Konstantin A. Kochetkov

Bio: Konstantin A. Kochetkov is an academic researcher from A. N. Nesmeyanov Institute of Organoelement Compounds. The author has contributed to research in topics: Enantioselective synthesis & Alkylation. The author has an hindex of 17, co-authored 133 publications receiving 1120 citations. Previous affiliations of Konstantin A. Kochetkov include Russian Academy of Sciences & Centre national de la recherche scientifique.

Synthesis of α-Amino Acids via Asymmetric Phase Transfer-Catalyzed Alkylation of Achiral Nickel(II) Complexes of Glycine-Derived Schiff Bases

Abstract: Achiral, diamagnetic Ni(II) complexes 1 and 3 have been synthesized from Ni(II) salts and the Schiff bases, generated from glycine and PBP (7) and PBA (11), respectively, in MeONa/MeOH solutions. The requisite carbonyl-derivatizing agents pyridine-2-carboxylic acid(2-benzoyl-phenyl)-amide 7 (PBP) and pyridine-2-carboxylic acid(2-formyl-phenyl)-amide 11 (PBA) were readily prepared from picolinic acid and o-aminobenzophenone or picolinic acid and methyl o-anthranilate, respectively. The structure of 1 was established by X-ray crystallography. Complexes 1 and 3 were found to undergo C-alkylation with alkyl halides under PTC conditions in the presence of beta-naphthol or benzyltriethylammonium bromide as catalysts to give mono- and bis-alkylated products, respectively. Decomposition of the complexes with aqueous HCl under mild conditions gave the required amino acids, and PBP and PBA were recovered. Alkylation of 1 with highly reactive alkyl halides, carried out under the PTC conditions in the presence of 10% mol of (S)- or (R)-2-hydroxy-2'-amino-1,1'-binaphthyl 31a (NOBIN) and/or its N-acyl derivatives and by (S)- or (R)-2-hydroxy-8'-amino-1,1'-binaphthyl 32a (iso-NOBIN) and its N-acyl derivatives, respectively, gave rise to alpha-amino acids with high enantioselectivities (90-98.5% ee) in good-to-excellent chemical yields at room temperature within several minutes. An unusually large positive nonlinear effect was observed in these reactions. The Michael addition of acrylic derivatives 37 to 1 was conducted under similar conditions with up to 96% ee. The (1)H NMR and IR spectra of a mixture of the sodium salt of NOBIN and 1 indicated formation of a complex between the two components. Implications of the association and self-association of NOBIN for the observed sense of asymmetric induction and nonlinear effects are 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

Abstract: 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.

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.

Highly Efficient Catalytic Synthesis of α-Amino Acids under Phase-Transfer Conditions with a Novel Catalyst/Substrate Pair

Abstract: A facile and fast enantioselective synthesis of α-amino acids with high ee values was achieved by the asymmetric alkylation of the glycine derivative under phase-transfer conditions with (R)- or (S)-2-amino-2'-hydroxy-1,1'-binaphthyl (NOBIN). The ee value of the catalyst can be as little as 40 % without decreasing the ee value of the amino acid products. This occurs as a result of a significant positive nonlinear effect in the alkylation reaction.

Asymmetric PTC C-alkylation mediated by TADDOL - Novel route to enantiomerically enriched α-alkyl-α-amino acids

Abstract: Compound (4R,5R)- or (4S,5S)-2,2-dimethyl-α,α,α′,α′-tetraphenyl-1,3-dioxolane-4,5-dimethanol (TADDOL) was shown to catalyze C-alkylation of aldimine Schiff's bases of alanine esters under phase-transfer catalysis conditions (solid NaOH, toluene, ambient temperature, 10% TADDOL) with the ee of the final α-methylphenylalanine or α-allylalanine reaching 82%

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design.

Abstract: The electronic properties and relatively small size of fluorine endow it with considerable versatility as a bioisostere and it has found application as a substitute for lone pairs of electrons, the hydrogen atom, and the methyl group while also acting as a functional mimetic of the carbonyl, carbinol, and nitrile moieties. In this context, fluorine substitution can influence the potency, conformation, metabolism, membrane permeability, and P-gp recognition of a molecule and temper inhibition of the hERG channel by basic amines. However, as a consequence of the unique properties of fluorine, it features prominently in the design of higher order structural metaphors that are more esoteric in their conception and which reflect a more sophisticated molecular construction that broadens biological mimesis. In this Perspective, applications of fluorine in the construction of bioisosteric elements designed to enhance the in vitro and in vivo properties of a molecule are summarized.

Cis-trans isomerization of organic molecules and biomolecules: implications and applications.

Abstract: Organic molecules as well as metal complexes may exist as several geometric isomers1 which display distinct physical properties and chemical reactivities. A molecule containing two atoms (in general, two carbons) attached together by a double bond with substituents W-Z may be found as two isomeric † C.D. dedicates this review to Professor Andrée Marquet as a mark of his admiration and gratitude. * To whom correspondence should be addressed: Tel: (33) 169 08 52 25. Fax: (33) 169 08 90 71. E-mail: christophe.dugave@cea.fr. ‡ Present address: Département de Chimie, Institut de Pharmacologie, Université de Sherbrooke, 3001, 12e Avenue nord, Sherbrooke, Québec, J1H 5N4 Canada. 2475 Chem. Rev. 2003, 103, 2475−2532