Structural Analysis of a Facile Lactonization System Facilitated by a “Trimethyl Lock”

Abstract

A “trimethyl lock” was shown earlier to significantly facilitate the lactonization of compounds of type1. Our renewed interests in such facile cyclization systems stemmed from their potential applications in the preparation of redox-, esterase-, and phosphatase-sensitive prodrugs. Furthermore, such systems have also been used for the development of redox-sensitive protecting groups for amines and alcohols. In an effort to probe the general applicability of such systems being used as prodrug moieties and protecting groups, we studied the effects of the functional groups (X,4) attached to the side chain carboxyl group on the overall conformations of such systems using X-ray crystallography. Through analysis of the crystal structures of4a–4dwith different functional groups attached to the side chain, we found that in all cases the side chain was folded back to bring the side chain carboxyl group within close proximity of the quinone oxygen, which is the potential attacking atom, and the X functional groups have minimal effect on the overall conformation of the system. In addition, severe strain was observed for4a–4d,which should be at least partially released upon cyclization. This would also help to explain the facile cyclization reaction brought about by the trimethyl lock.