4

1,6,7- Remote Asymmetric Induction1,7- Remote Asymmetric Induction

10

Asymmetric Synthesis of anti-β-Hydroxy-α-Amino Acid Derivatives Catalytic Enantio- and Diastereoselective Aldol Reactions of Glycine-Derived

Silicon Enolate with Aldehydes

R H

O

R OMe

O

OMe

OSiMe3

NF3C

OSiMe3Catalyst

toluene/ tBuOMe-20 0C, 12 h

0.5 M aq. KHSO4

OH

NHCOCF3

Catalyst:1. Zr(OtBu)4, ligand2. H2O (cat.), r.t., 1h

I

OH

OH

I

I

I

Ligand:

J. Am. Chem. Soc. 2004, 126, 9192-9193

11

H

MeO

H H8

910

1112

13

14

New approach toward the synthesis of steroid skeletons using

Mukaiyama reactions

(D)-Steroid Skeleton :

Tetrahedron 2006, 62,1726–1742

MeO

OSiR3

MeO

O

O

TrSbCl6C8-C14

bond formation

OSiR3

8

910

1112 13

14

Intermediary step

12

Thank You