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Development of a Concise and Robust Route to a Key Fragment of MCL‑1 Inhibitors via Stereoselective Defluoroborylation

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journal contribution
posted on 27.09.2021, 23:29 by Matthieu Jouffroy, Philip Pye, Soufyan Jerhaoui, Wenyong Chen, Michel Surkyn
MCL-1 is an attractive target for cancer therapy. We recently discovered highly potent and selective MCL-1 inhibitors containing a fluoroalkene fragment for which an efficient route to the main chiral gem-fluoro-BPin fragment was needed. The key step of this synthesis is a highly stereoselective defluoroborylation of a gem-difluorovinyl intermediate. The latter is reached via a copper-catalyzed diastereoselective opening of dimethyloxirane. These two features allowed a 30-fold improvement in yield, a shorter synthesis, and a decrease in the cost of this crucial building block.