Synthesis of epothilones via a silicon-tethered RCM reaction

Article abstract of DOI:10.1021/ol0500923

(Chemical Equation Presented) A short synthesis of epothilone B and D is reported. The key step for generating the C12-13-trisubstituted Z-double bond uses a ring-closing metathesis reaction of a disiloxane to form a nine-membered silicon-tethered ring.

Full text of DOI:10.1021/ol0500923

ORGANIC
LETTERS
2005
Vol. 7, No. 7
1311-1313
Synthesis of Epothilones via a
Silicon-Tethered RCM Reaction
Tanja Gaich and Johann Mulzer*
Institut fu¨r Organische Chemie, UniVersita¨t Wien,
Wa¨hringerstrasse 38, A-1090-Wien, Austria
johann.mulzer@uniVie.ac.at
Received January 17, 2005
ABSTRACT
A short synthesis of epothilone B and D is reported. The key step for generating the C12−13-trisubstituted Z-double bond uses a ring-closing
metathesis reaction of a disiloxane to form a nine-membered silicon-tethered ring.
Epothilones such as 1 and 2 (Figure 1) are forthcoming
application, notwithstanding the low overall yield (43% for
the preparation of 3, and 77% for the coupling) (Scheme 1).
Scheme 1. Danishefsky Approach to the 12,13-Double Bond
Figure 1. Epoxidation of epothilone D.
anticancer drugs with high cytotoxic activity combined with
low multidrug resistance.1 Although these compounds can
be procured from fermentation quite efficiently, the constant
search for more biologically active derivatives has inspired
an ever-increasing amount of total syntheses.2 All of these
routes, some of which are well-suited for the larger scale,
must cope with the nontrivial problem of introducing a (Z)-
double bond into the C12-C13 position. Among the various
approaches, Danishefsky’s Miyaura-Suzuki coupling3 of
vinyl iodide 3 with borane 4 to olefin 5 has found widespread
Following the standard aldol disconnection2 of 2 into the
northern fragment 7 and a southern fragment 8 (Scheme 2)
(2) For reviews, see: (a) Nicolaou, K. C.; Roschangar, F.; Vourloumis,
D. Angew. Chem., Int. Ed. 1998, 37, 2014. (b) Mulzer, J. Monatsh. Chem.
2000, 131, 205. (c) Altmann, K.-H. Org. Biomol. Chem. 2004, 2, 437. For
most recent syntheses, see: (d) Scheid, G.; Ruijter, E.; Konarzycka-Bessler,
M.; Bornscheuer, U. T.; Wessjohann, L. A. Tetrahedron: Asymmetry 2004,
15, 2861. (e) Jung, J.-J.; Kache, R.; Vines, K. K.; Zheng, Y.-S.; Bijoy, P.;
Valluri, M.; Avery, M. A. J. Org. Chem. 2004, 69, 9269.
(1) Ho¨fle, G.; Bedorf, N.; Gerth, K.; Reichenbach, H. (GBF), DE-B
4138042, 1993; Chem. Abstr. 1993, 120, 52841. Ho¨fle, G.; Bedorf, N.;
Steinmetz, H.; Schomburg, D.; Gerth, K.; Reichenbach, H. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 1567.
10.1021/ol0500923 CCC: $30.25
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In both cases, only dimers 15 and 16 were isolated in 9
and 19% yield (Scheme 3). From this result we concluded
Scheme 2. Retrosynthetic Considerations
Scheme 3. Attempted RCM of Diolefins 9 and 14
it occurred to us that the ring-closing metathesis (RCM)4 of
an ester such as 9 would incorporate the C12-C13 double
bond into an eight-membered lactone 10 with (Z)-configu-
ration because the ring strain is lower than in the case of the
(E)-isomer.
Moreover, 10 could serve for a chain elongation via diol
11 toward aldehyde 7, which constitutes the northern
fragment of 6 in Nicolaou’s5 and our synthesis6 (Scheme
2). Hence, diolefinic esters 9 and 14, serving as RCM
precursors, were prepared in 2 and 4 steps, respectively, from
lactate 12 in overall yields of 61% and 44% and subjected
to RCM with either the Grubbs catalyst7 a or the Grubbs-
Hoveyda catalyst b8 (Figure 2). Lactate 12 was obtained from
that the RCM was not able to overcome the ring strain in
the transition state.
Hence, our idea was to induce strain relief by using a
silicon tether. As silicon is bigger in size and has got more
polarizable soft d-orbitals, its bonds are more easily distorted.
Thus, cyclization causes less ring strain, and RCM seemed
to be more facile.9 Of course, we chose the tether in a form
to get ready access to aldehyde 7.
Thus, disiloxane 17 emerged as a suitable RCM substrate,
which was prepared from alcohol 134a in one pot in 84%
yield. RCM of 17 gave the nine-membered ring olefin 18
quantitatively with a Z/E ratio of 5/1 (Scheme 4).10 Yields
Scheme 4. Silicon-Tethered RCM
Figure 2. Structure of catalysts a and b.
commercially available (S)-methyllactate via protection with
Bundle’s reagent.
(3) (a) Meng, V.; Bertinato, P.; Balog, A.; Su, D.-S.; Kamenecka, T.;
Sorensen, E. J.; Danishefsky, S. J. J. Am. Chem. Soc. 1997, 119, 10073.
(b) For a variation, cf. Schinzer, D.; Bauer, A.; Schieber, J. Chem.sEur. J.
1999, 5, 2492.
(4) (a) Cf. Kalesse, M.; Gerlach, K.; Quitschalle, M. Tetrahedron Lett.
1999, 40, 3553. (b) Reviews on RCM: Fu¨rstner, A. Angew. Chem., Int.
Ed. 2000, 39, 3012. Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001,
34, 18. Schrock, R. R.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42,
4592. Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003, 42, 1900.
(5) Nicolaou, K. C.; Ninkovic, S.; Sarabia, F.; Vourloumis, D.; He, Y.;
Vallberg, H.; Finlay, M. R. V.; Yang, Z. J. Am. Chem. Soc. 1997, 119,
7974.
for RCM turned out to be strongly dependent on the rate of
catalyst addition. Quantitative yields where only obtained
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Org. Lett., Vol. 7, No. 7, 2005

when the catalyst was added over 16 h. By contrast, addition
of catalyst in one portion reduced the yield to 50%.
aldehyde 7 with a diastereoselectivity greater than 95% and
81% yield for the two steps (Scheme 6). The analytical data
Without separation, the E/Z mixture of 18 was desilylated
to give a stereoisomeric mixture of E and Z diols, separable
by column chromatography. The Z-diol was thus obtained
in 82% overall yield from 17. In one pot, the Z-diol was
converted into the di-TBS-ether and then mono-deprotected
to give 19 in 88% yield. One-carbon chain elongation of 19
was accomplished by a Mitsunobu reaction with acetone
cyanohydrin in 92% yield.11 p-Methoxybenzyl (PMB) depro-
tection, oxidation to the ketone and (E)-selective Wittig
reaction with phosphonium salt 20 generated thiazole nitrile
21 (overall yield of 81% for the three steps) (Scheme 5).
Scheme 6. Completion of the Northern Fragment 7
Scheme 5. Chain Elongation and Introduction of the Thiazole
Moiety
of 7 perfectly matched those described.5,6 The stereochemical
outcome of the tandem 1,4-reduction-methylation sequence
is rationalized via a chelate induced chirality transfer within
enolate 25 (Scheme 7). By using this procedure, aldehyde 7
Scheme 7. Stereoselectivity of the Tandem 1,4 Reduction
Methylation
Nitrile 21 was reduced to aldehyde 22 (84% yield), which
was subjected to a Horner-Wadsworth-Emmons reaction
with Oppolzer’s chiral phosphonate 23 to give enone 24 in
79% yield. A one-pot 1,4-reduction/methylation sequence12
followed by reduction with DIBAL-H applied to 24 led to
was available in 11 steps from alcohol 13 (overall yield 25%).
The endgame of the synthesis proceeds as described
earlier6 (Scheme 2). In an aldol reaction aldehyde 7 is
connected with ketone 8. An additional five steps lead to
seco acid 6, which after Keck lactonization and desilylation
gives 2, which is epoxidized with m-CPBA (5/1 selectivity)
to 1. In conclusion, we present a short route to 2 and 1 in
21/22 steps (longest linear sequence 18/19 steps) and with
an overall yield of 9%.
(6) (a) Mulzer, J.; Mantoulidis, A.; O¨ hler, E. Tetrahedron Lett. 1996,
37, 9179. (b) Mulzer, J.; Mantoulidis, A.; O¨ hler, E. J. Org. Chem. 2000,
65, 7456.
(7) Schwab, B.; Grubbs, R. K.; Ziller, J. W. J. Am. Chem Soc. 1996,
118, 100.
(8) (a) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J.
Am. Chem Soc. 2000, 122, 8168. (b) Gessler, S.; Randl, S.; Blechert, S.
Tetrahedron Lett. 2000, 41, 9973.
(9) (a) Harrison, B. A.; Verdine, G. L. Org. Lett. 2001, 3, 2157. (b)
Boiteau, J. G.; Van de Weghe, P.; Eustache, J. Tetrahedron Lett. 2001, 42,
239. For RCM with a sulfonate tether, see: (c) Le Flohic, A.; Meyer, C.;
Cossy, J. Org. Lett. 2005, 7, 339.
(10) (a) Promo, M. A.; Hoye, T. R. Tetrahedron Lett. 1999, 40, 1429.
(b) Evans, P. A.; Cui, J.; Buffone, G. P. Angew. Chem., Int. Ed. 2003, 42,
1734.
(11) (a) Wilk, B. Synth. Commun. 1993, 23, 2481. (b) Tsunoda, T.;
Uemoto, K.; Nagino, C.; Kawamura, M.; Kaku, H.; Ito, S. Tetrahedron
Lett. 1999, 40, 7355.
Acknowledgment. We thank Lothar Brecker, Hans-Peter
Ka¨hlig, Catrin Thyl, and Susanne Felsinger for NMR
analysis. We are grateful to Schering AG for the generous
donation of chemicals and to the Austrian Science Founda-
tion (FWF) for financial support.
Supporting Information Available: Experimental pro-
cedures and analytical data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(12) (a) Oppolzer, W.; Poli, G. Tetrahedron Lett. 1986, 27, 4717. (b)
Martin, H. J.; Drescher, M.; Mulzer, J. Angew. Chem., Int. Ed. 2000, 39,
581.
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