Total synthesis of (-)-epothilone A

Article abstract of DOI:10.1002/(SICI)1521-3765(19990903)5:9<2483::AID-CHEM2483>3.0.CO;2-N

The total synthesis of (-)-epothilone A by a convergent route is reported. The synthesis of the required key intermediates has been improved with respect to stereoselectivity and availability. The access to ethyl ketone 2 has been significantly improved b

Full text of DOI:10.1002/(SICI)1521-3765(19990903)5:9<2483::AID-CHEM2483>3.0.CO;2-N

FULL PAPER
Total Synthesis of ( )-Epothilone A
Dieter Schinzer,* Armin Bauer, Oliver M. Böhm, Anja Limberg, and Martin Cordes[a]
Abstract: The total synthesis of ( )-epothilone A by a convergent route is reported.
The synthesis of the required key intermediates has been improved with respect to
stereoselectivity and availability. The access to ethyl ketone 2 has been significantly
improved by employment of chiral acetate equivalents, which provided higher optical
and chemical yields. Key intermediate 3 was obtained by oxazolidinone auxiliary
techniques and stereoselectively coupled with 2 by an aldol reaction. After
esterification with thiazole fragment 4, ( )-epothilone A was finally constructed by
using ring-closing metathesis.
Keywords: cytotoxic
epothilones ´ macrolides ´ natural
products
agents
´
ment of new, powerful anti-cancer drugs. Owing to the
impressive biological profile of those compounds, several
groups engaged in synthetic-organic and natural product
chemistry focused their efforts on developing strategies for
the total synthesis of epothilones and their synthetic ana-
logues. Several total syntheses of epothilone A[4] and epothi-
lone B[5] as well as various partial syntheses have already been
achieved.[6]
In this paper, we report on the details of an improved total
synthesis of ( )-epothilone A based on our previously
communicated olefin metathesis approach,[6a] with a meta-
thesis reaction as the ring-closing step.[4e] The structure of
epothilone A (1) is characterized by a 16-membered macro-
cyclic lactone carrying a cis-epoxide moiety, seven stereo-
centers, and two geometrical elements that have to be built up
during the course of the synthesis. Disconnection gives three
key fragments which can be assembled in a convergent
manner: as shown in Scheme 1, the ester and the b-hydroxy
keto functions in 1 allow the indicated disconnection to the
ethyl ketone fragment 2, aldehyde 3, and thiazole fragment 4
as potential precursors.
Introduction
The fascinating biological activities of the epothilones, a new
class of macrolides isolated from the myxobacterium
Sorangium cellulosum by Höfle, Reichenbach, and co-work-
ers at the Gesellschaft für Biotechnologische Forschung
(GBF), Braunschweig (Germany)[1] have created tremendous
excitement in the scientific community.[2] Following a screen-
ing program aimed at the identification of substances with a
taxol-like mode of action, Daniel M. Bollag and co-workers at
the Merck research laboratories in West Point, PA, found in
1995 that the epothilones are powerful cytotoxic agents which
function through stabilization of cellular microtubules in the
same mode of action like paclitaxel and its analogues. The
biological activity spectrum of the epothilones is very close to
that of paclitaxel. Both compounds supposedly compete for
the same receptor, paclitaxel being displaced from the binding
site by the epothilones. They show similar kinetics in in vitro
tests and provide closely similar pictures of microtubule
structure and cell damage; the major difference in their effect
on cell lines is their efficacy against multiple-drug resistance.
Epothilones are between 2000 and 5000 times more active
than paclitaxel in these experiments.[3] Their important
antitumor activity combined with their relative structural
simplicity compared with paclitaxel, and a much better water
solubility of the epothilones define exciting opportunities for
synthetic chemists, biologists, and clinicians for the develop-
Results and Discussion
The synthesis of the ethyl ketone fragment 2 was accom-
plished as depicted in Scheme 2. In contrast to our previously
described asymmetric prenylborane synthesis of fragment 2,
the construction of the stereocenter at C3 in the epothilone
macrocycle is achieved by a diastereoselective aldol reaction
with the chiral acetate equivalent (S)-( )-HYTRA (1,1,2-
triphenyl-1,2-ethanediol acetate) (9).[7] Aldehyde 8 required
for this aldol reaction was obtained starting from a Refor-
matsky reaction of a-bromo ester 5 and 3-pentanone which
[a] Prof. Dr. D. Schinzer, Dr. A. Limberg, Dipl.-Chem. A. Bauer,
Dipl.-Chem. O. M. Böhm, Dr. M. Cordes
Chemisches Institut der Otto-von-Guericke-Universität
Universitätsplatz 2, D-39106 Magdeburg (Germany)
Fax : (‡ 49)391-6712223
E-mail: Dieter.Schinzer@chemie.uni-magdeburg.de
Chem. Eur. J. 1999, 5, No. 9
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2483

D. Schinzer et al.
FULL PAPER
THFat 788C resulted in the formation of crystalline ester 10
in excellent diastereoselectivity (96% de, by HPLC) and good
yield (75%). LAH reduction allowed the auxiliary to be
removed nearly quantitatively and led to the diol 11 (90%).
Finally, 11 was protected as the 1,3-dioxolane 12 (90%) and
ozonolysis gave the desired building block 2 in 85% yield,
identical with 2 prepared according to the prenyl borane
protocol.[6a]
Aldehyde building block 3 was prepared by employing an
Evans asymmetric-alkylation strategy, starting from Super-
Quat oxazolidinone 13,[10] which was deprotonated with
nBuLi and treated with 6-heptenoyl chloride to afford amide
14 in 65% yield. Alkylation of the sodium enolate of 14 with
MeI in THF at 788C provided compound 15 (85%, only one
isomer was detected by 1H and 13C NMR spectroscopy).
Alcohol 16 was then obtained in 88% yield after reductive
removal (LAH)[11] of the auxiliary (recovery: 89%); subse-
quent oxidation with TPAP/NMO[12] gave the desired a-chiral
aldehyde 3 (89%).
S
N
olefin metathesis,
epoxidation
O
OH
4
3
O
12
S
N
13
8
OH
7
6
15
aldol reaction
O
1
3
5
esterification
O
O
OH
epothilone A: 1
O
O
O
2
Scheme 1. Retrosynthetic analysis of epothilone A.
b
a
O
O
O
O
O
Br
HO
a
b
O
NH
Bn
O
N
O
O
6
5
Bn
14
13
c
O
O
O
O
c
N
O
O
OH
8
7
Bn
16
15
Ph Ph
Ph Ph
O
e
d
d
O
OH
OH
OH
O
Ph
O
Ph
O
3
9
10
Scheme 3. Synthesis of aldehyde 3. a) 1.15 equiv nBuLi, THF, 788C,
30 min; then 6-heptenoyl chloride, 788C to RT, 65%; b) 1.15 equiv
NaHMDS, THF, 788C, 30 min; then MeI (5 equiv), 788C, 30 min, 85%;
c) LAH (4 equiv), Et2O, 08C, 88%; d) NMO (1.5 equiv), TPAP
(0.05 equiv), CH2Cl2, 10 min, 89%; NaHMDS ˆ sodium hexamethyldisila-
zane, NMO ˆ N-methylmorpholine N-oxide, TPAP ˆ tetra-n-propylam-
monium perruthenate.
g
OH
f
O
O
OH
11
12
O
O
O
2
Alcohol 17 (80% ee, provided by the previously described
Sharpless resolution)[6a] was used as the starting material for
the construction of the thiazole fragment 4. Silylation
followed by ozonolysis gave methyl ketone 19 (68% over
two steps). Deprotonation of phosphonate 20[6a] with nBuLi
and reaction with 19 under Horner± Emmons conditions[13]
yielded the desired trisubstituted olefin 21 as a single stereo-
isomer in good yield (79%). Selective desilylation of the
primary hydroxy group from 21 was achieved by the action of
Scheme 2. Synthesis of the ethyl ketone fragment 2. a) 1.1 equiv Zn dust,
3-pentanone, THF/B(OMe)3 (1:1), reflux, 2 h, then RT, 20 h, 65%;
b) Sicapent[9], cyclohexane, reflux, 20 min, 80%; c) 1. LAH (2 equiv),
THF, reflux, 2 h; 2. Swern oxidation, 63%; d) LDA (2 equiv), THF, 08C,
1 h; then 1.2 equiv 8, 788C, 1.5 h, 75%; e) LAH (7 equiv), Et2O, reflux,
2.5 h, 90%; f) acetone, CuSO4 anhydr. (1.5 equiv), pTsOH ´ H2O
(0.2 equiv), pyridine (0.15 equiv), RT, 24 h, 90%; g) O3, CH2Cl2, 788C;
then PPh3 (1.2 equiv), 788C to RT, 4 h, 85%; LDA ˆ lithium diisopro-
pylamide, LAH ˆ lithium aluminium hydride.
[14]
aqueous HF and catalytic amounts of H2SiF6 in MeCN/
furnished b-hydroxyester 6 in 65% yield.[8] Dehydration with
P4O10 gave ester 7 (80%, only the E isomer was detected by
1H and 13C NMR spectroscopy), which then was converted to
the aldehyde 8 by LAH reduction and subsequent Swern
oxidation in 63% yield. Addition of the dianion of 9 to 8 in
Et2O, leading to hydroxy compound 22 (92%). Dess ± Martin
oxidation[15] then gave aldehyde 23 in 84% yield, which was
converted to the required thiazole alcohol 4 by the action of
ˆ
the Wittig reagent Ph3P CH2 and subsequent desilylation
with TBAF in THF (84% over two steps).
2484
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Chem. Eur. J. 1999, 5, No. 9

Epothilone A
2483±2491
S
N
a
b
O
HO
+
TBSO
OH
TBSO
OTBS
TBSO
OTBS
O
OTBS O
29
OTBS
OH
17
18
19
4
S
N
a
b
S
N
S
N
OTBS
O
c
e
OR
P(OEt)2
O
OTBS
O
OTBS O
20
21: R = TBS
22: R = H
30
d
S
N
OTBS
S
N
S
S
OTBS
O
g
+
X
N
N
O
O
OTBS
OH
O
OTBS O
31a
O
OTBS
23: X = O
4
31b
f
24: X = CH2
c
Scheme 4. Synthesis of the thiazole fragment 4. a) 1.3 equiv TBSCl,
2.6 equiv imidazole, DMF, RT, 10 h, 98%; b) O3, CH2Cl2, 788C; then
PPh3 (3 equiv), 788C to RT, 69%; c) 1.2 equiv nBuLi, THF, 788C, 1 h;
then 18 (1.0 equiv), 788C to RT, 12 h, 79%; d) HF aq. (40%), glass
splinters, MeCN/Et2O (1:1), 08C, 3 h, 92%; e) Dess ± Martin periodinane
(1.3 equiv), CH2Cl2, RT, 30 min, 84%; f) MePPh3Br/NaNH2 (1.85 equiv),
THF, RT, 25 min, 85%; g) TBAF (3 equiv), MS 4 Š, THF, 08C, 80 min,
99%; TBSCl ˆ tert-butyldimethylchlorosilane, TBAF ˆ tetra-n-butylam-
monium fluoride.
S
OH
S
N
OH
N
O
+
O
O
O
OH
O
O
OH
32b
epothilone C: 32a
d
The coupling of building blocks 2, 3, and 4, and the total
synthesis of epothilone A (1) are shown in Schemes 5 and 6.
Ethyl ketone 2 and aldehyde 3 were coupled in an aldol
O
S
N
OH
a
O
+
O
O
O
O
O
OH
O
3
2
epothilone A: 1
Scheme 6. Final steps in the total synthesis of epothilone A. a) DCC
(1.3 equiv), DMAP (0.2 equiv), CH2Cl2, RT, 16 h, 80%;
b
ˆ
b) [RuCl2( CHPh)(PCy3)] (0.06 equiv), CH2Cl2, RT, 16 h, 94%, (Z/E ˆ
1.7:1); c) HF aq. (40%), glass splinters, MeCN/Et2O (1:1), RT, 12 h, 65%;
d) dimethyl dioxirane, CH2Cl2, 358C, 2 h, 48%; DCC ˆ dicyclohexyl
carbodiimide, DMAP ˆ 4-dimethylaminopyridine.
O
O
O
OH
25
e
reaction, which proceeds with remarkable diastereoselectivity
(20:1) in favor of the desired anti Cram (6R,7S) [16] isomer 25
in high yield (73%). The optimum conditions for this coupling
reaction required generation of the syn-lithium enolate of 2
with 0.98 equivalents of LDA in THF at 788C, followed by
the addition of aldehyde 3, resulting almost exclusively in the
formation of 25, which was transformed to acid 29 by a four-
step sequence: Thus, cleavage of the dioxolane protective
group with PPTS in MeOH led to the triol 26 in 88% yield.[17]
Exposure of 26 to excess of TBSOTf and 2,6-lutidine gave tris-
silyl ether 27 almost quantitatively (99%). Selective depro-
tection of the primary TBS group of 27 was achieved by the
action of CSA in MeOH/CH2Cl2 (1:1), leading to alcohol 28 in
83% yield.[18] Finally, acid 29 was obtained from 28 by
oxidation with PDC in DMF in 79% yield.[19]
OR1 OR2
O
OR3
26: R1 = R2 = R3 = H
c
27: R1 = R2 = R3 = TBS
28: R1 = H, R2 = R3= TBS
d
HO
O
OTBS O
OTBS
29
Scheme 5. Coupling of building blocks 2 and 3. a) LDA (0.98 equiv), THF,
788C, 1 h; then 3, 788C, 45 min, 73%; b) PPTS (1.3 equiv), MeOH, RT,
36 h, 88%; c) TBSOTf (6 equiv), 2,6-lutidine (12 equiv), CH2Cl2, 788C,
30 min, then 08C, 3 h, 99%; d) CSA (0.2 equiv), MeOH/CH2Cl2 (1:1), 08C,
5 h, 83%; e) PDC (11 equiv), DMF, RT, 36 h, 79%; PPTS ˆ pyridinium p-
toluenesulfonate, TBSOTf ˆ tert-butyldimethylsilyl trifluoromethanesulfo-
nate, CSA ˆ camphorsulfonic acid, PDC ˆ pyridinium dichromate.
Acid 29 was coupled with thiazole building block 4 in
the presence of DCC and DMAP to afford the metathesis
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D. Schinzer et al.
FULL PAPER
1H; OH), 1.56 (m, 4H; H-4), 1.29 (t, 3J ˆ 7.1 Hz, 3H; CH3CH2OCO), 1.22
(s, 6H; C2-CH3), 0.93 (t, 3J ˆ 7.5 Hz, 6H; H-5); 13C NMR (100 MHz,
CDCl3): d ˆ 179.2, 76.2, 60.9, 50.3, 28.2, 21.6, 14.1, 8.9; MS (PCI, CH4): m/z
precursor 30 in 80% yield. The olefin-metathesis reac-
tion of 30 with 6 mol% of the Grubbs catalyst
[RuCl2( CHPh)(PCy3)][20] in CH2Cl2 gave a mixture of cyclic
ˆ
‡
‡
(%): 203.4 (100) [M‡H] , 185.4 (78) [M‡H H2O] , 171.1 (11), 155.1 (23),
145.1 (24), 111.1 (16); C11H22O3 (202.3): calcd C 65.31, H 10.96; found C
65.09, H 11.35.
systems 31a and 31b in 94% yield, the desired Z isomer being
slightly favored (Z/E ˆ 1.7:1). As the isomers could not be
separated by flash chromatography, they were subjected to
the following deprotection step with HF in MeCN/Et2O as a
mixture, leading to a mixture of 32a, whose spectroscopical
data were identical with the naturally occurring epothilone C,
and 32b in 65% yield. This mixture was treated with a freshly
prepared solution of dimethyl dioxirane[21] in CH2Cl2 at
358C leading to a mixture of epoxidation products. ( )-
epothilone A (1) with properties (TLC, [a]D, 1H and
13C NMR, MS) identical to an authentic sample could be
chromatographically isolated from this mixture in 48% yield.
Ethyl (E)-3-ethyl-2,2-dimethyl-3-pentenoate (7): Hydroxy ester 6 (9.74 g,
48.1 mmol) was heated under reflux with Sicapent[9] (11.84 g) in cyclo-
hexane (40 mL) for 20 min. The solvent was removed by distillation.
Vacuum distillation of the residue afforded ester 7 (7.10 g, 80%) as a
colorless liquid. B.p. 60 ± 638C3 mbar 1; IR (film): nÄmax ˆ 2976, 1776, 1730,
1
1472, 1383, 1255, 1134, 1027, 823, 670 cm
;
1H NMR (400 MHz, CDCl3):
d ˆ 5.41 (q, 3J ˆ 6.8 Hz, 1H; H-4), 4.11 (q, 3J ˆ 7.2 Hz, 2H; CH3CH2OCO),
3
3
ˆ
2.06 (q, J ˆ 7.6 Hz, 2H; CH3CH2C C), 1.65 (d, J ˆ 6.8 Hz, 3H; H-5), 1.28
(s, 6H; C2-CH3), 1.23 (t, 3J ˆ 7.1 Hz, 3H; CH3CH2OCO), 0.97 (t, 3J ˆ
7.5 Hz, 3H; CH3CH2C C); 13C NMR (100 MHz, CDCl3): d ˆ 177.2, 144.1,
ˆ
118.5, 60.3, 48.4, 24.9, 21.7, 14.1, 13.9, 13.5; MS (PCI, CH4): m/z (%): 185.1
‡
(69) [M‡H] , 169.1 (14), 157.1 (100), 153.0 (16), 139.0 (9), 124.9 (15), 111.0
(30), 57.0 (38); HRMS (EI): calcd for C11H20O2 184.1463, found 184.146.
(E)-3-Ethyl-2,2-dimethyl-3-pentenal (8): LAH (2.95 g, 77.6 mmol,
2.0 equiv) was added to a solution of ester 7 (7.15 g, 38.8 mmol) in THF
(40 mL). The mixture was refluxed for 2 h. After cooling to 08C, Et2O
(30 mL) was added, and the mixture was quenched by dropwise addition of
water (2.95 mL), 15% aqueous NaOH (2.95 mL), and water (4.50 mL).
Celite (400 mg) was added, and the mixture was stirred for 30 min at room
temperature. The precipitate was filtered off by suction and washed with
Et2O (4 Â 40 mL). The filtrate and the washings were combined and
concentrated in vacuo to furnish crude (E)-3-ethyl-2,2-dimethyl-3-penten-
1-ol as a colorless liquid, which was used for the preparation of aldehyde 8
without further purification. An analytical sample of the alcohol was
Conclusions
We have presented a very flexible and efficient route to ( )-
epothilone A (1). The asymmetric syntheses of the three key
fragments have been achieved in a straightforward way. The
coupling of the ketone and aldehyde fragment by a kinetically
controlled aldol reaction provided stereochemically homoge-
neous material with outstanding facial selectivity. Finally,
esterification, ring-closing metathesis, and selective epoxida-
tion gave ( )-epothilone A (1) in high optical purity. In
summary, our strategy offers the possibility to synthesize
epothilone analogues in sufficient quantities for in vitro and in
vivo biological studies.
obtained by vacuum distillation: B.p. 105 ± 1068C30 mbar 1; IR (film):
1
nÄmax ˆ 3393, 2970, 1702, 1476, 1377, 1046, 960, 822, 643 cm
;
1H NMR
(400 MHz, CDCl3): d ˆ 5.43 (q, 3J ˆ 6.7 Hz, 1H; H-4), 3.35 (s, 2H; H-1),
3
3
ˆ
2.07 (q, J ˆ 7.6 Hz, 2H; CH3CH2C C), 1.67 (d, J ˆ 6.7 Hz, 3H; H-5), 1.34
(brs, 1H; OH), 1.04 (s, 6H; C2-CH3), 1.00 (t, 3J ˆ 7.5 Hz, 3H;
CH3CH2C C); 13C NMR (100 MHz, CDCl3): d ˆ 145.2, 120.5, 69.7, 42.0,
ˆ
‡
24.0, 20.0, 14.2, 13.6; MS (70 eV, EI): m/z (%): 142.1 (7) [M] , 125.1 (48),
111.0 (34), 96.2 (14), 83.0 (35), 71.1 (37), 69.1 (100), 57.0 (42), 55.0 (66).
DMSO (6.59 mL, 93.0 mmol, 2.0 equiv) in CH2Cl2 (20 mL) was added
dropwise at 788C to a stirred solution of (COCl)2 (3.71 mL, 42.7 mmol,
1.1 equiv) in CH2Cl2 (97 mL) within 5 min. The mixture was stirred for
10 min at 708C. The crude (E)-3-ethyl-2,2-dimethyl-3-penten-1-ol dis-
solved in CH2Cl2 (38 mL) was added dropwise within 5 min. The mixture
was then stirred for 1 h at 708C. The reaction was quenched by dropwise
addition of NEt3 (27 mL, 194.0 mmol, 5.0 equiv). The mixture was warmed
to room temperature within 45 min. Water (97 mL) was added, and the
mixture was stirred for 10 min. The organic layer was separated and the
aqueous layer was extracted with CH2Cl2 (3 Â 100 mL). The combined
organic extracts were dried over MgSO4 and concentrated in vacuo.
Experimental Section
General: Solvents were dried by standard procedures and redistilled under
N2 atmosphere prior to use. All organometallic reactions were run under
nitrogen. The products were purified by flash chromatography on Merck
silica gel 60 (40 ± 63 mm). Melting points are uncorrected. Mass spectra
were recorded on Finnigan MAT 312, 8430, and SSQ 7000 spectrometers;
high-resolution mass spectra were obtained on the latter spectrometers
(reference PFK, peak matching method, accuracy Æ2 ppm). IR spectra
were recorded on Perkin ± Elmer 2000, 580, FT 1710, and Nicolet 320 FT-
IR spectrometers. UV spectra were recorded on Hewlett ± Packard 8452 A
and Perkin ± Elmer Lambda 19 spectrometers. NMR spectra were recorded
on Bruker AC 200, AM 400, and DPX 400 spectrometers. Optical rotations
were recorded with a Perkin ± Elmer 241 polarimeter.
Purification of the residue by vacuum distillation afforded aldehyde 8
1
(3.43 g, 63% over two steps) as a colorless liquid. B.p. 85 ± 868C28 mbar
IR (film): nÄmax ˆ 3403, 2974, 1728, 1472, 1376, 1144, 1086, 975, 825 cm
;
;
1
1H NMR (400 MHz, CDCl3): d ˆ 9.27 (s, 1H; H-1), 5.41 (q, 3J ˆ 6.8 Hz, 1H;
3
3
ˆ
H-4), 2.02 (q, J ˆ 7.6 Hz, 2H; CH3CH2C C), 1.69 (d, J ˆ 6.9 Hz, 3H; H-5),
Ethyl 3-ethyl-3-hydroxy-2,2-dimethylpentanoate (6): A suspension of zinc
dust (10.79 g, 0.165 mol) in THF (40 mL) and B(OMe)3 (40 mL) was
activated with 1,2-dibromoethane (0.26 mL, 3.0 mmol) and TESOTf
(0.34 mL, 1.5 mmol). A mixture of 3-pentanone (15.9 mL, 0.15 mol) and
ethyl 2-bromo-2-methylpropanoate 5 (23.4 mL, 0.165 mol) was added
slowly to the activated zinc suspension. The reaction mixture was heated
gently in a hot air stream until the reaction started. The addition was
performed at such a rate that the mixture gently refluxed. After addition of
the reactants, the mixture was refluxed for 2 h and stirred at room
temperature for 20 h. The reaction was quenched by addition of 25%
aqueous NH3 solution (45 mL) at 08C. Glycerine (45 mL) and Et2O
(40 mL) were added and the organic layer was separated. The aqueous
layer was extracted with Et2O (3 Â 40 mL). The combined organic layers
were dried over MgSO4 and concentrated in vacuo. Purification of the
residue by vacuum distillation afforded b-hydroxy alcohol 6 (19.72 g, 65%)
1.17 (s, 6H; C2-CH3), 0.96 (t, J ˆ 7.6 Hz, 3H; CH3CH2C C); 13C NMR
3
ˆ
(100 MHz, CDCl3): d ˆ 203.5, 141.4, 122.6, 52.7, 24.2, 20.9, 14.1, 13.8; MS
‡
(PCI, CH4): m/z (%): 141.0 (29) [M‡H] , 127.1 (98), 111.1 (100), 97.1 (2),
83.1 (3); HRMS (EI): calcd for C9H16O 140.1201, found 140.116.
(1S)-2-Hydroxy-1,2,2-triphenylethyl
(3S,5E)-5-ethyl-3-hydroxy-4,4-di-
methyl-5-heptenoate (10): nBuLi (3.20 mL, 8.0 mmol, 2.5m solution in
hexanes) was added at 788C to a solution of diisopropylamine (1.28 mL,
8.0 mmol) in THF (10 mL) cooled to 788C. This LDA solution was stirred
for 30 min at 08C and added dropwise to a solution of (S)-( )-2-hydroxy-
1,2,2-triphenyl acetate (9) (1.330 g, 4.0 mmol) in THF (25 mL) at 788C.
The mixture was stirred for 1 h at 08C. The resulting orange-red solution
was cooled to 788C, and a solution of aldehyde 8 (673 mg, 4.8 mmol,
1.2 equiv) in THF (5.0 mL) was added dropwise. The mixture was stirred
for 90 min. The reaction was quenched with saturated aqueous NH4Cl
solution (30 mL). The organic layer was separated and the aqueous layer
was extracted with CH2Cl2 (3 Â 50 mL). The combined organic extracts
were dried over MgSO4 and concentrated in vacuo. Purification of the
as a colorless liquid. B.p. 108 ± 1108C10 mbar 1; IR (film): nÄmax ˆ 3492,
1
2982, 1699, 1472, 1390, 1271, 1153, 1026, 968, 857, 776 cm
;
1H NMR
(400 MHz, CDCl3): d ˆ 4.17 (q, 3J ˆ 7.1 Hz, 2H; CH3CH2OCO), 3.78 (s,
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Chem. Eur. J. 1999, 5, No. 9

Epothilone A
2483±2491
residue by flash chromatography (pentane/Et2O 3:1) afforded b-hydroxy
(4S)-4-Benzyl-5,5-dimethyl-3-(6-heptenoyl)-1,3-oxazolidin-2-one (14): Ox-
alyl chloride (822 mL, 9.43 mmol, 2.0 equiv) was added dropwise at room
temperature to a solution of 6-heptenoic acid (604 mg, 4.71 mmol) in
CH2Cl2 (15 mL). The mixture was stirred for 3 h and then refluxed for
another 15 min. Evaporation at 40 mbar yielded the crude 6-heptenoyl
chloride, which was used without further purification for the synthesis of
oxazolidinone 14: SuperQuat 13 (774 mg, 3.77 mmol) was dissolved in THF
ester 10 (1.41 g, 75%, 94% de) as a colorless crystalline solid. M.p. 144 ±
20
1458C, [a]2D0
ˆ
163.3, [a]
ˆ
195.5 (c ˆ 1.0, CHCl3); IR (film): nÄmax
ˆ
546
1
3548, 3465, 2972, 1724, 1494, 1450, 1290, 1153, 990, 890, 751, 699 cm
;
1H NMR (400 MHz, CDCl3): d ˆ 7.59 ± 7.54 (m, 2H; Harom.), 7.38 ± 7.02 (m,
13H; Harom.), 6.70 (s, 1H; PhCH), 5.30 (q, 3J ˆ 6.8 Hz, 1H; H-6), 3.78 (ddd,
3J ˆ 10.0 Hz, 3J ˆ 2.7 Hz, 3J ˆ 2.5 Hz, 1H; H-3), 2.86 (s, 1H; Ph2COH), 2.31
(dd, 2J ˆ 15.7 Hz, 3J ˆ 2.2 Hz, 1H; H-2), 2.21 (dd, 2J ˆ 15.7 Hz, 3J ˆ 10.0 Hz,
(40 mL) and cooled to
788C. nBuLi (1.73 mL, 2.5 m in hexanes,
1H; H-2), 2.03 (d, 3J ˆ 3.1 Hz, 1H; C3-OH), 1.98 (dq, 4J ˆ 2.2 Hz, 3J ˆ
4.34 mmol, 1.15 equiv) was added and stirring was continued at 788C
for 30 min. A solution of the crude 6-heptenoyl chloride in THF (10 mL)
was added dropwise to the reaction mixture. The mixture was allowed to
warm to room temperature, quenched with saturated aqueous NaHCO3
solution (40 mL), and extracted with Et2O. The combined organic layers
were washed with brine, dried over MgSO4, and the solvent was removed
under reduced pressure. The crude product was purified by flash
chromatography (pentane/Et2O 4:1) to yield oxazolidinone 14 (969 mg,
3
ˆ
7.5 Hz, 2H; CH3CH2C C), 1.60 (d, J ˆ 6.8 Hz, 3H; H-7), 0.98, 0.91 (2s, 2 Â
3H; C2-CH3), 0.91 (t, J ˆ 7.6 Hz, 3H; CH3CH2C C); 13C NMR (100 MHz,
3
ˆ
CDCl3): d ˆ 172.2, 146.0, 144.7, 142.6, 135.6, 128.4, 128.3, 128.0, 127.8, 127.5,
127.3, 127.1, 126.3, 126.2, 120.3, 80.4, 78.9, 72.3, 44.0, 37.4, 22.9, 21.3, 20.2,
‡
14.3, 13.6; MS (70 eV, EI): m/z (%): 472.3 (<0.4) [M] , 455.2 (0.4), 290.3
(4), 273.1 (70), 256.1 (12), 195.1 (17), 183.1 (100), 167.2 (12), 112.0 (16),
105.0 (26), 69.2 (10); C31H36O4 (472.6): calcd C 78.78, H 7.68; found C 78.87,
H 7.73.
65% over two steps) as a colorless oil. [a]D20
ˆ
31.5 (c ˆ 1.68, CHCl3); IR
(film): nÄmax ˆ 2934, 1779, 1699, 1457, 1357, 1278, 1209, 1160, 100, 914, 734,
(3S,5E)-5-Ethyl-4,4-dimethyl-5-heptene-1,3-diol (11): LAH (1.325 g,
35.0 mmol, 7.0 equiv) was added portionwise to a refluxing solution of
ester 10 (2.364 g, 5.0 mmol) in Et2O (50 mL) within a period of 2 h.
Refluxing was continued for 30 min. After cooling to 08C, the reaction was
quenched by dropwise addition of water (1.35 mL) and 15% aqueous
NaOH (1.35 mL). Et2O (40 mL) and water (1.35 mL) were added. The
mixture was stirred for 1 h at room temperature until a white precipitate
formed which was filtered off by suction through a small plug of celite. The
precipitate was washed with Et2O (4 Â 40 mL). The filtrate and washings
were combined, and concentrated in vacuo. Purification of the residue by
flash chromatography (pentane/Et2O 2:1) afforded (S)-2,2,1-triphenyl-
1
700 cm
;
1H NMR (400 MHz, CDCl3): d ˆ 7.33 ± 7.20 (m, 5H; Ar-H),
5.86 ± 5.74 (m, 1H; H-6'), 5.05 ± 4.92 (m, 2H; H-7), 4.51 (dd, 3J ˆ 9.5 Hz,
3J ˆ 4.0 Hz, 1H; H-4), 3.14 (dd, 2J ˆ 14.3 Hz, 3J ˆ 4.0 Hz, 1H; C4-CH2),
2.98 ± 2.86 (m, 1H; H-2'), 2.88 (dd, 2J ˆ 14.3 Hz, 3J ˆ 9.5 Hz, 1H; C4-CH2),
2.12 ± 2.03 (m, 2H, H-5'), 1.69 ± 1.58 (m, 3H), 1.49 ± 1.40 (m, 2H)(H-2', H-3',
H-4'), 1.37, 1.35 (2s, 2  3H; C5-CH3); 13C NMR (100 MHz, CDCl3): d ˆ
173.4, 152.6, 138.4, 137.0, 129.1, 128.6, 126.8, 114.7, 82.1, 63.5, 35.5, 35.4, 33.4,
‡
28.5, 28.3, 23.8, 22.3; MS (PCI, CH4): m/z (%): 316.1 (100) [M‡H] , 300.1
(7), 272.1 (19), 234.0 (3); HRMS (EI): calcd for C19H25NO3 315.1834, found
315.184.
ethane-1,2-diol (9) (922 mg, 99%) as a colorless crystalline solid, and
(4S)-4-Benzyl-5,5-dimethyl-3-[(2S)-2-methyl-6-heptenoyl]-1,3-oxazolidin-
2-one (15): A solution of oxazolidinone 14 (949 mg, 3.01 mmol) in THF
(10 mL) was added slowly to a solution of NaHMDS (3.46 mL, 1.0m in
Et2O, 3.46 mmol) in THF (4 mL) at 788C. The mixture was stirred for 1 h
at 788C. MeI (937 mL, 15.0 mmol, 5.0 equiv) was added and stirring was
continued for 30 min at 788C. The reaction was quenched by addition of
saturated NH4Cl solution (30 mL), warmed to room temperature and
extracted with Et2O. The combined organic layers were washed with brine,
dried over MgSO4, and evaporated in vacuo. The crude product was
purified by flash chromatography (pentane/Et2O 6:1) to obtain alkylated
20
alcohol 11 (836 mg, 90%) as a colorless oil. [a]D20
ˆ
30.7, [a]
ˆ
37.5
546
(c ˆ 1.0, CHCl3); IR (film): nÄmax ˆ 3313, 2969, 1472, 1382, 1312, 1053, 956,
1
822, 659 cm
;
1H NMR (400 MHz, CDCl3): d ˆ 5.43 (q, 3J ˆ 6.8 Hz, 1H;
H-6), 3.86 ± 3.76 (m, 2H; H-1), 3.68 (dd, 3J ˆ 10.3 Hz, 3J ˆ 2.1 Hz, 1H; H-3),
ˆ
3.00 (brs, 1H; OH), 2.20 (brs, 1H; OH), 2.17 ± 2.02 (m, 2H; CH3CH2C C),
3
1.67 (d, J ˆ 6.8 Hz, 3H; H-7), 1.71 ± 1.52 (m, 2H; H-2), 1.03, 1.01 (2s, 2 Â
3H; C4-CH3), 0.91 (t, J ˆ 7.6 Hz, 3H; CH3CH2C C); 13C NMR (100 MHz,
3
ˆ
CDCl3): d ˆ 146.2, 121.1, 75.8, 62.6, 44.4, 32.7, 22.8, 21.1, 20.1, 14.3, 13.6; MS
‡
(70 eV, EI): m/z (%): 186.0 (0.6) [M] , 177.0 (1), 141.0 (3), 112.0 (100), 96.9
(19), 83.0 (75), 74.9 (13), 68.9 (60), 54.9 (34); HRMS (EI): calcd for
C11H22O2 186.1620, found 186.157.
amide 15 (841 mg, 85%) as a viscous, colorless oil. [a]D20
ˆ
5.7 (c ˆ 1.06,
CHCl3); IR (film): nÄmax ˆ 2976, 2935, 1774, 1698, 1457, 1353, 1277, 1242,
1
1099, 991, 915, 734, 700 cm
;
1H NMR (400 MHz, CDCl3): d ˆ 7.33 ± 7.20
(4S)-4-[(E)-2-Ethyl-1,1-dimethyl-2-butenyl]-2,2-dimethyl-1,3-dioxane
(12): Anhydrous CuSO4 (478 mg, 3.0 mmol, 1.5 equiv), pTsOH ´ H2O
(76 mg, 0.4 mmol, 0.2 equiv), and pyridine (24 mL, 0.3 mmol, 0.15 equiv)
was added to a solution of diol 11 (372 mg, 2.0 mmol) in acetone (30 mL).
The mixture was stirred for 24 h at room temperature. Saturated aqueous
NaHCO3 solution (40 mL) was added and the aqueous layer was extracted
with Et2O (4 Â 60 mL). The combined organic extracts were dried over
MgSO4 and carefully concentrated in vacuo. Purification of the residue by
(m, 5H; Ar-H), 5.84 ± 5.72 (m, 1H; H-6'), 5.03 ± 4.91 (m, 2H; H-7), 4.51 (dd,
3J ˆ 9.3 Hz, J ˆ 4.1 Hz, 1H; H-4), 3.79 ± 3.68 (m, 1H; H-2'), 3.08 (dd, J ˆ
3
2
3
2
3
14.3 Hz, J ˆ 4.0 Hz, 1H; C4-CH2), 2.88 (dd, J ˆ 14.3 Hz, J ˆ 9.3 Hz, 1H;
C4-CH2), 2.10 ± 1.97 (m, 2H; H-5), 1.76 ± 1.64 (m, 1H), 1.46 ± 1.38 (m,
3
3H)(H-3', H-4'), 1.38, 1.36 (2s, 2  3H; C5-CH3), 1.13 (d, J ˆ 6.8 Hz, 3H;
C2-CH3); 13C NMR (100 MHz, CDCl3): d ˆ 177.3, 152.3, 138.4, 136.9, 129.1,
128.6, 126.8, 114.7, 81.9, 63.6, 37.6, 35.5, 33.7, 33.0, 28.4, 26.5, 22.2, 17.4; MS
‡
‡
(PCI, CH4): m/z (%): 330.2 (100) [M‡H] , 314.2 (6) [M CH3] , 286.1
(14), 261.0 (1), 234.0 (3); HRMS (EI): calcd for C20H27NO3 329.1991, found
329.199.
flash chromatography (pentane/Et2O 40:1) gave acetonide 12 (812 mg,
20
90%) as a colorless oil. [a]D20 ˆ ‡14.3, [a] ˆ ‡17.0 (c ˆ 1.0, CHCl3); IR
546
(film): nÄmax ˆ 2970, 1475, 1380, 1271, 1197, 1108, 971, 860, 765 cm 1; 1H NMR
(400 MHz, CDCl3): d ˆ 5.32 (q, 3J ˆ 6.8 Hz, 1H; H-3'), 3.88 (dt, 2J ˆ
11.8 Hz, 3J ˆ 2.9 Hz, 1H; H-6), 3.80 (ddd, 2J ˆ 11.6 Hz, 3J ˆ 5.5 Hz, 3J ˆ
(S)-2-Methyl-6-hepten-1-ol (16): A solution of compound 15 (827 mg,
2.51 mmol) in Et2O (12 mL) was titrated at 08C with portions of a
suspension of LAH (approx. 250 mg consumed, 4 equiv) in Et2O until TLC
showed complete conversion of the starting material. Water (0.8 mL) was
added dropwise, and stirring was continued until the precipitate appeared
white. The suspension was filtered over celite, and the residue was washed
with Et2O (150 mL). The solvent was removed carefully under reduced
pressure. Flash chromatography (pentane/Et2O 3:1) yielded SuperQuat 13
(459 mg, 89%) as colorless crystals and alcohol 16 (282 mg, 88%) as a
3
3
2.0 Hz, 1H; H-6), 3.70 (dd, J ˆ 11.6 Hz, J ˆ 2.5 Hz, 1H; H-4), 2.18 ± 2.00
3
ˆ
(m, 2H; CH3CH2C C), 1.62 (d, J ˆ 6.8 Hz, 3H; H-4'), 1.59 ± 1.46 (m, 1H;
2
3
H-5), 1.41, 1.35 (2s, 2  3H; C2-CH3), 1.18 (ddd, J ˆ 13.1 Hz, J ˆ 4.7 Hz,
3J ˆ 2.6 Hz, 1H; H-5), 1.03, 1.00 (2s, 2  3H; C1'-CH3), 0.98 (t, 3J ˆ 7.5 Hz,
3H; CH3CH2C C); 13C NMR (100 MHz, CDCl3): d ˆ 146.1, 119.2, 98.3,
ˆ
74.2, 60.4, 42.9, 29.9, 26.1, 24.2, 21.2, 20.8, 19.1, 14.4, 13.6; MS (70 eV, EI):
‡
m/z (%): 226.1 (8) [M] , 211.1 (14), 205.1 (3), 151.0 (14), 114.9 (100), 94.7
(10), 72.9 (32), 58.9 (60); HRMS (EI): calcd for C14H26O2 226.1933, found
226.193.
colorless liquid. [a]D20
ˆ
12.5 (c ˆ 1.03, CDCl3); IR (film): nÄmax ˆ 3347,
2929, 2874, 1642, 1462, 1379, 1035, 910 cm 1; 1H NMR (400 MHz, CDCl3):
d ˆ 5.89 ± 5.79 (m, 1H; H-6), 5.06 ± 4.95 (m, 2H; H-7), 3.55 ± 3.42 (m, 2H;
H-1), 2.34 (s; OH), 2.12 ± 2.03 (m, 2H; H-5), 1.70 ± 1.33 (m, 5H; H-2, H-3,
H-4), 0.94 (d, 3J ˆ 6.8 Hz, 3H; C2-CH3); 13C NMR (100 MHz, CDCl3): d ˆ
138.9, 114.4, 68.2, 35.6, 34.0, 32.6, 26.3, 16.5; MS (70 eV, EI): m/z (%): 130
2-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]-2-methyl-3-pentanone (2): A stream
of ozone in oxygen was bubbled through a solution of acetonide 12 (226 mg,
1.0 mmol) in CH2Cl2 (40 mL) at 788C until the blue color of the solution
persisted. PPh3 (262 mg, 1.2 equiv) was added at 788C, the mixture was
allowed to warm to room temperature within 4 h and concentrated in
vacuo. Purification of the residue by flash chromatography (pentane/Et2O
5:1) furnished ethyl ketone 2 (182 mg, 85%) as colorless crystals, m.p.
378C, identical ([a], IR, 1H NMR, 13C NMR) with substance obtained from
the previously described prenyl borane protocol.[6a]
‡
(1) [M] , 128 (5), 110 (9), 97 (12), 95 (44), 81 (44), 71 (28), 69 (34), 68 (46),
67 (35), 56 (33), 55 (100), 54 (51), 43 (20); HRMS (EI): calcd for C8H16O
128.1201, found 128.108.
(S)-2-Methyl-6-heptenal (3): Dess ± Martin periodinane[15] (1.27 g,
2.99 mmol, 1.3 equiv) was added to a solution of alcohol 16 (295 mg,
Chem. Eur. J. 1999, 5, No. 9
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2487 $ 17.50+.50/0
2487

D. Schinzer et al.
FULL PAPER
2.30 mmol) in CH2Cl2 (5 mL). The mixture was stirred for 25 min at room
temperature and quenched with phosphate buffer solution (7 mL, 0.1m,
pH 7.0). The organic layer was separated and the aqueous layer was
extracted with CH2Cl2. The combined extracts were dried over MgSO4 and
concentrated carefully in vacuo. Flash chromatography (pentane/Et2O
10:1) of the residue afforded aldehyde 3 (224 mg, 77%) as a colorless
liquid. Alternative procedure: Freshly activated molecular sieves (500 mg,
4 Š) were added to a solution of alcohol 16 (275 mg, 2.15 mmol) and NMO
(377 mg, 3.22 mmol, 1.5 equiv) in CH2Cl2 (10 mL). The mixture was stirred
vigorously for 10 min, and TPAP (38 mg, 0.107 mmol, 0.05 equiv) was
added. After 10 min, the mixture was flash-filtered with CH2Cl2 over a
short silica gel column. The solvent was removed under ambient pressure to
yield aldehyde 3 (239 mg, 89%) as a colorless liquid. [a]2D0 ˆ ‡25.7 (c ˆ 1.0,
CHCl3); IR (film): nÄmax ˆ 2977, 2935, 2861, 2711, 1728, 1642, 1461, 998,
2.70 (s, 3H; C2'-CH3), 1.99 (d, 4J ˆ 1.1 Hz, 3H; C4-CH3), 1.83 ± 1.75 (m, 2H;
H-2), 0.89, 0.88 (2s, 2 Â 9H; OSiC(CH3)3), 0.06, 0.00 (2s, 2 Â 3H;
OSi(CH3)2), 0.03 (s, 6H; OSi(CH3)2); 13C NMR (100 MHz, CDCl3): d ˆ
164.3, 153.2, 142.6, 118.6, 115.0, 75.0, 59.6, 39.8, 25.9, 25.8, 19.2, 18.2, 13.8,
‡
4.6, 5.1, 5.3, 5.4; MS (70 eV, EI): m/z (%): 441.2 (35) [M] , 384.1
‡
‡
(89) [M tBu] , 356.1 (80), 309.1 (49), 282.1 (65) [C14H24NOSSi] , 252.0
(70), 178.0 (38), 147.0 (71), 73.1 (100); HRMS (EI): calcd for C22H43NO2SSi2
441.2553, found 441.255.
(3S,4E)-3-(tert-Butyldimethylsilyloxy)-4-methyl-5-(2-methyl-1,3-thiazol-4-
yl)-4-penten-1-ol (22): In a PE bottle, silyl ether 21 (13.255 g, 30.0 mmol)
was dissolved in a mixture of Et2O (120 mL) and MeCN (120 mL).
Aqueous 40% hydrofluoric acid (20 mL) and finely ground splinters of
glass (133 mg) were added at 08C to the vigorously stirred mixture. The
mixture was stirred for 2 h at 08C. Hydrofluoric acid (20 mL) was added
and stirring was continued for 1 h at 08C. The reaction was quenched by
carefully adding solid NaHCO3 (84.0 g, 1.0 mol) within 15 min at 08C. After
the mixture was stirred for 30 min at 08C, water was added until the solids
dissolved (the pH was adjusted to 6 ± 8 by further addition of NaHCO3, if
necessary). The mixture was extracted with CH2Cl2 (4 Â 200 mL). The
combined organic extracts were washed with brine (100 mL), dried over
MgSO4, and concentrated in vacuo. Purification of the residue by flash
chromatography (pentane/Et2O 4:1) afforded alcohol 22 (9.041 g, 92%) as
1
3
913 cm 1; H NMR (400 MHz, CDCl3): d ˆ 9.62 (d, J ˆ 1.9 Hz, 1H; H-1),
5.84 ± 5.74 (m, 1H; H-6), 5.04 ± 4.95 (m, 2H; H-7), 2.38 ± 2.32 (m, 1H; H-2),
2.10 ± 2.05 (m, 2H; H-5), 1.77 ± 1.33 (m, 4H; H-3, H-4), 1.10 (d, 3J ˆ 7.2 Hz,
3H; C2-CH3); 13C NMR (100 MHz, CDCl3): d ˆ 205.0, 138.1, 114.8, 46.1,
‡
33.6, 29.8, 26.1, 13.3; MS (EI, 70 eV): m/z (%) ˆ 126 (4) [M] , 125 (18)
‡
[M H] , 111 (24), 97 (39), 95 (18), 82 (21), 74 (42), 71 (26), 69 (100), 67
(20), 55 (90), 43 (31), 41 (50); HRMS (EI): calcd for C8H14O 126.1045,
found 126.100.
(S)-1,3-Di-(tert-butyldimethylsilyloxy)-4-methyl-4-pentene (18): Imidazole
(77 mg, 1.1 mmol, 2.6 equiv) and TBSCl (85 mg, 0.56 mmol, 1.3 equiv) were
added to a solution of alcohol 17 (100 mg, 0.43 mmol) in DMF (1.5 mL).
The mixture was stirred for 10 h at room temperature. Flash chromatog-
raphy (pentane/Et2O 20:1) of the reaction mixture yielded bis-silyl ether 18
a viscous, colorless oil. [a]D20
2955, 2857, 1472, 1252, 1074, 837, 777 cm
ˆ
5.7 (c ˆ 1.0, CHCl3); IR (film): nÄmax ˆ 3357,
1
;
1H NMR (400 MHz, CDCl3):
3
3
d ˆ 6.92 (s, 1H; H-5'), 6.52 (s, 1H; H-5), 4.38 (dd, J ˆ 7.4 Hz, J ˆ 4.5 Hz,
1H; H-3), 3.80 ± 3.67 (m, 2H; H-1), 2.70 (s, 3H; C2'-CH3), 2.40 (s, 1H; OH),
2.01 (d, 4J ˆ 1.2 Hz, 3H; C4-CH3), 1.93 ± 1.76 (m, 2H; H-2), 0.91 (s, 9H;
OSiC(CH3)3), 0.10, 0.03 (2s, 2 Â 3H; OSi(CH3)2); 13C NMR (100 MHz,
CDCl3): d ˆ 164.5, 153.0, 141.6, 118.8, 115.4, 77.5, 60.4, 38.2, 25.8, 19.2, 18.1,
(146 mg, 98%) as a colorless oil. [a]D20
ˆ
10.0 (c ˆ 1.0, CHCl3); IR (film):
1
nÄmax ˆ 2956, 2859, 1472, 1256, 1091, 836, 776 cm
;
1H NMR (400 MHz,
‡
CDCl3): d ˆ 4.89 ± 4.84 (m, 1H; H-5), 4.76 ± 4.70 (m, 1H; H-5), 4.21 (dd,
14.4, 4.6, 5.2; MS (70 eV, EI): m/z (%): 327 (18) [M] , 282 (39), 270 (94)
3
‡
3J ˆ 7.6 Hz, J ˆ 5.0 Hz, 1H; H-3), 3.67 ± 3.55 (m, 2H; H-1), 1.76 ± 1.58 (m,
[M tBu] , 268 (29), 252 (12), 240 (14), 178 (41), 168 (100), 164 (23), 105
2H; H-2), 1.68 (s, 3H; C2-CH3), 0.89, 0.88 (2s, 2 Â 9H; OSiC(CH3)3), 0.01,
0.00 (4s, 4  3H; OSi(CH3)2); 13C NMR (100 MHz, CDCl3): d ˆ 147.8,
110.4, 73.4, 59.8, 39.5, 25.9, 25.8, 18.3, 18.2, 17.1, 4.8, 5.2, 5.3; MS (PCI,
(27), 75 (59), 73 (42); HRMS (EI): calcd for C16H29NO2SSi 327.1688, found
327.168.
(3S,4E)-3-(tert-Butyldimethylsilyloxy)-4-methyl-5-(2-methyl-1,3-thiazol-4-
yl)-4-pentenal (23): Dess ± Martin periodinane[15] (478 mg, 2.91 mmol,
1.3 equiv) was added to a solution of alcohol 22 (732 mg, 2.24 mmol) in
CH2Cl2 (10 mL). The mixture was stirred for 30 min at room temperature.
The solvent was removed under reduced pressure. Flash chromatography
(pentane/Et2O 4:1) yielded aldehyde 23 (614 mg, 84%) as a pale yellow oil.
‡
‡
isobutane): m/z (%): 345 (100) [M‡H] , 329 (4) [M CH3] , 287 (28)
‡
[M tBu] , 259 (8), 213 (95), 206 (26), 164 (12), 132 (7), 98 (15); HRMS
(EI): calcd for C18H40O2Si2 344.2567, found 344.343.
(S)-3,5-Di-(tert-butyldimethylsilyloxy)-2-pentanone (19): A solution of bis-
silyl ether 18 (146 mg, 0.424 mmol) in CH2Cl2 (70 mL) was cooled to
788C. A stream of ozone in oxygen was bubbled through the solution
until the blue color persisted, then the excess of ozone was removed by
bubbling N2 through the solution. PPh3 (333 mg, 1.27 mmol, 3.0 equiv) was
added, and the mixture was allowed to warm to room temperature. Stirring
was continued until TLC indicated conversion of the intermediate product.
The solvent was removed under reduced pressure, and the residue was
purified by flash chromatography (pentane/Et2O 19:1) to yield methyl
[a]2D0
ˆ
11.9 (c ˆ 1.0, CHCl3); IR (film): nÄmax ˆ 2956, 2857, 1727, 1472, 1389,
1
1254, 1085, 838, 778 cm
;
1H NMR (400 MHz, CDCl3): d ˆ 9.79 (t, 3J ˆ
2.7 Hz, 1H; H-1), 6.94 (s, 1H; H-5'), 6.56 (s, 1H; H-5), 4.69 (dd, 3J ˆ 8.2 Hz,
3J ˆ 4.0 Hz, 1H; H-3), 2.75 (ddd, 2J ˆ 15.5 Hz, J ˆ 7.7 Hz, J ˆ 2.9 Hz, 1H;
H-2), 2.70 (s, 3H; C2'-CH3), 2.51 (ddd, 2J ˆ 15.5 Hz, 3J ˆ 4.0 Hz, 3J ˆ 2.1 Hz,
1H; H-2), 2.04 (d, 4J ˆ 1.2 Hz, 3H; C4-CH3), 0.88 (s, 9H; OSiC(CH3)3),
0.08, 0.03 (2s, 2  3H; OSi(CH3)2); 13C NMR (100 MHz, CDCl3): d ˆ 201.5,
164.8, 152.6, 140.5, 119.3, 115.9, 73.9, 50.1, 25.7, 19.2, 18.1, 14.1, 4.6, 5.2;
3
3
ketone 19 (101 mg, 69%) as a colorless oil. [a]D20
ˆ
8.9 (c ˆ 1.0, CHCl3);
1
‡
‡
IR (film): nÄmax ˆ 2957, 2859, 1720, 1473, 1361, 1256, 1106, 838, 778 cm
;
MS (70 eV, EI): m/z (%): 325 (6) [M] , 282 (24), 268 (98) [M tBu] , 250
(17), 194 (13), 176 (100), 164 (19), 135 (15), 101 (20), 75 (32), 73 (31);
HRMS (EI): calcd for C16H27NO2SSi 325.1532, found 325.153.
1H NMR (400 MHz, CDCl3): d ˆ 4.15 (dd, 3J ˆ 6.8 Hz, 3J ˆ 5.3 Hz, 1H;
H-3), 3.75 ± 3.58 (m, 2H; H-5), 2.16 (s, 3H; H-1), 1.88 ± 1.70 (m, 2H; H-4),
0.92, 0.88 (2s, 2 Â 9H; OSiC(CH3)3), 0.06, 0.06, 0.04, 0.03 (4s, 4 Â 3H;
OSi(CH3)2); 13C NMR (100 MHz, CDCl3): d ˆ 212.0, 75.8, 58.4, 37.8, 25.9,
25.7, 25.4, 18.3, 18.1, 5.0, 5.1, 5.4; MS (PCI, NH3): m/z (%): 347 (100)
(1E,3S)-3-(tert-Butyldimethylsilyloxy)-2-methyl-1-(2-methyl-1,3-thiazol-4-
yl)-1,5-hexadiene (24):
A mixture of methyl triphenyl phosphonium
bromide (1.197 g, 3.35 mmol, 1.85 equiv), NaNH2 (131 mg, 3.35 mmol,
1.85 equiv), and THF (10 mL) was stirred for 30 min at room temperature.
A solution of aldehyde 23 (589 mg, 1.81 mmol) in THF (5 mL) was added
dropwise over 10 min. The mixture was stirred for 15 min at room
temperature, poured into saturated aqueous NaHCO3 solution (60 mL),
and extracted with Et2O. The combined organic layers were washed with
brine and dried over MgSO4. After removal of the solvents under reduced
pressure, flash chromatography (pentane/Et2O 19:1) of the residue
afforded olefin 24 (498 mg, 85%) as a pale yellow oil. [a]2D0 ˆ ‡2.3 (c ˆ
1.0, CHCl3); IR (film): nÄmax ˆ 2929, 2857, 1472, 1255, 1076, 914, 836,
776 cm 1; 1H NMR (400 MHz, CDCl3): d ˆ 6.92 (s, 1H; H-5'), 6.46 (s, 1H;
H-1), 5.83 ± 5.72 (m, 1H; H-5), 5.08 ± 4.97 (m, 2H; H-6), 4.15 (t, 3J ˆ 6.4 Hz,
1H; H-3), 2.70 (s, 3H; C2'-CH3), 2.40 ± 2.25 (m, 2H; H-4), 2.00 (d, 4J ˆ
1.0 Hz, 3H; C2-CH3), 0.89 (s, 9H; OSiC(CH3)3), 0.06, 0.01 (2s, 2 Â 3H;
OSi(CH3)2); 13C NMR (100 MHz, CDCl3): d ˆ 164.4, 153.1, 142.0, 135.3,
118.8, 116.5, 115.1, 78.5, 41.4, 25.8, 19.2, 18.2, 13.9, 4.6, 5.0; MS (PCI,
‡
[M‡H] , 324 (17), 279 (93), 231 (4), 215 (7), 157 (8), 94 (11); HRMS (EI):
calcd for C17H38O3Si2 346.2360, found 346.235.
(3S,4E)-1,3-Di-(tert-butyldimethylsilyloxy)-4-methyl-5-(2-methyl-1,3-thia-
zol-4-yl)-4-pentene (21): nBuLi (23.5 mL, 58.7 mmol, 1.2 equiv of a 2.5m
solution in hexanes) was added dropwise to
a stirred solution of
phosphonate 20 (14.64 g, 58.7 mmol, 1.2 equiv) in THF (150 mL) cooled
to 788C. After the mixture was stirred at 788C for 1 h, a solution of
methyl ketone 19 (16.96 g, 48.9 mmol, 1.0 equiv) in THF (100 mL) was
added dropwise at 788C. The mixture was allowed to warm to room
temperature within 12 h. The reaction was quenched with saturated
aqueous NH4Cl solution (100 mL). The organic layer was separated and
the aqueous layer was extracted with Et2O (3 Â 100 mL). The combined
organic extracts were dried over MgSO4 and concentrated in vacuo. Flash
chromatography (CH2Cl2, then Et2O) yielded unconverted methyl ketone
19 (3.22 g, 22%) and E olefin 21 (17.07 g, 79%) as colorless oils. [a]D20
ˆ
‡
‡
0.7 (c ˆ 0.46, CH2Cl2); IR (film): nÄmax ˆ 2956, 2858, 1472, 1256, 1099, 836,
776 cm 1; 1H NMR (400 MHz, CDCl3): d ˆ 6.91 (s, 1H; H-5'), 6.47 (s, 1H;
H-5), 4.31 (dd, 3J ˆ 8.0 Hz, 3J ˆ 4.6 Hz, 1H; H-3), 3.71 ± 3.58 (m, 2H; H-1),
NH3): m/z (%): 324 (100) [M‡H] , 308 (1) [M CH3] , 282 (7), 266 (1)
‡
[M tBu] , 192 (4), 94 (3); HRMS (EI): calcd for C17H29NOSSi 323.1739,
found 323.173.
2488
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2488 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 9

Epothilone A
2483±2491
‡
(1E,3S)-2-Methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol
(4):
[M CH2(OH)CH2CH(OH)CH(CH3)2] , 165 (10), 156 (11), 127 (23),
109 (47), 100 (100), 82 (80), 69 (46), 57 (45), 43 (30); C17H32O4 (300.4): calcd
C 67.96, H 10.74; found C 67.83, H 11.04.
TBAF (4.0 mL, ꢀ1.0m in THF, 4 mmol, 3 equiv) was added at 08C to
freshly activated molecular sieves 4 Š in THF (16 mL). The mixture was
stirred for 45 min at room temperature. A solution of silyl ether 24 (444 mg,
1.37 mmol) in THF (2 mL) was added, and stirring was continued for
80 min at 08C. The mixture was poured into saturated aqueous NH4Cl
solution (35 mL) and extracted with Et2O (4 Â ). The combined organic
layers were washed with brine and dried over MgSO4. Evaporation of the
solvent under reduced pressure, followed by flash filtration with Et2O over
a short silica gel column afforded alcohol 4 (283 mg, 99%) as a colorless oil.
(3S,6R,7S,8S)-1,3,7-Tri-(tert-butyldimethylsilyloxy)-4,4,6,8-tetramethyl-1-
2-tridecen-5-one (27): 2,6-Lutidine (1.05 mL, 9.0 mmol, 12.0 equiv) and
TBSOTf (1.03 mL, 4.5 mmol, 6.0 equiv) were slowly added at 788C to a
solution of triol 26 (225 mg, 0.75 mmol) in CH2Cl2 (13.0 mL). The mixture
was stirred at 788C for 30 min and at 08C for 3 h. Saturated aqueous
NaHCO3 solution was added and the mixture was extracted with CH2Cl2.
The combined extracts were dried over MgSO4 and concentrated in vacuo.
Tris-silyl ether 27 (476 mg, 99%) was obtained as a colorless oil after
purification of the residue by flash chromatography (pentane/Et2O 20:1).
[a]2D0
ˆ
11.4 (c ˆ 1.0, CHCl3); IR (film): nÄmax ˆ 3078, 2931, 1642, 1507, 1473,
1361, 1256, 1076, 914, 836, 777, 728, 670 cm 1; 1H NMR (400 MHz, CDCl3):
d ˆ 6.91 (s, 1H; H-5'), 6.53 (s, 1H; H-1), 5.86 ± 5.73 (m, 1H; H-5), 5.18 ± 5.06
(m, 2H; H-6), 4.18 (dd, 3J ˆ 7.4 Hz, 3J ˆ 5.5 Hz, 1H; H-3), 2.68 (s, 3H; C2'-
CH3), 2.48 (brs, 1H; OH), 2.46 ± 2.30 (m, 2H; H-4), 2.01 (d, 4J ˆ 1.1 Hz,
3H; C2-CH3); 13C NMR (100 MHz, CDCl3): d ˆ 164.6, 152.7, 141.5, 134.6,
119.0, 117.7, 115.4, 76.4, 40.0, 19.1, 14.3; MS (70 eV, EI): m/z (%): 209 (41)
[a]2D0
ˆ
33.6, [a]2D0
ˆ
41.0 (c ˆ 1.0, CHCl3); IR (film): nÄmax ˆ 2957, 2931,
2886, 2858, 1697, 1473, 1256, 1103, 987, 836, 775 cm 1; 1H NMR (400 MHz,
CDCl3): d ˆ 5.83 ± 5.73 (m, 1H; H-12), 5.00 ± 4.91 (m, 2H; H-13), 3.88 (dd,
3J ˆ 7.6 Hz, 3J ˆ 2.7 Hz, 1H; H-3), 3.76 (dd, 3J ˆ 6.7 Hz, 3J ˆ 2.1 Hz, 1H;
H-7), 3.69 ± 3.63 (m, 1H; H-1), 3.59 ± 3.53 (m, 1H; H-1), 3.15 ± 3.11 (m, 1H;
H-6), 2.05 ± 1.99 (m, 2H; H-11), 1.58 ± 1.32 (m, 5H), 1.19 ± 1.11 (m,
‡
[M] , 190 (24), 168 (100), 142 (40), 100 (16), 75 (4); HRMS (EI): calcd for
C11H15NOS 209.0874, found 209.087; C17H29NSSiO (323.2): calcd C 63.10, H
9.03, N 4.33, S 9.91; found C 62.91, H 8.95, N 4.73, S 9.65.
3
2H)(H-2, H-8, H-9, H-10), 1.21 (s, 3H; C4-CH3), 1.03 (d, J ˆ 6.9 Hz, 3H;
C6-CH3), 1.01 (s, 3H; C4-CH3), 0.90 (d, 3H; C8-CH3), 0.89 (2s, 2 Â 9H;
OSiC(CH3)3), 0.87 (s, 9H; OSiC(CH3)3), 0.08, 0.05, 0.02, 0.01 (4s, 4 Â 3H;
OSi(CH3)2), 0.05 (s, 6H; OSi(CH3)2); 13C NMR (100 MHz, CDCl3): d ˆ
218.3, 138.9, 114.4, 77.4, 74.0, 61.0, 53.7, 45.0, 38.9, 38.1, 34.3, 30.5, 27.1, 26.2,
26.1, 26.0, 24.5, 19.3, 18.5, 18.3, 18.3, 17.5, 15.2, 3.7, 3.7, 3.8, 4.0, 5.2,
(4R,5S,6S,4'S)-2-(2,2-dimethyl-1,3-dioxan-4-yl)-5-hydroxy-2,4,6-tri-meth-
yl-10-undecen-3-one (25): A solution of ethyl ketone 2 (1.17 g, 5.45 mmol)
in THF (1.0 mL) was added to a freshly prepared solution of LDA [nBuLi
(3.34 mL, 1.6m solution in hexanes, 5.35 mmol, 0.98 equiv) was added to a
solution of diisopropylamine (749 mL, 5.35 mmol) in THF (4.0 mL) at 08C]
dropwise at 788C. The solution was stirred for 1 h at 788C. Aldehyde 3
(688 mg, 5.45 mmol, 1.0 equiv) was added dropwise and stirring was
continued for 45 min at 788C. The reaction mixture was quenched by
dropwise addition of saturated aqueous NH4Cl solution at 788C. The
organic layer was separated and the aqueous layer was extracted with Et2O.
The combined extracts were dried over MgSO4 and concentrated in vacuo.
Flash chromatography (pentane/Et2O 10:1) of the residue afforded anti
Cram aldol product 25 (1.36 g, 73%) and Cram aldol product (57 mg, 3%)
‡
5.3; MS (70 eV, EI): m/z (%): 643 (<1) [M‡H] , 546 (2), 413 (3), 373 (8),
303 (100), 241 (54), 187 (9), 171 (16), 145 (28), 115 (19), 109 (98), 89 (84),
73 (64); C35H74O4Si3 (643.2): calcd C 65.36, H 11.60; found C 65.36,
H 11.85.
(3S,6R,7S,8S)-3,7-Di-(tert-butyldimethylsilyloxy)-1-hydroxy-4,4,6,8-tetra-
methyl-12-tridecen-5-one (28): CSA (11 mg, 48 mmol, 0.2 equiv) was added
at 08C to a solution of tris-silyl ether 27 (156 mg, 0.243 mmol) in MeOH
(6.5 mL) and CH2Cl2 (6.5 mL). The reaction mixture was stirred for 5 h at
08C and quenched with saturated aqueous NaHCO3 solution. The phases
were separated and the aqueous layer was extracted with CH2Cl2. The
combined organic phases were dried over MgSO4 and concentrated in
vacuo. The residue was purified by flash chromatography (pentane/Et2O
as colorless oils. anti Cram diastereomer: [a]D20
ˆ
25.7 (c ˆ 1.0, CHCl3); IR
(film): nÄmax ˆ 3509, 2970, 2938, 2876, 1685, 1467, 1381, 1372, 1272, 1197, 1107,
1
971 cm
;
1H NMR (400 MHz, CDCl3): d ˆ 5.83 ± 5.75 (m, 1H, H-10),
5.00 ± 4.89 (m, 2H, H-11), 4.02 (dd, 3J ˆ 11.8 Hz, 3J ˆ 2.5 Hz, 1H; H-4'), 3.94
(dt, 3J ˆ 11.9 Hz, 3J ˆ 2.7 Hz, 1H; H-6), 3.84 (ddd, 2J ˆ 11.7 Hz, 3J ˆ 5.4 Hz,
3J ˆ 1.8 Hz, 1H; H-6'), 3.48 (s, 1H; OH), 3.35 (d, 3J ˆ 9.3 Hz, 1H; H-5), 3.26
3:1) to give alcohol 28 (106 mg, 83%) as a colorless oil. [a]D20
ˆ
23.6,
20
[a]
ˆ
27.0 (c ˆ 1.0, CHCl3); IR (film): nÄmax ˆ 3444, 2957, 2931, 2886,
546
1
2858, 1693, 1463, 1255, 1094, 987, 836, 775 cm
;
1H NMR (400 MHz,
(dq, 3J ˆ 7.0 Hz, J ˆ 1.4 Hz, 1H; H-4), 2.11 ± 1.96 (m, 2H; H-9), 1.80 ± 1.72
3
CDCl3): d ˆ 5.83 ± 5.73 (m, 1H; H-12), 5.01 ± 4.91 (m, 2H; H-13), 4.06 (dd,
3J ˆ 6.3 Hz, 3J ˆ 4.0 Hz, 1H; H-3), 3.79 (dd, 3J ˆ 7.3 Hz, 3J ˆ 1.8 Hz, 1H;
H-7), 3.64 ± 3.63 (m, 2H; H-1), 3.14 ± 3.10 (m, 1H; H-6), 2.05 ± 2.00 (m, 2H;
H-11), 1.87 ± 1.85 (m, 1H; OH), 1.61 ± 1.55 (m, 2H; H-2), 1.48 ± 1.30 (m,
3H), 1.24 ± 1.09 (m, 2H)(H-8, H-9, H-10), 1.21, 1.05 (2s, 2 Â 3H; C4-
(m, 1H; H-7), 1.66 ± 1.42 (m, 3H; H-5', H-6, H-8), 1.38, 1.31 (2s, 2 Â 3H;
C2'-CH3), 1.35 ± 1.22 (m, 2H; H-5', H-8), 1.18 (s, 3H; H-1), 1.15 ± 1.05 (m,
1H; H-7), 1.07 (s, 3H; C2-CH3), 1.00 (d, 3J ˆ 7.0 Hz, 3H; C4-CH3), 0.81 (d,
3J ˆ 6.8 Hz, 3H; C6-CH3); 13C NMR (100 MHz, CDCl3): d ˆ 223.0, 139.1,
114.2, 98.4, 74.8, 74.3, 59.9, 51.6, 41.2, 35.3, 34.2, 32.5, 29.7, 26.1, 25.1, 21.6,
3
(CH3)2), 1.05 (d, J ˆ 6.9 Hz, 3H; C6-CH3), 0.89 (d, 3H; C8-CH3), 0.89 (s,
‡
19.0, 18.5, 15.3, 9.3; MS (70 eV, EI): m/z (%): 340 (6) [M] , 325 (9) [M
18H; C3-OSiC(CH3)3, C7-OSiC(CH3)3), 0.10, 0.06 (2s, 2 Â 3H; C7-
OSi(CH3)2), 0.05 (s, 6H; C3-OSi(CH3)2); 13C NMR (100 MHz, CDCl3):
d ˆ 219.6, 138.9, 114.4, 77.6, 73.0, 60.3, 53.8, 45.1, 38.7, 38.4, 34.3, 30.3, 27.1,
26.2, 26.0, 24.9, 18.5, 18.3, 17.7, 17.7, 15.7, 3.6, 3.8, 3.9; MS (EI, 70 eV):
‡
CH3] , 282 (3), 264 (20), 214 (8), 185 (20), 183 (14) [M (dioxanyl ´
‡
C(CH3)2)] , 156 (86), 147 (72), 127 (38), 115 (82), 109 (63), 99 (28), 83
(68), 82 (100), 69 (24), 57 (24); HRMS (EI) calcd for C20H36O4 340.2614,
found 340.261; C20H36O4 (340.5) calcd C 70.55, H 10.66; found C 70.36, H
10.69.
‡
m/z (%) ˆ 472 (3) [M‡H tBu] , 413 (4), 345 (11), 299 (4), 271 (10), 241
(48), 189 (100), 145 (26), 109 (90), 75 (46), 73 (63); HRMS (EI) calcd for
C29H60O4Si2 528.4030, found 528.402; C29H60O4Si2 (529.0) calcd C 65.85, H
11.43; found C 65.51, H 11.83.
(3S,6R,7S,8S)-1,3,7-Trihydroxy-4,4,6,8-tetramethyl-12-tridecen-5-one (26):
PPTS (250 mg, 0.993 mmol, 1.3 equiv) was added to a solution of the aldol
product 25 (260 mg, 0.764 mmol) in MeOH (22.0 mL). The mixture was
stirred at room temperature for 36 h. Saturated aqueous NaHCO3 solution
was added, and the solvent was removed in vacuo. The residue was
dissolved in Et2O, and the resulting solution was washed with brine and
extracted with Et2O. The combined extracts were dried over MgSO4. After
removal of the solvent in vacuo and flash chromatography (Et2O) of the
(3S,6R,7S,8S)-3,7-Di-(tert-butyldimethylsilyloxy)-4,4,6,8-tetramethyl-5-
oxo-12-tridecenoic acid (29): A solution of PDC (2.37 g, 6.30 mmol,
11.0 equiv) in DMF (3 mL) was added to a solution of alcohol 28
(303 mg, 0.573 mmol) in DMF (6 mL). The reaction mixture was stirred
for 36 h at room temperature, mixed with brine (50 mL), diluted with
water, and extracted with CH2Cl2. The combined extracts were dried over
MgSO4 and concentrated in vacuo. The residue was purified by flash
residual alcohol, 26 (202 mg, 88%) was obtained as a colorless oil. [a]D20
ˆ
20
45.4, [a]
ˆ
56.0 (c ˆ 1.0, CHCl3); IR (film): nÄmax ˆ 3419, 2971, 2935,
chromatography (pentane/Et2O 2:1) to furnish acid 29 (247 mg, 79%) as a
546
1
20
2882, 1685, 1470, 1383, 1330, 1056, 996, 910 cm
;
1H NMR (400 MHz,
viscous, colorless oil. [a]D20
ˆ
31.7, [a]
ˆ
37.6 (c ˆ 1.0, CHCl3); IR
546
CDCl3): d ˆ 5.85 ± 5.61 (m, 1H; H-12), 5.00 ± 4.90 (m, 2H; H-13), 4.04 ± 4.01
(m, 1H; H-3), 3.88 ± 3.80 (m, 2H; H-1), 3.35 (brd, J ˆ 9.2 Hz, 3H; H-7, C3-
OH, C7-OH), 3.25 (q, 3J ˆ 6.9 Hz, 1H; H-6), 2.69 (brs, 1H; C1-OH), 2.07 ±
1.98 (m, 2H; H-11), 1.78 ± 1.70 (m, 1H; H-9), 1.63 ± 1.42 (m, 4H; H-2, H-8,
H-10), 1.35 ± 0.96 (m, 2H; H-9, H-10), 1.19, 1.12 (2s, 2 Â 3H; C4-CH3), 1.04
(d, 3J ˆ 6.9 Hz, 3H; C6-CH3), 0.84 (d, 3J ˆ 6.8 Hz, 3H; C8-CH3); 13C NMR
(100 MHz, CDCl3): d ˆ 223.7, 139.0, 114.3, 76.3, 74.6, 62.1, 52.6, 40.9,
35.5, 34.2, 32.5, 32.2, 26.1, 21.5, 18.5, 15.5, 10.1; MS (70 eV, EI): m/z (%):
(film): nÄmax ˆ 2957, 2931, 2858, 1713, 1473, 1389, 1361, 1303, 1254, 1092, 989,
836, 776 cm 1; 1H NMR (400 MHz, CDCl3): d ˆ 5.83 ± 5.73 (m, 1H; H-12),
5.01 ± 4.91 (m, 2H; H-13), 4.37 (dd, 3J ˆ 6.7 Hz, 3J ˆ 3.1 Hz, 1H; H-3), 3.77
(dd, 3J ˆ 7.3 Hz, J ˆ 1.9 Hz, 1H; H-7), 3.14 ± 3.11 (m, 1H; H-6), 2.48 (dd,
3
2J ˆ 16.5 Hz, 3J ˆ 3.1 Hz, 1H; H-2), 2.29 (d, 2J ˆ 16.5 Hz, 3J ˆ 6.8 Hz, 1H;
H-2), 2.05 ± 1.99 (m, 2H; H-11), 1.48 ± 1.29 (m, 3H), 1.24 ± 1.11 (m,
2H)(H-8, H-9, H-10), 1.22, 1.07 (2s, 2  3H; C4-(CH3)2), 1.04 (d, 3J ˆ
6.9 Hz, 3H; C6-CH3), 0.90 (d, 3H; C8-CH3), 0.89, 0.87 (2s, 2 Â 9H;
OSiC(CH3)3), 0.08, 0.04 (2s, 2 Â 3H; OSi(CH3)2), 0.04 (s, 6H; OSi(CH3)2);
‡
‡
300 (<1) [M] , 267 (1) [M H2O CH3] , 201 (13), 183 (19)
Chem. Eur. J. 1999, 5, No. 9 ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2489 $ 17.50+.50/0
2489

D. Schinzer et al.
FULL PAPER
13C NMR (100 MHz, CDCl3): d ˆ 218.2, 178.0, 138.9, 114.4, 77.6, 73.4, 53.5,
45.2, 40.2, 38.7, 34.3, 30.3, 27.1, 26.2, 26.0, 23.7, 19.0, 17.7, 15.7, 18.5, 18.2,
3.6, 3.8, 4.3, 4.6; MS (70 eV, EI): m/z (%): 528 (<1) [M‡H
53.9, 45.3, 41.4, 39.8, 36.4, 32.4, 30.0, 27.1, 26.2, 26.1, 23.5, 21.4, 19.3, 16.9,
18.5, 18.4, 17.1, 15.5, 3.5, 3.8, 4.0, 4.5; MS (Z/E mixture, PCI, CH4):
‡
m/z (%): 706.4 (100) [M‡H] , 690.4 (39), 648.3 (34), 478.2 (14), 404.2 (5),
‡
CH3] , 359 (14), 353 (13), 283 (14), 241 (20), 203 (100), 185 (12), 149
225.0 (8), 152.9 (15), 75.1 (17); HRMS (EI): calcd for C38H67NO5SSi2
705.4279, found 705.428.
(16), 115 (58), 109 (32), 75 (36), 73 (51); C29H58O5Si2 (542.9) calcd C 64.15,
H 10.77; found C 63.96, H 11.12.
(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-ethenyl]-1-oxa-cyclohexadec-13-en-2,6-dione,
mixture of the (13Z) and (13E) isomers, (32a) and (32b): A solution of bis-
silyl ethers 31a and 31b (Z:E ˆ 1.7:1, 35.3 mg, 0.05 mmol) in MeCN/Et2O
(1:1, 2.4 mL) at 08C was treated with aqueous hydrofluoric acid (0.27 mL,
40%) and some ground glass splinters, and the mixture was stirred for 12 h
at room temperature. The mixture was then poured slowly into saturated
NaHCO3 solution (10 mL) and extracted with Et2O (3 Â 20 mL). The
combined organic layers were dried over MgSO4 and the solvent was
removed in vacuo. Flash chromatography (Et2O) of the residue gave diols
32a (epothilone C) and 32b as a mixture of diastereomers (Z/E ˆ 1.7:1,
16.5 mg, 65%, colorless viscous oil). IR (Z/E mixture, film): nÄmax ˆ 3456,
(1S)-1-[(E)-1-Methyl-2-(2-methyl-1,3-thiazol-4-yl)-1-ethenyl]-3-butenyl
(3S,6R,7S,8S)-3,7-di-[tert-butyldimethylsilyloxy]-4,4,6,8-tetramethyl-5-
oxo-12-tridecenoate (30): DCC (72 mg, 0.35 mmol, 1.3 equiv) was added at
08C to a solution of acid 29 (145 mg, 0.27 mmol), alcohol 4 (56 mg,
0.27 mmol), and DMAP (6.5 mg, 0.054 mmol, 0.2 equiv) in CH2Cl2
(1.5 mL). The mixture was stirred for 10 min at 08C and for 16 h at room
temperature. The solvent was removed in vacuo and the product was
purified by flash chromatography (pentane/Et2O 20:1) to afford ester 30
20
(157 mg, 80%) as a colorless oil. [a]D20
ˆ
45.0, [a]
ˆ
53.8 (c ˆ 1.0,
546
CHCl3) [Lit.:[4b] [a]D
ˆ
41.2 (c ˆ 3.1, CHCl3)]; IR (film): nÄmax ˆ 3079, 2931,
1
1736, 1698, 1473, 1256, 1179, 989, 832, 777 cm
;
1H NMR (400 MHz,
1
CDCl3); d ˆ 6.94 (s, 1H; thiazole H-5), 6.49 (s, 1H; H-2''), 5.85 ± 5.66 (m,
2927, 1733, 1690, 1471, 1377, 1251, 978, 882, 731 cm 1; H NMR (Z isomer
3
2H; H-12, H-3'), 5.30 (t, J ˆ 6.7 Hz, 1H, H-1'), 5.14 ± 4.91 (m, 4H; H-13,
32a, 400 MHz, CDCl3): d ˆ 6.96 (s, 1H; H-19), 6.60 (brs, 1H; H-17), 5.56 ±
5.34 (m, 2H; H-12, H-13), 5.29 (dd, 3J ˆ 9.8 Hz, 3J ˆ 1.7 Hz, 1H; H-15), 4.23
(dd, 3J ˆ 11.2 Hz, 3J ˆ 2.3 Hz, 1H; H-3), 3.76 ± 3.71 (m, 1H; H-7), 3.33 (brs,
1H; OH), 3.14 (dq, 3J ˆ 6.8 Hz, 3J ˆ 2.1 Hz, 1H; H-6), 3.05 (brs, 1H; OH),
2.74 ± 2.63 (m, 1H; H-14), 2.70 (s, 3H; H-21), 2.48 (dd, 2J ˆ 15.1 Hz, 3J ˆ
11.2 Hz, 1H; H-2), 2.35 (dd, 2J ˆ 15.1 Hz, 3J ˆ 2.6 Hz, 1H; H-2), 2.09 (d,
4J ˆ 1.2 Hz, 3H; H-27), 2.30 ± 2.12 (m, 2H; H-15, H-11), 2.08 ± 1.97 (m, 1H;
H-11), 1.79 ± 1.60 (m, 2H; H-9, H-10), 1.36 ± 1.13 (m, 3H; H-8, H-9, H-10),
1.33 (s, 3H; H-22), 1.19 (d, 3J ˆ 6.8 Hz, 3H; H-24), 1.08 (s, 3H; H-23), 1.00
(d, 3J ˆ 6.8 Hz, 3H; H-25); 13C NMR (Z isomer 32a, 100 MHz, CDCl3): d ˆ
220.5, 170.3, 165.0, 152.0, 138.6, 133.4, 125.0, 119.5, 115.8, 78.4, 74.1, 72.4,
53.3, 41.8, 39.2, 38.5, 32.5, 31.7, 27.6, 27.5, 22.7, 19.0, 18.7, 15.8, 15.5, 13.5;
1H NMR (E isomer 32b, 400 MHz, CDCl3): d ˆ 6.98 (s, 1H; H-19), 6.57
(brs, 1H; H-17), 5.45 ± 5.34 (m, 3H; H-12, H-13, H-15), 4.19 (dd, 3J ˆ
10.2 Hz, 3J ˆ 2.9 Hz, 1H; H-3), 3.76 ± 3.71 (m, 1H; H-7), 3.29 ± 3.20 (m,
2H; H-7, OH), 2.78 (brs, 1H; OH), 2.71 (s, 3H; H-21), 2.56 (dd, 2J ˆ
15.1 Hz, 3J ˆ 10.1 Hz, 1H; H-2), 2.49 (dd, 2J ˆ 15.1 Hz, 3J ˆ 3.0 Hz, 1H;
H-2), 2.48 ± 2.42 (m, 2H; H-14), 2.21 ± 2.10 (m, 1H; H-11), 2.08 (d, 4J ˆ
1.1 Hz, 3H; H-27), 1.99 ± 1.91 (m, 1H; H-11), 1.72 ± 1.57 (m, 2H; H-9,
H-10), 1.52 ± 1.40 (m, 1H; H-9), 1.28 (s, 3H; H-22), 1.27 ± 1.15 (m, 2H; H-8,
H-10), 1.18 (d, 3J ˆ 4.8 Hz, 3H; H-24), 1.07 (s, 3H; H-23), 0.99 (d, 3J ˆ
6.4 Hz, 3H; H-25); 13C NMR (E isomer 32b, 100 MHz, CDCl3): d ˆ 219.9,
170.5, 164.9, 152.1, 137.1, 134.3, 125.7, 119.8, 116.0, 77.6, 75.8, 72.4, 52.5, 43.6,
38.9, 37.7, 36.2, 32.4, 30.5, 27.2, 21.0, 20.7, 19.1, 16.4, 15.7, 14.8; MS (Z/E
H-4'), 4.34 (dd, 3J ˆ 6.0 Hz, 3J ˆ 3.6 Hz, 1H; H-3), 3.74 (dd, 3J ˆ 6.8 Hz,
3
3
3J ˆ 2.3 Hz, 1H; H-7), 3.15 (dq, J ˆ 6.8 Hz, J ˆ 6.8 Hz, 1H; H-6), 2.70 (s,
3H; thiazole CH3), 2.57 ± 2.41 (m, 3H; H-2, H-2'), 2.29 (dd, 2J ˆ 17.0 Hz,
3J ˆ 6.0 Hz, 1H; H-2'), 2.07 (d, 4J ˆ 1.3 Hz, 3H; C1''-CH3), 2.06 ± 1.97 (m,
2H; H-11), 1.52 ± 1.29 (m, 3H), 1.27 ± 1.06 (m, 2H)(H-8, H-9, H-10), 1.24,
1.04 (2s, 2  3H; C4-CH3), 1.04 (d, 3J ˆ 6.8 Hz, 3H; C6-CH3), 0.90 (d, 3J ˆ
6.4 Hz, 3H; C8-CH3), 0.90, 0.88 (2s, 2 Â 9H; OSiC(CH3)3), 0.11, 0.06, 0.04,
0.03 (4s, 4  3H; OSi(CH3)2); 13C NMR (100 MHz, CDCl3); d ˆ 217.6,
171.1, 164.5, 152.6, 138.9, 136.8, 133.4, 121.1, 117.7, 116.4, 114.4, 78.7, 77.6,
74.1, 53.4, 45.2, 40.3, 38.9, 37.5, 34.3, 30.5, 27.1, 26.2, 26.0, 23.2, 20.4, 19.2,
18.5, 18.2, 17.6, 15.4, 14.6, 3.7, 3.8, 4.3, 4.7 ; MS (PCI, CH4): m/z (%):
‡
734.5 (15) [M‡H] , 399.2 (10), 241.1 (14), 191.9 (100); C40H71NO5SSi2
(734.2): calcd C 65.43, H 9.75, N 1.91, S 4.37; found C 65.36, H 9.65, N 2.29,
S 4.25.
(4S,7R,8S,9S,16S)-4,8-Di-tert-butyldimethylsilyloxy-5,5,7,9-tetra-methyl-1-
6-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)-1-ethenyl]-1-oxa-13-cyclo-
hexadecen-2,6-dione, mixture of the (13Z) and (13E) isomers, (31a) and
(31b):
Bis(tricyclohexylphosphine)benzylideneruthenium
dichloride
[20a]
ˆ
([RuCl2( CHPh)(PCy3)2]
7.4 mg, 9 mmol, 0.06 equiv) was added to a
solution of diene 30 (110 mg, 0.15 mmol) in CH2Cl2 (75 mL, 0.002m), and
the reaction mixture was stirred for 16 h at room temperature. The solvent
was removed in vacuo and the crude product was purified by flash
chromatography (pentane/Et2O 20:1) to give a mixture of diastereomers
31a and 31b (Z/E ˆ 1.7:1, 99 mg, 94%, colorless viscous oil). IR (Z/E
‡
mixture, 70 eV, EI): m/z (%): 477.3 (22) [M] , 459.3 (7), 405.2 (6), 290.1
(24), 168.0 (100), 151.0 (17), 111.0 (16); HRMS (EI): calcd for C26H39NO5S
477.2549, found 477.255.
mixture, film): nÄmax ˆ 2929, 2858, 1739, 1695, 1464, 1362, 1251, 828,
1
673 cm
;
1H NMR (Z isomer 31a, 400 MHz, CDCl3): d ˆ 6.96 (s, 1H;
H-19), 6.57 (brs, 1H; H-17), 5.53 (dt, J ˆ 11.2 Hz, 3J ˆ 3.5 Hz, 1H; H-12),
Epothilone A (1): A freshly prepared solution of dimethyl dioxirane in
acetone[21] (1.3 equiv) was added dropwise at 358C with stirring to a
solution of 32a and 32b (14.3 mg, 0.03 mmol, 1.7:1 ± Z:E mixture) in
CH2Cl2 (2.5 mL). Stirring was continued for 2 h at 358C. Aqueous iron(ii)
sulfate solution (10%, 5.0 mL) was added, and the mixture was extracted
with CH2Cl2 (3 Â 10 mL). The combined extracts were concentrated in
vacuo and the residue was purified by flash chromatography with Et2O to
3
5.49 ± 5.31 (m, 1H; H-13), 5.02 (d, J ˆ 10.0 Hz, 1H; H-15), 4.04 (dd, 3J ˆ
3
10.2 Hz, 3J ˆ 1.3 Hz, 1H; H-3), 3.90 (d, 3J ˆ 8.6 Hz, 1H; H-7), 3.01 (dq, 3J ˆ
8.6 Hz, 3J ˆ 6.9 Hz, 1H; H-6), 2.82 (dd, 2J ˆ 16.4 Hz, 3J ˆ 1.3 Hz, 1H; H-2),
2.81 ± 2.69 (m, 1H; H-14), 2.71 (s, 3H; H-21), 2.67 (dd, 2J ˆ 16.6 Hz, 3J ˆ
10.3 Hz, 1H; H-2), 2.42 ± 2.32 (m, 1H; H-10), 2.12 (d, 4J ˆ 1.2 Hz, 3H;
H-27), 2.11 ± 2.05 (m, 1H; H-14), 1.92 ± 1.81 (m, 1H; H-10), 1.63 ± 1.46 (m,
3H; H-8, H-9, H-11), 1.19 ± 1.00 (m, 2H; H-9, H-11), 1.19, 1.15 (2s, 2 Â 3H;
H-22, H-23), 1.09 (d, 3J ˆ 6.8 Hz, 3H; H-24), 0.96 (d, 3J ˆ 6.8 Hz, 3H;
H-25), 0.94, 0.84 (2s, 2 Â 9H; OSiC(CH3)3), 0.12, 0.10, 0.08, 0.09 (4s, 4 Â
3H; OSi(CH3)2); 13C NMR (Z isomer 31a, 100 MHz, CDCl3): d ˆ 215.0,
171.2, 164.6, 152.5, 138.6, 135.0, 122.8, 119.5, 116.0, 79.5, 79.2, 76.4, 53.4,
47.9, 38.9, 37.9, 31.8, 31.4, 29.2, 28.4, 26.4, 26.2, 24.9, 24.2, 19.2, 19.0, 18.7,
18.6, 17.6, 15.2, 3.2, 3.3, 3.7, 5.7; 1H NMR (E isomer 31b, 400 MHz,
CDCl3): d ˆ 6.94 (s, 1H; H-19), 6.54 (brs, 1H; H-17), 5.49 ± 5.31 (m, 2H;
H-12, H-13), 5.24 (dd, 3J ˆ 7.8 Hz, 3J ˆ 3.1 Hz, 1H; H-15), 4.42 (dd, 3J ˆ
give epothilone A (1) (7.1 mg, 48%; 76% based on pure Z isomer) as a
20
colorless foam. [a]D20
ˆ
43.8, [a]
ˆ
59.4 (c ˆ 0.17, MeOH) [Lit.:[1a]
546
[a]2D0
ˆ
47.1 (c ˆ 1.0, MeOH)]; 1H NMR (400 MHz, CDCl3): d ˆ 6.98 (s,
1H; H-19), 6.60 (brs, 1H; H-17), 5.44 (dd, 3J ˆ 9.8 Hz, 3J ˆ 1.7 Hz, 1H;
H-15), 4.20 (dd, 3J ˆ 10.8 Hz, 3J ˆ 3.0 Hz, 1H; H-3), 4.04 (brs, 1H; OH),
3.79 (dd, 3J ˆ 4.4 Hz, 3J ˆ 4.3 Hz, 1H; H-7), 3.23 (dq, 3J ˆ 6.9 Hz, 3J ˆ
4.7 Hz, 1H; H-6), 3.04 (ddd, 3J ˆ 8.1 Hz, 3J ˆ 4.2 Hz, 3J ˆ 4.0 Hz, 1H;
H-13), 2.92 (ddd, 3J ˆ 7.8 Hz, 3J ˆ 4.0 Hz, 3J ˆ 3.7 Hz, 1H; H-12), 2.70 (s,
3H; H-21), 2.63 (brs, 1H; OH), 2.54 (dd, 2J ˆ 14.4 Hz, 3J ˆ 10.6 Hz, 1H;
3
3
3
3
2
6.6 Hz, J ˆ 4.3 Hz, 1H; H-3), 3.93 (dd, J ˆ 6.9 Hz, J ˆ 1.5 Hz, 1H; H-7),
3.07 (dq, 3J ˆ 6.9 Hz, 3J ˆ 6.9 Hz, 1H; H-6), 2.71 (s, 3H; H-21), 2.66 (dd,
2J ˆ 15.7 Hz, 3J ˆ 4.2 Hz, 1H; H-2), 2.58 ± 2.42 (m, 2H; H-14); 2.56 (dd,
2J ˆ 15.7 Hz, 3J ˆ 6.6 Hz, 1H; H-2), 2.21 ± 2.11 (m, 1H; H-11), 2.15 (d, 4J ˆ
1.1 Hz, 3H; H-27), 1.96 ± 1.88 (m, 1H; H-11), 1.60 ± 1.37 (m, 3H; H-8, H-9,
H-10), 1.18 (s, 3H; H-22), 1.18 ± 1.14 (m, 1H; H-10), 1.15 (d, 3J ˆ 6.9 Hz,
3H; H-24), 1.09 (s, 3H; H-23), 1.02 ± 0.99 (m, 1H; H-9), 0.94 (d, 3J ˆ 8.0 Hz,
3H; H-25), 0.90, 0.88 (2s, 2 Â 9H; OSiC(CH3)3), 0.11, 0.08, 0.07, 0.05 (4s,
4  3H; OSi(CH3)2); 13C NMR (E isomer 31b, 100 MHz, CDCl3): d ˆ
216.3, 170.5, 164.6, 152.7, 137.8, 134.2, 125.7, 119.6, 116.2, 78.5, 77.0, 73.8,
H-2), 2.41 (dd, 2J ˆ 14.4 Hz, J ˆ 3.2 Hz, 1H; H-2), 2.14 (ddd, J ˆ 15.1 Hz,
3J ˆ 7.0 Hz, 3J ˆ 2.8 Hz, 1H; H-14), 2.09 (d, 4J ˆ 0.9 Hz, 3H; H-27), 1.88
2
3
3
(ddd, J ˆ 15.1 Hz, J ˆ 8.5 Hz, J ˆ 8.4 Hz, 1H; H-14), 1.81 ± 1.66 (m, 2H;
H-10, H-11), 1.61 ± 1.19 (m, 5H; H-8, H-9, H-10, H-11), 1.37 (s, 3H; H-22),
1.18 (d, 3J ˆ 6.9 Hz, 3H; H-24), 1.10 (s, 3H; H-23), 1.00 (d, 3J ˆ 7.0 Hz,
3H; H-25); 13C NMR (100 MHz, CDCl3): d ˆ 220.2, 170.6, 165.2, 151.8,
137.6, 119.8, 116.2, 76.6, 74.5, 73.3, 57.5, 54.6, 52.9, 43.4, 38.9, 36.2, 31.5, 30.6,
27.2, 23.5, 21.6, 20.6, 19.2, 17.2, 15.7, 14.1; MS (PCI, CH4,): m/z (%): 494.5
‡
(10) [M‡H] , 394.3 (7), 334.2 (6), 324.2 (53), 306.1 (100), 171.0 (12),
153.0 (18).
2490
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2490 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 9

Epothilone A
2483±2491
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Acknowledgment
We thank Prof. Dr. G. Höfle for authentic samples of the natural
epothilones A and C. We are grateful to Prof. Dr. L. Ernst, TU
Braunschweig (Germany) for determining the NMR data of the synthetic
epothilones. This work was supported by the Fonds der Chemischen
Industrie. We thank the Schering AG (Berlin) and the Novartis AG (Basel)
for financial support and generous gifts of chemicals.
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Received: March 4, 1999 [F 1648]
Chem. Eur. J. 1999, 5, No. 9
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