Stereocontrolled elaboration of quaternary carbon centers through the asymmetric Michael-type alkylation of chiral imines/secondary enamines: Enantioselective synthesis of (+)-vincamine

Article abstract of DOI:10.1021/jo9622690

An enantioselective synthesis of (+)-vincamine (1) has been developed. The key strategic element was the stereocontrolled elaboration of a quaternary carbon center (future C-20 center of 1) by using the asymmetric Michael reaction involving chiral imines/secondary enamines under neutral conditions. Thus, addition of enaminolactam (S)-12, derived from ketolactam 7 (itself prepared in four steps from commercially available tryptamine) and (S)-1-phenylethylamine, to methyl acrylate led, after hydrolytic workup, to adduct (R)-6 with a 90% stereoselectivity. The critical removal of the additional keto group of 6 was then examined. After extensive experimentation, we finally established that the most efficient deoxygenation procedure was the Wolff-Kishner reduction of the corresponding keto acid, which proceeded with a 55% yield. The cornerstone [ABD]-tricyclic lactam ester 38 thus obtained was next cyclized under Bischler-Napieralski reaction conditions to afford, after catalytic hydrogenation of the intermediary iminium perchlorate salt, a mixture of the desired, known indoloquinolizidine 5 and its epimer 39, in a ratio of 6:1, respectively. Basic treatment of 5 led to (+)-homoeburnamonine 4, which was finally converted, according to a known procedure, into our goal (+)-vincamine (1). Thus, synthesis of (+)-vincamine (1) has been achieved by a linear sequence of 15 chemical operations, starting from tryptamine, with an overall yield of 1.2%.