Selective ¹⁹F‐Labeling of Functionalized Carboxylic Acids with Difluoromethyl Diazomethane (CF₂HCHN₂)

Abstract

The incorporation of fluorinated moieties into organic structures is a particularly powerful approach for generating compounds with useful biological applications in industry, pharmacology, and agriculture. Here, the recently developed reagent-CF HCHN -selectively esterifies carboxyl groups on organic molecules in the presence of other polar functional groups. The reaction is remarkably simple, proceeding at room temperature in chloroform without addition of a catalyst. The procedure allows "last-step" incorporation of a fluorinated ester moiety into organic structures, including bioorganic molecules such as peptides and proteins. The fluorinated ester can subsequently function as a F-probe in biomolecules, thereby enabling molecular size determination by diffusion F NMR experiments.

Exploring hydrophobicity limits of polyproline helix with oligomeric octahydroindole‐2‐carboxylic acid

“…In contrast, the use of the peptides in nonpolar media would require nonionizable C‐terminal groups. Perhaps, the most common and simple choices are (1) amides introduced during synthesis on amide resins, (2) methyl esters prepared by post–resin esterification of peptides, and (3) recently reported C‐terminal 2,2‐difluoroethyl esters prepared using 2,2‐difluorodiazoethane . We previously determined the log P values of the N ‐acetyl proline derivatives, which are shown in Figure .…”

“…The synthesized peptides were cleaved from the resin using mild hexafluoroisopropanol‐dichloromethane cleavage conditions and purified on a short silica gel column. The peptides with free C‐termini were converted to the esters using 2,2‐difluorodiazoethane, as described previously . Purification of the esterified peptides was performed by silica gel chromatography.…”

“…Fractions were analyzed by dry weight after evaporation. C‐terminal 2,2‐difluoroethyl esters were prepared by applying 2,2‐difluorodiazoethane as described . The crude peptides were purified on a silica gel column using an ethyl acetate‐methanol (19:1) mixture as an eluent.…”

“…C-terminal 2,2-difluoroethyl esters were prepared by applying 2,2-difluorodiazoethane as described. 42,43 The crude peptides were purified on a silica gel column using an ethyl acetate-methanol For the nonamer PO9, the peptide sample (20 mg; after silica gel purification) was dissolved in methanol (0.5 mL). The resulting solution was kept at 277 K overnight to allow better precipitation.…”

“…Perhaps, the most common and simple choices are (1) amides introduced during synthesis on amide resins, (2) methyl esters prepared by post-resin esterification of peptides, and (3) recently reported C-terminal 2,2-difluoroethyl esters prepared using 2,2-difluorodiazoethane. 43,52 We previously determined the logP values of the N-acetyl proline derivatives, which are shown in Figure 3. 42 Notably, these results revealed strong hydrophilicity for the terminal amide, lower hydrophilicity for both esters, and the lowest hydrophilicity for the 2,2-difluoroethyl ester.…”