Asymmetric Synthesis of Sterically and Electronically Demanding Linear ω-Trifluoromethyl Containing Amino Acids via Alkylation of Chiral Equivalents of Nucleophilic Glycine and Alanine

Abstract

An operationally convenient, scalable asymmetric synthesis of linear, ω-trifluoromethyl-containing amino acids, which were not previously produced in their enantiomerically pure form, has been developed via alkylation of chiral equivalents of nucleophilic glycine and alanine. The simplicity of the experimental procedures and high stereochemical outcome (yields up to 90% and diastereoselectivity up to 99%) of the presented method render these fluorinated amino acids readily available for systematic medicinal chemistry studies and de novo peptide design.

Rational Design and Synthesis of Modified Teixobactin Analogues: In Vitro Antibacterial Activity against Staphylococcus aureus, Propionibacterium acnes and Pseudomonas aeruginosa

“…Wang et al. have previously reported a high diastereoselectivity (97 %), which was achieved with only 1.1 equivalents of NaOH . We have, however, obtained contradictory results.…”

“…Wang et al have previously reported ah igh diastereoselectivity (97 %), which was achieved with only 1.1 equivalents of NaOH. [45] We have, however,o btained contradictory results. Although the rate of the reactioni ncreased with an increased amount of NaOH, the diastereoselectivity between( S,S)-6 and (S,R)-6 was disappointingly low( Ta ble 1).…”

Recent advances in the trifluoromethylation methodology and new CF3-containing drugs

“…Structurally, the compound has an unusual fluorination pattern, such as v-CF 3 -containing side chain [114] linked to the diaryl ether core by forming the corresponding sulfonyl ester. Another cannabinoid receptor agonist reported by Bayer, BAY-59-3074 (41), sharing a similar structural scaffold, with the only difference in the substitutions on the ring A, exhibited noticeably lower agonist properties and acted as a CB1/CB2 partial agonist with antihyperalgesic and antiallodynic effects [115].…”

Convenient Asymmetric Synthesis of Fmoc-(S)-6,6,6-Trifluoro-Norleucine

“…One group of the methods is based on elaboration of functional groups in the already prearranged AA skeleton 2, such as additions of CF 3 radical to the terminal C=C bond [40,41] or biomimetic transamination [42,43]. However, a more general approach for synthesis of AA 1 includes alkyl halide alkylation of properly protected glycine derivatives 3 [44][45][46][47][48]. These reactions can be conducted under homogeneous [45][46][47][48], as well as PTC conditions [44].…”