Studies on higher sugars

This thesis describes the synthesis of three novel seven carbon bicyclic mimics of α-L-fucose, and of two new pyrrolidine amino sugars.
2,7-Anhydro- l-deoxy-β-L-gulo-heptulopyranose and l,2,7-trideoxy-2,7-imino-β- L-gulo-heptulopyranose were both synthesised from L-gulono-l,4-lactone. The addition of one equivalent of methyllithium to the diacetonide of L-gulono-1,4- lactone gave a keto-sugar, l-deoxy-3,4;6,7-di-0-isopropylidene-β-L-gulo- heptulofuranose. The anomeric configuration of this compound was determined by equilibrium nOe measurements. Hydrolysis in aqueous trifluoroacetic acid caused simultaneous deprotection, isomerisation and dehydration to yield 2,7-anhydro-l-deoxy-β-L-guloheptulopyranose, a highly stable, rigid bicyclic system. The structure of the bicyclic system was confirmed by X-ray crystallographic studies on a crystalline derivative.
The introduction of nitrogen at C-6 of L-gulono-l,4-lactone was achieved via the azide displacement of the known bromide, 6-bromo-6-deoxy-2,3-0- isopropylidene-L-gulono-l,4-lactone. Protection of the C-5 hydroxyl group as its silyl ether was followed by the addition of one equivalent of methyllithium to the carbonyl group to give a keto-sugar, 7-azido-6-(0-tert-butyldimethylsilyl-l,7- dideoxy-3,4-0-isopropylidene-β-L-gulo-heptulofuranose. Removal of the protecting groups followed by reduction of the azide functionality gave the bicyclic hemiaminal, l,2,7-trideoxy-2,7-imino-β-L-gulo-heptulopyranose, a stable but hygroscopic solid.
A third bicyclic system, 2,7-anhydro-l,2,6-trideoxy-2,6-imino-β-L-gulo- heptulopyranose, was synthesised from diacetone-D-mannose via the known ketosugar, 6-azido-7-0-tert-butyldimethylsilyl-l,6-dideoxy-3,4-0-isopropylidene-β- L-gulo-heptulofuranose. Removal of the protecting groups from this keto-sugar, followed by reduction of the azide functionality, gave the target system. Analysis of the NMR spectra showed that this existed as an equilibrium mixture of the closed, bicyclic hemiaminal form and the monocyclic imine form, with the bicyclic form predominating in all solvents investigated.
The sodium borohydride reduction of l-deoxy-3,4;6,7-di-0-isopropylidene-β-L-gulo-heptulofuranose gave a single product, the heptitol 7-deoxy-l,2;4,5-di-0-isopropylidene- L-glycero-D-gluco-heptitol. This was converted into two novel pyrrolidine amino sugars, l,2,5-trideoxy-2,5-imino-L-glycero-L-allo-heplitol and l,2,5-trideoxy-2,5-imino-L-allitol. The two free hydroxyl groups in the heptitol were converted into leaving groups and one was then displaced selectively with sodium azide. Reduction of the azide functionality gave an amine which cyclised onto the remaining leaving group to form the pyrrolidine framework. Complete deprotection of this product gave l,2,5-trideoxy-2,5-imino-L-glycero-L-allo- heptitol, the structure of which was confirmed by X-ray crystallographic studies on a crystalline derivative. Removal of the primary acetonide from the cyclisation product and subsequent periodate cleavage gave an aldehyde which was then reduced to an alcohol. Deprotection then gave the second pyrrolidine amino sugar l,2,5-trideoxy-2,5-imino-L-allitol.
The effect of all five target compounds on eleven human liver glycosidase enzymes was investigated, and these results are also reported.

Advisor: Fleet, G