Tesis:

1

Hunter, Stuart James. "Synthesis and Exploitation of Branched Sugars and Sugar Amino Acids". Thesis, University of Oxford, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.491619.

Texto completo

Resumen

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.