Enantio-Complementary Continuous-Flow Synthesis of 2-Aminobutane Using Covalently Immobilized Transaminases

Heckmann, Christian M.; Dominguez, Beatriz; Paradisi, Francesca

Abstract

Chiral amines are a common feature of many active pharmaceutical ingredients. The synthesis of very small chiral amines is particularly challenging, even via biocatalytic routes, as the level of discrimination between similarly sized R-groups must be exceptional, yet their synthesis creates attractive building blocks that may then be used to prepare diverse compounds in further steps. Herein, the synthesis of one of the smallest chiral amines, 2-aminobutane, using transaminases, is being investigated. After screening a panel of mainly wild-type transaminases, two candidates were identified: an (S)-selective transaminase from Halomonas elongata (HEwT) and a precommercial (R)-selective transaminase from Johnson Matthey (*RTA-X43). Notably, a single strategic point mutation enhanced the enantioselectivity of HEwT from 45 to >99.5% ee. By covalently immobilizing these candidates, both enantiomers of 2-aminobutane were synthesized on a multigram scale, and the feasibility of isolation by distillation without the need for any solvents other than water was demonstrated. The atom economy of the process was calculated to be 56% and the E-factors (including waste generated during enzyme expression and immobilization) were 55 and 48 for the synthesis of (R)-2-aminobutane and (S)-2-aminobutane, respectively.

Citation

Heckmann, C. M., Dominguez, B., & Paradisi, F. (2021). Enantio-Complementary Continuous-Flow Synthesis of 2-Aminobutane Using Covalently Immobilized Transaminases. ACS Sustainable Chemistry and Engineering, 9(11), 4122-4129. https://doi.org/10.1021/acssuschemeng.0c09075

• Journal Article Type: Article
• Acceptance Date: Feb 23, 2021
• Online Publication Date: Mar 5, 2021
• Publication Date: Mar 22, 2021
• Deposit Date: Jun 24, 2021
• Publicly Available Date: Mar 6, 2022
• Journal: ACS Sustainable Chemistry & Engineering
• Electronic ISSN: 2168-0485
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 9
• Issue: 11
• Pages: 4122-4129
• DOI: https://doi.org/10.1021/acssuschemeng.0c09075
• Public URL: https://nottingham-repository.worktribe.com/output/5376934
• Publisher URL: https://pubs.acs.org/doi/10.1021/acssuschemeng.0c09075
• Additional Information: This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Sustainable Chemistry and Engineering, copyright © 2021 American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://pubs.acs.org/doi/10.1021/acssuschemeng.0c09075