Selectivity in the addition reactions of organometallic reagents to aziridine-2-carboxaldehydes: the effects of protecting groups and substitution patterns

Good to excellent stereoselectivity has been found in the addition reactions of Grignard and organozinc reagents to N-protected aziridine-2-carboxaldehydes. Specifically, high syn selectivity was obtained with benzyl-protected cis, tert-butyloxycarbonyl-protected trans, and tosyl-protected 2,3-disubstituted aziridine-2-carboxaldehydes. Furthermore, rate and selectivity effects of ring substituents, temperature, solvent, and Lewis acid and base modifiers were studied. The diastereomeric preference of addition is dominated by the substrate aziridines' substitution pattern and especially the electronic character and conformational preferences of the nitrogen protecting groups. To help rationalize the observed stereochemical outcomes, conformational and electronic structural analyses of a series of model systems representing the various substitution patterns have been explored by density functional calculations at the B3LYP/6-31G* level of theory with the SM8 solvation model to account for solvent effects.