Α-carbon Atom Research Articles

Split-and-pool synthesis and characterization of peptide tertiary amide library.

Peptidomimetics are great sources of protein ligands. The oligomeric nature of these compounds enables us to access large synthetic libraries on solid phase by using combinatorial chemistry. One of the most well studied classes of peptidomimetics is peptoids. Peptoids are easy to synthesize and have been shown to be proteolysis-resistant and cell-permeable. Over the past decade, many useful protein ligands have been identified through screening of peptoid libraries. However, most of the ligands identified from peptoid libraries do not display high affinity, with rare exceptions. This may be due, in part, to the lack of chiral centers and conformational constraints in peptoid molecules. Recently, we described a new synthetic route to access peptide tertiary amides (PTAs). PTAs are a superfamily of peptidomimetics that include but are not limited to peptides, peptoids and N-methylated peptides. With side chains on both α-carbon and main chain nitrogen atoms, the conformation of these molecules are greatly constrained by sterical hindrance and allylic 1,3 strain. (Figure 1) Our study suggests that these PTA molecules are highly structured in solution and can be used to identify protein ligands. We believe that these molecules can be a future source of high-affinity protein ligands. Here we describe the synthetic method combining the power of both split-and-pool and sub-monomer strategies to synthesize a sample one-bead one-compound (OBOC) library of PTAs.

Hydroalumination of a chlorotrialkynylsilane: spontaneous stepwise 1,3-dyotropic rearrangement via an intermediate silyl cation.

A new functionalised alkynylsilane, Cl-Si(CC-CMe3 )3 (3), was obtained by a facile multistep synthesis. Treatment of 3 with equimolar quantities of the hydrides H-M(CMe3 )2 (M=Al, Ga) gave the mixed alkenyl-di(alkynyl)silanes, in which the chlorine atom adopts a bridging position between the aluminium and silicon atoms. Dual hydrogallation of 3 resulted in the formation of a di(alkenyl)-alkynylsilane containing two gallium atoms, one of which is coordinated to the chlorine atom, and the second is bonded to the α-carbon atom of the remaining alkynyl group. A tert-butylsilane was unexpectedly formed by a unique 1,3-dyotropic chlorine-tert-butyl exchange for the corresponding dialuminium compound. One aluminium atom is bonded to a tert-butyl group, a terminal chlorine atom and the α-carbon atom of the ethynyl moiety; the second is coordinatively unsaturated, with two terminal tert-butyl substituents. High-level quantum-chemical calculations favour a stepwise dyotropic rearrangement with an intermediate cationic silicon species over a simultaneous tert-butyl-chlorine migration via a five-coordinate silicon atom in the transition state.

Counteranion-Dependent Reaction Pathways in the Protonation of Cationic Ruthenium–Vinylidene Complexes

The tetraphenylborate salts of the cationic vinylidene complexes [Cp*Ru═C═CHR(iPr2PNHPy)]+ (R = p-C6H4CF3 (1a-BPh4), Ph (1b-BPh4), p-C6H4CH3 (1c-BPh4), p-C6H4Br (1d-BPh4), tBu (1e-BPh4), H (1f-BPh4)) have been protonated using an excess of HBF4·OEt2 in CD2Cl2, furnishing the dicationic carbyne complexes [Cp*Ru≡CCH2R(iPr2PNHPy)]2+ (R = p-C6H4CF3 (2a), Ph (2b), p-C6H4CH3 (2c), p-C6H4Br (2d), tBu (2e), H (2f)), which were characterized in solution at low temperature by NMR spectroscopy. The corresponding reaction of the chloride salts 1a-Cl, 1b-Cl, 1c-Cl, and 1d-Cl followed a different pathway, instead affording the novel alkene complexes [Cp*RuCl(κ1(N),η2(C,C)-C5H4N-NHPiPr2CH═CHR)][BF4] (3a–d). In these species, the entering proton is located at the α-carbon atom of the former vinylidene ligand, which also forms a P–C bond with the phosphorus atom of the iPr2PNHPy ligand. To shed light on the reaction mechanism, DFT calculations have been performed by considering several protonation sites. The computational...

Computed Propagation and Termination Steps in [(Cycloocta-2,6-dien-1-yl)RhIII(polymeryl)]+ Catalyzed Carbene Polymerization Reactions

This paper discloses the DFT-computed pathways for chain propagation, chain transfer, and chain termination during carbene polymerization catalyzed by cationic [(cycloocta-2,6-dien-1-yl)RhIII(alkyl)]+ species. In contrast to carbene polymerization calculated for neutral [(cod)RhI(alkyl)]+ catalysts, chain propagation at the cationic [(cycloocta-2,6-dien-1-yl)RhIII(alkyl)]+ species is clearly competitive with β-hydride elimination, thus explaining the formation of high molecular weight polymers. Computed chain-end-controlled chain propagation reveals a clear preference for syndiotactic polymerization. Chain transfer involving alcohol-mediated protonolysis is computed to be a more favorable pathway than β-hydride elimination. These results are all in agreement with experimental observations. Chain propagation from species with a stereoerror at the α-carbon atom of the growing chain is substantially slower compared to propagation from syndiotactic species without stereoerrors, providing a possible explanation for the experimentally observed low initiation efficiencies of the Rh catalysts in carbene polymerization reactions. These new computational insights, combined with experimental results disclosed in earlier reports, largely clarify the mechanism of Rh-mediated carbene polymerization reactions.

Relationship of mineralization of amino naphthalene sulfonic acids by Fenton oxidation and frontier molecular orbital energies

Six amino naphthalene sulfonic acids including mono-, di- and tri-sulfonic acid compounds were studied to find the relationship between the reactivity of this kind of compounds in Fenton oxidation process and energies of the frontier molecular orbital. It was found that the initial rates of TOC reduction and oxalic acid production correlated strongly to the frontier molecular orbital energies and can be estimated by EHOMO and the absolute electronegativity (χ). The cleavage of –SO3H and –NH2 groups to produce SO42− and NH4+ species was dependent on the electron density distribution on the –SO3H moiety and the α-carbon atom connecting the –NH2 moiety. The electron withdrawing effect of the –SO3H groups influenced the mineralization of naphthalene sulfonic acids significantly. The naphthalene sulfonic acid with more –SO3H groups was more recalcitrant to the Fenton oxidation.

The 2.05‐helix in hetero‐oligopeptides entirely composed of Cα,α‐disubstituted glycines with both side chains longer than methyls

The existence of the very uncommon, but potentially quite interesting, multiple, consecutive fully-extended conformation (2.0₅-helix) has been already clearly demonstrated in homo-oligopeptides based on quaternary α-amino acids with both side chains longer than methyls, but not cyclized on the α-carbon atom. To extend the scope of this research, in this work we investigated the occurrence of this flat 3D-structure in hetero-oligopeptides, each composed of two or three different residues of that class. The synthesis of a terminally protected peptide series to the tetrapeptide level was carried out by solution methods. The resulting oligomers were chemically and conformationally characterized. The data obtained point to an overwhelming population of the fully-extended conformation in CDCl3. However, a solvent-driven switch to a predominant 3₁₀-helical structure was seen in CD3CN. A delicate, local balance between these two conformations is confirmed to occur in the crystalline state. Molecular dynamics simulations in CHCl3 on a hetero-tetrapeptide converged to the fully-extended conformation even starting from the 3₁₀-helical structure.

Quantum mechanical investigations on the role of C-terminal residue in influencing the structural features of dipeptides containing N-terminal proline

This study investigates the influence of the side chain moiety of C-terminal residue on the structural and molecular properties of seven dipeptides having proline at their N-terminal positions. The C-terminal component of the dipeptides is varied with seven different combinations viz. Ala, Leu, Asp, Thr, Asn, Arg and Sec. The calculations are carried out using B3LYP/6-311++G(d,p) level of theory in gas and implicit aqueous phase. Effects of explicit aqueous environment on the dipeptide structures are also investigated for two systems. The results furnished by this DFT study provide valuable information regarding the role of the side chain groups of C-terminal residues in determining the structural features of the amide planes, values of the ψ and ф dihedrals, geometry about the α-carbon atoms, theoretical IR spectra as well as the number and type of intramolecular H-bond interactions existing in the dipeptides, and extend a fine corroboration to the earlier theoretical and experimental observations. In aqueous phase the dipeptide geometries exhibit larger values of total dipole moments, greater HOMO–LUMO energy gaps and enhanced thermodynamic stability than those in gas phase. The explicit water molecules are found to modify the geometrical parameters related to the amide planes and vibrational spectra of the dipeptides.

Reactions of Acetophenonyl Pyridinium Salts with Alcohols

Acetophenonyl pyridinium salts are versatile reagents in organic reactions, but the reactivities of their carbonyls were seldomly studied. It was found that the reactions of the carbonyls with alcohols occurred when acetophenonyl pyridinium salts were treated with alcohols (or phenol) in the presence of a base giving rise to benzoates, and the departure of pyridyl with the α-carbon atom was involved. High yields (80%~98%) were achieved when they reacted with alcohols, however a yield of 48% were obtained when phenol was used instead of alcohols.

SYNTHESIS AND NMR SPECTRA OF TETRAHYDROFURAN-2- 13 C

An original method was developed for the synthesis of THF labeled selectively with the 13 C isotope at the α-carbon atom. The effective reduction of symmetry brought about by the insertion of the isotopic label removes the excess degeneracy of the spin systems describing the multiplet structure of the 1 H and 13 C NMR spectra, making it possible to undertake a detailed analysis. Exact values for the 1 H– 1 H spin-spin coupling constants through four bonds and also the 13 C– 1 H and 13 C– 13 C spin-spin coupling constants involving the α-carbon atom were determined for the first time. The isotopic chemical shifts of the protons and 13 C nuclei caused by replacement of the 12 C nucleus by 13 C were determined. These data can be used to construct a quantitative model of the conformational behavior of THF as a molecular system in which pseudorotation in terms of vibrations with large amplitude is realized. Authors: A. V. Chertkov, A. K. Shestakova, and V. A. Chertkov. English Translation in Chemistry of Heterocyclic Compounds , 2012, 48 (3), pp 412-421 http://link.springer.com/article/10.1007/s10593-012-1008-0

REACTIONS OF 3,3-DIAMINOACRYLIC ACID DERIVATIVES WITH o -HALOARENECARBONITRILES. SYNTHESIS OF FUSED AZINES

The interaction of the ethyl ester or pyrrolidide of 3,3-diaminoacrylic acid with aromatic and heteroaromatic nitriles containing a labile halogen atom in the ortho position, leads to the formation of products of its substitution by the α-carbon atom of the diaminoacrylic acid derivative. The compounds obtained are cyclized smoothly into fused diaminoazines. Authors: E. M. Igumnova, S. I. Selivanov, D. V. Dar'in, and P. S. Lobanov. English Translation in Chemistry of Heterocyclic Compounds , 2012, 48 (3), pp 436-441 http://link.springer.com/article/10.1007/s10593-012-1011-5

Synthesis and Reactions of π-Conjugated Iminoboranes Stabilized by Intramolecular Imine Groups

Reduction of the boron difluorides HC[(CBut)(NAr)]2BF2 led to C–N bond cleavage to give the iminoborane [C(But)CHC(But)NAr]B═NAr (2, Ar = 2,6-Me2C6H3; 2′, Ar = 2,6-Pri2C6H3) stabilized by an intramolecular imine group. Reaction of 2 with NHC resulted in nucleophilic attack on the α-carbon atom to give [C(But)(NHC)CHC(But)NAr]B═NAr (3). 2 reacted with CO2 to give [C(But)CHC(But)NAr]B(CO2)NAr (4).

Marine Sponge/H3PO4: As a Naturally Occurring Chiral Catalyst for Solvent-free Fischer-Indole Synthesis

A new and efficient method have been developed for the synthesis of different indole derivatives from various ketones, having at least one hydrogen atom attached to each of their α-carbon atoms, and hydrazines in solvent-free conditions, using marine sponge/H3PO4 as a naturally occurring chiral catalyst. This study recommended the use of marine sponge/H3PO4 as a naturally occurring chiral catalyst for preparation of phenylhydrazones from ketones having one α-hydrogen and subsequent cyclisation of the products to indoles. The reaction was carried out by mixing the phenylhydrazine, ketone, and marine sponge/H3PO4 powder in mortar and pestle; the mixture was ground at room temperature in an appropriate time until TLC show the completion of the reaction. The product extracted by CH2Cl2 and evaporation of solvent yields the products. In this research work, several indoles are synthesized using phenylhydrazine and aliphatic or aromatic ketone as starting materials, in the presence of marine sponge/H3PO4 powder as a natural catalyst under solvent-free condition. We found marine sponge/H3PO4 to be an effective catalyst for indolisation of phenylhydrazones from ketones having α-hydrogens in solvent-free conditions.

Influence of C-terminal residues on the structural and molecular properties of dipeptides: a theoretical study in a vacuum and implicit and explicit aqueous environments

The role of C-terminal residues in influencing the structural and molecular properties of a set of six dipeptides was studied using the B3LYP/6-31++G(d,p) level of theory in a vacuum and implicit and explicit aqueous environment. The dipeptides were constructed by keeping pyrrolysine as a fixed component in the N-terminus whereas the component in the C-terminus was varied with six different combinations, viz. Val, Ile, Glu, Thr, Gln, and Lys. The C-terminal residues were chosen on the basis of the propensity of their side chain moieties to be in contact with a polar solvent like water. Frequency calculations on the fully optimized molecular geometries of the dipeptides confirmed them to be true minima. The HOMO/LUMO energies as well as their energy gaps, rotational constants, dipole moments, and theoretically predicted vibrational spectra of all the dipeptides were thoroughly analyzed. The identity of the varying C-terminal residue affects the value of the ϕ dihedral, planarity of the peptide plane, and geometry around the α-carbon atoms of a given dipeptide. Solvation effects of the implicit aqueous environment are found to modify the gas-phase conformation of a dipeptide around the angle ψ and influence the number and types of intramolecular H-bonds occurring in a dipeptide structure. The influence of the explicit aqueous environment is evident on the geometrical parameters associated with the geometries of amide planes and vibrational spectra of the dipeptides.

Structural and molecular properties of dipeptides containing N-terminal selenomethionine: a theoretical study

Although the genetic code encodes only 22 amino acids during protein bio-synthesis, there are more than 140 natural amino acids whose incorporation into the protein structures is vital for proper functioning of the chemical and bio-chemical machineries associated with living beings. Among these, selenium-containing amino acids are of special interest for amino acid biochemistry. During the last few decades, the structure–function relationships of proteins are being best pursued by considering amino acids, dipeptides as well as their analogs as model systems. By performing this theoretical study it is intended to investigate the influence of functional group/groups present in side chain moieties of the varying C-terminal residues on the molecular and structural features of a set of seven dipeptides, constructed by conserving selenomethionine at their N-terminal positions while the C-terminal ends are varied with one of the following amino acid residues—Val, Trp, Glu, Cys, Tyr, Arg, and Sec. Geometry optimization and vibrational frequency calculations were carried out in gas and aqueous phase using B3LYP/6-311++G(d,p) level of theory. The results furnished by this DFT study provide a good account of the role of the C-terminal residue’s identity in determining the structural features of the amide planes, values of the ψ and ф dihedrals, geometry about the α-carbon atoms, theoretical IR spectra and the number and type of intramolecular H-bond interactions existing in the dipeptides. In aqueous phase, the dipeptide geometries exhibit larger values of total dipole moments, greater HOMO–LUMO energy gaps and enhanced thermodynamic stability than those in gas phase.

Catalytic Enantioselective Synthesis of Tertiary Thiols From 5H‐Thiazol‐4‐ones and Nitroolefins: Bifunctional Ureidopeptide‐Based Brønsted Base Catalysis

Fully loaded: The ureidopeptide-based bifunctional Brønsted base 1 efficiently promotes the first direct catalytic Michael reaction of α-mercapto carboxylate surrogates with nitroolefins involving a fully substituted α-carbon atom construction.

Densities and Volumetric Properties of Butyl Acrylate + 1-Butanol, or +2-Butanol, or +2-Methyl-1-propanol, or +2-Methyl-2-propanol Binary Mixtures at Temperatures from 288.15 to 318.15 K

The densities, ρ, of binary mixtures of butyl acrylate with 1-butanol, 2-butanol, 2-methyl-1-propanol, and 2-methyl-2-propanol, including those of the pure liquids, were measured over the entire composition range at temperatures of (288.15, 293.15, 298.15, 303.15, 308.15, 313.15, and 318.15) K and atmospheric pressure. From the experimental data, the excess molar volume $$ V_{\text{m}}^{\text{E}} $$ , partial molar volumes $$ \overline{V}_{\text{m,1}} $$ and $$ \overline{V}_{\text{m,2}} $$ , and excess partial molar volumes $$ \overline{V}_{\text{m,1}}^{\text{E}} $$ and $$ \overline{V}_{\text{m,2}}^{\text{E}} $$ , were calculated over the whole composition range as were the partial molar volumes $$ \overline{V}_{\text{m,1}}^{^\circ } $$ and $$ \overline{V}_{\text{m,2}}^{^\circ } $$ , and excess partial molar volumes $$ \overline{V}_{\text{m,1}}^{{^\circ {\text{E}}}} $$ and $$ \overline{V}_{\text{m,2}}^{{^\circ {\text{E}}}} $$ , at infinite dilution,. The $$ V_{\text{m}}^{\text{E}} $$ values were found to be positive over the whole composition range for all the mixtures and at each temperature studied, indicating the presence of weak (non-specific) interactions between butyl acrylate and alkanol molecules. The deviations in $$ V_{\text{m}}^{\text{E}} $$ values follow the order: 1-butanol < 2-butanol < 2-methyl-1-propanol < 2-methyl-2-propanol. It is observed that the $$ V_{\text{m}}^{\text{E}} $$ values depend upon the position of alkyl groups in alkanol molecules and the interactions between butyl acrylate and isomeric butanols decrease with increase in the number of alkyl groups at α-carbon atom in the alkanol molecules.

Acetamidines and acetamidoximes containing an electron-withdrawing group at the α-carbon atom: their use in the synthesis of nitrogen heterocycles (review)*

Acetamidines and acetamidoximes containing an electron-withdrawing substituent at the α-position often exhibit unusual characteristics for compounds of these types. This is due to the presence of an "active" methylene group in the molecules of the compounds. This review is devoted to the most important syntheses of heterocyclic compounds from amidines and amidoximes involving the "active" methylene group. Amidines are important starting compounds in the synthesis of nitrogen heterocycles. In most of the reactions they act as N,N-dinucleophiles and deliver the triad of N–C–N atoms into the ring of the obtained heterocycle. They are widely used in the synthesis of pyrimidines and imidazoles. Acetamidines of type 1, containing an electron-withdrawing substituent at the α-position, have a different type of reactivity. The α-carbon atom in these compounds is a nucleophile that is often stronger than the nitrogen atoms. This is due to the fact that in the free base form these amidines exist as the

Nucleophilic fluoroalkylation of (bromomethyl)pinacolborane using silicon reagents

A method for the synthesis of pinacol boronic esters bearing a fluorinated group at the α-carbon atom (RfCH2Bpin) from corresponding bromomethyl borane (BrCH2Bpin) and fluorinated silanes (RfSiMe3) is described. The fluoroalkylation reaction involves formation of borate anions followed by intramolecular nucleophilic substitution of bromine.

Reaction of ethyl 3,3-diaminoacrylate with pyrimidine series o-chloro ketones. Synthesis of pyrido[4,3-d]pyrimidines and 6H-1,3,6,7-tetra-azaphenalenes

Cyclocondensation of ethyl 3,3-diaminoacrylate with 5-acetyl-4-chloropyrimidines gave ortho- and peri-condensed heterocycles formed through substitution of the chlorine atom by the α-carbon atom of the enediamine and condensation of the amino group with the carbonyl or by addition of the amino group to the pyridine ring.

Structure and Reactivity of the Glutathione Radical Cation: Radical Rearrangement from the Cysteine Sulfur to the Glutamic Acid α-Carbon Atom.

A gas-phase radical rearrangement through intramolecular hydrogen-atom transfer (HAT) was studied in the glutathione radical cation, [γ-ECG]+. , which was generated by a homolytic cleavage of the protonated S-nitrosoglutathione. Ion-molecule reactions suggested that the radical migrates from the original sulfur position to one of the α-carbon atoms. Experiments on the radical cations of dipeptides derived from the glutathione sequence, [γ-EC]+. and [CG]+. , pointed to the glutamic acid α-carbon atom as the most likely site of the radical migration. Infrared multiple-photon dissociation (IRMPD) spectroscopy was employed to generate complementary information. IRMPD of [γ-ECG]+. in the approximately 1000-1800 cm-1 region was inconclusive owing to the relatively broad, overlapping absorption bands. However, the IRMPD spectrum of [γ-EC]+. in this region was consistent with the radical migrating from the sulfur to the α-carbon atom of glutamic acid. IRMPD in the 2800-3700 cm-1 region performed on [γ-ECG]+. is consistent with a mixture of both the original sulfur-based radical and the resulting glutamic acid α-carbon-based species. Comparisons are made with previously published condensed and gas-phase studies on intramolecular HAT in glutathione.