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

Synthesis of N-Glucopyranosidic Derivatives as Potential Inhibitors that Bind at the Catalytic Site of Glycogen Phosphorylase

Glycogen phosphorylase (GP) is a promising molecular target for the treatment of Type 2 diabetes. The design of potential inhibitors for the catalytic site of the enzyme is based on the high affinity for $\beta$-D-glucopyranose and the presence of a $\beta$-cavity that extends from the sugar anomeric position forming a 15 × 7.5 × 10 {\AA} available space. This review is focused on our efforts towards the design and synthesis of various families of potential inhibitors, including N-$\beta$-Dglucopyranosyl oxamic acid esters and oxamides, N-$\beta$-D-glucopyranosylaminocarbonyl L-aminoacids and peptides, as well as glucose-derived purine and pyrimidine nucleosides, spiro- and other bicyclic derivatives. Kinetic and crystallographic study of the interactions of these inhibitors with GP has increased our understanding of the importance of the various functional groups within the catalytic site and has pointed the way towards the in silico prediction and design of potent inhibitors, which are both synthetically viable and pharmacologically relevant. {\textcopyright} 2010 Bentham Science Publishers Ltd

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