Stereoselective synthesis of (R)- and (S)-α-trifluoromethyl aspartic acid via titanium enolate addition to a sulfinimine of trifluoropyruvate

Mannich-type Reaction of Methylene Active Compounds with a Chiral Sulfinimine of Trifluoropyruvate: New Highly Stereoselective Synthesis of (S)-α-Trifluoromethyl-Aspartic Acid

“…The target (S)-Tfm-Asp 8 was obtained from (S)-6 by saponification with KOH at reflux, which also produced decarboxylation of the malonyl moiety, followed by the usual ion-exchange chromatography. Polarimetric analysis of 8 showed positive rotation, with a value in agreement with nearly enantiopure (S)-configurated Tfm-Asp [7].…”

“…Recently, we have been involved in a project aimed at the synthesis of RGD peptides incorporating Tfm-Asp [5]. Although many approaches to racemic Tfm-Asp and derivatives have been reported [6], the first synthesis of Tfm-Asp in non-racemic form was described very recently by our group [7] exploiting a stereoselective TiCl(O-iPr) 3 /LDA promoted Mannich-type addition of tert-butyl acetate to the sulfinimine [8] of trifluoropyruvate (S)-2 (Scheme 1). We now describe a highly efficient, improved approach to (S)-Tfm-Asp in high e.e., exploiting an extremely diastereoselective addition of lithium dimethyl malonate 3a to (S)-2, and a study of the addition of other methylene active compounds 3b-f to the same sulfinimine (S)-2.…”

Asymmetric synthesis of propargylamines as amino acid surrogates in peptidomimetics

“…Various trifluoromethyl-substituted ketones have been converted into N- sulfinylimines, which were subsequently transformed into sulfinamides attached to a tertiary C-atom by addition of nucleophiles [ 89 – 92 ]. N- Sulfinyl propargylamine 7k was prepared, following approach II under varying conditions ( Table 2 ).…”

Titanium Enolate Chemistry at the Beginning of the 21st Century

“…The stereochemical outcomes depended on the absolute configuration at the alkylsulfinyl moiety and on protection of the hydroxy group. Excellent diastereoselectivity was also observed for Mannich additions of titanium(IV) enolates derived from achiral acetates to chiral sulfinyl imines of trifluoropyruvic acid 91…”