Probes for narcotic receptor mediated phenomena. 37. Synthesis and opioid binding affinity of the final pair of oxide-bridged phenylmorphans, the ortho- and para-b-isomers and their N-phenethyl analogues, and the synthesis of the N-phenethyl analogues of the ortho- and para-d-isomers.

In the isomeric series of 12 racemic topologically rigid N-methyl analogues of oxide-bridged phenylmorphans, all but two of the racemates, the ortho- and para-b-oxide-bridged phenylmorphans 20 and 12, have remained to be synthesized. The b-isomers were very difficult to synthesize because of the highly strained 5,6-trans-fused ring junction that had to be formed. Our successful strategy required functionalization of the position para (or ortho) to a fluorine atom on the aromatic ring using an electron-withdrawing nitro group to activate that fluorine. The racemic N-phenethyl analogues 24 and 16 were moderately potent kappa-receptor antagonists in the [(35)S]GTPgammaS assay. We synthesized the N-phenethyl-substituted oxide-bridged phenylmorphans in the ortho- and para-d-oxide-bridged phenylmorphan series (51 and 52) which had not been previously evaluated using contemporary receptor binding assays to see whether they also have higher affinity for opioid receptors than their N-methyl relatives 46 and 47.

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.

Synthesis of rac-(1R,4aR,9aR)-2-methyl-1,3,4,9a-tetrahydro-2H-1,4a-propanobenzofuro[2,3-c]pyridin-6-ol. An unusual double rearrangement leading to the ortho- and para-f oxide-bridged phenylmorphan isomers.

In an attempt to obtain the para-f isomer, rac-(1R,4aR,9aR)-2-methyl-1,3,4,9a-tetrahydro-2H-1,4a-propanobenzofuro[2,3-c]pyridin-6-ol, via mesylation of an intermediate 9[small alpha]-hydroxyphenylmorphan, we obtained, instead, a rearranged chloro compound with a 5-membered nitrogen ring, 7-chloro-3a-(2,5-dimethoxyphenyl)-1-methyl-octahydroindole. This indole underwent a second rearrangement to give us the desired para-f isomer. The structures of the intermediate indole and the final product were unequivocally established by X-ray crystallography. A resynthesis of the known rac-(1R,4aR,9aR)-2-methyl-1,3,4,9a-tetrahydro-2H-1,4a-propanobenzofuro[2,3-c]pyridin-8-ol, the ortho-f isomer, was achieved using the reaction conditions for the para-f isomer, as well as under Mitsunobu reaction conditions where, unusually, the oxide-bridge ring in the 5-phenylmorphan was closed to obtain the desired product. The synthesis of the para-f isomer adds an additional compound to those oxide-bridged phenylmorphans that were initially visualized and synthesized; the establishment of the structure and configuration of 8 of the theoretically possible 12 racemates has now been achieved. The X-ray crystallographic structure analysis of the para-f isomer provides essential data that will be needed to establish the configuration of a ligand necessary to interact with an opioid receptor.