COMMUNICATIONS
mixture was stirred for 30 min. Methyl triflate (20 equiv) was added
dropwise, and the reaction mixture was warmed gradually to room
temperature and stirred for 5 h. Triethylamine (60 equiv) was added and
the reaction mixture stirred for 15 min. The polymer was filtered and
suspended in acetone in order to remove the molecular sieves. The polymer
was further washed with DMSO, acetone, CH2Cl2, and THF.
The Total Synthesis of Eleutherobin:
A Surprise Ending**
Xiao-Tao Chen, Bishan Zhou, Samit K. Bhattacharya,
Clare E. Gutteridge, Thomas R. R. Pettus, and
Samuel J. Danishefsky*
Analytical samples of the intermediates and the final product were cleaved
from the solid support following published procedures[12] and were purified
by flash column chromatography.
In memory of John K. Stille
1
10b: H NMR (CDCl3): d 7.89 (d, J 7.3 Hz, 2 H, SO2Ph), 7.46 (m, 1 H,
The ªeleuthesidesº comprise[1] a family of marine-derived
natural products that exhibit cytotoxic activity.[1, 2] Most
intriguing of these is eleutherobin (1),[3] which has a modality
of action and a potency to warrant its inclusion with paclitaxel,
the epothilones, and discodermolide as actual or potential
anticancer agents of mechanistic commonality. The first total
synthesis of eleutherobin (as well as that of sarcodictyin A)
was recently disclosed by Nicolaou et al.[4]
Our own efforts pursuant to the synthesis of the eleuthe-
sides were recently described.[5] The most advanced com-
pound in our synthesis was the ketone 2. We viewed this
compound as a platform structure through which naturally
occurring eleuthesides could be reached, and a large number
of analogues could be fashioned. We turned to the synthesis of
eleutherobin (1) from 2 (Scheme 1). The conventional
approach to this kind of problem would be to develop a
method to convert 2 into a suitable glycosyl acceptor (3) by
overall addition of a C1 fragment to carbon 3. We would also
synthesize a glycosyl donor (cf. suitably activated arabinosyl
donor 4). Classical glycosylation could eventually lead to 1. In
this simple formulation, we do not yet address the question of
the order of introduction of the sugar and the urocanic acid
appendages.
SO2Ph), 7.38 (m, 2 H, SO2Ph), 7.34 ± 7.18 (m, 10 H, Bn), 4.77 ± 4.67 (m, 3 H),
4.64 (d, J 8.2 Hz, 1 H), 4.59 (d, J 11 Hz, 1 H), 3.84 ± 3.78 (m, 1 H), 3.72 ±
3.65 (m, 1 H), 3.63 ± 3.57 (m, 2 H), 3.56 ± 3.48 (m, 1 H), 3.45 ± 3.39 (m, 1 H),
2.53 (q, J 7.6 Hz, 2 H, SCH2CH3), 1.91 (m, 1 H), 1.14 (t, J 7.6 Hz, 3 H,
SCH2CH3); Positive-ion electrospray (ES) MS: m/z: 566.2 ([M] Na );
Negative-ion ES MS: 578.2 ([M] Cl ).
27b: 1H NMR (CDCl3): d 7.86 (m, 2 H), 7.68 ± 7.56 (m, 3 H), 7.50 ± 7.17 (m,
65 H), 6.24 (d, J 6.0 Hz, 1 H), 5.29 ± 5.25 (m, 1 H), 5.20 ± 5.14 (m, 1 H),
5.11 ± 4.99 (m, 7 H), 4.89 ± 4.42 (m, 34 H), 4.37 ± 4.28 (m, 3 H), 4.12 ± 3.94
(m, 7 H), 4.00 ± 3.82 (m, 8 H), 3.79 ± 3.53 (m, 21 H), 1.11 ± 1.04 (dd, J 6.3,
6.2 Hz, 6 H); Positive-ion ES MS: 1490.5 ([M] Na ); Negative-ion ES
MS: 1466.7 ([M]
H ).
Received: November 1, 1997 [Z11109IE]
German version: Angew. Chem. 1998, 110, 831 ± 834
Keywords: glycals
solid-phase synthesis
´ glycosylations ´ oligosaccharides ´
[1] A. Varki, Glycobiology 1993, 3, 97; A. Giannis, Angew. Chem. 1994,
106, 188; Angew. Chem. Int. Ed. Engl. 1994, 33, 178; T. Feizi, Curr.
Opin. Struct. Biol. 1993, 3, 701.
[2] P. Falk, T. Boren, S. Normark, Methods Enzymol. 1994, 236, 353, and
references therein.
[3] T. Boren, P. Falk, K. A. Roth, G. Larson, S. Normark, Science 1993,
262, 1892.
It seemed possible that one-carbon homologation of enol
triflate 5[6] could serve as a possible route to reach acceptor 3.
In the event, ketone 2 was converted into 5 by deprotonation
and enol triflation. We shall return to this compound shortly.
While the matter of the relative configurations of the
aglycone and carbohydrate sectors of eleutherobin had not
yet been proven to our satisfaction,[7] we began with the
assumption that the compound is derived from d-arabinose.[4]
Following peracetylation and introduction of an ethylthiol
group at the anomeric carbon of d-arabinose, compound 6
became available (Scheme 2). Hydrolysis of the three acetate
[4] J. Alper, Sciene 1993, 260, 159.
[5] a) D. Y. Graham, G. M. Lew, P. D. Klein, D. G. Evans, D. J. Evans,
Z. A. Saeed, H. M. Malaty, Ann. Intern. Med. 1992, 116, 705; b) E.
Hentschel, G. Brandstatter, B. Dragosics, A. M. Hirschl, H. Nemeg, K.
Schutze, M. Taufer, H. Wurzer, N. Eng. J. Med. 1993, 328, 308.
[6] For syntheses of the Leb oligosaccharide see: S. S. Rana, J. J. Barlow,
K. L. Matta Carbohydr. Res. 1981, 96, 231; U. Spohr, R. U. Lemieux
ibid. 1988, 174, 211.
[7] S. J. Danishefsky, M. T. Bilodeau, Angew. Chem. 1996, 108, 1482;
Angew. Chem. Int. Ed. Engl. 1996, 35, 1380; P. H. Seeberger, M. T.
Bilodeau, S. J. Danishefsky, Aldrichimica Acta 1997, 30, 75.
[8] D. A. Griffith, S. J. Danishefsky, J. Am. Chem. Soc. 1990, 112, 5811; T.
Hamada, A. Nishida, O. Yonemitsu, ibid. 1986, 108, 140.
[9] C. Zheng, P. H. Seeberger, S. J. Danishefsky, J. Org. Chem. 1998, 63,
1126.
[*] Prof. S. J. Danishefsky,[] X.-T. Chen, B. Zhou, Dr. S. K. Bhatta-
charya, Dr. C. E. Gutteridge, Dr. T. R. R. Pettus
Department of Chemistry, Columbia University
[10] J. T. Randolph, S. J. Danishefsky, Angew. Chem. 1994, 106, 1538;
Angew. Chem. Int. Ed. Engl. 1994, 33, 1470.
Havemeyer Hall, New York, NY 10027 (USA)
[11] For couplings of thiodonors with glycals see: P. H. Seeberger, M.
Eckhardt, C. E. Gutteridge, S. J., Danishefsky J. Am. Chem. Soc. 1997,
119, 10064. For activation of thiodonors see: H. Lönn Carbohydr. Res.
1985, 135, 105; ibid. 1985, 139, 115; H. Lönn J. Carbohydr. Chem. 1987,
6, 301; P. Fügedi, P. J. Garegg Carbohydr. Res. 1986, 149, C9.
[12] J. T. Randolph, K. F. McClure, S. J. Danishefsky, J. Am. Chem. Soc.
1995, 117, 5712.
[ ] Other address:
Laboratory for Bioorganic Chemistry,
The Sloan-Kettering Institute for Cancer Research
1275 York Avenue, New York, NY 10021 (USA)
Fax : ( 1)212-772-8691
[**] Graduate Fellowships are gratefully acknowledged by X.-T.C. (Ka-
nagawa Academy of Science and Technology) and B.Z. (Pharmacia -
Upjohn). Postdoctoral Fellowships are gratefully acknowledged by
C.E.G. (The Royal Commission for the Exhibition of 1851) and
T.R.R.P. (The National Science Foundation). We are grateful to Vinka
Parmakovich and Barbara Sporer of the Columbia University Mass
Spectral Facility. We also thank Professor Fenical, University of
California, San Diego, for kindly providing us spectral data and a copy
of the NMR spectrum of natural eleutherobin.
Angew. Chem. Int. Ed. 1998, 37, No. 6
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