Synthesis Of Isofagomine Research Articles

Synthesis of isofagomine and some new azasugars as glycosidase inhibitors from d-mannitol derived nitroolefins

The synthesis of isofagomine, epi-isofagomine and isofagomine analogues along with some new azasugars from two different vinyl nitro compounds, that were derived from d-mannitol, has been carried out. Two different synthetic strategies were followed for each of the vinyl-nitro precursors. Many of the azasugars synthesized showed inhibition in the micromolar range when tested against various glycosidase enzymes, opening up the possibility of modifying structural features for better and selective inhibition.

ChemInform Abstract: Aza‐Claisen Rearrangement of 2‐C‐Hydroxymethyl Glycals as a Versatile Strategy Towards Synthesis of Isofagomine and Related Biologically Important Azasugars.

AbstractRearrangement of hydroxymethyl glycals (I) leads to glycosyl trichloroacetamidates (III) as a mixture of α‐ and β‐anomers which are versatile precursors for the synthesis of several biologically active azasugars such as isofagomine (IV).

Aza-Claisen rearrangement of 2-C-hydroxymethyl glycals as a versatile strategy towards synthesis of isofagomine and related biologically important azasugars

Synthesis of isofagomine has been achieved by implementation of aza-Claisen rearrangement of 2-C-hydroxymethyl glycals as a key step. The above rearrangement has also been utilized in the synthesis of biologically important polyhydroxylated piperidine frameworks such as isogalactofagomine, ent-isogalactofagomine and their analogues and some other azasugars as glycosidase inhibitors.

Synthesis of isofagomine, a novel glycosidase inhibitor

(3R, 4R, 5R)-3,4-Dihydroxy-5-hydroxymethyl-piperidine (Isofagomine, 1) a potent β-glucosidase inhibitor was synthesised in a 6 step synthesis in an overall yield of 34% starting from 1,6:2,3-dianhydro-4- O-benzyl-β- d-mannopyranose (7). A hydroxymethyl group was introduced at C-2 in 7 by epoxide opening with vinylmagnesium bromide followed by ozonolysis with reductive workup to give 1,6-anhydro-4- O- benzyl-2-deoxy-2- C-hydroxymethyl-β- d-glucopyranose, 9. Hydrolysis of the anhydro bond and subsequent oxidative carbon chain cleavage gave a pentodialdose, which was cyclised by reductive amination with ammonia affording the 4- O-benzyl derivative of 1. After the removing the protecting group by hydrogenation under acidic conditions 1 was isolated as its hydrochloride. Synthesis of 1 was also attempted from its lactam precursur. For this purpose 5-amino-2,3-anhydro-5-deoxy-4- O- tert-butyl-dimethylsily- d-lyxono-1,5-lactam 6 was synthesised in the 5 steps from d-galactose. However, epoxide opening of 6 or 7 with the α-alkoxy cuprate dilithium benzoxymethyl-2-thienylcyanocuprate was unsuccessful.