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

    • Christian M. Heckmanna
    • Beatriz Dominguezb
    • Francesca Paradisia,c
    • aSchool of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD, United Kingdom
    • bJohnson Matthey, 28 Cambridge Science Park, Milton Road, Cambridge, CB4 0FP, United Kingdom
    • cDept. of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, CH-3012, Bern, Switzerland

    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.

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