| Total synthesis of bryostatin 1, a complex natural product with promising antitumor and anti Alzheimer's activity, was pursued utilizing an efficient method for the preparation of its northern fragment (C1-C16). Desymmetrization of a C2-symmetric diene diol by ketalization/ring-closing metathesis provided a rigid 2,9-dioxabicyclo[3.3.1]nonane template for stereoselective functionalization of bryostatin 1 A-ring. B-ring was constructed via a diastereoselective hetero Diels-Alder reaction. Synthesis of bryostatin 1 northern fragment was completed after further elaboration in 23 steps from commercially available starting compounds and 0.52% overall yield. This synthesis highlights a significant improvement on the previous syntheses of bryostatins.;Novel end game strategies for the total synthesis of bryostatin 1 were also investigated. In this regard, work on a late stage B-ring formation strategy as the bryostatin 1 end game approach is currently underway in our laboratory. |
