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Synthesis of unexpected glucosidase inhibitors and determination of transition states for glucopyranose interconversion

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(Thesis) Ph.D.
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Over the past four decades, the study of glycosidase inhibitors has evolved from being a simple subject of research interest to the generation of molecules with medicinal properties. Besides, glycosidase inhibitors are also widely used as agrochemicals and therapeutic agents. Inspired by the abundance of irreversible inhibitors with cyclopropane rings in nature, we synthesized eight D-glucosides in order to study the active site residues of glucosidases. All compounds were synthesized from á-D-glucose in good yields. While the â-D-glucosides were shown to be good substrates for sweet almond â-glucosidase, we showed that the á-D-glucosides are tight binding but poor substrates for yeast á-D-glucosidase. For example, 1-(4-chlorophenylcyclopropyl)methyl-á-D-glucopyranoside binds with a Kd of 6.7 ìM. The synthesis of â-glucosidase inhibitors, in our second project, was conceptualized on the results obtained from the inhibition of yeast á-glucosidase by cyclopropanated valienamine derivative. Our â-analogue was synthesized from methyl á-D-glucose in 12 steps (4% overall yield). This compound was shown to inhibit almond â-glucosidase, albeit poorly, indicating that á- and â-glucosidases transition state structures are different. Molecules with spirocyclopropyl moieties, are known to be potent glucosidase inhibitors. The third project describes our attempts toward the synthesis of glucosidase inhibitors with spirocyclopropyl moieties. The starting material was methyl á-D-glucopyranoside and after successfully completing the first seven steps of the proposed reaction sequence (Figure 4.12), the project was terminated as an expected radical initiated cyclization reaction could not be effected successfully. The project was therefore not completed, although potential other synthetic routes could lead to the desired target compounds. Our last project was a collaborative initiative with Prof. V. L. Schramm and in this we describe the transition states for the mutarotation of glucose. We measured several kinetic isotope effects while the Schramm laboratories performed ab initio calculations. We showed that the transition state for the spontaneous glucopyranose interconversion most likely involves a single water molecule that act as a general-base catalysis.
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