Methodology Development for the Stereoselective Synthesis of Protected Pyrrolidines and à-Alkyl-à,á-Dihydroxy Esters.

Abstract

This thesis describes the development of methods for the stereoselective synthesis of protected pyrrolidines and -alkyl-,-dihydroxy esters. The method for the synthesis of protected pyrrolidines is a palladium-catalyzed carboamination of protected -amino alkenes with aryl halides, and accomplishes the formation of both a carbon-nitrogen and carbon-carbon bond and up to two stereocenters in a single step with up to >20:1 diastereoselectivity. The scope of this transformation is described in detail, along with a refinement of reaction conditions which improve the functional group tolerance, and broaden the range of substrates that can be effectively transformed. A discussion of the diastereoselectivity obtained in the formation of disubstituted protected pyrrolidines is also presented. This methodology has been applied to the stereoselective synthesis of antifungal and antitumor agents preussin and 3-epi-preussin, along with new preussin analogs that differ in their aromatic ring substitution. Studies towards the synthesis of pyrrolidine alkaloid anisomycin are also described. During the course of studies on Pd-catalyzed carboamination reactions that employ mild bases, we discovered a tandem directed carbopalladation/C–H bond functionalization that afforded cyclopentane-fused benzocyclobutene molecules. The scope of this new reaction is discussed along with a mechanistic hypothesis on the origin of these products. The second part of this thesis describes a new method for the synthesis of -alkyl-,-dihydroxy esters. This transformation involves a tandem Wittig rearrangement-aldolreaction of methyl O-benzyl and methyl O-allyl glycolate esters, and was discovered during our work towards the synthesis of anisomycin. The reaction affords -alkyl-,-dihydroxy esters in one step with >20:1 diastereoselectivity. The scope, limitations and mechanism of this new reaction are also discussed.