Abstract
The overall themes of the research described in this PhD thesis includes effects in β-mannosylation (part I) and synthesis of L-sugars by C-H activation (part II).
Part I:
One of the most difficult glycosidic linkage to synthesize is the β-mannosides (Chapter 1). These are tricky to prepare due to enhanced anomeric effect, lack of neighboring group participation, as well as steric effects disfavoring its formation (Chapter 2). The synthesis of β-mannosides was solved by Crich and coworkers who used a 4,6-O-benzylidene procteted thiomannoside donor under preactivation condition. Here, it was claimed that the β-selectivity arose from a SN2-like substitution of a covalently α-triflate or contact ion pair. The effect of the 4,6-O-benzylidene was to shift the equilibrium towards the attached α-triflate due to a torsional disarming stereoelectronic effect of locking the C6-O6 in a tg conformation.
In order to study whether the effect of the 4,6-O-benzylidene was due to a stereoelectronic or conformational effect, a model substrate was prepared (Chapter 3). This compound resembled the 4,6-Obenzylidene donor but lacked the electronegative O6 (exchanged with a methylene). Upon glycosylation with the model compound β-selectivity was observed. Furthermore, glycosyl intermediates, competition experiments, and calculation of oxocarbenium ion geometry was performed in order to compare the similarities between the model substrate and the 4,6-O-benzylidene protected donor. From the selectivity in the glycosylations it was concluded that the β-selectivity arise from a conformational effect induced by the 4,6-O-benzylidene. The stereoelectronic effect of the locked O6 in a tg position was less important.
Part II:
The rare but biologically important L-hexoses (and 6-deoxy-L-sugars) is not accesible from natural sources in large quantaties. Therefore, synthesis of the L-sugars must be prepared chemically in order to study them (Chapter 4).
The synthesis of all eight 6-deoxy-L-hexoses as their thiodonors were achieved and is decribed (Chapter 5). The preparation was based on the only two common 6-deoxy-L-hexoses (L-rhamnose and L-fucose) and performed by various epimerizations. This led to some general rules for inversions either using the Mitsunobu reaction or stereoselective reductions of ketones.
In order to obtain all eight L-hexoses, C-H activation of the corresponding eight 6-deoxy-L-hexoses were studied (Chapter 6). The C-H activation was directed by a 4-OH which was silylated, followed by an intramolecular iridium catalyzed C-H activation. The subsequent Fleming-Tamao oxidation and acetylation afforded the L-sugars. This method was used to synthesize both methyl L-mannosides and L-galactoside but more importantly; all eight L-hexoses as their thiodonors were prepared.
One of the most difficult glycosidic linkage to synthesize is the β-mannosides (Chapter 1). These are tricky to prepare due to enhanced anomeric effect, lack of neighboring group participation, as well as steric effects disfavoring its formation (Chapter 2). The synthesis of β-mannosides was solved by Crich and coworkers who used a 4,6-O-benzylidene procteted thiomannoside donor under preactivation condition. Here, it was claimed that the β-selectivity arose from a SN2-like substitution of a covalently α-triflate or contact ion pair. The effect of the 4,6-O-benzylidene was to shift the equilibrium towards the attached α-triflate due to a torsional disarming stereoelectronic effect of locking the C6-O6 in a tg conformation.
In order to study whether the effect of the 4,6-O-benzylidene was due to a stereoelectronic or conformational effect, a model substrate was prepared (Chapter 3). This compound resembled the 4,6-Obenzylidene donor but lacked the electronegative O6 (exchanged with a methylene). Upon glycosylation with the model compound β-selectivity was observed. Furthermore, glycosyl intermediates, competition experiments, and calculation of oxocarbenium ion geometry was performed in order to compare the similarities between the model substrate and the 4,6-O-benzylidene protected donor. From the selectivity in the glycosylations it was concluded that the β-selectivity arise from a conformational effect induced by the 4,6-O-benzylidene. The stereoelectronic effect of the locked O6 in a tg position was less important.
Part II:
The rare but biologically important L-hexoses (and 6-deoxy-L-sugars) is not accesible from natural sources in large quantaties. Therefore, synthesis of the L-sugars must be prepared chemically in order to study them (Chapter 4).
The synthesis of all eight 6-deoxy-L-hexoses as their thiodonors were achieved and is decribed (Chapter 5). The preparation was based on the only two common 6-deoxy-L-hexoses (L-rhamnose and L-fucose) and performed by various epimerizations. This led to some general rules for inversions either using the Mitsunobu reaction or stereoselective reductions of ketones.
In order to obtain all eight L-hexoses, C-H activation of the corresponding eight 6-deoxy-L-hexoses were studied (Chapter 6). The C-H activation was directed by a 4-OH which was silylated, followed by an intramolecular iridium catalyzed C-H activation. The subsequent Fleming-Tamao oxidation and acetylation afforded the L-sugars. This method was used to synthesize both methyl L-mannosides and L-galactoside but more importantly; all eight L-hexoses as their thiodonors were prepared.
| Originalsprog | Engelsk |
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| Forlag | Department of Chemistry, Faculty of Science, University of Copenhagen |
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| Antal sider | 218 |
| ISBN (Trykt) | 978-87-91963-39-1 |
| Status | Udgivet - 2014 |