A gram-scale laboratory synthesis of Annonaceous acetogenin mimic AA005

Abstract

AA005 (1), a potent anticancer mimicking molecule of natural Annonaceous acetogenin, features a central C2-symmetric triglycol moiety and three stereogenic centers. To support ongoing animal studies, a scalable 10-step synthesis of AA005 (1) has been studied, optimized and accomplished in this work, starting from commercially available economic materials ethylene glycol and (R)-epichlorohydrin. A regio- and stereo-controlled BF3·Et2O-promoted epoxide opening of (R)-epichlorohydrin with ethylene glycol was investigated, optimized and successfully applied to the scalable preparation of the crucial fragment 6a with C2-symmetry. Further successive epoxide openings elaborated both two side chains and the whole skeleton with proper nucleophiles and electrophiles. Comparison and optimization of the reaction sequences finally led to completion of a new multi-gram synthesis of AA005 (1) with satisfactory enantiomeric and diastereomeric purity.