Influence of Michael acceptor stereochemistry on intramolecular Morita-Baylis-Hillman reactions

Abstract

A study of the effect of Michael acceptor stereochemistry on the efficiency of intramolecular Morita-Baylis-Hillman (MBH) reactions has been performed. The reactions were catalyzed by a phosphine, and the reaction substrates studied were enones containing a pendant aldehyde moiety attached at the β-position of the alkene group. In all cases examined with PPh 3 as the catalyst, cyclization substrates possessing (Z)-alkene stereochemistry afforded a much higher yield of the desired product than did the E isomeric substrates under identical reaction conditions. This was also true when a polymer-supported phosphine catalyst was used. While both alkene isomers afforded the same product, in parallel reactions, the Z isomer afforded 2.5-8.5 times higher yield than did the corresponding E isomer. It is proposed that steric effects are a possible source of this dramatic difference in reactivity. Substrates where the β-substituent is cis to the electron-withdrawing substituent are relatively more accessible to react with the nucleophile catalyst than are their trans counterparts. These findings are expected to be useful in the design of synthetic intermediates, as intramolecular MBH reactions are being increasingly used in the preparation of complex synthetic targets. © 2006 American Chemical Society.