Peptide design using (alpha),(beta)-dehydro amino acids: From (beta)-turns to helical hairpins

It has been shown that fluorinated analogues of naturally occurring biological active compounds including amino acids often exhibit unique physiological activity. Among wide varieties of fluorine-containing amino acids, nonhydrolyzable phosphoamino acids possessing a substituent of the difluoromethylene (CF2) unit for the phosphoryl ester oxygen are of value in the medicinal and biological fields. We have engaged in the synthesis of these classes of nonhydrolyzable phosphoamino acids corresponding to pTyr 3, pSer 4, and pThr 5 with their incorporation into peptides using newly developed deprotecting procedures. In this article, stereoselective synthesis of the CF2-substituted pThr mimetics and development of a two-step deprotecting methodology for the nonhydrolyzable analogues are reviewed. In the course of the above synthetic study, we found that (gamma),(gamma)-difluoro-(alpha),(beta)-enoates were reduced to (gamma)-fluoro-(beta),(gamma)-enoates by organocopper reagents and then applied to the synthesis of (Z)fluoroalkene dipeptide isosteres, which have served as potential dipeptide mimetics having structural as well as electrostatic similarity to the parent peptide bonds. Furthermore, mechanistic investigation of the organocoppermediated reduction led us to development of a SmI2-mediated approach toward the synthesis of the fluoroalkene isosteres.