Phosphate Tethers in Synthesis: The Total Synthesis of Dolabelide C.

Abstract

The utilization of phosphate tethers in synthesis is the focus of the dissertation research described herein. Specifically, cross metathesis of various olefin partners with a phosphate tether has been demonstrated. These studies established the Type III olefin reactivity of the exocyclic olefin of the triply allylic bicyclic phosphate tether. Cross metathesis between the bicyclic phosphate and complex olefin partners allowed for rapid assembly of advanced polyol subunits. Understanding the reactivity of the bicyclic phosphate allowed for the application of this methodology toward the synthesis of a natural product. The target chosen was dolabelide C, a 24-membered macrolactone possessing cytotoxicity against HeLa-S3 cervical cancer cells. Retrosynthetic analysis of dolabelide C revealed two subunits that could be accessed by the developed bicyclic phosphate tether methodologies. In the synthesis of the C1-C14 subunit of dolabelide C the bicyclic phosphate tether mediates a selective cross metathesis with the terminal exocyclic olefin, differentiates the endocyclic and exocyclic olefins for selective hydrogenation, and serves as a leaving grouping for a regioselective palladium(0)-catalyzed hydride opening. Upon removal of the phosphate tether, the C1-C14 subunit of dolabelide C was completed in six subsequent steps. Studies toward the C15-C30 subunit of dolabelide C also utilized the bicyclic phosphate tether methodology. Three routes toward this subunit were realized, each took advantage of the latent leaving group ability of the phosphate tether to set the C23 stereocenter. These sequences supplied the C15-C30 of dolabelide C which was then prepared for pairing with the C1-C14 subunit. Final coupling of the C1-C14 and C15-C30 subunits of dolabelide C was accomplished and five more steps were successfully achieved, culminating in a macrocyclic ring-closing metathesis to completed the total synthesis of dolabelide C. The total synthesis of dolabelide C using our temporary phosphate tether methods was achieved in 24 steps (longest linear sequence from acetylacetone) and 54 total steps. The overall yield for this synthesis was 0.73% with an average yield per chemical step being 81.5%.