Valery P. Kukhar

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.

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.

β-Ethoxyvinyl polyfluoroalkyl ketones — versatile synthones in fluoroorganic chemistry

Abstract We have found readily available β-ethoxyvinyl trifluoromethyl ketone to be a convenient and comprehensive starting material for the synthesis of various fluoro-containing compounds such as heterocycles, enones, enaminones and chelate complexes. The 4,4,4-trifluoro-3-oxo-l-butenyl group formed by β-ethoxyvinyl trifluoromethyl ketone is a suitable protecting group for the N-H terminal of amino acids in peptide synthesis. The formation of peptides using these protected amino acids occurs without racemization.

Recent advances in the synthesis of fluorinated aminophosphonates and aminophosphonic acids

This review article surveys recent achievements in the preparation and biological properties evaluation of fluorinated aminophosphonates and aminophosphonic acids. Recently, in view of various important biological applications of the fluorinated aminophosphonic acid derivatives, the development of suitable synthetic methodologies for their preparation in racemic and in optically pure form has been a topic of great interest. Considerable progress has been made in asymmetric synthesis of fluorinated acyclic aminophosphonates and aminophosphonic acids using catalytic enantioselective reduction of fluorinated α-iminophosphonates, catalytic enantioselective addition of alkyl phosphites to fluorinated imines, and diastereoselective addition of alkyl phosphites to chiral fluorinated imines. A new efficient access to CF3-substituted cyclic α-aminophosphonates has been developed based on metal-catalyzed carbene transfer reactions with diethyl 1-diazo-2,2,2-trifluoroethylphosphonate. New processes, e.g. enantioselective alkynylation and nucleophilic aromatic substitution involving fluorinated substrates are also considered.

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 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.

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.

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.