Total synthesis of a protected aglycon of the kedarcidin chromophore

Article abstract of DOI:10.1002/anie.200805518

(Chemical Equation Presented) Strong support for the recently proposed structure of the kedarcidin chromophore has been obtained through the convergent synthesis of the aglycon. The key features of the synthesis are an efficient assembly of the four fragm

Full text of DOI:10.1002/anie.200805518

Communications
DOI: 10.1002/anie.200805518
Natural Products
Total Synthesis of a Protected Aglycon of the Kedarcidin
Chromophore**
Kouki Ogawa, Yasuhito Koyama, Isao Ohashi, Itaru Sato, and Masahiro Hirama*
The proposed structure for the chromophore of the chromo-
protein enediyne antitumor antibiotic kedarcidin[1,2] has
undergone several revisions because of its high reactivity
and complex architecture. The structure of the kedarcidin
chromophore was first proposed by scientists at Bristol-Myers
Squibb in 1992.[3] Subsequently, the a-azatyrosyl fragment of
the ansa-bridge was revised to the corresponding b-amino
acid derivative, and the absolute structure of the whole
molecule was updated as 1 in 1997.[4] In 2007, Myers and co-
workers completed the formidable total synthesis of 1, upon
and chemoselective SmI2-mediated reductive elimination of
1,2-diol derivatives,[7,8] which was applicable to the construc-
tion of the epoxybicyclo[7.3.0]dodecadienediyne core of 1,
enabling the formation of the epoxide moiety during the early
stages of the synthesis.[9] The application of our strategy
towards the synthesis of the aglycon fragment 24 of 2, which
includes the highly functionalized macrolactone and an
epimeric alcohol at C10, needed to be investigated. Herein,
we describe the successful application of our novel conver-
gent strategy towards the synthesis of the protected aglycon
24; the synthesis features alkynyl epoxide 9 as a key fragment,
a nine-membered ring cyclization between C5 and C6, and a
SmI2-mediated reductive olefination in the presence of both
the C8–C9 epoxide and the highly functionalized ansa-
macrolide. The resulting product exhibited an NMR spectrum
that was consistent with that of the natural chromophore.
The key cyclopentene alkynyl epoxide 9 was prepared
from the previously reported optically pure 3 (Scheme 1).[10]
After the transformation of 3 into iodoenone 6,[11] the
stereoselective synthesis was carried out by using an allenyl
zinc methodology[12] to efficiently afford 9. According to the
protocol reported by Chemla et al. and Caddick and co-
workers, 3-chloro-1-trimethylsilylpropyne (7) was reacted
with zinc bromide and subsequent treatment with lithium
diisopropylaminde at low temperatures to form the allenyl
1
which, the H NMR data led to an additional revision of the
C10 stereochemistry as shown in structure 2 (Figure 1).[5]
Figure 1. Structure of the kedarcidin chromophore.
In previous reports, the construction of the C8–C9
epoxide of the kedarcidin chromophore in the presence of
the ansa-bridge proved to be difficult at the later stages of the
synthesis.[6] Recently, however, we have developed a facile
[*] K. Ogawa, Dr. Y. Koyama, Dr. I. Ohashi, Dr. I. Sato,
Prof. Dr. M. Hirama
Department of Chemistry, Graduate School of Science
Tohoku University, Sendai (Japan)
Fax: (+81)22-795-6566
E-mail: hirama@mail.tains.tohoku.ac.jp
Prof. Dr. M. Hirama
Research and Analytical Center for Giant Molecules
Graduate School of Science, Tohoku University
Sendai 980-8578 (Japan)
Scheme 1. Synthesis of alkynyl epoxide 9: a) BzCl (1.5 equiv), pyridine
(3.0 equiv), CH2Cl2, RT, 16 h; b) CH3CN/6m HCl (5:1), RT, 70 h, 57%
(2 steps); c) MnO2 (6.0 equiv), CH2Cl2, RT, 15 h; d) TBSOTf
(1.5 equiv), 2,6-lutidine (3.0 equiv), CH2Cl2, ꢀ708C, 1 h, 35% (2
steps); e) I2 (2.2 equiv), pyridine (3.3 equiv), THF, RT, 3 h, 100%; f) 7
(2.0 equiv), ZnBr2 (4.0 equiv), LiN(iPr)2 (4.0 equiv), THF, ꢀ788C!
ꢀ188C, 16 h; g) K2CO3 (3.0 equiv), MeOH, RT, 1 h, 51% (from 6).
Bz=benzoyl, MOM=methoxymethyl, TBS=tert-butyldimethylsilyl,
Tf =Trifluoromethanesulfonyl.
[**] This work was supported financially by a Grant-in-Aid for Specially
Promoted Research from the Ministry of Education, Culture, Sports,
Science, and Technology (MEXT), SORST (Japan), and the Science
and Technology Agency (JST). We are especially grateful to Dr.
John E. Leet at Bristol-Myers Squibb for kindly providing the
1H NMR spectra of the natural kedarcidin chromophore.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200805518.
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zinc reagent. Ketone 6 was then added to this reagent, and
subsequent methanolysis of the benzoate using K2CO3 in
MeOH, provided 9 almost exclusively in 51% overall yield
via the chlorohydrin intermediate 8. The stereochemistry of
the newly formed alkynyl epoxide 9 was confirmed on the
basis of NOE correlations between the protons on C8 and
C11. This remarkable stereochemical outcome can be attrib-
uted to a transition state that minimizes the steric interactions
between the substituents on the cyclopentenone ring
(C11 benzoate and C10 OTBS groups) and the chlorine
atom of the allenyl zinc.[12b]
The assembly of the four fragments is illustrated
in Scheme 2. The aryl ether bond between 9 and the
b-2-chloroazatyrosine derivative 10[4,10] was formed by using
a Mitsunobu reaction to afford 11 with stereochemical
inversion.[13] Upon protection of the alkyne terminus of 11
with a TMS group (82% yield), alkenyl iodide 12 and alkyne
13[14] were coupled by using a Sonogashira coupling[15] to
afford 14. The selective removal of the TMS group using
TBAF at low temperature afforded 15 in 71% yield (two
steps). Alkaline hydrolysis of the methyl ester of 15 and
subsequent macrolactonization of the corresponding carbox-
ylic acid and the primary alcohol was effectively achieved by
using the protocol reported by Shiina et al.[16] to give 16 as a
single atropisomer in 62% yield (two steps). The stereo-
chemistry of 16 was determined by NOESY correlations
between the protons at C8 and C4’ (Figure 2a). The remain-
ing tertiary alcohol of 16 was protected by using a TES group
and the Boc group of 17 was removed by using TBSOTf and
2,6-lutidine[17] without affecting the reactive epoxide to yield
free amine 18. Compound 18 was then immediately con-
densed with naphthoic acid 19[10] to give amide 20 in 71%
overall yield.
The next step in our synthetic methodology was the
cyclization, in the presence of the highly functionalized ansa-
macrolide bridge, to form a nine-membered diyne ring. We
have previously encountered severe difficulties in forming the
nine-membered ring by bond formation between C7 and C8
Scheme 2. Total synthesis of protected aglycon of kedarcidin chromophore: a) 10 (1.0 equiv), DEAD (1.3 equiv), Ph3P (1.3 equiv), benzene, 08C,
1 h, 67%; b) TMSCl (20.0 equiv), LiN(TMS)2 (22.5 equiv), THF, ꢀ608C, 20 min, 82%; c) 13 (1.5 equiv), CuI (0.4 equiv), Pd(PPh3)4 (0.1 equiv),
iPr2NEt (3.0 equiv), DMF, RT, 1 h; d) TBAF (1.2 equiv), THF, ꢀ708C, 30 min, 71% (2 steps); e) 0.3m aq. KOH (2.7 equiv), THF/MeOH (2:1), RT,
5 h; f) m-nitrobenzoic anhydride (2.5 equiv), DMAP (5.0 equiv), CH2Cl2, reflux, 20 h, 62% (2 steps); g) TESCl (3.0 equiv), imidazole (6.0 equiv),
DMF, RT, 1 d; h) TBSOTf (6.0 equiv), 2,6-lutidine (8.0 equiv), CH2Cl2, ꢀ508C, 30 min to 08C, 1 h; i) SiO2, CH2Cl2, RT, 20 h; j) 19 (1.0 equiv),
EDC·HCl (5.0 equiv), HOAt (5.2 equiv), CH2Cl2, RT, 23 h, 71% overall yield (from 16); k) DDQ (10.0 equiv), CH2Cl2/H2O (5:1), RT, 1.5 h; l) Dess–
Martin periodinane (3.0 equiv), NaHCO3 (9.0 equiv), CH2Cl2, RT, 1 h, 95% (2 steps); m) CeCl3 (26.5 equiv), LiN(TMS)2 (25.1 equiv), THF, ꢀ308C,
20 min, 61%; n) TBAF (2.0 equiv), THF, ꢀ788C; o) Ms2O (3.0 equiv), pyridine (6.0 equiv), CH2Cl2, 08C, 20 min; p) TFBzCl (10.0 equiv), DMAP
(20.0 equiv), CH2Cl2, 08C, 6 min, 35% (3 steps); q) SmI2 (1.5 equiv), THF, ꢀ208C, 8 min, 57%. Boc=tert-butoxycarbonyl, DEAD=diethyl
azodicarboxylate, TMS=trimethylsilyl, NAP=2-naphtylmethyl, TBAF=tetra-n-butylammonium fluoride, TES=triethylsilyl, DMAP=N,N-4-
dimethylaminopyridine, EDC=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, HOAt=1-hydroxy-7-azabenzotriazole, DDQ=2,3-dichloro-5,6-
dicyano-1,4-benzoquinone, TFBz=4-trifluoromethylbenzoyl.
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Figure 2. a) NOESY correlation (400 MHz 1HNMR instrument) for 16),
Scheme 3. Spontaneous Masamune–Bergmann cycloaromatization of
24.
and b) ROESY (600 MHz 1HNMR instrument) for 22 (b).
and therefore attempted another route.[6] The cyclization
precursor 21 was effectively obtained in 95% yield (two
steps) by the selective removal of the NAP protecting group
of the primary alcohol at C5 using excess DDQ under mild
conditions[18] and subsequent Dess–Martin oxidation.[19] The
cyclization 21 was carried out by using the CeCl3/LHMDS-
mediated protocol[20] at ꢀ308C to generate unstable 22 in
61% yield; during the cyclization in the TES group migrated
to the newly formed secondary alcohol at C5. This acetylide/
aldehyde condensation to form a bond between C5 and C6
proved to be an efficient and practical scheme.[21] The
configuration of the cis-C4,C5-diol 22, including the single
atropisomerism, was unambiguously determined by using
ROESY experiments (Figure 2b). Notably, cyclized com-
pounds that possess free hydroxy groups on the nine-
membered cyclic core, such as 22, require careful treatment
because of their instability at ambient temperatures.
on C10 and C4’, and the presence of a strong NOE between
the protons on C10 and C11, as well as their coupling constant
(J = 6.0 Hz), were consistent with the data reported for the
reduction-induced aromatized compound derived from the
natural chromophore.[3b] The results of our spectroscopic
studies strongly support the recently revised stereochemical
structure as proposed by Myers and co-workers.[5]
In summary, we have developed an enantioselective
synthetic route for the protected aglycon of kedarcidin
chromophore with the revised stereochemistry at C10.[23]
The key features of our methodology are: 1) the efficient
convergent assembly of four fragments (Scheme 2), 2) a novel
strategy involving alkynyl epoxide 9 as a key fragment, 3) a
cerium amide promoted nine-membered diyne ring cycliza-
tion between C5 and C6, and 4) a SmI2-mediated reductive
1,2-elimination for the chemoselective olefination in the
presence of the C8–C9 epoxide and the highly functionalized
ansa-macrolide. Additional studies on the total synthesis of
chromophore 2 are currently underway in our laboratory.
Lastly, the most uncertain step involved the final reductive
1,2-elimination of the C4,C5-diol of 22 to complete the highly
functionalized ansa-bridged nine-membered epoxyenediyne
structure. Upon removal of the TES group of the 22 using
TBAF at ꢀ788C, the resulting highly labile diol was imme-
diately mesylated, and then quickly treated with 4-trifluoro-
methylbenzoyl chloride and DMAP at 08C to provide 23 in a
moderate yield. Subsequently, 23 was subjected to a SmI2-
mediated 1,2-elimination at ꢀ208C for eight minutes to yield
the protected aglycon fragment 24 of the kedarcidin chromo-
phore as a single atropisomer in 57% yield. Again, the
elimination reaction was remarkable in terms of high chemo-
selectivity and compatibility with the functional groups
present.[7,9] The resulting unstable aglycon 24 underwent
spontaneous cycloaromatization without chemical activa-
tion,[3a] in 1,4-cyclohexadiene and benzene (1:1), to give
aromatized 25 via an equilibrated p-benzyne biradical inter-
mediate (Scheme 3).[22]
Received: November 12, 2008
Published online: December 29, 2008
Keywords: antitumor agents · chromophores · cyclization ·
.
enediynes · total synthesis
[1] K. S. Lam, G. A. Hesler, D. R. Gustavson, A. R. Crosswell, J. M.
Veitch, S. Forenza, K. Tomita, J. Antibiot. 1991, 44, 472.
[2] For reviews, see: a) A. L. Smith, K. C. Nicolaou, J. Med. Chem.
1996, 39, 2103; b) Z. Xi, I. H. Goldberg in Comprehensive
Natural Product Chemistry, Vol. 7 (Eds.: D. H. R. Barton, K.
Nakanishi), Pergamon, Oxford, 1999, p. 553.
[3] a) J. E. Leet, D. R. Schroeder, S. J. Hofstead, J. Golik, K. L.
Colson, S. Huang, S. E. Klohr, T. W. Doyle, J. A. Matson, J. Am.
Chem. Soc. 1992, 114, 7946; b) J. E. Leet, D. R. Schroeder, D. R.
Langley, K. L. Colson, S. Huang, S. E. Klohr, M. S. Lee, J. Golik,
S. J. Hofstead, T. W. Doyle, J. A. Matson, J. Am. Chem. Soc.
1993, 115, 8432; J. E. Leet, D. R. Schroeder, D. R. Langley, K. L.
Colson, S. Huang, S. E. Klohr, M. S. Lee, J. Golik, S. J. Hofstead,
T. W. Doyle, J. A. Matson, J. Am. Chem. Soc. 1994, 116, 2233.
[4] S. Kawata, S. Ashizawa, M. Hirama, J. Am. Chem. Soc. 1997, 119,
12012.
1
The H NMR spectra of synthetic 24 were compared to
those of the natural chromophore. The observed coupling
constants for the protons on C10 and C11 (J = 5.6 Hz), and on
C11 and C12 (J = 2.8 Hz) of 24 in CDCl3 were similar to those
of the authentic kedarcidin chromophore (generously pro-
vided by Dr. John E. Leet).[3] Moreover, the chemical shifts of
the protons on C10, C11, and C12 of 24 were comparable to
those of the authentic compound (see the Supporting
Information) while the synthetic compound 24 is a protected
aglycon. For 25, the absence of an NOE between the protons
[5] F. Ren, P. C. Hogan, A. J. Anderson, A. G. Myers, J. Am. Chem.
Soc. 2007, 129, 5381.
[6] F. Yoshimura, M. J. Lear, I. Ohashi, Y. Koyama, M. Hirama,
Chem. Commun. 2007, 3057.
1112
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[7] a) K. Komano, S. Shimamura, M. Inoue, M. Hirama, J. Am.
Chem. Soc. 2007, 129, 14184; b) M. Inoue, I. Ohashi, T.
Kawaguchi, M. Hirama, Angew. Chem. 2008, 120, 1801;
Angew. Chem. Int. Ed. 2008, 47, 1777.
[8] For related reactions, see: a) J. M. Concellꢀn, H. Rodrꢁguez-
Solla, C. Simal, M. Huerta, Org. Lett. 2005, 7, 5833; b) A. S.
Kende, J. S. Mendoza, Tetrahedron Lett. 1990, 31, 7105; c) S.
Ihara, S. Suzuki, T. Taniguchi, Y. Tokunaga, K. Fukumoto,
Tetrahedron 1995, 51, 9873; d) I. E. Markꢀ, F. Murphy, L.
Kumps, A. Ates, R. Touillaux, D. Craig, S. Carballares, S. Dolan,
Tetrahedron 2001, 57, 2609.
[9] K. Ogawa, Y. Koyama, I. Ohashi, I. Sato, M. Hirama, Chem.
Commun. 2008, 6327.
[10] Y. Koyama, M. J. Lear, F. Yoshimura, I. Ohashi, T. Mashimo, M.
Hirama, Org. Lett. 2005, 7, 267.
[11] K. Toyama, S. Iguchi, H Sakazaki, T. Oishi, M. Hirama, Bull.
Chem. Soc. Jpn. 2001, 74, 997.
[12] a) F. Chemla, N. Bernard, F. Ferreira, J. F. Normant, Eur. J. Org.
Chem. 2001, 3295; b) J. R. Baker, O. Thominet, H. Britton, S.
Caddick, Org. Lett. 2007, 9, 45.
[16] a) I. Shiina, R. Ibuka, M. Kubota, Chem. Lett. 2002, 286; b) I.
Shiina, M. Kubota, H. Oshiumi, M. Hashizume, J. Org. Chem.
2004, 69, 1822.
[17] M. Sakaitani, Y. Ohfune, J. Org. Chem. 1990, 55, 870.
[18] a) J. Xia, S. A. Abbas, R. D. Locke, C. F. Piskorz, J. L. Alderfer,
K. L. Matta, Tetrahedron Lett. 2000, 41, 169; b) J. A. Wright, J.
Yu, J. B. Spencer, Tetrahedron Lett. 2001, 42, 4033.
[19] D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155.
[20] a) K. Iida, M. Hirama, J. Am. Chem. Soc. 1994, 116, 10310. Also
see: b) A. G. Myers, P. M. Harrington, E. Y. Kuo, J. Am. Chem.
Soc. 1991, 113, 694; c) T. Nishikawa, M. Isobe, T. Goto, Synlett
1991, 393.
[21] a) I. Sato, T. Toyama, T. Kikuchi, M. Hirama, Synlett 1998, 1308;
b) M. Inoue, S. Hatano, M. Kodama, T. Sasaki, T. Kikuchi, M.
Hirama, Org. Lett. 2004, 6, 3833; c) M. Inoue, T. Kikuchi, M.
Hirama, Tetrahedron Lett. 2004, 45, 6439.
[22] a) K. Iida, M. Hirama, J. Am. Chem. Soc. 1995, 117, 8875;
b) A. G. Myers, A. R. Hurd, P. C. Hogan, J. Am. Chem. Soc.
2002, 124, 4583.
[23] For glycosylation, see: a) M. J. Lear, F. Yoshimura, M. Hirama,
Angew. Chem. 2001, 113, 972; Angew. Chem. Int. Ed. 2001, 40,
946; b) I. Ohashi, M. J. Lear, F. Yoshimura, M. Hirama, Org.
Lett. 2004, 6, 719; c) F. Ren, P. C. Hogan, A. J. Anderson, A. G.
Myers, Org. Lett. 2007, 9, 1923.
[13] O. Mitsunobu, Synthesis 1981, 1.
[14] See the Supporting Information.
[15] K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett. 1975,
16, 4467.
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