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Total synthesis of bryostatin 3

Stitching alkynes into bryostatin 3 The bryostatin family of marine natural products has been explored for a wide variety of pharmaceutical applications but remains challenging to source. The general structure comprises a macrocycle that contains three smaller, six-membered rings. Bryostatin 3 is distinguished by the added complexity of a fourth, fused lactone ring. Trost et al. report a convergent synthesis of this complex molecule, taking advantage of alkyne coupling reactions to stitch together three main fragments and asymmetric dihydroxylation and propargylation reactions to set stereochemistry. Science, this issue p. 1007 A convergent strategy reliant on alkyne couplings offers a streamlined route to a macrocyclic natural product. Bryostatins are a family of 21 complex marine natural products with a wide range of potent biological activities. Among all the 21 bryostatins, bryostatin 3 is structurally the most complex. Whereas nine total syntheses of bryostatins have been achieved to date, bryostatin 3 has only been targeted once and required the highest number of steps to synthesize (43 steps in the longest linear sequence and 88 total steps). Here, we report a concise total synthesis of bryostatin 3 using 22 steps in the longest linear sequence and 31 total steps through a highly convergent synthetic plan by the use of highly atom-economical and chemoselective transformations in which alkynes played a major role in reducing step count.