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

Abstract

The synthesis of (2R,3S)‐3,4,4,4‐tetrafluorovaline, a fluorinated derivative of the canonical α‐amino acid l‐valine, is reported for the first time. A highly enantio‐ and diastereoselective direct catalytic asymmetric Mannich‐type reaction was applied as the key C–C bond‐forming step to afford gram quantities of a central synthetic intermediate. The conformation of the novel fluorinated α‐amino acid was analyzed by X‐ray crystallography, NMR spectroscopy, and computational methods, which, together with its calculated and experimental physicochemical properties, indicated that the fluorinated valine is a bioisostere of l‐isoleucine.

Progress in Catalytic Asymmetric Reactions with 7-Azaindoline as the Directing Group

“…The further conversion of product 9f to other compounds with an unchanged chiral configuration also demonstrates the potential synthetic utility of the methodology. Notably, Product 9f also can be converted into (2R,3S)-3,4,4,4-tetrafluorovaline hydrochloride product 12a in 34% yield via a series of transformations [74] (Scheme 6).…”

“…The further conversion of product 9f to other compounds with an unchanged chiral configuration also demonstrates the potential synthetic utility of the methodology. Notably, Product 9f also can be converted into (2R,3S)-3,4,4,4-tetrafluorovaline hydrochloride product 12a in 34% yield via a series of transformations [74] (Scheme 6). More importantly, some products can be converted into biologically active substances in a few steps [75]; for example, the β-amino acid derivative 9c can be converted Scheme 5.…”

Exploring F/CF3substituted oxocarbenium ions for the diastereoselective assembly of highly substituted tetrahydrofurans

“…13 One question also arises behind this strategy: how could the CF 3 dÀ /F dÀ complete charge inversion (versus CH 3 d+ /H d+ ) influence the stereochemical outcome of the nucleophilic trapping of a postulated phenyl-substituted oxocarbenium ion A, generated after hemiketal activation (Scheme 1A)? 14,15 Stereoelectronic models have been nicely recommended by Woerpel to explain the highly stereoselective reaction of five-membered ring oxocarbenium ions with nucleophiles (Scheme 1B). 16 The ''inside'' attack model, based on the stereoelectronically controlled inside attack of the nucleophile on the lower energy conformer, allows for predicting Lewis acid-promoted substitution to form the product in the lowest energy conformation.…”