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F. Frigerio et al.
LETTER
intermediate based on N-hydroxypyridone. O-Alkylation
of N-hydroxypyridone with the piperidinone bromide 6
gave lactam 7. Exposure of this intermediate to the eno-
lization and cyclization conditions that had been devel-
oped for cytisine (1) failed to give the desired adduct; see
reaction pathway illustrated with enolate 8. Instead a
clean fragmentation was observed to give aldehyde 913 in
89% yield.
References and Notes
(1) For a review of the lupin alkaloids, see: Leonard, N. J. In
The Alkaloids: Chemistry and Physiology, Vol. 3; Manske,
R. H. F.; Holmes, H. L., Eds.; Academic Press: New York,
1953, 119–192.
(2) For a review of the synthetic routes to cytisine, see: Stead,
D.; O’Brien, P. Tetrahedron 2007, 63, 1885.
(3) For an overview of the pharmacology of cytisine, see:
(a) Cassels, B. K.; Bermudez, I.; Dajas, F.; Abin-Carriquiry,
J. A.; Wonnacott, S. Drug Discovery Today 2005, 10, 1657.
(b) Marks, M. J.; Whiteaker, P.; Collins, A. C. Mol.
Pharmacol. 2006, 70, 947. (c) Luetje, C. W.; Patrick, J.
J. Neurosci. 1991, 11, 837.
(4) Power, F. B.; Salway, A. H. J. Chem. Soc. 1913, 191.
(5) Murakoshi, I.; Kidoguchi, E.; Haginiwa, J.; Ohmiya, S.;
Higashiyama, K.; Otomasu, H. Phytochemistry 1981, 20,
1407.
This chemistry is interesting in terms of its relationship to
the transformations shown in Scheme 1 and the earlier
work of Rouden7,8a and others14 involving (presumably)
carbonyl-directed metalation of an N-alkyl pyridone. This
directing effect is powerful but the cyclization pathway
outlined within structure 8 also involves formation of a
seven-membered ring, which represents a larger ring than
we had previously achieved with this cyclization protocol.
In that sense, a feasible explanation is that (as might be ex-
pected) lactam enolization does occur but the desired ring
closure (see 8) is slow compared to (feasibly intramolec-
ular) proton abstraction associated with the lactam enolate
derived from 7 which triggers the elimination step that
provides aldehyde 9.
(6) Honda, T.; Takahashi, R.; Namiki, H. J. Org. Chem. 2005,
70, 499.
(7) Rouden, J.; Ragot, A.; Gouault, S.; Cahard, D.; Plaquevent,
J. C.; Lasne, M. C. Tetrahedron: Asymmetry 2002, 13, 1299.
(8) (a) Houllier, N.; Gouault, S.; Lasne, M. C.; Rouden, J.
Tetrahedron 2006, 62, 11679. (b) Chellappan, S. K.; Xiao,
Y. X.; Tueckmantel, W.; Kellar, K. J.; Kozikowski, A. P.
J. Med. Chem. 2006, 49, 2673.
(9) For silane 4, the key NMR signals [1H NMR (500 MHz,
CDCl3): d = 4.34 (1 H, d, J = 1.0 Hz, H10) and 13C NMR
(126 MHz, CDCl3): d = 54.2 (C10)] showed the presence of
a single diastereomer. The small coupling constant (J = 1.0
Hz) suggested an equatorial–equatorial coupling between
H9 and H10. The equatorial assignment of H10 was further
supported by NOE data: irradiation of H10 showed
enhancements of H9, H11 and SiCH3, while irradiation of
H8ax and H8eq showed no enhancement associated with H10.
(10) (a) Fleming, I.; Henning, R.; Plaut, H. J. Chem. Soc., Chem.
Commun. 1984, 29. (b) Fleming, I.; Sanderson, P. E. J.
Tetrahedron Lett. 1987, 28, 4229. (c) Tamao, K.; Ishida, N.;
Kumada, M. J. Org. Chem. 1983, 48, 2120. (d) Tamao, K.;
Ishida, N.; Tanaka, T.; Kumada, M. Organometallics 1983,
2, 1694. (e) For a review on the oxidation of carbon–silicon
bonds, see: Jones, G. R.; Landais, Y. Tetrahedron 1996, 52,
7599.
NBn
Br
NBn
O
O
HO
O
O
NaOMe,
O
N
N
MeOH, 70 °C
+
48%
6
7
NBn
NBn
LiHMDS,
O
O
THF, –78 °C
89%
O
O
O
N
9
8
Scheme 3 Lactam enolate addition approach to (+)-kuraramine (3)
In summary, the first synthesis of (+)-kuraramine (3) has
been accomplished via a biomimetic transformation of N-
methylcytisine (2).15 The ability to cleave N-methyl-
cytisine (and the same chemistry works as efficiently with
N-benzylcytisine) opens an entry to a range of substituted
piperidines in a stereocontrolled fashion, that are, based
on earlier work in this area, not trivial to access.
(11) For carbinol 5, the key NMR signal [1H NMR (400 MHz,
CDCl3): d = 5.80 (1 H, s, H10)] showed the presence of a
single diastereomer and suggested the same (likely
thermodynamic) stereochemical preference as silane 4.
(12) (a) Gray, D.; Gallagher, T. Angew. Chem. Int. Ed. 2006, 45,
2419. (b) Botuha, C.; Galley, C. M. S.; Gallagher, T. Org.
Biomol. Chem. 2004, 2, 1825.
(13) Key NMR signals for aldehyde 9: 1H NMR (400 MHz,
CDCl3): d = 9.63 (1 H, s, H10). 13C NMR (101 MHz,
CDCl3): d = 200.3 (C10).
(14) (a) Katritzky, A. R.; Arrowsmith, J.; Binbahari, Z.; Jayaram,
C.; Siddiqui, T.; Vassilatos, S. J. Chem. Soc., Perkin Trans.
1 1980, 2851. (b) Meghani, P.; Joule, J. J. Chem. Soc.,
Perkin Trans. 1 1988, 1.
Supporting Information for this article is available online at
Acknowledgment
(15) Supporting Information (as a pdf) is available with this paper
and contains full experimental details of all compounds
reported and copies of spectra, including NOE experiments.
We thank the EPSRC and University of Milan for financial support.
Synlett 2010, No. 5, 729–730 © Thieme Stuttgart · New York