Vasili M. Belikov

General method for the asymmetric synthesis of α-amino acids via alkylation of the chiral nickel(II) Schiff base complexes of glycine and alanine

Nickel(II) complexes of Schiff bases derived from (S)-o-[(N-benzylprolyl)amino] benzaldehyde and alanine (3), or (S)-O-[(N-benzylpropyl)amino]benzophenone and alanine (4), or glycine (5) have been used for the asymmetric synthesis of α-amino acids under a variety of conditions. The method of choice consists of the reaction of the corresponding complex with the appropriate alkyl halide in DMF at 25 °C using solid NaOH as a catalyst. Low diastereoselective excess (d.e.) is observed for the alkylation of complex (3) with benzyl bromide and allyl bromide. Large selectivity (80%) is observed for the alkylation of complex (4). Optically pure (R)- and (S)-α-methyl-α-amino acids [(S)-α-methylphenylalanine, (S)-α-allylalanine and (S)-O-benzyl-α-methyltyrosine] were obtained (70–90%) after the alkylated diastereoisomeric complexes had been separated on SiO2 and hydrolysed with aqueous HCl. The initial chiral reagents were recovered (80–92%). The alkylation of complex (5) gave (S)-alanine, (S)-valine, (S)-phenylalanine, (S)-tryptophan, (S)-isoleucine, (S)-2-aminohexanoic acid, and 3,4dimethoxyphenylalanine with optical yields of 70–92%. The optically pure α-amino acids were obtained after the separation of the alkylated diastereoisomeric complexes on SiO2. The stereochemical mechanism of the alkylation reaction is discussed.

Synthesis of enantio- and diastereo-isomerically pure β- and γ-substituted glutamic acids via glycine condensation with activated olefins

The glycine fragment in the nickel(II) complex formed from the Schiff base of glycine and (S)-o[(N-benzylprolyl)amino]benzophenone undergoes base-catalysed Michael addition in methanol in the presence of MeONa to the activated olefins methyl acrylate, acrylonitrile, methyl methacrylate, acrolein, and methyl trans-cinnamate. Complexes of substituted (S)-glutamic acid or its derivatives were formed in good chemical yields with almost complete diastereoselection at the α-carbon atom of the amino acid moiety. Diastereoselection at the β- and γ-atoms was not significant, but the isomeric complexes could be easily separated chromatographically. Cleavage of the pure diastereo-isomers with aqueous HCl gave, in good yields, optically pure glutamic acids and regenerated the original chiral reagent. The configurations of the amino acid β- and γ-carbon atoms were determined by 1H n.m.r. spectroscopy and crystal structure X-ray analysis of the corresponding original complexes. The addition to acrolein, catalysed by triethylamine in methanol, leads to the 1,4-adduct exclusively. The amino acid thus obtained could be converted into (S)-proline by reduction with NaBH4.

General method for the asymmetric synthesis of anti-diastereoisomers of β-substituted L-2-aminobutanoic acids via chiral nickel(II) Schiff's base complexes of dehydroaminobutanoic acid. X-Ray crystal and molecular structure of the nickel(II) complex of the Schiff's base from [(benzylprolyl)amino]benzophenone and dehydroaminobutanoic acid

An efficient approach to the asymmetric synthesis of (L)-allo-isomers of β-substituted α-aminobutanoic acid is described. The chiral NiII complex of a Schiffs base derived from (S)-o-[N-(N-benzylprolyl)amino]benzophenone (BBP) and glycine was treated with acetaldehyde in MeOH. The addition proceeds with high diastereoselectivity to give, if catalysed by MeONa, the corresponding complex of (R)-threonine, and, if catalysed by Et3N, the corresponding complex of (S)-allo-threonine. The (R)-threonine complex was converted into the chiral NiII complex of dehydroaminobutanoic acid, and a X-ray diffraction structural study of its major isomer showed that the dehydroaminobutanoic acid moiety was in the E-configuration. The complex, in turn, entered into Michael addition reactions with nucleophiles, including MeOH, EtOH, PhSH, and PhCH2SH. The reaction proceeded with high diastereoselectivity, producing predominantly complexes of the allo-threonine derivatives (d.e. > 90%). Diastereoisomerically and enantiomerically pure α-amino acids were obtained after chromatographic purification, decomposition of the complexes, and recovery of the initial chiral auxiliary, BBP. The thiol addition reaction is accompanied by a side reaction leading to the formation of sizeable amounts of the vinylglycine complex. An approach to the synthesis of optically active vinylglycine starting with racemic methionine is described.

Preparation of optically pure α-methyl-α-amino acids via alkylation of the nickel(II) Schiff base of (R,S)-alanine with (S)-2-N-(N′-benzylprolyl)aminobenzaldehyde

Chiral nickel(II) complexes of Ala with (S)-2-N-(N′-benzylprolyl)aminobenzaldehyde [(S)-bba] were alkylated with alkyl halides and the diastereoisomeric complexes formed were separated on SiO2; their decomposition led to the isolation of enantiomerically pure (R)- and (S)-α-alkyl-α-amino acids with recovery of the initial (S)-bba.

Synthesis of enantio- and diastereoiso-merically pure substituted prolines via condensation of glycine with olefins activated by a carbonyl group

The glycine fragment in the nickel(II) complex (1) formed from the Schiff′s base of glycine and (S)-o-[(N-benzylprolyl)amino]benzophenone (2) undergoes base-catalysed Michael addition to acrylaldehyde, α-methylacrylaldehyde, (E)-crotonaldehyde, (E)-cinnamaldehyde, and methyl vinyl ketone. No products of 1,2-addition were found in the Et3N-catalysed reactions. Addition followed by epimerization of the isomeric complexes proceeds with high diastereoselectivity at Cα(90%) and Cβ of the corresponding amino acid side chains. After chromatographic separation, the diastereoisomerically pure complexes were decomposed and the resulting dihydropyrrole-2-carboxylic acids reduced with NaBH3CN to give (S)-proline, trans-3-methyl-(S)-proline, trans-5-phenyl-(S)-proline, and a mixture of cis- and trans-5-methyl-(S)-prolines. The chiral auxiliary (2) was recovered in 80–90% yield.

Synthesis of a chiral nickel(II) complex of an electrophilic glycinate, and its use for asymmetric preparation of α-amino acids

A chiral NiII complex of a Schiffs base derived from (S)-o-[(benzylpropyl)amino]benzophenone and α-bromoglycine has been obtained and its stereoselective reaction with nucleophiles studied; the synthesis of aspartic acid with 80% optical purity is described.

Enantioselectivity of nickel(II) and copper(II) complexes of Schiff bases derived from amino acids and (S)-o-[(N-benzylprolyl)amino]-acetophenone or (S)-o-[(N-benzylprolyl)amino]benzaldehyde. Crystal and molecular structures of [Ni{(S)-bap-(S)-Val}] and [Cu{(S)-bap-(S)-Val}]

Copper(II) and nickel(II) complexes of Schiff bases derived from (S)-o-[(N-benzylprolyl)amino]-acetophenone [(S)-bap] and the amino acids (aa) : glycine, (R)- and (S)- and (S)-valine (val), (R)- and (S)-adamant-1-ylalanine, and (R)- and (S)-adamant-1-ylglycine have been synthesized. The structure of the complexes has been determined by physical and chemical methods; in addition the structures of [Cu{(S)-bap-(S)-Val}] and [Ni{(S)-bap-(S)-Val}] have been determined by X-ray crystallographic analysis. The kinetic CH-acidity and deuterium exchange of the hydrogen of an amino acid moiety under the action of bases has been studied. The deuterium exchange is accompained with epimerization which results in 80% excess of the (S)-2-[2H]amino acid. The stereoselectivity in the nickel complexes has been found to be higher than in the copper ones. The epimerization rate constant lies within the range 5 × 10–4–1.2 × 10–1 dm3 mol–1 s–1. The observed stereoselective effects are interpreted on the basis of X-ray analysis, circular dichroism, and 1H n.m.r. spectroscopic data. It is suggested that the [Ni{(S)-bap-aa}] complexes can be used for determining the absolute configuration of the amino acids.

Chiral complexes of copper(II), containing polyether podands and a quaternary ammonium group, as potential receptors and carriers of α-amino acid anions

In an attempt to develop a viable metalloreceptor for the recognition of α-amino acid anions a detailed study of proline (Pro) complexation by {(R)-7,8,15,18-tetrahydro-5,10-bis(2′-methoxyethoxy-5′-methylphenyl)-7-(p-trimethylammoniophenyl)dibenzo[e, m]-[1,4,8,11]tetra-azacyclotetradecine-16,17-dionato(1–)-N6N9N15N18}copper(II) chloride (1) in D2O at pD 11.0, using n.m.r. relaxation techniques, was undertaken. Structural information has been obtained, including the distances between hydrogen or carbon atoms of proline (Pro) and copper ion in the mixed complex where Pro occupies the apical position. Preliminary data on the ability of (1) to serve as a phase-transfer carrier for α-amino acid anions (Phe, Leu, Pro, or Hyp) are also reported. The extraction constants were correlated with those found using a routine phase-transfer agent, tetrapentylammonium iodide. Noticeable differences in phase-transfer properties were detected for these reagents.

Structure of a solvated nickel(II) complex of (S)-2'-(N-benzylprolyl)aminoacetophenone and (R)-valine Schiff base, C25H29N3NiO3.1/2C4H8O. Conformational calculation of diastereomeric complexes of (R)-valine and (S)-valine

{(R)-[N-(1-{2-[N-(S)-Benzylprolylamino]95·26 (1) 0 , V = 2535 (2) A3, Z = 4, Dx = phenyl}ethylidene)]valinato}nickel(II}-tetrahydrofuran 1·35 Mg m-3, Mo Ka, A.= 0·71069 A, fJ. = (2/1), Mr= 514·3, monoclinic, P2 1, a= 0·796 mm1 , F(OOO) = 1088, room temperature, R 10· 779 (1), b = 11·800 (5), c = 20·014 (2) A, p = = 0·055 for 5284 independent reflections. In the crystal 0108-2701/85/091290-06

(S)-o-N-(N-benzylprolyl)aminobenzaldehyde and (S)-o-N-(N-benzylprolyl)aminoacetophenone as reagents for asymmetric synthesis of threonine

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