Synthesis of isofagomine, a novel glycosidase inhibitor

Tina M. Jespersen, Mikael Bols, Michael R. Sierks, Troels Skrydstrup

Research output: Contribution to journalArticlepeer-review

79 Scopus citations

Abstract

(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.

Original languageEnglish (US)
Pages (from-to)13449-13460
Number of pages12
JournalTetrahedron
Volume50
Issue number47
DOIs
StatePublished - 1994
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

Fingerprint Dive into the research topics of 'Synthesis of isofagomine, a novel glycosidase inhibitor'. Together they form a unique fingerprint.

Cite this