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A study of the substituent effects of protecting groups in hydroxypiperidines was carried out and compared with the electronic effects in glycosylation chemistry. 1-Deoxynojirimycin, the aza-sugar analogue of 1-deoxy-D-glucose, was used as a carbohydrate model, and protected with the most common carbohydrate protecting groups. The different stabilization of positive charge on the ring heteroatom was determined by pK(a) measurements. The protecting groups could be ranked in the following way after their destabilization of the piperidinium ion: benzoyl ≥ acetyl ≫ 4,6-O-benzylidine >benzyl ≈ methyl > H > 3,6-anhydro > tert-butyldimethylsilyl. The observed effects of having protecting groups with different electronic characteristics were found to be in agreement with the "armed-disarmed" concept. Comparison of the pK(a) of benzylated and benzoylated epimers of 3-hydroxy-6-hydroxymethyl piperidines showed increased stabilization of the piperidinium ion in the axial epimer. The difference between axial and equatorial epimers was larger in the benzylated than in the benzoylated piperidines.

An investigation was carried out on the influence of the stereochemistry of substituents, particularly hydroxyl groups, on their electronic effects in piperidines, carbohydrates (pyranosides), and related compounds. Polar groups, such as OH, OR, and F, were found in the 3 and 4 position to be much more electron-withdrawing when positioned equatorially rather than axially. In contrast, little difference in electronic effects was observed from apolar groups as a result of epimerization. These observations were believed to be caused by differences in charge-dipole interactions and were used to explain why stereoisomeric glycosides hydrolyze with different rates. The conformational changes of hydroxylated piperidines and related compounds as a function of pH were likewise explained from the different substituent effects of axial and equatorial OH groups.

The synthesis of isofagomine lactams (2-oxoisofagomines) corresponding to the biologically important hexoses is presented. The D-glucose/D-mannose analogue (3S,4R,5R)-3,4-dihydroxy-5-hydroxymethylpiperidin-2-one (9) was synthesised in 9 steps from D-arabinose, the D-galactose analogue (3S,4S,5R)-3,4-dihydroxy-5-hydroxymethylpiperidin-2-one (10) was synthesised in 11 steps from D-arabinose and the L-fucose analogue (3R,4R,5R)-3,4-dihydroxy-5-methylpiperidin-2-one (11) was synthesised in 12 steps from L-arabinose. The three lactams 9-11 were found to be glycosidase inhibitors with micro- to nanomolar inhibition constants. The lactam 10 showed slow onset inhibition of beta-galactosidase from A. Oryzae. The rate constants for this process were determined to be k(on) = 2.55 x 10(4) M-1 s-1 and k(off) = 1.7 x 10(-3) s-1. The activation energies and standard thermodynamic functions were also determined.

Starting from D-arabinose the synthesis of the very strong glycosidase inhibitors isofagomine (2) and noeuromycin (3) was achieved in six and seven steps, respectively. Keystep in the reaction sequence is the application of an efficient C-4 oxidation method to benzyl alpha-D-arabino-pyranoside. Subsequent Henry reaction of the obtained aldoketose with nitromethane provided the required branched carbohydrate precursors, which gave access to 2 and 3 in 17-21% overall yield.

A new chemoenzymatic synthesis of optically pure isogalactofagomine 2 starting from achiral starting materials is presented. Dimethyl 4-hydroxypyridine-3,5-dicarboxylate (7) was synthesized and converted to the corresponding saturated piperidine 8. Then the key step of the synthesis was carried out: Lipase M catalyzed hydrolysis of the prochiral diester 8 to cause formation of an asymmetric monoacid with at least 98% enantiomeric excess. Reduction of the acid, saponification of the remaining ester, and radical iododecarboxylation gave an iodide that after substitution with silver trifluoroacetate and hydrolysis gave 2.

A pseudo-aza-monosaccharide and several pseudo-aza-disaccharide compounds were constructed based on replacement of the anomeric carbon with a nitrogen and the ring oxygen with a carbon. The inhibition constants of these compounds toward five different glycosidases, alpha-glucosidase, beta-glucosidase, isomaltase, alpha-mannosidase, and glucoamylase, were obtained. Isofagomine, the pseudo-aza-monosaccharide, shows a broad spectrum of strong inhibition against glycosidases. It is the most potent inhibitor of beta-glucosidase from sweet almonds reported to date and also a strong inhibitor of glucoamylase, isomaltase, and alpha-glucosidase. Isofagomine inhibits beta-glucosidase, glucoamylase, and isomaltase more strongly than 1-deoxynojirimycin where the ring oxygen has been replaced with a nitrogen. The alpha-1,6- linked pseudo-disaccharide showed very strong inhibition toward glucoamylase, being nearly as potent an inhibitor as acarbose. Pseudo-disaccharides in which the anomeric nitrogen was methylated to favor formation of either the alpha or beta substrate linkage generally had weakened inhibition for the glycosidases studied most likely due to steric interference with the various active sites. These results indicate that the presence of a basic group at the anomeric center is important for carbohydrase inhibition. The presence of a charged carboxylate group near the anomeric carbon which interacts with the basic nitrogen is suggested for these enzymes, particularly for beta-glucosidase. The presence of a second alpha-linked glucosyl residue is also critical for strong inhibition of glucoamylase.