Preparative Asymmetric Synthesis of Canonical and Non‐canonical α‐amino Acids Through Formal Enantioselective Biocatalytic Amination of Carboxylic Acids

Chemical and biocatalytic synthesis of non‐canonical α‐amino acids (ncAAs) from renewable feedstocks and using mild reaction conditions has not efficiently been solved. Here, we show the development of a three‐step, scalable and modular one‐pot biocascade for linear conversion of renewable fatty acids (FAs) into enantiopure l‐α‐amino acids. In module 1, selective α‐hydroxylation of FAs is catalyzed by the P450 peroxygenase P450CLA. By using an automated H2O2 supplementation system, efficient conversion (46 to >99%; TTN>3300) of a broad range of FAs (C6:0 to C16:0) into valuable α‐hydroxy acids (α‐HAs; >90% α‐selective) is shown on preparative scale (up to 2.3 g L−1 isolated product). In module 2, a redox‐neutral hydrogen borrowing cascade (alcohol dehydrogenase/amino acid dehydrogenase) allowed further conversion of α‐HAs into l‐α‐AAs (20 to 99%). Enantiopure l‐α‐AAs (e.e. >99%) including the pharma synthon l‐homo‐phenylalanine can be obtained at product titers of up to 2.5 g L−1. Based on renewables and excellent atom economy, this biocascade is among the shortest and greenest synthetic routes to structurally diverse and industrially relevant ncAAs.