Mimicry of peptide backbone geometry and heteroatomic side-chain functionality: synthesis of enantiopure indolizidin-2-one amino acids possessing alcohol, acid, and azide functional groups.

Abstract

Indolizidinone amino acids possessing various heteroatomic side chains at their 5- and 7-positions have been synthesized through modification of hydroxymethyl indolizidinone amino acids 5 and 6. Displacements of the methanesulfonates from alcohols 5 and 6 with sodium azide, as well as oxidation of alcohol 5, have been used to furnish orthogonally protected indolizidin-2-one diamino carboxylates 7 and 8, and indolizidin-2-one amino dicarboxylate 9. Both 5- and 7-hydroxymethylindolizidinone amino acids 5 and 6 were obtained from sequences commencing with the Claisen condensation of alpha-tert-butyl gamma-methyl l-N-(PhF)-L-glutamate to furnish di-tert-butyl 4-carbomethoxy-5-oxo-2,8-di-[N-(PhF)amino]azelate 10 (PhF = 9-(9-phenylfluorenyl)). Subsequent hydride reduction of 10 to an isomeric mixture of diols 12, selective protection of the primary alcohol as tert-butyldimethylsilyl ether 14 and oxidation of the secondary alcohol gave di-tert-butyl 4-tert-butyldimethylsilyloxymethyl-5-oxo-2,8-di-[N-(PhF)amino]azelate 15 as a separable diastereomeric mixture. Linear ketone 15 and alcohol 14 were then converted to the indolizidinone heterocycles by routes featuring reductive aminations, methanesulfonate displacements, and lactam cyclizations. A series of rigid scaffolds designed to mimic the conformations of dipeptides possessing serine, lysine, and glutamate residues has thus been synthesized by this new route for installing heteroatomic side-chain functional groups onto the indolizidin-2-one system.