Efficient resolution of N-Boc-7-azabicyclo[2.2.1]hept-5-en-2-one: Formal syntheses of natural epibatidine and its enantiomer

Article abstract of DOI:10.1016/j.tetasy.2003.08.021

The efficient resolution of racemic N-Boc-7-azabicyclo[2.2.1]hept-5-en-2- one (±)-2 via aminal formation with (R,R)-1,2-diphenylethylenediamine 4 is reported. Acidic hydrolysis furnishes the enantiomeric ketones (+)-2 and (-)-2 that were transformed into 7-azabicyclo[2.2.1]heptan-2-one (-)-3 and (+)-3. The process constitutes a formal synthesis of (+)- and (-)-epibatidine.

Full text of DOI:10.1016/j.tetasy.2003.08.021

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3173–3176
Efficient resolution of N-Boc-7-azabicyclo[2.2.1]hept-5-en-2-one:
formal syntheses of natural epibatidine and its enantiomer
Antonio J. Moreno-Vargas and Pierre Vogel*
Institut de Chimie Mole´culaire et Biologique de l’Ecole Polytechnique Fe´de´rale de Lausanne, BCH-EPFL,
CH-1015 Lausanne-Dorigny, Switzerland
Received 12 June 2003; accepted 21 August 2003
Abstract—The efficient resolution of racemic N-Boc-7-azabicyclo[2.2.1]hept-5-en-2-one ( )-2 via aminal formation with (R,R)-1,2-
diphenylethylenediamine 4 is reported. Acidic hydrolysis furnishes the enantiomeric ketones (+)-2 and (−)-2 that were transformed
into 7-azabicyclo[2.2.1]heptan-2-one (−)-3 and (+)-3. The process constitutes a formal synthesis of (+)- and (−)-epibatidine.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
en-2-one has been reported in 1999 by Trudell et al.3
and its synthesis has been improved recently by
Kozikowski et al.,4a for both groups in the racemic
form ( )-2 (Chart 1).
For several years our research group has developed the
‘naked sugar’ methodology,1 which converts furan and
derivatives into enantiomerically pure monosaccharides
and rare analogues, into carbopyranoses, long-chain
carbohydrates, iminodeoxyalditols, C-linked disaccha-
rides and into imino-C-disaccharides and analogues,
including a new type of polyhydroxylated quinolizid-
ines. The key intermediate to develop this methodology
was the (+)- and (−)-7-oxabicyclo[2.2.1]hept-5-en-2-one
(+)-1, (−)-1.2 The aza-analog 7-azabicyclo[2.2.1]hept-5-
The interest of this molecule is related to the synthesis
of epibatidine, a natural alkaloid5 that has been
reported to be a highly potent non-opioid analgesic
agent with a potency 200-fold greater than that of
morphine in mice. Due to the novel structure and its
remarkable analgesic activity, an unprecedent large
number of syntheses of epibatidine,6 and recently of
analogs,4 have been described. In many of these synthe-
ses, racemic N-Boc-7-azabicyclo[2.2.1]heptan-2-one ( )-
3, that can be easily obtained from ( )-2, has been used
as an advanced key intermediate in the synthesis.2,6 The
enantiospecific synthesis of (+)-3 and (−)-3 involve mul-
tiple manipulations.6b,d–h,k
As part of a program to develop the ‘naked aza-sugar’
methodology (by analogy to the ‘naked sugar’
methodology1), we report here the resolution of racemic
7-azabicyclo[2.2.1]hept-5-en-2-one ( )-2 based on the
formation of aminals derived from (R,R)-1,2-
diphenylethylenediamine 4. The same method had been
successful in the case of the resolution of ketone ( )-1.7
The assignment of the absolute configuration of (+)-2
and (−)-2 was realized by chemical correlation with
known enantiomerically pure ketones (+)-3 and (−)-3.
Enantiomerically pure (+)-2 and (−)-2 have been further
characterized by their circular dichroism spectra.
Chart 1.
* Corresponding author. Tel.: +41-21-693-9371; fax: +41-21-693-9375;
e-mail: pierre.vogel@epfl.ch
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.08.021

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A. J. Moreno-Vargas, P. Vogel / Tetrahedron: Asymmetry 14 (2003) 3173–3176
Diphenylethylenediamine 4 is commercially available
and can easily be prepared in enantiomerically pure
form.10 The diasteroisomeric aminals (+)-6 and (+)-7
are thus formed in nearly quantitative yield by reaction
of racemic 7-azabicyclo[2.2.1]hept-5-en-2-one ( )-2 with
(R,R)-1,2-diphenylethylenediamine 4 in CH2Cl2 con-
,
taining 4 A molecular sieves (20°C, 24 h) (Scheme 2).
Scheme 1. Synthesis of racemic ketone ( )-2.
The aminals (+)-6 and (+)-7 were not stable in solution
unless 2% triethylamine was added to it. Under these
conditions, it was possible to separate easily the two
diasteroisomers by flash chromatography on silica gel
(DRf=0.2). The diastereomerically pure aminals were
hydrolyzed by treatment with 0.1 M phosphoric acid–
THF affording enantiomerically pure (+)-2 and (−)-2
nearly quantitatively. This hydrolysis is much easier
that in the case of O-acetal analogues.11 The chiral
diamine 4 was also recovered nearly quantitatively.7
The hydrogenation of (+)-2 and (−)-2 in the presence of
catalytic amounts of Pd/C (10%) afforded the known
enantiomerically pure ketones (−)-3 and (+)-3, respec-
tively, in quantitative yields. The [h] values were in
agreement with those reported for these compounds;
[h]=+70 for (+)-3 (lit.6b=+73.5) and −71 for (−)-3
(lit.6b=−72.6). Ketone (−)-3 has been converted into
(−)-epibatidine.6a,c Therefore, the syntheses of (−)-3 and
(+)-3 constitute formal syntheses of natural (−)-epiba-
tidine and of its enantiomer.
The absolute configuration (1S,4S) of enone (−)-2 was
confirmed by its circular dichroism spectrum (Fig. 1)
which shows a negative Cotton effect at u=304 nm for
its n“pC*O transition. Similar negative Cotton effect
have been observed for the n“p*CO transitions of
(1S,4S)-(−)-7-oxabicyclo[2.2.1]hept-5-en-2-one2
and
(1S,4S)-(−)-bicyclo[2.2.2]oct-5-en-2-one.12 The CD
spectra of these three latter enones show an ‘extra’
negative Cotton effect between u 205 and 215 nm
associated with a mixed transition resulting from
through-space (p(alkene)“p*CO) and through-bond
(n(CO)“s“p*(alkene)) interactions.12 The CD spec-
trum of (−)-2 also present a negative Cotton effect at
212 nm which could be assigned to a similar mixed type
of transition. The surprise, nevertheless, is the observa-
tion of a third negative Cotton effect at u=233 nm seen
only for enone (−)-2 and not for the other analogs. This
suggests that the 7-(t-butoxycarbonyl)aza bridge intro-
duces further electronic interaction between the chro-
mophores of (−)-2. This is also indicated by the UV
absorption spectrum of (−)-2 (Fig. 2).
Scheme 2.
2. Results and discussion
The b-keto sulfone 5 was obtained readily from N-Boc-
pyrrole and 2-bromoethynyl p-tolyl sulfone according
to a literature procedure.3 As reported by Kozikowski
et al.,4a desulfonylation of b-keto sulfone 5 was carried
8
out employing SmI2 at −78°C. This provided ketone
( )-2 in good yield (75%) (Scheme 1).
Recently,
it
was
shown
that
(R,R)-1,2-
diphenylethylenediamine 4 is an efficient reagent to
determine the enantiomeric purity of the substituted
cycloalkanones.9 To our knowledge, only the resolution
of ketone ( )-1 via the formation of the corresponding
aminals with diamine 4 has been reported thus far.
Figure 1. CD spectrum of (−)-2 (0.0024 M−1 in isooctane).

A. J. Moreno-Vargas, P. Vogel / Tetrahedron: Asymmetry 14 (2003) 3173–3176
3175
vacuo. The resultant residue was purified by flash chro-
matography (ether:petroleum ether, 1:2) affording 2
(431 mg, 75%) as a colorless oil. IR wmax 2978, 2933,
1767, 1709, 1369, 1170, 1125 cm−1; 1H NMR (400
MHz, CDCl3, l ppm, J Hz) l 6.73 (dd, 1H, J5,6=5.4,
J1,6=1.7, H-5), 6.43 (br. d, 1H, H-6), 5.10 (br. s, 1H,
H-4), 4.53 (br. s, 1H, H-1), 2.41 (dd, 1H, J3a,3b=15.7,
J
3a,4=0.8, H-3a), 2.02 (d, 1H, H-3b), 1.56 (s, 9H,
(CH3)3C); 13C NMR (100.5 MHz, CDCl3, l ppm) l
205.7 (CO of ketone), 155.4 (CO of carbamate), 143.4
(C-5), 130.8 (C-6), 81.8 ((CH3)3C), 68.6 (C-1), 60.4
(C-4), 36.2 (C-3), 28.5 ((CH3)3C); CIMS: m/z 210
(100%, [M+H]+), m/z 227 (100%, [M+NH4]+). Anal.
calcd for C11H15NO3 (209.24): C, 63.14;H, 7.22; N,
6.69. Found: C, 63.23;H, 7.29; N, 6.65.
Figure 2. UV absorption spectrum of (−)-2 (0.0024 M−1
isooctane).
3. Conclusions
An efficient resolution method of racemic N-Boc-7-
azabicyclo[2.2.1]hept-2-en-5-one has been found. By
analogy with the enantiomerically pure 7-oxabicy-
clo[2.2.1]hept-5-en-2-ones (+)-1 and (−)-1 (‘naked
sugar’), the azaanalogs (+)-2 and (−)-2 are expected to
open the ‘naked azasugar’ methodology. The use of
(R,R)- and (S,S)-1,2-diphenylethylenediamine should
find wider application for the resolution of chiral
ketones.
4.3. (1R,4R,4%R,5%R)- and (1S,4S,4%R,5%R)-4%,5%-
Diphenylspiro[7-(tert-butoxycarbonyl)-7-azabicyclo-
[2.2.1]hept-5-en-2,2%-imidazolidine] (+)-6 and (+)-7
(R,R)-Diphenylethylenediamine 4 (200 mg, 0.94 mmol)
was added under N2 to a solution of ketone ( )-2 (188
mg, 0.90 mmol) in dry CH2Cl2 (3 ml) containing 4 A
molecular sieves. The reaction mixture was stirred for
24 h, Et3N (0.5 ml) was added and the molecular sieves
then eliminated by filtration. The filtrate was concen-
trated and the resultant residue purified by flash chro-
,
4. Experimental
4.1. General
matography
(ether:petroleum
ether:Et3N,
10:15:1“15:10:1) affording first (1S,4S)-(+)-6 (156 mg,
43%) and then (+)-7 (154 mg, 42%), both as white
solids. Data for (+)-6: mp 133–135°C; [h]D=+19 (c 0.5,
CHCl3); IR wmax 3361, 3027, 2975, 1704, 1367, 1168,
CH2Cl2 was distilled from CaH2. For flash column
chromatography (FC), silica gel 60 (Merck, 230–400
mesh) was used. TLC was performed on HF254
(Merck), with detection by UV light and charring with
ninhydrin or spraying with a solution of 25 g phospho-
molybdic acid, 10 g Ce(SO4)2(H2O)4, 60 ml conc.
H2SO4 and 940 ml water and subsequent heating. Mp’s
are not corrected. Optical rotations were measured at
1
699 cm−1; H NMR (400 MHz, CDCl3, l ppm, J Hz) l
7.28–7.18 (m, 10H, H-aromat.), 6.63 (br. d, 1H, H-5),
6.50 (br. d, 1H, H-6), 4.72 (br. s, 1H, H-4), 4.50 (br. s,
1H, H-1), 4.24, 4.18 (2d, 1H each, J4%,5%=8.5, H-4% and
H-5%), 2.42 (br. s, 2H, NH), 2.41 (dd, 1H, J3a,3b=11.8,
J3a,4=4.4, H-3a), 1.61 (d, 1H, H-3b), 1.43 (s, 9H,
1
(CH3)3C); 13C NMR (100.5 MHz, CDCl3, l ppm) l
155.9 (CO), 141.8, 140.2 (2 C-1 aromat.), 137.7, 135.1
(br., C-5 and C-6), 128.0, 127.4, 127.2, 127.0 (10 C-aro-
mat.), 83.9 (br., C-2), 80.0 ((CH3)3C), 70.1, 69.5 (C-4%,
C-5%), 68.5 (C-1), 60.5 (C-4), 46.9 (C-3), 28.2 ((CH3)3C);
CIMS: m/z 404 (90%, [M+H]+). Anal. calcd for
C25H29N3O2 (403.52): C, 74.41;H, 7.24; N, 10.41.
Found: C, 74.43;H, 7.22; N, 10.30. Data for (+)-7: mp
110–112°C; [h]D=+60 (c 1.5, CHCl3); IR wmax 3346,
25°C in a spectropolarimeter, Jasco DIP-370. H and
13C NMR spectra were registered in a Bruker ARX 400
apparatus. The spectra were obtained for solutions in
1
CDCl3 and chemical shifts in H and 13C NMR spectra
are reported in parts per million (l) relative to the
1
peaks for CDCl3 (7.27 and 77.0, respectively). H and
13C NMR signals assignments were confirmed by 2D
COSY and HMQC when necessary. The CIMS spectra
were measured with a Nermag R-10-10C mass spec-
trometer. The IR spectra were obtained from a Perkin–
Elmer Parangon-1000 FT-IR spectrometer, the CD
spectra on a JASCO J500-C dichrograph (Dm (u in nm)).
3028, 2976, 1698, 1455, 1367, 1171, 760, 700 cm−1; H
1
NMR (400 MHz, CDCl3, l ppm, J Hz) l 7.32–7.47 (m,
10H, H-aromat.), 6.53–6.49 (m, 1H, H-5 and H-6), 4.80
(br. s, 1H, H-4), 4.64 (br. s, 1H, H-1), 4.36, 4.17 (2d,
1H each, J4%,5%=8.4, H-4% and H-5%), 2.44 (br. s, 2H,
NH), 2.33 (dd, 1H, J3a,3b=11.6, J3a,4=4.3, H-3a), 1.65
(d, 1H, H-3b), 1.49 (s, 9H, (CH3)3C); 13C NMR (100.5
MHz, CDCl3, l ppm) l 155.4 (CO), 140.4 (2 C-1
aromat.), 138.8, 134.1 (br., C-5 and C-6), 128.4, 128.2,
127.6, 127.2, 126.9, 126.4 (10 C-aromat.), 84.5 (br.,
C-2), 80.0 ((CH3)3C), 70.6, 69.8 (C-4%, C-5%), 69.0, 68.9
(C-1, rotamers), 60.5 (C-4), 45.6 (C-3), 28.3 ((CH3)3C);
CIMS: m/z 404 (45%, [M+H]+). Anal. calcd for
C25H29N3O2 (403.52): C, 74.41;H, 7.24; N, 10.41.
Found: C, 74.37;H, 7.24; N, 10.40.
4.2. (1RS,4RS)-7-(tert-Butoxycarbonyl)-7-azabicyclo-
[2.2.1]hept-5-en-2-one ( )-2
To a solution of SmI2 (0.1 M) in THF (70 ml) cooled to
−78°C, a solution of keto sulfone 5 (1 g, 2.75 mmoles)
in THF–MeOH (3:1, 8 ml) cooled at −78°C was added.
The resultant brown mixture was stirred for 10 min at
−78°C, warmed to room temperature, and then poured
into saturated aqueous solution of K2CO3. The
aqueous phase was extracted with Et2O, the combined
extracts were dried (MgSO4) and concentrated in

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A. J. Moreno-Vargas, P. Vogel / Tetrahedron: Asymmetry 14 (2003) 3173–3176
4.4. (1S,4S)-7-(tert-Butoxycarbonyl)-7-azabicyclo-
[2.2.1]hept-5-en-2-one (−)-2
Springer-Verlag: Berlin, 2001; Vol. II, Chapter 4.4, pp.
1023–1174; (c) Vogel, P.; Fattori, D.; Gasparini, F.; Le
Drian, C. Synlett 1990, 173–185; (d) Vogel, P.; Auberson,
Y.; Bimwala, M.; de Guchteneere, E.; Vieiera, E.; Wag-
ner, J. In Trends in Synthetic Carbohydrate Chemistry;
Horton, D.; Hawkins, L. D.; McGarvey, G. L., Eds.;
ACS Symposium Series 386; American Chemical Society:
Washington, DC, 1989; pp. 197–241.
A solution of (+)-6 (112 mg, 0.28 mmol) in 0.1 M
H3PO4–THF (2:1, 15 ml) was stirred for 30 min at
20°C. Then, the mixture was diluted with H2O and
extracted with ether. The combined extracts were dried
(MgSO4) and the solvent was evaporated. The resultant
residue was purified by flash chromatography
(ether:petroleum ether, 1:1) affording (−)-2 (54 mg,
95%), as a colorless oil. [h]D=−360 (c 0.25, CHCl3).
CD (isooctane): molar ellipticity [q](212 nm)=−75000,
[q](233 nm)=−40000, [q](304 nm)=−25000 (see Fig.
1). Other spectral data are identical to those of ( )-2.
2. Vieira, E.; Vogel, P. Helv. Chim. Acta 1983, 66, 1865–
1871.
3. Zhang, C.; Ballay, C. J., II; Trudell, M. L. J. Chem. Soc.,
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R. H.; Hobbs, S. C.; Thomas, S. R.; Vernier, H. M.;
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Org. Chem. 1995, 60, 2683–2691; (c) Zhang, C.; Trudell,
M. L. J. Org. Chem. 1996, 61, 7189–7191; (d) Albertini,
E.; Barco, A.; Benetti, S.; De Risi, C.; Pollini, G. P.;
Zanirato, V. Tetrahedron 1997, 53, 17177–17194; (e)
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4.5. (1R,4R)-7-(tert-Butoxycarbonyl)-7-azabicyclo-
[2.2.1]hept-5-en-2-one (+)-2
Compound 2 was prepared according to the procedure
described for (−)-2, starting from (+)-7 (120 mg, 0.3
mmol): (+)-2 (60 mg, 96%), a colorless oil. [h]D=+384
(c 0.9, CHCl3).
4.6. (1S,4R)-7-(tert-Butoxycarbonyl)-7-azabicyclo-
[2.2.1]heptan-2-one (+)-3
A mixture of (−)-2 (30 mg, 0.14 mmol) in MeOH (2 ml)
and Pd/C (10%, 7 mg) was hydrogenated under atmo-
spheric pressure for 1 h. The Pd/C was removed by
filtration, washed with MeOH and the filtrate concen-
trated to dryness affording pure (+)-3 (30 mg, 100%) as
a colorless oil. [h]D=+70 (c 1.5, CHCl3); lit.6b +74 (c
1.0, CHCl3).
4.7. (1R,4S)-7-(tert-Butoxycarbonyl)-7-azabicyclo-
[2.2.1]heptan-2-one (−)-3
Compound 3 was prepared according to the procedure
described for (+)-3, starting from (+)-2 (25 mg, 0.12
mmol): (−)-3 (25 mg, 100%) as a colorless oil. [h]D=
−71 (c 1.25, CHCl3); lit.6b −73 (c 1.0, CHCl3).
Acknowledgements
We are grateful to the Swiss National Science Fonda-
tion (Grant No. 20.63667.00), the ‘Office Fe´de´ral de
l’Education et de la Science’ (Bern, COST D13/0001/
99) and the Direccio´n General de Investigacio´n Cien-
t´ıfica y Te´cnica of Spain (Grant No. BQU-2001-3779)
for generous support. We thank Dr. Arunan Chan-
dravarkar for the CD spectra.
8. For the use of SmI2 in desulfonylation of b-keto sulfones,
see: Molander, G. A.; Hahn, G. J. Org. Chem. 1986, 51,
1135–1138.
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1. For reviews on the ‘naked sugars’ methodology and
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