Approaches to the total synthesis of viridenomycin

Abstract

Viridenomycin is a polyene macrolide possessing considerable biological activity. Much work has been performed previously within the Whiting group on the development of methodology for the stereoselective synthesis of polyenes and this project builds on this work. New conditions have been developed to allow the HM reactions of electron-poor vinyl iodides with vinylboronate esters. This, combined with previously developed methodology involving the use of iodine monochloride and sodium methoxide to substitute the boronate ester function with an iodide group in a stereoslective manner, allowed the stereoselective synthesis of the Z,Z,E-triene northern hemisphere of viridenomycin. Conditions have been developed to allow further HM reactions and amide couplings of this fragment. In developing conditions for the HM reactions of electron-poor vinyl iodides, a number of side reactions were observed, often in competition with the desired processes. Presented within is a study of these reactions with regard to their generality and mechanism. A number of routes to the highly substituted cyclopentenone fragment of viridenomycin have been developed with the most successful of these showing high yield as well as enantio- and diastereo-selectivity. In this process, a number of unusual cross-ozomides have been isolated in which two new chiral centres were formed with complete diastereoselectivity. Conditions to permit diastereoselective conjugate additions to the cyclopentenones synthesised have been developed. The yields and diastereoselectivites of these reactions were somewhat variable, however, in the best case both proved to be high. Thus, one of the three fragments of viridenomycin have been synthesised whilst another is at a very advanced stage. In addition, some work has been performed on the conditions required for the final assembly.