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Amination of a Green Solvent via Immobilized Biocatalysis for the Synthesis of Nemtabrutinib
ACS Catalysis ( IF 11.3 ) Pub Date : 2023-05-26 , DOI: 10.1021/acscatal.3c00941 Christopher K. Prier 1 , Karla Camacho Soto 1 , Jacob H. Forstater 1 , Nadine Kuhl 1 , Jeffrey T. Kuethe 1 , Wai Ling Cheung-Lee 1 , Michael J. Di Maso 1 , Claire M. Eberle 1 , Shane T. Grosser 1 , Hsing-I Ho 1 , Erik Hoyt 2 , Anne Maguire 1 , Kevin M. Maloney 1 , Amanda Makarewicz 1 , Jonathan P. McMullen 1 , Jeffrey C. Moore 1 , Grant S. Murphy 1 , Karthik Narsimhan 1 , Weilan Pan 1 , Nelo R. Rivera 2 , Anumita Saha-Shah 2 , David A. Thaisrivongs 1 , Deeptak Verma 3 , Adeya Wyatt 1 , Daniel Zewge 2
ACS Catalysis ( IF 11.3 ) Pub Date : 2023-05-26 , DOI: 10.1021/acscatal.3c00941 Christopher K. Prier 1 , Karla Camacho Soto 1 , Jacob H. Forstater 1 , Nadine Kuhl 1 , Jeffrey T. Kuethe 1 , Wai Ling Cheung-Lee 1 , Michael J. Di Maso 1 , Claire M. Eberle 1 , Shane T. Grosser 1 , Hsing-I Ho 1 , Erik Hoyt 2 , Anne Maguire 1 , Kevin M. Maloney 1 , Amanda Makarewicz 1 , Jonathan P. McMullen 1 , Jeffrey C. Moore 1 , Grant S. Murphy 1 , Karthik Narsimhan 1 , Weilan Pan 1 , Nelo R. Rivera 2 , Anumita Saha-Shah 2 , David A. Thaisrivongs 1 , Deeptak Verma 3 , Adeya Wyatt 1 , Daniel Zewge 2
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Enzymes are capable of unique and selective transformations that can enable efficient chemical production. While many industrial processes have been developed using free enzymes in aqueous solutions, immobilizing enzymes on a solid support can offer considerable advantages, including improved reaction efficiency, enzyme stability, the ability to perform reactions in non-aqueous media, and simplified separation of the product from the enzyme. Herein, we describe the development of a biocatalytic transaminase reaction of Cyrene (2) utilizing an immobilized, evolved transaminase enzyme in an organic solvent to provide amine intermediate 3a en route to Bruton’s tyrosine kinase (BTK) inhibitor nemtabrutinib. Enzyme immobilization is critical to facile isolation of the water-soluble product. Improved reaction kinetics and diastereoselectivity were achieved by bridging directed enzyme evolution with the selection of an optimal reaction solvent and solid support for immobilization, enabling a unified solvent system and direct isolation of 3a as a crystalline salt with dr > 50:1.
中文翻译：
通过固定化生物催化胺化绿色溶剂合成 Nemtabrutinib
酶能够进行独特的选择性转化，从而实现高效的化学生产。虽然许多工业工艺是使用水溶液中的游离酶开发的，但将酶固定在固体支持物上可以提供相当大的优势，包括提高反应效率、酶稳定性、在非水介质中进行反应的能力以及简化产物分离来自酶。在此，我们描述了 Cyrene ( 2 )的生物催化转氨酶反应的开发，利用有机溶剂中的固定化进化转氨酶来提供胺中间体3a正在开发布鲁顿酪氨酸激酶 (BTK) 抑制剂 nemtabrutinib。酶固定对于水溶性产物的轻松分离至关重要。通过将定向酶进化与选择最佳反应溶剂和用于固定的固体支持物桥接，实现了反应动力学和非对映选择性的改进，从而实现了统一的溶剂系统和以dr > 50:1 的结晶盐形式直接分离 3a 。
更新日期：2023-05-26
中文翻译：
通过固定化生物催化胺化绿色溶剂合成 Nemtabrutinib
酶能够进行独特的选择性转化，从而实现高效的化学生产。虽然许多工业工艺是使用水溶液中的游离酶开发的，但将酶固定在固体支持物上可以提供相当大的优势，包括提高反应效率、酶稳定性、在非水介质中进行反应的能力以及简化产物分离来自酶。在此，我们描述了 Cyrene ( 2 )的生物催化转氨酶反应的开发，利用有机溶剂中的固定化进化转氨酶来提供胺中间体3a正在开发布鲁顿酪氨酸激酶 (BTK) 抑制剂 nemtabrutinib。酶固定对于水溶性产物的轻松分离至关重要。通过将定向酶进化与选择最佳反应溶剂和用于固定的固体支持物桥接，实现了反应动力学和非对映选择性的改进，从而实现了统一的溶剂系统和以dr > 50:1 的结晶盐形式直接分离 3a 。
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