New asymmetric approach to β-trifluoromethyl isoserines

Abstract

Enantiomerically pure N,O-protected b-trifluoromethyl isoserine derivatives of (2S,3S)-and (2R,3S)-absolute configurations have been easily prepared by diastereoselective addition of the enolates, derived from O-protected a-hydroxyacetates, to (S)-N-tert-butanesulfinyl (3,3,3)-trifluoroacetaldimine with high combined yield and good syn/anti stereoselectivity. To explain the unusual stereochemical outcome in these reactions a mechanistic rationale involving the addition of Z-enolates to (S)-imines via open transition states was proposed on the basis of the experimental data. Elaboration of these products via chemoselective manipulation of the protecting groups has been demonstrated.

Synthesis of (2S,3S)-β-(trifluoromethyl)-α,β-diamino acid by Mannich addition of glycine Schiff base Ni(II) complexes to N-tert-butylsulfinyl-3,3,3-trifluoroacetaldimine

“…Thus, it is well established that kinetic control in the alkylation reactions of Ni(II) complex (S)-1 usually affords up to 85:15 diastereoselectivity, favoring the corresponding (S) configuration at the a-carbon [21], and that was also the case in the previously shown example of a Mannich reaction with an achiral imine [6] (Scheme 1). On the other hand, the high facial selectivity displayed by chiral sulfinimine 7 was also demonstrated [9][10][11][12][13][14][15]. Therefore, the reaction of complex (S)-1 with sulfinimine (S S )-7 constituted a perfectly matched case since essentially only one diastereomer (S)(2S,3S)(S S )-11 was observed (Scheme 3).…”

“…This compound has been employed for the expedient synthesis of a wide variety of a-(trifluoromethyl)amines [9]. For instance, several Mannich-type processes have been performed with (S S )-or (R S )-7 by reaction with enolates derived from a-hydroxyesters [10], malonates [11] or indanones [12], as well as with other nucleophiles such as phosphites [13], lithium anions derived from phosphonates [14] or heterocycles [15].…”

N‐tert‐Butylsulfinyl‐3,3,3‐trifluoroacetaldimine: Versatile Reagent for Asymmetric Synthesis of Trifluoromethyl‐Containing Amines and Amino Acids of Pharmaceutical Importance

“…Another type of fluorinated β‐amino acids – β‐(trifluoromethyl)isoserines – can be obtained through addition between imine ( S s )‐ 7 and enolates derived from O ‐protected α‐(hydroxy)acetates 60 (Scheme ) …”

New Chiral Reagent for Installation of Pharmacophoric (S)‐ or (R)‐2‐(Alkoxyphosphono)‐1‐amino‐2,2‐difluoroethyl Groups

“…Taking into account that PGK is associated with the development of gastric cancer and in vivo activation of HIV drugs, one might expect an exciting pharmaceutical potential for β‐amino‐α,α‐difluorophosphonic acids 2 and their derivatives. Drawing inspiration from the original work, and our own experience,– we decided to design N ‐ tert ‐butanesulfinyl‐phosphoryldifluoro‐imine ( 3 ) as a new broad‐spectrum reagent for asymmetric installation of pharmacophoric 2‐(alkoxyphosphono)‐1‐amino‐2,2‐difluoroethyl group into organic compounds. As a proof‐of‐concept, we present here Lewis acid BF 3 ⋅OEt 2 ‐catalyzed Friedel–Crafts reactions of chiral reagent 3 with indoles.…”