Radical-based alkylation of guanine derivatives in aqueous medium

The radical-based alkylation of 8-bromoguanosine (1a) and 8-bromo-2'-deoxyguanosine (1b) at the C8 position has been investigated in aqueous solutions. Alkyl radicals were generated by scavenging of the primary species of γ-radiolysis by the alcohol substrate. These reactions result in the efficient formation of intermolecular C-C bonds in aqueous media, by using the reactivity of α-hydroxyalkyl radicals derived from alcohols with 1a and 1b. A mechanism for the formation of C8 guanine alkylated adducts has been proposed, based on the quantification of radiation chemical yields for the disappearance of starting material and the formation of all products. Two α-hydroxyalkyl radicals are needed to form an alkylated guanine, the first one adding to C8 followed by ejection of Br(-) with formation of guanyl adduct and the second one acting as reducing agent of the guanyl adduct.     

The mechanism of guanine alkylation by nitrogen mustards: a computational study

The thermodynamics and kinetics for the monofunctional binding of nitrogen mustard class of anticancer drugs to purine bases of DNA were studied computationally using guanine and adenine as model substrates. Mechlorethamine and melphalan are used as model systems in order to better understand the difference in antitumor activity of aliphatic and aromatic mustards, respectively. In good agreement with experiments that suggested the accumulation of a reactive intermediate in the case of mechlorethamine, our model predicts a significant preference for the formation of corresponding aziridinium ion for mechlorethamine, while the formation of the aziridinium ion is not computed to be preferred when melphalan is used. Two effects are found that contribute to this difference. First, the ground state of the drug shows a highly delocalized lone pair on the amine nitrogen of the melphalan, which makes the subsequent cyclization more difficult. Second, because of the aromatic substituent connected to the amine nitrogen of melphalan, a large energy penalty has to be paid for solvation. A detailed study of energy profiles for the two-step mechanism for alkylation of guanine and adenine was performed. Alkylation of guanine is ～6 kcal mol(-1) preferred over adenine, and the factors contributing to this preference were explained in our previous study of cisplatin binding to purine bases. A detailed analysis of energy profiles of mechlorethamine and melphalan binding to guanine and adenine are presented to provide an insight into rate limiting step and the difference in reactivity and stability of the intermediate in both nitrogen mustards, respectively.     

Regioselective alkylation of guanine derivatives in the synthesis of peptide nucleic acid monomers

A method for the synthesis of 6-O-benzyl- and 6-O-benzyl-2-N-benzyloxycarbonyl-protected guanine derivatives starting from 2-amino-6-chloropurin is described. A regioselective alkylation of these N(9)-protected guanine derivatives gave the corresponding α-monomers of chiral peptide nucleic acids, the L-glutamic acid derivatives. It was shown that these compound do not inhibit (in the concentrations <20 µmol L^–1) the topoisomerase I activity.     

Study on the alkylation reaction of guanine and N-acetylguanine and the synthesis of 1''''-C alkylated carba-DHPG analogues

The alkylation reaction of guanine and N-acetylguanine with model compounds such as isopropyl bromide or 4-heptyl tosylate were studied. The reaction conditions such as temperature, solvent, base, and catalyst were examined for their effects on the reaction rate, and the yield and regioselectivity of the coupling reaction. The highest yield was obtained by using DMSO as the solvent. The reaction proceeded in a homogenous manner to give higher yield of 9-N and 7-N substituted product in a mole ratio of 1:1. The ratio could be raised to 2:1 if dibenzo-18-crown-6 was used as a catalyst. Using the above procedure, three carba-DHPG analogues bearing different 1'-C alkyl side chains were synthesized.     

Synthesis of monomers containing guanine or guanine precursors as substituent groups

The synthesis of four new monomers containing guanine or a guanine precursor was achieved. These were two isomeric acid ester derivatives of guanine and two isomeric vinyl ether derivatives of N²-acetylguanine. In the case of the synthesis of the guanine acid esters IV and V, it was necessary to prepare first the guanine alcohol derivatives II and III. These N-7 and N-9 isomeric alcohols of guanine were separated by fractional crystallization. Subsequent esterification of these alcohols with maleic anhydride gave the desired products. In the other case, N²-acetylguanine was alkylated with 2-chloroethyl vinyl ether to yield the N-7 and N-9 isomer VI and VII, respectively. These were separated using flash column chromatography.     

Catalytic alkylation of tetralin

Summary In the catalytic alkylation of tetralin with C₈-C₉, C₁₀-C₁₁, and C₁₂ alkene fractions from the cracking of paraffins. 6-isooctyltetralins, 6-isodecyl-, and 6-isoundecyltetralins, and 6-isododecyltetralins were obtained in yields of 52.0%, 80.0%, and 59.1%, respectively, based on the amounts of alkenes contained in the original fractions.     

Regioselective alkylation of hydroxysalicylaldehydes

Schiff-base ligands are often used as backbone ligands for mono- and dinuclear complexes that serve as catalysts during aerobic oxidation reactions. However, their water solubility is low and limits their applicability as catalysts to transform highly water-soluble biomolecules, such as carbohydrates or amino alcohols. A new method to regioselectively incorporate water solubility-promoting polyethylene glycol side chains into a frequently used aldehyde building block of Schiff-base ligands has been developed.     

High-pressure alkylation of azomethines

Reaction of anils with alkyl halides under high pressure (10 kbar) was studied. Alkylation in polar media (dioxane or acetonitrile) followed by hydrolysis yields pureN-monoalkylamines in high yields. Optimum conditions for high-pressure alkylation were found.     

Electrophilic alkylation of fluoroolefins

Conclusions The electrophilic alkylation of fluoro-containing ethylenes by tert-butyl chloride and adamantane was accomplished.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 6, pp. 1433–1434, June, 1978.The authors express their gratitude to P. V. Petrovskii for taking and interpreting the¹³C NMR spectra of (VIII).     

Reductive alkylation of lipase

Candida rugosa lipase was modified via reductive alkylation to increase its hydrophobicity to work better in organic solvents. The free amino group of lysines was alkylated using propionaldehyde with different degrees of modification obtained (49 and 86%). Far-ultraviolet circular dichroism (CD) spectroscopy of the lipase in aqueous solvent showed that such chemical modifications at the enzyme surface caused a loss in secondary and tertiary structure that is attributed to the enzyme unfolding. Using molecular modeling, we propose that in an aqueous environment the loss in protein structure of the modified lipase is owing to disruption of stabilizing salt bridges, particularly of surface lysines. Indeed, molecular modeling and simulation of a salt bridge formed by Lys-75 to Asp-79, in a nonpolar environment, suggests the adoption of a more flexible alkylated lysine that may explain higher lipase activity in organic solvents on alkylation.     

Catalytic alkylation of benzofurans

The alkylation of benzofuran with tert-butyl chloride in various solvents with a zinc chloride catalyst was studied. It was found that the alkylation proceeds primarily at the 3-position. The ratio of the 2- and 3-tert-butylbenzofurans is 12 regardless of the nature of the solvent.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 156–159, February, 1971.     

Site-specific alkylation of tetra-alkylpyrroles

Intramolecular cyclisation of the trifluoromethanesulphonate esters of the β-(4-hydroxy-n-butyl)-pyrroles (5a) and (5b) in each case yields a mixture of the α- and β-alkylated products whereas exclusive β-alkylation is observed for the β-(5-hydroxy-n-pentyl)-pyrrole (5c).     

Asymmetric alkylation of N-pivaloyl-o-benzylaniline

Alkylation of 2-methoxyethoxyphenyl phenylmethane using sec-BuLi and (−)-sparteine has been carried out in excellent yields and up to 76% ee. The use of O’Brien’s (+)-sparteine surrogate gave the opposite sense of asymmetric induction at 80% ee while the use of chiral lithium amide bases gave modest yields and ees.