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

Abstract

Synthetic methods for the preparation of compounds containing trifluoromethyl groups are in extremely high demand in nearly every sector of the chemical industry. Over the last several years the chemistry of N‐tert‐butylsulfinyl‐3,3,3‐trifluoroacetaldimine has undergone particular development. Currently, it is commonly used as a versatile reagent for general asymmetric synthesis of trifluoromethyl‐containing amines and amino acids of pharmaceutical potential. This review provides a critical and comprehensive overview of synthetic applications of this reagent as well as of several relevant analogues, such as aldimines containing –CHF2, –CClF2, –CBrF2, and –CF2P(O)(OEt)2 groups and N‐tert‐butylsulfinyl‐3,3,3‐trifluoromethyl‐substituted ketimines. Where it is possible, we emphasize the structural novelty and pharmaceutic value of the products obtainable by application of these reagents.

Asymmetric Synthesis of Cyclic Fluorinated Amino Acids

“…Taking into account the ever‐growing importance of fluorinated compounds and our ongoing interest in the development of fluorinated tailor‐made amino acids, we were interested in the development of suitable approaches for the preparation of enantiomerically pure trifluoromethylated analogues of β‐proline and (iso)nipecotic acid. According to Scheme , we envisaged the synthesis of the target molecules from N ‐ tert ‐butanesulfinyl‐(3,3,3)‐trifluoroacetaldimine 1 , which is a very useful starting material for the stereoselective synthesis of fluorinated amino acids …”

Self-disproportionation of enantiomers (SDE) of chiral sulfur-containing compounds via achiral chromatography

“…First of all they are recognized as valuable and efficient reagents in synthetic chemistry, particularly for asymmetric synthesis due to high asymmetric induction exerted by a sulfinyl fragment, and its configurational stability. 69,71,[74][75][76] Several review articles are devoted to this topic. [77][78][79][80][81][82][83][84] Moreover, sulfoxides are present in many natural products and they play an important role in biology.…”

Diastereoselective Regiodivergent Mannich Versus Tandem Mannich‐Cyclization Reactions

“…The reactions show wide structural generality, rendering them of certain synthetic value for preparation of new fluorine-containing polyfunctional compounds of biological relevance. [10] We [11] and others [12] reported Mannich addition reactions of imine 1 with various CÀH acidic compounds, demonstrating remarkable Scheme 1. [3] In particular, fluorine containing amines, [4] amino acids [5] and their analogs [6] serve as key structural units in the design of peptidic compounds with presupposed threedimensional structure and enhanced bio-receptor affinity.…”

“…[7] One of active directions of the current research is the development of generalized approaches to fluorinated derivatives bearing keto/hydroxy/amino groups. [10] We [11] and others [12] reported Mannich addition reactions of imine 1 with various CÀH acidic compounds, demonstrating remarkable Scheme 1. Consistent with our continuous interest in preparation of fluorinated amino compounds [8] our recent activity was largely invested in the discovery of detrifluoroacetylative in situ generation of fluoro-enolates [9] and chemistry of N-t-butylsulfinyl-3,3,3-trifluoro-acetaldimine 1 (Scheme 1).…”

“…The most challenging aspect in this area is the control of absolute and relative configurations of multiple stereogenic centers, as well is the position of target functionalities. [10] However, the reactivity of imine 1 with tertiary enolates bearing additional functional groups, except for a fluorine atom, [13] still remains unexplored area of research. [10] We [11] and others [12] reported Mannich addition reactions of imine 1 with various CÀH acidic compounds, demonstrating remarkable Scheme 1.…”