Synthesis Of α-Methyl α-Amino Acids Research Articles

Influence of the metal and chiral diamine on metal(II)salen catalysed, asymmetric synthesis of α-methyl α-amino acids

The influence of the metal ion and chiral diamine used to form a metal(salen) complex on the catalytic activity of the complex in the asymmetric benzylation of an alanine enolate was investigated. Only metal ions which could form square-planar complexes gave catalytically active complexes, and best results were obtained with metal ions from the first row of transition metals, particularly copper(II) and cobalt(II). Salen ligands derived from acyclic, chiral 1,2-diamines were found to generate poor catalysts, an effect which seems to correlate with the ability of the substituents within the diamine to adopt a conformation in which they are anti to one another. Complexes derived from a variety of 5- and 6-membered cyclic 1,2-diamines did form active catalysts, but the enantioselectivity was always far lower than that of the parent cyclohexane-1,2-diamine derived complex.

ChemInform Abstract: A Practical Asymmetric Synthesis of α-Methyl α-Amino Acids Using a Chiral Cu-Salen Complex as a Phase-Transfer Catalyst.

Abstract The asymmetric C -alkylation of N -benzylidene alanine methyl ester has been achieved using a copper(II) (salen) complex as an asymmetric phase transfer catalyst and provides a practical synthesis of α-methyl α-amino acids with up to 86% enantiomeric excess.

A practical asymmetric synthesis of α-methyl α-amino acids using a chiral Cu–salen complex as a phase transfer catalyst

The asymmetric C-alkylation of N-benzylidene alanine methyl ester has been achieved using a copper(II) (salen) complex as an asymmetric phase transfer catalyst and provides a practical synthesis of α-methyl α-amino acids with up to 86% enantiomeric excess.

Asymmetric Synthesis of α-Methyl α-Amino Acids through Diastereoselective Alkylation under Mild Reaction Conditions of an Iminic Alanine Template with a 1,2,3,6-Tetrahydro-2-pyrazinone Structure

Asymmetric Synthesis of α-Methyl α-Amino Acids through Diastereoselective Alkylation under Mild Reaction Conditions of an Iminic Alanine Template with a 1,2,3,6-Tetrahydro-2-pyrazinone Structure

Chiral 3,6-Dihydro-2H-1,4-oxazin-2-ones as Alanine Equivalents for the Asymmetric Synthesis of α-Methyl α-Amino Acids (AMAAs) under Mild Reaction Conditions

3,6-Dihydro-2H-1,4-oxazin-2-ones 1 act as very reactive chiral cyclic alanine equivalents and can be diastereoselectively alkylated or allylated using mild reaction conditions: potassium carbonate under phase-transfer catalysis (PTC) conditions when using activated alkyl halides, organic bases such as tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) when using unactivated alkyl halides, and neutral Pd(0)-catalysis when allylic carbonates are used. In most cases, the diastereoselectivity under all these different reaction conditions is excellent although the reactions are always carried out at room temperature. Hydrolysis of the obtained alkylated or allylated oxazinones allows the preparation of enantiomerically enriched (S)-α-methyl α-amino acids (S)-AMAAs. The PTC and organic base methodologies have also been applied to the synthesis of (R)-α-methyl α-amino acids starting from (R)-alanine. When dihalides are used as electrophiles under PTC or BEMP conditions, a spontaneous N-alkylation also takes place giving bicyclic oxazinones, which can be hydrolyzed to enantiomerically pure cyclic (S)-AMAAs.

New chiral alanine template with a 1,2,3,6-tetrahydro-2-pyrazinone structure for the asymmetric synthesis of α-methyl α-amino acids

( R)-6-Isopropyl-5-phenyl-1,2,3,6-tetrahydro-2-pyrazinone, prepared from ( R)-valine and ( S)-alanine, reacts with activated alkyl halides and electrophilic olefins under solid–liquid PTC conditions with K 2CO 3 as base, at room temperature and with high diastereoselectivity (>94%). The palladium-catalyzed allylation reaction of this alanine derivative under neutral conditions at room temperature also takes place with a de>96%. Final hydrolysis of alkylated pyrazinones affords enantiomerically pure α-methyl α-amino acids.