Monofluoroalkene‐Isostere as a ¹⁹F NMR Label for the Peptide Backbone: Synthesis and Evaluation in Membrane‐Bound PGLa and (KIGAKI)₃

Abstract

Solid-state 19 FNMR is ap owerful methodt o study the interactions of biologically active peptides with membranes. So far,i nl abelled peptides, the 19 F-reporter group has alwaysb een installed on the side chain of an amino acid. Given the fact that monofluoroalkenes are non-hydrolyzable peptideb ond mimics, we have synthesized am onofluoroalkene-based dipeptide isostere, Val-Y[(Z)-CF=CH]-Gly,a nd insertedi ti nt he sequence of two well-studied antimicrobial peptides:P GLa and (KIGAKI) 3 are representatives of an a-helix and a b-sheet. The conformations and biological activities of these labeled peptides were studied to assess the suitability of monofluoroalkenes for 19 FNMR structure analysis.[a] M.

Chemoselective catalytic hydrodefluorination of trifluoromethylalkenes towards mono-/gem-di-fluoroalkenes under metal-free conditions

“…The introduction of fluorine-containing motifs is a commonly used strategy for improving the properties of target molecules in medicines, agrochemicals, and materials 1 – 8 , because of the specific characteristics of the fluorine atom, e.g., high lipophilicity, good absorbability, and strong electron-withdrawing ability 5 , 6 , 9 . Among these important fluorine-containing motifs, gem -difluoroalkenes 10 – 13 and terminal monofluoroalkenes 14 – 17 , deemed, respectively, as mimics of carbonyl and amide groups, have attracted much attention in the modification of bioactive molecules (Fig. 1 ).…”

Solid-Phase Synthesis of Gly-Ψ[CH(CF3)NH]-Peptides

“…Methyl 6,158.9,157.1,156.6,144.0,143.8,141.4,138.4,132.8,132.3,129.4,128.4,127.8,127.1,126.8,125.2,125.0,124.7,120.0,117.6,86.4,66.8,60.6,58.2 (q,J = 26.4 Hz),53.4,52.6,47.2,43.3,39.7,37.2,28.6,25.4,19.3,17.9,12.5;19 Solid Phase Peptide Synthesis: General Procedures. Synthesis of Peptides 6−9: General Procedures.…”

“…In previous works, we introduced the stereogenic trifluoroethylamino function −CH­(CF 3 )­NH– as a hydrolytically stable peptide bond surrogate in which the carbonyl bond was replaced by the isopolar CH–CF 3 bond (Figure ). Besides the hydrolytic stability, the main characteristics featured by this unit that make it very promising for the replacement of the amide bond are (1) planarity and low basicity of the amino group; (2) isopolarity of the CH–CF 3 bond with the carbonyl bond; (3) the good hydrogen bond donor ability of the NH moiety; (4) the possibility to induce conformational orientation similar to the biologically active ones due to the bulkiness and spatial arrangement of the CF 3 group; and (5) the possibility to study the properties of the peptide by 19 F NMR in solution and solid state (Figure ). Indeed, this surrogate has been exploited at Merck-Frosst in Canada for the synthesis of Odanacatib, an inhibitor of Cathepsin K that reached phase III clinical trials for the treatment of postmenopausal osteoporosis …”

Ligand-controlled regioselective and chemodivergent defluorinative functionalization of gem-difluorocyclopropanes with simple ketones

“… 7–9 Despite the flourishing advances, the deconstructive transformation of gem -difluorocyclopropanes that incorporate functionalities into the sterically hindered internal position, delivering kinetically favored α-monofluorinated alkenes with branched selectivity, remains a challenging task. In addition, α-monofluorinated alkenes are attractive structures, which mimic amides and enols in drug discovery and medicinal chemistry, 10 particularly with the presence of synthetically versatile fluorinated terminal C C bonds. 11 Therefore, an alternative strategy that allows for the incorporation of the functional group into the gem -difluorocyclopropanes with complementary regioselectivity and an innovative reaction manifold is highly desirable.…”