Improvement of σ1 receptor affinity by late-stage C-H-bond arylation of spirocyclic lactones

Christina Meyer, Benedikt Neue, Dirk Schepmann, Shuichi Yanagisawa, Junichiro Yamaguchi, Ernst Ulrich Würthwein, Kenichiro Itami, Bernhard Wünsch

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

The direct C-H-bond arylation of the complex spirocyclic lactones 13, 14, and 18 allows the introduction of diverse aryl moieties in the last step of the synthesis. A selective α-arylation of the thiophene moiety was performed with the catalytic system PdCl2/2,2′-bipyridyl/Ag 2CO3, whereas the β-position of the thiophene ring was addressed by using the alternative catalytic system PdCl2/ P[OCH(CF3)2]3/Ag2CO3. Due to electronic and steric reasons the arylation of the five-membered lactone 18 occurred in both α-positions providing 4′-mono-, 6′-mono- and 4′,6′-diarylated thiophenes 22-26a-c. Compounds with an additional aryl moiety at the 'upper left (top)' position (1′-position of 13, 3′-position of 14, 4′-position of 18) showed increased σ1 affinity compared to the non-arylated parent compounds. A phenyl moiety at the 'left' position (2′-position in 20a) also increased the σ1 affinity but to a lower extent. A considerable reduction of σ1 affinity was observed after introducing an aryl moiety in 6′-position of 18, which might result from shielding the tertiary amine, which is crucial for interaction with the σ1 receptor. The discussion of the experimental results is supported by high-level quantum chemical DFT-calculations of the NBO-charges of 13 and 18 and the relative energies of the related arylated products.

Original languageEnglish
Pages (from-to)1844-1856
Number of pages13
JournalBioorganic and Medicinal Chemistry
Volume21
Issue number7
DOIs
Publication statusPublished - 2013 Apr 1
Externally publishedYes

Fingerprint

Thiophenes
Lactones
2,2'-Dipyridyl
Discrete Fourier transforms
Shielding
Amines
palladium chloride

Keywords

  • σ Ligands
  • C-H-bond arylation of complex thiophenes
  • DFT calculations
  • Hydrophobic pocket
  • Spirocyclic lactones

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

Improvement of σ1 receptor affinity by late-stage C-H-bond arylation of spirocyclic lactones. / Meyer, Christina; Neue, Benedikt; Schepmann, Dirk; Yanagisawa, Shuichi; Yamaguchi, Junichiro; Würthwein, Ernst Ulrich; Itami, Kenichiro; Wünsch, Bernhard.

In: Bioorganic and Medicinal Chemistry, Vol. 21, No. 7, 01.04.2013, p. 1844-1856.

Research output: Contribution to journalArticle

Meyer, C, Neue, B, Schepmann, D, Yanagisawa, S, Yamaguchi, J, Würthwein, EU, Itami, K & Wünsch, B 2013, 'Improvement of σ1 receptor affinity by late-stage C-H-bond arylation of spirocyclic lactones', Bioorganic and Medicinal Chemistry, vol. 21, no. 7, pp. 1844-1856. https://doi.org/10.1016/j.bmc.2013.01.038
Meyer, Christina ; Neue, Benedikt ; Schepmann, Dirk ; Yanagisawa, Shuichi ; Yamaguchi, Junichiro ; Würthwein, Ernst Ulrich ; Itami, Kenichiro ; Wünsch, Bernhard. / Improvement of σ1 receptor affinity by late-stage C-H-bond arylation of spirocyclic lactones. In: Bioorganic and Medicinal Chemistry. 2013 ; Vol. 21, No. 7. pp. 1844-1856.
@article{8286d874fb16439d96b2249fa53407d5,
title = "Improvement of σ1 receptor affinity by late-stage C-H-bond arylation of spirocyclic lactones",
abstract = "The direct C-H-bond arylation of the complex spirocyclic lactones 13, 14, and 18 allows the introduction of diverse aryl moieties in the last step of the synthesis. A selective α-arylation of the thiophene moiety was performed with the catalytic system PdCl2/2,2′-bipyridyl/Ag 2CO3, whereas the β-position of the thiophene ring was addressed by using the alternative catalytic system PdCl2/ P[OCH(CF3)2]3/Ag2CO3. Due to electronic and steric reasons the arylation of the five-membered lactone 18 occurred in both α-positions providing 4′-mono-, 6′-mono- and 4′,6′-diarylated thiophenes 22-26a-c. Compounds with an additional aryl moiety at the 'upper left (top)' position (1′-position of 13, 3′-position of 14, 4′-position of 18) showed increased σ1 affinity compared to the non-arylated parent compounds. A phenyl moiety at the 'left' position (2′-position in 20a) also increased the σ1 affinity but to a lower extent. A considerable reduction of σ1 affinity was observed after introducing an aryl moiety in 6′-position of 18, which might result from shielding the tertiary amine, which is crucial for interaction with the σ1 receptor. The discussion of the experimental results is supported by high-level quantum chemical DFT-calculations of the NBO-charges of 13 and 18 and the relative energies of the related arylated products.",
keywords = "σ Ligands, C-H-bond arylation of complex thiophenes, DFT calculations, Hydrophobic pocket, Spirocyclic lactones",
author = "Christina Meyer and Benedikt Neue and Dirk Schepmann and Shuichi Yanagisawa and Junichiro Yamaguchi and W{\"u}rthwein, {Ernst Ulrich} and Kenichiro Itami and Bernhard W{\"u}nsch",
year = "2013",
month = "4",
day = "1",
doi = "10.1016/j.bmc.2013.01.038",
language = "English",
volume = "21",
pages = "1844--1856",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
publisher = "Elsevier Limited",
number = "7",

}

TY - JOUR

T1 - Improvement of σ1 receptor affinity by late-stage C-H-bond arylation of spirocyclic lactones

AU - Meyer, Christina

AU - Neue, Benedikt

AU - Schepmann, Dirk

AU - Yanagisawa, Shuichi

AU - Yamaguchi, Junichiro

AU - Würthwein, Ernst Ulrich

AU - Itami, Kenichiro

AU - Wünsch, Bernhard

PY - 2013/4/1

Y1 - 2013/4/1

N2 - The direct C-H-bond arylation of the complex spirocyclic lactones 13, 14, and 18 allows the introduction of diverse aryl moieties in the last step of the synthesis. A selective α-arylation of the thiophene moiety was performed with the catalytic system PdCl2/2,2′-bipyridyl/Ag 2CO3, whereas the β-position of the thiophene ring was addressed by using the alternative catalytic system PdCl2/ P[OCH(CF3)2]3/Ag2CO3. Due to electronic and steric reasons the arylation of the five-membered lactone 18 occurred in both α-positions providing 4′-mono-, 6′-mono- and 4′,6′-diarylated thiophenes 22-26a-c. Compounds with an additional aryl moiety at the 'upper left (top)' position (1′-position of 13, 3′-position of 14, 4′-position of 18) showed increased σ1 affinity compared to the non-arylated parent compounds. A phenyl moiety at the 'left' position (2′-position in 20a) also increased the σ1 affinity but to a lower extent. A considerable reduction of σ1 affinity was observed after introducing an aryl moiety in 6′-position of 18, which might result from shielding the tertiary amine, which is crucial for interaction with the σ1 receptor. The discussion of the experimental results is supported by high-level quantum chemical DFT-calculations of the NBO-charges of 13 and 18 and the relative energies of the related arylated products.

AB - The direct C-H-bond arylation of the complex spirocyclic lactones 13, 14, and 18 allows the introduction of diverse aryl moieties in the last step of the synthesis. A selective α-arylation of the thiophene moiety was performed with the catalytic system PdCl2/2,2′-bipyridyl/Ag 2CO3, whereas the β-position of the thiophene ring was addressed by using the alternative catalytic system PdCl2/ P[OCH(CF3)2]3/Ag2CO3. Due to electronic and steric reasons the arylation of the five-membered lactone 18 occurred in both α-positions providing 4′-mono-, 6′-mono- and 4′,6′-diarylated thiophenes 22-26a-c. Compounds with an additional aryl moiety at the 'upper left (top)' position (1′-position of 13, 3′-position of 14, 4′-position of 18) showed increased σ1 affinity compared to the non-arylated parent compounds. A phenyl moiety at the 'left' position (2′-position in 20a) also increased the σ1 affinity but to a lower extent. A considerable reduction of σ1 affinity was observed after introducing an aryl moiety in 6′-position of 18, which might result from shielding the tertiary amine, which is crucial for interaction with the σ1 receptor. The discussion of the experimental results is supported by high-level quantum chemical DFT-calculations of the NBO-charges of 13 and 18 and the relative energies of the related arylated products.

KW - σ Ligands

KW - C-H-bond arylation of complex thiophenes

KW - DFT calculations

KW - Hydrophobic pocket

KW - Spirocyclic lactones

UR - http://www.scopus.com/inward/record.url?scp=84875212566&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84875212566&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2013.01.038

DO - 10.1016/j.bmc.2013.01.038

M3 - Article

C2 - 23462714

AN - SCOPUS:84875212566

VL - 21

SP - 1844

EP - 1856

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 7

ER -