Formal Total Synthesis of Hemibrevetoxin B by an Oxiranyl Anion Strategy.

Abstract

The synthesis of the tetracyclic structure of hemibrevetoxin B (1) was achieved through a linear approach involving sequential coupling of three kinds of sulfonyl-stabilized oxiranyl anions, 5b, 6b, and 7b, to the monocyclic tetrahydropyran 4 containing the requisite substituents. Two iterations of alkylation of an oxiranyl anion and 6-endo cyclization provided the 6,6,6-tricyclic ring system 34, which was efficiently transformed into the 6,6,7-ring system 35 by ring expansion using trimethylsilyldiazomethane. Installation of the final oxepane ring into 38 was carried out using a combination of the oxiranyl anion methodology and ring enlargement just described. Stereoselective introduction of a tertiary methyl group into 41 provided the tetracyclic compound 42a, which contains all the asymmetric centers of 1. Elaboration of 42a to the known compound 2, which was already transformed into hemibrevetoxin B, completed the formal total synthesis of the natural product.