TY - JOUR
T1 - Synthesis of isofagomine, a novel glycosidase inhibitor
AU - M. Jespersen, Tina
AU - Bols, Mikael
AU - R. Sierks, Michael
AU - Skrydstrup, Troels
PY - 1994
Y1 - 1994
N2 - (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-lac tam 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.
AB - (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-lac tam 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.
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U2 - 10.1016/S0040-4020(01)89351-0
DO - 10.1016/S0040-4020(01)89351-0
M3 - Article
AN - SCOPUS:0028035151
VL - 50
SP - 13449
EP - 13460
JO - Tetrahedron
JF - Tetrahedron
SN - 0040-4020
IS - 47
ER -