Vadim A. Soloshonok

Asymmetric Synthesis of Phosphorus Analogs of Amino Acids

Abstract Data available in literature on asymmetric synthesis of phosphorus analogs of amino acids are summarized. The methods described are arranged according to the type of bond formation during a chiral center creation. The asymmetric synthesis was shown to be in dynamic development and can be considered as a valuable approach for production of optically active phosphorus analogs of amino acids.

Erythro-Selective aldol-type reaction of N-sulfonylaldimines with methyl isocyanoacetate catalyzed by gold(I)

Reaction of N-tosylaldimines 1 with methyl isocyanoacetate in the presence of 1 mol % of AuCl(c-HexNC) gave 4-methoxycarbonyl-5-alkyl-2-imidazolines 2 with high (over 89%) cis selectivity. The cis-imidazolinecarboxylates were isomerized into trans isomers by treatment with triethylamine. Hydrolysis of the cis- and trans- imidazolinecarboxylates gave erythro- and threo-α,β-diamino acids, respectively.

Biocatalytic approach to enantiomerically pure β-amino acids

β-Aryl-β-amino acids were prepared in good chemical yield and high enantiomeric purity (>95% ee) via penicillin acylase-catalyzed hydrolysis of the corresponding N-phenylacetyl derivatives. The (R)-enantiomers were the fast-reacting isomers in all cases studied. The biocatalytic procedure described employs very simple set of reactions using inexpensive commercially available chemicals and enzyme, and could be easily scaled up.

Practical synthesis of fluorine-containing α- and β-amino acids: recipes from Kiev, Ukraine

Naturally occurring compounds containing a C-F bond are extremely rare; only a handful of fluorine-containing carboxylic acids have been described so far. By contrast, man-made fluorine-containing derivatives of all major classes of biologically important compounds are extremely promising medicinal targets used in the elucidation of biochemical, metabolic transformations and the development of new pharmaceuticals. Among the fluorine-containing derivatives of natural products, fluorinated analogs of amino acids are of particular interest and medicinal potential. This article presents a concise review of various synthetic methods, developed by the Kievs school of bioorganic chemistry, for the preparation of fluorine-containing analogs of α- and β-amino acids, α-hydroxy acids, amines, as well as their phosphorus and sulfur-derived compounds, in enantiomerically pure form. One of the major methodological goals of the study was practicality, which is understood by us as stereochemical generality, operational convenience and synthetic affordance for each reaction step and isolation of the target products. The synthetic methods developed by our group can be roughly divided in two general categories: fluorine-adaptation of known synthetic approaches and discovery of new reactions. The former approach is most prominently represented by asymmetric homologation of nucleophilic glycine equivalents using fluorinated substrates via alkyl halide alkylations, aldol and Michael addition reactions. A plethora of discovered unexpected reaction outcomes, in particular stereochemical, are emphasized in this review and the particular role of fluorine, in altering the normal reaction result, is explained. The latter direction is notably represented by the novel 1,3-proton shift reaction, a biomimetic reductive amination of fluorinated carbonyl compounds to the corresponding amines and amino acids, as well as the development of α-fluoroalkyl epoxides as true fluorinated synthons for generalized asymmetric synthesis of various biologically relevant compounds. Despite the highly anticipated potential of fluorine-containing amino compounds, their medicinal chemistry still remains underexplored. The major obstacle, in our opinion, is that these selectively fluorinated compounds are generally unavailable to the medicinal chemists for comprehensive, systematic study. We hope this review of synthetic methods will highlight and bring attention to particular types of fluorinated amino acids and related compounds readily available on a laboratory scale using methods developed by our group.

New fluorinated chiral synthons

Abstract the syntheses of new optically pure poly-halo and poly-fluoro oxiranes 5b-e by addition of diazomethane on the corresponding β-ketoγ-fluorosubstituted sulphoxide intermediates, both in keto 3 , hydrate 4 or in keto/ hydrate form are described. Syntheses of sulphur-free fluorinated oxiranes 18b-e , β-hydroxy-β-trifluoromethyl amine 21d , α- acid 25d and β,γ-dihydroxy-β-trifluoro- and -chlorodifluoromethyl amines 26c and 26d are shown as examples of their chemical versatility

Catalytic asymmetric synthesis of β-fluoroalkyl-β-amino acids via biomimetic [1,3]-proton shift reaction

Abstract [1,3]-Proton shift reaction of N -benzylenamines 1a-e , derived from β-polyfluoroalkyl-β-ketocarboxylic esters and benzylamine, was catalyzed by (-)-cinchonidine (5–13 mol %) to give good yields (67–89%) of enantiomerically enriched (up to 36% ee) N -benzylidene derivatives 3a-e . The resulting products 3a-e were readily hydrolyzed into the corresponding optically active ( R )-β-polyfluoroalkyl-β-amino acids 4a-e (87–93% yield).

Asymmetric synthesis of phosphorus analogues of dicarboxylic α-amino acids

An efficient approach to the asymmetric synthesis of phosphorus analogues of dicarboxylic α-amino acids is described. The method of choice consists in the reaction of the nickel(II) complex (4) of the Schiffs base derived from (S)-o-[(N-benzylprolyl)amino]benzophenone 3 and glycine with the appropriate alkyl halide, substituted with an alkylphosphonate group. The reactions were carried out in MeCN at 25 °C, with solid KOH as a catalyst. Michael-type base-catalysed addition of vinyl-phosphonate and vinylphosphinate to complex 4 in dimethylformamide (DMF) at 50–70 °C could also be employed. Significant diastereoselectivity (90% d.e.) was observed for the alkylation of complex 4. Optically pure (S)-phosphinothrieine, (S)-2-amino-3-phosphonopropanoic acid, (S)-2-amino-4-phosphonobutanoic acid and (S)-2-amino-5-phosphonopentanoic acid were obtained after the alkylated diastereoisomeric complexes had been separated on SiO2 and hydrolysed with aq. HCl. The initial chiral reagent 3 was recovered (60–85%). Novel amino acids 9, having free carboxy groups and esterified phosphonic and phosphinic groups, could also be obtained as intermediates due to the mild conditions of the decomposition of the alkylated diastereoisomeric complexes.

Asymmetric aldol reactions of chiral Ni(II)-complex of glycine with aliphatic aldehydes. Stereodivergent synthesis of syn-(2S)- and syn-(2R)-β-alkylserines

Abstract Stereoselectivity of aldol reactions between aliphatic aldehydes and Ni(II)-complex of chiral non-racemic Schiff base of glycine with ( S )- o -[ N -( N -benzylprolyl)amino]benzophenone (BPB) in the presence of excess of MeONa, has been studied as a function of time, reaction conditions and nature of an aldehyde. Two salient features of the reaction, very high pseudokinetic syn -(2 S )-diastereoselectivity, and dependence of thermodynamic syn -(2 R )-diastereoselectivity on the steric bulk of an aldehyde side chain, were disclosed and used for efficient (more than 90% de and ee) asymmetric synthesis of both syn -(2 S ) and syn -(2 R )-3-alkyl substituted serines. Synthetic potential and reliability of this asymmetric method are demonstrated with the large scale (2–20 g) preparation of enantiomerically pure amino acids.

Transamination of fluorinated β-keto carboxylic esters. A biomimetic approach to β-polyfluoroalkyl-β-amino acids.

Abstract The base-catalyzed isomerization of N-benzylimines (or enamines) of β-polyfluoroalkyl-β-ketocarboxylic esters cleanly affords the N-benzylidene derivatives of β-polyfluoro-β-aminocarboxylic esters which are hydrolyzed to corresponding amino acids in high overall yields.

General method for the synthesis of enantiomerically pure β-hydroxy-α-amino acids, containing fluorine atoms in the side chains. Case of stereochemical distinction between methyl and trifluoromethyl groups. X-Ray crystal and molecular structure of the nickel(II) complex of (2S,3S)-2(trifluoromethyl)threonine

The chiral NiII complex 1 of a Schiffs base derived from (S)-o-[N-(N-benzylprolyl)amino] benzophenone (BPB) and glycine was treated with fluoro-substituted aldehydes (aliphatic and aromatic)in MeOH or CHCl3. The addition proceeds with high diastereoselectivity to give, if catalysed by MeONa in MeOH, the corresponding complexes of syn-(2R)-3-fluorophenylserines (84–100% d.e.) and syn-(2S)-fluoroalkylserines (90% d.e.), and, if catalysed by NEt3 or DABCO (MeOH or CHCl3), the corresponding complexes of syn-(2S)-, and anti-(2S)-3-fluorophenylserines and fluoroalkylserines. The second-order asymmetric transformation may be successfully employed to obtain diastereoisomerically pure complexes of anti-(2R)-3-fluorophenylserines. Condensation of trifluoroacetone with complex 1, catalysed by MeONa, gave predominantly (at least >95% d.e.) the diastereoisomeric complex, containing (2S,3S)-β-(trifluoromethyl)threonine, as shown by an X-ray diffraction structural study. Diastereoisomerically and enantiomerically pure fluorine-containing 3-phenyl- and 3-alkyl-serines were obtained from the corresponding diastereoisomerically pure complexes, separated by chromatography or crystallization. The initial chiral auxiliary BPS was recovered (80–98%). The influence of the reactions conditions and the nature of the corresponding fluoro-substituted aldehydes on the diastereoselectivity of the reactions is discussed.