Studies in acyclic diastereocontrol. I. Investigations into the transition states of the methyl ketone aldol reaction, and, II. Studies towards the total synthesis of durhamycin A.

Abstract

The studies in this thesis describe two discreet research projects. The first two chapters describe an effort to elucidate the challenging issue of diastereocontrol in the methyl ketone aldol reaction. Models for predicting the diastereoselectivity of the methyl ketone aldol reaction traditionally cite the competition between chair-like and boat-like Zimmerman-Traxler transition states. Unfortunately, the lack of stereochemical information in the final aldol products prevents a rigorous verification of these models. The author describes the synthesis and application of an <italic>E</italic>(O)-deuterium labeled silyl enol ether which, when treated with methyl lithium, releases a configurationally stable <italic>E</italic>(O)-deuterium labeled lithium enolate. This enolate is then used to prove that the lithium mediated methyl ketone aldol reaction highly prefers chair-like transition states in both achiral and chiral aldol reactions. This conservation was found to be consistent across a wide subset of aldol reactions and ranged from approximately 7 : 1 to greater than 50 : 1. These data indicate that diastereoselectivity in the lithium mediated methyl ketone aldol reaction is due to a competition between two chair-like transition states, and not between a chair-like and a boat-like state as previously believed. This study represents the first rigorous evidence of such conservation. The third chapter of this thesis describes the attempt to extend this methodology into the aldol reactions of boron enolates derived from methyl ketones. Although several orthogonal techniques for the generation of deuterium labeled boron enolates are described, the author found that the boron enolates were configurationally unstable. Potential causes of this instability are discussed. The fourth and final chapter of this thesis describes exploratory studies towards a total synthesis of the aureolic acid durhamycin A. The unique anti-HIV activity of this natural product makes it an attractive target for synthetic studies. The author describes a potential synthesis of durhamycin based on a novel addition of silyl metal nucleophiles to <italic>ortho</italic>-quinone methides for the generation of benzylic allyl silanes.