Application of aryl siloxane cross-coupling to the synthesis of allocolchicinoids

Article abstract of DOI:10.1021/ol061413t

In this communication, we report a new approach to the allocolchicine carbocyclic skeleton based upon an aryl siloxane coupling reaction and a phenanthrol ring expansion. These key steps allow for the selective functionalization of every carbon within the

Full text of DOI:10.1021/ol061413t

ORGANIC
LETTERS
2
006
Vol. 8, No. 18
951-3954
Application of Aryl Siloxane
Cross-Coupling to the Synthesis of
Allocolchicinoids
3
W. Michael Seganish and Philip DeShong*
Department of Chemistry and Biochemistry, UniVersity of Maryland,
College Park, Maryland 20742
deshong@umd.edu
Received June 9, 2006
ABSTRACT
In this communication, we report a new approach to the allocolchicine carbocyclic skeleton based upon an aryl siloxane coupling reaction
and a phenanthrol ring expansion. These key steps allow for the selective functionalization of every carbon within the carbocyclic framework.
The siloxane coupling−phenanthrol sequence was applied to the synthesis of two allocolchicinoids, including the first fully synthetic approach
to N-acetyl colchinol-O-methyl ether (NCME).
Allocolchicine (1) and N-acetyl colchinol-O-methyl ether
approaches have been reported for the partial synthesis of
2
(NCME) (2) possess a 6-7-6 carbocyclic framework, related
allocolchicine or derivatives. Additionally, several total
3
to the 6-7-7 tricylic system present in colchicine (3). Like
syntheses of allocolchicine exist; however, there are no
1
colchicine, the allocolchicinoids are potent tubulin inhibitors.
reported total syntheses of NCME (2). This allocolchicinoid
The majority of the synthetic work related to allocolchicine
has relied on chemical degradation of colchicine to provide
allocolchicine and its analogues, and this has limited access
to novel derivatives possessing reduced toxicity. Several
possesses tubulin inhibition activity that is greater than that
of colchicine itself.
1
a
It has been demonstrated that the A and C allocolchicinoid
rings are required to maintain full biological activity.3
a,4
(
2) (a) Banwell, M. G.; Fam, M.-A.; Gable, R. W.; Hamel, E. J. Chem.
(
1) (a) Nakagawa-Goto, K.; Jung, M. K.; Hamel, E.; Wu, C.-C.; Bastow,
K. F.; Brossi, A.; Ohta, S.; Lee, K.-H. Heterocycles 2005, 65, 541-550.
b) Shi, Q.; Chen, K.; Chen, X.; Brossi, A.; Verdier-Pinard, P.; Hamel, E.;
McPhail, A. T.; Tropsha, A.; Lee, K.-H. J. Org. Chem. 1998, 63, 4018-
025. (c) Bergemann, S.; Brecht, R.; Buttner, F.; Guenard, D.; Gust, R.;
Soc., Chem Commun. 1994, 2647-2649. (b) Banwell, M. G.; Cameron, J.
M.; Corbett, M.; Dupuche, J. R.; Hamel, E.; Lambert, J. N.; Lin, C. M.;
Mackay, M. F. Aust. J. Chem. 1992, 45, 1967-1982. (c) Itoh, Y.; Brossi,
A.; Hamel, E.; Lin, C. M. HelV. Chim. Acta 1988, 71, 1199-1209. (d)
Boye, O.; Itoh, Y.; Brossi, A. HelV. Chim. Acta 1989, 72, 1690-1696. (e)
Boye, O.; Brossi, A.; Yeh, H. J. C.; Hamel, E.; Wegrzynski, B.; Toome,
V. Can. J. Chem. 1992, 70, 1237-1249.
(3) (a) Sawyer, J. S.; Macdonald, T. L. Tetrahedron Lett. 1988, 29, 4839-
4842. (b) Buettner, F.; Bergemann, S.; Guenard, D.; Gust, R.; Seitz, G.;
Thoret, S. Bioorg. Med. Chem. 2005, 13, 3497-3511. (c) Vorogushin, A.
V.; Predeus, A. V.; Wulff, W. D.; Hansen, H.-J. J. Org. Chem. 2003, 68,
5826-5831. (d) Leblanc, M.; Fagnou, K. Org. Lett. 2005, 7, 2849-2852.
(4) (a) Rossi, M.; Gorbunoff, M. J.; Caruso, F.; Wing, B.; Perez-Ramirez,
B.; Timasheff, S. N. Biochemistry 1996, 35, 3286-3289. (b) Perez-Ramirez,
B.; Gorbunoff, M. J.; Timasheff, S. N. Biochemistry 1998, 37, 1646-1661.
(
4
Seitz, G.; Stubbs, M. T.; Thoret, S. Bioorg. Med. Chem. 2003, 11, 1269-
281. (d) Brecht, R.; Seitz, G.; Guenard, D.; Thoret, S. Bioorg. Med. Chem.
1
2
000, 8, 557-562. (e) Roesner, M.; Capraro, H.-G.; Jacobson, A. E.; Atwell,
L.; Brossi, A.; Iorio, M. A.; Williams, T. H.; Sik, R. H.; Chignell, C. F. J.
Med. Chem. 1981, 24, 257-261. (f) Brossi, A.; Sharma, P. N.; Atwell, L.;
Jacobson, A. E.; Iorio, M. A.; Molinari, M.; Chignell, C. F. J. Med. Chem.
1
983, 26, 1365-1369. (g) Han, S.; Hamel, E.; Bastow, K. F.; McPhail, A.
T.; Brossi, A.; Lee, K.-H. Bioorg. Med. Chem. Lett. 2002, 12, 2851-2853.
h) Shi, Q.; Chen, K.; Brossi, A.; Verdier-Pinard, P.; Hamel, E.; McPhail,
A. T.; Lee, K.-H. HelV. Chim. Acta 1998, 81, 1023-1037.
(
1
0.1021/ol061413t CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/10/2006

Scheme 2. Annulation Model System
However, the B ring can be manipulated to generate
analogues that retain the antitumor activity, while moderating
the toxicity of these compounds. The existing total syntheses
do not readily provide access to B ring analogues. Accord-
ingly, a synthetic approach that would allow for the facile
construction of the A, B, and C rings, while also permitting
functionalization of all of the rings, would have great
synthetic value. Our approach seeks to satisfy this goal by
utilizing an aryl siloxane coupling reaction developed within
Having successfully generated the allocolchicine carbocy-
clic framework in ketone 12, our attention focused on
derivatization of chloroenone 11 (Scheme 3). This compound
5
our laboratory to form the A-C biaryl core and a phenan-
throl ring expansion to provide the seven-membered B ring
(Scheme 1).
Scheme 3. Functionalization of R-Chloro Ketone 11
Scheme 1. Retrosynthesis
possesses a high degree of functionalization which could be
utilized to generate allocolchicine B ring analogues. Ac-
cordingly, enone 11 was hydrogenated to benzyl alcohol 13.
Alternatively, by switching the hydrogenation solvent from
EtOH to EtOAc, hydrogenation was stopped at the chlo-
roketone, which was eliminated to generate the Michael
acceptor 14.
Our first task was to explore the phenanthrol ring expan-
sion. The one-carbon expansion of phenanthrene has been
6
studied, but the corresponding ring expansion of phenanthrol
has not been investigated. Accordingly, a model system
utilizing 9-phenanthrol (8) as the substrate was examined.
Protection of the hydroxyl moiety of 9-phenanthrol (8) as a
MOM ether proceeded smoothly to provide ether 9 (Scheme
6a
The palladium-catalyzed cross-coupling of the chloride
moiety of R-chloroenone 11 was also investigated. Gratify-
ingly, when chloroenone 11 was subjected to standard Suzuki
2
(
). Reaction of this compound under optimized conditions
CHCl , 50% NaOH, BnEt NCl, room temperature, 5 h) led
3
3
to the formation of the dichlorocyclopropyl adduct 10 in
excellent yield. Treatment of compound 10 with dilute acid
removed the MOM ether and induced cyclopropane ring
opening to provide the ring-expanded chloroenone 11.
Hydrogenation of the chloroenone, using conditions devel-
oped by Jones and Coburn,6 provided aryl ketone 12.
7
coupling conditions, a good yield of the coupled product
1
5 was obtained. This result is particularly noteworthy
because it constitutes only the second example of the cross-
coupling of an R-chloroenone. The coupling of iodides and
8
bromides has been studied previously, but until recently,
a
there was not an example of the coupling of a chloride
9
substrate.
(
5) (a) Mowery, M. E.; DeShong, P. Org. Lett. 1999, 1, 2137-2140.
Having established that the R-chloroenone would be
suitable for derivatization, we sought to apply the ring
expansion protocol to the synthesis of several allocolchici-
(
b) Mowery, M. E.; DeShong, P. J. Org. Chem. 1999, 64, 1684-1688. (c)
McElroy, W. T.; DeShong, P. Org. Lett. 2003, 5, 4779-4782. (d) Seganish,
W. M.; DeShong, P. J. Org. Chem. 2004, 69, 1137-1143.
(
6) (a) Coburn, T. T.; Jones, W. M. J. Am. Chem. Soc. 1974, 96, 5218-
5
227. (b) Joshi, G. C.; Singh, N.; Pande, L. M. Synthesis 1972, 317. (c)
Halton, B.; Officer, D. L. Aust. J. Chem. 1983, 36, 1167-1175. (d) Nerdel,
F.; Buddrus, J.; Brodowski, W.; Windhoff, J.; Klamann, D. Tetrahedron
Lett. 1968, 9, 1175-1179.
(7) Miyaura, N. In Metal-Catalyzed Cross-Coupling Reactions; de
Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim, Germany, 2004;
Vol. 1, pp 41-124.
3952
Org. Lett., Vol. 8, No. 18, 2006

noids. An aryl siloxane coupling reaction would be used to
generate the unsymmetrical A-C biaryl bond. Under opti-
mized conditions, the siloxane coupling reaction provided
several unsymmetrical biaryls, including substrates that can
be utilized for the synthesis of NCME (2), and allocolchicine
Scheme 5. Phenanthrol Ring Expansion
(1) (Table 1, entries 2 and 4, respectively). This coupling
Table 1. Synthesis of Biaryl Derivatives Using
Palladium-Catalyzed Siloxane Couplinga
entry
R
yieldb
1
2
3
4
H
OMe
Me
94
93
87
94
CO2Et
ably occurring via deprotected alcohol 21, proceeded to
provide chloroenone 22. Hydrogenation of enone 22 gave
saturated ketone 23. Reductive amination followed by
acylation provided the known allocolchicinoid 24.
Having successfully generated allocolchicinoid 24, our
attention turned to the synthesis of NCME (2) (Scheme 6).
a
Conditions: 5% Pd(OAc)2, 25% PPh3, 1.5 equiv of aryl siloxane, 1.5
equiv of TBAF, THF. Isolated yield of purified product.
b
3
d
reaction could be used to synthesize a variety of A-C ring
modified allocolchicinoid precursors.
The first allocolchicinoid assembled was derived from
biaryl 16 (Table 1, entry 1) (Scheme 4). The biaryl was
Scheme 6. Synthesis of NCME Phenanthrol
Scheme 4. Synthesis of MOM-Protected Phenanthrol
Biaryl 25 (Table 1, entry 2) was homologated to acid 26.
Ring closure was effected in good yield by stirring in neat
methanesulfonic acid (MSA) for 2.5 h at room temperature.10
Formation of the MOM ether proceeded smoothly to give
homologated by Wittig reaction, followed by oxidation, to
provide acid 17 (Scheme 4). Friedel-Crafts ring closure
generated air-sensitive phenanthrol 18 which was im-
mediately protected to provide MOM ether 19.
1
1
protected phenanthrol 28.
Conversion of protected phenanthrol 28 to ketone 29 was
accomplished as described above (Scheme 7). Additionally,
it was found that only a single purification step was needed
to provide aryl ketone 29 in good yield for the three-step
procedure. Reductive amination of ketone 29 followed by
acylation provided the first fully synthetic NCME (2).
In summary, a short and versatile synthesis of the
allocolchicinoid carbon skeleton has been presented. It is
Cyclopropanation of MOM ether 19 provided dichloro-
cyclopropyl adduct 20 (Scheme 5). Ring expansion, presum-
(
8) (a) Negishi, E.-i. J. Organomet. Chem. 1999, 576, 179-194. (b)
Dyker, G.; Markwitz, H.; Henkel, G. Eur. J. Org. Chem. 2001, 2415-
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2
Soc. 2002, 124, 4628-4641. (d) Scott, T. L.; Soderberg, B. C. G.
Tetrahedron Lett. 2002, 43, 1621-1624. (e) Scott, T. L.; Soderberg, B. C.
G. Tetrahedron 2003, 59, 6323-6332. (f) Ohshima, T.; Xu, Y.; Takita, R.;
Shimizu, S.; Zhong, D.; Shibasaki, M. J. Am. Chem. Soc. 2002, 124, 14546-
1
4547. (g) Banwell, M. G.; Kelly, B. D.; Kokas, O. J.; Lupton, D. W. Org.
Lett. 2003, 5, 2497-2500. (h) Ruel, R. S.; Braun, M. P.; Johnson, C. R.
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D. J.; Bowen, J. P. Tetrahedron Lett. 1999, 40, 459-462. (j) Felpin, F.-X.
J. Org. Chem. 2005, 70, 8575-8578.
(10) Leon, A. A.; Daub, G.; Silverman, I. R. J. Org. Chem. 1984, 49,
4544-4545.
(11) Attempts to close the ring using a Friedel-Crafts approach (as for
18, Scheme 4) yielded complex mixtures, presumably due to the increased
reactivity of the activated C ring. Conversely, MSA proved ineffective for
the synthesis of 18.
(
9) Banks, J. C.; Van Mele, D.; Frost, C. G. Tetrahedron Lett. 2006, 47,
2
863-2866.
Org. Lett., Vol. 8, No. 18, 2006
3953

disclosure of our results, as well as the synthesis of novel
allocolchicinoids, will be reported in due course.
Scheme 7. Final Stage of NCME Synthesis
Acknowledgment. We thank the National Cancer Insti-
tute (CA 82169-01) and the University of Maryland for
generous financial support. We also thank Yiu-Fai Lam and
Noel Whittaker (University of Maryland) for their assistance
in obtaining spectral data. W.M.S. thanks the Organic
Division of the American Chemical Society for a graduate
fellowship (sponsored by Procter and Gamble).
Supporting Information Available: Detailed experi-
based upon a siloxane coupling reaction to form the A-C
biaryl ring system and a phenanthrol ring expansion reaction
to provide the seven-membered B ring. In combination, these
protocols allow for the potential selective functionalization
of every carbon present in the allocolchicine skeleton. Full
mental procedures and characterization information for all
1
compounds including copies of H NMR data. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL061413T
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Org. Lett., Vol. 8, No. 18, 2006