Total synthesis of (-)-epibatidine using an asymmetric Diels-Alder reaction with a chiral n-acylnitroso dienophile

Article abstract of DOI:10.1021/jo9813078

An asymmetric total synthesis of (-)-epibatidine (1), isolated from the skin of the Ecuadorian poison frog, Epipedobates tricolor, of the family Dendrobatidae, has been achieved by virtue of the development of asymmetric hereto Diels-Alder (D-A) cycloaddition with an N-acylnitroso dienophile bearing the optically active 8-arylmenthol as a chiral source. Thus, in situ oxidation of the hydroxamic acid ent-12f incorporating the (1S,2R,5S)-8-(2- naphthyl)menthyl auxiliary was performed using the Swern conditions to produce the acylnitroso dienophile, which reacted at once with 2-chloro-5- (1,5-cyclohexadienyl)pyridine (7) to provide the (1S,4R)-meta-aza cycloadduct 24 as a major diastereoisomer. The observed facial diastereoselectivity is consistent with a transition-state model with the naphthyl group in 'stacked' position and with the acylnitroso group in the s-cis conformation, wherein π attractive interaction between the naphthyl and nitrosocarbonyl groups may contribute to facial control. Compound 24 underwent hydrogenation followed by removal of the chiral auxiliary with LiH₂NBH₃ and reductive cleavage of the N-O bond with Mo(CO)₆ to give the amino alcohol derivative 29, which was converted to (-)-epibatidine via bromination followed by cyclization.

Full text of DOI:10.1021/jo9813078

J . Org. Chem. 1998, 63, 8397-8406
8397
Tota l Syn th esis of (-)-Ep iba tid in e Usin g a n Asym m etr ic
Diels-Ald er Rea ction w ith a Ch ir a l N-Acyln itr oso Dien op h ile
Sakae Aoyagi, Ryuta Tanaka, Masaichi Naruse, and Chihiro Kibayashi*
School of Pharmacy, Tokyo University of Pharmacy & Life Science, Horinouchi, Hachioji,
Tokyo 192-03,92 J apan
Received J uly 6, 1998
An asymmetric total synthesis of (-)-epibatidine (1), isolated from the skin of the Ecuadorian poison
frog, Epipedobates tricolor, of the family Dendrobatidae, has been achieved by virtue of the
development of asymmetric hetero Diels-Alder (D-A) cycloaddition with an N-acylnitroso
dienophile bearing the optically active 8-arylmenthol as a chiral source. Thus, in situ oxidation of
the hydroxamic acid ent-12f incorporating the (1S,2R,5S)-8-(2-naphthyl)menthyl auxiliary was
performed using the Swern conditions to produce the acylnitroso dienophile, which reacted at once
with 2-chloro-5-(1,5-cyclohexadienyl)pyridine (7) to provide the (1S,4R)-meta-aza cycloadduct 24
as a major diastereoisomer. The observed facial diastereoselectivity is consistent with a transition-
state model with the naphthyl group in “stacked” position and with the acylnitroso group in the
s-cis conformation, wherein π attractive interaction between the naphthyl and nitrosocarbonyl
groups may contribute to facial control. Compound 24 underwent hydrogenation followed by
removal of the chiral auxiliary with LiH2NBH3 and reductive cleavage of the N-O bond with
Mo(CO)6 to give the amino alcohol derivative 29, which was converted to (-)-epibatidine via
bromination followed by cyclization.
In tr od u ction
attributed to its unique property as an extremely potent
nicotinic acetylcholine receptor (nAChR) agonist in the
central and autonomic nervous systems.4,5,7,9-13 A num-
ber of nAChR ligands have been reported that are
selective for neuronal nAChR subtypes and may have
potential in the treatment of Alzheimer’s disease and
Parkinson’s disease.14
Due to its outstanding pharmacological action, unique
structure, and scarcity in nature, epibatidine has at-
tracted the unprecedentedly great interest of synthetic
chemists around the world,15 and in a relatively short
time a vast number of synthetic approaches has been
In the mid-1970s a novel class of amphibian alkaloid
epibatidine was first isolated by Daly and co-workers at
the National Institutes of Health in a trace amount from
the skin of the Ecuadorian poison frog, Epipedobates
tricolor, of the family Dendrobatidae.1 Its structure 1 was
elucidated by this research group in 1992,2 revealing the
relative stereochemistry and unprecedented feature with
a strained nitrogen-bridged six-membered carbon ring
system (7-azabicyclo[2.2.1]heptane) with an exooriented
3-(6-chloropyridyl) substituent. Because of the very small
quantities of the natural product (less than 1 mg isolated
from 750 frogs), the assignment of absolute stereochem-
istry was investigated subsequently by Fletcher et al.3
in 1994, establishing it as 1R,2R,4S as shown.
(9) Damaj, M. I.; Creasy, K. R.; Grove, A. D.; Rosecrans, J . A.;
Martin, B. R. Brain Res. 1994, 664, 34.
(10) Houghtling, R. A.; Da´vila-Garc´ıa, M. I.; Hurt, S.; Kellar, K. J .
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In preliminary tests on mice, it proved to be at least
200 times more potent than morphine in bioassays of
analgesic effects, but its effect was not blocked by the
potent opioid receptor antagonist naloxone, confirming
that its strong analgesic action evolves via a nonopioid
mechanism.2,4-8 Subsequent studies showed that the
remarkable pharmacological activity of epibatidine is
(13) Sullivan, J . P.; Briggs, C. A.; Donnelly-Roberts, D.; Brioni, J .
D.; Radek, R. J .; McKenna, D. G.; Campbell, J . E.; Arneric, S.; P.;
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Radek, R. J .; Raszkiewicz, J . L.; Kang, C. H.; Kim, D. J . B.; Giardina,
W. J .; Wasicak, J . T.; Garvey, D. S.; Williams, M.; Arneric, S. P. J .
Pharmacol. Exp. Ther. 1994, 270, 319. (b) Decker, M. W.; Bannnon,
A. W.; Curzon, P.; Gunther, K. L.; Brioni, J . D.; Holladay, M. W.; Lin,
N.-H.; Li, Y.; Daanen, J . F.; Buccafusuco, J . J .; Prendergast, M. A.;
J ackson, W. J .; Arneric, S. P. J . Pharmacol. Exp. Ther. 1997, 283, 247.
(c) Lippiello, P. M.; Bencherif, M.; Gray, J . A.; Peters, S.; Grigoryan,
G.; Hodges, H.; Collins, A. C. J . Pharmacol. Exp. Ther. 1996, 279, 1422.
(d) Meyer, E. M.; de Fiebre, C. M.; Hunter, B. E.; Simpkins, C. E.;
Frauworth, N.; de Fiebre, N. E. C. Drug Dev. Res. 1994, 31, 127. (e)
Menzaghi, F.; Whelan, K. T.; Risbrough, V. B.; Rao, T. S.; Lloyd, G. K.
J . Pharmacol. Exp. Ther. 1997, 280, 393.
(15) For reviews on the total synthesis of epibatidine, see: (a)
Sza´ntay, C.; Kardos-Balogh, Z.; Sza´ntay, C., J r. In The Alkaloids;
Cordell, G. A., Ed.; Academic Press: San Diego, 1995; Vol. 46, pp 95-
125. (b) Chen, Z.; Trudell, M. L. Chem. Rev. 1996, 96, 1179. (c)
Kibayashi, C.; Aoyagi, S. In Studies in Natural Products Chemistry;
Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 1997; Vol. 19, pp 66-
81.
(1) Daly, J . W. J . Nat. Prod. 1998, 61, 162.
(2) Spande, T. F.; Garraffo, H. M.; Edwards, M. W.; Yeh, H. J . C.;
Pannel, L.; Daly, J . W. J . Am. Chem. Soc. 1992, 114, 3475-3478.
(3) (a) Fletcher, S. R.; Baker, R.; Chambers, M. S.; Hobbs, S. C.;
Mitchell, P. J . J . Chem. Soc., Chem. Commun. 1993, 1216. (b) Fletcher,
S. R.; Baker, R. B.; Chambers, M. S.; Herbert, R. H.; Hobbs, S. C.;
Thomas, S. R.; Verrier, H. M.; Watt, A. P.; Ball, R. G. J . Org. Chem.
1994, 59, 1771.
(4) Badio, B.; Daly, J . W. Mol. Pharmacol. 1994, 45, 563.
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Lett. 1993, 3, 2759.
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10.1021/jo9813078 CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/27/1998

8398 J . Org. Chem., Vol. 63, No. 23, 1998
Aoyagi et al.
published.16,17 Furthermore, the fact that the collection
of dendrobatid frogs has been prevented by an inter-
national treaty18 enacted in 1984 for the protection of
endangered species has also spurred synthetic efforts to
prepare needed material for further investigation. Of
these synthetic approaches, however, only two asym-
metric total syntheses of (-)-epibatidine (1), which is the
natural enantiomer, have been reported: in one case via
Pd-catalyzed desymmetrization reported by Trost16p and
in the other case via asymmetric protonation reported
by Kosugi.16s In connection with our ongoing projects
related to the use of acylnitroso Diels-Alder method-
ology in alkaloid synthesis,19,20 we now report a new
asymmetric approach to 1 based on asymmetric hetero
Diels-Alder cycloaddition with an acylnitroso dienophile
bearing the optically active 8-arylmenthol as a chiral
source.21
Sch em e 1
Resu lts a n d Discu ssion
Our strategy for the synthesis of 1 is outlined in the
retrosynthetic pathway depicted in Scheme 1. The basic
approach featured the general methodology for the asym-
metric hetero Diels-Alder reaction of 2-chloro-5-(1,5-
cyclohexadienyl)pyridine (7) with the acylnitroso com-
pound 6 bearing an appropriate chiral auxiliary as the
key step, in which either enantioselective pathway, via
(16) For the total synthesis of epibatidine, see: (a) Broka, C. A.
Tetrahedron Lett. 1993, 34, 3251. (b) Huang, D. F.; Shen, T. Y.
Tetrahedron Lett. 1993, 34, 4477. (c) Corey, E. J .; Loh, T.-P.;
AchyuthaRao, S.; Daley, D. C.; Sarshar, S. J . Org. Chem. 1993, 58,
5600. (d) Clayton, S. C.; Regan, A. C. Tetrahedron Lett. 1993, 34, 7493.
(e) Senokuchi, K.; Nakai, H.; Kawamura, M.; Katsube, N.; Nonaka,
S.; Sawaragi, H.; Hamanaka, N. Synlett 1994, 343. (f) Sza´ntay, C.;
Kardos-Balogh, Z.; Moldvai, I.; Sza´ntay, C., J r.; Temesva´ri-Major, E.;
Blasko´, G. Tetrahedron Lett. 1994, 35, 3171. (g) Sestanj, K.; Melenski,
E.; J irkovsky, I. Tetrahedron Lett. 1994, 35, 5417. (h) Pandey, G.;
Bagul, T. D.; Lakshmaiah, G. Tetrahedron Lett. 1994, 35, 7439. (i)
Albertini, E.; Barco, A.; Benetti, S.; De Risi, C.; Pollini, G. P.;
Romagnoli, R.; Zanirato, V. Tetrahedron Lett. 1994, 35, 9297. (j) Ko,
S. Y.; Lerpiniere, J .; Linney, I. D.; Wrigglesworth, R. J . Chem. Soc.,
Chem. Commun. 1994, 1775. (k) Okabe, K.; Natsume, M. Chem.
Pharm. Bull. J pn. 1994, 42, 1432. (l) Kotian, P. L.; Carroll, F. I. Synth.
Commun. 1995, 25, 63. (m) Xu, R.; Chu, G.; Bai, D. Tetrahedron Lett.
1996, 37, 1463. (n) Bai, D.; Xu, R.; Chu, G.; Zhu, X. J . Org. Chem.
1996, 61, 4600. (o) Zhang, C.; Trudell, M. L. J . Org. Chem. 1996, 61,
7189. (p) Trost, B. M.; Cook, G. R. Tetrahedron Lett. 1996, 37, 7485.
(q) Sza´ntay, C.; Kardos-Balogh, Z.; Moldvai, I.; Sza´ntay, C., J r.;
Temesva´ri-Major, E.; Blasko´, G. Tetrahedron 1996, 52, 11053. (r)
Giblin, G. M.; J ones, C. D.; Simpkins, N. S. Synlett 1997, 589. (s)
Kosugi, H.; Abe, M.; Hatsuda, R.; Uda, H.; Kato, M. Chem. Commun.
1997, 1857. (t) Pavri, N. P.; Trudell, M. L. Tetrahedron Lett. 1997, 38,
7993. (u) J ones, C. D.; Simpkins, N. S.; Giblin, G. M. Tetrahedron Lett.
1998, 39, 1023. (v) Pandey, G.; Bagul, T. D.; Sahoo, A. K. J . Org. Chem.
1998, 63, 760. (w) Sirisoma, N. S.; J ohnson, C. R. Tetrahedron Lett.
1998, 39, 2059. See also ref 3.
(17) For formal synthesis of epibatidine, see: (a) Herna´ndez, A.;
Marcos, M.; Rapoport, H. J . Org. Chem. 1995, 60, 2683. (b) Davis, C.
R.; J ohnson, R. A.; Cialdella, J . I.; Liggett, W. F.; Mizsak, S. A.;
Marshall, V. P. J . Org. Chem. 1997, 62, 2244. (c) Singh, S.; Basmadjian,
G. P. Tetrahedron Lett. 1997, 38, 6829. (d) Ikeda, M.; Kugo, Y.; Kondo,
Y.; Yamazaki, T.; Sato, T. J . Chem. Soc., Perkin Trans. 1 1997, 3339.
(e) Albertini, E.; Barco, A.; Benetti, S.; De Risi, C.; Pollini, G. P.;
Zanirato, V. Tetrahedron 1977, 53, 17177. (f) Clive, D. L. J .; Yeh, V.
S. C. Tetrahedron Lett. 1998, 39, 4789.
(18) The Convention on International Trade in Endangered Species
(CITES) put all the dendrobatid frogs on their Appendix II listing.1
(19) For a review of our own achievements in natural products
synthesis via acylnitroso Diels-Alder methodology, see: Kibayashi,
C.; Aoyagi, S. Synlett 1995, 873.
the 1R,4S adduct 3 or 1S,4R adduct 5, is available
depending on the para-aza or meta-aza regioselectivity,
respectively, in the cycloaddition. Although the pathway
involving (1S,4R)-meta-aza-cycloadduct 5 was actually
employed in the present synthesis of 1, at the beginning
of the project, it was difficult to determine which one of
these pathways would be operative for the synthesis of
1, since para/meta regioselectivity in the acylnitroso
cycloaddition with the 2-substituted 1,3-cyclohexadiene
was uncertain and unpredictable.
On the basis of this retrosynthetic argument, our initial
efforts were directed at developing a general methodology
for the asymmetric hetero Diels-Alder reaction with
acylnitroso dienophiles bearing appropriate chiral aux-
iliaries. We have recently recognized22 efficient asym-
metric conjugate allylation of N-acyl-2,3-dihydro-4-
pyridones using the 8-arylmenthol moiety as a chiral
inducer, wherein the presence of π attractive interaction
between the aromatic ring and the enamido portion was
suggested for control of the facial selectivity. Since
introduction of 8-phehylmenthol by Corey in 1975,23
cyclohexyl-based chiral auxiliaries of the 8-phenylmen-
thol type24 have proved to behave as effective chiral
inductors in a variety of different types of asymmetric
reactions, including Diels-Alder reaction, ene reaction,
and conjugate addition to enoates, which are suggested
(20) For reviews on the application of nitroso Diels-Alder reactions
in natural products synthesis, see: (a) Boger, D. L.; Weinreb, S. M.
Hetero Diels-Alder Methodology in Organic Synthesis; Academic
Press: San Diego, 1987. (b) Streith, J .; Defoin, A. Synthesis 1994, 1107.
(21) For a part of a preliminary account of this work on the synthesis
of (-)-epibatidine, see: Aoyagi, S.; Tanaka, R.; Naruse, M.; Kibayashi,
C. Teterahedron Lett. 1998, 39, 4513.
(22) Sato, M.; Aoyagi, S.; Yago, S.; Kibayashi, C. Tetrahedron Lett.
1996, 37, 9063.
(23) Corey, E. J .; Ensley, H. E. J . Am. Chem. Soc. 1975, 97, 6908.
(24) Whitesell, J . K. Chem. Rev. 1992, 92, 953.

Total Synthesis of (-)-Epibatidine
J . Org. Chem., Vol. 63, No. 23, 1998 8399
Sch em e 2
Sch em e 3
Ta ble 1. Asym m etr ic Heter o Diels-Ald er Rea ction of
N-Acyln itr oso Com p ou n d s w ith 1,3-Cycloh exa d ien e
hydroxamic acid 12
(% yield from 9)
major
adduct 14
14/15
yield
(%)b
ratioa
to lie in π-stacking interactions between the aromatic
ring and the π system.25 In consideration of these results,
we envisioned the use of (1R,2S,5R)-(-)-menthol 9a and
its 8-substituted derivatives 9b-f as chiral inducers in
the asymmetric hetero Diels-Alder reaction with acyl-
nitroso dienophiles for evaluating the effect of these chiral
inducers and the stereochemistry of the cycloadducts.26
The auxiliaries 9b,c,f were prepared from (R)-(+)-pule-
gone (8) in analogy with Corey’s procedure,23,27 and the
auxiliaries 9d ,e were derived from 8-phenylmenthol (9b),
as shown in Scheme 2. Thus, 8-(4-bromophenyl)menthol
(9d ) was readily available by the usual bromination (Br2,
AcOH-CCl4) of 9b in 60% yield. Otherwise, conversion
of 9b to 8-(4-nitrophenyl)menthol (9e) was accomplished
via protection of the hydroxy group as an acetate 10,
entry
1
2
3
4
5
6
12a , R ) H (85)
12b, R ) Ph (94)
12c, R ) 4-MeOPh (89)
12d , R ) 4-BrPh (85)
12e, R ) 4-NO2Ph (92)
12f, R ) 2-naphthyl (88)
14a
14b
14c
14d
14e
14f
1.2:1
8.9:1
9.1:1
13.2:1
22.7:1
14.0:1
96
95
94
95
94
95
a
Determined by HPLC analysis: Shim-pack CLC-SIL column;
hexanes-EtOAc ) 16:1 (entries 1, 2), 9:1 (entries 3, 4), 6:1 (entry
b
5); UVdetector, 254 nm. Isolated combined yield of 14 and 15.
followed by nitration with nitronium trifluoroacetate and
subsequent deprotection of 11 in 84% overall yield from
9b.
(1R,2S,5R)-Menthol (9a ) and its 8-substituted deriva-
tives 9b-f thus obtained were treated with triphosgen
and pyridine in dichloromethane to form the chlorofor-
mates, which immediately underwent reaction with N,O-
bis(trimethylsilyl)hydroxylamine followed by acid treat-
ment in the same reaction vessel, affording the correspond-
ing hydroxamic acids 12a -f in 85-94% overall yields (see
Scheme 3 and Table 1). In a preliminary experiment, in
situ oxidation of 12f in the presence of 1,3-cyclohexadiene
was performed using Pr4NIO4 in chloroform at room
temperature to produce the acylnitroso dienophile 13f,
which reacted at once with 1,3-cyclohexadiene to give the
(1R,4S)- and (1S,4R)-cycloadducts, 14f (vide infra) and
15f, with a 5.6:1 ratio in 73% combined yield. When this
cycloaddition of 13f with 1,3-cyclohexadiene was per-
formed at -78 °C by using the Swern oxidation protocol,26i
both the diastereoselectivity and chemical yield were
found to be remarkably enhanced to 14.0:1 and 95%,
respectively (Table 1, entry 6). The molecular structure
with the 1R,4S absolute configuration of the major
(25) For a review on π-stacking effects in asymmetric synthesis,
see: J ones, G. B.; Chapman, B. J . Synthesis 1995, 475.
(26) For examples of hetero Diels-Alder reactions with chiral
acylnitroso dienophiles, see: (a) Defoin, A.; Fritz, H.; Schmidlin, C.;
Streith, J . Helv. Chim. Acta 1987, 70, 554. (b) Kirby, G. W.; Nazeer,
M. Tetrhedron Lett. 1988, 29, 6173; J . Chem. Soc., Perkin Trans. 1
1993, 1397. (c) Millar, A.; Paterson, T. McC.; Procter, G. Synlett 1989,
32. (d) Brouillard-Poichet, A.; Defoin, A.; Streith, J . Tetrahedron Lett.
1989, 30, 7061. Defoin, A.; Brouillard-Poichet, A.; Streith, J . Helv.
Chim. Acta 1992, 75, 109. (e) Gouverneur, V.; Ghosez, L. Tetrahe-
dron: Asymmetry 1990, 1, 363. (f) Gouverneur, V.; Dive, G.; Ghosez,
L. Tetrahedron: Asymmetry 1991, 2, 1173. (g) Gouverneur, V.; Ghosez,
L. Tetrahedron Lett. 1991, 32, 5349. (h) Defoin, A.; Brouillard-Poichet,
A.; Streith, J . Helv. Chim. Acta 1991, 74, 103. (i) Martin, S. F.;
Hartmann, M.; J osey, J . A. Tetrahedron Lett. 1992, 35, 3583-3586.
(j) Cardillo, B.; Galeazzi, R.; Mobbili, G.; Orena, M.; Rossetti, M. J . N.
Tetrahedron: Asymmetry 1994, 5, 1535. (k) Ritter, A. R.; Miller, M. J .
J . Org. Chem. 1994, 59, 4602. (l) Shustov, G. V.; Rauk, A. Tetrahedron
Lett. 1995, 36, 5449. (m) Lin, C.-C.; Wang, Y.-C.; Hsu, J .-L.; Chiang,
C.-C.; Su, D.-W.; Yan, T.-H. J . Org. Chem. 1997, 62, 3806.
(27) (a) Herzog, H.; Scharf, H. D. Synthesis 1986, 420. (b) Potin, D.;
Dumas, F.; Maddaluno, J . Synth. Commun. 1990, 20, 805.

8400 J . Org. Chem., Vol. 63, No. 23, 1998
Aoyagi et al.
F igu r e 1. ORTEP drawing of 14f (ellipsoids at 50% probability).
cycloadduct 14f was unambiguously established by single-
crystal X-ray analysis (Figure 1).
bonyl groups, forcing the diene to “endo approach”26e,f,h
preferentially from the front side. The s-cis/s-trans
On the basis of the above experimental results, we
employed the Swern oxidation conditions for the cyclo-
addition with the rest of the hydroxamic acids 12a -e,
and the results are presented in Table 1. In entry 1, 12a
lacking the aryl substituent group at C(8) shows almost
no selectivity in the cycloaddition. On the other hand,
as can be seen in entries 2-5, the reactions with 12b-e
provide the (1R,4S)-cycloadducts 14b-e as major dia-
stereomers in good to very high diastereoselectivity and
excellent yield; these results clearly demonstrate the
importance of the aromatic moiety of the menthol aux-
iliary to attain high levels of asymmetric induction.
Each 1H NMR spectrum of the major cycloadducts
14b-e with the 8-arylmenthyl moiety shows the chemi-
cal shift attributed to the C(4) bridgehead proton at
higher field (δ 3.5-4.1) as a characteristic very broad
singlet, in contrast to that observed for 14a with no aryl
group where the corresponding proton resonance occurs
at δ 4.72. It appears that the upfield shifts observed for
these protons in 14b-e are due to the influence of the
anisotropic shielding effect of the aromatic rings, indicat-
ing that 14b-e adopt a conformation with the aryl group
in “stacked” position (vide infra) consistent with the solid-
state conformation of 14f elucidated by X-ray analysis
as depicted in Figure 1.
arrangement, as well as the exo/endo mode approach, is
a crucial factor dictating the sense of the asymmetric
induction; however, this aspect is generally not well-
understood in the [4 + 2] cycloaddition with acylnitroso
dienophiles. One reason for this may be that the
RCONdO species are very short-lived and hence spec-
troscopically undetectable.29 However, in the case of
8-phenylmenthyl glyoxalates, the glyoxalate moiety has
been proved to lie in the s-cis arrangement, wherein π
attractive interaction is presumed to hold the two car-
bonyl groups in the s-cis conformation.30 A similar
situation should be expected for the acylnitroso com-
pounds 13a -f, whose structural and electronic features
are similar to those of the 8-phenylmenthyl glyoxalates,
to show the s-cis preference in the cyclization of transition
state 16.
The facial diastereoselectivity observed in the cyclo-
additions of the hydroxamic acids 12b-f with aromatic
menthyl auxiliaries is consistent with a transition-state
model 16 with the aryl group in “stacked” position28 and
with the acylnitroso group in the s-cis conformation with
respect to the C-N bond, wherein the aromatic ring
shields selectively the face of the nitroso group by π
attractive interaction between the aryl and nitrosocar-
(29) Kirby, G. W. Chem. Soc. Rev. 1977, 6, 1.
(30) (a) Whitesell, J . K.; Bhattacharya, A.; Aguilar, D. A.; Henke,
K. J . Chem. Soc., Chem. Commun. 1982, 989. (b) Whitesell, J . K.;
Younathan, J . N.; Hurst, J . R.; Fox, M. A. J . Org. Chem. 1985, 50,
5499. (c) Solladie-Cavallo, A.; Khiar, N. Tetrahedron Lett. 1988, 29,
2189. (d) Solladie-Cavallo, A.; Bencheqroun, M. Tetrahedron: Asym-
metry 1991, 2, 1163.
(28) Maddaluno, J . F.; Gresh, N.; Giessner-Prettre, C. J . Org. Chem.
1994, 59, 793.

Total Synthesis of (-)-Epibatidine
J . Org. Chem., Vol. 63, No. 23, 1998 8401
Sch em e 4
cycloadduct 5 rather than the (1R,4S)-para-aza-cyclo-
adduct 3. The need for 5 suggested the use of the
(1S,2R,5S)-menthyl auxiliary for inducing the correct
sense of chirality. Thus, due to the ease of preparation
and providing high π-facial discrimination, the 2-naph-
thyl group34 was selected as a C(8) substitution, and
(1S,2R,5S)-8-(2-naphthyl)menthol (ent-9f) was prepared
from (S)-(-)-pulegone (ent-8)35 according to the known
procedure.23,27 Conversion of ent-9f to the hydroxamic
acid ent-12f was achieved in the same manner as
described above for the preparation of 12f. Oxidation of
ent-12f in the presence of 7 under the Swern conditions
resulted in cylcloaddition to form 24 (42%), 25 (20%), and
26 (4%) (Scheme 5).36 The major product 24 resulted
from the meta-aza regioselective process and the opposite
asymmetric induction to that obtained with the hydrox-
amic acids 12 (via transition state 16), which results are
in agreement with the prediction based on the π-attrac-
tive transition-state model 27.
Having established the feasibility of the asymmetric
cycloaddition with a menthol-based chiral auxiliary, in
an attempt to apply this method to the asymmetric
synthesis of epibatidine, we next examined the regio-
selectivity in the cycloaddition using 2-chloro-5-(1,5-
cyclohexadienyl)pyridine (7) as a diene component. Thus,
palladium-catalyzed cross-coupling of 2-chloro-5-iodo-
pyridine (17)31 with 2-(1,3-cyclohexadienyl)magnesium
bromide (18), prepared from 2-bromo-1,3-cyclohexa-
diene32 led to 7 in 50% yield. The cycloaddition of 7 with
commercially available tert-butyl N-hydroxycarbamate 19
was performed utilizing Swern conditions as described
above to give a chromatographically unseparable mixture
of the cycloadducts 20 and 21 in 79% combined yield
(Scheme 4). This mixture underwent catalytic hydrogen-
ation over PtO2 to furnish the regioisomers 22 and 23 in
a 3:2 ratio (76% combined yield) with complete endo
selectivity. The major isomer 22 was crystallized, and
X-ray crystallographic analysis revealed its regio- and
stereochemistry as shown in Figure 2. These results
indicate that the meta-aza regioisomer is favored over
the para-aza one in this cycloaddition with a strongly
electron-withdrawing 2-substituted cyclohexadiene such
as 7. This finding is in contrast to that reported for the
cycloaddition of acylnitroso compounds to an electron-
deficient 2-substituted 1,3-cyclohexadiene, which pre-
dominantly affords para-aza adducts consistent with
either a normal (HOMO-diene controlled) or inverse
electron demand (LUMO-diene controlled) Diels-Alder
reaction.33
The (1S,4R)-meta-aza isomer 24 thus obtained was
hydrogenated over PtO2 to give the exo product 28 (81%)
as a single diastereomer (Scheme 6), which underwent
removal of the chiral auxiliary with LiH2NBH3, prepared
from BH3‚NH3 and BuLi,37 followed by tert-butoxycar-
bonylation to give (-)-22 (58% from 28), identical with
the above-described compound 22, except for the optical
rotation. After reductive cleavage of the N-O bond with
molybdenum hexacarbonyl,38 the resulting N-Boc amino
alcohol 29 (85%) was brominated with triphenylphos-
phine and carbon tetrabromide with inversion of config-
uration to afford the bromide 30 (42%), which was then
deprotected with trifluoroacetic acid to give the bromo-
amine 31 in 96% yield. Finally, refluxing of 31 in
chloroform for 3 days provided (-)-epibatidine, mp 61-
62 °C; [R]27 -6.26 (c 0.80, CHCl3), in 97% yield, which
D
was identical with the spectral data (1H and 13C NMR)
reported in the literature.15a
(34) The efficiency of the menthol chiral auxiliary bearing
a
Considering the diastereo- and regioselectivities ob-
served in these cycloadditions with the hydroxamic acids
12f and 19, respectively, we employed the asymmetric
approach to (-)-epibatidine based on the retrosynthetic
route depicted in Scheme 1 via the (1S,4R)-meta-aza-
naphthalene nucleus has been demonstrated. (a) Mezrhab, B.; Dumas,
F.; d’Angelo, J .; Riche, C. J . Org. Chem. 1994, 59, 500. (b) Dumas, F.;
Mezrhab, B.; d’Angelo, J . J . Org. Chem. 1996, 61, 2293. See also ref
22.
(35) A sample of (S)-(-)-pulegone was kindly provided by Takasago
International Co.
(36) In this cycloaddition, the use of ent-12e is expected to lead to
a better selectivity for the desired (1S,4R)-meta-aza isomer, since, as
can be seen from the results summarized in Table 1, 12e gives the
best diastereoselectivity in the cycloaddition with 1,3-cyclohexadiene.
Work in this area is underway in our laboratory.
(37) Myers, A. G.; Yang, B. H.; Kopecky, D. J . Tetrahedron Lett.
1996, 37, 3623.
(31) (a) Ogura, F.; Otsubo, T.; Aso, T.; Nobuhara, Y.; Hama, Y. Bull.
Chem. Soc. J pn. 1988, 61, 1683. (b) Magidson, O.; Menschikoff, G.
Chem. Ber. 1925, 58, 113.
(32) (a) Sonnenberg, J .; Winstein, S. J . Org. Chem. 1961, 27, 748.
(b) Bottini, A. T.; Schear, W. J . Org. Chem. 1965, 30, 3205.
(33) (a) Boger, D. L.; Patel, M.; Takusagawa, F. J . Org. Chem. 1985,
50, 1911.
(38) Cicchi, S.; Goti, A.; Guarna, A.; De Salo, F. Tetrahedron Lett.
1990, 31, 3351.

8402 J . Org. Chem., Vol. 63, No. 23, 1998
Aoyagi et al.
F igu r e 2. ORTEP drawing of 22 (ellipsoids at 50% probability).
Sch em e 5
Sch em e 6
Exp er im en ta l Section
Gen er a l P r oced u r es. All melting points are uncorrected.
1H NMR spectra were recorded at 400 MHz using residual
CHCl3 (7.26 ppm) as reference.13C NMR spectra were recorded
at 100.6 MHz with CDCl3 (77.05 ppm) as reference. Mass
spectra were measured at an ionizing voltage of 70 eV.
Organic solvents used were dried by standard methods.
Commercially obtained reagents were used without further
purification. Silica gel 60 (230-400 mesh, Merck) was used
for column chromatography, and silica gel 70 FM plates (0.25
mm, Wako) were used for TLC. HPLC analysis was performed
with a Shim-pack CLC-SIL column.
In conclusion, the asymmetric synthesis of (-)-epi-
batidine has been accomplished by a ten-step route in
5.9% overall yield from ent-9f based on asymmetric
hetero Diels-Alder cycloaddition with an acylnitroso
dienophile incorporating (1S)-8-(2-naphthyl)menthol as
a chiral inducer, wherein π-attracting interaction be-
tween the naphthyl and nitrosocarbonyl groups may
contribute to facial control.

Total Synthesis of (-)-Epibatidine
J . Org. Chem., Vol. 63, No. 23, 1998 8403
(1R,2S,5R)-5-Met h yl-2-[1-m et h yl-1-(4-b r om op h en yl)-
eth yl]cycloh exa n ol (9d ). To a cooled (0 °C), stirred solution
of (-)-8-phenylmenthol (9b) (360 mg, 1.55 mmol) in CCl4 (1.5
mL) and acetic acid (7 mL) was added bromine (0.99 g, 6.2
mmol), and the mixture was stirred at room temperature. After
5 h, 20% aqueous K2CO3 (50 mL) was added and the resulting
mixture was extracted with ether (2 × 100 mL). The combined
extracts were washed with saturated aqueous Na2S2O3 (30 mL)
and brine, dried (MgSO4), and concentrated in vacuo. The
residue was purified by column chromatography on silica gel
(hexane-EtOAc, 50:1) to give 9d (288 mg, 60%) as a colorless
td, J ) 9.0, 2.4 Hz); 13C NMR (CDCl3) δ 21.9, 25.8, 26.7, 27.4,
31.7, 34.7, 40.9, 46.2, 54.3, 73.0, 123.3 (2C), 126.7 (2C), 145.7,
160.0; EIMS m/z (%) 277 (M+, 2), 165 (100), 148 (83), 118 (39).
Gen er a l P r oced u r e for th e P r ep a r a tion of Hyd r ox-
a m ic Acid s 12. The preparation of [[(1R,2S,5R)-5-methyl-2-
isopropylcyclohexyl]oxy]carbonylhydroxylamine (12a ) is rep-
resentative. To a solution of 9a (600 mg, 3.84 mmol) in CH2Cl2
(18 mL) was added pyridine (402 mg, 5.08 mmol), and the
mixture was cooled to 0 °C. To this was added a solution of
triphosgene (456 mg, 1.54 mmol) in CH2Cl2 (5 mL), and the
mixture was stirred at 0 °C. After 30 min, to this mixture
were successively added pyridine (608 mg, 7.69 mmol) and
N,O-bis(trimethylsilyl)hydroxylamine (820 mg, 4.62 mmol),
and the mixture was stirred at 0 °C. After 2 h, the reaction
was quenched by addition of 1 N HCl (20 mL), and the mixture
was extracted with CHCl3 (3 × 50 mL). The combined extracts
were washed with brine, dried (MgSO4), and concentrated in
vacuo. The residue was purified by column chromatography
on silica gel (hexane-EtOAc, 7:1) to provide 12a (703 mg,
oil: [R]26 -8.0 (c 0.25, CHCl3); IR (film) 3413 cm-1; 1H NMR
D
(CDCl3) δ 0.77-1.04 (4H, m), 0.88 (3H, d, J ) 6.6 Hz), 1.28
(3H, s), 1.32-1.45 (1H, m), 1.40 (3H, s), 1.58-1.66 (3H, m),
1.83-1.88 (1H, m), 3.49 (1H, td, J ) 10.2, 4.2 Hz), 7.25 (2H,
dt, J ) 8.7, 2.3 Hz), 7.42 (2H, dt, J ) 8.7, 2.3 Hz); 13C NMR
(CDCl3) δ 22.0, 25.3, 26.6, 28.0, 31.6, 34.8, 39.9, 45.8, 54.2,
73.1, 119.4, 127.8 (2C), 131.3 (2C), 150.6; EIMS m/z (rel intens)
312 (M+ + 2, 5), 310 (M+, 5), 197 (100).
(1R,2S,5R)-5-Meth yl-2-(1-m eth yl-1-p h en yleth yl)cyclo-
h exyl Aceta te (10). A mixture of 9b (1.57 g, 6.76 mmol),
acetic anhydride (1.38 g, 13.5 mmol), and 4-(dimethylamino)-
pyridine (0.90 g, 7.4 mmol) in pyridine (8 mL) was stirred at
room temperature for 22 h. The mixture was poured into 5%
aqueous NaHCO3 (50 mL) and extracted with EtOAc (3 × 100
mL). The combined extracts were washed sequentially with
5% aqueous HCl (2 × 50 mL), saturated aqueous NaHCO3 (50
mL), and brine, dried (MgSO4), and concentrated in vacuo. The
residue was purified by column chromatography on silica gel
(hexane-EtOAc, 30:1) to give 10 (1.76 g, 95%) as a colorless
85%) as a white solid: mp 138-139 °C; [R]26 -82.5 (c 1.0,
D
1
CHCl3); IR (KBr) 3346, 1696, 1681 cm-1; H NMR (CDCl3) δ
0.76 (3H, d, J ) 7.0 Hz), 0.87 (3H, d, J ) 7.1 Hz), 0.89 (3H, d,
J ) 6.6 Hz), 0.92-1.10 (3H, m), 1.28-1.35 (1H, m), 1.41-1.53
(1H, m), 1.66 (2H, br d, J ) 12.2 Hz), 1.83-1.91 (1H, m), 2.02
(1H, br d, J ) 11.9 Hz), 4.63 (1H, td, J ) 10.9, 4.4 Hz), 7.29
(1H, br s), 7.58 (1H, br s); 13C NMR (CDCl3) δ 16.3, 20.7, 22.0,
23.5, 26.2, 31.4, 34.1, 41.1, 47.2, 76.6, 159.6; CIMS (isobutane)
m/z (rel intens) 216 (M+ + 1, 12), 139 (100).
[[(1R,2S,5R)-5-Met h yl-2-[1-m et h yl-1-p h en ylet h yl]cy-
cloh exyl]oxy]ca r bon ylh yd r oxyla m in e (12b) was prepared
from 9b according to the general procedure in 94% yield as a
oil: [R]26 -6.4 (c 2.47, CHCl3); IR (film) 1732 cm-1; 1H NMR
D
(CDCl3) δ 0.82-0.99 (2H, m), 0.87 (3H, d, J ) 6.5 Hz), 1.11
(1H, qd, J ) 12.9, 3.3 Hz), 1.21 (3H, s), 1.31 (3H, s), 1.40-
1.54 (1 H, m, including 3H, s at δ 1.54), 1.63-1.68 (1H, m),
1.72 (1H, qd, J ) 13.3, 3.5 Hz), 1.83-1.88 (1H, m), 2.01 (1H,
ddd, J ) 12.3, 10.6, 3.6 Hz), 4.79 (1H, td, J ) 10.7, 4.5 Hz),
7.11-7.16 (1H, m), 7.25-7.32 (4H, m); 13C NMR (CDCl3) δ
21.1, 21.8, 24.5, 26.5, 28.3, 31.3, 34.6, 39.6, 41.8, 50.4, 74.0,
125.0, 125.4 (2C), 127.9 (2C), 151.7, 170.4; EIMS m/z (rel
intens) 274 (M+, 7), 214 (38), 119 (100).
colorless oil: [R]26 -40.0 (c 1.0, CHCl3); IR (film) 3306, 1719
D
cm-1; H NMR (CDCl3) δ 0.88 (3H, d, J ) 6.5 Hz), 0.81-1.01
1
(2H, m), 1.16 (1H, m), 1.22 (3H, s), 1.31 (3H, s), 1.42-1.54 (1H,
m), 1.69 (1H, m), 1.82-1.93 (2H, m), 2.04 (1H, m), 4.71 (1H,
td, J ) 10.8, 4.4 Hz), 6.24 (1H, br s), 7.15-7.20 (1H, m), 7.30-
7.35 (4H, m); 13C NMR (CDCl3) d 21.8, 22.8, 26.2, 29.3, 31.3,
34.5, 39.4, 41.7, 51.0, 76.3, 124.8, 125.5 (2C), 127.9 (2C), 152.5,
158.4; CIMS (isobutane) m/z (rel intens) 292 (M+ + 1, 10), 215
(100).
(1R,2S,5R)-5-Meth yl-2-[1-m eth yl-1-(4-n itr op h en yl)eth -
yl]cycloh exyl Aceta te (11). To a cooled (0 °C), stirred
solution of 10 (560 mg, 2.04 mmol) in CHCl3 (3 mL) was added
ammonium nitrate (324 mg, 4.06 mmol) and trifluoroacetic
anhydride (3.00 g, 14.3 mmol). After being stirred at room
temperature for 4.5 h, the mixture was poured into water (10
mL) and then extracted with CHCl3 (4 × 50 mL). The
combined extracts were washed with brine, dried (MgSO4), and
concentrated in vacuo. Purification of the residue by column
chromatography on silica gel (hexane-EtOAc, 20:1) gave 11
(640 mg, 98%) as a pale yellow oil: [R]26D +33.3 (c 3.84, CHCl3);
IR (film) 1732, 1519, 1348 cm-1; 1H NMR (CDCl3) δ 0.82-1.02
(2H, m, including 3H, d, J ) 6.5 Hz at δ 0.88), 1.16 (1H, qd, J
) 12.9, 3.4 Hz), 1.22 (3H, s), 1.34 (3H, s), 1.42-1.53 (1H, m,
including 3H, s at δ 1.45), 1.70 (1H, m), 1.87 (1H, m), 2.06
(1H, ddd, J ) 12.2, 10.6, 3.5 Hz), 4.77 (1H, td, J ) 10.7, 4.4
Hz), 7.45 (2H, dt, J ) 9.0, 2.4 Hz), 8.15 (2H, dt, J ) 9.0, 2.4
Hz); 13C NMR (CDCl3) δ 21.0, 21.7, 23.5, 26.3, 28.7, 31.2, 34.4,
40.4, 41.6, 50.4, 73.9, 123.1 (2C), 126.3 (2C), 145.6, 160.0, 170.0;
EIMS m/z (rel intens) 319 (M+, 1), 165 (97), 164 (82), 155 (58),
118 (42), 95 (89), 91 (31), 43 (100).
[[(1R,2S,5R)-5-Meth yl-2-[1-m eth yl-1-(4-m eth oxyph en yl)-
eth yl]cycloh exyl]oxy]ca r bon ylh yd r oxyla m in e (12c) was
prepared from 9c according to the general procedure in 89%
yield as a colorless oil: [R]26 -23.7 (c 2.7, CHCl3); IR (film)
D
3316, 1718 cm-1; H NMR (CDCl3) δ 0.81-1.01 (2H, m), 0.87
1
(3H, d, J ) 6.5 Hz), 1.10 (1H, qd, J ) 12.9, 3.2 Hz), 1.20 (3H,
s), 1.28 (3H, s), 1.40-1.52 (1H, m), 1.66 (1H, m), 1.77 (1H, m),
1.88-1.97 (2H, m), 3.79 (3H, s), 4.71 (1H, td, J ) 10.8, 4.4
Hz), 6.84-6.87 (2H, m), 7.19-7.22 (2H, m); 13C NMR (CDCl3)
δ 21.8, 23.9, 26.4, 28.8, 31.3, 34.5, 38.9, 41.8, 51.0, 55.3, 76.5,
113.1 (2C), 126.4 (2C), 144.2, 156.9, 158.6; EIMS m/z (rel
intens) 321 (M+, 2), 149 (100).
[[(1R,2S,5R)-5-Meth yl-2-[1-m eth yl-1-(4-br om op h en yl)-
eth yl]cycloh exyl]oxy]ca r bon ylh yd r oxyla m in e (12d ) was
prepared from 9d according to the general procedure in 85%
yield as a white solid: [R]24D -4.9 (c 1.0, CHCl3); IR (film) 3305,
1719 cm-1; 1H NMR (CDCl3) δ 0.81-0.99 (2H, m), 0.87 (3H, d,
J ) 6.5 Hz), 1.05-1.15 (1H, m), 1.20 (3H, s), 1.28 (3H, s), 1.39-
1.53 (1H, m), 1.66 (1H, m), 1.74 (1H, m), 1.88-1.96 (2H, m),
4.71 (1H, td, J ) 10.7, 4.4 Hz), 6.42 (2H, br s), 7.16 (2H, d, J
) 8.6 Hz), 7.42 (2H, d, J ) 8.6 Hz); 13C NMR (CDCl3) δ 21.7,
23.9, 26.4, 28.3, 31.2, 34.4, 39.5, 41.8, 51.0, 76.5, 118.6, 127.4
(2C), 130.9 (2C), 151.1, 158.4; CIMS (isobutane) m/z (rel intens)
372 (M+ + 3, 5), 370 (M+ + 1, 5), 295 (94), 293 (100).
(1R,2S,5R)-5-Meth yl-2-[1-m eth yl-1-(4-n itr op h en yl)eth -
yl]cycloh exa n ol (9e). To a solution of 11 (4.31 g, 13.5 mmol)
in MeOH (23 mL) was added 33% aqueous KOH (20 mL), and
the mixture was refluxed for 3.5 h. Water (50 mL) and EtOAc
(150 mL) was added to this mixture, and the layers were
separated. The aqueous layer was extracted with EtOAc (2
× 150 mL), and the combined organic layers were washed with
brine and dried (MgSO4). Evaporation of the solvent followed
by chromatography on silica gel (hexane-EtOAc, 20:1) gave
[[(1R,2S,5R)-5-Met h yl-2-[1-m et h yl-1-(4-n it r op h en yl)-
eth yl]cycloh exyl]oxy]ca r bon ylh yd r oxyla m in e (12e) was
prepared from 9e according to the general procedure in 94%
yield as a pale yellow solid: mp 146-147 °C; [R]26 -13.8 (c
D
1
1.0, CHCl3); IR (KBr) 3349, 1718, 1516, 1348 cm-1; H NMR
(CDCl3) δ 0.83-1.00 (2H, m), 0.88 (3H, d, J ) 6.5 Hz), 1.10-
1.21 (1H, m), 1.25 (3H, s), 1.36 (3H, s), 1.42-1.55 (1H, m),
1.65-1.79 (2H, m), 1.87-1.93 (1H, m), 1.98-2.04 (1H, m), 4.73
(1H, td, J ) 10.8, 4.4 Hz), 6.31 (1H, br s), 7.44 (2H, d, J ) 8.9
Hz), 8.15 (2H, d, J ) 8.9 Hz); 13C NMR (CDCl3) δ 21.7, 23.7,
26.4, 28.4, 31.2, 34.3, 40.4, 41.7, 51.1, 76.4, 123.2 (2C), 126.3
9e (3.37 g, 90%) as a pale yellow solid: mp 63-64 °C; [R]28
D
-20.7 (c 0.56, CHCl3); IR (KBr) 3442, 1515, 1347 cm-1 1H
;
NMR (CDCl3) δ 0.78-1.04 (2H, m), 0.89 (3H, d, J ) 6.5 Hz),
1.34 (3H, s), 1.36-1.72 (6H, m, including 3H, s at δ 1.47), 1.87
(1H, m), 3.50 (1H, m), 7.51 (2H, td, J ) 9.0, 2.4 Hz), 8.15 (2H,

8404 J . Org. Chem., Vol. 63, No. 23, 1998
Aoyagi et al.
(2C), 145.5, 158.0, 159.9; EIMS m/z (rel intens) 337 (M+ + 1,
1), 150 (100), 109 (34).
1.05 (3H, m), 0.84 (3H, d, J ) 6.5 Hz), 1.19 (3H, s), 1.22-1.62
(5H, m), 1.27 (3H, s), 1.86-1.98 (3H, m), 2.08-2.18 (1H, m),
3.78 (3H, s), 4.0 (1H, very br s), 4.61-4.69 (2H, m), 6.42-6.50
[[(1R,2S,5R)-5-Meth yl-2-[1-m eth yl-1-(2-n a p h th yl)eth yl]-
cycloh exyl]oxy]ca r bon ylh yd r oxyla m in e (12f) was pre-
pared from 9f according to the general procedure in 88% yield
as a white solid: mp 69-70 °C; [R]27D -31.5 (c 2.0, CHCl3); IR
(KBr) 3305, 1719 cm-1; 1H NMR (CDCl3) δ 0.79-1.03 (2H, m),
0.88 (3H, d, J ) 6.5 Hz), 1.19 (1H, qd, J ) 13.0, 3.3 Hz), 1.31
(3H, s), 1.43 (3H, s), 1.48 (1H, m), 1.64-1.71 (1H, m), 1.81-
1.92 (2H, m), 2.10-2.16 (1H, m), 4.79 (1H, td, J ) 10.7, 4.4
Hz), 5.88 (1H, br s), 7.41-7.48 (3H, m), 4.52 (1H, dd, J ) 8.7,
1.7 Hz), 7.66 (1H, s), 7.78-7.83 (3H, m); 13C NMR (CDCl3) δ
21.8, 23.4, 26.4, 28.6, 31.3, 34.5, 39.7, 41.8, 50.7, 76.4, 122.7,
125.2, 125.5, 126.2, 127.1, 127.3, 127.8, 131.1, 133.1, 149.6,
158.0; EIMS m/z (rel intens) 341 (M+, 3), 169 (100), 141 (39);
HRMS calcd for C21H27NO3 (M+) 341.1991, found 341.1991.
Gen er a l P r oced u r e for Asym m etr ic Heter o Diels-
Ald er Rea ction of N-Acyln itr oso Com p ou n d s 14 w ith 1,3-
Cycloh exa d ien e (En tr ies 1-6 in Ta ble 1). A representa-
tive experiment is as follows. To a cooled (-78 °C), stirred
solution of oxalyl chloride (1.5 mmol) in CH2Cl2 (7 mL) was
added a solution of dimethyl sulfoxide (3.0 mmol) in CH2Cl2
(1 mL), and the mixture was stirred at -78 °C for 30 min. To
this mixture was added a solution of the hydroxamic acid 14
(1.0 mmol) in CH2Cl2 (7 mL), and stirring was continued at
-78 °C. After 15 min, 1,3-cyclohexadiene (10 mmol) was
added via syringe followed by Et3N (6.0 mmol), and the
mixture was stirred for an additional 1 h. The reaction was
quenched by addition of water (10 mL) at -78 °C. The organic
layer was separated, and the aqueous layer was extracted with
CHCl3 (30 mL × 3). The combined organic layers were washed
with water, dried (MgSO4), and concentrated in vacuo. The
residue was subjected to HPLC analysis for determination of
diastereoisomer ratios. Reported yields listed in Table 1 are
based on material isolated by column chromatography on silica
gel using hexane-EtOAc as the eluent system.
(2H, m), 6.82 (2H, d, J ) 8.8 Hz), 7.18 (2H, d, J ) 8.8 Hz); 13
C
NMR (CDCl3) δ 20.2, 21.8, 23.7, 26.8, 31.2, 34.6, 39.2, 41.8,
49.8, 50.9, 55.1, 70.8, 76.7, 113.1 (2C), 126.4 (2C), 131.4, 132.0,
143.7, 156.9, 157.8; EIMS m/z (rel intens) 399 (M+, 2), 149 (77),
135 (100), 121 (38); HRMS calcd for C24H33NO4 (M+) 399.2410,
found 399.2393.
(1R,2S,5R)-5-Met h yl-2-[1-m et h yl-1-(4-b r om op h en yl)-
eth yl]cycloh exyl (1R,4S)-2-Oxa -3-a za bicyclo[2.2.2]oct-5-
en e-3-ca r boxyla te (14d ). Colorless oil; [R]26 -15.2 (c 1.5,
D
CHCl3); IR (film) 1729 cm-1; 1H NMR (CDCl3) δ 0.79-1.12 (3H,
m), 0.85 (3H, d, J ) 6.5 Hz), 1.16 (3H, s), 1.20-1.75 (5H, m),
1.25 (3H, s), 1.88-2.01 (3H, m), 2.08-2.15 (1H, m), 3.8 (1H,
very br s), 4.59-4.68 (2H, m), 6.33-6.48 (2H, m), 7.15 (2H, d,
J ) 8.6 Hz), 7.39 (2H, d, J ) 8.6 Hz); 13C NMR (CDCl3) δ 20.2,
21.7, 23.7, 26.3, 31.2, 34.6, 39.5, 41.6, 49.9, 50.8, 70.8, 76.5,
118.5, 127.4 (2C), 130.9 (2C), 131.4, 131.7, 151.2, 157.6; EIMS
m/z (rel intens) 447 (M+, 0.2), 183 (34), 111 (40), 80 (51), 79
(100); HRMS calcd for C23H30NO3Br (M+) 447.1409, found
447.1397.
(1R,2S,5R)-5-Meth yl-2-[1-m eth yl-1-(4-n itr op h en yl)eth -
yl]cycloh exyl (1R,4S)-2-Oxa -3-a za bicyclo[2.2.2]oct-5-en e-
3-ca r boxyla te (14e). Pale yellow solid; mp 182-183 °C; [R]26
D
-22.7 (c 1.0, CHCl3); IR (KBr) 1728, 1510, 1344 cm-1; 1H NMR
(CDCl3) δ 0.80-0.96 (2H, m), 0.85 (3H, d, J ) 6.5 Hz), 1.05-
1.36 (3H, m), 1.21 (3H, s), 1.31 (3H, s), 1.40-1.53 (1H, m),
1.63-1.78 (3H, m), 1.86-1.92 (1H, m), 2.02-2.08 (2H, m), 3.7
(1H, very br s), 4.57 (1H, br s), 4.64 (1H, td, J ) 10.7, 4.2 Hz),
6.27-6.44 (2H, m), 7.43 (2H, d, J ) 8.8 Hz), 8.13 (2H, d, J )
8.8 Hz); 13C NMR (CDCl3) δ 20.0, 21.7, 23.5, 26.4, 28.6, 31.1,
34.4, 40.3, 41.5, 49.8, 51.0, 70.8, 76.2, 123.2 (2C), 126.3 (2C),
131.5 (2C), 145.4, 157.1, 160.2; EIMS m/z (rel intens) 414 (M+,
0.5), 164 (65), 111 (53), 79 (100); HRMS calcd for C23H30N2O5
(M+) 414.2155, found 414.2157.
(1R,2S,5R)-5-Meth yl-2-isop r op ylcycloh exyl (1R,4S)-2-
Oxa -3-a za bicyclo[2.2.2]oct-5-en e-3-ca r boxyla te (14a ). Col-
(1R,2S,5R)-5-Meth yl-2-[1-m eth yl-1-(2-n a p h th yl)eth yl]-
cycloh exyl (1R,4S)-2-Oxa -3-a za bicyclo[2.2.2]oct-5-en e-3-
ca r boxyla te (14f). Colorless needles (CHCl3-hexane); mp
orless oil; [R]26D -39.4 (c 0.9, CHCl3); IR (film) 1740, 1699 cm-1
;
1H NMR (CDCl3) δ 0.75 (3H, d, J ) 7.0 Hz), 0.78-1.08 (3H,
m), 0.86 (3H, d, J ) 7.1 Hz), 0.88 (3H, d, J ) 6.5 Hz), 1.32-
1.53 (4H, m), 1.62-1.68 (2H, m), 1.82-1.89 (1H, m), 1.97-
2.03 (1H, m), 2.08-2.22 (2H, m), 4.60 (1H, td, J ) 10.9, 4.4
Hz), 4.72 (1H, m), 4.78 (1H, m), 6.49-6.58 (2H, m); 13C NMR
(CDCl3) δ 16.5, 20.4, 20.6, 22.0, 23.7 (2C), 26.3, 31.4, 34.3, 41.0,
47.1, 50.3, 70.8, 76.3, 131.5, 132.1, 158.8; EIMS m/z (rel intens)
293 (M+, 4), 83 (76), 79 (100); HRMS calcd for C17H27NO3 (M+)
293.1991, found 293.1969.
122-123 °C; [R]26 -40.5 (c 1.0, CHCl3); IR (KBr) 1729, 1700
D
cm-1; H NMR (CDCl3) δ 0.81-1.17 (5H, m), 0.86 (3H, d, J )
1
6.5 Hz), 1.22-1.54 (2H, m), 1.29 (3H, s), 1.41 (3H, s), 1.59-
1.72 (2H, m), 1.85-1.99 (2H, m), 2.17 (1H, m), 3.5 (1H, very
br s), 4.52 (1H, d, J ) 3.0 Hz), 4.74 (1H, td, J ) 10.7, 4.2 Hz),
6.29 (2H, br s), 7.38-7.46 (2H, m), 7.50-7.54 (1H, m), 7.66
(1H, s), 7.75-7.83 (3H, m); 13C NMR (CDCl3) δ 19.2, 21.8, 23.5,
26.7, 31.2, 34.6, 39.8, 41.8, 49.6, 50.4, 70.7, 76.6, 123.0, 124.9,
125.1, 125.7, 127.2 (2C), 128.2, 131.1, 131.4, 131.8, 133.5,
149.4, 157.7; EIMS m/z (rel intens) 419 (M+, 1), 169 (62), 155
(100), 141 (37). Anal. Calcd for C27H33NO3: C, 77.29; H,7.93;
N, 3.34. Found: C, 77.29; H, 7.94; N, 3.64. An X-ray crystal
structure was obtained: monoclinic, space group P21, a )
17.78(1) Å, b ) 6.062(4) Å, c ) 11.292(6) Å, â ) 102.20(4)°, V
) 1190(1) Å3, Z ) 2, Dx ) 1.169 g cm-3, λ(Cu KR) ) 1.541 78
Å. Final R ) 0.048 for 2176 observed reflections.
(1R,2S,5R)-5-Meth yl-2-isop r op ylcycloh exyl (1S,4R)-2-
Oxa -3-a za bicyclo[2.2.2]oct-5-en e-3-ca r boxyla te (15a ). Col-
orless oil; [R]26 -77.2 (c 0.65, CHCl3); IR (film) 1738, 1699
D
cm-1; H NMR (CDCl3) δ 0.74-1.09 (3H, m), 0.77 (3H, d, J )
1
7.0 Hz), 0.88 (3H, d, J ) 6.6 Hz), 0.89 (3H, d, J ) 7.0 Hz),
1.33-1.52 (4H, m), 1.62-1.79 (2H, m), 1.82-2.03 (2H, m),
2.08-2.23 (2H, m), 4.61 (1H, td, J ) 10.9, 4.3 Hz), 4.71-4.80
(2H, m), 6.48-6.59 (2H, m); 13C NMR (CDCl3) δ 16.2, 20.6,
20.8, 22.0, 23.4, 23.6, 26.3, 31.4, 34.3, 41.1, 47.1, 50.3, 70.8,
76.4, 131.6, 131.8, 158.6; EIMS m/z (rel intens) 293 (M+, 4),
111 (34), 83 (95), 79 (100).
2-Ch lor o-5-(1,5-cycloh exa d ien yl)p yr id in e (7). To a ben-
zene (40 mL) solution containing 17 (6.08 g, 25.4 mmol) and
(Ph3P)4Pd (880 mg, 0.76 mmol) was added 2-(1,3-cyclohexadi-
enyl)magnesium bromide (18) prepared in 50 mL of THF from
2-bromo-1,3-cyclohexadiene (4.00 g, 25.2 mmol) and magne-
sium shavings (0.674 g, 27.7 mmol). After being stirred at
room temperature for 10 h, the mixture was diluted with ether
(400 mL), washed with 5% aqueous NH4Cl (100 mL) and brine
(50 mL), and dried (MgSO4). Concentration in vacuo followed
by purification by column chromatography on silica gel (hex-
ane-EtOAc, 100:1) afforded 7 (2.42 g, 50%) as a colorless
(1R,2S,5R)-5-Meth yl-2-[1-m eth yl-1-p h en yleth yl]cyclo-
h exyl (1R,4S)-2-Oxa -3-a za bicyclo[2.2.2]oct-5-en e-3-ca r -
boxyla te (14b). Colorless oil; [R]26 -24.6 (c 1.3, CHCl3); IR
D
(film) 1735, 1698 cm-1; 1H NMR (CDCl3) δ 0.76-1.08 (3H, m),
0.85 (3H, d, J ) 6.5 Hz), 1.13-1.63 (5H, m), 1.21 (3H, s), 1.30
(3H, s), 1.87-2.20 (4H, m), 3.9 (1H, very br s), 4.62-4.72 (2H,
m), 6.38-6.50 (2H, m), 7.10-7.16 (1H, m), 7.27-7.30 (4H, m);
13C NMR (CDCl3) δ 20.2, 21.8, 23.7, 26.8, 31.2, 34.6, 39.8, 41.7,
49.7, 50.8, 70.8, 76.7, 124.9, 125.5 (2C), 127.9 (2C), 131.3, 132.0,
151.6, 157.8; EIMS m/z (rel intens) 369 (M+, 2), 119 (58), 105
1
oil: IR (film) 1679 cm-1; H NMR (CDCl3) δ 2.15-2.23 (2H,
m), 2.30-2.36 (2H, m), 6.04 (1H, dt, J ) 9.7, 4.3 Hz), 6.10 (1H,
t, J ) 4.6 Hz), 6.19 (1H, dd, J ) 9.7, 1.7 Hz), 7.25 (1H, d, J )
8.3 Hz), 7.60 (1H, dd, J ) 8.3, 2.5 Hz), 8.38 (1H, d, J ) 2.5
Hz); 13C NMR (CDCl3) δ 21.6, 22.7, 123.8, 124.3, 125.1, 129.0,
132.0, 135.0, 135.5, 146.6, 149.5; EIMS m/z (rel intens) 193
(M+ + 2, 34), 191 (M+, 100), 154 (41), 128 (50), 126 (46); HRMS
calcd for C11H10NCl (M+) 191.0502, found 191.0502.
(100); HRMS calcd for
369.2284.
C
23H31NO3 (M+) 369.2304, found
(1R,2S,5R)-5-Meth yl-2-[1-m eth yl-1-(4-m eth oxyp h en yl)-
eth yl]cycloh exyl (1R,4S)-2-Oxa -3-a za bicyclo[2.2.2]oct-5-
en e-3-ca r boxyla te (14c). Colorless oil; [R]26 -23.8 (c 1.0,
D
CHCl3); IR (film) 1729, 1698 cm-1; H NMR (CDCl3) δ 0.72-
1

Total Synthesis of (-)-Epibatidine
J . Org. Chem., Vol. 63, No. 23, 1998 8405
ter t-Bu tyl (1S*,4R*,5R*)-5-(6-Ch lor o-3-p yr id yl)-2-oxa -
3-a za bicyclo[2.2.2]octa n e-3-ca r boxyla te (22) a n d ter t-
Bu t yl (1S*,4R*,6S*)-6-(6-Ch lor o-3-p yr id yl)-2-oxa -3-a za -
bicyclo[2.2.2]octa n e-3-ca r boxyla te (23). To a cooled (-78
°C), stirred solution of oxalyl chloride (1.99 g, 15.6 mmol) in
CH2Cl2 (65 mL) was added dropwise a solution of dimethyl
sulfoxide (2.42 g, 31.0 mmol) in CH2Cl2 (10 mL). The mixture
was stirred at -78 °C for 30 min. To this was added a solution
of 19 (1.40 g, 10.5 mmol) in CH2Cl2 (27 mL), and the mixture
was stirred at -78 °C. After 15 min, a solution of 7 (1.00 g,
5.22 mmol) in CH2Cl2 (10 mL) was added dropwise via syringe,
followed by addition of Et3N. The mixture was stirred for 1 h
at -78 °C and then quenched by addition of water (10 mL) at
-78 °C. The organic layer was separated, and the aqueous
layer was extracted with CHCl3 (3 × 30 mL). The combined
organic layers were washed with water, dried (MgSO4), and
concentrated in vacuo. The residue was chromatographed on
silica gel (hexane-EtOAc, 4:1) to give a mixture of the
cycloadducts 20 and 21 as a colorless oil (1.33 g, 79%), which
was subjected to catalytic hydrogenation. Thus, a part of the
cycloadducts 20 /21 (225 mg) was dissolved in dioxane (8 mL),
PtO2 (11 mg) was added to this solution, and the mixture was
stirred under 1 atm of hydrogen at room temperature. After
22 h the mixture was filtered through a Celite pad to remove
the catalyst and concentrated in vacuo. The residue was
subjected to column chromatography on silica gel (hexane-
EtOAc, 10:1) to afford 22 (105 mg, 46%) as a white solid, which
was recrystallized from CHCl3-hexane to give colorless cubics
and 23 (68 mg, 30%) as a white solid.
20%) as a white solid: mp 84-85 °C; [R]24 +65.5 (c 2.2,
D
CHCl3); IR (KBr) 1728, 1703, 1632 cm-1; H NMR (CDCl3) δ
1
0.80-1.13 (4H, m), 0.85 (3H, d, J ) 6.4 Hz), 1.18-1.75 (6H,
m), 1.25 (3H, s), 1.34 (3H, s), 1.92 (1H, br d, J ) 11.4 Hz),
2.00-2.25 (2H, m), 4.74 (1H, td, J ) 10.6, 4.0 Hz), 5.02 (1H,
br s), 6.61 (1H, br s), 7.24-7.55 (5H, m), 7.64 (1H, s), 7.76-
7.82 (3H, m), 8.32 (1H, s); 13C NMR (CDCl3) δ 19.7, 21.8, 23.7,
26.8, 29.7, 31.3, 34.6, 39.9, 41.8, 49.8, 50.0, 50.4, 71.9, 72.2,
77.3, 123.0, 124.2, 124.8, 125.2, 125.8, 127.2, 127.3, 128.2,
130.2, 131.4, 133.5, 134.9, 135.0, 139.0, 146.3, 149.0, 150.9,
157.4; EIMS m/z (rel intens) 532 (M+ + 2, 0.2), 530 (M+, 0.5),
169 (89), 155 (100), 141 (74). The third fraction afforded
(1S,2R,5S)-5-methyl-2-[1-methyl-1-(2-naphthyl)ethyl]cyclohex-
yl (1S,4R)-5-(6-chloro-3-pyridyl)-2-oxa-3-azabicyclo[2.2.2]oct-
5-ene-3-carboxylate (24) (1.83 g, 42%) as a white solid: mp
73-74 °C; [R]24 -26.1 (c 1.7, CHCl3); IR (KBr) 1730, 1657,
D
1629 cm-1; 1H NMR (CDCl3) δ 0.71 (3H, d, J ) 6.0 Hz), 0.77-
0.94 (2H, m), 1.10-1.70 (7H, m), 1.20 (3H, s), 1.36 (3H, s), 1.91
(2H, br s), 2.15 (1H, td, J ) 11.4, 3.2 Hz), 2.9 (1H, very br s),
4.57 (1H, td, J ) 10.4, 3.2 Hz), 4.65 (1H, br s), 6.53 (1H, br s),
7.30 (1H, d, J ) 8.3 Hz), 7.38-7.47 (3H, m), 7.60 (1H, d, J )
7.3 Hz), 7.70 (1H, br s), 7.78 (1H, d, J ) 8.0 Hz), 7.84 (1H, br
s), 8.20 (1H, br s); 13C NMR (CDCl3) δ 18.7, 21.6, 23.8, 26.2,
31.0, 34.4, 39.4, 41.4, 50.4, 50.6, 71.0, 77.1, 122.9, 123.9, 124.8,
125.2, 125.9, 127.2 (2C), 128.2, 129.6, 131.3, 133.6, 135.0,
139.0, 146.6, 150.3, 150.9, 157.2; EIMS m/z (rel intens) 532
(M+ + 2, 0.6), 530 (M+, 1.2), 169 (78), 155 (100), 141 (42);
HRMS calcd for C32H35N2O3Cl (M+) 530.2336, found 530.2354.
(1S,2R,5S)-5-Meth yl-2-[1-m eth yl-1-(2-n a p h th yl)eth yl]-
cycloh exyl (1S,4R,5R)-5-(6-Ch lor o-3-p yr id yl)-2-oxa -3-a za -
bicyclo[2.2.2]octa n e-3-ca r boxyla te (28). To a solution of
24 (600 mg, 1.13 mmol) in dioxane (20 mL) was added PtO2
(30 mg), and the mixture was stirred under 1 atm of hydrogen
at room temperature. After 20 h the reaction mixture was
filtered through a Celite pad to remove the catalyst. The
filtrate was concentrated in vacuo, and the residue was
purified by column chromatography on silica gel (hexane-
EtOAc, 5:1) to afford 28 (487 mg, 81%) as a white solid: mp
Data for 22: mp 174-175 °C; IR (KBr) 1718 cm-1; 1H NMR
(CDCl3) δ 1.36 (9H, s), 1.73-1.88 (2H, m), 2.12-2.30 (4H, m),
3.19 (1H, dd, J ) 10.8, 2.9 Hz), 4.04 (1H, br s), 4.37 (1H, br s),
7.27 (1H, d, J ) 8.1 Hz), 7.80 (1H, br d, J ) 8.1 Hz), 8.30 (1H,
d, J ) 2.0 Hz); 13C NMR (CDCl3) δ 24.3 (2C), 28.2 (3C), 32.6,
39.1, 53.2, 71.3, 81.5, 124.2, 138.0, 138.7, 149.4, 149.8, 155.3;
CIMS (isobutane) m/z (rel intens) 327 (M+ + 3, 33), 325 (M+
+ 1, 100), 269 (52). Anal. Calcd for C16H21N2O3Cl: C, 59.17;
H, 6.52; N, 8.62. Found: C, 59.04; H, 6.49; N, 8.65. An X-ray
crystal structure was obtained: monoclinic, space group P21/
a, a ) 22.666(7) Å, b ) 10.999(2) Å, c ) 12.992(3) Å, â )
94.43(2)°, V ) 3229(1) Å3, Z ) 8, Dx ) 1.336 g cm-3, λ(Cu KR)
) 1.541 78 Å. Final R ) 0.049 for 4803 observed reflections.
Data for 23: mp 112-113 °C; IR (KBr) 1728, 1697 cm-1; 1H
NMR (CDCl3) δ 1.50 (9H, s), 1.64-1.77 (1H, m), 1.86-1.95 (1H,
m), 2.07 (1H, ddt, J ) 13.9, 7.2, 2.5 Hz), 2.15-2.28 (2H, m),
2.33 (1H, ddd, J ) 13.8, 10.9, 3.6 Hz), 2.95 (1H, dd, J ) 10.9,
7.3 Hz), 4.10 (1H, br s), 4.18 (1H, br s), 7.28 (1H, d, J ) 8.3
Hz), 7.92 (1H, dd, J ) 8.3, 2.4 Hz), 8.27 (1H, d, J ) 2.4 Hz);
13C NMR (CDCl3) δ 22.0, 25.4, 28.3 (3C), 34.1, 38.1, 48.9, 75.7,
81.7, 124.4, 138.3, 138.8, 149.0, 149.9, 156.7; EIMS m/z (rel
intens) 324 (M+ + 2, 0.5), 324 (M+, 1.4), 57 (100); HRMS calcd
for C16H21N2O3Cl (M+) 324.1241, found 324.1259.
62-63 °C; [R]23D +2.7 (c 1.0, CHCl3); IR (KBr) 1708, 1632 cm-1
;
1H NMR (CDCl3) δ 0.73-0.93 (2H, m), 0.84 (3H, d, J ) 6.4
Hz), 1.00-1.83 (5H, m), 1.20 (3H, br s), 1.37 (3H, s), 1.86-
2.28 (5H, m), 2.75 (2H, br s), 4.09-4.25 (1H, m), 4.59 (1H, br
s), 7.25 (1H, d, J ) 8.1 Hz), 7.37-7.77 (5H, m), 7.68-7.80 (3H,
m), 8.13 (1H, br s); EIMS m/z (rel intens) 534 (M+ + 2, 1.5),
532 (M+, 4), 224 (33), 169 (77), 155 (100), 141 (57); HRMS calcd
for C32H37N2O3Cl (M+) 532.2493, found 532.2500.
ter t-Bu t yl (1S,4R,5R)-5-(6-Ch lor o-3-p yr id yl)-2-oxa -3-
azabicyclo[2.2.2]octan e-3-car boxylate [(-)-22]. To a stirred,
cooled (0 °C) suspension of borane-ammonia complex (90%,
119 mg, 3.47 mmol) in THF (5 mL) was added a 1.69 M
solution of butyllithium in hexane (3.0 mL, 3.38 mmol). The
mixture was stirred at 0 °C for 10 min and then at room
temperature for 10 min. After cooling the mixture to 0 °C, a
solution of 28 (180 mg, 0.338 mmol) in THF (2 mL) was added
dropwise and the mixture was stirred at room temperature
for 3 h. The reaction was quenched by addition of 10% aqueous
Na2CO3 (1.1 mL), and the mixture was cooled to 0 °C. To this
mixture was added dropwise with stirring a solution of di-tert-
butyl dicarbonate (369 mg, 1.69 mmol) in CHCl3 (2 mL), and
stirring was maintained at room temperature for 1 h. After
being diluted with CHCl3 (50 mL), the mixture was washed
with water, dried (MgSO4), and concentrated in vacuo. Puri-
fication by column chromatography on silica gel (hexane-
EtOAc, 4:1) provided (-)-22 (64 mg, 58%) as a white solid,
[R]25D -3.2 (c 1.4, CHCl3), spectral data of which were identical
with those of racemic 22.
[[(1S,2R,5S)-5-Meth yl-2-[1-m eth yl-1-(2-n a p h th yl)eth yl]-
cycloh exyl]oxy]ca r bon ylh yd r oxyla m in e (en t-12f). Title
compound, having [R]26 +30.1 (c 1.6, CHCl3), was prepared
D
in 90% yield from ent-9f according to the general procedure
for the preparation of hydroxamic acid 14.
Acyln itr oso Cycloa d d ition of Hyd r oxa m ic Acid en t-
12f a n d Dien e 7. Compound ent-12f (2.80 g, 8.20 mmol) and
7 (2.08 g, 10.9 mmol) was treated in a manner similar to that
used for the cycloaddition of 19 with 7, and the resulting crude
product was chromatographed on silica gel (hexane-EtOAc,
10:1). The first fraction afforded (1S,2R,5S)-5-methyl-2-[1-
methyl-1-(2-naphthyl)ethyl]cyclohexyl (1R,4S)-5-(6-chloro-3-
pyridyl)-2-oxa-3-azabicyclo[2.2.2]oct-5-ene-3-carboxylate (26)
(190 mg, 4%) as a white solid: 1H NMR (CDCl3) δ 0.75-1.12
(4H, m), 0.78 (3H, d, J ) 6.4 Hz),, 1.20-2.00 (8H, m), 1.35
(3H, s), 1.44 (3H, s), 2.12-2.18 (1H, m), 4.60 (1H, m), 4.82 (1H,
td, J ) 10.7, 4.5 Hz), 5.03 (1H, d, J ) 2.4 Hz), 6.61 (1H, dd, J
) 6.0, 2.1 Hz), 7.32 (1H, d, J ) 8.3 Hz), 7.39-7.45 (2H, m),
7.50 (1H, dd, J ) 8.7, 1.5 Hz), 7.64 (1H, s), 7.76-7.85 (4H, m),
8.46 (1H, d, J ) 2.4 Hz).
ter t-Bu t yl N-[(1R,2R,4S)-2-(6-Ch lor o-3-p yr id yl)-4-h y-
d r oxycycloh exyl]ca r ba m a te (29). To a solution of (-)-22
(280 mg, 0.862 mmol) in acetonitrile-water (15:1, 16 mL) was
added Mo(CO)6 (182 mg, 0.689 mmol), and the mixture was
refluxed for 3 h. The mixture was diluted with CHCl3 (50 mL),
washed with brine, dried (MgSO4), and concentrated in vacuo.
The residue was purified by column chromatography on silica
gel (hexane-EtOAc, 3:1) to afford 29 (240 mg, 85%) as a white
The second fraction afforded (1S,2R,5S)-5-methyl-2-[1-meth-
yl-1-(2-naphthyl)ethyl]cyclohexyl (1S,4R)-6-(6-chloro-3-pyridyl)-
2-oxa-3-azabicyclo[2.2.2]oct-5-ene-3-carboxylate (25) (888 mg,
solid: mp 188-190 °C; [R]25 -41.1 (c 0.9, CHCl3); IR (KBr)
D

8406 J . Org. Chem., Vol. 63, No. 23, 1998
3357, 1695 cm-1 1H NMR (CDCl3) δ 1.24 (9H, s), 1.39 (1H,
Aoyagi et al.
;
give 31 (35.5 mg, 96%) as a colorless oil: [R]26 -32.7 (c 1.1,
D
m), 1.73 (2H, tt, J ) 14.2, 3.9 Hz), 1.92-2.10 (3H, m), 2.56
(1H, br s), 2.89 (1H, d, J ) 13.0 Hz), 3.76 (1H, br s), 4.01 (1H,
br s), 4.85 (1H, br s), 7.23 (1H, d, J ) 8.2 Hz), 7.50 (1H, dd, J
) 8.2, 2.5 Hz), 8.21 (1H, s); 13C NMR (CDCl3) δ 28.1 (3C), 29.5,
29.7, 34.3, 42.1, 48.4, 69.6, 79.6, 123.8, 136.2, 138.3, 148.6,
149.6, 155.0; EIMS m/z (rel intens) 328 (M+ + 2, 1), 270 (35),
170 (50), 140 (96), 127 (49), 57 (100); HRMS calcd for
CHCl3); IR (film) 3373, 3301 cm-1
;
1H NMR (CDCl3) δ 1.31
(2H, br s), 1.64-1.69 (1H, m), 1.87-1.92 (1H, m), 1.98 (1H,
dd, J ) 14.1, 2.8 Hz), 2.26 (1H, tt, J ) 13.5, 3.1 Hz), 2.35 (1H,
tt, J ) 13.5, 3.1 Hz), 2.66 (1H, ddd, J ) 12.9, 12.8, 3.1 Hz),
3.34 (1H, t, J ) 2.8 Hz), 3.44 (1H, dt, J ) 12.7, 3.0 Hz), 4.87
(1H, t, J ) 2.8 Hz), 7.29 (1H, d, J ) 8.2 Hz), 7.52 (1H, dd, J )
8.2, 2.5 Hz), 8.28 (1H, d, J ) 2.5 Hz); 13C NMR (CDCl3) δ 27.7,
28.5, 31.9, 39.2, 50.0, 54.2, 124.0, 137.4, 138.3, 149.3, 149.8;
EIMS m/z (rel intens) 209 (M+ - Br, 2), 208 (M+ - HBr, 5),
69 (100); HRMS calcd for C11H14N2BrCl (M+ - Br) 209.0846,
found 209.0821.
C
C
16H23N2O3Cl (M+) 326.1397, found 326.1383. Anal. Calcd for
16H23N2O3Cl: C, 58.80; H, 7.09; N, 8.57. Found: C, 58.76;
H, 7.07; N, 8.55.
ter t-Bu tyl N-[(1R,2R,4R)-4-Br om o-2-(6-ch lor o-3-pyr idyl)-
cycloh exyl]ca r ba m a te (30). To a solution of 29 (220 mg,
0.673 mmol) in acetonitrile (22 mL) was added Ph3P (354 mg,
1.35 mmol) and CBr4 (448 mg, 1.35 mmol). The mixture was
allowed to warm to 70 °C and stirred for 45 min at this
temperature. The reaction mixture was diluted with CHCl3
(100 mL), washed with saturated aqueous NaHCO3 (20 mL)
and brine, dried (MgSO4), and concentrated in vacuo. The
residue was purified by column chromatography on silica gel
(hexane-EtOAc, 10:1) to give 30 (110 mg, 42%) as a white
(-)-Ep iba tid in e (1). A solution of 31 (30 mg, 0.104 mmol)
in CHCl3 (2 mL) was refluxed for 3 days and rendered to basic
with 10% aqueous K2CO3. The organic layer was separated,
dried (K2CO3), and concentrated in vacuo. Purification of the
crude residue by column chromatography on silica gel (CHCl3-
MeOH-concentrated NH4OH, 100:9:1) provided 1 (21 mg,
97%) as a white solid: mp 61-62 °C; [R]27 -6.26 (c 0.8,
D
CHCl3); IR (film) 3269, 2962, 2873, 1582, 1563, 1457, 1104,
1025, 820 cm-1; H NMR (CDCl3) δ 1.48-1.65 (5H, m), 2.77
1
solid: mp 174-175 °C; [R]28 -25.7 (c 1.30, CHCl3); IR (film)
(1H, dd, J ) 9.0, 4.9 Hz), 3.6 (1H, d, J ) 2.0 Hz), 3.80 (1H, t,
J ) 4.0 Hz), 7.23 (1H, d, J ) 8.3 Hz), 7.76 (1H, dd, J ) 8.3,
2.5 Hz), 8.27 (1H, d, J ) 2.5 Hz); 13C NMR (CDCl3) δ 30.2,
31.4, 40.4, 44.6, 56.5, 62.8, 124.0, 137.7, 141.1, 148.9, 149.0;
EIMS m/z (rel intens) 210 (M+ + 2, 3), 208 (M+, 8), 179 (4),
149 (4), 140 (13), 104 (4), 77 (7), 69 (100), 68 (55); HRMS calcd
for C11H13N2Cl (M+) 208.0767, found 208.0761.
D
3266, 1695 cm-1; H NMR (CDCl3) δ 1.25 (9 H, s), 1.35-1.47
1
(1 H, m), 1.72-2.50 (7 H, m), 3.50 (1 H, br d, J ) 10.1 Hz),
3.92-4.15 (1 H, m), 4.80 (1 H, s), 7.27 (1 H, d, J ) 8.2 Hz),
7.52 (1 H, br d, J ) 8.2 Hz), 8.22 (1 H, s); 13C NMR (CDCl3) δ
26.6, 28.1 (3 carbon), 29.1, 33.4, 38.4, 49.3, 51.8, 79.8, 123.8,
136.0, 138.5, 148.6, 149.7, 155.0; EIMS m/z (rel intens) 392
(M+ + 4, 0.1), 390 (M+ + 2, 0.4), 388 (M+, 0.3), 336 (M+, 1),
167 (36), 149 (76), 57 (100); HRMS calcd for C16H22N2O2BrCl
(M+) 388.0553, found 388.0550. Anal. Calcd for C16H22N2O2-
BrCl: C, 49.31; H, 5.69; N, 7.19. Found: C, 49.24; H, 5.63;
N, 7.22.
Ack n ow led gm en t. C.K. thanks the Ministry of
Education, Science, Sports and Culture, J apan for a
Grant-in-Aid for Science Research (No. 08672450).
[(1R,2R,4R)-4-Br om o-2-(6-ch lor o-3-p yr idyl)cycloh exa n -
1-a m in e (31). To a cooled (0 °C), stirred solution of 30 (50
mg, 0.13 mmol) in CH2Cl2 (3 mL) was added trifluoroacetic
acid (292 mg, 2.56 mmol), and the mixture was stirred at room
temperature for 3 h and concentrated in vacuo. After 10%
aqueous K2CO3 (1 mL) was added to the residue, the mixture
was extracted with CHCl3 (3 × 20 mL). The combined extracts
were dried (K2CO3) and concentrated in vacuo to give a crude
residue, which was purified by column chromatography on
silica gel (CHCl3-MeOH-concentrated NH4OH, 100:9:1) to
Su p p or tin g In for m a tion Ava ila ble: Figures showing 1H
NMR spectra of compounds 1, 7, 9d , 9e, 10, 11, 12a -f, 14a -
e, 15a , 23-26, 28, and 31 and ORTEP diagrams of 14f and
22 and tables listing and X-ray data of compounds 14f and 22
(42 pages). This material is contained in libraries on micro-
fiche, immediately follows this article in the microfilm version
of the journal, and can be ordered from the ACS; see any
current masthead page for ordering information.J O9813078
J O9813078