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

18 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
Externally publishedYes

Fingerprint

Thiophenes
Ligands
ligands
Lactones
thiophenes
Bearings (structural)
Acetals
Sulfur
Ether
Functional groups
Amines
affinity
Atoms
Electrons
acetals
rings
Proteins
ethers
amines
sulfur

Keywords

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

ASJC Scopus subject areas

  • Organic Chemistry
  • Physical and Theoretical Chemistry

Cite this

Late-stage C-H bond arylation of spirocyclic σ 1 ligands for analysis of complementary σ 1 receptor surface. / Meyer, Christina; Schepmann, Dirk; Yanagisawa, Shuichi; Yamaguchi, Junichiro; Itami, Kenichiro; Wünsch, Bernhard.

In: European Journal of Organic Chemistry, No. 30, 10.2012, p. 5972-5979.

Research output: Contribution to journalArticle

Meyer, Christina ; Schepmann, Dirk ; Yanagisawa, Shuichi ; Yamaguchi, Junichiro ; Itami, Kenichiro ; Wünsch, Bernhard. / Late-stage C-H bond arylation of spirocyclic σ 1 ligands for analysis of complementary σ 1 receptor surface. In: European Journal of Organic Chemistry. 2012 ; No. 30. pp. 5972-5979.
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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 {\"I} 1 affinities (e.g., 4a: K i = 1.6 nM; 5a: K i = 2.4 nM), indicating an additional hydrophobic pocket on the complementary {\"I} 1 receptor protein. A phenyl moiety in position C (at the bottom position) is not tolerated by the {\"I} 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 {\"I} 1 affinity.",
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AU - Meyer, Christina

AU - Schepmann, Dirk

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AU - Itami, Kenichiro

AU - Wünsch, Bernhard

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AB - 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.

KW - Arylation

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KW - Ligand design

KW - Protein structures

KW - Spiro compounds

KW - Sulfur heterocycles

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