Total synthesis of (±)-clavubicyclone

Article abstract of DOI:10.1021/ol061947u

(Chemical Equation Presented) The total synthesis of racemic clavubicyclone (1), which was isolated from Okinawan soft coral by our group, is described. The bicyclo[3.2.1]-octane skeleton was prepared by Cope rearrangement of a divinylcyclopropane derivat

Full text of DOI:10.1021/ol061947u

ORGANIC
LETTERS
2006
Vol. 8, No. 21
4883-4885
Total Synthesis of (±)-Clavubicyclone
Hisanaka Ito,* Shunta Takeguchi, Takahiro Kawagishi, and Kazuo Iguchi*
School of Life Sciences, Tokyo UniVersity of Pharmacy and Life Sciences,
1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
itohisa@ls.toyaku.ac.jp; onocerin@ls.toyaku.ac.jp
Received August 6, 2006
ABSTRACT
The total synthesis of racemic clavubicyclone (1), which was isolated from Okinawan soft coral by our group, is described. The bicyclo[3.2.1]-
octane skeleton was prepared by Cope rearrangement of a divinylcyclopropane derivative. Three functional groups on the skeleton were
constructed by Barton decarboxylation, Wittig reaction, and alkylation.
Clavubicyclone (1) and tricycloclavulone were recently
isolated from Okinawan soft coral, ClaVularia Viridis, by
our group as novel prostanoid-related compounds which have
a bicyclo[3.2.1]octane skeleton (clavubicyclone) and a
tricyclo[5.3.0.01,4]decane skeleton (tricycloclavulone) (Figure
1).1 Although the planar structures and relative stereochem-
relative and absolute stereochemistries2 was attained. Clavu-
bicyclone (1), having a bicyclo[3.2.1]octane skeleton, two
side chains, and an acetoxyl group on the bridgehead
position, is a quite attractive synthetic target for organic
chemists. Therefore, effective construction of the bicyclic
core of 1 was examined, and we report herein the total
synthesis of (()-clavubicyclone (1).
Our strategy for the total synthesis of clavubicyclone (1)
focused on the use of Cope rearrangement of 4 to construct
the bicyclo[3.2.1]octane skeleton3,4 and Barton decarboxyl-
ation to create the bridgehead acetoxyl group (Scheme 1).
For the preparation of compound 4, aldol reaction of 6 with
dienolate and the following intramolecular cyclopropanation
using a Rh catalyst were employed. Conversion of the
methoxycarbonyl group of 3 to an acetoxyl group would be
achieved through Barton decarboxylation and the following
oxidation of the resulting radical intermediate by oxygen.
The construction of both side chains would achieve the total
synthesis of clavubicyclone (1).
Figure 1. The structures of marine prostanoid-related compounds,
clavubicyclone (1) and tricycloclavulone.
istries of the chiral centers on the cyclic cores were
determined by spectroscopic analysis, the stereochemistry
of the carbon bearing the acetoxyl group on the side chain
as well as the absolute stereochemistry had not yet been
examined. We recently achieved an enantioselective total
synthesis of tricycloclavulone, and the determination of the
(2) (a) Ito, H.; Kobayashi, T.; Hasegawa, M.; Iguchi, K. Tetrahedron
Lett. 2003, 44, 1259-1261. (b) Ito, H.; Hasegawa, M.; Takenaka, Y.;
Kobayashi, T.; Iguchi, K. J. Am. Chem. Soc. 2004, 126, 4520-4521.
(3) (a) Wong, H. N. C.; Hon, M. Y.; Tse, C. W.; Yip, Y. C. Chem. ReV.
1989, 89, 165-198. (b) Doering, W. v. E.; Roth, W. R. Tetrahedron 1963,
19, 715-737. (c) Arai, M.; Crawford, R. J. Can. J. Chem. 1972, 50, 2158-
2162. (d) Baldwin, J. E.; Gilbert, K. E. J. Am. Chem. Soc. 1976, 98, 8283-
8284.
(4) For an example of a synthesis of natural product through Cope
rearrangement of divinylcyclopropane, see: Fukuyama, T.; Liu, G. J. Am.
Chem. Soc. 1996, 118, 7426-7427.
(1) Iwashima, M.; Terada, I.; Okamoto, K.; Iguchi, K. J. Org. Chem.
2002, 67, 2977-2981.
10.1021/ol061947u CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/13/2006

steps. Intramolecular cyclopropanation of 5 proceeded under
the presence of a catalytic amount of rhodium acetate dimer,
and compound 9 was obtained in 90% yield as a diastereo-
meric mixture (3:1). Elimination of the alkoxyl group on
the cyclopentanone ring of the diastereomeric mixture of 9
proceeded by treating it with DBU to afford compound 4
(single isomer) as a precursor of Cope rearrangement.
Cope rearrangement of 4 was examined under several
conditions. In toluene, the reaction was carried out at 110
°C for 72 h, and the product 3 was obtained in 34% yield
along with undetectable byproducts. When the reaction was
carried out at 140 °C in xylene, compound 4 disappeared
after 18 h; however, the yield was almost the same (36%)
as that in the case of toluene. In the case of diphenyl ether,
the reaction proceeded at 180 °C within 0.5 h, and the yield
significantly increased and compound 3 was obtained in 58%
yield.
Scheme 1. Retrosynthetic Analysis of Clavubicyclone
The effort for the total synthesis of clavubicyclone (1) is
shown in Scheme 3. Prior to the conversion of three
The synthesis of the bicyclo[3.2.1]octane skeleton is shown
in Scheme 2. Compound 7 was prepared according to the
reported procedure in two steps from cis-2-butene-1,4-diol.5
Wittig reaction of 7 with 2-triphenylphosphoranylidene-γ-
butyrolactone,6 reduction of the lactone moiety to diol, and
selective oxidation of the allylic alcohol moiety with MnO2
gave aldehyde 6. Reaction of the dianion of methyl aceto-
acetate with 6 gave compound 8, which could be converted
to 5, a precursor for intramolecular cyclopropanation in two
Scheme 3. Total Synthesis of Clavubicyclone
Scheme 2. Construction of Bicyclo[3.2.1]octane Skeleton
functional groups on the bicyclo[3.2.1]octane skeleton,
protection of the ketone group was examined. The reaction
for the formation of a ketal group, however, did not proceed.
Therefore, the ketone was reduced to a hydroxyl group in a
(5) Murga, J.; Garcia-Fortanet, J.; Carda, M.; Marco, J. M. Synlett 2004,
15, 2830-2832.
(6) Lyga, J. W.; Secrist, J. A., III. J. Org. Chem. 1983, 48, 1982-1988.
4884
Org. Lett., Vol. 8, No. 21, 2006

diastereoselective manner (10:1), and the resulting hydroxyl
group was protected with a TBS group. The stereochemistry
of the newly formed chiral center was not determined.
Hydrolysis of the methoxycarbonyl group was carried out
in the presence of LiOH, but the TBDPS group was also
cleaved. Therefore, the primary hydroxyl group was protected
by a TBS group again to give compound 10. Conversion of
compound 10 to 11 was achieved by Barton decarboxyl-
ation.7,8 Thus, after the Barton ester formation under dark
condition, oxygen gas was introduced to the reaction mixture,
and the decarboxylation reaction and subsequent oxidation
of the Barton ester were carried out under fluorescent light,
and the following acetylation gave compound 11 in 57% (two
steps). Selective cleavage of the TBS groups of 11 to obtain
primary alcohol proceeded under acid hydrolysis conditions.
Oxidation of the hydroxyl group and Wittig reaction of the
resulting aldehyde with the ylide, which was prepared from
hexyltriphenylphosphonium bromide with NaHMDS in ether,
proceeded to give 12 in a highly Z-selective manner (>95:
5). If the reaction was carried out in THF, migration of the
carbon-carbon double bond to form an R,â-unsaturated
aldehyde occurred and the product was not obtained. With
the use of n-BuLi as a base for the preparation of the ylide,
a Z:E mixture (3:1) of 12 was obtained.
of the synthesis of an enantiomerically pure compound. After
the separation of the diastereomers, acetylation of the
hydroxyl group of the one diastereomer gave compound 2.9
Selective deprotection of the primary silyl ether of 2 and
the following oxidation of the resulting hydroxyl group to a
hydroxycarbonyl group was achieved by treating 2 with Jones
reagent for 15 min. If longer reaction time (more than 30
min) was employed for the deprotection and subsequent
oxidation of the secondary silyl ether, decomposition was
observed. The following methyl esterification of the resulting
hydroxycarbonyl group by treating it with diazomethane gave
a methyl ester in 88% yield (two steps). Deprotection of the
secondary silyl ether and the following oxidation of the
resulting hydroxyl group by Swern oxidation achieved the
total synthesis of (()-clavubicyclone (1). The spectral data
(1H, 13C, and MS) of synthetic clavubicyclone (1) were
identical with those of natural 1.1
In conclusion, the total synthesis of (()-clavubicyclone
was achieved through Cope rearrangement for the construc-
tion of a bicyclo[3.2.1]octane skeleton. Work for the
synthesis of 1 as an enantiomerically pure form and the
determination of the absolute stereochemistry is now under-
way.
Deprotection of the MPM group of 12 and subsequent
oxidation of the resulting hydroxyl group gave the aldehyde.
Introduction of a three-carbon unit was performed by
alkylation of the aldehyde with 3-(tert-butyldimethylsilyl-
oxy)propylmagnesium bromide (diastereomeric ratio was
1:1). Although the diastereoselectivity of the introduction
of the three-carbon unit was not observed, it would be
resolved by the use of an asymmetric allylation in the case
Acknowledgment. H.I. thanks the Mitsubishi Chemical
Corporation Fund for financial support of this work.
Supporting Information Available: Experimental details
and spectral data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL061947U
(7) (a) Barton, D. H. R.; Crich, D.; Motherwell, W. B. J. Chem. Soc.,
Chem. Commun. 1984, 242-244. (b) Barton, D. H. R.; Bridon, D.; Zard,
S. Z. Tetrahedron 1989, 45, 2615-2626.
(9) We also examined the use of another diastereomer for the total
synthesis. The final compound derived from another diastereomer was not
identical to clavubicyclone (1).
(8) Ramaiah, M. Tetrahedron 1987, 43, 3541-3676.
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