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Preparation of (S)-1-Cyclopropyl-2-methoxyethanamine by a Chemoenzymatic Route Using Leucine Dehydrogenase
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2012-02-17 00:00:00 , DOI: 10.1021/op2003562
William L. Parker 1 , Ronald L. Hanson 1 , Steven L. Goldberg 1 , Thomas P. Tully 1 , Animesh Goswami 1
Affiliation  

(S)-1-Cyclopropyl-2-methoxyethanamine is a key chiral intermediate for the synthesis of a corticotropin-releasing factor-1(CRF-1) receptor antagonist. Resolution of the racemic amine by transaminase from Vibrio fluvalis gave a 38% yield of the S-amine with 53% ee. Resolution by lipase-catalyzed acylation provided the S-amine in 35% yield with 91% ee. With limited success of these resolution approaches, an efficient chemo-enzymatic route to (S)-1-cyclopropyl-2-methoxyethanamine was devised starting from methylcyclopropyl ketone. Permanganate oxidation of the ketone gave cyclopropylglyoxylic acid, which was converted to (S)-cyclopropylglycine by reductive amination using leucine dehydrogenase from Thermoactinomyces intermedius with NADH cofactor recycling by formate dehydrogenase from Pichia pastoris. Both enzymes were cloned and expressed in recombinant E. coli. (S)-Cyclopropylglycine obtained from enzymatic reductive amination was isolated as the N-Boc derivative and converted to the desired amine by reduction, methylation, and deprotection to give (S)-1-cyclopropyl-2-methoxyethanamine in 62% overall yield from cyclopropylglyoxylic acid, with no detectable R-enantiomer.

中文翻译:

亮氨酸脱氢酶的化学酶法制备(S)-1-环丙基-2-甲氧基乙胺

S)-1-环丙基-2-甲氧基乙胺是合成促肾上腺皮质激素释放因子-1(CRF-1)受体拮抗剂的关键手性中间体。通过来自流感病毒弧菌的转氨酶拆分外消旋胺,得到38%的S-胺收率和ee的53%。通过脂肪酶催化的酰化作用的拆分提供了S-胺,产率为35%,ee为91%。在这些拆分方法的成功有限的情况下,从甲基环丙基酮开始,设计了一种有效的化学酶促途径来合成(S)-1-环丙基-2-甲氧基乙胺。酮的高锰酸盐氧化得到环丙基乙醛酸,将其转化为(S)-环丙基甘氨酸的还原胺化反应,使用了来自中间嗜热放线菌的亮氨酸脱氢酶和来自巴斯德毕赤酵母的甲酸脱氢酶对NADH辅助因子进行的循环利用。两种酶都被克隆并在重组大肠杆菌中表达。(小号)-Cyclopropylglycine从酶促还原胺化得到的,分离到Ñ -Boc衍生物和转化为所需的胺进行还原,甲基化,和脱保护,得到(小号)-1-环丙基-2-甲氧基乙胺在62%的总收率从环丙基乙醛酸,无可检测的R-对映体。
更新日期:2012-02-17
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