Enantioselective synthesis of (R)-tolterodine using lithiation/borylation-protodeboronation methodology

Stefan Roesner, Varinder K. Aggarwal*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)

13 Citations (Scopus)

Abstract

The synthesis of the pharmaceutical (R)-tolterodine is reported using lithiation/borylation-protodeboronation of a homoallyl carbamate as the key step. This step was tested with two permutations: an electron-neutral aryl Li-carbamate reacting with an electron-rich boronic ester and an electron-rich aryl Li-carbamate reacting with an electron-neutral boronic ester. It was found that the latter arrangement was considerably better than the former. Further improvements were achieved using magnesium bromide in methanol leading to a process that gave high yield and high enantioselectivity in the lithiation/borylation reaction. The key step was used in an efficient synthesis of (R)-tolterodine in a total of eight steps in a 30% overall yield and 90% ee.

Original languageEnglish
Pages (from-to)965-974
Number of pages10
JournalCanadian Journal of Chemistry
Volume90
Issue number11
DOIs
Publication statusPublished - Nov 2012

Keywords

  • asymmetric synthesis
  • boronic esters
  • gem-diarylalkyl
  • lithiation/borylation reaction
  • tolterodine
  • MUSCARINIC RECEPTOR ANTAGONIST
  • ASYMMETRIC TOTAL-SYNTHESIS
  • TERTIARY BORONIC ESTERS
  • ARYL GRIGNARD-REAGENTS
  • ELECTROPHILIC SUBSTITUTION
  • SECONDARY ALCOHOLS
  • ARYLBORONIC ACIDS
  • 1,4-ADDITION
  • INHIBITOR
  • SEROTONIN

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