Constrained Dipeptide Surrogates: 5- and 7-Hydroxy Indolizidin-2-one Amino Acid Synthesis from Iodolactonization of Dehydro-2,8-diamino Azelates.

The constrained dipeptide surrogates 5- and 7-hydroxy indolizidin-2-one -(Boc)amino acids have been synthesized from L-serine as a chiral educt. A linear precursor ∆-unsaturated (2,8)-2,8-bis[-(Boc)amino]azelic acid was prepared in five steps from L-serine. Although epoxidation and dihydroxylation pathways gave mixtures of hydroxy indolizidin-2-one diastereomers, iodolactonization of the ∆-azelate stereoselectively delivered a lactone iodide from which separable (5)- and (7)-hydroxy indolizidin-2-one -(Boc)amino esters were synthesized by sequences featuring intramolecular iodide displacement and lactam formation. X-ray analysis of the (7)-hydroxy indolizidin-2-one -(Boc)amino ester indicated that the backbone dihedral angles embedded in the bicyclic ring system resembled those of the central residues of an ideal type II' β-turn indicating the potential for peptide mimicry.