biologically active analogues of the epothilones, such as
epothilones C and D, Figure 1, which may be accessible
through genetic engineering.
accomplished via an asymmetric Brown allylation14 with
lithiated allyl methyl ether in the presence of BF3·OEt2 to
afford the alcohol 4 as a single diastereomer in >95% ee15
and 88% yield, Scheme 1. The undersired syn-stereochem-
istry was easily converted to the anti-diastereomer via a two-
step sequence. First, oxidation of the alcohol was achieved
with Dess-Martin periodinane16 followed by a highly
diastereoselective Luche reduction of the R,ꢀ-unsaturated
ketone.17 This reduction yielded the optically pure anti-
diastereomer 5 as a 93:7 mixture of diastereomers in 96%
yield. The free hydroxyl group was protected with tert-
butoxydiphenylsilyl chloride (TBODPSCl), and subsequent
oxidative cleavage of the terminal olefin under standard
conditions afforded the desired aldehyde fragment 6.
Figure 1. Structures and biogenetic pattern for epothilones C and
D; the structure of (S)-14-methoxyepothilone D.
Scheme 2. Sequential NHK Coupling/Thionyl Chloride
Rearrangement for Trisubstituted Olefin Generation
Herein we report the total synthesis and biological evalu-
ation of (S)-14-methoxyepothilone D 2, a novel epothilone
analogue. The stereochemistry of the C14-substitution was
chosen to provide further support for the proposed binding
conformation in the C11-C15 region.7 Moreover, the
incorporation of a methoxy group at this position represents
a target potentially available through modification to the
acyltransferase domain of module 3 in the epothilone PKS
gene cluster8 and the incorporation of an extender unit
derived from methoxymalonyl CoA.9
The significant efforts required to develop a fermentation
based route could be justified if the biological activity of
the target were significant. Thus, a synthetic strategy for the
production of (S)-14-methoxyepothilone D was developed
on the basis of modificatons to our previously reported route
to epothilones B and D.10 This route relied on a sequential
Nozaki-Hiyama-Kishi (NHK)11 coupling-thionyl chloride
induced allylic rearrangement12 to stereoselectively generate
the C12-C13 trisubstituted olefin.
As shown in Scheme 2, fragment coupling of aldehyde 6
with known vinyl iodide fragment 7, prepared according to
a previously reported route,10 was achieved via a NHK
(5) An alternative binding conformation has been proposed on the basis
of electron crystallography: Nettles, J. H.; Li, H.; Cornett, B.; Krahn, J. M.;
Snyder, J. P.; Downing, K. H. Science 2004, 305, 866–869.
(6) A critical review of published efforts toward identification of the
binding conformation of the epothilones has been published: Heinz, D. W.;
Schubert, W.-D.; Ho¨fle, G. Angew. Chem., Int. Ed. 2005, 44, 1298–1301.
(7) Taylor, R. E.; Chen, Y.; Beatty, A.; Myles, D. C.; Zhou, Y. J. Am.
Chem. Soc. 2003, 125, 26–27.
(8) Tang, L.; Shah, S.; Chung, L.; Carney, J.; Katz, L.; Khosla, C.; Julien,
B. Science 2000, 199, 640–642.
Scheme 1. Installation of C14-Methoxy Substituent
(9) Chan, Y. A.; Boyne, M. T., II; Podevels, A. M.; Klimowicz, A. K.;
Handelsman, J.; Kelleher, N. L.; Thomas, M. G. Proc. Nat. Acad. Sci. U.S.A.
2006, 103, 14349–14354.
(10) Taylor, R. E.; Chen, Y. Org. Lett. 2001, 3, 2221–2224.
(11) (a) Takai, K.; Tagashira, M.; Kuroda, T.; Oshima, K.; Utimoto,
K.; Nozaki, H. J. Am. Chem. Soc. 1986, 108, 6048–6050. (b) Jin, H.;
Uenishi, J.-I.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc. 1986, 108, 5644–
5646.
(12) Caserio, F. F.; Dennis, G. E.; DeWolfe, R. H.; Young, W. G. J. Am.
Chem. Soc. 1955, 77, 4182–4183.
(13) Taylor, R. E.; Haley, J. D. Tetrahedron Lett. 1997, 38, 2061–2064.
(14) (a) Brown, H. C.; Jadhav, P. K.; Bhat, K. S. J. Am. Chem. Soc.
1988, 110, 1535–1538. (b) Hoffmann, R. W.; Kemper, B.; Metternich, R.;
Lehmeier, T. Liebigs Ann. Chem. 1985, 2246–2260.
(15) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512–519.
(16) (a) Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem. 1999,
64, 4537–4538. (b) Boeckman, R. K.; Shao, P.; Mullins, J. J. Org. Syn
2004, 77, 141–146.
(17) Luche, J.-L.; Rodriguez-Hahn, L.; Crabbe, P. J. Chem. Soc., Chem.
Commun. 1978, 601–602.
(18) Slougui, N.; Rousseau, G. Synth. Commun. 1987, 17, 1–11.
(19) Inukai, T.; Yoshizawa, R. J. Org. Chem. 1967, 32, 404–407.
(20) Kiyooka, S.-I.; Kira, H.; Hena, M. A. Tetrahedron Lett. 1996, 37,
2597–2600.
The starting thiazole aldehyde fragment 3 was prepared
by previously described methods and detailed in Scheme 1.13
The introduction of the C14 methoxy substituent was
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