【作者】 李明；

【导师】 陆群；

【作者基本信息】 西南交通大学 ， 生物化工， 2014， 硕士

【摘要】 含有哌啶环的环状α-氨基酸被用来制备含有多种生物活性的重要化合物。哌啶酸是一种非天然氨基酸,最初发现于真菌、植物、人类的生理体液中的代谢物中,具有高效的生物活性。4-取代衍生物是哌啶酸最常见的衍生物,其是一种经过修饰的非天然氨基酸,常常表现出有效地生物活性,在这些化合物中,4-甲基-2-哌啶酸乙酯是制备选择性凝血酶抑制剂（2R,4R）-MQPA和阿加曲班的一个关键中间体。本论文主要对4-甲基-2-哌啶酸乙酯的合成及活性拆分进行了深入研究。首先以手性S-甲基苄胺和乙醛酸乙酯为原料合成手性亚胺,然后与异戊二烯进行不对称Diels-Alder反应得到（6R/S）-[1-（S）-甲基-苄基]-4-甲基-3,4-烯-6-哌啶酸乙酯,即4-甲基-2-哌啶酸已酯的前体化合物。对该前体化合物的手性拆分本文也做了大量研究,我们发现使用Lipase PS Amano SD和猪肝酯酶对（6R/S）-[1-（S）-甲基-苄基]₄-甲基-3,4-烯-6-哌啶酸乙酯进行生物拆分活性时,猪肝酯酶可专一的水解6R型化合物得到（6R）-[1-（S）-甲基-苄基]-4-甲基-3,4-烯-6-哌啶酸（de值高达99%）,进而可以获得（6S）-[1-（S）-甲基-苄基]-4-甲基-3,4-烯-6-哌啶酸乙酯,收率8%（de值71%）。然后,我们对（6S）-[1-（S）-甲基-苄基]-4-甲基-3,4-烯-6-哌啶酸乙酯的氢化还原做了一系列条件考察,结果显示Pd/C可在一定条件下可同时氢化还原（6S）-[1-（S）-甲基-苄基]-4-甲基-3,4-烯-6-哌啶酸乙酯结构中3,4-双键和1-叔胺,得到（2S,4R）-4-甲基-2-哌啶甲酸乙酯,收率为61%,而PtO2.3H2O只能选择性的催化还原（6S）-[1-（S）-甲基-苄基]-4-甲基-3,4-烯-6-哌啶酸乙酯结构中3,4-双键,得到（2S,4R）-[1-（S）-甲基-苄基]-4-甲基-2-哌啶甲酸乙酯和（2S,4S）-[1-（S）-甲基-苄基]-4-甲基-2-哌啶甲酸乙酯,收率分别为18%和6.1%。最后,我们还对（2S,4R/4S）-哌啶甲酸乙酯的生物拆分活性进行了一系列尝试,但并没有获得理想结果。更多还原

【Abstract】 Cyclic a-amino acids containing a piperidine ring are often employed in producing important muti-biological activities compounds. Pipecolic acids,which always show high biological activity, are non-natural amino acids,they were first found in fungi, plant and biological fluids of human. The largest subgroup of pipecolicacid derivatives is4-substituted compounds. The4-Substituted pipecolic acid derivatives are unnatural amino acids with modification, which often present very important biological activities. Among the4-substituted derivatives,(2R,4R)-4-methylpipecolic acid is a key intermediate for the preparation of the high selectivity thrombin inhibitor Argatroban. This paper is focusing on the research of synthesis and chiral separation of (2R,4R)-4-methylpipecolic acid. S-methyl-benzylamine and ethyl glyoxylate were employed to give chiral imine,and then chiral imine was combined with isoprene to give (6R/S)-[1-(S)-benzyl]-4-methyl-3-ene-6-ethyl piperidine via Diels-Alder reacition, which is the precursor of (2R,4R)-4-methylpipecolic acid. We also found that Lipase PS Amano SD and pig liver esterase can specially degrade the (6R)-[1-(S)-benzyl]-4-methyl-3-ene-6-ethyl piperidine to give (6R)-[1-(S)-benzyl]-4-methyl-3-en-6-pipecolic acid(de:99%), which means we can obtain (6S)-[1-(S)-benzyl]-4-methyl-3-ene-6-ethyl piperidine via this method. After that, a lot experiments have been done in the hydrogenation of [1-(S)-benzyl]-4-methyl-3-ene-6-ethyl piperidine to obtain optimized reaction conditions. Actually, we found that [1-(S)-benzyl]-4-methyl-3-ene-6-ethyl piperidine can be deoxygenized by Pd/C completely, while PtO2.3H2O can only deoxygenize them partly. In detail,(2S,4R)-4-methyl-2-piperidinecarboxylate and (2S,4R/S)-[1-(S)-benzyl]-4-methyl-2-piperidinecarboxylate were obtain by using above-mentioned catalysts respectively. In addtion, this paper were trying to achieve the chiral separation of (2S,4R/S)[1-(S)-benzyl]-4-methyl-2-piperidinecarboxylate,but none positive results were obtained.更多还原