Total synthesis of epothilones B and D

Article abstract of DOI:10.1021/ol010094x

(Matrix presented) A highly convergent total synthesis of the natural products epothilone B and D is described. The route is highlighted by efficient generation of a C12-C13 trisubstituted olefin which exploits a sequential Nozaki-Hiyama-Kishi coupling and a stereoselective thionyl chloride rearrangement.

Full text of DOI:10.1021/ol010094x

ORGANIC
LETTERS
2001
Vol. 3, No. 14
2221-2224
Total Synthesis of Epothilones B and D
Richard E. Taylor* and Yue Chen
Department of Chemistry & Biochemistry, UniVersity of Notre Dame,
251 Nieuwland Science Hall, Notre Dame, Indiana 46556-5670
taylor.61@nd.edu
Received May 9, 2001
ABSTRACT
A highly convergent total synthesis of the natural products epothilone B and D is described. The route is highlighted by efficient generation
of a C12−C13 trisubstituted olefin which exploits a sequential Nozaki−Hiyama−Kishi coupling and a stereoselective thionyl chloride rearrangement.
Epothilones B and D represent exciting new leads in the
search for novel cancer chemotherapeutic agents.1 The
combination of their potent biological activity and their
relatively simple structure has stimulated substantial interest
from the synthetic community.2 Several total syntheses of
these macrolide natural products have been reported. Critical
to a practical approach to epothilone B is a convergent
strategy which allows for the selective construction of the
C12-C13 trisubstituted olefin (epoD).3
represent a significant synthetic challenge. Previous syntheses
of the epothilones B and D have explored methods for
construction of this region through either olefin metathesis3b,f,g,l
or Wittig olefination3c strategies which have shown little
geometric selectivity. Alternative selective routes, which
proceed through intermediate trisubstituted vinyl halides,
have been prone to low yields.3a,b,f,i,j,l To date, Nicolaou3d,k
and Mulzer’s3q use of stabilized-Wittig and Horner-Emmons
(3) (a) Su, D.-S.; Meng, D.; Bertinato, P.; Balog, A.; Sorensen, E. J.;
Danishefsky, S. J.; Zheng, Y.-H.; Chou, T.-C.; He, L.; Horwitz, S. B. Angew.
Chem., Int. Ed. Engl. 1997, 36, 757. (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) Nicolaou, K. C.; Winssinger, N.; Pastor,
J.; Ninkovic, S.; Sarabia, F.; He, Y.; Vourloumis, D.; Yang, Z.; Li, T.;
Giannakakou, P.; Hamel, E. Nature 1997, 387, 268. (d) 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. (e) Balog, A.;
Harris, C. R.; Savin, K.; Zhang, X.-G.; Chou, T.-C.; Danishefsky, S. J.
Angew. Chem., Int. Ed. 1998, 37, 2675. (f) Schinzer, D.; Bauer, A.; Schieber,
J. Synlett 1998, 861. (g) May, S. A.; Grieco, P. A. Chem. Commun. 1998,
1597. (h) Mulzer, J.; Mantoulidis, A.; O¨ hler, E. Tetrahedron Lett. 1998,
39, 8633. (i) White, J. D.; Carter, R. G.; Sundermann, K. F. J. Org. Chem.
1999, 64, 684. (j) White, J. D.; Sundermann, K. F.; Carter, R. G. Org. Lett.
1999, 1, 1431. (k) Nicolaou, K. C.; Hepworth, D.; Finlay, M. R. V.; King,
N. P.; Werschkun, B.; Bigot, A. Chem. Commun. 1999, 519. (l) Schinzer,
D.; Bauer, A.; Schieber, J. Chem. Eur. J. 1999, 5, 2492. (m) Harris, C. R.;
Kuduk, S. D.; Balog, A.; Savin, K.; Danishefsky, S. J. Tetrahedron Lett.
1999, 40, 2263. (n) Harris, C. R.; Kuduk, S. D.; Balog, A.; Savin, K.;
Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121, 7050. (o) Martin, H. J.;
Drescher, M.; Mulzer, J. Angew. Chem., Int. Ed. 2000, 39, 581. (p) Sawada,
D.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 10521. (q)
Mulzer, J.; Mantoulidis, A.; O¨ hler, E. J. Org. Chem. 2000, 65, 7456.
These structural units, common to biologically active
natural products, have for a long time and continue to
(1) (a) Ho¨fle, G.; Bedorf, N.; Gerth, K.; Reichenbach, H. German Patent
DE 4138042, 1993. (b) Gerth, K.; Bedorf, N.; Ho¨fle, G.; Irschik, H.;
Reichenbach, H. J. Antibiot. 1996, 49, 560. (c) Ho¨fle, G.; Bedorf, N.;
Steinmetz, H.; Schomburg, D.; Gerth, K.; Reichenbach, H. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 1567-1569. (d) Bollag, D. M.; McQueney, P. A.;
Zhu, J.; Hensens, O.; Koupal, L.; Liesch, J.; Goetz, M.; Lazarides, E.;
Woods, C. M. Cancer Res. 1995, 55, 2325.
(2) (a) For a recent review of efforts to synthesize the epothilones, see:
Mulzer, J. Monatsh. Chem. 2000, 131, 205.
10.1021/ol010094x CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/12/2001

reagents has been shown to offer the most reliable combina-
tion of high geometric selectivity and overall yield. We have
chosen to explore an alternative route which relies on a
Nozaki-Hiyama-Kishi (NHK) coupling4 for the formation
of the C12-C13 carbon-carbon bond and a thionyl chloride
induced allylic rearrangement5 to control the trisubstituted
olefin geometry. Herein we report the application of these
methods for the total synthesis of epothilones B and D.
The connectivity analysis which guides our synthetic
strategy is outlined in Figure 1. Similar to our approach to
Scheme 1
for large-scale synthetic work. As shown in Scheme 1
exposure of conjugated aldehyde 1 to (+)Ipc2B(allyl) gave
the corresponding allylic alcohol in excellent yield (>91%
ee by chiral gc analysis) on a multigram scale. The secondary
alcohol was protected as a tert-butyldimethylsilyl ether under
classic conditions, and a two-step oxidative cleavage pro-
vided aldehyde 2.8
The construction of fragment A proceeded with use of
Evan’s chiral enolate alkylation chemistry.9 Alkyne 3 was
prepared from commercially available 6-heptynoic acid using
the unsymmetric anhydride method. Hydrogen iodide addi-
tion, using trimethylsilyl chloride/sodium iodide in aqueous
acetonitrile,10 provided the internal vinyl iodide in 60% yield
(31% recovered starting material), Scheme 2. Generation of
Figure 1. Connectivity analysis.
epothilone A, we chose a convergent route6 which has
assembled the 16-membered macrolide from three fragments
of similar complexity. Simplification of epothilone D was
considered through three strategic disconnections.
Scheme 2
First, the C5-C7 â-hydroxy ketone could be formed, in
a synthetic direction, from an aldol reaction between the
enolate of the C5 ketone and a C7 chiral aldehyde. An
additional disconnection through the C12-C13 olefin reveals
the necessary chiral aldehyde A for the C7-C12 fragment.
Retrosynthetic disconnection of the ester (lactone) linkage
then exposes a C1-C6 fragment such as chiral ketone B.
This leaves behind our choice for the side chain, aldehyde
C. Novel to this approach to epothilone D is the formation
of the C12-C13 trisubstituted olefin through a sequential
NHK coupling followed by a stereoselective allylic rear-
rangement. While we considered using this coupling in the
macrocyclization, a late-stage reductive cleavage of the allylic
chloride would have provided a significant challenge.
Thiazole fragment C was prepared using a method similar
to one that we have reported.6a Previously we had generated
the C15 allylic alcohol using Keck’s Ti‚BINOL-catalyzed
allylation.7a However, in this case we chose to use Brown’s
asymmetric allylboration7b which we found more suitable
the enolate was then accomplished with NaHMDS, and
alkylation with methyl iodide generated in the C8 stereogenic
center in 90% yield (>96:4 dr).
We had previously reported an efficient route to the chiral
ketone necessary for the preparation of epothilone A.6b
However, the synthesis of the chiral starting material for that
route was dependent on an enzymatic resolution of a
secondary alcohol which was found to make large-scale
production tedious. Scheme 3 describes an alternative route
Scheme 3
(4) (a) Takai, K.; Tagashira, M.; Kuroda, T.; Oshima, K.; Utimoto, K.;
Nozaki, H. J. Am. Chem. Soc. 1986, 108, 6048. (b) Jin, H.; Uenishi, J.-I.;
Christ, W. J.; Kishi, Y. J. Am. Chem. Soc. 1986, 108, 5644.
(5) Caserio, F. F.; Dennis, G. E.; DeWolfe, R. H.; Young, W. G. J. Am.
Chem. Soc. 1955, 77, 4182. From a mechanistic perspective, this reaction
has been restudied on numerous occasions. However, to the best of our
knowledge only Johnson has exploited the stereoselectivity of this interesting
reaction from a synthetic perspective; Johnson, W. S.; Li, T.-T.; Harbert,
C. A.; Bartlett, W. R.; Herrin, T. R.; Staskun, B.; Rich, D. H. J. Am. Chem.
Soc. 1970, 92, 4461. See also: Taylor, R. E.; Ciavarri, J. P.; Hearn, B. R.
Tetrahedron Lett. 1998, 39, 9361.
(6) (a) Taylor, R. E.; Haley, J. Tetrahedron Lett. 1997, 38, 2061. (b)
Taylor, R. E.; Galvin, G. M.; Hilfiker, K. A.; Chen, Y. J. Org. Chem. 1998,
63, 9580.
(7) (a) Keck, G. E.; Geraci, L. S. Tetrahedron Lett. 1993, 34, 7827. (b)
Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56, 401.
which exploits the elegant chemistry of Kiyooka.11 The
reaction of 2-methyl-1-phenoxy-1-trimethylsilyloxy-1-pro-
2222
Org. Lett., Vol. 3, No. 14, 2001

pene with readily available aldehyde 5 under the influence
of Kiyooka’s chiral boron reagent (100 mol %) provided
aldol adduct 6 in 71% yield (96% ee by chiral GC analysis).
A similar route to this chiral fragment has been recently
reported by Mulzer.3q Our original contribution to preparation
of this fragment is the use of the phenoxy-ketene acetal
which not only provides higher enantioselectivity than the
commercially available methoxy-ketene acetal but also
allows for a one-step ester-to-ketone conversion. Protection
of the secondary alcohol was followed by exposure to
ethylmagnesium bromide in the presence of triethylamine12
to provide the desired ethyl ketone 7 directly.
D and B by Schinzer,3l Mulzer,3q and Nicolaou3d and thus
represents a formal total synthesis of epothilones B and D,
we chose to complete the total synthesis by the following
synthetic sequence.
As highlighted in Scheme 5, the completion of the total
Scheme 5
With all three fragments in hand, we next chose to explore
the convergence of fragments A and C, Scheme 4. Inter-
Scheme 4
synthesis began with an aldol reaction. The lithium enolate
of ethyl ketone 7 was generated by exposure to LDA at -78
°C. Addition of aldehyde 10b provided the desired syn,anti-
aldol adduct as the major product in 83% yield and 8:1
selectivity. After protection of the C7 hydroxyl as a TBS
ether, the primary alcohol was liberated by exposure to acidic
methanol solution. The C1-carboxylic acid was generated
by two-step oxidation in 90% yield. Subsequent selective
removal of the C15 TBS ether was then accomplished with
TBAF. Macrolactonization proceeded efficiently using the
Yamaguchi method13 to provide the 16-membered lactone
in 77% yield. Deprotection of the C3 and C7 silyl ethers
was carried out using HF‚pyr, providing epothilone D.
Finally, incorporation of the C12-C13 epoxide was carried
out by exposure to mCPBA, yielding epothilone B in 65%
yield. This material was identical to an authentic sample of
epothilone B.
molecular Ni/Cr coupling of vinyl iodide 4 with aldehyde 2
(2 equiv) provided the desired allylic alcohol 8 in 93% yield
as a mixture of diastereomers (1:1). Exposure of this mixture
to thionyl chloride in ether-pentane provided the desired
primary chloride 9 in 87% yield. While the olefin geometry
was completely selective, a small amount of the secondary
allylic chloride could be observed in the crude proton NMR
spectrum. After exploration of a number of hydride reducing
agents, we ultimately found that LiEt3BH not only reduc-
tively cleaved the chiral auxiliary but also efficiently reduced
the allylic chloride in 88% yield, providing primary alcohol
10a which contained ∼10% of an unidentified inseparable
isomer. Presumably a small amount of epimerization of the
C8 stereogenic center occurred during the reductive cleavage.
Oxidation with PCC then provided aldehyde 10b. While this
intermediate has been previously converted to epothilones
In summary, we have completed a convergent synthesis
of the natural products epothilone B and D.14 The route is
highlighted by the efficient generation of a C12-C13
trisubstituted olefin which exploits a sequential Nozaki-
Hiyama-Kishi coupling and a stereoselective thionyl chlo-
ride rearrangement. The chemistry described in this Letter
(8) Aldehyde 2 was previously reported by Nicolaou (ref 3d).
(9) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982,
104, 1737.
(10) Kamiya, N.; Chikami, Y.; Ishii, Y. SynLett 1990, 675.
(11) Kiyooka, S.-I.; Kira, H.; Hena, M. A. Tetrahedron Lett. 1996, 37,
2597.
(13) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
(14) Satisfactory spectroscopic and HRMS data have been obtained for
all compounds.
(12) Kikkawa, I.; Yorifuji, T. Synthesis 1980, 877.
(15) Taylor, R. E.; Zajicek, J. J. Org. Chem. 1999, 64, 7224.
Org. Lett., Vol. 3, No. 14, 2001
2223

has led to an 18-step synthesis of epothilone D and allowed
for the preparation of significant quantities of the desired
material for biological, conformational,15 and structure/
conformation-activity studies. The application of this chem-
istry to the preparation of novel epothilone analogues will
be reported in due course.
is acknowledged for providing us with an authentic sample
of epothilone B. R.E.T. is an Eli Lilly Grantee award
recipient.
Supporting Information Available: Full experimental
and 1H and 13C NMR spectra for compounds 8, 9, and 10a.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. This work is supported by the Na-
tional Institutes of Health/National Cancer Institute (R01-
CA85499). Dr. Gabriel M. Galvin (Bristol-Myers Squibb)
OL010094X
2224
Org. Lett., Vol. 3, No. 14, 2001