An expeditious formal synthesis of (-)-epibatidine

Article abstract of DOI:10.1016/S0957-4166(00)00211-1

A short route to (-)-epibatidine is described. It includes a hetero-Diels-Alder reaction of a chiral non-racemic acyl-nitroso derivative and 2-t-butyldimethylsilyloxycyclohexadiene followed by chemical manipulations to furnish a known precursor of the natural product in 11% overall yield. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00211-1

Tetrahedron: Asymmetry 11 (2000) 2525±2529
An expeditious formal synthesis of (^)-epibatidine
Isabelle Cabanal-Duvillard,a Jean-Francois Berrienb and Jacques Royera,*
a
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Laboratoire de Chimie Therapeutique (associe au CNRS et a l'Universite Rene Descartes, UMR 8638),
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Biocis, UPRESA 8076, Faculte de Pharmacie, 5 avenue Jean-Baptiste Clement, 92296 Chatenay-Malabry cedex, France
Faculte de Pharmacie, 4 avenue de l'Observatoire, 75270 Paris cedex 06, France
b
Received 25 April 2000; accepted 25 May 2000
Abstract
A short route to (^)-epibatidine is described. It includes a hetero-Diels±Alder reaction of a chiral non-
racemic acyl-nitroso derivative and 2-t-butyldimethylsilyloxycyclohexadiene followed by chemical manip-
ulations to furnish a known precursor of the natural product in 11% overall yield. # 2000 Elsevier Science
Ltd. All rights reserved.
1. Introduction
The alkaloid epibatidine 1 (Scheme 1) has attracted a great deal of attention since its isolation
from the skin of the frog Epipedobates tricolor.1 Its structure was elucidated in 1992 enlightening
its relative con®guration.2 Interestingly, it had a 7-azabicyclo[2.2.1]heptane frame with an original
exo oriented 3-(6-chloropyridyl) substituent. The absolute con®guration of (^)-epibatidine was
reported by Fletcher et al. to be 1R,2R,4S.3
Epibatidine excited the interest of synthetic chemists because of its powerful pharmacological
activity as a non-opioid analgesic. Indeed, it was shown to be a very potent nicotinic acetylcholine
receptor (nAChR) agonist.4 Therefore a large number of syntheses have emerged.5
We recently reported a formal synthesis of (^)-epibatidine 16 based on an asymmetric hetero-
Diels±Alder reaction between a chiral acyl-nitroso derivative 2 and 2-t-butyldimethylsilyloxy-
cyclohexadiene 3 (Scheme 1).7 This cycloaddition proceeded very eciently to give the enone
(+)-5 in 64% overall yield as a unique diastereomer after reduction of the N±O bond of cycloadduct
4 with Mo(CO)6. Enone (+)-5 was transformed in eight steps into bicyclic ketone (^)-6a, a known
precursor5a,b of natural (^)-epibatidine.
We have now explored a shorter route to ketone 6 which is described herein. Such a shorter
route should involve the cleavage of the N±O bond of cycloadduct 4 to give a compound of type
7 (Scheme 1). The latter should be a precursor of the bicyclic ketone (^)-6 after inversion of
con®guration and activation of the thus formed secondary alcohol.
* Corresponding author. E-mail: jroyer@pharmacie.univ-paris5.fr
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00211-1

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Scheme 1.
2. Results and discussion
Despite numerous attempts using various conditions (TiCl3, HCl, MeOH and Na/Hg,
Na2HPO4, MeOH), we were not able to cleave the N±O bond without b-elimination which led to
enone (+)-5. Some attempts were also made to transform the silylated enol ether function of 4
into a ketal function. These attempts were also unsuccessful due to the facile cleavage of the N±O
bond with concomitant b-elimination.
Thus, enone (+)-5 still constituted the key-intermediate in our synthesis. It was sequentially
treated with TMSI in acetonitrile and then ethylene glycol8 to give the trans-iodo acetal 8 in 88%
yield (Scheme 2). Unfortunately, compound 8 consisted of a 65:35 mixture of diastereomers (+)-8a
and (+)-8b possessing the same trans relative relationship and consequently were precursors of
each enantiomer of epibatidine. The major diastereomer (+)-8a was readily separated from the
mixture by column chromatography and obtained in 57% yield.
A poorly stereocontrolled iodine addition followed by an epimerization during the ketalization
step could explain the formation of the mixture of isomers 8a+8b. The epimerization gave exclu-
sively the thermodynamically more stable trans (di-equatorial) iodo-amides (+)-8a and (+)-8b.
It was anticipated that the major diastereomer (+)-8a was the precursor of natural (^)-epibatidine
and the last three steps of the synthesis were performed with this compound. Basic hydrolytic
cleavage of the sultam moiety using LiOH in t-butanol underwent spontaneous aminocyclization
to give compound 9: The latter was not isolated and immediately subjected to acidic cleavage of
the ketal, followed by protection of amine as a N-BOC to give known (^)-6b ([ꢀ]D ^73 (CHCl3,
c=1.6); lit.: [ꢀ]D ^72.6 (CHCl3, c=1.1)9a; [ꢀ]D ^75.5 (CHCl3, c=1.0)9b) in 45% yield from 8a.
Despite the epimerization and the subsequent separation, the synthesis described herein represents
a very rapid (seven steps) and ecient asymmetric synthesis (11% overall yield) of enantiopure

I. Cabanal-Duvillard et al. / Tetrahedron: Asymmetry 11 (2000) 2525±2529
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Scheme 2. Reageants: (i) (a) TMSI, NaI, (b) HOCH2CH2OH, (c) separation (chromatography); (ii) LiOH, t-BuOH;
(iii) (a) 4N HCl, Á, (b) BOC2O, Et3N
ketone (^)-6b, a known precursor3,5a,b of (^)-epibatidine and compares favorably with the other
published asymmetric syntheses.
3. Experimental
1
IR spectra were recorded with a Genesis Matteson infrared spectrophotometer. H NMR
spectra were recorded on a Bruker AC 250 apparatus (250 MHz, ꢁ=0 (TMS), in CDCl3 if not
speci®ed otherwise, J in Hertz). 13C NMR spectra were recorded at 75 MHz on a Bruker AC 300
apparatus (ꢁ in ppm relative to internal TMS). Samples were dissolved in CDCl3 unless stated.
Multiplicities in the 13C spectra were determined by DEPT experiments. Elemental analyses
were performed by the service of microanalyse, ICSN, CNRS, Gif-sur-Yvette. Mass spectra were
recorded with an AEI MS-50 (Electronic Impact 50 eV) or AEI MS-9 (Chemical Ionisation with
isobutane as ionising gas). Optical rotations were measured on polarimeter Perkin±Elmer 241
MC at rt. Chromatographic solvents were distilled before use. Flash chromatographies were per-
formed on Merck 60 silica gel (230±400 mesh). TLC were performed on Merck 60 F254 aluminum
plates. All the reactions were carried out under inert atmosphere unless water was used as the
solvent. Solvents were distilled prior to use (CH3CN and CH2Cl2 over CaH2, THF and Et2O
over Na, benzophenone). The other solvents were used in their commercial quality grades.
3.1. 10,10-Dimethyl-3,3-dioxo-3l6-thia-4-aza-tricyclo[5.2.1.01,5]decane-4-carboxylic acid-(9-iodo-
1,4-dioxa-spiro[4,5]dec-6-yl)-amide (+)-8a and (+)-8b
In a 10 ml ¯ask were introduced enone (+)-56 (341 mg, 0.96 mmol), NaI (654 mg, 4.5 equiv.)
and 5 mL of dry CH3CN. The temperature was cooled to 0ꢀC to give a white slurry solution.
Then TMSCl (0.553 mL, 4.5 equiv.) was added dropwise and stirring was maintained for 15 min.
Ethyleneglycol (0.065 mL, 1.2 equiv.) was added and the cooling bath was removed. After 30 min

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stirring at room temperature, the reaction was quenched with a saturated aqueous solution of
NaHCO3 and 10 mL of pentane were added. The aqueous phase was removed and the organic
layer was washed successively with 10 mL of a 5% aqueous solution of Na2S2O3, 10 mL of a
saturated solution of NaCl and three times with 10 mL H2O. The aqueous layers were joined and
extracted twice with 15 mL CH2Cl2. The organic layers were gathered, dried over Na2SO4 and the
solvents evaporated under reduced pressure. The crude product was puri®ed by ¯ash chromato-
graphy to give iodoacetals 8a (263 mg, 57%) and 8b (142 mg, 31%) as white solids.
(1R, R) (+)-8a: [ꢀ]d +25.1 (c=2.2; CHCl3); 1H NMR (CDCl3) ꢁ (ppm): 0.95 (s, 3H), 1.1 (s, 3H),
1.2±2.6 (m, 13H), 3.35 (s, 2H), 3.6±4.2 (m, 7H), 6.0 (d, 1H, J=9.2 Hz); 13C NMR (CDCl3) ꢁ
(ppm): 19.8, 20.1, 21.5, 26.6, 31.6, 31.9, 32.1, 37.4, 37.8, 44.0, 47.8, 47.9, 48.5, 51.6, 52.5, 64.0,
65.2, 107.8, 150.5; IR (KBr, cm^1): 3020, 1686; m/z (C.I.): 525 (MH+). Anal. calcd for
C19H29N2O5IS: C, 43.51; H, 5.53; N, 5.34. Found: C, 43.55; H, 5.75; N, 5.24.
(1S,9S) (+)-8b: [ꢀ]d +96.0 (c=2.3; CHCl3); 1H NMR (CDCl3) ꢁ (ppm): 0.95 (s, 3H), 1.1 (s, 3H),
1.2±2.6 (m, 13H), 3.35 (s, 2H), 3.6±4.2 (m, 7H), 6.0 (d, 1H, J=8.9 Hz); 13C NMR (CDCl3) ꢁ
(ppm): 19.8, 20.0, 21.2, 26.5, 31.7, 31.9, 37.6, 37.7, 44.0, 47.8, 48.7, 51.7, 52.7, 64.1, 65.1, 65.5,
108.2, 150.4; IR (KBr, cm^1) 3020 (NH), 1686 (CO); m/z (C.I.): 525 (MH+).
3.2. (1R,4S)-N-(tert-Butyloxycarbonyl)-7-azabicyclo[2.2.1]heptan-2-one (^)-6b
In a 10 mL ¯ask were introduced the iodoacetal (+)-8a (600 mg, 1.14 mmol, 1 equiv.), LiOH
56% (171 mg, 2 equiv.) and 10 mL of tBuOH. After heating for 20 h at 90ꢀC under vigorous
stirring, the reaction mixture was cooled to room temperature and a 5% aqueous solution of HCl
was added to pH 2±3. The solvents were removed under reduced pressure. The residue was sus-
pended in 20 mL of 1N HCl solution and extracted twice with 20 mL Et2O. The organic layer was
washed four times with a 5% aqueous solution of HCl, dried over Na2SO4 and the solvent
evaporated under reduced pressure to give (+)-camphorsultam (220 mg, 89%) in good purity. The
aqueous layers were joined, and the water removed under reduced pressure. The resulting green±
white crude salt was then heated in 15 mL of a 12% aqueous solution of HCl to 90ꢀC for 5 h. The
aqueous phase was removed under pressure and 20 mL portions of ethanol were successively
added and evaporated under reduced pressure for azeotropic removal of water (three times).
To the crude amine hydrochloride were added 30 mL of CH2Cl2, (BOC)2O (500 mg, 2 equiv.) and
Et3N (2.37 mL, 15 equiv.). The solution was stirred at 35ꢀC for 12 h and treated with 10 mL of a
saturated aqueous solution of K2CO3. After stirring for 2 h, the organic layer was decanted and
the aqueous phase extracted twice with 20 mL of CH2Cl2. The organic layers were joined, dried
over Na2SO4 and the solvents were evaporated under reduced pressure. The crude carbamate was
puri®ed by ¯ash chromatography (hexane:ethyl acetate, 9:1) to give bicycle (^)-6 (110 mg, 45%
overall) as a standing-solidifying colorless oil. [ꢀ]d ^72.8 (c=1.6; CHCl3); lit.: [ꢀ]d ^72.6 (c=1.1;
CHCl3)9a; [ꢀ]d ^75.5 (c=1.0; CHCl3);9b 1H NMR (CDCl3) ꢁ (ppm): 1.7 (s, 9H), 1.8±2.0 (m, 5H),
2.25 (ddd, 1H, J=1.1, 5.2, 17.5 Hz), 4.1 (d, 1H, J=4.9 Hz), 4.3 (t, 1H, J=4.4 Hz).
Acknowledgements
The authors thank Professor L. Ghosez and Professor H.-P. Husson for helpful discussions.
I.C.-D. and J.-F.B. are deeply indebted to Professor L. Ghosez for the worthwhile year spent in
his laboratory.

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