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

Abstract

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^a 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 κ-receptor antagonists in the [³⁵S]GTPγS assay. We synthesized the N-phenethyl-substituted oxide-bridged phenylmorphans in the ortho- and para-d oxide-bridged phenylmorphan^a 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.

Introduction

The ability of an opioid-like ligand to interact with an opioid receptor is likely to depend on the structure and configuration of the ligand as well as its receptor. The structure of the opioid receptor complex has not been experimentally determined, although the crystal structure of the human β₂-adrenergic receptor, also a G-protein-coupled receptor, has been obtained using X-ray diffraction techniques at high-resolution.^2–4 Until similar experiments are successful with opioid receptors, attempts to understand the ligand - opioid receptor interaction at the molecular level will continue to rely heavily on the knowledge of the structures of ligands that can or cannot interact with it. The interaction of these ligands with their receptors has been further complicated by the determination that μ- and δ-opioid receptors not only exist in monomeric form, they can interact as homodimers or as heterodimeric complexes. In accord with that finding, δ-selective ligands have been found that can influence the effects of μ-opioid receptors. The oligomerization and heterodimerization of G-protein-coupled receptors enabling complex ligand-receptor interactions has been discussed.^{5, 6}

Because of our inability to directly visualize the ligand-opioid receptor interaction, information about the opioid receptor’s binding mode has been inferred from the structure of the interacting ligand, and it would probably be most beneficial to do this with a set of isomeric and rigid ligands. It would be especially interesting if these topologically different ligands were found to selectively interact with their specific receptor as either agonists or antagonists. For these and other reasons, we have selected an isomeric series of 12 racemic (24 enantiomeric) topologically rigid N-methyl analogues of oxide-bridged phenylmorphans where spatial characteristics could be determined from both X-ray crystallographic analyses and quantum chemical calculations. Only 2 of the 12 racemates, which we have termed the ortho- and para-b-oxide-bridged phenylmorphans^a (N-methyl substituted, Figure 1), have remained to be synthesized, and that has now been accomplished. The N-methyl ortho- and para-hydroxyphenyl-substituted a through f isomers can be seen in Figure 1.^{1, 7–16} If we assume that the topology of the rigid oxide-bridged phenylmorphans influences their interaction with opioid receptors, the isomeric a-f compounds should display different affinities and, perhaps, act differently in vivo as agonists or antagonists, since they all have different topologies. Although many of the a-f compounds in Figure 1 have not been evaluated, some have, and the (−)-N-phenethyl ortho-f isomer^a was found to have high affinity for μ-(Ki = 7 nM) and κ–receptors and was more potent than naloxone as a μ-opioid antagonist in the [³⁵S]GTPγS assay.¹ In contrast, the (−)-N-phenethyl para-e isomer^a was a morphine-like antinociceptive.¹ We also found that the N-methyl analogues of the ortho-d¹² and para-d isomers (Table 2), as well as the N-phenethyl derivative of the ortho-e isomer¹ have relatively little affinity for any opioid receptor. The isomeric, topologically rigid oxide-bridged phenylmorphans, then, have been noted to display a wide spectrum of activity, ranging from inactive to reasonably potent μ-agonist and antagonists. We now report on the synthesis of the difficult to access N-methyl (20 and 12) and N-phenethyl (24 and 16) ortho- and para-b-series of compounds, and have determined the opioid binding affinity of these compounds and of the N-methyl (46 and 47) and N-phenethyl (51 and 52) analogues of ortho- and para- hydroxyphenyl-substituted d-oxide-bridged compounds, ^{a,10, 12} (Figure 1), to see if conversion from the N-methyl substituent to an N-phenethyl alters the affinity of these ligands for opioid receptors.

Figure 1.

Oxide-bridged phenylmorphan structures

Table 2.

[¹²⁵I]Ioxy Binding Data for ortho- and para-d Oxide-bridged Phenylmorphans^a.

Ki (nM ± SD)
Cmpd #	R1	R2	R3	μ	d	κ
46	Me	OH	H	8000 ± 406	3430 ± 92	4820 ± 198
51	Phenethyl	OH	H	560 ± 27	2840 ± 56	200 ± 3
47	Me	H	OH	2930 ± 203	2780 ± 54	620 ± 21
52	Phenethyl	H	OH	1220 ± 56	2530 ± 76	560 ± 25

^aAssays were conducted using CHO cells, which were stably transfected and express the μ-, δ- or κ-opioid receptors respectively, as described previously.¹⁹ All results n=3.

Chemistry

The b-isomers, like the e-isomers, were very difficult to synthesize because of the highly strained transfused ring junction that had to be formed.¹⁵ In order to obtain the b-isomers we initially applied a strategy similar to one that succeeded with other isomers, in which the oxide-bridged ring was closed by interaction between a phenolate anion and a suitable leaving group on the morphan moiety.¹⁴ These attempts failed with the b-isomers. The successful strategy for the b-isomers (and with the e-isomers) 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 synthesis of 12, the para-b isomer, was accomplished as shown in Scheme 1. The starting material, (S*)-2-(2-(dimethylamino)ethyl)-2-(2-fluorophenyl)cyclohexanone (1) was obtained according to the published procedure.¹⁵ The piperidine ring in (1S*,5R*)-5-(2-fluorophenyl)-2-methyl-2-aza-bicyclo[3.3.1]non-7-en-6-one (6) was formed from (S*)-6-(2-(dimethylamino)ethyl)-6-(2-fluorophenyl)cyclohex-2-enone hydrochloride (5) using N-bromosuccinimide, followed by heating the intermediate dimethylammonium hydrobromide salt in diphenylether at 170 °C (Scheme 1). Hydrogenation of 6 to the ketone, reduction to the alcohol 8, and nitration para to the fluorine in the aromatic ring gave a compound (9) that could undergo oxide-ring closure to the desired azocine 10 in 85% yield.

Scheme 1^a.

^a Reagents and conditions: (a) HC(OMe)₃, H₂SO₄, MeOH; (b) NBA, MeOH; (c) t-BuOK, THF; (d) i) HCO₂H, H₂O, ii) HCl; (e) NBS, ethylene glycol, 40 °C; (f) Ph₂O, 170 °C; (g) H₂, 10% Pd-C EtOH (quantitative); (h) Super Hydride-THF; (i) Ac₂O, AcOH 90 °C; (j) fuming HNO₃; (k) 5N NaOH-MeOH; (l) NaH-THF; (m) 10% Pd-C, EtOH, H₂; (n) NaNO₂, Cu(NO₃)₂·2.5 H₂O, Cu₂O, 35% H₂SO₄

Conversion of the nitrophenyl compound 10 to 12, the N-Me para-b isomer, through amine 11 was accomplished using standard reactions (Scheme 1). The nitrophenyl compound 10 was converted to the N-phenethyl analog 16 using standard procedures (Scheme 2). The structure of 20 was established by single crystal X-ray crystallography (Figure 3).

Scheme 2^a.

^a Reagents and conditions: (a) 1-chloroethylchloroformate, Cl(CH₂)₂Cl, reflux; (b) MeOH, reflux; (c) Ph(CH₂)₂Br, NaI, CH₃CN, reflux; (d) 10% Pd-C, EtOH; (e) NaNO₂, Cu(NO₃)₂· 2.5H₂O, Cu₂O, 35% H₂SO₄

Figure 3.

X-ray crystallographic structure of (top) 20·HCl (N-methyl ortho-b) and (bottom) 51·HCl (N-phenethyl ortho-d). For both compounds displacement ellipsoids are shown at the 50% level.

The N-methyl analogue 20 was also obtained from amine 11 by conversion to the chlorophenyl compound (17, Scheme 3), nitration in the aromatic ring ortho to the oxide-bridge, and the usual reduction to 19, and diazotization to give the desired ortho-b analogue 20. The removable chlorine atom in 17 was used to block the position from unwanted nitration. Reduction of the correctly substituted 18 removed the chlorine atom and reduced the nitro moiety. This gave the amino compound 19 that was needed as the precursor for the target compound 20 with the required phenolic hydroxyl group. The structure of 20 was established by single crystal X-ray crystallography (Figure 2).

Scheme 3^a.

^a Reagents and conditions: (a) NaNO₂, 37% HCl, CuSO₄, NaCl, sodium bisulfite, NaOH; (b) NaNO₂, CF₃CO₂H; (c) H₂, 10% Pd-C, EtOH; (d) NaNO₂, Cu(NO₃)₂·2.5H₂O, Cu₂O, 35% H₂SO₄

Figure 2.

X-ray crystallographic structure of (top) 12·HCl (N-methyl para-b isomer) and (bottom) 47·HCl ·EtOH (N-methyl para-d). For both compounds displacement ellipsoids are shown at the 50% level.

The N-phenethyl ortho-b compound 24 (Scheme 4) was obtained through replacement of the N-methyl with N-phenethyl using the nitrophenyl compound 18 and subsequent removal of the chlorine and conversion of the nitro moiety to the desired ortho-b phenol (24). The N-phenethyl ortho- and para-d-isomers 51 and 52 were prepared as shown in Schemes 5 and 6.

Scheme 4^a.

^a Reagents and conditions: (a) 1-Chloroethylchloroformate, Cl(CH₂)₂Cl, reflux; (b) MeOH, reflux; (c) Ph(CH₂)₂Br, K₂CO₃, NaI, CH₃CN, reflux; (d) 10% Pd-C, HCO₂NH₄, EtOH; (e) NaNO₂, Cu(NO₃)₂·2.5 H₂O, Cu₂O, 35% H₂SO₄

Scheme 5^a.

^a Reagents: (a) n-BuLi, Et₂O; (b) p-toluenesulfonic acid, toluene; (c) sec-BuLi, THF, allyl bromide; (d) HCO₂H, H₃PO₄; (e) NBA, THF; (f) 37% HCl, NaCNBH₃; (g) BBr₃, CH₂Cl₂.

Scheme 6^a.

^a Reagents: (a) t-BuOK, THF; (b) H₂, 10% Pd-C, HOAc/MeOH; (c) H₂, Escat 103 (5% Pd-C), HCHO/MeOH; (d) t-BuOK, DMF, (bromomethyl)cyclopropane; (e) phenethyltosylate, DMF; (f) 37% HCl/MeOH

Scheme 5 describes the synthesis of the properly substituted bromo-derivatives 40 and 41 that were used to prepare the ortho-d and para-d compounds shown in Scheme 6. Similar methodology was formerly used to prepare N-methyl para-d isomers by Linders et al.¹²

In Scheme 6, the oxide ring in 42 was formed from 40 in 45% yield using potassium tert-butoxide in dry THF under argon. The N-debenzylation of 42 was accomplished directly to give 44, or after protection of the phenolic hydroxyl by forming the cyclopropymethyl ether with (bromomethyl)cyclopropane under basic conditions (potassium tert-butoxide) in dry DMF, to give 48 in 83% yield. N-Debenzylation of 42 or 48 (Pd-C catalyzed) gave the secondary amine 44 in 98% yield or the cyclopropymethyl ether derivative of the secondary amine 49 in 83% yield. The secondary amine 44 was directly N-methylated using aqueous Pd-C, hydrogen, and 37% formaldehyde in 85% yield to give the N-methyl ortho-d compound 46, but addition of the phenethyl moiety was most successful when the phenolic hydroxyl was blocked. Thus, 49 was converted to 50 using phenethyl tosylate in DMF under basic conditions and the ether was cleaved under acidic conditions to give the desired N-phenethyl ortho-d compound 51 in 69% yield. Compound 41 was used to obtain the related para-d compounds 47 and 52 using the direct route as described in 41 to 46. The structures of the compounds 47 and 51 were definitively ascertained by single crystal X-ray crystallography (Figures 2 and 3).

Results and discussion

The opioid binding affinities of the ortho- and para-b isomers, each with an N-methyl (20 and 12, Table 1) or N-phenethyl substituent (24 and 16, Table 1), indicated that the ortho-b isomers had higher affinity than the para-b isomers at almost all opioid receptors, whether N-methyl or N-phenethyl substituted, and that the N-phenethyl ortho- and para-b isomers 24 and 16 appeared to interact best with κ-receptors (Ki <100 nM), and had less affinity at the other opioid receptors (e.g., Ki = 190 nM at μ-receptors for the N-phenethyl ortho-b compound 24). The N-phenethyl para-b isomer 16 had little affinity (Ki = 740 nM) at μ-receptors, and none of the b- or d-oxide-bridged phenylmorphan analogues had much affinity for δ-receptors. The N-phenethyl ortho- and para-d compounds 51 and 52 had only slight affinity for μ-receptors, albeit somewhat better affinity than the comparable N-methyl analogues (46 and 47, Table 2).

Table 1.

[¹²⁵I]Ioxy Binding Data for ortho- and para-b Oxide-bridged Phenylmorphans^a

Ki (nM ± SD)
Cmpd #	R1	R2	R3	μ	δ	κ
12	Me	OH	H	>10,000	>10,000	>10,000
16	Phenethyl	OH	H	740 ± 49	4760 ± 254	78 ± 3.0
20	Me	H	OH	3210 ± 260	>10,000	910 ± 51
24	Phenethyl	H	OH	190 ± 15	3710 ± 208	26 ± 1.6

^aAssays were conducted using CHO cells, which were stably transfected and express the μ-, δ- or κ-opioid receptors respectively, as described previously.¹⁹ All results n=3.

The ortho- and para-b compounds were screened for opioid receptor activity and based on those results a few of the compounds (24 and 16) were selected for further study by examining their efficacy in the [³⁵S]GTPγS assay (Table 3). Both of the N-phenethyl b-oxide-bridged phenylmorphans 24 and 16 that had some affinity for the κ-opioid receptor acted as moderately active κ-antagonists in the functional assay. The N-phenethyl ortho-b isomer 24 had weak μ-antagonist activity. Since the examined compounds were racemates, it is possible that at least one of the enantiomeric N-phenethyl ortho-b isomers will have appreciable affinity and efficacy for κ-receptors. The synthesis of the enantiomers of these racemates will be the subject of future work, with the hope that an enantiomer might provide compounds with greater κ-selectivity. We have focused on their κ-activity because of the contemporary interest in selective kappa antagonists as potential antidepressants¹⁷ and their actions in reducing stress.¹⁸

Table 3.

Functional data ([³⁵S]GTP-γ-S)^a for the N-phenethyl substituted para- (16) and ortho-b isomers (24)

16: R1 = H, R2 = OH 24: R1 = OH, R2 = H
Cmpd #	μ-Antagonism Ke (nM)b	δ-Antagonism Ke (μM)c	κ-Antagonism Ke (nM)c
16	260 ± 79	17 ± 4.2	19 ± 5.2
24	77 ± 13	8 ± 1.5	21 ± 3.4
Naloxone	2.3 ± 0.3	-	-
Naltrindole	-	0.18 ± 0.01	-
norBNI	-	-	0.11 ± 0.02

^a[³⁵S]-GTP-γ-S binding was conducted as previously described.¹⁹, ²⁰

^bFor μ-receptors, Ke values were calculated according to the equation: [test drug]/(EC_50-2/EC_50-1 − 1), where EC_50-2 is the EC₅₀ value of DAMGO in the presence of a fixed concentration of the test drug and EC_50-1 is the value in the absence of the test drug.

^cFor δ and κ receptors, Ke values were determined as described in the section “Data analysis and statistics” in Hiebel et al.¹⁹ Each parameter value is ± SD.

Among the rigid oxide-bridged phenylmorphans that have been examined, we have previously found that the (−)-N-phenethyl ortho-f isomer^a had high affinity as a μ-antagonist as well as having naloxone-like efficacy as a κ-antagonist,¹ the (−)-N-phenethyl para-e isomer was a weak μ- and δ-agonist ex vivo but had morphine-like antinociceptive activity,¹ and, now, that the racemic N-phenethyl ortho-b compound 24 acts as a κ-antagonist. Thus we have found several rigid oxide-bridged phenylmorphans that interact with μ- or κ-opioid receptors. We have previously postulated^{1, 19} a possible mechanism for the action of oxide-bridged phenylmorphans on μ-receptors via proton transfer from the protonated nitrogen to a proton acceptor in the μ-opioid receptor complex facilitated by a water molecule.¹⁹

Examination of the b-oxide-bridged phenylmorphan series of rigid topological analogues indicated that the mechanism proposed to account for the very high affinity of the N-phenethyl substituted phenylmorphan agonist ((1R,5R,9S)-(−)-9-hydroxy-5-(3-hydroxyphenyl-2-phenylethyl-2-azabicyclo[3.3.1]nonane) at the μ-receptor,¹⁹ is unlikely to be applicable to the N-phenethyl substituted ortho-b isomer 24 (and even less feasible for the comparable ortho-d-isomer 51). The geometries of these compounds were optimized with density functional theory at the B3LYP/6-31G* level. The phenolic ring of the energy minimized ortho-f compound was found to have little overlap with the phenolic ring of the high-affinity azabicyclo[3.3.1]nonane agonist (Figure 4). The phenolic hydroxyl group and epoxide oxygen are clearly in different areas of 3-dimensional space in these two molecules, and this might be related to the major difference in their pharmacological activity (agonist vs. antagonist), although both have high affinity for the μ-opioid receptor. If we assume that the ortho-f has at least some of the topological characteristics needed to interact with μ-receptors as a μ-antagonist, then the ortho-b compound should have fewer of those characteristics since it has considerably lower μ-affinity and antagonist efficacy.

Figure 4.

Overlay of the energy minimized (1R,5R,9S)-(−)-9-hydroxy-5-(3-hydroxyphenyl-2-phenethyl-2-azabicyclo[3.3.1]nonane¹⁹ and (−)-N-phenethyl ortho-f isomer.¹⁹ Atoms are represented by colors as follows: white, hydrogen; green, carbon; blue, nitrogen; red, oxygen.

As seen in Figure 5, the phenolic ring of the ortho-b isomer (one of the enantiomers in the racemate) is out of the plane of the ortho-f ring and its oxygen atoms are quite distant from those in the ortho-f compound (the epoxide oxygen atoms are 4.0 Å apart, and the phenolic oxygen atoms are 6.7 Å apart). The ortho-b racemate was found to have 27 fold less affinity for the μ-receptor than the ortho-f enantiomer (Ki = 190 nM vs 7 nM). The ortho-d’s phenolic ring is even further from the plane of the ortho-f’s phenolic ring (Figure 6); it is nearly perpendicular to the phenolic ring in ortho-f and has lost almost all affinity for μ-receptors. With the relatively few oxide-bridged phenylmorphans available that have μ-antagonist activity, and the few that have κ-antagonist activity, it is not possible to hypothesize the mechanisms through which they interact with those receptors. We feel that it is likely, however, that the topological characteristics of these compounds will be found to be one of the factors that are important in their interaction with opioid receptors.

Figure 5.

Two views of the overlay of the energy minimized ortho-f and ortho-b isomers.

Figure 6.

Two views of the overlay of the energy minimized ortho-f and ortho-d isomers.

Experimental

Thin layer chromatography (TLC) analyses were carried out on Analtech silica gel GHLF 0.25 mm plates using various gradients of CHCl₃/MeOH containing 1% NH₄OH or gradients of ethyl acetate/n-hexanes. Visualization was accomplished under UV or by staining in an iodine chamber. Melting points were determined in open glass capillaries on Thomas-Hoover melting-point apparatus and are uncorrected. ¹H and ¹³C NMR spectra were recorded at 300 MHz on a Varian Gemini spectrometer. Chemical shifts are reported in ppm using tetramethylsilane (TMS) as the internal standard. FAB and HRMS were recorded on a VG 7070E or JEOL SX 102a mass spectrometer. Flash column chromatography was performed with Fluka silica gel 60 (mesh 220–400). Elemental analyses were performed by Atlantic Microlabs, Inc., Norcross, GA, and the results were within ±0.4% of the theoretical values.

(S*)-2-(1-(2-Fluorophenyl)-2,2-dimethoxycyclohex-3-enyl)-N,N-dimethylethanamine (2)

A solution of (S*)-2-(2-(dimethylamino)ethyl)-2-(2-fluorophenyl)cyclohexanone¹⁵ (1) (18 g, 68.35 mmol) and trimethyl orthoformate (40 mL, 340 mmol, 5 equiv in MeOH (550 mL) was stirred under an atmosphere of Ar for 12 h at room temperature in the presence of H₂SO₄ (7.3 mL, 137 mmol, 2 equiv). The reaction mixture was quenched with saturated NaHCO₃ at 0 °C and then extracted with CHCl₃. The organic layer was washed with H₂O and brine. The solution was dried and the solvent was evaporated under reduced pressure to give a yellow oil (21 g). The crude product was purified by crystallization with oxalic acid from 2-propanol affording 26.7 g of salt, mp 157–158 °C. After conversion to the base, compound 2 was obtained as an oil (18.42 g, 97%). ¹H NMR (CDCl₃): δ 1.02–1.20 (m, 1H), 1.42–1.53 (m, 1H), 1.77 (dt, J = 13.18 and 2.75 Hz, 1H), 2.00–2.31 (m, 6H), 2.23 (s, 6H), 2.50 (dt, J = 11.53 and 4.67 Hz, 1H), 3.54 (s, 3H), 4.93 (t, J = 3.84 Hz, 1H), 6.94–7.20 (m, 4H). HRMS (FAB) m/z calcd for C₁₇H₂₅ONF, 278.1920; found: 278.1923.

2-((1S*)-3-Bromo-1-(2-fluorophenyl)-2,2-dimethoxycyclohexyl)-N,N-dimethylethanamine (3)

To a solution of 2 (4.86 g, 17.5 mmol) and CH₃SO₃H (1.58 mL, 24.5 mmol, 1.4 equiv) in MeOH (240 mL) was added NBA (2.78 g, 20.12 mmol, 1.15 equiv) portionwise under an atmosphere of Ar at 0 °C. The mixture was stirred vigorously for 1.5 h. Then the reaction mixture was quenched with saturated NaHCO₃ and extracted with CHCl₃. The organic layer was washed with H₂O and brine. The solution was dried and the solvent was evaporated under reduced pressure to give a yellow oil (7.57 g). The crude product was purified by column chromatography with CHCl₃:MeOH:28% NH₄OH (100:3:0.5) affording 6.56 g (96%) of 3 as a yellow oil that crystallized. ¹H NMR (CDCl₃): δ 1.59–1.70 (m, 1H), 1.75–1.90 (m, 2H), 1.99–2.39 (m, 5H), 2.22 (s, 6H), 2.45–2.85 (m, 2H), 2.66 (s, 3H), 3.38 (s, 3H), 4.36 (t, J = 3.84 Hz, 1H), 6.91–7.09 (m, 2H), 7.18–7.26 (m, 1H), 7.54–7.62 (m, 1H). HRMS (FAB) m/z calcd for C₁₈H₂₈O₂NFBr, 388.1287; found, 388.1290.

(S*)-2-(1-(2-Fluorophenyl)-2,2-dimethoxycyclohex-3-enyl)-N,N-dimethylethanamine (4)

To a solution of 3 (11.8 g, 30.4 mmol) in THF (120 mL) was added 10.2 g (91 mmol, 3 equiv) of potassium t-butoxide portionwise at 0–5 °C under an atmosphere of Ar. The temperature was allowed to warm to room temperature and the mixture was allowed to stand overnight. The resulting suspension was cooled in an ice bath and H₂O was added. The mixture was extracted with CHCl₃. The organic layer was washed with brine, dried and evaporated in vacuo to give 8.5 g (91%) of 4 as a yellow oil. The crude product (4) was pure enough to be used in the next step without any additional purification. ¹H NMR (CDCl₃): δ 1.75–1.92 (m, 2H), 2.00–2.25 (m, 4H), 2.18 (s, 6H), 2.50–2.70 (m, 2H), 3.16 (s, 3H), 3.26 (s, 3H), 5.83 (td, J = 10.44, 2.20 Hz, 1H), 5.97–6.04 (m, 1H), 6.95 (ddd, J = 13.80, 7.96, 1.37 Hz, 1H), 7.04 (ddd, J = 7.96, 7.28, 1.37 Hz, 1H), 7.15–7.22 (m, 1H), 7.55 (ddd, J = 8.24, 8.24,1.93 Hz, 1H). HRMS (FAB) m/z calcd for C₁₈H₂₇O₂NF, 308.2026; found: 308.2031.

(S*)-6-(2-(Dimethylamino)ethyl)-6-(2-fluorophenyl)cyclohex-2-enone (5)

A mixture of formic acid (88%, 70 mL) and H₂O (370 mL) was added to 4 (27.4 g, 89.1 mmol) and stirred for 1.5 h. The reaction mixture was washed with AcOEt (200 mL) and the aqueous layer was neutralized with 5N NaOH and extracted with CHCl₃ (2 × 200 mL). Combined organic layers were washed with saturated aqueous NaCl and dried over MgSO₄. After removal of CHCl₃ under reduced pressure, the residue was dissolved in MeOH (100 mL) and a 1.25M HCl-MeOH (100 mL) solution was added. Removal of MeOH afforded a solid that was washed with ether-acetone to give 5·HCl (16.7g, 72%) as a white powder, mp: 162–163 °C. HRMS (M + H)⁺ calcd for C₁₆H₂₁NOF, 262.1607; found: 262.1607. ¹H NMR (CDCl₃, free base) δ 12.40 (br s, 1H), 7.25–7.36 (m, 1H), 7.00–7.17 (m, 3H), 6.78–6.88 (m, 1H), 6.06–6.16 (m, 1H), 3.26–3.42 (m, 1H), 2.79 (d, J = 4.8 Hz, 3H), 2.58–2.74 (m, 5H), 2.25–2.50 (m, 3H), 1.98–2.18 (2H, m). ¹³C NMR (CDCl₃, free base): δ 201.36, 162.95, 159.67, 150.06, 130.08, 129.97, 129.64, 129.58, 129.21, 125.30, 125.15, 124.89, 124.84, 117.11, 116.80, 54.82, 51.23, 51.20, 43.22, 42.51, 34.48, 34.42, 30.74, 30.77, 24.21. Anal. (C₁₆H₂₁ClFNO) C, H, N, F.

(1S*,5R*)-5-(2-Fluorophenyl)-2-methyl-2-azabicyclo[3.3.1]non-7-en-6-one (6)

N-Bromosuccinimide (6.3g, 35.3 mmol) was added to a solution of 5 (7.0 g, 23.6 mmol) in ethylene glycol (105 mL) and the mixture was stirred at 40 °C for 1 h. After further addition of NBS (0.75g, 4.2 mmol), the reaction mixture was stirred for 2 h. A saturated NaHCO₃ solution (100 mL) was added to the reaction mixture followed by extraction with CH₂Cl₂ (2 × 200 mL). The combined organic layers were dried over MgSO₄ and concentrated to give a crude intermediate bromide that was used without purification. Diphenyl ether (80 mL) was added to the residue and the mixture was stirred at 170 °C for 2 h. The mixture was cooled to room temperature, dissolved in AcOEt (100 mL), and extracted with 2M hydrochloric acid (2 × 50 mL). The combined aqueous acidic layers were neutralized with a 20% NaOH solution and extracted with CHCl₃ (2 × 100 mL). The organic material was dried over MgSO₄ and concentrated to give a brown oil that was purified by chromatography (silica gel, CH₂Cl₂: MeOH, 50:1) to afford 6 (1.97 g, 34%) as a light yellow powder, mp 139–140 °C. HRMS (M + H)⁺ calcd for C₁₅H₁₇NOF, 246.1294; found: 246.1320. ¹H NMR (CDCl₃): δ 7.22–7.35 (m, 2H), 7.11–7.19 (m, 1H), 7.00 (ddd, J = 1.5, 8.1, 11.4 Hz, 1H), 6.90 (ddd, J = 1.8, 6.0, 12.0 Hz, 1H), 6.52 (d, J = 9.9 Hz, 1H), 3.61 (dt, J = 5.7, 2.7 Hz, 1H), 2.85–2.95 (m, 1H), 2.71–2.81 (m, 1H), 2.24–2.51 (m, 5H), 2.07–2.20 (m, 2H). ¹³C NMR (CDCl₃): δ 201.09, 162.33, 159.06, 142.85, 133.56, 133.54, 131.90, 131.73, 128.98, 128.87, 127.28, 127.21, 124.38, 124.34, 116.10, 115.80, 53.90, 47.32, 47.33, 46.27, 43.15, 40.24, 40.19, 33.05. Anal. (C₁₅H₁₆FNO) C, H, N, F.

(1R*,5R*)-5-(2-Fluorophenyl)-2-methyl-2-azabicyclo[3.3.1]nonan-6-one (7)

To a solution of 6 (1.10 g, 4.5 mmol) in EtOH (20 mL) was added 10% Pd-C (0.11 g) and the mixture was stirred for 2 h under a hydrogen atmosphere. Filtration of the catalyst and removal of EtOH under reduced pressure gave compound 7 (1.11g, quantitative) as a white powder, mp: 95–96 °C. HRMS (M + H)⁺ calcd for C₁₅H₁₉NOF, 248.1451; found: 248.1450. ¹H NMR (CDCl₃): δ 7.29–7.38 (m, 1H), 7.19–7.28(m, 1H), 7.10–7.18 (m, 1H), 7.00 (ddd, J = 1.2, 7.8, 11.7 Hz, 1H), 3.21–3.33 (m, 1H), 2.88–3.04 (m, 1H), 2.72–2.83 (m, 1H), 2.57–2.67 (m, 1H), 2.27–2.54 (m, 3H), 2.06–2.26 (m, 2H), 1.89–2.04 (m, 2H). ¹³C NMR (CDCl₃): δ 216.88, 162.50, 159.25, 132.37, 132.19, 128.87, 128.75, 127.49, 127.42, 124.55, 124.51, 116.08, 115.77, 52.64, 48.27, 47.10, 42.57, 37.78, 37.73, 37.63, 37.57, 34.62, 18.45. Anal. (C₁₅H₁₈FNO) C, H, N, F.

(1R*,5R*,6S*)-5-(2-Fluorophenyl)-2-methyl-2-azabicyclo[3.3.1]nonan-6-ol (8)

1M Super Hydride in THF solution (11.6 mL, 11.6 mmol) was slowly added to a solution of 7 (0.96 g, 3.88 mmol) in THF (10 mL) at −78 °C, and the mixture was stirred for 1 h at room temperature. The reaction mixture was quenched with 2M hydrochloric acid, and the organic solvent was removed from the mixture in vacuo. The aqueous phase was neutralized with a 20% NaOH solution and extracted with CH₂Cl₂ (2 × 30 mL). The combined organic extracts were dried over MgSO₄ and evaporated. The residual material was dissolved in MeOH and a small excess of a 1.25M HCl-methanol solution (4.3 mL) was added. Removal of MeOH in vacuo gave a white solid that was crystallized from EtOH (15 mL) to afford 8.HCl as a white powder. The structure of 8·HCl was established by single crystal X-ray analysis. 5N NaOH was added to the hydrochloride salt and the base 8 was extracted with CHCl₃ (30 mL × 2). The combined CHCl₃ layers were dried over MgSO₄. Removal of CHCl₃ afforded 8 (0.68g, 70.8%) as a white powder, mp 122–123 °C. HRMS calcd for C₁₅H₂₁NOF (M + H)⁺, 250.1607; found: 250.1612. ¹H NMR (CDCl₃) δ 7.32–7.41 (m, 1H), 7.18–7.25 (m, 1H), 7.08–7.15 (m, 1H), 7.02 (ddd, J = 1.5, 7.8, 13.8 Hz, 1H), 4.22 (dd, J = 7.2, 10.8 Hz, 1H), 2.81–3.06 (m, 3H), 2.52–2.64 (m, 1H), 2.43 (3H, s), 2.36–2.42 (m, 1H), 2.20–2.32 (m, 1H), 1.91–2.11 (m, 3H), 1.70–1.88 (m, 1H), 1.46–1.66 (m, 2H). ¹³C NMR (CDCl₃) δ 163.65, 160.36, 134.18, 129.14, 128.47, 124.25, 117.24, 116.91, 74.05, 53.40, 51.00, 43.29, 40.92, 37.88, 37.79, 31.43, 31.35, 29.00, 24.26. Anal. (C₁₅H₂₁ClFNO) C, H, N, F.

(1R*,5R*,6S*)-5-(2-Fluoro-5-nitrophenyl)-2-methyl-2-azabicyclo[3.3.1]nonan-6-ol (9)

A mixture of 8 (0.20 g, 0.8 mmol) and Ac₂O (0.15 g, 1.5 mmol) in AcOH (0.5 mL) was stirred at 90 °C for 15 h. After removal of AcOH under reduced pressure, cool fuming HNO₃ (1.0 mL) was added to the residue slowly at 0 °C. The mixture was stirred for 10 min at 0 °C and 10 min at room temperature. The reaction mixture was evaporated and dissolved in MeOH (8 mL). 5N NaOH (8 mL) was slowly added to the solution and the mixture was stirred for 0.5 h at 0 °C. After removal of MeOH the mixture was extracted with CHCl₃ (3 × 20 mL) and the combined organic layers were washed with brine and dried over MgSO₄. Removal of CHCl₃ in vacuo afforded a crude solid that was purified by chromatography (silica gel, CH₂Cl₂:MeOH, 50:1 to CH₂Cl₂:MeOH:28% NH₄OH, 100:10:1) to give 9 (0.15 g, 62%); mp: 160–161 °C. HRMS calcd for C₁₅H₂₀FN₂O₃ (M + H)⁺, 295.1458; found, 295.1473. ¹H NMR (CDCl₃) δ 8.35 (dd, J = 3.0, 7.2 Hz, 1H), 8.08–8.18 (m, 1H), 7.16 (dd, J = 9.0, 12.3 Hz, 1H), 4.12–4.26 (m, 1H), 2.80–3.06 (m, 3H), 2.53–2.68 (m, 1H), 2.44 (s, 3H), 2.18–2.34 (m, 2H), 1.94–2.14 (m, 3H), 1.46–1.92 (m, 3H). ¹³C NMR (CDCl₃) δ 167.20, 163.75, 144.27, 136.38, 136.23, 125.73, 125.62, 124.26, 124.11, 118.02, 117.65, 73.42, 73.39, 53.28, 50.49, 43.14, 41.16, 41.09, 37.05, 36.96, 31.95, 28.60, 28.57, 24.29. Anal. (C₁₅H₁₉FN₂O₃) C, H, N, F.

(4R*,6aS*,11bR*)-2,3,4,5,6,6a-Hexahydro-3-methyl-10-nitro-1H-4,11b-methanobenzofuro[3,2-d]azocine (10)

NaH (92 mg, 2.3 mmol) was added to a solution of compound 9 (0.45 g, 1.5 mmol) in THF (22.5 mL) at 0 °C and stirred for 4 h at room temperature. H₂O was added cautiously to the reaction mixture at 0 °C and the THF was removed in vacuo. The mixture was extracted with CH₂Cl₂ (2 × 50 mL). The combined organic solution was washed with brine and dried over MgSO₄. Removal of the solvent under reduced pressure afforded crude solid that was purified by chromatography (silica gel, CH₂Cl₂: MeOH, 25:1 to 10: 1) to afford 10 (0.36 g, 85%) as a light yellow powder, mp: 131–132 °C. HRMS calcd for C₁₅H₁₉N₂O₃ (M + H)⁺, 275.1396; found: 275.1385. ¹H NMR (CDCl₃) δ 8.12 (dd, J = 2.4, 8.7 Hz, 1H), 7.97 (d, J = 2.4 Hz, 1H), 6.92 (d, J = 9.0 Hz, 1H), 4.27 (dd, J = 7.2, 11.4 Hz, 1H), 2.95–3.03 (m, 1H), 2.72–2.92 (m, 2H), 2.46–2.57 (m, 2H), 2.43 (s, 3H), 2.22–2.36 (m, 2H), 1.66–1.92 (m, 3H), 1.40–1.56 (m, 1H). ¹³C NMR (CDCl₃) δ 164.89, 142.57, 139.11, 125.60, 118.56, 110.63, 93.45, 54.43, 50.69, 43.35, 43.31, 38.14, 32.45, 27.40, 21.93. Anal. (C₁₅H₁₈N₂O₃) C, H, N.

(4R*,6aS*,11bR*)-10-Amino-2,3,4,5,6,6a-hexahydro-3-methyl-1H-4,11b-methanobenzofuro[3,2-d]azocine (11)

To a solution of 9 (0.11 g, 0.4 mmol) in EtOH (2 mL) 10% Pd-C (50 mg) was added and stirred for 1 h under H₂ atmosphere. The catalyst was removed by filtration and EtOH was removed in vacuo to give 11 (96 mg, 98%) as a white powder, mp: 176–177 °C. HRMS calcd for C₁₅H₂₁N₂O (M + H)⁺, 245.1654; found; 245.1666. ¹H NMR (CDCl₃) δ 6.66–6.72 (m, 1H), 6.44–6.51 (m, 2H), 4.01–4.12 (m, 1H), 3.43 (br s, 2H), 2.71–2.96 (m, 3H), 2.34–2.46 (m, 5H), 2.15–2.27 (m, 2H), 1.38–1.88 (m, 4H). ¹³C NMR (CDCl₃) δ 152.39, 140.75, 138.74, 114.44, 110.79, 110.03, 91.45, 54.78, 50.99, 43.48, 48.42, 38.51, 32.03, 27.69, 21.97. Anal. (C₁₅H₂₀N₂O) C, H, N.

(4R*,6aS*,11bR*)-2,3,4,5,6,6a-Hexahydro-3-methyl-1H-4,11b-methanobenzofuro[3,2-d]azocine-10-ol (12)

A solution of NaNO₂ (30 mg, 0.43 mmol) in H₂O (0.32 mL) was added to a solution of 11 (80 mg, 0.33 mmol) in 35% H₂SO₄ (0.32 mL) at 0 °C. The mixture was stirred for 5 min and urea was added until KI-starch indicator paper did not turn purple when a drop of the mixture was placed on it. A solution of Cu(NO₃)₂·2.5 H₂O (1.18 g, 5.1 mmol) in H₂O (11.2 mL) was added, followed by Cu₂O (47 mg, 0.33 mmol) and the mixture was vigorously stirred for 30 min at room temperature. A 28% NH₄OH solution was added to the reaction mixture to adjust the pH to 11 and the mixture was extracted with CHCl₃ (3 × 20 mL). The combined organic solution was dried over MgSO₄ and concentrated to give a crude base that was purified by preparative TLC (silica gel, CH₂Cl₂:MeOH, 10:1) to give 12. It was dissolved in MeOH and converted to 12·HCl by adding 1.25 N HCl in MeOH to the solution. MeOH was removed in vacuo to give 12·HCl (38 mg, 41%) as a light yellow powder. The salt was crystallized from isopropanol/H₂O, mp 317–318 °C (dec.). The structure of 12 was established by single crystal X-ray analysis. HRMS calcd for C₁₅H₂₀NO₂ (M + H)⁺, 246.1494; found, 246.14888. ¹H NMR (CDCl₃, free base) δ 6.79 (d, J = 2.7 Hz, 1H), 6.76 (d, J = 8.1Hz, 1H), 6.63 (dd, J = 2.7, 8.4 Hz, 1H), 4.20–4.90 (m, 1H), 3.00–3.50 (m, 1H), 2.82–2.88 (m, 2H), 2.38–2.64 (m, 5H), 2.16–2.32 (m, 2H), 1.80–1.88 (m, 3H), 1.44–1.62 (m, 1H). ¹³C NMR (CDCl₃:CD₃OD, 5:1, free base) δ 152.07, 151.55, 137.89, 113.99, 110.62, 109.34, 91.17, 54.67, 50.63, 43.08, 42.80, 37.33, 31.34, 27.26, 21.67. Anal. (C₁₅H₂₀ClNO₂·0.1 H₂O) C, H, N.

(4R*,6aS*,11bR*)-2,3,4,5,6,6a-Hexahydro-10-nitro-1H-4,11b-methanobenzofuro[3,2-d]azocine (13)

1-Chloroethyl chlorformate (0.09 mL, 0.80 mmol) was slowly added to a solution of 10 (0.20 g, 0.73 mmol) in 1,2-dichloroethane (2 mL), and the mixture was refluxed for 15 h. After further addition of 1-chloroethyl chloroformate (52 mg, 0.36 mmol) the reaction mixture was refluxed for 3 h. 1,2-Dichloroethane was removed in vacuo and the residue was dissolved in MeOH (2 mL). The mixture was refluxed for 2 h. MeOH was removed in vacuo to give crude 13. It was dissolved in CH₂Cl₂ (20 mL), washed with saturated aqueous NaHCO₃ solution and the separated organic solution was dried over MgSO₄. Removal of CH₂Cl₂ gave a product that was purified by chromatography (silica gel, CH₂Cl₂:MeOH, 50:1 to CH₂Cl₂:MeOH:28% NH₄OH, 100:10:1) to afford 13 (107 mg, 56%) as a yellow powder that was sufficiently pure for the next step. Starting material 10 was recovered (33mg, 17%). Mp: 211–212 °C; HRMS calcd for C₁₄H₁₇N₂O₃ (M + H)⁺, 261.1239; found 261.1239. ¹H NMR (CDCl₃) δ 8.15 (dd, J = 2.4, 8.7 Hz, 1H), 8.01 (d, J = 2.7 Hz, 1H), 6.95 (d, J = 8.7 Hz, 1H), 4.27 (dd, J = 5.4, 12.3 Hz, 1H), 3.40–3.66 (m, 2H), 3.04–3.20 (m, 1H), 2.30–2.64 (m, 5H), 1.60–2.10 (m, 4H). ¹³C NMR (CDCl₃) δ 164.81, 142.61, 139.34, 125.67, 118.59, 110.81, 93.48, 47.61, 44.02, 41.97, 38.02, 32.94, 30.97, 27.17. Anal. (C₁₄H₁₆N₂O₃ ·1.5 H₂O) C, H, N: calcd, 6.53; found, 6.06.

(4R*,6aS*,11bR*)-2,3,4,5,6,6a-Hexahydro-10-nitro-3-N-phenethyl-1H-4,11b-methanobenzofuro[3,2-d]azocine (14)

A mixture of 13 (77 mg, 0.30 mmol), K₂CO₃ (82 mg, 0.59 mmol), NaI (53 mg, 0.36 mmol) and (2-bromoethyl)benzene (66 mg, 0.36 mmol) in acetonitrile (2 mL) was refluxed for 2 h. CH₂Cl₂ (30 mL) was added to the reaction mixture, and the organic solution was washed with H₂O. The separated organic solution was dried over MgSO₄ and CH₂Cl₂ was removed in vacuo. Purification by chromatography (silica gel, hexane:EtOAc, 3:1) afforded 14 (81 mg, 74%), mp: 150–151 °C. HRMS calcd for C₂₂H₂₅N₂O₃ (M + H)⁺, 365.1865; found 365.1859. ¹H NMR (CDCl₃) δ 8.36 (dd, J = 2.4, 9.0 Hz. 1H), 8.00 (d, J = 2.4 Hz, 1H), 7.17–7.38 (m, 5H), 6.92 (d, J = 8.7 Hz, 1H), 4.27 (dd, J = 6.6, 12.0 Hz, 1H), 3.08–3.20 (m, 1H), 2.64–3.02 (m, 6H), 2.20–2.60 (m, 4H), 1.40–1.92 (m, 4H). ¹³C NMR (CDCl₃) δ 164.90, 142.61, 140.52, 139.19, 128.88, 128.57, 126.28, 125.62, 118.63, 110.67, 93.53, 58.05, 52.90, 49.01, 43.79, 37.91, 34.80, 32.45, 27.33, 23.06. Anal. (C₂₂H₂₄N₂O₃·0.25 H₂O) C, H, N.

(4R*,6aS*,11bR*)-10-Amino-2,3,4,5,6,6a-hexahydro-3-N-phenethyl-1H-4,11b-methanobenzofuro[3,2-d]azocine (15)

To a solution of 14 (75 mg, 0.21 mmol) in EtOH was added 10% Pd-C (30 mg) and the mixture was stirred for 1 h under H₂. After filtration to remove the catalyst, EtOH was removed to give 15 (67 mg, 97%) as a white powder, mp: 125–126 °C. HRMS calcd for C₂₂H₂₇N₂O (M + H)⁺, 335.2123; found 335.2115. ¹H NMR (CDCl₃) δ 7.16–7.34 (m, 5H), 6.65–6.70 (m, 1H), 6.43–6.58 (m, 2H), 4.05 (dd, J = 6.6, 12.0 Hz, 1H), 2.60–3.40 (m, 9H), 2.11–2.45 (m, 4H), 1.66–1.91 (m, 3H), 1.38–1.55 (m, 1H). ¹³C NMR (CDCl₃) δ 152.37, 140.76, 140.51, 138.70, 128.92, 128.60, 126.30, 114.47, 110.82, 110.07, 91.43, 58.15, 53.09, 49.40, 43.94, 38.13, 34.71, 31.88, 27.56, 22.93. Anal. (C₂₂H₂₆N₂O·0.25 H₂O) C, H, N.

(4R*,6aS*,11bR*)-2,3,4,5,6,6a-Hexahydro-3-phenethyl-1H-4,11b-methanobenzofuro[3,2-d]azocine-10-ol (16)

A solution of NaNO₂ (16 mg, 0.24 mmol) in H₂O (0.30 mL) was added to a solution of 15 (61 mg, 0.18 mmol) in 35% H₂SO₄ (0.30 mL) at 0 °C. The mixture was stirred for 1 h at 0 °C and urea was then added until a drop of the mixture placed on KI-starch indicator paper no longer gave a purple color. A solution of Cu(NO₃)₂·2.5H₂O (0.66 g, 2.8 mmol) in H₂O (8.40 mL) was added to the mixture, followed by Cu₂O (26 mg, 0.18 mmol) and the mixture was vigorously stirred for 30 min at room temperature. The pH of the reaction mixture was adjusted to 11 by addition of 28% NH₄OH and the mixture was extracted with CH₂Cl₂ (3 × 20 mL). The combined organic layers were dried over MgSO₄ and concentrated to give crude 16 that was purified by preparative TLC (silica gel, CH₂Cl₂:MeOH, 10:1). The free base of 16 was dissolved in MeOH and a 1.25M hydrochloric acid solution was added. The MeOH was removed in vacuo to give 14.HCl (24 mg, 36%) as a light yellow powder, mp: 271–272 °C (dec). HRMS calcd for C₂₂H₂₆NO₂ (M + H)⁺, 336.1964; found, 336.1960. ¹H NMR (CDCl₃, free base) δ 7.17–7.36 (m, 5H), 6.74 (d, J = 8.4 Hz, 1H), 6.71 (d, J = 2.4 Hz, 1H), 6.62 (dd, J = 2.4, 8.7 Hz, 1H), 4.05–4.18 (m, 1H), 3.13–3.21 (m, 1H), 2.60–3.05 (m, 6H), 2.45–2.58 (m, 1H), 2.30–2.58 (m, 1H), 2.15–2.28 (m, 2H), 1.70–1.94 (m, 3H), 1.40–1.60 (m, 1H). ¹³C NMR (CDCl₃, free base) δ 153.02, 151.07, 150.43, 138.58, 128.97, 128.66, 126.37, 115.13, 111.14, 110.17, 91.66, 58.14, 52.76, 49.45, 44.11, 38.07, 34.28, 31.95, 27.59, 22.60. Anal. (C₂₂H₂₆ClNO₂·1.0 H₂O) C, H, N.

(4R*,6aS*,11bR*)-10-Chloro-2,3,4,5,6,6a-hexahydro-3-methyl-1H-4,11b-methanobenzofuro[3,2-d]azocine (17)

Compound 11 (0.34 g, 1.40 mmol) was dissolved in concentrated hydrochloric acid (5 mL) and stirred at 0 °C in an ice bath. A solution of NaNO₂ (0.11 g, 1.53 mmol) in H₂O (2.5 mL) was added dropwise. The mixture was stirred at 0 °C. Meanwhile a solution of CuSO₄ (0.26 g, 1.60 mmol) and NaCl (0.34 g, 5.80 mmol) in H₂O (3.8 mL) was heated to 65 °C. To this solution was added slowly a solution of 1M NaOH (1.4 mL) and sodium bisulfite (90 mg, 0.46 mmol) in H₂O (1 mL). This mixture was stirred at 65 °C for 15 min. Urea was added to the colored diazonium solution with stirring until a drop of the mixture on KI-starch indicator paper did not show a purple color. This mixture was added to the previously prepared mixture of of CuSO₄ with sodium bisulfite and the new mixture was stirred at 65 °C overnight. The reaction mixture was then basified with 28% NH₄OH and extracted with CHCl₃ (3 × 50 mL). Combined CHCl₃ layers were dried over MgSO₄, evaporated under reduced pressure to give a light brown solid that was purified by chromatography (silica gel, CH₂Cl₂: MeOH, 50:1 to 30:1) to afford 17 (0.23 g, 63%) as a light orange powder, mp 131–132 °C. HRMS calcd for C₁₅H₁₉ClNO (M + H)⁺, 246.1155; found, 264.1158. ¹H NMR (CDCl₃) δ 7.09 (dd, J = 2.4, 8.7 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 6.79 (d, J = 8.1 Hz, 1H), 4.13 (dd, J = 7.2, 11.4 Hz, 1H), 2.71–2.95 (m, 3H), 2.36–2.48 (m, 5H), 2.16–2.32 (m, 2H), 1.58–1.88 (m, 3H), 1.38–1.54 (m, 1H). ¹³C NMR (CDCl₃) δ 158.06, 139.69, 127.85, 126.05, 122.53, 111.70, 92.18, 54.65, 50.89, 43.72, 43.42, 38.40, 32.25, 27.56, 21.95. Anal. (C₁₅H₁₈ClNO) C, H, N.

(4R*,6aS*,11bR*)-10-Chloro-2,3,4,5,6,6a-hexahydro-3-methyl-8-nitro-1H-4,11b-methanobenzofuro[3,2-d]azocine (18)

To a solution of 17 (85 mg, 0.32 mmol) in CF₃COOH (2 mL) was added NaNO₂ (45 mg, 0.65 mmol) and the mixture was stirred for 3 h. The reaction mixture was basified with 28% NH₄OH and extracted with CHCl₃ (3 × 30 mL). The combined CHCl₃ solution was dried over MgSO₄ and evaporated to give a crude product that was purified by chromatography (silica gel, CH₂Cl₂:MeOH, 50:1) to afford 18 (77 mg, 77%) as a light yellow powder, mp 199–200 °C. HRMS calcd for C₁₅H₁₈ClN₂O₃ (M + H)⁺, 309.1006; found, 309.0962. ¹H NMR (CDCl₃) δ 7.93 (d, J = 2.1Hz, 1H), 7.27 (d, J = 2.1 Hz, 1H), 4.28–4.40 (m, 1H), 2.72–3.02 (m, 3H), 2.30–2.55 (m, 7H), 1.60–1.92 (m, 2H), 1.40–1.55 (m, 1H). ¹³C NMR (CDCl₃) δ 153.23, 144.17, 133.57, 128.35, 122.27, 123.40, 94.37, 54.37, 50.63, 43.60, 43.34, 38.25, 32.47, 27.40, 21.85. Anal. (C₁₅H₁₇ClN₂O₃) C, H, N.

(4R*,6aS*,11bR*)-8-Amino-2,3,4,5,6,6a-hexahydro-3-methyl-1H-4,11b-methanobenzofuro[3,2-d]azocine (19)

A mixture of 16 (67 mg, 0.22 mmol), ammonium formate (68 mg, 1.10 mmol) and 10% Pd-C (30 mg) in EtOH was refluxed for 2.5 h. The Pd-C was removed by filtration and the solvent was removed in vacuo. The residue was dissolved in CH₂Cl₂ (20 mL) and washed with an aqueous saturated NaHCO₃ solution (2 × 20 mL). The combined organic material was dried over MgSO₄ and the solvent was evaporated to give crude 19. Purification by chromatography (silica gel, CH₂Cl₂:MeOH, 50:1 to 20:1) afforded 19 (48mg, 79%) as a white powder, mp: 152–153 °C. HRMS calcd for C₁₅H₂₁N₂O (M + H)⁺, 245.1654; found, 245.1670. ¹H NMR (CDCl₃) δ 6.71–6.78 (m, 1H), 6.54–6.60 (m, 2H), 4.12 (dd, J = 6.6, 11.7 Hz, 1H), 3.59 (br s, 2H), 2.70–2.96 (m, 3H), 2.35–2.50 (m, 5H), 2.15–2.31 (m, 2H), 1.60–1.90 (m, 3H), 1.39–1.55 (m, 1H). ¹³C NMR (CDCl₃) δ 146.77, 137.82, 131.33, 122.02, 115.18, 112.19, 91.88, 54.80, 51.01, 43.70, 43.48, 38.73, 31.95, 27.73, 22.06. Anal. (C₁₅H₂₀N₂O) C. H, N.

(4R*,6aS*,11bR*)-2,3,4,5,6,6a-Hexahydro-3-methyl-1H-4,11b-methanobenzofuro[3,2-d]azocine-8-ol (20)

A solution of NaNO₂ (12 mg, 0.16 mmol) in H₂O (0.1 mL) was added to a solution of 19 (30 mg, 0.12 mmol) in 35% H₂SO₄ (0.1 mL) at 0 °C. The mixture was stirred for 1 h and urea was then added until a drop of the mixture on KI-starch indicator paper no longer showed a purple color. A solution of Cu(NO₃)₂·2.5H₂O (0.44 g, 1.9 mmol) in H₂O (4.2 mL) was added, followed by Cu₂O (18 mg, 0.12 mmol), and the mixture was vigorously stirred for 30 min at room temperature. A 28% solution of NH₄OH was added to the mixture to adjust the pH to ~11), and the mixture was extracted with CHCl₃ (3 × 20 mL). The combined organic layers were dried over MgSO₄ and concentrated to give a crude mixture that was purified by preparative TLC (silica gel, CH₂Cl₂: MeOH, 10:1) to afford 20 as a free base. It was dissolved in MeOH and 1.25 N HCl in MeOH was added to the solution. The MeOH was removed under reduced pressure to give 20·HCl (7.8 mg, 23%) as a light yellow powder that crystallized from isopropanol/H₂O, mp: 322–324 °C (dec). The structure of 20 was determined by single crystal X-ray analysis. HRMS calcd for C₁₅H₂₀NO₂ (M + H)⁺, 246.1494; found, 246.1501. ¹H NMR (CDCl₃) δ 6.79 (dd, J = 6.9, 8.0 Hz, 2H), 6.71 (dd, J = 1.5, 8.0 Hz, 1H), 6.65 (dd, J = 1., 7.2 Hz, 1H), 4.15(dd, J = 7.2, 11.6 Hz, 1H), 2.96–3.08 (m, 1H), 2.78–2.94 (m, 2H), 2.15–2.59 (m, 7H), 1.70–1.90 (m, 3H), 1.41–1.61 (m, 1H). ¹³C NMR (CDCl₃) δ 146.38, 141.71, 138.64, 122.28, 115.78, 113.67, 92.16, 54.67, 50.74, 43.67, 43.12, 37.95, 31.61, 27.51, 22.07. Anal. (C₁₅H₂₀ClNO₂·0.5 H₂O) C, H, N.

(4R*,6aS*,11bR*)-10-Chloro-2,3,4,5,6,6a-hexahydro-8-nitro-1H-4,11b-methanobenzofuro[3,2-d]azocine (21)

1-Chloroethylchloroformate (0.08 mL, 0.74 mmol) was slowly added to a solution of 18 (0.19 g, 0.62 mmol) in 1,2-dichloroethane (3 mL), and the mixture was refluxed for 2 h. After further addition of 1-chloroethyl chloroformate (0.04 mL, 0.36mmol) the mixture was refluxed overnight. 1,2-Dichloroethane was removed in vacuo and the residue was dissolved in MeOH (2 mL). The solution was refluxed for 3 h. Solvent was removed in vacuo and the residue was dissolved in CH₂Cl₂ (20 mL) and washed with a saturated aqueous solution of NaHCO₃. The organic solution was dried over MgSO₄ and the CH₂Cl₂ removed in vacuo to give crude 21. It was purified by chromatography (silica gel, CH₂Cl₂:MeOH, 50:1 to CH₂Cl₂:MeOH:aqueous NH₄OH, 100:10:1) to afford 21 (94 mg, 52%) as a yellow powder, mp: 175–176 °C. Some of the starting material (18) was recovered (80 mg, 42%). HRMS calcd for C₁₄H₁₆ClN₂O₃ (M + H)⁺, 295.0849; found, 295.0847. ¹H NMR (CDCl3) δ 7.93 (d, J = 2.1 Hz, 1H), 7.29 (d, J = 2.1 Hz, 1H), 4.40 (dd, J = 5.7, 12.9 Hz, 1H), 3.30–3.55 (m, 2H), 2.90–3.30 (m, 1H), 2.50–2.70 (m, 1H), 2.12–2.48 (m, 3H), 1.75–2.02 (m, 4H), 1.48–1.65 (m, 1H). ¹³C NMR (CDCl₃) δ 153.13, 144.40, 133.60, 128.32, 126.25, 123.35, 94.42, 47.53, 44.30, 41.78, 37.98, 32.94, 31.20, 27.18. Anal. (C₁₄H₁₅ClN₂O₃·0.25 H₂O) C, H, N.

(4R*,6aS*,11bR*)-10-Chloro-8-nitro-3-N-phenylethyl-2,3,4,5,6,6a-hexahydro-1H-4,11b-methanobenzofuro[3,2-d]azocine (22)

A mixture of 21 (84 mg, 0.29 mmol), K₂CO₃ (79 mg, 0.57 mmol), NaI (64 mg, 0.36 mmol) and (2-bromoethyl)benzene (79 mg, 0.36 mmol) in CH₃CN (2 mL) was refluxed for 3 h. To the reaction mixture was added CH₂Cl₂ (30 mL), and the mixture was washed with H₂O. The organic solution was dried over MgSO₄ and the CH₂Cl₂ was removed in vacuo. Purification by chromatography (silica gel, hexane:EtOAc, 3:1) gave 22 (94 mg, 83%) as a light yellow powder, mp 165–166 °C. HRMS calcd for C₂₂H₂₄ClN₂O₃ (M + H)⁺, 399.1475; found, 399.1473. ¹H NMR (CDCl₃) δ 7.94 (d, J = 2.4 Hz, 1H), 7.27–7.34 (m, 3H), 7.18–7.25 (m, 3H), 4.58–4.80 (m, 1H), 3.19–3.28 (m, 1H), 2.67–3.02 (m, 6H), 2.30–2.52 (m, 4H), 1.80–1.96 (m, 2H), 1.40–1.78 (m, 2H). ¹³C NMR (CDCl₃) δ 153.22, 144.23, 140.42, 133.56, 128.87, 128.59, 128.37, 126.32, 126.24, 123.36, 94.43, 57.99, 52.83, 48.93, 44.05, 38.01, 34.77, 32.44, 27.32, 22.93. Anal. (C₂₂H₂₃ClN₂O₃) C, H, N.

(4R*,6aS*,11bR*)-8-Amino-2,3,4,5,6,6a-hexahydro-3-N-phenylethyl-1H-4,11b-methanobenzofuro[3,2-d]azocine (23)

A mixture of 22 (0.13 g, 0.34 mmol), ammonium formate (0.11 g, 1.7 mmol) and 10% Pd-C (50 mg) in EtOH was refluxed for 3 h. After filtration of Pd-C, EtOH was removed in vacuo. The residue was dissolved in CH₂Cl₂ (20 mL) and washed with a saturated aqueous solution of NaHCO₃. The organic solution was dried over MgSO₄ and CH₂Cl₂ was removed in vacuo to give a mixture that was purified by chromatography (silica gel, hexane:EtOAc, 3:1 to 1:1) to afford 23 (69 mg, 61%) as a white powder, mp: 105–106 °C. HRMS calcd for C₂₂H₂₇N₂O (M + H)⁺, 335.2123; found, 335.211. ¹H NMR (CDCl₃) δ 7.26–7.34 (m, 2H), 7.16–7.26 (m, 3H), 4.05–4.20 (m, 1H), 3.25–3.80 (br s, 2H), 3.05–3.15 (m, 1H), 2.62–3.02 (m, 5H), 2.12–2.52 (m, 4H), 1.40–2.00 (m, 5H). ¹³C NMR (CDCl₃) δ 146.76, 140.67, 137.86, 128.92, 128.57, 126.25, 122.02, 115.19, 112.21, 91.90, 58.24, 53.08, 49.40, 44.17, 38.43, 34.85, 31.87, 27.62, 23.04. Anal. (C₂₂H₂₆N₂O·0.33 H₂O) C, H, N.

(4R*,6aS*,11bR*)-2,3,4,5,6,6a-Hexahydro-3-phenethyl-1H-4,11b-methanobenzofuro[3,2-d]azocine-8-ol (24)

A solution of NaNO₂ (16 mg, 0.24 mmol) in H₂O (0.3 mL) was added to a solution of 23 (60 mg, 0.18 mmol) in 35% H₂SO₄ (0.3 mL) at 0 °C. The mixture was stirred for 1 h and urea was then added until a drop of the mixture on KI-starch indicator paper did not show a purple color. A solution of Cu(NO₃)₂·2.5H₂O (0.66 g, 2.8 mmol) in H₂O (8.4 mL) was added, followed by Cu₂O (26 mg, 0.18 mmol) and the mixture was vigorously stirred for 30 min at room temperature. Then, 28% NH₄OH was added to adjust the pH of the reaction mixture to ~11, and it was extracted with CH₂Cl₂ (3 × 20 mL). The combined organic layers were dried over MgSO₄ and solvent removed in vacuo. Purification by preparative TLC (silica gel, hexane:EtOAc, 1:1) gave 24 as a free base. It was dissolved in MeOH and a 1.25M hydrochloric acid solution was added to the methanol solution. The mixture was concentrated in vacuo to afford 24 (23 mg, 33%) as a white powder, mp 288–289 °C (dec). HRMS calcd for C₂₂H₂₆NO₂ (M + H)⁺, 336.1964; found, 336.1965. ¹H NMR (CDCl₃) δ 7.15–7.35 (m, 5H), 6.65–6.85 (m, 3H), 4.16 (d, J = 6.3, 12.0 Hz, 1H), 3.15 (br s, 1H), 2.68–3.16 (m, 6H), 2.13–2.56 (m, 4H), 1.68–1.92 (m, 3H), 1.39–1.58 (m, 1H). ¹³C NMR (CDCl₃) δ 146.22, 141.27, 140.48, 138.86, 128.92, 128.61, 126.32, 122.32, 115.65, 113.93, 92.48, 58.18, 53.03, 49.30, 44.27, 38.06, 34.55, 31.78, 27.53, 22.94. Anal. (C₂₂H₂₆ClNO₂) C, H, N.

1-Benzyl-4-(2,3-dimethoxyphenyl)piperidin-4-ol (28)

A solution of 1,2-dimethoxybenzene (25, 36.36 g, 0.25 mol) in anhydrous Et₂O (225 mL) was cooled in an ice bath and stirred under Ar while a 2.5 M solution of n-BuLi (80 mL, 0.20 mol) was added over a period of 30 min. The ice bath was removed, and the solution was stirred at room temperature for 19 h. The resulting white suspension was cooled to 0 °C, and a solution of 1-benzylpiperidin-4-one (27, 38.23 g, 0.20 mol) in Et₂O (38 mL) was slowly added over 20 min to give a cloudy yellow solution that was washed with aqueous NaHCO₃ and filtered to remove white solid. The organic phase was washed with H₂O and brine, dried over Na₂SO₄, and evaporated to give a crude alcohol. Column chromatography of the crude material with EtOAc:hexanes (5:1) gave 28 (40 g, 62%) as a yellow oil. ¹H-NMR (CDCl₃): δ 1.91 (d, J = 11.4 Hz, 2H), 2.14 (td, J = 12.6, 4.2 Hz, 2H), 2.59 (t, J = 11.1 Hz, 2H), 2.77 (d, J = 10.8Hz, 2H), 3.59 (s, 2H), 3.87 (s, 3H), 3.97 (s, 3H), 4.25 (s, 1H), 6.86 (dd, J = 7.8, 1.5 Hz, 1H), 6.92 (dd, J = 7.8, 1.5 Hz, 1H), 7.02 (t, J = 7.8 Hz, 1H), 7.30–7.39 (m, 5H); HRMS calcd for C₂₀H₂₆NO₃ (M+H)⁺, 328.1913; found 328.1897.

4-(2,5-Dimethoxyphenyl)-1-benzylpiperidin-4-ol (29)

A solution of 1,4-dimethoxybenzene (104.0 g, 0.75 mol) in 1000 mL of dry Et₂O was cooled in an ice bath and stirred under Ar while a 2.5 M solution of n-BuLi (260 mL, 0.65 mol) was added over a period of 30 min. The ice bath was removed, and the solution was stirred for 24 h. The resulting white suspension was cooled to 0 °C, and a solution of 1-benzyl-4-piperidinone (123.0 g, 0.65 mol) in 100 mL of dry Et₂O was slowly added (20 min). The light yellow, clear solution was stirred for 45 min. To the mixture was added 200 mL of saturated aqueous NaHCO₃, the mixture was stirred for 20 min and filtered. The layers were separated, and the organic phase was washed with saturated aqueous NaHCO₃ (2 × 100 mL) and H₂O (2 × 50 mL). The organic phase was partly evaporated, and 4 N HCl (100 mL) was added. The organic layer was re-extracted with 200 mL of 4N HCl. The combined aqueous layer was basified with 28% NH₄OH, and extracted with Et₂O (3×100 mL). The combined organic phase was washed with H₂O (50 mL) and brine, dried over Na₂SO₄, and evaporated to give a crude alcohol 29 (200 g).

1-Benzyl-4-(2,3-dimethoxyphenyl)-1,2,3,6-tetrahydropyridine (30)

A mixture of the crude alcohol 28 (40 g, 0.122 mol) and p-toluenesulfonic acid monohydrate (30 g, 0.158 mol) in toluene (650 mL) was refluxed for 18 h with a Dean-Stark trap to remove water. After removal of toluene, the residual material was diluted with EtOAc and saturated NaHCO₃. The aqueous layer was extracted with EtOAc (4 × 100 mL). The combined organic phase was washed with H₂O and brine, dried over Na₂SO₄, and concentrated to dryness. Column chromatography of the crude material with EtOAc:hexanes (1:5) gave 30 (26 g, 70%) as light yellow oil. ¹H-NMR (CDCl₃): δ 2.54–2.58 (m, 2H), 2.68–2.72 (m, 2H), 3.16–3.19 (m, 2H), 3.66 (s, 2H), 3.77 (s, 3H), 3.86 (s, 3H), 5.79–5.82 (m, 1H), 6.80 (dd, J = 7.8, 1.8 Hz, 1H), 6.82 (dd, J = 8.7, 1.8 Hz, 1H), 6.99 (t, J = 8.1 Hz, 1H), 7.26–7.41 (m, 5H).

4-(2,5-Dimethoxyphenyl)-1,2,3,6-tetrahydro-1-benzylpyridine (31)

The mixture of the crude alcohol 29 (200 g, 0.61 mol) and p-toluenesulfonic acid monohydrate (124 g, 0.65 mol) in toluene (1000 mL) was refluxed for 18 h with a Dean-Stark trap to remove H₂O. After removal of toluene, the residual material was diluted with Et₂O (200 mL) and saturated NaHCO₃. The aqueous layer was extracted with Et₂O (3 × 200 mL). The combined organic phase was washed with H₂O and brine, dried over Na₂SO₄, and concentrated to dryness. Column chromatography of the crude material with EtOAc:hexanes (1:5) gave 31 (144 g, 72% over two steps) as a white solid. ¹H-NMR (CDCl₃): δ 2.54–2.56 (m, 2H), 2.66–2.70 (m, 2H), 3.15–3.18 (m, 2H), 3.65 (s, 2H), 3.77 (s, 6H), 5.79–5.81 (m, 1H), 6.74–6.77 (m, 3H), 7.26–7.41 (m, 5H).

(R*)-4-Allyl-1-benzyl-4-(2,3-dimethoxyphenyl)-1,2,3,4-tetrahydropyridine (32)

sec-BuLi (1.4 M) in cyclohexane (62 mL, 0.086 mol) was added dropwise to a solution of 30 (26 g, 0.084 mol) in THF (500 mL) at −50 °C and the mixture was allowed to warm slowly to −20 °C over 1 h. After cooling to −50 °C, allyl bromide (7.44 mL, 0.086 mol) was added, and the mixture was allowed to warm slowly to room temperature and stirred overnight. The reaction was quenched by addition of H₂O, diluted with EtOAc, washed with H₂O and brine, dried over Na₂SO₄, filtered, and concentrated to give the crude enamine 32. Column chromatography of the crude material with EtOAc:hexanes (1:8) gave 32 (20.6 g, 70%) as a yellow oil. ¹H-NMR (CDCl₃): δ 1.78–1.86 (m, 1H), 2.33–2.51 (m, 3H), 2.68 (d, J = 12.0 Hz, 1H), 2.84 (dd, J = 12.9, 5.1 Hz, 1H), 3.78 (brs, 6H), 3.90 (brs, 2H), 4.54 (d, J = 7.2 Hz, 1H), 4.82–4.93 (m, 2H), 5.42–5.50 (m, 1H), 6.05 (d, J = 8.4 Hz, 1H), 6.73 (d, J = 7.2 Hz, 1H), 6.83–6.92 (m, 2H), 7.15–7.21 (m, 5H).

(R*)-4-Allyl-1-benzyl-4-(2,5-dimethoxyphenyl)-1,2,3,4-tetrahydropyridine (33)

sec-BuLi (1.4 M) in cyclohexane (343 mL, 0.48 mol) was added dropwise to a solution of 31 (144 g, 0.466 mol) in THF (1000 mL) at −50 °C and the mixture was allowed to warm slowly to −20 °C over 4 h. After cooling to −50 °C, allyl bromide (41.0 mL, 0.48 mol) was added, and the mixture was allowed to warm slowly to 0 °C over 4 h and stirred overnight. The reaction was quenched by addition of H₂O, diluted with CH₂Cl₂, washed with H₂O and brine, dried over Na₂SO₄, filtered, and concentrated to give a crude enamine 33. Column chromatography of the crude material with EtOAc:hexanes (1:8) gave 33 (112 g, 70%) as a white-yellow solid.

(1R*,5R*)-2-Benzyl-5-(2,3-dimethoxyphenyl)-2-azabicyclo[3.3.1]non-3-ene (34)

Crude 32 (20.6 g, 0.059 mol) was dissolved in a mixture of 152 mL of 88% HCOOH and 152 mL of 85% H₃PO₄ at 0 °C. The mixture was stirred for 4 days at room temperature. Then the reaction mixture was diluted with 400 mL of H₂O, cooled in ice, and treated with 40% NaOH solution (to pH ~8) and extracted with EtOAc (5 × 40 mL). The organic layer was washed with H₂O and brine, dried over Na₂SO₄, and concentrated to give crude enamine 34 as dark-brown oil (20 g).

(1R*,5R*)-2-Benzyl-5-(2,5-dimethoxyphenyl)-2-azabicyclo[3.3.1]non-3-ene (35)

Crude 33 (52 g, 0.149 mol) was dissolved in a mixture of 300 mL of 88% HCOOH and 300 mL of 85% H₃PO₄ at 0 °C. The mixture was stirred for 4 days at room temperature. Then the reaction mixture was diluted with 1000 mL of H₂O, cooled in ice, and treated with 40% NaOH solution (to pH ~ 8) and extracted with Et₂O (5 × 100 mL). The organic layer washed with H₂O and brine, dried over Na₂SO₄, and concentrated to give crude enamine 35 as a dark-brown oil (35 g).

(1R*,5S*)-2-Benzyl-4-bromo-5-(2,3-dimethoxyphenyl)-2-azabicyclo[3.3.1]non-3-ene (36)

The crude 34 (20 g, 0.058 mol) was dissolved in 200 mL of dry THF, cooled to −78 °C, and N–bromoacetamide (8.76 g, 0.063 mol) solution in THF (40 mL) was slowly added. After stirring for 30 min at −78 °C, the mixture was allowed to warm up slowly to room temperature and stirred at room temperature for 20 min. The solvents were evaporated, and the oily residue was partitioned between saturated aqueous NaHCO₃ and CH₂Cl₂. The organic layer was washed with H₂O and brine, dried over Na₂SO₄. Evaporation of solvent gave the crude 36 (21 g).

(1R*,5S*)-2-Benzyl-4-bromo-5-(2,5-dimethoxyphenyl)-2-azabicyclo[3.3.1]non-3-ene (37)

The crude 35 (35 g, 0.10 mol) was dissolved in 400 mL of dry THF, cooled to −78 °C, and N–bromoacetamide (14.7 g, 0.104 mol) was added in several portions. After stirring for 30 min at −78 °C, the mixture was allowed to warm up slowly to room temperature and stirred at room temperature for 20 min. The solvents were evaporated, and the oily residue was partitioned between aqueous saturated NaHCO₃ and CH₂Cl₂. The organic layer was washed with H₂O and brine, dried over Na₂SO₄. Evaporation of solvent gave the crude 37 (37.5 g).

(1R*,4S*,5S*)-2-Benzyl-4-bromo-5-(2,3-dimethoxyphenyl)-2-azabicyclo[3.3.1]nonane (38)

Addition of 37% HCl (17.5 mL) to a suspension of crude 36 (21 g, 0.049 mol) in MeOH (250 mL) gave a dark brown solution to which was added NaCNBH₃ (3.74 g, 0.060 mol). The resulting milky mixture was stirred 30 min at room temperature and then diluted with saturated aqueous NaHCO₃ (100 mL). After removal of MeOH, the residue was extracted with CH₂Cl₂ (3 × 50 mL). The combined organic phase was washed with H₂O and brine, dried over Na₂SO₄. Evaporation of solvent gave crude oil. Column chromatography of the crude material with EtOAc:hexanes (1:10) gave 38 (5.0 g, 20% over three steps) as a white foam. ¹H-NMR (CDCl₃): δ 1.43–1.55 (m, 1H), 1.81–2.17 (m, 5H), 2.55–2.64 (m, 1H), 2.86 (d, J = 12.9 Hz, 1H), 3.01(brs, 1H), 3.19 (dd, J = 12.0, 7.5 Hz, 1H), 3.44 (t, J = 12.0 Hz, 1H), 3.78 (d, J = 9.6 Hz, 2H), 3.86 (s, 3H), 3.95 (s, 3H), 5.36 (dd, J = 11.1, 6.9 Hz, 1H), 6.88 (dd, J = 6.9, 2.4 Hz, 1H), 6.97–7.05 (m, 2H), 7.23–7.39 (m, 5H); HRMS calcd for C₂₃H₂₉NO₂Br (M + H)⁺, 430.1382, found 430.1385.

(1R*,4S*,5S*)-2-Benzyl-4-bromo-5-(2,5-dimethoxyphenyl)-2-azabicyclo[3.3.1]nonane (39)

Addition of 37% HCl (30 mL) to a suspension of crude 37 (37.5 g, 0.087 mol) in MeOH (600 mL) gave a dark brown solution to which was added NaCNBH₃ (7.0 g, 0.112 mol). The resulting milky mixture was stirred 30 min at room temperature and then diluted with saturated aqueous NaHCO₃ (100 mL). After removal of MeOH, the residue was extracted with CH₂Cl₂ (3 × 50 mL). The combined organic phase was washed with H₂O and brine, dried over Na₂SO₄. Removal of the solvent under reduced pressure afforded a crude oil (37.5 g). Column chromatography of the crude material with EtOAc:hexanes (1:10) gave 14 (9.8 g, 26% over three steps) as a white foam. ¹H-NMR (CDCl₃): δ 1.43–1.51 (m, 1H), 1.70–1.75 (dd, J = 12.3, 1.8 Hz, 1H), 1.84–1.96 (m, 2H), 1.99–2.07 (m, 1H), 2.13–2.19 (m, 1H), 2.54–2.58 (m, 1H), 2.99–3.03 (m, 2H), 3.18 (dd, J = 12.0, 7.2 Hz, 1H), 3.44 (t, J = 12.0 Hz, 1H), 3.73 (d, J = 13.8 Hz, 1H), 3.81 (d, J = 13.2 Hz, 1H), 3.77 (s, 3H), 3.85 (s, 3H), 5.52 (dd, J = 12.0, 7.2 Hz, 1H), 6.74 (dd, J = 9.0, 3.0 Hz, 1H), 6.83 (d, J = 9.0 Hz, 1H), 6.94 (d, J = 3.0 Hz, 1H), 7.23–7.39 (m, 5H); EI-MS m/z [M]⁺ 430.0.

3-((1R*,4S*,5S*)-2-Benzyl-4-bromo-2-azabicyclo[3.3.1]nonan-5-yl)benzene-1,2-diol (40)

A solution of compound 38 (10.5 g, 0.024 mol) in CH₂Cl₂ (120 mL) was stirred at room temperature, while BBr₃ (1.0 M) in CH₂Cl₂ (78 mL) was slowly added, giving an emulsion. After 1 h the reaction was terminated by cautious addition of MeOH (100 mL). Solvent was evaporated and a crude dark colored product obtained.

2-((1R*,4S*,5S*)-2-Benzyl-4-bromo-2-azabicyclo[3.3.1]nonan-5-yl)benzene-1,4-diol (41)

A solution of compound 39 (9 g, 0.021 mol) in CH₂Cl₂ (120 mL) was stirred at room temperature, while BBr₃ (1.0 M) in CH₂Cl₂ (80 mL) was slowly added, giving an emulsion. After 1 h the reaction was terminated by cautious addition of MeOH (100 mL). Solvent was evaporated and a crude dark colored product obtained.

(3R*,6aS*,11aR*)-2-Benzyl-1,3,4,5,6,11a-hexahydro-2H-3,6a-methanobenzofuro[2,3-c]azocin-10-ol (42)

Potassium tert-butoxide (8.4 g, 0.075 mol) was added to a suspension of crude 40 (10 g, 0.024 mol) in dry THF (400 mL). The resulting grey suspension was stirred at room temperature under Ar for 30 min and then acidified with 37% HCl (10 mL), evaporated to an off-white solid, and partitioned between dilute aqueous NaHCO₃ and CH₂Cl₂. The organic phase was washed with H₂O and brine, and dried over Na₂SO₄. Evaporation of solvent gave crude 42 as a light yellow foam. Column chromatography of the crude product with EtOAc:hexanes (1:10) gave 42 (3.5 g, 45% over two steps) as a white foam. ¹H-NMR (CDCl₃): δ 1.16–1.26 (m, 1H), 1.47 (dd, J = 13.2, 1.8 Hz, 1H), 1.59 (d, J = 13.5 Hz, 2H), 1.71 (d, J = 11.1 Hz, 1H), 1.83 (td, J = 13.2, 4.8 Hz, 1H), 2.01–2.15 (m, 2H), 2.74 (dd, J = 10.8, 9.6 Hz, 1H), 3.00 (brs, 1H), 3.10 (dd, J = 10.8, 6.9 Hz, 1H), 3.70 (d, J = 13.5 Hz, 1H), 3.78 (d, J = 13.5 Hz, 1H), 4.68 (dd, J = 9.0, 6.9 Hz, 1H), 6.61 (dd, J = 6.6, 1.8 Hz, 1H), 6.69–6.77 (m, 2H), 7.25–7.34 (m, 5H); HRMS calcd for C₂₁H₂₄NO₂ (M + H)⁺, 322.1807, found 322.1825.

(3R*,6aS*,11aR*)-2-Benzyl-1,3,4,5,6,11a-hexahydro-2H-3,6a-methanobenzofuro [2,3-c]azocin-10-ol (43)

To a suspension of crude 41 (8.0 g, 0.02 mol) in dry THF (400 mL) was added potassium tert-butoxide (8.0 g, 0.06 mol). The resulting grey suspension was stirred at room temperature under Ar for 30 min and then acidified with 37% HCl (10 mL), evaporated to an off-white solid, and partitioned between dilute aqueous NH₄OH and CH₂Cl₂. The organic phase was washed with H₂O and brine, and dried over Na₂SO₄. Removal of the solvent under reduced pressure gave crude 43 as pale-yellow foam. Column chromatography of the crude product with EtOAc:hexanes (1:10) gave 43 (3.4 g, 50% over two steps) as a light yellow foam. ¹H-NMR (CDCl₃): δ 1.16–1.23 (m, 1H), 1.40–1.44 (m, 1H), 1.56–1.62 (m, 2H), 1.73–1.83 (m, 2H), 2.01–2.14 (m, 2H), 2.71 (dd, J = 10.5, 9.6 Hz, 1H), 2.98 (brs, 1H), 3.07 (dd, J = 11.1, 6.9 Hz, 1H), 3.69 (d, J = 13.5 Hz, 1H), 3.76 (d, J = 13.5 Hz, 1H), 4.37 (brs, 1H), 4.61 (dd, J = 9.0, 6.6 Hz, 1H), 6.53–6.55 (m, 3H), 7.31–7.33 (m, 5H).

(3R*,6aS*,11aR*)-1,3,4,5,6,11a-Hexahydro-2H-3,6a-methanobenzofuro[2,3-c]azocin-10-ol (44)

A mixture of 42 (850 mg, 2.63 mmol), 10% Pd-C (151 mg), and HOAc (15 drops) in MeOH (50 mL) was heated at 60 °C for 4 h in a hydrogen atmosphere. After cooling to room temperature, it was basified with 28% NH₄OH (pH ~ 9), filtered through a pad of Celite, washed with MeOH, and concentrated to provide the crude product. Column chromatography of the crude product with CH₂Cl₂:MeOH:28% NH₄OH (90:10:1) gave 44 (600 mg, 98%) as light yellow solid. ¹H-NMR (CDCl₃): δ 1.53 (d, J = 13.2 Hz, 2H), 1.64–1.78 (m, 3H), 1.80–1.90 (m, 2H), 2.05 (d, J = 13.2 Hz, 1H), 3.03 (dd, J = 13.2, 9.0 Hz, 1H), 3.37 (dd, J = 13.2, 6.6 Hz, 1H), 3.46 (brs, 1H), 3.93 (brs, 2H), 4.59 (dd, J = 9.0, 6.6 Hz, 1H), 6.60 (dd, J = 7.2, 1.5 Hz, 1H), 6.69–6.79 (m, 2H).

(3R*,6aS*,11aR*)-1,3,4,5,6,11a-Hexahydro-2H-3,6a-methanobenzofuro[2,3-c]azocin-8-ol (45)

A mixture of 43 (0.510 g, 1.58 mmol), 10% Pd-C (90 mg), and HOAc (12 drops) in MeOH (40 mL) was heated at 60 °C for 4 h in a hydrogen atmosphere. After cooling to room temperature, it was basified with NH₄OH (pH ~ 9), filtered through a pad of Celite, washed with MeOH, and concentrated to provide the crude product. Column chromatography of the crude product with CH₂Cl₂:MeOH:28% NH₄OH (91:9:1) gave 45 (0.320 g, 87%) as white solid. ¹H-NMR (CD₃OD): δ 1.54–1.59 (m, 2H), 1.64–1.71 (m, 4H), 1.89–2.01 (m, 4H), 2.87 (dd, J = 13.5, 9.0 Hz, 1H), 3.23 (dd, J = 13.5, 6.6 Hz, 1H), 4.51 (dd, J = 9.0, 6.6 Hz, 1H), 6.51–6.55 (m, 3H).

(3R*,6aS*,11aR*)-1,3,4,5,6,11a-Hexahydro-2-methyl-2H-3,6a-methanobenzofuro[2,3-c]azocin-10-ol (46)

A mixture of 44 (200 mg, 0.86 mmol), Escat 103 ((5% Pd/C + 50% H₂O), 80 mg), and 37% formaldehyde (80 μL, 1.07 mmol) in MeOH (10 mL) was stirred at room temperature for 4 h in a hydrogen atmosphere. The reaction was stopped and the mixture was filtered through a pad of Celite, washed with MeOH, and concentrated to provide the crude product. Column chromatography of the crude material with CH₂Cl₂:MeOH:28% NH₄OH (95:5:1) gave 46 (180 mg, 85%) as a white solid. Crude 46 (300 mg) was dissolved in 5 mL of MeOH, and 3 mL of methanolic HCl was added. The precipitate was dissolved by heating. Upon cooling to room temperature and scratching, 46·HCl crystallized (260 mg, 87%) as a white salt. ¹H-NMR (CD₃OD, free base): δ 1.80–1.94 (m, 5H), 1.98–2.08 (m, 1H), 2.12–2.26 (m, 2H), 2.97 (s, 3H), 3.58 (brs, 1H), 3.64–3.74 (m, 1H), 3.74–3.86 (m, 1H), 4.57 (brs, 1H), 6.67–6.72 (m, 2H), 6.77–6.82 (m, 1H); HRMS calcd for C₁₅H₂₀NO₂ (M + H)⁺, 246.1494, found 246.1494. Anal. (C₁₅H₁₉NO₂·HCl·0.75 H₂O): C, H, N.

(3R*,6aS*,11aR*)-1,3,4,5,6,11a-Hexahydro-2-methyl-2H-3,6a-methanobenzofuro [2,3-c]azocin-8-ol (47)

A mixture of 45 (0.314 g, 1.36 mmol), Escat 103 ((5% Pd-C + 50% H₂O), 126 mg), and 37% HCHO (111 μL, 1.496 mmol) in MeOH (10 mL) was stirred at room temperature for 4 h in a hydrogen atmosphere. The mixture was filtered through a pad of Celite, washed with MeOH, and concentrated to provide the crude product. Column chromatography of the crude material with CH₂Cl₂:MeOH:28% NH₄OH (95:5:1) gave 47 (0.312 g, 94%) as a light-brown foam. Crude 47 was dissolved in 5 mL of EtOH, and 3 mL of ethanolic HCl was added. The precipitate was dissolved by heating. Upon cooling to room temperature and scratching, 47·HCl crystallized (0.203 g, 65%) as a white salt. ¹H-NMR (CDCl₃, free base): δ 1.22–1.31 (m, 1H), 1.42 (dd, J = 13.2, 2.1 Hz, 1H), 1.59–1.64 (m, 1H), 1.69–1.92 (m, 4H), 2.01–2.06 (m, 1H), 2.44 (s, 3H), 2.77 (brs, 1H), 2.84 (dd, J = 11.7, 8.1 Hz, 1H), 3.07 (dd, J = 11.4, 6.3 Hz, 1H), 4.60 (t, J = 7.2 Hz, 1H), 6.54–6.58 (m, 3H). Anal. (C₁₅H₁₉NO₂·HCl·0.75 H₂O): C, H, N.

(3R*,6aS*,11aR*)-2-Benzyl-10-cyclopropylmethoxy-1,3,4,5,6,11a-hexahydro-2H-3,6a-methanobenzofuro[2,3-c]azocin (48)

Potassium tert-butoxide (142 mg, 1.268 mmol) in dry DMF (4.0 mL) was added to a solution of 42 (340 mg, 1.058 mmol) in dry THF (5.0 mL) over a period of 10 min at 0 °C, and the mixture was stirred at 0 °C for 20 min. (Bromomethyl)cyclopropane (1.5 mL, 1.5 mmol) in dry THF was added, and the mixture was stirred at room temperature for 20 min and heated at 50 °C for 3 h. After filtration and removal of DMF, the residue was extracted with CH₂Cl₂. The organic phase was washed with H₂O, brine, and dried over Na₂SO₄. After evaporation of solvent, column chromatography of the crude product with EtOAc:hexanes (1:12) gave 48 (330 mg, 83%) of a yellow oil. ¹H-NMR (CDCl₃): δ 0.29–0.34 (m, 2H), 0.56–0.63 (m, 2H), 1.13–1.33 (m, 2H), 1.45 (dd, J = 12.9, 1.8 Hz, 1H), 1.54–1.57 (m, 2H), 1.67–1.72 (m, 1H), 1.83 (td, J = 12.9, 4.5 Hz, 1H), 2.02–2.15 (m, 2H), 2.75 (dd, J = 11.1, 9.6 Hz, 1H), 2.98 (brs, 1H), 3.15 (dd, J =10.8, 6.9 Hz, 1H), 3.77 (d, J = 13.5 Hz, 1H), 3.70 (d, J = 13.5 Hz, 1H), 3.83 (d, J = 7.2 Hz, 2H), 4.70 (dd, J = 9.6, 6.9 Hz, 1H), 6.64–6.79 (m, 3H), 7.23–7.32 (m, 5H).

(3R*,6aS*,11aR*)-10-Cyclopropylmethoxyl-1,3,4,5,6,11a-hexahydro-2H-3,6a-methanobenzofuro[2,3-c]azocin (49)

A mixture of 48 (230 mg, 0.612 mmol), 10% Pd-C (34 mg), and HOAc (4 drops) in MeOH (10 mL) was heated at 60 °C for 4 h in a hydrogen atmosphere. After cooling to room temperature, it was basified with 28% NH₄OH (pH ~ 9), filtered through a pad of Celite, washed with MeOH, and concentrated to provide the crude product. Column chromatography of the crude product with CH₂Cl₂:MeOH:28% NH₄OH (95:5:0.4) gave 49 (160 mg, 92%) as a yellow solid. ¹H-NMR (CDCl₃): δ 0.33–0.36 (m, 2H), 0.59–0.65 (m, 2H), 1.26–1.34 (m, 1H), 1.45–1.67 (m, 5H), 1.72–1.96 (m, 3H), 2.06–2.14 (m, 1H), 3.04 (dd, J = 13.2, 9.6 Hz, 1H), 3.37 (dd, J = 13.2, 6.6 Hz, 1H), 3.44 (brs, 1H), 3.86 (d, J = 7.2 Hz, 2H), 4.64 (dd, J = 9.6, 6.9 Hz, 1H), 6.65–6.82 (m, 3H).

(3R*,6aS*,11aR*)-10-Cyclopropylmethoxyl-1,3,4,5,6,11a-hexahydro-2-phenethyl-2H-3,6a-methanobenzofuro [2,3-c]azocin (50)

A mixture of 49 (160 mg, 0.56 mmol), phenethyl tosylate (310 mg, 2.0 equiv) and K₂CO₃ (155 mg, 3.0 equiv) in dry DMF (5.0 mL, ~0.15 M concentration) was heated at 60 °C for 4 h. After the cooled mixture was filtered and the solvent evaporated, the residue was diluted with EtOAc, washed with H₂O and brine, dried over Na₂SO₄ and concentrated to give a crude product. Column chromatography of the crude product with EtOAc:hexanes (1:12) gave 50 (109 mg, 50%) as yellow oil. ¹H-NMR (CDCl₃): δ 0.33–0.36 (m, 2H), 0.59–0.65 (m, 2H), 1.23–1.35 (m, 2H), 1.45–1.87 (m, 7H), 2.09–2.14 (m, 1H), 2.79–2.94 (m, 5H), 3.25 (dd, J = 10.8, 6.9 Hz, 1H), 3.86 (dd, J = 6.9, 0.9 Hz, 2H), 4.75 (dd, J = 9.6, 6.9Hz, 1H), 6.64–6.81 (m, 3H), 7.19–7.30 (m, 5H).

(3R*,6aS*,11aR*)-1,3,4,5,6,11a-Hexahydro-2-phenethyl-2H-3,6a-methanobenzofuro [2,3-c]azocin-10-ol (51)

The compound 50 (109 mg, 0.28 mmol) was dissolved in 37% HCl:MeOH (5 mL:5mL, 0.03 M) and the solution was refluxed for 2 h under Ar. After cooling to room temperature, it was basified with 28% NH₄OH (to pH ~ 10), and extracted with EtOAc. The organic phase was washed with H₂O and brine, and dried over Na₂SO₄. Evaporation of solvent gave a crude product. Column chromatography of the crude material with EtOAc:hexanes (1:6) gave 51 (65 mg, 69%) as a yellow foam.

(3R*,6aS*,11aR*)-1,3,4,5,6,11a-Hexahydro-2-phenethyl-2H-3,6a-methanobenzofuro[2,3-c]azocin-10-ol (52)

A mixture of 45 (600 mg, 2.63 mmol), NaHCO₃ (660 mg, 7.8 mmol), and phenethyl tosylate (780 mg, 2.82 mmol) in DMF (12 mL) was heated at 80–90 °C for 4 h under Ar. After cooling to room temperature, it was diluted with CH₂Cl₂ (20 mL), washed with H₂O and brine, and dried over Na₂SO₄. Evaporation of solvent gave a crude product. Column chromatography of the crude material with EtOAc:hexanes (1:6) gave 52 (630 mg, 72%) as a white solid. Crude 52 was dissolved in 5 mL of EtOH, and 3 mL of ethanolic HCl was added. More EtOH (5 mL) was added, and the precipitate was dissolved by heating. Upon cooling to room temperature and scratching, 52·HCl crystallized (570 mg, 90%) as a white salt. M.p. 250~ 251°C; ¹H-NMR (CDCl₃, free base): δ 1.23–1.28 (m, 2H), 1.49 (dd, J = 13.2, 1.8 Hz, 1H), 1.54–1.90 (m, 5H), 2.08–2.14 (m, 1H), 2.79–2.94 (m, 5H), 2.97 (brs, 1H), 3.19 (dd, J = 10.8, 6.6 Hz, 1H), 4.72 (dd, J = 9.3, 6.6 Hz, 1H), 6.61 (dd, J = 6.3, 2.1 Hz, 1H), 6.71–6.78 (m, 2H), 7.19–7.31 (m, 5H); ¹³C-NMR (CDCl₃, free base): δ 18.14, 30.34, 33.93, 34.85, 35.77, 44.14, 49.77, 52.84, 58.88, 87.29, 114.56, 114.99, 121.34, 125.96, 128.33, 128.71, 136.11, 140.19, 149.39, 145.52; HRMS calcd for C₂₂H₂₆NO₂ (M + H)⁺, 336.1964, found 336.1974. Anal. (C₂₂H₂₅NO₂·HCl·0.25 H₂O): C, H, N; Anal. (C₂₂H₂₅NO₂·0.75 H₂O): C, H, N.

Binding and Efficacy assays

The methodology used has been previously discussed.^{19, 20}

X-ray Crystal Structure of (4R*,6aS*,11bR*)-2,3,4,5,6,6a-hexahydro-3-methyl-1H-4,11b-methanobenzofuro[3,2-d]azocine-10-ol (12), (4R*,6aS*,11bR*)-2,3,4,5,6,6a-hexahydro-3-methyl-1H-4,11b-methanobenzofuro[3,2-d]azocine-8-ol (20), (3R*,6aS*,11aR*)-1,3,4,5,6,11a-hexahydro-2-methyl-2H-3,6a-methanobenzofuro [2,3-c]azocin-8-ol (47), and (3R*,6aS*,11aR*)-1,3,4,5,6,11a-hexahydro-2-phenethyl-2H-3,6a-methanobenzofuro [2,3-c]azocin-10-ol (51)

Single-crystal X-ray diffraction data on compounds 12, 20, 47, and 51 were collected using MoKα radiation and a Bruker APEX 2 CCD area detector. The structures was solved by direct methods and refined by full-matrix least squares on F² values using the programs found in the SHELXTL suite (Bruker, SHELXTL v6.10, 2000, Bruker AXS Inc., Madison, WI). Parameters refined included atomic coordinates and anisotropic thermal parameters for all non-hydrogen atoms. Hydrogen atoms on carbons were included using a riding model [coordinate shifts of C applied to H atoms] with C-H distance set at 0.96 Å.

(4R*,6aS*,11bR*)-2,3,4,5,6,6a-Hexahydro-3-methyl-1H-4,11b-methanobenzofuro[3,2-d]azocine-10-ol (12)

A 0.49 × 0.34 × 0.05 mm³ crystal of 12 was prepared for data collection coating with high viscosity microscope oil (Paratone-N, Hampton Research). The oil-coated crystal was mounted on a glass rod and transferred immediately to the cold stream (103 °K) on the diffractometer. The crystal was monoclinic in space group P2₁/c with unit cell dimensions a = 11.7456(9) Å, b = 10.3351(6) Å, c = 11.5850(9) Å, and β= 107.823(4)°. Corrections were applied for Lorentz, polarization, and absorption effects. Data were 98.9% complete to 29.58° θ (approximately 0.72 Å) with an average redundancy of 3.5.

(4R*,6aS*,11bR*)-2,3,4,5,6,6a-Hexahydro-3-methyl-1H-4,11b-methanobenzofuro[3,2-d]azocine-8-ol (20)

A 0.24 × 0.24 × 0.06 mm³ crystal of 20 was prepared for data collection coating with high viscosity microscope oil (Paratone-N, Hampton Research). The oil-coated crystal was mounted on a glass rod and transferred immediately to the cold stream (103 °K) on the diffractometer. The crystal was monoclinic in space group P2₁/c with unit cell dimensions a = 11.8590(15) Å, b = 10.2338(13) Å, c = 11.9158(15) Å, and β= 111.168(2)°. Corrections were applied for Lorentz, polarization, and absorption effects. Data were 100% complete to 28.34° θ (approximately 0.75 Å) with an average redundancy of 4.0.

(3R*,6aS*,11aR*)-1,3,4,5,6,11a-Hexahydro-2-methyl-2H-3,6a-methanobenzofuro [2,3-c]azocin-8-ol (47)

A 0.62 × 0.28 × 0.19 mm³ crystal of 47 was prepared for data collection coating with high viscosity microscope oil (Paratone-N, Hampton Research). The oil-coated crystal was mounted on a glass rod and transferred immediately to the cold stream (103 °K) on the diffractometer. The crystal was triclinic in space group P-1 with unit cell dimensions a = 6.9290(9) Å, b = 11.9176(15) Å, c = 12.103(2) Å, α = 118.820(3)°, β = 102.080(4)°, and γ = 95.427(3)°. Corrections were applied for Lorentz, polarization, and absorption effects. Data were 97.1% complete to 29.57° θ (approximately 0.72 Å) with an average redundancy of 1.97.

(3R*,6aS*,11aR*)-1,3,4,5,6,11a-Hexahydro-2-phenethyl-2H-3,6a-methanobenzofuro [2,3-c]azocin-10-ol (51)

A 0.84 × 0.54 × 0.30 mm³ crystal of 51 was mounted on a glass rod and transferred to the diffractometer and data collected at room temperature (298 °K) on the. The crystal was triclinic in space group P-1 with unit cell dimensions a = 7.3609(6) Å, b = 11.5732(12) Å, c = 13.7532(13) Å, α = 75.948(4)°, β = 88.850(4)°, and γ = 74.693(4)°. Corrections were applied for Lorentz, polarization, and absorption effects. Data were 96.2% complete to 29.56° θ (approximately 0.72 Å) with an average redundancy of 1.95.

Quantum Chemical Method and Superposition

Geometry optimization for the ortho-b, ortho-d and ortho-f (Figures 4–6) compounds was done in the gaseous phase with the density functional theory at the level of B3LYP/6-31G*.²¹ These optimized structures were overlaid onto a previously described high affinity μ-ligand (1R,5R,9S)-(−)-9-hydroxy-5-(3-hydroxyphenyl-2-phenylethyl-2-azabicyclo[3.3.1]nonane¹⁹ using the rigid fit of Quanta 2008 (Accelrys). The C1-C9 atoms of the morphan moiety of (1R,5R,9S)-(−)-9-hydroxy-5-(3-hydroxyphenyl-2-phenylethyl-2-azabicyclo[3.3.1]nonane¹⁹ was used a common docking point.

Supplementary Material

2. Supporting Information Available.

Elemental analysis results and crystallographic data. This material is available free of charge via the Internet at http://pubs.acs.org. Atomic coordinates for compounds 12, 20, 47, and 51 have been deposited with the Cambridge Crystallographic Data Centre (deposition numbers 683056, 683057, 683054, and 683055, respectively). Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK [fax: +44(0)-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk. This material is also available free of charge via the Internet at http://pubs.acs.org.