Syntheses of Atypically Fluorinated Peptidyl Macrocycles through Sequential Vinylic Substitutions

Abstract

Small peptides containing combinations of cysteine, tyrosine, histidine, and serine residues react with octafluorocyclopentene (OFCP) to afford atypically structured macrocycles through successive vinylic substitutions. The reactions proceed rapidly in air at 0 °C and are tolerant of spectating tryptophan, asparagine, glutamine, and threonine residues. Hexapeptides of consensus sequence YXCXXC displace four fluorine atoms from OFCP to generate fluorinated macrobicyclic compounds that display dual‐turn surfaces. The method provides facile access to a wide range of previously unknown heterocyclic structures.

Expedient Synthesis of gem-CF2-2H-Thiophenes from Enaminothiones

“…1 2 3 4 5 For instance, they exhibit outstanding pharmacological activities such as anticancer, antiviral, and antibacterial properties since fluorine atoms are believed to enhance the stability and bioavailability of druglike molecules. 6–10 Despite several strategies have been disclosed in recent years to synthesize heterocycles with installing fluorine atoms in the core rings, 11–14 Wan and Song groups independently developed a distinguished method to construct gem -CF 2 -2 H -furans from enaminones and CF 2 carbene precursors. 15 16 On the other hand, although the skeleton of 2 H -thiophenes constitutes as a core fragment in a variety of biological molecules and has been discovered in numerous potential therapeutic applications.…”

Unprotected peptide macrocyclization and stapling via a fluorine-thiol displacement reaction

“…Direct crosslinking based on bromo or iodo-alkyl/benzyl chemistry, on the other hand, could produce over-alkylated species due to their increased cross-reactivity [20][21][22]25 . Most strategies hinge on reactions with native amino acid residues such as cysteines 23,26,[28][29][30][31] , which however often play essential roles in protein-protein intermolecular interactions and could be also necessary to retain the desired structures and functions [32][33][34] . More importantly, the vast majority of stapled peptides still had limited cell permeability 35 .…”