Synthesis of cyclopropane-containing leu-enkephalin analogs

The use of substituted cyclopropanes as conformationally constrained peptidomimetics has received considerable attention recently (1-6). The efforts from our laboratory in this area have focused on the use 1,2,3-trisubstituted cyclopropanes as novel isosteric replacements in several biological systems (7-10). A common theme of this program has been the use of trans-substituted cyclopropanes to enforce extended or "β-strand" secondary structure while orienting the amino acid side chain in a predictable conformation (11). In an effort to explore further the utility of this novel isostere, modeling and calculations suggested that a cis-substituted cyclopropane dipeptide subunit could stabilize a turn structure. The focus of this chapter is to describe the preparation of a novel cyclopropane-containing cis-substituted (-Glyψ[CHOH-cp-CONH]-) subunit, which replaces Gly(2)-Gly(3) subunit of the Leu-enkephalin (Tyr-Gly-Gly-Phe-Leu) framework shown in Fig. 1. Fig. 1. Leu-Enkephalin analog 1.