Abstract
The overall objective of the research presented in this PhD thesis was to investigate torsional arming of thiogalacto- and thiomannosyl donors (part 1) and to investigate the possible synthesis and attachment of a pH regulated conformational switch to an α-cyclodextrin (part 2).
Part 1:
It is well established that glycoside donors containing axial polar substituents are more reactive in glycosylations than their equatorial counterpart (Chapter 1). This is due to the higher degree of oxocarbenium ion stabilization exerted by the axial substituents. Therefore, the reactivity of a glycoside donor can be controlled by manipulating the stereochemistry. There are many examples of conformational arming, where an
equatorial rich donor is forced towards its more axial rich conformation resulting in a significant increase in reactivity.
In order to study this conformational arming further, attempts at synthesizing “super-armed” thiogalactosyl and thiomannosyl donors were carried out (Chapter 2). This resulted in three model substrates of the manno stereochemistry where one was torsionally “super-armed”. These three donors were synthesized by the introduction of a cis-decaline system at O2 and O3 containing a phenyl group that controls the
conformation due to its equatorial preference. The three thiomannosyl donors were investigated in terms of
reactivity and selectivity in glycosylations. As with previous reported examples, the more axial rich donor
displayed the highest reactivity. Low selectivity was observed in apolar solvents, and was reasoned to be
caused by the high reactivity.
Part 2:
Azasugars are biologically important compounds. They have mainly been studied for their ability to
mimic the enzyme-substrate transition state giving them glycosidase inhibition properties. Some studies have
also demonstrated their ability to change conformation under different conditions. These conformational
changes are connected to various intramolecular interactions and can to some extent, be controlled by pH
(Chapter 3). Fusing these conformationally labile compounds to the rim of a cyclodextrin would create
compounds that could release molecules at a specified change in pH conditions.
To investigate this, four hexahydropyridazines were synthesized and investigated for their pH induced
conformational change (Chapter 4). Out of the four compounds, one revealed to flip between two
conformations depending on pH. A relationship between conformation and pKa was established by showing
that the pKa directly reflects the conformational equilibrium of conformers. Unfortunately, attaching the
hexahydropyridazine to the secondary rim of an α-cyclodextrine was not achieved.
Chapter 5 describes the attempted synthesis of seven-membered azasugars as potential new glycosidase inhibitors. It also describes the successful synthesis of 1-deoxynojirimycin derivatives, containing a Abstract (English)
The overall objective of the research presented in this PhD thesis was to investigate torsional arming of
thiogalacto- and thiomannosyl donors (part 1) and to investigate the possible synthesis and attachment of a pH
regulated conformational switch to an α-cyclodextrin (part 2).
Part 1:
It is well established that glycoside donors containing axial polar substituents are more reactive in
glycosylations than their equatorial counterpart (Chapter 1). This is due to the higher degree of oxocarbenium
ion stabilization exerted by the axial substituents. Therefore, the reactivity of a glycoside donor can be
controlled by manipulating the stereochemistry. There are many examples of conformational arming, where an
equatorial rich donor is forced towards its more axial rich conformation resulting in a significant increase in
reactivity.
In order to study this conformational arming further, attempts at synthesizing “super-armed”
thiogalactosyl and thiomannosyl donors were carried out (Chapter 2). This resulted in three model substrates
of the manno stereochemistry where one was torsionally “super-armed”. These three donors were synthesized
by the introduction of a cis-decaline system at O2 and O3 containing a phenyl group that controls the
conformation due to its equatorial preference. The three thiomannosyl donors were investigated in terms of
reactivity and selectivity in glycosylations. As with previous reported examples, the more axial rich donor
displayed the highest reactivity. Low selectivity was observed in apolar solvents, and was reasoned to be
caused by the high reactivity.
Part 2:
Azasugars are biologically important compounds. They have mainly been studied for their ability to
mimic the enzyme-substrate transition state giving them glycosidase inhibition properties. Some studies have
also demonstrated their ability to change conformation under different conditions. These conformational
changes are connected to various intramolecular interactions and can to some extent, be controlled by pH
(Chapter 3). Fusing these conformationally labile compounds to the rim of a cyclodextrin would create
compounds that could release molecules at a specified change in pH conditions.
To investigate this, four hexahydropyridazines were synthesized and investigated for their pH induced
conformational change (Chapter 4). Out of the four compounds, one revealed to flip between two
conformations depending on pH. A relationship between conformation and pKa was established by showing
that the pKa directly reflects the conformational equilibrium of conformers. Unfortunately, attaching the
hexahydropyridazine to the secondary rim of an α-cyclodextrine was not achieved.
Chapter 5 describes the attempted synthesis of seven-membered azasugars as potential new
glycosidase inhibitors. It also describes the successful synthesis of 1-deoxynojirimycin derivatives, containing a
selenourea functionality selenourea functionality
Part 1:
It is well established that glycoside donors containing axial polar substituents are more reactive in glycosylations than their equatorial counterpart (Chapter 1). This is due to the higher degree of oxocarbenium ion stabilization exerted by the axial substituents. Therefore, the reactivity of a glycoside donor can be controlled by manipulating the stereochemistry. There are many examples of conformational arming, where an
equatorial rich donor is forced towards its more axial rich conformation resulting in a significant increase in reactivity.
In order to study this conformational arming further, attempts at synthesizing “super-armed” thiogalactosyl and thiomannosyl donors were carried out (Chapter 2). This resulted in three model substrates of the manno stereochemistry where one was torsionally “super-armed”. These three donors were synthesized by the introduction of a cis-decaline system at O2 and O3 containing a phenyl group that controls the
conformation due to its equatorial preference. The three thiomannosyl donors were investigated in terms of
reactivity and selectivity in glycosylations. As with previous reported examples, the more axial rich donor
displayed the highest reactivity. Low selectivity was observed in apolar solvents, and was reasoned to be
caused by the high reactivity.
Part 2:
Azasugars are biologically important compounds. They have mainly been studied for their ability to
mimic the enzyme-substrate transition state giving them glycosidase inhibition properties. Some studies have
also demonstrated their ability to change conformation under different conditions. These conformational
changes are connected to various intramolecular interactions and can to some extent, be controlled by pH
(Chapter 3). Fusing these conformationally labile compounds to the rim of a cyclodextrin would create
compounds that could release molecules at a specified change in pH conditions.
To investigate this, four hexahydropyridazines were synthesized and investigated for their pH induced
conformational change (Chapter 4). Out of the four compounds, one revealed to flip between two
conformations depending on pH. A relationship between conformation and pKa was established by showing
that the pKa directly reflects the conformational equilibrium of conformers. Unfortunately, attaching the
hexahydropyridazine to the secondary rim of an α-cyclodextrine was not achieved.
Chapter 5 describes the attempted synthesis of seven-membered azasugars as potential new glycosidase inhibitors. It also describes the successful synthesis of 1-deoxynojirimycin derivatives, containing a Abstract (English)
The overall objective of the research presented in this PhD thesis was to investigate torsional arming of
thiogalacto- and thiomannosyl donors (part 1) and to investigate the possible synthesis and attachment of a pH
regulated conformational switch to an α-cyclodextrin (part 2).
Part 1:
It is well established that glycoside donors containing axial polar substituents are more reactive in
glycosylations than their equatorial counterpart (Chapter 1). This is due to the higher degree of oxocarbenium
ion stabilization exerted by the axial substituents. Therefore, the reactivity of a glycoside donor can be
controlled by manipulating the stereochemistry. There are many examples of conformational arming, where an
equatorial rich donor is forced towards its more axial rich conformation resulting in a significant increase in
reactivity.
In order to study this conformational arming further, attempts at synthesizing “super-armed”
thiogalactosyl and thiomannosyl donors were carried out (Chapter 2). This resulted in three model substrates
of the manno stereochemistry where one was torsionally “super-armed”. These three donors were synthesized
by the introduction of a cis-decaline system at O2 and O3 containing a phenyl group that controls the
conformation due to its equatorial preference. The three thiomannosyl donors were investigated in terms of
reactivity and selectivity in glycosylations. As with previous reported examples, the more axial rich donor
displayed the highest reactivity. Low selectivity was observed in apolar solvents, and was reasoned to be
caused by the high reactivity.
Part 2:
Azasugars are biologically important compounds. They have mainly been studied for their ability to
mimic the enzyme-substrate transition state giving them glycosidase inhibition properties. Some studies have
also demonstrated their ability to change conformation under different conditions. These conformational
changes are connected to various intramolecular interactions and can to some extent, be controlled by pH
(Chapter 3). Fusing these conformationally labile compounds to the rim of a cyclodextrin would create
compounds that could release molecules at a specified change in pH conditions.
To investigate this, four hexahydropyridazines were synthesized and investigated for their pH induced
conformational change (Chapter 4). Out of the four compounds, one revealed to flip between two
conformations depending on pH. A relationship between conformation and pKa was established by showing
that the pKa directly reflects the conformational equilibrium of conformers. Unfortunately, attaching the
hexahydropyridazine to the secondary rim of an α-cyclodextrine was not achieved.
Chapter 5 describes the attempted synthesis of seven-membered azasugars as potential new
glycosidase inhibitors. It also describes the successful synthesis of 1-deoxynojirimycin derivatives, containing a
selenourea functionality selenourea functionality
| Original language | English |
|---|
| Publisher | Department of Chemistry, Faculty of Science, University of Copenhagen |
|---|---|
| Number of pages | 142 |
| Publication status | Published - 2015 |