Harnessing transaminases to construct azacyclic non-canonical amino acids

Non-canonical amino acids (ncAAs) are prized building blocks in the synthesis of natural products, designer peptides and drug molecules. Despite their general utility, the structural complexity of these molecules still presents an enormous challenge for chemical synthesis. Here we develop a one-pot chemoenzymatic approach for the construction of azacyclic ncAAs with multiple substitutions and various ring sizes. A promiscuous transaminase was identified to convert a wide range of diketoacids to the corresponding alpha-amino acids. A spontaneous cyclic imine formation was followed by a stereocontrolled chemical reduction to generate the corresponding products in one pot with high stereoselectivity. More than 25 azacyclic ncAAs were successfully prepared using this approach. This work demonstrates the value of developing hybrid biocatalytic-chemocatalytic approaches to prepare privileged small molecule motifs. Non-canonical amino acids are important building blocks in the synthesis of natural products, peptides and drugs. Now, a one-pot chemoenzymatic approach to synthesize branched azacyclic non-canonical amino acids is reported. This method combines enzymatic transamination of 2,n-diketoacids and stereocontrolled chemical reduction to provide the desired products with high stereoselectivity.