Chen Jing, Chen Xi, Song Jinsong, Zhang Hongliu, Yang Hongjiang, Feng Jinhui, Wu Qiaqing, Zhu Dunming
School of Biotechnology, Tianjin University of Science and Technology Tianjin 300457 China.
Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences Tianjin 300308 China
RSC Adv. 2025 Jun 26;15(26):21133-21141. doi: 10.1039/d5ra02485d. eCollection 2025 Jun 16.
Chiral 3-substituted-4-hydroxypiperidines are highly valuable in pharmaceutical applications due to their diverse and potent biological activities. Biocatalytic ketone reduction by carbonyl reductases represents a promising approach for synthesizing these compounds. In this study, two structurally similar yet stereoselectively distinct carbonyl reductases, HeCR and DbCR, were identified. Both enzymes exhibited exceptional catalytic performance, with >99% enantiomeric excess (ee) and >99% conversion rate in the reduction of -butyl 4-oxo-3-phenylpiperidine-1-carboxylate (1a). We found that 1a exhibits a relatively low rate of racemization under the mild reaction conditions. Subsequently, analogs of 1a were synthesized and reduced with high enantioselectivity (ee > 99%) using HeCR and DbCR. Carbonyl reductases demonstrated excellent catalytic activity and stereoselectivity in the synthesis of 3-substituted-4-hydroxypiperidines with dual chiral centers, underscoring their potential for pharmaceutical applications.
手性3-取代-4-羟基哌啶因其多样且强大的生物活性在药物应用中具有很高的价值。通过羰基还原酶进行生物催化酮还原是合成这些化合物的一种有前景的方法。在本研究中，鉴定出了两种结构相似但立体选择性不同的羰基还原酶，即HeCR和DbCR。在还原4-氧代-3-苯基哌啶-1-羧酸叔丁酯（1a）时，这两种酶均表现出卓越的催化性能，对映体过量（ee）>99%且转化率>99%。我们发现1a在温和反应条件下的外消旋化速率相对较低。随后，合成了1a的类似物，并使用HeCR和DbCR以高对映选择性（ee>99%）进行还原。羰基还原酶在合成具有双 chiral 中心的3-取代-4-羟基哌啶时表现出优异的催化活性和立体选择性，突显了它们在药物应用中的潜力。 （注：原文中“chiral”重复出现，推测可能有误，这里保留原文进行翻译）
