Title:
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Synthesis and Exploitation of Branched Sugars and Sugar Amino Acids
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This thesis describes the synthesis of 2-C-branched carbohydrate derivatives from ketohexoses and
some useful synthetic applications thereof.
Chapter 1 encompasses a general introduction to branched-chain sugars, with the emphasis upon 2C-
hydroxymethyl and -methyl branched sugars. Strategies for their synthesis are discussed, both
from nucleophilic and electrophilic carbohydrate derivatives. Some synthetic applications of
carbohydrates and consequently branched carbohydrates are highlighted, with a view to the
derivatisation of a proposed chiron from the Kiliani ascension of L-sorbose, 2-C-hydroxymethyl2,3:
5,6-di-O-isopropylidene-L-gulono,1,4-lactone. In chapter 2, the Kiliani ascension of L-sorbose
and two subsequent complementary di-O-isopropylidene protections of the branched-chain lactones
generated (thermodynamic and kinetic) are discussed. Further studies into the same transformations
of three other ketohexoses, D-fructose, D-tagatose and D-psicose are then discussed. Further useful
synthetic derivatives of the three major isomeric L-sorbose-derived branched di-protected lactones:
selective deprotections and cleavage of C5-C6 bonds.
One major area wh!ch utilizes carbohydrate building blocks is iminosugar synthesis. Iminosugars
are the major compound class of interest in the realm of glycosidase inhibition, and also have other
therapeutic properties, thus making them desirable synthetic targets. The application of 2-C-
. branched sugar derivatives in the synthesis of novel iminosugars is proposed. Chapter 4 describes
the syntheses of eight novel 2-C- hydroxymethyl and -methyl branched iminosugars from the major
thermodynamic product (2-C-hydroxymethyl-2,3 :5,6-di-O-isopropylidene-L-gulono-l ,4-lactone)
obtained from the Kiliani ascension of L-sorbose, as described in chapter 2. The syntheses of two
additional novel iminosugars from isomeric 2,3:5,6-di-O-isopropylidene branched derivatives is
described. Some results of inhibitory activity follow the synthetic results.
The last two chapters provide a general introduction to macrocycles, and some synthetic
investigations into macrocycles based on open-chain sugar amino acids (SAAs). SAA-derived
macrocycles are structural hybrids of macrocyclic peptides and cyclodextrins. Strategies for the
synthesis of large rings and previous work on D-galactose-derived-SAA macrocycles within the
group is described with a view to the extension of this work towards novel asymmetric macrocycles
with functionalisable rings. Chapter 6 reports synthetic investigations into three related families of
macrocycles, each based on an open-chain galacto SAA. The pure galacto SAA macrocycles are
revisited and two novel families of macrocycles are born, one containing proteinogenic amino acids
and the other incorporating branched-chain SAAs. The branched-chain SAA itself is derived from
2-C-hydroxymethyl-2,3 :5,6-di-O-isopropylidene-D-mannono-l ,4-lactone, the major protected
Kiliani lactone derived from D-fructose. Two major improvements to the original methodology for
macrocycle formation are reported. Some structural analysis of macrocylic compounds through
NMR and CD spectroscopy.
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