Progress toward the total synthesis of the marine natural product amphidinol 3

A convergent synthesis of the C31-C52 bis-tetrahydropyran core of the natural product amphidinol 3 is reported. A common intermediate was synthesized from D-tartaric acid utilizing an asymmetric glycolate alkylation/ring-closing metathesis sequence to construct the THP rings. Differential elaboration of the common intermediate allowed the synthesis of two distinct coupling partners, which were joined through a modified Horner-Wadsworth-Emmons olefination to provide the bis-tetrahydropyran core. A convergent approach to the C9-C29 fragment has also been achieved, utilizing Julia-Kocienski olefination to unite key fragments. Exploiting the repeating units of the C1-C17 domain of the polyol fragment, stereocenters C2, C6, C10, and C14 have all been introduced via the asymmetric glycolate alkylation reaction. An iterative acetate aldol sequence followed by a propionate aldol provided the carbon skeleton and required stereocenters of the C21-C29 domain. Following completion of the polyol domain, union with the bis-tetrahydropyran core is envisioned to introduce the C1-C52 domain of amphidinol 3