V. A. Soloshonok

Chiral sulfoxide controlled asymmetric additions to CN double bond. An efficient approach to stereochemically defined α-fluoroalkyl amino compounds

Abstract This paper presents a full account of studies into the asymmetric addition reactions between α-lithium derivatives of enantiomerically pure methyl and benzyl p-tolyl sulfoxides and the N-(p-methoxyphenyl)aldimines, bearing trifluoromethyl, pentafluoroethyl and ω-hydrotetrafluoroethyl groups, to afford the corresponding α-fluoroalkyl β-sulfinylamines, synthetically versatile precursors of a series of enantiomerically pure biomedicinally important α-fluoroalkylalkylamines and α-fluoroalkyl-β-hydroxyalkylamines. The addition reactions were found to proceed under mild conditions allowing for convenient preparation of the corresponding α-fluoroalkyl β-sulfinylamines in excellent yields and good enantiomeric purity. The stereochemical outcomes of these reactions were shown to be subject to kinetic control, that is in sharp contrast to the corresponding reactions of fluorine-free imines. The absolute configurations of the addition products suggest that the fluoroalkyl group on starting imines plays a role of enantiodirecting, sterically larger substituent causing realization of an unusual for this type of reactions transition states.

The effect of substituents on the feasibility of azomethine-azomethine isomerization: New synthetic opportunities for biomimetic transamination

Abstract The azomethine-azomethine isomerization of the Schiff bases derived from fluoroalkyl carbonyl compounds and arylmethylamines has been studied as a function of substitution on the amine site. The present study indicates that regardless of the nature of the substitution, the position of the isomerization equilibrium is overwhelmingly controlled by the electron-withdrawing effect of the perfluoroalkyl group, while the reaction rate strongly dependsion both CH acidity and steric availability of the transferring proton. Specifically, we have found that the presence of electron-releasing substituent on the phenyl of the benzylamine site largely retards the isomerization of the corresponding imines. In contrary, azomethine-azomethine isomerizations of the imines derived from the benzylamines containing electron-withdrawing substituent on the phenyl ring or picolylamines, possessing electron-deficient pyridine ring, occur with remarkably higher reaction rates as compared with the established isomerizations of N -benzylimines. In particular, the use of 4-picolylamine allows for truly biomimetic one-stage transamination of fluorocarbonyl compounds to afford the Schiff bases of the corresponding amines. The exciting synthetic aspects of this finding are demonstrated by the improved procedure for transamination of certain fluoroalkyl carbonyl compounds representing aldehydes, ketones, and β-keto carboxylic acids.

Asymmetric aldol reactions of trifluoromethyl ketones with a chiral Ni(II) complex of glycine: Stereocontrolling effect of the trifluoromethyl group

Asymmetric aldol reactions between trifluoromethyl ketones and a Ni(II) complex of the Schiff base of glycine with (S)-o-[N-(N-benzylprolyl)amino]benzophenone (BPB) have been studied. Sterically demanding aryl and sec-alkyl trifluoromethyl ketones, and highly enolizable benzyl trifluoromethyl ketone failed to react with the Ni(II) complex, while n-alkyl and acetylenyl trifluoromethyl ketones reacted readily and gave good yields (56–87%) of the aldol products with high diastereomeric excess (90–98%). Decomposition of the resultant complexes gave diastereo and enantiomerically pure (2S,3S)-3-trifluoromethyl-3-substituted serines of biomedicinal interest. A mechanistic working model that accounts for the observed sense of diastereoselectivity is discussed.

Highly diastereoselective aza-aldol reactions of a chiral Ni(II) complex of glycine with imines. An efficient asymmetric approach to 3-perfluoroalkyl-2,3-diamino acids

Abstract The LiCl/base-assisted asymmetric aldol-type addition reaction between the N -( p -methoxyphenyl)imine of trifluoroacetaldehyde and the chiral non-racemic Ni(II) complex of the Schiff base of glycine with ( S )- o -[ N -( N -benzylprolyl)amino]benzophenone was found to proceed with excellent chemical and stereochemical outcomes allowing for an efficient access to hitherto unknown stereochemically defined β-perfluoroalkyl-α,β-diamino carboxylic acids. A mechanistic rationale for the observed stereochemical preferences is proposed.

An efficient asymmetric synthesis of (2S,3S)-3-trifluoromethylpyroglutamic acid

Abstract The stereochemical outcome of the Michael reaction between ethyl 4,4,4-trifluorocrotonate and a Ni(II) complex of the Schiff base of glycine with (S)-o-[N-(N-benzylprolyl)amino]benzophenone was found to be subjected to kinetic and thermodynamic control. Thus, under kinetically controlled conditions high values of diastereo-selectivity, up to 94% de, allowing for an efficient asymmetric synthesis of (2S,3S)-3-trifluoromethylpyroglutamic acid, could be obtained, while the thermodynamically controlled stereoselectivity is rather modest (54–60% de).

Biomimetic transamination of α-keto perfluorocarboxylic esters. An efficient preparative synthesis of β,β,β-trifluoroalanine

Abstract An efficient large-scale preparative synthesis of biologically interesting β,β,β-trifluoroalanine through the biomimetic transamination of the ethyl trifluoropyruvate has been developed. The azomethine—azomethine isomerization of the N-(1-phenyl)ethylimine of ethyl trifluoropyruvate to the N-(1-phenyl)ethylidene alanine ethyl ester, a key stage of the process, was found to occur under the mild reaction conditions, in a triethylamine solution at rt. The proposed working mechanistic rationale accounting for the easiness of the isomerization and its stereochemical outcome, involves unusual non-asymmetric [1,5]-proton shift transfer from the methine carbon to the enolate oxygen.

Highly diastereoselective asymmetric aldol reactions of chiral Ni(II)-complex of glycine with alkyl trifluoromethyl ketones

Abstract Asymmetric aldol reactions between prochiral trifluoromethyl ketones and Ni(II)-complex of monochiral Schiff base of glycine with ( S )- o -[ N -( N -benzylprolyl)amino]benzophenone (BBP) are described. General stereodirecting features of the trifluoromethyl group controlling (2 S ,3 S )-absolute configuration (90–98 %de) of the resultant amino acids is demonstrated. New set of reaction conditions allowing preparative synthesis of diastereo and enantiomerically pure (2 S ,3 S )-3-trifluoromethyl-3-substituted serines of biomedicinal interest is presented.

Asymmetric synthesis of α-arylglycinols via additions of lithium methyl p-tolyl sulfoxide to N-(PMP)arylaldimines followed by “non oxidative” Pummerer reaction

Abstract The results presented in this paper demonstrate that the stereochemical outcome of the reversible additions of lithium (R)-methyl p-tolyl sulfoxide to N-arylidene-p-anisidines (N-PMP imines) is a function of a) the reaction conditions used and b) the electronic properties of the arylidene moiety on the starting imine. High kinetically controlled (2S,RS) diastereoselectivity (−70 °C) was achieved for additions of imines bearing relatively electron-rich N-arylidene groups, while an electron-deficient nature of this group was found to favor the opposite stereochemical outcome. On the other hand, the reactions run under thermodynamically controlled conditions (0 °C) afforded equimolar mixtures of the diastereomeric products regardless of the pattern of substitution on the starting imines. Enantiopure α-arylglycinols were readily synthesized by “non-oxidative” Pummerer rearrangement of diastereomerically pure β-aryl-β-N-(acyl)aminoalkyl sulfoxides, prepared from the corresponding N-PMP derivatives.

Biomimetic base-catalyzed [1,3]-proton shift reaction. A practical synthesis of β-fluoroalkyl-β-amino acids

Abstract An efficient approach to practical synthesis of β-fluoroalkyl-β-amino acids is described. The method consists in the reducing reagent-free base-catalyzed biomimetic transamination reaction between fluorinated β-keto carboxylic esters and benzylamine. This transformation involves two sequential base-catalyzed [1,3]-proton transfers giving rise to corresponding N -benzylidene derivatives as the products of final thermodynamic equilibration, directed by the electron-withdrawing character of fluoroalkyl groups. Opportunity for catalytic enantiocontrolled synthesis of targeted β-amino acids with application of monochiral base, as a catalyst for these isomerizations, is demonstrated.

Highly diastereoselective methylene transfer from diazomethane to the carbonyl of β-keto sulfoxides. A general approach to synthetically versatile fluorine-containing chiral building blocks

Abstract This paper describes the reactions of diazomethane with α-alkyl and α-phenyl-substituted (RS)-β-keto sulfoxides bearing difluoro-, trifluoro- and difluorochloromethyl groups on the terminal site, to afford the corresponding diastereo- and enantiomerically pure epoxides. A plausible mechanistic rationale for the origin of the stereochemical preferences in these reactions has been provided. Synthetic versatility of the resultant epoxides has been demonstrated by a series of key transformations of the epoxide ring and the sulfinyl group including ring-opening, reductive desulfurization and syn-elimination reactions.