yield. Transformation of the ketone into the pyrrolidine
enamine and subsequent alkylation with 3-methoxybenzyl
chloride afforded 7 in a 58% overall yield.3 The double bond
was next introduced utilizing the IBX protocol developed
by Nicolaou et al.4 to give R,â-unsaturated ketone 8 in 90%
yield. The reaction of enone 8 with 3-methoxyphenylmag-
nesium bromide proceeded regioselectively to afford the 1,2-
addition product, tertiary alcohol 9, in 75% yield.5
Scheme 1
With the tertiary alcohol in place, the acid-catalyzed
cyclization was examined. Upon addition of a solution of
the alcohol to a 1:1 mixture of TfOH/CH2Cl2, a smooth
reaction took place to afford two closely related cyclization
products. The major component, isolated in 55% yield, was
1
determined by H NMR and decoupling experiments to be
bridged bicyclic compound 10. The Friedel-Crafts reaction
evidently took place such that the less hindered carbon of
the putative allylic carbocation intermediate was intercepted
by the aromatic ring at a position para to the methoxy group.
The minor product (11) was formed in the same way but by
attack of the aromatic ring at the position ortho to the
methoxy group.
The above model study showed that although the Friedel-
Crafts alkylation can take place readily, it does so to produce
the less congested product: the reaction occurs primarily para
to the methoxy group and exclusively at the less substituted
carbon of the putative allylic carbocation intermediate.
Fortunately, it was possible to address both of these
regioselectivity issues.
Given the inherent preference for the undesired para-attack,
we decided to install a blocking group at this position
(Scheme 3). The para position of ketone intermediate 7 was
selectively brominated using NBS in CH3CN to afford 12
in 99% yield.6 The brominated compound (12) was then
subjected to the IBX protocol to install the double bond in
95% yield. Regioselective addition of 3-methoxyphenyl-
magnesium bromide to the carbonyl carbon of the resulting
R,â-unsaturated ketone (13) afforded tertiary alcohol 14 in
76% yield.5 The cyclization of this intermediate, carried out
under the triflic acid conditions described above, proceeded
cleanly and gave exclusively isomer 15, resulting from attack
by the ortho position of aromatic ring C. As before, the
cyclization gave the bridged-bicyclic product rather than the
desired indeno-tetrahydropyridine ring system.
dropyridine core of 3 by either a transition metal-catalyzed
reaction or an acid-catalyzed reaction. The latter, a Friedel-
Crafts reaction, was appealing for its simplicity.2 The
electron-rich C ring of 4 was expected to cyclize readily onto
an allylic carbocation on the piperidine ring. From stereo-
electronic and strain considerations, the cyclization was
expected to produce the cis-fused product.
The feasibility of the Friedel-Crafts cyclization route was
evaluated through a model system (Scheme 2). The com-
mercially available HCl salt of 3-hydroxypiperidine (5) was
reacted with dimethyl dicarbonate to afford the amino-
protected piperidine in quantitative yield. The alcohol was
oxidized under Swern conditions to yield ketone 6 in 96%
Scheme 2
With the ortho/para issue resolved, the next problem to
address was the regioselectivity of the cyclization about the
piperidinone ring. To determine if cyclization was even
(2) Friedel-Crafts cyclizations have been used extensively in the
synthesis of alkaloids. For relevant examples, see: (a) Grewe, R.;
Friedrichsen, W. Chem. Ber. 1967, 100, 1550-1558. (b) Rice, K. C.; Ripka,
W. C.; Reden, J.; Brossi, A. J. Org. Chem. 1980, 45, 601-607. (c)
Passarella, D.; Consonni, A.; Giardini, A.; Lesma, G.; Silvani, A. Bioorg.
Med. Chem. Lett. 2002, 12, 1981-1983.
(3) (a) Masamune, T.; Hayashi, H.; Takasugi, M.; Fukuoka, S. J. Org.
Chem. 1972, 37, 2343-2345. (b) Brubaker, A. N.; Colley, M. J. Med. Chem.
1986, 29, 1528-1531.
(4) (a) Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc.
2000, 122, 7596-7597. (b) Nicolaou, K. C.; Montagnon, T.; Baran, P. S.
Angew. Chem., Int. Ed. 2002, 41, 993-996.
(5) 1,2-Addition product was obtained as a single diastereomer of as
yet undetermined relative stereochemistry.
(6) Carreno, M. C.; Ruano, J. L. G.; Sanz, G.; Toledo, M. A.; Urbano,
A. J. Org. Chem. 1995, 60, 5328-5331.
4310
Org. Lett., Vol. 7, No. 20, 2005