Analogues of insulin secretagogue (2 S,3 R,4 S)-4-hydroxyisoleucine: synthesis by 1,3-dipolar cycloaddition reactions of chiral nitrones to alkenes

Abstract

(2 S,3 R,4 S)-4-Hydroxyisoleucine, found in fenugreek, is an insulin secretagogue molecule. Non-natural analogues of (2 S,3 R,4 R)- and (2 R,3 S,4 S)-4-hydroxyisoleucine were efficiently prepared by 1,3-dipolar cycloaddition reactions of chiral nitrones derived from either (−)- or (+)-menthone to alkenes. The cycloadducts, obtained via the exo-approach of the alkenes to the nitrone’s less hindered face, led after a reductive step and cleavage of the chiral auxiliary, to enantiopure non-natural amino acids in good overall yield.