1450
D. L. Comins, E. D. Smith / Tetrahedron Letters 47 (2006) 1449–1451
selective synthesis of various nicotine analogs of poten-
tial pharmaceutical value.
E
N
2
N
SIB-1508Y
Acknowledgements
NMR and mass spectra were obtained at NCSU instru-
mentation laboratories, which were established by
grants from the North Carolina Biotechnology Center
and the National Science Foundation (Grants CHE-
E+
9
509532 and CHE-0078253).
E
5
5
N
N
N
CO R
N
CO R
2
References and notes
. (a) Jensen, A. A.; Frølund, B.; Liljefors, T.; Krogsgaard-
2
1
Larsen, P. J. Med. Chem. 2005, 48, 4705; (b) Breining, S.
R. Curr. Top. Med. Chem. 2004, 4, 609; (c) Levin, E. D. J.
Neurobiol. 2002, 53, 633; (d) Newhouse, P. A.; Kelton, M.
Pharm. Acta Helv. 2000, 74, 91; (e) Holladay, M. K.; Dart,
M. J.; Lynch, J. K. J. Med. Chem. 1997, 40, 4169.
2
. (a) Wang, D. X.; Booth, H.; Lerner-Marmarosh, N.;
Osdene, T. S.; Abood, L. G. Drug Devel. Res. 1998, 45, 10;
1
(S)-nicotine
(
b) Cosford, N. D. P.; Bleicher, L. S.; Vernier, J. M.;
Scheme 1. Retrosynthetic analysis.
Noriega, L. C.; Rao, T. S.; Siegel, R. S.; Suto, C.;
Washburn, M.; Lloyd, G. K.; McDonald, I. A. Pharm.
Acta Helv. 2000, 74, 125.
3
4
. Bleicher, L. S.; Cosford, N. D. P.; Herbaut, A.; McCal-
lum, J. S.; McDonald, I. A. J. Org. Chem. 1998, 63, 1109.
. (a) Felpin, F.-X.; Vo-Thanh, G.; Villi e´ ras, J.; Lebreton, J.
Tetrahedron: Asymmetry 2001, 12, 1121; (b) Felpin, F.-X.;
Bertrand, M.-J.; Lebreton, J. Tetrahedron 2002, 58, 7381.
. (a) Comins, D. L.; King, L. S.; Smith, E. D.; F e´ vrier, F. C.
Org. Lett. 2005, 7, 5059; (b) Smith, E. D.; F e´ vrier, F. C.;
Comins, D. L. Org. Lett. 2006, 8, in press; (c) F e´ vrier, F.
C.; Smith, E. D.; Comins, D. L. Org. Lett. 2005, 7, 5457;
Si
Li
N
N
(
MeO) O
2
N
TMSCl
5%
N
N
N
10% TBAF
91%
5
9
Si
1
O
OMe
4
3
(
d) King, L. S.; Despagnet, E.; Comins, D. L U.S. Patent
Application No.: 10/715,147; (e) Comins, D. L.; Despag-
net, E. U.S. Patent Application No.: 10/925,516; (f)
Comins, D. L.; F e´ vrier, F. C.; Despagnet, E. U. S. Patent
Application No.: 10/926,821.
OHC
OHC
POCl3
DMF
N
N
TEA
6. For reviews on dihydropyridines, see: (a) Lavilla, R. J.
Chem. Soc., Perkin Trans. 1 2002, 1141; (b) Kumar, R.;
Chandra, R. Adv. Heterocycl. Chem. 2001, 78, 269; (c)
Comins, D. L.; O’Connor, S. Adv. Heterocycl. Chem.
N
MeOH, rt
100%
N
H
5
4%
O
OMe
5
6
1
988, 44, 199.
7
. For formylation and acylation of 1-acyldihydropyridines,
see: (a) Comins, D. L.; Mantlo, N. B. Tetrahedron Lett.
1
983, 24, 3683; (b) Comins, D. L.; Herrick, J. J. Hetero-
OHC
(
MeO) POCHN2
S8
N
2
cycles 1987, 26, 2159; (c) Comins, D. L.; Myoung, Y. C.
J. Org. Chem. 1990, 55, 292.
2
toluene, ∆
3%
N
t-BuOK
8. Formylation of 1-acyl-1,4-dihydropyridines via the Vils-
meier–Haack reaction has been reported to give yields in
the 43–71% range, see Ref. 7b.
8
5
1%
7
9
. Brown, D. G.; Velthuisen, E. J.; Commerford, J.; Comm-
erford, J. R.; Brisbois, R. G.; Hoye, T. R. J. Org. Chem.
Scheme 2. Synthesis of SIB-1508Y (2).
1
996, 61, 2540.
1
0. All compounds showed spectroscopic and characterization
data in accordance with structure. Spectroscopic data for
completed by using the Seyferth–Gilbert homologation9
to convert 7 to SIB-1508Y (2) in 51% yield. The spectral
properties and optical rotation of our (ꢀ)-2 are in agree-
3
1
selected compounds: Compound 2: clear oil; H NMR
(
400 MHz, CDCl ) d 8.60 (d, J = 2.4 Hz, 1H), 8.49 (d,
3
2
D
4
3
J = 2.4 Hz, 1H), 7.80 (t, J = 2.4 Hz, 1H), 3.25 (t,
J = 8.4 Hz, 1H), 3.20 (s, 1H), 3.09 (t, J = 8.4 Hz, 1H),
ment with reported data [½aꢁ ꢀ160 (c 0.31, EtOH); lit.
[
a] ꢀ164 (c 5, EtOH)].
D
2
1
.36–2.26 (m, 1H), 2.26–2.15 (m, 1H), 2.17 (s, 3H), 2.02–
13
.90 (m, 1H), 1.88–1.76 (m, 1H), 1.75–1.64 (m, 1H);
C
In summary, enantiopure SIB-1508Y was prepared via a
six-step sequence from natural nicotine in 20% overall
NMR (100 MHz, CDCl
3
) d 151.7, 149.2, 138.9, 138.2,
2
4
119.3, 80.8, 80.5, 68.6, 57.2, 40.6, 35.5, 22.9; ½aꢁ ꢀ160 (c
D
1
0
3
yield. This strategy should be amenable to the enantio-
0.31, EtOH); lit. [a]
D
ꢀ164 (c 5, EtOH).