A Collaborative Journey towards the Late-Stage Functionalization of Added-Value Chemicals Using Engineered Halogenases

In 2017, two companies, Novartis AG and Syngenta AG, joined forces with the group of Prof. Buller, head of the Competence Center for Biocatalysis (CCBIO), to tackle the challenge of enzymatic late-stage halogenation. This biocatalytic method was considered to provide a more sustainable approach to late-stage halogenation of complex molecules than traditional synthetic approaches. Using machine-learning guided protein engineering, alpha-ketoglutarate dependent halogenases were evolved into versatile catalysts capable of selectively chlorinating inactivated C-H bonds. Structurally diverse molecules, namely an analogue of martinelline as well as two members of the soraphen natural product family, were enzymatically chlorinated at two distinct positions in a regio- and stereoselective manner, thus demonstrating the synthetic usefulness of such a strategy. As part of our three-year collaboration, flavin-dependent halogenases were also studied.