Synthesis of the bicyclo[7.3.0]dodecatrienediyne core of the C-1027 chromophore

Article abstract of DOI:10.1021/ol048494i

(Chemical Equation Presented) C-1027, an extremely potent antitumor agent, is composed of chromophore 1 and an apoprotein. Here we report a general and efficient route to the exceedingly reactive bicyclo[7.3.0]dodecatrienediyne core of 1, utilizing seleno

Full text of DOI:10.1021/ol048494i

ORGANIC
LETTERS
2004
Vol. 6, No. 21
3833-3836
Synthesis of the
Bicyclo[7.3.0]dodecatrienediyne Core of
the C-1027 Chromophore
Masayuki Inoue,*,†,‡ Suguru Hatano,† Masaki Kodama,† Takeo Sasaki,†
Tsukasa Kikuchi,† and Masahiro Hirama*,†
Department of Chemistry, and Research and Analytical Center for Giant Molecules,
Graduate School of Science, Tohoku UniVersity, Sendai 980-8578, Japan
inoue@ykbsc.chem.tohoku.ac.jp; hirama@ykbsc.chem.tohoku.ac.jp
Received July 30, 2004
ABSTRACT
C-1027, an extremely potent antitumor agent, is composed of chromophore 1 and an apoprotein. Here we report a general and efficient route
to the exceedingly reactive bicyclo[7.3.0]dodecatrienediyne core of 1, utilizing selenoxide elimination and epoxide deoxygenation to build the
cyclopentadiene and enediyne structures, respectively.
The chromoprotein C-10271 is composed of an 11-kDa
apoprotein2 and a highly reactive chromophore (1, Figure
1)3 and displays potent antitumor activity. C-1027 chro-
mophore 1 is bound noncovalently in a cleft of the apopro-
tein and is dissociable.4,5 When not bound to the apoprotein,
1 quickly aromatizes via Masamune-Bergman rearrange-
ment6 at room temperature without any external activators
(1 f 3).7 p-Benzyne biradical 2, generated from 1, exerts
its potent biological activity by abstracting hydrogens from
the sugar portions of double-stranded DNA, which ultimately
leads to oxidative cleavage.8
The highly reactive bicyclo[7.3.0]dodecatrienediyne struc-
ture of 1 is central to this potent biological activity. The
chromophore components of other related agents such as
maduropeptin,9 kedarcidin,10 and neocarzinostatin11 share a
† Department of Chemistry.
‡ Research and Analytical Center for Giant Molecules.
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10.1021/ol048494i CCC: $27.50
© 2004 American Chemical Society
Published on Web 09/16/2004

Scheme 1. Synthetic Plan of the
Bicyclo[7.3.0]dodecatrienediyne Structure
Figure 1. Structure of the C-1027 chromophore and its Masam-
une-Bergman rearrangement.
common bicyclo[7.3.0]dodecadiyne core but differ in the
degree of oxidation and unsaturation. Chromophore 1 has
the most unsaturated structure among these enediyne natural
products: only two sp3 carbons are present within the
dodecacycle while the other 10 carbons are conjugated. Here,
we report a general and efficient route to the trienediyne
structure, which is to date the only synthetic construct that
bears the fused ring system of the cyclopentadiene and
enediyne structures.12-16
membered ring cyclization (Scheme 1).17 The most formi-
dable problem for the total synthesis of 1 from diyne 4 is
apparently the formation of the reactive bicyclo[7.3.0]-
dodecatrienediyne. We therefore undertook, as a model study,
the synthesis of trienediyne 7 from diyne 5, which possesses
the same structure as 4 except for the â-tyrosine moiety.
Because of the general instability of the strained nine-
membered diynes,18 a synthetic scheme en route to 5 should
constitute a series of mild reaction conditions. More-
over, introduction of the C4-C5 olefin should be at the last
stage in order to avoid the consumption of synthetic
intermediates via Bergman rearrangement. Hence, the cy-
clopentadiene structure was planned to be constructed prior
to the enediyne through dehydration of the C11 alcohol (5
f 6). The C4-C5 olefin was then to be directly installed
In prior work, we efficiently constructed the C-1027
chromophore framework 4 through atropselective macrolac-
tonization and subsequent LiN(TMS)2/CeCl3-promoted nine-
(11) Neocarzinostatin; Maeda, H., Edo, K., Ishida, N., Eds.; Springer:
Tokyo, 1997.
(12) For synthetic studies of the C-1027 chromophore from this labora-
tory, see: (a) Iida, K.; Ishii, T.; Hirama, M.; Otani, T.; Minami, Y.; Yoshida,
K. Tetrahedron Lett. 1993, 34, 4079-4082. (b) Iida, K.; Hirama, M. J.
Am. Chem. Soc. 1995, 117, 8875-8876. (c) Sato, I.; Toyama, K.; Kikuchi,
T.; Hirama, M. Synlett 1998, 1308-1310. (d) Sato, I.; Akahori, Y.; Sasaki,
T.; Kikuchi, T.; Hirama, M. Chem Lett. 1999, 867-868. (e) Sato, I.; Kikuchi,
T.; Hirama, M. Chem. Lett. 1999, 511-512. (f) Sasaki, T.; Inoue, M.;
Hirama, M. Tetrahedron Lett. 2001, 42, 5299-5303. (g) Inoue, M.; Kikuchi,
T.; Hirama, M. Tetrahedron Lett. 2004, 45, 6439-6442.
(13) Total syntheses of natural products with bicyclo[7.3.0]dodecadiyne
strucures have been reported. N-1999-A2: (a) Kobayashi, S.; Ashizawa,
S.; Takahashi, Y.; Sugiura, Y.; Nagaoka, M.; Lear, M. J.; Hirama, M. J.
Am. Chem. Soc. 2001, 123, 11294-11295. Neocarzinostatin chro-
mophore: (b) Myers, A. G.; Liang, J.; Hammond, M.; Harrington, P. M.;
Wu, Y.; Kuo, E, Y. J. Am. Chem. Soc. 1998, 120, 5319-5320. (c) Myers,
A. G.; Glatthar, R.; Hammond, M.; Harrington, P. M.; Kuo, E. Y.; Liang,
J.; Schaus, S. E.; Wu, Y.; Xiang, J.-N. J. Am. Chem. Soc. 2002, 124, 5380-
5401.
(14) For recent synthetic studies of the other enediyne natural products
from this laboratory, see the following. Neocarzinostatin chromophore: (a)
Toyama, K.; Iguchi, S.; Sakazaki, H.; Oishi, T.; Hirama, M. Bull. Chem.
Soc. Jpn. 2001, 74, 997-1008. Kedarcidin: (b) Yoshimura, F.; Kawata,
S.; Hirama, M. Tetrahedron Lett. 1999, 40, 8281-8285. (c) Lear, M. J.;
Yoshimura, F.; Hirama, M. Angew. Chem., Int. Ed. 2001, 40, 946-949.
(d) Ohashi, I.; Lear, M. J.; Yoshimura, F.; Hirama, M. Org. Lett. 2004, 6,
719-722. Maduropeptin: (e) Kato, N.; Shimamura, S.; Khan, S.; Takeda,
F.; Kikai, Y.; Hirama, M. Tetrahedron 2004, 60, 3161-3172. (f) Kato, N.;
Shimamura, S.; Kikai, Y.; Hirama, M. Synlett In press, and references
therein.
(15) For other syntheses of bicyclo[7.3.0]dodecadiyne structures, see:
(a) Wender, P. A.; Harmata, M.; Jeffery, D.; Mukai, C.; Suffert, J.
Tetrahedron Lett. 1988, 29, 909-912. (b) Wender, P. A.; McKinney, J.
A.; Mukai, C. J. Am. Chem. Soc. 1990, 112, 5369-5370. (c) Myers, A. G.;
Harrington, P. M.; Kuo, E. Y. J. Am. Chem. Soc. 1991, 113, 694-695. (d)
Doi, T.; Takahashi, T. J. Org. Chem. 1991, 56, 3465-3467. (e) Magnus,
P.; Carter, R.; Davies, M.; Elliott, J.; Pitterna, T. Tetrahedron 1996, 52,
6283-6306. (f) Tanaka, H.; Yamada, H.; Matsuda, A.; Takahashi, T. Synlett
1997, 381-383. (g) Caddick, S.; Delisser, V. M.; Doyle, V. E.; Khan, S.;
Avent, A. G.; Vile, S. Tetrahedron 1999, 55, 2737-2754. (h) Myers, A.
G.; Hogan, P. C.; Hurd, A. R.; Goldberg, S. D. Angew. Chem., Int. Ed.
2002, 41, 1062-1066 and references therein.
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Nicolaou, K. C.; Dai, W.-M. Angew. Chem., Int. Ed. Engl. 1991, 30, 1387-
1416. (b) Danishefsky, S. J.; Shair, M. D. J. Org. Chem. 1996, 61, 16-44.
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(18) Iida, K.; Hirama, M. J. Am. Chem. Soc. 1994, 116, 10310-10311.
3834
Org. Lett., Vol. 6, No. 21, 2004

Scheme 2
via deoxygenation of epoxide 6,19 which in turn would be
nine-membered diyne 5 as the sole isomer in 98% yield.
After derivatization of 5 to its mesylate 17 (78% yield), the
desired trans relationship of the C4- and C5-hydroxy groups
was unambiguously determined by the NOE experiment.
formed from the protected C4,C5-trans-diol 5. Although
epoxide deoxygenation has been demonstrated with various
substrates in the context of natural product synthesis, the
feasibility of this reaction, particularly given the highly
unsaturated and strained structure of 6, was uncertain.
Synthesis of diyne 5 started with the previously published
intermediate 817 (Scheme 2). First, CsF-promoted addition12e,20
of phenol to epoxide 8 produced the aryl ether 9 in 83%
yield. The tertiary alcohol of 9 was converted into TES ether
10, and then a TMS group was introduced to the terminal
acetylene to afford 11 in 91% yield over two steps.
Sonogashira coupling21 of 11 and acetylene moiety 1212f in
the presence of catalytic Pd2(dba)3 and CuI led to adduct
13. The acetylenic TMS of 13 was selectively removed in
the presence of the O-TES groups using TBAF at -78 °C
to generate 14 in 63% yield over two steps. Removal of the
DMTr group from 14 using ZnBr2, followed by Dess-Martin
oxidation (88% yield),22 afforded aldehyde 16 in 71% yield.
Next, cyclization of 16 was promoted by a 1:1 mixture of
LiN(TMS)2 and CeCl3 in THF,18 giving rise to the strained
After successful synthesis of the nine-membered diyne,
we turned our attention to epoxide formation at C4-C5 and
olefination at C10-C11. Selective deprotection of the MOM
group in the presence of other potentially reactive protective
groups (MPM and TES) was achieved using Me2BBr23 in
CH2Cl2 at -90 °C, which resulted in alcohol 18 in 88% yield.
TBAF treatment of bis-TES ether 18 under carefully
controlled temperature conditions (-60 to -50 °C) led to
chemoselective deprotection of the C4-OTES and concomi-
tant epoxide formation to afford 19 in 86% yield.13a
Dehydration of allylic alcohol 19 turned out to be no easy
task. Introduction of the leaving group to 19 did not in-
duce anti elimination but typically resulted in decompo-
sition. We therefore decided to utilize an arylselenoxide
derivative, which could produce the olefin through syn
elimination in neutral conditions. Treatment of R-alcohol 19
with 2-nitrophenyl selenocyanate and tributylphosphine in
THF24 produced â-selenide 20 through SN2 displacement.
The resultant 20 was oxidized with hydrogen peroxide at
room temperature to afford the desired cyclopentadiene 6 in
73% yield over two steps. Fortunately, the syn elimination25
was predominant over the [2,3]-sigmatropic rearrangement
(19) For reviews, see: (a) Sonet, P. E. Tetrahedron 1980, 36, 557-604.
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8, pp 871-893.
(20) Kawata, S.; Hirama, M. Tetrahedron Lett. 1998, 39, 8707-8710.
(21) (a) Sonogashira, K.; Tohda, Y.; Hagiwara, N. Tetrahedron Lett.
1975, 16, 4467-4470. (b) Sonogashira, K. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: London, 1990; Vol.
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(23) Guindon, Y.; Yoakim, C.; Morton, H. E. J. Org. Chem. 1984, 49,
3912-3920.
(22) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-
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(24) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41,
1485-1486.
Org. Lett., Vol. 6, No. 21, 2004
3835

of C11-selenoxide 21 to C1,26 presumably as a result of the
pseudoequatorial orientation of the selenoxide and/or the
unfavorable energy loss through deconjugation of the eneyne
(C12-C1/C2-C3).
The last reaction of this model study was deoxygenation
from epoxide 6 (Scheme 3). To isolate the target product 7,
to olefins, were applied to 6. However, treatment of epoxide
6 with Cp2TiCl only produced propargyl alcohol 22 (10%
yield), which arose from C4-O cleavage and subsequent
reduction at C4.31 SmI2-mediated reduction of 6 proceeded
smoothly, but the undesired exo-olefin 24 was isolated in
51% yield. In this reaction, elimination of the C13-OMPM
in organosamarium intermediate 23 preceded elimination of
the samarium alkoxide at C5 that would lead to the desired
product 7.32
The conditions reported by Sharpless (WCl6/n-BuLi) were
found to generate the targeted bicyclo[7.3.0]dodecatrienediyne
7. Upon exposure of 6 to low-valent tungsten in deuterated
THF, epoxide deoxygenation took place at room temperature,
and the exceedingly labile enediyne 7 was isolated in 10%
yield (1H NMR determination) after rapid purification with
HPLC (silica gel, 5% EtOAc/hexane). In ethanol, 7 was
quickly transformed to aromatized compound 25. The half-
life of 7 in deuterated dichloromethane was 35 min at 25
°C, which is even shorter than that of the natural product 17
and the previously synthesized nine-membered enediyne
compound.12,33
Scheme 3. Synthesis of Bicyclo[7.3.0]dodecatrienediyne
through Deoxygenation
In summary, this study has resulted in the first synthesis
of the highly reactive bicyclo[7.3.0]dodecatrienediyne core
of the C-1027 chromophore 1. By virtue of its neutral nature
and high chemoselectivity, the synthetic route described here
would be applicable for the total synthesis of 1 from its
framework 4. In addition to the effective service for the
C-1027 chromophore synthesis, the present deoxygenation
strategy represents a potentially general solution to the
problem of the enediyne syntheses. Application of the present
methodology to 1 and other molecules is currently underway
in our laboratory.
Acknowledgment. This work was supported by CREST,
Japan Science and Technology Agency (JST). A fellowship
to T.S. from the Japan Society for the Promotion of Science
(JSPS) is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for selected compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
deoxygenation of 6 should be faster than the Masamune-
Bergman reaction of the resultant enediyne. For this purpose,
three powerful but mild metal reductants (Cp2TiCl,27 SmI2,28
and WCl4/n-BuLi29,30), which are known to reduce epoxides
OL048494I
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