Fluorine-Containing Prolines: Synthetic Strategies, Applications, and Opportunities

Abstract

Fluorinated prolines play an important role in peptide studies, protein engineering, medicinal chemistry, drug discovery, and agrochemistry. Since the first synthesis of 4-fluoroprolines by Gottlieb and Witkop in 1965, their popularity started to grow exponentially. For example, during the past two decades, all isomeric trifluoromethyl-substituted prolines have been synthesized. In this Perspective, chemical properties and applications of fluorinated prolines are discussed. Synthetic approaches to all known fluorine-containing prolines are also discussed and analyzed. This analysis unexpectedly revealed an unsolved problem: in strict contrast to fluoro- and trifluoromethyl-substituted prolines, the corresponding analogues with fluoromethyl and difluoromethyl groups are mostly unknown. At the end of the paper, structures of several interesting, yet unknown, fluorinated prolines are discloseda good opportunity for chemists to make them.

Synthesis of Functionalized Azepines via Cu(I)-Catalyzed Tandem Amination/Cyclization Reaction of Fluorinated Allenynes

“…Given our recent finding that an allene system is readily capable of undergoing the selective hydroamination with secondary and primary amines in the presence of copper catalysts [41], we were curious to investigate what will happen with allenyne bearing propargyl group with acidic proton on terminal triple bond under the similar catalytic conditions. To answer this question, we began our study by testing the reaction between allenyne 2a and aniline.…”

“…This fact stimulates synthetic chemists to develop new efficient methodologies for the selective introduction of fluorine and fluorinated groups into different organic molecules. In this context, fluorine-containing amino acids, especially their constrained cyclic derivatives, attract a considerable interest as crucial targets in bioorganic and medicinal chemistry for the design of potent and highly selective bioactive compounds [38][39][40][41].…”

4,4-Difluoroproline as a Unique 19F NMR Probe of Proline Conformation

“…23,31 Moreover, in contrast to the monosubstituted 4R-and 4S-fluoroprolines, Dfp has a minimal effect on proline conformational preferences. 19,21,[23][24][25]27,29,30 Thus, as either simple acetylated amino acids or within peptides, Dfp and Pro exhibit similar relative populations of cis and trans amide bonds as well as similar overall conformational preferences. Consistent with the NMR data on model compounds, both the globular protein barstar and collagen-mimetic peptides have similar T m values in their native forms with proline or with Pro substituted by Dfp.…”

Impact of β-perfluoroalkyl substitution of proline on the proteolytic stability of its peptide derivatives

“…32 A recent review by Mykhailiuk has outlined multiple synthetic approaches toward all known fluorinated prolines bearing either fluorine atoms or (per)fluoroalkyl substituents attached directly to the five-membered ring. 33 Several of them have found their application as the structural substitutes of proline for 19 F-NMR peptide studies. [34][35][36] Among others, 4-(S)-CF 3 -proline was introduced into the structure of a gramicidin S analog to study the peptide alignment in lipid membranes (Fig.…”