Bryostatin 1 is a marine natural product that is a very promising lead compound due to the potent biological activity it displays against a variety of human disease states. We describe herein the first total synthesis of this agent. The synthetic route adopted is a highly convergent one in which preformed and heavily functionalized pyran rings A and C are united by "pyran annulation": the TMSOTf promoted reaction between a hydroxy allylsilane appended to the A ring fragment and an aldehyde contained in the C ring fragment, with concomitant formation of the B ring. Further elaborations of the resulting very highly functionalized intermediate include macrolactonization and selective cleavage of just one of five ester linkages present.Bryostatin 1 is a now well-known natural product originally isolated by Pettit and coworkers from the marine organism Bugula neritina. 1 Since that time, other members of this family have been isolated such that some 20 members are now known. 2 It has also been established that the true source of the bryostatins is not actually Bugula neritina, but rather a bacterial symbiont. 3 Interest in the bryostatins, and bryostatin 1 in particular, has been intense due to the wide range of potent bioactivity associated with bryostatin 1. Bryostatin 1 has shown activity against a range of cancers, and has also shown synergism with established oncolytic agents such as Taxol®. 4 This has led to the use of bryostatin 1 in numerous clinical trials for cancer, despite the absence of any renewable supply for this compound at present. In addition, bryostatin 1 has shown promising activity relevant to a number of other diseases and conditions, including diabetes, 5 stroke, 6 and Alzheimer's disease. 7 A clinical trial for Alzheimer's disease is commencing. 8 This wide range of promising potential indications for bryostatin 1 becomes more understandable when it is recognized that at least one mechanism for function of this agent involves activity on protein kinase C (PKC) isozymes and on other C1 domain containing proteins. 9 These signaling proteins are known to regulate some of the most critical cellular processes and properties, including proliferation, differentiation, motility and adhesion, inflammation, and apoptosis. 10 Given this backdrop, it is not surprising that synthetic activity directed towards the bryostatins has been intense. What is surprising, perhaps, is that bryostatin 1 itself has not been previously synthesized, while other members of the family have been prepared. Previous total syntheses include those of bryostatin 7 (2, by Masamune), bryostatin 2 (3, by Evans), bryostatin 3 (4, by Yamamura), and bryostatin 16 (5, by Trost). In addition, Hale has described a formal synthesis of bryostatin 7, and Trost has recently reported a synthesis of C20-epi-bryostatin 7. 11 * keck@chem.utah.edu .Supporting Information Available Experimental procedures and spectral data. This material is available free of charge via the Internet at http://pubs.acs.org. Another very important aspect...