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

• Published in: Organic process research & development Vol. 28; no. 9; pp. 3545 - 3559
• Main Authors: Shaw, Megan H., Fryszkowska, Anna, Alvizo, Oscar, Attadgie, Ilana, Borra-Garske, Margie, Devine, Paul N., Duan, Da, Grosser, Shane T., Forstater, Jacob H., Hughes, Gregory J., Maloney, Kevin M., Margelefsky, Eric L., Mattern, Keith A., Miller, Margaret T., Nawrat, Christopher C., Nazor, Jovana, Orth, Peter, Ouimet, Claire M., Robaire, Sandra A., Ruccolo, Serge, Schwalm, Erica L., Verma, Deeptak, Xiao, Li, Zhang, Victoria
• Format: Journal Article
• Language: English
• Published: American Chemical Society 20-09-2024
• Subjects: oxidation; drug manufacture; process development; enzymatic cascades; biocatalysis
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/acs.oprd.4c00075

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).