Multi-step application of immobilized reagents and scavengers: A total synthesis of epothilone C

Article abstract of DOI:10.1002/chem.200305669

The total synthesis of the cytotoxic antitumour natural product epothilone C has provided a stage for the exploitation and further development of immobilized reagent methods. A stereoselective convergent synthetic strategy was applied, incorporating polymer-supported reagents, catalysts, scavengers and catch-and-release techniques to avoid frequent aqueous work-up and chromatographic purification.

Full text of DOI:10.1002/chem.200305669

FULL PAPER
Multi-Step Application of Immobilized Reagents and Scavengers: A Total
Synthesis of Epothilone C
[a]
[b]
R.Ian Storer, [a] Toshiyasu Takemoto,[a] Philip S.Jackson, Dearg S.Brown,
[a]
[a]
Ian R.Baxendale, and Steven V.Ley*
Abstract: The total synthesis of the cytotoxic antitumour natural product epothilo-
ne C has provided a stage for the exploitation and further development of immobi-
lized reagent methods. A stereoselective convergent synthetic strategy was applied,
incorporating polymer-supported reagents, catalysts, scavengers and catch-and-re-
lease techniques to avoid frequent aqueous work-up and chromatographic purifica-
tion.
Keywords: aldol reaction ¥ antitu-
mor agents ¥ immobilized reagents ¥
polyketides ¥ polymers
Introduction
them to their full capacity.[2,6] During this period we have
started to explore the combined application of immobilized
reagents and scavengers for the parallel syntheses of drug
compound collections and natural products.[7,8] This has
proven to be a versatile means for molecular conversion and
impurity elimination, offering the opportunity to omit con-
ventional labour intensive approaches to reaction quench-
ing, extraction and purification.
Epothilones A and B (Figure 1) were discovered by
Hˆfle, Reichenbach and their co-workers in the early
1990s.[9] In 1995 widespread interest was triggered when the
epothilones were found to be potent inhibitors of tumor cell
proliferation inducing mitotic arrest by the same mechanism
as Taxol.[10] Accordingly, significant advances in both syn-
thetic chemistry and biology have emerged from the result-
ing studies that may ultimately result in the development of
new and more effective chemotherapeutic agents for the
treatment of cancers.[11]
There have been many total syntheses of both natural and
designed epothilones reported since the disclosure of their
full structural assignments.[12 27] However, these conventional
syntheses all required extensive silica gel chromatography to
provide material free from contaminating by-products.
While this is generally accepted in the research laboratory,
such processes are not ideal for larger scale production, nor
are they appropriate for the high-throughput synthesis of li-
braries of analogues.
Developments in high-throughput screening and automated
technologies have revolutionised both pharmaceutical and
agrochemical research. The capacity to design and test thou-
sands of compounds per day has resulted in an increasing
burden on synthetic chemists to construct an unprecedented
number of new molecules that possess wide structural diver-
sity. Consequently, methods have been sought to allow effi-
cient, multi-parallel synthesis and offer a practical simplicity
that is readily applicable to both automation and scale-
up.[1,2]
Investigations into solid phase organic synthesis heralded
the birth of combinatorial chemistry, offering conceptual
compatibility with parallel and automated approaches.[3]
However, despite the advantages this technology continues
to suffer from inherent limitations that have catalyzed the
search for superior alternatives.[4] Arguably the most promis-
ing of these advances has been the application of immobi-
lized reagents, catalysts and scavengers.[1,2]
Although there have been numerous applications of sup-
ported reagents during the past fifty years,[5] it was only
during the last decade that chemists have begun to exploit
[a]Dr. R. I. Storer, Dr. T. Takemoto, Dr. P. S. Jackson,
Dr. I. R. Baxendale, Prof. Dr. S. V. Ley
Department of Chemistry
University of Cambridge
Recently we reported the application of immobilized re-
agent techniques to the total synthesis of epothilone C and
concurrent formal synthesis of epothilone A.[7] Herein these
results are further discussed in context with several alterna-
tive approaches that were also investigated to elucidate this
technology as an advancing concept within complex molecu-
lar assembly.
Lensfield Road
Cambridge, CB2 1EW (UK)
Fax : (+44)1223-336-442
E-mail: svl1000@cam.ac.uk
[b]Dr. D. S. Brown
AstraZeneca
Mereside, Alderley Park
Cheshire, SK10 4TG (UK)
2529
Chem. Eur. J. 2004, 10, 2529 2547
DOI: 10.1002/chem.200305669
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

FULL PAPER
Fragment 2 (4) was generated from a commercially availa-
ble Roche ester derivative to provide the C8 stereochemis-
try.
Fragment 3 (5) was obtained by two independent meth-
ods: Initially the C15 stereocentre was installed using a
Brown allylation in conjunction with a catch-and-release
method to isolate the resulting allyl alcohol;[17] while the
second method incorporated a commercially available asym-
metric a-hydroxylactone derivative of malic acid to intro-
duce the C15 stereocentre.[14,15,21]
Figure 1. The natural epothilones.
Synthetic plan: Previous synthetic routes to the epothilone
16-membered macrocycle commonly involved convergent
strategies, connecting fragments by a stereoselective C6 C7
aldol coupling, prior to either C1 C15 macrolactonization or
C12 C13 ring-closing metathesis.[17,18,28]
Accordingly, our route incorporated the enantioselective
preparation of three fragments 1 (3), 2 (4), and 3 (5), and
their subsequent diastereoselective coupling to provide a
convergent approach to epothilone C (2) (Figure 2). The
synthesis included some well-established chemistry whilst in-
tegrating existing and newly devised immobilized reagent
methodologies.
Results and Discussion
Ketone fragment 1: It was initially planned to derive frag-
ment 1 (3) from pantolactone 6, readily available as a single
enantiomer with the requisite geminal dimethyl group in
place.[24] Pantolactone 6 was TBS-protected using tert-butyl-
dimethylsilylchloride in conjunction with a supported guani-
dine base (TBD), followed by reduction by treatment with
DIBAL-H (Scheme 1). The reduction was quenched using
sodium sulfate decahydrate to precipitate the aluminium
salts, necessitating only filtration and concentration to pro-
vide lactol 8. Successful transformation to olefin 10 was car-
ried out via a Peterson olefination, involving the addition of
(trimethylsilylmethyl)magnesium chloride followed by
a
scavenger quench using Amberlite IRC-50 immobilized car-
boxylic acid. Subsequent treatment with Lewis acid,
quenched using a polymeric carbonate then affected the
elimination to provide alkene 10. The primary alcohol of
diol 10 was selectively protected as the benzoate ester 11,
followed by a hydroboration oxidation sequence to gener-
ate diol 12. The derived material 12 was then purified by its
covalent attachment to a trityl functionalized resin; this per-
mitted extensive washing to remove contaminating by-prod-
ucts prior to its cleavage from the resin. A double TBS pro-
tection, followed by selective removal of the benzoate group
of 13 using DIBAL-H provided alcohol 14. Oxidation of the
primary alcohol 14 using pyridinium chlorochromate (PCC)
on alumina, extracting the product by filtration through Flo-
risil, furnished aldehyde 15 which was further homologated
to the desired ketone 3 via an ethylmagnesium chloride ad-
dition oxidation sequence. Work-up of intermediate alcohol
16 was smoothly facilitated by polymer-supported acid
quench (Amberlite IRC-50). Subsequent oxidation using
PCC on basic alumina afforded the target fragment 3 in
12 steps.
Although this route provided the desired fragment 1 (3)
in high enantiopurity, the synthesis was somewhat lengthy.
In an attempt to develop a more efficient route, several al-
ternative strategies were investigated. It was decided that
methods to selectively construct the stereocentre would
offer improved synthetic efficiency.
Asymmetric aldol reaction using Oppolzer×s chiral auxili-
ary 19 was employed to establish a more efficient route for
the synthesis of the fragment 3 (Scheme 2). Sultam 19 was
acylated with excess 2-bromoisobutyryl bromide 20 in the
presence of sodium hydride. Excess acyl bromide 20 was ef-
ficiently scavenged using polymer-supported-trisamine to
Figure 2. Synthetic plan.
The stereoselective union of fragments 1 (3) and 2 (4) by
C6 C7 lithium aldol was followed by a C12 C13 Wittig re-
action to incorporate fragment 3 (5). Ring closure by C1
C15 macrolactonization subsequently provided the natural
product epothilone C (2), from which there is precedent for
epoxidation to epothilone A (1) (Figure 2).[13]
Three independent methods were simultaneously investi-
gated to construct fragment 1 (3): The first incorporated
stereochemistry available from the application of pantolac-
tone 6;[24,29] the second applied Oppolzer×s sultam chiral aux-
iliary to induce the desired asymmetry;[30] while the final ap-
proach utilised Kiyooka×s chiral borane Lewis acid method-
ology[31] to install the C3 chiral centre via an asymmetric
Mukaiyama aldol reaction.[21,22]
2530
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 2529 2547

A Total Synthesis of Epothilone C
2529 2547
OH
OTBS
O
OTBS
OH
a)
O
Al2O3•HCrO3Cl
b) DIBAL-H
a) TBSCl
N
HO
OTBS
OTBS
O
18
17
O
O
O
O
c)
8
6
7
N
N
b)
Br
Br
20
MgCl
TMS
CO2H
O
NaH
Br
NH
N
e) BzCl
NH2
NH2
S
S
c) CrCl2
N
21
O
O
O O
N
N
H
N
H
OH OTBS
OH OH
d) BF3•Et2O
H2N
N
NMe3OH
OH
H2N
19
TMS
d) TBSOTf
N
NEt3 NaCO3
OH
10
9
N
N
O
O
OTBS
O
f) BH3•THF
then MeOH
N
OTBS
N
OTBS
OBz OH
S
S
OBz OH
NEt3 NaCO3
22
O
O
O
O
RRNC(O), 23
H2C(OH), 14
OH
H2O2
h) TBSOTf
N
2
12
11
NMe3 S2O3
e) DIBAL-H
2
g)
Ph
f)
Al2O3•HCrO3Cl
then
5% TFA
O
Cl
NEt3
Ph
O
OTBS
g) EtMgCl
CO2H
Al2O3•HCrO3Cl
O
OTBS
O
OTBS
OBz OTBS
i) DIBAL-H
Al2O3•HCrO3Cl
H
OTBS
OTBS
H
OTBS
OTBS
3
j)
CHO, 15
EtC(OH), 16
h)
CHO, 15
EtC(OH), 16
k) EtMgCl
CO2H
Al2O3•HCrO3Cl
OBz, 13
OH, 14
Scheme 2. Auxiliary route to fragment 1. a) PCC on basic alumina
(3.0 equiv, 1.0 mmolgꢀ1), CH2Cl2, RT, 1 h, then silica gel (Et2O), 87%;
b) NaH (1.2 equiv, 60% dispersion), PhMe, 08C ! RT, 1 h, then 20
(1.5 equiv), 08C ! RT, 1 h, then PS-trisamine (3.0 equiv, 3.4 mmolgꢀ1),
then silica gel (Et2O), 92%; c) CrCl2 (4.0 equiv), LiI (0.1 equiv), 18
(2.0 equiv), THF, RT, 1 h, then Ambersep 900 (OHꢀ form) (19.5 equiv,
3.2 mmolgꢀ1), then silica gel (hexane/EtOAc 10:1), 92%; d) TBS triflate
(1.5 equiv), PS-NMM (5.0 equiv, 3.5 mmolgꢀ1), HCH2Cl2, 08C, 1 h, then
MeOH, then silica gel (hexane/EtOAc 10:1), 89%; e) DIBAL-H
(2.5 equiv, 1.0m in CH2Cl2), CH2Cl2, ꢀ788C, 1 h, then Na2SO4¥10H2O,
RT, then silica gel (hexane/EtOAc 10:1), 90%; f) PCC on basic alumina
(4.0 equiv, 1.0 mmolgꢀ1), CH2Cl2, RT, 20 h, then silica gel (Et2O), 100%;
g) EtMgBr (2.0 equiv, 2.0m in Et2O), THF, ꢀ788C, 2 h, then Amberlite
IRC-50, then silica gel (hexane/EtOAc 5:1), 98%; h) PCC on basic alu-
mina (3.0 equiv, 1.0 mmolgꢀ1), CH2Cl2, RT, 20 h, then silica gel (Et2O),
98%.[32]
l)
O
OTBS
OTBS
3
Scheme 1. Pantolactone route to fragment 1. a) TBSCl (2.0 equiv), PS-
TBD (5.0 equiv, 2.6 mmolgꢀ1), CH2Cl2, RT, 10 h, then MeOH, 96%;
b) DIBAL-H (1.3 equiv, 1.0m in PhMe), PhMe, ꢀ788C, 30 min, then
Na2SO4¥10H2O, RT, 99%; c) TMSCH2MgCl (4.0 equiv, 1.0m in Et2O),
THF, 608C, 10 h, then Amberlite IRC-50 (28 equiv, 10 mmolgꢀ1), RT,
94%; d) BF3¥Et2O (1.0 equiv), RT, 15 h, then MeOH, PS-carbonate
(5.0 equiv, 3.2 mmolgꢀ1), RT, 5 h, 98%; e) benzoyl chloride (1.2 equiv),
PS-TBD (3.0 equiv, 2.6 mmolgꢀ1), CH2Cl2, RT, 5 h, then PS-trisamine
(1.0 equiv, 4.27 mmolgꢀ1), RT, 73%; f) BH3¥THF (3.0 equiv, 1.0m in
THF), THF, 08C, 20 h, then MeOH, PS-carbonate (15.0 equiv,
3.23 mmolgꢀ1), 30% H2O2, PS-thiosulfate (4.0 equiv, 2.0 mmolgꢀ1), then
silica gel (Et2O), 68%; g) Et3N (3.0 equiv), PS-tritylchloride (2.0 equiv,
1.23 mmolgꢀ1), CH2Cl2, RT, 4 h, then CH2Cl2, 5% TFA, RT, 1 h, 88%;
h) TBS triflate (3.0 equiv), PS-NMM (10 equiv, 3.5 mmolgꢀ1), CH2Cl2,
08C ! RT, 20 h, then MeOH, 98%; i) DIBAL-H (3 equiv, 1m in hex-
anes), THF, ꢀ788C, 1 h, then Na2SO4¥10H2O, RT, then silica gel (hexane/
EtOAc 10:1), 77%; j) PCC on basic alumina (4.0 equiv, 1.0 mmolgꢀ1),
CH2Cl2, RT, 20 h, then silica gel (Et2O), 100%; k) EtMgBr (2.0 equiv,
2.0m in Et2O), THF, ꢀ788C, 2 h, then Amberlite IRC-50, then silica gel
(hexane/EtOAc 5:1), 98%; l) PCC on basic alumina (3.0 equiv,
1.0 mmolgꢀ1), CH2Cl2, RT, 20 h, then silica gel (Et2O), 98%.[32]
(Scheme 1) to afford fragment 1 (3) in a total of eight steps
(>95% de).
A final method to construct fragment 1 (3) was investigat-
ed in an attempt to provide an even more efficient route to
the desired molecule. This route is similar to those illustrat-
ed in the syntheses of Mulzer and Taylor.[21,22] As it offered
both the shortest synthetic sequence and proved readily
scalable, this method was subsequently adopted for the total
ꢀ
synthesis. Formation of the C3 C4 bond proceeded with
concomitant introduction of the desired C3 stereocentre by
application of the asymmetric Mukaiyama aldol reaction de-
veloped by Kiyooka (Scheme 3).[33]
isolate amide 21. The chromium enolate of amide 21 was
coupled with aldehyde 18 and quenched using polymer-sup-
ported-ammonium hydroxide to hydrolyze both the inter-
mediate chromium complex and precipitate the unwanted
chromium salts. Filtration of the subsequent suspension
through a bond elute silica gel pad yielded Reformatsky
adduct 22. Secondary alcohol 22 was silylated and the chiral
auxiliary removed by DIBAL-H reduction of amide 23 to
produce the corresponding alcohol 14. The final three steps
from alcohol 14 were carried out as previously described
Aldol reaction, mediated by a complex of borane with N-
tosyl-phenylalanine 26, provided the desired product 28 in
92% enantiomeric excess.[34] Work-up necessitated addition
of water and Amberlite IRA-743 27, a boron selective scav-
enger to quench the reaction and additionally remove con-
taminating boric acid. Filtration and solvent removal yielded
a suspension of amino acid in aldol product 28. The insolu-
bility of the N-protected amino acid 26 in non-polar organic
solvents permitted selective dissolution of the product 28.
Subsequent filtration enabled the amino acid residue to be
2531
Chem. Eur. J. 2004, 10, 2529 2547
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

S. V. Ley et al.
FULL PAPER
b) O3
PPh2
a) TBSCl
O
a)
OH
OTBS
25
OTBS
O
DMAP
Br
OH
I
OTHP
c) CuI
18
24
NH2
SO3H
O
33
CO2H
OH, 31
c)
Ph
b) NaI
OH
OTHP, 32
N
OH OH
NHTs
BH3•THF
OTMS
N
H
26
OH
O
MgBr
N
H2N
d) MeOH
SO3H
OH OH
27
O
MeO
OH
OTHP
H
e)
Al2O3•HCrO3Cl
O
OTBS
d) TBSOTf
NEt2
4
OTHP, 34
OH, 35
MeO
OTBS
MeO
OTBS
29
er >96:4 28
Scheme 4. Synthesis of fragment 2. a) 3,4-Dihydro-2H-pyran (1.02 equiv),
PS-TsOH (0.05 equiv, 4.2 mmolgꢀ1), neat, 30 min, 98%; b) NaI (3 equiv),
2-butanone, 758C, 1 h, then silica gel filtration (Et2O), 96%; c) CuI
(1.0 equiv), 3-butenylmagnesium bromide (4.0 equiv, 0.5m in THF), THF,
ꢀ108C!08C, 2 h 15 min, then Amberlite IRC-50 (15 equiv,
e) TMSCH2Li
CO2H
O
OTBS
O
OTBS
f) LDA, then MeI,
CO2H
10.0 mmolgꢀ1
)
and PS-trisamine (3.0 equiv, 4.36 mmolgꢀ1), RT, 24 h,
OTBS
OTBS
97%; d) MP-TsOH (0.04 equiv, 4.2 mmolgꢀ1), MeOH, RT, 7 h 30 min,
97%; e) PCC on basic alumina (3.0 equiv, 1.0 mmolgꢀ1), CH2Cl2, RT, 3 h
30 min, 80%.[32]
30
3
Scheme 3. Final synthesis of fragment 1. a) TBSCl (1.4 equiv), PS-DMAP
(2.0 equiv, 1.49 mmolgꢀ1), CH2Cl2, RT, 2 h 30 min, 96%; b) O3, CH2Cl2,
ꢀ788C, 20 min, then PS-triphenylphosphine (1.5 equiv, 3.3 mmolgꢀ1),
ꢀ788C!RT, 14 h, 93 %; c) N-Ts-d-phenylalanine (1.2 equiv), BH3¥THF
(1.05 equiv, 1.5m in THF), CH2Cl2, 08C!RT, 30 min, then aldehyde 18
(1.0 equiv), ꢀ968C, 15 min, then 1-methoxy-2-methyl-1-trimethylsilyloxy-
propene (1.0 equiv), ꢀ968C!ꢀ788C, 1 h 45 min, then H2O (5 equiv),
Amberlite IRA-743 (1.2 equiv, 1.0 mmolgꢀ1), ꢀ788C!RT, 6 h, 92%,
92% ee (92% of N-Ts-d-phenylalanine recovered); d) TBS triflate
(2.0 equiv), diethylaminomethylpolystyrene (5.0 equiv, 3.2 mmolgꢀ1),
CH2Cl2, 08C!RT, 2 h 45 min, then MeOH (25 equiv), RT, 1 h, 100%;
e) TMSCH2Li (2.2 equiv, 1.0m in pentane), pentane, 08C, 3 h 15 min,
then MeOH (50 equiv), 08C!RT, 5 h, then Amberlite IRC-50
(25.5 equiv, 10.0 mmolgꢀ1), RT, 1 h 30 min, 100%; f) LDA (2.3 equiv),
THF, ꢀ788C!ꢀ158C, 25 min, then MeI (3.1 equiv), ꢀ788C!ꢀ408C,
2 h, then Amberlite IRC-50 (25 equiv, 10.0 mmolgꢀ1), RT, 2 h, 94%.[32]
33. Work-up required the addition of Et2O to precipitate the
sodium salts, followed by slurring the mixture with silica gel;
filtration and solvent removal then yielded the iodide 33 as
a yellow oil.
Displacement of iodide 33 with the cuprate derived from
3-butenylmagnesium bromide gave the required alkene 34
(Scheme 4). Addition of carboxylic acid resin and trisamine
resin quenched the reaction and scavenged dissolved copper
salts. The resulting mixtures of dark precipitate and green
copper-chelated resins were removed by filtration through a
pad of silica gel followed by solvent removal to provide
alkene 34 as a pale yellow oil.
Hydrolysis of tetrahydropyran(THP)-acetal 34 was affect-
ed using catalytic sulfonic acid resin in methanol. The vola-
tility of the methoxy tetrahydropyran by-product allowed
straightforward purification of desired alcohol product 35.
Although a number of oxidative procedures proceeded to
completion, including tetrapropylammonium perruthenate
(TPAP)/NMO and Dess Martin reagent, PCC on basic alu-
mina was employed as the most expedient reagent provide
aldehyde fragment 2 (4) in five steps.
recovered and recycled whilst concentration of the filtrate
allowed isolation of adduct 28.
Protection of aldol adduct 28 proceeded using polymer-
supported-triethylamine equivalent and excess TBS triflate
to provide 29. Any residual TBS triflate was quenched by
the addition of methanol and the triflic acid retained within
the basic polymer, necessitating only simple filtration and
concentration to isolate the product 29.
A successful method for conversion of methyl ester 29 to
methyl ketone 30 had been demonstrated by Mulzer using
(trimethylsilylmethyl)lithium.[21] Application of this method
in combination with a scavenger-quench using a carboxylic
acid resin, yielded ketone 30 (Scheme 3).
Methyl alkylation of 30 was achieved by treatment of the
corresponding lithium enolate with iodomethane followed
by a polymer-supported acid quench to provide ethyl ketone
fragment 1 (3) in six steps.[21]
Fragment 3: Two methods were used to construct fragment 3
(5). Although attempts were made to generate the C15 ster-
eocentre by an asymmetric reduction using polymer-sup-
ported ligands, these proceeded with only low enantioselec-
tivities. As a result, a conventional boron allylation strategy
was successfully applied to provide a route to the desired
fragment 3 (5). A shorter alternative method was also devel-
oped that incorporated a commercially available enantio-
pure lactone 47 (Scheme 6).
Fragment 2: Commercially available (R)-(ꢀ)-3-bromo-2-
methyl-1-propanol 31, derived from the (R)-Roche ester,
was used as starting material for the synthesis of fragment 2
(4) (Scheme 4). Initial protection to form the tetrahydropyr-
anyl ether 32 proceeded smoothly under acid catalysis using
a polymeric sulfonic acid.
The initial route to fragment 3 (5) applied a Hantzsch
thiazole synthesis between dibromoacetone and thioaceta-
mide in dioxane to yield hydrobromide salt 36 as a precipi-
tate (Scheme 5). The free base 37 was obtained by treatment
of the salt with a polymer-supported carbonate, followed by
refluxing with polymer-supported triphenylphosphine to
form the polymer-supported-phosphonium bromide 38.
Treatment of the phosphonium salt 38 with an excess of
A Finkelstein halide exchange reaction then allowed con-
version of primary bromide 32 to the corresponding iodide
2532
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 2529 2547

A Total Synthesis of Epothilone C
2529 2547
sodium bis(trimethylsilyl)amide followed by resin washing
permitted the isolation of the immobilized ylide.[35] The
ylide was treated with THP protected a-hydroxyacetone 39
to yield the desired Wittig product 40 with a 10:1 E:Z ratio.
The corresponding triphenylphosphine oxide and unreacted
ylide remained bound to the polymer support and were re-
moved by simple filtration. Treatment of the resulting THP-
ether 40 with acidic Dowex-50X8 resin deprotected the alco-
hol and captured the thiazole via the basic nitrogen. Wash-
ing of the resin conveniently removed contaminants and
subsequent treatment with a solution of triethylamine in
methanol released the alcohol 41 from the resin support.
Oxidation of the primary alcohol to the required aldehyde
42 was achieved using catalytic polymer-supported per-
ruthenate at reflux under an atmosphere of oxygen.[36,37] The
key part of this route was the installation of the C15 chiral
centre in alcohol 43. A precedented route using Brown×s
(+)-diisopinocamphenylallyborane gave the best results,[13]
followed by an acid resin catch-and-release purification to
yield the desired alcohol 43 in 92% ee. Alcohol 43 was pro-
tected as the TBS ether 44, followed by conversion of
alkene 44 to aldehyde 46 via a dihydroxylation oxidative
cleavage sequence. It was initially envisaged that these reac-
tions could be achieved sequentially in a single reaction
vessel, however, it proved impossible to carry out both reac-
tions in the same solvent so a conventional two-step process
was applied. Dihydroxylation was achieved using catalytic
osmium tetroxide and polymer-supported N-methylmorpho-
line oxide as the co-oxidant. Polyvinyl pyridine was later
added to scavenge the osmium tetroxide from solution, and
the diol 45 was cleaved using polymer-supported periodate
with a simple filtration yielding fragment precursor aldehyde
46 in 12 steps.
S
a)
NH2
NEt3 NaCO3
S
O
Br
Br
c)
Br
N
b)
N•HCl, 36
PPh2
N, 37
S
S
d) NaHMDS
Ph
Ph
P
N
N
O
e)
Br
OTHP
40
OTHP
38
39
f)
g)
SO3H
Et3N
S
+
S
NMe3 RuO4
h)
N
N
42
O
O2
41
OH
(Ipc)2B
i)
j)
SO3H
k)
Et3N
S
N
S
l) TBSOTf, Et3N
N
N
OTBS
OH
N
N
43
C=C, 44
C(OH)C(OH), 45
S
N
O
N
m)
OsO4
O
OTBS
n)
o)
N
46
+
O
NMe3 IO4
Scheme 5. Asymmetric allylation route to fragment 3. a) Thioacetamide
(0.9 equiv), dioxane, reflux, 30 min, 82%; b) PS-carbonate (2.5 equiv,
4.5 mmolgꢀ1), MeOH, RT, 3 h, 96%; c) PS-triphenylphosphine
(0.78 equiv, 3.0 mmolgꢀ1), PhMe, 908C, 5 h; d) NaHMDS (6 equiv, 1.0m
in THF), THF, RT, 45 min; e) 39 (0.33 equiv), THF, RT, 15 h, 94%;
f) Dowex 50X8, MeOH, RT, 5 h; g) Et3N (10 equiv), MeOH, RT, 4 h,
92%; h) PS-perruthenate (0.2 equiv, 0.5 mmolgꢀ1), PhMe, O2, reflux,
16 h, 60%; i) (+)-diisopinocamphenylallylborane (1.5 equiv), Et2O,
ꢀ1008C, 3 h; j) Dowex 50X8, MeOH, RT, 5 h; k) Et3N (10 equiv),
MeOH, RT, 4 h, 89%; l) TBS triflate (1.2 equiv), Et3N (1.5 equiv), PS-
TBD (3.4 equiv, 2.2 mmolgꢀ1), CH2Cl2, RT, 16 h, 97%; m) PS-NMO
(8.5 equiv, ꢁ3.0 mmolgꢀ1), OsO4 (0.7 equiv), acetone/H2O 9:1, 408C,
16 h; n) polyvinylpyridine (6.8 equiv, ꢁ9.5 mmolgꢀ1), 97%; o) PS-perio-
dinate, methanol/H2O 5:1, RT, 24 h, 95%.[32]
As an alternative, it was chosen to adapt the methods first
described by Mulzer in which the C15 stereocentre was in-
stalled from commercially available (S)-a-hydroxy-g-lactone
47 (Scheme 6).[21,38]
Hydroxy lactone 47 was protected using TBSCl with poly-
mer-supported DMAP, followed by addition of methyllithi-
um, which was quenched with a carboxylic acid resin to pro-
duce hemiketal 49. This could be protected as the double
TBS ether ketone 50.
Phosphonate 53 was formed from thiazole chloride 52
(prepared from commercially available 51) by heating in
excess neat triethylphosphite. Most residual phosphite was
later removed under reduced pressure, although some phos-
phorus by-products remained and were carried through sub-
sequent steps. It was anticipated that the final formation of
polymer-supported phosphonium salt 56 for Wittig fragment
coupling would permit a catch-and-release purification, al-
lowing these residual impurities to be removed at this latter
stage.[35]
Phosphonate 53 was deprotonated and reacted with
ketone 50 (Scheme 6). An excess phosphonate anion was
used and later scavenged using a polymer-supported alde-
hyde, and addition of silica gel to bind any phosphorus by-
products. Although attempts were made to develop a sup-
ported version of this phosphonate, these proved to give
only poor loadings, and so were not applied.[39]
Selective mono-deprotection of bis-silyl protected thiazole
54 was affected using camphorsulfonic acid (CSA) in metha-
nol. The resulting mixture was scavenger-quenched by the
use of carbonate on support to provide the corresponding
alcohol 55.
Conversion of primary alcohol 55 to iodide 5 proceeded
using iodine with polymer-supported triphenylphosphine
and a polymer-supported triethylamine equivalents to yield
the fragment in a total of nine steps (seven steps longest
linear sequence) (Scheme 6).
Iodide 5 was converted to phosphonium salt 56 by heating
with polymer-supported triphenylphosphine in toluene. This
provided a supported phosphonium salt 56 with a loading of
0.9 mmolgꢀ1. The efficiency of the loading procedure was
enhanced by the recovery of any unloaded iodide 5 for sub-
sequent reuse.
2533
Chem. Eur. J. 2004, 10, 2529 2547
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

S. V. Ley et al.
FULL PAPER
The C12 alkene was cleaved by ozonolysis, quenching the
ozonide with polymer-supported triphenylphosphine to suc-
cessfully yield aldehyde 59 for application in a Wittig frag-
ment coupling (Scheme 7).[42]
OH
a) TBSCl
DMAP
c) TBSCl
DMAP
OTBS
OH
OTBS
O
OTBS
O
b) MeLi
CO2H
O
O
OH, 47
50
49
OTBS, 48
Resin-bound phosphonium salt 56 of fragment 3 was
treated with an excess of sodium hexamethyldisilazide
(NaHMDS), followed by washing with dry THF. This per-
mitted isolation of the corresponding salt-free ylide which
was coupled with aldehyde 59 to install the required C12
C13 cis-olefin 60. An excess of the polymer-supported salt
56 was used in order to ensure good conversion with respect
to the aldehyde fragment 59. Isolation of alkene intermedi-
ate 60 then required only filtration and concentration.
Although polymer-supported sulfonic acids efficiently re-
moved the C1 protecting group in 60 some double C1/15 de-
protection occurred. Furthermore, protonation of the thia-
zole ring caused unwanted sequestration by the polymer. To
circumvent this problem, a dilute solution of camphorsulfon-
ic acid in methanol was used to selectively remove the pri-
mary TBS group of compound 60. A polymeric carbonate
base was added following the reaction to quench and scav-
enge the acid with the volatile MeOTBS by-product being
removed under reduced pressure.
Oxidation of the resulting primary alcohol 61 to aldehyde
62 was successful using TPAP/NMO, applying filtration
through silica gel to remove the morpholine and ruthenium
by-products.[37,43]
Further oxidation of aldehyde 62 to the corresponding
carboxylic acid 65 was achieved by application of a modified
Pinnick oxidation using a polymer-supported chlorite re-
agent 63.
f) BuLi
O
d)
S
S
NEt3 NaCO3
e) P(OEt)3
O
Cl
N
•HCl
H
P(OEt)2
N
N•HCl, 51
N, 52
53
S
N
S
N
g) CSA
NEt3 NaCO3
OTBS
OTBS
OTBS
55
54
OH
h) I2
PPh2
NEt2
S
N
S
N
i)
PPh2
OTBS
OTBS
PPh2I
5
56
I
Scheme 6. Final synthesis of fragment 3. a) TBSCl (1.4 equiv), PS-DMAP
(2.0 equiv, 1.49 mmolgꢀ1), CH2Cl2, RT, 1 h 30 min, 97%; b) MeLi
(1.05 equiv), THF, ꢀ788C, 40 min, then Amberlite IRC-50 (21 equiv,
~10 mmolgꢀ1), RT, 45min, 98%; c) TBSCl (1.48 equiv), PS-DMAP
(2.0 equiv, 1.49 mmolgꢀ1), CH2Cl2, RT, 2 h 30 min, 98%; d) PS-carbonate
(2 equiv, 3.5 mmolgꢀ1), MeOH, RT, 45 min, 98%; e) triethylphosphite
(1.2 equiv), neat, 1608C, 3 h, 84 %; f) 53 (3.5 equiv), nBuLi (3.5 equiv,
1.6m in hexanes), THF, ꢀ788C, then 50 (1.0 equiv), ꢀ788C!RT, 1.5 h,
then PS-benzaldehyde (5.0 equiv, 1.2 mmolgꢀ1), RT, 30 min, then silica
gel (Et2O), 105%; g) CSA (1.5 equiv), MeOH/CH2Cl2 (1:1), 08C, 2 h
30 min, then PS-carbonate (2.2 equiv, 3.5 mmolgꢀ1), 2 h, 104%; h) iodine
(4.0 equiv), PS-triphenylphosphine (5.0 equiv, 3.3 mmolgꢀ1), MeCN/Et2O
3:1, then diethylaminomethylpolystyrene (8.0 equiv, 3.2 mmolgꢀ1), RT,
19 h, 73%; i) PS-triphenylphosphine (1.0 equiv, 3.3 mmolgꢀ1), PhMe,
908C, 18 h.[32]
The selective deprotection of the C15 secondary allylic
TBS ether 65 proved to be difficult. Although precedented
conditions using tetrabutylammonium fluoride (TBAF) solu-
tion effected clean conversion to alcohol 66, they required
aqueous work-up to remove excess fluoride reagent. Alter-
native conditions, applying a polymer-supported or solution-
phase sulfonic acids were tested to avoid the work-up, but
proved unsuccessful resulting in complex mixtures of start-
ing material and mono-, di- and tri-deprotected products.[44]
The final steps: Coupling at C6 C7 has been extensively in-
vestigated using a wide variety of substrates, and shown to
be highly sensitive to proximal and remote functionality in
both fragments.[20,40] Our approach, although bearing close
analogy to those already published, incorporated a novel
fragment combination of ketone 3 and aldehyde 4. This cou-
pling proceeded with high diastereoselectivity (>13:1) using
lithium diisopropylamide (LDA) as base (Scheme 7).[41] At-
tempts to apply an immobilized acid quench resulted in a
destructive retro-aldol reaction. For this reason, acetic acid
was used since it permitted a lower temperature quench and
alleviated product decomposition. Excess acetic acid and al-
dehyde 4 were subsequently removed from the mixture
using a diamine functionalized polymer. Simple filtration
then allowed isolation of the secondary alcohol aldol prod-
uct 57.
A
polymer-supported fluoride and polyvinylpyridine
(PVP)¥HF were investigated, but also proved ineffective.
Consequently, it was deemed necessary to adopt the original
TBAF reaction applying aqueous extraction, although no
further purification was undertaken (Scheme 7).
A Yamaguchi macrolactonisation using polymer-supported
DMAP successfully cyclized 66 to macrolactone 67.[18,25] Al-
though treatment with a mixture of weakly acidic and
weakly basic polymers was sufficient to remove most impur-
ities following reaction, the product was still contaminated.
Product capture via the thiazole was therefore undertaken
using a polymeric sulfonic acid resin. The loaded polymer
was washed to remove all unbound impurities followed by
treatment with a solution of ammonia or triethylamine in
methanol to release the product from the resin. The wash-
ings were concentrated to provide an oil which was identi-
fied as epothilone C (2). Therefore, not only was the capture
and release effective, but the necessary double deprotection
to cleave the final TBS ethers occurred. A single chromatog-
The TBS protection of adduct 57 was successfully com-
pleted using TBS triflate with a polymeric triethylamine
equivalent. Methanol was added after completion of the re-
action to consume excess TBS triflate. Filtration, followed
by concentration under reduced pressure, allowed isolation
of the desired product 58.
2534
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 2529 2547

A Total Synthesis of Epothilone C
2529 2547
O
OTBS
S
N
b) TBSOTf
NEt2
TBSO
TBSO
OTBS
O
OTBS
O
OTBS
H
a) LDA
O
3
OTBS
PPh2I
O
c) O3
PPh2
NH2
N
H
OH
OTBS
4
59
56
OH, 57
OTBS, 58
d) NaHMDS
e) CSA
NEt3 NaCO3
S
S
S
N
S
N
N
N
OH
HO
OTBS
O
O
O
OH
OTBS
O
O
f) TPAP, NMO
OH
OH
O
OTBS
i) trichloro-
benzoyl chloride
o
O
k)
4A MS
DMAP
NMe3 ClO2
63
g)
O
O
O
OTBS
NH2
OH
OH
OTBS
N
H
NMe3 H2PO4
1
CO2H
64
h) TBAF
CH2OTBS, 60
CH2OH, 61
CHO, 62
OTBS, 65
OH, 66
67
2
j)
SO3H
then NH3/MeOH
Scheme 7. Fragment coupling and cyclization. a) LDA (1.6 equiv), THF, ꢀ788C!ꢀ408C, 1 h 30 min, 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 mmolgꢀ1), RT, 2 h, 100% (13.5:1); b) TBS triflate (1.5 equiv), diethylaminome-
thylpolystyrene (3.0 equiv, 3.2 mmolgꢀ1), CH2Cl2, 08C!RT, 3 h 25 min, then MeOH (3.0 equiv), RT, 2 h, 99%; c) O3, CH2Cl2, ꢀ788C, 20 min, then PS-
triphenylphosphine (5.0 equiv, 3.3 mmolgꢀ1), ꢀ788C!RT, 15 h, 100%; d) phosphonium salt 56 (2.5 equiv, 0.8 mmolgꢀ1), NaHMDS (10.0 equiv, 1m in
THF), THF, RT, 10 min, then THF wash, then aldehyde 59 (1.0 equiv), ꢀ788C, 10 min, 93%; e) CSA (1.0 equiv), MeOH/CH2Cl2 1:1, 08C, 4 h, then
CH2Cl2, PS-carbonate (4 equiv, 2.8 mmolgꢀ1), 2 h, RT, 99%; f) TPAP (0.05 equiv), NMO (1.5 equiv), 4 ä MS, CH2Cl2, 08C!RT, 3 h 10 min, then silica
gel (Et2O), 93%; g) PS-chlorite 63 (2 equiv, ~0.5 mmolgꢀ1), PS-dihydrogenphosphate 64 (3 equiv, ~0.5 mmolgꢀ1), 2,3-dimethyl-2-butene (5 equiv, 2m
THF), tBuOH/H2O 1:2, RT, 6 h, 99%; h) TBAF (6 equiv, 1m THF), THF, RT, 4 h, 100%; i) 2,4,6-trichlorobenzoylchloride (10.0 equiv), Et3N (12 equiv),
RT, 50 min, then added to PS-DMAP (20 equiv, 1.48 mmolgꢀ1), THF/toluene (1:25), 808C, 2 h 30 min, then PS-diamine (63equiv, 3.8 mmolgꢀ1), Amber-
lite IRC-50 (333 equiv, 10.0 mmolgꢀ1), 2 h, RT; j) PS-TsOH (12 equiv, 1.5 mmolgꢀ1), CH2Cl2, 1 h, then wash CH2Cl2 and Et2O, then wash release NH3
(2m in MeOH), 81% (2 steps), k) ref. [13].[32]
and tetrahydrofuran (THF) were distilled over sodium/benzophenone;
dichloromethane (CH2Cl2), acetonitrile (MeCN), methanol (MeOH),
benzene and toluene (PhMe) were distilled from calcium hydride; trie-
thylamine (Et3N), diisopropylethylamine (DIPEA) and diisopropylamine
raphy column was run on this final material to remove both
residual impurities and small quantities of minor diaster-
eoisomers that had been carried through the synthesis.
(DIPA) were distilled from potassium hydroxide. All other solvents and
reagents were used as supplied unless otherwise stated. Ozonolyses were
carried out using a Peak Scientific ozone generator. Flash column chro-
matography was carried out using Merck 60 Kieselgel (230 400 mesh)
under pressure unless otherwise stated. Analytical thin-layer chromatog-
Conclusion
In summary, by the synthesis of epothilone C we have dem-
raphy (TLC) was performed on glass plates pre-coated with Merck Kie-
onstrated the scope and utility of supported reagents and
scavenging techniques within a stereocontrolled multi-step
natural product synthesis. The high selectivity and overall
efficiency was comparable with the best of the previous con-
ventional syntheses, preparing the target molecule in
29 steps with a longest linear sequence of only 17 steps from
readily available materials. As epothilone C is the most chal-
lenging target that has been accomplished using solid-phase
reagent and scavenging techniques, we hope that this will
encourage their future integration alongside conventional
methods for application within general synthesis pro-
grams.[45]
selgel 60 F254, and visualised by UV irradiation (254 nm), or by staining
with aqueous acidic ammonium molybdate, or aqueous acidic potassium
permanganate solutions as appropriate. Melting points were measured on
a Reichert hot stage apparatus, and are uncorrected. Optical rotations
were measured on an Perkin Elmer Model 343 polarimeter, and [a]D
values are reported in 10ꢀ1 degcm2 gꢀ1; concentration (c) is in g100 mLꢀ1
.
IR spectra were obtained on a Spectrum One FT-IR ATR (Attenuated
Total Reflectance) spectrometer, from a thin film deposited onto the
ATR. Microanalyses were performed in the microanalytical laboratories
at the Department of Chemistry, University of Cambridge, Lensfield
Road, Cambridge using a CE-440 Elemental Analyser. Mass spectra and
accurate mass data were obtained on a Micromass Platform LC-MS,
Kratos MS890MS, Kratos Concept IH, Micromass Q-TOF, or Bruker BI-
OAPEX 4.7 T FTICR spectrometer, by electron ionisation, chemical ion-
isation or fast atom/ion bombardment techniques at the Department of
Chemistry, Uniiversity of Cambridge, Lensfield Road, Cambridge.
1H NMR spectra were recorded at ambient temperature on Bruker DPX-
400, DRX-400, DRX-500 or Bruker-DRX-600 spectrometers, at 200, 400,
500 or 600 MHz, with residual protic solvent as the internal reference
(CHCl3 dH =7.26 ppm; MeOH dH =3.30 ppm); chemical shifts (d) are
given in parts per million (ppm), and coupling constants (J) are given in
Hertz (Hz). The proton spectra are reported as follows dppmꢀ1 (multi-
plicity, coupling constant JHzꢀ1, number of protons, assignment). Assign-
ments of numbered protons are made according to the numbering of the
Experimental Section
General: All reactions were carried out under an atmosphere of argon,
and those not involving aqueous reagents were carried out in oven-dried
(2008C) glassware, cooled under vacuum. All reagents were used as sup-
plied or purified using standard procedures, as necessary. Ether (Et2O)
2535
Chem. Eur. J. 2004, 10, 2529 2547
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

S. V. Ley et al.
FULL PAPER
natural product epothilone C, as shown. 13C NMR spectra were recorded
at ambient temperature on the same spectrometers at 50, 100 or
150 MHz, with the central peak of CHCl3 as the internal reference (dC =
77.0 ppm). Assignments of numbered carbons are made according to the
numbering of the natural product epothilone C, as shown. DEPT135 and
two-dimensional (COSY, HMQC, HMBC) NMR spectroscopy were used
where appropriate, to aid in the assignment of signals in the 1H and
13C NMR spectra. Where coincident coupling constants have been ob-
served in the NMR spectrum, the apparent multiplicity of the proton res-
onance concerned has been reported.
(3R)-3-(tert-Butyldimethylsilyloxy)-4,4-dimethyltetrahydro-furan-2-ol
(8):[46] A solution of DIBAL-H (53.3 mL, 1.0m in toluene) was added to
furanone 7 (10 g, 41.0 mmol) in toluene (200 mL) at ꢀ788C. The mixture
was stirred for 30 min at ꢀ788C then Et2O and ground sodium sulfate
decahydrate were added to the mixture followed by gradual warming to
RT. Filtration and concentration under reduced pressure yielded alcohol
8 as a white solid (9.9 g, 99%). M.p. 50 528C; [a]2D5 = +29.7 (c = 1.30,
CHCl3); 1H NMR (400 MHz, CDCl3): d=5.16 (d, 3J(H,H)=3.1 Hz, 1H,
OCHOH), 3.78 (d, 3J(H,H)=8.3 Hz, 1H, CHHOH), 3.67 (d, 3J(H,H)=
3.1 Hz, 1H, CHOTBS), 3.64 (d, 3J(H,H)=8.3 Hz, 1H, CHHOH), 3.12
(brs, 1H, OH), 1.06 (s, 3H, CH3CCH3), 1.01 (s, 3H, CH3CCH3), 0.91 (s,
9H, SiC(CH3)3), 0.09 (s, 3H, SiCH3), 0.07 (s, 3H, SiCH3); 13C NMR
(100 MHz, CDCl3): d=104.6, 85.4, 78.5, 42.3, 25.8, 23.7, 20.2, 18.1, ꢀ4.5,
ꢀ5.0; IR (film): n˜ = 3290, 2953, 2930, 1461, 1249, 1123, 1009, 985, 864,
835, 776 cmꢀ1; MS (EI): m/z: calcd for C12H26O3SiNa: 269.1549; found:
269.1545 [M+Na]+.
Preparation of the polymer-supported (PS) reagents
Fluka triphenylphosphine, polymer bound: Washed using MeOH (3î),
CH2Cl2 (3î), Et2O (3î), then dried to constant mass under reduced
pressure at room temperature before use.
Fluka carbonate on polymer support: Used directly as supplied.
Fluka diethylaminomethyl-polystyrene: Washed using MeOH (3î),
CH2Cl2 (3î), Et2O (3î), then dried to constant mass under reduced
pressure at room temperature before use.
(3R)-3-(tert-Butyldimethylsilyloxy)-2,2-dimethyl-5-trimethylsilylpentane-
1,4-diol (9):
A solution of trimethylsilylmethylmagnesium chloride
(35.6 mL, 1.0m in Et2O) was added to furanol 8 (2.18 g, 8.90 mmol) in
THF (35 mL) at RT. The mixture was heated at 608C for 10 h, then
cooled to RT and polymer-supported-COOH (Amberlite IRC-50, 25 g,
250 mmol, 10 mmolgꢀ1) was added. The mixture was filtered and concen-
trated under reduced pressure to afford the diol 9 as a white solid (2.8 g,
94%). The two diastereoisomers were separated by flash chromatogra-
phy (hexane/Et2O 15:1).
Fluka DMAP on polystyrene: Washed using MeOH (3î), CH2Cl2 (3î),
Et2O (3î), then dried to constant mass under reduced pressure at 50
608C before use.
Fluka bromopolystyrene: Washed using MeOH (3î), then used directly.
Argonaut DMAP on polystyrene: For silyl protections: Used directly as
supplied.
Major isomer: m.p. 79 808C; [a]2D5 = +3.5 (c = 0.82, CHCl3); 1H NMR
(400 MHz, CDCl3): d=4.05 (dd, 3J(H,H)=9.8, 4.8 Hz, 1H, CHOH), 3.86
(brs, 1H, OH), 3.66 (d, 3J(H,H)=11.6 Hz, 1H, CHHOH), 3.25 (s, 1H,
CHOTBS), 3.04 (d, 3J(H,H)=11.6 Hz, 1H, CHHOH), 2.76 (brs, 1H,
OH), 1.02 (dd, 3J(H,H)=14.5, 9.8 Hz, 1H, CHHSi(CH3)3), 0.97 (s, 3H,
CH3CCH3), 0.95 (s, 9H, SiC(CH3)3), 0.84 (s, 3H, CH3CCH3), 0.64 (dd,
3J(H,H)=14.5, 4.8 Hz, 1H, CHHSi(CH3)3), 0.16 (s, 3H, SiCH3), 0.14 (s,
3H, SiCH3), 0.04 (s, 9H, Si(CH3)3); 13C NMR (100 MHz, CDCl3): d=
83.7, 66.9, 66.5, 40.0, 26.4, 26.1, 25.4, 21.9, 18.8, ꢀ0.86, ꢀ3.00, ꢀ3.52; IR
(film): n˜ = 3123, 2956, 2854, 1472, 1245, 1205, 1060, 1032, 862, 832, 772,
691, 670 cmꢀ1; MS (EI): m/z: calcd for C16H38O3Si2Na: 357.2257; found:
357.2248 [M+Na]+.
For macrocyclisation: Washed using MeOH (3î), CH2Cl2 (3î), Et2O
(3î), then dried to constant mass under reduced pressure at 50 608C
before use.
Argonaut polymer-supported benzaldehyde: Used directly as supplied.
Argonaut MP-TsOH(I), (II) or Amberlyst-15 (MP: macroporous poly-
mer): For reactions when used as an acid catalyst: Used directly as sup-
plied.
For final multi-stoichiometric catch-and-release: Washed using MeOH
(3î), CH2Cl2 (3î), Et2O (3î), then dried to constant mass under re-
duced pressure at room temperature before use.
NovaBiochem tris-(2-aminoethyl)amine polystyrene (trisamine): Used di-
Minor isomer: m.p. 79 808C; [a]2D5 = ꢀ5.1 (c = 0.74, CHCl3); 1H NMR
rectly as supplied.
3
NovaBiochem N-(2-aminoethyl)aminomethyl polystyrene (diamine):
Used directly as supplied.
(400 MHz, CDCl3): d=3.98 (ddd, J(H,H)=6.0, 2.4, 2.2 Hz, 1H, CHOH),
3
3
3.47 (d, J(H,H)=2.4 Hz, 1H, CHOTBS), 3.46 (d, J(H,H)=11.3 Hz, 1H,
CHHOH), 3.34 (d, 3J(H,H)=11.3 Hz, 1H, CHHOH), 2.19 (brs, 1H,
OH), 1.68 (brs, 1H, OH), 1.04 (dd, 3J(H,H)=14.8, 6.0 Hz, 1H,
CHHSi(CH3)3), 0.98 (s, 3H, CH3CCH3), 0.94 (s, 3H, CH3CCH3), 0.93 (s,
9H, SiC(CH3)3), 0.79 (dd, 3J(H,H)=14.8, 2.2 Hz, 1H, CHHSi(CH3)3),
0.11 (s, 3H, SiCH3), 0.10 (s, 3H, SiCH3), 0.05 (s, 9H, Si(CH3)3); 13C NMR
(100 MHz, CDCl3): d=84.0, 72.2, 68.7, 39.9, 26.1, 24.9, 22.9, 20.7, 18.4,
ꢀ0.87, ꢀ3.55, ꢀ4.62; IR (film): n˜ = 3114, 2951, 2855, 1472, 1386, 1247,
NovaBiochem dibutylphenylphosphine on polystyrene: Used directly as
supplied.
NovaBiochem
(polystyrylmethyl)trimethylammonium
perruthenate:
Used directly as supplied.
NovaBiochem morpholinomethyl polystyrene: Used directly as supplied.
Amberlite IRC-50 carboxylic acid polymer: Washed using MeOH (3î),
CH2Cl2 (3î), Et2O (3î), then dried to constant mass under reduced
pressure at room temperature before use.
1081, 1048, 854, 832, 772, 672 cmꢀ1
;
MS (EI): m/z: calcd for
C16H38O3Si2Na: 357.2257; found: 357.2251 [M+Na]+.
(3S)-2,2-Dimethylpent-4-ene-1,3-diol (10): BF3¥Et2O
Amberlite IRA-743 boron scavenger: Washed using MeOH (3î),
CH2Cl2 (3î), Et2O (3î), then dried to constant mass under reduced
pressure at room temperature before use.
(0.964 mL,
7.84 mmol) was added to a solution of diol 9 (2.6 g, 7.84 mmol) in CH2Cl2
(15 mL) at RT. The mixture was stirred for 15 h, then MeOH (25 mL)
and polymer-supported-carbonate (12 g, 3.23 mmolgꢀ1) were added. The
suspension was stirred for 5 h then filtered. The filtrate was concentrated
under reduced pressure to afford alkene 10 as a pale yellow oil (1.0 g,
98%). [a]2D5 = ꢀ20.5 (c = 0.74, CHCl3); 1H NMR (400 MHz, CDCl3):
d=5.96 (ddd, 3J(H,H)=17.2, 10.5, 6.7 Hz, 1H, CH=CH2), 5.27 (dd,
3J(H,H)=17.2, 1.1 Hz, 1H, CH=CHcisHtrans), 5.22 (dd, 3J(H,H)=10.5,
1.1 Hz, 1H, CH=CHcisHtrans), 4.02 (dd, 3J(H,H)=6.7, 3.3 Hz, 1H,
CHOH), 3.58 (dd, 3J(H,H)=10.8, 5.6 Hz, 1H, CHHOH), 3.47 (dd,
3J(H,H)=10.8, 4.8 Hz, 1H, CHHOH), 2.46 (dd, 3J(H,H)=5.6, 4.8 Hz,
1H, (C1)OH), 2.39 (d, 3J(H,H)=3.3 Hz, 1H, (C3)OH), 0.93 (s, 3H,
CH3CCH3), 0.89 (s, 3H, CH3CCH3); 13C NMR (100 MHz, CDCl3): d=
137.5, 116.6, 80.6, 71.6, 38.2, 22.3, 18.9; IR (film): n˜ = 3334, 2960, 2875,
1473, 1425, 1390, 1366, 1250, 1118, 1039, 992, 923 cmꢀ1; MS (EI): m/z:
calcd for C7H14O2Na: 153.0891; found: 153.0883 [M+Na]+.
Aldrich pyridinium chlorochromate on basic alumina: Used directly as
supplied.
Fragment 1
(3R)-3-(tert-Butyldimethylsilyloxy)-4,4-dimethyldihydrofuran-2-one
(7):[46] Polymer-supported-1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) (82 g,
2.6 mmolgꢀ1) and TBSCl (12.9 g, 85.4 mmol) were added to a solution of
(R)-pantolactone 6 (5.6 g, 42.7 mmol) in CH2Cl2 (600 mL) at RT. After
stirring for 10 h, MeOH (10 mL) was added. The mixture was filtered
and concentrated under reduced pressure. The residue was dissolved in
MeOH and concentrated three times to yield lactone 7 as a white solid
(10 g, 96%). M.p. 93 948C; [a]2D5 = +30.6 (c = 1.45, CHCl3); 1H NMR
(400 MHz, CDCl3): d=3.98 (s, 1H, CHOTBS), 3.97 (d, 3J(H,H)=8.8 Hz,
1H, CHHO), 3.86 (d, 3J(H,H)=8.8 Hz, 1H, CHHO), 1.13 (s, 3H,
CH3CCH3), 1.04 (s, 3H, CH3CCH3), 0.93 (s, 9H, SiC(CH3)3), 0.19 (s, 3H,
SiCH3), 0.12 (s, 3H, SiCH3); 13C NMR (100 MHz, CDCl3): d=175.8, 75.8,
40.9, 25.6, 23.1, 19.1, 18.3, ꢀ4.5, ꢀ5.4; IR (film): n˜ = 2953, 2929, 1792,
1764, 1460, 1246, 1246, 1210, 1133, 1008, 861, 834, 778 cmꢀ1; MS (EI): m/
z: calcd for C12H24O3SiNa: 267.1392; found: 267.1398 [M+Na]+.
(3S)-3-Hydroxy-2,2-dimethylpent-4-enyl benzoate (11): Polymer-support-
ed-TBD (8.9 g, 2.6 mmolgꢀ1) and BzCl (1.07 mL, 9.25 mmol) was added
to a solution of diol 10 (1.0 g, 7.71 mmol) in CH2Cl2 (100 mL) at RT.
After stirring for 5 h, polymer-supported-trisamine (1.8 g, 4.27 mmolgꢀ1
)
2536
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 2529 2547

A Total Synthesis of Epothilone C
2529 2547
was added then the suspension was filtered and concentrated under re-
duced pressure. The residue was filtered through a silica gel pad eluting
with Et2O to obtain benzoate 11 as a pale yellow oil (1.32 g, 73%). [a]D25
= ꢀ21.5 (c = 0.84, CHCl3); 1H NMR (400 MHz, CDCl3): d=8.04 (dd,
3J(H,H)=7.5, 1.2 Hz, 2H, m-Ph), 7.56 (dd, 3J(H,H)=7.4, 1.2 Hz, 1H, p-
From benzoate 13: A solution of diisobutylaluminum hydride (8.7 mL,
1.0m in hexane) was added to
a solution of benzoate 13 (1.4 g,
2.91 mmol) in THF (30 mL) at ꢀ788C. The mixture was stirred for 1 h
before addition of sodium sulfate decahydrate and Et2O. The mixture
was filtered and concentrated under reduced pressure. The residue was
filtered through a silica gel pad eluting with hexane and EtOAc (10:1) to
obtain alcohol 14 as a colourless oil (850 mg, 77%). [a]2D5 = ꢀ14.8 (c =
0.77, CHCl3); 1H NMR (400 MHz, CDCl3): d=3.78 3.61 (m, 4H,
CH2OTBS, CHOTBS, CHHOH), 3.29 (dd, 3J(H,H)=10.9, 7.4 Hz, 1H,
CHHOH), 2.95 (dd, 3J(H,H)=7.4, 3.8 Hz, 1H, OH), 1.98 1.86 (m, 1H,
CHHCH2OTBS), 1.72 1.59 (m, 1H, CHHCH2OTBS), 1.01 (s, 3H,
CH3CCH3), 0.90 (s, 9H, SiC(CH3)3), 0.89 (s, 9H, SiC(CH3)3), 0.80 (s, 3H,
CH3CCH3), 0.11 (s, 3H, SiCH3), 0.10 (s, 3H, SiCH3), 0.06 (s, 6H, 2î
SiCH3); 13C NMR (100 MHz, CDCl3): d=76.9, 70.2, 60.7, 39.3, 36.4, 26.0,
25.9, 22.9, 22.1, 18.3, 18.2, ꢀ4.01, ꢀ4.25, ꢀ5.28, 5.32; IR (film): n˜ = 3440,
2955, 2929, 2857, 1472, 1252, 1090, 1041, 833, 772 cmꢀ1; MS (EI): m/z:
calcd for C19H44O3Si2Na: 399.2727; found: 399.2730 [M+Na]+.
3
3
Ph), 7.45 (dd, J(H,H)=7.5, 7.4 Hz, 2H, m-Ph), 5.96 (ddd, J(H,H)=17.2,
10.5, 6.7 Hz, 1H, CH=CH2), 5.29 (dd, 3J(H,H)=17.2, 0.8 Hz, 1H, CH=
3
CHcisHtrans), 5.21 (dd, J(H,H)=10.5, 0.8 Hz, 1H, CH=CHcisHtrans), 4.36 (d,
3J(H,H)=11.0 Hz, 1H, BzOCHH), 4.08 (d, 3J(H,H)=11.0 Hz, 1H,
BzOCHH), 4.04 (d, 3J(H,H)=6.7 Hz, 1H, CHOH), 1.03 (s, 3H,
CH3CCH3), 1.02 (s, 3H, CH3CCH3); 13C NMR (100 MHz, CDCl3): d=
166.8, 136.9, 133.0, 130.2, 130.1, 129.6, 128.4, 117.1, 70.8, 38.7, 21.4, 19.6;
IR (film): n˜ = 3466, 2966, 1703, 1602, 1451, 1371, 1315, 1272, 1177, 1115,
992, 927, 711 cmꢀ1; MS (EI): m/z: calcd for C14H18O3Na: 257.1154; found:
257.1154 [M+Na]+.
(3S)-3,5-Dihydroxy-2,2-dimethylpentyl benzoate (12):
A solution of
BH3¥THF complex (16.9 mL, 1.0m in THF) was added to a solution of
benzoate 11 (1.32 g, 5.63 mmol) in THF (10 mL) at 08C. The mixture was
stirred at RT for 20 h then MeOH (50 mL) was added to the mixture at
08C, followed by successive additions of polymer-supported carbonate
(26 g, 3.23 mmolgꢀ1), 30% aq. H2O2 (2.0 mL) and polymer-supported-
(3S)-3,5-Bis-(tert-butyldimethylsilyloxy)-2,2-dimethylpentanal
(15):[47]
Supported-PCC (6.0 g, 5.56 mmol, 20% on basic alumina) was added to a
solution of alcohol 14 (524 mg, 1.39 mmol) in CH2Cl2 (30 mL) at RT. The
mixture was stirred for 20 h then filtered through a silica gel pad eluting
with Et2O to afford the aldehyde 15 as a colourless oil (520 mg, 100%).
[a]2D5 = ꢀ14.6 (c = 0.84, CHCl3); 1H NMR (400 MHz, CDCl3): d=9.56
(s, 1H, CHO), 3.98 (dd, 3J(H,H)=7.4, 4.3 Hz, 1H, CHOTBS), 3.69 3.58
(m, 2H, CH2OTBS), 1.77 1.66 (m, 1H, CHHCH2OTBS), 1.64 1.53 (m,
1H, CHHCH2OTBS), 1.06 (s, 3H, CH3CCH3), 1.00 (s, 3H, CH3CCH3),
0.89 (s, 9H, SiC(CH3)3), 0.86 (s, 9H, SiC(CH3)3), 0.09 (s, 3H, SiCH3), 0.04
(s, 9H, 3îSiCH3); 13C NMR (100 MHz, CDCl3): d=206.3, 72.8, 59.7,
51.2, 36.5, 25.94, 25.88, 19.0, 18.22, 18.20, 17.5, ꢀ3.93, ꢀ4.29, ꢀ5.32, 5.34;
2ꢀ
S2O3 (10 g, 2.0 mmolgꢀ1). The suspension was filtered and concentrated
under reduced pressure. The residue was filtered through a silica gel pad
eluting with Et2O to afford diol 12 (970 mg, 68%). Diol 12 and Et3N
(1.62 mL, 11.6 mmol) were dissolved in CH2Cl2 (30 mL). PS-TrCl (9.3 g,
1.23 mmolgꢀ1) was added at RT and stirred for 4 h, then filtered. The
resin was washed with CH2Cl2 and the filtrate was concentrated under re-
duced pressure. The residue was suspended in CH2Cl2 (30 mL) and 5%
TFA in CH2Cl2 (5.0 mL) was added and the mixture was stirred for 1 h
then filtered. The filtrate was concentrated under reduced pressure to
obtain the diol 12 as a colourless oil (850 mg, 88%). [a]2D5 = ꢀ2.3 (c =
1.50, CHCl3); 1H NMR (400 MHz, CDCl3): d=8.04 (dd, 3J(H,H)=7.5,
1.2 Hz, 2H, o-Ph), 7.58 (dd, 3J(H,H)=7.4, 1.2 Hz, 1H, p-Ph), 7.45 (dd,
3J(H,H)=7.5, 7.4 Hz, 2H, m-Ph), 4.51 (d, 3J(H,H)=11.1 Hz, 1H,
BzOCHH), 3.94 (d, 3J(H,H)=11.1 Hz, 1H, BzOCHH), 3.92 3.78 (m,
2H, CH2OH), 3.73 3.62 (m, 1H, CHOH), 3.28 (brs, 1H, OH), 2.61 (brs,
1H, OH), 1.78 1.66 (m, 2H, CH2CH2OH), 1.02 (s, 3H, CH3CCH3), 1.00
(s, 3H, CH3CCH3); 13C NMR (100 MHz, CDCl3): d=167.2, 133.2, 129.9,
129.7, 128.5, 75.6, 70.9, 62.5, 39.0, 32.2, 21.8, 19.0; IR (film): n˜ = 3371,
2965, 2878, 1724, 1700, 1602, 1473, 1451, 1371, 1315, 1272, 1177, 1115,
IR (film): n˜
= 2956, 2929, 2853, 1728, 1472, 1361, 1253, 1093, 834,
774 cmꢀ1
; MS (EI): m/z: calcd for C19H42O3Si2Na: 397.2570; found:
397.2564 [M+Na]+.
(5S)-5,7-Bis-(tert-butyldimethylsilyloxy)-4,4-dimethylheptan-3-ol
(16):[21,26] A solution of EtMgBr (1.33 mL, 2.0m in Et2O) was added drop-
wise to a solution of aldehyde 15 (500 mg, 1.33 mmol) in THF (6.0 mL)
at ꢀ788C. After stirring for 2 h, polymer-supported-COOH (2.6 g,
26 mmol, 10 mmolgꢀ1) was added to the mixture to quench the excess of
Grignard reagent. The reaction mixture was filtered through a silica gel
pad eluting with hexane and EtOAc (5:1) and concentrated under re-
duced pressure to obtain alcohol 16 as a pale yellow oil (530 mg, 98%).
The two diastereoisomers were separated by flash chromatography
(hexane/Et2O 20:1).
1069, 1054, 1026, 709 cmꢀ1
; MS (EI): m/z: calcd for C14H20O4Na:
275.1259; found: 275.1269 [M+Na]+.
Major isomer: [a]2D5 = ꢀ36.6 (c = 0.35, CHCl3); 1H NMR (400 MHz,
CDCl3): d=4.26 (s, 1H, OH), 3.77 3.58 (m, 4H, CH2OTBS, CHOTBS,
CHOH), 1.98 1.89 (m, 1H, CHHCH2OTBS), 1.78 1.67 (m, 1H,
CHHCH2OTBS), 1.45 1.23 (m, 2H, CH3CH2), 1.11 (t, 3J(H,H)=7.3 Hz,
3H, CH3CH2), 0.97 (s, 3H, CH3CCH3), 0.90 (s, 9H, SiC(CH3)3), 0.89 (s,
9H, SiC(CH3)3), 0.74 (s, 3H, CH3CCH3), 0.12 (s, 6H, 2îSiCH3), 0.05 (s,
6H, 2îSiCH3); 13C NMR (100 MHz, CDCl3): d=80.5, 77.4, 60.1, 40.7,
36.0, 26.1, 25.9, 24.5, 23.5, 20.5, 18.2, 11.3, ꢀ3.93, ꢀ4.34, ꢀ5.28, 5.32; IR
(3S)-3,5-Bis-(tert-butyldimethylsilyloxy)-2,2-dimethylpentyl
benzoate
(13): Polymer-supported-NMM (9.6 g, 3.5 mmolgꢀ1) was added to a solu-
tion of diol 12 (850 mg, 3.37 mmol) in CH2Cl2 (30 mL) at RT. Following a
slow addition of TBSOTf (2.32 mL, 10.1 mmol) to the solution at 08C the
mixture was stirred at RT for 20 h. Excess of TBSOTf was quenched by
addition of MeOH. The mixture was filtered and concentrated under re-
duced pressure to obtain benzoate 13 as a colourless oil (1.58 g, 98%).
[a]2D5 = ꢀ9.2 (c = 0.79, CHCl3); 1H NMR (400 MHz, CDCl3): d=8.04
3
3
(film): n˜ = 3498, 2956, 2929, 1472, 1389, 1362, 1253, 1079, 833, 774 cmꢀ1
;
(dd, J(H,H)=7.8, 1.2 Hz, 2H, o-Ph), 7.56 (dd, J(H,H)=7.5, 1.2 Hz, 1H,
p-Ph), 7.44 (dd, 3J(H,H)=7.8, 7.5 Hz, 2H, m-Ph), 4.13 (s, 2H, BzOCH2),
3.86 (dd, 3J(H,H)=7.5, 2.8 Hz, 1H, CHOTBS), 3.77 3.63 (m, 2H,
CH2OTBS), 1.92 1.81 (m, 1H, CHHCH2OTBS), 1.65 1.54 (m, 1H,
CHHCH2OTBS), 0.99 (s, 3H, CH3CCH3), 0.98 (s, 3H, CH3CCH3), 0.89
(s, 18H, 2îSiC(CH3)3), 0.09 (s, 3H, SiCH3), 0.05 (s, 3H, SiCH3), 0.04 (s,
3H, SiCH3), 0.02 (s, 3H, SiCH3); 13C NMR (100 MHz, CDCl3): d=166.6,
132.8, 130.5, 129.5, 128.4, 72.7, 71.1, 60.4, 39.3, 36.1, 26.1, 25.9, 22.2, 19.7,
18.4, 18.2, ꢀ3.83, ꢀ4.35, ꢀ5.25, 5.28; IR (film): n˜ = 2955, 2929, 1724,
1472, 1271, 1252, 1092, 1069, 833, 774, 709 cmꢀ1; MS (EI): m/z: calcd for
C26H48O4Si2Na: 503.2989; found: 503.3008 [M+Na]+.
MS (EI): m/z: calcd for C21H48O3Si2Na: 427.3040; found: 427.3048
[M+Na]+.
Minor isomer: [a]D25
=
ꢀ4.5 (c
=
0.45, CHCl3); 1H NMR (400 MHz,
CDCl3): d=3.78 3.63 (m, 3H, CH2OTBS, CHOTBS), 3.37 3.28 (m, 1H,
CHOH), 2.73 (brs, 1H, OH), 2.07 1.96 (m, 1H, CHHCH2OTBS), 1.54
1.45 (m, 2H, CHHCH2OTBS, CH3CHH), 1.38 1.22 (m, 1H, CH3CHH),
0.99 (t, 3J(H,H)=7.3 Hz, 3H, CH3CH2), 0.91 (s, 9H, SiC(CH3)3), 0.89 (s,
9H, SiC(CH3)3), 0.86 (s, 3H, CH3CCH3), 0.75 (s, 3H, CH3CCH3), 0.07 (s,
6H, 2îSiCH3), 0.08 (s, 6H, 2îSiCH3); 13C NMR (100 MHz, CDCl3): d=
78.0, 75.5, 61.9, 42.8, 36.5, 26.1, 25.9, 24.2, 18.7, 18.5, 18.4, 18.3, 11.7,
ꢀ3.57, ꢀ4.38, ꢀ5.39; IR (film): n˜ = 3497, 2956, 2930, 1472, 1388, 1361,
(3S)-3,5-Bis-(tert-butyldimethylsilyloxy)-2,2-dimethylpentan-1-ol (14)[21]
1253, 1087, 1004, 937, 832, 772 cmꢀ1
; MS (EI): m/z: calcd for
From sultam 23: A solution of diisobutylaluminum hydride (4.7 mL, 1.0m
in CH2Cl2) was added to a solution of sultam 23 (1.05 g, 1.88 mmol) in
CH2Cl2 (20 mL) at ꢀ788C. The mixture was stirred for 1 h, then
quenched by addition of Et2O and powdered sodium sulfate decahydrate.
The mixture was filtered and concentrated under reduced pressure. The
residue was filtered through a bond elute silica gel cartridge eluting with
hexane/EtOAc (10:1) to obtain alcohol 14 as a colourless oil (640 mg,
90%).
C21H48O3Si2Na: 427.3040; found: 427.3043 [M+Na]+.
(S)-N-[2-Bromo-2-methylpropanoyl]bornane-10,2-sultam (21): Sodium
hydride (444 mg, 11.1 mmol, ca. 60% dispersion with mineral oil) was
added to a solution of camphorsultam 19 (2.0 g, 9.29 mmol) in toluene
(40 mL) at 08C. The reaction mixture was stirred at RT for 1 h before ad-
dition of 2-bromo-2-methylpropanoyl bromide (20; 1.8 mL, 14.9 mmol) at
08C. After the mixture had been stirred for a further 1 h at RT, CH2Cl2
2537
Chem. Eur. J. 2004, 10, 2529 2547
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

S. V. Ley et al.
FULL PAPER
(200 mL) and polymer-supported trisamine (8.8 g, 29.8 mmol,
3.4 mmolgꢀ1) were added to the mixture. The suspension was filtered
through a bond elute cartridge and concentrated to obtain a white solid
which was washed with Et2O and dried under reduced pressure to afford
3J(H,H)=17.3, 10.4, 6.8 Hz, 1H, H-2), 5.10 5.06 (dd, 3J(H,H)=17.3 Hz,
2J(H,H)=1.4 Hz, 1H, CHtransHcis=CH), 5.06 5.02 (d, 3J(H,H)=10.4 Hz,
1H, CHtransHcis=CH), 3.67 (t, 3J(H,H)=6.8 Hz, 2H, H-4), 2.28 (app. q,
3J(H,H)=6.8 Hz, 2H, H-3), 0.90 (s, 9H, SiC(CH3)3), 0.06 (s, 6H,
Si(CH3)2); 13C NMR (100 MHz, CDCl3): d=135.4 (CH2=CH), 116.3
(CH2=CH), 62.8 (C-4), 37.5 (C-3), 25.9 (SiC(CH3)3), 18.0 (SiC(CH3)3),
ꢀ5.6 (Si(CH3)2); IR (film): n˜ = 2956, 2930, 2896, 2858, 1473, 1255, 1096,
909, 833, 773 cmꢀ1; MS (+EI): m/z: calcd for C6H13OSi: 129.0736; found:
129.0743 [MꢀtBu]+.
sultam 21 (3.11 g, 92%). M.p. 177 1798C; [a]D25
=
ꢀ42.0 (c
= 1.29,
CHCl3); 1H NMR (400 MHz, CDCl3): d=4.08 (dd, 3J(H,H)=7.2, 3.7 Hz,
3
3
1H, CHN), 3.51 (d, J(H,H)=13.6 Hz, 1H, CHHSO2), 3.47 (d, J(H,H)=
13.6 Hz, 1H, CHHSO2), 2.12 (s, 3H, BrCCH3), 2.04 (s, 3H, BrCCH3),
2.04 1.97 (m, 1H, CH), 1.93 1.82 (m, 4H, 2îCH2), 1.52 1.33 (m, 2H,
CH2), 1.20 (s, 3H, CH3CCH3), 0.97 (s, 3H, CH3CCH3); 13C NMR
(100 MHz, CDCl3): d=172.2, 68.1, 59.0, 54.2, 48.6, 48.3, 44.6, 38.6, 33.2,
32.5, 31.1, 27.0, 20.9, 20.3; IR (film): n˜ = 2959, 1698, 1456, 1330, 1266,
1241, 1171, 1157, 1128, 1096, 1054; MS (EI): m/z: calcd for
C14H22BrNO3SNa: 386.0401; found: 386.0422 [M+Na]+.
3-(tert-Butyldimethylsilyloxy)-propanal 18:[21]
From alcohol 17: PCC on basic alumina (51.1 g, 51.1 mmol, ~1 mmolgꢀ1
)
was added to a solution of alcohol 17 (3.0 g, 15.8 mmol) in CH2Cl2
(350 mL) at RT. The reaction mixture was stirred for 1 h then Et2O
(500 mL) was added. The resulting suspension was filtered through a
bond elute silica gel pad and concentrated under reduced pressure to
yield aldehyde 18 (2.58 g, 87%).
(S)-N-[5-tert-Butyldimethylsilyloxy-(3S)-hydroxy-2,2-dimethylpentanoyl]-
bornane-10,2-sultam (22): Sultam 21 (1.50 g, 4.12 mmol), CrCl2 (2.03 g,
16.5 mmol) and LiI (54.9 mg, 0.41 mmol) were suspended in THF
(15 mL). Dropwise addition of aldehyde 18 (1.55 g, 8.24 mmol) in THF
(15 mL) was made at 208C and the mixture stirred for 1 h. Additions of
From alkene 25: Alkene 25 (3.0 g, 16.1 mmol) was dissolved in CH2Cl2
(100 mL) and cooled to ꢀ788C. Ozone was bubbled through the solution
for 10 min until the reaction mixture turned blue. Polymer-supported tri-
phenylphosphine (Fluka, 3.0 mmolgꢀ1, 8.06 g, 24.2 mmol) was added at
ꢀ788C and the suspension allowed to warm to RT and stirred for 14 h.
Filtration, washing the resin with Et2O, followed by concentration of the
filtrate under reduced pressure yielded aldehyde 18 as a pale yellow oil
(2.80 g, 93%). The bulk of the material was used in subsequent reactions
without further purification. A portion of the product was purified by
chromatography (silica gel, EtOAc/petrol 1:10). Rf = 0.61 (petrol/EtOAc
5:1); 1H NMR (400 MHz, CDCl3): d=9.79 (s, 1H, CHO), 3.98 (t,
3J(H,H)=6.0 Hz, 2H, H-3), 2.58 (td, 3J(H,H)=6.0, 1.9 Hz, 2H, H-2),
0.87 (s, 9H, SiC(CH3)3), 0.05 (s, 6H, Si(CH3)2); 13C NMR (100 MHz,
CDCl3): d=202.0 (CHO), 57.3 (C-3), 46.5 (C-2), 25.7 (SiC(CH3)3), 18.2
CH2Cl2 (200 mL) and polymer-supported hydroxide (25 g, 3.2 mmolgꢀ1
,
Ambersep 900 OH) were made and the mixture was filtered and concen-
trated under reduced pressure. The crude product was filtered through a
bond elut silica gel cartridge eluting with hexane/EtOAc (10:1) to obtain
sultam 22 as a colourless oil (1.80 g, 92%). [a]2D5 = ꢀ28.6 (c = 0.44,
CHCl3); 1H NMR (400 MHz, CDCl3): d=4.24 (ddd, 3J(H,H)=9.7, 4.6,
1.8 Hz, 1H, CHOH), 4.06 (dd, 3J(H,H)=7.6, 4.8 Hz, 1H, CHN), 3.82
(ddd, 3J(H,H)=5.9, 5.8, 1.6 Hz, 2H, CH2OTBS), 3.50 (d, 3J(H,H)=
13.6 Hz, 1H, CHHSO2), 3.44 (d, 3J(H,H)=13.6 Hz, 1H, CHHSO2), 3.15
3
3
(d, J(H,H)=4.6 Hz, 1H, CH), 2.01 (dd, J(H,H)=13.6, 7.7 Hz, 1H, CH),
1.96 1.72 (m, 4H, 4îCH), 1.67 1.56 (m, 2H, CH2CH2OTBS), 1.48 1.41
(m, 1H, CH), 1.38 1.32 (m, 1H, CH), 1.34 (s, 3H, C(O)CCH3), 1.32 (s,
3H, C(O)CCH3), 1.16 (s, 3H, CCH3), 0.96 (s, 3H, CCH3), 0.90 (s, 9H,
SiC(CH3)3), 0.08 (s, 6H, 2îSiCH3); 13C NMR (100 MHz, CDCl3): d=
179.1, 67.6, 61.7, 54.0, 50.9, 48.0, 47.7, 44.4, 38.9, 34.0, 32.9, 26.6, 25.9,
20.68, 20.64, 20.58, 20.39, 19.9, ꢀ5.43, ꢀ5.48; IR (film): n˜ = 3529, 2957,
2885, 2857, 1684, 1472, 1410, 1387, 1332, 1251, 1172, 1150, 1094, 1052,
837, 776 cmꢀ1; MS (EI): m/z: calcd for C23H43NO5SiNa: 496.2532; found:
496.2529 [M+Na]+.
(SiC(CH3)3), ꢀ5.5 (Si(CH3)2); IR (film): n˜
=
2956, 2930, 2887, 2858,
1727, 1473, 1254, 1095, 833, 775 cmꢀ1
; MS (+EI): m/z: calcd for
C9H20NaO2Si: 211.1130; found: 211.1120 [M+Na]+.
(3S)-Methyl-5-(tert-butyldimethylsilyloxy)-3-hydroxy-2,2-dimethylpenta-
noate (28):[21]
Racemic method: A solution of aldehyde 18 (481 mg, 2.56 mmol) in THF
(5 mL) was cooled to ꢀ788C before addition of BF3¥THF (376 mg,
2.69 mmol). 1-Methoxy-2-methyl-1-trimethylsiloxy-1-propene (468 mg,
2.69 mmol) was added dropwise and the mixture warmed to RT. After
stirring at RT for 15 min the reaction was diluted with Et2O (20 mL) and
quenched with water (20 mL). The aqueous phase was extracted using
Et2O (3î10 mL), and the combined organics were dried over MgSO4, fil-
tered and concentrated under reduced pressure to give a colourless crude
oil. Purification by flash column chromatography (silica gel, petrol/
EtOAc 5:1) yielded racemic alcohol 28 as a colourless oil (571 mg, 77%).
(S)-N-[(3S),5-Bis-tert-butyldimethylsilyloxy-2,2-dimethylpentanoyl]bor-
nane-10,2-sultam (23): Polymer-supported-NMM (4.09 g, 14.3 mmol,
3.5 mmolgꢀ1) was added to a solution of sultam 22 (1.35 g, 2.85 mmol) in
CH2Cl2 (120 mL). The mixture was cooled to 08C and TBSOTf (0.98 mL,
4.28 mmol) added and stirred for 1 h. Methanol (1 mL) was added to
quench the excess of TBSOTf and the suspension was filtered and con-
centrated under reduced pressure. The product was filtered through a
bond elute silica gel cartridge eluting with hexane/Et2O (10:1) to yield
the bis-TBS ether 23 as a white solid (1.42 g, 89%). M.p. 78 808C; [a]D25
= ꢀ19.1 (c = 0.44, CHCl3); 1H NMR (400 MHz, CDCl3): d=4.35 (dd,
3J(H,H)=8.5, 2.0 Hz, 1H, CHOTBS), 4.01 (dd, 3J(H,H)=7.7, 4.5 Hz,
1H, CHN), 3.75 (ddd, 3J(H,H)=15.4, 10.0, 5.3 Hz, 1H, CHHSO2), 3.52
(ddd, 3J(H,H)=15.6, 10.0, 5.7 Hz, 1H, CHHSO2), 3.44 (m, 2H,
CH2OTBS), 2.01 (dd, 3J(H,H)=12.2, 6.7 Hz, 1H), 1.94 1.78 (m, 4H),
1.74 1.61 (m, 1H), 1.53 1.42 (m, 2H), 1.38 1.29 (m, 1H), 1.33 (s, 3H,
C(O)C(CH3)2), 1.24 (s, 3H, C(O)C(CH3)2), 1.14 (s, 3H, C(CH3)2), 0.95 (s,
3H, C(CH3)2), 0.89 (s, 9H, SiC(CH3)3), 0.88 (s, 9H, SiC(CH3)3), 0.08 (s,
3H, Si(CH3)2), 0.07 (s, 3H, Si(CH3)2), 0.02 (s, 6H, 2îSi(CH3)2);
13C NMR (100 MHz, CDCl3): d=177.7, 72.0, 67.7, 61.7, 53.9, 51.8, 47.8,
47.7, 44.3, 38.8, 37.8, 32.9, 26.6, 26.0, 25.9, 22.8, 20.4, 19.9, 19.4, 18.3, 18.2,
ꢀ3.5, ꢀ4.1, ꢀ5.2, ꢀ5.3; IR (film): n˜ = 2956, 2880, 1729, 1473, 1393, 1337,
1299, 1259, 1138, 1080, 838, 776 cmꢀ1; MS (EI): m/z: calcd for C29H57NO5-
Si2Na: 610.3394; found: 610.3371 [M+Na]+.
Asymmetric procedure: A suspension of N-tosyl-d-phenylalanine (26;
2.53 g, 7.91 mmol) in CH2Cl2 (58 mL) was cooled to 08C over 15 min
before addition of
a solution of BH3¥THF (1.5m in THF, 4.61 mL,
6.91 mmol) over 4 min. The mixture was allowed to warm to RT over
10 min and stirred at RT for 30 min. The reaction was cooled to ꢀ968C
over 15 min, then a pre-cooled (ꢀ788C) solution of aldehyde 18 (1.30 g,
6.91 mmol) in CH2Cl2 (6 mL) was added dropwise over 10 min, followed
by the addition of a pre-cooled (ꢀ788C) solution of 1-methoxy-2-methyl-
1-trimethylsiloxy-1-propene (1.15 g, 6.59 mmol) in CH2Cl2 (6 mL) over
10 min. The reaction mixture was warmed slowly to ꢀ788C over 1.5 h
and quenched by addition of Amberlite IRA-743 27 (1 mmolgꢀ1, 8.17 g,
13.2 mmol) and water (0.6 mL) with stirring. The quenched mixture was
warmed slowly to RT over 2 h (resin turned yellow) and stirred for a fur-
ther 4 h. Filtration, washing the resin with Et2O, followed by solvent re-
moval yielded a suspension of white solid (amino acid 26) suspended in
oil. The residue was diluted using petroleum ether 40 60 (10 mL) and re-
filtered. The residual amino acid 26 was collected as a white solid (2.33 g,
93%) and the filtrate was concentrated under reduced pressure to pro-
vide the aldol adduct 28 as a colourless oil (1.78 g, 93%). The enantio-
meric excess (92% ee) was measured by 1H NMR (C6D6) analysis of
MTPA-OCH3 signals of both (R) and (S) Mosher×s esters and compared
with those of the racemic aldol adduct. The bulk of the material was
used in subsequent reactions without further purification. A portion of
the product 28 was purified by chromatography (silica gel, EtOAc/petrol
4-(tert-Butyldimethylsilyloxy)-but-1-ene (25):[48] Alcohol 24 (1.60 g,
22.2 mmol) and polymer-supported DMAP (Argonaut, 1.49 mmolgꢀ1
,
29.8 g, 44.4 mmol) were suspended in CH2Cl2 (150 mL) at RT. Solid
TBSCl (4.69 g, 31.1 mmol) was added portionwise to the reaction mixture
and stirred at RT for 2.5 h. The reaction mixture was filtered and concen-
trated under reduced pressure to give the TBS ether product 25 as a col-
ourless oil (3.97 g, 96%). The bulk of the material was used in subse-
quent reactions without further purification. A portion of the product
was purified by chromatography (silica gel, EtOAc/petrol 1:20). Rf
=
0.74 (petrol/EtOAc 5:1); 1H NMR (400 MHz, CDCl3): d=5.88 5.77 (ddt,
1:5). Rf = 0.35 (petrol/EtOAc 5:1); [a]D25
= +0.34 (c = 3.26, CHCl3)
2538
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 2529 2547

A Total Synthesis of Epothilone C
2529 2547
1
(lit. [a]2D0 = +0.30 (c = 1.88, CHCl3)); H NMR (400 MHz, CDCl3): d=
to 08C over 15 min, then cooled back to ꢀ788C to give a colourless solu-
3.93 3.77 (m, 3H, H-3, H-5), 3.67 (s, 3H, OCH3), 3.35 (d, 3J(H,H)=
3.2 Hz, 1H, OH), 1.57 (ddd, J(H,H)=11.0, 5.5, 1.0 Hz, 2H, H-2), 1.18 (s,
3H, CH3CCH3), 1.15 (s, 3H, CH3CCH3), 0.88 (s, 9H, SiC(CH3)3), 0.06 (s,
6H, Si(CH3)2); 13C NMR (100 MHz, CDCl3): d=177.7 (C-1), 75.9 (C-3),
62.5 (C-5), 51.7 (OCH3), 47.0 (C-2), 33.7 (C-4), 25.8 (SiC(CH3)3), 21.2
tion.
3
A solution of ketone 30 (402 mg, 1.04 mmol) in THF (10 mL) was added
to the solution of freshly prepared LDA at ꢀ788C with stirring, causing a
colour change from colourless to yellow. The solution was warmed to
ꢀ158C for 10 min, then cooled back to ꢀ788C for 15 min before addition
of MeI (0.25 mL, 4 mmol). The reaction mixture was warmed to ꢀ408C
for 2 h, quenched by the addition of Amberlite IRC-50 carboxylic acid
resin (2.6 g, 26 mmol, 10 mmolgꢀ1) and warmed to RT. After 2 h the mix-
ture was filtered and the resin washed with Et2O (3î10 mL). The filtrate
was concentrated under reduced pressure to give ethyl ketone 3 as
yellow oil (394 mg, 94%). The bulk of the material was used in subse-
quent reactions without further purification. A portion of the product
(CH3), 20.5 (CH3), 18.1 (SiC(CH3)3), ꢀ5.5 (Si(CH3)2); IR (film): n˜
=
3528, 2956, 2954, 2887, 2858, 1733, 1472, 1256, 1086, 836, 776 cmꢀ1; MS
(+ESI): m/z: calcd for C14H30O4SiNa: 313.1811; found: 313.1809
[M+Na]+.
(ꢀ)-(3S)-Methyl-3,5-bis(tert-butyldimethylsilyloxy)-2,2-dimethylpenta-
noate (29):[21] A suspension of alcohol 28 (900 mg, 3.10 mmol) and diethy-
lamino-polystyrene resin (Fluka, 3.2 mmolgꢀ1
, 4.84 g, 15.5 mmol) in
was purified by chromatography (silica gel, EtOAc/petrol 1:20). Rf
=
CH2Cl2 (30 mL) was cooled to 08C before dropwise addition of TBSOTf
(1.42 mL, 6.20 mmol). The resin changed colour from yellow to deep
orange and the reaction was stirred at 08C for 2.5 h before MeOH
(2.5 mL) was added. The mixture was warmed to RT and stirring contin-
ued for 1 h. Filtration, washing the resin with alternate CH2Cl2 (3î5 mL)
and Et2O (3î5 mL), and concentration under reduced pressure yielded
the product 29 as a yellow oil (1.26 g, 100%). The bulk of the material
was used in subsequent reactions without further purification. A portion
of the product 29 was purified by chromatography (silica gel, EtOAc/
0.50 (petrol/EtOAc 20:1); [a]2D5 = ꢀ9.4 (c = 1.23, CHCl3) (lit. [a]2D0
=
ꢀ8.3 (c
=
2.10, CHCl3)); 1H NMR (400 MHz, CDCl3): d=4.07 (dd,
3J(H,H)=7.7, 2.8 Hz, 1H, H-5), 3.66 3.59 (m, 2H, H-7), 2.60 2.51 (dq,
3J(H,H)=11.2, 7.2 Hz, 1H, Ha-2), 2.50 2.44 (dq, 3J(H,H)=11.2, 7.2 Hz,
1H, Hb-2), 1.58 1.45 (m, 2H, H-6), 1.12 (s, 3H, 4-CH3), 1.06 (s, 3H, 4-
CH3), 1.01 (t, 3J(H,H)=7.2 Hz, 3H, H-1), 0.90 (s, 9H, SiC(CH3)3), 0.89
(s, 9H, SiC(CH3)3), 0.10 (s, 3H, SiCH3), 0.052 (s, 3H, SiCH3), 0.046 (s,
3H, SiCH3), 0.037 (s, 3H, SiCH3); 13C NMR (100 MHz, CDCl3): d=215.6
(C-3), 73.5 (C-5), 60.1 (C-7), 53.0 (C-4), 37.3 (C-6), 31.5 (C-2), 26.0
(SiC(CH3)3), 25.9 (SiC(CH3)3), 22.1 (CH3), 20.0 (CH3), 18.3 (SiC(CH3)3),
18.2 (SiC(CH3)3), 7.7 (CH3CH2), ꢀ4.0 (SiCH3), ꢀ4.1 (SiCH3), ꢀ5.3
(SiCH3), ꢀ5.4 (SiCH3); IR (film): n˜ = 2957, 2930, 2887, 2858, 1707, 1472,
1464, 1388, 1361, 1253, 1091, 833, 773 cmꢀ1; MS (+ESI): m/z: calcd for
C21H46O3Si2Na: 425.2883; found: 425.2898 [M+Na]+.
petrol 1:20). Rf = 0.30 (petrol/EtOAc 10:1) viewed: moly dip; [a]D25
=
ꢀ5.4 (c = 1.03, CHCl3) (lit. [a]2D0 = ꢀ6.0 (c = 3.91, CHCl3)); 1H NMR
(400 MHz, CDCl3): d=4.05 (dd, 3J(H,H)=7.6, 3.0 Hz, 1H, H-3), 3.64 (s,
3H, OCH3), 3.69 3.57 (m, 2H, H-5), 1.66 1.51 (m, 2H, H-4), 1.16 (s, 3H,
CH3CCH3), 1.09 (s, 3H, CH3CCH3), 0.89 (s, 9H, SiC(CH3)3), 0.87 (s, 9H,
SiC(CH3)3), 0.082 (s, 3H, Si(CH3)2, 0.043 (s, 3H, Si(CH3)2, 0.038 (s, 3H,
Si(CH3)2), 0.03 (s, 3H, Si(CH3)2); 13C NMR (100 MHz, CDCl3): d=177.5
(C-5), 73.3 (C-3), 60.3 (C-3), 51.6 (OCH3), 48.3 (C-2), 36.8 (C-4), 26.0
(SiC(CH3)3), 25.9 (SiC(CH3)3), 21.7 (CH3), 20.3 (CH3), 18.3 (SiC(CH3)3),
18.2 (SiC(CH3)3), ꢀ4.0 (SiCH3), ꢀ4.3 (SiCH3), ꢀ5.28 (SiCH3), ꢀ5.29
(SiCH3); IR (film): n˜ = 2954, 2929, 2886, 2857, 1734, 1472, 1464, 1253,
1095, 833, 776 cmꢀ1; MS (+ESI): m/z: calcd for C20H44O4Si2Na: 427.2670;
found: 427.2670 [M+Na]+.
N-(4-Methylbenzenesulfonyl)-d-phenylalanine (26):[50] A solution of TsCl
(8.65 g, 45.4 mmol) in Et2O (150 mL) was added to a stirred solution of
d-phenylalanine (6.25 g, 37.8 mmol) dissolved in an aqueous solution of
NaOH (1.5m, 63 mL, 94.6 mmol) at RT. After 6 h of stirring, concentrat-
ed HCl was added to the viscous white suspension until it was homogene-
ous and acidified. The organic phase was separated and the aqueous
layer extracted twice with Et2O (2î100 mL). The combined extracts
were dried over MgSO4 and concentrated under reduced pressure. The
crude product was isolated as a white solid (9.73 g, 81%) and recrystal-
lized from Et2O to yield amino acid 26 as a white solid. M.p. 166 1678C
(4S)-4,6-Bis(tert-butyldimethylsilyloxy)-3,3-dimethylhexan-2-one (30):[21]
A solution of methyl ester 29 (555 mg, 1.37 mmol) in pentane (6.0 mL)
was cooled to 08C. A solution of trimethylsilylmethyllithium (1.0m solu-
tion in pentane, 3.0 mL, 3.0 mmol) was added dropwise at 08C and the
reaction stirred for 3.5 h before the addition of MeOH (2.5 mL). The
mixture was warmed to RT and stirred for 5 h then Amberlite IRC-50
carboxylic acid resin (3.5 g, 35 mmolgꢀ1, 10 mmolgꢀ1) was added and stir-
red for 1.5 h. Filtration and concentration under reduced pressure yielded
methyl ketone 30 as a pale yellow oil (534 mg, 100%). The bulk of the
material was used in subsequent reactions without further purification. A
portion of the product 30 was purified by chromatography (silica gel,
EtOAc/petrol 1:20). Rf = 0.40 (petrol/EtOAc 20:1); [a]2D5 = ꢀ13.3 (c =
2.0, CHCl3) (lit. [a]2D0 = ꢀ11.5 (c = 0.71, CHCl3)); 1H NMR (400 MHz,
CDCl3): d=4.05 (dd, 3J(H,H)=7.8, 2.7 Hz, 1H, H-4), 3.68 3.58 (m, 2H,
H-6), 2.15 (s, 3H, H-1), 1.59 1.44 (m, 2H, H-5), 1.11 (s, 3H, CCH3), 1.06
(s, 3H, CCH3), 0.89 (s, 9H, SiC(CH3)3), 0.88 (s, 9H, SiC(CH3)3), 0.10 (s,
3H, SiCH3), 0.07 (s, 3H, SiCH3), 0.05 (s, 3H, SiCH3), 0.04 (s, 3H,
SiCH3); 13C NMR (100 MHz, CDCl3): d=213.4 (C-5), 73.3 (C-3), 59.9
(C-6), 53.4 (C-3), 37.2 (C-5), 26.8 (C-1), 26.0 (SiC(CH3)3), 25.9
(SiC(CH3)3), 21.9 (CH3), 19.9 (CH3), 18.3 (SiC(CH3)3), 18.2 (SiC(CH3)3),
ꢀ4.0 (SiCH3), ꢀ4.1 (SiCH3), ꢀ5.3 (SiCH3), ꢀ5.4 (SiCH3); IR (film): n˜ =
2956, 2929, 2887, 2857, 1706, 1472, 1464, 1388, 1361, 1252, 1092, 833,
774 cmꢀ1; MS (+ESI): m/z: calcd for C20H44NaO3Si2: 411.2727; found:
411.2729 [M+Na]+.
(lit. 164 1658C recrystallised from EtOH); Rf
= 0.39 (CHCl3/MeOH
9:1); [a]2D5 = ꢀ3.0 (c = 1.64, EtOH) (lit. [a]1D9 = ꢀ2.4 (c = 7.50, ace-
tone)); 1H NMR (400 MHz, CD3OD): d=7.53 (d, 3J(H,H)=8.2 Hz, 2H,
CHmeta), 7.22 (d, 3J(H,H)=8.1 Hz, 2H, CHortho), 7.23 7.09 (m, 5H, Ph),
3.99 (dd, 3J(H,H)=8.2, 5.7 Hz, 1H, CHNH), 3.01 (dd, 3J(H,H)=13.7,
5.6 Hz, 1H, PhCHH), 2.82 (dd, 3J(H,H) = 13.7, 8.3 Hz, 1H, PhCHH),
2.37 (s, 3H, CCH3); 13C NMR (100 MHz, CD3OD): d=174.4 (CO2H),
144.4 (CCH3), 139.1 (CCH2), 137.8 (SO2C), 130.5 (Ar), 130.4 (Ar), 129.4
(Ar), 128.0 (Ar), 127.7 (Ar), 58.8 (CHNH), 39.9 (PhCH2), 21.4 (CCH3);
IR (film): n˜ = 3283, 3031, 1729, 1671, 1426, 1335, 1210, 1155, 1073, 924,
906, 829, 813, 746, 701, 674, 655 cmꢀ1; MS (+ESI): m/z: calcd for
C16H17NO4SNa: 342.0776; found: 342.0769 [M+Na]+.
Fragment 2
(2R)-1-Bromo-2-methyl-3-(tetrahydropyranyloxy)-propane (32):[51] Neat
3,4-dihydro-2H-pyran (7.56 g, 89.9 mmol) was added to a stirred RT sus-
pension of polymer-supported sulfonic acid resin (Argonaut MP-
TsOH(I), 1.4 mmolgꢀ1
, 1.53 g, 2.1 mmol) and bromide 31 (13.1 g,
85.6 mmol). The resulting suspension was stirred at RT for 30 min. The
reaction mixture was then filtered and concentrated under reduced pres-
sure to yield the THP protected product 32 as a colourless oil (19.9 g,
98%), characterised as a mixture of diastereoisomers. The bulk of the
material was used in subsequent reactions without further purification. A
portion of the product was purified by chromatography (silica gel,
Fragment 1–(ꢀ)-(5S)-5,7-Bis(tert-butyldimethylsilyloxy)-4,4-dimethyl-
heptan-3-one (3):[21,26,49]
EtOAc/petrol 1:10). Analysed as a mixture of diastereoisomers: Rf
=
0.59 (petrol/EtOAc 2:1) viewed: moly dip; [a]2D5 = ꢀ11.6 (c
= 0.60,
From alcohol 16: PCC on basic alumina (3.85 g, 3.85 mmol,
~1 mmolgꢀ1) was added to a solution of alcohol 16 (480 mg, 1.19 mmol)
in CH2Cl2 (30 mL) at RT. The mixture was stirred for 20 h and filtered
through a silica gel pad eluting with ether to afford ketone 3 as a colour-
less oil (471 mg, 98%).
CHCl3) (lit. [a]D21
=
ꢀ13.5 (c
=
1.04, CHCl3)); 1H NMR (400 MHz,
CDCl3): d=4.61 4.57 (m, 1H, OCHO), 3.88 3.83 (m, 1H, OCHOCHH),
3.71 3.64, 3.55 3.41 (m, 1H, Ha-3), 3.34 3.33 (m, 3H, OCHOCHH, H-1),
3.31 3.21 (m, 1H, Hb-3), 2.16 2.01 (m, 1H, H-2), 1.84 1.74 (m, 1H,
CHHCH2CHOO), 1.69 1.60 (m, 1H, CHHCHOO), 1.59 1.40 (m, 4H,
CHHCHOO, CHHCH2CHOO, CH2CH2CH2CHOO), 1.04 (t, 3H,
3J(H,H)=6.5 Hz, CH3); 13C NMR (100 MHz, CDCl3): d=99.3/98.6
(OCHO), 70.1/69.7 (C-7), 62.3/62.0 (OCHOCH2), 38.2/38.0 (C-9), 35.7/
From methyl ketone 30:
A solution of LDA was prepared: nBuLi
(1.24 mL, 2.3m solution in hexanes, 2.40 mmol) was added to diisopropyl-
amine (243 mg, 0.34 mL, 2.40 mmol) in THF (10 mL) at ꢀ788C, warmed
2539
Chem. Eur. J. 2004, 10, 2529 2547
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

S. V. Ley et al.
FULL PAPER
35.6 (C-8), 30.6/30.5 (CH2CHOO), 25.5/25.4 (CH2CH2CH2CHOO), 19.5/
19.3 (CH2CH2CH2CHOO), 15.9/15.8 (CH3); IR (film): n˜ = 2941, 2872,
6.2 Hz, 1H, Ha-1), 3.45 3.41 (dd, 3J(H,H)=10.5, 6.5 Hz, 1H, Hb-1), 2.07
2.01 (m, 2H, H-5), 1.67 1.60 (m, 1H, H-2), 1.53 1.34 (m, 3H, Ha-3, Hab
-
1121, 1064, 1032, 975, 904, 869 cmꢀ1
; MS (+ESI): m/z: calcd for
4), 1.19 1.08 (m, 1H, Hb-3), 0.92 (d, 3J(H,H)=6.5 Hz, 3H, CH3);
13C NMR (100 MHz, CDCl3): d=138.9 (C-6), 114.4 (C-7), 68.3 (C-1), 35.7
C9H16BrO2: 235.0334; found: 235.0342 [MꢀH]+.
(2R)-1-Iodo-2-methyl-3-tetrahydropyranyloxypropane (33):[52] Bromide
32 (19.7 g, 83.0 mmol) was dissolved in butanone (200 mL) before addi-
tion of NaI (37.5 g, 250 mmol). The reaction was heated at 758C for 1 h,
then cooled to RT. The mixture was diluted with Et2O (50 mL) and sili-
ca gel (50 g) was added. The suspension was filtered and the filtrate was
concentrated under reduced pressure to yield the iodide 33 as a yellow
oil (22.7 g, 96%). The bulk of the material was used in subsequent reac-
tions without further purification. A portion of the product was purified
by chromatography (silica gel, EtOAc/petrol 1:10); analysed as a mixture
of diastereoisomers: Rf = 0.59 (petrol/EtOAc 2:1) viewed: UV (254 nm)
or moly dip; [a]2D5 = ꢀ10.2 (c = 4.87, CHCl3) (lit. [a]2D2 = ꢀ11.0 (c =
1.16, CHCl3)); 1H NMR (400 MHz, CDCl3): d=4.58 4.55 (dt, 3J(H,H)=
10.5, 3.3 Hz, 1H, OCHO), 3.86 3.80 (m, 1H, CHHOCHO), 3.64 3.61/
3.56 3.53 (m, 1H, Ha-3), 3.50 3.47 (m, 1H, CHHOCHO), 3.33 3.15 (m,
(C-2), 34.0 (CH2), 32.6 (CH2), 26.3 (CH2), 16.5 (CH3); IR (film): n˜
=
3316, 2927, 2858, 1641 cmꢀ1; MS (+EI): m/z: calcd for C8H16O: 128.1201;
found: 128.1207 [M]+.
Fragment 2–(S)-2-Methyl-6-heptenal (4):[14,16] Pyridinium chlorochro-
mate (PCC) on basic alumina (11.7 g, ~1.0 mmolgꢀ1, 11.7 mmol) was
added at RT to a stirred solution of alcohol 35 (500 mg, 3.9 mmol) in
CH2Cl2 (20 mL). The reaction was stirred for 3.5 h at RT until oxidation
was complete. The mixture was filtered through Florisil, washing through
with 10:1 petroleum ether 30 40/Et2O dried over MgSO4, refiltered and
concentrated under reduced pressure to yield aldehyde 4 as a pale yellow
oil (398 mg, 80%). The bulk of the material was used in subsequent reac-
tions without further purification. A portion of the product was purified
by chromatography (silica gel, EtOAc/petrol 1:10). Rf = 0.47 (petrol/
EtOAc 2:1) viewed: KMnO4; [a]2D5 = +23.0 (c = 0.7, CHCl3) (lit. [a]2D0
=
+25.7 (c = 1.00, CHCl3), (lit. [a]D25
= +19.4 (c = 0.75, CHCl3));
3H,
Hb-3,
H-1),
1.81 1.64
1.58 1.48
(m,
3H,
(m,
H-2,
4H,
CHHCHOO,
CHHCHOO,
1H NMR (400 MHz, CDCl3): d=9.62 (d, 3J(H,H)=1.9 Hz, 1H, H-1),
5.85 5.75 (m, 1H, H-6), 5.00 (dd, 3J(H,H)=17.2, 1.6 Hz, 1H, CH=
CHcisHtrans), 4.97 (d, 3J(H,H)=10.2 Hz, 1H, CH=CHcisHtrans), 2.39 2.32 (d
of sextets, 3J(H,H)=6.9, 1.8 Hz, 1H, H-2), 2.11 2.06 (m, 2H, H-5), 1.77
1.66 (m, 1H, Ha-3), 1.50 1.34 (m, 3H, Hb-3, H-4), 1.10 (d, 3J(H,H)=
7.0 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3): d=205.1 (C-1), 138.2
(C-6), 114.9 (C-7), 46.2 (C-2), 33.6 (CH2), 29.9 (CH2), 26.2 (CH2), 13.3
(CH3); IR (film): n˜ = 2932, 2864, 1704, 1641, 1464, 1236, 910 cmꢀ1; MS
(+EI): m/z: calcd for C8H15O 127.2041; found: 127.1123 [M+H]+.
CH2CHHCH2CHOO),
CH2CHHCH2CHOO, CH2CH2CH2CHOO), 0.98/0.96 (d, 3J(H,H)=
6.7 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3): d=99.2/98.5 (OCHO),
71.4/71.0 (C-3), 62.3/62.0 (CH2OCHO), 35.3/35.1 (C-2), 30.6/30.5
(CH2CHOO),
25.4/25.4
(CH2CH2CH2CHOO),
19.5/19.3
(CH2CH2CH2CHOO), 17.8/17.6 (CH3), 14.0/13.5 (C-1); IR (film): n˜
=
2940, 2869, 1454, 1200, 1120, 1063, 1032, 975, 904, 869 cmꢀ1; MS (+EI):
m/z: calcd for C9H17O2I: 284.0273; found: 284.0264 [M]+.
(6R)-6-Methyl-7-tetrahydropyranyloxyhept-1-ene (34): Iodide 33 (8.10 g,
28.3 mmol) was dissolved in THF (50 mL) and copper iodide (5.5 g,
28.3 mmol) was added. The suspension was cooled to ꢀ108C under a
strict Ar atmosphere. A solution of 3-butenylmagnesium bromide (0.5m
solution in THF, 226 mL, 113 mmol) was added dropwise with stirring
over 15 min. The reaction mixture was allowed to warm slowly to 08C
and stirred for 2 h before being quenched by addition of a polymer-sup-
Fragment 3
1-(Tetrahydropyran-2-yloxy)propan-2-one (39): 1-Hydroxypropan-2-one
(7.5 mL, 0.11 mol) and 3,4-dihydro-2H-pyran (20.1 mL, 0.22 mol) were
added to
a suspension of polyvinylpyridine-hydrochloride (2.0 g) in
CH2Cl2 (40 mL). The reaction mixture was heated at reflux for 16 h.
After cooling to RT the mixture was filtered and the filtrate concentrated
under reduced pressure to yield the ketone 39 (16.8 g, 97%) as a colour-
less oil. The bulk of the material was used in subsequent reactions with-
out further purification. A portion of the product was purified by chro-
matography (silica gel, EtOAc/petrol 20:80). Rf = 0.16 (EtOAc/petrol
20:80); 1H NMR (400 MHz, CDCl3): d=4.64 (t, 3J(H,H)=3.5 Hz, 1H,
OCHO), 4.24 (d, 3J(H,H)=17.3 Hz, 1H, Ha-1), 4.11 (d, 3J(H,H)=
ported carboxylic acid (Amberlite IRC-50, 43 g, 430 mmol, 10 mmolgꢀ1
)
and polymer-supported trisamine (NovaBiochem, ~4.36 mmolgꢀ1, 20 g,
106 mmol). The suspension was shaken at RT for 24 h, then filtered
through silica using Et2O and concentrated under reduced pressure to
yield 34 as a yellow oil (5.8 g, 97%). The bulk of the material was used
in subsequent reactions without further purification. A portion of the
product was purified by chromatography (silica gel, EtOAc/petrol 1:20).
Analysed as a mixture of diastereoisomers: Rf = 0.67 (petrol/EtOAc
2:1); [a]2D5 = ꢀ3.4 (c = 0.41, CHCl3); 1H NMR (600 MHz, CDCl3): d=
5.84 5.78 (m, 1H, CH=CH2), 4.99 (dd, 3J(H,H)=7.1, 1.5 Hz, 1H, CH=
CHcisH), 4.93 (d, 3J(H,H)=10.0 Hz, 1H, CH=CHHtrans), 4.57 4.55 (m,
1H, OCHO), 3.87 3.83 (m, 1H, CHHOCHO), 3.60 3.59/3.51 3.49 (m,
2H, OCHHCHCH3, CHHOCHO), 3.25 3.22/3.15 3.15 (m, 1H,
OCHHCHCH3), 2.07 2.01 (m, 2H, CH2CH=CH2), 1.84 1.75 (m, 1H,
CH2CHHCH2CHOO), 1.74 1.62 (m, 2H, CHHCHOO, CHCH3), 1.60
1.30 (m, 7H, CH(CH3)CH2CH2, CHHCHOO, CH(CH)3CHH,
3
17.3 Hz, 1H, Hb-1), 3.84 (td, J(H,H)=11.3 Hz, 3.2 Hz, 1H, OCHH), 3.51
(m, 1H, OCHH), 2.18 (s, 3H, H-3), 1.53 1.91 (m, 6H, 3îCH2);
13C NMR (100 MHz, CDCl3): d=206.7 (C-2), 98.7, 72.3 (C-1), 62.3, 30.2,
26.4 (C-3), 25.2, 19.1, IR (film): n˜
= 2943, 2871, 1719, 1442, 1387,
1354 cmꢀ1
; MS (+EI): m/z: calcd for C8H14O3Na: 181.0841; found:
181.0833 [M+Na]+.
(4-Bromomethyl-2-methyl)thiazole hydrobromide (36): Thioacetamide
(5.0 g, 66.7 mmol) was added portionwise over 10 min to a solution of
1,3-dibromoacetone (15.8 g, 73.4 mmol) in dioxane (200 mL). After stir-
ring for 5 min at RT a white precipitate formed. The reaction was heated
at reflux for 30 min. On reaching reflux the white precipitate dissolved to
give a yellow solution. On standing for 10 min a dark yellow oil separated
from the mixture which, on cooling, solidified to give thiazole salt 36
(14.9 g, 82%) as a pale brown, granular solid. M.p. decomposed at
>1608C; 1H NMR (400 MHz, CD3OD): d=7.93 (s, 1H, H-5), 4.73 (s,
2H, CH2Br), 2.94 (s, 3H, 2-CH3); 13C NMR (100 MHz, CD3OD, 258C):
d=174.2 (C-2), 144.6 (C-4), 121.0 (C-5), 20.3 (CH2), 15.4 (CH3); IR
(solid): n˜ = 2470, 1790, 1581, 1491, 1411, 1381, 1293, 1238 cmꢀ1; elemen-
tal analysis calcd (%) for C5H7NSBr2: C 22.00, H 2.58, N 5.13; found C
22.30, H 2.56, N 5.03; MS (+EI): m/z: calcd for C5H6NSBr: 190.9404;
found: 190.9402 [MꢀHBr]+.
CH2CHHCH2CHOO,
CH2CH2CH2CHOO),
1.16 1.10
(m,
1H,
CH(CH3)CHH), 0.93/0.91 (d, 3J(H,H)=6.7 Hz, 3H, CH3); 13C NMR
(150 MHz, CDCl3): d=139.03/139.01 (CH=CH2), 114.20/114.18 (CH=
CH2), 99.0/98.8 (OCHO), 73.1/72.9 (C-7), 62.2/62.0 (CH2OCHO), 34.01/
34.00 (C-3), 33.32/33.27 (C-6), 33.20/33.16 (C-5), 30.70 (CH2CHOO),
26.29
(CH2CH2CH2CHOO),
25.52
(C-4),
19.58/19.52
= 2927, 1641,
(CH2CH2CH2CHOO), 17.15/17.07 (CH3); IR (film): n˜
1454, 1201, 1120, 1063, 1032, 977, 905, 869 cmꢀ1; MS (+EI): m/z: calcd
for C13H24O2: 212.1776; found: 212.1772 [MꢀH]+.
(S)-2-Methyl-6-hepten-1-ol (35):[14,16] Tetrahydropyranyl acetal 34 (5.30 g,
25 mmol) was dissolved in MeOH (20 mL). Polymer-supported sulfonic
acid (Argonaut, MP-TsOH(II) ~4.2 mmolgꢀ1, 240 mg, 1.00 mmol) was
added at RT and the mixture stirred for 7.5 h. Filtration, followed by con-
centration under reduced pressure yielded alcohol 35 as a yellow oil
(3.10 g, 97%). The bulk of the material was used in subsequent reactions
without further purification. A portion of the product was purified by
chromatography (silica gel, EtOAc/petrol 1:5). Rf = 0.36 (petrol/EtOAc
2:1) viewed: moly dip or KMnO4; [a]2D5 = ꢀ12.8 (c = 0.50, CHCl3) (lit.
(4-Bromomethyl-2-methyl)thiazole (37): Hydrobromide salt 36 (20 mg,
73.2 mmol) was dissolved in MeOH (3 mL) and polymer supported car-
bonate (40 mg, 4.5 mmolgꢀ1, 0.18 mmol, 2% 4-divinylbenzene, DVB) was
added. The reaction mixture was shaken at RT for 3 h. The mixture was
filtered and the filtrate concentrated under reduced pressure to yield the
thiazole bromide free base 37 as
a colourless oil (13.5 mg, 96%).
1H NMR (400 MHz, CDCl3): d=7.12 (s, 1H, H-5), 4.53 (s, 2H, CH2Br),
2.70 (s, 3H, 2-CH3); 13C NMR (400 MHz, CDCl3, 258C): d=166.9 (C-2),
151.7 (C-4), 117.2 (C-5), 27.1 (CH2), 19.2 (CH3); IR (film): n˜ = 1517,
1
[a]2D0 = ꢀ12.5 (c = 1.03, CHCl3)); H NMR (400 MHz, CDCl3): d=5.87
5.77 (m, 1H, H-6), 4.99 (d, 3J(H,H)=18.1 Hz, 1H, CH=CHcisHtrans), 4.97
3
3
(d, J(H,H)=10.1 Hz, 1H, CH=CHcisHtrans), 3.54 3.48 (dd, J(H,H)=10.3,
2540
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 2529 2547

A Total Synthesis of Epothilone C
2529 2547
1485, 1423, 1375, 1324, 1214 cmꢀ1; MS (+EI): m/z: calcd for C5H6NSBr:
192.9385; found: 192.9383 [M]+.
mixture was filtered and the filtrate concentrated under reduced pres-
sure, to give aldehyde 42 (116 mg, 60%) as a yellow oil which, on stand-
ing at RT for 1 h, crystallised to give yellow needles. The bulk of the ma-
terial was used in subsequent reactions without further purification. A
portion of the product was purified by chromatography (silica gel,
(2-Methylthiazol-4-ylmethyl)triphenylphosphonium bromide, polymer-
supported 38: Pre-washed polymer-supported triphenylphosphine (5.20 g,
15.6 mmol, 3 mmolgꢀ1) was added to a solution of 4-bromomethyl-2-
methylthiazole (37; 3.85 g, 20.0 mmol) in PhMe (80 mL). The reaction
was heated at 908C for 5 h. The resin was recovered by filtration and
washed with alternating aliquots of CH2Cl2 (3î100 mL) and Et2O (3î
100 mL) to give the product salt 38 as a yellowy brown solid (7.9 g,
~1.75 mmolgꢀ1 loading). Remaining unloaded thiazole bromide 37 was
recovered as yellow oil (1.13 g). IR (solid): n˜ = 2924, 2854, 2217, 1597,
1515, 1484, 1439, 1409, 1322, 1189 cmꢀ1; elemental analysis found: N 2.31
(loading 1.65 mmolgꢀ1).
EtOAc/petrol 20:80). Rf
= 0.18 (EtOAc/petrol 20:80); m.p. 578C;
1H NMR (400 MHz, CDCl3): d=9.54 (s, 1H, H-3’), 7.43 (s, 1H, H-5),
7.23 (s, 1H, H-1’), 2.75 (s, 3H, 2-CH3), 2.19 (s, 3H, 2’-CH3); 13C NMR
(100 MHz, CDCl3): d=195.3 (C-3’), 165.9 (C-2), 151.6 (C-5), 141.0 (C-1’),
138.5 (C-2’), 122.7 (C-5), 19.3 (2-CH3), 11.0 (2’-CH3); IR (film): n˜
=
3091, 2917, 2818, 2718, 1675, 1624, 1573, 1435, 1334, 1193 cmꢀ1; MS
(+EI): m/z: calcd for C8H9NOS: 167.0405; found: 167.0399 [M]+.
(S)-2-Methyl-4-([1E]-2’-methylhexa-1’,5’-dien-3’-ol)thiazole (43): (+)-Di-
isopinocamphenylallylborane (5.7 mL, 0.63m in pentane, 3.6 mmol) was
added dropwise at ꢀ1008C to a solution of 2-methyl-4-([1E]-2-methyl-
propenal)-thiazole (42; 0.40 g, 2.4 mmol) in Et2O (10 mL). The mixture
was stirred at ꢀ1008C for 3 h. The reaction was diluted with MeOH
(10 mL) and Dowex 50X8 (3 g, 20% DVB) was added. The reaction mix-
ture was shaken at RT for 5 h and then filtered. The resin was washed
with MeOH (20 mL) and the resin re-suspended in MeOH (10 mL). Trie-
thylamine (2 mL) was added and the reaction mixture shaken at RT for
4 h. The mixture was filtered and the resin washed with MeOH (3î
10 mL). The filtrate was concentrated under reduced pressure to give al-
cohol 43 as a yellow oil (449 mg, 89%). The bulk of the material was
used in subsequent reactions without further purification. A portion of
the product was purified by chromatography (silica gel, EtOAc/petrol
40:60). Rf = 0.21 (EtOAc/petrol 40:60); HPLC (Chiracel OD, MeCN/
hexane 25:75) indicated 93% ee; [a]2D5 = ꢀ19.8 (c = 0.97 in CHCl3).
Rf = 0.21 (EtOAc/petrol 40:60; 1H NMR (400 MHz, CDCl3, 258C): d=
6.94 (s, 1H, H-5), 6.55 (s, 1H, H-1’), 5.87 5.77 (m, 1H, H-5’), 5.15 (d,
2-Methyl-4-(2’-methyl-3’-[tetrahydropyran-2’-yloxy]propenyl)thiazole
(40): NaHMDS (3.6 mL, 1m solution in THF, 3.60 mmol) was added to a
suspension of polymer-supported (2-methylthiazol-4-ylmethyl)triphenyl-
phosphonium bromide 38 (200 mg, ~0.60 mmol) in THF (2 mL). The re-
action was shaken at RT for 45 min. The mixture was filtered under
argon and the resin washed with alternating aliquots of THF (3î10 mL)
and Et2O (3î10 mL). The resin was re-suspended in THF (2 mL) and
ketone 39 (26 mg, 0.20 mmol) was added as a solution in THF (0.5 mL).
The reaction mixture was shaken at RT for 15 h. The mixture was filtered
and the filtrate concentrated under reduced pressure to give the product
alkenes 40 as a yellow oil (47 mg, 94%, 43:4 E:Z). The bulk of the mate-
rial was used in subsequent reactions without further purification. A por-
tion of the product was purified by chromatography (silica gel, EtOAc/
petrol 20:80).
2-Methyl-4-([E]-2’-methyl-3’-[tetrahydropyran-2’-yloxy]-propenyl)thia-
zole (40): Rf = 0.24 (EtOAc/petrol 20:80); 1H NMR (400 MHz, CDCl3,
258C): d=6.97 (s, 1H, H-5), 6.57 (s, 1H, H-1’), 4.68 (t, 3J(H,H)=3.4 Hz,
1H, OCHO), 4.27 (d, 3J(H,H)=13.0 Hz, 1H, Ha-3’), 4.08 (d, 3J(H,H)=
13.0 Hz, 1H, Hb-3’), 3.90 (td, 3J(H,H)=11.3 Hz, 3.1 Hz, 1H, OCHH),
3.53 (m, 1H, OCHH), 2.70 (s, 3H, 2-CH3), 2.06 (s, 3H, 2’-CH3), 1.89 1.52
(m, 6H, 3îCH2); 13C NMR (100 MHz, CDCl3): d=164.2 (C-2), 153.0 (C-
4), 136.8 (C-2’), 119.5 (C-1’), 115.3 (C-5), 97.7, 72.4 (C-3’), 62.1, 30.7, 25.5,
19.4, 19.2 (2-CH3), 16.2 (2’-CH3); IR (film): n˜ = 2914, 2164, 1505, 1439,
1354, 1261 cmꢀ1; MS (+EI): m/z: calcd for C13H19NO2S: 253.1136; found:
253.1139 [M]+.
3
3J(H,H)=17.2 Hz, 1H, Ha-6’), 5.11 (d, J(H,H)=10.2 Hz, 1H, Hb-6’), 4.21
3
(t, J(H,H)=5.8 Hz, 1H, H-3’), 2.70 (s, 3H, 2-CH3), 2.45 2.33 (m, 2H, H-
4’), 2.04 (s, 3H, 2’-CH3); 13C NMR (100 MHz, CDCl3, 258C): d=164.6
(C-2), 152.8 (C-4), 141.3 (C-2’), 134.5 (C-5’), 119.1 (C-1’), 118.1 (C-6’),
115.6 (C-5), 76.4 (C-3’), 40.0 (C-4’), 19.2 (2-CH3), 14.4 (2’-CH3); IR
(film): n˜ = 3340, 2923, 2105, 1640, 1506, 1435, 1377, 1271, 1188 cmꢀ1; MS
(+EI): m/z: calcd for C11H15NOSNa: 232.0772; found: 232.0769
[M+Na]+.
(S)-2-Methyl-4-([E]-2’-methyl-3’-(tert-butyldimethylsilanyloxy)hexa-1’,5’-
dienyl)thiazole (44): TBSOTf (26 mL, 115 mmol) and Et3N (0.02 mL,
143 mmol) were added to a solution of alkene 43 (20 mg, 96 mmol) in
CH2Cl2 (2 mL). The reaction mixture was stirred at RT for 30 min. Poly-
mer-supported-TBD (150 mg, 2.2 mmolgꢀ1, 330 mmol, 2% DVB) was
added and the reaction mixture shaken at RT for 16 h. The mixture was
filtered and the filtrate concentrated under reduced pressure to yield
TBS ether 44 as a yellow oil (30 mg, 97%). The bulk of the material was
used in subsequent reactions without further purification. A portion of
the product was purified by chromatography (silica gel, EtOAc/petrol
2-Methyl-4-([Z]-2’-methyl-3’-[tetrahydropyran-2’-yloxy]-propenyl)thia-
zole: Rf = (Z) 0.28 (EtOAc/petrol 20:80); 1H NMR (400 MHz, CDCl3):
d=6.98 (s, 1H, H-5), 6.43 (s, 1H, H-1’), 4.66 (t, 3J(H,H)=3.5 Hz, 1H,
OCHO), 4.49 (t, 3J(H,H)=12.0 Hz, 2H, H-3’), 3.90 (td, 3J(H,H)=
11.1 Hz, 3.2 Hz, 1H, CHHO), 3.50 (m, 1H, CHHO), 2.68 (s, 3H, 2-CH3),
1.99 (s, 3H, 2-CH3), 1.88 1.74 (m, 6H, 3îCH2); 13C NMR (100 MHz,
CDCl3): d=164.6 (C-2), 152.2 (C-4), 137.6 (C-2’), 122.0 (C-1’), 115.3 (C-
5), 98.3, 66.8 (C-3’), 62.2, 30.7, 25.5, 22.5 (2’-CH3), 19.5, 19.1 (2-CH3); IR
(film): n˜ = 2914.3, 1736.1, 1505.6, 1373.4, 1319.7, 1257.2, 1181.5 cmꢀ1; MS
(+EI): m/z: calcd for C13H19NO2S: 253.1136; found: 253.1134 [M]+.
20:80). Rf =0.55 (EtOAc/petrol 20:80); [a]D25
= +1.46 (c = 0.97 in
CHCl3); 1H NMR (400 MHz, CDCl3): d=6.92 (s, 1H, H-5), 6.46 (s, 1H,
H-1’), 5.84 5.73 (m, 1H, H-5’), 5.04 (d, 3J(H,H)=17.4 Hz, 1H, Ha-6’),
5.00 (d, 3J(H,H)=10.4 Hz, 1H, Hb-6’), 4.16 (t, 3J(H,H)=6.5 Hz, 1H, H-
3’), 2.67 (s, 3H, 2-CH3), 2.38 2.28 (m, 2H, H-4’), 1.93 (s, 3H, 2-CH3), 0.87
(s, 9H, SiC(CH3)2), 0.10 (s, 3H, SiCH3), 0.01 (s, 3H, SiCH3); 13C NMR
(100 MHz, CDCl3): d=164.3 (C-2), 153.2 (C-4), 142.0 (C-2’), 135.3 (C-5’),
118.9 (C-1’), 116.5 (C-6’), 115.1 (C-5), 78.5 (C-3’), 41.4 (C-4’), 25.7
(SiC(CH3)3), 19.2 (SiC(CH3)3), 18.2 (2-CH3), 13.9 (2’-CH3), ꢀ3.8 (SiCH3),
ꢀ4.6 (SiCH3); IR (film): n˜ = 2927, 1504, 1471, 1251, 1181, 1071 cmꢀ1; MS
(+EI): m/z: calcd for C17H29NOSSiNa: 380.1692; found: 380.1675
[M+Na]+.
2-Methyl-4-([E]-2’-methylprop-1’-en-3’-ol)thiazole (41): Thiazole 40
(353 mg, 1.56 mmol) was dissolved in MeOH (10 mL) and Dowex 50X8
(4 g, 20% DVB) was added. The reaction mixture was shaken at RT for
5 h. The reaction mixture was filtered and the resin washed with MeOH
(20 mL). The resin was re-suspended in MeOH (10 mL) and Et3N (2 mL)
was added. The reaction mixture was shaken at RT for 4 h. The reaction
mixture was filtered and the resin washed with MeOH (30 mL). The fil-
trate was concentrated under reduced pressure to give alcohol 41
(208 mg, 92%) as a yellow oil. The bulk of the material was used in sub-
sequent reactions without further purification. A portion of the product
was purified by chromatography (silica gel, EtOAc/petrol 40:60). Rf
=
0.28 (EtOAc/petrol 40:60); 1H NMR (400 MHz, CDCl3): d=6.94 (s, 1H,
H-5), 6.55 (s, 1H, H-1’), 4.19 (s, 2H, H-3’), 2.71 (s, 3H, 2-CH3), 2.07 (s,
3H, 2’CH3); 13C NMR (100 MHz, CDCl3): 164.7 (C-2), 152.9 (C-5), 140.1
(C-2’), 117.7 (C-1’), 115.0 (C-5), 68.0 (C-3’), 19.1 (2-CH3), 15.8 (2’-CH3);
2-Methyl-4-([E]-2’-methyl-3’-(S)-(tert-butyldimethylsilanyloxy)hex-1’-en-
5’,6’-diol)thiazole (45): Alkene 44 (23 mg, 71 mmol) and OsO4 (0.06 mL,
2.5 wt% in tBuOH, 5 mmol) was added to a suspension of polymer-sup-
ported 4-methylmorpholine-N-oxide[55] (200 mg) in acetone/H2O (2 mL,
9:1). The reaction mixture was heated at 408C for 16 h. Polyvinylpyridine
(50 mg, 0.48 mmol, ꢁ9.5 mmolgꢀ1) was added and the mixture stirred at
RT for 4 h. The reaction was filtered and the filtrate concentrated under
reduced pressure to yield diol 45 as a dark brown oil (25 mg, 97%, 5R:5S
1:1). The bulk of the material was used in subsequent reactions without
further purification. A portion of the product was purified by chromatog-
IR (film): n˜ = 3276, 2922, 2856, 1665, 1506, 1440, 1375, 1270, 1189 cmꢀ1
MS (+EI): m/z: calcd for C8H11NOS: 169.0561; found: 169.0557 [M]+.
;
2-Methyl-4-([E]-2’-methylpropen-2’-al)thiazole (42): Alcohol 41 (196 mg,
1.17 mmol) was dissolved in toluene (10 mL) and oxygen was bubbled
through the solution for 5 min. Polymer-supported perruthenate (430 mg,
0.5 mmolgꢀ1, 0.23 mmol, 20% DVB) was added and the reaction mixture
heated at reflux under an atmosphere of oxygen for 16 h. The reaction
raphy (silica gel, EtOAc). Rf
=
0.49 (EtOAc); 1H NMR (400 MHz,
2541
Chem. Eur. J. 2004, 10, 2529 2547
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

S. V. Ley et al.
FULL PAPER
CDCl3): d=6.94, 6.92 (s, 1H, H-5), 6.58, 6.50 (s, 1H, H-1’), 4.50 4.43 (m,
1H, H-3’), 3.95 3.89 (m, 1H, H-5’), 3.63 3.59 (m, 1H, Ha-6’), 3.50 3.43
(m, 1H, Hb-6’), 2.71 (s, 3H, 2-CH3), 2.03, 2.02 (s, 3H, 2-CH3), 1.89 1.82
(m, 1H, Ha-4’), 1.70 1.60 (m, 1H, Hb-4’), 0.93, 0.92 (s, 9H, SiC(CH3)3),
0.08, 0.04 (2îs, 3H, 2îSiCH3); 13C NMR (100 MHz, CDCl3): d=164.7/
164.6 (C-2), 153.0, 152.6 (C-4), 141.4 and 141.0 (C-2’), 119.5/118.7 (C-1’),
115.6, 115.5 (C-5), 77.3 and 75.8 (C-3’), 71.1/69.0 (C-5’), 66.8, 66.5 (C-6’),
39.0/38.3 (C-4’), 25.8 (SiC(CH3)3), 19.3, 19.2 (SiC(CH3)3), 18.2, 18.0 (2-
CH3), 15.1, 13.8 (2’-CH3), ꢀ4.8 (SiCH3), ꢀ4.4 (SiCCH3), ꢀ5.3 (SiCH3),
3J(H,H)=8.8, 3.2 Hz, 1H, Ha-5), 4.19 (td, 3J(H,H)=9.0, 6.4 Hz, 1H, Hb-
5), 2.50 2.43 (m, 1H, Ha-4), 2.22 (m, 1H, Hb-4), 0.91 (s, 9H, SiC(CH3)3),
0.017 (s, 3H, Si(CH3)2), 1.014 (s, 3H, Si(CH3)2); 13C NMR (100 MHz,
CDCl3): d=175.9 (C-2), 68.2 (C-3), 64.7 (C-5), 32.3 (C-4), 25.6
(SiC(CH3)3), 18.2 (SiC(CH3)3), ꢀ4.8 (SiCH3), ꢀ5.3 (SiCH3); IR (film):
n˜ = 2955, 2930, 2858, 1783, 1473, 1361, 1252, 1219, 1148, 1107, 1020, 998,
836, 778 cmꢀ1; HRMS (+ESI): m/z: calcd for C10H20O3SiNa: 239.1079;
found: 239.1065 [M+Na]+.
(ꢀ)-(3S)-3-(tert-Butyldimethylsilyloxy)-5-hydroxypentan-2-one (49):[15]
A
ꢀ5.2 (SiCH3); IR (film): n˜
= 3346, 2921, 1501, 1436, 1357, 1251,
solution of MeLi (1.6m in Et2O, 10.6 mL, 17.0 mmol) was added dropwise
to a stirred solution of lactone 48 (3.5 g, 16.2 mmol) in THF (55 mL) at
ꢀ788C over 10 min to provide a yellow solution. The mixture was stirred
at ꢀ788C for 30 min before quenching the reaction by the addition of a
polymer-supported carboxylic acid (Amberlite IRC-50, 34 g, 340 mmol,
10 mmolgꢀ1). The reaction was allowed to warm to RT, stirred for 45 min
before filtration and concentration under reduced pressure to yield a
yellow oil. On standing at RT this oil crystallised as a pale yellow solid
49 (3.68 g, 98%). The bulk of the material was used in subsequent reac-
tions without further purification. A portion of the product was purified
by chromatography (silica gel, EtOAc/petrol 1:3). Analysed as an equili-
brium mixture of lactol and ring opened isomer; m.p. 54 558C (lit. 53
608C); Rf = 0.34 (petrol/EtOAc 5:3); [a]2D5 = +24.76 (c = 2.2, CHCl3);
1H and 13C NMR spectra were both complex due to being a mixture of
three isomers; IR (film): n˜ = 3412, 2955, 2930, 2859, 1472, 1251, 1139,
1021, 867, 836, 776, 671 cmꢀ1; MS (+ESI): m/z: calcd for C10H20O3SiNa:
239.1079; found: 255.1408 [M+Na]+.
1067 cmꢀ1
.
2-Methyl-4-([E]-2-methyl-3-[S]-(tert-butyldimethylsilanyloxy)hex-1-ene-
5-al)-thiazole (46): Amberlyst A27 (periodate form) (200 mg, 0.4 mmol,
2 mmolgꢀ1) was added to a solution of diol 45 (45 mg, 0.13 mmol) in
MeOH/H2O (3 mL, 5:1). The mixture was shaken at RT for 1 d. The re-
action was filtered and the resin washed with MeOH (10 mL) and the fil-
trate concentrated under reduced pressure. The residue was dissolved in
CH2Cl2 (2 mL) and the mixture filtered. The filtrate was concentrated
under reduced pressure to yield aldehyde 46 as a brown oil (39 mg,
95%). A portion of the product was purified by chromatography (silica
gel, EtOAc/petrol 50:50). Rf = 0.45 (EtOAc/petrol 50:50); [a]2D5 = ꢀ15.6
(c = 3.58, CHCl3); 1H NMR (400 MHz, CDCl3): d=9.78 (t, 3J(H,H)=
2.5 Hz, 1H, H-5’), 6.94 (s, 1H, H-5), 6.55 (s, 1H, H-1’), 4.68 (dd,
3J(H,H)=8.2 Hz, 4.0 Hz, 1H, H-3’), 2.73 (ddd, 3J(H,H)=15.5 Hz, 8.3 Hz,
2.9 Hz, 1H, Ha-4’), 2.69 (s, 3H, 2-CH3), 2.50 (ddd, 3J(H,H)=15.6, 4.0,
2.1 Hz, 1H, Hb-4’), 2.03 (s, 3H, 2’-CH3), 0.87 (s, 9H, SiCCH3), 0.07 (s,
3H, SiCH3), 0.02 (s, 3H, SiCH3); 13C NMR (100 MHz, CDCl3, 258C): d=
201.6 (C-5’), 164.7 (C-2), 152.6 (C-4), 140.4 (C-2’), 119.3 (C-1’), 115.9 (C-
5), 73.9 (C-3’), 50.1 (C-4’), 25.7 (SiC(CH3)3), 19.2 (SiC(CH3)3), 18.1 (2-
CH3), 14.1 (2’-CH3), ꢀ5.6 (SiCH3), ꢀ5.2 (SiCH3); IR (film): n˜ = 2954,
2928, 1725, 1501, 1436, 1252, 1077 cmꢀ1; MS (+EI): m/z: calcd for
C16H27NO2SSi: 325.1532; found: 325.1537 [M]+.
4-Chloromethyl-2-methyl-thiazole (52):[53] Thiazole chloride hydrochlo-
ride salt 51 (12.70 g, 68.9 mmol) was dissolved in methanol (150 mL) and
polymer supported carbonate (Fluka, 39.3 g, 3.50 mmolgꢀ1, 138 mmol)
was added. The reaction mixture was shaken at RT for 30 min. The mix-
ture was filtered and the filtrate concentrated under reduced pressure to
yield thiazole free base 52 as a brown oil (10.0 g, 98%). The product was
used in the subsequent reaction without further purification. Rf = 0.67
(CH2Cl2/MeOH 19:1); 1H NMR (400 MHz; CDCl3): d = 7.12 (s, 1H, H-
5), 4.65 (s, 2H, CH2), 2.71 (s, 3H, CH3).
(2-Methyl-thiazol-4-ylmethyl)-phosphonic acid diethyl ester (53):[15]
Triethyl phosphite (13.23 g, 79.6 mmol) was added to thiazole chloride 52
and heated to 1608C for 3 h. A colour change from colourless to deep
red occurred. The reaction was cooled to RT and excess triethyl phos-
phite removed under reduced pressure at 608C to yield phosphonate 53
as a red oil (15.43 g, 84%). The bulk of the material was used in subse-
quent reactions without further purification. A portion of the product
was purified by chromatography (silica gel, Et2O/MeOH 19:1). Rf = 0.21
(CH2Cl2/MeOH 19:1) viewed: UV (254 nm) or KMnO4; 1H NMR
(400 MHz, CDCl3): d=6.83 (d, 1H, 3J(H,H)=3.5 Hz, H-5), 3.86 (q,
3J(H,H)=7.4 Hz, 4H, 2îOCH2), 3.12 (d, 3J(H,H)=11.0 Hz, 2H, CH2),
2.45 (s, 3H, 2-CH3), 1.06 (t, 3J(H,H)=7.4 Hz, 6H, 2îCH2CH3);
13C NMR (100 MHz, CDCl3): d=164.7 (d, 4J(C,P)=1.1 Hz, C-2), 145.5
(d, 2J=8.2 Hz, C-4), 115.1 (d, 3J(C,P)=7.6 Hz, C-5), 61.6 (d, 2J=6.6 Hz,
OCH2), 28.9 (d, 1J(C,P)=140 Hz, CH2), 18.5 (s, 2-CH3), 15.8 (d, 3J=6.0,
CH2CH3); IR (film): n˜ = 2980, 2237, 1519, 1247, 1054, 1024, 952, 925,
726 cmꢀ1; MS (+ESI): m/z: calcd for C9H16NO3PSNa: 272.0486; found:
272.0489 [M+Na]+.
(ꢀ)-(3S)-3,5-Bis-(tert-butyldimethylsilyloxy)-pentan-2-one
(50):[14,15]
Lactol 49 (3.0 g, 12.9 mmol) and polymer-supported DMAP (Argonaut,
1.49 mmolgꢀ1, 17.3 g, 2.6 mmol) were suspended in CH2Cl2 (50 mL) at
RT before the portionwise addition of TBSCl (2.72 g, 18.1 mmol). The
mixture was stirred for 2.5 h at RT, then filtered and concentrated under
reduced pressure to yield ketone 50 as a pale yellow oil (3.68 g, 98%).
The bulk of the material was used in subsequent reactions without fur-
ther purification. A portion of the product was purified by chromatogra-
phy (silica gel, EtOAc/petrol 1:10). Rf
= 0.73 (petrol/EtOAc 5:2)
viewed: moly dip; [a]D25 = ꢀ12.2 (c = 3.4, CHCl3) (lit. [a]2D0 = ꢀ12.9
1
3
(c = 1.00, CHCl3)); H NMR (400 MHz, CDCl3): d=4.15 (dd, J(H,H)=
6.3, 5.6 Hz, 1H, H-3), 3.74 3.63 (m, 2H, H-5), 2.15 (s, 3H, H-1), 1.86
1.74 (m, 2H, H-4), 0.91 (s, 9H, SiC(CH3)3), 0.86 (s, 9H, SiC(CH3)3), 0.05
(s, 3H, SiCH3), 0.05 (s, 3H, SiCH3), 0.023 (s, 3H, SiCH3), 0.019 (s, 3H,
Si(CH3)2); 13C NMR (100 MHz, CDCl3): d=212.1 (C-2), 75.7 (C-3), 58.3
(C-5), 37.7 (C-1), 25.9 (SiC(CH3)3), 25.7 (SiC(CH3)3), 25.6 (C-4), 18.2
(SiC(CH3)3), 18.1 (SiC(CH3)3), ꢀ3.6 (SiCH3), ꢀ5.0 (SiCH3), ꢀ5.48
(SiCH3), ꢀ5.5 (SiCH3); IR (film): n˜ = 2955, 2929, 2885, 2858, 1718, 1472,
1464, 1361, 1253, 1101, 1005, 833, 774 cmꢀ1; MS (+ESI): m/z: calcd for
C17H38O3Si2Na 369.2257; found: 369.2257 [M+Na]+.
(3S)-4-[(E)-3,5-Bis-(tert-butyldimethylsilyloxy)-2’-methylpent-1-enyl]-2-
methylthiazole (54):[14] A solution of nBuLi (25.3 mL, 1.6m solution in
hexanes, 40.5 mmol) was added to a stirred solution of phosphonate 53
(11.20 g, 40.5 mmol) in THF (32 mL) at ꢀ788C over 7 min. A colour
change occurred from pale red to dark red/brown. The reaction mixture
was stirred at ꢀ788C for 10 min before addition of ketone 50 (4.00 g,
11.6 mmol) over 5 min at ꢀ788C. The mixture was stirred for 5 min at
ꢀ788C, then allowed to warm slowly to RT and stirred for 45 min. Poly-
mer-supported
benzaldehyde
(Argonaut,
1.2 mmolgꢀ1
,
48.30 g,
58.0 mmol) was added and the mixture diluted with Et2O (100 mL) and
stirred at RT for 30 min. Silica gel (200 mL dry) and Et2O (200 mL) were
added causing a colour change from deep red to pale yellow. The suspen-
sion was filtered and washed using Et2O. The filtrate was concentrated,
then dissolved in Et2O (50 mL) and silica gel (50 mL dry) was added.
The mixture was filtered and concentrated under reduced pressure to
yield 54 as a yellow oil (5.36 g, 105%). The bulk of the material was used
in subsequent reactions without further purification. A portion of the
product was purified by chromatography (silica gel). Rf = 0.40 (CH2Cl2)
viewed: UV (254 nm) or moly dip; [a]2D5 = ꢀ1.0 (c = 5.0, CHCl3) (lit.
[a]2D0 = ꢀ0.7 (c = 0.46, CHCl3)); 1H NMR (600 MHz, CDCl3): d=6.90
(s, 1H, H-5), 6.48 (s, 1H, H-1’), 4.33 (dd, 1H, 3J(H,H)=7.7, 4.7 Hz, H-
3’), 3.73 3.62 (m, 2H, H-4’), 2.70 (s, 3H, 2-CH3), 2.00 (s, 3H, 2’-CH3),
1.81 1.71 (m, 2H, H-5’), 0.902 (s, 9H, SiC(CH3)3), 0.900 (s, 9H,
SiC(CH3)3), 0.08 (s, 3H, SiCH3), 0.04 (s, 6H, SiCH3), 0.01 (s, 3H,
Si(CH3)2); 1H NMR (150 MHz, CDCl3): d=164.2 (C-2), 153.3 (C-4),
(ꢀ)-(3S)-3-(tert-Butyldimethylsilyloxy)dihydrofuran-2-one (48):[15,21] Hy-
droxy lactone 47 (2.05 g, 19.6 mmol) was dissolved in CH2Cl2 (80 mL).
Polymer-supported DMAP (Argonaut, 1.49 mmolgꢀ1, 26.30 g, 39.2 mmol)
was added to the mixture at RT before addition of TBSCl (4.13 g,
27.4 mmol). The reaction was stirred for 1.5 h at RT then filtered and
concentrated under reduced pressure to yield lactone 48 as a pale yellow
oil (3.92 g, 93%) that crystallised on standing at ꢀ108C. The bulk of the
material was used in subsequent reactions without further purification. A
portion of the product was purified by chromatography (silica gel,
EtOAc/petrol 1:5). M.p. 17 188C; Rf = 0.31 (petrol/EtOAc 5:1); [a]D25
=
1
ꢀ32.5 (c = 1.72, CHCl3) (lit. [a]2D0 = ꢀ30.5 (c = 5.82, CHCl3)); H NMR
(400 MHz, CDCl3): d=4.41 (app. t, 3J(H,H)=8.4 Hz, 1H, H-3), 4.37 (td,
2542
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 2529 2547

A Total Synthesis of Epothilone C
2529 2547
142.5 (C-2’), 118.6 (C-5), 114.9 (C-1’), 75.1 (C-3’), 59.6 (C-5’), 39.9 (2’-
CH3), 25.9 (SiC(CH3)3), 25.8 (SiC(CH3)3), 19.1 (C-14), 18.22 (SiC(CH3)3),
18.21 (SiC(CH3)3), 13.8 (C-21), ꢀ4.6 (SiCH3), ꢀ5.1 (SiCH3), ꢀ5.3
(SiCH3), ꢀ5.4 (SiCH3); IR (film): n˜ = 2953, 2928, 2856, 1472, 1463, 1251,
1183, 1083, 1005, 832, 774 cmꢀ1; MS (+ESI): m/z: calcd for C22H43NO2S-
Si2Na: 464.2451; found: 464.2466 [M+Na]+.
1.00 mmol) in THF (3 mL) at ꢀ788C, warmed to 08C over 10 min, then
cooled back to ꢀ788C to give a colourless solution.
A solution of ketone 3 (250 mg, 0.62 mmol) in THF (1.0 mL) was added
dropwise over 5 min to the freshly prepared solution of LDA at ꢀ788C.
After being stirred for 20 min at ꢀ788C, the pale yellow solution was
slowly warmed to ꢀ408C and after 30 min it was cooled back to ꢀ788C
(colourless solution). A solution of aldehyde 4 (118 mg, 0.93 mmol) in
THF (1 mL) was added dropwise at ꢀ788C over 10 min down the side of
the cooled reaction vessel, and the resulting mixture was stirred for
25 min and then quenched at ꢀ788C by slow addition of glacial acetic
acid (0.5 mL). The reaction mixture was warmed to RT and diluted with
Et2O before diamine resin (NovaBiochem, 1.0 g, 3.0 mmolgꢀ1, 3.0 mmol)
was added. The mixture was stirred for 2 h, filtered and the filtrate was
concentrated under reduced pressure to yield 57 as a colourless oil
(333 mg, 100%, 13:1 mix of diastereoisomers). The bulk of the material
was used in subsequent reactions without further purification. A portion
of the product was purified by chromatography (silica gel, EtOAc/petrol
1:20).
(E)-3S-(tert-Butyldimethylsilyloxy)-4-methyl-5-(2-methylthiazol-4-yl)-
pent-4-en-1-ol (55):[14,19,21,27] A solution of CSA (3.80 g, 16.4 mmol) in
MeOH (200 mL) was added to a solution of di-silyl ether 54 (4.80 g,
10.9 mmol) in MeOH/CH2Cl2 (1:1, 200 mL) at 08C. The reaction mixture
was stirred at 08C for 2.5 h before the addition of polymer-supported car-
bonate and the mixture was allowed to warm to RT. Filtration and sol-
vent removal under reduced pressure yielded mono-silyl ether 55 as a
pale yellow viscous oil (3.70 g, 104%). The bulk of the material was used
in subsequent reactions without further purification. A portion of the
product was purified by chromatography (silica gel, MeOH/CH2Cl2 1:30).
Rf = 0.46 (CH2Cl2/MeOH 19:1) viewed: UV (254 nm) or moly dip; [a]D25
=
ꢀ34.1 (c
=
0.595, CHCl3) (lit. [a]D20
=
ꢀ31.5 (c
= 2.81, CHCl3));
1H NMR (600 MHz, CDCl3): d=6.93 (s, 1H, H-5’), 6.53 (s, 1H, H-5),
(3S,6R,7S,8S)-Major diastereoisomer 57: Rf = 0.22 (petrol 40 60/EtOAc
20:1); [a]2D5 = ꢀ54.1 (c = 0.75, CHCl3); 1H NMR (600 MHz, CDCl3):
d=5.85 5.78 (m, 1H, H-12), 4.99 (d, 3J(H,H)=17.1 Hz, 1H, CH=
CHtransCHcis), 4.92 (d, 3J(H,H)=10.0 Hz, 1H, CH=CHtransCHcis), 3.90 (dd,
3J(H,H)=7.4, 2.6 Hz, 1H, H-3), 3.69 3.65 (m, 1H, Ha-1), 3.62 3.57 (m,
1H, Hb-1), 3.48 (s, 1H, OH), 3.32 3.27 (m, 2H, H-6, H-7), 2.08 2.02 (m,
2H, H-11), 1.82 1.77 (m, 1H, Ha-2), 1.64 1.61 (m, 1H, Hb-2), 1.61 1.42
(m, 4H, Ha-9, H-8, H-10), 1.20 (s, 3H, H-22), 1.10 1.09 (m, 1H, Hb-9),
1.09 (s, 3H, H-23), 1.02 (d, 3J(H,H)=6.8 Hz, 3H, H-24), 0.90 (s, 9H,
SiC(CH3)3), 0.88 (s, 9H, SiC(CH3)3), 0.82 (d, 3J(H,H)=6.8 Hz, 3H, H-
17), 0.10 (s, 3H, Si(CH3)2), 0.08 (s, 3H, Si(CH3)2), 0.03 (s, 6H, 2î
Si(CH3)2); 13C NMR (150 MHz, CDCl3): d=218.1 (C-5), 139.1 (C-12),
114.2 (C-13), 74.8 (C-7), 74.1 (C-3), 60.5 (C-1), 54.0 (C-4), 41.3 (C-6),
37.9 (C-2), 35.5 (C-8), 34.2 (C-11), 32.4 (C-9), 26.1 (C-10), 26.1
(SiC(CH3)3), 25.9 (SiC(CH3)3), 22.8 (C-22), 20.4 (C-23), 18.3 (SiC(CH3)3),
18.2 (SiC(CH3)3), 15.3 (C-25), 9.59 (C-24), ꢀ3.8 (Si(CH3)2), ꢀ4.1
(Si(CH3)2), ꢀ5.3 (Si(CH3)2), ꢀ5.30 (Si(CH3)2); IR (film): n˜ = 3506 (br),
2956, 2929, 2857, 1682, 1472, 1254, 1090, 994, 834, 774 cmꢀ1; HRMS
(+ESI): m/z: calcd for C29H60O4Si2Na: 551.3928; found: 551.3923 [M+Na]+.
3
4.39 (dd, J(H,H)=7.3, 4.6 Hz, 1H, H-3), 3.79 3.72 (m, 2H, H-1), 2.72 (s,
3H, 2’-CH3), 2.30 (brs, 1H, OH), 2.03 (d, 3J(H,H)=0.6 Hz, 3H, 4-CH3),
1.93 1.87 (m, 1H, Ha-2), 1.84 1.72 (m, 1H, Hb-2), 0.92 (s, 9H,
SiC(CH3)3), 0.12 (s, 3H, SiCH3), 0.05 (s, 3H, SiCH3); 13C NMR
(150 MHz, CDCl3): d=164.5 (C-2’), 153.0 (C-1), 141.6 (C-4), 118.8 (C-4’),
115.4 (C-5), 77.5 (C-3), 60.4 (C-1), 38.2 (2’-CH3), 25.8 (SiC(CH3)3), 19.2
(C-4’), 18.1 (SiC(CH3)3), 14.4 (2-CH3), ꢀ4.6 (SiCH3), ꢀ5.2 (SiCH3); IR
(film): n˜ = 3403, 2928, 2857, 1472, 1253, 1185, 1074, 837, 777 cmꢀ1; MS
(+EI): m/z: calcd for C16H29NO2SSi: 327.1688; found: 327.1675 [M]+.
Fragment 3–4-[(E)-3S-(tert-Butyldimethylsilyloxy)-5-iodo-2-methylpent-
1-enyl]-2-methylthiazole (5):[19] Iodine (1.55 g, 6.12 mmol) was added to a
suspension of alcohol 55 (500 mg, 1.53 mmol) diethylaminomethylpoly-
styrene (Fluka, 3.2 mmolgꢀ1, 2.87 g, 9.17 mmol) with polymer-supported
triphenylphosphine (Fluka, 3.3 mmolgꢀ1, 2.32 g, 7.65 mmol) in MeCN/
Et2O (3:1, 13.5 mL) at RT. The reaction mixture was stirred at RT for
19 h before filtration and concentration under reduced pressure to yield
the iodide 5 as a yellow oil (489 mg, 73%). The bulk of the material was
used in subsequent reactions without further purification. A portion of
the product was purified by chromatography (silica gel, EtOAc/petrol
(3S,6S,7R,8S)-Minor diastereoisomer 57: Rf = 0.15 (petrol 40 60/EtOAc
20:1) viewed: moly dip; 1H NMR (600 MHz, CDCl3): d=5.84 5.81 (m,
1H, H-12), 5.03 (d, 3J(H,H)=17.1 Hz, 1H, CH=CHtransCHcis), 4.97 (d,
3J(H,H)=10.2 Hz, 1H, CH=CHtransCHcis), 4.06 (dd, 7.0, 3.3 Hz, 1H, H-3),
3.69 3.65 (m, 1H, Ha-1), 3.65 3.57 (m, 1H, Hb-1), 3.44 (s, 1H, OH), 3.32
3.20 (m, 2H, H-6, H-7), 2.08 2.00 (m, 2H, H-11), 1.82 1.77 (m, 1H, Ha-
2), 1.64 1.61 (m, 1H, Hb-2), 1.61 1.42 (m, 4H, Ha-9, H-8, H-10), 1.16 (s,
3H, H-22), 1.10 1.09 (m, 1H, Hb-9), 1.12 (s, 3H, H-23), 1.00 (d, 3H,
3J(H,H)=6.8 Hz, H-24), 0.92 (d, 3J(H,H)=6.8 Hz, 3H, H-25), 0.90 (s,
9H, SiC(CH3)3), 0.88 (s, 9H, SiC(CH3)3), 0.10 (s, 3H, Si(CH3)2), 0.08 (s,
3H, Si(CH3)2), 0.03 (m, 6H, 2îSi(CH3)2); 13C NMR (150 MHz, CDCl3):
d=222.1 (C-5), 138.7 (C-12), 114.6 (C-13), 75.1 (C-7), 72.8 (C-3), 60.2 (C-
1), 54.4 (C-4), 41.4 (C-6), 37.8 (C-2), 35.3 (C-8), 33.9 (C-11), 32.2 (C-9),
26.2 (C-10), 26.15 (SiC(CH3)3), 26.11 (SiC(CH3)3), 22.9 (C-22), 19.5 (C-
23), 18.3 (SiC(CH3)3), 18.2 (SiC(CH3)3), 15.6 (C-25), 10.8 (C-24), ꢀ3.80
(Si(CH3)2), ꢀ4.10 (Si(CH3)2), ꢀ5.29 (Si(CH3)2), ꢀ5.30 (Si(CH3)2); IR
(film): n˜ = 3506 (br), 2956, 2929, 2857, 1682, 1472, 1254, 1090, 994, 834,
1:5). Rf = 0.58 (petrol/EtOAc 3:1); [a]D25
= +12.8 (c = 0.76, CHCl3)
(lit. [a]2D0 = +11.0 (c = 1.00, CHCl3)); H NMR (600 MHz, CDCl3): d=
6.94 (s, 1H, H-5), 6.52 (s, 1H, H-1’), 4.23 (dd, 3J(H,H)=7.4, 4.5 Hz, 1H,
H-3’), 3.21 (t, 3J(H,H)=7.2 Hz, 2H, H-5’), 2.72 (s, 3H, 2-CH3), 2.14 2.06
(m, 1H, Ha-4’), 2.05 2.00 (m, 1H, Hb-4’), 2.01 (d, 3J(H,H)=0.6 Hz, 3H,
2-CH3), 0.91 (s, 9H, SiC(CH3)3), 0.13 (s, 3H, SiCH3), 0.04 (s, 3H, SiCH3);
13C NMR (150 MHz, CDCl3): d=164.5 (C-2), 152.9 (C-4), 141.0 (C-2’),
119.5 (C-5), 115.5 (C-1’), 78.1 (C-3’), 40.4 (2’-CH3), 25.8 (SiC(CH3)3), 19.2
(C-4’), 18.1 (SiC(CH3)3), 13.9 (2-CH3), 3.0 (C-5’), ꢀ4.6 (SiCH3), ꢀ4.9
1
(SiCH3); IR (film): n˜ = 2928, 2857, 1471, 1252, 1080, 935, 834, 775 cmꢀ1
;
MS (+EI): m/z: calcd for C16H28INOSSi: 437.0706; found: 437.0708 [M]+
.
(ꢀ)-(3S,4E)-3-(tert-Butyldimethylsilyloxy)-4-(methyl-5-(2-methyl-1,3-
thiazol-4-yl)pent-4-enyl)-triphenylphosphonium iodide on polystyrene
(56):[19] Polymer-supported triphenylphosphine (Fluka, 3.3 mmolgꢀ1
,
774 cmꢀ1
.
518 mg, 1.71 mmol) was added to iodide 5 (490 mg, 1.12 mmol) in PhMe
(2 mL) and the mixture was heated to 908C for 18 h without stirring. The
reaction was cooled to RT, filtered and the resin washed using CH2Cl2
(3î5mL), then Et2O (3î5mL). The polymer was dried under reduced
pressure to yield the immobilized phosphonium salt 56 as a yellow solid
(870 mg, 0.90 mmolgꢀ1 calculated based on mass increase of polymer and
recovered iodide). The unloaded iodide 5 was recovered as yellow oil
(172 mg) from the washings and recycled. The product was used in the
subsequent reaction without further purification. IR (solid): n˜ = 2930,
1586, 1435, 1253, 1180, 1110 cmꢀ1; elemental analysis found: P 5.34 (load-
ing 1.72 mmolgꢀ1), N 1.10 (loading: 0.8 mmolgꢀ1).
(3S,6R,7S,8S)-1,3,7-Tris-(tert-butyldimethylsilyloxy)-4,4,6,8-tetramethyl-
12-tridecen-5-one (58): Aldol adduct 57 (600 mg, 1.14 mmol) was dis-
solved in CH2Cl2 (12 mL) and treated at 08C with diethylaminomethyl-
polystyrene (1.07 g, 3.2 mmolgꢀ1
, 3.40 mmol) and TBSOTf (450 mg,
1.7 mmol). After stirring for 3.5 h (reaction complete by TLC), the reac-
tion was quenched by the addition methanol (0.2 mL), warmed to RT
and stirred for 2 h. The mixture was filtered and the filtrate concentrated
under reduced pressure to yield the tris-tert-butyldimethylsilyl ether
product 58 (728 mg, 99%) as pale yellow oil. The bulk of the material
was used in subsequent reactions without further purification. A portion
of the product was purified by chromatography (silica gel, EtOAc/petrol
1:20). Rf = 0.45 (petrol/EtOAc 20:1) viewed: moly dip; [a]2D5 = ꢀ32.8
(c = 0.81, CHCl3); 1H NMR (600 MHz, CDCl3): d=5.82 5.77 (m, 1H,
H-12), 4.97 (d, 3J(H,H)=17.1 Hz, 1H, CH=CHtransCHcis), 4.94 (d,
3J(H,H)=10.0 Hz, 1H, CH=CHtransCHcis), 3.90 (dd, 5.0, 2.5 Hz, 1H, H-3),
3.77 (dd, 3J(H,H)=4.9, 2.5 Hz, 1H, H-7), 3.68 3.64 (app. qn, 3J(H,H)=
Fragment coupling and cyclisation (compound numbering is based on
epothilone structure)
1,3-Bis-(tert-butyldimethylsilyloxy)-7-hydroxy-4,4,6,8-tetramethyl-12-tri-
decen-5-one (57): A solution of LDA was prepared: nBuLi (0.63 mL,
1.6m solution in hexanes, 1.00 mmol) was added to DIPA (101 mg,
2543
Chem. Eur. J. 2004, 10, 2529 2547
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

S. V. Ley et al.
FULL PAPER
6.8 Hz, 1H, Ha-1), 3.60 3.56 (m, 1H, Hb-1), 3.15 3.13 (m, 1H, H-6), 2.03
(m, 2H, H-11), 1.65 1.55 (m, 1H, Ha-2), 1.50 1.34 (m, 4H, Hb-2, H-8, H-
10), 1.26 1.21 (m, 1H, Ha-9), 1.22 (s, 3H, H-22), 1.20 1.09 (m, 1H, Hb-9),
1.05 (d, 3J(H,H)=6.8 Hz, 3H, H-24), 1.03 (s, 3H, H-23), 0.92 (d,
3J(H,H)=6.8 Hz, 3H, H-25), 0.91 (s, 9H, SiC(CH3)3), 0.90 (s, 9H,
SiC(CH3)3), 0.88 (s, 9H, SiC(CH3)3), 0.092 (s, 3H, Si(CH3)2), 0.066 (s,
3H, Si(CH3)2), 0.060 (s, 3H, Si(CH3)2), 0.030 (s, 3H, Si(CH3)2), 0.028 (s,
3H, Si(CH3)2), 0.016 (s, 3H, Si(CH3)2); 13C NMR (150 MHz, CDCl3): d=
218.1 (C-5), 138.9 (C-12), 114.4 (C-13), 77.4 (C-7), 74.0 (C-3), 60.9 (C-1),
53.7 (C-4), 45.0 (C-6), 38.9 (C-8), 38.1 (C-2), 34.3 (C-11), 30.5 (C-9), 27.1
(C-10), 26.2 (SiC(CH3)3), 26.1 (SiC(CH3)3), 25.9 (SiC(CH3)3), 24.5 (C-22),
19.4 (C-23), 18.5 (SiC(CH3)3), 18.3 (SiC(CH3)3), 18.2 (SiC(CH3)3), 17.4
(C-25), 15.1 (C-24), ꢀ3.72 (Si(CH3)2), ꢀ3.8 (Si(CH3)2), ꢀ3.9 (Si(CH3)2),
ꢀ4.0 (Si(CH3)2), ꢀ5.27 (Si(CH3)2), ꢀ5.30 (Si(CH3)2); IR (film): n˜ = 2955,
2929, 2857, 1696, 1472, 1463, 1253, 1093, 985, 833, 773 cmꢀ1; MS (+ESI):
m/z: calcd for C35H74O4Si3Na: 665.4793; found: 665.4812 [M+Na]+.
H-22), 1.20 1.05 (m, 2H, H-10), 1.04 (d, 3J(H,H)=6.9 Hz, 3H, H-24),
1.02 (s, 3H, H-23), 0.90 (m, 12H, SiC(CH3)3, H-25), 0.88 (s, 9H,
SiC(CH3)3), 0.875 (s, 9H, SiC(CH3)3), 0.87 (s, 9H, SiC(CH3)3), 0.086 (s,
3H, SiCH3), 0.058 (s, 9H, 3îSiCH3), 0.027 (s, 9H, 3îSiCH3), 0.022 (s,
3H, SiCH3); 13C NMR (150 MHz, CDCl3): d=218.2 (C-8), 164.3 (C-20),
153.2 (C-18), 142.1 (C-16), 131.2 (C-12), 125.9 (C-13), 118.9 (C-17), 115.0
(C-19), 78.6 (C-15), 77.4 (C-7), 74.0 (C-3), 61.0 (C-1), 53.7 (C-4), 45.0 (C-
6), 39.0 (C-8), 38.1 (C-2), 34.7 (C-14), 30.8 (C-9), 28.0 (C-11), 27.9 (C-10),
26.2 (SiC(CH3)3), 26.1 (SiC(CH3)3), 25.9 (SiC(CH3)3), 25.8 (SiC(CH3)3),
24.5 (C-22), 19.2 (C-23), 19.1 (C-21), 18.5 (SiC(CH3)3), 18.4 (SiC(CH3)3),
18.3 (SiC(CH3)3), 18.2 (SiC(CH3)3), 17.5 (C-25), 15.1 (C-24), 13.8 (C-26),
ꢀ3.7 (SiCH3), ꢀ3.8 (SiCH3), ꢀ4.0 (SiCH3), ꢀ4.7 (SiCH3), ꢀ4.9 (SiCH3),
ꢀ5.26 (SiCH3), ꢀ5.28 (SiCH3), ꢀ5.31 (SiCH3); IR (film): n˜ = 2955, 2929,
2885, 2857, 1695, 1472, 1253, 1088, 985, 834, 774 cmꢀ1; MS (+ESI): m/z:
calcd for C50H99NO5SSi4Na: 960.6213; found: 960.6186 [M+Na]+.
(3S,6R,7S,8S,12Z,15S,16E)-3,7,15-Tris(tert-butyldimethylsilyloxy)-1-hy-
droxy-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)heptadeca-
12,16-dien-5-one (61): A solution of tetra-(tert-butyl(dimethyl)silyl ether
60 (94 mg, 0.10 mmol) in MeOH/CH2Cl2 (1:1, 4.4 mL) was cooled to 08C.
Camphorsulfonic acid (48.0 mg, 0.20 mmol) was added portionwise and
the mixture stirred at 08C for 4 h. Upon completion of reaction, the mix-
ture was diluted with CH2Cl2 (5 mL), quenched and scavenged by the ad-
(3S,6R,7S,8S,12Z,15S,16E)-6,10,12-Tris-(tert-butyldimethylsilyloxy)-
5,7,9,9-tetramethyl-8-oxo-dodecanal
(59):
Tris-tert-butyldimethylsilyl
ether 58 (300 mg, 0.47 mmol) was dissolved in CH2Cl2 (12.0 mL) and
cooled to ꢀ788C. The mixture was treated with O3 for 7 min until all
starting material had been consumed (by TLC) and solution turned blue.
Polymer-supported triphenylphosphine (Fluka, 780 mg, 3.0 mmolgꢀ1
,
2.3 mmol) was added at ꢀ788C and allowed to warm slowly to RT and
shaken for 15 h. The suspension was filtered and the filtrate concentrated
under reduced pressure to yield the corresponding aldehyde 59 as colour-
less oil (300 mg, 100%). The bulk of the material was used in subsequent
reactions without further purification. A portion of the product was puri-
dition of polymer-supported carbonate (Argonaut, 143 mg, 2.8 mmolgꢀ1
,
0.40 mmol) and stirred for 2 h at RT. The mixture was filtered and con-
centrated under reduced pressure to yield colourless oil 61 (82.7 mg,
99%). The bulk of the material was used in subsequent reactions without
further purification. A portion of the product was purified by chromatog-
fied by chromatography (silica gel, EtOAc/petrol 1:20). Rf
=
0.25
raphy (silica gel, EtOAc/petrol 1:10). Rf 0.14 (petrol/EtOAc 10:1)
=
(petrol/EtOAc 20:1) viewed: moly dip; [a]2D5 = ꢀ34.9 (c = 0.49, CHCl3);
viewed: moly dip; [a]2D5 0.475, CHCl3); 1H NMR
=
ꢀ18.5 (c
=
1H NMR (600 MHz, CDCl3): d=9.72 (s, 1H, H-12), 3.87 (dd, 3J(H,H)=
(600 MHz, CDCl3): d=6.91 (s, 1H, H-19), 6.45 (s, 1H, H-17), 5.42 5.36
(m, 2H, H-12, H-13), 4.12 (app. t, 3J(H,H)=6.4 Hz, 1H, H-15), 4.06 (dd,
3
7.4, 2.4 Hz, 1H, H-3), 3.75 (dd, J(H,H)=6.7, 2.0 Hz, 1H, H-7), 3.64 3.62
(m, 1H, Ha-1), 3.56 3.54 (m, 1H, Hb-1), 3.10 (app. qn, 3J(H,H)=6.8 Hz,
1H, H-6), 2.37 (dd, m, 2H, H-11), 1.73 1.64 (m, 1H, Ha-10), 1.58 1.50
(m, 1H, Ha-2), 1.47 1.37 (m, 4H, Hb-10, H-8, Ha-9, Hb-2), 1.19 (s, 3H, H-
22), 1.18 1.08 (m, 1H, Hb-9), 1.02 (d, 3J(H,H)=6.9, 3H, H-24), 1.00 (s,
3J(H,H)=6.3, 3.9 Hz, 1H, H-3), 3.79 (dd, J(H,H)=7.1, 2.5 Hz, 1H, H-7),
3
3.64 (d, 3J(H,H)=5.5 Hz, 2H, H-1), 3.12 (app. qn, 3J(H,H)=7.0 Hz, 1H,
H-6), 2.70 (s, 3H, H-21), 2.33 2.27 (m, 2H, H-14), 2.04 1.92 (m, 2H, H-
11), 1.99 (s, 3H, H-26), 1.92 (brs, 1H, OH), 1.60 1.56 (m, 2H, H-2),
1.42 1.38 (m, 2H, H-10), 1.32 (m, 1H, H-8), 1.22 (s, 3H, H-22), 1.19 1.14
(m, 2H, H-9), 1.06 (s, 3H, H-23), 1.06 (d, 3J(H,H)=6.6 Hz, 3H, H-24),
0.91 (d, 3J(H,H)=6.5 Hz, 3H, H-25), 0.90 (s, 9H, SiC(CH3)3), 0.89 (s,
9H, SiC(CH3)3), 0.88 (s, 9H, SiC(CH3)3), 0.10 (s, 3H, SiCH3), 0.067 (s,
3H, SiCH3), 0.063 (s, 3H, SiCH3), 0.056 (s, 3H, SiCH3), 0.04 (s, 3H,
SiCH3), 0.01 (s, 3H, SiCH3); 13C NMR (150 MHz, CDCl3): d=218.0 (C-
8), 164.3 (C-20), 153.2 (C-18), 142.2 (C-16), 131.2 (C-12), 126.0 (C-13),
118.8 (C-17), 115.0 (C-19), 78.6 (C-15), 77.5 (C-7), 73.1 (C-3), 60.2 (C-1),
53.8 (C-4), 45.0 (C-6), 38.8 (C-8), 38.4 (C-2), 34.7 (C-14), 30.5 (C-9), 28.0
(C-11), 27.8 (C-10), 26.2 (SiC(CH3)3), 26.0 (SiC(CH3)3), 25.8 (SiC(CH3)3),
24.9 (C-22), 19.2 (C-21), 18.5 (SiC(CH3)3), 18.24 (SiC(CH3)3), 18.19
(SiC(CH3)3), 17.7 (C-23), 17.6 (C-25), 15.6 (C-24), 13.8 (C-26), ꢀ3.7
(SiCH3), ꢀ3.8 (SiCH3), ꢀ3.9 (SiCH3), ꢀ4.0 (SiCH3), ꢀ4.7 (SiCH3), ꢀ4.9
(SiCH3); IR (film): n˜ = 3395, 2955, 2929, 2857, 1693, 1472, 1254, 1081,
986, 836, 775 cmꢀ1; MS: m/z: calcd for C44H86NO5SSi3: 824.5534; found:
824.55210 [M+H]+.
3
3H, H-23), 0.91 (d, J(H,H)=6.8 Hz, 3H, H-25), 0.87 (s, 9H, SiC(CH3)3),
0.86 (s, 9H, SiC(CH3)3), 0.85 (s, 9H, SiC(CH3)3), 0.06 (s, 3H, SiCH3),
0.037 (s, 3H, SiCH3), 0.034 (s, 3H, SiCH3), 0.029 (s, 3H, SiCH3), ꢀ0.002
(s, 3H, SiCH3), ꢀ0.006 (s, 3H, Si(CH3)2); 13C NMR (150 MHz, CDCl3):
d=217.9 (C-5), 202.1 (C-12), 77.4 (C-7), 73.9 (C-3), 60.8 (C-1), 53.6 (C-
4), 45.2 (C-6), 44.3 (C-11), 38.7 (C-8), 38.1 (C-2), 30.5 (C-9), 26.2
((SiC(CH3)3), 26.1 ((SiC(CH3)3), 25.9 ((SiC(CH3)3), 24.4 (C-22), 20.3 (C-
10), 19.4 (C-23), 18.5 (SiC(CH3)3), 18.3 (SiC(CH3)3), 18.2 (SiC(CH3)3),
17.5 (C-25), 15.2 (C-24), ꢀ3.7 (Si(CH3)2), ꢀ3.75 (SiCH3), ꢀ3.8 (SiCH3),
ꢀ4.0 (SiCH3), ꢀ5.28 (SiCH3), ꢀ5.31 (SiCH3); IR (film): n˜ = 2955, 2929,
2857, 1730, 1693, 1473, 1256, 1101, 986, 836, 775 cmꢀ1; MS (+ESI): m/z:
calcd for C34H72O5Si3Na: 667.4585; found: 667.45710 [M+Na]+.
(3S,6R,7S,8S,12Z,15S,16E)-1,3,7,15-Tetrakis(tert-butyldimethylsilyloxy)-
4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)heptadeca-12,16-
dien-5-one (60): Polymer-supported phosphonium salt 56 (430 mg,
0.8 mmolgꢀ1, 0.34 mmol) was dried by PhMe azeotrope before being
washed using dry CH2Cl2 (5î1 mL), then THF (5î1 mL) in a fritted
tube. The resin was suspended in THF (2 mL) and NaHMDS (1m solu-
tion in THF, 1.6 mL, 1.6 mmol) was slowly added at RT (colour change
from light brown to black). The mixture was stirred at RT for 10 min,
then filtered under Ar, washed with THF (5î2 mL) and the ylide resus-
pended in THF (2 mL). The reaction mixture was cooled to ꢀ788C and a
solution of aldehyde 59 (100 mg, 0.16 mmol) was added slowly over
1 min. The mixture was stirred at ꢀ788C for 10 min then filtered through
celite and concentrated under reduced pressure to yield alkene adduct 60
as a pale yellow oil (135 mg, 93%). The bulk of the material was used in
subsequent reactions without further purification. A portion of the prod-
(3S,6R,7S,8S,12Z,15S,16E)-3,7,15-Tris-(tert-Butyldimethylsilyloxy)-
4,4,6,8,16-pentamethyl-17-(2-methyl-thiazol-4-yl)-5-oxo-heptadeca-12,16-
dienal (62): Powdered 4 ä molecular sieves, NMO (16.5 mg, 0.14 mmol),
and TPAP (1.65 mg, 0.005 mmol) were added at 08C to a solution of al-
cohol 61 (75 mg, 0.094 mmol) in CH2Cl2 (2 mL). The mixture was allowed
to warm to RT and stirred for 3 h 10 min. The reaction was loaded onto
silica and filtered through using petroleum ether 40 60/EtOAc 10:1 until
all aldehyde had been collected. Concentration under reduced pressure
yielded the aldehyde product 62 as a colourless oil (67 mg, 93%). The
bulk of the material was used in subsequent reactions without further pu-
rification. A portion of the product was purified by chromatography
uct was purified by chromatography (silica gel, EtOAc/petrol 1:15). Rf
=
(silica gel, EtOAc/petrol 1:20). Rf = 0.45 (petrol/EtOAc 10:1); [a]D25
=
0.45 (petrol/EtOAc 10:1) viewed: UV (254 nm) or moly dip; [a]D25
=
ꢀ15.1 (c = 1.04, CHCl3); 1H NMR (600 MHz, CDCl3): d=9.75 (s, 1H,
H-1), 6.90 (s, 1H, H-19), 6.45 (s, 1H, H-17), 5.42 5.34 (m, 2H, H-12, H-
13), 4.47 (app. t, 3J(H,H)=5.0 Hz, 1H, H-3), 4.12 (app. t, 3J(H,H)=
6.4 Hz, 1H, H-15), 3.76 (dd, 3J(H,H)=6.6, 2.0 Hz, 1H, H-7), 3.11 (app.
qn, 3J(H,H)=7.0 Hz, 1H, H-6), 2.69 (s, 3H, H-21), 2.51 (ddd, 3J(H,H)=
16.9, 3.4, 1.6 Hz, 1H, Ha-2), 2.39 (ddd, 3J(H,H)=16.9, 5.4, 2.7 Hz, 1H,
Hb-2), 2.35 2.25 (m, 2H, H-14), 2.01 1.99 (m, 2H, H-11), 1.99 (s, 3H, H-
26), 1.42 1.30 (m, 2H, H-10), 1.29 1.25 (m, 1H, H-8), 1.23 (s, 3H, H-22),
ꢀ31.0 (c = 0.40, CHCl3); 1H NMR (600 MHz, CDCl3): d=6.91 (s, 1H,
H-19), 6.45 (s, 1H, H-17), 5.40 5.37 (m, 2H, H-12, H-13), 4.12 (dd,
3J(H,H)=6.3, 6.2 Hz, 1H, H-15), 3.89 (d, 3J(H,H)=5.5 Hz, 1H, H-3),
3
3.76 (d, J(H,H)=5.5 Hz, 1H, H-7), 3.66 (m, 1H, Ha-1), 3.57 (m, 1H, Hb-
1), 3.14 (app. qn, 3J(H,H)=6.8 Hz, 1H, H-6), 2.70 (s, 3H, H-21), 2.33
2.29 (m, 2H, H-14), 2.10 1.90 (m, 2H, H-11), 2.00 (s, 3H, H-26), 1.57 (m,
1H, Ha-2), 1.49 (m, 1H, Hb-2), 1.40 1.34 (m, 3H, H-9, H-8), 1.22 (s, 3H,
2544
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 2529 2547

A Total Synthesis of Epothilone C
2529 2547
3
1.19 1.10 (m, 2H, H-9), 1.07 (s, 3H, H-23), 1.03 (d, J(H,H)=6.9 Hz, 3H,
H-24), 0.90 0.87 (m, 30H, H-25, 3îSiC(CH3)3), 0.09 (s, 3H, SiCH3),
0.051 (s, 3H, SiCH3), 0.050 (s, 3H, SiCH3), 0.049 (s, 3H, SiCH3), 0.03 (s,
3H, SiCH3), 0.003 (s, 3H, SiCH3); 13C NMR (150 MHz, CDCl3): d=218.0
(C-5), 201.0 (C-1), 164.3 (C-20), 153.2 (C-18), 142.1 (C-16), 131.2 (C-12),
126.0 (C-13), 118.9 (C-17), 115.0 (C-19), 78.6 (C-15), 77.5 (C-7), 73.3 (C-
3), 53.4 (C-4), 49.5 (C-2), 45.1 (C-6), 38.8 (C-8), 34.7 (C-14), 30.6 (C-9),
28.0 (C-11), 27.9 (C-10), 26.2 (SiC(CH3)3), 25.9 (SiC(CH3)3), 25.85
(SiC(CH3)3), 24.1 (C-22), 19.2 (C-21), 18.8 (C-23), 18.5 (SiC(CH3)3), 18.2
(SiC(CH3)3), 18.1 (SiC(CH3)3), 17.7 (C-25), 15.5 (C-24), 13.9 (C-26), ꢀ3.7
(SiCH3), ꢀ3.8 (SiCH3), ꢀ4.1 (SiCH3), ꢀ4.5 (SiCH3), ꢀ4.7 (SiCH3), ꢀ4.9
(SiCH3); IR (film): n˜ = 2955, 2930, 2857, 1729, 1693, 1472, 1255, 1083,
988, 836, 775 cmꢀ1; MS (+ESI): m/z: calcd for C44H83NO5SSi3: 822.5378;
found: 822.5372 [M]+.
(3S,6R,7S,8S,12Z,15S,16E)-3,7-Bis-(tert-butyldimethylsilyloxy)-15-hy-
droxy-4,4,6,8,16-pentamethyl-17-(2-methyl-thiazol-4-yl)-5-oxo-heptadeca-
12,16-dienoic acid (66):[13,19] A solution of tris-silyl ether 65 (36.5 mg,
0.044 mmol) in THF (0.8 mL) at RT was treated with TBAF (0.26 mL,
1m solution in THF, 0.25 mmol)). After being stirred for 4 h, the reaction
mixture was diluted with Et2O (5 mL) and H2O (2.5 mL) washed with
aqueous HCl (5 mL, 1m solution). The aqueous phase was extracted with
Et2O (3î5mL), and the combined organic phase was washed with brine
(10 mL), dried over MgSO4, and concentrated under reduced pressure to
yield hydroxy acid 66 as pale yellow oil (31.5 mg, 100%). The bulk of the
material was used in subsequent reactions without further purification. A
portion of the product was purified by chromatography (silica gel,
MeOH/CH2Cl2 1:19). Rf
= 0.20 (CH2Cl2/MeOH 19:1) viewed: UV
(254 nm) or moly dip; [a]2D5 = ꢀ19.1 (c = 0.56, CHCl3) (lit. [a]2D2
=
ꢀ19.2 (c = 0.1, CHCl3)); 1H NMR (600 MHz, CDCl3): d=6.96 (s, 1H,
H-19), 6.65 (s, 1H, H-17), 5.60 5.54 (m, 1H, H-12), 5.46 5.39 (m, 1H, H-
13), 4.41 (dd, 3J(H,H)=6.1, 3.5 Hz, 1H, H-3), 4.20 (dd, 3J(H,H)=6.9,
6.0 Hz, 1H, H-15), 3.80 (dd, 3J(H,H)=6.5, 1.1 Hz, 1H, H-7), 3.14 (app.
qn, 3J(H,H)=6.8 Hz, 1H, H-6), 2.72 (s, 3H, H-21), 2.51 (dd, 3J(H,H)=
Polymer-supported chlorite 63:[54] Amberlite IRA 900 (Clꢀ form) poly-
styrene resin (Fluka, 4.0 mmolgꢀ1 containing 10% H2O, 10.0 g,
36.0 mmol) was washed with H2O (2î50 mL). The resin was suspended
in a solution of sodium chlorite (18.1 g, 0.20 mol) in water (100 mL). The
mixture was shaken at RT for 24 h before filtration. The polymer was
washed with H2O (4î50 mL), MeCN (4î50 mL) and Et2O (2î50 mL),
then dried under reduced pressure at room temperature to give a yellow
solid resin 63 (16.9 g, estimated 2.1 mmolgꢀ1 of ClO2). The polymer was
stored under argon at ꢀ208C and used within a month. IR (solid): n˜ =
3378 (br), 3025, 2929, 1636, 1613, 1482, 1476, 1420, 1379, 1219, 1090, 973,
3
16.4, 3.4 Hz, 2H, H-2), 2.46 2.23 (m, 2H, H-14), 2.38 (dd, J(H,H)=16.4,
6.4 Hz, 2H, H-2), 2.18 2.11 (m, 1H, Ha-11), 2.03 (s, 3H, H-26), 2.10 1.95
(m, 1H, Hb-11), 1.48 1.32 (m, 5H, H-8, 2îCH2, H-9/H-10), 1.23 (s, 3H,
3
H-22), 1.14 (s, 3H, H-23), 1.07 (d, 3H, J(H,H)=6.8 Hz, H-24), 0.91 0.84
(m, 21H, H-25, 2îSiC(CH3)3), 0.11 (s, 3H, SiCH3), 0.08 (s, 3H, SiCH3),
0.07 (s, 3H, SiCH3), 0.06 (s, 3H, SiCH3); 13C NMR (150 MHz, CDCl3):
d=218.0 (C-5), 175.1 (C-1), 165.1 (C-20), 152.5 (C-18), 141.8 (C-16),
133.4 (C-12), 125.0 (C-13), 118.8 (C-17), 115.2 (C-19), 77.3 (C-7), 76.8 (C-
15), 73.5 (C-3), 53.7 (C-4), 44.8 (C-6), 40.0 (C-2), 39.0 (C-8), 33.4 (C-14),
30.9 (C-9), 28.0 (C-11), 27.9 (C-10), 26.2 (SiC(CH3)3), 26.0 (SiC(CH3)3),
23.5 (C-22), 19.2 (C-21), 18.8 (C-23), 18.5 (SiC(CH3)3), 18.2 (SiC(CH3)3),
17.1 (C-25), 16.0 (C-24), 14.5 (C-26), ꢀ3.8 (SiCH3), ꢀ3.9 (SiCH3), ꢀ4.2
(SiCH3), ꢀ4.6 (SiCH3); IR (film): n˜ = 3299 (br), 2952, 2929, 2856, 1712,
1695, 1472, 1460, 1384, 1361, 1252, 1085, 988, 836, 775 cmꢀ1; MS (+ESI):
m/z: calcd for C44H83NO6SSi3Na: 860.5147; found: 860.5124 [M+Na]+.
920, 889, 858, 825, 707 cmꢀ1
.
Polymer-supported dihydrogenphosphate 64:[54] Amberlite IRA 900 (Clꢀ
form) polystyrene resin (Fluka, 4.0 mmolgꢀ1 containing 10% H2O, 10.0 g,
36.0 mmol) was washed with H2O (2î50 mL). The resin was suspended
in a solution of potassium dihydrogen phosphate (27.2 g, 200 mmol) in
H2O (100 mL). The mixture was shaken at RT for 24 h before filtration.
The polymer was washed with water (4î50 mL), and ether (2î50 mL),
then dried under reduced pressure at RT to give a yellow solid resin 64
(18.5 g, estimated 2.0 mmolgꢀ1 of H2PO4). IR (solid): n˜
1639, 1485, 1476, 1135, 1071, 928, 855, 822 cmꢀ1
= 3338 (br),
.
(4S,7R,8S,9S,16S)-4,8-Bis-(tert-butyldimethylsilyloxy)-5,5,7,9-tetramethyl-
16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)-1-vinyl]-(13Z)-1-oxacyclo-
hexadec-13-ene-2,6-dione (67):[13,14,19,23] A solution of hydroxy acid 66
(10.9 mg, 0.015 mmol) in THF (0.9 mL) was treated at RT with Et3N
(17.6 mg, 0.024 mL, 0.17 mmol) and 2,4,6-trichlorobenzoyl chloride
(37.6 mg, 0.024 mL, 0.15 mmol). The reaction mixture was stirred at RT
for 50 min, then diluted with PhMe (4.0 mL) and added slowly over
40 min to a solution of polymer-supported DMAP (210 mg, 0.31 mmol,
1.48 mmolgꢀ1) in PhMe (20 mL) at 808C and stirred at that temperature
for 2 h. The reaction mixture was cooled to RT and polymer-supported
diamine resin (NovaBiochem, 250 mg, 3.8 mmolgꢀ1, 0.95 mmol) and Am-
berlite IRC-50 carboxylic acid resin (500 mg, 5 mmol, 10 mmolgꢀ1) were
added. The suspension was shaken at RT for 2 h, then filtered and con-
centrated under reduced pressure. The resulting crude oil 67 (19 mg) was
contaminated with reagent by-products. The bulk of the material was
used in subsequent reactions without further purification. A portion of
the product was purified by chromatography (silica gel, Et2O/petrol 1:7).
(3S,6R,7S,8S,12Z,15S,16E)-3,7,15-Tris-(tert-butyldimethylsilyloxy)-
4,4,6,8,16-pentamethyl-17-(2-methyl-thiazol-4-yl)-5-oxo-heptadeca-12,16-
dienoic acid (65):[19] A mixture of polymer-supported chlorite 63 (229 mg,
~0.5 mmolgꢀ1, 0.11 mmol) and polymer-supported dihydrogenphosphate
64 (343 mg, ~0.5 mmolgꢀ1, 0.17 mmol) resins was added to a solution of
aldehyde 62 (47 mg, 0.057 mmol) in tert-butyl alcohol (3 mL), water
(0.6 mL), and 2,3-dimethylbut-2-ene (0.14 mL, 2m solution in THF,
0.29 mmol). The mixture was stirred for 6 h until all material had been
oxidised, then filtered using Et2O to wash the resins. The filtrate was col-
lected and concentrated under reduced pressure to yield carboxylic acid
65 as a colourless oil (47.4 mg, 99%). The bulk of the material was used
in subsequent reactions without further purification. A portion of the
product was purified by chromatography (silica gel, EtOAc/petrol 1:10,
then 1:5, then 1:3). Rf = 0.07 (petrol 40 60/EtOAc 10:1) viewed: UV
(254 nm) or moly dip; [a]D25 = ꢀ15.5 (c = 3.77, CHCl3) (lit. [a]D22 = ꢀ8.8
(c = 0.80, CHCl3)); 1H NMR (600 MHz, CDCl3): d=6.92 (s, 1H, H-19),
6.52 (s, 1H, H-17), 5.43 5.36 (m, 2H, H-12, H-13), 4.39 (dd, 3J(H,H)=
Rf = 0.24 (petrol/Et2O 7:1) sviewed: UV (254 nm) or moly dip; [a]D25
=
3
1
ꢀ25.5 (c = 0.29, CHCl3) (lit. [a]2D2 = ꢀ22.9 (c = 0.30, CHCl3); H NMR
(600 MHz, CDCl3): d=6.96 (s, 1H, H-19), 6.57 (s, 1H, H-17), 5.57 5.48
(m, 1H, H-12), 5.42 5.34 (m, 1H, H-13), 5.01 (d, 3J(H,H)=10.3 Hz, 1H,
H-15), 4.04 (d, 3J(H,H)=10.1 Hz, 1H, H-3), 3.90 (d, 3J(H,H)=8.6 Hz,
1H, H-7), 3.01 (app. qn, 3J(H,H)=7.3 Hz, 1H, H-6), 2.82 (d, 3J(H,H)=
16.3 Hz, 1H, Ha-2), 2.80 2.70 (m, 1H, Ha-14), 2.71 (s, 3H, H-21), 2.67
6.5, 3.1 Hz, 1H, H-3), 4.15 (app. t, J(H,H)=6.5 Hz, 1H, H-15), 3.77 (dd,
3J(H,H)=7.4, 1.5 Hz, 1H, H-7), 3.14 (app. qn, 3J(H,H)=6.8 Hz, 1H, H-
6), 2.71 (s, 3H, H-21), 2.48 (dd, 3J(H,H)=16.4, 3.0 Hz, 1H, Ha-2), 2.32
(dd, 3J(H,H)=14.9, 6.9 Hz, 1H, Hb-2), 2.33 2.26 (m, 2H, H-14), 2.07
2.02 (m, 1H, Ha-11), 2.02 1.94 (m, 1H, Hb-11), 1.97 (s, 3H, H-26), 1.43
1.36 (m, 5H, H-8, H-9, H-10), 1.21 (s, 3H, H-22), 1.11 (s, 3H, H-23), 1.05
3
3
(d, J(H,H)=6.8 Hz, 3H, H-25), 0.90 0.88 (m, 30H, H-24, 3îSiC(CH3)3),
(dd, J(H,H)=16.5, 10.5 Hz, 1H, Ha-2), 2.41 2.31 (m, 1H, Ha-11), 2.12 (s,
0.10 (s, 3H, SiCH3), 0.062 (s, 3H, SiCH3), 0.060 (s, 3H, SiCH3), 0.056 (s,
3H, SiCH3), 0.05 (s, 3H, SiCH3), 0.01 (s, 3H, SiCH3); 13C NMR
(150 MHz, CDCl3): d=218.0 (C-5), 176.5 (C-1), 164.8 (C-20), 152.9 (C-
18), 142.7 (C-16), 131.4 (C-12), 126.0 (C-13), 118.6 (C-17), 114.7 (C-19),
78.7 (C-15), 77.3 (C-7), 73.5 (C-3), 53.6 (C-4), 44.9 (C-6), 40.1 (C-2), 39.0
(C-8), 34.7 (C-14), 30.8 (C-9), 28.0 (C-11), 27.8 (C-10), 26.2 (SiC(CH3)3),
26.0 (SiC(CH3)3), 25.8 (SiC(CH3)3), 23.6 (C-22), 19.2 (C-21), 18.9 (C-23),
18.5 (SiC(CH3)3), 18.19 (SiC(CH3)3), 18.18 (SiC(CH3)3), 17.3 (C-25), 15.7
(C-24), 13.8 (C-26), ꢀ3.8 (SiCH3), ꢀ3.9 (SiCH3), ꢀ4.2 (SiCH3), ꢀ4.6
(SiCH3), ꢀ4.7 (SiCH3), ꢀ4.9 (SiCH3); IR (film): n˜ = 2954, 2930, 2857,
1713, 1472, 1252, 1081, 988, 836, 775 cmꢀ1; MS (+ESI): m/z: calcd for
C44H83NO6SSi3Na: 860.5147; found: 860.5124 [M+Na]+.
3H, H-26), 2.16 2.06 (m, 1H, Hb-14), 1.92 1.82 (m, 1H, Hb-11), 1.63 1.46
(m, 3H, H-8, Ha-9, Ha-10), 1.19 1.00 (m, 2H, Hb-9, Hb-10), 1.19 (s, 3H,
H-22), 1.15 (s, 3H, H-23), 1.10 (d, 3J(H,H)=6.7 Hz, 3H, H-24), 0.96 (d,
3J(H,H)=7.0 Hz, 3H, H-25), 0.94 (s, 9H, SiC(CH3)3), 0.85 (s, 9H,
SiC(CH3)3), 0.12 (s, 3H, SiCH3), 0.10 (s, 3H, SiCH3), 0.08 (s, 3H, SiCH3),
ꢀ0.09 (s, 3H, SiCH3); 13C NMR (150 MHz, CDCl3): d=215.0 (C-5), 171.3
(C-1), 164.6 (C-20), 152.5 (C-18), 138.6 (C-16), 135.0 (C-12), 122.8 (C-13),
119.5 (C-17), 116.0 (C-19), 79.5 (C-15), 79.2 (C-7), 76.4 (C-3), 53.4 (C-4),
47.9 (C-6), 38.9 (C-2), 37.9 (C-8), 31.8 (C-14), 31.4 (C-9), 29.1 (C-11),
28.4 (C-10), 26.3 (SiC(CH3)3), 26.1 (SiC(CH3)3), 24.9 (C-22), 24.2 (C-23),
19.2 (C-21), 19.0 (C-24), 18.7 (SiC(CH3)3), 18.6 (SiC(CH3)3), 17.6 (C-25),
15.2 (C-26), ꢀ3.2 (SiCH3), ꢀ3.4 (SiCH3), ꢀ3.7 (SiCH3), ꢀ5.7 (SiCH3); IR
2545
Chem. Eur. J. 2004, 10, 2529 2547
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

S. V. Ley et al.
FULL PAPER
(film): n˜ = 2946, 2929, 2856, 1741, 1697, 1465, 1463, 1380, 1255, 1183,
1160, 1095, 1062, 1019, 984, 937, 875, 836, 775 cmꢀ1; MS (+ESI): m/z:
calcd for C38H67NO5SSi2Na: 728.4176; found: 728.4199 [M+Na]+.
Chem. Soc. Perkin Trans. 1 2002, 1850; f) I. R. Baxendale, A. L. Lee,
S. V. Ley, Synlett 2001, 1482; g) I. R. Baxendale, A. L. Lee, S. V. Ley,
Synlett 2001, 2004; h) I. R. Baxendale, S. V. Ley, Bioorg. Med.
Chem. Lett. 2000, 10, 1983; i) S. V. Ley, O. Schucht, A. W. Thomas,
P. J. Murray, J. Chem. Soc. Perkin Trans. 1 1999, 1251; j) J. Haber-
mann, S. V. Ley, J. S. Scott, J. Chem. Soc. Perkin Trans. 1 1999, 1253;
k) J. Habermann, S. V. Ley, J. J. Scicinski, J. S. Scott, R. Smits, A. W.
Thomas, J. Chem. Soc. Perkin Trans. 1 1999, 2425; l) J. Habermann,
S. V. Ley, R. Smits, J. Chem. Soc. Perkin Trans. 1 1999, 2421; m) S. V.
Ley, A. Massi, J. Comb. Chem. 2000, 2, 104; n) S. V. Ley, A. Massi,
F. Rodriguez, D. C. Horwell, R. A. Lewthwaite, M. C. Pritchard,
A. M. Reid, Angew. Chem. 2001, 113, 9999; Angew. Chem. Int. Ed.
2001, 40, 1053; o) I. R. Baxendale, G. Brusotti, M. Matsuoka, S. V.
Ley, J. Chem. Soc. Perkin Trans. 1 2002, 143.
Epothilone C
(4S,7R,8S,9S,16S)-4,8-Dihydroxy-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-
(2-methyl-1,3-thiazol-4-yl)-1-vinyl]-(13Z)-1-oxacyclohexadec-13-ene-2,6-
dione (2): Crude bis-TBS-epothilone C macrolactone 67 was dissolved in
CH2Cl2 (2.0 mL) at RT. Polymer-supported sulfonic acid resin (Argonaut
MP-TsOH(I), ~1.5 mmolgꢀ1, 116 mg, 0.18 mmol) was added and the mix-
ture shaken at RT for 1 h. Analysis by TLC showed complete capture of
the macrolactone. The resin was filtered and washed using CH2Cl2
(3 mL), then Et2O (3 mL), then MeOH (3 mL), to remove all unbound
impurities. The product was released using a solution of NH3 in MeOH
(3 mL, 2m solution). The filtrate was concentrated under reduced pres-
sure to give epothilone C (2) as a yellow oil (5.8 mg, 81% over 2 steps).
The product (2.9 mg) was purified by flash column chromatography
(silica gel, CH2Cl2/MeOH 99:1) to yield epothilone C (2.2 mg, 76%) as a
colourless foam. Rf = 0.51 (CH2Cl2/MeOH 95:5); [a]2D5 = ꢀ80.6 (c =
[9]K. Gerth, N. Bedorf, G. Hˆfle, H. Irschik, H. Reichenbach, J. Anti-
biot. 1996, 49, 560.
[10]D. M. Bollag, P. A. McQueney, J. Zhu, O. Hensens, L. Koupal, J.
Liesch, M. Goetz, E. Lazarides, C. M. Woods, Cancer Res. 1995, 55,
2325.
[11]a) A. Rivkin, F. Yoshimura, A. E. Gabarda, T. C. Chou, H. J. Dong,
W. P. Tong, S. J. Danishefsky, J. Am. Chem. Soc. 2003, 125, 2899;
b) J. T. Njardarson, K. Biswas, S. J. Danishefsky, Chem. Commun.
2002, 2759; c) C. B. Lee, Z. C. Wu, F. Zhang, M. D. Chappell, S. J.
Stachel, T. C. Chou, Y. B. Guan, S. J. Danishefsky, J. Am. Chem.
Soc. 2001, 123, 5249; d) F. Yoshimura, A. Rivkin, A. E. Gabarda,
T. C. Chou, H. J. Dong, G. Sukenick, F. F. Morel, R. E. Taylor, S. J.
Danishefsky, Angew. Chem. 2003, 115, 2622; Angew. Chem. Int. Ed.
2003, 42, 2518; e) K. C. Nicolaou, A. Ritzen, K. Namoto, Chem.
Commun. 2001, 1523.
1
0.17, CHCl3) (lit. [a]2D2 = ꢀ80.2 (c = 1.70, CHCl3)); H NMR (600 MHz,
CDCl3): d=6.96 (s, 1H, H-19), 6.59 (brs, 1H, H-17), 5.46 5.43 (td,
3J(H,H)=10.3, 4.3 Hz, 1H, H-12), 5.41 5.37 (td, 3J(H,H)=9.7, 4.5 Hz,
1H, H-13), 5.29 (dd, 3J(H,H)=9.8, 1.7 Hz, 1H, H-15), 4.23 (dd,
3J(H,H)=11.4, 2.2 Hz, 1H, H-3), 3.74 3.73 (m, 1H, H-7), 3.25 (brs, 1H,
C(3)HOH), 3.14 (dq, 3J(H,H)=6.8, 2.0 Hz, 1H, H-6), 3.00 (brs, 1H,
C(7)HOH), 2.71 2.66 (m, 1H, Ha-14), 2.70 (s, 3H, H-21), 2.49 (dd,
3J(H,H)=15.1, 11.4, 1H, Ha-2), 2.36 (dd, 3J(H,H)=15.1, 2.4 Hz, 1H, Hb-
2), 2.30 2.24 (m, 1H, Hb-14), 2.24 2.17 (m, 1H, Ha-11), 2.09 (brs, 3H, H-
26), 2.04 1.97 (m, 1H, Hb-11), 1.79 1.74 (m, 1H, H-8), 1.74 1.55 (m, 1H,
Ha-10), 1.40 1.28 (m, 1H, Ha-9), 1.33 (s, 3H, H-22), 1.26 1.14 (m, 2H,
Hb-9, Hb-10), 1.18 (d, 3J(H,H)=6.8 Hz, 3H, H-24), 1.09 (s, 3H, H-23),
1.00 (d, 3J(H,H)=6.9 Hz, 3H, H-25); 13C NMR (125 MHz, CDCl3): d=
220.5 (C-5), 170.4 (C-1), 165.0 (C-20), 151.9 (C-18), 138.7 (C-16), 133.4
(C-12), 125.0 (C-13), 119.4 (C-17), 115.8 (C-19), 78.4 (C-15), 74.1 (C-7),
72.3 (C-3), 53.3 (C-4), 41.7 (C-6), 39.2 (C-2), 38.5 (C-8), 32.4 (C-14), 31.8
(C-9), 27.6 (C-11), 27.5 (C-10), 22.7 (C-22), 19.0 (C-21), 18.6 (C-23), 15.9
(C-24), 15.5 (C-25), 13.5 (C-26); IR (film): n˜ = 3450, 2934, 1735, 1686,
1462, 1292, 1250, 1183, 1146, 1043, 1004, 975, 730 cmꢀ1; MS: m/z: calcd
for C26H39NO5SNa: 500.2447; found: 500.2449 [M+Na]+.
[12]a) A. Balog, D. F. Meng, T. Kamenecka, P. Bertinato, D. S. Su, E. J.
Sorensen, S. Danishefsky, Angew. Chem. 1996, 108, 2976; Angew.
Chem. Int. Ed. Engl. 1996, 35, 2801; b) D. S. Su, D. F. Meng, P. Berti-
nato, A. Balog, E. J. Sorensen, S. J. Danishefsky, Y. H. Zheng, T. C.
Chou, L. F. He, S. B. Horwitz, Angew. Chem. 1997, 109, 775; Angew.
Chem. Int. Ed. Engl. 1997, 36, 757; c) A. Balog, C. Harris, K. Savin,
X. G. Zhang, T. C. Chou, S. J. Danishefsky, Angew. Chem. 1998, 110,
2821; Angew. Chem. Int. Ed. 1998, 37, 2675; d) M. D. Chappell, S. J.
Stachel, C. B. Lee, S. J. Danishefsky, Org. Lett. 2000, 2, 1633; e) D.
Schinzer, A. Limberg, A. Bauer, O. M. Bohm, M. Cordes, Angew.
Chem. 1997, 109, 543; Angew. Chem. Int. Ed. Engl. 1997, 36, 523;
f) Z. Yang, Y. He, D. Vourloumis, H. Vallberg, K. C. Nicolaou,
Angew. Chem. 1997, 109, 170; Angew. Chem. Int. Ed. Engl. 1997, 36,
166; g) K. C. Nicolaou, Y. He, F. Roschangar, N. P. King, D. Vour-
loumis, T. H. Li, Angew. Chem. 1998, 110, 89; Angew. Chem. Int.
Ed. 1998, 37, 84; h) J. Mulzer, G. Karig, P. Pojarliev, Tetrahedron
Lett. 2000, 41, 7635; i) H. J. Martin, M. Drescher, J. Mulzer, Angew.
Chem. 2000, 112, 591; Angew. Chem. Int. Ed. 2000, 39, 581; j) J. W.
Bode, E. M. Carreira, J. Am. Chem. Soc. 2001, 123, 3611; k) J. W.
Bode, E. M. Carreira, J. Org. Chem. 2001, 66, 6410; l) R. E. Taylor,
G. M. Galvin, K. A. Hilfiker, Y. Chen, J. Org. Chem. 1998, 63, 9580;
m) A. Furstner, C. Mathes, K. Grela, Chem. Commun. 2001, 1057;
n) J. D. White, K. F. Sundermann, R. G. Carter, Org. Lett. 1999, 1,
1431; o) J. D. White, R. G. Carter, K. F. Sundermann, J. Org. Chem.
1999, 64, 684; p) J. D. White, R. G. Carter, K. F. Sundermann, M.
Wartmann, J. Am. Chem. Soc. 2001, 123, 5407; q) D. Sawada, M.
Kanai, M. Shibasaki, J. Am. Chem. Soc. 2000, 122, 10521; r) D.
Sawada, M. Shibasaki, Angew. Chem. 2000, 112, 215; Angew. Chem.
Int. Ed. 2000, 39, 209; s) M. Valluri, R. M. Hindupur, P. Bijoy, G.
Labadie, J. C. Jung, M. A. Avery, Org. Lett. 2001, 3, 3607; t) R. M.
Hindupur, B. Panicker, M. Valluri, M. A. Avery, Tetrahedron Lett.
2001, 42, 7341; u) S. C. Sinha, J. Sun, G. P. Miller, M. Wartmann,
R. A. Lerner, Chem. Eur. J. 2001, 7, 1691; v) S. A. May, P. A. Grieco,
Chem. Commun. 1998, 1597; w) J. Sun, S. C. Sinha, Angew. Chem.
2002, 114, 1439; Angew. Chem. Int. Ed. 2002, 41, 1381; x) B. Zhu,
J. S. Panek, Org. Lett. 2000, 2, 2575; y) M. S. Ermolenko, P. Potier,
Tetrahedron Lett. 2002, 43, 2895; z) C. R. Harris, S. D. Kuduk, A.
Balog, K. Savin, P. W. Glunz, S. J. Danishefsky, J. Am. Chem. Soc.
1999, 121, 7050.
Acknowledgement
This work was financially supported by AstraZeneca (to R.I.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. Karl-Heinz
Altmann and Novartis, Switzerland for a generous donation of authentic
materials.
[1]A. Kirschning, H. Monenschein, R. Wittenberg, Angew. Chem. 2001,
113, 670; Angew . Chem. Int. Ed. 2001, 40, 650.
[2]S. V. Ley, I. R. Baxendale, R. N. Bream, P. S. Jackson, A. G. Leach,
D. A. Longbottom, M. Nesi, J. S. Scott, R. I. Storer, S. J. Taylor, J.
Chem. Soc. Perkin Trans. 1 2000, 3815.
[3]a) R. B. Merrifield, J. Am. Chem. Soc. 1963, 85, 2149; b) R. L. Let-
singer, M. J. Kornet, J. Am. Chem. Soc. 1963, 85, 3045.
[4]D. P. Curran, Med. Res. Rev. 1999, 19, 432.
[5]a) B. A. Adams, H. E. Lee, J. Soc. Chem. Ind. London 1935, 54;
b) W. P. Hohenstein, H. Mark, J. Polym. Sci. 1946, 127.
[6]B. J. Cohen, M. A. Kraus, A. Patchornik, J. Am. Chem. Soc. 1977,
99, 4165.
[7]R. I. Storer, T. Takemoto, P. S. Jackson, S. V. Ley, Angew. Chem.
2003, 115, 2625; Angew. Chem. Int. Ed. 2003, 42, 2521.
[8]a) R. N. Bream, S. V. Ley, B. McDermott, P. A. Procopiou, J. Chem.
Soc. Perkin Trans. 1 2002, 2237; b) R. N. Bream, S. V. Ley, P. A. Pro-
copiou, Org. Lett. 2002, 4, 3793; c) I. R. Baxendale, S. V. Ley, C.
Piutti, Angew. Chem. 2002, 114, 2298; Angew. Chem. Int. Ed. 2002,
41, 2194; d) I. R. Baxendale, S. V. Ley, M. Nessi, C. Piutti, Tetrahe-
dron 2002, 58, 6285; e) I. R. Baxendale, A. L. Lee, S. V. Ley, J.
[13]D. F. Meng, P. Bertinato, A. Balog, D. S. Su, T. Kamenecka, E. J.
Sorensen, S. J. Danishefsky, J. Am. Chem. Soc. 1997, 119, 10073.
[14]D. Schinzer, A. Bauer, O. M. Bohm, A. Limberg, M. Cordes, Chem.
Eur. J. 1999, 5, 2483.
2546
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 2529 2547

A Total Synthesis of Epothilone C
2529 2547
[15]D. Schinzer, A. Bauer, J. Schieber, Chem. Eur. J. 1999, 5, 2492.
[16]K. C. Nicolaou, Y. He, D. Vourloumis, H. Vallberg, F. Roschangar,
F. Sarabia, S. Ninkovic, Z. Yang, J. I. Trujillo, J. Am. Chem. Soc.
1997, 119, 7960.
[37]S. V. Ley, J. Norman, W. P. Griffith, S. P. Marsden, Synthesis 1994,
639.
[38]J. Mulzer, A. Mantoulidis, E. Ohler, Tetrahedron Lett. 1997, 38,
7725.
[17]K. C. Nicolaou, N. Winssinger, J. Pastor, S. Ninkovic, F. Sarabia, Y.
He, D. Vourloumis, Z. Yang, T. Li, P. Giannakakou, E. Hamel,
Nature 1997, 387, 268.
[39]a) A. E. Qureshi, W. T. Ford, Br. Polym. J. 1984, 16, 231; b) G. Cai-
nelli, M. Contento, F. Manescalchi, R. Regnoli, J. Chem. Soc. Perkin
Trans. 1 1980, 2516.
[18]K. C. Nicolaou, F. Sarabia, S. Ninkovic, Z. Yang, Angew. Chem.
1997, 109, 539; Angew. Chem. Int. Ed. Engl. 1997, 36, 525.
[19]K. C. Nicolaou, S. Ninkovic, F. Sarabia, D. Vourloumis, Y. He, H.
Vallberg, M. R. V. Finlay, Z. Yang, J. Am. Chem. Soc. 1997, 119,
7974.
[20]a) K. C. Nicolaou, D. Hepworth, M. R. V. Finlay, N. P. King, B.
Werschkun, A. Bigot, Chem. Commun. 1999, 519; b) G. Koch, O.
Loiseleur, D. Fuentes, A. Jantsch, K. H. Altmann, Org. Lett. 2002, 4,
3811; c) Z. C. Wu, F. Zhang, S. J. Danishefsky, Angew. Chem. 2000,
112, 4679; Angew. Chem. Int. Ed. 2000, 39, 4505.
[40]C. R. Harris, S. D. Kuduk, A. Balog, K. A. Savin, S. J. Danishefsky,
Tetrahedron Lett. 1999, 40, 2267.
[41]It was necessary to perform a filtration through silica gel to remove
baseline impurities from ketone fragment 1 (3) prior to the aldol
coupling. The same reaction also proceeded well in diethyl ether al-
though the selectivity appeared capricious.
[42]P. Ferraboschi, C. Gambero, M. N. Azadani, E. Santaniello, Synth.
Commun. 1986, 16, 667.
[43]G. Green, W. P. Griffith, D. M. Hollinshead, S. V. Ley, M. Schroder,
J. Chem. Soc. Perkin Trans. 1 1984, 681.
[21]J. Mulzer, A. Mantoulidis, E. Ohler, J. Org. Chem. 2000, 65, 7456.
[22]R. E. Taylor, Y. Chen, Org. Lett. 2001, 3, 2221.
[44]J. J. Parlow, M. L. Vazquez, D. L. Flynn, Bioorg. Med. Chem. Lett.
1998, 8, 2391.
[23]A. Furstner, C. Mathes, C. W. Lehmann, Chem. Eur. J. 2001, 7, 5299.
[24]N. Martin, E. J. Thomas, Tetrahedron Lett. 2001, 42, 8373.
[25]Z. Y. Liu, Z. C. Chen, C. Z. Yu, R. F. Wang, R. Z. Zhang, C. S.
Huang, Z. Yan, D. R. Cao, J. B. Sun, G. Li, Chem. Eur. J. 2002, 8,
3747.
[45]During this synthesis the polymer supported reagents were not recy-
cled, although this remains an option for larger scale processes.
[46]H. Miyaoka, S. Sagawa, H. Nagaoka, Y. Yamada, Tetrahedron:
Asymmetry 1995, 6, 587.
[47]E. Claus, A. Pahl, P. G. Jones, H. M. Meyer, M. Kalesse, Tetrahedron
Lett. 1997, 38, 1359.
[48]W. R. Dolbier, X. X. Rong, M. D. Bartberger, H. Koroniak, B. E.
Smart, Z.-Y. Yang, J. Chem. Soc. Perkin Trans. 2 1998, 219.
[49]K. C. Nicolaou, K. Namoto, A. Ritzen, T. Ulven, M. Shoji, J. Li, G.
D×Amico, D. Liotta, C. T. French, M. Wartmann, K. H. Altmann, P.
Giannakakou, J. Am. Chem. Soc. 2001, 123, 9313.
[26]M. Kalesse, M. Quitschalle, E. Claus, K. Gerlach, A. Pahl, H. H.
Meyer, Eur. J. Org. Chem. 1999, 2817.
[27]B. Zhu, J. S. Panek, Eur. J. Org. Chem. 2001, 1701.
[28]K. C. Nicolaou, Y. He, D. Vourloumis, H. Vallberg, Z. Yang, Angew.
Chem. 1996, 108, 2554; Angew. Chem. Int. Ed. Engl. 1996, 35, 2399.
[29]F. A. Akbutina, I. F. Sadretdinov, N. K. Selezneva, M. S. Miftakhov,
Mendeleev Commun. 2003, 151.
[50]E. Fischer, Chem. Ber. 1915, 48, 374.
[30]J. De Brabander, S. Rosset, G. Bernardinelli, Synlett 1998, 692; J. De
Brabander, S. Rosset, G. Bernardinelli, Synlett 1998, 328.
[31]S. Kiyooka, Y. Kaneko, M. Komura, H. Matsuo, N. Nakano, J. Org.
Chem. 1991, 56, 2276.
[32]All yields quoted are based on mass recovery assuming quantitative
conversion of starting materials to products.
[51]K. Mori, S. Senda, Tetrahedron 1985, 41, 541.
[52]Y. Nakamura, K. Mori, Eur. J. Org. Chem. 2000, 2745.
[53]J. Gasteiger, C. Herzig, Tetrahedron 1981, 37, 2607.
[54]a) T. Takemoto, K. Yasuda, S. V. Ley, Synlett 2001, 1555; b) K.
Yasuda, S. V. Ley, J. Chem. Soc. Perkin Trans. 1 2002, 1024.
[55]a) D. S. Brown, W. J. Kerr, D. M. Lindsay, K. G. Pike, P. D. Ratcliffe,
Synlett 2001, 1257; b) W. J. Kerr, D. M. Lindsay, S. P. Watson, Chem.
Commun. 1999, 2551.
[33]a) S. Kiyooka, J. Synth. Org. Chem. Jpn. 1997, 55, 313; b) S. Kiyoo-
ka, Rev. Heteroat. Chem. 1997, 17, 245.
[34]Ratio determined by Mosher×s esters in 1H NMR spectra.
[35]M. H. Bolli, S. V. Ley, J. Chem. Soc. Perkin Trans. 1 1998, 2243.
[36]a) S. V. Ley, C. Ramarao, M. D. Smith, Chem. Commun. 2001, 2278;
b) B. Hinzen, S. V. Ley, J. Chem. Soc. Perkin Trans. 1 1997, 1907;
c) B. Hinzen, R. Lenz, S. V. Ley, Synthesis 1998, 977.
Received: October 29, 2003 [F5669]
Published online: April 26, 2004
2547
Chem. Eur. J. 2004, 10, 2529 2547
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim