Christian W. Ekhart

Two isosteric fluorinated derivatives of the powerful glucosidase inhibitors, 1-deoxynojirimycin and 2,5-dideoxy-2,5-imino-d-mannitol: Syntheses and glucosidase-inhibitory activities of 1,2,5-trideoxy-2-fluoro-1,5-imino-d-glucitol and of 1,2,5-trideoxy-1-fluoro-2,5-imino-d-mannitol

Abstract 1,2,5-Trideoxy-2-fluoro-1,5-imino- d -glucitol, the 2-deoxyfluoro derivative of 1-deoxynojirimycin, as well as 1,2,5-trideoxy-1-fluoro-2,5-imino- d -mannitol and 2,5-dideoxy-2,5-imino-1- O -methyl-d-mannitol, two new analogues of the natural product and powerful glucosidase inhibitor 2,5-dideoxy-2,5-imino- d -mannitol, were synthesised featuring glucose isomerase-catalysed aldose-ketose interconversion reactions as the key steps of the syntheses. Results of inhibition studies conducted with these compounds and previously obtained deoxyfluoro derivatives of 1-deoxynojirimycin, employing glucosidases from various sources, showed that the replacement of a hydroxyl function by fluorine caused an impairment of the inhibitory potency. This effect was smallest for the hydroxyl group at C-6 up to four orders of magnitude larger for replacements at C-2 and C-3. Title compounds were synthesized by chemical and chemo-enzymatic routes.

Syntheses of sugar-related trihydroxyazepanes from simple carbohydrates and their activities as reversible glycosidase inhibitors.

Five diastereomeric trideoxy-1,6-iminohexitols were synthesised, and their inhibitory activities were determined against selected glycosidases. For comparison, 1,4,5-trideoxy-1,5-imino-D-lyxo-hexitol, the 4-deoxy derivative of 1-deoxymannojirimicin, was prepared by enzymatic isomerisation of 6-azido-3,6-dideoxy-D-ribo-hexose into the corresponding 2-ulose and subsequent hydrogenation accompanied by intramolecular reductive amination.

2,5-dideoxy-2,5-imino-d-mannitol and -d-glucitol. Two-step bio-organic syntheses from 5-azido-5-deoxy-d-glucofuranose and -l-idofuranose; evaluation as glucosidase inhibitors and application in affinity purification and characterisation of invertase from yeast

Abstract Glucose isomerase (EC 5.3.1.5) catalyzes the quantitative isomerisation of 5-azido-5-deoxy- d -gluco- ( 7 and - l -idofuranose ( 9 ), respectively, into the corresponding ketoses, 5-azido-5-deoxy- d -fructo-pyranose ( 8 ) and - l -sorbopyranose ( 10 ), respectively. Upon catalytic hydrogenation over palladium-on-charcoal, the fructose derivative 8 gives the natural product and the efficient glycosidase inhibitor 2,5-dideoxy-2,5-imino- d -mannitol ( 4 ), while the sorbose derivative 10 affords 2,5-dideoxy-2,5-imino- d -glucitol ( 5 ). This represents a preparatively very simple and efficient two-step synthesis of these biologically active compounds. Both are strong inhibitors of α- and β-glucosidases from various sources, the d - manno -isomer 4 being distinctly more active. Because of its structural relationship with β- d -fructofuranose, compound 4 is also a very good inhibitor of invertase from yeast and, as such, was for the first time employed, after immobilization on aminohexyl-sepharose, for the purification of this enzyme.

Glucose isomerase (EC 5.3.1.5) as a reagent in carbohydrate synthesis: success and failures with the isomerisation of non-natural derivatives of d-

Abstract The properties of glucose isomerase (EC 5.3.1.5) and its synthetic applications are briefly reviewed and recent results with non-natural substrates are discussed. Commercially available immobilized glucose isomerase from Streptomyces murinus, previously discovered to accept d -glucose as well as d -fructose derivatives with modifications at C-3, C-5, and C-6, was also found to be an efficient catalyst for the conversion of 5,6-dimodified derivatives of d -glucose as well as 5-modified d -xylofuranose into the corresponding open-chain 2-ketoses. The equilibrium mixture in all but one case investigated favoured the respective ketose in ratios of 3:1 to 4:1. These results are in agreement with molecular modelling experiments suggesting that the free energies of the furanoid aldoses serving as starting materials are generally slightly higher than the values for the corresponding open-chain ketose. Dimerisation of the open-chain sugar derivatives was not observed.