Efficient Synthesis of Enantiopure Pyrrolizidinone Amino Acid

• Published in: Journal of organic chemistry Vol. 68; no. 18; pp. 6988 - 6996
• Main Authors: Dietrich, Evelyne, Lubell, William D
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 05.09.2003; Amer Chemical Soc
• Subjects: Aspartic Acid - chemistry; Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis; Chemistry; Chemistry, Organic; Crystallography, X-Ray; Dipeptides - chemistry; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Indicators and Reagents; Magnetic Resonance Spectroscopy; Mass Spectrometry; Models, Molecular; Molecular Conformation; Organic chemistry; Physical Sciences; Preparations and properties; Science & Technology; Stereoisomerism; PYRAZOLIDINONE ANTIBACTERIAL AGENTS; CYCLO-ADDITION REACTIONS; SIDE-CHAIN FUNCTIONALITY; RECEPTOR MODULATING ACTIVITY; CARBAPENICILLANIC ACIDS; PEPTIDE BACKBONE GEOMETRY; CONFORMATIONAL-ANALYSIS; GAMMA-LACTAM ANALOGS; IN-VITRO ACTIVITY; BICYCLIC PYRAZOLIDINONES; Molecular rigidity; Condensation reaction; Molecular structure; Nitrogen heterocycle; NMR spectrometry; Aldehyde; Ketone; X ray diffraction; Chemical reduction; Amination; Cyclization; Pyrrolizidine derivatives; Aminoacid; Bicyclic compound; Dipeptides; Acetylation; Chemical synthesis
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo034739d

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 β-aldehyde 7. Carbene-catalyzed acyloin condensation of 7, followed by acetylation and samarium iodide reduction, gave linear precursor (2S,7S)-α,ω-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 (ψ = −149°, φ = −49°) were in good agreement with the ideal values for a type II‘ β-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.