Total Synthesis of Bryostatin 16 Using a Pd-Catalyzed Diyne Coupling as Macrocyclization Method and Synthesis of C20-epi-Bryostatin 7 as a Potent Anticancer Agent

Asymmetric total synthesis of bryostatin 16 was achieved in 26 steps in the longest linear sequence and in 39 total steps from aldehyde 10. A Pd-catalyzed alkyne-alkyne coupling was employed for the first time as a macrocyclization method in a natural product synthesis. A route to convert bryostatin 116 to a new family of bryostatin analogues was developed. Toward this end, 20-epi-bryostatin 7 was synthesized from a bryostatin 16-like intermediate; the key step involves a Re-catalyzed epoxidation/ring-opening reaction. Preliminary biological studies indicated that this new analogue exhibits nanomolar anticancer activity against several cancer cell lines.