Total Synthesis of Bryostatin 2

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.