AN EFFICIENT AND PRACTICAL TOTAL SYNTHESIS OF (+)-VINCAMINE FROM L-ASPARTIC ACID
AN EFFICIENT AND PRACTICAL TOTAL SYNTHESIS OF (+)-VINCAMINE FROM L-ASPARTIC ACID
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DOI：
10.1021/jo00297a023
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发表时间：
1990-05-11
影响因子：
3.6
通讯作者：
RAPOPORT, H
中科院分区：
文献类型：
--
作者：
GMEINER, P;FELDMAN, PL;RAPOPORT, H
光学纯的α-叔丁基β-以L-天冬氨酸为起始原料合成了（2S，3R）-3-乙基六氢喹啉酸甲酯（18），产率为54-59%，为（+）-长春胺的实际合成奠定了基础。L-天冬氨酸向18的转化通过两种途径完成。在第一条路线中，酯化之后是单-N-烷基化以连接三碳残基。氮保护和分子内C-烷基化得到哌啶，其随后被加工成六氢喹啉18。在第二条路线中，顺序颠倒。在适当的N-保护后，天冬氨酸酯在β-位被C-烷基化。碳，然后分子内N-烷基化。这两种路线都得到对映体纯的18;然而，后一种序列在执行中更简单，并且得到高得多的产率。18与溴代十六烷基化得到形成四环吲哚并喹嗪的底物。这可以通过直接加热苯基膦酰二氯中的甲酯或通过α-膦酰二氯水解后产生的磷酰二氯离子的环化来实现。叔丁基酯。C3非对映异构体容易分离和平衡，得到所需的C3-α H差向异构体。四环吲哚并喹嗪10的转化遵循文献先例，并在确定中间体醛不会通过逆曼尼希反应失去构型完整性后得到五环（+）-长春胺。该合成以24-26%的总产率从L-天冬氨酸提供（+）-长春胺，其被证明是> 99%对映体纯的。
Synthesis of optically pure .alpha.-tert-butyl .beta.-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 .beta.-carbon and then intramolecularly N-alkylated. Both routes gave enantiomerically pure 18; however, the latter sequences 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 minium ion generated after hydrolysis of the .alpha.-tert-butyl ester. The C3 diastereomers are easily separated and equilibrated, resulting in the required C3-.alpha.H 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.