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

Tuning the reactivity of O-tert-butyldimethylsilylimidazolyl aminals towards organolithium reagents

O-tert-Butyldimethylsilylimidazolyl aminals are N,O-acetals that form readily from aldehydes, and although they function as aldehyde stabilizing and protecting groups under various conditions, we report here that they react with organolithium reagents similarly to the parent aldehydes. The mechanism involves the intermediate formation of a 2-imidazolyl anion as is exemplified by the isolation of 2-TBDMS-imidazole. Substitution of the imidazolyl moiety at the 2-position renders these aldehyde derivatives stable to organolithium reagents, thus allowing for the tuning of their reactivity

Tuning the reactivity of O-tert-butyldimethylsilylimidazolyl aminals towards organolithium reagents

O-tert-Butyldimethylsilylimidazolyl aminals are N,O-acetals that form readily from aldehydes, and although they function as aldehyde stabilizing and protecting groups under various conditions, we report here that they react with organolithium reagents similarly to the parent aldehydes. The mechanism involves the intermediate formation of a 2-imidazolyl anion as is exemplified by the isolation of 2-TBDMS-imidazole. Substitution of the imidazolyl moiety at the 2-position renders these aldehyde derivatives stable to organolithium reagents, thus allowing for the tuning of their reactivity

Radical transformations of nucleosides with (Me3Si)3SiH. Generation of a C-1' radical through 1,2-migration of an acyloxy group

A number of nucleoside substrates has been reduced under free radical conditions with tris(trimethylsilyl)silane. In one case a novel type of a $\beta$-(acyloxy)alkyl radical rearrangement has been observed, which leads through the generation of a C-1' radical species to the stereoselective preparation of an $\alpha$-ribonucleoside. The rate of the above 1,2-migration has been estimated, and a comparison with previously reported results has been made