Development of a Biocatalytic Aerobic Oxidation for the Manufacturing Route to Islatravir

Biocatalytic oxidations have the potential to address many synthetic challenges, enabling the selective synthesis of chiral intermediates, such as carbonyl compounds, alcohols, or amines. The use of oxygen-dependent enzymes can dramatically reduce the environmental footprint of redox transformations at the manufacturing scale. Here, as part of the biocatalytic cascade to the anti-HIV investigational drug islatravir (1), we describe the development of an aerobic oxidation process delivering (R)-ethynylglyceraldehyde-3-phosphate (3) using an evolved galactose oxidase enzyme. Integrated enzyme and reaction engineering were critical for achieving a robust, high-yielding oxidation performed at pilot-plant scale (>20 kg, 90% yield).生物催化氧化反应具备解决诸多合成难题的潜力，可实现手性中间体的选择性合成，例如羰基化合物、醇类或胺类物质。采用需氧酶可大幅降低工业规模下氧化还原转化过程的环境足迹。本研究作为抗HIV研究性药物艾夫拉维（islatravir，编号1）的生物催化级联合成路线的一部分，报道了一种需氧氧化工艺的开发：该工艺利用经过进化改造的半乳糖氧化酶，制备得到(R)-乙炔基甘油醛-3-磷酸（编号3）。整合酶工程与反应工程技术，是实现中试规模（>20 kg，收率90%）下稳定、高收率氧化反应的关键。