Probes for narcotic receptor mediated phenomena. 37.1 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

7866

J. Med. Chem. 2008, 51, 7866–7881

Probes for Narcotic Receptor Mediated Phenomena. 37.¹Synthesis 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

Muneaki Kurimura,^‡,|,§Hehua Liu,^‡,|Agnieszka Sulima,^{‡,|, [}Akihiro Hashimoto,^‡,|,Anna K. Przybyl,^‡,|,∆Etsuo Ohshima,^‡,|,O

Shinichi Kodato,^‡,|,†Jeffrey R. Deschamps,^×Christina M. Dersch,^¶Richard B. Rothman,^¶Yong Sok Lee,^∞

Arthur E. Jacobson,^‡,|and Kenner C. Rice*^,‡,|

Drug Design and Synthesis Section, Chemical Biology Research Branch, National Institute on Drug Abuse and the National Institute on

Alcohol Abuse and Alcoholism, National Institutes of Health, Department of Health and Human SerVices, 5625 Fishers Lane, Room 4N03,

Bethesda, Maryland 20892-9415, Clinical Psychopharmacology Section, Chemical Biology Research Branch, National Institute on Drug Abuse,

Addiction Research Center, National Institutes of Health, Department of Health and Human SerVices, Baltimore, Maryland 21224, Laboratory

for the Structure of Matter, NaVal Research Laboratory, Washington, D.C. 20375, and Center for Molecular Modeling, DiVision of

Computational Bioscience, CIT, National Institutes of Health, DHHS, Bethesda, Maryland 20892

ReceiVed July 22, 2008

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 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 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

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 but 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 have 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 phe-

nylmorphans where spatial characteristics could be determined

from both X-ray crystallographic analyses and quantum chemi-

cal 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 synthe-

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 yet,

although the crystal structure of the human ꢀ₂-adrenergic

receptor, also a G-protein-coupled receptor, has been obtained

using X-ray diffraction techniques at high resolution.^2-4Until

similar experiments are successful with opioid receptors, at-

tempts 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

* To whom correspondence should be addressed. Phone: 301-496-1856.

Fax: 301-402-0589. E-mail: kr21f@nih.gov.

‡

Drug Design and Synthesis Section, National Institute on Drug Abuse

and the National Institute on Alcohol Abuse and Alcoholism, Department

of Health and Human Services.

|

This work was initiated while these authors were members of the Drug

Design and Synthesis Section, Laboratory of Medicinal Chemistry, National

Institute of Diabetes, Digestive and Kidney Diseases, NIH.

§

Current address: Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno

Kawauchi-cho, Tokushima 771-0192, Japan.

[

Current address: Imaging Probe Development Center, NHLBI, NIH.

Current address: Achillion Pharmaceuticals, Inc., New Haven, CT

06511.

∆

^aAbbreviations: ortho-b-oxide-bridged phenylmorphan, (4R*,6aS*,11bR*)-

2,3,4,5,6,6a-hexahydro-3-methyl-1H-4,11b-methanobenzofuro[3,2-d]azocine-

8-ol; para-b-oxide-bridged phenylmorphans, (4R*,6aS*,11bR*)-2,3,4,5,6,6a-

hexahydro-3-methyl-1H-4,11b-methanobenzofuro[3,2-d]azocine-10-ol; ortho-

d-oxide-bridged phenylmorphan, (3R*,6aS*11aR*)-1,3,4,5,6,11a-hexahydro-

2H-3,6a-methanobenzofuro[2,3-c]azocin-10-ol;para-d-oxide-bridgedphenylmorphan,

(3R*,6aS*11aR*)-1,3,4,5,6,11a-hexahydro-2H-3,6a-methanobenzofuro[2,3-

c]azocin-8-ol; (-)-N-phenethyl ortho-f-isomer, (1R,4aR,9aR)-(-)-8-hydroxy-

2-(2-phenylethyl)-1,3,4,9a-tetrahydro-2H-1,4a-propanobenzofuro[2,3-c]py-

Current address: Faculty of Chemistry, Adam Mickiewicz University,

60-780 Poznan, Poland.

O

Current address: Kyowa Hakko Kogyo Co., Ltd., Shizuoka, 411-8731

Japan.

†

Current address: Bushu Pharmaceuticals Ltd., Saitama, 350-0801, Japan.

Naval Research Laboratory.

Clinical Psychopharmacology Section, National Institute on Drug

×

¶

Abuse.

∞

CIT.

10.1021/jm800913d This article not subject to U.S. Copyright. Published 2008 by the American Chemical Society

Published on Web 11/18/2008

Oxide-Bridged 5-Phenylmorphans

Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24 7867

Figure 1. Oxide-bridged phenylmorphan structures.

sized, and that has now been accomplished. The N-methyl ortho-

and para-hydroxyphenyl-substituted a through f isomers can be

seen in Figure 1.^1,7-16If 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 topolo-

gies. Although many of the a-f compounds in Figure 1 have

not been evaluated yet, some have, and the (-)-N-phenethyl

ortho-f-isomer was found to have high afﬁnity for µ- (K_i) 7

nM) and κ-receptors and was more potent than naloxone as a

µ-opioid antagonist in the [³⁵S]GTPγS assay.¹In contrast, the

(-)-N-phenethyl para-e-isomer was a morphine-like antinoci-

ceptive.¹We also found that the N-methyl analogues of the

ortho-d-¹²and para-d-isomers (Table 2), as well as the N-

phenethyl derivative of the ortho-e-isomer,¹have 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,^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.

junction that had to be formed.¹⁵In 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.¹⁴These 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.¹⁵The 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 hy-

drochloride (5) using N-bromosuccinimide, followed by heating

of the intermediate dimethylammonium hydrobromide salt in

diphenyl ether 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.

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 analogue 16 using standard

procedures (Scheme 2). The structure of 12 was established by

single crystal X-ray crystallography (Figure 2).

Chemistry

The b-isomers, like the e-isomers, were very difﬁcult to

synthesize because of the highly strained trans-fused ring

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

ridine; (-)-N-phenethyl para-e isomer, (1S,4aS,9aR)-(-)-2-phenethyl-

1,3,4,9a-tetrahydro-2H-1,4a-propanobenzofuro[2.3-c]pyridin-8-ol.

7868 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24

Kurimura et al.

Scheme 1^a

^aReagents 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) 5 N NaOH-MeOH;

(l) NaH-THF; (m) 10% Pd-C, EtOH, H₂; (n) NaNO₂, Cu(NO₃)₂·2.5H₂O, Cu₂O, 35% H₂SO₄.

Scheme 2^a

odology 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)cyclo-

propane 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

^aReagents 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.

N-methylated using aqueous Pd-C, hydrogen, and 37% form-

aldehyde 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

ortho-b analogue 20. The removable chlorine atom in 17 was

converted to 50 using phenethyl tosylate in DMF under basic

used to block the position from unwanted nitration. Reduction

conditions and the ether was cleaved under acidic conditions

of the correctly substituted 18 removed the chlorine atom and

to give the desired N-phenethyl ortho-d-compound 51 in 69%

reduced the nitro moiety. This gave the amino compound 19

yield. Compound 41 was used to obtain the related para-d-

that was needed as the precursor for the target compound 20

compounds 47 and 52 using the direct route as described in 41

with the required phenolic hydroxyl group. The structure of 20

to 46. The structures of the compounds 47 and 51 were

was established by single crystal X-ray crystallography (Figure

deﬁnitively ascertained by single crystal X-ray crystallography

2).

(Figure 3).

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

Results and Discussion

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 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 meth-

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 substi-

tuted, and that the N-phenethyl ortho- and para-b-isomers 24

Oxide-Bridged 5-Phenylmorphans

Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24 7869

Figure 2. X-ray crystallographic structure of (top) 12·HCl (N-methyl para-b-isomer) and (bottom) 20·HCl (N-methyl ortho-b). For all four compounds

displacement ellipsoids are shown at the 50% level.

Scheme 3^a

Scheme 4^a

^aReagents 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.

^aReagents 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.

and 16 appeared to interact best with κ-receptors (K_i< 100

nM) and had less afﬁnity at the other opioid receptors (e.g., K_i

) 190 nM at µ-receptors for the N-phenethyl ortho-b-compound

24). The N-phenethyl para-b-isomer 16 had little afﬁnity (K_i)

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).

The ortho- and para-b compounds were screened for opioid

receptor activity, and on the basis of those results, a few of the

compounds (24 and 16) were selected for further study by

7870 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24

Kurimura et al.

Scheme 5^a

at the µ-receptor¹⁹is 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 com-

pounds were optimized with density functional theory at the

B3LYP/6-31G* level. The phenolic ring of the energy mini-

mized 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 three-

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-compound 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 consider-

ably lower µ-afﬁnity and antagonist efﬁcacy.

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 (K_i) 190 vs 7

nM). The ortho-d-compound’s phenolic ring is even further from

the plane of the ortho-f-compound’s phenolic ring (Figure 6);

it is nearly perpendicular to the phenolic ring in ortho-f-

compound 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.

^aReagents: (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.

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 κ antagonists as potential antidepressants¹⁷and their

actions in reducing stress.¹⁸

Among the rigid oxide-bridged phenylmorphans that have

been examined, we have previously found that the (-)-N-

phenethyl ortho-f-isomer had high afﬁnity as a µ-antagonist as

well as having naloxone-like efﬁcacy as a κ-antagonist,¹the

(-)-N-phenethyl para-e-isomer was a weak µ- and δ- agonist ex

vivo but had morphine-like antinociceptive activity,¹and, 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^1,19a 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 mol-

ecule.¹⁹

Experimental Section

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

1

and are uncorrected. H 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-(dimethy-

lamino)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

NaHCO₃at 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,

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)

Oxide-Bridged 5-Phenylmorphans

Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24 7871

Scheme 6^a

^aReagents: (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)cy-

clopropane; (e) phenethyl tosylate, DMF; (f) 37% HCl/MeOH.

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.

CHCl₃(2 × 200 mL). Combined organic layers were washed with

saturated aqueous NaCl and dried over MgSO₄. After removal of

CHCl₃under reduced pressure, the residue was dissolved in MeOH

(100 mL) and a 1.25 M HCl-MeOH (100 mL) solution was added.

Removal of MeOH afforded a solid that was washed with

ether-acetone to give 5·HCl (16.7 g, 72%) as a white powder,

mp 162-163 °C. HRMS (M + H)⁺calcd for C₁₆H₂₁NOF,

2-((1S*)-3-Bromo-1-(2-ﬂuorophenyl)-2,2-dimethoxycyclo-

hexyl)-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 NaHCO₃and 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 chroma-

tography 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 tert-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.

1

262.1607; found, 262.1607. H 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 (6.3 g, 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 (0.75 g, 4.2 mmol), the reaction mixture was stirred

for 2 h. A saturated NaHCO₃solution (100 mL) was added to the

reaction mixture followed by extraction with CH₂Cl₂(2 × 200 mL).

The combined organic layers were dried over MgSO₄and concen-

trated 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 2 M 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 MgSO₄and 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,

(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 5 N NaOH and extracted with

7872 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24

Kurimura et al.

Figure 3. X-ray crystallographic structure of (top) 47·HCl·EtOH (N-methyl para-d) and (bottom) 51·HCl (N-phenethyl ortho-d). For all four

compounds displacement ellipsoids are shown at the 50% level.

Table 1. [¹²⁵I]Ioxy Binding Data for Ortho- and Para-b Oxide-Bridged

Table 2. [¹²⁵I]Ioxy Binding Data for Ortho- and Para-d Oxide-Bridged

Phenylmorphans^a

K_i( SD, nM

compd

R₁

R₂R₃

µ

δ

κ

compd

R₁

R₂R₃

µ

δ

κ

12

16

20

24

Me

OH

H

>10000

46

51

47

52

Me

OH

H

8000 ( 406 3430 ( 92 4820 ( 198

560 ( 27 2840 ( 56 200 ( 3

phenethyl OH

Me

phenethyl

740 ( 49

4760 ( 254 78 ( 3.0

phenethyl OH

Me

phenethyl

H

OH 3210 ( 260 >10,000

OH 190 ( 15

910 ( 51

H

OH 2930 ( 203 2780 ( 54 620 ( 21

OH 1220 ( 56 2530 ( 76 560 ( 25

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.¹⁹For all results, n ) 3.

^aAssays were conducted using CHO cells, which were stably transfected

and express the µ-, δ-, or κ-opioid receptors, respectively, as described

previously.¹⁹For all results, n ) 3.

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 (1.11

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]-

Oxide-Bridged 5-Phenylmorphans

Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24 7873

Table 3. Functional Data ([³⁵S]GTP-γ-S)^afor the N-Phenethyl

Substituted Para- (16) and Ortho-b-Isomers (24)

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 CHCl₃in 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

1

(M + H)⁺, 295.1458; found, 295.1473. H 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.

µ-antagonism

K_e(nM)^b

δ-antagonism

K_e(µM)^c

κ-antagonism

K_e(nM)^c

compd

16

260 ( 79

77 ( 13

2.3 ( 0.3

17 ( 4.2

8 ( 1.5

19 ( 5.2

21 ( 3.4

24

(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) was added 10%

Pd-C (50 mg), and the mixture was 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)₂·2.5H₂O (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 MgSO₄and 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 ) 8.1 Hz, 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

naloxone

naltrindole

norBNI

a

0.18 ( 0.01

0.11 ( 0.02

[

³⁵S]GTP-γ-S binding was conducted as previously described.^{19,20 b}For

µ-receptors, K_evalues were calculated according to the equation [test drug]/

(EC_50-2/EC_50-1- 1), where EC_50-2is the EC₅₀value of DAMGO in the

presence of a ﬁxed concentration of the test drug and EC_50-1is the value

in the absence of the test drug. ^cFor δ and κ receptors, K_evalues were

determined as described in the section “Data Analysis and Statistics” in

Hiebel et al.¹⁹Each parameter value is listed with (SD.

g, quantitative) as a white powder, mp 95-96 °C. HRMS (M +

H)⁺calcd for C₁₅H₁₉NOF, 248.1451; found, 248.1450. H NMR

1

(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). A sample of 1 M 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 2 M 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 MgSO₄and

evaporated. The residual material was dissolved in MeOH, and a

small excess of a 1.25 M 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. Then 5 N NaOH was added to the hydrochloride salt and

the base 8 was extracted with CHCl₃(30 mL × 2). The combined

CHCl₃layers were dried over MgSO₄. Removal of CHCl₃afforded

8 (0.68 g, 70.8%) as a white powder, mp 122-123 °C. HRMS calcd

for C₁₅H₂₁NOF (M + H)⁺, 250.1607; found, 250.1612. H NMR

1

(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 for 10 min at

room temperature. The reaction mixture was evaporated and

dissolved in MeOH (8 mL). The 5 N NaOH (8 mL) was slowly

7874 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24

Kurimura et al.

Figure 4. Overlay of the energy minimized (1R,5R,9S)-(-)-9-hydroxy-5-(3-hydroxyphenyl-2-phenethyl-2-azabicyclo[3.3.1]nonane¹⁹and (-)-N-

phenethyl ortho-f-isomer.¹⁹Atoms are represented by colors as follows: white, hydrogen; green, carbon; blue, nitrogen; red, oxygen.

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. (C₁₅H₂₀ClNO₂·0.1H₂O) 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 chloro-

formate (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) and washed with saturated aqueous NaHCO₃

solution, and the separated organic solution was dried over MgSO₄.

Removal of CH₂Cl₂gave a product that was puriﬁed by chroma-

tography (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 (33 mg, 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. (C₁₄H₁₆N₂O₃·1.5H₂O) C, H. N: calcd, 6.53;

found, 6.06.

washed with H₂O. The separated organic solution was dried over

MgSO₄, and CH₂Cl₂was 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 +

1

H)⁺, 365.1865; found, 365.1859. H 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.

(C₂₂H₂₄N₂O₃·0.25H₂O) 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

1

for C₂₂H₂₇N₂O (M + H)⁺, 335.2123; found, 335.2115. H 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·0.25H₂O) 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

(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

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

Oxide-Bridged 5-Phenylmorphans

Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24 7875

Figure 5. Two views of the overlay of the energy minimized ortho-f- and ortho-b-isomers.

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 MgSO₄and

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 1.25 M 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. (C₂₂H₂₆ClNO₂·1.0H₂O) 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). Com-

pound 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 1 M 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 CuSO₄with 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 CHCl₃layers were dried over

MgSO₄and 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 CHCl₃solution

was dried over MgSO₄and 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,

1

309.0962. H NMR (CDCl₃) δ 7.93 (d, J ) 2.1 Hz, 1H), 7.27 (d,

7876 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24

Kurimura et al.

Figure 6. Two views of the overlay of the energy minimized ortho-f- and ortho-d-isomers.

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.

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.

(C₁₅H₂₀ClNO₂·0.5H₂O) 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 NaHCO₃solution (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 (48 mg, 79%) as a white powder, mp 152-153 °C. HRMS calcd

1

for C₁₅H₂₁N₂O (M + H)⁺, 245.1654; found, 245.1670. H 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*)-10-Chloro-2,3,4,5,6,6a-hexahydro-8-

nitro-1H-4,11b-methanobenzofuro[3,2-d]azocine (21). 1-Chlo-

roethylchloroformate (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-chloroethylchloroformate (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

(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

Oxide-Bridged 5-Phenylmorphans

Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24 7877

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

MgSO₄and the CH₂Cl₂removed 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

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 solu-

tion 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 NaHCO₃and 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%)

1

C₁₄H₁₆ClN₂O₃(M + H)⁺, 295.0849; found, 295.0847. H 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. (C₁₄H₁₅ClN₂O₃·0.25H₂O) 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 CH₂Cl₂was removed in vacuo. Puriﬁcation by chroma-

tography (silica gel, hexane/EtOAc, 3:1) gave 22 (94 mg, 83%) as

a light-yellow powder, mp 165-166 °C. HRMS calcd for

1

as a yellow oil. H 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 ) 10.8 Hz, 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 solu-

tion 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, and 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 4 N 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

C₂₂H₂₄ClN₂O₃(M + H)⁺, 399.1475; found, 399.1473. H 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 CH₂Cl₂was 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·0.33H₂O) 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 was 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 1.25 M 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)⁺,

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 concen-

trated 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). A 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

1

steps) as a white solid. H NMR (CDCl₃) δ 2.54-2.56 (m, 2H),

1

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).

336.1964; found, 336.1965. H 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,

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

7878 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24

Kurimura et al.

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 the mixture

was cooled to -50 °C, allyl bromide (7.44 mL, 0.086 mol) was

added. The mixture was allowed to warm slowly to room temper-

ature 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%

H₃PO₄at 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 concen-

trated 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%

H₃PO₄at 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 and cooled to -78 °C, and

N-bromoacetamide (8.76 g, 0.063 mol) solution in THF (40 mL)

was slowly added. After being stirred for 30 min at -78 °C, the

mixture was allowed to warm 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 NaHCO₃and CH₂Cl₂. The organic layer was washed with

H₂O and brine and dried over Na₂SO₄. Evaporation of solvent gave

the crude 36 (21 g).

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 and 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

1

white foam. H 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 and 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)

1

gave 14 (9.8 g, 26% over three steps) as a white foam. H 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 gray

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 NaHCO₃and

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

(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 and cooled to -78 °C, and

N-bromoacetamide (14.7 g, 0.104 mol) was added in several

portions. After being stirred for 30 min at -78 °C, the mixture

was allowed to warm 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

and dried over Na₂SO₄. Evaporation of solvent gave the crude 37

(37.5 g).

1

white foam. H 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.

(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)

(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 suspen-

sion of crude 41 (8.0 g, 0.02 mol) in dry THF (400 mL) was added

Oxide-Bridged 5-Phenylmorphans

Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24 7879

potassium tert-butoxide (8.0 g, 0.06 mol). The resulting gray

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, the mixture 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

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·0.75H₂O) 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). Potas-

sium 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 and brine and

dried over Na₂SO₄. After evaporation of solvent, column chroma-

tography of the crude product with EtOAc/hexanes (1:12) gave 48

1

(330 mg, 83%) of a yellow oil. H 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).

1

solid. H 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).

3(R*,6aS*,11aR*)-10-Cyclopropylmethoxyl-1,3,4,5,6,11a-

hexahydro-2H-3,6a-methanobenzofuro[2,3-c]azocin (49).

A

(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, the mixture 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/

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).

1

28% NH₄OH (91:9:1) gave 45 (0.320 g, 87%) as white solid. H

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*)-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) 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 a 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, 6.9 Hz,

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). Compound

50 (109 mg, 0.28 mmol) was dissolved in 37% HCl/MeOH (5 mL/5

mL, 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

(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·0.75H₂O) 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

7880 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24

Kurimura et al.

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, mp

(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 mm³crystal of 51 was mounted on a glass rod and transferred

to the diffractometer and data collected at room temperature

j

(298 K). The crystal was triclinic in space group P1 with unit cell

dimensions a ) 7.3609(6) Å, b ) 11.5732(12) Å, c ) 13.7532(13)

Å, R ) 75.948(4)°, ꢀ ) 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-compounds

(Figures 4-6) was done in the gaseous phase with the density

functional theory at the level of B3LYP/6-31G*.²¹These optimized

structures were overlaid onto a previously described high afﬁnity

µ-ligand (1R,5R,9S)-(-)-9-hydroxy-5-(3-hydroxyphenyl-2-phenyl-

ethyl-2-azabicyclo[3.3.1]nonane¹⁹using 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]nonane¹⁹were used a common docking point.

1

250-251 °C. H 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·0.25H₂O) C, H, N. Anal. (C₂₂H₂₅NO₂·0.75H₂O) 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 of compounds 12, 20, 47, and

51 were collected using Mo KR radiation and a Bruker APEX 2

CCD area detector. The structures was solved by direct methods

and reﬁned by full-matrix least-squares on F²values using the

programs found in the SHELXTL suite (Bruker, SHELXTL, version

6.10, 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 mm³crystal 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 ꢀ ) 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.

Acknowledgment. The research of the Drug Design and

Synthesis Section, CBRB, NIDA and NIAAA, was supported

by the NIH Intramural Research Programs of the National

Institute of Diabetes and Digestive and Kidney Diseases, the

National Institute on Drug Abuse (NIDA), and the National

Institute of Alcohol Abuse and Alcoholism, and NIDA supported

the research of the Clinical Psychopharmacology Section. We

thank Dr. John Lloyd (NIDDK) for the mass spectral data, and

we thank NIDA for support of the X-ray crystallographic studies

(NIDA Contract Y1-DA6002). The quantum chemical study

utilized PC/LINUX clusters at the Center for Molecular Model-

ing of the NIH (http://cit.nih.gov) and this research was

supported by the NIH Intramural Research Program through

the Center for Information Technology.

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, U.K. [fax +44(0)-1223-336033

or e-mail deposit@ccdc.cam.ac.uk.

(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 mm³crystal 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 ꢀ ) 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.

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JM800913D

Article Doi

Probes for narcotic receptor mediated phenomena. 37.1 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

DOI: 10.1021/jm800913d

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Article abstract of DOI:10.1021/jm800913d

Full text of DOI:10.1021/jm800913d

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