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 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.