Small Peptides as Nucleophillic Catalysts for the Kinetic Resolution of Amine-Based Substrates and the Site-Selective Modification of Polyfunctional Natural Products

The first chapter reviews twelve reports pertaining to the synthesis of natural product analogues in which the syntheses begin from the parent natural product itself. These semisynthetic approaches are categorized as protecting group-mediated synthesis, degradative synthesis, enzyme-controlled modifications, and small molecule-controlled modifications. The latter topic includes four examples of peptide-mediated natural product functionalization reported by Miller and co-workers. Energetic considerations for enantio- and site-selective catalysis are also discussed.;The second chapter describes the peptide-catalyzed site-selective thiocarbonylation of vancomycin derivatives as a means to access deoxygenated analogues of the glycopeptide antibiotic. Catalysts were discovered by library screening and by design based on the biological target of vancomycin. Enhancement and reversal of the inherent site-selectivity were observed in the peptide-catalyzed reactions. Deoxygenation, deprotection, and purification of the thionocarbonates provided the deoxyvancomycins and revealed an unexpected structural stabilization associated with the Z6-hydroxyl group.;The third chapter describes the peptide-catalyzed kinetic resolution of simple formamides and thioformamides in the context of catalytic, non-enzymatic, enantioselective amine functionalization. Background topics include the synthetic utility of formamides and the unusual properties of thioformamides. The thioformamide substrate is shown to be much more reactive than the corresponding formamide without degrading selectivity. Mechanistic insight and a modest substrate scope for the lead catalyst are presented.;The final chapter describes efforts toward the site-selective modification of aminoglycoside polyformamide derivatives as a means to access deamino-aminoglycoside analogues. An introduction to aminoglycosides includes several examples of aminoglycoside modification as well as two previous approaches to deamination via the corresponding formamides and isocyanides. Two approaches to peptide-catalyzed modification of neamine-based polyformamides are presented and include selective Boc-transfer and selective formamide dehydration. The chapter concludes by discussing the challenges associated with each strategy and the future directions for the site-selective deamination of aminoglycosides.