Synthesis of Enantiopure Fluoropiperidines via Biocatalytic Desymmetrization and Flow Photochemical Decarboxylative Fluorination

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2024-09-30 DOI:10.1021/acs.oprd.4c00139

Caroline A. Blakemore, John M. Humphrey, Eddie Yang, Jeffrey T. Kohrt, Peter Daniel Morse, Roger M. Howard, Hatice G. Yayla, Thomas Knauber, Longfei Xie, Teresa Makowski, Jeffrey W. Raggon, Rebecca B. Watson, Christopher W. am Ende, Tim Ryder, Ormacinda White, Martin R. M. Koos, Rajesh Kumar, Feng Shi, Jie Li, Huan Wang, Like Chen, Julai Wang

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Abstract

Low-molecular weight chiral amines are valuable components in medicinal chemistry as they serve as core templates, linking units, and substituent appendages. The piperidine scaffold is particularly useful among privileged small amines, with substituted variants having a great number of potential regio- and diastereoisomers, which allow for high stereochemical definition to enable a variety of productive protein interactions. Herein, we describe the successful enablement, scale-up, and delivery of >400 g of a single isomer, (3S,5S)-1-((benzyloxy)carbonyl)-5-fluoropiperidine-3-carboxylic acid (>98% de and >96% ee), via 450 g-scale biocatalytic desymmetrization and 335 g-scale flow photochemical decarboxylative fluorination.

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通过生物催化去对称化和流动光化学脱羧氟化反应合成对映体不纯的氟哌啶类化合物

低分子量手性胺是药物化学中的重要成分，因为它们可以作为核心模板、连接单元和取代基附属物。哌啶支架在特优小胺中尤其有用，其取代变体具有大量潜在的区域和非对映异构体，可实现高度的立体化学定义，从而实现各种富有成效的蛋白质相互作用。在此，我们介绍了通过 450 克规模的生物催化非对称反应和 335 克规模的流动光化学脱羧氟化反应，成功制备、放大和提供了 400 克的单一异构体--(3S,5S)-1-((苄氧基)羰基)-5-氟哌啶-3-羧酸（98% de 和 96% ee）。

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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.