DIASTEREOSELECTIVE SYNTHESIS OF (Z)-FLUOROALKENE DIPEPTIDE ISOSTERES BASED ON ORGANOCOPPER-MEDIATED REDUCTION/DIRECT ALKYLATION VIA TRANSMETALATION

摘要

Replacement of native hydrolyzable peptide bonds with non-hydrolyzable mimetics is an established approach toward overcoming their major drawbacks including rapid proteolysis. Furthermore, conformationally restricted analogues represent attractive structural approaches toward more effective agents. In particular, alkene-type dipeptide isosteres containing (E)-alkene or (Z)-fluoroalkene units are thought to be potential dipeptide mimetics. (Z)-Fluoroalkene dipeptide isosteres are structurally similar to (E)-alkene dipeptide isosteres (EADIs), but differ in their electrostatic nature. This plays a significant role in their intra- and inter-molecular interactions. Of note, due to the presence of the highly electronegative fluorine substituent, (Z)-fluoroalkene dipeptide isosteres more faithfully resemble native peptides than do EADIs.