Β-alkyl Groups Research Articles

Pronucleotides of 2',3'-Dideoxy-2',3'-Didehydrothymidine as Potent Anti-HIV Compounds.

We report on the synthesis and evaluation of three different nucleotide prodrug systems: (i) nucleoside triphosphate analogues in which the γ-phosph(on)ate has two different lipophilic nonbioreversible alkyl residues with d4TDP as the released nucleotide analogue; (ii) nucleoside diphosphate analogues bearing a bioreversible and a stable β-alkyl group; or (iii) nucleoside diphosphate analogues bearing two nonhydrolysable lipophilic alkyl moieties. The delivery of d4TDP (for the triphosphate precursor) and d4TMP (for the diphosphate precursor) was demonstrated in CD4+ T-lymphocyte CEM cell extracts as well as in phosphate buffer saline (PBS). In primer extension assay, we found that γ-dialkylated d4TTP derivatives and d4TDP were accepted as substrates by HIV-RT. Several of these compounds were observed to be extremely active against HIV-1/2 replication in HIV-infected cells. A more than 45,000-fold increase in the anti-HIV activity was detected for compound 18a as compared to the parent d4T which results in a selectivity index value of 37,000.

Decrypting the programming of β-methylation in virginiamycin M biosynthesis

During biosynthesis by multi-modular trans-AT polyketide synthases, polyketide structural space can be expanded by conversion of initially-formed electrophilic β-ketones into β-alkyl groups. These multi-step transformations are catalysed by 3-hydroxy-3-methylgluratryl synthase cassettes of enzymes. While mechanistic aspects of these reactions have been delineated, little information is available concerning how the cassettes select the specific polyketide intermediate(s) to target. Here we use integrative structural biology to identify the basis for substrate choice in module 5 of the virginiamycin M trans-AT polyketide synthase. Additionally, we show in vitro that module 7, at minimum, is a potential additional site for β-methylation. Indeed, analysis by HPLC-MS coupled with isotopic labelling and pathway inactivation identifies a metabolite bearing a second β-methyl at the expected position. Collectively, our results demonstrate that several control mechanisms acting in concert underpin β-branching programming. Furthermore, variations in this control – whether natural or by design – open up avenues for diversifying polyketide structures towards high-value derivatives.

ChemInform Abstract: Diphenylprolinol Silyl Ether Catalyzed Asymmetric Michael Reaction of Nitroalkanes and β,β‐Disubstituted α,β‐Unsaturated Aldehydes for the Construction of All‐Carbon Quaternary Stereogenic Centers.

The asymmetric Michael reaction of nitroalkanes and β,β-disubstituted α,β-unsaturated aldehydes was catalyzed by diphenylprolinol silyl ether to afford 1,4-addition products with an all-carbon quaternary stereogenic center with excellent enantioselectivity. The reaction is general for β-substituents such as β-aryl and β-alkyl groups, and both nitromethane and nitroethane can be employed. The addition of nitroethane is considered a synthetic equivalent of the asymmetric Michael reaction of ethyl and acetyl substituents by means of radical denitration and Nef reaction, respectively. The short asymmetric synthesis of (S)-ethosuximide with a quaternary carbon center was accomplished by using the present asymmetric Michael reaction as the key step. The reaction mechanism that involves the E/Z isomerization of α,β-unsaturated aldehydes, the retro-Michael reaction, and the different reactivity between nitromethane and nitroethane is discussed.

Diphenylprolinol silyl ether catalyzed asymmetric Michael reaction of nitroalkanes and β,β-disubstituted α,β-unsaturated aldehydes for the construction of all-carbon quaternary stereogenic centers.

The asymmetric Michael reaction of nitroalkanes and β,β-disubstituted α,β-unsaturated aldehydes was catalyzed by diphenylprolinol silyl ether to afford 1,4-addition products with an all-carbon quaternary stereogenic center with excellent enantioselectivity. The reaction is general for β-substituents such as β-aryl and β-alkyl groups, and both nitromethane and nitroethane can be employed. The addition of nitroethane is considered a synthetic equivalent of the asymmetric Michael reaction of ethyl and acetyl substituents by means of radical denitration and Nef reaction, respectively. The short asymmetric synthesis of (S)-ethosuximide with a quaternary carbon center was accomplished by using the present asymmetric Michael reaction as the key step. The reaction mechanism that involves the E/Z isomerization of α,β-unsaturated aldehydes, the retro-Michael reaction, and the different reactivity between nitromethane and nitroethane is discussed.

The photo-Nazarov reaction: scope and application.

The reaction conditions and scope of the photo-Nazarov reaction of aryl vinyl ketones were investigated. In contrast to the conventional acid-catalyzed methods, this photolytic electrocyclization proceeds in the neutral or basic conditions. Irradiating substrates bearing various aromatic rings, acid-sensitive groups, cyclohexenyl, cycloheptenyl, and unsaturated pyran with UV-light (254 nm) smoothly yielded hexahydrofluorenones and related structures. This photo-Nazarov reaction could also be applicable to the substrates carrying β-alkyl groups on the enone, which gave corresponding polycyclic rings containing quaternary centers. These photo-electrocyclized products may prove useful for synthesizing a variety of natural products and their derivatives. Further application of this mild photo-Nazarov reaction in the synthesis of taiwaniaquinol B was achieved.

Study on 1,3,5‐Triazine Chemistry in Dehydrocondensation: Gauche Effect on the Generation of Active Triazinylammonium Species

The reaction of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) with various nitrogen-containing compounds, particularly tertiary amines (tert-amines), has been studied for the preparation of 2-(4,6-dimethoxy-1,3,5-triazinyl)trialkylammonium salts [DMT-Am(s)]. DMT-Ams derived from aliphatic tert-amines exhibited activity for the dehydrocondensation between a carboxylic acid and an amine to form an amide in a model reaction. Based on a conformational analysis of DMT-Ams and tert-amines by NMR and X-ray diffraction methods, we concluded that a β-alkyl group maintained in a gauche relationship with the nitrogen lone pair of tert-amines significantly hinders the approach of CDMT to the nitrogen. Thus, trimethylamine and quinuclidine without such alkyl groups readily react with CDMT whereas triethylamine, possessing two or three such gauche β-alkyl groups in the stable conformations, does not react at all. The theory of "gauche β-alkyl group effect" proposed here provides useful guidelines for the preparation of DMT-Ams possessing various tertiary amine moieties. An investigation of the dehydrocondensation activity of tert-amines in a CDMT/tert-amine system that involves in situ generation of DMT-Am, showed that the gauche effect of the β-alkyl group becomes quite pronounced; the yield of the amide decreases significantly with tert-amines possessing an unavoidable gauche β-alkyl group. Thus, the tert-amine/CDMT systems are useful for judging whether tert-amines can readily react with CDMT without isolation of DMT-Ams.

Solution-processable oligothiophenes with solubilizing β-alkyl groups for organic photovoltaic cells

Two linear-type π-conjugated small molecules based on thiophene and benzothiadiazole, β-DH5TB(1) and β-DH5TB(2), were synthesized using the Suzuki coupling reaction to have β-substituted solubilizing alkyl groups. The solubility of β-DH5TBs was significantly improved by changing the direction of the alkyl group compared to α-substituted oligothiophene (α-DH5TB). The relationship between the alkyl substitution pattern and the photovoltaic properties was investigated by measuring the optical and electrochemical properties and the film morphology. Among them, the 4-hexyl substituted β-DH5TB(2) showed the lowest optical band gap and HOMO level together with a red-shifted broad UV absorption. In addition, a high degree of molecular alignment was also observed in β-DH5TB(2), indicative of good charge transport. The β-DH5TB(2) film showed higher field-effect mobility (μFET) of 6.28×10−4cm2V−1s−1 than β-DH5TB(1) film. Owing to the improved solubility, two of the synthesized β-DH5TBs could be used as donor materials in solution-processed organic photovoltaic cells (OPVs), whereas the α-DH5TB:PC71BM blend film showed no photovoltaic properties due to the poor solubility of α-DH5TB. The improved absorption and molecular alignment of the β-DH5TB(2) yielded a device efficiency (0.98%) higher than that of β-DH5TB(1).

Structure–activity relationships for abiotic thiol reactivity and aquatic toxicity of halo-substituted carbonyl compounds‖

Using abiotic thiol reactivity (EC50) and Tetrahymena pyriformis toxicity (IGC50) data for a group of halo-substituted ketones, esters and amides (i.e. SN2 electrophiles) and related compounds a series of structure–activity relationships are illustrated. Only the α-halo-carbonyl-containing compounds are observed to be thiol reactive with the order I > Br > Cl > F. Further comparisons disclose α-halo-carbonyl compounds to be more reactive than non-α-halo-carbonyl compounds; in addition, the reactivity is reduced when the number of C atoms between the carbonyl and halogen is greater than one. Comparing reactivity among α-halo-carbonyl-containing compounds with different β-alkyl groups shows the greater the size of the β-alkyl group the lesser the reactivity. A comparison of reactivity data for 2-bromoacetyl-containing compounds of differing dimensions reveals little difference in reactivity. Regression analysis demonstrates a linear relationship between toxicity and thiol reactivity: ; n = 19, s = 0.250, r 2 = 0.926, r 2(pred) = 0.905, F = 199, Pr > F = 0.0001. ‖Presented at the 12th International Workshop on Quantitative Structure--Activity Relationships in Environmental Toxicology (QSAR2006), 8--12 May 2006, Lyon, France.

Metallophosphite‐Induced Nucleophilic Acylation of α,β‐Unsaturated Amides: Facilitated Catalysis by a Diastereoselective Retro [1,4] Brook Rearrangement

Metallophosphite‐Induced Nucleophilic Acylation of α,β‐Unsaturated Amides: Facilitated Catalysis by a Diastereoselective Retro [1,4] Brook Rearrangement

Enantioselective electrochemical oxidation of enol acetates using a chiral supporting electrolyte.

Anodic oxidation of 1-acetoxy-3,4-dihydronaphthalene (1) and alpha-acetoxy-beta-alkylstyrenes (3) at -78 degrees C in a mixed solvent of acetonitrile (CH(3)CN), tetrahydrofuran (THF), and acetic acid (AcOH) containing (S)-tetraethylammonium camphorsulfonate as a chiral supporting electrolyte brought about enantioselective formation of the corresponding 2-acetoxy-1-tetralones (2) and (R)-2-acetoxy-1-phenyl-1-alkanone (4) with maximum enantiomeric excess (ee) of 44% and 21%, respectively. Introduction of a 7-methoxy group into 1 and increase in bulkiness of a beta-alkyl group in 3 resulted in improvement of enantioselectivity of the reactions.

Geometry and tautomerism of sapphyrin—DFT studies

The structure and total energy have been investigated, applying the density functional theory (DFT), for idealized sapphyrin derivatives, created by replacements of meso-phenyl groups of 5,10,15,20-tetraphenylsapphyrin or β-alkyl groups of decaalkylsapphyrin with hydrogens or two methyl groups, respectively. The following species have been considered: the dication of plain sapphyrin (SapH 5 2+) 12,13-dimethylsapphyrin (12,13-DMSapH 3), 12,13-dimethylsapphyrin dication (12,13-DMSapH 5 2+), and the 10,15-dimethylsapphyrin dication (10,15-DMSapH 5 2+). To address the issue of tautomerization the calculations have been carried out for the six feasible distribution patterns of NH protons among the five nitrogen centers of the planar sapphyrin P 0 i ( i=1–6). The B3LYP/6-31G optimized bond lengths and angles of sapphyrin or (dimethylated sapphyrin) skeletons are in satisfactory agreement with X-ray crystallographic values determined for decaalkylsapphyrin dications. The calculated total energies, using the B3LYP/6-31G**//3-21G approach demonstrate that the plain sapphyrin and 12,13-dimethylsapphyrin dications favor the planar geometry of the macrocycle. Localization of the methyl groups at the 10,15- meso positions of sapphyrin reversed the order of stability leading to the energy preference for the inverted structure. Thus, this steric factor related to the meso substitution seems to be instrumental in the C pyrrolic ring inversion. The DFT calculation also provided the relative stability frame for the complex tautomeric equilibria of SapH 3 which involve six different forms. Their relative stability decreases in the range: {25-NH, 26-N, 27-NH, 28-NH, 29-N} P 0 3>({25-NH, 26-N, 27-NH, 28-N, 29-NH} P 0 1>{25-NH, 26-NH, 27-N, 28-NH, 29-N} P 0 5>{25-N, 26-NH, 27-NH, 28-NH, 29-N} P 0 2>{25-NH, 26-N, 27-N, 28-NH, 29-NH} P 0 6>{25-N, 26-N, 27-NH, 28-NH, 29-NH} P 0 4. The stability order can be qualitatively related to the number and the nature of the cis NH interactions present in the sapphyrin core.

Substituent effects on the gas-phase basicities of 1-arylpropynes and 1-aryl-3,3-dimethylbutynes effects of the β-alkyl groups on the resonance demand of vinyl cations

The relative stabilities of 1-aryl-2-methylvinyl cations (1) and 1-aryl-2- t-butylvinyl cations (II) were determined by measuring the proton-transfer equilibria of 1-arylpropynes and 1-aryl-3,3-dimethylbutynes in the gas phase. The stabilities of 1-phenyl-2-methylvinyl cation and 1-phenyl-2- t-butylvinyl cation were found to be 1.8 and 5.5 kcal mol −1 higher than that of 1-phenylvinyl cation, respectively. The substituent effects on the stability of these vinyl cations could be correlated in terms of the Yukawa-Tsuno equation, giving an r + of 1.13 and a p of −9.5 for I, and 1.03 and −9.4 for II. Combined with the previous results, it was found that the r + value decreases with the increase in stability of the unsubstituted member of the respective vinylic carbocations while the p values remain constant for a series of the phenylvinyl cation system. This indicates that the π-delocalization of the positive charge into the aryl π-system decreases with the stabilization of a vinyl cation by the β-substituent. This trend is consistent with the observation for a series of ordinary sp 2-hybridized benzylic carbocations. In addition, it has been shown that both sp- and sp 2-carbocation systems obey a single linear relationship between the r + values and carbocation stabilities of the unsubstituted member of respective series. This result clearly demonstrates a continuous spectrum of varying resonance demands characteristic of the stabilities of carbocations. It was concluded that the π-delocalization mechanism in the vinyl cation system has no unique feature but it is a part of a continuous spectrum of resonance demands of varying benzylic carbocations.

Synthesis and structure of a 5,15-bis(4-pyridyl)purpurin

Base catalyzed cyclization of a 5,15-di(4-pyridyl)octaalkylporphyrin-5-acrylate 6 yields smoothly the corresponding purpurin 2. Quaternization with methyl iodide yielded the corresponding cationic N,N′-dimethylpyridiniumpurpurin 3; X-ray crystallography of purpurin 2, the first purpurin to be studied crystallographically, shows the two β-alkyl groups on the saturated ring of the purpurin have a syn configuration, and the macrocycle to have a slight saddle shape with a mean deviation of 0.230 Å from the least-squares plane calculated for the core atoms.

Oxidative Dehydrogenation of Isobutane over Monoliths at Short Contact Times

Isobutylene can be produced with high selectivity and conversion by oxidative dehydrogenation of isobutane in air or oxygen over a ceramic foam monolith coated with Pt at contact times of ∼ 5 ms in an atmospheric pressure reactor operating at 800 to 900°C. Total olefin selectivities up to 80% (40% isobutylene, 40% propylene) at 60% conversion of isobutane are achieved in an autothermal process with higher reactant conversion when the reactants are preheated up to 400°C. No carbon build-up is observed at molar isobutane-to-oxygen feed ratios up to 2.5, and the catalyst shows no deactivation over at least several weeks of operation. Maximum isobutylene selectivity occurs at a fuel-to-oxygen ratio of 1.4 at contact times ≤ 5 ms, while propylene yield is maximized at longer contact times and at higher fuel-to-oxygen ratios. The total selectivity to methane, ethane, and ethylene is always much less than the total selectivity to isobutylene and propylene. A simple reaction mechanism can explain these products. Surface oxygen abstracts a hydrogen from isobutane resulting in an isobutyl group on the surface. On the Pt surface, β-elimination reactions than take place, leading to either isobutylene or propylene production. The small amounts of smaller hydrocarbons compared to n-butane oxidation or to homogeneous cracking are explained by the absence of a β-alkyl group on the isobutyl species adsorbed at a 3° carbon.

Herpes simplex virus ribonucleotide reductase subunit association inhibitors: the effect and conformation of β-alkylated aspartic acid derivatives

Incorporating β-alkylated aspartic acid derivatives into herpes simplex virus ribonucleotide reductase subunit association inhibitors can improve inhibitor potency up to 50 times over the corresponding inhibitors containing an unsubstituted aspartic acid. A combination of NMR studies, conformational analysis, and molecular mechanics calculations suggests that the β-alkyl group improvesinhibitor potency b is provided by a potent conformationally restricted aspartic acid derivative in which the carboxyl group is locked in the putative bioactive conformation.

Eliminations from 1-phenyl-2-alkyl tosylates promoted by MeONa in MeOH. Steric effects in alkene-forming elimination

Reactions of PhCH2CH(OTs)R [R = Me (1), Et (2), Pri(3), Bus(4), But(5)] with MeONa in MeOH have been studied. The reactions produce both conjugated and unconjugated alkenes. The yields of the conjugated alkenes are nearly the same for 1–4, while the E/Z ratios depend strongly upon the α-alkyl group. The rates of eliminations forming the conjugated E alkenes are decreased by a bulkier alkyl group as indicated by the relative rate of 1, 0.8, 0.7, 0.6, 0.2 for 1, 2, 3, 4, 5, respectively. On the other hand, the relative rates for the formation of the unconjugated alkenes are 1, 1.7, 2.8, 1.9 for 1, 2, 3, 4 respectively, indicating that the rate increases with the double bond stabilizing ability of the alkyl groups and decreases with their steric effect. From these results, the relative steric effect of the α- and β-alkyl groups in alkene-forming elimination is assessed.

The effect of solvent interaction with the hydroxy group of saturated monohydroxy alcohols from measurement of hydroxy stretching vibrations

The nature of the interaction of solvent molecules with the hydroxy group of saturated monohydroxy alcohols in specific rotamer conformations has been examined. For non-polar and nucleophilic-type solvents, the interaction centres at the OH proton, causing a decrease in the OH stretching frequency. Shielding of the hydroxy hydrogen by β-alkyl groups reduces the magnitude of the shift. In chloroform solution, evidence is given for an association of the solvent molecules with the oxygen lone-pair sites in conjunction with an association with the OH proton. The interaction of chloroform with the lone-pair sites causes an apparent increase in the OH stretching frequency which is counterbalanced by the decrease caused by association with the OH proton. Shielding of either the lone-pair sites or the OH proton by β-alkyl groups influences the accessibility of the solvent and consequently influences the OH stretching frequency.

Cyanoacrylate Inhibitors of the Hill Reaction IV. Binding Characteristics of the Hydrophobic Domain

Aryl- and aralkyl-amino derivatives of 2-cyanoacrylic esters were synthesized and assayed as inhibitors of the Hill reaction in isolated pea chloroplast fragments. Aryl- and aralkyl-amino 2-cyanoacrylates unsubstituted in the β-position were weak inhibitors but activity could be greatly enhanced by inclusion of a β-alkyl group with the increase in potency being dependent on the carbon chain length of the β-substituent. The magnitude of this effect appeared independent of the nature of the aryl- or aralkyl-amino function. Inclusion of a carbon chain between the phenyl and amino functions of phenylamino-2-cyano- acrylates produced a stepwise increase in activity with increasing chain length, indicating a prefer- red orientation for the phenyl ring within the hydrophobic binding domain.

α-Substituierte phosphonate—38: 1-dimethylamino-1-cyano-methanphosphonsäurediethylester, ein neues edukt zur darstellung von carbonsäuren, 1-cyanoenaminen und homoenolaten

Alkylation of 1-dimethylamino-1-cyanomethanephosphonic acid diethyl ester ( 8), easily obtainable from diethyl phosphite and the 0,N-acetal 9, yields 1-alkyl derivatives 14. Elimination of HCN converts 14 into 1-phosphonoenamines 6. Carbonyl compounds react with 8 to give 1-cyanoenamines 15 which may be hydrolyzed to from the homologous carboxylic acid. Alternatively, deprotonation of 15 yields the homoenolate anions 17 which can be alkylated or hydroxyalkylated, permitting chain extension of carbonyl compounds through introduction of an α-carboxyl and a β-alkyl group. Acid catalyzed hydrolysis of 8 results in cleavage of the PC bond, leading to the corresponding α-dimethylamino alkanoic acids. A phosphonic acid 11 can be obtained from 8 by application of the silylester method. An unambigous assignment of E/ Z-isomers of the cyanoenamines 15 has been derived from 13C-NMR spectroscopy.

Structural information from OH stretching frequencies—VII. Preferential OH-rotamers in saturated tertiary alcohols

The presence of preferential OH-rotamers in tertiary alcohols dissolved in CCl 4 has been studied by means of the infrared absorption of the OH-stretching band. It appears that the position of the OH group in these molecules is related to the presence and the orientation of α- and β-alkyl groups. The oxygen lone pairs play a role as well. In some compounds the preferred rotamer proves to be the only one present.