Total Syntheses of Bryostatins 1, 7, 9 and 9-N3

Abstract

Bryostatins are a family of marine natural products that have garnered significant interests, as evidenced by over 40 clinical trials. However, their extremely low natural abundance has severely limited further research. Despite significant efforts, which have led to the total synthesis of seven bryostatin members by eight independent research groups, these complex molecules present persistent challenges for stereocontrolled, large-scale, and especially divergent synthesis. Here, we report the divergent total syntheses of bryostatins 1, 7, 9 and 9-N₃. Notably, 1.5 g of bryostatin 1 was obtained in a single sequence of the final three steps. Key transformations include Ni-catalyzed reductive cross-coupling to rapidly assemble the northern fragment, the flow chemistry-assisted visible light-induced alkyl radical conjugate addition to convergently construct the southern fragment, and an intramolecular geminal bis(silyl) Prins cyclization to establish the cis-Z selectivity on the B-ring. The syntheses consist of 20–22 steps in the longest linear sequence and 33–35 total steps, with overall yields ranging from 3.3 % to 4.5 %.