“Trimethyl lock” facilitated spirocyclizations: A structural analysis

Abstract

A “trimethyl lock” was shown earlier to significantly facilitate certain cyclization reactions. 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. However, there is an undesirable spirocyclization reaction associated with certain “trimethyl lock” facilitated cyclization systems. In an effort to probe factors important for the controlling of the undesirable spirocyclization reaction, we undertook the X-ray crystallographic studies of the such “trimethyl lock” facilitated spirocyclization systems. The spirocyclization product was crystallized from ethyl acetate/hexane mixture (space group: P21/c,a=13.467(1),b=13.297(2),c=13.626(8) A, β=92.120(6)°. It was found that spirocyclization results in release of steric congestion caused by the “trimethyl lock” to a larger degree than the desired lactonization. However, this release of steric congestion itself is not enough to bring about the cyclization. A kinetically reactive nucleophile is also essential for the initiation of the spirocyclization reaction. This is consistent with the fact that such spirocyclization reactions require specific base catalysis.