Stereochemistry of Conjugate Addition Reactions

Mohrig, Jerry

Abstract

The objective of this project is a comprehensive understanding of the stereochemistry of 1,4-conjugate (Michael) additions with simple, conjugated acyclic carbonyl compounds. These will serve as model systems for increased understanding of enzymatic Michael additions, especially those which provide a major class of enzyme-activated irreversible inhibition, or suicide inactivation, reactions. In addition, the project could lead to improved methods for the control of Michael addition steps in the stereoselective organic synthesis of conformationally-mobile acyclic molecules. Since our discovery that the addition of EtOD across the C=C of ethyl crotonate to give ethyl 3-ethoxy(2-2H1) butanoate is highly stereoselective (greater than 93% anti), we have been searching for the causes of this dramatic and unexpected anti addition. The proposed research will focus upon the reactions of esters and thioesters of the four-carbon substrate, crotonic acid (CH3CH=CHCO2H), with a variety of nucleophiles. These reactions will allow systematic investigation of the electronic and steric factors which relate to the stereochemistry of the Michael addition. A major part of the research will be devoted to examination of structural factors in the stereoselectivity of the protonation of enolate anions. Our earlier research on the stereochemistry of 1,2-elimination reactions that produce acyclic, conjugated esters and thioesters has led to the development of straightforward methods for configurational assignments in isotopically-labelled substrates and products through the use of FT NMR. The availability of a 200 MHz FT NMR spectrometer and a GC with a Mass Selective Detector, along with a strong undergraduate program and excellent students, make the research feasible at Carleton College.