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Discovery of an Imine Reductase for Reductive Amination of Carbonyl Compounds with Sterically Challenging Amines
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2023-01-20 , DOI: 10.1021/jacs.2c11354 Fei-Fei Chen 1 , Xue-Feng He 1 , Xin-Xin Zhu 1 , Zhi Zhang 1 , Xin-Yuan Shen 1 , Qi Chen 1 , Jian-He Xu 1 , Nicholas J Turner 2 , Gao-Wei Zheng 1
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2023-01-20 , DOI: 10.1021/jacs.2c11354 Fei-Fei Chen 1 , Xue-Feng He 1 , Xin-Xin Zhu 1 , Zhi Zhang 1 , Xin-Yuan Shen 1 , Qi Chen 1 , Jian-He Xu 1 , Nicholas J Turner 2 , Gao-Wei Zheng 1
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The synthesis of structurally diverse amines is of fundamental significance in the pharmaceutical industry due to the ubiquitous presence of amine motifs in biologically active molecules. Biocatalytic reductive amination for amine production has attracted great interest owing to its synthetic advantages. Herein, we report the direct synthesis of a wide range of sterically demanding secondary amines, including several important active pharmaceutical ingredients and pharmaceutical intermediates, via reductive amination of carbonyl substrates and bulky amine nucleophiles employing imine reductases. Key to success for this route is the identification of an imine reductase from Penicillium camemberti with unusual substrate specificity and its further engineering, which empowered the accommodation of a broad range of sterically demanding amine nucleophiles encompassing linear alkyl and (hetero)aromatic (oxy)alkyl substituents and the formation of final amine products with up to >99% conversion. The practical utility of the biocatalytic route has been demonstrated by its application in the preparative synthesis of the anti-hyperparathyroidism drug cinacalcet.
中文翻译：
发现一种亚胺还原酶，用于羰基化合物与空间挑战胺的还原胺化
由于生物活性分子中普遍存在胺基序，结构多样的胺的合成在制药工业中具有根本意义。用于胺生产的生物催化还原胺化由于其合成优势而引起了人们的极大兴趣。在此，我们报道了通过使用亚胺还原酶对羰基底物和大胺亲核试剂进行还原胺化，直接合成了各种空间要求较高的仲胺，包括几种重要的活性药物成分和药物中间体。该路线成功的关键是从卡门贝尔青霉中鉴定出具有不寻常底物特异性的亚胺还原酶及其进一步的工程设计，从而能够适应各种空间要求高的胺亲核试剂，包括直链烷基和（杂）芳族（氧基）烷基取代基和最终胺产物的形成，转化率高达 >99%。该生物催化路线的实用性已通过其在抗甲状旁腺功能亢进药物西那卡塞的制备合成中的应用得到证明。
更新日期：2023-01-20
中文翻译：
发现一种亚胺还原酶，用于羰基化合物与空间挑战胺的还原胺化
由于生物活性分子中普遍存在胺基序，结构多样的胺的合成在制药工业中具有根本意义。用于胺生产的生物催化还原胺化由于其合成优势而引起了人们的极大兴趣。在此，我们报道了通过使用亚胺还原酶对羰基底物和大胺亲核试剂进行还原胺化，直接合成了各种空间要求较高的仲胺，包括几种重要的活性药物成分和药物中间体。该路线成功的关键是从卡门贝尔青霉中鉴定出具有不寻常底物特异性的亚胺还原酶及其进一步的工程设计，从而能够适应各种空间要求高的胺亲核试剂，包括直链烷基和（杂）芳族（氧基）烷基取代基和最终胺产物的形成，转化率高达 >99%。该生物催化路线的实用性已通过其在抗甲状旁腺功能亢进药物西那卡塞的制备合成中的应用得到证明。
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