Kwok, Wun Sang. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (leaves 147-152). / Abstracts in English and Chinese. / Acknowledgment --- p.i / Table of Contents --- p.ii / Abstract --- p.iii / Abstract (Chinese Version) --- p.iv / Abbreviation --- p.v / Chapter 1. --- Introduction --- p.1 / Chapter 1.1 --- General Background --- p.1 / Chapter 1.1.1 --- "1,3-Dipolar Cycloaddition" --- p.1 / Chapter 1.1.2 --- Structure of Preparation of Nitrile Oxide --- p.3 / Chapter 1.2 --- Intramolecular Nitrile Oxide Alkene Cyclization (INOC) --- p.7 / Chapter 1.2.1 --- INOC in Organic Synthesis --- p.7 / Chapter 1.2.2 --- Formation of Oximolactone as Unwanted Reaction in INOC --- p.10 / Chapter 1.2.3 --- Nitrile Oxide Alkene Cyclization with Free Hydroxyl Group --- p.11 / Chapter 1.3 --- Natural Occurring Gabosine --- p.14 / Chapter 1.3.1 --- "Structure, Biological Effect and Syntheses of Gabosines" --- p.14 / Chapter 1.3.2 --- Synthesis of Gabosine O and its 4-epimer --- p.17 / Chapter 1.4 --- Protected 6-dehydroxy-Pseudo-a-D-Talose --- p.21 / Chapter 1.4.1 --- Structures and Biological Effects of Valienamine and its Derivatives --- p.21 / Chapter 1.4.2 --- Structural and Biological Studies of Valienamine by Our Group --- p.23 / Chapter 2. --- Results and Discussion --- p.28 / Chapter 2.1 --- Studies on INOC of Sugar Derivatives with Free Hydroxyl Group(s) --- p.28 / Chapter 2.2 --- Enantiospecific Synthesis of 4-epi-Gabosine O --- p.47 / Chapter 2.3 --- Enantiospecific Synthesis of Gabosine O --- p.84 / Chapter 2.4 --- Synthesis of 6-Deoxy-Pseudo-a-D-Talose --- p.87 / Chapter 3. --- Conclusion --- p.95 / Chapter 4. --- Experimental --- p.100 / References --- p.147 / Appendix NMR spectra --- p.153

A major problem associated with cellular cryopreservation is the recovery of cellular viability upon thawing. Current cryopreservation techniques use additives such as DMSO, sucrose and fetal bovine serum. However, each have their own respective cytotoxic issues. A significant factor in cryotoxicity is the formation of large ice crystals which can damage cellular components and cause dehydration. This has significant impacts for applications such as food preservation, scientific research, and tissue preservation. To this end, our laboratory is interested in synthesizing biologically-relevant compounds that can act as cryoprotectants by preventing the formation of large ice crystals in sub-zero temperatures. Our lab has previously synthesized structural analogues of native antifreeze glycoproteins (AFGPs, found in the blood of Antarctic cod), that possess the unique ability to inhibit ice-recrystallization. However, the mechanism by which they inhibit ice recrystallization is unclear. This thesis focuses on efforts made to understand this mechanism, and synthesize molecules that are more potent in ice recrystallization inhibition (IRI) activity compared to previously synthesized analogues. By assessing the IRI activity of various mono- and disaccharides, we have shown that the density of water molecules that surround a carbohydrate (Hydration Index) is directly proportional to the ability of sugars to inhibit ice crystal growth. In an effort to design functional AFGP analogues, various C-linked analogues were synthesized that contained different spacer lengths between the carbohydrate and the peptide backbone. Analyses of the solution conformations of these analogues showed that IRI-active AFGP analogues contain a distinct conformation in which the carbohydrate is oriented to form a hydrophobic pocket with the side chain. We hypothesize that this change in glycoconjugate hydration is responsible for disturbing its surrounding waters, thereby preventing water from adding to the ice lattice required for ice growth. Finally, SAR studies showed that threonine-containing AFGP and antifreeze proteins are more potent in antifreeze activity than serine-containing analogues. As the most potent AFGP analogue previously synthesized by our lab contains a C-linked-α-galactosyl -serine residue, we hypothesized that the analogous glycopeptide containing a C-α-galactosyl-threonine residue will be more potent in antifreeze activity. The final section describes efforts to synthesize a C-linked α-galactosyl-threonine glycoconjugate.

Dioxanones (1) are ketal- or acetal protected forms of 1,3-dihydroxyacetone (DHA). The thesis presents the stereoselective aldol transformations of dioxanones and applications to the synthesis of natural and higher carbohydrates listed in Scheme 1.<p> The field of organocatalysis has recently gained much popularity among the chemical research community. In our group, a set of conditions are developed to perform stereoselective aldol reactions on dioxanone substrate. Cs-symmetrical dioxanones have superior diasteroselectivities than C2v-symmetrical dioxanones (de up to 88% from 34%) and presence of mild Lewis acid (LiCl) or Brønsted acid additives (PyPTS) enhance the enantioselectivity into synthetically useful ranges (from 60 up to 96 % ee).<p> The first aldol addition of dioxanone (1) to desired aldehydes (possessing masked carbonyl functionality), followed by reduction of the corresponding aldol adduct and upon unmasking the aldehyde functionality (i.e dithiane or dimethoxy acetal hydrolysis) resulted in furanose (II) and pyranose (III) forms of D-ribose.<p> A new protocol was developed for the synthesis of biologically important deoxyiminosugars such as L-1-deoxymannojirimycin (DMJ, IV), L-1-deoxyidonojirimycin (DIJ, V) and N-isopropyl DIJ (IV) from readily available dioxanone (1) precursor. The key steps include diastereoselective proline-catalyzed syn-aldol transformation and a reductive amination / cyclization.<p> D-glycero-D-manno-2-octulose (VII), a higher-carbon sugar isolated from opium poppies has been synthesized in enantiomerically pure form. The short synthetic sequence involved two proline-catalyzed aldol addition reactions of dioxanone (1) to appropriate aldehydes. Here, we developed a complete dioxanone methodology towards the higher monosaccharide in a stereocontrolled fashion.<p> The enantioselective stereodivergent first total synthesis of DD- and LL-glycero-β-alloheptopyranose (IX, ent-IX) was accomplished from readily available non-chiral starting materials. The short synthetic sequence involves enamine and enolate mediated aldol reactions at α and α' positions of dioxanone (1) hence demonstrated the complementary nature of organocatalysis and organometallic methods.

In dogs, nutrition has been implicated in the development of numerous chronic diseases, including obesity, diabetes and cardiovascular disease. Health claims for dog food are not regulated in Canada, thus many claims do not have a scientific basis. The development of a pet food with proven health benefits is important to pet owners as well as the pet food industry. The purpose of this study was to develop a low glycemic canine diet that will provide health benefits for dogs, namely decreased serum insulin and glucose concentrations, reduced food intake and weight gain, and improved cardiovascular health. To achieve this objective, four studies were performed. These studies examined the acute and longer term health effects of feeding unprocessed as well as extruded carbohydrate sources as both single ingredients and in complete dog diets. In addition, metabolic and cardiovascular health parameters were measured in dogs when they were lean, obese and after weight loss. Post-prandial serum glucose and insulin responses were used to determine glycemic index of the carbohydrate sources and to evaluate glucose tolerance. Flow-mediated dilation, echocardiography and blood pressure were used to assess cardiovascular health. Computed tomography was performed to measure body fat amount and distribution. Leptin, adiponectin and C-reactive protein were also analyzed. The results of these studies found that peas had a lower glycemic index compared to barley and rice, but that after extrusion, the glycemic index of the pea diet was not different than the rice diet. Post-prandial hyperglycemia in dogs was associated with acute changes in endothelial function which may be related to increased methylglyoxal concentrations. However, several negative health effects were observed in dogs after only 12 weeks of obesity and weight loss reversed some, but not all, of these changes. The pea-based diet reduced post-prandial insulin response in obese dogs after 12 weeks on the diet even though no changes were observed in body fat amount or distribution. In conclusion, this research supports the usefulness of peas as an ingredient in canine diets and provides valuable data for the pet food and pulse industries, as well as for veterinarians and pet owners.

Dioxanones (1) are ketal- or acetal protected forms of 1,3-dihydroxyacetone (DHA). The thesis presents the stereoselective aldol transformations of dioxanones and applications to the synthesis of natural and higher carbohydrates listed in Scheme 1.<p> The field of organocatalysis has recently gained much popularity among the chemical research community. In our group, a set of conditions are developed to perform stereoselective aldol reactions on dioxanone substrate. Cs-symmetrical dioxanones have superior diasteroselectivities than C2v-symmetrical dioxanones (de up to 88% from 34%) and presence of mild Lewis acid (LiCl) or Brønsted acid additives (PyPTS) enhance the enantioselectivity into synthetically useful ranges (from 60 up to 96 % ee).<p> The first aldol addition of dioxanone (1) to desired aldehydes (possessing masked carbonyl functionality), followed by reduction of the corresponding aldol adduct and upon unmasking the aldehyde functionality (i.e dithiane or dimethoxy acetal hydrolysis) resulted in furanose (II) and pyranose (III) forms of D-ribose.<p> A new protocol was developed for the synthesis of biologically important deoxyiminosugars such as L-1-deoxymannojirimycin (DMJ, IV), L-1-deoxyidonojirimycin (DIJ, V) and N-isopropyl DIJ (IV) from readily available dioxanone (1) precursor. The key steps include diastereoselective proline-catalyzed syn-aldol transformation and a reductive amination / cyclization.<p> D-glycero-D-manno-2-octulose (VII), a higher-carbon sugar isolated from opium poppies has been synthesized in enantiomerically pure form. The short synthetic sequence involved two proline-catalyzed aldol addition reactions of dioxanone (1) to appropriate aldehydes. Here, we developed a complete dioxanone methodology towards the higher monosaccharide in a stereocontrolled fashion.<p> The enantioselective stereodivergent first total synthesis of DD- and LL-glycero-β-alloheptopyranose (IX, ent-IX) was accomplished from readily available non-chiral starting materials. The short synthetic sequence involves enamine and enolate mediated aldol reactions at α and α' positions of dioxanone (1) hence demonstrated the complementary nature of organocatalysis and organometallic methods.

A major problem associated with cellular cryopreservation is the recovery of cellular viability upon thawing. Current cryopreservation techniques use additives such as DMSO, sucrose and fetal bovine serum. However, each have their own respective cytotoxic issues. A significant factor in cryotoxicity is the formation of large ice crystals which can damage cellular components and cause dehydration. This has significant impacts for applications such as food preservation, scientific research, and tissue preservation. To this end, our laboratory is interested in synthesizing biologically-relevant compounds that can act as cryoprotectants by preventing the formation of large ice crystals in sub-zero temperatures. Our lab has previously synthesized structural analogues of native antifreeze glycoproteins (AFGPs, found in the blood of Antarctic cod), that possess the unique ability to inhibit ice-recrystallization. However, the mechanism by which they inhibit ice recrystallization is unclear. This thesis focuses on efforts made to understand this mechanism, and synthesize molecules that are more potent in ice recrystallization inhibition (IRI) activity compared to previously synthesized analogues. By assessing the IRI activity of various mono- and disaccharides, we have shown that the density of water molecules that surround a carbohydrate (Hydration Index) is directly proportional to the ability of sugars to inhibit ice crystal growth. In an effort to design functional AFGP analogues, various C-linked analogues were synthesized that contained different spacer lengths between the carbohydrate and the peptide backbone. Analyses of the solution conformations of these analogues showed that IRI-active AFGP analogues contain a distinct conformation in which the carbohydrate is oriented to form a hydrophobic pocket with the side chain. We hypothesize that this change in glycoconjugate hydration is responsible for disturbing its surrounding waters, thereby preventing water from adding to the ice lattice required for ice growth. Finally, SAR studies showed that threonine-containing AFGP and antifreeze proteins are more potent in antifreeze activity than serine-containing analogues. As the most potent AFGP analogue previously synthesized by our lab contains a C-linked-α-galactosyl -serine residue, we hypothesized that the analogous glycopeptide containing a C-α-galactosyl-threonine residue will be more potent in antifreeze activity. The final section describes efforts to synthesize a C-linked α-galactosyl-threonine glycoconjugate.

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