Abstract
The design of cyclic analogues of 4-hydroxyisoleucine, a natural remedy used by type-2 diabetic patients, can provide putative hypoglycemic drugs. To this end, the 1,3-dipolar cycloaddition of a (–)-menthone-derived nitrone to cycloalkenes afforded isoxazolidines in high yields and with high stereoselectivity. The cycloadducts led to α-amino lactones after a one-pot cleavage of the N–O, amide, and N–C–N bonds. Subsequent base-catalyzed hydrolysis provided enantiopure cycloalkylglycine derivatives in good overall yields (>40 %) in three simple synthetic steps from the menthone-based chiral nitrone. The conformational analysis of these analogues by DFT calculations highlight some interesting features of the volume occupied by the cycloalkyl residues in comparison to that occupied by the natural 4-hydroxyisoleucine.