Synthetic studies towards the CDE fragment of pectenotoxin-4

Abstract

This thesis describes the synthesis of the structurally complex CDE fragment 187 of PTX-4 (5) which was achieved in 25 steps. The retrosynthetic approach used is depicted below. Formation of the bicyclic D ring involved a tandem cyclisation which was initiated upon vanadyl acetylacetonate promoted epoxidation of alkene 189. The stereochemistry at C18 and C21 has tentatively been assigned as (18S,21S) based on initial molecular modelling experiments, which mirrors the natural stereochemistry present in PTX-4 (5). Acyclic CDE fragment 189 was prepared by the addition of an α-sulfonyl carbanion derived from sulfone 234 to E ring aldehyde 190. Elaborated C ring adduct 234 was accessed via an indium-mediated addition of allylic bromide 240 to model C ring aldehyde 185. Adoption of a Felkin-Anh transition state was required to effect installation of the correct anti (2S,1'R)-stereθchernistry. Unequivocal assignment of the C16 Stereocentre was achieved via analysis of the Mosher ester derivatives. The 2,5-trans E ring 190 was prepared via iodoetherification of tertiary alcohol 193A. A late stage homoallyl Grignard addition of metallated 4-bromobutene was used to furnish the desired tertiary alcohol 193A. The stereochemistry at C25 was established by derivatisation of the tertiary alcohol 193 together with extensive NOE experiments. The Stereogenic centre at C27 in alcohol 193 was derived via initial use of the commercially available Roche ester 195.