Concise Asymmetric Synthesis of β‐Trifluoromethylated α,β‐Diamino Esters through Addition Reactions of Glycine Esters to CF₃‐Sulfinylimine

Abstract

(S)‐N‐(tert‐Butylsulfinyl)‐3,3,3‐trifluoroacetaldimine underwent reactions with enolates of glycine esters with quite remarkable stereochemical results, that is, with virtually complete (>99 % de) diastereoselectivity and excellent (>98 %) yields. Furthermore, the reactions are conducted under operationally convenient conditions (Cs2CO3‐catalyzed, ambient temperature) to provide the most advanced, general, and scalable access to biologically important β‐trifluoromethylated α,β‐diamino acids.

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

“…Optimization of the reaction condition revealed that application of Cs 2 CO 3 as a base in THF at ambient temperature afforded target addition product ( S s )(2 S ,3 S )‐ 96 with both excellent yield (98 %) and diastereomeric purity ( dr 99:1). To account for the role of cesium in controlling the observed stereochemical preferences, the authors suggested tightly chelated TS‐9 , in which the Cs ion coordinates both oxygen and nitrogen in the glycine enolate, as well as the oxygen atom of the sulfinamide moiety. This addition was reproduced on about 5 g scale with virtually no deterioration in the stereochemical outcome …”

“…β‐(Trifluoromethyl) α,β‐diamino acid 94 is a very appealing, multifunctional structural unit, and was also pursued by another approach based on addition between imine ( S s )‐ 7 and glycine Schiff bases 95 (Scheme ), derived from glycine alkyl esters and benzophenone . The reaction was found to take place in the presence of various organic bases, including Et 3 N, DABCO, DBU, DBN, tetramethylguanidine, and DMAP.…”

Trifluoromethyl aldimines: an overview in the last ten years

“…47 After chemoselective deprotection under mild conditions of the labile imine function, the resulting free amine 32 (R = t-Bu) was isolated in good yield (93%). Nevertheless, implementation of this approach may not be feasible on a large scale due to the relative instability of 30.…”

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

“…Recently, it was found that Mannich adducts (2S,3S)(S S )-9 were formed in very good yield and excellent diastereoselectivity upon reactions of sulfinimine (S S )-7 with benzophenone imines of glycine esters 8 [16] (Scheme 2). Nevertheless, implementation of this approach for the preparation of the corresponding free a,bdiamino acid (2S,3S)-10 may not be feasible on a large scale due to the relative instability of NGEs 8.…”