Enantioselective Synthesis of β-Trifluoromethyl α-Amino Acids

Abstract

We report herein the three-step enantioselective synthesis of beta-trifluoromethyl alpha-amino acids including trifluorovaline (TFV) using stereoselective hydrogenation with [((R)-trichickenfootphos)Rh(cod)]BF(4) catalyst as the key step.

Recent Advances in the Synthesis of Fluorinated Amino Acids

“…Very recently, also in view of the important role of TFV, Benhaim's group [33] achieved a three-step enantioselective synthesis of 4,4,4-trifluorovaline based on the stereoselective hydrogenation of tetrasubstituted trifluoromethyl alkenes of type 94 (Scheme 10), prepared by Schöllkopf's procedure in 68-80 % yields. [34] The selection of formyl groups instead of acetyl groups as protecting groups in the alkenes 94 was based on the observation that no racemization oc- Scheme 9. curred upon deprotection.…”

Stereoselective Construction of an Asymmetric Carbon Center Possessing a Trifluoromethyl Group

“…The synthesis of -trifluoromethyl -amino acids via enantioselective hydrogenation using chiral rhodium catalyst has also been published very recently [80]. Thus on treating the prochiral alkenes 106, prepared readily from Schollkopf's procedure starting from trifluoromethyl ketones, with H 2 in the presence of (R)-Ph-BPE-Rh 107 or (R)-TCFP-Rh 108 in MeOH at 60 °C for 16 h, the corresponding hydrogenated compounds are obtained in a highly enantioselective manner.…”

(2R,3S)‐3,4,4,4‐Tetrafluorovaline: A Fluorinated Bioisostere of Isoleucine

“…The asymmetric syntheses of fluorinated amino acids 2 and 3 have been previously reported, with both diastereomers being individually accessed via auxiliary‐based approaches or enzymatic kinetic resolutions, while syn ‐diastereomer 2 can also be prepared via catalytic asymmetric hydrogenation, and anti ‐diastereomer 3 through a diastereoselective allylation …”

“…Bioisosteric relationship between L-isoleucine (Ile, 5) and the fluorinated derivatives 2, 3, and 4 of L-valine (Val, 1). Nomenclature according to Koksch et al [2a] The asymmetric syntheses of fluorinated amino acids 2 and 3 have been previously reported, with both diastereomers being individually accessed via auxiliary-based approaches [11] or enzymatic kinetic resolutions, [12] while syn-diastereomer 2 can also be prepared via catalytic asymmetric hydrogenation, [13] and anti-diastereomer 3 through a diastereoselective allylation. [14] The fluorinated amino acid (2R,3S)-4 3 ,3 1 -F 4 Val (4) bears one additional fluorine atom at the C 3 -position compared to fluorinated amino acids 2 and 3, which presumably affects both its physicochemical properties (e.g., lipophilicity, surface area) and its conformation.…”