Belactosin A is a naturally occurring proteasome inhibitor with potent anti-tumor activity.  Several other proteasome inhibitors, such as carfilzomib and bortezomib are used to treat myelomas, however belactosin A itself is not used clinically.  Key structural features of the natural product include a cyclopropane ring, as well as a terminal beta-lactone, and activity is conferred by acylation of the beta-lactone with a threonine of the proteasome.  Several syntheses have been reported, however only a few analogs have been prepared.  Although beta-lactams are classic serine traps, there is only one prior report of beta-lactam analogs as proteasome inhibitors.  The synthesis of several novel analogs of belactosin A is reported here, with the key step being coupling of cyclopropyl peptidomimetics to beta-lactams.   Cyclopropyl peptidomimetics are synthesized in an efficient four-step process from amino acid-derived Weinreb amides. The use of phenylalanine, leucine, isoleucine and valine as starting materials leads to benzyl, isobutyl, sec-butyl and isopropyl analogs of the natural product.<br/>

Synthesis of beta-lactam analogs of the proteasome inhibitor belactosin A

253rd National Meeting (2017)

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