Total Synthesis of Bryostatin 2

Abstract

The total synthesis of the marine macrolide bryostatin 2 is described. The synthesis plan relies on aldol and directed reduction steps in order to construct the anti-1,3-diol array present in each of the principal subunits (A, B, and C). These fragments were coupled using a Julia olefination and subsequent sulfone alkylation. A series of functionalization reactions provided a bryopyran seco acid, which was macrolactonized under Yamaguchi conditions. Installation of the two enoate moieties took advantage of asymmetric phosphonate and aldol condensation strategies. Reduction of the C20 ketone and simple protecting group operations then completed the synthesis of bryostatin 2. This flexible approach should provide access to a series of new analogues of this clinically important marine natural product.