Recent developments in the stereoselective synthesis of α-aminoacids

Stereoselective synthesis of quaternary α-amino acids. Part 1: Acyclic compounds

A compound of formula (I) wherein R1 is a straight or branched alkyl group having from 1 to 6 carbon atoms, phenyl, or cycloalkyl having from 3 to 6 carbon atoms; R2 is hydrogen or methyl; and R3 is hydrogen, methyl or carboxyl; which is useful in the treatment of seizure disorders. Processes are also disclosed for the preparation of the compound. Intermediates prepared during the synthesis of the compound are further disclosed.

GABA and L-glutamic acid analogs for antiseizure treatment

Chiral enolates of imidazolidinones and oxazolidinones from the title amino acids react with carbonyl compounds to afford the corresponding alcohols in excellent yields (see Scheme 5). Furthermore, the addition to aldehydes proceeds with high diastereoselectivity to give, after acid hydrolysis, threo-α-amino-β-hydroxy acids of high enantiomeric purity. Some of the threo-α-amino-β-hydroxy acids prepared in this work are the proteinogenic (S)-threonine (26), the naturally occurring (S)-3-phenylserine (28), and (S)-3-hydroxyleucine (27) as well as the unnatural (S)-4,4,4-trifluorothreonine (30) and (S)-3-(4-pyridyl)serine (31). The N-methylamide of (2S,3R,4R,6E)-3-hydroxy-4-methyl-2-(methylamino)-6-octenoic acid (32), the unique amino acid in the immunosuppressive cyclosporine, was prepared by the new method. This report presents also information suggesting that both steric and stereoelectronic effects are responsible for the good stereoselectivities observed.

Addition of chiral glycine, methionine, and vinylglycine enolate derivatives to aldehydes and ketones in the preparation of enantiomerically pure α-amino-β-hydroxy acids

Resolution and use in α-amino acid synthesis of imidazolidinone glycine derivatives

Synthese en particulier de serine, hydroxy-3 valine, hydroxy-2 phenylserine, phenylserine et methylenedioxy-3,4 phenylserine

General method of diastereo- and enantioselective synthesis of β-hydroxy-α-amino acids by condensation of aldehydes and ketones with glycine

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.

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

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 nmr 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

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

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.

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}]

S. V. Vitt

Papers

General method of diastereo- and enantioselective synthesis of β-hydroxy-α-amino acids by condensation of aldehydes and ketones with glycine

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

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

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}]

The termination of an optical purity by V.P.C.