Efficient synthesis of enantiopure pyrrolizidinone amino acid.
Enantiopure (3S,5R,8S)-3-[N-(Boc)amino]-1-azabicyclo[3.3.0]octan-2-one 8-carboxylic acid (1) was synthesized in nine steps and 16% overall yield from aspartate beta-aldehyde 7. Carbene-catalyzed acyloin condensation of 7, followed by acetylation and samarium iodide reduction, gave linear precursor (2S,7S)-alpha,omega-diamino-4-oxosuberate 11, which was converted to N-(Boc)aminopyrrolizidin-2-one carboxylic acid 1 by a reductive amination/lactam cyclization sequence. X-ray analysis of (3S,5R,8S)-methyl N-(Boc)aminopyrrolizidin-2-one carboxylate 21 showed that its internal backbone dihedral angles (psi = -149 degrees, phi = -49 degrees ) were in good agreement with the ideal values for a type II' beta-turn. Proton NMR experiments on N'-methyl-N-(Boc)aminopyrrolizidin-2-one carboxamide 23 demonstrated significantly different NH chemical displacements and temperature coefficients suggestive of solvent shielded and exposed hydrogens indicative of a turn conformation. Because pyrrolizidinone amino acids can serve as conformationally rigid dipeptide surrogates, this synthesis should facilitate their application in the exploration of conformation-activity relationships of various biologically active peptides.
Dietrich
Evelyne
E
Département de chimie, Université de Montréal, C. P. 6128, Succ. A, Montréal, Québec, Canada H3C 3J7.
Lubell
William D
WD
D001224:Aspartic Acid / Q000737:chemistry; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis*; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000737:chemistry*; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D008968:Molecular Conformation; D013237:Stereoisomerism
C481924:(3S,5R,8S)-3-(N-(Boc)amino)-1-azabicyclo(3.3.0)octan-2-one 8-carboxylic acid; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004151:Dipeptides; D007202:Indicators and Reagents; D001224:Aspartic Acid