Synthesis of N4-aryl-β-d-glucopyranosylcytosines: a methodology study

A number of leaving groups, including arylsulfonates, triazoles, 3-nitrotriazoles, and tetrazoles, have been studied for the substitution reaction by aryl and alkyl amines at the 4-position of β-d-glucopyranosyluracils. Examination of the stability, ease of purification and reactivity in the substitution reaction led to a number of optimized conditions with the most convenient involving substitution of triazole derivatives under microwave conditions in the presence of silica gel. Under these conditions, a number of N4-aryl-substituted β-d-glucopyranosylcytosines were prepared as potential inhibitors of glycogen phosphorylase, a molecular target for type-2 diabetes mellitus

Tautomerism in the Guanyl Radical

Despite a few decades of intense study, a full description of tautomers of one-electron-oxidized guanine remains to be achieved. Here we show that two of these tautomers are produced by the protonation of an 8-haloguanine electron adduct. The rate constants for the reactions of hydrated electrons (e_(aq)-) with a variety of 8-substituted guanine derivatives have been measured by a pulse radiolysis technique and correlated with both inductive and resonance components of the substituents. The fate of electron adducts was investigated by radiolytic methods coupled with product studies and addressed computationally by means of time-dependent DFT (TD-B3LYP/6-311G**//B1B95/6-31+G**) calculations. The reaction of eaq- with 8-haloguanosine or 8-halo-2‘-deoxyguanosine produces the first observable transient species that decay unimolecularly (k = 1 × 10^5 s^(-1) at 22 °C) to give the one-electron oxidized guanosine or 2‘-deoxyguanosine. Theory suggests that the electron adducts of 8-bromoguanine derivatives protonated at C8 form a π-complex, with the Br atom situated above the molecular plane, that is prompt to eject Br-. The two short-lived intermediates, which show a substantial difference in their absorption spectra, are recognized to be the two purine tautomers (i.e., iminic 7 and aminic 3 forms). The spin density distributions of the two tautomers are quite different at the O6 and N10 positions, whereas they are very similar at the N3, C5, and C8 positions. The resonance structures of the two tautomers are discussed in some detail. B1B95/6-31+G** calculations show also that the tautomerization from the iminic (7) to the aminic (3) arrangement is a water-assisted process

Synthetic studies towards substituted aceanthrenes: Synthesis of 3 -methyl-7-tosyloxy-8-bromoaceanthrene, 11H -benz(bc)aceanthrylene, and 3-methylcholanthrene.

Different synthetic approaches to the synthesis of substituted aceanthrenes and aceanthrylenes have been studied. A novel approach has been developed for the construction of the aceanthrene skeleton by the initial reaction of N,N-diethylarylamides with in situ protected homophthalic anhydrides, featuring a highly regioselective double Friedel-Crafts cyclization reaction. The chemistry of the 6-hydroxy-1(2H)-aceanthrylenones that are produced from the above cyclization, has been studied, and the synthesis of 3-methyl-7-tosyloxy-8-bromoaceanthrene has been completed. This aceanthrene corresponds to the requisite aryne precursor for the employment of the "aryne-furan" methodology to the synthesis of the optically pure active diol epoxide metabolites of 3-MC. The double Friedel-Crafts cyclization method has been successfully applied to the synthesis of the benzannulated analogues of aceanthrene. The syntheses of an environmental contaminant and tumorigen, 11H-benz (bc) aceanthrylene, and a potent carcinogen, 3-methylcholanthrene (14), have been completed in five steps in 28% and 55% overall yields, respectively. In both cases, these new synthetic routes compare favorably with previously reported syntheses in terms of yields and availability of the starting compounds. Moreover, in the 11H-benz(bc) aceanthrylene system, a re-evaluation of the structure of two previously reported intermediates has been conducted, leading to the unequivocal assignment of the structure of one intermediate through single-crystal x-ray crystallography. These results, along with the serendipitous preparation of 4-methoxy-benz(d) indeno(2,1-b) pyran-5(7H)one, provided evidence that, under acidic conditions, cyclization of ortho-(1-(2-alkoxy)indenyl) - or ortho- (1-(2-keto)acenaphthyl) -benzoic acid leads to the corresponding pyranone skeleton. The scope and efficacy of a number of established experimental procedures, such as ortho-lithiation of N,N-diethylarylamides, Friedel-Crafts cyclization in PPA, and activated zinc reduction were augmented. More importantly, the application of a novel double Friedel-Crafts cyclization method towards both aceanthrene and benz (a) aceanthrene systems that contain peripherally fused five-membered rings completed our study and demonstrated the potential of this new methodology.Ph.D.ChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/103592/1/9332069.pdfDescription of 9332069.pdf : Restricted to UM users only

A highly efficient synthesis of 3-methylcholanthrene

A five-step synthesis of 3-methylcholanthrene (1) has been achieved starting from 5-methylhomophthalic anhydride and N,N-diethyl-1-naphthamide in 55% over all yield. Treatment of a solution of the preformed lithium enolate of 5-methylhomophthalic anhydride (3) with an equimolar solution of 2-lithio-1-naphthamide (4), followed by acid hydrolysis, provides cleanly the spirobislactone 5 in 80% overall yield. In addition, the synthesis features a unique, highly selective double Friedel-Crafts cyclization of the aryl diacid 2 with PPA to give rise, after acetylation, to keto acetate 6

exo-N-[2-(4-Azido-2,3,5,6-tetrafluorobenzamido)ethyl]-dC: a novel intermediate in the synthesis of dCTP derivatives for photoaffinity labelling

An alternative route for the synthesis of a photoaffinity labelling (PAL) dCTP derivative is reported. This method involves the intermediacy of exo-N-[2-(4-azido-2,3,5,6-tetrafluorobenzamido)ethyl]-dC. The latter is prepared from the coupling of known N-(2-aminoethyl)-4-azido-2,3,5,6-tetrafluorobenzamide, prepared in an improved three-step sequence, with an activated 4-triazolyl derivative of dU, followed by deprotection. 19F NMR spectroscopy proved extremely useful in following the synthetic transformations, and enabled control of any adventitious reduction of the azides. 2007 Elsevier Ltd. All rights reserved

{Fate of the C-1′ peroxyl radical in the 2′-deoxyuridine system}

The mechanism of 2-deoxyribonolactone formation from the reaction of photogenerated 2′-deoxyuridin-1′-yl radical with molecular oxygen in water has been investigated

Isolation, Characterization, and Independent Synthesis of Guanine Oxidation Products

Oxidatively produced DNA damage is a physiological process that has been associated with many human conditions. Of the four DNA bases, guanine is the most easily oxidized and exhibits a large number of oxidation products. The focus of this Microreview is on the structure of the proposed intermediates and final products of guanine oxidation, as determined by spectroscopic methods and independent synthetic studies. The major and minor primary and secondary oxidative DNA lesions that arise from the oxidation of guanine under a variety of conditions, as well as associated structures, are described and all the relevant information regarding the isolation, characterization, and independent synthesis or generation of these lesions in synthetic oligonucleotides is presented. Finally, information on the biological studies that have been advanced, based on the basic molecular information obtained by the aforementioned studies, is provided. Wiley-VCH Verlag GmbH & Co. KGaA, 2006

{Anionically induced formation of anomeric spironucleosides from 1′-C-cyano-2′-deoxyuridine}

The reaction of the 1'-C-cyano-2'-deoxyuridine derivative 1 with organolithium reagents can be favorably tuned to give a new class of anomeric spironucleosides

Picolinamide Residue-Based Hydrogen-Selective ISEs for the Potentiometric Measurement of Subzero pH Values

The development of new hydrogen selective neutral carriers based on 3-hydroxypicolinic acid derivatives, and its application to pH selective liquid membrane ISE based on these compounds is described. The optimization of the sensor has been based on the use of different plasticizers, additives, and mole ratios of the picolinate derivatives. Based on these results it is shown that the membrane composition can be adjusted for the measurement of pH at very low pH values (down to pH -0.5) and up to at least pH 10. The ability of the presented carriers to measure hydrogen activities up to 3N gives new directions in the use of these sensors for a variety of critical applications