Catalytic stereoselective synthesis of 2-deoxyglycosides

• Main Author: Balmond, Edward Iain
• Published: University of Bristol 2014
• Subjects: 547
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.649362

The work described in this thesis deals with the development of catalytic methods for the stereoselective synthesis of 2-deoxyglycosides A thiourea has been successfully demonstrated as an efficient and mild catalyst for glycosylations of various protected galactals with a series of glycoside acceptors to afford 2- deoxy-a-D-galactosides, in yields of 72-98%. Complete a-selectivity was observed in all cases. The high a-selectivity is independent of the glycoside substitution pattern and reactivity profile. The method is tolerant of most common protecting groups and is orthogonal to thioglycosylation type reactions; this has allowed for a one-pot tandem glycosylation reaction to afford a trisaccharide in 58% yield with complete stereocontrol. Details of mechanistic investigations are described. Subjection of glucal substrates to the thiourea-catalysed conditions did not afford the same success, due to significant reactivity differences. Attempts to find a new, more active organocatalyst were also unsuccessful. The use of a cyclic protecting group on glucal substrates was found, under acid catalysis, to afford 2-deoxY-D-glucosides in high yields (81-89%), with high (20:1) to complete astereoselectivity. The 3,4-0-disiloxane cyclic protecting group was shown to work for a wide range of acceptors, which included monosaccharides, amino acids and a natural product. This protecting group was also shown to be successful for the synthesis of 2,6-dideoxY-Lglucosides in high yields (81-95%), with moderate (3.5:1) to good a-selectivity. Details of mechanistic and computational investigations are described. The activation of 2-nitro-o-galactals towards nucleophilic attack by alcohols via thiourea catalysis was found to be possible. Initial studies show that a thiourea bearing two cinchona alkaloid substituents is an effective catalyst; details of reaction optimisation will be described.