| Abstract
| - 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) aspartateβ-aldehyde (10). Carbene-catalyzed acyloin condensation of β-aldehyde 10 followed by acetylationprovided 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-raycrystallographic study of (6R)-1 indicated dihedral angles constrained within the heterocycle that wereconsistent with the ideal values for the i + 1 and i + 2 residues of a type II‘ β-turn. Hydrogen-bondingstudies 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 andcarbamate protons, indicative of solvent shielded and exposed hydrogens in a turn conformation. 6-Hydroxypyrrolizidinone amino carboxylate 1 may thus find application as a constrained alaninylhydroxyprolinedipeptide mimic. In addition, alkylation of the hydroxyl group provided orthogonally protectedpyrrolizidinone amino dicarboxylate (6R)-25, demonstrating potential for expanding the diversity of theserigid dipeptide surrogates for the exploration of peptide conformation−activity relationships.
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