Synthesis of new fluorinated proline analogues from polyfluoroalkyl β-ketoacetals and ethyl isocyanoacetate

Abstract

The reaction of trifluoroaldol acetal and other polyfluoroalkyl β-ketoacetals with ethyl isocyanoacetate was applied for the preparation of hitherto unknown fluorinated amino acids, cis- and trans-3-CF3/C2F5-prolines as well as trans-3-CF2Br/CF2Cl/CHF2-3-hydroxyprolines.

Conformational landscape of substituted prolines

“…Such 3-substituted fluoroproline derivatives were used as molecular probes to study prolyl cis-trans isomerization via 19 F NMR (Kim et al 2006;Thomas et al 2009). Since fluorine and hydrogen atoms are nearly isosteric and the trifluoromethyl group is only modestly electron-withdrawing (comparable to either hydroxyl and fluorine), (2S,3S)-trifluoromethylproline exhibits multiple conformations that access both the exo and the endo ring pucker conformations, with multiple backbone conformations within the same crystal structure (Tolmachova et al 2018).…”

Fluorinated Prolines as Conformational Tools and Reporters for Peptide and Protein Chemistry

“…66,67 Very recently, the synthesis of novel R-and S-3-CF 3 (14a and 14b, respectively) and 3-CF 2 CF 3 (16a and 16b) prolines were reported. 68 However, these have not been incorporated into proteins at the time of submission.…”

“…Unlike other fluorinated prolines, Ulrich also showed TfmPro, in the Ac-TfmPro-OMe model system, to be significantly more “native proline-like” with regard to (i) its backbone conformational propensities, (ii) its K trans/cis equilibrium constant (4.0 for TfmPro and 4.8 for Pro at 300 K), (iii) its activation energy for cis → trans rotation (81.8 kJ/mol for TfmPro and 84.5 kJ/mol for Pro), and (iv) its incorporation into cyclic peptide gramicidin S, which showed virtually no structural perturbation by circular dichroism as compared with the natural product. The synthesis of other trifluoromethyl-containing proline derivatives, e.g., 5-CF 3 ( 13 ), has been reported. , Very recently, the synthesis of novel R - and S -3-CF 3 ( 14a and 14b , respectively) and 3-CF 2 CF 3 ( 16a and 16b ) prolines were reported . However, these have not been incorporated into proteins at the time of submission.…”

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

“…In 2018, Tolmachova, Haufe, and colleagues developed a general approach to all isomers of 3-trifluoromethyl proline. 119 Reaction of enone 198 (obtained from CH 2 CHOEt and (CF 3 CO) 2 O) 120 with ethylene glycol gave acetal 199 in 62% yield (Scheme 35). 121 The subsequent reaction with ethyl isocyanoacetate followed by acidic hydrolysis of the isocyanate group gave alkene 200 in 67% yield.…”