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1-(2-Pyrrolidinyl)cyclopropanecarboxylic acids (alpha-cyclopropyl-beta-homoprolines) were prepared by 1,3-dipolar cycloadditions of cyclic nitrones onto bicyclopropylidene followed by trifluoroacetic acid induced thermal fragmentative rearrangement. With the use of enantiopure pyrroline N-oxides derived from easily available chiral pool molecules, beta-homoprolines were formed with high stereocontrol. The incorporation of one of these new cyclic beta-amino acids into a simple tripeptide was also evaluated. In particular, the sterically hindered nitrogen atom of the highly substituted pyrrolidine 30 was smoothly acylated through the intermediate formation of a mixed anhydride.

The formation of structurally differentiated indolizidinones is guided by a diverse behaviour of spirocyclopropaneisoxazolidine precursors under fluorination reactions.

Keywords: Nitrogen heterocycles / Spiro compounds / Density functional calculations / Reaction mechanisms / RearrangementProtonation at the nitrogen of 5-spirocyclopropane-isoxazolidines induces clean thermal rearrangement/fragmentation to β-lactams and ethylene. Under the same conditions, homologous 5-spirocyclobutane-isoxazolidines undergo unselective fragmentation to give cyclobutyl derivatives through a completely different mechanism. Experimental data and DFT calculations show that the process is initiated with less-favored protonation at the isoxazolidine oxygen rather than nitrogen. Highly energetic O-protonated isoxazolidines undergo N-O cleavage with concomitant endo-or exocyclic deprotonation to give iminium ions that, in the presence of trifluoroacetate, evolve into 2-(1-hydroxycyclobutyl)ethanones and N-[2-(1-hydroxycyclobutyl)ethyl]trifluoroacetamides, respectively. DFT data validate protonation at oxygen of 5-spirocyclobut-