Brevibacterium epidermidis催化酮不对称还原胺化合成(S)-手性胺

doi:10.1016/S1872-2067(18)63108-0

催化学报 ›› 2018, Vol. 39 ›› Issue (10): 1625-1632.DOI: 10.1016/S1872-2067(18)63108-0

Brevibacterium epidermidis催化酮不对称还原胺化合成(S)-手性胺

李清华^a, 董源^b, 陈飞飞^a, 柳磊^a, 李春秀^a, 许建和^a, 郑高伟^a

a 华东理工大学生物反应器工程国家重点实验室, 上海 200237;
b 中国人民解放军第三〇二医院药学部, 北京 100039

收稿日期:2018-04-30 修回日期:2018-05-24 出版日期:2018-10-18 发布日期:2018-08-03
通讯作者: 郑高伟
基金资助:
国家自然科学基金（21472045，21536004）；国防科技创新特区项目（17-163-12-ZT-003-055-01）.

Reductive amination of ketones with ammonium catalyzed by a newly identified Brevibacterium epidermidis strain for the synthesis of (S)-chiral amines

Qing-Hua Li^a, Yuan Dong^b, Fei-Fei Chen^a, Lei Liu^a, Chun-Xiu Li^a, Jian-He Xu^a, Gao-Wei Zheng^a

a State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China;
b Department of Pharmacy, 302 Hospital of People's Liberation Army, Beijing 100039, China

Received:2018-04-30 Revised:2018-05-24 Online:2018-10-18 Published:2018-08-03
Contact: 10.1016/S1872-2067(18)63108-0
Supported by:
This work was supported by the National Natural Science Foundation of China (21472045, 21536004), and the National Defense Scientific and Technological Innovation Special Zone (17-163-12-ZT-003-055-01).

摘要/Abstract

摘要：

光学纯手性胺是一类非常重要的手性化学品，作为手性砌块和手性拆分剂广泛用于医药、农业化学品、精细化学品等产品的合成中.据统计，美国FDA近年来批准的约40%药物中都含有一个或多个手性胺结构单元.胺脱氢酶（AmDH）是由氨基酸脱氢酶改造而来的一类催化酮不对称还原胺化的新酶，其在手性胺的合成中展现出较强的潜力，已引起国内外学术界和工业界的广泛关注.这是因为该酶能够利用廉价的无机铵为胺供体，且具有催化效率高、原子经济性好和环境友好等优点.迄今为止已经有数个高效的胺脱氢酶被成功开发和报道，但是这些通过蛋白质工程改造的胺脱氢酶均为（R）-选择性，因此只能合成（R）-选择性的手性胺，遗憾的是还未见有（S）-选择性胺脱氢酶的报道.因此，本文主要目的是期望从自然环境中鉴定能够不对称还原胺化酮合成（S）-手性胺的微生物，进而从中分离得到能够以无机铵作为胺供体合成（S）-手性胺的（S）-选择性酶.
本文首先利用苯乙胺作为唯一氮源，从土壤中筛选能够利用苯乙胺生长的菌株，进而利用苯乙酮作为初筛底物对得到的菌株进行胺化能力筛选，再利用（4-氟苯基）丙酮作为模式底物进行进一步的筛选.幸运的是，我们获得了能够利用无机铵作为胺供体催化（4-氟苯基）丙酮不对称还原胺化合成（S）-4-氟-α-甲基苯乙胺的菌株，经过16S RNA鉴定为表皮短杆菌，命名为B.epidermidis ECU1015.
接下来，我们对B.epidermidisECU1015催化的胺化反应中的关键参数如胺基供体及其最适浓度、反应温度、pH值和底物浓度等进行了优化，确定最佳反应条件：胺供体为NH₄Cl（1.25mol/L），反应温度为30℃，KPB缓冲液（200mmol/L，pH 7.5），底物浓度10mmol/L.最后，在最适的反应条件下，我们对B.epidermidis ECU1015催化的底物谱进行了研究.结果表明，该微生物不能催化大位阻芳香酮和链状酮的胺化，对位阻较小的苯乙酮及（4-氟苯基）丙酮具有较好的还原胺化能力，而且对苯环上带有吸电子取代基的酮化合物具有更好的转化效果.经手性分析，所有生成的手性胺均为（S）-构型，产品的光学纯度均>99%.
B.epidermidis催化酮不对称胺化所形成的产物构型均为（S）-选择性，这不同于已报道的（R）-选择性胺脱氢酶.该菌株的发现为（S）-选择性胺脱氢酶的进一步鉴定奠定了一定的研究基础，相关蛋白的分离纯化工作正在进行.

关键词: 生物催化, 还原胺化, 不对称合成, 潜手性酮, 手型胺

Abstract:

The asymmetric reductive amination of achiral ketones with ammonia is a particularly attractive reaction for the synthesis of chiral amines. Although several engineered amine dehydrogenases have been developed by protein engineering for the asymmetric reductive amination of ketones, they all display (R)-stereoselectivity. To date, there is no report of an (S)-stereoselective biocatalyst for this reaction. Herein, a microorganism named Brevibacterium epidermidis ECU1015 that catalyzes the (S)-selective reductive amination of ketones with ammonium has been successfully isolated from soil. Using B. epidermidis ECU1015 as the catalyst, the asymmetric reductive amination of a set of phenylacetone derivatives was successfully carried out, yielding the corresponding (S)-chiral amines with moderate conversion and >99% enantiomeric excess.

Key words: Biocatalysis, Reductive amination, Asymmetric synthesis, Prochiral ketones, Chiral amine

李清华, 董源, 陈飞飞, 柳磊, 李春秀, 许建和, 郑高伟. Brevibacterium epidermidis催化酮不对称还原胺化合成(S)-手性胺[J]. 催化学报, 2018, 39(10): 1625-1632.

Qing-Hua Li, Yuan Dong, Fei-Fei Chen, Lei Liu, Chun-Xiu Li, Jian-He Xu, Gao-Wei Zheng. Reductive amination of ketones with ammonium catalyzed by a newly identified Brevibacterium epidermidis strain for the synthesis of (S)-chiral amines[J]. Chinese Journal of Catalysis, 2018, 39(10): 1625-1632.

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Brevibacterium epidermidis催化酮不对称还原胺化合成(S)-手性胺

Reductive amination of ketones with ammonium catalyzed by a newly identified Brevibacterium epidermidis strain for the synthesis of (S)-chiral amines

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