Alkynones Derived from Tartaric Acid : Efficient Building Blocks for the Synthesis of Macrolactone Natural Products

Abstract

The thesis describes the synthesis and application of various alkynones derived from the bis-Weinreb amide of tartaric acid in the total synthesis of macrolactone natural products. The thesis is divided into three sections. First section of the thesis describes the optimization and generalization of the procedure for the addition of alkynyl Grignard / lithium reagents to the bis-Weinreb amide derived from tartaric acid to yield the mono alkynyl ketones was developed. Application of the formed γ-oxo amides was demonstrated in the synthesis of polyols with varied substitutions particularly the synthesis of 1,2,4-triols was accomplished using Ley’s dithianylation as the key step. Scheme 1: Synthesis of polyols from the bis-weinreb amide of tartaric acid. Application of the strategy to the total synthesis of decanolactone natural products achaetolide and (Z)-isomer of (6S,7R,9R)-6,7-dihydroxy-9-propylnon-4-eno-9-lactone was featured. Section B of the thesis deals with the enantiospecific total synthesis of 14-membered macrolactone Sch 725674. Key reactions in the synthesis include the synthesis of the 1,2,4-triol unit from tartaric acid, olefin cross metathesis and ring closing metathesis. Scheme 4: Enantiospecific total synthesis of Sch 725674. Section C of the thesis describes the enantiospecific synthesis of the C9-C22 fragment of the 28-membered polyene polyol macrolide pentamycin. Although isolated in 1958, total synthesis of this antifungal compound was not reported. In application of the methodology developed, the alkynone prepared from the bis-Weinreb amide was elaborated to the required fragment.