Preliminary Efforts Towards Achieving Transient Directing Group Chemistry Enabled via a Tandem and Cooperative Concurrent Chemoenzymatic Cascade

Abstract

Directing groups (DGs) are moieties installed onto organic molecules to confer regioselectivity in subsequent reactions. DGs have found utility in selective CH activations catalyzed by transition metal (TM) catalysis on starting materials with multiple CH bonds. Despite their utility, DGs are scarcely used in industrial applications due to the generally wasteful nature of conventional DG strategies and their associated increase in step-count. Transient directing groups (TDGs) have been developed to overcome these limitations, with additives reversibly forming adducts with compounds of interest prior to the DG-mediated CH activation, in one-pot processes. However, the use of TDGs still requires harsh conditions to achieve significant yields, hindering broad applications. Chemoenzymatic catalytic cascades have attracted attention due to the mild and environmentally friendly nature of biocatalysis, with the greatest challenge being compatibility issues between biocatalytic and traditional chemical transformations. Here we propose a concurrent chemoenzymatic catalytic cascade that would enable TM-catalyzed DG chemistry via flanking biocatalytic reductive amination to install, and oxidative deamination to remove, a TDG. Preliminary efforts have identified some incompatibilities arising from the biocatalytic portion of the cascade, namely substrate specificity and organic co-solvent tolerance, that need to be addressed to achieve the proposed chemoenzymatic cascade in a one-pot concurrent protocol.