Department of Chemistry, University of Manchester, Manchester Institute of Biotechnology, 131 Princess Street, Manchester M1 7DN, United Kingdom.
School of Engineering Sciences in Chemistry, Biotechnology and Health, Department of Industrial Biotechnology, KTH Royal Institute of Technology, AlbaNova University Center, 11421 Stockholm, Sweden.
J Am Chem Soc. 2023 Oct 11;145(40):22041-22046. doi: 10.1021/jacs.3c07010. Epub 2023 Oct 2.
Novel building blocks are in constant demand during the search for innovative bioactive small molecule therapeutics by enabling the construction of structure-activity-property-toxicology relationships. Complex chiral molecules containing multiple stereocenters are an important component in compound library expansion but can be difficult to access by traditional organic synthesis. Herein, we report a biocatalytic process to access a specific diastereomer of a chiral amine building block used in drug discovery. A reductive aminase (RedAm) was engineered following a structure-guided mutagenesis strategy to produce the desired isomer. The engineered RedAm (IR-09 W204R) was able to generate the (,,)-isomer in 45% conversion and 95% ee from the racemic ketone . Subsequent palladium-catalyzed deallylation of yielded the target primary amine in a 73% yield. This engineered biocatalyst was used at preparative scale and represents a potential starting point for further engineering and process development.
在寻找创新型生物活性小分子治疗药物的过程中，新型结构单元的需求一直很高，因为它们能够构建结构-活性-性质-毒性关系。含有多个手性中心的复杂手性分子是化合物库扩展的重要组成部分，但通过传统的有机合成方法很难获得。本文报道了一种生物催化方法，用于获得药物发现中使用的手性胺砌块的特定非对映异构体。采用基于结构的突变策略对还原胺酶（RedAm）进行了工程改造，以产生所需的异构体。工程化的 RedAm（IR-09 W204R）能够将外消旋酮 转化为 45%的目标（,,）-异构体，ee 值为 95%。随后，钯催化的 脱烯丙基化反应以 73%的收率得到目标伯胺 。该工程化的生物催化剂已用于制备规模，代表了进一步工程化和工艺开发的潜在起点。
