Anomeric 5-Aza-7-deaza-2′-deoxyguanosines in Silver-Ion-Mediated Homo and Hybrid Base Pairs: Impact of Mismatch Structure,Helical Environment,and Nucleobase Substituents on DNA Stability

Nucleoside configuration (α-d vs. β-d ), nucleobase substituents, and the helical DNA environment of silver-mediated 5-aza-7-deazaguanine-cytosine base pairs have a strong impact on DNA stability. This has been demonstrated by investigations on oligonucleotide duplexes with silver-mediated base pairs of α-d and β-d anomeric 5-aza-7-deaza-2′-deoxyguanosines and anomeric 2′-deoxycytidines incorporated in 12-mer duplexes. To this end, a new synthetic protocol has been developed to access the pure anomers of 5-aza-7-deaza-2′-deoxyguanosine by glycosylation of either the protected nucleobase or its salt followed by separation of the glycosylation products by crystallization and chromatography. Thermal stability measurements were performed on duplexes with α-d /α-d and β-d /β-d homo base pairs or α-d /β-d and β-d /α-d hybrid pairs within two sequence environments, positions 6 or 7, of oligonucleotide duplexes. The respective T_m stability increases observed after silver ion addition differ significantly. Homo base pairs with β-d /β-d or α-d /α-d nucleoside combinations are more stable than α-d /β-d hybrid base pairs. The positional switch of silver-ion-mediated base pairs has a significant impact on stability. Nucleobase substituents introduced at the 5-position of the dC site of silver-mediated base pairs affect base pair stability to a minor extent. Our investigation might lead to applications in the construction of bioinspired nanodevices, in DNA diagnostics, or metal-DNA hybrid materials.     

Ketoreductases in the synthesis of valuable chiral intermediates: application in the synthesis of α-hydroxy β-amino and β-hydroxy γ-amino acids

A general method for the synthesis of β-alkyl α-hydroxy β-amino and α- and γ-alkyl substituted β-hydroxy-γ-amino acids is described. The synthesis of all three classes of amino acids proceeds through a common chiral alcohol intermediate that is generated from a pro-chiral ketone diester via the action of a nicotinamide-dependent ketoreductase. Regioselective chemical or enzymatic hydrolysis followed by rearrangement under Hofmann or Curtius conditions gives the final amino acid products. High yields of single diastereomers of the final amino acids are obtained. Amino acids with both natural and unnatural alkyl substituents can be accessed using this methodology.     

Mass spectral studies of some β-diketones and their beryllium complexes

Detailed comparison of the fragmentation behavior of a series of beryllium β-diketonates with that of the corresponding series of β-diketones reveals a number of striking differences. A-typical fragmentations are observed for diketones and diketonates with trifluoromethyl and α-phenyl substituents.     

Reaction of dianions derived from β-ketoesters with epoxides-utility in the preparation of synthetically useful tetrahydrofurans

Presented here are several examples which demonstrate that ether substituents α- or β- to an epoxide ring can be tolerated in the ring-opening reaction with β-keto ester dianions. Subsequent acid-promoted cyclisation of the γ-hydroxy β-ketoesters then leads to synthetically useful tetrahydrofurans, as demonstrated by application of this approach to the preparation of (±)-methyl nonactate and (±)-methyl 8-epi-nonactate.     

Highly stereoselective synthesis of erythro-α, β-epoxy alcohols by the reduction of α, β-epoxy ketones with zinc borohydride

$\text{Erythro}$-α, β-epoxy alcohols were prepared in high stereoselectivity by zinc borohydride reduction of the corresponding α, β-epoxy ketones regardless of the substituents on the epoxide ring.     

Almond oxynitrilase-catalyzed transformation of aldehydes is strongly influenced by naphthyl and alkoxy substituents

Different α- and β-substituted aldehydes have been submitted to the catalytic action of almond oxynitrilase (PaHNL), in order to explore the influence of a stereocenter already present in the substrate on the selectivity of this enzyme.[1]The results indicate that naphthyl and alkoxy substituents in the α- and also in the β-position to the aldehyde group significantly influence the stereochemical outcome of the PaHNL-catalyzed transformation.     

A Substrate-Driven Approach to Determine Reactivities of α,β-Unsaturated Carboxylic Esters Towards Asymmetric Bioreduction

The degree of C?C bond activation in the asymmetric bioreduction of α,β-unsaturated carboxylic esters by ene-reductases was studied, and general recommendations to render these "borderline-substrates" more reactive towards enzymatic reduction are proposed. The concept of "supported substrate activation" was developed. In general, an additional α-halogenated substituent proved to be beneficial for enzymatic activity, whereas β-alkyl or β-aryl substituents were detrimental for the reactivity of nonhalogenated substrates, and α-cyano groups showed little effect. The alcohol moiety of the ester functionality was found to have a strong influence on the reaction rate. Overall, activities were determined by both steric and electronic effects.     

Carbon-13 NMR spectra of DDT,its analogues and related compounds

Carbon-13 NMR spectra of mono- and disubstituted aromatic compounds including DDT, its analogues, homologues, derivatives and certain model compounds have been studied. The Savitsky scheme of carbon chemical shifts in disubstituted benzenes is applicable to these compounds. The data obtained show that in mono- and disubstituted aromatic compounds containing two different substituents in the α- and β-positions of the side chain, the substituted ring carbon atom shifts follow the additivity rule and can be calculated from substituent increments. Mutual effects of substituents in the ring and in the side chains are analysed. The chlorine atoms in α-position to the phenyl ring give rise to an additive α-effect of about 25 ppm, as in perchloroalkanes. The influence of a β-chlorine atom in the side chain on the substituted carbon atom in the ring is, however, only 3 ppm as against the usual value of about 10 ppm for the β-effect in alkyl chains. Moreover, the first β-chlorine substituent has no noticeable influence on the substituted ring carbon chemical shift: the effect of 3 ppm is transferred to the para-carbon atom almost without attenuation. The ring substituted carbon atom signal shifts caused by the γ-effect of chlorine in the side chain are similar to those observed in aliphatic chains. The ortho-chlorine substituents shift the side chain α-carbon atom signal by 3.6-5.2 ppm to high field compared to para-chlorophenyl compounds. This is similar to the chlorine γ-effect in aliphatic chains.     

C−H Bond Arylation of Pyrazoles at the β-Position: General Conditions and Computational Elucidation for a High Regioselectivity

Direct arylation of most five-membered ring heterocycles are generally easily accessible and strongly favored at the α-position using classical palladium-catalysis. Conversely, regioselective functionalization of such heterocycles at the concurrent β-position remains currently very challenging. Herein, we report general conditions for regioselective direct arylation at the β-position of pyrazoles, while C−H α-position is free. By using aryl bromides as the aryl source and a judicious choice of solvent, the arylation reaction of variously N-substituted pyrazoles simply proceeds via β-C−H bond functionalization. The β-regioselectivity is promoted by a ligand-free palladium catalyst and a simple base without oxidant or further additive, and tolerates a variety of substituents on the bromoarene. DFT calculations revealed that a protic solvent such as 2-ethoxyethan-1-ol significantly enhances the acidity of the proton at β-position of the pyrazoles and thus favors this direct β-C−H bond arylation. This selective pyrazoles β-C−H bond arylation was successfully applied for the straightforward building of π-extended poly(hetero)aromatic structures via further Pd-catalyzed combined α-C−H intermolecular and intramolecular C−H bond arylation in an overall highly atom-economical process.     

Lewis acid-promoted reaction of β,γ-unsaturated α,α-dimethoxy esters with silyl nucleophiles

The Lewis acid-promoted reaction of β,γ-unsaturated α,α-dimethoxy esters, which are easily prepared by the acetalization of β,γ-unsaturated α-keto esters, with silyl nucleophiles is presented. By employing trimethylsilyl enolate and allyltrimethylsilane as nucleophiles, the BF₃-promoted reactions of a series of β,γ-unsaturated α,α-dimethoxy esters bearing aromatic and aliphatic substituents proceeded at the γ-position in an SN2′ manner to furnish γ-substituted α,β-unsaturated α-methoxy esters in good yields with high regioselectivity. In contrast, the reaction using trimethylsilyl cyanide predominantly occurred at the α-position, and the reaction of silyl hydride resulted in a mixture of α- and γ-regioisomers in favor of the γ-substitution products.     

One-pot three component α-aminoalkylation of conjugated nitroalkenes and nitrodienes

Nitroethylenes possessing aryl, heteroaryl, and alkyl substituents at the β-position as well as δ-substituted nitrobutadienes undergo facile aminoalkylation at the α-position upon treatment with formaldehyde and a secondary amine in the presence of imidazole and trifluoroacetic acid to afford α-aminoalkylated nitroalkenes and nitrodienes in good to excellent yield and stereoselectivity.     

Preparation of α-alkyl-β-amino acids via β-alanine Ni(II) complex

A new β-amino acrylic acid Ni(II) complex has been developed and used for the synthesis of α-alkyl-β-amino acids via alkylation with alkyl halides under operationally convenient conditions. The pivotal α-alkylated intermediate can be converted into the corresponding α-alkyl-β-amino acids via two steps with a wide range of substituents.     

Silicon-Directed Nazarov Reactions II. Preparation and Cyclization of β-Silyl-substituted Divinyl Ketones

Two general methods for the preparation of β-silyl-substituted divinyl ketones have been developed starting from either α, β-unsaturated aldehydes or simple ketones. Anhydrous FeCl₃ induces the cyclization to cyclopentenones under mild conditions and in good yields with predictable and complete control over the position of the double bond in the five-membered ring. The observed effects of substituents on rate can be explained by a rate-determining cationic electrocyclization. Silyl substitution has been shown to retard the reaction.     

Asymmetric synthesis of chiral tertiary borylated phosphonates by copper-catalyzed conjugate borylation

Enantioselective copper-catalyzed conjugate borylation of α,β-unsaturated phosphonates with bis(pinacolato)diboron affords chiral tertiary organoboronate esters with a vicinal phosphonate group in good yields and enantiomeric excess. Linear aliphatic, aromatic, and heteroaromatic substituents at the β-position can be accommodated, and oxidation of the borylated organophosphonate products leads to β-hydroxyphosphonates.     

Construction of 2,3- and 3,4-Functionalized Silacyclopentanes: Synthesis of 6-Aza-2,2-Diphenyl-2-Silabicyclo[3.1.0]Hexane and 6-Aza-3,3-Diphenyl-3-Silabicyclo[3.1.0]Hexane Derivatives

The synthesis of five azasilabicyclo[3.1.0]hexanes containing an aziridine function in the α- or the β- position of the silicon atom is described. These bicyclic heterocompounds differ by the various substituents (H, Me, CO₂Et, CPh₃) on the nitrogen atom.     

Friedel crafts reactions of three-member ileterocycles II: Alkylation of aromatic compounds with aziridines

The Friedel Crafts reaction of propylenimine with symmetrical arenes in the presence of aluminum chloride was investigated. Electron donating substituents increase the α-methyl-β-phenethylamine/ β-methyl-β-phenethylaimine ratio, while increasing the temperature has the opposite effect. In the reaction of chlorobenzene or toluene with aziridine, the nature of the substituent has little effect on the ortho/para ratio.     

Lewis acid-catalyzed one-pot sequential reaction for the synthesis of α-halogenated β-keto esters

A Lewis acid-catalyzed one-pot sequential transformation of β-keto esters, aromatic aldehydes, and NCS/NBS was reported. The reaction proceeds by way of Knoevenagel condensation/Nazarov cyclization/halogenation to give α-chloro- and α-bromo-β-keto esters in moderate yields with high diastereoselectivities. However, several aromatic aldehydes with electron-withdrawing substituents afforded unexpected α,β′-dichloro-β-keto esters in good to high yields.     

Kinetics and stereochemistry of hydrolysis of an N-(phenylacetyl)-α-hydroxyglycine ester catalyzed by serine β-lactamases and dd-peptidases

The α-hydroxydepsipeptide 3-carboxyphenyl N-(phenylacetyl)-α-hydroxyglycinate () is a quite effective substrate of serine β-lactamases and low molecular mass dd-peptidases. The class C P99 and ampC β-lactamases catalyze the hydrolysis of both enantiomers of , although they show a strong preference for one of them. The class A TEM-2 and class D OXA-1 β-lactamases and the Streptomyces R61 and Actinomadura R39 dd-peptidases catalyze hydrolysis of only one enantiomer of at any significant rate. Experiments show that all of the above enzymes strongly prefer the same enantiomer, a surprising result since β-lactamases usually prefer l(S) enantiomers and dd-peptidases d(R). Product analysis, employing peptidylglycine α-amidating lyase, showed that the preferred enantiomer is d(R). Thus, it is the β-lactamases that have switched preference rather than the dd-peptidases. Molecular modeling of the P99 β-lactamase active site suggests that the α-hydroxyl of may interact with conserved Asn and Lys residues. Both α-hydroxy and α-amido substituents on a glycine ester substrate can therefore enhance its productive interaction with the β-lactamase active site, although their effects are not additive; this may also be true for inhibitors.     

Hydrogen abstraction by chlorine atom from amino acids: remarkable influence of polar effects on regioselectivity

Quantum chemistry computations have been used to investigate hydrogen-atom abstraction by chlorine atom from protonated and N-acetylated amino acids. The results are consistent with the decreased reactivity at the backbone α-carbon and adjacent side-chain positions that is observed experimentally. The individual effects of NH(3)(+), COOH, and NHAc substituents have been examined and reveal important insights. The NH(3)(+) group in isolation is found to be deactivating at the α-position, while the acetamido group is activating. For the COOH group, polar effects lead to a contrathermodynamic deactivation of the thermodynamically most favorable α-abstraction. In the N-acetylamino acid, the α-position is deactivated by the combined inductive effect of the substituents and the presence of an early transition structure, again overriding the greater thermodynamic stability of the α-centered radical product. Deactivation of the α-, β-, and γ-positions results in a peculiar stability for amino acids and peptides and their derivatives with respect to radical degradation.     

Acetylation of secondary hydroxy groups of α- and β-cyclodextrines silyl derivatives

The application of acetyl chloride in the combination with different solvents and bases permitted the preparation of silyl derivatives of α- and β-cyclodextrines containing a definite amount of acetyl substituents on the secondary hydroxy groups. It was found that by means of the ¹H and ¹³C NMR spectroscopy it is possible to make an exact attribution of acetyl groups to C² or C³ carbon atoms of carbohydrate fragments of α- and β-cyclodextrines. Desilylation with ammonium fluoride in methanol gives acetyl derivatives of cyclodextrines containing free primary hydroxy groups.