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Why is monoalkylation versus bis-alkylation of the Ni(II) complex of the Schiff base of (S)-N-(2-benzoylphenyl)-1-benzylpyrrolidine-2-carboxamide and glycine so selective? MP2 modelling and topological QTAIM analysis of chiral metallocomplex synthons of α-amino acids used for the preparation of radiopharmaceuticals for positron emission tomography.

Popkov A, Breza M - J Radioanal Nucl Chem (2010)

Bottom Line: They enable the selective monoalkylation of a glycine synthon with high stereoselectivity and the preparation of enantiomerically pure α-amino acids with quarternary α-carbon.Molecular modelling of non-, mono- and di-substituted complexes using quantum theory of atoms-in-molecule (QTAIM) topological analysis of electron density allowed us to formulate a new theory explaining the reasons for highly selective monomethylation of the complexes.In the non-substituted complex (GK), the α-carbon atom exhibits a higher atomic volume and a more positive charge in comparison with mono- and di-substituted complexes.

View Article: PubMed Central - PubMed

Affiliation: Department of Theoretical Chemistry, Zernike Institute for Advanced Materials, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands ; Department of Cognitive Research and Tomographic Imaging Methods, Samo University in Pardubice, Na Klínku 1082, 530 06 Pardubice, Czech Republic ; Institute of Physical Biology, University of South Bohemia, Zámek 136, 373 33 Nové Hrady, Czech Republic.

ABSTRACT

Chiral Ni(II) complexes are used for the preparation of carbon-11 or fluorine-18 enantiomerically pure α-amino acids for positron emission tomography (PET). They enable the selective monoalkylation of a glycine synthon with high stereoselectivity and the preparation of enantiomerically pure α-amino acids with quarternary α-carbon. Molecular modelling of non-, mono- and di-substituted complexes using quantum theory of atoms-in-molecule (QTAIM) topological analysis of electron density allowed us to formulate a new theory explaining the reasons for highly selective monomethylation of the complexes. In the non-substituted complex (GK), the α-carbon atom exhibits a higher atomic volume and a more positive charge in comparison with mono- and di-substituted complexes. This unusual behaviour is accompanied by increasing the bond critical point (BCP) ellipticity of the iminic bond in GK explained by the higher mechanical strain. Both phenomena indicate the increased reactivity and probably originate in more compact core of GK where shorter distances in the internal coordination sphere result in the higher strain of its bonds.

No MeSH data available.


Related in: MedlinePlus

Selective monomethylation of the second-generation synthon. For the 2-aminobenzophenone-derived complex (GK) a bulkier electrofile can be used in the second alkylation step for the preparation of enantiomerically pure α-methyl amino acids
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Sch1: Selective monomethylation of the second-generation synthon. For the 2-aminobenzophenone-derived complex (GK) a bulkier electrofile can be used in the second alkylation step for the preparation of enantiomerically pure α-methyl amino acids

Mentions: An important improvement occurred when the first generation synthons based on substituted 2-aminobenzaldehyde (as biomimetic analogues of pyridoxal-5-phosphate) [13] were overperformed in asymmetric alkylation reactions by derivatives of 2-aminoacetophenone followed by even more efficient derivatives of 2-aminobenzophenone [14]. The second generation synthons delivered a higher selectivity of C19 monomethylation and much higher ratio of diastereomers of alkylated products under thermodynamically controlled conditions when C19 is epimerised in a basic reaction mixture or in a separate epimerisation step carried out in NaOMe/MeOH [15, 16] (Y. N. Belokon, personal communication). For example, equilibrium ratio of diastereomers of the alanine complex increased from 15% d.e. for the first generation to 82% d.e. for the second generation [15]. New synthons enabled the preparation of enantiomerically pure α-methyl amino acids by sequential monomethylation of the glycine complex followed by the introduction of a bulkier second C19 substituent (Scheme 1) [17].Scheme 1


Why is monoalkylation versus bis-alkylation of the Ni(II) complex of the Schiff base of (S)-N-(2-benzoylphenyl)-1-benzylpyrrolidine-2-carboxamide and glycine so selective? MP2 modelling and topological QTAIM analysis of chiral metallocomplex synthons of α-amino acids used for the preparation of radiopharmaceuticals for positron emission tomography.

Popkov A, Breza M - J Radioanal Nucl Chem (2010)

Selective monomethylation of the second-generation synthon. For the 2-aminobenzophenone-derived complex (GK) a bulkier electrofile can be used in the second alkylation step for the preparation of enantiomerically pure α-methyl amino acids
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4514639&req=5

Sch1: Selective monomethylation of the second-generation synthon. For the 2-aminobenzophenone-derived complex (GK) a bulkier electrofile can be used in the second alkylation step for the preparation of enantiomerically pure α-methyl amino acids
Mentions: An important improvement occurred when the first generation synthons based on substituted 2-aminobenzaldehyde (as biomimetic analogues of pyridoxal-5-phosphate) [13] were overperformed in asymmetric alkylation reactions by derivatives of 2-aminoacetophenone followed by even more efficient derivatives of 2-aminobenzophenone [14]. The second generation synthons delivered a higher selectivity of C19 monomethylation and much higher ratio of diastereomers of alkylated products under thermodynamically controlled conditions when C19 is epimerised in a basic reaction mixture or in a separate epimerisation step carried out in NaOMe/MeOH [15, 16] (Y. N. Belokon, personal communication). For example, equilibrium ratio of diastereomers of the alanine complex increased from 15% d.e. for the first generation to 82% d.e. for the second generation [15]. New synthons enabled the preparation of enantiomerically pure α-methyl amino acids by sequential monomethylation of the glycine complex followed by the introduction of a bulkier second C19 substituent (Scheme 1) [17].Scheme 1

Bottom Line: They enable the selective monoalkylation of a glycine synthon with high stereoselectivity and the preparation of enantiomerically pure α-amino acids with quarternary α-carbon.Molecular modelling of non-, mono- and di-substituted complexes using quantum theory of atoms-in-molecule (QTAIM) topological analysis of electron density allowed us to formulate a new theory explaining the reasons for highly selective monomethylation of the complexes.In the non-substituted complex (GK), the α-carbon atom exhibits a higher atomic volume and a more positive charge in comparison with mono- and di-substituted complexes.

View Article: PubMed Central - PubMed

Affiliation: Department of Theoretical Chemistry, Zernike Institute for Advanced Materials, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands ; Department of Cognitive Research and Tomographic Imaging Methods, Samo University in Pardubice, Na Klínku 1082, 530 06 Pardubice, Czech Republic ; Institute of Physical Biology, University of South Bohemia, Zámek 136, 373 33 Nové Hrady, Czech Republic.

ABSTRACT

Chiral Ni(II) complexes are used for the preparation of carbon-11 or fluorine-18 enantiomerically pure α-amino acids for positron emission tomography (PET). They enable the selective monoalkylation of a glycine synthon with high stereoselectivity and the preparation of enantiomerically pure α-amino acids with quarternary α-carbon. Molecular modelling of non-, mono- and di-substituted complexes using quantum theory of atoms-in-molecule (QTAIM) topological analysis of electron density allowed us to formulate a new theory explaining the reasons for highly selective monomethylation of the complexes. In the non-substituted complex (GK), the α-carbon atom exhibits a higher atomic volume and a more positive charge in comparison with mono- and di-substituted complexes. This unusual behaviour is accompanied by increasing the bond critical point (BCP) ellipticity of the iminic bond in GK explained by the higher mechanical strain. Both phenomena indicate the increased reactivity and probably originate in more compact core of GK where shorter distances in the internal coordination sphere result in the higher strain of its bonds.

No MeSH data available.


Related in: MedlinePlus