Total Synthesis and Structural Studies of the Antiviral Marine Natural Product Hennoxazole A

Abstract

A concise synthetic strategy and the structure elucidation of hennoxazole A are presented. A meta-xylene degradation is used to construct the pyran segment, and the preparation of the skipped polyene moiety is accomplished via asymmetric reduction of β-stannyl enone, an S_N2 displacement of an allylic trimethylbenzoate with vinyl cuprate, and coupling of a vinyl-zinc reagent with a π-allyl palladium species. The final steps of the convergent total synthesis of (2S,4S,6S,8S,22R)-hennoxazole A involve an amide coupling followed by the construction of the bisoxazole core. The combined use of circular dichroism, total synthesis, and optical rotation serves to unequivocally establish the relative and absolute configuration of the marine natural product. A new empirical CD helicity rule is proposed that allows the assignment of bisallylic stereocenters in acyclic homoconjugated dienes. In addition, an independent proof of the configuration of hennoxazole A is based on an extensive study of van't Hoff's principle of optical superposition. This chiroptical analysis employs the additivity of the molar rotation [Φ] of the individual stereocenters.