3948
G. Pandey et al. / Tetrahedron Letters 42 (2001) 3947–3949
Scheme 2. Reagents and conditions: (a) NaH (2.2 equiv.), THF, 0°C to rt, 2.5 h, 85%; (b) Na/Hg 6%, NaH2PO4·H2O, 0°C, 3 h,
95%; (c) (i) TMSCl, NaI, CH3CN, 15 h, rt, (ii) (Boc)2O, Et3N, CH2Cl2, 20 h, rt, 95% (two steps); (d) Pd/C, H2, 55 psi,
EtOH:EtOAc, 10 h, 90%.
THF at 0°C for about 2.5 h (Scheme 2). After allowing
Boc-azabicyclo[2.2.1]heptan-2-one, a versatile precursor
for the synthesis of (−)-epibatidine. Furthermore, appli-
cation of the ketone 2 to the synthesis of optically
active ferruginine is in progress and will be reported
elsewhere.
the reaction mixture to reach rt, it was quenched by the
1
addition of MeOH. The crude H NMR spectrum of
the desymmetrized product displayed only one signal
for H-3 at l 3.65 (singlet), indicating it to be a single
diastereomer, which was further confirmed by HPLC
analysis (Merck, Purospher® RP-18e, 4×250 mm,
CH3CN:H2O (3:2) isocratic, flow rate, 1 mL/min, reten-
tion time 3.56 min). Silica-gel column purification of
the crude mixture gave 5 as a white fluffy solid, mp
Acknowledgements
1
188–189°C in 85% yield, fully characterized by H and
The authors would like to thank the Department of
Science and Technology, New Delhi, for financial sup-
port. S.K.T. thanks Dr. H. R. Sonawane for support
and encouragement. R.S.S. thanks the CSIR, New
Delhi, for the award of a Research Associateship.
13C NMR and mass spectral analysis.13 The stereo-
chemistry of H-3 in 5 was established to be endo
because we observed no coupling with the adjacent
bridgehead H-4 in the 1H NMR spectrum. It is
known9b that no coupling is observed between bridge-
head protons and adjacent endo-hydrogens in the 7-
azabicyclo[2.2.1]alkane skeleton due to the dihedral
angle of 90° between them.
References
1. For a review, see: Chen, Z.; Trudell, M. L. Chem. Rev.
1996, 96, 1179.
2. Spande, T. F.; Garraffo, H. M.; Edwards, M. W.; Yeh,
H. J. C.; Pannell, L.; Daly, J. W. J. Am. Chem. Soc. 1992,
114, 3475.
Removal of the chiral acetal moiety from 5 proved
somewhat troublesome. Reaction with many acidic
reagents,14 including harsh reaction conditions, such as
boiling with conc. HCl, was unsuccessful. The most
probable reason for the unexpected stability of this
chiral acetal moiety could be either due to the high
steric hindrance or long-range intramolecular hydrogen
bonding after protonation. Our attempt to cleave the
acetal moiety after reductive elimination of the phenyl
sulfonyl group, using Na–Hg amalgam as the reagent,15
was also unsuccessful. Reaction of 6 with TMSI cleaved
only the -N-CO2Me but not the acetal moiety. There-
fore, left without much viable alternative at this stage,
the resultant free amine product was reprotected as the
corresponding N-Boc derivative 7 and was then sub-
jected to catalytic hydrogenation (Pd/C, 10%, 55 psi, 10
h) to provide ketone 2, which was characterized by IR,
1H and 13C NMR and mass spectral analysis.16 All the
spectral data was found to be in excellent agreement
with that reported in the literature. {[h]2D5 +77.3 (c 0.6,
CHCl3)} lit.8a {[h]D22 +73.5 (c 1.00, CHCl3)}.8
3. (a) Badio, B.; Daly, J. W. Mol. Pharmacol. 1994, 45, 563;
(b) Bannon, A. W.; Decker, M. W.; Holladay, M. W.;
Curzon, P.; Donnelly-Roberts, D.; Puttfarcken, P. S.;
Bitner, R. S.; Diaz, A.; Dickenson, A. H.; Porsolt, R. D.;
Williams, M.; Arneric, S. P. Science 1998, 279, 77.
4. For selected references on the synthesis of racemic epiba-
tidine, see: (a) Fletcher, S. R.; Baker, R.; Chambers, M.
S.; Hobbs, S. C.; Mitchell, P. J. J. Chem. Soc., Chem.
Commun. 1993, 1216; (b) Zhang, C.; Trudell, M. L. J.
Org. Chem. 1996, 61, 7189; (c) Giblin, G. M. P.; Jones, C.
D.; Simpkins, N. S. J. Chem. Soc., Perkin Trans. 1 1998,
3689; (d) Palmgren, A.; Larsson, A. L. E.; Backvall, J.-E.
J. Org. Chem. 1999, 64, 836 and references cited therein.
5. Broka, C. A. Tetrahedron Lett. 1993, 34, 3251.
6. For selected references on the asymmetric synthesis of
epibatidine, see: (a) Corey, E. J.; Loh, T.-P.;
AchyuthaRao, S.; Daley, D. C.; Sarshar, S. J. Org.
Chem. 1993, 58, 5600; (b) Trost, B. M.; Cook, G. R.
Tetrahedron Lett. 1996, 37, 7485; (c) Aoyagi, S.; Tanaka,
R.; Naruse, M.; Kibayashi, C. J. Org. Chem. 1998, 63,
In conclusion, we have developed a short and efficient
route for the synthesis of highly enantiopure (+)-N-