Novel domino oxidative coupling: C-C bond formation sequence to highly functionalized dibenzo[ a, c ]cycloheptenes

Article abstract of DOI:10.1021/ol102969k

A domino sequence involving various MoCl₅-mediated oxidations followed by trapping and supposed [3,3]-sigmatropic rearrangement provides a fast access to the full carbon skeleton of metasequirin-B. A variety of different moieties R¹

Full text of DOI:10.1021/ol102969k

ORGANIC
LETTERS
2011
Vol. 13, No. 5
916–919
Novel Domino Oxidative Coupling: C-C
Bond Formation Sequence to Highly
Functionalized Dibenzo-
[a,c]cycloheptenes
Kristina Hackeloer,† Gregor Schnakenburg,‡ and Siegfried R. Waldvogel*,§
ꢀ
Kekule Institute for Organic Chemistry and Biochemistry, Bonn University,
Gerhard-Domagk-Strasse 1, 53121 Bonn, Germany, X-ray Analysis Department,
Institute for Inorganic Chemistry, Bonn University, Gerhard-Domagk-Strasse 1,
53121 Bonn, Germany, and Institute for Organic Chemistry, Johannes Gutenberg-
University Mainz, Duesbergweg 10-14, 55128 Mainz, Germany
waldvogel@uni-mainz.de
Received December 8, 2010
ABSTRACT
A domino sequence involving various MoCl5-mediated oxidations followed by trapping and supposed [3,3]-sigmatropic rearrangement provides a
fast access to the full carbon skeleton of metasequirin-B. A variety of different moieties R1 and R2 are tolerated.
Seven-membered ring systems with annulated benzo
moieties are found in many natural products such as
cycloneolignans, as well as alkaloids.1 Among the latter
colchicine is the most prominent example.2 Colchicine
derivatives, such as allocolchicine or the bicyclic analogue
combretastatin, are of major medicinal and biological
interest because of their pharmacological properties.3 It
is well-known that colchicine binds to the β-subunit of the
protein tubulin in the protofilaments and causes destabi-
lization of the microtubules,4 which are required for the
formation of the mitotic spindle in eukaryotic cells. The
potential application of colchicine in cancer therapy is
limited by its high toxicity, but this has given rise to a
demand for structural analogues. The lignane steganacine,
which features a lactone moiety attached to the central
†
ꢀ
Kekule Institute for Organic Chemistry and Biochemistry, Bonn Uni-
versity.
‡ X-ray Analysis Department, Institute for Inorganic Chemistry, Bonn
University.
§ Institute for Organic Chemistry, Johannes Gutenberg-University Mainz.
(1) (a) Friedman, M.; Mackey, B. E.; Kim, H.-J.; Lee, I.-S.; Lee,
K.-R.; Lee, S.-U.; Kozukue, E.; Kozukue, N. J. Agric. Food Chem. 2007,
55, 243. (b) Uruma, Y.; Sakamoto, K.; Takumi, K.; Doe, M.; Usuki, Y.;
Iio, H. Tetrahedron 2007, 63, 5548. (c) Zarga, M. H. A.; Sabri, S. S.;
Al-Tel, T. H.; Atta-ur-Rahman; Shah, Z.; Feroz, M. J. Nat. Prod. 1991,
54, 936. (d) Lin, R. J.; Cheng, M. J.; Huang, J. C.; Lo, W. L.; Yeh, Y. T.;
Yen, C. M.; Lu, C. M.; Chen, C. Y. J. Nat. Prod. 2009, 1816. (e) Tojo, E.
J. Nat. Prod. 1989, 52, 909.
(3) (a) ter Haar, E.; Rosenkranz, H. S.; Hamel, E.; Day, B. W. Bioorg.
Med. Chem. 1996, 4, 1659. (b) Itoh, Y.; Brossi, A.; Hamel, E.; Lin, C. M.
Helv. Chim. Acta 1988, 71, 1199. (c) Petti, G. R.; Singh, S. B.; Hamel, E.;
Lin, C. M.; Alberts, D. S.; Garcia-Knebel, D. Experentia 1989, 45, 209.
(4) (a) Wolff, J.; Knipling, L.; Cahnmann, H. J.; Palumbo, G.
Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 2820. (b) Rao, S.; He, L. F.;
Chakravarty, S.; Ojima, I.; Orr, G. A.; Horwitz, S. B. J. Biol. Chem.
1999, 274, 37990.
(2) (a) Pelletier, P. S.; Caventon, J. Ann. Chim. Phys. 1820, 14, 69. (b)
Corrodi, H.; Hardegger, E. Helv. Chim. Acta 1955, 38, 2030.
r
10.1021/ol102969k
Published on Web 01/31/2011
2011 American Chemical Society

Scheme 1. Synthesis of the Substrate
access to a variety of dibenzo[a,c]cycloheptenes.10 MoCl5
is a versatile reagent for the oxidative transformation of
arenes11 whichtoleratesnumerousfunctionalgroups12 and
prefers a specific substitution pattern on the aryl moiety.13
In the course of the reaction, hydrogen chloride is liberated
from the reagent. In order to keep the reaction mixture
electrophilic and active, Lewis acids can be used for
binding the hydrogen chloride.14 The reagent waste con-
sists of electrophilic metal chlorides which form multi-
nuclear clusters and may serve as templates in a stereo-
selective oxidative coupling process.15
Here we report an oxidative coupling sequence which
does not stop at the intramolecular arylation product but,
rather, proceeds with further C-H functionalization. In a
one-pot procedure, carboxymethyl fragments can also be
installed upon oxidative cyclization. The synthesis of the
substrate 2 commenced with phosphono acetate 1. After
deprotonation and installation of the first aryl moiety via a
benzylation, the second aryl group was introduced, using a
Horner-Wadsworth-Emmons olefination. Compound
2, prepared in a modular fashion, was formed in an E/Z
ratio of 3:1 (Scheme 1).
Treatment of 2 with MoCl5/TiCl4 in CH2Cl2 not only
affected the aryl-aryl bond formation but also brought
about oxidation of the central cycloheptatriene system (3)
to the tropylium intermediate 4. Benzo annulations on
bonds a and c of the seven-membered ring usually desta-
bilize a tropylium system since the planar geometry is
difficult to maintain.16 However, trapping such a reactive
intermediate with a carbonyl oxygen provides 5 which
forms a 1,5-diene system (6) in the presence of a base. This
might undergo a [3,3]-sigmatropic rearrangement leading
to the observed product 7.
Figure 1. Structures of metasequirin-B, alllocolchicine, and
steganacine.
eight-membered ring system, also binds to the colchicine
binding site on tubulin.5
Among the naturally occurring norcycloneolignans
metasequrin-B is the only known natural product with a
bisbenzocycloheptene skeleton fused to a tetrahydrofuran
system. It was isolated from the heartwood of Metasequoia
glyptostroboides.6 The close structural relationship of
metasequirin-B to the well investigated allocolchicine, as
well as steganacine (Figure 1), promises an interesting
pharmacological profile. The described tubulin-binding
compounds are classified as vascular disrupting agents be-
cause of their mechanism of action. In contrast to anti-
angiogenesis drugs, the vascular disrupting agents act on
existing blood vessels that feed a solid tumor resulting in
tumor ischemia and necrosis. Such drugs offer a nonsurgi-
cal treatment in the case of advanced disease which is of
major interest in cancer therapy.7 Most synthetic ap-
proaches construct the biaryl intermediate at an early
stage, and the central seven-membered ring is subsequently
formed. Synthetic efforts to these tricyclic architectures
usually require many steps.8
Despite the atom economic nature of oxidative coupling
reactions, the direct conversion ofthe corresponding diaryl
substrates via this technology has not received much atten-
tion due to the low yields that are usually observed for such
reactions.9
Use of the powerful oxidant MoCl5 provides, in the
conversion of 1,3-diaryl propanes, a fast and modular
If the workup was performed with an ethyl acetate/
triethyl amine mixture the ethyloxycarbonylmethyl-
modified product 8 was isolated in 70% yield (Table 1,
entry 1). An increased steric demand in the alkyl portion
of the ester has little influence (entry 2). The strong
electrophilic reaction conditions promote elimination of
secondary alkyl moieties. Therefore, other auxiliaries
had to be applied but showed no diastereoselectivity
ꢀ
(5) (a) Joncour, A.; Decor, A.; Liu, J. M.; Tran Huu Dau, M. E.;
Baudoin, O. Chem.;Eur. J. 2007, 13, 5450. (b) Wang, R. W.; Rebhuhn,
L. I.; Kupchan, S. M. Cancer Res. 1977, 37, 3071.
(6) (a) Enoki, A.; Takahama, S.; Kitao, K. Chem. Abstr. 1978, 88,
71429. (b) Sanceau, J. Y.; Dhal, R.; Brown, E. Nat. Prod. Lett. 1992, 221.
(7) Lippert, J. W. Bioorg. Med. Chem. 2007, 15, 605.
(8) Graening, T.; Schmalz, H. G. Angew. Chem., Int. Ed. 2004, 43,
3230.
(9) Scott, A. I. Nature 1960, 186, 556.
(10) Kramer, B.; Waldvogel, S. R. Angew .Chem. Int. Ed. 2004, 43,
2446.
(13) (a) Mirk, D.; Waldvogel, S. R. Tetrahedron Lett. 2004, 45, 7911.
(b) Waldvogel, S. R. Synlett 2002, 622.
€
(14) Kramer, B.; Frohlich, R.; Waldvogel, S. R. Eur. J. Org. Chem.
(11) (a) Spurg, A.; Schnakenburg, G.; Waldvogel, S. R. Chem.;Eur.
J. 2009, 15, 13313. (b) Rempala, P.; Kroulik, J.; King, B. T. J. Org.
Chem. 2006, 71, 5067. (c) King, B. T.; Kroulik, J.; Robertson, C. R.;
Rempala, P.; Hilton, C. L.; Korinek, J. D.; Gortari, L. M. J. Org. Chem.
2007, 72, 2279.
2003, 3549.
(15) Boshta, N.; Bomkamp, M.; Schnakenburg, G.; Waldvogel, S. R.
Chem.;Eur. J. 2010, 16, 3459. Boshta, N.; Bomkamp, M.; Schnakenburg,
G.; Waldvogel, S. R. Eur. J. Org. Chem. 2011in press.
(16) (a) Cook, J. W.; Dickson, G. T.; Loudon, J. D. J. Chem. Soc.
1947, 746. (b) Dewar, M. J.; Ganellin, C. R. J. Chem. Soc. 1959, 3139. (c)
Pomerantz, M.; Dassanayake, N. L.; Mc Manus, T. R.; Reynolds, C. H.
J. Org. Chem. 1984, 49, 4029.
€
(12) (a) Waldvogel, S. R.; Frohlich, R.; Schalley, C. A. Angew.
Chem., Int. Ed. 2000, 39, 2472. (b) Waldvogel, S. R.; Wartini, A. R.;
Rasmussen, P. H.; Rebek, J. Tetrahedron Lett. 1999, 40, 3515. (c)
€
Waldvogel, S. R.; Aits, E.; Holst, C.; Frohlich, R. Chem. Commun.
€
2002, 1278. (d) Kramer, B.; Frohlich, R.; Bergander, K.; Waldvogel,
S. R. Synthesis 2003, 91.
Org. Lett., Vol. 13, No. 5, 2011
917

Table 1. Scope of Carbonyl Components for Domino Sequence
Scheme 2. Potential Mechanism for the Product Formation
for the domino sequence (entries 5-11). Ethyl propio-
nate and isovalerate were successfully subjected to the
transformation providing 12 and 13 in 60% and 69%
yield, respectively. The proximity to the newly formed
stereocenters caused a diastereoselectivity (entries 5 and
6). Lactones are also suitable substrates for this C-C
bond formation. γ-Butyrolactone led to product 14 with
a similar diastereoselectivity found for ethyl propionate
(entry 7).
Introduction of further stereogenic information led to a
set of three diastereomers (entry 8). Further functionalities
are tolerated in the domino sequence. Phenylacetic ester
was coupled to the seven-membered ring to give 16 in 50%
yield and pronounced diastereoselectivity (entry 9). Re-
markably, cyano esters can serve as appropriate coupling
partners (entry 10). In addition, the scope can be extended
to ketones as substrates. Cyclohexanone was converted to
18 in 55% yield (entry 11). Aromatic ketones were ex-
pected to support the transformation since the enolization
is facilitated. Consequently, the conversion of acetophe-
none was achieved in almost 50% yield, whereas the 3,4-
dimethoxyacetophenone reacted in lower yield since the
enolate formation was disfavored by the electron-rich
moieties. The anticipated course of the reaction (Scheme 2)
was supported by two major observations: A stronger
influence of the R-modified carbonyl components on the
stereochemistry was found and moieties which stabilized
the enol ether6; for example, electron withdrawing systems
or cyclic substrates led to significantly higher yields. X-ray
analyses of suitable single crystals of 15 and 16 (Figure 2)
revealed a favored anti-conformation of the newly formed
carbon-carbon bond (highlighted blue). Furthermore,
we found that the carbonyl component was exclusively
(entries 3 and 4). (R)-2-Methylbutyl acetate provided an
equimolar mixture of diastereomers. A similar result was
obtained when (þ)-R-fenchyl acetate was used in the
workup procedure. Carbonyl components with an R
modification also represent suitable coupling partners
918
Org. Lett., Vol. 13, No. 5, 2011

biaryl portion and new stereogenic center in the ring.
Together with the adjacent exocyclic stereocenter a domino
product with relative configuration R,R,R (S,S,S) or R,R,S
(S,S,R) is formed. Only if cyclic carbonyl components or
aromatic substituents on the new stereogenic center are
involved, a pronounced stereoselectivity is found.
The unique character of MoCl5/TiCl4 for this domino
sequence became obvious when 2 was subjected to ferrous
chloride or other common electrophilic coupling media.
Following the same workup protocol neither product 3,
formed by 2-fold C-H activation, nor product 7, in
consequence of the oxidative domino coupling sequence,
was observed. Only traces of the domino product were
detected when an analogous mixture of FeCl3/TiCl4 was
applied (SI). Further indication for the domino sequence
with a prior tropylium formation was found when tropy-
lium tetrafluoroborate was subjected to the workup pro-
tocol. In the presence of TiCl4 the ethyl acetate/
triethylamine mixture led to the installation of an ethoxy-
carbonylmethyl moiety at the cycloheptatriene (SI). Re-
cently, Cozzi et al. have demonstrated that cyclo-
heptatriene can be organocatalytically functionalized by
oxidative C-H activation.17
Figure 2. Molecular structure of 16 (major diastereomer) ob-
tained by X-ray analysis.
located in the axial position at the sp3 carbon of the
seven-membered ring system. Consequently, the orienta-
tion of the biaryl axis was determined by this adjacent
stereocenter in the central ring system. Because of this
stereochemical preference, a sole diastereomer was ob-
tained if an achiral primary alkyl moiety was used as
a coupling partner in the domino sequence (entries 1,
2, 12, 13).
When achiral secondary alkylcarbonyl components
served as reaction partners, as in the case for 16, two
diastereomers were observed (entry 9). The structure of
the major diastereomer of 16 was similar to that found for
15 (Supporting Information (SI)). In 16 the biaryl axis is
tilted by 41.6°. The benzylic sp3 carbon is almost perfectly
tetrahedral, arranged 109.3° withrespect toits neighboring
atoms in the central ring system. The geometry of 16
provides a consistent picture with the NMR data. The
atropisomeric biaryl moiety forms, in all the examples
investigated, the same geometric arrangement with respect
to the newly formed stereogenic center in the seven-mem-
bered ring. The nucleophilic attack to the planar and C2
symmetric dibenzo[a,c]tropylium 4 (Scheme 2) can occur
from both sides onto the central ring system creating the
stereochemical relationship between the atropisomeric
In conclusion, we have developed a fast and reliable
domino sequence to highly functionalized dibenzo[a,c]cyclo-
heptenes. The installation of the carboxy methyl moiety on
the seven-membered ring can only be achieved by the MoCl5/
TiCl4 mixture. The unprecedented domino transformation
consists of three C-H activation steps. The sequence pro-
vides the full carbon skeleton of metasequirin-B.
Acknowledgment. K. H. thanks to the Degussa Stiftung
€
and the Jurgen Manchot Stiftung for granting fellowships.
S.R.W. appreciates the collaboration with the Kompe-
tenzzentrum der Integrierten Naturstoff-Forschung
(University of Mainz).
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds 2-20. CIF files for compounds 15 and 16. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(17) Benfatti, F.; Capdevilla, M. G.; Zoli, L.; Benedetto, E.; Cozzi,
P. G. Chem. Commun. 2009, 39, 5919.
Org. Lett., Vol. 13, No. 5, 2011
919