Rigid Dipeptide Mimics:  Synthesis of Enantiopure C6-Functionalized Pyrrolizidinone Amino Acids

Enantiopure (3S,5S,6R,8S)- and (3S,5S,6S,8S)-6-hydroxypyrrolizidinone 3-N-(Boc)amino 8-methyl carboxylates (6R)- and (6S)-1 were synthesized in seven steps starting from (2S)-α-tert-butyl N-(PhF) aspartate β-aldehyde (10). Carbene-catalyzed acyloin condensation of β-aldehyde 10 followed by acetylation provided a separable mixture of diastereomeric (2S,5RS,7S)-diamino-4-oxo-5-acetoxysuberates (13). Reductive amination and lactam annulation of the respective α-acetoxy ketones 13 provided hydroxypyrrolizidinones (6R)- and (6S)-1 with retention of the C6-position stereochemistry. The X-ray crystallographic study of (6R)-1 indicated dihedral angles constrained within the heterocycle that were consistent with the ideal values for the i + 1 and i + 2 residues of a type II‘ β-turn. Hydrogen-bonding studies on N‘-methyl-N-(Boc)aminopyrrolizidin-2-one carboxamides (6R)- and (6S)-21 in DMSO-d₆, demonstrated different NH chemical shift displacements and temperature coefficients for the amide and carbamate protons, indicative of solvent shielded and exposed hydrogens in a turn conformation. 6-Hydroxy pyrrolizidinone amino carboxylate 1 may thus find application as a constrained alaninylhydroxyproline dipeptide mimic. In addition, alkylation of the hydroxyl group provided orthogonally protected pyrrolizidinone amino dicarboxylate (6R)-25, demonstrating potential for expanding the diversity of these rigid dipeptide surrogates for the exploration of peptide conformation−activity relationships.