Enantiopure 5-CF₃–Proline: Synthesis, Incorporation in Peptides, and Tuning of the Peptide Bond Geometry

Abstract

The straightforward synthesis of enantiopure 5-(R)-and 5-(S)-trifluoromethylproline is reported. The key steps are a Ruppert-Prakash reagent addition on l-pyroglutamic esters followed by an elimination reaction and a selective reduction. The solution-phase and solid-phase incorporation of this unprotected enantiopure fluorinated amino acid in a short peptide chain was demonstrated. Compared to proline, the CF3 group provides a decrease of the trans to cis amide bond isomerization energy and an increase of the cis conformer population.

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

“…In 2021, Chelain, Brigaud, and co-workers developed an improved synthesis of enantiopure 5-(R)-and 5-(S)-trifluoromethylprolines (Scheme 50). 147 The synthesis started from pyroglutamic acid (292). N/C protection followed by a reaction with CF 3 TMS in dry tetrahydrofuran with a catalytic amount of cesium fluoride (CsF) gave the trifluoromethyl-substituted compound 293 in 66% yield as a mixture of two isomers.…”

Late-stage gem-difluoroallylation of phenol in bioactive molecules and peptides with 3,3-difluoroallyl sulfonium salts

“…Compared to traditional solid phase peptide synthesis (SPPS), 5 this LSF strategy features synthetic convenience and simplicity without the tedious synthesis of fluorinated amino acids. However, most developed methods focus on the S -fluoroalkylation of highly nucleophilic cysteine.…”

Constrained Dipeptide Surrogates: 5- and 7-Hydroxy Indolizidin-2-one Amino Acid Synthesis from Iodolactonization of Dehydro-2,8-diamino Azelates

“…In peptide science, conformationally constrained dipeptides serve effectively as tools for structure–activity relationship studies to identify biologically active conformers [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. Among approaches for creating constrained dipeptides that employ steric [ 2 , 3 ], stereo-electronic [ 4 , 5 ], and covalent constraints [ 1 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ], the use of azabicyclo[X.Y.0]alkanone amino acids offers unique potential for locking the polyamide backbone into specific orientations that may mimic natural secondary structures such as β-turns.…”

“…In peptide science, conformationally constrained dipeptides serve effectively as tools for structure–activity relationship studies to identify biologically active conformers [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. Among approaches for creating constrained dipeptides that employ steric [ 2 , 3 ], stereo-electronic [ 4 , 5 ], and covalent constraints [ 1 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ], the use of azabicyclo[X.Y.0]alkanone amino acids offers unique potential for locking the polyamide backbone into specific orientations that may mimic natural secondary structures such as β-turns. Among such bicyclic systems, the azabicyclo[4.3.0]alkanone amino acids, so-called indolizidine-2-one amino acid (I 2 aa) analogs and their ring-substituted derivatives (e.g., 1 – 3 , Figure 1 ), are among the most studied for utility in dissecting the backbone geometry and side chain alignment responsible for peptide activity towards the development of receptor ligands (e.g., 4 ) and enzyme inhibitors (e.g., 5 – 7 ) [ …”