AN EFFICIENT AND PRACTICAL TOTAL SYNTHESIS OF (+)-VINCAMINE FROM L-ASPARTIC ACID

Synthesis of optically pure α-terf-butyl β-methyl (2S,3R)-3-ethylhexahydroquinolinate (18) in 54-59% yield from L-aspartic acid was the foundation for a practical synthesis of (+)-vincamine. Conversion of L-aspartic acid to 18 was accomplished via two routes. In the first route, esterification was followed by mono-N-alkylation to attach the three-carbon residue. Nitrogen protection and intramolecular C-alkylation gave the piperidine, which was subsequently elaborated to hexahydroquinolinate 18. In the second route, the sequence was inverted. After appropriate N-protection, the aspartate was C-alkylated at the β-carbon and then intramolecularly N-alkylated. Both routes gave enantiomerically pure 18; however, the latter sequence was simpler in execution and gave much higher yields. Alkylation of 18 with tryptophyl bromide gave the substrate for formation of the tetracyclic indoloquinolizine. This was accomplished either by directly heating the methyl ester in phenylphosphonic dichloride or by cyclization of the iminium ion generated after hydrolysis of the a-tert-butyl ester. The C3 diastereomers are easily separated and equilibrated, resulting in the required C3-aH epimer. Transformation of the tetracyclic indoloquinolizine 10 followed literature precedent and led to the pentacyclic (+)-vincamine after it was established that the intermediate aldehyde did not lose configurational integrity via a retro-Mannich reaction. This synthesis provides (+)-vincamine, demonstrated to be =99% enantiomerically pure, in 24-26% overall yield from L-aspartic acid. © 1990, American Chemical Society. All rights reserved.