Engineering a Keto-Reductase for the Mass-Efficient Synthesis of a Key Building Block, Trans-Ethyl (3-Hydroxycyclobutyl)Acetate

IF 3.3 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2026-08-21 Epub Date: 2026-07-13 DOI:10.1021/acs.oprd.6c00230

Qikang Huang, Wei Wang, Yaqin Peng, Keke Dong, Pan Wu, Qian Yang, Youyong Xu, Yuanxian Wang, Hongjun Gao, Ye Zhang

引用次数: 0

Abstract

The chiral building block ethyl (3-hydroxycyclobutyl)acetate is vital for synthesizing several drug classes. Traditional chemical synthesis often suffers from multi-step routes with low overall yield and significant challenges in achieving efficient stereocontrol for this chiral cyclobutane derivative. This study develops a new route to its trans isomer via AI-driven enzyme engineering. A tailored keto-reductase (BuKRED-M3) was created using semi-rational design and machine learning method, achieving >98.0% de for this non-native substrate. The resulting biocatalytic process cuts production costs by 33.8% versus prior routes, featuring a shorter, higher-yielding synthesis with reduced PMI, thereby offering a promising approach to more efficient manufacturing of this chiral intermediate.

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设计一种酮还原酶，用于高质量高效合成一种关键结构块，反式（3-羟基环丁基）乙酸乙酯

手性构建块（3-羟基环丁基）乙酸乙酯是合成几种药物的关键。传统的化学合成方法存在多步路线、总收率低的问题，对手性环丁烷衍生物进行高效立体控制的难度很大。本研究通过人工智能驱动的酶工程开发了一种新的反式异构体的途径。使用半理性设计和机器学习方法创建了定制的酮还原酶（BuKRED-M3），对这种非天然底物的降解率达到了98.0%。由此产生的生物催化工艺与之前的路线相比，生产成本降低了33.8%，具有更短，更高收率和更低PMI的合成特点，从而为更有效地制造这种手性中间体提供了一种有希望的方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Organic Process Research & Development 化学-应用化学

CiteScore

6.90

自引率

14.70%

发文量

251

审稿时长

2 months

期刊介绍： The journal Organic Process Research & Development serves as a communication tool between industrial chemists and chemists working in universities and research institutes. As such, it reports original work from the broad field of industrial process chemistry but also presents academic results that are relevant, or potentially relevant, to industrial applications. Process chemistry is the science that enables the safe, environmentally benign and ultimately economical manufacturing of organic compounds that are required in larger amounts to help address the needs of society. Consequently, the Journal encompasses every aspect of organic chemistry, including all aspects of catalysis, synthetic methodology development and synthetic strategy exploration, but also includes aspects from analytical and solid-state chemistry and chemical engineering, such as work-up tools，process safety, or flow-chemistry. The goal of development and optimization of chemical reactions and processes is their transfer to a larger scale; original work describing such studies and the actual implementation on scale is highly relevant to the journal. However, studies on new developments from either industry, research institutes or academia that have not yet been demonstrated on scale, but where an industrial utility can be expected and where the study has addressed important prerequisites for a scale-up and has given confidence into the reliability and practicality of the chemistry, also serve the mission of OPR&D as a communication tool between the different contributors to the field.