A total synthesis of epothilones using solid-supported reagents and scavengers

Article abstract of DOI:10.1002/anie.200351413

A total synthesis of epothilone C(1) with concomitant formal synthesis of epothilone A is described, using immobilized reagents and scavengers to effect multistep synthetic transformations and purifications.

Full text of DOI:10.1002/anie.200351413

Angewandte
Chemie
sites in b-tubulin as taxol.[2] However,certain epothilones
exhibit a higher activity than taxol,even against multiple-
drug-resistant cells,and are more soluble in water,making
them interesting drug candidates.
Several total syntheses of both natural and analogous
epothilones have been reported reported since the disclosure
[
3–12]
of their biological importance.
However,as a result of the
complexity of these molecules,all previous synthetic pro-
grams have required extensive silica-gel chromatography to
provide material free from contaminating by-products.
Although acceptable in the research laboratory,such proc-
esses cannot be efficiently accommodated within larger-scale
production,nor are they appropriate for the high-throughput
preparation of libraries of analogues,in which speed and
simplicity of operation are important criteria.
In recent years we have begun to explore the utility of
commercially available immobilized reagents and scaven-
[
13]
[14]
gers in the synthesis of drugs and natural products. The
combined application of these tools has been shown to
provide versatile methods for molecular conversion and
elimination of impurities,thereby offering the opportunity
to avoid conventional approaches to reaction quenching,
extraction,and purification.
Herein we describe how immobilized reagents and
scavengers have been employed in a multistep sequence
leading to epothilones A (1) and C (2),avoiding frequent use
of conventional workup and purification procedures,includ-
ing flash-column chromatography,recrystallization,and dis-
tillation (Scheme 1).
Our approach to the 16-membered macrocycle is similar
to several previously published syntheses in that it utilizes a
stereoselective union of three fragments by lithium aldol
Solid-Supported Total Synthesis
(C6–C7) and Wittig (C12–C13) reactions,followed by
A Total Synthesis of Epothilones Using Solid-
Supported Reagents and Scavengers**
macrolactonization (C1–C15) to provide epothilone C
[
7,8,15]
(2; Scheme 1).
Epoxidation can then be applied to the
R. Ian Storer, Toshiyasu Takemoto, Philip S. Jackson,
and Steven V. Ley*
The epothilone natural products[1] exhibit extraordinary
cytotoxic biological activity by promoting GTP-independent
tubulin polymerization. This mode of action inhibits the
growth of tumors by inducing mitotic arrest,followed by cell
apoptosis. Mechanistic investigations have revealed that the
epothilones bind competitively to the same,or overlapping,
[
*] Prof. S. V. Ley, R. I. Storer, Dr. T. Takemoto, Dr. P. S. Jackson
University Chemical Laboratories, University of Cambridge
Lensfield Road, Cambridge, CB2 1EW (UK)
Fax: (+44)1223-336-442
E-mail: svl1000@cam.ac.uk
[
**] We gratefully acknowledge financial support for this work from
AstraZeneca (to I.R.S.), the EPSRC (to P.S.J.), Merck Sharp &
Dohme (to P.S.J.), Sankyo Co. Ltd., Japan (to T.T.), a B.P.
endowment (to S.V.L.), and a Novartis Research Fellowship (to
S.V.L.). The authors would like to thank Dr. Dearg Brown of
AstraZeneca for support and useful discussions and Dr. Karl-Heinz
Altmann of Novartis, Switzerland for a generous donation of
authentic materials.
Scheme 1. Synthetic plan.
Angew. Chem. Int. Ed. 2003, 42, 2521 – 2525
DOI: 10.1002/anie.200351413
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2521

Communications
C12–C13 double bond to complete the synthesis of epo-
thilone A (1).
The stereogenic center in fragment 1 (3) was efficiently
Synthesis of aldehyde fragment 2 (4) utilized a popular
strategy that allowed access from a commercially available
“(R)-Roche ester” derivative. Protection of (R)-(ꢀ)-3-
bromo-2-methyl-1-propanol (13) as the tetrahydropyranyl
acetal was achieved with polymeric sulfonic acid catalysis and
was followed by a Finkelstein halide exchange to provide the
more reactive primary iodide 14 (Scheme 3). Workup
required addition of diethyl ether and silica gel to bind any
remaining dissolved inorganic salts prior to filtration. CuI-
mediated substitution with 3-butenylmagnesium bromide,
followed by Amberlite IRC-50 acidic quench and a trisamine
copper scavenge,yielded desired alkene 15. Acid-catalyzed
deprotection in methanol and oxidation of the corresponding
alcohol with pyridinium chlorochromate on alumina,pro-
vided fragment 2 (4).
[
5]
installed by using Kiyooka's asymmetric Lewis acid catalyzed
Mukaiyama aldol methodology between readily accessible
[
16]
aldehyde 8 and silyl enol ether 9 in a similar manner to the
groups of Mulzer and Taylor.[
10,11]
Sulfonamide-protected d-
phenylalanine in combination with borane gave optimal
results,providing the desired alcohol adduct 10 in > 92% ee
[
17]
(
Scheme 2). The reaction was quenched by the addition of a
small amount of water and Amberlite IRA-743,a boron-
specific scavenging resin,allowing efficient separation of the
desired product and quantitative recovery of the amino acid.
A silyl protecting group was introduced by using tert-
butyldimethylsilyl triflate in the presence of basic diethyl-
aminomethyl polystyrene. Ester 11 was converted into ethyl
ketone fragment 1 (3) by the single addition of (trimethylsi-
lylmethyl)lithium followed by monoalkylation. Both steps
were quenched by a supported carboxylic acid to neutralize
the reactions and scavenge the lithium ions.[
10]
Scheme 3. Synthesis of fragment 2. a) 3,4-Dihydropyran (1.02 equiv),
ꢀ
1
PS TsOH (0.05 equiv, 4.2 mmolg ), neat, 30 min, 100%; b) NaI
3 equiv), 2-butanone, 758C, 1 h, then Et O, silica-gel filtration, 96%;
(
2
c) CuI (1.0 equiv), 3-butenylmagnesium bromide (4.0 equiv), THF,
ꢀ
108C!08C, 2 h, then Amberlite IRC-50 (3.0 equiv, ~5.0 mmolgꢀ1)
ꢀ
1
and PS trisamine (3.0 equiv, 4.36 mmolg ), room temperature, 24 h,
ꢀ1
97%; d) MP-TsOH (0.04 equiv, 4.2 mmolg ), MeOH, RT, 7 h 30 min,
ꢀ
1
97%; e) pyridinium chlorochromate on Al O (3.0 equiv, 1.0 mmolg ),
2
3
CH Cl , room temperature, 3.5 h, 80%. MP=macroporous polymer.
2
2
A precedented,convergent route was applied to the
formation of thiazole fragment 3 (5). A commercially avail-
able lactone derivative of malic acid was used to provide the
necessary stereochemistry at C15. Silyl protection of S-(ꢀ)-a-
hydroxy-g-butyrolactone (16) was followed by the addition of
1 equivalent of methyllithium to give lactol 17,which was
subsequently trapped as the open-chain ketone 18 upon the
[
18]
Scheme 2. Synthesis of fragment 1. a) TBSCl (1.4 equiv), PS DMAP
ꢀ1
(
2.0 equiv, 1.49 mmolg ), CH Cl , room temperature, 2.5 h, 96%;
2 2
ꢀ1
b) O , CH Cl , ꢀ788C, 20 min, then PS PPh (1.5 equiv, 3.3 mmolg ),
3
2
2
3
[
6]
ꢀ
788C!RT, 12 h, 93%; c) N-Ts-d-phenylalanine (1.2 equiv), BH ·THF
formation of a second TBS ether (Scheme 4). In parallel,the
hydrochloride salt of 4-chloromethyl-2-methylthiazole (19)
was deprotonated with polymer-supported carbonate,before
heating with excess triethylphosphite to yield phosphonate
20. The residual triethylphosphite was subsequently removed
3
(
1.05 equiv, 1.5m), CH Cl , 08C!RT, 1 h, then 8 (1.0 equiv), ꢀ948C,
2
2
1
5 min, then 9 (1.0 equiv), ꢀ948C!ꢀ788C, 105 min, then H O
2
(
5 equiv), Amberlite IRA-743 (1.3 equiv), ꢀ788C!RT, 6 h, 93% (92%
of N-Ts-d-phenylalanine recovered); d) TBSOTf (2.0 equiv), diethylami-
ꢀ
1
nopolystyrene (5.0 equiv, 3.2 mmolg ), CH Cl , 08C!RT, 165 min,
2
2
[
6]
under reduced pressure. Deprotonation of phosphonate 20
with butyllithium,followed by Horner–Wadsworth–
then MeOH (25 equiv), room temperature, 1 h, 100%; e) (trimethyl-
silylmethyl)lithium (2.2 equiv, 1.0m pentane), pentane, 08C, 195 min,
then MeOH (50 equiv), 08C!RT, 5 h, then Amberlite IRC-50
a
Emmons olefination with ketone 18 provided thiazole
adduct 21. An excess of the phosphonate anion was used,
which was later scavenged by a polymeric benzaldehyde
equivalent,followed by the addition of silica gel to bind the
polar phosphorus by-products. This provided the desired E-
trisubstituted olefin 21 after simple filtration. Selective
deprotection of the primary hydroxy group was effected in
ꢀ
1
(
2.5 equiv, ~5.0 mmolg ), room temperature, 75 min, 100%; f) LDA
2.3 equiv), THF, ꢀ788C!ꢀ158C, 30 min, then MeI (3.1 equiv),
(
ꢀ
788C!ꢀ408C, 2 h, then Amberlite IRC-50 (12 equiv,
ꢀ1
~
5.0 mmolg ), room temperature, 2 h, 94%. TBS=tert-butyldimeth-
ylsilyl, PS=polymer-supported, DMAP=4-dimethylaminopyridine,
Tf =trifluoromethanesulfonyl, LDA=lithium diisopropylamide,
Ts =para-toluenesulfonyl, TMS=trimethylsilyl.
2
522
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Angew. Chem. Int. Ed. 2003, 42, 2521 – 2525

Angewandte
Chemie
fragment combination of ketone 3 and aldehyde 4.[20] The use
of freshly prepared lithium diisopropylamide in THF reliably
gave excellent selectivity (> 13:1) for the desired anti-
[
21]
Felkin–Anh adduct 24,
with an excess of the aldehyde
required to force the reaction to completion. After quenching
with acetic acid,diamine polymer was added to scavenge
excess acid and aldehyde fragment from the crude reaction
mixture. Protection of aldol adduct 24 followed by ozonolysis,
using polymer-supported triphenylphosphane to reduce the
ozonide,efficiently gave aldehyde 25 in preparation for Wittig
coupling with fragment 3 (5).
Treatment of immobilized phosphonium salt 23 with
excess sodium bis(trimethylsilyl)amide followed by washing
with dry THF allowed the isolation of the corresponding salt-
[
22]
free ylide. Coupling of aldehyde 25 with this ylide installed
the necessary cis olefin exclusively (Scheme 5). Selective
primary alcohol deprotection yielded 26,which after a two-
step oxidation with catalytic TPAP in the presence of NMO[
followed by polymer-supported chlorite,gave the correspond-
23]
[
24]
ing carboxylic acid. Selective removal of the allylic TBS
[
25]
ether by using excess TBAF provided hydroxy acid 27 in
[
8]
readiness for macrolactonization.
Macrolactonization of linear hydroxy acid 27 proceeded
under Yamaguchi conditions,using a polymer-supported
DMAP equivalent,to furnish the required 16-membered
[
8,12]
lactone.
Polymeric sulfonic acid resin was used not only to
Scheme 4. Synthesis of fragment 3. a) TBSCl (1.4 equiv), PS DMAP
remove both TBS protecting groups,but also to protonate the
thiazole nitrogen atom and to capture the natural product as
an ion-exchanged salt. Unbound impurities were removed by
washing the resin with dichloromethane,before subsequent
release of epothilone C by using a basic solution of ammonia
in methanol. Having obtained the natural product as a
mixture containing over 90% of the desired diastereoisomer,
the material was then finally purified by flash column
chromatography to provide pure epothilone C (2). Epoxida-
tion of epothilone C has been shown to proceed with facial
ꢀ1
(
2.0 equiv, 1.49 mmolg ), CH Cl , RT, 1 h 30 min, 97%; b) MeLi
2 2
(
~
1
1.05 equiv), THF, ꢀ788C, 1 h, then Amberlite IRC-50 (20 equiv,
ꢀ1
10 mmolg ), 98%; c) TBSCl (1.48 equiv), PS DMAP (2.0 equiv,
ꢀ1
.49 mmolg ), CH Cl , room temperature, 2.5 h, 98%; d) PS carbon-
2 2
ꢀ1
ate (2 equiv, 3.5 mmolg ), MeOH, room temperature, 45 min, 98%;
e) triethylphosphite (1.2 equiv), neat, 1608C, 3.5 h, 84%; f) 20
(
(
3.5 equiv), nBuLi (3.5 equiv), THF/hexanes, ꢀ788C, then 18
1.0 equiv), ꢀ788C!RT, 1.5 h, then PS benzaldehyde (5.0 equiv, 1.2
ꢀ1
mmolg-1) and Amberlite IRC-50 (10 equiv, ~5 mmolg ), 105% by
mass w.r.t. ketone 18; g) CSA (1.5 equiv), MeOH/CH Cl (1:1), 08C,
2
2
2
ꢀ
1
.5 h, then PS carbonate (2.2 equiv, 3.5 mmolg ), 2 h, 104%;
ꢀ1
[3]
h) iodine (4.0 equiv), PS PPh (5.0 equiv, 3.3 mmolg ), imidazole
selectivity to provide a formal synthesis of epothilone A (1).
3
(
(
6.0 equiv), MeCN/Et O (3:1), then diethylaminomethylpolystyrene
2
8.0 equiv, 3.2 mmolg ), Amberlite IRC-50 (13.0 equiv, ~5 mmolg ),
In summary,we have demonstrated the scope and utility
of supported reagents and scavenging techniques within a
multistep synthesis by stereoselectively providing epothi-
lone C in 29 steps overall and with a longest linear sequence
of only 17 steps from commercially available materials.[ The
high selectivity and overall efficiency is comparable with the
best of the previous conventional syntheses. As epothilone C
is the most challenging target that has been synthesized by
using solid-phase reagent and scavenging techniques,we hope
that this will encourage their future integration alongside
conventional methods for application within general synthesis
programs.
ꢀ
1
ꢀ1
toluene, room temperature, 105 min, 73%; i) PS PPh (1.0 equiv,
3
ꢀ
1
3
.3 mmolg ), toluene, 908C, 18 h. CSA=10-camphorsulfonic acid.
26]
acidic solution and quenched by a polymer-supported car-
bonate,before conversion of the resulting alcohol 22 into
iodide 5 by treatment with polymer-supported triphenylphos-
phane and iodine. The corresponding resin-bound phospho-
nium iodide salt 23 of fragment 3 was then formed,in
preparation for Wittig coupling,by heating iodide 5 with
polymer-supported triphenylphosphane in toluene. This final
“
catch” step also permitted separation from minor phospho-
rus contaminants that had remained following the olefination
coupling.
Received: March 17,2003 [Z51413]
Aldol coupling between fragments 1 (3) and 2 (4) gen-
erates two new stereocenters,so a highly diastereoselective
process was required. Coupling at C6–C7 has been exten-
sively investigated on a wide variety of substrates,and shown
to be highly sensitive to proximal and remote functionality in
Keywords: aldol reaction · antitumor agents · natural products ·
polyketides · polymers
.
[
9,19]
both fragments.
Our approach,although bearing close
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Angew. Chem. Int. Ed. 2003, 42, 2521 – 2525
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2523

Communications
Scheme 5. Fragment coupling and cyclization. a) LDA (1.6 equiv), THF, ꢀ788C!ꢀ408C, 1.5 h, then aldehyde 4 (1.5 equiv), ꢀ788C, 20 min, then
AcOH (5 equiv), ꢀ788C!RT, 30 min, then PS diamine (4.8 equiv, 3.0 mmolg ), room temperature, 2 h, 100% (13.5:1); b) TBSOTf (1.5 equiv),
diethylaminopolystyrene (3.0 equiv, 3.2 mmolg ), CH Cl , 08C!RT, 205 min, then MeOH (3.0 equiv), room temperature, 2 h, 99%; c) O ,
ꢀ1
ꢀ1
2
2
3
ꢀ
1
CH Cl , ꢀ788C, 20 min, then PS PPh (5.0 equiv, 3.3 mmolg ), ꢀ788C!RT, 15 h, 100%; d) phosphonium salt 23 (2.5 equiv), NaHMDS
2
2
3
(
10.0 equiv), THF, room temperature, 15 min, then THF wash, then aldehyde 25 (1.0 equiv), ꢀ788C!ꢀ408C, 15 min, 93%; e) CSA (1.0 equiv),
MeOH/CH Cl (1:1), 08C, 4 h, 99%; f) TPAP (0.05 equiv), NMO (1.5 equiv), CH Cl , 08C!RT, 3 h 10 min, then Et O through silica pad, 93%;
2
2
2
2
2
ꢀ
1
ꢀ1
g) PS chlorite (2 equiv, ~0.5 mmolg ), PS dihydrogenphosphate (3 equiv, ~0.5 mmolg ), 2-methyl-2-butene (5 equiv, 2m in THF), tBuOH/H O
2
(
1:2), room temperature, 6 h, 99%; h) TBAF (6 equiv, 1m in THF), THF, room temperature, 12 h, 95%; i) 2,4,6-trichlorobenzoylchloride
(
10.0 equiv), triethylamine (12 equiv), room temperature, 50 min, then added to PS DMAP (20 equiv), THF/toluene (1:25), 808C, 2.5 h; j) PS
ꢀ
1
TsOH (12 equiv, 1.5 mmolg ), CH Cl , 1 h, then CH Cl and Et O wash, then release with NH (2m in MeOH), 81% (over two steps), k) refer-
ence [ . HMDS=bis(trimethylsilyl)amide, NMO=4-methylmorpholine N-oxide, TBAF=tetrabutylammonium fluoride, TPAP=tetra-N-propylam-
2
2
2
2
2
3
4]
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[
[
5
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[
[
[
[
17] Enantiomeric excess determined by 1H NMR spectroscopy
(
Mosher esters).
18] All yields quoted are based on mass recovery,assuming
quantitative conversion into products.
19] C. R. Harris,S. D. Kuduk,A. Balog,K. A. Savin,S. J. Danishef-
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20] It was necessary to perform a filtration through silica gel to
remove baseline impurities from ketone fragment 1 (3) prior to
the aldol coupling.
[
21] The same reaction also proceeded well in diethyl ether,although
the selectivity appeared to be more capricious,varying from 10:1
to as high as > 30:1.
[
[
22] M. H. Bolli,S. V. Ley, J. Chem. Soc. Perkin Trans. 1 1998,2243.
23] W. P. Griffith,S. V. Ley,G. P. Whitcombe,A. D. White, J. Chem.
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[
[
24] T. Takemoto,K. Yasuda,S. V. Ley, Synlett 2001,1555.
25] It proved to be necessary to perform an aqueous workup to
remove the excess TBAF from the reaction.
[
26] Although no attempt was made to recycle or regenerate the
immobilized reagents,owing to the scale of this particular
synthesis,recycling remains an option for larger-scale processes.
Angew. Chem. Int. Ed. 2003, 42, 2521 – 2525
www.angewandte.org
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2525