Late-stage C-H bond arylation of spirocyclic σ 1 ligands for analysis of complementary σ 1 receptor surface

Christina Meyer, Dirk Schepmann, Shuichi Yanagisawa, Junichiro Yamaguchi, Kenichiro Itami, Bernhard Wünsch

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Direct C-H bond arylation in the α- and β-positions of spirocyclic thiophenes containing various functional groups (amine, ether, acetal, lactone) was accomplished. Selective phenylation in the α-position of the thiophene ring was achieved by using the catalytic system PdCl 2/bipy/Ag 2CO 3. The introduction of phenyl moieties to the β-position was performed with the catalytic system PdCl 2/P[OCH(CF 3) 2] 3/Ag 2CO 3. Even the five-membered lactone 10 with an electron-withdrawing carbonyl moiety directly attached to the thiophene ring was arylated. Spirocyclic thiophenes substituted with a phenyl moiety in position A (top position) or B (left position) display low nanomolar Ï 1 affinities (e.g., 4a: K i = 1.6 nM; 5a: K i = 2.4 nM), indicating an additional hydrophobic pocket on the complementary Ï 1 receptor protein. A phenyl moiety in position C (at the bottom position) is not tolerated by the Ï 1 receptor (e.g., 12: K i = 483 nM). However, an additional phenyl moiety in position A is able to compensate at least partially the unfavorable effects of the phenyl moiety in position C. Diverse spirocyclic thiophenes were synthesized regioselectively by direct C-H bond arylation using the catalytic systems PdCl 2/bipy/Ag 2CO 3 and PdCl 2/ P[OCH(CF 3) 2] 3/Ag 2CO 3. Compounds bearing the phenyl moiety at the top position and the sulfur atom in left position show the highest Ï 1 affinity.

Original languageEnglish
Pages (from-to)5972-5979
Number of pages8
JournalEuropean Journal of Organic Chemistry
Issue number30
DOIs
Publication statusPublished - 2012 Oct 1
Externally publishedYes

Keywords

  • Arylation
  • C-C coupling
  • Ligand design
  • Protein structures
  • Spiro compounds
  • Sulfur heterocycles

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Organic Chemistry

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