Merging enzymes with chemocatalysis for amide bond synthesis

Luis Bering,Sarah A Shepherd,Elliott J Craven,Stanley A Sowerby Thomas,Jason Micklefield

doi:10.1038/s41467-022-28005-4

Abstract

Amides are one of the most fundamental chemical bonds in nature. In addition to proteins and other metabolites, many valuable synthetic products comprise amide bonds. Despite this, there is a need for more sustainable amide synthesis. Herein, we report an integrated next generation multi-catalytic system, merging nitrile hydratase enzymes with a Cu-catalysed N-arylation reaction in a single reaction vessel, for the construction of ubiquitous amide bonds. This synergistic one-pot combination of chemo- and biocatalysis provides an amide bond disconnection to precursors, that are orthogonal to those in classical amide synthesis, obviating the need for protecting groups and delivering amides in a manner unachievable using existing catalytic regimes. Our integrated approach also affords broad scope, very high (molar) substrate loading, and has excellent functional group tolerance, telescoping routes to natural product derivatives, drug molecules, and challenging chiral amides under environmentally friendly conditions at scale.

Highlights

Amides are one of the most fundamental chemical bonds in nature
Issues of catalyst compatibility were overcome by retaining nitrile hydratase (NHase) enzymes within cells, while very high substrate loadings were achieved by the inclusion of micellar organo-compartments, enabling clean, practical, and scalable synthesis of diverse target amides
The approach affords excellent regio- and stereo-selectivity that is difficult to achieve with chemocatalysis alone

Summary

Introduction

Amides are one of the most fundamental chemical bonds in nature. In addition to proteins and other metabolites, many valuable synthetic products comprise amide bonds. The development of catalytic methods to access amide containing molecules has received increasing attention, with examples including direct amidation via boronbased catalysis, oxidative amination, ester amidation and carbonylative amidation (Fig. 1B) These approaches have not been widely adopted, due to limitations in scale, substrate scopes, efficiency, toxicity, and sustainability. The combination of chemocatalysis and biocatalysis in the same reaction has emerged as an efficient and environmentally benign alternative to traditional chemical methods Whilst such integrated catalysis has yet to be applied to catalytic amide synthesis, it has the potential to improve overall synthetic efficiency through decreasing solvent consumption and waste production, whilst reducing work-up and isolation steps. Issues of catalyst compatibility were overcome by retaining NHase enzymes within cells, while very high substrate loadings were achieved by the inclusion of micellar organo-compartments, enabling clean, practical, and scalable synthesis of diverse target amides

Methods

Results

Conclusion