Total synthesis of belizentrin methyl ester: the polyhydroxylated sidechain

Abstract

Herein, the first concise total synthesis of belizentrin methyl ester as a stable derivative of the natural product is described. Belizentrin was isolated as a structurally complex secondary metabolite from the marine dinoflagellate Prorocentrum belizeanum. This polyketide is a potent neurotoxin decorated with 16 stereocentres in total, comprising of a polyunsaturated macrocyclic core structure and a polyhydroxylated sugar-based sidechain. Key steps of the synthesis of the western polyhydroxylated sidechain enclosed an E-selective Wittig olefination and a Sharpless dihydroxylation aiming for the central all-syn-triol motif. The route towards its C-glucosidic core involved the preparation of a highly enolizable phosphorus ylide which could only be obtained after P-alkylation of the corresponding bromo ketone in benzene glass. The western belizentrin fragment was obtained in 17 steps (LLS) with an overall yield of 3-5% starting from the commercially available amino acid L-glutamic acid and the per-Oacetyl derivative of alpha-D-glucose. The final coupling of the western and eastern belizentrin counterparts was finally achieved via the Kocienski modification of the Julia olefination after transmetallation to zinc regarding the vulnerability of the highly base-sensitive polyene motif.