Diketopiperazines (DKPs) are well-known motifs in natural products, which possess a variety of different bioactivities, and often referred to as a �privileged structure� for hit and lead identification in drug discovery. Furthermore its cyclic dipeptide nature makes it a proteolytically stable peptide mimetic with favorable pharmacokinetic properties. In here, we wish to report our recent progress towards the stereoselective syntheses of natural product-like fused diketopiperazines. Two general pathways on solid-phase were developed in order to access all stereochemical variants of the target scaffolds, including all cis- and trans-configured products. The first pathway (P1) employed oxidative cleavage of a solid supported peptide with a terminal serine followed by acid-mediated intramolecular N-acyliminium Pictet-Spengler type cyclization to give trans-configured diketopiperazine products in excellent yields. The second pathway (P2) relied on intramolecular iminium Pictet-Spengler reactions of glyoxylates with a solid-supported peptide. The products were then coupled at either the amino- or the carboxylate functionality and finally cyclized to give cis-configured diketopiperazine products in high yields. In summary we have developed methodology that provides efficient access to natural product-like compound libraries from simple peptide precursors with excellent control of skeletal and stereochemical structural elements.

Towards complete stereochemical control in the synthesis of natural product-like diketopiperazines from simple peptides

247th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.