Total Synthesis Facilitates Reconstitution of the C-S Bond-Forming P450 in Griseoviridin Biosynthesis.

Griseoviridin is a group A streptogramin natural product from with broad-spectrum antibacterial activity. A hybrid polyketide-nonribosomal peptide, it comprises a 23-membered macrocycle, an embedded oxazole motif, and a macrolactone with a unique ene-thiol linkage. Recent analysis of the griseoviridin biosynthetic gene cluster implicated SgvP, a cytochrome P450 monooxygenase, in late-stage installation of the critical C-S bond.

Self-sufficient P450-reductase chimeras for biocatalysis.

In recent years, cytochromes P450 have emerged as powerful, versatile biocatalysts for the site-selective functionalization of small molecules. Catalyzing an impressive range of chemical transformations, these enzymes have been widely used to effect C-H oxidation, biaryl coupling, and carbon-heteroatom bond formation, among many other reactions. However, the majority of P450s are multi-protein systems that employ secondary redox partners in key steps of the catalytic cycle, which limits their broader applicability.

Charting the Evolution of Chemoenzymatic Strategies in the Syntheses of Complex Natural Products.

Bolstered by recent advances in bioinformatics, genetics, and enzyme engineering, the field of chemoenzymatic synthesis has enjoyed a rapid increase in popularity and utility. This Perspective explores the integration of enzymes into multistep chemical syntheses, highlighting the unique potential of biocatalytic transformations to streamline the synthesis of complex natural products. In particular, we identify four primary conceptual approaches to chemoenzymatic synthesis and illustrate each with a number of landmark case studies.

Reinvigorating the Chiral Pool: Chemoenzymatic Approaches to Complex Peptides and Terpenoids.

Biocatalytic transformations that leverage the selectivity and efficiency of enzymes represent powerful tools for the construction of complex natural products. Enabled by innovations in genome mining, bioinformatics, and enzyme engineering, synthetic chemists are now more than ever able to develop and employ enzymes to solve outstanding chemical problems, one of which is the reliable and facile generation of stereochemistry within natural product scaffolds. In recognition of this unmet need, our group has sought to advance novel chemoenzymatic strategies to both expand and reinvigorate the chiral pool.