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.
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.
Akihiro
A
Hashimoto
Anna K
AK
Przybyl
Joannes T M
JT
Linders
Shinichi
S
Kodato
Xinrong
X
Tian
Jeffrey R
JR
Deschamps
Clifford
C
George
Judith L
JL
Flippen-Anderson
Arthur E
AE
Jacobson
Kenner C
KC
Rice
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