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 .

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