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Title: Rare monosaccharides and biologically active iminosugars from carbohydrate chirons
Author: Best, Daniel
ISNI:       0000 0004 2710 9102
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2011
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Iminosugars are polyhydroxylated alkaloids, and can be viewed as sugar analogues in which the endocyclic oxygen atom has been replaced with nitrogen. These compounds are highly medically relevant and their biological activity is largely due to their inhibition of glycosidases. Several examples of the iminosugar class are currently marketed as drugs, and many more are in earlier stages of development for a variety of diseases and disorders. The most fruitful approaches to the chemical synthesis of iminosugars have utilised carbohydrate starting materials as optically pure chiral building blocks, or chirons. Most of the monosaccharides are not readily available, but the relatively few naturally abundant cheap sugars have been exploited as chirons for over a century. The availability of the rare sugars is growing with the development of a new biotechnological approach to their synthesis, known as Izumoring. This thesis is primarily concerned with the chemical synthesis of iminosugars from carbohydrate starting materials. The synthesis of unnaturally functionalised sugar polyols and their suitability as substrates for the Izumoring process is also discussed. Chapter 1 provides a brief general overview of the history, natural occurrence and therapeutic application of iminosugars. General strategies for their synthesis from carbohydrate chirons are discussed. Chapter 2 concerns divergent syntheses of several iminosugar targets from both enantiomers of glucuronolactone and their biological evaluation. A new scaleable synthesis of the natural product 1-deoxynojirimycin is presented that has since been adopted for commercial purposes, as well as an efficient strategy for the synthesis of both enantiomers of 2,5-dideoxy-2,5-imino- mannitol and their novel amino acid analogues. Access to hexosaminidase inhibiting acetamido- substituted piperidines is presented, including 2-acetamido-1,5-imino-1,2,5-trideoxy-D- galactitol, which has been found to be one of the few known potent and specific inhibitors of α- N-acetyl-galactosaminidase. This inhibitory profile may allow the compound’s use for further investigation of a strategy for cancer treatment. Chapter 3 concerns the synthesis of carbon branched pyrrolidines and their biological evaluation. A novel and highly potent α-glycosidase inhibitor has been discovered, synthesised by a strategy that utilises the benzhydryl ether as key protecting group. A mild method for the introduction of this protecting group has been shown to be general to a range of sterically congested and/or acid/base sensitive carbohydrate lactones. Chapter 4 concerns the synthesis of deoxygenated and fluorinated sugar alcohols and their successful biotechnological transformation into ketoses by the Izumoring process. Publications arising from this work are included in the Appendix.
Supervisor: Fleet, George W. J. Sponsor: Summit plc
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Organic chemistry ; Organic synthesis ; Synthetic organic chemistry ; Iminosugar ; carbohydrate ; monosaccharide ; glycosidase inhibitor ; Izumoring ; hexosaminidase inhibitor