Total synthesis and structure revision of the (-)-maduropeptin chromophore

Article abstract of DOI:10.1021/ja905397p

(Chemical Equation Presented) The proposed structure of the maduropeptin chromophore, the biologically active component of the highly potent chromoprotein antitumor antibiotics, was stereoselectively synthesized but did not satisfy the spectra of the natu

Full text of DOI:10.1021/ja905397p

Published on Web 08/05/2009
Total Synthesis and Structure Revision of the (-)-Maduropeptin
Chromophore
Kazuo Komano,† Satoshi Shimamura,† Yutaro Norizuki,† Donglin Zhao,† Chizuko Kabuto,‡
Itaru Sato,*,‡ and Masahiro Hirama*,†,‡
Department of Chemistry, Graduate School of Science, Tohoku UniVersity, and Research and Analytical Center for
Giant Molecules, Graduate School of Science, Tohoku UniVersity, Sendai 980-8578, Japan
Received July 1, 2009; E-mail: isato@mail.tains.tohoku.ac.jp; hirama@mail.tains.tohoku.ac.jp
Maduropeptin, a novel member among the family of chromopro-
tein antitumor antibiotics, was isolated from the broth filtrate of
Actinomadura madurae by scientists at Bristol-Myers Squibb in
1991.1,2 The isolated chromophore 1 was composed of a unique
nine-membered diyne core and a glycoside side chain (Figure 1).
Although 1 is the methanol adduct of a structurally undefined labile
chromophore, it showed a DNA cleavage site selectivity similar to
that of holoprotein.1a Presumably, the activation mechanism of 1
is initiated by the formation of the highly strained nine-membered
enediyne ring via intramolecular SN2′ substitution of methanol by
the macrolactam nitrogen. To realize its biological activity, the
equilibrated p-benzyne biradical abstracts hydrogen atoms from
double-strand DNAs,3 whereas the glycoside side chain is essential
Figure 1. Structure of maduropeptin chromophore and its retrosynthesis.
for sequence-selective binding on the DNA.1 The highly function-
alized and complex architecture of chromophore 1 clearly presents
Scheme 1. Synthesis of 1
a daunting challenge to its chemical synthesis.4-6 In this com-
munication, we describe the total synthesis and the structural
revision of the (-)-maduropeptin chromophore.
The first phase in the total synthesis of the chromophore involves
the enantioselective synthesis of the protected aglycon 2 (Figure
1).4c Next, ꢀ-selective glycosylation of the tertiary alcohol derived
from 2 could be carried out following the Schmidt protocol.
Trichloroacetimidate donor 3 could be prepared from lactone 4,
which has been previously reported by Nicolaou and co-workers.5d
Careful transformation of 2, which was prepared from 5,4c,7 into
the desired glycosyl acceptor 7 is outlined in Scheme 1. Removal
of the acetonide group, followed by selective protection of the
secondary hydroxyl group as the benzoate, gave 6 in 93% yield
(2 steps). Benzoyl protection of the C10 hydroxyl group was
necessary to prevent the deterioration of the nine-membered diyne
core during the subsequent removal of the methoxymethyl (MOM)
laou’s procedure.5d Lactone 4 was readily converted to trichloro-
group. It should be noted that 6 was obtained as a mixture of
atropisomers: although the isomers are chromatographically sepa-
rable, the separated isomers reverted to an equilibrium mixture of
the isomers within several hours at rt.4c,8 The ratio of the isomers
was strongly influenced by the polarity of the solvent. In CDCl3,
the ratio between the natural and unnatural atropisomers was found
acetoimidate 3 as a single anomer (JH1′′-H2′′ ) 6.6 Hz) via DIBAL
reduction followed by treatment with CCl3CN and DBU.
Glycosylation of the C9 tertiary hydroxyl group of 7 in CH2Cl2
using TMSOTf as a Lewis acid proceeded smoothly, to afford axial
glycoside 8 in 40% yield,9 without the formation of the anomeric
isomer or the migration of the benzoyl group. Based on the
relatively small 1H NMR coupling constants between H1′′ and H2′′
(JH1′′-H2′′ ) 1.3 or 2.2 Hz in CDCl3 for two atropisomers,
respectively), and the corresponding ROESY experiments, the
pyranose ring of 8 was determined to adopt a flipped chair
conformation in relation to that of 3. NOE correlations between
the protons of the C3′′ methyl group with H2′′, H4′′, and axial
H5′′ suggest that C3′′ methyl exists in the axial position. This
conformational change can be attributed to the steric repulsion
between the C10 benzoate and the C2′′ OTES groups. Finally, after
removal of both benzoyl groups of 8 by DIBAL reduction, all the
TES ethers were cleaved by treatment with Bu4NF to complete the
1
to be 4.5:1 using H NMR analysis. The MOM group of 6 was
removed by treatment with 4 M H2SO4/MeOH at rt. Protection of
the resulting benzylic hydroxyl group as the benzoate provided
glycosyl acceptor 7 in 30% yield (2 steps and after 2 cycles of the
reaction). Although the macrolactam of 7 still exhibited atropi-
somerism, the natural form was dominant in CD3OD, as confirmed
using NOE experiments.
Glycosyl donor 3 was then prepared from known lactone 4, which
was enantioselectively prepared from L-serine according to Nico-
† Department of Chemistry.
‡ Research and Analytical Center for Giant Molecules.
9
12072 J. AM. CHEM. SOC. 2009, 131, 12072–12073
10.1021/ja905397p CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Total Synthesis of the (-)-Maduropeptin Chromophore
A fellowship to K.K. from the Japan Society for the Promotion of
Science (JSPS) is gratefully acknowledged. We also thank Dr. John
E. Leet at Bristol-Myers Squibb for kindly providing the 1H NMR
spectra of the natural maduropeptin chromophore.
Supporting Information Available: Detailed experimental proce-
dures and spectroscopic data (1H and 13C NMR, FT-IR, and MS spectra)
for all new compounds, and X-ray crystallographic analysis data of 5.
This material is available free of charge via the Internet at http://
pubs.acs.org.
References
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total synthesis of 1. In CH2Cl2, 1 exhibited atropisomerism that
resulted in an equilibrium mixture of isomers at rt (detected by
TLC analysis). Fortunately, in polar solvents such as CD3OD or
DMSO-d6, 1 existed exclusively as the natural-type atropisomer.
(3) For the structure and reactivities of nine-membered enediynes, see: (a)
Hirama, M.; Akiyama, K.; Das, P.; Mita, T.; Lear, M. J.; Iida, K.; Sato, I.;
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(4) For synthetic studies of maduropeptin chromophore from our laboratories,
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2008, 5372. (b) Iso, K.; Inoue, M.; Kato, N.; Hirama, M. Chem. Asian J.
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Chem. Soc. 2007, 129, 14184. (d) Kato, N.; Shimamura, S.; Kikai, Y.;
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Takeda, F.; Kikai, Y.; Hirama, M. Tetrahedron 2004, 60, 3161. (f) Khan,
S.; Kato, N.; Hirama, M. Synlett 2000, 1494.
(5) For synthetic studies of maduropeptin chromophore from other laboratories,
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Nishimoto, S. J. Org. Chem. 1999, 64, 682. (b) Roger, C.; Grierson, D.
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1
Upon closer inspection, however, the H and 13C NMR spectra
of synthetic 1 were found to differ from those of the natural product.
1
In the case of H NMR, the differences (|∆δ| > 0.1 ppm) were
observed for the signals corresponding to the C9 glycoside (H10,
H1′′, and H5′′, see Supporting Information). Significant downfield
shifts (∆δ ) +1.33 and +2.42 ppm) were observed for the two
exchangeable protons of synthetic 1 (C10-OH and C2′′-OH,
respectively) that can be attributed to intramolecular hydrogen
bonding. Consequently, the proposed structure of the natural
chromophore of maduropeptin was revised as structure 1′, which
possesses the antipodal madurosamine moiety.
The synthesis of chromophore 1′ is shown in Scheme 2.
Stereoselective glycosylation using enantiomeric sugar moiety ent-
3, which was derived from D-serine, was conducted under Lewis
acidic conditions (30% yield based on 50% recovery of 7).
Deprotection of the benzoyl group of 9 with DIBAL, followed by
the removal of all TES groups by Bu4NF in THF, afforded the
desired chromophore 1′. Although atropisomeric equilibration was
also observed for synthetic 1′, the natural type isomer was
(6) For the structures of related chromoprotein antibiotics, C-1027, see: (a)
Iida, K.; Fukuda, S.; Tanaka, T.; Hirama, M.; Imajo, S.; Ishiguro, M.;
Yoshida, K.; Otani, T. Tetrahedron Lett. 1996, 37, 4997. (b) Iida, K.; Ishii,
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34, 4079. (c) Yoshida, K.; Minami, Y.; Azuma, R.; Saeki, M.; Otani, T.
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Y.; Ohashi, I.; Sato, I.; Hirama, M. Angew. Chem., Int. Ed. 2009, 48, 1110.
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Chem. Soc. 1997, 119, 12012. (g) Leet, J. E.; Schroeder, D. R.; Hofstead,
S. J.; Golik, J.; Colson, K. L.; Huang, S.; Klohr, S. E.; Doyle, T. W.;
Matson, J. A. J. Am. Chem. Soc. 1992, 114, 7946.
1
predominant in DMSO-d6. H and 13C NMR spectra, as well as
HRMS and NOE correlations, were in good agreement with those
of the natural product.
(7) The structure and absolute configuration of 5 was determined by X-ray
crystallographic analysis (see Supporting Information).
In summary, the first total synthesis and structure revision of
(-)-maduropeptin chromophore were successfully accomplished.
Our studies involved the synthesis and characterization of 1 and
its diastereomer 1′ possessing the antipodal madurosamine. The
spectroscopic data of 1′ were in good agreement with those of the
natural product. The absolute structure of the chromophore,
however, remains yet to be determined.10,11
(8) (a) Oki, M. Top. Stereochem. 1983, 14, 1. (b) Oki, M. The Chemistry of
Rotational Isomers; Hafner, K.; Lehn, J.-M.; Rees, C. W.; Schleyer, P.
von R.; Trost, B. M.; Zahradn´ık, R., Eds.; Springer-Verlag: Berlin, 1993.
(c) Myers, A. G.; Hurd, A. R.; Hogan, P. C. J. Am. Chem. Soc. 2002, 124,
4583.
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Angew. Chem., Int. Ed. Engl. 1986, 25, 212.
(10) NMR spectra were kind gifts from Dr. John E. Leet (Bristol-Myers Squibb);
we were informed that any data relating to the chirality, such as [R]D and
CD, for the chromophore and/or degraded products are currently not
available.1b
Acknowledgment. This work was financially supported by a
Grant-in-Aid for Specially Promoted Research from the Ministry
of Education, Culture, Sports, Science, and Technology (MEXT),
and by SORST, Japan Science and Technology Agency (J.S.T.).
(11) For a discussion from a view of the hypothetical biosynthetic pathway,
see: Van Lanen, S. G.; Oh, T.-j.; Liu, W.; Wendt-Pienkowski, E.; Shen, B.
J. Am. Chem. Soc. 2007, 129, 13082.
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