Belactosin A is a naturally occurring proteasome inhibitor with potent anti-tumor activity. Key structural features include a cyclopropane ring, as well as a terminal beta-lactone, and activity is conferred by acylation of the beta-lactone with Threonine 1 of the proteasome. Several syntheses have been reported, however only a few analogs have been prepared. An approach to the synthesis of novel analogs is reported here, with the key step being the cyclopropanation of an amino-acid derived enone to access both nitrocyclopropyl and estercyclopropyl peptidomimetics. Efforts to improve stereoselectivity in the cyclopropanation using quinine-based catalysts are reported, as well as coupling of the cyclopropyl peptidomimetic core to beta-lactams as alternates to the beta-lactone. The use of phenylalanine, leucine, isoleucine and valine as starting materials leads to benzyl, isobutyl, sec-butyl and isopropyl analogs of the natural product.

Synthesis of analogs of the proteasome inhibitor belactosin A

251st National Meeting (2016)

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