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 language | English |
|---|---|
| Pages (from-to) | 1844-1856 |
| Number of pages | 13 |
| Journal | Bioorganic and Medicinal Chemistry |
| Volume | 21 |
| Issue number | 7 |
| DOIs | |
| Publication status | Published - 2013 Apr 1 |
| Externally published | Yes |
Fingerprint
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 journal › Article
}
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 -