β-Selective C-Arylation of Diisobutylaluminum Hydride Modified 1,6-Anhydroglucose: Synthesis of Canagliflozin without Recourse to Conventional Protecting Groups

J Org Chem. 2015 May 15;80(10):5189-95. doi: 10.1021/acs.joc.5b00601. Epub 2015 Apr 24.

Abstract

The β-selective phenylation of benzyl and boronate protected 1,6-anhydroglucose and the direct phenylation of unprotected 1,6-anhydroglucose (10), pretreated with i-Bu2AlH, i-Bu3Al, Et3Al, Me3Al, or n-octyl3Al, with triphenylalane or aryl(chloro)alanes is reported. The utility of the unprotected version of the method is demonstrated by the synthesis of the SGLT2 inhibitor, canagliflozin (1a), from commercially available 10 in one C-C bond-forming step. This approach circumvents the need for conventional protecting groups, and therefore no formal protection and deprotection steps are required.

MeSH terms

  • Canagliflozin / chemical synthesis*
  • Canagliflozin / chemistry
  • Catalysis
  • Glucose / analogs & derivatives*
  • Glucose / chemistry*
  • Hypoglycemic Agents
  • Molecular Structure
  • Organometallic Compounds / chemistry*

Substances

  • Hypoglycemic Agents
  • Organometallic Compounds
  • Canagliflozin
  • diisobutylaluminum
  • Glucose