A versatile and stereoselective synthesis of (±)-epibatidine

Article abstract of DOI:10.1055/s-1998-6096

A new synthesis of (±)-epibatidine has been achieved, involving a Diels-Alder cycloaddition of (Z)-4-[5'-(2'-chloropyridylmethylene)]-2-phenyl-5(4H)-oxazolone with Danishefsky's diene, and an intramolecular nucleophilic displacement in a trans-1,4-methanesulfonyloxycyclohexylamide derivative as key steps.

Full text of DOI:10.1055/s-1998-6096

SYNTHESIS
September 1998
1335
A Versatile and Stereoselective Synthesis of (±)-Epibatidine
A. Avenoza,*a J. H. Busto,a C. Cativiela,*b J. M. Peregrinaa
a
Department of Chemistry (Organic Chemistry), Edificio Científico-Técnico, Sección Ciencias, Universidad de La Rioja, ES-26001 Logroño, Spain.
Fax +34(941)259431; E-mail: alberto.avenoza@dq.unirioja.es
Department of Organic Chemistry, Instituto de Ciencia de Materiales de Aragón, Universidad de Zaragoza-C.S.I.C., ES-50009 Zaragoza, Spain.
b
Fax +34(976)762077; E-mail: cativiela@posta.unizar.es
Received 14 November 1997; revised 19 January 1998
Abstract: A new synthesis of (±)-epibatidine has been achieved,
involving a Diels–Alder cycloaddition of (Z)-4-[5'-(2'-chloro-
pyridylmethylene)]-2-phenyl-5(4H)-oxazolone with Danishefsky's
is subsequently reduced and cyclized to give a new type
diene, and an intramolecular nucleophilic displacement in a trans-
1,4-methanesulfonyloxycyclohexylamide derivative as key steps.
diene [1-methoxy-3-(trimethylsilyloxy)-1,3-butadiene] as
the key step in the preparation of the cycloadduct 3, which
of constrained proline analogue 4.12 This is an interesting
amino acid in that when it is exchanged for a natural ami-
Key words: epibatidine, Diels–Alder reaction, Danishefsky’s
no acid into the backbone of a parent peptide, it could pos-
sibly play a dual role as a conformational probe and a bio-
active peptidomimetic13 (Scheme 1).
diene, O-acyl thiohydroxamate derivative, radical decarboxyl-
ation, 7-azabicyclo[2.2.1]heptane system
Since the discovery of the biological activity of epibati-
dine (1) (an alkaloid isolated from the skin extract of the
Ecuadorian poisonous frog Epipedobates tricolor in 1992
by Daly and co-workers1) as a powerful analgesic that acts
through a non-opioid mechanism and is at least two hun-
dred times more potent than morphine, several synthetic
approaches have been reported by numerous research
groups, even in its enantiomerically pure form.2,3 Interest-
ingly, both enantiomers of epibatidine are nearly equipo-
tent in analgesic tests.4 This feature suggests that (–)- and
(+)-epibatidine can both act with the neuronal nicotinic
receptor, so the availability of epibatidine in enantiomeri-
cally pure form is not crucial for its biological activity.
Scheme 1
Taking into account the fact that the proline analogue 4 is
closely related to epibatidine (1), and due to the impor-
tance of epibatidine as a new class of alkaloid possessing
a 7-azabicyclo[2.2.1]heptane skeleton,14 we have devel-
oped a synthetic approach to this target molecule, in its
racemic form, by the strategy outlined in Scheme 2.
Epibatidine (1) has been synthesized employing different
methods, including Diels–Alder cycloaddition of N-pro-
tected pyrroles with activated dienophiles5 or by a [3+2]
cycloaddition of the non-stabilized azomethine ylide
[N-benzyl-2,5-di(trimethylsilyl)pyrrolidine] and dipo-
larophiles, such as substituted 6-chloro-3-vinylpyridine6
and creation of the carbon–carbon bond between the 2-
chloro-5-pyridyl substituent and the carbon-2 of azabi-
cyclic ring.7–9 However, the most common procedure in-
cludes an intramolecular nucleophilic displacement of a
trans-1,4-aminocyclohexane derivative, with a leaving
group in the δ position of the amino group for the con-
struction of the 7-azabicyclo[2.2.1]heptane system.2,10
Our synthesis utilizes, as a starting material, the readily
available (Z)-4-[5'-(2'-chloropyridylmethylene)]-2-phe-
nyl-5(4H)-oxazolone (6), which is prepared by the Erlen-
meyer–Plöchl method15 from 6-chloropyridine-3-carbox-
aldehyde (5)16 and hippuric acid. The reaction of 5(4H)-
oxazolone (6) with Danishefsky’s diene, followed by sub-
sequent treatment with 0.005 N HCl/THF (1:4) solution,
gives a mixture of two compounds (cis- and trans-2-meth-
oxy-1-spiro-oxazolone cycloadducts). Both cycloadducts
are converted into the sole product, corresponding to the
enone 7, by elimination of their methoxy groups using
DBU/methanol.
Hydrogenation of the double bond in 7 could only be
achieved in good yield using 10% platinum/carbon as a
catalyst in ethanol at room temperature to afford com-
pound 8. Further reduction of the cyclohexanone deriva-
tive 8 with L-Selectride® in THF at –78°C17 gave a mix-
ture of axial and equatorial alcohols 9 and 10 in a ratio
70:30.18 This mixture was treated with methanesulfonyl
chloride in triethylamine to obtain the corresponding
methanesulfonate derivatives 11 and 12 in excellent yield.
The desired axial methanesulfonate derivative 11 was iso-
lated by column chromatography. The 7-azabicyc-
lo[2.2.1]heptane ring system of epibatidine was formed
by base-promoted internal nucleophilic displacement, us-
In the course of our investigations into the synthesis of
new non-proteinogenic and unusual conformationally re-
stricted α-amino acids, we have developed a new method-
ology involving the use of (Z)-2-phenyl-4-benzylidene-
5(4H)-oxazolone (2) as a dienophile with several dienes,
allowing the synthesis of new and interesting com-
pounds.11 In particular, we have recently reported the
Diels–Alder reaction of oxazolone 2 with Danishefsky’s

SYNTHESIS
Papers
1336
Because of this problem we decided to use a reductive
radical decarboxylation after hydrolysis of the methoxy-
carbonyl group by treatment with lithium hydroxide in
aqueous methanol to form the carboxylic acid 14 in essen-
tially quantitative yield. Sequential formation of the acti-
vated ester of carboxylic acid 14 was achieved by the ac-
tion of 2-chloro-N-methylpyridinium iodide in triethy-
lamine, followed by coupling with N-hydroxy-2-
thiopyridone to afford the corresponding O-acyl thiohy-
droxamate. This compound was then photolyzed with
tributyltin hydride, using a 200 W tungsten lamp,13,21 to
give the epibatidine precursor 15. After purification of
compound 15 by column chromatography, the benzamido
group was hydrolyzed in aqueous 6 N HCl under reflux
and further neutralization of the reaction mixture gave
(±)-epibatidine22 as an oil in 11% yield from 5(4H)-ox-
azolone 6.
In conclusion, we have developed a straightforward syn-
thetic route for (±)-epibatidine (1) using a method devel-
oped in our research group, which involves the use of a
5(4H)-oxazolone derivative as a dienophile in the Diels–
Alder cycloaddition with Danishefsky's diene. The advan-
tage of this synthetic approach is its versatility for the syn-
thesis of anologues of epibatidine (1) simply starting from
different aliphatic or aromatic aldehydes. Such a facile
synthetic route will allow further determination of the
pharmacological behaviour and potential applications of
such derivatives.
Solvents were purified according to standard procedures. Analytical
TLC was performed using Polychrom SI F254 plates. 1H and 13C NMR
spectra were recorded using a Bruker ARX-300 spectrometer in
CDCl3 or DMSO-d6 with TMS as an internal standard. Chemical
shifts are reported in ppm on the δ scale and coupling constants in Hz.
Melting points were determined using a Büchi SMP-20 melting point
apparatus and are uncorrected. Microanalyses were carried out using
a Perkin-Elmer 240-C analyzer and were in good agreement with the
calculated values: C ± 0.25, H ± 0.25, N ± 0.15.
Scheme 2
ing potassium tert-butoxide in THF at –78°C, which
transformed compound 11 into the bridged compound 13.
The reaction sequence to synthesize epibatidine from
compound 13 required a decarboxylation step. Initially,
we attempted a method used in the elimination of a meth-
oxycarbonyl group directly attached to a bridged carbon
atom.19 This method consists of the transformation of the
methoxycarbonyl group into a carboxaldehyde group to
obtain compound 16, followed by further elimination of
the carboxaldehyde group by treatment with Wilkinson’s
catalyst in refluxing xylene.20 Although the aldehyde 16 is
obtained in good yield by reduction of methyl ester 13
with DIBAL at –78°C, the second reaction produced a
complicated mixture of several products which were dif-
ficult to identify and separate (Scheme 3).
(Z)-4-[5'-(2'-Chloropyridylmethylene)]-2-phenyl-5(4H)-oxazo-
lone (6):
A mixture of 5 (3 g, 21 mmol), N-benzoylglycine (3.8 g, 21 mmol),
Ac2O (1.7 g, 21 mmol) and anhyd NaOAc (6.5 g, 63 mmol) was heat-
ed at 100°C for 1 h. The mixture was then allowed to cool to r.t. and
poured into EtOH/H2O (2:3, 20 mL). The solid 5(4H)-oxazolone was
filtered off, washed with cold EtOH and dried to give 3.6 g (60%) of
6 as a yellow solid; mp 200°C (dec).
1H NMR (CDCl3 /DMSO-d6): δ = 7.16 (s, 1 H), 7.44–7.68 (m, 5 H),
8.14–8.19 (m, 1 H), 8.68–8.74 (m, 1 H), 8.92–8.95 (m, 1 H).
13C NMR (CDCl3/DMSO-d6): δ = 124.1, 124.5, 125.5, 128.0, 128.3,
128.5, 128.9, 129.4, 133.9, 139.5, 140.8 (arom, C=C), 150.8 (C=N),
152.6 (C=O).
Methyl 1-Benzamido-t-6-[5'-(2'-chloropyridyl)]-4-oxocyclohex-2-
ene-r-1-carboxylate (7):
Danishefsky’s diene [1-methoxy-3-(trimethylsilyloxy)-1,3-butadi-
ene] (1.4 g, 12.00 mmol) was added to a solution of 6 (1.7 g,
6.00 mmol) in anhyd toluene (30 mL). After stirring under reflux for
1 d, the solvent was evaporated in vacuo and a solution of 0.005 N
HCl/THF (1:4, 20 mL) was added to the residue. The mixture was
stirred for 7 h, the solvent removed and the mixture was diluted with
CH2Cl2 (30 mL). This solution was washed with brine (2 × 20 mL)
Scheme 3

SYNTHESIS
September 1998
1337
and aq 5% NaHCO3 solution (2 × 20 mL), dried (MgSO4) and fil-
tered. Evaporation of the solvent gave a residue that was dissolved in
MeOH (20 mL) and treated with DBU (150 mg, 1.00 mmol). The
mixture was stirred for 12 h at 0°C and after evaporation of the sol-
vent, the residue was chromatographed on silica gel eluting with hex-
ane/EtOAc (70:30) to yield 816 mg of enone 7 as an oil. (71%).
1H NMR (CDCl3): δ = 2.87 (dd, 1 H, J5e,5a = 16.8, J5e,6a = 5.1, H-5e),
3.31–3.43 (m, 1 H, H-5a), 3.87 (s, 3 H, CO2CH3), 4.23 (dd, 1 H, J6a,5a
= 9.3, J6a,5e = 5.1, H-6a), 6.38 (br d, 1 H, J2,3 = 9.9, H-2), 6.82 (br s, 1
H, NH), 6.90 (br d, 1 H, J3,2 = 9.9, H-3), 7.21–7.62 (m, 7 H, arom),
8.15–8.19 (m, 1 H, arom).
tography eluting with hexane/EtOAc (50:50) to yield 319 mg (90%)
of 13 as an oil.
1H NMR (CDCl3): δ = 1.64–1.76 (m, 2 H, H-5n, H-5x), 1.95–2.06 (m,
1 H, H-6n), 2.15–2.39 (m, 2 H, H-3n, H-3x), 2.54 ('t'd, 1 H, J6x,6n
~ J6x,5x = 12.6, J6x,5n = 5.1, H-6x), 3.24 (dd, 1 H, J2n,3n = 9.0, J2n,3x
=
5.4, H-2n), 3.32 (s, 3 H, CO2CH3), 4.40 ('t', 1 H, J4,5x ~ J4,3x = 4.8, H-
4), 7.26–7.82 (m, 7 H, arom), 8.29–8.32 (m, 1 H, arom).
13C NMR (CDCl3): δ = 30.1 (C-6), 30.8 (C-5), 39.6 (C-3), 50.0 (C-2),
51.6 (CO2CH3), 62.4 (C-4), 72.6 (C-1), 123.6, 128.5, 128.9, 132.2,
134.1, 136.7, 139.1, 149.4, 150.3 (arom), 169.3 (CON), 174.3
(CO2CH3).
13C NMR (CDCl3): δ = 29.8, 44.4, 51.4 (C-5,6, CO2CH3), 76.5 (C-1),
126.6, 127.0, 128.1, 128.3, 128.5, 128.6, 128.8, 129.1, 131.6, 133.4,
142.9 (arom, C-2,3); 165.8 (CONH), 171.6 (CO2CH3), 197.7 (CO).
N-Benzoyl-exo-2-[5'-(2'-chloropyridyl)]-7-azabicyclo[2.2.1]hep-
tane-1-carboxylic acid (14):
Compound 13 (100 mg, 0.27 mmol) was dissolved in a mixture of
•
Methyl 1-Benzamido-t-2-[5'-(2'-chloropyridyl)]-4-oxocyclohex-
ane-r-1-carboxylate (8):
MeOH/H2O (3:2, 21 mL) and LiOH H2O (113 mg, 2.70 mmol) was
added. The mixture was refluxed for 12 h and the solvent was evapo-
rated in vacuo. The residue was diluted with H2O (10 mL) and washed
with CH2Cl2 (2 × 20 mL). The aqueous phase was acidified with a
6 N HCl solution and extracted with CH2Cl2 (2 × 20 mL). The organ-
ic layer was dried (Na2SO4), filtered and evaporated to give 95 mg
(99%) of a residue corresponding to compound 14, which was used in
the next step without purification.
A solution of enone 7 (816 mg, 2.12 mmol) in anhyd EtOH (100 mL)
was hydrogenated at atmospheric pressure for 48 h using 10% Pt/C
(50 mg) as a catalyst. Removal of the catalyst and the solvent gave a
residue which was chromatographed on silica gel eluting with hex-
ane/EtOAc (50:50) to yield 713 mg (87%) of 8 as an oil.
1H NMR (CDCl3): δ = 2.53–2.88 (m, 4 H), 3.08–3.12 (m, 1 H), 3.21–
3.29 (m, 1 H), 3.78 (s, 3 H, CO2CH3), 3.84 (dd, 1 H, J2a,3a = 10.5, J2a,3e
= 5.4, H-2a), 6.33 (br s, 1 H, NH), 7.12–7.80 (m, 8 H, arom).
13C NMR (CDCl3): δ = 31.1, 36.3, 42.3, 42.8 (C-2,3,5,6), 53.2
(CO2CH3), 61.4 (C-1), 126.0, 128.2, 128.4, 131.9, 132.6, 139.0,
141.1, 141.5, 147.7 (arom), 167.8 (CONH), 172.4 (CO2CH3), 208.5
(CO).
1H NMR (CDCl3): δ = 1.71 (ddd, 1 H, J5n,5x = 13.2, J5n,6n = 9.0, J5n,6x
= 4.5, H-5n), 1.90–1.99 (m, 1 H, H-5x), 2.06–2.19 (m, 2 H, H-3n, H-
3x), 2.31 (ddd, 1 H, J6n,6x = 13.2, J6n,5n = 9.0, J6n,5x = 4.5, H-6n), 2.48
('t'd, 1 H, J6x,6n ~ J6x,5x = 13.2, J6x,5n = 4.5, H-6x), 3.51(dd, 1 H, J2n,3n
= 9.0, J2n,3x = 5.4, H-2n), 4.51 ('t', 1 H, J4,5x ~ J4,3x = 4.8, H-4), 7.25–
8.07 (m, 7 H, arom), 8.30–8.33 (m, 1 H, arom).
13C NMR (CDCl3): δ = 28.8, 34.9, 37.9, 49.9, 62.3(C-2 to C-6),
77.1(C-1), 124.4, 127.4, 128.9, 131.9, 133.9, 136.4, 138.7, 148.7,
150.5(arom), 169.2(CONH), 171.5(CO2H).
Methyl 1-Benzamido-t-2-[5'-(2'-chloropyridyl)]-c-4-methane-
sulfonyloxycyclohexane-r-1-carboxylate (11):
To a solution of 8 (650 mg, 1.68 mmol) in anhyd THF (15 mL) was
added dropwise L-Selectride® (350 mg, 1.84 mmol) at –78°C under
an inert atmosphere. After stirring for 12 h at the same temperature,
the reaction was quenched by the addition of aq satd NH4Cl solution
(2 mL). The resulting mixture was allowed to warm up to r.t. and ex-
tracted with EtOAc (3 × 30 mL). The organic layer was dried
(MgSO4), filtered and evaporated to give a mixture of compounds 9
and 10 in a ratio 70:30 as determined by 1H NMR spectroscopy.18 The
mixture of products was dissolved in CH2Cl2, filtered through a short
silica gel column and was used in the next step without separation.
After evaporation of the solvent, the mixture of compounds 9 and 10
was dissolved in CH2Cl2 (20 mL), and Et3N (204 mg, 2.01 mmol) and
MeSO2Cl (230 mg, 2.01 mmol) were added. The mixture was stirred
at r.t. for 24 h and evaporated to give a residue, which was purified by
silica gel column chromatography eluting with hexane/EtOAc
(50:50) to yield 432 mg (55%) of 11 as an oil.
N-Benzoyl-exo-2-[5'-(2'-chloropyridyl)]-7-azabicyclo[2.2.1]hep-
tane (15):
A mixture of N-hydroxy-2-thiopyridone (59 mg, 0.40 mmol), 2-chlo-
ro-N-methylpyridinium iodide (82 mg, 0.32 mmol), Et3N (65 mg,
0.64 mmol) and carboxylic acid 14 (100 mg, 0.27 mmol) in CH2Cl2
(20 mL) was stirred under reflux for 12 h. The solvent was evaporated
and the oily mixture was purified by silica gel column chromatogra-
phy, using hexane/EtOAc (50:50) to give the corresponding O-acyl
thiohydroxamate, which was dissolved in anhyd CH2Cl2 (10 mL). Af-
ter addition of Bu3SnH (0.2 mL), the reaction was irradiated at r.t.
using a 200 W tungsten lamp for 2 h. The solvent was removed in
vacuo and the residue was purified by silica gel column chromatogra-
phy, eluting with hexane/EtOAc (50:50) to yield 41 mg (49%) of epi-
batidine precursor 15 as an oil.
The signals in the 1H and 13C NMR spectra appeared in duplicate as
a consequence of the conformational equilibrium of the amide group,
as described by Daly and co-workers1 (Scheme 4).
1H NMR(CDCl3): δ = 1.85–1.97 (m, 1 H), 2.02–2.13 (m, 1 H), 2.20–
2.31 (m, 1 H), 2.37–2.42 (m, 1 H), 2.48–2.60 (m, 1 H), 3.02–3.22 (m,
4 H, H, SO2CH3), 3.62 (s, 3 H, CO2CH3), 3.78 (dd, 1 H, J2a,3a = 13.2,
J2a,3e = 3.3, H-2a), 5.18–5.22 (m, 1 H, H-4e), 6.02 (br s, 1 H, NH),
7.14–7.68 (m, 7 H, arom), 8.26–8.28 (m, 1 H, arom).
13C NMR (CDCl3): δ = 25.7, 26.0, 31.5, 38.7, 41.3, 52.5, 63.1, 69.6
(C-1 to C-6, SO2CH3, CO2CH3), 124.3, 126.8, 128.3, 128.7, 131.9,
133.2, 134.1, 138.4, 148.7 (arom), 168.2 (CONH), 172.1 (CO2CH3).
Scheme 4
Methyl N-Benzoyl-exo-2-[5'-(2'-chloropyridyl)]-7-azabicyclo-
[2.2.1]heptane-1-carboxylate (13):
1H NMR (CDCl3): δ = 1.23–2.08 (m, 12 H), 2.98–3.08 (m, 2 H), 3.99
(br s, 1 H, H-1a), 4.35 (br s, 1 H, H-4b), 4.79 (br s, 1 H, H-1b), 4.97
(br s, 1 H, H-4a), 7.08–7.74 (m, 14 H, arom), 8.25–8.29 (m, 2 H,
arom).
To a solution of 11 (450 mg, 0.96 mmol) in anhyd THF (20 mL) was
added a 1 M solution of t-BuOK in THF (1.1 mL, 1.1 mmol) under an
inert atmosphere at –78°C. After stirring for 1 h at –78°C, the reac-
tion was warmed at 0°C and allowed to stand at this temperature for
16 h. The reaction was quenched by the addition of 0.5 N HCl solu-
tion (2 mL) and the resulting mixture was extracted with EtOAc (3 ×
20 mL). The organic layer was dried (Na2SO4), filtered and evaporat-
ed to give a residue, which was purified by silica gel column chroma-
13C NMR (CDCl3): δ = 27.5, 28.9, 36.7, 40.2, 43.3, 45.1, 49.0, 53.2,
57.8, 58.3, 61.2, 64.1 (C-1 to C-6), 123.1, 123.4, 126.5, 127.4, 130.7,
131.1, 133.2, 135.1, 135.8, 136.2, 147.7, 147.9 (arom), 168.5, 169.1
(CON).

SYNTHESIS
Papers
1338
exo-2-[5'-(2'-Chloropyridyl)]-7-azabicyclo[2.2.1]heptane (Epiba-
tidine) (1):
(10) Broka, C. A. Tetrahedron Lett. 1993, 34, 3251.
Corey, E. J., Loh, T.-P., AchyuthaRao, S., Daley, D. C., Sarshar,
S. J. Org. Chem. 1993, 58, 5600.
Albertini, E., Barco, A., Benetti, S., De Risi, C., Pollini, G. P.,
Romagnoli, R., Zanirato, V. Tetrahedron Lett. 1994, 35, 9297.
Sestanj, K., Melenski, E., Jirkovsky, I. Tetrahedron Lett. 1994,
35, 5417.
Szántay, C., Kardos Balogh, Z., Moldvai, I., Szántay Jr., C., Te-
mesvári-Major, E., Blaskó, G. Tetrahedron Lett. 1994, 35,
3171.
Compound 15 (40 mg, 0.13 mmol) was suspended in aq 6 N HCl (15
mL) and refluxed for 24 h. The mixture was concentrated in vacuo
and the residue dissolved in H2O (15 mL) and washed with CH2Cl2
(2 × 20 mL). The aqueous phase was neutralized and then extracted
with CH2Cl2 (2 × 20 mL). The organic layer was dried (Na2SO4), fil-
tered and evaporated to give 21 mg (77%) of an oily residue corre-
sponding to epibatidine.22
N-Benzoyl-exo-2-[5'-(2'-chloropyridyl)]-7-azabicyclo[2.2.1]hep-
tane-1-carboxaldehyde (16):
Ko, S. Y., Lerpiniere, J., Linney, I. D., Wrigglesworth, R.
J. Chem. Soc., Chem. Commun. 1994, 1775.
To a solution of 13 (100 mg, 0.27 mmol) in anhyd toluene (10 mL)
was added a 1 M solution of DIBAL in THF (0.46 mL) under an inert
atmosphere at –78°C. The mixture was stirred at the same tempera-
ture for 17 h and the reaction was quenched by the dropwise addition
of H2O (2 mL) and aq 2 N HCl (5 mL). This mixture was extracted
with EtOAc (3 × 30 mL) and the organic layer was dried (MgSO4),
filtered and evaporated. The residue was then purified by silica gel
column chromatography eluting with hexane/EtOAc (50:50) to give
a mixture of aldehyde 16 and compound 13 in a ratio 9:1 (78%).
1H NMR (CDCl3): δ = 1.50–2.40 (m, 6 H, H-3n, H-3x, H-5n, H-5x,
H-6n, H-6x), 3.24 (dd, 1 H, J2n,3n = 9.0, J2n,3x = 6.0, H-2n), 4.53 ('t', 1
H, J4,5x ~ J4,3x = 3.0, H-4), 7.13–7.76 (m, 7 H, arom), 8.39–8.42 (m,
1 H, arom), 9.60 (s, 1 H, CHO).
(11) Avenoza, A., Cativiela, C., González, M., Mayoral, J. A., Roy,
M. A. Synthesis 1990, 1114.
Avenoza, A., Cativiela, C., Díaz-de-Villegas, M. D., Mayoral,
J. A., Peregrina, J. M. Tetrahedron 1993, 49, 677.
Avenoza, A., Cativiela, C., Díaz-de-Villegas, M. D., Peregrina,
J. M. Tetrahedron 1993, 49, 10987.
Avenoza, A., Cativiela, C., Peregrina, J. M. Tetrahedron 1994,
50, 10021.
Avenoza, A., Busto, J. H., Cativiela, C., Peregrina, J. M. Tetra-
hedron 1994, 50, 12989.
Avenoza, A., Busto, J. H., Cativiela, C., Peregrina, J. M. Synthe-
sis 1995, 6, 671.
Avenoza, A., Busto, J. H., Cativiela, C., París, M., Peregrina, J.
M. J. Heterocycl. Chem. 1997, 34, 1099.
Avenoza, A., Busto, J. H., Cativiela, C., Peregrina, J. M. Anales
de Química Int. Ed. 1998, 94, 50.
13C NMR (CDCl3): δ = 29.6, 30.5, 40.3, 48.8, 61.3 (C-2 to C-6), 75.5
(C-1), 124.3, 125.2, 128.1, 128.3, 128.6, 128.9, 132.1, 138.5, 149.3
(arom), 173.1 (CON), 197.3 (CHO).
(12) Avenoza, A., Busto, J. H., Cativiela, C., Peregrina, J. M. Tetra-
hedron Lett. 1995, 36, 7123.
(13) Campbell, J. A., Rapoport, H. J. Org. Chem. 1996, 61, 6313.
(14) Chen, Z. A., Trudell, M. L. Chem. Rev. 1996, 96, 1179.
(15) Plöchl, J. Ber. Dtsch. Chem. Ges. 1883, 16, 2815.
Carter, H. E. Org. React. 1946, 3, 198.
(16) 6-Chloropyridine-3-carboxaldehyde (5) was prepared accord-
ing to the literature method described by Corey et al. (J. Org.
Chem. 1993, 58, 5600, see reference 5), starting from 6-chloro-
pyridine-3-carboxylic acid by reduction to the corresponding
primary alcohol (DIBAL, toluene, r.t., 2 h, 70%, instead of
We are indebted to the Dirección General de Investigación Científica
y Técnica (project PB94-0578-C02-02) and to the Universidad de La
Rioja (project API-97/B03) for their generous support. J. H. Busto
thanks the Ministerio de Educación y Ciencia for a doctoral fellow-
ship.
(1) Spande, T. F., Garrafo, H. M., Edwards, M. W., Yeh, H. J. C.,
Pannell, L., Daly, J. W. J. Am. Chem. Soc. 1992, 114, 3475.
(2) Trost, B. M., Cook, G. R. Tetrahedron Lett. 1996, 37, 7485.
(3) Szántay, C., Kardos Balogh, Z., Moldvai, I., Szántay Jr., C., Te-
mesvári-Major, E., Blaskó, G. Tetrahedron 1996, 52, 11053.
Albertini, E., Barco, A., Benetti, S., De Risi, C., Pollini, G. P.,
Zanirato, V. Tetrahedron Lett. 1997, 38, 681.
used by Corey) followed by oxidation (pyridinium chlo-
LiAlH4
rochromate/CH2Cl2, r.t., 2 h, 88%).
(17) Jackson, R. F. W., Wood, A., Wythes, M. J. Synlett 1990, 735.
Krishanamurthy, S., Brown, H. C. J. Am. Chem. Soc. 1976, 98,
3383.
(18) The stereochemical assignment of axial and equatorial alcohols
9 and 10 is made on the basis of their 1H NMR data, in particular
the H-4 protons. The values of the coupling constants for the H-
4e proton in the axial alcohol 9 are smaller than those described
for H-4a in equatorial alcohol 10, corresponding to axial-equa-
torial and equatorial-equatorial couplings.
Kosugi, H., Abe, M., Hatsuda, R., Uda, H., Kato, M. J. Chem.
Soc., Chem. Commun. 1997, 1857.
(4) Bai, D., Chu, G., Xu, R., Zhu, X. J. Org. Chem. 1996, 61, 4600.
Badio, B., Daly, J. W. Mol. Pharmacol. 1994, 45, 563.
(5) Shen, T. Y., Huang, D. F. Tetrahedron Lett. 1993, 34, 3251.
(6) Pandey, G., Bagul, T. D., Lakshmaiah, G. Tetrahedron Lett.
1994, 35, 7439.
(7) Fletcher, S. R., Baker, R., Chambers, M. S., Hobbs, S. C., Mit-
chell, P. J. J. Chem. Soc., Chem. Commun. 1993, 1216.
Fletcher, S. R., Baker, R., Chambers, M. S., Hobbs, S. C., Her-
bert, R. H., Thomas, S. R., Verrier, H. M., Watt, A. P., Ball, R.
G. J. Org. Chem. 1994, 59, 1771.
The ratio 9/10 = 70:30 is measured by the integration of the sig-
nals corresponding to the H-4e proton in the axial alcohol 9 and
H-4a proton in the equatorial alcohol 10 in the 1H NMR spec-
trum of the reaction mixture starting from reduction of ketone 8
with L-Selectride®. 9: δ = 5.18–5.22 (m, 1 H, H-4e); 10: δ =
4.83–4.91 (br m, 1 H, H-4a).
(19) Sato, T., Kugo, Y., Nakaumi, E., Ishibashi, H., Ikeda, M.
J. Chem. Soc., Perkin Trans. 1 1995, 1801.
(20) Tsuji, J., Ohno, K. Tetrahedron Lett. 1965, 3969.
(21) Hernández, A., Marcos, M., Rapoport, H. J. Org. Chem. 1995,
60, 2683.
(22) The physical data for (±)-epibatidine (1) are in accordance with
those described in the literature by Fletcher (J. Org. Chem.
1994, 59, 1771, see reference 7) and Sestanj (Tetrahedron Lett.
1994, 35, 5417, see reference 10).
Truddell, M. L., Zhang, Ch. J. Org. Chem. 1996, 61, 7189.
Nakai, H., Senokuchi, K., Kawamura, M., Katsube, N., Nonaka,
S., Sawaragi, H., Hamanaka, N. Synlett 1994, 343.
Kotian, P. L., Carroll, F. I. Synth. Commun. 1995, 25, 63.
(8) Bai, D., Chu, G., Xu, R. Tetrahedron Lett. 1996, 37, 1463.
Simpkins, N. S., Giblin, G. M. P., Jones, C. D. Synlett 1997,
589.
(9) Regan, A. C., Clayton, S. C. Tetrahedron Lett. 1994, 35, 7493.