Probes for narcotic receptor-mediated phenomena. 33. Construction of a strained trans-5,6-ring system by displacement of a nitro-activated aromatic fluorine. synthesis of the penultimate oxide-bridged phenylmorphans.
The synthesis of the ortho- and para-e isomers in the oxide-bridged 5-phenylmorphan series of rigid tetracyclic compounds was accomplished via rac-5-(2-fluoro-5-nitrophenyl)-2-methyl-2-azabicyclo[3.3.1]nonan-9beta-ol ((+/-)-10), an intermediate containing an aromatic nitro-activated fluorine atom. The fluorine atom was used as the leaving group for the formation of the strained tetracyclic trans-fused 5,6-ring system in rac-(1alpha,4aalpha,9aalpha)-1,3,4,9a-tetrahydro-2-methyl-6-nitro-2H-1,4a-propanobenzofuro[2,3-c]pyridine ((+/-)-11), although preference for cis ring fusion during the formation of tricyclic tetra- and hexahydrodibenzofurans has been well-documented. Single-crystal X-ray crystallographic study of the desired para-e isomer ((+/-)-2), as well as of two intermediates in its synthesis, provided assurance of the correct structures. The e-isomers are among the last of the 12 oxide-bridged 5-phenylmorphans to be synthesized. We envisioned the syntheses of these rigid, tetracyclic compounds in order to determine the three-dimensional pattern of a ligand that would enable interaction with opioid receptors as agonists or antagonists.
Hashimoto
Akihiro
A
Laboratory of Medicinal Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, 20892-0815, USA.
Przybyl
Anna K
AK
Linders
Joannes T M
JT
Kodato
Shinichi
S
Tian
Xinrong
X
Deschamps
Jeffrey R
JR
George
Clifford
C
Flippen-Anderson
Judith L
JL
Jacobson
Arthur E
AE
Rice
Kenner C
KC
D001952:Bridged-Ring Compounds / Q000737:chemistry; D018360:Crystallography, X-Ray; D005461:Fluorine / Q000737:chemistry; D015335:Molecular Probes / Q000138:chemical synthesis*; D015394:Molecular Structure; D009019:Morphinans / Q000138:chemical synthesis*; D011957:Receptors, Opioid / Q000378:metabolism*; D013237:Stereoisomerism
D001952:Bridged-Ring Compounds; D015335:Molecular Probes; D009019:Morphinans; D011957:Receptors, Opioid; D005461:Fluorine; C042531:phenylmorphan