Catalytic antibody route to the naturally occurring epothilones: Total synthesis of epothilones A-F

Article abstract of DOI:10.1002/1521-3765(20010417)7:8<1691::AID-CHEM16910>3.0.CO;2-9

Naturally occurring epothilones have been synthesized starting from enantiomerically pure aldol compounds 9-11, which were obtained by antibody catalysis. Aldolase antibody 38C2 catalyzed the resolution of (±)-9 by enantioselective retro-aldol reaction to afford 9 in 90% ee at 50% conversion. Compounds 10 and 11 were obtained in more than 99% ee at 50% conversion by resolution of their racemic mixtures using newly developed aldolase antibodies 84G3, 85H6 or 93F3. Compounds 9, 10 and 11 were resolved in multigram quantities and then converted to the epothilones by metathesis processes, which were catalyzed by Grubbs' catalysts.

Full text of DOI:10.1002/1521-3765(20010417)7:8<1691::AID-CHEM16910>3.0.CO;2-9

FULL PAPER
Catalytic Antibody Route to the Naturally Occurring Epothilones:
Total Synthesis of Epothilones A ± F
Subhash C. Sinha,*[a] Jian Sun,[a] Gregory P. Miller,[a] Markus Wartmann,[b] and
Richard A. Lerner*[a]
Abstract: Naturally occurring epothilones have been synthesized starting from
enantiomerically pure aldol compounds 9 ± 11, which were obtained by antibody
catalysis. Aldolase antibody 38C2 catalyzed the resolution of (Æ)-9 by enantiose-
Keywords: antibodies
agents ´ chiral resolution ´ epothi-
lones ´ retro-aldol reactions
´
antitumor
lective retro-aldol reaction to afford 9 in 90% ee at 50% conversion. Compounds 10
and 11 were obtained in more than 99% ee at 50% conversion by resolution of their
racemic mixtures using newly developed aldolase antibodies 84G3, 85H6 or 93F3.
Compounds 9, 10 and 11 were resolved in multigram quantities and then converted to
the epothilones by metathesis processes, which were catalyzed by Grubbsꢀ catalysts.
over, unlike natural aldolase enzymes, they accept a much
broader range of substrates. In order to demonstrate the
efficacy of antibody catalysis for natural product synthesis, we
used these aldolase antibody catalysts in the total synthesis of
epothilones, which are molecules of current interests due to
their possible anticancer chemotherapeutic activity.[7]
Introduction
Since the inception of the concept of antibody catalysis,[1]
a
number of chemical transformations have been catalyzed by
monoclonal antibody catalysts, which were generated against
respective transition state analogues by normal immunization
techniques.[2] Recently, the reactive immunization technique[3]
was introduced to generate antibody catalysts. Two sets of
catalytic aldolase monoclonal antibodies (38C2 and 33F12,
and 84G3, 85H6 and 93F3) were raised against b-diketone
haptens I and II (Figure 1), respectively, by the reactive
immunization technique.[4, 5] Similar to natural aldolase en-
zymes, these antibody catalysts work by an enamine mecha-
nism and were found to be very useful for synthetic organic
chemistry.[6] These two sets of aldolase antibodies comple-
ment each other by having antipodal properties and thus
produce compounds with opposite facial selectivities. More-
O
O
O
O
S
O
O
HO2C
HO2C
HN
HN
I
II
O
O
Figure 1. Structures of hapten I used to generate antibodies 38C2 and
33F12, and hapten II to generate 84G3, 85H6 and 93F3.
Epothilones A ± F (1 ± 6, see Figure 2) are sixteen-mem-
bered macrolides isolated from myxobacteria (Sorangium
cellulosum strain 90).[7, 8] These compounds possess a taxol-
like mode of action and function through the stabilization of
cellular microtubules. They exhibit cytotoxicity even in taxol-
resistant cell lines.[9] Epothilone B has been reported to be
about 3400 times more active than taxol against the resistant
human leukemic cell line CCRF-CEM/VBL in cell-culture
cytotoxicity studies. Danishefsky and co-workers reported the
first total synthesis of epothilones A and B (1 and 2).[10] Soon
after, Nicolaou[11] and Schinzer[12] also reported syntheses of
these compounds. Since then numerous syntheses of epothi-
lones A ± D have been achieved.[13] In addition, naturally
occurring epothilone E,[14] and many analogues of 1 ± 5 have
also been synthesized and their biological studies have been
reported.[15]
[a] Prof. S. C. Sinha, Prof. R. A. Lerner, Dr. J. Sun, G. P. Miller
Department of Molecular Biology and the Skaggs Institute
for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, California 92037 (USA)
Fax : (‡1)858-784-8732
E-mail: subhash@scripps.edu
[b] Dr. M. Wartmann
Oncology Business Unit
Novartis Pharma AG, Klybeckstrasse 141
4057 Basel (Switzerland)
E-mail: markus.wartmann@pharma.novartis.com
Supporting information for this article is available on the WWW under
http://www.wiley-vch.de/home/chemistry/ or from the author. 1H and
13C NMR spectra for selected compounds, syntheses of compounds
(Æ)-9, (Æ)-10 and (Æ)-11, ORTEP diagram of compound 15 (35 pages).
Chem. Eur. J. 2001, 7, No. 8
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S. C. Sinha, R. A. Lerner et al.
FULL PAPER
Monoclonal catalytic antibodies have been used effectively
in the total synthesis of natural products as demonstrated by
the construction of brevicomins,[18] multistriatin,[19] and other
compounds.[20] In these cases, the antibody catalysts were used
to catalyze stereoselective reactions with high rates, thereby
yielding precursors to these molecules. The stereochemistry
obtained by the antibody-catalyzed reactions guided the
remaining configurations of the molecule. Following the same
principle, we have now generated the chiral starting materials
by using aldolase antibodies and converted these precursors
to the naturally occurring epothilones.
O
OH O
O
OH O
O
O
N
S
N
S
OH
OH
X
X
O
R
R
1: Epothilone A, and 3: Epothilone C: R = H, X = Me
2: Epothilone B, and 4: Epothilone D: R = X = Me
5: Epothilone E, and 7: Deoxyepothilone E: R = H, X = CH2OH
6: Epothilone F, and 8: Deoxyepothilone F: R = Me, X = CH2OH
Figure 2. Structures of epothilones and analogues.
Recently, we reported an antibody catalyzed route to the
syntheses of epothilones A and C (1 and 3) and desoxyepo-
thilone E (7) by the macrolactonization/metathesis approach
starting from 9 ± 11.[16] Using the same precursors 9 ± 11, we
have now synthesized epothilones B (2), D (4) and F (6). In
this article, we describe, including full details of our previous
communication,[16] syntheses of epothilones A ± F (1 ± 6).[17]
Resolution of compound 9 by retro-aldol reaction using
antibody 38C2: Based on previous studies on aldol and retro-
aldol reactions with aldolase antibodies 38C2 and 33F12,[6]
compound (Æ)-9 was chosen as the substrate for resolution
using antibody 38C2. When compound (Æ)-9 was incubated
with a catalytic amount of antibody 38C2, enantioselective
retro-aldol reaction of (Æ)-9 was observed affording aldehyde
12 and pentan-3-one. At 60% conversion, the reaction
mixture contained essentially the enantiomerically pure
compound 9.[21] This reaction was also amenable to gram
scale. Typically, 0.75 g (2.85 mmol) of compound (Æ)-9 was
resolved using antibody 38C2 (0.5 g, 0.00357 mmol, 0.125 mo-
lar percent) to afford enantiomerically pure 9 (0.3 g, 40%
yield).[16a] Alternatively, in a step-wise process, comparatively
lesser amount of antibodies were used to give similar results.
Thus, compound (Æ)-9 (0.825 g, 3.15 mmol) was first resolved
with 38C2 (0.1 g, 0.67 mmol, 0.021 molar percent) to afford
enantiomerically enriched (Æ)-9 (60 ± 70% ee). Using the
same antibody an additional amount of (Æ)-9 (0.5 g,
1.9 mmol) was first resolved in a similar manner to afford
the additional amount of enantiomerically enriched (Æ)-9
(60 ± 70% ee). The combined enriched 9 (684 mg, 52%, 70%
ee) from previous two experiments were resolved in a new
container using the antibody 38C2 (25 mg, 0.179 mmol) to
afford enantiomerically pure 9 (480 mg, 36%). Apparently,
the aldehyde 12 is an inhibitor of this reaction and slows down
the resolution as the former is produced.
Results and Discussion
In several reported syntheses of compounds 1 ± 4 by the
metathesis approach, intermediate III in its partially or fully
protected form have been used.[8] Considering the relevance
of aldolase antibodies to the total syntheses of epothilones, we
imagined that III could be synthesized through intermediates
IV and 29 ± 30, starting from precursors 9 ± 11 (Scheme 1).
Epothilones and
Desoxyepothilones
1-8
esterification
O
R
OPG O
O
N
S
OPG
X
O
III: R= H, Me; X= Me, CH2OTBS
OH
O
*
OPG O
OH
HO2C
R
38C2
9
MeO
MeO
N
Ar
PBS, pH 7.4
OH
+
*
X
+
S
OPG
60% conversion
36% yield
CHO
29: X= Me
30: X= CH2OTBS
98% ee
(±)-9
MeO
IV
12
Scheme 2. Resolution of (Æ)-9 to 9 by antibody 38C2 catalyzed retro-aldol
reaction of ent-9 to aldehyde 12. The other product, pentane-3-one, is not
shown in the Scheme.
O
OH
N
X
OH
S
O
Production of 10 by aldol reaction and resolution of (Æ)-10
using aldolase antibody 38C2: Once again, our studies with
the aldolase antibody 38C2 guided us to use aldol reaction of
aldehyde 13 with acetone to produce compound 10. As
10: X= Me
11: X= CH2OH
MeO
9
Scheme 1. Retrosynthesis of epothilones 1 ± 8.
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Epothilone F
1691±1702
expected, the antibody 38C2 catalyzed this reaction. The
enantiomeric excess of the aldol product 10 was found to
reach 75% at 10% conversion (Scheme 3A), however, the
enantiomeric purity decreased as the reaction progressed. The
reason for this is that as higher concentrations of the aldol
product were achieved, the retro-aldol process started and
was significantly faster than the forward reaction. Hence, at
20% conversion of 13 the ratio between 10 and ent-10
dropped to 4:1. Obviously, both the formation of 10 from 13
and acetone, and the conversion of 10 to 13 and acetone were
catalyzed by antibody 38C2 and were faster than the
analogous reactions for ent-10.
OH
N
S
X
X
O
10: X = Me
OH
11: X = CH2OH
84G3, PBS, pH 7.4
N
S
+
X
50% conversion,
>98% ee
CHO
O
N
S
(±)-10: X = Me
(±)-11: X = CH2OH
13: X = Me
14: X = CH2OH
Scheme 4. Resolution of compounds (Æ)-10 and (Æ)-11 by retro-aldol
reaction, catalyzed by antibody 84G3, to give compounds 10 and 11. The
other product, acetone, is not shown in the Scheme.
OH
A.
CHO
OH
O
N
S
N
S
38C2, PBS, pH 7.4
+
at 0.003 and 0.005 molar percent, respectively, (see Exper-
imental Section). Progress of these reactions was followed by
disappearance of the peak for ent-10 and ent-11 in the HPLC
traces. In this way, the racemic mixture was resolved,
affording 10 and 11 with more than 98% enantiomeric excess
in 45 and 48% isolated yields, respectively. The corresponding
aldehydes 13 and 14 were isolated in 40 and 45% yields,
respectively. The thiazole aldehydes obtained from these
reactions were reused to synthesize the aldol starting materi-
als. Thus, even though the process is a kinetic resolution, the
overall yield is good because the produced aldehydes can be
recycled.
10% conversion,
75% ee
O
13
10
OH
B.
N
S
N
S
38C2, PBS, pH 7.4
+ 13
60% conversion,
90% ee
O
O
(±)-10
ent-10
Scheme 3. Production of compounds 10 and ent-10 by antibody 38C2
catalyzed reactions. A) Aldol reaction of aldehyde 13 with acetone,
B) resolution of (Æ)-10.
In order to quantify the relative rate of the retro-aldol
reactions of 10 and ent-10 with antibody 38C2, we checked the
resolution of their racemic mixture. It was found that the
retro-aldol reaction of (Æ)-10 was catalyzed by antibody 38C2
to afford a 5:1 selectivity in favor of ent-10 at 50% conversion
and this selectivity was increased up to 90 ± 95% ee at a higher
conversion. In a typical reaction, the retro-aldol reaction of
(Æ)-10 with 0.06 mol percent of antibody 38C2 afforded ent-10
with an enantiomeric purity of 90% at 60% conversion.[22]
Conversion of compounds 9 ± 11 to epothilones: With starting
materials 9 ± 11 in hand, syntheses of epothilones A, B, E and
F (1, 2, 5 and 6) were achieved via their desoxyepothilones (3,
4, 7 and 8) using the metathesis approach (see Schemes 5
and 6).
Synthesis of acids 25 and 26 from compound 9: Compound 9
was hydrogenated using Rh/Al2O3 to afford a 1:1 mixture of
compounds 15 and 2-epi-15, which were then separated by
column chromatography over silica gel. The structure of 15,
which possessed three vicinal stereogenic centers (at C-6, C-7
and C-8) of epothilones, was confirmed by X-ray analysis.[26]
The free alcohol function in compound 15 was silylated as its
TBS ether using TBSCl and imidazole in dry DMF at 508C to
afford 15a. The latter compound was then monomethylated at
the less substituted carbon alpha to the carbonyl function to
give compound 16. Aldol reaction of 16 with 3-tert-butyldi-
methylsilyloxy propanal took place at the same a-carbon
mentioned above, affording the aldol product 17a accompa-
nied with 3-epi-17a in a 1.6:1 diastereomeric ratio at C-3 in
favor of the desired isomer. The other possible product by
aldol reaction at C-6 was not detected. The aldol product thus
obtained was silylated as its TBS ether using TBSOTf and
then purified from its minor 3-epimer to give 17b. The
methoxy substituted aromatic ring was exhaustively degraded
to the corresponding carboxylic acid 18a, using the RuCl3/
NaIO4 system.[27] Esterification of the acid 18a was achieved
with diazomethane providing ester 18b. Reduction of this
ester afforded the corresponding primary alcohol in com-
pound 18c. The latter product was converted to the corre-
Resolution of compounds (Æ)-10 and (Æ)-11 by retro-aldol
reaction using antibody 84G3, 85H6 or 93F3: Nine more
aldolase antibodies were generated against hapten II,[5] three
of which (84G3, 85H6 and 93F3) efficiently catalyzed the
retro-aldol reaction of (Æ)-10 to aldehyde 13 and acetone
(Scheme 4).[16b] All three antibodies, 84G3, 85H6 and 93F3,
showed complementarity with respect to antibody 38C2. Thus,
the retro-aldol reaction of (Æ)-10 with any of the three
antibodies, 84G3, 85H6, and 93F3, afforded compound 10 as a
major enantiomer. At 50% conversion of the starting racemic
aldol (Æ)-10, compound 10[23] was obtained in essentially
enantiomerically pure form.[24]
Just as (Æ)-10, its analogue (Æ)-11 was also resolved using
any of the three antibodies 84G3, 85H6 and 93F3 to afford
enantiomerically pure 11 at 50% conversion.[25] All three
catalysts gave similar results with 84G3 and 93F3 demonstrat-
ing a rate enhancement slightly greater than with 85H6. These
antibodies could also be used to resolve (Æ)-10 and (Æ)-11 on
a synthetically useful scale. Here, antibody 84G3 was used to
perform the gram-scale resolution of compounds (Æ)-10 and
(Æ)-11. We therefore incubated compounds (Æ)-10 (16.8 g,
75.0 mmol) and (Æ)-11 (1.45 g, 6.0 mmol) with antibody 84G3
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FULL PAPER
TBS
TBSO
O
O
2
TBSO
OPG O
3
O
O
O
2
6
a
b
c
d
+
9
2
93%
76%
56%
42%
OTBS
OTBS
OPG
OTBS
OH
8
Ar
15: PG = H
15a: PG = TBS
Ar
Ar
17a: PG = H
R
Ar
2-epi-15
16
18a: R = CO2H
18b: R = CO2Me
18c: R = CH2OH
17b: PG = TBS
TBS
TBSO
TBS
TBSO
TBS
TBSO
O
O
O
O
O
O
TBSO
O
HO2C
h
f
g
e
95-97%
84-92%
88-89%
OTBS
OTBS
OTBS
OTBS
O
O
12
R
R
R
R
19: R = OEt
20: R = Me
21: R = OEt
22: R = Me
25: R = H
26: R = Me
23: R = H
24: R = Me
Scheme 5. Syntheses of acids 25 and 26 from the enantiomerically pure aldol compound 9. Key steps: a) H2, Rh/Al2O3, THF, 18 h; b) i) TBSCl, imidazole,
DMF, 40 ± 508C, 48 h, ii) LDA, THF, 788C, 2 h then MeI, HMPA, 78 to 408C, 4 h; c) i) LDA, THF, 78 to 408C, 2 h then TBSOCH2CH2CHO,
788C, 0.5 h (3S:3R, 1.6:1), ii) TBSOTf, lutidine, CH2Cl2, 78 to 08C, 4 h, 3-epi-17b was isolated in 35% (two steps); d) i) RuCl3, NaIO4, CCl4/CH3CN 1:1,
PBS buffer (pH 7.4), 16 h, ii) CH2N2, EtOH/Et2O, 0 8C, 12 h, iii) DIBAL-H, THF, 78 to 558C, 1 h; e) i) Dess ± Martin reagent, CH2Cl2, 2 h, ii) for
compound 19: (EtO)2P(O)CH2CO2Et, NaH, THF, 08C, 0.5 h; for compound 20: MeCOCHPPh3, benzene, reflux, 4 h; f) H2, Rh/Al2O3, THF; for compound
21: 16 h, for compound 22, 1 h; g) for compound 23: i) DIBAL-H, THF, 788C, 2 h, ii) Dess ± Martin reagent, CH2Cl2, 2 h, iii) MePPh3I, nBuLi, THF, 08C,
0.5 h; for compound 24: MePPh3I, nBuLi, THF, 08C, 0.5 h; h) see ref. [12c] and [12d].
sponding aldehyde, which was used in the synthesis of both 25
and 26.
sponding diol. The primary hydroxyl group of this product
was then selectively protected with TBSCl to afford com-
pound 30.
The above mentioned aldehyde obtained from the oxida-
tion of 18c was olefinated by Wittig and Wittig ± Horner
reactions to afford alkenes 19 and 20, respectively. The latter
alkenes, 19 and 20, were hydrogenated over Rh/Al2O3 to yield
the saturated ester 21 and ketone 22. The ester function in
compound 21 was reduced to the corresponding alcohol,
which was oxidized to the aldehyde and then olefinated by
Wittig reaction with methylenetriphenylphosphorane to af-
ford alkene 23. Ketone 22 was also olefinated by Wittig
reaction with methylenetriphenylphosphorane to afford com-
Esterification of thiazole alcohol 29 with acids 25 and 26
yielded esters 31 and 32, respectively. Similarly, thiazole
alcohol 30 was esterified with acids 25 and 26 to afford
compounds 33 and 34, respectively. Metathesis of 31 and 33
was achieved with Grubbsꢀ catalyst V (Figure 3) to afford the
cyclized compounds 35 and 37 along with their trans isomers,
(E)-35 and (E)-37, in a ratio of 3:2 in favor of compounds 35
and 37. Similar treatment of dienes 32 and 34 with Grubbsꢀ
catalyst V, however, resulted in their corresponding dimers
after prolonged treatment. We also tested Hoveydaꢀs modi-
fied catalyst, VI,[30] which gave similar results. At the time of
these experiments, Grubbs reported a new catalyst, VII,
which possesses comparable activity to Schrockꢀs catalyst
VIII,[31] and described it as a powerful catalyst using a wide
variety of substrates.[32] Following the reported procedure by
Grubbs,[32a] catalyst VII was synthesized which was proven to
be fairly stable to air and moisture. Recently, we have used
VII as a RCM catalyst for the synthesis of 13-alkyl epothi-
lones.[33] Using the catalyst VII, metathesis of 32 and 34 in
refluxing CH2Cl2 was successfully achieved to afford the
mixture of cyclized olefins 36 and 38, and their respective
trans isomers in a ratio of 1.1:1 in favor of 36 and 38. In fact,
this is the first occasion that Grubbsꢀ catalyst, VII, has been
used as a RCM catalyst for macrocyclization in the synthesis
of naturally occurring epothilones. The cyclized products in
each case were deprotected using trifluoroacetic acid or HF/
pyridine to afford desoxyepothilones 3, 4, 7 and 8 and their
trans isomers. The physical and spectral data (1H NMR,
13C NMR, MS, optical rotation) of 3, 4, 7 and 8 were identical
to the published data.[10±14, 17] Epoxidation of 3, 4, 7 and 8 was
accomplished using methyl(trifluoromethyl)dioxirane to af-
ford 1, 2, 5, 6 and their a-stereoisomer, as previously reported.
1
pound 24. The H and 13C NMR spectra of 23 and 24 were
identical to those for the same compounds used in the
Schinzerꢀs synthesis of 1 and 3.[12c,d] The selective deprotection
of the primary hydroxy group in 23 and 24 with TsOH in
methanol/CH2Cl2 at 08C followed by two-step oxidations of
the primary alcohol via their corresponding aldehydes afford-
ed acids 25 and 26, respectively.[12c,d]
The thiazole fragments, 29 and 30, to be used in the
syntheses of 1 ± 8, were prepared starting from 10 and 11
respectively, as shown in Scheme 6. The hydroxy groups in
compounds 10 and 11 were first protected as their TBS ethers
to afford 10a and 11a. Reaction of 10a and 11a with lutidine
and TMSOTf at 788C gave the corresponding trimethylsilyl
enol ether derivatives, which were then oxidized using OsO4/
NMO to afford the primary hydroxy ketones, 27 and 28,
respectively.[28] Reduction of the ketone function in com-
pounds 27 and 28 afforded the corresponding vicinal diols,
which were then cleaved with Pb(OAc)4 to give aldehydes
29a[29] and 30a. Wittig reactions of 29a and 30a with
methylenetriphenylphosphorane afforded alkenes 29b and
30b. The TBS protecting group in compound 29b was cleaved
by exposure to TBAF yielding the corresponding alcohol 29.
Similar treatment with compound 30b afforded the corre-
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Epothilone F
1691±1702
Scheme 6. Total syntheses of epothilones A ± F (1 ± 6) by metathesis approach. Key steps: a) i) TBSCl, imidazole, DMF, rt, 8 h, ii) TMSOTf, lutidine,
CH2Cl2, 78 to 08C, 4 h then OsO4, NMO, CH2Cl2, rt, 5 h; b) i) NaBH4, MeOH, 08C, 0.5 h, ii) Pb(OAc)4, CH2Cl2, 08C, 0.5 h, iii) MePPh3I, nBuLi, THF,
08C, 0.5 h; c) for compound 29: TBAF, THF, 08C, 1 h; for compound 30: i) TBAF, THF, 08C, 1 h, ii) TBSCl, iPr2EtN, CH2Cl2, 08C to RT, 8 h; d) for
compounds 31 and 33: 25, EDC, DMAP (cat.), CH2Cl2, 08C to RT, 5 h; for compounds 32 and 34: 26, EDC, DMAP (cat.), CH2Cl2, 08C to RT, 5 h; e) for
compounds 35, (E)-35, 37 and (E)-37: Grubbsꢀ catalyst V, CH2Cl2, RT, 5 h; for compounds 36, (E)-36, 38 and (E)-38: Grubbsꢀ catalyst VII, CH2Cl2, reflux,
16 h; f) HF/pyridine, THF, RT, 2 ± 6 h; g) CF3COMe, oxone, NaHCO3, CH3CN, CH2Cl2, Na2EDTA, 0 8C, 1 h.
pure b-hydroxy ketones 9 ± 11, which were obtained by
resolution of their racemic mixtures using two aldolase
Cl Cl
Mes
N
N
Mes
Ph
PCy3
Ru
O
Ru PCy3
iPr
iPr
Ph
antibodies. Three stereogenic centers of 9 and 10 ± 11 were
incorporated into the epothilone molecules by the antibody-
catalyzed steps. The remaining four stereogenic centers
including the epoxide ring were guided by the structure of
the substrates. Metathesis of corresponding dienes to produce
cyclized products, enroute to 2 and 6, was catalyzed by the
Grubbsꢀ new catalyst VII. The catalyst VII was proven to be
superior to other air- and moisture-sensitive catalysts. Bio-
logical evaluations suggest that epothilone F and desoxyepo-
thilone F are equally potent to epothilones B and D,
respectively.
Cl
Cl
Ph
Cl
Cl
Ru
N
Me
Me
(F3C)2MeCO
(F3C)2MeCO
PCy3
Mo
PCy3
V
VI
VII
VIII
Figure 3. Structures of metathesis catalysts, V± VIII.
The biological effect of the synthetic epothilone F (6),
desoxyepothilone F (8) and (E)-desoxyepothilone F [(E)-8]
were studied using tubulin polymerization and cell growth
inhibition experiments. Both the epothilone F and desoxy-
epothilone F produced 77% and 75% tubulin polymeriza-
tion, respectively. As expected, (E)-desoxyepothilone F
showed greatly reduced activty, producing less than 10%
tubulin polymerization. Under the same conditions, epothi-
lones A and B produced 67% and 84% tubulin polymer-
ization, respectively. Epothilone F was eight times more
potent than desoxyepothilone F with respect to growth
inhibition of KB-31 epidermoid carcinoma cells, with IC50
values of 0.4nm and 3.3nm, respectively. Thus, epothilone F
and desoxyepothilone F are almost equally potent to epothi-
lone B and epothilone D, respectively.
Experimental Section
1
General: H and 13C NMR spectra were measured in CDCl3. Positive ion
mass spectra, using the fast ion bombardment (FIB) technique, were
obtained on a VG ZAB-VSE double focusing, high-resolution mass
spectrometer equipped with either a cesium or sodium ion gun. Optical
rotations were measured in a one-decimeter (1.3 mL) cell using an Autopol
III automatic polarimeter at room temperature (22 ± 238C). TLC was
performed on glass sheets precoated with silica gel (Merck, Kieselgel 60,
F
254, Art. No. 5715). Column chromatographic separations were performed
on silica gel (Mallinckrodt, 230 ± 400 mesh, V150) under pressure. HPLC
analyses were carried out using a reverse phase ODR column (Daicel
In conclusion, we have achieved syntheses of naturally
occurring epothilones A ± F starting from enantiomerically
Chemical Industries) monitored by
a
UV spectrophotometer at
Chem. Eur. J. 2001, 7, No. 8
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0708-1695 $ 17.50+.50/0
1695

S. C. Sinha, R. A. Lerner et al.
FULL PAPER
lmax ˆ 254 nm. THF was dried and distilled over sodium/benzophenone. All
antibody reactions were first degassed by passing a slow stream of argon
through the reaction mixture and then carried out under an argon
atmosphere.
CHOH), 3.11 (brs, 1H; OH), 3.09 (dd, J ˆ 13.5, 3.3 Hz, 1H; CH2Ar), 2.72
(qd, J ˆ 7.2, 2.4 Hz, 1H; CHCO), 2.57 (dq, J ˆ 18.0, 7.3 Hz, 1H; CH2CH3),
2.45 (dq, J ˆ 18.0, 7.3 Hz, 1H; CH2CH3), 2.29 (dd, J ˆ 13.5, 9.3 Hz, 1H;
CH2Ar), 1.75 (m, 1H; CHCH2Ar), 1.12 (d, J ˆ 7.2 Hz, 3H; CH3CHCO),
1.05 (t, J ˆ 7.3 Hz, 3H; CH3CH2), 0.71 (d, J ˆ 6.8 Hz, 3H; CH3CHCH2);
13C NMR (150.9 MHz): d ˆ 217.2, 157.7, 132.6, 130.5, 113.5, 74.1, 55.2, 46.7,
38.0, 37.5, 34.8, 15.0, 9.1, 7.6; HRMS: calcd for C16H24O3Na: 287.1623;
Kinetic resolution of (Æ)-9 to 9 by antibody 38C2 catalyzed enantioselec-
tive retro-aldol reaction: In a typical process,[34] a dialysis bag containing
antibody 38C2 (0.1 g, 0.714 mmol in 6.3 mL PBS buffer) was introduced to a
mixture of compound (Æ)-9 (0.825 g, 3.15 mmol in 50 mL CH3CN) in PBS
buffer (pH 7.4, 500 mL). Progress of the reaction was monitored by HPLC
(see: Supporting Information) and when that slowed down substantially (at
60 ± 70% ee), the reaction was interrupted. The dialysis bag was dialyzed
(3 Â 200 mL) with 10% CH3CN in PBS buffer (pH 7.4) and introduced to a
new batch of substrate (0.5 g, 1.9 mmol in 20 mL CH3CN) in PBS buffer
(pH 7.4, 200 mL). The process was repeated as above. The combined
aqueous solution from dialysis was extracted with EtOAc. The organic
layer was washed with brine and dried over MgSO4. The solvent was
evaporated and the resultant residue was purified by column chromatog-
raphy to afford enriched 9 (684 mg, 52%, 70% ee). First part of the process
was repeated using a new dialysis bag containing the antibody 38C2 (25 mg,
0.179 mmol), enriched 9 (684 mg, 2.61 mmol) in CH3CN (20 mL) and PBS
buffer (pH 7.4, 200 mL). At >98% consumption of one enantiomer as
judged by HPLC analysis, the reaction mixture was worked up and purified,
‡
found: 287.1624 [M‡Na] .
Physical data of 2-epi-15: m.p. 94 ± 968C; [a]D ˆ ‡7.08 (c ˆ 1.00, CHCl3);
1H NMR (600 MHz): d ˆ 7.04 (d, J ˆ 8.6 Hz, 2H; ArH), 6.82 (d, J ˆ 8.6 Hz,
2H; ArH), 3.78 (s, 3H; OCH3), 3.67 (t, J ˆ 5.7 Hz, 1H; CHOH), 2.80 (qd,
J ˆ 7.1, 5.3 Hz, 1H; CHCO), 2.66 (dd, J ˆ 13.5, 5.6 Hz, 1H; CH2Ar), 2.51
(dq, J ˆ 18.0, 7.3 Hz, 1H; CH2CH3), 2.43 (dq, J ˆ 18.0, 7.3 Hz, 1H;
CH2CH3), 2.37 (brs, 1H; OH), 2.29 (dd, J ˆ 13.5, 9.2 Hz, 1H; CH2Ar),
1.76 (m, 1H; CHCH2Ar), 1.16 (d, J ˆ 7.1 Hz, 3H; CH3CHCO), 1.03 (t, J ˆ
7.3 Hz, 3H; CH3CH2), 0.88 (d, J ˆ 6.6 Hz, 3H; CH3CHCH2); 13C NMR
(150.9 MHz): d ˆ 215.8, 157.8, 132.3, 129.9, 113.7, 74.5, 55.2, 48.3, 39.0, 37.7,
‡
34.9, 14.3, 11.5, 7.6; MS: 287 [M‡Na] .
Compound 15a: TBSCl (1.1 g, 7.3 mmol) was added to a solution of
compound 15 (0.96 g, 3.64 mmol) and imidazole (1.1 g, 16.2 mmol) in dry
DMF (3 mL) and stirred at 40 ± 508C for 48 h. The reaction mixture was
cooled to room temperature, diluted with water and extracted with Et2O.
The combined organic layer was washed with brine and dried over MgSO4.
Solvents were removed under vacuum and the crude silyl ether was purified
over silica gel (hexanes/EtOAc 19:1) to afford pure silyl ether 15a (1.15 g,
84%) and recovered 15 (0.15 g, 16%). 1H NMR (600 MHz): d ˆ 7.02 (d,
J ˆ 8.4 Hz, 2H; ArH), 6.81 (d, J ˆ 8.4 Hz, 2H; ArH), 3.92 (dd, J ˆ 5.6,
4.1 Hz, 1H; CHOTBS), 3.77 (s, 3H; OCH3), 2.79 (dd, J ˆ 13.6, 4.0 Hz, 1H;
CH2Ar), 2.76 (m, 1H; CHCO), 2.50 (qd, J ˆ 7.5, 4.0 Hz, 1H; CH2CH3), 2.46
(qd, J ˆ 7.5, 4.0 Hz, 1H; CH2CH3), 2.08 (dd, J ˆ 13.6, 10.4 Hz, 1H; CH2Ar),
1.72 (m, 1H; CHCH2Ar), 1.11 (d, J ˆ 7.2 Hz, 3H; CH3CHCO), 1.04 (t, J ˆ
7.2 Hz, 3H; CH3CH2), 0.92 (s, 9H; SiC(CH3)3), 0.80 (d, J ˆ 7.2 Hz, 3H;
CH3CHCH2), 0.08 (s, 3H; Si(CH3)2), 0.02 (s, 3H, Si(CH3)2); 13C NMR
(150.9 MHz): d ˆ 214.0, 157.7, 133.4, 129.9, 113.6, 76.7, 55.2, 49.7, 40.7, 37.4,
35.3, 26.1, 18.4, 16.4, 13.4, 7.7, 3.9, 4.2; HRMS: calcd for C22H39O3Si:
as above, to afford enantiomerically pure 9 (480 mg, overall 36%). [a]D
ˆ
‡44.98 (c ˆ 2.1, CHCl3); 1H NMR (600 MHz): d ˆ 7.21 (d, J ˆ 8.7 Hz, 2H;
ˆ
ArH), 6.85 (d, J ˆ 8.7 Hz, 2H; ArH), 6.51 (s, 1H; ArCH C), 4.43 (brs, 1H;
CHOH), 3.79 (s, 3H; OCH3), 2.83 (m, 1H; CHCOCH3), 2.56 (m, 2H;
ˆ
CH2CO), 1.81 (s, 3H; CH3C CH), 1.12 (d, J ˆ 7.2 Hz, 3H; CH3CH), 1.04 (t,
J ˆ 7.2 Hz, 3H; CH3CH2); 13C NMR (150.9 MHz): d ˆ 216.0, 158.1, 135.0,
‡
125.5, 113.5, 75.9, 55.2, 48.3, 35.2, 15.1, 10.4, 7.6; MS (FAB): 262 [M] , 285
‡
[M‡Na] .
Kinetic resolutions of (Æ)-10 and (Æ)-11 to 10 and 11 by antibody 84G3
catalyzed enantioselective retro-aldol reactions
Compound 10: Antibody 84G3 (12.5 mg per mL, 27.2 mL, 0.34 g,
0.00227 mmol) was added to a degassed solution of compound (Æ)-10
(16.8 g, 75 mmol) in PBS buffer (1.55 L, pH 7.4) and CH3CN (140 mL), and
the mixture was incubated under an argon atmosphere at 378C for 5 d. At
more than 98% consumption of one enantiomer as judged by HPLC
analysis (for HPLC conditions, see Supporting Information), the mixture
was dialyzed using amicon membranes to recover the antibody and the
filtrate was passed through a reverse phase column (C-18) to elute first
water, and then the compounds were isolated using methanol as eluent. The
solvents were removed under vacuum and the residue was purified over
silica gel (hexanes/EtOAc 9:1 ! 2:1) to afford compounds 10 (7.6 g, 45%,
‡
379.2668; found: 379.2665 [M‡H] .
Compound 16: nBuLi (1.6m in hexanes, 2.4 mL, 3.8 mmol) was added
dropwise to a solution of iPr2NH (0.58 mL, 4.13 mmol) in dry THF (10 mL)
at 08C. After stirring for 0.5 h, the mixture was cooled to 788C and
compound 15a (1.3 g, 3.44 mmol) in dry THF (5 mL) was added dropwise
to the solution. After stirring for another 2 h, HMPA (0.58 mL, 4.1 mmol)
and MeI (0.5 mL, 8.0 mmol) in dry THF (2 mL) were added dropwise to
the solution. The reaction mixture was stirred at 78 to 408C for 4 h and
then quenched with a saturated aqueous solution of NH4Cl, diluted with
water and extracted with Et2O. The combined organic layer was washed
with brine and dried over MgSO4. Solvents were removed under vacuum to
give crude product that was purified over silica gel (hexanes/EtOAc 49:1)
to give 16 (1.02 g, 76%) and 15a (0.17 g, 13%).
>98% ee) and the aldehyde 13 (5.29 g, 42%). For 10: [a]D
ˆ
34.38 (c ˆ
1.62, CHCl3); 1H NMR (600 MHz): d ˆ 6.89 (s, 1H; ArH), 6.55 (s, 1H;
ˆ
ArCH C), 4.58 (dd, J ˆ 9.3, 2.2 Hz, 1H; CHOH), 3.72 (brs, 1H; OH), 2.72
(dd, J ˆ 16.7, 9.4 Hz, 1H; CH2CO), 2.65 (s, 3H; ArCH3), 2.64 (dd, J ˆ 16.7,
ˆ
3.0 Hz, 1H; CH2CO), 2.18 (s, 3H; CH3CO), 1.98 (s, 3H; CH3C CH);
13C NMR (150.9 MHz): d ˆ 208.9, 164.7, 152.5, 140.5, 118.6, 115.7, 72.6, 48.7,
1
Physical data of 16: [a]D
ˆ
2.78 (c ˆ 1.15, CHCl3); H NMR (400 MHz):
‡
‡
30.9, 19.0, 14.7; MS: 226 [M‡H] , 248 [M‡Na] .
d ˆ 7.01 (d, J ˆ 7.7 Hz, 2H; ArH), 6.80 (d, J ˆ 7.7 Hz, 2H; ArH), 3.90 (dd,
J ˆ 6.5, 3.2 Hz, 1H; CHOTBS), 3.77 (s, 3H; OCH3), 2.97 (pentet, J ˆ
6.8 Hz, 1H; CH3CHCO), 2.82 (m, 1H; (CH3)2CHCO), 2.76 (dd, J ˆ 13.7,
4.0 Hz, 1H; ArCH2), 2.13 (dd, J ˆ 13.7, 10.6 Hz, 1H; ArCH2), 1.70 (m, 1H;
CHCH2Ar), 1.11 (d, J ˆ 7.0 Hz, 3H; CH3CHCO), 1.10 (d, J ˆ 7.0 Hz, 3H;
(CH3)2CH), 1.09 (d, J ˆ 6.8 Hz, 3H; (CH3)2CH), 0.92 (s, 9H; SiC(CH3)3),
0.81 (d, J ˆ 6.9 Hz, 3H; CH3CHCH2), 0.09 (s, 3H; Si(CH3)2), 0.05 (s, 3H;
Si(CH3)2); 13C NMR (100.6 MHz): d ˆ 217.2, 157.7, 133.4, 129.9, 113.7, 76.8,
55.2, 48.1, 40.7, 40.2, 36.9, 26.1, 18.8, 18.4, 18.2, 16.7, 14.5, 3.8, 4.1; MS:
Compound 11: In a similar manner as above (see compound 10 for the
detailed process and Supporting Information for HPLC system), (Æ)-11
(1.45 g, 6.0 mmol) and antibody 84G3 (45 mg, 0.0003 mmol) in PBS
(pH 7.4, 90 mL) and CH3CN (4 mL) were incubated for 96 h at 378C to
afford compound 11 (0.69 g, 48%, >98% ee) and aldehyde 14 (0.44 g,
40%). For 11: [a]D
7.07(s, 1H; ArH), 6.58 (s, 1H; ArCH C), 4.92 (s, 2H; CH2OH), 4.60 (m,
1H; CHOH), 3.32 (br, 1H; OH), 3.01 (br, 1H; OH), 2.73 (m, 2H; CH2CO),
2.22 (s, 3H; CH3CO), 2.03 (s, 3H; CH3C CH); 13C NMR (125.75 MHz,
ˆ
26.78 (c ˆ 0.9, CHCl3); 1H NMR (500 MHz): d ˆ
ˆ
ˆ
‡
‡
393 [M‡H] , 415 [M‡Na] .
CDCl3): d ˆ 209.2, 170.0, 152.8, 140.8, 118.5, 116.4, 72.6, 62.0, 48.6, 30.9,
Compounds 17a and 3-epi-17a: nBuLi (1.6m in hexane, 1.8 mL, 2.9 mmol)
was added dropwise to a solution of iPr2NH (0.45 mL, 3.2 mmol) in dry
THF (10 mL) at 08C. After stirring for 0.5 h, the mixture was cooled to
788C and compound 16 (1.02 g, 2.6 mmol) in dry THF (5 mL) was added
dropwise to the solution. After stirring for another 2 h at 78 to 408C,
‡
14.8; MS: 264 [M‡Na] .
Compounds 15 and 2-epi-15:
A heterogeneous mixture of 9 (2.2 g,
8.4 mmol) and Rh/Al2O3 (10% w/w, 440 mg) in THF (85 mL) was stirred
at room temperature under a H2 atmosphere using balloon for 18 h. The
solution was filtered through Celite, solvents were removed under vacuum
and the residue was chromatographed over silica gel (hexanes/EtOAc 3:1)
to give 15 (1.06 g, 48%) and 2-epi-15 (0.99 g, 45%).
the reaction mixture was recooled to
788C and a solution of
TBSOCH2CH2CHO (0.98 g, 5.2 mmol) in dry THF (2 mL) was added
dropwise. The reaction mixture was stirred at 788C for 0.5 h and then
quenched with a saturated aqueous solution of NH4Cl, and worked-up with
Et2O and water. The combined organic layer was washed with brine, dried
over MgSO4 and solvents were removed under vacuum to give the crude
Physical data of 15: m.p. 68 ± 708C; [a]D
ˆ
3.38 (c ˆ 1.00, CHCl3);
1H NMR (600 MHz): d ˆ 7.10 (d, J ˆ 8.3 Hz, 2H; ArH), 6.81 (d, J ˆ
8.3 Hz, 2H; ArH), 3.77 (s, 3H; OCH3), 3.63 (dd, J ˆ 9.0, 1.8 Hz, 1H;
1696
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0708-1696 $ 17.50+.50/0
Chem. Eur. J. 2001, 7, No. 8

Epothilone F
1691±1702
product. Purification over silica gel (hexanes/EtOAc 49:1) gave the aldol
product (diastereomeric ratio 1.6:1 in favor of the desired compound
1.54 g), which was contaminated with a small amount of small inseparable
impurities. This product was taken to the next step without further
0.08/0.07/0.05 (4s, 12H; Si(CH3)2), 0.02 (s, 6H; Si(CH3)2); MS: 655
[M‡Na] .
‡
Ester 18b: A freshly distilled solution of CH2N2 (prepared from 10 mmol
Diazald in ether/ethanol, 25 mL) was added to a cold (08C) solution of the
crude acid 18a (1.21 g) in Et2O (10 mL) and the mixture was allowed to
warm to room temperature overnight. Solvents were removed and the
residue was purified over silica gel (hexanes/EtOAc 9:1) to afford pure
1
purification. H NMR (400 MHz): d ˆ 7.02 (d, J ˆ 8.6 Hz, 2H; ArH), 6.79/
6.78 (d, J ˆ 8.6 Hz; d, J ˆ 8.5 Hz, together 2H; ArH), 4.06 ± 3.75 (m, 4H;
TBSOCH2, CHOH, CH(OTBS)), 3.77/3.76 (2s, together 3H; OCH3), 3.54/
3.45 (2brs, together 1H; OH), 3.26 (m, 1H; CH3CHCO), 2.79 (dd, J ˆ 13.8,
3.8 Hz, 1H; ArCH2), 2.25/2.24 (2dd, J ˆ 13.8, 11.2 Hz each, together 1H;
ArCH2), 1.73 (m, 1H; CH3CHCH2), 1.56 (m, 2H; TBSOCH2CH2), 1.21/1.20
(2s, together 3H; (CH3)2C), 1.16/1.13 (2s, together 3H; (CH3)2C), 1.11/1.09
(2d, J ˆ 7.0 Hz each, together 3H; CH3CHCO), 0.94 (s, 9H; SiC(CH3)3),
0.88/0.87 (2s, together 9H; SiC(CH3)3), 0.80/0.79 (2d, J ˆ 7.2 Hz each,
together 3H; CH3CHCH2), 0.10/0.09/0.07/0.05 (4s, together 12H;
Si(CH3)2); 13C NMR (100.6 MHz): d ˆ 219.9, 157.6, 133.4, 129.9, 113.6,
77.4, 76.4/75.6, 63.0/62.6, 55.2, 52.3/52.1, 45.1/45.0, 40.5/40.2, 36.0/35.8, 35.6/
33.3, 31.6, 26.3, 25.9, 22.2/22.0, 19.9/19.7, 18.6/18.2, 17.5/17.4, 16.1, 15.9, 14.1,
1
ester 18b (1.08 g, 53%, two steps). H NMR (600 MHz): d ˆ 3.89 (dd, J ˆ
7.8, 2.6 Hz, 1H; CH2CHOTBS), 3.81 (dd, J ˆ 7.8, 1.8 Hz, 1H;
CHCHOTBS), 3.66 (m, 1H; TBSOCH2), 3.64 (s, 3H; CO2CH3), 3.58 (m,
1H; TBSOCH2), 3.08 (m, 1H; CHCO), 2.45 (dd, J ˆ 15.6, 3.2 Hz, 1H;
CH2CO2), 2.11 (dd, J ˆ 15.6, 10.6 Hz, 1H; CH2CO2), 1.85 (m, 1H;
CHCH2CO2), 1.55 (m, 1H; TBSOCH2CH2), 1.50 (m, 1H; TBSOCH2CH2),
1.22 (s, 3H; (CH3)2C), 1.06 (s, 3H; (CH3)2C), 1.05 (d, J ˆ 6.7 Hz, 3H;
CH3CHCO), 0.96 (d, J ˆ 6.8 Hz, 3H; CH3CHCH2), 0.90/0.89/0.87 (3s, 27H;
SiC(CH3)3), 0.08/0.076/0.068/0.055 (4s, 12H; Si(CH3)2), 0.021/0.019 (2s,
6H; Si(CH3)2); 13C NMR (150.9 MHz): d ˆ 218.1, 173.9, 73.8, 60.9, 53.7,
51.4, 46.0, 38.1, 35.7, 35.5, 26.2, 26.1, 25.9, 24.4, 19.1, 18.9, 18.5, 18.3, 18.2,
‡
3.5, 3.7, 3.8, 5.5; MS: 581 [M‡H] .
‡
Compounds 17b and 3-epi-17b: TBSOTf (0.76 mL, 3.3 mmol) was added
dropwise to a solution of the above-mentioned mixture of aldol products
17a and 3-epi-17a (1.54 g, 2.66 mmol) and lutidine (0.45 mL, 3.84 mmol) in
dry CH2Cl2 (10 mL) at 788C and stirred at 78 ! 08C for 4 h. The
reaction mixture was quenched with a saturated aqueous NaHCO3, diluted
with water and extracted with CH2Cl2. The organic layer was washed with
water and dried over anhydrous MgSO4. Solvents were removed and the
residue was chromatographed over silica gel (hexanes/EtOAc 49:1) to give
17b (1.02 g, 56%) and 3-epi-17b (0.64 g, 35%) in two steps.
15.4, 2.74, 3.77, 3.99, 5.28, 5.31; MS (ESI): 669 [M‡Na] , 681
[M‡Cl] .
Alcohol 18c: A solution of DIBAL-H (1.0m in toluene, 5 mL, 5 mmol) was
added to a solution of compound 18b (1.08 g, 1.67 mmol) in dry THF
(20 mL) and the reaction was stirred at 78 to 558C for 1 h. The reaction
mixture was quenched by careful addition of a saturated aqueous NH4Cl
and diluted with Et2O. Celite was added and the mixture was stirred at 08C
until all solid material precipitated out (ca. 0.5 h). Inorganic material was
filtered off, solvents were removed, and the residue was purified over silica
gel (hexanes/EtOAc 6:1) to afford pure alcohol 18c (820 mg, 79%).
1H NMR (600 MHz): d ˆ 3.92 (dd, J ˆ 7.6, 2.7 Hz, 1H; CH2CHOTBS), 3.85
(dd, J ˆ 7.6, 1.9 Hz, 1H; CHCHOTBS), 3.71 (m, 1H; CH2OH), 3.68 (m,
1H; CH2OH), 3.59 (m, 2H; TBSOCH2), 3.18 (m, 1H; CHCO), 1.70 (m,
1H; CH3CHCH2), 1.60 (m, 2H; CH2), 1.50 (m, 2H; CH2), 1.22 (s, 3H;
(CH3)2C), 1.06 (d, J ˆ 7.0 Hz, 3H; CH3CHCO), 1.05 (s, 3H; (CH3)2C), 0.95
(d, J ˆ 6.8 Hz, 3H; CH3CHCH2), 0.91/0.89/0.88 (3s, 27H; SiC(CH3)3),
0.092/0.089/0.082/0.05/0.026/0.023 (6s, 18H; Si(CH3)2); 13C NMR
(150.9 MHz): d ˆ 218.5, 77.9, 73.7, 61.1, 60.7, 53.8, 45.6, 38.1, 35.0, 33.7,
26.2, 26.1, 25.9, 24.8, 22.6, 18.9, 18.5, 18.3, 15.6, 3.63, 3.72, 3.93, 5.28;
Physical data of 17b: 1H NMR (400 MHz): d ˆ 7.03 (d, J ˆ 8.6 Hz, 2H;
ArH), 6.80 (d, J ˆ 8.6 Hz, 2H; ArH), 4.13 (t, J ˆ 5.2 Hz, 1H;
CH2CHOTBS), 3.92 (dd, J ˆ 6.3, 2.4 Hz, 1H; CHCHOTBS), 3.77 (s, 3H;
OCH3), 3.66 (m, 2H; TBSOCH2), 3.17 (m, 1H; CH3CHCO), 2.80 (dd, J ˆ
13.8, 3.7 Hz, 1H; ArCH2), 2.25 (dd, J ˆ 13.7, 11.0 Hz, 1H; ArCH2), 1.69 (m,
1H; CH3CHCH2), 1.52 (m, 2H; TBSOCH2CH2), 1.20 (s, 3H; (CH3)2C),
1.09 (d, J ˆ 7.0 Hz, 3H; CH3CHCO), 1.08 (s, 3H; (CH3)2C), 0.95/0.89/0.87
(3s, 27H; SiC(CH3)3), 0.82 (d, J ˆ 6.8 Hz, 3H; CH3CHCH2), 0.11/0.04/0.02/
0.01 (4s, 12H; Si(CH3)2), 0.10 (s, 6H; Si(CH3)2); 13C NMR (100.6 MHz):
d ˆ 217.5, 157.7, 133.3, 129.9, 113.6, 77.1, 72.2, 60.4, 55.2, 54.1, 45.0, 40.7, 37.6,
36.2, 26.3, 26.2, 25.9, 23.0, 19.2, 18.7, 18.4, 18.2, 17.4, 15.5, 3.5, 3.6, 3.8,
‡
‡
MS: 619 [M‡H] , 641 [M‡Na] .
‡
4.0, 5.3; MS: 717 [M‡Na] .
Synthesis of compounds 19 and 20: Dess ± Martin reagent (581 mg,
1.37 mmol) was added to a solution of alcohol 18c (410 mg, 0.66 mmol)
in CH2Cl2 (10 mL) at room temperature and the mixture was stirred for 2 h.
The reaction was diluted with Et2O (20 mL) and quenched with a saturated
aqueous NaHCO3 (5 mL) and a 10% aqueous solution of Na2S2O5 (5 mL),
stirred for 10 min and then extracted with Et2O. The combined Et2O layer
was washed with brine and dried over anhydrous MgSO4. Solvents were
evaporated under vacuum and the residue was passed through a small bed
of silica gel (hexanes/EtOAc 10:1) to afford the corresponding aldehyde
(390 mg, 95%), which was used in the next step to synthesize compounds 19
and 20 immediately.
Physical data of 3-epi-17b: 1H NMR (400 MHz): d ˆ 7.03 (d, J ˆ 8.6 Hz,
2H; ArH), 6.81 (d, J ˆ 8.6 Hz, 2H; ArH), 3.93 (dd, J ˆ 7.6, 2.6 Hz, 1H;
CH2CHOTBS), 3.90 (dd, J ˆ 6.5, 2.4 Hz, 1H; CHCHOTBS), 3.77 (s, 3H;
OCH3), 3.68 (m, 1H; TBSOCH2), 3.59 (m, 1H; TBSOCH2), 3.23 (m, 1H;
CH3CHCO), 2.82 (dd, J ˆ 13.8, 3.7 Hz, 1H; ArCH2), 2.26 (dd, J ˆ 13.8,
11.1 Hz, 1H; ArCH2), 1.70 (m, 1H; CH3CHCH2), 1.60 (m, 1H;
TBSOCH2CH2), 1.52 (m, 1H; TBSOCH2CH2), 1.26 (s, 3H; (CH3)2C),
1.10 (s, 3H; (CH3)2C), 1.09 (d, J ˆ 6.6 Hz, 3H; CH3CHCO), 0.96/0.91/0.89
(3s, 27H; SiC(CH3)3), 0.81 (d, J ˆ 6.9 Hz, 3H; CH3CHCH2), 0.10 (2s,
together 9H; Si(CH3)2), 0.08 (s, 3H; Si(CH3)2), 0.02 (2s, together 6H;
Si(CH3)2); 13C NMR (100.6 MHz): d ˆ 218.0, 157.7, 133.3, 129.9, 113.6, 77.2,
74.0, 60.9, 55.2, 53.6, 45.5, 40.5, 38.1, 36.1, 26.3, 26.1, 26.0, 24.8, 19.4, 18.6,
Compound 19: (EtO)2P(O)CH2CO2Et (0.2 mL, 1.0 mmol) was added
dropwise to a mixture of NaH (40 mg, 1.0 mmol) in dry THF (2.0 mL) at
08C. After 10 min, a solution of the above-mentioned aldehyde (89 mg,
0.14 mmol) in THF (0.5 mL) was added and the reaction mixture was
stirred at the same temperature for 0.5 h. The reaction was then quenched
with a saturated aqueous solution of NH4Cl, diluted with water and
extracted with Et2O. The combined organic layer was washed with brine,
dried over anhydrous MgSO4 and concentrated under vacuum. The
resultant residue was purified by column chromatography over silica gel
(hexanes/EtOAc 15:1) to afford pure ester 19 (93 mg, 94%). 1H NMR
‡
18.3, 18.2, 17.4, 15.0, 3.5, 3.6, 3.8, 4.0, 5.2, 5.3; MS: 695 [M‡H] .
Acid 18a: RuCl3 ´ H2O (69 mg, 0.31 mmol) was added to a heterogeneous
mixture of compound 17b (2.2 g, 3.2 mmol) and NaIO4 (13.52 g,
63.2 mmol) in CCl4 (21 mL), CH3CN (21 mL) and phosphate buffer
(0.25m, pH 7.4, 21 mL) at room temperature and stirred for 16 h. The
reaction mixture was diluted with water and EtOAc and filtered over
Celite. The organic layer was separated and the aqueous layer was
extracted with EtOAc. The combined organic layer was washed with brine
and dried over MgSO4. Solvents were removed under vacuum and the
resultant residue was purified by chromatography over silica gel (hexanes/
EtOAc 4:1) to afford acid 18a (1.21 g) with trace of impurities, which was
taken to the next step without further purification. 1H NMR (400 MHz):
d ˆ 3.88 (dd, J ˆ 7.6, 2.8 Hz, 1H; CH2CHOTBS), 3.81 (dd, J ˆ 7.9, 1.8 Hz,
1H; CHCHOTBS), 3.66 (m, 1H; TBSOCH2), 3.58 (m, 1H; TBSOCH2),
3.09 (m, 1H; CH3CHCO), 2.48 (dd, J ˆ 15.7, 3.3 Hz, 1H; CH2CO2H), 2.13
(dd, J ˆ 15.7, 10.4 Hz, 1H; CH2CO2H), 1.87 (m, 1H; CHCH2CO2H), 1.56
(m, 1H; TBSOCH2CH2), 1.48 (m, 1H; TBSOCH2CH2), 1.21 (s, 3H;
(CH3)2C), 1.06 (d, J ˆ 6.8 Hz, 3H; CH3CHCO), 1.04 (s, 3H; (CH3)2C), 1.00
(d, J ˆ 6.8 Hz, 3H; CH3CHCH2), 0.90/0.88/0.87 (3s, 27H; SiC(CH3)3), 0.09/
ˆ
(600 MHz): d ˆ 6.88 (ddd, J ˆ 15.2, 8.5, 6.4 Hz, 1H; CH CHCO2), 5.80 (d,
ˆ
J ˆ 15.2 Hz, 1H; CH CHCO2), 4.17 (q, J ˆ 7.1 Hz, 2 H ; CO2CH2CH3), 3.89
(dd, J ˆ 7.5, 2.7 Hz, 1H; CH2CHOTBS), 3.81 (dd, J ˆ 7.5, 2.0 Hz, 1H;
CHCHOTBS), 3.67 (m, 1H; TBSOCH2), 3.57 (m, 1H; TBSOCH2), 3.13
ˆ
(m, 1H; CHCO), 2.35 (m, 1H; CH2CH CH), 2.01 (dt, J ˆ 14.5, 9.7 Hz, 1H;
ˆ
CH2CH CH), 1.70 ± 1.40 (m, 3H; CH2, CH), 1.27 (t, J ˆ 7.1 Hz, 3H;
CO2CH2CH3), 1.21 (s, 3H; (CH3)2C), 1.06 (d, J ˆ 6.8 Hz, 3H; CH3CHCO),
1.03 (s, 3H; (CH3)2C), 0.92 (d, J ˆ 6.9 Hz, 3H; CH3CHCH2), 0.91/0.89/0.87
(3s, 27H; SiC(CH3)3), 0.09 (s, 3H; Si(CH3)2), 0.07/0.02 (2s, 12H; Si(CH3)2),
0.06 (s, 3H; Si(CH3)2); 13C NMR (150.9 MHz): d ˆ 218.0, 166.5, 148.4,
122.6, 77.6, 73.9, 60.9, 60.2, 53.7, 45.8, 38.1, 37.5, 33.7, 31.6, 26.2, 26.1, 25.9,
Chem. Eur. J. 2001, 7, No. 8
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0708-1697 $ 17.50+.50/0
1697

S. C. Sinha, R. A. Lerner et al.
FULL PAPER
24.4, 22.6, 19.4, 18.6, 18.3, 15.5, 14.2, 14.1, 3.5, 3.6, 3.7, 4.0, 5.3;
MS: 709 [M‡Na] .
over silica gel (hexanes/EtOAc 10:1) and was taken to the next step
immediately.
‡
BuLi (1.6m in hexane, 1.5 mL, 2.4 mmol) was added to a heterogeneous
solution of MePPh3I (1.01 g, 2.5 mmol) in dry THF (15 mL) at 08C. After
stirring for 0.5 h, a solution of the above-mentioned aldehyde (350 mg,
0.54 mmol) in dry THF (5 mL) was added to the reaction mixture. After
stirring for an additional 0.5 h, the reaction mixture was quenched with a
saturated aqueous NH4Cl and extracted with Et2O. The combined organic
layer was washed with brine, dried over anhydrous MgSO4, and solvents
were removed. The resulting residue was purified over silica gel (hexanes/
EtOAc 9:1) to afford the known olefin 23 (310 mg, 89%). Physical and
spectral data of compound 23 were identical to the reported data.[12c]
Compound 20: A solution of the aldehyde (37 mg, 0.063 mmol), obtained
from the oxidation of alcohol 18c, and MeC(O)CHPPh3 (20 mg,
0.063 mmol) in dry benzene (1 mL), was refluxed for 4 h. Solvents were
removed under vacuum and the residue was purified over silica gel
(hexanes/EtOAc 15:1) to afford ketone 20 (38 mg, 93%). 1H NMR
ˆ
(500 MHz): d ˆ 6.71 (ddd, J ˆ 15.8, 8.5, 6.6 Hz, 1H; CH CHCO), 6.06 (d,
ˆ
J ˆ 15.8 Hz, 1H; CH CHCO), 3.89 (dd, J ˆ 7.8, 2.9 Hz, 1H;
CH2CHOTBS), 3.82 (dd, J ˆ 7.4, 1.9 Hz, 1H; CHCHOTBS), 3.65 (td, J ˆ
9.9, 4.8 Hz, 1H; TBSOCH2), 3.57 (dt, J ˆ 9.9, 7.7 Hz, 1H; TBSOCH2), 3.13
ˆ
(m, 1H; CHCO), 2.37 (m, 1H; CH2CH CH), 2.22 (s, 3H; CH3CO), 2.03
ˆ
(m, 1H; CH2CH CH), 1.64 ± 1.45 (m, 3H; CH2, CH), 1.21 (s, 3H;
Alkene 24: nBuLi (1.6m in hexane, 54 mL, 86 mmol) was added to a
heterogeneous solution of MePPh3I (38 mg, 0.091 mmol) in dry THF
(0.1 mL) at 08C. After stirring for 0.5 h, a solution of ketone 22 (30 mg,
46 mmol) in dry THF (0.1 mL) was added to the reaction mixture. After
stirring for an additional 20 min at room temperature, the reaction mixture
was worked up as above (see synthesis of 23) to afford known olefin 24
(28 mg, 92%) after purification over silica gel (hexanes/EtOAc 15:1).
Physical and spectral data of compound 24 were identical to the reported
data.[12d]
(CH3)2C), 1.06 (d, J ˆ 6.6 Hz, 3H; CH3CHCO), 1.01 (s, 3H; (CH3)2C),
0.94 (d, J ˆ 6.3 Hz, 3H; CH3CHCH2), 0.91 (s, 9H; SiC(CH3)3), 0.89 (s, 9H;
SiC(CH3)3), 0.87 (s, 9H; SiC(CH3)3), 0.083/0.075/0.072/0.051/0.02/0.018 (6s,
18H; Si(CH3)2); 13C NMR (125.75 MHz): d ˆ 217.9, 198.3, 147.4, 132.5, 77.6,
73.9, 60.9, 53.7, 45.8, 38.1, 37.7, 34.0, 27.0, 26.2, 26.1, 25.9, 24.3, 19.6, 18.5, 18.3,
‡
‡
15.5, 3.5, 3.6, 3.7, 4.0, 5.2, 5.3; MS: 657 [M‡H] , 679 [M‡Na] ,
691 [M‡Cl] .
Compound 21: A mixture of 19 (411 mg, 0.6 mmol) and Rh/Al2O3 (10%
w/w, 80 mg) in THF (10 mL) was stirred under H2 atmosphere (using
balloon) for 16 h. The reaction mixture was filtered over Celite to afford
Conversion of compounds 23 and 24 to acids 25 and 26: For selective
deprotection and subsequent oxidation of compounds 23 and 24 to acids 25
and 26, see references [12c] and [12d]; physical and spectral data of the
produced compounds were identical to the values reported in latter
references.
1
pure 21 (400 mg, 97%). H NMR (400 MHz): d ˆ 4.10 (q, J ˆ 7.6 Hz, 2H;
CO2CH2CH3), 3.88 (dd, J ˆ 7.6, 2.8 Hz, 1H; CH2CHOTBS), 3.76 (dd, J ˆ
7.2, 2.2 Hz, 1H; CHCHOTBS), 3.65 (td, J ˆ 9.8, 5.1 Hz, 1H; TBSOCH2),
3.56 (dt, J ˆ 9.8, 7.5 Hz, 1H; TBSOCH2), 3.10 (m, 1H; CHCO), 2.26 (m,
2H; CH2CO), 1.69 (m, 1H), 1.68 ± 1.39 (m, 5H), 1.24 (t, J ˆ 7.2 Hz, 3H;
CO2CH2CH3), 1.21 (m, 1H), 1.21 (s, 3H; (CH3)2C), 1.03 (d, J ˆ 6.8 Hz, 3H;
CH3CHCO), 1.01 (s, 3H; (CH3)2C), 0.92 (d, J ˆ 6.8 Hz, 3H; CH3CHCH2),
0.88 (s, 18H; SiC(CH3)3), 0.86 (s, 9H; SiC(CH3)3), 0.07 (s, 3H; Si(CH3)2),
0.05 (s, 3H; Si(CH3)2), 0.04/0.01 (2s, 12H; Si(CH3)2); 13C NMR
(100.6 MHz): d ˆ 218.2, 173.6, 77.6, 73.8, 61.0, 60.2, 53.7, 45.2, 38.5, 38.1,
34.9, 30.3, 26.2, 26.1, 25.9, 24.5, 23.2, 19.2, 18.5, 18.3, 17.6, 15.3, 14.2, 3.6,
Compounds 10a and 11a: TBSCl (402 mg, 2.66 mmol) was added to a
solution of compound 10 (300 mg, 1.33 mmol) and imidazole (271 mg,
3.99 mmol) in dry DMF (1 mL) and stirred at room temperature for 8 h.
The reaction mixture was diluted with Et2O and water. The organic layer
was separated and the aqueous layer was extracted with Et2O. The
combined ether layer was washed with brine and dried over anhydrous
MgSO4. Solvents were removed under vacuum and the residue was purified
over silica gel (hexanes/EtOAc 10:1) to afford pure silyl ether 10a (400 mg,
‡
3.7, 3.8, 4.0, 5.3; MS: 711 [M‡Na] .
89%). [a]D
ˆ
33.78 (c ˆ 1.18, CHCl3); 1H NMR (500 MHz): d ˆ 6.90 (s,
ˆ
1H; ArH), 6.50 (s, 1H; ArCH C), 4.62 (dd, J ˆ 9.0, 3.6 Hz, 1H;
CHOTBS), 2.79 (dd, J ˆ 14.8, 9.2 Hz, 1H; CH2CO), 2.68 (s, 3H; ArCH3),
2.42 (dd, J ˆ 14.8, 3.6 Hz, 1H; CH2CO), 2.16 (s, 3H; COCH3), 2.00 (s, 3H;
Compound 22: In a similar manner as above, a mixture of 20 (35.0 mg,
0.053 mmol), Rh/Al2O3 (10% w/w, 20 mg) in THF (2 mL) was stirred under
H2 atmosphere (using balloon) for 1 h and filtered over Celite to afford
pure 22 (33 mg, 95%). 1H NMR (500 MHz): d ˆ 3.88 (dd, J ˆ 7.7, 2.6 Hz,
1H; CH2CHOTBS), 3.76 (dd, J ˆ 7.0, 2.2 Hz, 1H; CHCHOTBS), 3.65 (td,
J ˆ 9.5, 4.8 Hz, 1H; TBSOCH2), 3.56 (dt, J ˆ 9.5, 8.1 Hz, 1H; TBSOCH2),
3.11 (m, 1H; CHCO), 2.39 (t, J ˆ 6.6 Hz, 2H; CH2CO), 2.11 (s, 3H;
CH3CO), 1.67 ± 1.58 (m, 1H), 1.57 ± 1.50 (m, 1H), 1.49 ± 1.42 (m, 1H), 1.40 ±
1.31 (m, 3H), 1.21 (s, 3H; (CH3)2C), 1.08 (m, 1H), 1.02 (d, J ˆ 7.0 Hz, 3H;
CH3CHCO), 1.01 (s, 3H; (CH3)2C), 0.91 (d, J ˆ 6.6 Hz, 3H; CH3CHCH2),
0.88 (s, 18H; SiC(CH3)3), 0.85 (s, 9H; SiC(CH3)3), 0.09 (s, 3H; Si(CH3)2),
0.06 (s, 6H; Si(CH3)2), 0.04 (s, 3H; Si(CH3)2), 0.01 (s, 6H; Si(CH3)2);
13C NMR (125.75 MHz): d ˆ 218.2, 208.8, 77.7, 73.9, 61.0, 53.7, 45.2, 44.2,
38.7, 38.1, 30.9, 30.4, 29.9, 26.2, 26.1, 25.9, 26.0, 24.5, 22.0, 19.2, 18.5, 18.3,
ˆ
CH3C CH), 0.84 (s, 9H; SiC(CH3)3), 0.03 (s, 3H; Si(CH3)2), 0.01 (s, 3H;
Si(CH3)2); 13C NMR (125.75 MHz): d ˆ 207.3, 164.5, 152.8, 141.1, 119.0,
115.6, 75.2, 50.4, 31.8, 25.7, 25.6, 19.2, 18.0, 14.0, 4.7, 5.4; MS: 340
‡
‡
[M‡H] , 362 [M‡Na] .
In a similar manner, compound 11 (500 mg, 2.07 mmol) was treated with
TBSCl (773 mg, 4.97 mmol) and imidazole (862 mg, 12.42 mmol) in dry
DMF (2 mL) at room temperature for 8 h to afford 11a (874 mg, 90%)
after purification over silica gel (hexanes/EtOAc 20:1). [a]D
ˆ
26.58 (c ˆ
1.70, CHCl3); 1H NMR (400 MHz): d ˆ 7.00 (s, 1H; ArH), 6.50 (s, 1H;
ˆ
ArCH C), 4.93 (s, 2H; CH2OTBS), 4.63 (dd, J ˆ 9.0, 3.1 Hz, 1H;
CHOTBS), 2.80 (dd, J ˆ 14.6, 9.0 Hz, 1H; CH2CO), 2.43 (dd, J ˆ 14.6,
3.6 Hz, 1H; CH2CO), 2.16 (s, 3H; COCH3), 2.00 (d, J ˆ 1.2 Hz, 3H;
‡
17.6, 15.3, 1.0, 3.6, 3.7, 3.9, 5.2, 5.3; MS: 659 [M‡H] , 681
‡
‡
[M‡Na] , 693 [M‡Cl] .
ˆ
CH3C CH), 0.93 (s, 9H; SiC(CH3)3), 0.84 (s, 9H; Si(CH3)2), 0.11 (s, 6H;
Si(CH3)2), 0.03 (s, 3H; Si(CH3)2), 0.01 (s, 3H; Si(CH3)2); 13C NMR
Alkene 23: Compound 21 (400 mg, 0.58 mmol) was reduced with DIBAL-
H (1m in toluene, 1.7 mL, 1.7 mmol) at 788C (for details, see preparation
of 18c) to afford the corresponding alcohol (355 mg, 95%) after
purification over silica gel (hexanes/EtOAc 7:1). 1H NMR (600 MHz):
d ˆ 3.88 (dd, J ˆ 7.6, 2.6 Hz, 1H; CH2CHOTBS), 3.77 (dd, J ˆ 6.9, 2.0 Hz,
1H; CHCHOTBS), 3.67 (td, J ˆ 9.7, 4.8 Hz, 1H; TBSOCH2), 3.63 (t, J ˆ
6.6 Hz, 2H; CH2OH), 3.58 (dt, J ˆ 9.7, 7.8 Hz, 1H; TBSOCH2), 3.13 (m,
1H; CHCO), 1.75 ± 1.15 (m, 9H), 1.22 (s, 3H; (CH3)2C), 1.04 (d, J ˆ 6.8 Hz,
3H; CH3CHCO), 1.02 (s, 3H; (CH3)2C), 0.91 (d, J ˆ 7.0 Hz, 3H;
CH3CHCH2), 0.90 (s, 9H; SiC(CH3)3), 0.89 (s, 9H; SiC(CH3)3), 0.87 (s,
9H; SiC(CH3)3), 0.08/0.06 (2s, 6H; Si(CH3)2), 0.05/0.02 (2s, 12H;
Si(CH3)2); 13C NMR (150.9 MHz): d ˆ 218.3, 77.4, 73.9, 62.9, 61.0, 53.7,
45.0, 38.9, 38.1, 33.3, 31.6, 30.7, 26.2, 26.1, 25.9, 24.5, 23.9, 22.6, 19.3, 18.5,
18.3, 17.5, 15.3, 14.1, 3.68, 3.71, 3.79, 3.99, 5.26, 5.29; MS: 779
(100.6 MHz): d ˆ 207.3, 172.0, 153.1, 141.1, 119.1, 115.8, 75.2, 63.2, 50.4, 31.8,
‡
25.7, 18.2, 18.1, 14.0, 4.7, 5.3, 5.5; MS: 470 [M‡H] .
Keto alcohol 27: TMSOTf (1.07 mL, 5.9 mmol) was added to a solution of
compound 10a (1.0 g, 2.95 mmol) and lutidine (1.37 mL, 11.8 mmol) in dry
CH2Cl2 (15 mL) at 788C. The reaction mixture was stirred at 78 to 08C
for 4 h and then diluted with CH2Cl2 and washed with a saturated aqueous
solution of NaHCO3. The organic layer was separated and the aqueous
layer was extracted with CH2Cl2. The combined CH2Cl2 layer was washed
with water, dried over anhydrous MgSO4, and evaporated to give the
corresponding silyl enol ether derivative (1.1 g), which was taken to the
next step without purification.
OsO4 (0.2m in toluene, 0.5 mL, 0.1 mmol) and NMO (50% aqueous,
1.57 mL, 7.6 mmol) was added sequentially to a solution of the above-
mentioned silyl enol ether (1.1 g) in CH2Cl2 (15 mL) and the mixture was
stirred at room temperature for 5 h. After the reaction was complete, as
judged by TLC, a solution of Na2S2O5 (10% aqueous, 10 mL) was added
and stirred for 10 min, and then extracted with CH2Cl2. The combined
organic layer was washed with brine and dried over anhydrous MgSO4.
‡
[M‡Cs] .
The above-mentioned alcohol (355 mg, 0.55 mmol) was oxidized with
Dess ± Martin reagent (466 mg, 1.1 mmol) in CH2Cl2 (5 mL) at room
temperature (for details, see oxidation of 18c in the preparation of 19). The
corresponding aldehyde (350 mg, 99%) was obtained after purification
1698
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0708-1698 $ 17.50+.50/0
Chem. Eur. J. 2001, 7, No. 8

Epothilone F
1691±1702
Solvents were removed under vacuum and the resultant residue was
purified by column chromatography (silica gel, hexanes/EtOAc 4:1) to
afford pure keto alcohol 27 (684 mg, 68% from 10a). Physical data of 27:
[a]D
ˆ
0.368 (c ˆ 1.11, CHCl3); 1H NMR (500 MHz): d ˆ 9.77 (t, J ˆ
ˆ
2.6 Hz, 1H; CHO), 7.03 (s, 1H; ArH), 6.54 (s, 1H; ArCH C), 4.94 (s,
2H; CH2OTBS), 4.67 (dd, J ˆ 8.4, 4.1 Hz, 1H; CHOTBS), 2.72 (ddd, J ˆ
15.8, 8.4, 2.9 Hz, 1H; CH2CHO), 2.50 (ddd, J ˆ 15.4, 4.1, 2.2 Hz, 1H;
[a]D
ˆ
52.88 (c ˆ 1.52, CHCl3); 1H NMR (400 MHz): d ˆ 6.92 (s, 1H;
ˆ
ˆ
ArH), 6.52 (s, 1H; ArCH C), 4.64 (dd, J ˆ 9.3, 3.4 Hz, 1H; CHOTBS), 4.25
(ABqd, DnÄ ˆ 12.9 Hz, J ˆ 19.2 Hz, 2H; CH2OH), 3.14 (t, J ˆ 4.8 Hz, 1H;
OH), 2.78 (dd, J ˆ 13.8, 9.3 Hz, 1H; CH2CO), 2.69 (s, 3H; ArCH3), 2.43
CH2CHO), 2.03 (d, J ˆ 1.1 Hz, 3H; CH3C CH), 0.94 (s, 9H; SiC(CH3)3),
0.87 (s, 9H; SiC(CH3)3), 0.12 (s, 6H; Si(CH3)2), 0.07/0.02 (2s, 6H;
Si(CH3)2); 13C NMR (125.75 MHz): d ˆ 201.4, 172.1, 152.9, 140.4, 119.4,
‡
ˆ
(dd, J ˆ 13.8, 3.3 Hz, 1H; CH2CO), 2.03 (s, 3H; CH3C CH), 0.84 (s, 9H;
116.0, 73.9, 63.2, 50.1, 25.7, 14.1, 4.6, 5.2, 5.5; MS: 456 [M‡H] .
SiC(CH3)3), 0.01 (s, 3H; Si(CH3)2), 0.01 (s, 3H; Si(CH3)2); 13C NMR
Compound 29b: nBuLi (1.6m in hexane, 0.6 mL, 0.96 mmol) was added to a
heterogeneous solution of MePPh3I (404 mg, 1 mmol) in dry THF (5 mL)
at 08C. After stirring for 0.5 h, a solution of aldehyde 29a (170 mg,
0.52 mmol) in dry THF (2 mL) was added to the reaction mixture. After the
reaction mixture was stirred for an additional 0.5 h, it was quenched with a
saturated aqueous solution of NH4Cl and extracted with Et2O. The organic
layer was washed with brine and dried over anhydrous MgSO4. Solvents
were removed under vacuum and the resultant residue was purified over
silica gel (hexanes/EtOAc 9:1) to afford olefin 29b (152 mg, 90%). The
physical and spectral data of compound 29b were identical to the reported
data (see refs. [10d] and [12c]).
(100.6 MHz): d ˆ 208.4, 164.7, 152.6, 140.4, 119.4, 116.0, 75.4, 70.0, 45.6, 25.7,
‡
‡
19.3, 18.0, 14.0, 4.8, 5.5; MS: 356 [M‡H] , 378 [M‡Na] .
Keto alcohol 28: In a similar manner as above, compound 11a (795 mg,
1.7 mmol) was treated with TMSOTf (0.62 mL, 3.4 mmol) and lutidine
(0.79 mL, 6.8 mmol) in dry CH2Cl2 (10 mL) at 78 to 08C for 4 h to afford
the corresponding crude enol ether (1.0 g). The product was then treated
with OsO4 (0.2m in toluene, 0.37 mL, 0.074 mmol) and NMO (50%
aqueous, 0.92 mL, 4.4 mmol) in CH2Cl2 (10 mL) at room temperature for
5 h to afford pure compound 28 (691 mg, 84% from 11a) after purification
over silica gel (hexanes/EtOAc 6:1).
1
Compound 30b: In a similar manner as above, compound 30a (330 mg,
0.73 mmol) was treated with the Wittig reagent, prepared from MePPh3I
(590 mg, 1.46 mmol) and nBuLi (1.6m in hexane, 0.87 mL, 1.39 mmol) in
dry THF (5 mL), at 08C to afford compound 30b (300 mg, 91%) after
Physical data of 28: [a]D
ˆ
45.38 (c ˆ 0.8, CHCl3); H NMR (400 MHz):
ˆ
d ˆ 7.01 (s, 1H; ArH), 6.50 (s, 1H; ArCH C), 4.93 (s, 2H; CH2OTBS), 4.63
(dd, J ˆ 9.4, 3.0 Hz, 1H; CHOTBS), 4.24 (ABq, Dn ˆ 11.0, J ˆ 19.4 Hz, 2H;
CH2OH), 3.22 (brs, 1H; OH), 2.75 (dd, J ˆ 14.1, 9.4 Hz, 1H; CH2CO), 2.42
ˆ
purification over silica gel (hexanes/EtOAc 15:1). [a]D
ˆ
19.58 (c ˆ 1.08,
(dd, J ˆ 14.1, 3.2 Hz, 1H; CH2CO), 2.01 (s, 3H; CH3C CH), 0.92/0.83 (2s,
CHCl3); 1H NMR (500 MHz): d ˆ 7.01 (s, 1H; ArH), 6.44 (s, 1H;
18H; SiC(CH3)3), 0.11 (s, 6H; Si(CH3)2), 0.00 (s, 3H; Si(CH3)2), 0.03 (s,
3H; Si(CH3)2); 13C NMR (100.6 MHz): d ˆ 208.4, 172.1, 152.8, 140.3, 119.4,
116.1, 75.3, 69.9, 63.1, 45.5, 25.7, 18.2, 18.0, 13.9, 4.8, 5.5; MS: 508
ˆ
ˆ
ˆ
ArCH C), 5.77 (m, 1H; CH CH2), 5.00 (m, 2H; CH CH2), 4.95 (s, 2H;
CH2OTBS), 4.14 (t, J ˆ 6.3 Hz, 1H; CHOTBS), 2.30 (m, 2H;
‡
‡
ˆ
ˆ
CH2CH CH2), 1.99 (s, 3H; CH3C CH), 0.95/0.88 (2s, 18H; SiC(CH3)3),
0.12 (s, 6H; Si(CH3)2), 0.05/0.00 (2s, 6H; Si(CH3)2); 13C NMR
(125.75 MHz): d ˆ 172.3, 153.8, 142.4, 135.8, 119.3, 117.0, 115.7, 78.8, 63.7,
[M‡Na] , 524 [M‡K] , 520 [M‡Cl] .
Aldehyde 29a: NaBH4 (120 mg, 3.16 mmol) was added to a solution of 27
(561 mg, 1.58 mmol) in methanol (10 mL) at 08C. After the mixture was
stirred for 0.5 h, acetone (5 mL) was added and stirring was continued for
an additional 5 min. Saturated aqueous NH4Cl (1 mL) and ethyl acetate
(10 mL) were added sequentially. The mixture was filtered through Celite
and the filtrate was passed through a small silica gel column to afford the
corresponding diol (511 mg, 91%), which contained two diastereomers
(2.5:1, by 1H NMR analysis). 1H NMR (400 MHz): d ˆ 6.88/6.86 (2s,
‡
41.8, 26.2, 18.7, 14.4, 1.5, 4.2, 4.5, 5.0; MS: 454 [M‡H] .
Deprotection of 29b[35] and 30b: TBAF (1m in THF, 2.5 mL, 2.5 mmol) was
added to a solution of olefin 30b (290 mg, 0.64 mmol) in dry THF (3.0 mL)
at 08C. After the reaction mixture was stirred for 1 h at this temperature, it
was worked-up with ether and water. The combined organic layer was
washed with brine and dried over anhydrous MgSO4. Solvents were
removed under vacuum and the residue was purified over silica gel
(hexanes/EtOAc 1:1) to afford the corresponding diol (138 mg, 96%).
ˆ
together 1H; ArH), 6.51/6.45 (2s, together 1H; ArCH C), 4.40 (m, 1H;
CHOTBS), 3.86/3.77 (2m, together 1H; CHOH), 3.82/3.53 (2d, J ˆ 2.4,
2.6 Hz, together 1H), 3.53 (m, 1H), 3.43 (m, 1H), 3.36/3.25 (2m, together
1H), 2.65 (s, 3H; ArCH3), 1.95/1.93 (2d, J ˆ 0.9, 1.2 Hz, together 3H;
[a]D
ˆ
8.68 (c ˆ 1.49, CHCl3); 1H NMR (500 MHz): d ˆ 7.05 (s, 1H; ArH),
ˆ
ˆ
ˆ
6.52 (s, 1H; ArCH C), 5.80 (m, 1H; CH CH2), 5.11 (m, 2H; CH CH2),
4.89 (s, 2H; CH2OH), 4.18 (dd, J ˆ 7.4, 5.3 Hz, 1H; CHOH), 2.52 (brs, 1H;
ˆ
CH3C CH), 1.84 ± 1.54 (m, 2H; CH2CHOH), 0.86/0.85 (2s, together 9H;
OH), 2.45 ± 2.31 (m, 2H; CH2CH CH2), 1.99 (s, 3H; CH3C CH); 13C NMR
(150.9 MHz): d ˆ 170.0, 152.9, 142.1, 134.4, 118.7, 118.0, 116.1, 76.3, 61.9,
ˆ
ˆ
SiC(CH3)3), 0.064/0.056 (2s, together 3H; Si(CH3)2), 0.002, 0.02 (2s,
together 3H; Si(CH3)2); 13C NMR (100.6 MHz): d ˆ 164.6, 152.8, 152.4,
141.5, 119.4, 118.4, 115.3, 115.2, 78.1, 75.4, 70.5, 68.8, 66.8, 66.5, 38.9, 38.7,
25.7, 19.1, 19.0, 18.1, 17.9, 14.7, 13.5, 4.6, 4.8, 5.2, 5.3; MS: 380
‡
39.9, 14.4; MS: 226 [M‡H] .
TBSCl (115 mg, 0.74 mmol) was added to a solution of the above-
mentioned diol (138 mg, 0.61 mmol) and iPr2EtN (0.22 mL, 1.23 mmol) in
dry CH2Cl2 (5 mL) at 08C and the reaction mixture was stirred at 08C to
room temperature for 8 h. Work-up (CH2Cl2 and water) and purification
over silica gel (hexanes/EtOAc 3:1) afforded pure 30 (180 mg, 83%).
‡
[M‡Na] , 356 [M H] .
Lead(iv) acetate (500 mg, 1.13 mmol) was added to a solution of the above
mentioned diol (190 mg, 0.53 mmol) in CH2Cl2 (5 mL) at 08C. After the
reaction mixture was stirred for 0.5 h at this temperature, it was quenched
by addition of silica gel. The heterogeneous mixture was then loaded over a
silica gel column and eluted with hexane/EtOAc 4:1 to afford the known
aldehyde 29a (170 mg, 99%). Physical and spectral data of 29a were
identical to the reported data (see refs. [10d] and [12c]).
[a]D
ˆ
13.48 (c ˆ 0.37, CHCl3); 1H NMR (400 MHz): d ˆ 7.01 (s, 1H;
ˆ
ˆ
ArH), 6.52 (s, 1H; ArCH C), 5.81 (m, 1H; CH CH2), 5.11 (m, 2H;
ˆ
CH CH2), 4.93 (s, 2H; CH2OTBS), 4.18 (t, J ˆ 6.7 Hz, 1H; CHOH), 2.40
ˆ
ˆ
(m, 3H; CH2CH CH2, OH), 2.00 (s, 3H; CH3C CH), 0.93 (s, 9H;
SiC(CH3)3), 0.11 (s, 6H; Si(CH3)2); 13C NMR (100.6 MHz): d ˆ 172.1, 153.0,
141.4, 134.6, 119.0, 117.8, 115.6, 76.4, 63.2, 40.0, 25.7, 18.2, 5.5; MS: 340
Aldehyde 30a: In a similar manner as above, compound 28 (667 mg,
1.38 mmol) was treated with NaBH4 (120 mg, 3.16 mmol) in methanol
(10 mL) to provide the corresponding diol (620 mg, 92%) after purifica-
tion, which contained two diastereomers (2.5:1 by 1H NMR analysis).
1H NMR (400 MHz): d ˆ 7.00/6.98 (2s, together 1H; ArH), 6.52/6.46 (2s,
‡
‡
[M‡H] , 362 [M‡Na] .
Esterification of acids 25 and 26 with alcohols 29 and 30 to esters 31 ± 34[36]
Compound 33: EDC (38 mg, 0.2 mmol) was added to a solution of alcohol
30 (64 mg, 0.19 mmol), acid 25 (85 mg, 0.16 mmol) and DMAP (2 mg,
0.016 mmol) in dry CH2Cl2 (1 mL) at 08C. The reaction mixture was stirred
for 5 h at 08C to room temperature and the crude mixture was chromato-
graphed over a column of silica gel (hexanes/EtOAc 10:1) to afford pure
ester 33 (99 mg, 72% based on acid 25) and recovered alcohol 30 (9 mg).
ˆ
together 1H; ArCH C), 4.92 (s, 2H; CH2OTBS), 4.40 (m, 1H; CHOTBS),
3.80 (m, 1H), 3.73 (brs, 1H), 3.47 (m, 2H), 3.05 (brs, 1H; OH), 1.96/1.95
(2s, together 3H; CH3C CH), 1.80/1.61 (2m, together 2H; CH2CHOH),
ˆ
0.92 (s, 9H; SiC(CH3)3), 0.88/0.87 (2s, together 9H; SiC(CH3)3), 0.12 (s,
6H; Si(CH3)2), 0.08/0.07 (2s, together 3H; Si(CH3)2), 0.01/0.00 (2s,
together 3H; Si(CH3)2); 13C NMR (100.6 MHz): d ˆ 172.1, 171.9, 153.1,
152.7, 141.3, 119.5, 118.6, 115.6, 115.4, 78.3, 75.5, 70.8, 68.9, 66.8, 66.6, 63.1,
63.0, 38.9, 38.5, 25.8, 25.7, 18.2, 18.1, 17.9, 14.8/14.1, 13.6, 4.5, 4.8, 5.2,
5.3, 5.5, 5.6; MS 488 [M‡H] , 510 [M‡Na] , 486 [M H] .
The above-mentioned diol (620 mg, 1.27 mmol) was treated with Pb(OAc)4
(1.27 g, 2.72 mmol) in CH2Cl2 (10 mL) at 08C to afford compound 30a
(550 mg, 95%) after purification over silica gel (hexanes/EtOAc 10:1).
Physical data of 33: [a]D
ˆ
31.28 (c ˆ 2.50, CHCl3); 1H NMR (400 MHz):
ˆ
ˆ
d ˆ 7.04 (s, 1H; ArH), 6.47 (s, 1H; ArCH C), 5.74 (m, 2H; 2  CH CH2),
ˆ
5.28 (t, J ˆ 6.7 Hz, 1H; CO2CHCH2), 5.08 (d, J ˆ 17.1 Hz, 1H; CH CH2),
‡
‡
ˆ
ˆ
5.02 (d, J ˆ 10.2 Hz, 1H; CH CH2), 4.97 (d, J ˆ 17.2 Hz, 1H; CH CH2),
ˆ
4.94 (s, 2H; CH2OTBS), 4.92 (d, J ˆ 10.3 Hz, 1H; CH CH2), 4.33 (dd, J ˆ
6.0, 3.6 Hz, 1H; TBSOCHCH2), 3.72 (dd, J ˆ 7.0, 2.2 Hz, 1H;
TBSOCHCH), 3.14 (pentet, J ˆ 6.8 Hz, 1H; CHCO), 2.48 (m, 3H), 2.27
Chem. Eur. J. 2001, 7, No. 8
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0708-1699 $ 17.50+.50/0
1699

S. C. Sinha, R. A. Lerner et al.
FULL PAPER
ˆ
(dd, J ˆ 17.0, 6.1 Hz, 1H), 2.05 (s, 3H; CH3C CH), 1.98 (m, 2H), 1.50 ± 1.10
(m, 5H), 1.22 (s, 3H; (CH3)2C), 1.02 (s, 3H; (CH3)2C), 1.02 (d, J ˆ 6.8 Hz,
3H; CH3CHCO), 0.94 (s, 9H; SiC(CH3)3), 0.88 (s, 9H; SiC(CH3)3), 0.88 (d,
J ˆ 6.8 Hz, 3H; CH2CHCH3), 0.86 (s, 9H; SiC(CH3)3), 0.11 (s, 6H;
Si(CH3)2), 0.09 (s, 3H; Si(CH3)2), 0.04 (s, 3H; Si(CH3)2), 0.02 (s, 6H;
Si(CH3)2); 13C NMR (100.6 MHz): d ˆ 217.7, 172.0, 171.1, 152.8, 138.9, 136.7,
133.4, 121.2, 117.8, 116.5, 114.4, 78.7, 77.6, 74.0, 63.2, 53.3, 45.2, 40.3, 38.8,
37.5, 34.3, 30.4, 27.0, 26.2, 26.0, 25.8, 23.2, 20.3, 18.5, 18.2, 17.6, 15.4, 14.5,
(s, 3H; Si(CH3)2), 0.06 (s, 3H; Si(CH3)2), 0.03 (s, 3H; Si(CH3)2); 13C NMR
(127.75 MHz): d ˆ 216.3, 172.1, 170.5, 152.8, 137.7, 134.3, 125.6, 119.6, 116.4,
78.7, 76.8, 73.8, 63.2, 53.9, 45.3, 41.3, 39.8, 36.4, 32.4, 30.0, 27.1, 26.4, 26.2,
26.0, 25.7, 23.5, 21.5, 18.5, 18.4, 15.5, 14.5, 3.6, 3.7, 4.0, 4.6, 5.4;
‡
HRMS: calcd for C44H82NO6SSi3: 836.5171; found: 836.5140 [M‡H] .
HF/pyridine (0.5 mL) was added dropwise to a solution of the above-
mentioned mixture of 37 and (E)-37 (41 mg, 0.049 mmol) in THF (1 mL) at
room temperature. The mixture was stirred at room temperature for 2 h
and then slowly poured into a cold saturated aqueous NaHCO3 (20 mL)
and extracted with EtOAc. The combined organic layer was washed with
brine and dried over anhydrous MgSO4. Solvents were removed under
vacuum and the residue was chromatographed over silica gel (hexanes/
EtOAc 1:1) to afford pure 7 (9 mg, 37%) and (E)-7 (10 mg, 41%). For 7:
3.7,
3.8,
4.3,
4.7,
5.5; HRMS: calcd for C46H85NO6SSi3Cs:
‡
996.4460; found: 996.4494 [M‡Cs] .
Compound 34: In a similar manner as above, alcohol 30 (90 mg, 0.27 mmol)
was treated with acid 26 (177 mg, 0.32 mmol), EDC (156 mg, 0.80 mmol)
and DMAP (3.3 mg, 0.027 mmol) to afford pure ester 34 (225 mg, 97%).
43.78 (c ˆ 0.3, CHCl3), lit.:[14a] 44.28 (c ˆ 0.6, CHCl3); for (E)-7:
[a]D
ˆ
31.78 (c ˆ 1.17, CHCl3); 1H NMR (400 MHz): d ˆ 7.04 (s, 1H;
[a]D
[a]D
ˆ
41.18 (c ˆ 0.29, CHCl3), lit.:[14a] 31.58 (c ˆ 0.6, CHCl3). For the
ˆ
ˆ
ArH), 6.47 (s, 1H; ArCH C), 5.70 (m, 1H; CH CH2), 5.28 (t, J ˆ 6.8 Hz,
ˆ
ˆ
1H; CO2CHCH2), 5.08 (d, J ˆ 17.1 Hz, 1H; CH CH2), 5.02 (d, J ˆ 10.2 Hz,
conversion of 7 to epothilone E (5), and physical and spectral data of 5 and
ˆ
ˆ
1H; CH CH2), 4.93 (s, 2H; CH2OTBS), 4.67 (s, 1H; CH2 CCH3), 4.64 (s,
its precursors see reference [14a,b].
ˆ
1H, CH2 CCH3), 4.33 (m, 1H; TBSOCHCH2), 3.72 (dd, J ˆ 10.1, 3.1 Hz,
Desoxyepothilone F (8) and (E)-desoxyepothilone F [(E)-8]: Using the
same process as above for the conversion of 32 to 36, compound 34 (97 mg,
0.11 mmol) was metathesized by using Grubbsꢀ catalyst VII (21 mg,
0.024 mmol) in CH2Cl2 (30 mL) at reflux for 16 h to afford 38 (40 mg,
43%) and (E)-38 (39 mg, 42%) after purification by preparative TLC
(hexanes/EtOAc 49:1).
1H; TBSOCHCH), 3.14 (pentet, J ˆ 10.1 Hz, 1H; CHCO), 2.54 ± 2.43 (m,
ˆ
3H), 2.27 (dd, J ˆ 17.0, 6.1 Hz, 1H), 2.05 (d, J ˆ 1.8 Hz, 3H; CH3C CH),
ˆ
1.96 (m, 1H), 1.68 (s, 3H; CH3C CH2), 1.53 ± 1.44 (m, 1H), 1.40 ± 1.28 (m,
2H), 1.27 ± 1.19 (m, 2H), 1.22 (s, 3H; (CH3)2C), 1.03 (d, J ˆ 6.8 Hz, 3H;
CH3CHCO), 1.02 (s, 3H; (CH3)2C), 0.94 (s, 9H; SiC(CH3)3), 0.89 (s, 9H;
SiC(CH3)3), 0.88 (d, J ˆ 6.8 Hz, 3H; CH2CHCH3), 0.86 (s, 9H; SiC(CH3)3),
0.11 (s, 6H; Si(CH3)2), 0.09 (s, 3H; Si(CH3)2), 0.03 (s, 3H; Si(CH3)2), 0.02 (s,
6H; Si(CH3)2); 13C NMR (100.6 MHz): d ˆ 217.7, 172.0, 171.1, 152.7, 145.9,
136.7, 133.4, 121.2, 117.7, 116.5, 109.8, 78.6, 77.6, 74.0, 63.2, 53.3, 45.2, 40.3,
38.7, 38.3, 37.5, 31.5, 30.5, 26.2, 25.9, 25.7, 25.6, 23.1, 20.3, 18.5, 18.2, 18.1, 17.6,
1
Physical data of compound 38: [a]D
ˆ
22.58 (c ˆ 1.14, CHCl3); H NMR
ˆ
(600 MHz): d ˆ 7.05 (s, 1H; ArH), 6.54 (s, 1H; ArCH C), 5.15 (t, J ˆ
ˆ
8.0 Hz, 1H; CH C(CH3)CH2), 4.95 (d, J ˆ 10.1 Hz, 1H; CO2CHCH2),
4.94 (s, 2H; CH2OTBS), 4.01 (d, J ˆ 10.0 Hz, 1H; TBSOCHCH2), 3.88 (d,
J ˆ 9.0 Hz, 1H; TBSOCHCH), 3.01 (m, 1H; CHCO), 2.80 ± 2.62 (m, 3H),
‡
15.4, 14.5, 3.7, 3.8, 4.3, 4.8, 5.5; MS: 878 [M‡H] .
ˆ
2.44 (m, 1H), 2.09 (s, 3H; CH3C CH), 2.04 (m, 1H), 1.72 ± 1.67 (m, 3H),
Conversion of esters 31 ± 34 to desoxyepothilones and epothilones[37]
ˆ
1.66 (s, 3H; CH C(CH3)CH2), 1.60 ± 1.48 (m, 3H), 1.17 (s, 3H; (CH3)2C),
Epothilone B (2) and D (4): Grubbsꢀ catalyst VII (3.4 mg, 0.004 mmol) was
added to a solution of 32 (15 mg, 0.02 mmol) in CH2Cl2 (5 mL) and the
solution was stirred at reflux for 8 h. Solvents were evaporated and the
residue was purified over silica gel (hexanes/EtOAc 20:1) to afford an
inseparable mixture (1.1:1, by 1H NMR analysis) of stereoisomeric alkenes
36 and (E)-36 (11.7 mg, 81%). For the conversion of the above-mentioned
mixture to 4 and then to epothilone B (2), see references [10d], [11d], and
[12d].
1.12 (s, 3H; (CH3)2C), 1.07 (d, J ˆ 6.9 Hz, 3H; CH3CHCO), 0.96 (d, J ˆ
6.9 Hz, 3H; CH3CHCH2), 0.94/0.93/0.83 (3s, 27H; SiC(CH3)3), 0.12 (s, 6H;
Si(CH3)2), 0.095 (s, 3H; Si(CH3)2), 0.091/0.06/ 0.13 (3s, 9H; Si(CH3)2);
13C NMR (150.9 MHz): d ˆ 215.1, 172.0, 152.7, 138.7, 119.5, 119.1, 116.1,
79.9, 76.3, 63.2, 53.4, 39.1, 32.4, 31.9, 31.4, 30.9, 29.2, 27.4, 26.4, 26.2, 25.7,
24.6, 24.3, 23.1, 18.7, 18.6, 18.3, 17.8, 15.2, 3.3, 3.7, 5.5, 5.7; MS: 850
‡
[M‡H] , 884 [M‡Cl] .
Physical data of compound (E)-38: [a]D
ˆ
27.78 (c ˆ 0.82, CHCl3);
Desoxyepothilone E (7) and (E)-desoxyepothilone E [(E)-7]: Grubbsꢀ
catalyst V (10 mg, 0.012 mmol) was added to a solution of 33 (50 mg,
0.058 mmol) in degassed CH2Cl2 (10 mL) and the solution was stirred at
room temperature for 5 h. Solvents were removed under vacuum and the
residue was purified by chromatography over silica gel (hexanes/EtOAc
50:1) to afford a (1:1) mixture (41 mg, 85%) of 37 and (E)-37, which was
taken to the next step without separation. A small amount of pure 37 and
(E)-37 was purified by preparative TLC (hexanes/EtOAc 20:1) for analysis.
1
ˆ
H NMR (600 MHz): d ˆ 7.02 (s, 1H; ArH), 6.53 (s, 1H; ArCH C), 5.26
(dd, J ˆ 8.1, 2.9 Hz, 1H; CO2CHCH2), 5.16 (t, J ˆ 7.0 Hz, 1H;
ˆ
CH C(CH3)CH2), 4.95 (s, 2H; CH2OTBS), 4.47 (t, J ˆ 5.2 Hz, 1H;
TBSOCHCH2), 3.88 (dd, J ˆ 6.2, 2.6 Hz, 1H; TBSOCHCH), 3.05 (pentet,
J ˆ 6.6 Hz, 1H; CHCO), 2.61 (dd, J ˆ 15.8, 5.5 Hz, 1H), 2.57 (m, 1H), 2.47
ˆ
(m, 2H), 2.12 (s, 3H; CH3C CH), 2.09 (m, 1H), 1.91 (m, 1H), 1.73 ± 1.64
(m, 1H), 1.56 (s, 3H), 1.54 ± 1.47 (m, 2H), 1.32 ± 1.21 (m, 4H), 1.17 (s, 3H;
(CH3)2C), 1.11 (d, J ˆ 7.0 Hz, 3H; CH3CHCO), 1.07 (s, 3H; (CH3)2C), 0.95
(s, 9H; SiC(CH3)3), 0.91 (d, J ˆ 7.3 Hz, 3H; CH3CHCH2), 0.89 (s, 9H;
SiC(CH3)3), 0.88 (s, 9H; SiC(CH3)3), 0.12 (s, 6H; Si(CH3)2), 0.086/0.084/
0.07/0.04 (4s, 12H; Si(CH3)2); 13C NMR (150.9 MHz): d ˆ 216.3, 172.0,
170.5, 153.0, 138.0, 137.5, 120.0, 119.4, 116.3, 79.1, 73.0, 63.3, 54.0, 44.0, 41.9,
40.3, 39.3, 31.9, 26.1, 26.0, 25.7, 24.7, 22.7, 22.6, 20.2, 18.4, 18.3, 18.2, 16.8,
Physical data of 37: 1H NMR (500 MHz): d ˆ 7.06 (s, 1H; ArH), 6.52 (s, 1H;
ˆ
ˆ
ˆ
ArCH C), 5.52 (td, J ˆ 11.0, 3.0 Hz, 1H; CH CH), 5.37 (m, 1H; CH CH),
5.00 (d, J ˆ 10.5 Hz, 1H; CO2CHCH2), 4.95 (s, 2H; CH2OTBS), 4.02 (d, J ˆ
9.5 Hz, 1H; TBSOCHCH2), 3.88 (d, J ˆ 9.0 Hz, 1H; TBSOCHCH), 3.00
(m, 1H; CHCO), 2.76 (m, 1H), 2.66 (dd, J ˆ 16.5, 10.0 Hz, 1H), 2.35 (m,
‡
ˆ
16.0, 15.7, 15.4, 14.1, 3.6, 4.0, 4.3, 4.4, 5.5; MS: 850 [M‡H] , 884
1H), 2.10 (s, 3H; CH3C CH), 2.06 (dd, J ˆ 13.5, 5.5 Hz, 1H), 1.85 (m, 1H),
[M‡Cl] .
1.52 (m, 2H), 1.27 (m, 3H), 1.18 (s, 3H; (CH3)2C), 1.13 (s, 3H; (CH3)2C),
1.08 (d, J ˆ 7.0 Hz, 3H; CH3CHCO), 0.95 (m, 12H), 0.93 (s, 9H;
SiC(CH3)3), 0.84 (s, 9H; SiC(CH3)3), 0.12 (s, 6H; Si(CH3)2), 0.11 (s, 3H;
Si(CH3)2), 0.10 (s, 3H; Si(CH3)2), 0.09 (s, 3H; Si(CH3)2), 0.11 (s, 3H;
Si(CH3)2); 13C NMR (127.75 MHz): d ˆ 215.0, 172.1, 171.3, 152.7, 138.5,
135.0, 122.8, 119.6, 116.3, 79.6, 76.7, 76.4, 63.2, 53.4, 38.9, 37.8, 31.8, 31.3, 29.7,
29.2, 28.4, 26.3, 26.0, 25.7, 24.9, 24.2, 18.7, 18.6, 17.7, 15.1, 14.1, 3.2, 3.4,
3.7, 5.4, 5.8; HRMS: calcd for C44H82NO6SSi3: 836.5171; found:
According to the process for the conversion of 37 to 7, the above-mentioned
compound 38 (33 mg, 0.039 mmol) was treated with HF/pyridine (0.4 mL)
in THF (0.8 mL) at room temperature for 6 h to afford 8 (19 mg, 97%)
after purification over silica gel (hexanes/EtOAc 1:1). [a]D
ˆ
75.58 (c ˆ
0.93, CHCl3); 1H NMR (600 MHz): d ˆ 7.08 (s, 1H; ArH), 6.58 (s, 1H;
ˆ
ArCH C), 5.23 (d, J ˆ 9.2 Hz, 1H; CO2CHCH2), 5.12 (dd, J ˆ 9.7, 4.8 Hz,
ˆ
1H; CH C(CH3)CH2), 4.85 (s, 2H; CH2OH), 4.30 (d, J ˆ 11.0 Hz, 1H;
‡
836.5141 [M‡H] .
CH(OH)CH2), 3.90 (brs, 1H; CH(OH)CH), 3.67 (brs, 1H; OH), 3.11 (m,
1H; CHCO), 3.09 (brs, 1H; OH), 2.60 (m, 1H), 2.44 (dd, J ˆ 14.5, 11.0 Hz,
Physical data of compound (E)-37: 1H NMR (500 MHz): d ˆ 7.03 (s, 1H;
ˆ
ˆ
ˆ
ArH), 6.53 (s, 1H; ArCH C), 5.43 (m, 1H; CH CH), 5.37 (m, 1H;
1H), 2.29 ± 2.21 (m, 3H), 2.02 (s, 3H; CH3C CH), 1.88 (m, 1H), 1.73 (m,
ˆ
ˆ
CH CH), 5.22 (dd, J ˆ 8.0, 3.0 Hz, 1H; CO2CHCH2), 4.95 (s, 2H;
1H), 1.68 ± 1.59 (m, 1H), 1.64 (s, 3H; CH C(CH3)CH2), 1.32 (s, 3H;
CH2OTBS), 4.00 (dd, J ˆ 6.5, 4.0 Hz, 1H; TBSOCHCH2), 3.91 (d, J ˆ
(CH3)2C), 1.28 ± 1.20 (m, 3H), 1.17 (d, J ˆ 7.0 Hz, 3H; CH3CHCO), 1.01 (s,
3H; (CH3)2C), 0.99 (d, J ˆ 7.0 Hz, 3H; CH3CHCH2); 13C NMR
(150.9 MHz): d ˆ 220.7, 170.3, 170.2, 152.2, 139.6, 138.3, 120.9, 118.4,
116.3, 78.6, 74.2, 71.9, 61.3, 53.7, 41.4, 39.6, 38.5, 32.4, 31.6, 31.4, 29.2, 25.2,
23.1, 22.9, 17.4, 16.2, 15.5, 13.4; HRMS: calcd for C27H41NO6SNa: 530.2547;
6.0 Hz, 1H; TBSOCHCH), 3.05 (m, 1H; CHCO), 2.76 (m, 1H), 2.64 (dd,
ˆ
J ˆ 15.5, 4.0 Hz, 1H), 2.54 (m, 1H), 2.45 (m, 1H), 2.12 (s, 3H; CH3C CH),
1.90 (m, 1H), 1.68 ± 1.48 (m, 3H), 1.24 (m, 2H), 1.17 (s, 3H; (CH3)2C), 1.14
(d, J ˆ 7.0 Hz, 3H; CH3CHCO), 0.94 (m, 12H), 0.89 (s, 9H; SiC(CH3)3),
0.86 (s, 9H; SiC(CH3)3), 0.13 (s, 6H; Si(CH3)2), 0.09 (s, 3H; Si(CH3)2), 0.07
‡
found: 530.2541 [M‡Na] .
1700
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0947-6539/01/0708-1700 $ 17.50+.50/0
Chem. Eur. J. 2001, 7, No. 8

Epothilone F
1691±1702
In a similar manner as above, (E)-38 (40 mg, 0.047 mmol) was treated with
HF/pyridine (0.4 mL) in THF (0.8 mL) at room temperature for 6 h to
Sinha, R. A. Lerner, C. F. Barbas, III, Angew. Chem. 1998, 110, 2609;
Angew. Chem. Int. Ed. 1998, 37, 2481; f) B. List, D. Shabat, G. Zhong,
J. M. Turner, A. Li, T. Bui, J. Anderson, R. A. Lerner, C. F. Barbas, III,
J. Am. Chem. Soc. 1999, 121, 7283.
afford (E)-8 (23 mg, 96%). [a]D
ˆ
89.08 (c ˆ 0.90, CHCl3); 1H NMR
ˆ
(600 MHz): d ˆ 7.10 (s, 1H; ArH), 6.59 (s, 1H; ArCH C), 5.40 (t, J ˆ
ˆ
4.8 Hz, 1H; CH C(CH3)CH2), 5.06 (t, J ˆ 6.6 Hz, 1H; CO2CHCH2), 4.86
[7] a) 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; b) K. Gerth, N. Bedorf, G. Höfle, H. Irschik, H. Reichenbach, J.
Antibiot. 1996, 49, 560; c) G. Höfle, N. Bedorf, H. Steinmetz, D.
Schomburg, K. Gerth, H. Reichenbach, Angew. Chem. 1996, 108,
1671; Angew. Chem. Int. Ed. Engl. 1996, 35, 1567; d) For epothilones E
(5) and F (6), see: G. Höfle, N. Glaser, M. Kiffe, H.-J. Hecht, F. Sasse,
H. Reichenbach, Angew. Chem. 1999, 111, 2090; Angew. Chem. Int.
Ed. 1999, 38, 1971.
[8] For recent reviews, see a) K. C. Nicolaou, F. Roschangar, D. Vourlou-
mis, Angew. Chem. 1998, 110, 2120; Angew. Chem. Int. Ed. 1998, 37,
2014; b) K. C. Nicolaou, M. R. V. Finlay, S. Ninkovic, N. P. King, Y.
He, T. Li, F. Sarabia, D. Vourloumis, Chem. Biol. 1998, 5, 365; c) G.
Appendino, G. Casiraghi, Chemtracts 1998, 11, 678; d) S. B. Buck, S. F.
Victory, R. H. Himes, G. I. Georg, Chemtracts 1998, 11, 671; e) K. C.
Nicolaou, D. Hepworth, N. P. King, M. R. V. Finlay, Pure Appl. Chem.
1999, 71, 989; f) C. R. Harris, S. J. Danishefsky, J. Org. Chem. 1999, 64,
8434; g) J. Mulzer, Monatsh. Chem. 2000, 131, 205; h) L. A. Wessjo-
hann, Curr. Opin. Chem. Biol. 2000, 4, 303; i) K.-H. Altmann, M.
Wartmann, T. OꢀReilly, Biochim. Biophys. Acta. 2000, 1470, M79 ±
M91, and references therein.
[9] For biological studies, see: a) ref. [7a] and [8]; b) P. F. Muhlradt, F.
Sasse, Cancer Res. 1997, 57, 3344; c) A. Wolff, A. Technau, G.
Brandner, Int. J. Oncol. 1997, 11, 123; d) R. J. Kowalski, P. Gianna-
kakou, E. Hamel, J. Biol. Chem. 1997, 272, 2534; e) D.-S. Su, A. Balog,
D. Meng, P. Bertinato, S. J. Danishefsky, Y.-H. Zheng, T.-C. Chou, L.
He, S. B. Horwitz, Angew. Chem. 1997, 109, 2178; Angew. Chem. Int.
Ed. Engl. 1997, 36, 2093; f) M. M. Moasser, L. Sepplorenzino, N. E.
Kohl, A. Oliff, A. Balog, D.-S. Su, S. J. Danishefsky, N. Rosen, Proc.
Natl. Acad. Sci. USA 1998, 95, 1369; g) T.-C. Chou, X. G. Zhang, A.
Balog, D.-S. Su, D. Meng, K. Savin, J. R. Bertino, S. J. Danishefsky,
Proc. Natl. Acad. Sci. USA 1998, 95, 9642; h) T.-C. Chou, X.-G. Zhang,
C. R. Harris, S. D. Kuduk, A. Balog, K. A. Savin, J. R. Bertino, S. J.
Danishefsky, Proc. Natl. Acad. Sci. USA 1998, 95, 15798.
[10] For the total syntheses of epothilones A ± D from Danishefsky
laboratory, see: a) A. Balog, D. Meng, T. Kamenecka, P. Bertinato,
D.-S. Su, E. J. Sorensen, S. J. Danishefsky, Angew. Chem. 1996, 108,
2976; Angew. Chem. Int. Ed. Engl. 1996, 35, 2801; b) D.-S. Su, D.
Meng, P. Bertinato, 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. Eng. 1997, 36, 757; c) D. Meng, D.-S. Su, A.
Balog, P. Bertinato, E. J. Sorensen, S. J. Danishefsky, Y. H. Zheng, T.-
C. Chou, L.-F. He, S. B. Horwitz, J. Am. Chem. Soc. 1997, 119, 2733;
d) D. Meng, P. Bertinato, A. Balog, D.-S. Su, T. Kamenecka, E. J.
Sorensen, S. J. Danishefsky, J. Am. Chem. Soc. 1997, 119, 10073; e) 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;
f) C. Harris, S. D. Kuduk, A. Balog, K. Savin, P. W. Glunz, S. J.
Danishefsky, J. Am. Chem. Soc. 1999, 121, 7050; g) M. D. Chappell,
S. J. Stachel, C. B. Lee, S. J. Danishefsky, Org. Lett. 2000, 2, 1633; and
references therein.
(d, J ˆ 1.7 Hz, 2H; CH2OH), 4.41 (dd, J ˆ 10.1, 2.6 Hz, 1H; CH(OH)CH2),
3.63 (t, J ˆ 3.7 Hz, 1H; CH(OH)CH), 3.24 (m, 1H; CHCO), 2.56 (ddd, J ˆ
ˆ
15.3, 7.9, 3.8 Hz, 1H; CH2CH CCH3), 2.49 (dd, J ˆ 15.4, 10.1 Hz, 1H;
ˆ
CH2CO2), 2.45 ± 2.36 (m, 2H), 2.13 (m, 1H), 2.03 (s, 3H; CH3C CHAr),
ˆ
1.94 (m, 1H), 1.60 (m, 2H), 1.56 (s, 3H; CH C(CH3)CH2), 1.36 (m, 1H),
1.27 (m, 2H), 1.25 (s, 3H; (CH3)2C), 1.15 (d, J ˆ 6.6 Hz, 3H; CH3CHCO),
1.01 (s, 3H; (CH3)2C), 0.96 (d, J ˆ 6.6 Hz, 3H; CH3CHCH2); 13C NMR
(100.6 MHz): d ˆ 220.0, 170.2, 170.0, 152.3, 138.3, 137.7, 119.2, 118.7, 116.0,
76.5, 71.5, 61.3, 60.4, 52.9, 43.2, 39.6, 39.4, 37.4, 30.5, 29.2, 24.4, 21.1, 19.5,
16.4, 16.3, 15.8, 14.7, 14.2; HRMS: calcd for C27H41NO6S: 508.2727; found:
‡
508.2712 [M‡H] .
Epothilone F (6): Oxone (38 mg, 0.062 mmol) and NaHCO3 (8.4 mg,
0.1 mmol) were added in portions to a mixture of 8 (18 mg, 0.036 mmol), an
aqueous solution of Na2EDTA (4 Â 10 4 m, 0.31 mL) and 1,1,1-trifluoro-
acetone (0.3 mL, 3.35 mmol) in CH3CN (0.42 mL) and CH2Cl2 (0.21 mL).
After the reaction was complete as determined by TLC, the mixture was
diluted with EtOAc and passed quickly through a pad of silica gel. Solvents
were removed under vacuum and the residue was purified by preparative
TLC (CH2Cl2/MeOH 18:1) to afford epothilone Fand its a-epoxide (15 mg,
81%, b:a ˆ 5:1). A second preparative TLC (hexanes/EtOAc 1:2) afforded
pure epothilone F (11 mg, 59%). [a]D
ˆ
25.08 (c ˆ 0.1, methanol);
1
ˆ
H NMR (600 MHz): d ˆ 7.12 (s, 1H; ArH), 6.59 (s, 1H; ArCH C), 5.43
(dd, J ˆ 7.4, 3.1 Hz, 1H; CO2CHCH2), 4.92 (s, 2H; CH2OH), 4.17 (m, 1H;
CH(OH)CH2), 4.01 (m, 1H; CH(OH)CH), 3.76 (brs, 1H; OH), 3.29 (m,
1H; CHCO), 2.86 (brs, 1H; OH), 2.80 (dd, J ˆ 7.4, 5.3 Hz, 1H; CH-
O(epoxide)), 2.59 (brs, 1H; OH), 2.54 (dd, J ˆ 14.0, 10.1 Hz, 1H;
CH2CO2), 2.38 (dd, J ˆ 14.0, 3.1 Hz, 1H; CH2CO2), 2.09 (s, 3H;
ˆ
CH3C CH), 2.06 (m, 1H), 1.93 (dt, J ˆ 15.4, 7.4 Hz, 1H), 1.74 ± 1.67 (m,
2H), 1.49 (m, 1H), 1.46 ± 1.36 (m, 4H), 1.35 (s, 3H; CH3C-O(epoxide)), 1.27
(s, 3H; (CH3)2C), 1.16 (d, J ˆ 6.6 Hz, 3H; CH3CHCO), 1.07 (s, 3H;
(CH3)2C), 0.99 (d, J ˆ 7.0 Hz, 3H; CH3CHCH2); 13C NMR (100.6 MHz):
d ˆ 220.6, 170.6, 170.0, 152.2, 137.6, 119.5, 116.9, 73.2, 62.2, 61.5, 61.3, 60.4,
52.8, 43.1, 39.1, 36.4, 32.1, 31.8, 30.7, 29.7, 22.8, 22.5, 21.2, 20.2, 17.1, 15.8,
14.2; HRMS: calcd for C27H41NO7SNa: 546.2456; found: 546.2479
‡
[M‡Na] .
Acknowledgement
We are grateful to Professors Carlos F. Barbas and Samuel J. Danishefsky
for helpful discussions and Ms. Diane Kubitz and Dr. G. Zhong for
providing antibodies. We are thankful to Dr. Raj Chadha for X-ray analysis
of compound 15, Dr. Karl-Heinz Altmann, Ms. Jacqueline Loretan and Mr.
Robert Reuter for the biological evaluations of epothilones and Professor
D. Schinzer for providing us with the spectral data of intermediates and Ms.
A. Pervin and T. Yang for technical support.
[1] a) A. Tramontano, K. D. Janda, R. A. Lerner, Science 1986, 234, 1566;
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[11] For the total syntheses of epothilones A ± D from Nicolaou laboratory,
see: a) Z. Yang, Y. He, D. Vourloumins, H. Vallberg, K. C. Nicolaou,
Angew. Chem. 1997, 109, 170; Angew. Chem. Int. Ed. Engl. 1997, 36,
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c) 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,
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M. Cordes, Angew. Chem. 1997, 109, 543; Angew. Chem. Int. Ed. Engl.
Chem. Eur. J. 2001, 7, No. 8
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0708-1701 $ 17.50+.50/0
1701

S. C. Sinha, R. A. Lerner et al.
FULL PAPER
1997, 36, 523; b) D. Schinzer, A. Bauer, J. Schieber, Synlett 1998, 861;
c) D. Schinzer, A. Bauer, O. M. Böhm, A. Limberg, M. Cordes, Chem.
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Paterson (I. Paterson, J. M. Goodman, M. A. Lister, R. C. Schumann,
C. K. McClure, R. D. Norcross, Tetrahedron 1990, 46, 4663).
[22] Antibody 38C2 catalyzed resolution of (Æ)-10 was not optimized. Our
studies suggested that the amount of antibody used here can be
decreased to 0.01 molar percent ratio instead of 0.06.
[23] The unreacted aldol compound was identified as 10 by comparison
(For HPLC conditions, see: Supporting Information) with the
synthetic sample of 10 as well as one derived from the resolution of
(Æ)-10 with the antibody 38C2. Synthetic 10 was synthesized by the
reaction of prop-1-en-2-ol diisocampheylborinate (prepared from
(‡)-(Ipc)2BOTf and acetone) with the aldehyde 13 using the method-
ology of Paterson, see ref. [21].
[24] A solution (100 mL) of compound (Æ)-10 (0.01m in CH3CN, 10 mL)
and antibody 84G3 (6 mM, 90 mL in PBS buffer, pH 7.4) was kept at
room temperature under argon atmosphere for 12 h. The reaction
mixture was then shown to contain only one enantiomer of (Æ)-10 by
HPLC analysis equipped with a chiral reverse phase column (Daicel
Chemical Industries; for HPLC conditions see: Supporting Informa-
tion).
[25] Compound (Æ)-11 (0.01m solution in CH3CN, 10 mL) was incubated
with the antibody 84G3, 85H6 or 93G3 (6 mm antibody solution in PBS
buffer, pH 7.4, 90 mL) and the progress of the reaction was followed by
HPLC equipped with a chiral reverse phase ODR column. The
absolute stereochemistry was determined by comparison of the
specific rotation and HPLC trace of 11 with those of 10.
[26] Crystallographic data (excluding structure factors) for structure 15
reported in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication no.
CCDC-146207. Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB21EZ, UK (fax:
(‡44)1223-336-033; e-mail: deposit@ccdc.cam.ac.uk); see also Sup-
porting Information.
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Roschangar, N. P. King, D. Vourloumis, T. Li, Angew. Chem. 1998, 110,
89; Angew. Chem. Int. Ed. 1998, 37, 84; b) K. C. Nicolaou, N. P. King,
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ref. [7d].
[15] For the syntheses of analogues of epothilones, see: a) refs. [7 ± 14];
b) A. Balog, P. Bertinato, D.-S. Su, D. Meng, E. J. Sorensen, S. J.
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Pastor, N. Winssinger, Y. He, S. Ninkovic, F. Sarabia, H. Vallberg, F.
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[17] Synthesis of desoxyepothilone F and epothilone F were reported after
the paper was submitted for publication, see: a) C. B. Lee, T.-C. Chou,
X.-G. Zhang, Z. G. Wang, S. D. Kuduk, M. D. Chappell, S. J. Stachel,
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[28] m-CPBA or dioxirane could also be used to epoxidize the silylenol
ethers, but the results were not reproducibile.
[29] Aldehyde 29a was used in Danishefskyꢀs and Nicolaouꢀs syntheses of
epothilones by macrolactonization approach and prepared in three
steps from 29 (see refs. [10d] and [11d]). The same compound was
prepared from 10a, although in five steps, but the overall processes
were carried out with minimum number (2) of column chromatog-
raphy.
[30] J. S. Kingsbury, J. P. A. Harrity, P. J. Bonitatebus, Jr., A. H. Hoveyda,
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[34] For the previously described method, see ref. [16a].
[35] For the deprotection of the compound 29b to 29, and for the physical
and spectral data of 29, see ref. [12c].
[36] Esterification of acids 25 and 26 with alcohols 29 and 30, respectively,
to produce 31 and 32 were achieved as reported (see refs. [11c], [12c],
and [12d]). Physical and spectral data of the products matched the
reported data (see refs. [10d], [11c], [12c], and [12d]).
[37] Epothilones A (1) and C (3): Following a known method, compound
31 was metathesized to produce a mixture of 35 and (E)-35, which was
deprotected using HF/pyridine and the crude product was separated
to afford 3 and (E)-3. Compound 3 was then converted to epothilo-
ne A (1) and its a-epoxide. Physical and spectral data of 1, 3 and all the
intermediates were identical to the reported data (see refs. [10d],
[11c]).
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[21] The absolute structure of the resolved product by reaction with
antibody 38C2 was determined by a comparison with the synthetic
sample of 9. A synthetic sample of 9 for comparison was obtained by
the reaction of pent-2-en-3-ol diisocampheyl-borinate (prepared from
(‡)-(Ipc)2BOTf and 3-pentanone) with aldehyde 12 by the method of
Received: September 26, 2000 [F2755]
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