An efficient total synthesis of (-)-epothilone B

Article abstract of DOI:10.1021/ol303148g

An efficient total synthesis of (-)-epothilone B has been achieved in ca. 8% yield over 11 steps from 9 (or 10 steps from 7/8), which features a bissiloxane-tethered ring closing metathesis reaction to approach the trisubstituted (Z) double bond and forms a new basis for further development of an industrial process for epothilone B and ixabepilone.

Full text of DOI:10.1021/ol303148g

ORGANIC
LETTERS
2012
Vol. 14, No. 24
6354–6357
An Efficient Total Synthesis
of (À)-Epothilone B
Jie Wang, Bing-Feng Sun,* Kai Cui, and Guo-Qiang Lin*
CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute
of Organic Chemistry, CAS, 345 Lingling Road, Shanghai 200032, China
bfsun@sioc.ac.cn; lingq@sioc.ac.cn
Received November 15, 2012
ABSTRACT
An efficient total synthesis of (À)-epothilone B has been achieved in ca. 8% yield over 11 steps from 9 (or 10 steps from 7/8), which features a
bissiloxane-tethered ring closing metathesis reaction to approach the trisubstituted (Z) double bond and forms a new basis for further
development of an industrial process for epothilone B and ixabepilone.
Epothilones AÀF are a group of macrolides isolated
from myxobacteria Sorangium cellulosum.1 Like taxanes,
epothilones interrupt the cell mitosis through interfering
with the binding and functioning of tubulins. Interestingly,
these natural products exhibit potent cytotoxicities even
in taxol-resistant cell lines.2 Among these, epothilone B (1)
is the most prominent member whose aza analogue,
ixabepilone, has been approved by the FDA as an anti-
breast cancer drug (Figure 1). Moreover, investigations on
the potential of 1 to fight against other types of cancers are
still ongoing.
In view of the biological profile of 1, despite the fact that
these compounds can be procured quite efficiently from
fermentation, the constant quest for active derivatives with
optimal therapeutic indices has stimulated an ever-increasing
number of total syntheses.3 An efficient total synthesis
that provides opportunities for variations on the scaffold
to access new analogues is still highly desirable. Critical to
an efficient synthesis of epothilone B is a convergent strat-
egy which allows for the selective establishment of the
trisubstituted (Z) olefin at C12ÀC13. Although the strat-
egies based on palladium-catalyzed coupling reactions4
or Wittig-type reactions5 could address this issue with success,
they generally fell short of step economy. Notably, Avery’s
group realized the efficient construction of the trisubsti-
tuted double bond with a Normant coupling reaction.6
(1) (a) 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, 2325–2333. (b) Gerth, K.; Bedorf, N.; Hofle, G.; Irschik,
€
H.; Reichenbach, H. J. Antibiot. 1996, 49, 560. (c) Hofle, G.; Bedorf, N.;
Steinmetz, H.; Schomburg, D.; Gerth, K.; Reichenbach, H. Angew.
€
Chem., Int. Ed. 1996, 35, 1567. (d) Hofle, G.; Glaser, N.; Kiffe, M.; H.-J.
(4) (a) Meng, D.; Bertinato, P.; Balog, A.; Su, D. S.; Kamenecka, T.;
Sorensen, E. J.; Danishefsky, S. J. J. Am. Chem. Soc. 1997, 119, 10073–
10092. (b) Schinzer, K. C.; Bauer, A.; Schieber, J. Chem.;Eur. J. 1999,
5, 2492–2500.
Hecht, H.-J.; Sasse, F.; Reichenbach, H. Angew. Chem., Int. Ed. 1999,
38, 1971.
(2) Bollag, D. M. Exp. Opin. Invest. Drugs 1997, 6, 867–873.
(3) For a review on syntheses of epothilones, see: (a) Altmann, K.-H.;
Hofle, G.; Muller, R.; Mulzer, J.; Prantz, K. The Epothilones: An
Outstanding Family of Anti-Tumor Agents-From Soil to the Clinic, Vol.
90; Springer: Vienna, 2009. For a most recent formal synthesis of epothilone
D, see: (b) Prantz, K.; Mulzer, J. Angew. Chem., Int. Ed. 2009, 48, 5030–
5033.
(5) (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, 7974–7991. (b) Mulzer, J.; Mantoulidis, A.; Ohler, E. Tetrahedron
Lett. 1998, 39, 8633–8636.
(6) Jung, J.-C.; Kache, R.; Vines, K. K.; Zheng, Y.-S.; Bijoy, P.;
Valluri, M.; Avery, M. A. J. Org. Chem. 2004, 69, 9269–9284.
r
10.1021/ol303148g
Published on Web 12/07/2012
2012 American Chemical Society

More recently, Mulzer’s group devised a Grob fragmen-
tation enabled stereospecific construction of such a dou-
ble bond.3b Herein we report an efficient total synthesis of
epothilone B featuring a bissiloxane-tethered ring closing
metathesis (RCM) reaction to approach the trisubstituted
(Z) double bond.
catalyzed by (R)-CBS delivered alcohol 10 in 61% yield
with 96% ee.7 Compound 10 was protected as TBS ether
11, followed by treatment with KHMDS/Tf2NPh to
furnish vinyl triflate 12. The Negishi coupling reaction
of 12 with Et2Zn proceeded smoothly in the presence of
5 mol % Pd(Ph3P)4 to generate alkene 5, which was subse-
quently exposed to ozonolysis to produce 3 in 58% yield
over two steps. This catalytic enantioselective procedure
delivers 3 in 30% overall yield spanning five steps from 9.
Scheme 2. Asymmetric Synthesis of 3
Figure 1. Epothilone AÀF and Ixabepilone.
Scheme 1. Retrosynthesis of Epothilone B (1)
Stereoseletive construction of the trisubstituted (Z)
double bond in 1 via RCM represents a significant chal-
lenge due to the lack of stereocontrol. Usually, the (E)
isomer was formed as the major product.8 In 2005, Mul-
zer’s group successfully established this double bond with
5/1 selectivity by employing a silicon-tethered RCM reac-
tion, although the follow-up steps leading to 4 (R = TBS)
were lacking step economy.9 In our tethered-RCM strat-
egy, the whole segment 8 would be utilized to improve the
overall synthetic efficiency. It was anticipated that the
stereoselectivity of the RCM reaction could be controlled
by the tethers which, toward that end, would vary both
sterically and electronically.
A model study wasinitiatedby employing7 and 13asthe
components which were first assembled with various
tethers to give the RCM precursors 14aÀm and then
subjected to RCM conditions, respectively (Scheme 3).
Generally, the macrocyclization was successful (14aÀg,
14iÀm), except that the cyclophane-type substrate 14h
failed to give any cyclization product probably due to
the ring strain. On the other hand, most of the tethered
substrates (14aÀf, 14k) produced the (E) isomers predo-
minantly (E/Z > 10/1). Interestingly, meta-cyclophanes
(14g, 14i, 14j) delivered the isomers with improved selec-
tivity (E/Z > 2/1). To our delight, bissiloxane-tethered
substrates were found capable of producing the olefins
with improved selectivities for the (Z) isomer. Thus, with
14l as the substrate, alkene 15l was obtained with a Z/E
ratio of 1/1.9. Further, with 14m as the substrate, the
selectivity was enhanced to 1.7/1, favoring the (Z) isomer.
Notably, these represent the first examples employing
bissiloxane tethers for RCM reactions.
Our retrosynthesis of 1 was depicted in Scheme 1.
Epothilone B (1) was reduced to epothilone D (2) by removal
of the epoxide oxygen.4a,5a The 16-membered macrocycle
of 2 was envisaged to stem from the aldol reaction of 3 and
4 and the subsequent macrolactonization.4a,5a Ketoacid 3
could be traced back to 5 by way of ozonolytic cleavage of
the cyclopentene ring. Aldehyde 4 containing the trisub-
stituted Z double bond was anticipated to derive from a
tethered RCM reaction of 6, which in turn could be
assembled from segments 74a,5a and 8.4b
(7) Yeung, Y. Y.; Chein, R. J.; Corey, E. J. J. Am. Chem. Soc. 2007,
129, 10346–10347.
(8) Nicolaou, K. C.; Roschangar, F.; Vourloumis, D. Angew. Chem.,
Int. Ed. 1998, 37, 2014–2045.
Our synthetic journeycommenced witha novelsynthesis
of ketoacid 3 (Scheme 2). Thus, asymmetric reduction of
2,2-dimethyl-1,3-cyclopentandione (9) with catecholborane
(9) Mulzer, J.; Gaich, T. Org. Lett. 2005, 7, 1311.
Org. Lett., Vol. 14, No. 24, 2012
6355

Scheme 3. A Model Study of the Tethered RCM Reactions
Scheme 4. Synthesis of 4 via Bissiloxane-Tethered RCM Reac-
tion
Scheme 5. Total Synthesis of (À)-Epothilone D (2) and (À)-
Epothilone B (1)
The optimal conditions obtained from the model study
were applied to the construction of 4 (Scheme 4). Segments
7 and 8 were joined with ClSi(iPr)2OSi(iPr)2Cl (ClSOSCl)
in the presence of DBU to deliver 6 in 82% yield. Gratify-
ingly, the RCM reaction of 6 proceeded efficiently in the
presence of the Grubbs-II catalyst (5 mol %) to give 16 in a
nearly quantitative yield (95%) with a selectivity of 1.7/1
favoring the desired (Z) isomer. The subsequent cleavage
of the SOS tether was critical for an efficient protecting-
group manipulation. After examining several reagents,
HF pyridine was found capable of selectively cleaving
3
the least hindered SiÀO bond, generating FSi(iPr)2OSi-
(iPr)2 (FSOS) group attaching to the more hindered
C15ÀO atom. After separation of the two stereoisomers
by chromatography followed by oxidation of the (Z) isomer
with Dess-Martin periodinan, aldehyde 4 was obtained in
40% yield over three steps from 6. Notably, this new syn-
thetic route delivers 4 in 33% overall yield covering merely
four steps from 7 (8), which is so far the most step-economic
synthesis of this key segment.10
With both 3 and 4 in hand, the stage was now set for the
critical aldol reaction (Scheme 5). In the previously re-
ported syntheses, the aldol reaction with ketoacid 3 as the
substrate had generally been ineffective in controlling the
diastereoselectivity of the newly generated stereocenters at
C6 and C7.5a,6 To achieve efficient stereocontrol, it had been
necessary to use substrates with protected alcohols4b,6 or an
auxiliary6 in place of the free carboxylic acid. We anticipated
realizing the aldol reaction with the direct use of the carbox-
ylic acid as the substrate for higher synthetic efficiency. Em-
ployment of LDA (2.5 equiv) generated the aldol product
with a diastereoselectivity of ca. 1/1. Fortunately, treatment
of 3 with TiCl4/DIPEA6 (2 equiv for each) followed by
addition of 4 afforded 17 in 51% yield (73% brsm) as a
single diastereomer as determined by 1H NMR. Both the
compact transition state A and the extended transition
state B could account for the observed stereochemical
outcome of this reaction. However, transition state B
appears more reasonable based on the evidence that usage
of 2 equiv of TiCl4 was necessary for the reaction to
proceed effectively.
(10) Both 7 and 8 were synthesized in three steps. See Supporting
Information for the details. For previous syntheses of 4 (R = TBS), see:
References 5a (17 steps), 4b (12 steps), 9 (11 steps), and 3b (16 steps). For
previous syntheses of 4 (R = SEM), see: Reference 6 (8 steps).
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Org. Lett., Vol. 14, No. 24, 2012

The aldol product 17 was advanced into the targets
(Scheme 5). Protection of C7-OH with TBSOTf/2,
6-lutidine followed by the selective removal of FSOS with
TBAF generated 18. Finally, by following the known
procedure, 18 was converted to epothilone D (2) and
epothilone B (1) successfully.5a Thus, 18 was exposed to
Yamaguchi’s conditions to effect the macrolactonization
to engender 19 in 81% yield. Global deprotection with
TFA afforded epothilone D (2) in 91% yield. Finally,
treatment of 2 with m-CPBA produced epothilone B (1)
and its isomer in 4/1 ratio with 83% overall yield. The
spectroscopic data of synthetic 2 and 1 matched those
reported for the natural products.
In conclusion, an efficient total synthesis of (À)-epothilone
B (1) has been achieved in ca. 8% yield over 11 steps
from 9 or 10 steps from 7/8 (each being synthesized in three
steps), which forms a new basis for further development of
an industrial process for epothilone B and ixabepilone.
This new synthetic route of epothilone B features a novel
and efficient synthesis of 3, a bissiloxane-tethered RCM
reaction which efficiently realized the assemblage of
segments 7 and 8 with selective formation of the trisub-
stituted (Z) double bond, and a stereochemically well con-
trolledaldol reactionofunmasked carboxylic acid3 with4.
The demonstrated successinthe bissiloxanetetheredRCM
reactions, along with the success in the partial cleavage of
the SOS tether and the selective removal of FSOS in the
presence of TBS, points to the potential broader interests
of SOS in organic synthesis, especially in the total synthesis
of complex molecules.
Acknowledgment. Financial support from the National
Natural Science Foundation of China (Grant Nos.
20902101, 21172246, 21290180) and National Basic Re-
search Program of China (973 Program, Grant No.
2010CB833206) are gratefully appreciated.
Supporting Information Available. Experimental pro-
cedures, characterization data for new compounds, and
selected copies of NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 24, 2012
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