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 complex structure 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 α-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 twenty azacyclic ncAAs were successfully prepared with this approach. This work demonstrates the value of developing hybrid biocatalytic-chemocatalytic approaches to privileged small molecule motifs.