Preparation of bicyclic reverse turn for Leu-enkephalin analogues

ORGN 792

Xuyuan Gu, Jinfa Ying, Jimes P. Cain, Byoung Min, and Victor J. Hruby. Hruby group, Department of Chemistry, University of Arizona, 1306 E. University, Tucson, AZ 85721
Bicyclic dipeptide reverse turns occupy a very important position in peptidomimetic research. It is tremendously important to develop such a methodology so that different sizes of bicyclic dipeptide can be inserted into targeted peptides by combinatorial chemistry. Here we report a novel strategy which generates all possible sizes of bicyclic scaffolds inserted into peptides using Fmoc based nonconventional solid-phase synthesis. This methodology is well illustrated by the synthesis of [3.3.0]-, [4.3.0.]-, and [5.3.0]- bicyclic Leu-enkephalin analogues on Wang resin. The chemistry was carefully optimized and the configurations were confirmed by 2D NMR. The SAR and MCMM modeling studies will be discussed. [Supported by grants from the USPHS and NIDA.]