Synthesis of hydantoin analogues of (2 S,3 R,4 S)-4-hydroxyisoleucine with insulinotropic properties

Abstract

The first synthesis of an optically pure (2 R,3 R,4 S) -hydantoin 2, analogue of (2 S,3 R,4 S) -4-hydroxyisoleucine, was achieved in two steps in un-optimized 35% overall yield from previously reported aldehyde synthon 1. (2 R,3 R,4 S) -Hydantoin is stable at acidic pH. This solves the major drawback of (2 S,3 R,4 S)-4-hydroxyisoleucine that easily cyclizes into inactive lactone. Furthermore, (2 R,3 R,4 S) -hydantoin stimulates the insulin secretion by 150% at 25 μM compared with 4-hydroxyisoleucine and insulin secretagogue drug repaglinide. In view of its stability and biological activity, (2 R,3 R,4 S) -hydantoin represents a good candidate for type-2 diabetes management and control.