Convergent Synthesis of Complex Diketopiperazines Derived from Pipecolic Acid Scaffolds and Parallel Screening against GPCR Targets

A convergent approach to highly functionalized diketopiperazines (DKPs) using enantioenriched pipecolic
acids is described. Scandium triflate-catalyzed [4 + 2] aza-annulation was employed to produce
stereochemically well-defined building blocks. A resin “catch and release” strategy was devised to convert
annulation products to pipecolic acid monomers. Complex diketopiperazines were efficiently assembled
utilizing one-pot cyclodimerization of pipecolic acids. Massively parallel screening of the complex DKPs
against a panel of molecular targets identified novel ligands for a number of G-protein-coupled receptors
(GPCRs).