Efficient Synthesis of Isofagomine and Noeuromycin

Abstract

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.

Rational Design and Synthesis of Highly Potent β‐Glucocerebrosidase Inhibitors

“…Numerous syntheses of IFG and its derivatives have been reported,11 but the synthesis of 6‐alkyl IFGs remains unexplored. As previously described,11c the synthesis of 1 was difficult because of the lack of a suitably branched carbohydrate precursor. In this regard, 6‐alkyl IFGs with an additional chiral center might yet be more difficult to synthesize in a straightforward fashion.…”

Glycosidase inhibition: assessing mimicry of the transition state

“…Although 9 is a potent glycosidase inhibitor, it was predicted that the inclusion of a hydroxyl group at the C2 position would increase this potency as this group had been shown to contribute considerable binding energy to stabilisation of the transition state, predominantly through interactions with the nucleophile 102. Although synthesised as a mixture of anomers at C2, noeuromycin 10 strongly inhibits both α- and β-glycosidases 97,103. Another isofagomine analogue, tetrahydrooxazine 11 , which was also synthesised by Bols and co-workers,104 possesses an endocyclic oxygen atom as found in native glycosides which enables additional hydrogen bonding potential that is unavailable in 9 and 10 .…”

Astrocyte glycogen metabolism is required for neural activity during aglycemia or intense stimulation in mouse white matter

“…Isofagomine (Andersch and Bols, 2001) has proved effective in inhibiting mouse brain glycogen phosphorylase activity (Waagepetersen et al, 2000). Isofagomine is a pseudo‐aza monosaccharide where glucose with nitrogen replaces one of the ring carbons, and the ring oxygen is replaced with a carbon (Dong et al, 1996).…”