Insight into the Stereoselective Synthesis of (1S)‐Nor(pseudo)ephedrine Analogues by a Two‐Steps Biocatalytic Process

• Published in: ChemCatChem 2024-02, Vol.16 (3), p.n/a
• Main Authors: Fracchiolla, Noemi, Patti, Stefania, Sangalli, Fabio, Monti, Daniela, Presini, Francesco, Giovannini, Pier Paolo, Parmeggiani, Fabio, Brenna, Elisabetta, Tessaro, Davide, Ferrandi, Erica Elisa
• Format: Article
• Language: English
• Subjects: Alcohols; Benzoin; biocatalysis; Biological activity; Chemical synthesis; chiral drugs; Condensates; Ephedrine; green chemistry; stereoselective synthesis; Stereoselectivity; transaminases
• ISSN: 1867-3880; 1867-3899
• DOI: 10.1002/cctc.202301199

Nor(pseudo)ephedrines (N(P)Es), vicinal amino alcohols possessing sympathomimetic biological activity, constitute valuable intermediates and chiral building blocks for the organic synthesis of several active pharmaceutical ingredients (APIs). Due to the presence of two chiral centers, their conventional chemical asymmetric syntheses often involve long, multi‐step procedures, frequently with the aid of expensive and harmful metal catalysts, making it challenging to achieve high yields and optical purities overall. A two‐steps biocatalytic synthetic sequence for the preparation of (1S)‐N(P)E analogues was therefore designed and carried out, consisting of a benzoin‐type condensation catalysed by the (S)‐selective acetoin:dichlorophenolindophenol oxidoreductase (Ao:DCPIP OR) and a transamination mediated by either an (S)‐ or (R)‐selective amine transaminase (ATA). A multistep chemical synthesis of racemic N(P)Es was also optimised in order to obtain reference material for evaluating the performance of the biocatalysed reactions. The novel bi‐enzymatic synthesis provided the desired products with acceptable yields and good diastereo‐ and enantiomeric excesses, thereby paving the way for greener production of these important building blocks. The stereodivergent synthesis of variously substituted norephedrines has been attained starting from the cheap and commercially available corresponding aromatic aldehydes through a bi‐enzymatic synthetic sequence. In the first step, a benzoin‐type condensation is mediated by the (S)‐selective acetoin:dichlorophenolindophenol oxidoreductase (Ao:DCPIP OR), while in the second step either a (R)‐ or a (S)‐amino transaminase (ATA) is employed to carry out a transamination and obtain the final products. An array of 14 substrates has been combined with 6 different ATAs, and the products have been characterised in terms of conversion and enantiomeric excess.