Α-carbon Atom Research Articles

Quantitative Criteria of Chirality in Hierarchical Protein Structures

Based on the theory of the formation of sign-alternating hierarchical structures in macromolecular systems, a quantitative approach was developed to assess the chirality sign of individual levels in hierarchical protein structures. Quantitative estimates are necessary for modeling the folding of proteins and their function as molecular machines. Mutual attraction between the α-carbon atoms of amino acids is a sufficient condition for characterizing the level in the hierarchical structure and determining the chirality sign of protein blocks. A quantitative estimate of the twist in helical (secondary) and superhelical (tertiary) structures is provided by the absolute value of the sum of vector cross products. The sign of the scalar product of the direction vector to the vector of the sum of vector products indicates the direction of the twist. Chiral maps were constructed for the secondary and tertiary structures of several proteins. The reliability of the maps was confirmed by analyzing the respective real structures.

Umpolung Reactivity of Ynamides: An Unconventional [1,3]-Sulfonyl and [1,5]-Sulfinyl Migration Cascade.

A regioselective sulfonyl/sulfinyl migration cycloisomerization cascade of alkyne-tethered ynamides is developed in the presence of XPhosgold catalyst. This reaction is the first example of a general [1,3]-sulfonyl migration from the nitrogen center to the β-carbon atom of ynamides, followed by umpolung 5-endo-dig cyclization of the ynamide α-carbon atom to the gold-activated alkyne, and final deaurative [1,5]-sulfinylation. This process allows the synthesis of peripherally decorated unconventional 4-sulfinylated pyrroles with broad scope from N-propargyl-tethered ynamides. In contrast, N-homopropargyl-tethered ynamides undergo intramolecular tetradehydro Diels-Alder reaction to provide 2,3-dihydro-benzo[f]indole derivatives. Control experiments and density-functional theory studies were used to study the reaction pathways.

The Formation of Glycerol Oligomers with Two New Types of End Groups in the Presence of a Homogeneous Alkaline Catalyst.

The purpose of this work was to synthesize and characterize oligoglycerols with the chains of more than four repeating units. Those oligoglycerols may have some interesting applications, among others, as polyoxyalkylation starters. The glycerol oligomerization process was carried out during 12 h, at 230 °C, under the pressure of 0.4 bar, with the use of sodium carbonate as a homogeneous basic catalyst; various concentrations of the catalyst in the reaction medium were used. The reaction products were analyzed with the use of direct infusion electrospray ionization mass spectrometry (ESI-MS), nuclear magnetic resonance (13C NMR) and Fourier transform infrared spectroscopy (FTIR) techniques. Based on the analytical findings, the compositions of the obtained product mixtures and the structures of oligoglycerols present in individual fractions were determined. The effect of catalyst concentration on the composition of the post-reaction mixture was observed. Moreover, in addition to the conventional linear oligomers (α,α-oligoglycerols), two new types of the oligomers were for the first time detected in the post-reaction mixture: one with two hydroxyl groups and the other with a carboxylate group at the α-carbon atom.

In Russian

The results of experimental data obtained using UV spectroscopy, due to a comparative study on the interaction of α- and β-cyclodextrins with alpha aromatic amino acids differing in molecular size and substituent structure at the α-carbon atom in aqueous solutions with various pH (L-phenylalanine, L-tyrosine and L‑tryptophan) have been analyzed. The features of the interaction of selected amino acids with cyclodextrins have been clarified. Molecular cationic and zwitterionic forms of amino acids at the same content of components in the solution and an excess of cyclodextrin form 1: 1 host-guest inclusion complexes, regardless of the pH value of the medium. This is manifested by a long-wavelength shift and an increase in the intensity of the characteristic absorption band in the UV spectra of solutions. It has been proved that inclusion complexes are formed due to the van der Waals interactions by partial displacing water molecules and incomplete (in the case of α-cyclodextrin) immersion of the amino acid aromatic radical into the internal hydrophobic cavity of α-cyclodextrin and of β-cyclodextrin. Stabilization of the complexes is due to hydrogen bonds, and the geometric parameter makes the main contribution to the formation of inclusion complexes. It has been found that the hydrogen bond is formed between the nitrogen atom of a-amino group or the oxygen atom of a-carboxyl group of the amino acid molecule with hydrogen of the primary hydroxyl group located on the surface of the wide edge of the torus, as well as between the nitrogen atom of the imino group of the L‑tryptophan molecule and glycoside hydrogen atom within the cyclodextrin cavity. The values of the stability constants (Ks) of the complexes and the thermodynamic parameters of the formation of inclusion compounds (ΔG, ΔH, and ΔS) have been calculated. The use of a smaller macrocycle (a-CD) leads to a decrease in the stability of the inclusion complexes. Negative values of the change in the free Gibbs energy indicate a spontaneous complexation reaction between a- or b-cyclodextrins and alpha aromatic aminoacids. Negative values of the enthalpy DH and entropy DS indicate that the complexes are mostly stabilized due to the entropy contribution.

Side-chain loss reactions of collisionally activated protonated peptoids: A mechanistic insight

Peptoids constitute an emergent class of synthetic biocompatible macromolecules that are best described as polymers of N-substituted glycines. Peptides and peptoids are regioisomers with the side chains appended in peptoids to the nitrogen atoms rather than to the α-carbon atoms as in peptides. Peptide sequencing now takes great advantage of collision-induced dissociation experiments, based on the elucidation of the decomposition pathways of protonated peptides. In contrast, data on peptoid ion decompositions are to date scarcely present in the literature. Upon CID, protonated peptoids were recently shown to mostly dissociate by cleavages at the backbone amide bonds yielding B- and Y-fragment ions. In addition, the loss of the side-chain group and/or the formation of the side-chain fragment ion are common reactions for peptoids containing protonated N-α-aromatic side chain.In the present paper, we submitted protonated tailor-made peptoids to (energy-resolved) collision-induced dissociation experiments to investigate the side-chain loss reaction mechanisms. We also used orthogonal methods, such as quantum chemistry, ion mobility spectrometry and infrared photodissociation spectroscopy to establish the structures of the fragment ions. We ended up with different mechanistic scenarios consistent with the nature of the fragment ions and the kinetic energy dependence of decomposition reactions. Our mechanistic proposals associate the proton mobile model, proton bound dimer intermediacy and concerted rearrangement reactions.

Theoretical Investigation on the Mechanism and Kinetics of Atmospheric Reaction of Methyldichloroacetate with Hydroxyl Radical.

The atmospheric reaction of methyldichloroacetate (MDCA) with OH radical is studied using electronic structure calculations. Five different pathways were considered for the initial reactions, which results in the formation of alkyl radical of MDCA along with H2O, HOCl, and CH3O•. Among the five pathways studied, the α-carbon atom (-CHCl2 site) H atom abstraction reaction, which leads to the formation of the alkyl radical intermediate •CCl2C(O)OCH3 (I1) is found to be more favorable with an energy barrier of 7.3 kcal/mol, and Cl-atom abstraction reaction is having high energy barrier of 21.3 kcal/mol at M06-2X/6-311++G(2df,2p) level. The calculated thermochemical parameters show that except Cl-atom abstraction channel the other initial reaction channels are highly exothermic. The rate constant is calculated for the initial H atom abstraction reactions using canonical variational transition state theory over the temperature range of 278 to 350 K. The Arrhenius plot shows positive temperature dependence for both the reactions. The results from the calculated thermochemical parameters and rate constants show that the formation of the alkyl radical intermediate (I1) is more favorable with the rate constant of 2.07 × 10-13 cm3 molecule-1 s-1 at 298 K. The calculated atmospheric lifetime of MDCA is 28 days at normal atmospheric OH concentration. The results obtained from secondary reactions show that the major product formed from the oxidation chemistry of MDCA is methyl-2-chloro-2-oxoacetate (or) methyl oxalyl chloride.

Consorted Vinylene Mechanism for Cobalt Fischer–Tropsch Synthesis Encompassing Water or Hydroxyl Assisted CO-Activation

A mechanistic model for Fischer–Tropsch synthesis is proposed. The model contains four key steps. The first step is hydrogen assisted CO activation to formyl. This is followed by hydrogen transfer from either water or hydroxyl to a hydroxycarbene intermediate to generate CH* surface species on cobalt as chain building blocks. Further, chain propagation is by adding methylidyne (CH*) to an alkylidene (CHCH2R) chain to create a vinylene (CHCHR) chain end unit. Last, hydrogenation finalizes the chain-building step or terminates the chain depending on whether hydrogen is added to the β- or α-carbon atom, respectively. The result is that the main product is α-olefins. Chain growth probability is independent of hydrogen partial pressure and depends solely on the surface coverage of CH* monomers. Short-chain (Me) branching and variation in chain growth with chain length are also rationalized. Derived kinetic equations depend on details of the mechanism, but generally encompass water in the expressions and can account for both positive and negative water responses. The expression for the Anderson–Schulz–Flory (ASF) α is dependent on CO, and can contains the water vapor pressure as well, in a way consistent with higher α when more CO and water are present for production of CH* chain growth monomers.

α-Cyanocarbanion complexes and their application in synthesis

α-Cyanocarbanion complexes feature nitrile ligands containing deprotonated α-carbon atoms. This short review will focus on the various synthetic methods employed to prepare these complexes, the different binding modes they exhibit and their applications to the synthesis of alkylnitriles including β-hydroxy- and β-aminonitriles, the formation of unique coupling products and as key intermediates in the reaction of acrylonitrile with various substrates in hydrophosphination and copolymerisation reactions.

Reversible σ-Bond Formation in Bowl-Shaped π-Radical Cations: The Effects of Curved and Planar Structures.

The reversible formation of σ-bonds between organic radicals has been widely investigated. However, reports on the formation of σ-dimers from delocalized π-radical cations are scarce. Herein, we report the reversible σ-dimerization behavior of a bowl-shaped π-radical cation generated from a nitrogen-embedded buckybowl, both in the crystalline state and in solution. The detailed structure of the σ-dimer in the crystalline state was determined by a single-crystal X-ray diffraction analysis. The monomeric radical cation exists predominantly in solution at room temperature, while dimerization of the radical cations occurs through carbon-carbon σ-bond formation upon reducing the temperature. 1H NMR and optical spectroscopy measurements confirmed the formation of a σ-dimer at low temperature. Comparative studies with a similar yet planar π-conjugated system suggested that the curved structure of the bowl-shaped π-radical cation facilitates the σ-dimerization at one of the internal sp2-hybridized carbon atoms. This trend was also observed for the nucleophilic addition reaction of methanol to the π-radical cations. The methoxylation reaction proceeded only for the curved π-radical cation. Theoretical calculations revealed that the large relief of structural strain at the α-carbon atom during the dimerization or nucleophilic addition reactions accelerated the bond formation at the internal carbon atom of the curved radical cation.

Chiral Guanidines-catalyzed Nucleophilic Addition Reactions Using 5<i>H</i>-Oxazol-4-ones: Development of Catalytic Asymmetric Syntheses of Chiral α-Tetrasubstituted Hydroxycarboxylic Acid Derivatives

Chiral α-hydroxycarboxylic acids and their derivatives bearing a tetrasubstituted α-carbon atom are well-recognized chiral synthons and components of various pharmaceuticals and biologically active natural products. Despite their high demand, preparative methods of these compounds are quite limited due to the difficulty in achieving stereoselective construction of the tetrasubstituted carbon stereogenic center at the α-position. To address this issue, we developed asymmetric nucleophilic addition reactions of 5H-oxazol-4-ones to carbon electrophiles using chiral bicyclic guanidine catalysts containing a hydroxyl group at the appropriate position as a preparative method of α-tetrasubstituted hydroxycarboxylic acid derivatives. In this article, we introduce the nucleophilic addition reactions with several types of electrophiles, such as aldehydes, alkynyl carbonyl compounds, allenyl carbonyl compounds, vinyl ketones, dienones, and 2-chloroacrylnitrile. Derivatizations of the products of these reactions into corresponding α-hydroxycarboxylic acid derivatives and their application to a natural product synthesis are also described.

Ring-size-selective construction of fluorine-containing carbocycles via intramolecular iodoarylation of 1,1-difluoro-1-alkenes.

1,1-Difluoro-1-alkenes bearing a biaryl-2-yl group effectively underwent site-selective intramolecular iodoarylation by the appropriate cationic iodine species. Iodoarylation of 2-(2-aryl-3,3-difluoroallyl)biaryls proceeded via regioselective carbon–carbon bond formation at the carbon atoms in β-position to the fluorine substituents, thereby constructing dibenzo-fused six-membered carbocycles bearing a difluoroiodomethyl group. In contrast, 2-(3,3-difluoroallyl)biaryls underwent a similar cyclization at the α-carbon atoms to afford ring-difluorinated seven-membered carbocycles.

Nucleophilic Arylation of N,O-Ketene Acetals with Triaryl Aluminum Reagents: Access to α-Aryl Amides through an Umpolung Process.

A novel approach for the umpolung α-arylation of amides is presented. By the nucleophilic phenylation of O-silyl N,O-ketene acetals, generated in situ from N-alkoxy amides, a phenyl group can be introduced onto the α-carbon atom of amides through N-O bond cleavage in a two-step, one-pot process. The asymmetric synthesis of α-aryl amides through the diastereoselective arylation of a chiral N,O-ketene acetal is also described.

Reactions of 6-(Dimethylamino)fulvene with diazoazoles and arene- and azolediazonium salts

6-(Dimethylamino)fulvene reacted with 3- and 4-substituted 5-diazoazoles, as well as with 4-substituted benzene- and pyrazole-5-diazonium salts, in an aprotic solvent with high regioselectivity at an extremely high rate to give acyclic coupling products at the α-carbon atom of the cyclopenta-1,3-diene fragment. The nature of the diazo component did not affect the reaction direction, rate, or yield. Hydrolysis of the azo compounds obtained from arenediazonium salts involved elimination of the dimethylamino group with formation of aldehydes, and their reaction with pyrrolidine resulted in replacement of the dimethylamino group by pyrrolidine ring.

Xanthates As Useful Probes for Testing the Active Sites of Cytochromes P450 4A11 and 2E1.

Xanthates (alkyl or aryl derivatives of dithiocarbonic acid) have been shown to be selective mechanism-based inactivators of cytochromes P450 2B1/2B6 and 2E1 due to covalent binding of a reactive intermediate to apoprotein after double hydrogen abstraction at α-carbon atom, suggesting interaction of the xanthate dithiocarbonic head with the enzyme heme. The structures of xanthates with a long alkyl chain are similar to the fatty acids. Saturated fatty acids (FA) such as lauric acid (LA), are metabolized by different cytochrome P450 isoforms to ω- and (ω-1)-hydroxy products, in humans done by CYP4A11 and CYP2E1, respectively. In the present study we aimed at elucidating the possible interactions of xanthates with two cytochrome P450 isoforms CYP4A11 and CYP2E1 involved in the metabolism of the FA. Our experiments showed that LA-ω-hydroxylation by CYP4A11 is inhibited in a competitive manner by xanthates with long alkyl chain (C12-xanthate being the most potent inhibitor). On the other hand LA-(ω-1)-hydroxylation reaction by purified CYP2E1 is inactivated by a mechanism-based type. The suggested differences in the interactions of C12-xanthate with the two cytochrome P450 isoforms were investigated by molecular modeling using docking approach. The results suggested that in CYP2E1 active site C12-xanthate coordinates to the heme with its most vulnerable dithiocarbonic head leading to a mechanism-based inactivation. In CYP4A11 xanthate alkyl chain is exposed to the heme, thus, a potenial ω-hydroxylated xanthate product could be formed, which could inhibit in a competitive manner the hydroxylation of LA. The observed differences of xanthates interactions with the active sites of the two similar cytochrome P450 isoforms (CYP4A11 and CYP2E1) involved in the metabolism of FA, which lead to different changes in the enzyme activity, suggest that xanthates can be used as probing tools for analyzing enzyme active sites when exploring useful and selective compounds influencing FA homeostasis.

Synthesis and evaluation of the inhibitory activity of the four stereoisomers of the potent and selective human γ-glutamyl transpeptidase inhibitor GGsTop

2-Amino-4-{[3-(carboxymethyl)phenoxy](methoxy)phosphoryl}butanoic acid (GGsTop) is a potent, highly selective, nontoxic, and irreversible inhibitor of γ-glutamyl transpeptidase (GGT). GGsTop has been widely used in academic and medicinal research, and also as an active ingredient (Nahlsgen) in commercial anti-aging cosmetics. GGsTop consists of four stereoisomers due to the presence of two stereogenic centers, i.e., the α-carbon atom of the glutamate mimic (l/d) and the phosphorus atom (RP/SP). In this study, each stereoisomer of GGsTop was synthesized stereoselectively and their inhibitory activity against human GGT was evaluated. The l- and d-configurations of each stereoisomer were determined by a combination of a chiral pool synthesis and chiral HPLC analysis. The synthesis of the four stereoisomers of GGsTop used chiral synthetic precursors that were separated by chiral HPLC on a preparative scale. With respect to the configuration of the α-carbon atom of the glutamate mimic, the l-isomer (kon=174M−1s−1) was ca. 8-fold more potent than the d-isomer (kon=21.5M−1s−1). In contrast, the configuration of the phosphorus atom is critical for GGT inhibitory activity. Based on a molecular modeling approach, the absolute configuration of the phosphorus atom of the active GGsTop isomers was postulated to be SP. The SP-isomers inhibited human GGT (kon=21.5–174M−1s−1), while the RP-isomers were inactive even at concentrations of 0.1mM.

Electrochemical Reactions of White Phosphorus and Ketones

The reaction of phosphine oxide, H3PO, generated electrochemically from white phosphorus, P4, with ketones is of particular interest due to its selectivity and simplicity. In this work, we studied the process of electrochemical reduction of P4 in acidic water-ethanol solution in a single electrochemical cell supplied with a cathode of high hydrogen overvoltage (Pb) and a sacrificial anode (Al, Mg, Zn) [1]. We found that the in situ electrochemical interaction of white phosphorus P4 with ketones results in formation of mono- and bis-(α-hydroxyalkyl)phosphine oxides RR’C(OH)P(O)H2 and {RR’C(OH)}2P(O)H, where R = Me, R’ = Me, Et, n-Pr, i-Pr, t-Bu; R = R’ = Et, -(R-R’)- = -(CH2)4-, -(CH2)5-, -(CH2)6-. The proposed mechanism of the product formation is a cathodic electrochemical generation of phosphine, PH3, followed by its anodic oxidation to H3PO and reaction of the formed intermediate with ketones. This mechanism was proved by comparison of two methods of synthesis: in divided and undivided electrochemical cells (Fig. 1). In a divided cell, the reaction of ketone with formed PH3 does not occur, because the anodic surface is separated, and the oxidation of PH3 to H3PO does not happen. According to literature data, chemical interaction of ketones with PH3 is possible only under strict conditions: highly acidic or basic medium, high temperatures and high pressure. Moreover, the interaction of РН3 with ketones leads to the formation of only primary alkylphosphine oxides R2С(Н)P(O)H2, without a hydroxyl group at the α-carbon atom in the alkyl substituent of the phosphorus atom [2]. Unlike chemical methods of phosphine synthesis, electrochemical reduction of P4 proved to be less expensive and gives PH3with a sufficient degree of purity [3]. The obtained phosphine oxides RR’C(OH)P(O)H2 and {RR’C(OH)}2P(O)H have different kinetic and thermodynamic stability, which can be explained by steric hindrance from aliphatic groups attached to the carbonyl atom of the ketones. Quantum chemical calculations of the thermodynamic stability of the products from the reaction of H3PO with ketones were performed with density functional theory (DFT). The used electrochemical method of synthesis is simple, does not require complicated equipment and is ecologically safe. a) D. Yakhvarov, M. Caporali, L. Gonsalvi, Sh. Latypov, V. Mirabello, I. Rizvanov, O. Sinyashin, P. Stoppioni, M. Peruzzini, W. Schipper, Angew. Chem. Int. Ed., 23, 5370 (2011); b) D. G. Yakhvarov, E. V. Gorbachuk, R. M. Kagirov, O. G. Sinyashin, Russ. Chem. Bull., 7, 1285 (2012); c) D. G. Yakhvarov, E. V. Gorbachuk, O. G. Sinyashin, Eur. J. Inorg. Chem., 4709 (2013); d) D. G. Yakhvarov, E. V. Gorbachuk, Kh. R. Khayarov, V. I. Morozov, I. Kh. Rizvanov, O. G. Sinyashin, Russ. Chem. Bull., 63, 2423 (2014); e) E. V. Gorbachuk, Kh. R. Khayarov, O. G. Sinyashin, D. G. Yakhvarov, Mendeleev Commun., 24, 334 (2014); f) E. V. Gorbachuk., E. K. Badeeva, V. M. Babaev, I. Kh. Rizvanov, R. G. Zinnatullin, P. O. Pavlov, Kh. R. Khayarov, D. G. Yakhvarov, Russ. Chem. Bull., 65, 1289 (2016); g) E. V. Gorbachuk, E. K. Badeeva, S. A. Katsyuba, P. O. Pavlov, Kh. R. Khayarov, O. G. Sinyashin, D. G. Yakhvarov, Phosphorus, Sulfur Silicon Relat. Elem., 191, 1480 (2016).B. A. Trofimov, S. N. Arbuzova, N. K. Gusarova, Russ. Chem. Rev., 68, 215 (1999).I. M. Osadchenko, A. P. Tomilov, Russ. J. Appl. Chem., 43, 1255 (1970). Figure 1

A Phosphonium Ylide as an Ionic Nucleophilic Catalyst for Primary Hydroxyl Group Selective Acylation of Diols

Carbonyl-stabilized phosphonium ylides exhibit great utility in modern organic synthesis, and they are known as an ambident nucleophile at the carbonyl oxygen atom and at the α-carbon atom. However, they have found limited use as catalysts. We focused on the inherent nucleophilicity of the oxygen atom to develop an ionic nucleophilic catalysis, and the phosphonium ylide-catalyzed primary alcohol selective acylation of mixed diols with acid anhydrides has been demonstrated. Mechanistic studies revealed the behavior of a catalyst, which would contribute to the field of ylide chemistry.

Decomposition Mechanism of C5F10O: An Environmentally Friendly Insulation Medium.

SF6, the most widely used electrical-equipment-insulation gas, has serious greenhouse effects. C5F10O has attracted much attention as an alternative gas in recent two years, but the environmental impact of its decomposition products is unclear. In this work, the decomposition characteristics of C5F10O were studied based on gas chromatography-mass spectrometry and density functional theory. We found that the amount of decomposition products of C5F10O, namely, CF4, C2F6, C3F6, C3F8, C4F10, and C6F14, increased with increased number of discharges. Under a high-energy electric field, the C-C bond of C5F10O between carbonyl carbon and α-carbon atoms was most likely to break and generate CF3CO•, C3F7• or C3F7CO•, CF3• free radicals. CF3•, and C3F7• free radicals produced by the breakage more easily recombined to form small molecular products. By analyzing the ionization parameters, toxicity, and environmental effects of C5F10O and its decomposition products, we found that C5F10O gas mixtures exhibit great decomposition and environmental characteristics with low toxicity, with great potential to replace SF6.

Cross-aldol reactions of levoglucosenone and its derivatives with cyclohex-1-en-1-ol ethers

The reaction of levoglucosenone with cyclohex-1-en-1-yl trimethylsilyl ether under Mukaiyama reaction conditions gave [1 + 2]-Michael–aldol condensation product with participation of the acetal center. The reaction was accompanied by opening of the 1,6-anhydro bridge and intramolecular hemiketalization by the hydroxy group of the 2-oxocyclohex-1-enyl fragment. Under analogous conditions, dihydrolevoglucosenone gave rise to four diastereoisomeric 1,2-addition products. Internal cyclohex-1-en-1-ol ether obtained by treatment of the Michael adduct of levoglucosenone and cyclohexanone with Ac2O–ZnCl2 underwent intramolecular Mukaiyama reaction involving substituted α-carbon atom of the cyclohexanone fragment and acetal moiety to afford spiro derivative and product of subsequent AdE1 acetylation of intermediate α′-cyclohexenyl ether fragment.

Iridium-Catalyzed Regio- and Enantioselective Hydroarylation of Alkenyl Ethers by Olefin Isomerization.

Iridium-catalyzed hydroarylation of alkenyl ethers, such as allylic and homoallylic ethers, by C-H bond activation gave high yields of the corresponding addition products, where the aryl groups were selectively installed at the α-carbon atom to the alkoxy group. The reaction involves an isomerization of the alkenyl ethers into the corresponding 1-alkenyl ethers, which then undergo the regio- and enantioselective hydroarylation.