A highly stereoselective synthesis of epothilone B

Full text of DOI:10.1021/jo982108r

684
J . Org. Chem. 1999, 64, 684-685
Synthesis of fragment X began from (Z)-3-iodo-2-methyl-
2-propen-1-ol (3), prepared in geometrically pure form from
propargyl alcohol.6 After protection as 4, the iodoalkene was
converted to the corresponding cuprate, which underwent
clean conjugate addition to (S)-3-acryloyl-4-benzyl-2-oxazo-
lidinone (5)7 to yield 6. Hydroxylation8 of the sodium enolate
derived from 6 with Davis’ oxaziridine9 gave 7, the config-
uration of which was confirmed by oxidative degradation to
dimethyl (S)-malate.10 Protection of alcohol 7 as silyl ether
8, followed by exposure to catalytic potassium thioethoxide
in ethanethiol,11 afforded 9 along with recovered oxazolidi-
none (93%). Treatment of thioester 9 with lithium dimeth-
ylcuprate furnished ketone 10, which upon Horner-Em-
mons condensation with phosphonate 1112 produced diene
12 in excellent yield, accompanied by 5% of its (Z,Z) isomer.
Removal of the tetrahydropyranyl ether was accomplished
with magnesium bromide,13 and the liberated alcohol 13 was
converted to bromide 14. Homologation of 14 to phospho-
nium bromide 15 using triphenylmethylenephosphorane
completed the synthesis of fragment X.
A High ly Ster eoselective Syn th esis of
Ep oth ilon e B
J ames D. White,* Rich G. Carter, and
Kurt F. Sundermann
Department of Chemistry, Oregon State University, Corvallis,
Oregon 97331-4003
Received October 20, 1998
Epothilones A (1) and B (2) were discovered by Ho¨fle and
co-workers1 during the course of an examination of metabo-
lites of the cellulose-degrading myxobacterium Sorangium
cellulosum (Myxococcales) as potential antifungal agents.2
Although the antifungal spectrum of 1 and 2 proved to be
quite narrow, scientists at Merck found that these mac-
rolides exhibit a high level of cytotoxicity.3 The novel
structures and potential utility of the epothilones as che-
motherapeutic agents has stimulated intense interest in
their synthesis, resulting in four total syntheses of 24 and
several as yet incomplete approaches to this structure.5 Our
plan for the synthesis of 2 differs from other pathways in
assembling the macrolide from two segments, X and Y,
which are first connected at C9-C10 before macrolacton-
ization. Fragment X is constructed around a preformed (Z)
trisubstituted alkene, thus circumventing stereochemical
problems that have afflicted previous routes. The (Z)-9,10
olefin arising from convergence of X with Y confers rigidity
on the one portion of the epothilone macrocycle that exhibits
flexibility.
(1) Ho¨fle, G.; Bedorf, N.; Gerth, H.; Reichenbach (GBF), DE-B 4138042,
1993; Chem. Abstr. 1993, 120, 52841.
(2) Ho¨fle, G.; Bedorf, N.; Steinmeth, H.; Schomburg, D.; Gerth. H.;
Reichenbach, H. Angew. Chem., Int. Ed. Engl. 1996, 35, 1567.
(3) For
a recent review of the chemical biology of epothilones, see:
Nicolaou, K. C.; Roschangar, F.; Vourloumis, F. Angew. Chem., Int. Ed. Engl.
1998, 37, 2014.
(4) (a) 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.
(b) Meng, D.; Bertinato, P.; Balog, A.; Su, D.-S.; Kamenecka, T.; Sorensen,
E. J .; Danishefsky, S. J . J . Am. Chem. Soc. 1997, 119, 10073. (c) May, S.
A.; Grieco, P. Chem. Commun. 1998, 1597. (d) Schinzer, D.; Bauer, A.;
Schieber, J . Synlett 1998, 861.
(5) (a) Mulzer, J .; Mantoulidis, A. Tetrahedron Lett. 1996, 37, 9179. (b)
Claus, E.; Pahl, A.; J ones, P. G.; Meyer, H. M.; Kalesse, M. Tetrahedron
Lett. 1997, 38, 1359. (c) Gabriel, T.; Wessjohann, L. Tetrahedron Lett. 1997,
38, 1363. (d) Taylor, R. E.; Haley, J . D. Tetrahedron Lett. 1997, 38, 2061.
(e) Brabander, J . D.; Rosset, S.; Bernardinelli, G. Synlett 1997, 824. (f)
Chakraborty, J . K.; Dutta, S. Tetrahedron Lett. 1998, 39, 101. (g) Liu, Z.-
Y.; Yu, C.-Z.; Yang, J . D. Synlett 1997, 1383. (h) Liu, Z.-Y.; Yu, C.-Z.; Wang,
R.-F.; Li, G. Tetrahedron Lett. 1998, 39, 5261. (i) Mulzer, J .; Mantoulidis,
A.; O¨ hler, E. Tetrahedron Lett. 1997, 38, 7725. (j) Bijoy, P.; Avery, M. A.
Tetrahedron Lett. 1998, 39 1209.
Fragment Y was prepared along lines already established
by Mulzer5a and Meyer5b in their approach to 1 and entailed
as a key construction the aldol condensation of the known
ketone 164a with aldehyde 17.5a This double stereodifferen-
10.1021/jo982108r CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/05/1999

Communications
J . Org. Chem., Vol. 64, No. 3, 1999 685
tiating reaction proceeded in good yield to give anti-Felkin
product 18 as the sole stereoisomer. An important contribu-
tion to the stereoselectivity of this condensation is made by
the p-methoxybenzyl (PMB) ether of 17, since the TBS-
protected version of this aldehyde resulted only in a 3:2
mixture of 18 and its Felkin diastereomer, respectively. The
favorable outcome with 17 is consistent with chelation of
the aldehyde carboxyl with both the lithium enolate from
16 and the PMB ether.14 After protection of 18 as tris ether
19, the terminal olefin was cleaved oxidatively to carboxylic
acid 20, which was converted to its methyl ester 21.
Hydrogenolysis of the PMB ether and oxidation of the
resultant alcohol 22 yielded aldehyde 23.
Wittig coupling of the ylide from 15 with aldehyde 23 at
low temperature afforded triene 24 as a single stereoisomer
in excellent yield. After saponification to carboxylic acid 25
deprotection was accomplished with tetra-n-butylammonium
fluoride. Macrolactonization of seco acid 26 was carried out
under Yamaguchi’s conditions15 to furnish 27, from which
both silyl ethers were cleaved with acid to yield 9,10-
dehydrodesepoxyepothilone B (28). Selective hydrogenation
of the disubstituted olefin of 28 with diimide gave the known
lactone 29,16,17 which underwent epoxidation with dimeth-
yldioxirane to produce 2. Characterization data for 29
matched those in the literature,4a,b and the NMR spectra of
2 were in excellent agreement with those of natural material.
In summary, we have completed a convergent synthesis
of epothilone B (2) that generates all seven of its asymmetric
centers in a completely stereoselective fashion. In addition,
clean Z configuration at the 12,13-double bond is incorpo-
rated by this pathway. Finally, the Z olefin at C9-C10
affords a locus at which exploratory structural modifications
can now be made.
(6) Duboudin, J . G.; J ousseaume, B.; Bonakdar, A. J . Organomet. Chem.
1979, 168, 227.
(7) Evans, D. A.; Chapman, K. T.; Bisaha, J . J . Am. Chem. Soc. 1998,
110, 1238.
(8) Evans, D. A.; Morrissey, M. M.; Dorow, R. L. J . Am. Chem. Soc. 1985,
107, 4346.
(9) Davis, F. A.; Chaltophadhyay, S.; Towson, J . C.; Lol, S.; Reddy, T. J .
Org. Chem. 1988, 53, 2087.
Ack n ow led gm en t. We are grateful to Professor K. C.
Nicolaou, Scripps Research Institute, and to Professor Paul
Grieco, Montana State University, for the NMR spectra of
epothilone B and to Dr. Duncan Wardrop for initial studies
of the aldol condensation used here. Financial support was
provided by the National Institutes of Health (GM50574),
by Pfizer, Inc., and by Dupont Pharmaceutical Co. One of
us (R.G.C.) thanks the National Institutes of Health for a
Postdoctoral Fellowship (F32 CA76743).
(10) Ozonolysis of 7 followed by oxidation and exposure to (trimethylsilyl)-
diazomethane gave a methyl ester that upon treatment with magnesium
methoxide afforded dimethyl (S)-malate, [R]23 ) +3.5 (c 1.20).
D
(11) Evans, D. A.; Ripin, D. H. B.; J ohnson, J . S.; Shaughnessy, E. A.
Angew. Chem., Int. Ed. Engl. 1997, 36, 2117.
(12) Schinzer, D.; Limberg, A.; Bo¨hm, O. M. Chem.sEur. J . 1996, 2, 1477.
(13) Kim, S.; Park, J . H. Tetrahedron Lett. 1987, 28, 439.
(14) For an analogous example of stereocontrolled aldol condensation via
double chelation, see: White, J . D.; Porter, W. J .; Tiller, T. Synlett 1993,
535.
(15) Inanaga, J .; Kirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. J pn. 1979, 52, 1989.
Su p p or tin g In for m a tion Ava ila ble: Full characterization
data and experimental procedures for all compounds.
(16) 29: -86.7 (c 0.19, CHCl3) (lit.6a -91.5 (c 0.30, CHCl3)).
(17) Nicolaou, K. C.; Finlay, M. R. V.; Ninkovic, S.; Sarabia, F. Tetra-
hedron 1998, 54, 7127.
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