Straightforward chemo-enzymatic synthesis of new aminocyclitols, analogues of valiolamine and their evaluation as glycosidase inhibitors

An efficient fructose-1,6-bisphosphate aldolase mediated synthesis of new aminocyclitol analogues of valiolamine is described. The one-pot process where four stereocentres are created involves the formation of two carbon–carbon bonds. One is catalysed by the aldolase, coupling dihydroxyacetone phosphate to nitrobutyraldehydes. The other is the result of a highly stereoselective intramolecular Henry reaction occurring on the intermediate nitroketones. Depending on the configuration of the hydroxyl which is α to the nitro group, two series of configuration are accessible. The lipase resolution of the nitroalcohol ketal, precursor of the nitroaldehyde, is presented. The inhibition properties of the aminocyclitols obtained after the reduction of the nitro group are evaluated towards five commercial glycosidases.

Figure optionsDownload as PowerPoint slide

4,4-Diethoxy-1-nitrobutan-2-olC8H17NO5Ee = 92% by HPLC on Chiracel OD column[α]D23 = −10.4 (c 1.22, CHCl3)Source of chirality: Candida antartica lipase catalysed desymmetrisation by acylationAbsolute configuration: R

1-(Hydroxymethyl)-6-nitrocyclohexane-1,2,3,5-tetraolC7H13NO7[α]D23 = −33.3 (c 4.25, CH3OH)Source of chirality: RAMA aldolase catalysed aldolisationAbsolute configuration: 1S,2S,3R,5S,6R

1-(Hydroxymethyl)-6-nitrocyclohexane-1,2,3,5-tetraolC7H13NO7[α]D23 = +27 (c 2.67, CH3OH)Source of chirality: RAMA aldolase catalysed aldolisationAbsolute configuration: 1R,2S,3R,5R,6S

6-Amino-1-(hydroxymethyl)cyclohexane-1,2,3,5-tetraolC7H15NO5[α]D23 = −7.9 (c 1.1, H2O)Source of chirality: RAMA aldolase catalysed aldolisationAbsolute configuration: 1S,2S,3R,5S,6R

6-Amino-1-(hydroxymethyl)cyclohexane-1,2,3,5-tetraolC7H15NO5[α]D23 = +6.6 (c 1.2, H2O)Source of chirality: RAMA aldolase catalysed aldolisationAbsolute configuration: 1R,2S,3R,5R,6S