Solvent Switching in Continuous Multistep Chemoenzymatic Synthesis: Telescoping Enzymatic Synthesis of Chiral, Pyridine-Containing Amines with Cross-Coupling as a Case Study

Abstract

Chiral α-(hetero)aryl primary amines are gaining momentum for their biological activities and their use as building blocks in more complex molecules. Here we report a continuous chemoenzymatic strategy from 2-acetyl-6-bromopyridine enabled by careful solvent selection and phase switching. Combining a first biocatalytic transamination reaction performed by TsRTA in a biphasic system in continuous flow, with inline Boc-protection and Suzuki coupling of a (substituted)phenylboronic acid, achieves conversions up to >99% toward tert-butyl (R)-(1-(6-(substituted) phenylpyridin-2-yl)ethyl)carbamate as the final product. This strategy not only constitutes an important example of chemoenzymatic combinations in continuous flow but also highlights the importance of the reaction design to minimize waste (through unreacted substrate recirculation), avoid time intensive workups (through inline extractions), and achieve the product in a space time yield of 68 mg L–1 h–1 with excellent enantiomeric excess (99% ee).