Scheme 2. Synthesis of Azatricyclic Ketone 7
Figure 1. Structures of the hexacyclic alkaloids.
calyciphylline A and a hydroxymethyl substituent in daph-
niglaucins D-F.
In this work, we report our studies on the synthesis of the
ABC tricyclic framework of calyciphylline A and daph-
niglaucins D-F, based on the palladium-catalyzed coupling
of vinyl halides and ketone enolates,10,11 which could allow
the cyclization process II f I (Scheme 1). In turn, we
Scheme 1. Retrosynthetic Plan for Synthesis of the ABC
Rings of Calyciphylline A
acetal of the 1,4-cyclohexanedione (Scheme 2). Treating the
ketone 3 with (i-Pr)2NMgBr in Et2O followed by entrapment
of the enolate with TMSCl14 smoothly furnished the more
substituted TMS-enol ether (not shown), which upon treat-
ment with methyllithium and reaction of the resulting enolate
with methyl iodide gave rise to 415 in 85% overall yield.16
The required azabicyclic compound 5c was prepared from
4 either by a tandem process of ozonolysis and double
reductive amination to elaborate the octahydroindole ring
(36%) or via the N-benzyl derivative 5a. The latter was
transformed into 5c through a sluggish debenzylation and
alkylation with 2,3-dibromopropene of the resulting 5b, thus
avoiding the use of toxic 2-bromoallylamine17 required for
the direct synthesis of 5c. The aminocyclization leading to
both 5a and 5c was stereoselective, only the cis ring-fused
octahydroindoles being isolated.18 Hydrolysis of the acetal
planned to obtain the required octahydroindole derivative II
through a one-pot procedure of ozonolysis and double
reductive amination of an appropriate R-allyl ketone, such
as III.12
The starting material was the known R-allylcyclohex-
anedione 3,13 prepared in three steps from the monoethylene
(9) (a) Quesada, M. L.; Kim, D.; Ahn, S. K.; Jeong, N. S.; Hwang, Y.;
Kim, M. Y.; Kim, J. W. Heterocycles 1987, 25, 283-286. (b) Angle, S.
R.; Fevig, J. M.; Knight, S. D.; Marquis, R. W., Jr.; Overman, L. E. J. Am.
Chem. Soc. 1993, 115, 3966-3976. (c) Bonjoch, J.; Sole´, D.; Garc´ıa-Rubio,
S.; Bosch, J. J. Am. Chem. Soc. 1997, 119, 7230-7240. (d) Sole´, D.;
Bonjoch, J.; Garc´ıa-Rubio, S.; Peidro´, E.; Bosch, J. Chem. Eur. J. 2000, 6,
655-665.
(10) (a) Sole´, D.; Peidro´, E.; Bonjoch, J. Org. Lett. 2000, 2, 2225-2228.
(b) Sole´, D.; Diaba, J.; Bonjoch, J. J. Org. Chem. 2003, 68, 5746-5749.
(c) Bonjoch, J.; Diaba, F.; Puigbo´, G.; Peidro´, E.; Sole´, D. Tetrahedron
Lett. 2003, 44, 8387-8390. (d) Sole´, D.; Urbaneja, X.; Bonjoch, J. AdV.
Synth. Catal. 2004, 346, 1646-1650.
(11) For other examples of intramolecular Pd-catalyzed vinylations,
see: (a) Piers, E.; Oballa, R. M. Tetrahedron Lett. 1995, 36, 5857-5860
and references therein. (b) Yu, J.; Wang, T.; Liu, X.; Deschamps, J.; Flippen-
Anderson, J.; Liao, X.; Cook, J. M. J. Org. Chem. 2003, 68, 7565-7581
and references therein.
(13) Zhou, G.-C.; Zhu, D.-Y. Synth. Commun. 2002, 32, 37-44. See
also: Montgomery, J.; Overman, L. E. J. Org. Chem. 1993, 58, 6476-
6479.
(14) Krafft, M. E.; Holton, R. A. Tetrahedron Lett. 1983, 24, 1345-
1348.
(15) The first enantioselective synthesis of 4 by a Tsuji allylation process
has been recently described: Behenna, D. C.; Stoltz, B. M. J. Am. Chem.
Soc. 2004, 126, 15044-15045.
(16) Regioselective methylation of 3 to give R,R-disubstituted ketone 4
was also carried out in only one step (KOtBu, MeI), but in lower yield
(65%).
(12) For the use of this methodology to arrive at 3a-substituted
octahydroindol-4-ones, see: Sole´, D.; Bosch, J.; Bonjoch, J. Tetrahedron
1996, 52, 4013-4028.
(17) Bottini, A. T.; Dev, V. J. Org. Chem. 1962, 27, 968-973.
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