Sharpless Asymmetric Epoxidation

Nobel prize in 2001

Contents
Biography Introduction The need of epoxides Background knowledge Reagents Reaction New synthetic approach Modification References

Biography
Dr. Barry Sharpless

Born in Philadephia,1941,U.S.A.
Ph.D. from Stanford University 1968. Research on chiral synthesis

and catalysts at the Scripps Institute.

Received half Nobel Prize in 2001 for his work on stereoselective oxidation reactions.

Dr. Barry Sharpless receiving Noble prize

Introduction
The epoxide functional group consists of a three-member ring with two carbon atoms and one oxygen atom. These compounds are found in many naturally occurring organic molecules, as well as in industrial starting materials. One of the most widely used epoxidizing reagents is metachloroperoxybenzoic acid, or m-CPBA, because of its mild conditions and high yield. Assymetric epoxides Sharpless Epoxidation method.

The need of epoxides

Background knowledge

Stereoselectivity
Stereoselectivity is the property of a chemical reaction in which a

single reactant forms an unequal mixture of stereoisomers.

Depends on stereochemistry of transition states. If the transition states are enantiotopic, they have the same energy. The addition proceeds through each of them to the same extent and we thus obtain a 50:50 ratio of enantiomers, no enantioselectivity.

If the transition states are diastereotopic, they may have different

energies. The addition preferentially takes place via the lower energy transition state and preferentially results in more of one stereoisomer,

Background knowledge
A reaction that converts an achiral starting material into

predominantly one enantiomer is called an asymmetric reaction. If the formation of only one enantiomer is favored, the reaction is said to be enantioselective. There are many methods to synthesis epoxide but the most effective stereoselective method is Sharpless method of epoxidation.

Sharpless Asymmetric Epoxidation (SAE)

R3 R2
OH

O
magic
R2

R3 OH

R1

R1

R4

R4

Converts primary and secondary allylic alcohols into 2,3 epoxyalcohols. The reaction is enantioselective. Enantiomer formed depends on stereochemistry of catalyst.

The magic
Titanium isopropoxide Diethyl tartarate or diisopropyl tartarate tert-butyl hydroperoxide Dichloromethane- solvent Temperature 253K

Advantages of the Reagents

Titanium (IV) reagents are cheap and readily available.

Low toxicity compared to other transition metal catalysts. Less reactive than Li or Mg organometallics.
DET and DIPT are byproducts in wine making

Highly stereoselective (90% ee)

The Reaction
R2 R1
R2

R3 R4
OH

Ti(OiPr)4(+ +) DET tBuOOH CH2Cl2, -20C

R1 O R3 R4 OH

R2 R1

R2

Ti(OiPr)4(- -) DET
R3

R1 O R3 R4 OH

R4
OH

tBuOOH CH2Cl2, -20C

Reaction with Selectivity:

The catalyst is titanium tetra (isopropoxide) with diethyltartrate. The use of + or tartrate will yield different enantiomers. Tertbutylperoxide is used as the oxidizing agent. Dichloromethane solvent and -20C temperature.

The Catalyst
O
Ti

Ti(OiPr)4 catalyst
O O
OH OH

O O

Diethyl Tartrate (DET)

Diametric form of catalyst

The Successful Reaction

Epoxides can be easily converted into diols, amino alcohols & ethers. The Sharpless Epoxidation reacts with many primary and secondary allylic alcohols. The products of the Sharpless Epoxidation frequently have enantiomeric excesses above 90%. The products of the Sharpless Epoxidation are predictable using the Sharpless Epoxidation model. The reactants for the Sharpless Epoxidation are commercially available and relatively cheap.

Improvements
Stoichiometric amount of catalyst required. Water soluble substrates (Polymer Support) cannot be isolated after reaction. Requirement for low temperatures (high cost for SAE). The substrate may not be soluble in the solvent (low propoxide ion concentration) Heterogeneous reaction

References:
http://www.mosaicsciencemagazine.org/pdf/m16_01_85_04.pdf Kurti, L. and Czako, B. Strategic Application of Named Reactions in Organic Synthesis: Elsevier Academic Press, 2005. http://www.orgsyn.org/orgsyn/prep.asp?prep=cv7p0461 Journal of the Chemical Society " href="J._Chem._Soc.">Journal of the Chem.ical Society Tetrahedron Letters, Vo[. 38, No. 3, pp. 383-386. 1997Copyright 1996 Elsevier Science Ltd Printed in Great Britain David W. Knight *, Ian R. Morgan School of Chemistry, Cardiff University, Main College, Park Place, Cardiff, CF10 3AT, UK Tetrahedron Letters ,2008 Elsevier Ltd. Organic Mechanism/Reaction Stereochemistry and Synthesis/ Edited by Michael Harmata/With a foreword by Paul A. Wender/ Springer publication

References
Tetrahedron Letters, Vol. 38, No. 1, pp. 101-104, 1997Copyright 1996 Elsevier Science LtdPrinted in Great Britain. All rights reserved0040-4039/97. Organic Chemistry/Solomons and Fryhle/Fifth edition/Wiely India Publications.

vRushali s. raut
M.Sc. Sem- i