An approach to the production of tethered gbs-turn peptidomimetics by geminal acylation

Abstract

The aim of this research was to develop a synthetic route to produce 5,6-fused-l-aza-2-oxobicycloalkane amino acids. Geminal acylation of a ketone or its acetal provides ready access to a 2,2-disubstituted 1,3-cyclopentanedione derivative. Double geminal acylation of diketones with long acyclic tethers between the carbonyls is envisaged as a core strategy for the development of synthetic access to tethered peptidomimetics. The focus of this research was to develop a route to 5,6-fused-1-aza-2-oxobicycloalkane amino acids which are β-turn peptidomimetics, with carbon-based bridgehead substituents. Geminal acylation of the acetal derived from hexadeca-1,15-diene-5,12-dione gave the 1,3-cyclopentanedione 52 in 29% yield along with numerous interesting side-products. A successful route to form lactams via Beckmann rearrangement was established. The development of this synthetic route, including the elucidation of the structures of side-products, is discussed in detail.