The dimeric diketopiperazines (DKPs) are a large family of alkaloid natural products with a diverse array of biological activities. The selective chemical synthesis of the unsymmetrical DKP dimers frequently requires pre-functionalization of one or both monomers to guide the formation of the desired C–C or C–N bond, or leverages the innate reactivity of a given monomer, resulting in regio- and stereospecific outcomes which are substrate controlled. We recently identified and characterized NasB, a bacterial cytochrome P450 that catalyzes a regio- and stereoselective carbon-nitrogen and carbon-carbon bond-forming cascade resulting in the unsymmetrical dimerization of brevianamide F to afford cryptic natural product, (–)-naseseazine C. The chemoenzymatic synthesis of (–)-naseseazine C was completed on preparatory scale in 4 steps, and the initial substrate scope of NasB was explored using a small library of DKP monomers. Rational mutagenesis was employed to expand the substrate scope of NasB and the resulting variants were utilized in biocatalytic syntheses of (–)-naseseazine C derivatives for evaluation of their anti-plasmodial activity.

Biocatalytic synthesis of unsymmetrical diketopiperazine dimers via enzymatic C-H functionalization

256th National Meeting (2018)

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