Preparation of (S)-1-Cyclopropyl-2-methoxyethanamine by a Chemoenzymatic Route Using Leucine Dehydrogenase

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• 作者：William L. Parker ; Ronald L. Hanson ; Steven L. Goldberg ; Thomas P. Tully ; Animesh Goswami
• 刊名：Organic Process Research & Development
• 出版年：2012
• 出版时间：March 16, 2012
• 年：2012
• 卷：16
• 期：3
• 页码：464-469
• 全文大小：209K
• 年卷期：v.16,no.3(March 16, 2012)
• ISSN：1520-586X

文摘

(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.