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)-alpha-tert-butyl N-(PhF) aspartate beta-aldehyde (10). Carbene-catalyzed acyloin condensation of beta-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 alpha-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' beta-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.
Rao
Mallem H V Ramana
MH
Départment de Chimie, Université de Montréal, C. P. 6128, Succursale Centre Ville, Montréal, Québec, Canada H3C 3J7.
Pinyol
Eulàlia
E
Lubell
William D
WD
D000478:Alkylation; D000596:Amino Acids / Q000737:chemistry*; D002244:Carbon / Q000737:chemistry*; D002264:Carboxylic Acids / Q000737:chemistry; D002384:Catalysis; D018360:Crystallography, X-Ray; D004121:Dimethyl Sulfoxide / Q000737:chemistry; D004133:Diminazene / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D004151:Dipeptides / Q000138:chemical synthesis*; D006838:Hydrocarbons / Q000737:chemistry; D006859:Hydrogen / Q000737:chemistry; D006860:Hydrogen Bonding; D008697:Methane / Q000031:analogs & derivatives / Q000737:chemistry; D008956:Models, Chemical; D018716:Molecular Mimicry; D015394:Molecular Structure; D011758:Pyrroles / Q000138:chemical synthesis*; D011760:Pyrrolidinones / Q000737:chemistry*; D013237:Stereoisomerism; D013696:Temperature
C518678:(3S,5S,6S,8S)-6-hydroxypyrrolizidinone 3-N-(Boc)amino 8-methyl carboxylate; D000596:Amino Acids; D002264:Carboxylic Acids; D004151:Dipeptides; D006838:Hydrocarbons; D011758:Pyrroles; D011760:Pyrrolidinones; C030011:carbene; D002244:Carbon; D006859:Hydrogen; D008697:Methane; D004133:Diminazene; D004121:Dimethyl Sulfoxide