Stereocontrolled synthesis and pharmacological evaluation of cis-2, 6-diphenethyl-1-azabicyclo[2.2.2]octanes as lobelane analogues

Article abstract of DOI:10.1021/jo901082r

(Chemical Equation Presented) An efficient and highly stereocontrolled approach for the synthesis of the quinuclidine incorporated lobelane analogues, endo,endo- and exo,exo-2,6-cis-diphenethyl-1-azabicyclo-[2.2.2]octane (2 and 3), has been developed. Ana

Full text of DOI:10.1021/jo901082r

pubs.acs.org/joc
Stereocontrolled Synthesis and Pharmacological Evaluation of cis-2,
6-Diphenethyl-1-azabicyclo[2.2.2]octanes as Lobelane Analogues
Guangrong Zheng, Linda P. Dwoskin, Agripina G. Deaciuc, and Peter A. Crooks*
College of Pharmacy, University of Kentucky, Lexington, Kentucky 40536-0082
pcrooks@email.uky.edu
Received June 1, 2009
An efficient and highly stereocontrolled approach for the synthesis of the quinuclidine incorporated
lobelane analogues, endo,endo- and exo,exo-2,6-cis-diphenethyl-1-azabicyclo-[2.2.2]octane (2 and 3),
has been developed. Analogues 2 and 3 were designed to mimic the axial and equatorial geometry,
respectively, of the vesicular monoamine transporter-2 (VMAT2) inhibitor, lobelane. The exo,exo
analogue 2 had comparable affinity to lobelane and had greater affinity than the endo,endo analogue
3 at the tetrabenazine binding site on VMAT2, indicating that the preferred binding mode of lobelane
is likely the extended conformation.
Introduction
that this molecule has potential as a novel treatment for
methamphetamine abuse.
The brain vesicular monoamine transporter-2 (VMAT2),
an integral membrane protein responsible for transporting
monoamines from presynaptic cytosol into vesicles, plays
an important role in mediating the neurochemical and
behavioral effects of psychostimulants.1 This transporter is
considered to be a valid target for the development of drug
candidates for the treatment of psychostimulant abuse.2 cis-
Lobelane (N-methyl-2,6-diphenethylpiperidine; 1, Figure 1),
a minor alkaloid of Lobelia inflata,3 exhibits good affinity
and selectivity for the tetrabenazine binding site on VMAT24
and good inhibitory potency for vesicular dopamine uptake.
Importantly, behavioral studies in rats have shown that
lobelane is effective in decreasing methamphetamine self-
administration without altering food response,5 suggesting
Given the flexibility that lobelane exhibits, it can exist in a
range of conformers; the two phenethyl groups attached to
the C-2 and C-6 of the central piperidine ring can position
themselves either in the axial or in the energetically favorable
equatorial orientations. However, the low-energy confor-
mers of ligand molecules may not always be the one that
binds to the biological target. Thus, it is of interest to identify
the “biologically” active conformation of lobelane that binds
to the tetrabenazine binding site on VMAT2. Such knowl-
edge may provide insight into the optimal pharmacophoric
requirements for high-affinity binding of lobelane analogues
to this transporter. In the present investigation, we designed
two model compounds, 2 and 3 (Figure 1), in which a rigid
1-azabicyclo[2.2.2]octane (quinuclidine) moiety has replaced
the piperidine ring in the lobelane molecule. The incorpora-
tion of the quinuclidine ring into the molecule allows the
design of analogues that can mimic the stereochemistry of
either the confined axial, axial conformer of lobelane (i.e.,
the endo,endo analogue 2) or the fully extended equatorial,
equatorial lobelane conformer (i.e., the exo,exo analogue 3).
Restriction of conformational flexibility is an extensively
used tactic in medicinal chemistry to predispose a ligand into
(1) Zheng, G.; Dwoskin, L. P.; Crooks, P. A. AAPS J. 2006, 8, E682-
E692 and the references cited therein.
(2) Dwoskin, L. P.; Crooks, P. A. Biochem. Pharmacol. 2002, 63, 89–98.
€
(3) Wieland, H.; Schopf, C.; Hermsen, W. Liebigs Ann. Chem. 1925, 444,
40–68.
(4) Zheng, G.; Dwoskin, L. P.; Deaciuc, A. G.; Norrholm, S. D.; Crooks,
P. A. J. Med. Chem. 2005, 48, 5551–5560.
(5) Neugebauer, N. M.; Harrod, S. B.; Stairs, D. J.; Crooks, P. A.;
Dwoskin, L. P.; Bardo, M. T. Eur. J. Pharmacol. 2007, 571, 33–38.
6072 J. Org. Chem. 2009, 74, 6072–6076
Published on Web 07/02/2009
DOI: 10.1021/jo901082r
r
2009 American Chemical Society

Zheng et al.
JOCArticle
of the resulting product 10 with BnBr in the presence of
K2CO3 in DMF (87% yield), afforded the O-benzylated
product 11. N-Benzylation of 11 by treatment with excess
BnBr (20 equiv) in ACN afforded the quaternary ammon-
ium product 12.9 Reduction of 12 with NaBH4 in EtOH
afforded the tetrahydropyridine product 13 (89% yield),
which upon treatment with CF3COOH in DCM/H2O yielded
piperidinone 14 (92% yield). The N-benzyl group in 14
was then replaced with an N-Troc group by initial Pd/C-
catalyzed hydrogenolysis (96% yield), followed by reaction
of the N-deprotected product with 2,2,2-trichloroethyl chloro-
formate (TrocCl) (92% yield), to afford the desired inter-
mediate 6.
FIGURE 1. Lobelane (1) and the conformationally restricted ana-
logues 2 and 3.
SCHEME 1. Retrosynthetic Analysis of Analogues 2 and 3
Although the above synthetic approach afforded the
requisite intermediate 6, it suffered from a somewhat lengthy
procedure, poor overall yield, and more importantly, it
lacked the flexibility for preparing nonsymmetrical analo-
gues, i.e., with different substituents at C-2 and C-6 of the
central piperidine ring. In this respect, we were particularly
interested in preparing analogues in which the ethylene
linkers between the phenyl rings and the central ring have
been replaced with different carbon linker lengths.10 Thus,
we turned to the preparation of 6 utilizing a strategy deve-
loped by the Comins group,11 which involves sequential
stereoselective nucleophilic additions to N-acyl pyridinium
salts of 4-methoxypyridine (8). The synthesis commenced
with an in situ preparation of the N-acyl pyridinium salt
formed on treatment of 8 with TrocCl. Phenethyl magnesium
chloride (PEMgCl) was then added to the pyridinium salt,
and after the reaction was completed, the resulting mixture
was treated with aqueous HCl to furnish 2-phenethyl-3,4-
dihydro-4-pyridone 15 (78% yield) (Scheme 3).11a 15 was
also prepared via hydrogenation of compound 16 (94%
yield), which was readily prepared from 8 (70% yield) by
adapting a method of CuI-catalyzed direct alkyne addition
to an N-acylated aza-aromatic ion.12
a desired conformation.6 The constrained positional and
stereochemical orientations of compounds 2 and 3 could
provide a preliminary structural model to probe the spatial
and conformational requirements for the binding of lobelane
analogues at VMAT2.
Results and Discussion
A retrosynthetic analysis of analogues 2 and 3 in Scheme 1
shows that both should be accessible from a SN2-type
cyclization of intermediates 4 and 5, respectively. We expected
that 4 and 5 could be obtained via a Horner-Wadsworth-
Emmons (HWE) reaction of 6, followed by the stereoselective
reduction method developed by Watson et al.,7 and finally
bromination.
We originally planned to prepare the piperidinone inter-
mediate 6from 2,6-dimethyl-4-hydroxypyridine (7) (Scheme 2).
7 was reacted with excess benzaldehyde in acetic anhydride
under reflux to form the conjugated product 9 (38% yield).8
Reduction of the two double bonds in 9 by Pd/C-catalyzed
hydrogenation (quantitative yield), followed by treatment
With 15 in hand, we first attempted the Cu-mediated
conjugate addition with PEMgCl in the presence of CuBr
SMe2 and BF3 OEt2, a frequently used condition that was
3
3
introduced by Comins to selectively generate cis-2,6-disub-
stituted piperidinones.13 Disappointingly, the reaction
yielded a mixture of cis/trans isomers (i.e., 6 and the trans
isomer 17) in an approximate ratio of 60:40 (determined by
1H NMR of the crude mixture, entry 1 in Table 1).14 The two
(10) Zheng, G.; Dwoskin, L. P.; Deaciuc, A. G.; Crooks, P. A. Bioorg.
Med. Chem. Lett. 2008, 18, 6509–6512.
(11) (a) Comins, D. L.; Brown, J. D. Tetrahedron Lett. 1986, 27, 4549–
4552. (b) Brown, J. D.; Foley, M. A.; Comins, D. L. J. Am. Chem. Soc. 1988,
110, 7445–7447. (c) Comins, D. L.; LaMunyon, D. H. Tetrahedron Lett.
1989, 30, 5053–5056. (d) Comins, D. L.; Joseph, S. P.; Goehring, R. R. J. Am.
Chem. Soc. 1994, 116, 4719–4728.
(12) (a) Yadav, J. S.; Reddy, B. V. S.; Sreenivas, M.; Sathaiah, K.
Tetrahedron Lett. 2005, 46, 8905–8908. (b) Black, D. A.; Beveridge, R. E.;
Arndtsen, B. A. J. Org. Chem. 2008, 73, 1906–1910.
(6) Mann, A. In The Practice of Medicinal Chemistry, 3rd ed.; Wermuth,
C. G., Ed.; Elsevier/Academic Press: Burlington/San Diego/London, 2008;
Chapter 17, pp 363-379.
(7) (a) Watson, P. S.; Jiang, B.; Scott, B. Org. Lett. 2000, 2, 3679–3681.
(b) Watson, P. S.; Jiang, B.; Harrison, K.; Asakawa, N.; Welch, P. K.;
Covington, M.; Stowell, N. C.; Wadman, E. A.; Davies, P.; Solomon, K. A.;
Newton, R. C.; Trainor, G. L.; Friedman, S. M.; Decicco, C. P.; Ko, S. S.
Bioorg. Med. Chem. Lett. 2006, 16, 5695–5699.
(8) (a) The reaction was completed in 12 days, reduced to 5 days when
the reaction temperature was increased by using propionic anhydride;
however, the yield dropped to ca. 25%. (b) The isolation and purification
of 9 turned out to be tedious.
(9) Compound 12 was obtained in only 36% yield even after reflux for 4
days, along with the recovery of 45% of the starting material 11. Similar
results were observed when acetone was used as the solvent. When alcohols
were used as solvent, only the debenzylation product (i.e., compound 10)
could be detected. For example, a quantitative amount of 10 was obtained
when 11 was treated with BnBr in 4-methyl-2-pentanol (bp 131-134 °C)
under reflux for 4 h.
(13) For examples, see: (a) Reference 11b. (b) Comins, D. L.; Zeller, E.
Tetrahedron Lett. 1991, 32, 5889–5892. (c) Comins, D. L.; Dehghani, A. J. Org.
Chem. 1995, 60, 794–795. (d) Comins, D. L.; Lamunyon, D. H.; Chen, X. J. Org.
~
ꢀ
Chem. 1997, 62, 8182–8187. (e) Mancheno, O. G.; Arrayas, R. G.; Adrio, J.;
Carretero, J. C. J. Org. Chem. 2007, 72, 10294–10297. (f) McCall, W. S.; Grillo,
T. A.; Comins, D. L. Org. Lett. 2008, 10, 3255–3257.
(14) For examples of low selective Grignard addition under the treatment
of CuBr and BF3, see: (a) Klegraf, E.; Follmann, M.; Schollmeyer, D.; Kunz,
H. Eur. J. Org. Chem. 2004, 69, 3346–3360. (b) Richards, S.; Sorensen, B.;
Jae, H.; Winn, M.; Chen, Y.; Wang, J.; Fung, S.; Monzon, K.; Frevert, E. U.;
Jacobson, P.; Sham, H.; Link, J. T. Bioorg. Med. Chem. Lett. 2006, 16, 6241–
6245.
J. Org. Chem. Vol. 74, No. 16, 2009 6073

Zheng et al.
JOCArticle
SCHEME 2. Synthesis of Intermediate 6 from 7
TABLE 1. Grignard Addition of 15 and 16
reagents (equiv)
product ratioa
entry
PhCH2CH2MgCl
CuBr SMe2
CuI
2.0
BF3 OEt2
Me3SiCl
5.0
cis (%)
trans (%)
yieldc (%)
3
2.0
3
2.0
1
2
3
4
5
15
16
2.0
2.0
2.0
2.0
2.0
60
50
100
100
45
40
50
0b
0b
55
91
81
75
90
86
2.0
2.0
2.0
1.5
2.0
6
7
8
9
3.0
3.0
2.0
2.0
3.0
3.0
2.0
69
100
91
31
0b
9
84
70
5.0
NDd
1.5
27
73
NDd
aEstimated by 1H NMR integrations of the crude reaction mixtures. bNo trans product observed from NMR analysis. cCombined yield of cis and
trans products after column chromatography separation. dNot determined.
SCHEME 3. Synthesis of Intermediate 6 from 8
isomers were readily separable by silica gel flash chromato-
graphy, and the structure of the trans isomer 17 was con-
firmed by X-ray crystallography.
To improve selectivity for the cis isomer 6, a number of
conditions were examined for the Grignard addition reaction
(Table 1). When PEMgCl was treated with CuI and BF3
3
OEt2,11b an increased amount of trans isomer was detected
(ca. 50:50 cis/trans, entry 2) . When PEMgCl was treated
with CuBr SMe2 in the absence of BF3 OEt2, only the cis
3
3
product (6) was detected (75% yield, entry 3).15 The yield was
improved to 90% in the presence of chlorotrimethylsilane
(TMSCl) (entry 4).16 Since BF3 OEt2 appears to cause an
3
increase in trans-isomer production, we next attempted the
reaction without Cu(I). The reaction proceeded smoothly
and the ratio of trans product (17) was increased (ca. 45:55
of cis/trans, entry 5). Similar results were obtained when
the above conditions were applied to compound 16 (entries
6-9).17
As evidenced by the X-ray crystal structure of 16 (see
Supporting Information), the phenethyl group at C-2 of 15
and the phenethynyl group at C-2 of 16 prefer to occupy the
axial/pseudoaxial positions, due to their strong A(1,3)-inter-
actions18 with the N-Troc group. The crystal structure of 16
also indicates that these molecules adopt a sofa conforma-
tion, in which C-3, C-4, C-5, C-6, and the N-acyl group are
approximately coplanar. The Grignard conjugate addition
of the R,β-enone system in 20 (15 and 16) (Figure 2) favors
axial attack owing to stereoelectronic effects.11b,19 As shown
in Figure 2, addition of the nucleophile (R2M) to the bottom
face of 20 (path b) affords the unfavorable twisted-boat-like
conformation product, 22 (2,6-trans-), while top face attack
(path a) leads to the stable chair conformation product
(15) For example of copper-mediated cis selective Grignard addition in
the absence of BF3, see: Heintzelman, G. R.; Fang, W.; Keen, S. P.; Wallace,
G. A.; Weinreb, S. M. J. Am. Chem. Soc. 2001, 123, 8851-8853 and 2002,
124, 3939-3945.
(16) (a) Bertz, S. H.; Miao, G.; Rossiter, B. E.; Snyder, J. P. J. Am. Chem.
Soc. 1995, 117, 11023–11024. (b) Xie, C.; Runnegar, M. T. C.; Snider, B. B. J.
Am. Chem. Soc. 2000, 122, 5017–5024.
(17) The stoichiometries of PEMgCl and additives, as listed in Table 1,
were adjusted to ensure the completion of the reactions, but were not fully
optimized.
(18) Hoffmann, R. W. Chem. Rev. 1989, 89, 1841–1873.
(19) Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry;
Pergamon: New York, 1983; Chapter 6, pp 209-290.
6074 J. Org. Chem. Vol. 74, No. 16, 2009

Zheng et al.
JOCArticle
SCHEME 4. Synthesis of the Final Products 2 and 3
TABLE 2. Inhibition Constants (Ki) for Analogues at the [3H]DTBZ
Binding Site (VMAT2) on Rat Synaptic Vesicle Membranes
compd
Ki, μM ((SEM)a
lobelane (1)
2
3
0.97 ( 0.19
9.83 ( 2.42
1.36 ( 0.19
aEach Ki value represents data from four independent experiments,
each performed in duplicate.
HPLC) (38% yield). The Troc group was also removed
during the reaction. In contrast, compound 24 furnished
exclusively the 2,4-cis-isomer 26 under similar reaction con-
ditions (75% yield).24 Compounds 25 and 26, both of which
contained small amounts of Birch reduction products, were
purified by silica gel column chromatography after treat-
ment with MnO2. Bromination of 25 and 26 with CBr4/PPh3
followed by cyclization afforded the desired lobelane analo-
gues 2 (77% yield) and 3 (84% yield), respectively.
The ability of compounds 2 and 3 to interact with VMAT2
(Table 2) was assessed by determining inhibition of [3H]-
dihydrotetrabenazine ([3H]DTBZ) binding to rat brain vesicle
preparations, using a high-throughput 96-well assay.10 The
exo,exo analogue 3 exhibited similar affinity for VMAT2 as
lobelane (1), while the endo,endo analogue 2 displayed 10-fold
less potency compared to lobelane in inhibiting [3H]DTBZ
binding. These results suggest that lobelane binds to VMAT2
likely in a fully extent form, in which the two phenethyl
substituents at C-2 and C-6 of piperidine ring are in an
equatorial, equatorial conformation.
FIGURE 2. Stereochemical course of the conjugated addition re-
action.
21 (2,6-cis-). Thus the formation of the cis product via top
face attack should be preferential. However, when the size of
the nucleophile is large, the facial selectivity may be de-
creased20 or reversed.21 In addition, the selectivity could also
be dramatically affected by reaction conditions, as indicated
in the present study, and in the literature.11b In the present
study, BF3 OEt2 appears to promote the bottom face attack
to form the trans isomers. It is well-established that BF3
3
3
OEt2 generates kinetically more reactive organocuprates,
and therefore increases the reaction rate of nucleophilic
additions,22 which may explain the increased amount of
the kinetically controlled product (i.e., trans isomer).
HWE olefination of 6 with triethyl phosphonoacetate
furnished the corresponding R,β-unsaturated ester 23 (95%
yield) (Scheme 4). It is worth mentioning that reduction of
the double bond in 23, by catalytic hydrogenation with
various catalysts, was unsuccessful. However, the double
bond in 24, which was obtained by removing the Troc
protecting group in 23 (90% yield), was readily reduced by
hydrogenation to afford a mixture of two inseparable iso-
mers in a ratio of approximately 7 to 3 (cis to trans).23
Dissolving metal reduction of compound 23, a procedure
developed by Watson et al.,7 provided the 2,4-trans-isomer
25 with high stereoselectivity (16:1, trans:cis, as measured by
Conclusion
In conclusion, two conformational restricted quinucli-
dine-containing lobelane analogues were synthesized via an
efficient and highly stereocontrolled synthetic route.
Although no improvement in binding affinity at VMAT2
was observed with these rigidified analogues, we expected
analogue 3 to have improved selectivity for VMAT2; this
work is currently under investigation.
(20) Munoz, B.; Chen, C.; McDonald, I. A. Biotechnol. Bioeng. 2000, 71,
78–84.
Experimental Section
(21) Christopher, L.; Hamblett, C. L.; Sloman, D. L.; Kliman, L. T.;
Adams, B.; Ball, R. G.; Stantona, M. G. Tetrahedron Lett. 2007, 48, 2079–
2082.
(22) (a) Lipshutz, B. H.; Ellsworth, E. L.; Siahaan, T. J. J. Am. Chem.
Soc. 1988, 110, 4834–4835. (b) Lipshutz, B. H.; Ellsworth, E. L.; Siahaan, T.
J. J. Am. Chem. Soc. 1989, 111, 1351–1358.
{cis-N-[(2,2,2-Trichloroethoxy)carbonyl]-2,6-diphenethylpi-
peridine-4-ylidene}acetic Acid Methyl Ester (23). To a suspension
of NaH (160 mg, 60% dispersion in mineral oil, 4.01 mmol) in
(23) As measured by HPLC, after DIBAL-H reduction to a mixture of
hydroxyl compounds (i.e., 25 and 26).
(24) The stereochemistry at C-4 of 25 and 26 was confirmed by NOESY
experiments of their corresponding cyclization products 2 and 3.
J. Org. Chem. Vol. 74, No. 16, 2009 6075

Zheng et al.
JOCArticle
THF (20 mL) at 0 °C was added triethyl phosphonoacetate
(899 mg, 4.01 mmol) in THF (10 mL) and the resulting mixture
was stirred for 30 min. A solution of 6 (1.29 g, 2.67 mmol) in THF
(10 mL) was added dropwise, and the reaction was stirred at 0 °C
for 4 h before quenching with saturated aqueous NH4Cl and
dilution with water. The aqueous phase was extracted with
EtOAc. The combined organic layers were washed with water
and brine, dried over anhydrous Na2SO4, filtered, and concen-
trated under reduced pressure. The crude product was chroma-
tographed on silica (hexanes/EtOAc 10:1) to afford 23 (1.40 g,
95%) as a colorless oil: 1H NMR (300 MHz) δ 1.30 (t, J =7.2 Hz,
3H), 1.65-1.98 (m, 4H), 2.22-2.35 (m, 2H), 2.51-2.70 (m, 4H),
2.75-2.90 (m, 1H), 4.07 (br d, J = 12.9 Hz, 1H), 4.19 (q, J = 7.2
Hz, 2H), 4.48-4.72 (m, 3H), 4.94 (br t, J =12.9 Hz, 1H), 5.85 (s,
1H), 7.05-7.32 (m, 10H); 13C NMR (75 MHz) δ 14.6, 31.3, 33.8,
34.1, 37.0, 37.4, 38.1, 39.3, 53.8, 54.0, 60.2, 75.4, 95.8, 118.8, 126.0,
126.2, 128.39, 128.43, 128.5, 141.2, 141.7, 153.0, 153.9, 165.9; MS
(EI) m/z 551/553/555, 446/448/450, 400/402/404 (100), 342/344/
346, 181, 117, 91; HRMS calcd for C28H3235Cl3NO4 (Mþ) m/z
551.1396, found 551.1383.
(cis-2,6-Diphenethylpiperidine-4-ylidene)acetic Acid Methyl
Ester (24). To a solution of 23 (1.04 g, 1.88 mmol) in HOAc/
CH2Cl2 (3/1, 20 mL) at 0 °C was added zinc dust (1.0 g) in
portions and the resulting suspension was stirred vigorously at
roomtemperature for 6 h. The mixture was filtered, concentrated,
neutralized with saturated aqueous K2CO3, and extracted with
CH2Cl2. The combined organic layers were dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The
crude product was chromatographed on silica (hexanes/EtOAc
2:1) to afford 24 (639 mg, 90%) as a colorless oil: 1H NMR (300
MHz) δ 1.28 (t, J = 7.2 Hz, 3H), 1.44 (br s, 1H), 1.62-1.90 (m,
5H), 1.97 (t, J = 12.0 Hz, 1H), 2.24 (d, J =12.6 Hz, 1H), 2.51-
2.73 (m, 6H), 3.95 (d, J = 13.5 Hz, 1H), 4.15 (q, J =7.2 Hz, 2H),
5.63 (s, 1H), 7.14-7.33 (m, 10H); 13C NMR (75 MHz) δ 14.6,
32.6, 32.7, 36.7, 38.8, 39.0, 44.3, 57.1, 57.6, 59.9, 114.3, 126.0,
126.1, 128.4, 128.5, 128.6, 141.8, 141.9, 159.3, 166.7; MS (EI) m/z
377 (Mþ), 348, 332, 272 (100), 250, 226, 117, 91; HRMS calcd for
C25H31NO2 (Mþ) m/z 377.2354, found 377.2353.
(m, 10H); 13C NMR (75 MHz, CDCl3) δ 28.9, 32.8, 35.4, 37.1,
39.3, 51.3, 61.7, 126.0, 128.46, 128.54, 142.3; MS (EI) m/z 337
(Mþ) 336, 319, 290, 246, 232 (100), 91; HRMS calcd for
C23H31NO (Mþ) m/z 337.2405, found 337.2406.
(cis-2,6-Diphenethylpiperidine-cis-4-yl)ethanol (26). Starting
from 24 (118 mg, 0.31 mmol), 26 was prepared as a colorless
oil (79 mg, 75%) utilizing a similar procedure to that described
above for 25: 1H NMR (300 MHz, CDCl3) δ 0.83 (q, J=11.4 Hz,
2H), 1.45-1.63 (m, 3H), 1.65-1.78 (m, 6H), 1.80-2.10 (m,
NH), 2.54 (ddt, J=8.7, 6.6, 2.1 Hz, 2H), 2.62 (t, J = 8.1 Hz, 4H),
3.67 (t, J = 6.6 Hz, 2H), 7.12-7.36 (m, 10H); 13C NMR (75
MHz, CDCl3) δ 32.7, 32.9, 38.7, 39.3, 40.1, 56.4, 60.4, 125.9,
128.4, 128.5, 142.1; MS (EI) m/z 337 (Mþ) 336, 319, 290, 246, 232
(100), 91; HRMS calcd for C23H31NO (Mþ) m/z 337.2405,
found 337.2406.
endo,endo-2,6-Diphenethyl-1-azabicyclo[2.2.2]octane (2). To a
solution of 25 (92 mg, 0.27 mmol) and CBr4 (136 mg, 0.41 mmol)
in CH2Cl2 (10 mL) at 0 °C was added dropwise a solution of
PPh3 (108 mg, 0.41 mmol) in CH2Cl2 (5 mL). The mixture was
stirred at 0 °C for 30 min and poured into hexanes/EtOAc (4:1)
(60 mL). The resulting suspension was filtered through a silica
column, and eluted with hexanes/EtOAc (4:1) and then CH2Cl2/
MeOH (30:1). The combined filtrates were concentrated. The
crude product was dissolved in THF/H2O (3:1, 25 mL) and 15%
aqueous NaOH (5 mL) was added. The resulting mixture was
heated under reflux for 24 h. Brine (20 mL) was added to the
mixture and the aqueous phase was extracted with CHCl3. The
combined organic layers were dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The crude
product was chromatographed on silica (CH2Cl2/MeOH/
NH4OH 20:1:0.2) to afford 2 (66 mg, 77%) as a colorless oil:
1H NMR (300 MHz, CDCl3) δ 1.17-1.34 (m, 2H), 1.43-1.57
(m, 2H), 1.72-1.96 (m, 5H), 2.05-2.21 (m, 2H), 2.67 (t, J=7.8
Hz, 4H), 2.70-3.03 (m, 4H), 7.07-7.38 (m, 10H); 13C NMR (75
MHz, CDCl3) δ 23.2, 24.4, 34.0, 35.0, 40.8, 54.5, 57.8, 125.9,
128.5, 128.6, 142.2; MS (EI) m/z 319, 304, 278, 228, 214 (100),
124, 91; HRMS calcd for C23H29N (Mþ) m/z 319.2300, found
319.2299.
(cis-2,6-Diphenethylpiperidine-trans-4-yl)ethanol (25). To a
solution of anhydrous liquid NH3 (40 mL) and THF (30 mL)
at -78 °C was added lithium wire (500 mg, 72 mmol), cut into
small pieces. The resulting blue solution was stirred for 30 min.
A solution of 23 (400 mg, 0.72 mmol) in THF (10 mL) was added
dropwise and the reaction temperature was allowed to slowly
increase to -30 °C over 1 h, and maintained at this temperature
for another 30 min. The reaction was then quenched with solid
NH4Cl (4.15 g, 79 mmol) and with continual stirring at room
temperature until the ammonia was completely evaporated. The
residue was taken up into water and extracted with CH2Cl2. The
combined organic layers were dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The crude
product was filtered through a short silica column, eluted with
CH2Cl2/MeOH/NH4OH (10:1:0.2). The resulting product was
dissolved in CHCl3 (20 mL) and MnO2 (120 mg) was added.
After being stirred for 24 h at room temperature, the reaction
mixture was filtered through Celite and the solvent was removed
under reduced pressure. The crude product was chromato-
graphed on silica (CH2Cl2/MeOH/NH4OH 30:1:0.2) to afford
25 (92 mg, 38%) as a colorless oil: 1H NMR (300 MHz, CDCl3)
δ 1.20-1.78 (m, 11H), 1.97-2.04 (m, NH), 2.62 (t, J = 8.1 Hz,
4H), 2.63-2.77 (m, 2H), 3.67 (t, J = 6.9 Hz, 2H), 7.10-7.34
exo,exo-2,6-Diphenethyl-1-azabicyclo[2.2.2]octane (3). Com-
pound 3 (62 mg, 84%) was prepared as a colorless oil utilizing a
similar procedure to that described above for 2, from starting
material 26 (79 mg, 0.23 mmol): 1H NMR (300 MHz, CDCl3) δ
1.15 (dt, J = 13.2, 3.0 Hz, 2H), 1.42 (br t, J = 6.6 Hz, 2H), 1.66-
1.86 (m, 5H), 2.07-2.21 (m, 2H), 2.70 (t, J =7.8 Hz, 4H), 2.68-
2.82 (m, 2H), 2.91 (t, J =7.8 Hz, 2H), 7.10-7.35 (m, 10H); 13
C
NMR (75 MHz, CDCl3) δ 23.4, 27.0, 32.8, 33.0, 35.7, 37.2, 58.2,
125.9, 128.4, 128.6, 142.3; MS (EI) m/z 319, 304, 278, 228 (100),
214, 186, 117, 91; HRMS calcd for C23H29N (Mþ) m/z 319.2300,
found 319.2300.
Acknowledgment. We are grateful to NIH/NIDA
(DA13519) for financial support. We thank Dr. Sean Parkin
for the crystal structure analysis and Dr. Jack Goodman for
the HRMS analysis.
Supporting Information Available: Full experimental pro-
cedures, copies of 1H and 13C NMR spectra for all compounds,
crystal structures, and crystallographic information files (CIFs)
for compounds 16 and 17. This material is available free of
charge via the Internet at http://pubs.acs.org.
6076 J. Org. Chem. Vol. 74, No. 16, 2009