Developing sustainable chemistry is important if we are to continue meeting human needs. Therefore, generating reactions that are environmentally friendly, whilst also expanding chemistries, is highly desirable. Amide bond formation — important in many drugs, proteins and materials — has many avenues for execution; however, limited substrate scope and scale, the need for stoichiometric coupling agents and a desire to reduce organic solvent use remain a challenge for this fundamental reaction. Writing in Nature Communications, Jason Micklefield and colleagues from the University of Manchester describe the use of integrated bio- and chemocatalysis to generate one-pot amide bond formation from aromatic and aliphatic nitriles under mild conditions with high substrate scope.
In addition, “The combination of biocatalysis and chemocatalysis led to a completely new reaction pathway to amides,” says Micklefield. “Our integrated approach delivers an unusual amide bond disconnection to nitriles and aryl halide precursors, which is quite different to the well-established coupling of carboxylic acids and amines.” Additionally, this method works in the absence of protecting groups, enabling high functional-group tolerance while cutting the need for follow-up reactions, again reducing required resources and time. In addition, using an enzymatic process immediately offers the opportunity to perform the reaction enantioselectively, which was investigated by the synthesis of chiral amides from racemic nitriles. “We were delighted to see that this approach is very robust and affords a broad substrate scope (>50 examples provided), including bioactive compounds, natural product-derived molecules and could deliver desirable drug targets.” The team also explored gram-scale reactions to determine the applicability of their set-up. Example reactions were performed without a detriment to yield.
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