Total synthesis of the C-1027 chromophore core: Extremely facile enediyne formation through SmI2-mediated 1,2-elimination

Article abstract of DOI:10.1002/anie.200704842

(Chemical Equation Presented) The spontaneous aromatization of the enediyne chromophore of the potent antitumor agent C-1027 generates a p-benzyne biradical, which cleaves double-stranded DNA. The title reaction was developed for the construction of nine-membered-ring enediynes and applied as the final step in the synthesis of the exceptionally unstable core structure of the C-1027 chromophore (see scheme; Boc, MOM, MPM, and TES are protecting groups; Ms=methanesulfonyl).

Full text of DOI:10.1002/anie.200704842

Angewandte
Chemie
DOI: 10.1002/anie.200704842
Natural Product Synthesis
Total Synthesis of the C-1027 Chromophore Core: Extremely Facile
Enediyne Formation through SmI2-Mediated 1,2-Elimination**
Masayuki Inoue,* Isao Ohashi, Teruko Kawaguchi, and Masahiro Hirama*
The antitumor antibiotic C-1027[1] is a complex between the
ism.We reported previously the synthesis of the framework 7
(Scheme 2) by a route that featured atropselective macro-
cyclization prior to the formation of the nine-membered
ring.[6] Herein we describe the design and development of new
and effective methodology for the construction of enediyne
structures.This approach enabled the first synthesis of the
exceedingly unstable core structure of the chromophore 1.[7]
The synthesis of the nine-membered enediyne ring 14
from diyne 7 required the highly chemoselective formation of
the C4,C5 alkene from the protected C4,C5,C13,C14-tetraol
structure in the presence of other sensitive functionalities
(Scheme 2).Moreover, to isolate the targeted compound 14 in
reasonable yield before its self-degradation through rear-
rangement, the reductive 1,2-elimination reaction needed to
be complete within 10 min below room temperature.[8] The
olefination was unsuccessful when existing methodologies
were used, including our own,[9] so we sought alternative
reaction conditions and substrates.
reactive chromophore 1 (Scheme 1) and an apoprotein.[2] The
Scheme 1. Structure of the C-1027 chromophore and its Masamune–
Bergman rearrangement.
Model experiments with 4 revealed that an SmI2-mediated
elimination reaction[10] had significant potential for the
formation of enediynes (Table 1).[11] The acyclic enediyne 5
was generated efficiently in the presence of SmI2 in THF from
the dimesylate 4a (Table 1, entry 1); however, the reaction
was faster for the dibenzoate 4b (Table 1, entry 2).The
reactivity of dibenzoate substrates was found to be highly
sensitive to the substituents on the benzene rings (Table 1,
entries 2–5): The reaction was slower when an electron-
donating methoxy group was present (Table 1, entry 3) and
chromophore 1 is responsible for DNA recognition and
damage, and the apoprotein functions as an effective drug-
delivery system.As the free chromophore, 1 is the most labile
enediyne studied to date:[3,4] It is transformed into 3 in 82%
yield by Masamune–Bergman rearrangement and subsequent
hydrogen abstraction (ethanol, 258C) with a half-life of
50 min.[5] In a biological setting, the p-benzyne biradical 2
abstracts hydrogen atoms from DNA in a sequence-selective
manner to cause oxidative double-strand cleavage.
The structure of 1 is highly unusual.Its complicated fused-
ring system comprises a cyclopentadiene ring, a nine-mem-
bered enediyne ring, and a chlorocatechol-containing 17-
membered macrolactone that displays nonbiaryl atropisomer-
Table 1: SmI2-mediated 1,2-elimination reaction.
[*] Prof. Dr. M. Inoue
Graduate School of Pharmaceutical Sciences
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax: (+81)3-3395-5214
Entry
4
a
b
R1
R2
t
Yield [%]
1
2
Ms
Ms
2 h
94
80
E-mail: inoue@mol.f.u-tokyo.ac.jp
0.7 h
7 h
Dr. I. Ohashi, T. Kawaguchi, Prof. Dr. M. Hirama
Department of Chemistry
Graduate School of Science, Tohoku University
Sendai 980-8578 (Japan)
Fax: (+81)22-795-6566
E-mail: hirama@mail.tains.tohoku.ac.jp
3
4
5
6
c[a]
d
87
98
0.5 h
[**] This research was supported financially by SORST, Japan Science
and Technology Agency (JST). A fellowship to I.O. from the Japan
Society for the Promotion of Science (JSPS) is gratefully acknowl-
edged.
e
5 min 95
1 min 93
f
Ms
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
[a] The reaction mixture was warmed from 08C to room temperature.
Piv=pivaloyl, TMS=trimethylsilyl.
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significantly faster with an electron-withdrawing trifluoro-
methyl substituent (Table 1, entry 5).Remarkably, the trans-
formation of the mesylated mono-p-trifluoromethylbenzoate
4 f into 5 (Table 1, entry 6) took only 1 min.Thus, a facile 1,2-
elimination method was discovered by means of substrate
design.
A likely mechanism for the elimination reaction involves
expulsion of the benzoate group from the a-oxy benzylic
radical species generated upon SmI2-promoted carbonyl
reduction of the benzoate at C4, followed by reduction of
the resulting C4 radical to afford the organosamarium
intermediate 6.Elimination of the ester at C5 then delivers
the C4,C5 alkene 5 (Table 1).The
high reactivity of the electron-defi-
cient p-trifluoromethylbenzoates 4e
and 4 f reflects their potency in
accepting electrons from SmI2.For-
mation of the C4,C13 alkene from 6
was not observed, as the C5 benzoate
and mesylate groups in the sub-
strates are better leaving groups
than the OMPM group at C13.
Having developed a powerful olefination of the protected
tetraol 4, we turned our attention to the construction of the
cyclic enediyne structure with the macrolactone bridge
(Scheme 2).The prerequisites for reaching the final olefina-
tion step were judicious protecting-group manipulations and
the construction of the cyclopentadiene substructure in the
presence of the unstable nine-membered diyne.[6,12] Following
the conversion of the secondary alcohol 7 into its mesylate 8,
one MOM group (at the C11 hydroxy group) and one of the
two Boc groups on the amino group at C18 were removed
selectively to give 9 by treatment with Me2BBr in CH2Cl2 at
ꢀ808C.[13] The MOM ether at C23 remained intact under
these conditions, presumably as a result of the lower Lewis
basicity of the phenolic oxygen atom.The liberated allylic
alcohol in 9 underwent SN2 displacement in the presence of
o-nitrophenyl selenocyanate and tributylphosphine to form
the selenide 10,[14] which was oxidized with hydrogen peroxide
to afford the cyclopentadiene 11 through a smooth syn
elimination.Next, the C4 hydroxy group was deprotected
selectively by treatment with TBAF at ꢀ808C, and the
resulting tertiary alcohol 12 was subjected to benzoylation
with p-trifluoromethylbenzoyl chloride and DMAP to pro-
vide 13.Finally, the 1,2-elimination of 13 in [D8]THF in the
presence of SmI2 was complete within 5 min at 08C[15] to give
the C-1027 chromophore core 14 in 87% yield (as determined
by 1H NMR spectroscopy in CD2Cl2).This efficient trans-
formation demonstrates clearly the high chemoselectivity and
functional-group compatibility of the elimination reaction:
Potentially reactive functionalities, such as the doubly allylic
OTES group at C9 and the propargylic OAr moiety at C8,
remained untouched.
Scheme 2. Total synthesis of the C-1027 chromophore core: a) MsCl,
Et3N, CH2Cl2, 08C, 86%; b) Me2BBr, CH2Cl2, ꢀ808C, 89%; c) o-
NO2PhSeCN, nBu3P, THF, 08C!RT; d) H2O2, THF, room temperature,
54% (2 steps); e) TBAF, THF, ꢀ808C, 76%; f) p-CF3C6H4COCl, DMAP,
CH2Cl2, 08C, 99%; g) SmI2, [D8]THF, 08C, 5 min, 87%. Boc=tert-
butoxycarbonyl, DMAP=4-dimethylaminopyridine, MOM=methoxy-
methyl, MPM=p-methoxyphenylmethyl, Ms=methanesulfonyl,
TBAF=tetrabutylammonium fluoride, TES=triethylsilyl.
generated 16 (39%), without the MPM protecting group, in
addition to 15 (34%).We believe the alcohol 16 to originate
Surprisingly, 14, which has the same fused-ring system as
the natural product 1, appears to be significantly more labile
1
(t = ꢁ 20 min; CD2Cl2, 258C) than 1 and reacts rapidly in
2
ethanol.This unexpected physicochemical property
prompted us to investigate the cycloaromatization reaction
further (Scheme 3).The treatment of
14 with ethanol
Scheme 3. Possible reaction of 14 involving 1,5-hydrogen transfer.
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Angewandte
Chemie
[7] The total synthesis of the proposed structure of kedarcidin, a
from intramolecular 1,5-hydrogen abstraction by the phenyl
radical at C3 in 17 to form the better stabilized benzylic
radical 18,[16] followed by the addition of molecular oxygen
and oxidative cleavage.[4] This pathway would contribute to
the shorter half-life of 14 relative to that of 1, which has no
proximal hydrogen atoms in a 1,5-relationship with C3 or C6.
In summary, an extremely facile SmI2-mediated 1,2-
elimination was developed with p-trifluoromethylbenzoate
as an electron acceptor.This method enabled the synthesis of
the unusually labile C-1027 chromophore core in the form of
compound 14.The powerful yet mild nature of this method-
ology should enable access not only to the chromophore 1,
related enediyne natural products, and their analogues,[17] but
also to other natural and non-natural unsaturated compounds
with highly complex structures.
closely related enediyne chromophore, was completed recently
by an elegant strategy: a) F.Ren, P.C.Hogan, A.J.Anderson,
A.G. Myers, J. Am. Chem. Soc. 2007, 129, 5381; see also:
b) A.G. Myers, A.R. Hurd, P.C. Hogan,
J. Am. Chem. Soc.
2002, 124, 4583; c) A.G.Myers, P.C.Hogan, A.R.Hurd, S.D.
Goldberg, Angew. Chem. 2002, 114, 1104; Angew. Chem. Int. Ed.
2002, 41, 1062.
[8] The phosphine-mediated elimination of thiocarbonate groups
formed from cis 1,2-diols has been used to construct ten-
membered-ring enediyne analogues: a) M.F. Semmelhack, J.
Gallagher, Tetrahedron Lett. 1993, 34, 4121; b) D.Crick, A.B.
Pavlovic, D.J.Wink, Synth. Commun. 1999, 29, 359.However,
this method was not applicable to our substrate with a trans 1,2-
diol.Furthermore, the slow reaction rate is incompatible with
the less stable nine-membered-ring enediyne systems.
[9] M.Inoue, S.Hatano, M.Kodama, T.Sasaki, T.Kikuchi, M.
Hirama, Org. Lett. 2004, 6, 3833.
[10] For recent reviews of SmI2-mediated reactions, see: a) J.M.
Concellón, H.Rodríguez-Solla, Chem. Soc. Rev. 2004, 33, 599;
b) H.B.Kagan, Tetrahedron 2003, 59, 10351; c) G.A.Molander,
C.R.Harris, Chem. Rev. 1996, 96, 307.
Received: October 18, 2007
Published online: January 21, 2008
Keywords: antitumor agents · elimination · enediynes ·
ˇ
[11] For recent examples of related reactions, see: a) J.Pospís il, I.E.
.
natural products · reduction
Markó, J. Am. Chem. Soc. 2007, 129, 3516; b) J.M.Concellón, H.
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[15] The rate of cycloaromatization of nine-membered enediyne ring
systems depends on the solvent.Deuterated THF decelerated
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[17] The total synthesis of the maduropeptin aglycon was carried out
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