Total Syntheses of Epothilones B and D

Article abstract of DOI:10.1021/jo0007480

Total syntheses of the microtubule stabilizing antitumor drugs epothilone B and D are described, starting from optically pure (S)-malic acid and methyl (R)-3-hydroxy-2-methylpropionate. The synthesis is highly convergent by coupling the three fragments C1-C6 (fragment D), C7-C10 (fragment C), and C11-C21 (fragment B). Key steps are two stereoselective Wittig type olefinations to generate the 12,13- and 16,17-double bonds, an enantioselective Mukaiyama aldol addition to synthesize fragment D, and a sulfone anion allyl iodide alkylation to connect fragments B and C. Finally fragment D was attached to the B + C fragment via aldol addition.

Full text of DOI:10.1021/jo0007480

7456
J . Org. Chem. 2000, 65, 7456-7467
Tota l Syn th eses of Ep oth ilon es B a n d D
J ohann Mulzer,* Andreas Mantoulidis, and Elisabeth O¨ hler
Institut fuer Organische Chemie, Universitaet Wien,Waehringerstrasse 38, A-1090 Wien, Austria
mulzer@felix.orc.univie.ac.at
Received May 16, 2000
Total syntheses of the microtubule stabilizing antitumor drugs epothilone B and D are described,
starting from optically pure (S)-malic acid and methyl (R)-3-hydroxy-2-methylpropionate. The
synthesis is highly convergent by coupling the three fragments C1-C6 (fragment D), C7-C10
(fragment C), and C11-C21 (fragment B). Key steps are two stereoselective Wittig type olefinations
to generate the 12,13- and 16,17-double bonds, an enantioselective Mukaiyama aldol addition to
synthesize fragment D, and a sulfone anion allyl iodide alkylation to connect fragments B and C.
Finally fragment D was attached to the B + C fragment via aldol addition.
In tr od u ction
In contrast to 2, the desoxy compound 4 is not readily
available from fermentation, nor can it be prepared in
reasonable yield by partial synthesis from 2, i.e., by
deoxygenation of the epoxide.4 This means that an
efficient total synthesis of 4 is of the essence, which
should be flexible enough to ensure a ready access to
other interesting members of the epothilone family. In
this paper we give a full account of our synthesis of 2
and 4 and we also attempt to outline the history how our
approach has evolved.
Paclitaxel (Taxol) is clinically successful as a novel drug
for the chemotherapy of ovarian carcinomas. It is also in
clinical trials for the treatment of lung, head, neck, and
other cancers. Unfortunately, paclitaxel is not an ideal
drug for several reasons, e.g. multidrug resistance, poor
bioavailability, and several serious side effects.1 As a
consequence, new anticancer agents that also function
by microtubule stabilization but avoid some of the
problems of taxol are currently of great interest. Of these
potential post-paclitaxel agents (Figure 1), the epothilones
A (1) and B (2) (Figure 2), first isolated and characterized
by Ho¨fle and co-workers, have advanced the furthest and
several total syntheses of 1 and 2 as well as numerous
derivatives thereof have been reported.2
Resu lts a n d Discu ssion
F ir st Gen er a tion Ap p r oa ch . A strategy common to
all syntheses reported so far is to dissect the carbon
skeleton into two or three fragments. Our first synthetic
plan envisaged disconnection at the C10-C11 bond to
form the fragments A and B which could be connected
by a sulfone alkylation with subsequent reductive de-
sulfonylation (Figure 3). The preparation of fragment A
(Scheme 1) was started with an aldol reaction between
the known aldehyde 65 (providing C7-C9) and Mori’s
ketone 56 (providing C3-C6), which should preferentially
lead to a syn arrangement of the 6-Me and the 7-OH
function. The relative stereochemistry of the 7-OH and
the 8-Me was not clear at the beginning, but we hoped
that by means of chelate formation in the transition state
this would be anti as desired.7,8 Indeed, alcohols 7a ,b
were formed in a ratio of 4:1, and after chromatographic
separation, the synthesis was continued with the main
diastereoisomer 7a whose 1,3-diol function was protected
as PMP-acetal to form intermediate 8. Carbons C1-C3
were introduced via ozonolysis of the terminal double
bond to deliver the aldehyde, which was without isolation
The evaluation of a broad range of in vitro tests
initially showed epothilone B (2) to be a potential
paclitaxel successor. However, recent in vivo tests with
nude mice have shown 12,13-desoxyepothilone
B
()epothilone D, 4) to be the best candidate of the
epothilone family with respect to further development.
For instance, the superiority of 4 over 2 is impressively
borne out by the results of in vivo tests with normal
athymic nude mice bearing human mammary adenocar-
cinoma MX-1 xenografts. When a daily dose of 0.6 mg/
kg of 2 was applied intraperitonally (ip) to normal nude
mice all the mice died within 7 days. When however 25
mg/kg of 4 was applied ip, all the mice survived. More
importantly, 2 had only a marginal therapeutic effect,
whereas 4 led to a drastic reduction of the tumor size, so
that one out of six mice was without a detectable tumor
after 35 days. When tumor therapy combined with low
toxicity is considered, 4 is superior not only to 2 but also
to paclitaxel and other antitumor drugs, such as adria-
mycin. It has also been demonstrated that, again in the
nude mice test, 4 is curative for human tumor xenografts
that are refractory to paclitaxel.3
(3) Chou, T. C.; Zhang, X. G.; Harris, C. R.; Kuduk, S.; Balog, A.;
Savin, K. A.; Bertino, J . R.; Danishefsky, S. J . Proc. Natl. Acad. Sci.
U.S.A. 1998, 95, 15798.
(4) Bristol Myers Squibb Co., Int. Patent Application Number PCT/
US98/12550, Int. Publication Number WO 99/02514, 1999.
(5) Walkup, R. D.; Boatman, P. D.; Kane, R. R.; Cunningham, R. T.
Tetrahedron Lett. 1990, 31, 7587-7590.
* Corresponding author. Tel: ++43-1-4277-52190. Fax:++43-1-
4277-9521.
(1) Landino, L. M.; MacDonald, T. L. In The Chemistry and
Pharmacology of Taxol and its Derivatives; Farin, V.; Ed.; Elsevier:
New York, 1995; Chapter 7.
(2) Reviews: (a) Nicolaou, K. C.; Roschangar, F.; Vourloumis, D.
Angew. Chem. 1998, 110, 2121-2153; Angew. Chem., Int. Ed. Engl.
1998, 37, 2014-2045. (b) Mulzer, J . Chem. Mon. 2000, 131, 205-238.
(6) Mori, I.; Ishihara, K.; Heathcock, C. H. J . Org. Chem. 1990, 55,
1114-1117.
(7) Reetz, M. Angew. Chem. 1984, 96, 542-555; Angew. Chem., Int.
Ed. Engl. 1984, 23, 556-569.
(8) This C6-C7 aldol type addition was first reported by our group9a
and has been used in analogous9b and modified forms by others.2
10.1021/jo0007480 CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/05/2000

Total Syntheses of Epothilones B and D
J . Org. Chem., Vol. 65, No. 22, 2000 7457
F igu r e 1.
Sch em e 1
a
Reagents and conditions: (a) 5, LDA, -90 °C, 30 min, then 6, 15 min, THF (87%, 4:1); (b) DDQ, 4 Å molecular sieves, -20 °C, rt
(room temperature), 2 h, CH2Cl2 (89%); (c) O3, -78 °C, rt, Me2S workup, CH2Cl2/MeOH (20:1) (93%); (d) (+)-Allyl-B(Ipc)2, -78 °C, 1 h,
Et2O, oxidative workup (74%); (e) TBSOTf, 2,6-lutidine, 0 °C, 2 h, CH2Cl2 (99%).
F igu r e 3.
Next we tried to selectively open the PMP acetal with
DIBALH at the less hindered position to liberate the C9-
F igu r e 2.
subjected to an asymmetric Brown allylation to give the
allylic alcohols 9a ,b in a 4:1 ratio. The main diastereo-
isomer 9a was protected as the TBS-ether 10.9
OH group for further manipulation (eq 1). However, the
reduction furnished regioisomer 11 exclusively, presum-
ably due to an internal delivery of the hydride to C7-

7458 J . Org. Chem., Vol. 65, No. 22, 2000
Mulzer et al.
Sch em e 2
Sch em e 3
a
Reagents and conditions: (a) TsCl (2 equiv), 0 °C, 1 h, pyridine;
(b) methyl phenyl sulfone (1.5 equiv), n-BuLi, -20 °C, 12 h (96%);
(c) TBAF, rt, 10 h, THF (88%); (d) Swern oxidation; (e) 5 (1.5
equiv), LDA, -78 °C, 25 min, then aldehyde, 5 min, THF (88%,
4:1 for the desired syn diastereoisomer 19); (f) TBSOTf (2 equiv),
2,6-lutidine, -20 °C, 0 °C, 4 h, CH2Cl2 (87%); (g) (i) O3, -78 °C,
rt, CH2Cl2/MeOH (20:1), Ph3P workup (98%), (ii) (+)-Allyl-B(Ipc)2,
-78 °C, 1 h, Et2O, oxidative workup (53%), (iii) TBSOTf (2 equiv),
2,6-lutidine, -20 °C, rt, 5 h, CH2Cl2 (96%).
a
Reagents and conditions: (a) TFAA, then MeOH; (b) BH3‚THF,
(c) 4-MeOC6H4CH(OMe)2, CSA, reflux, 6 h, toluene (53% yield for
these three steps); (d) MeLi, -100 °C, 2 h, THF (86%); (e) (2-
methylthiazol-4-yl)methyltriphenylphosphonium chloride, NaH-
MDS, -78 °C, then 23, 40 °C, 1 h, THF (95%, E/Z ) 3.6:1); (f)
DIBALH (4 equiv), CH2Cl2, 4 h, -20 °C (89%, 5.6:1 for the desired
regioisomer 24); (g) (i) Swern oxidation, then (ii) (CF3CH2O)2P-
(O)CH(CH3)CO2Et, KHMDS, 18-crown-6, -78 °C, 1 h, THF (86%,
Z/ E ) 15:1); (h) DIBALH (3.5 equiv), -20 °C, 3 h, THF (98%); (i)
D-(-)-diisopropyl tartrate, Ti(OiPr)4, 4 Å molecular sieves, tert-
BuOOH, -30 °C, 3 d, CH2Cl2 (95%, 8.5:1).
OR via a carbonylaluminum complex. We therefore
continued with alcohol 7a , whose C7-OH was silylated
to 13, and the PMB protective group was removed
oxidatively to furnish the alcohol 14. Due to the fact that
the open chain isomer 14b coexisted as a minor compo-
nent in an equilibrium mixture with cyclic hemiacetals
14a and 14c, tosylation of the primary OH function was
extremely slow. So we abandoned this approach and
restarted our synthesis with the known alcohol 1710
(Scheme 2), which was tosylated and alkylated with
methyl phenyl sulfone anion to furnish sulfone 18 in 78%
overall yield. Oxidation to the aldehyde and aldol addition
with ketone 5 provided adduct 19 with 4:1-diastereo-
selectivity. Ozonolysis and Brown allylation followed by
TBS protection led to the C1-C10 fragment 21.
the desired (E)-olefin with a selectivity of 3.6:1. The cyclic
acetal was regioselectively (5.6:1) opened to liberate the
terminal hydroxyl group. Compound 24 was oxidized and
immediately subjected to a (Z)-selective Wadsworth-
Horner-Emmons olefination under Still-Gennari condi-
tions12 (86%, Z/ E ) 15:1). Reduction of the ester with
DIBALH furnished the allylic alcohol 25a which was
used as a model system for asymmetric epoxidation under
Sharpless conditions.13 Although the compound 25a bears
a trisubstituted double bond with a Z configuration, the
epoxide 26 was obtained in 95% yield and 8.5:1 dia-
stereoselectivity (Scheme 3).14
For the synthesis of the C11-C21 segment B, (S)-malic
acid (22) was converted via the 1-methyl ester and (S)-
(-)-methyl 2,4-dihydroxybutyrate11 into ketone 23. For
the Wittig olefination we first tried (2-methylthiazol-4-
yl)methyltriphenylphosphonium chloride, which afforded
(11) (a) Gong, B.; Lynn, D. G. J . Org. Chem. 1990, 55, 4763-4765.
(b) Wu¨nsch, B.; Diekmann, H.; Ho¨fner, G. Liebigs Ann. Chem. 1993,
1273-1278.
(12) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405-4408.
The reagent was prepared according to an improved procedure: Patois,
C.; Savignac, P.; About-J audet, E.; Collignon, N. Synth. Commun. 1991,
21, 2391-2396.
(13) Gao, Y.; Hanson, R. M.; Klunder, J . M.; Soo, Y. K.; Masamune,
H.; Sharpless, K. B. J . Am. Chem. Soc. 1987, 109, 5765-5789.
(14) Mulzer, J .; Mantoulidis, A.; O¨ hler, E. Tetrahedron Lett. 1997,
38, 7725-7728.
(9) (a) Thomas, E. J .; Whitehead, J . W. F. J . Chem Soc., Perkin
Trans.1 1989, 507-518. (b) Corey, E. J .; Cho, H.; Ru¨cker, C.; Hua, D.
H. Tetrahedron Lett. 1981, 36, 3455-3458.
(10) (a) Mulzer, J .; Mantoulidis, A. Tetrahedron Lett. 1996, 37,
9179-9182. (b) White, J . D.; Carter, R. G.; Sundermann, K. F. J . Org.
Chem. 1999, 64, 684-685.

Total Syntheses of Epothilones B and D
J . Org. Chem., Vol. 65, No. 22, 2000 7459
For the crucial C10-C11 coupling, the allylic alcohol
25a was converted into the allyl iodide and treated with
the lithium salt of 21 (eq 2). However, none of the desired
diastereomeric coupling products were formed. Instead,
we isolated a mixture of enone 27, TBS ether 28, and
sulfone 29. Obviously, anion 21a had undergone an
intramolecular proton shift followed by an E1cB elimina-
tion. In this way enone 27 was generated, and the
liberated OTBS anion underwent a SN2-displacement
reaction with the allyl iodide to give 28. With excess
butyllithium, sulfone 27 was deprotonated and alkylated
by the allylic iodide to form 29. From these considerations
it became clear that the presence of both the 5-carbonyl
and the 10-sulfonyl functions in compound 21 were
incompatible with the envisaged anionic alkylation.
Secon d Gen er a tion Syn th esis. At this stage, an
alternative retrosynthetic disconnection was envisaged
(Figure 4). The C11-C21 fragment B remained un-
changed; however, the sulfone moiety was now located
in a smaller C7-C10 fragment C, which could be con-
nected to B by sulfone alkylation. After that, the C1-C6
fragment D could be attached via the familiar C6-C7-
aldol addition.
For the allyl iodide B a slightly modified preparation
was developed, starting from hydroxylactone 31, easily
available in two steps from (S)-malic acid (22)15 (Scheme
4). Two different protecting groups were tested for the
later C15-OH function. Thus PMB protection of the
2-hydroxyl function furnished 32a , which was treated
with methyllithium to give 33 as a mixture of cyclic
hemiacetals and hydroxy ketone. This mixture was
subjected to a Wittig reaction with (2-methylthiazol-4-
yl)methyltri-n-butylphosphonium chloride (34) to furnish
the olefin 24a in excellent yield and >95% (E)-selectiv-
ity.16 Conversion of 24a into the allyl iodide via (Z)-
selective Horner-Wadworth-Emmons reaction12 and
reduction to the allylic alcohol was achieved as described
above. An analogous sequence of operations was per-
formed with C15-OTBS protection.
Furthermore, an extremely short and efficient synthe-
sis was developed for the C1-C6 fragment (Scheme 5).
Utilizing a protocol by Kiyooka,17 the commercially
available ketene acetal 36 was added to the aldehyde 3518
under mediation of the oxazaborolidinone prepared in
situ from diborane and N-tosyl-D-valine. Hydroxy ester
37 was obtained with >90% ee, as determined by chiral
HPLC. O-Silylation of 37 gave 38, which was transformed
to the desired ketone 41 by two alternative methods: (a)
Ester 38 was treated with trimethylsilylmethyllithium
to give, after methanolysis, methyl ketone 39,19 which
was then deprotonated and methylated to furnish 41. (b)
Ethylmagnesium bromide was added to the aldehyde
generated from 38 to deliver alcohol 40, which was
oxidized to 41.
The connection of the fragments started from sulfone
18a which was prepared from alcohol 17a as shown in
Scheme 2. Alkylation of 18a with the iodide prepared
from allylic alcohol 25a proceeded smoothly to give the
epimeric sulfones, which were desulfonated to 42a and
deprotected to form the C7-alcohol 43a (Scheme 6). Swern
oxidation and aldol addition with ketone 41 furnished
the desired adduct 44a with a diastereoselectivity of 4:1.
Silyl protection of the C7-OH gave 45a . The C1-OTBS
protective group was removed selectively to give the
primary alcohol 46a , which was oxidized to carboxylic
acid 47a . However, all attempts to remove the C15-
(15) (a) Collum, D. B.; McDonald, J . H.; Still, W. C. J . Am. Chem.
Soc. 1980, 102, 2118-2120. (b) Green, D. L. C.; Kiddle, J . J .; Thompson,
C. M. Tetrahedron 1995, 51, 2865-2874.
(16) Analogous substituted oxazolyltributylphosphonium salts have
been investigated as olefination reagents in connection with synthetic
studies on the calyculins,a ulapualides,b and phorboxazolesc and have
been found to give excellent (E)-selectivities and better yields than the
corresponding phosphonates. Thiazolylphosphonium salt 34 has inde-
pendently been used by a Chinese group for the synthesis of the C7-
C21 segment of epothilone A:d (a) Zhao, Z.; Scarlato, G. S.; Armstrong,
R. W. Tetrahedron Lett. 1991, 32, 1609-1612. Evans, D. A.; Gage, J .
R.; Leighton, J . L. J . Am. Chem. Soc. 1992, 114, 9434-9453. Evans,
D. A.; Gage, J . R.; Leighton, J . L. J . Org. Chem. 1992, 57, 1964-1966.
(b) Celatka, C. A.; Liu, P. Panek, Y. S.; Tetrahedron Lett. 1997, 38,
5449-5452. (c) Paterson, I.; Arnott, E. A. Tetrahedron Lett. 1998, 39,
7185-7188. (d) Liu, Z. Y.; Yu, C.-Z.; Wang, R.-F.; Li, G. Tetrahedron
Lett. 1998, 39, 5261-5264.
(17) Kiyooka, S.-I.; Kaneko, Y.; Komura, M., Matsuo, H.; Nakano,
M. J . Org. Chem. 1991, 56, 2276-2278.
(18) (a) J enmalm, A.; Berts, W.; Li, Y.-L.; Luthman, K.; Cso˜regh,
I.; Hacksell, U. J . Org. Chem. 1994, 59, 1139-1148. (b) McDougal, P.
G.; Rico, J . G.; Oh, Y.-I.; Condon, B. D. J . Org. Chem. 1986, 51, 3388-
3390.
F igu r e 4.
(19) Demuth, M. Helv. Chim. Acta 1978, 61, 3136-3138.

7460 J . Org. Chem., Vol. 65, No. 22, 2000
Mulzer et al.
Sch em e 4
a
Reagents and conditions: (a) dimethoxypropane, cataalyst pTsOH, rt, 3 h (79%); (b) (i) BH3‚DMS (1.05 equiv), -78 °C, rt, 12 h, (ii)
catalyst pTsOH, 65 °C, 1 h, toluene (48%). P a th a : (for R ) PMB): (c) PMBOC(dNH)CCl3, catalyst CSA, rt, 12 h, CH2Cl2 (96%); (d) MeLi
(1.02 equiv), -78 °C, 90 min, THF (98%); (e) 34, KHMDS, -78 °C, 15 min, then 33a , 50 °C, 30 min, THF (86% E-isomer, 5% Z-isomer);
(f) (i) Swern oxidation, (ii) (CF3CH2O)2P(O)CH(CH3)CO2Et, KHMDS, 18-crown-6, -78 °C, 1 h, THF (86%), Z:E ) 5:1; (g) DIBALH (3.5
equiv), -20 °C, 3 h, THF (98%). P a th b: (for R ) TBS): (c) TBSCl (1.3 equiv), imidazole (2 equiv), 0 °C, 3 h, DMF (99%); (d) MeLi (1.2
equiv), -78 °C, 90 min, THF (88%); (e) 34, LiHMDS, 0 °C, 40 min, then 33b, 40-50 °C, 20 min, THF (77% E- and <1% Z-olefin); (f) (i)
Swern oxidation, (ii) (CF3CH2O)2P(O)CH(CH3)CO2Et, KHMDS, 18-crown-6, -78 °C, 1.5 h, THF (89%); (g) DIBALH (3 equiv), 0 °C, 2.5 h,
THF (98%).
Sch em e 5
a
Reagents and conditions: (a) N-Ts- D -valine (1 equiv), BH3‚THF (1 equiv), rt, 30 min, then 35 (1 equiv) and 36 (1 equiv), -78 °C, 4
h, CH2Cl2 (88%, >90% ee and 95% recovered N-Ts-D-valine); (b) TBSOTf (3 equiv), 2,6-lutidine, 0 °C, 3 h, CH2Cl2 (96%); (c) TMSCH2Li,
0 °C, 4 h, pentane, then MeOH, 1 h, rt (97%); (d) LDA, -78 °C, 30 min, then MeI, -78 °C, rt, THF (85%); (e) DIBALH (3 equiv), -20 °C,
2 h, toluene (94%); (f) (i) Dess-Martin periodinane (1.3 equiv), 0 °C, 2 h, CH2Cl2, (ii) ethylmagnesium bromide (1.05 equiv), 0 °C, 2 h,
Et2O (60% and 38.5% reduction product); (g) Dess-Martin periodinane (1.5 equiv), 0 °C, 2 h, CH2Cl2 (99%).
OPMB group failed. The only defined reaction we got was
oxidation with DDQ, which led to the C15 ketone.
Therefore, the whole synthetic sequence was repeated
with a C15-OTBS protecting group instead of the C15-
OPMB. Thus, 18b and the allylic iodide prepared from
25b were connected to 42b whose deprotection furnished
43b, which was converted into 46b in a sequence
completely analogous to the one with the C15-OPMB
protective group. Compound 46b was identical with
Nicolaou’s intermediate in every respect (1H and 13C
NMR, etc.).20 The synthesis was concluded with C1-
OTBS deprotection, oxidation of C1 to the carboxylic acid,
and C15-OTBS deprotection to generate seco acid 48b,
which gave lactone 49 via Keck macrolactonization.
Global deprotection of 49 furnished 4 which was epoxi-
dized with m-CPBA to 2 with a diastereoselectivity of
4-5:1. Our synthetic samples of 2 and 4 were identical
with epothilones B and D with respect to all reported
properties.
(20) Nicolaou, K. C.; Ninkovic, S.; Sarabia, F.; Vourloumis, D.; He.
Y.; Vallberg, H.; Finlay, M. R. V.; Yang, Z. J . Am. Chem. Soc. 1997,
119, 7974-7991.

Total Syntheses of Epothilones B and D
J . Org. Chem., Vol. 65, No. 22, 2000 7461
Sch em e 6
a
Reagents and conditions: P a th a (for R1 ) TBDPS, R2 ) PMB): (a) (i) Ph3P (1.3 equiv), imidazole (1.35 equiv), I2 (1.4 equiv), CH3-
CN/Et2O (3:2), rt, 1 h, (ii) Li salt of 18a , -78 °C, 1 h, then allylic iodide from 25a , 1 h, THF (77%); (b) activated Mg, catalyst HgCl2,
controlled addition of MeOH, 40-50 °C, 2 h, EtOH (70% + 20% educt); (c) TBAF (2 equiv), rt, 3 h, THF (98%); (d) (i) Dess-Martin
periodinane (1.3 equiv), rt, 2 h, CH2Cl2, (ii) lithium enolate from 41, -90 °C, 30 min, THF (81% and recovered aldehyde, ca. 9:1 for the
desired syn diastereoisomer 44a ); (e) TBSOTf (4 equiv), 2,6-lutidine, -15 °C, rt, 4 h, CH2Cl2 (98%); (f) CSA (1 equiv), 0 °C, 5 h, MeOH/
CH2Cl2 (1:1) (98%); (g) (i) Dess-Martin periodinane (1.3 equiv), rt, 2 h, CH2Cl2, (ii) NaClO2, NaH2PO4, 2,3-dimethyl-but-2-ene, 3 h, tert-
butyl alcohol/water (96%). P a th b (for R1 ) R2 ) TBS): (a) (i) Ph3P (1.3 equiv), imidazole (1.35 equiv), I2 (1.4 equiv), CH3CN/Et2O (3:2),
rt, 1 h, (ii) 18b, KHMDS, 18-crown-6, -78 °C, 1 h, then allylic iodide from 25b, 1 h, THF (93%); (b) 5% Na/Hg, Na2HPO4, -15 °C, rt, 2
h, MeOH/THF (65%); (c) CSA (1 equiv), 0 °C, 5 h, MeOH/CH2Cl2 (1:1) (99%); (d) (i) Dess-Martin periodinane (1.3 equiv), rt, 4 h, CH2Cl2,
(ii) lithium enolate from 41, -95 °C, -85 °C, 90 min, THF (69%, 4:1 for the desired syn diastereoisomer 44b); (e) TBSOTf (3 equiv),
2,6-lutidine, 0 °C, 3 h, CH2Cl2 (99%); (f) CSA (1 equiv), 0 °C, 4 h, MeOH/CH2Cl2 (1:1) (87%); (g) (i) Dess-Martin periodinane (1.3 equiv),
rt, 2 h, CH2Cl2, (ii) NaClO2, NaH2PO4, 2,3-dimethyl-but-2-ene, 3 h, tert-butyl alcohol/water (96%); (h) TBAF (5 equiv), rt, 10 h, THF
(62%); (i) EDCI (2 equiv), DMAP (3 equiv), DMAP‚HCl (2 equiv), reflux, 17 h, CHCl3 (69%); (j) excess buffered HF‚py, rt, 36 h, THF (96%);
(k) mCPBA (1.5 equiv), -18 °C, 5 h, CHCl3 (81%, with 4-5:1 diastereoselectivity for 2).
unless specified otherwise. All reactions were performed in
oven-dried glassware under Ar. Chromatography and chro-
matographic refers to flash column chromatography on silica
gel 60 (230-400 mesh with eluents given in parentheses).
Analytical thin-layer chromatography (TLC) was performed
on precoated glass-backed plates (Merck silica gel 60 F254) and
visualized by using either a UV lamp, ceric molybdate (CM),
phosphomolybdic acid (PMA), sulfuric acidic/anisaldehyde (A),
sulfuric acidic/vanilline (V), or potassium permanganate solu-
tion. Melting points (mp) are uncorrected. Optical rotations
are reported in g/100 mL. Infrared spectra (IR) were measured
as film on single-crystal silica plates and reported in wave-
numbers (cm-1) with broad signals denoted by (br). High-
resolution mass spectra were obtained using electron ioniza-
tion (EI), field ionization (FI), or fast atom bombardment
(FAB).
(+)-(2S)-3-{[ter t-Bu t yl(d ip h en yl)silyl]oxy}-2-m et h yl-
p r op a n -1-ol (17a ).10a (2R)-3-{[ter t-Bu tyl(d ip h en yl)silyl]-
oxy}-2-m eth ylp r op ion a te. To a solution of (R)-methyl 3-hy-
droxy-2-methylpropionate (10 mL, 90.24 mmol) in dry DMF
(200 mL) was added imidazole (12.3 g, 180.5 mmol) and tert-
butyldiphenylsilyl chloride (TBDPSCl, 30.7 mL, 117.3 mmol).
After being stirred overnight at room temperature, the mixture
was quenched with ice water (200 mL). The aqueous DMF
phase was extracted four times with Et2O, and the organic
solution was washed with saturated aqueous NH4Cl, dried over
MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by chromatography (silica gel, elution
with hexanes-EtOAc, 7:1) to give 38.34 g (>100%, contami-
Con clu sion
In conclusion, we have reported total syntheses of
epothilones B and D in 18 (17) steps for the longest linear
sequence and with about 8% overall yield. The stereo-
genic units (stereogenic centers and double bonds) were
introduced with excellent to good stereoselectivity so that
our synthesis compares very favorably with the ones that
have been reported so far. A main advantage of our
synthesis is that the two stereogenic centers at C8 and
C15 are adapted from the chiral carbon pool with
unambiguous configuration and reliable optical purity.
The synthesis is modular and convergent, which means
there is wide flexibility with respect to the individual
subsections B-D. For instance, the construction of the
12,13-olefin moiety by Wittig type olefinations allows the
introduction of almost any kind of a 13-substituent in
an (E)- or (Z)-olefin geometry. The syntheses of other
structurally interesting epothilone derivatives using this
strategy will be disclosed soon.
Exp er im en ta l Section
Gen er a l P r oced u r es. Unless otherwise stated, solvents
were dried by distillation under Ar, from sodium (PhMe), Na/K
(Et2O), potassium (THF), CaH2 (CH2Cl2, DMF, MeCN, Et3N,
pentane), and Mg (MeOH, EtOH). All other commercially
available reagents were used without further purification

7462 J . Org. Chem., Vol. 65, No. 22, 2000
Mulzer et al.
nated with silanol) of the TBDPS ether as a colorless oil: Rf
0.45 (hexanes-EtOAc, 10:1, CM: blue); IR (film) 1742, 1257,
residue was purified by flash chromatography (silica gel,
elution with hexanes-EtOAc, 10:1) to give 8.67 g (18.6 mmol,
93%) of the tosylate as a viscous colorless oil, which was used
directly in the next step.
1
1200 cm-1; H NMR (CDCl3, 400 MHz) δ 7.64 (m, 4H), 7.40
(m, 6H), 3.80 (dd, J ) 10.0, 7.5 Hz, 2H), 3.68 (s, 3H), 2.77 (sext,
J ) 6.3 Hz, 1H), 1.20 (d, J ) 7.5 Hz, 3H), 1.09 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 175.3, 135.5, 133.5, 129.6, 127.6,
65.9, 51.5, 42.3, 26.7, 19.2, 13.4; MS(EI) m/e 341 (M - CH3)+.
Alcoh ol 17a . To a solution of the above crude ester in dry
THF (1000 mL) was added dropwise DIBALH (270 mL, 1 M
in toluene, 270 mmol) at 0 °C, and the mixture was stirred
for 4 h, allowing to warm to room temperature. The cooled (0
°C) mixture was treated sequentially dropwise with MeOH (5
mL) and with saturated aqueous NaK tartrate (1000 mL). The
cooling bath was removed, and after 3 h the phases were
separated. The aqueous phase was extracted four times with
Et2O/hexanes (1:1). The combined organic solutions were dried
over MgSO4, filtered, and concentrated under reduced pres-
sure. The residue was purified by chromatography (silica gel,
elution with hexanes-EtOAc, 5:1) to give 26.06 g (79.3 mmol,
88%) of the alcohol 17a as a colorless oil: Rf 0.40 (hexanes-
EtOAc, 3:1, CM: blue; A, red brown); IR (film) 3350 br, 1260,
To a solution of methyl phenyl sulfone (4.34 g, 27.9 mmol)
in THF (180 mL) was added dropwise n-BuLi (16.77 mL, 1.6
M in hexanes, 26.83 mmol) at -20 °C, the cooling bath was
removed, and the reaction was allowed to warm to room
temperature over a period of 30 min. To the solution of the Li
salt was added the above-mentioned tosylate in dry THF (20
mL) at -20 °C, and the reaction was stirred overnight,
allowing to warm to room temperature. The violet reaction
mixture was quenched by addition of saturated aqueous NH4Cl
and NaK tartrate. The phases were separated, and the
aqueous phase was extracted with Et2O. The combined organic
solutions were dried over MgSO4, filtered through a short pad
of silica gel, and concentrated under reduced pressure. Puri-
fication by chromatography (silica gel, elution with hexanes-
EtOAc, 5:1) provided sequentially 630 mg unreacted tosylate
and 7.69 g (82% or 89% with respect to the recovered tosylate,
respectively) of the sulfone 18a both as colorless oils: tosylate,
Rf 0.60 (hexanes-EtOAc, 3:1; PMA, blue; A, light blue); 18a ,
1
1188, 1112, 1087, 1041, 939, 740, cm-1; H NMR (CDCl3, 400
MHz) δ 7.68 (m, 4H), 7.40 (m, 6H), 3.72 (ddd, J ) 20.0, 10.0,
5.0 Hz, 2H), 3.62 (dd, J ) 10.0, 2.0 Hz, 2H), 3.68 (s, 3H), 2.62
(br t, 1H), 1.99 (sext, J ) 6.3 Hz, 1H), 1.05 (s, 9H), 0.84 (d, J
) 7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 135.5, 133.1,
129.8, 127.7, 68.6, 67.6, 37.3, 26.8, 19.1, 13.1; MS(EI) m/e 271
(M - t-Bu)+.
Rf 0.39 (hexanes-EtOAc, 3:1, PMA, light blue); [R]20 -5.8 (c
D
2.01, CHCl3); IR (film) 1447, 1428, 1318, 1306, 1112, 1087
cm-1 1H NMR (CDCl3, 400 MHz) δ 7.88 (mc, 2H), 7.63 (m,
;
1H), 7.55 (m, 6H), 7.37 (m, 6H), 3.44 (dd, J ) 9.8, 5.0 Hz, 1H),
3.36 (dd, J ) 9.8, 6.4 Hz, 1H), 3.09 (mc, 2H), 1.86 (dddd, J )
12.8, 8.9, 7.9, 5.9 Hz, 1H), 1.70 (mc, 1H), 1.60 (ddt, J ) 12.8,
8.9, 7.4 Hz, 1H), 0.96 (s, 9H), 0.84 (d, J ) 6.4 Hz, 3H); 13C
NMR (62.5 MHz, CDCl3) δ 135.54, 135.51, 133.6, 133.5, 129.7,
129.2, 128.1, 127.7, 68.0, 54.5, 34.7, 26.8, 26.4, 19.2, 16.4; MS
(EI) m/e 468 (M + H)+. Anal. Calcd for C27H34O3SSi: C, 69.5;
H, 7.3. Found: C, 69.39; H, 7.50.
(2S)-3-{[ter t-Bu tyl(dim eth yl)silyl]oxy}-2-m eth ylpr opan -
1-ol (17b).10b (-)-(2R)-3-{[ter t-Bu tyl(d im eth yl)silyl]oxy}-
2-m eth ylp r op ion a te. To a solution of (R)-methyl 3-hydroxy-
2-methylpropionate (10.76 g, 91.09 mmol) and imidazole (9.3
g, 136.6 mmol) in dry DMF (150 mL) was added TBSCl (17.85
g, 118.4 mmol) at 0 °C, and the mixture was stirred for 5 h
allowing to reach room temperature. The mixture was quenched
with saturated aqueous NH4Cl, extracted with Et2O, dried over
MgSO4, filtered through a short pad of silica gel, and concen-
trated under reduced pressure. The residue was purified by
bulb-to-bulb distillation (12-18 mbar) at 90-100 °C to furnish
18.34 g (78.9 mmol, 86%) of the TBS ether as a colorless oil:
(-)-(3S)-4-{[ter t-Bu t yl(d im et h yl)silyl]oxy}-3-m et h yl-
bu tyl P h en yl Su lfon e (18b). To a solution of (3S)-3-methyl-
1-phenylsulfonylbutan-4-ol (prepared by desilylation of 18a
with 1.5 equiv of TBAF, rt, 10 h, THF (88%)) (5.55 g, 24.3
mmol) and imidazole (3.31 g, 48.6 mmol) in dry DMF (30 mL)
was added TBSCl (4.75 g, 31.6 mmol) at 0 °C, and the mixture
was stirred for 3 h, allowing to reach room temperature. The
mixture was quenched by addition of saturated aqueous NH4Cl
(50 mL) at 0 °C, the aqueous phase was extracted with Et2O,
and the combined organic solutions were dried over MgSO4,
filtered through a short pad of silica gel, and concentrated.
Flash column chromatography (silica gel, elution with hex-
anes-EtOAc, 5:1) furnished 8.2 g (24 mmol, 99%) of the TBS-
protected sulfone 18b as a colorless oil: Rf 0.53 (hexanes-
Rf 0.24 (hexanes-EtOAc, 3:1, A, violet); [R]20 -18.1 (c 3.03;
D
CHCl3); IR (film) 2955, 2858, 1744, 1257, 838, 777 cm-1; H
1
NMR (CDCl3, 400 MHz) δ 3.76 (dd, J ) 9.5, 7.0 Hz, 1H), 3.66
(s, 3H), 3.63 (dd, J ) 9.5, 6.0 Hz, 1H), 2.63 (mc, 1H), 1.12 (d,
J ) 7.0 Hz, 3H), 0.86 (s, 9H), 0.023 (s, 3H), 0.021 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 175.4, 65.2, 51.5, 42.5, 25.6, 18.2,
13.4, -5.5.
Alcoh ol 17b. To a solution of the above ester (15.2 g, 65.5
mmol) in dry THF (200 mL) was added dropwise DIBALH (197
mL, 1 M in toluene, 197 mmol) at -20 °C. After 2.5 h the
reaction was quenched with MeOH (10 mL) at 0 °C and
saturated aqueous NaK tartrate (200 mL) and Et2O (150 mL)
were added, and the mixture was stirred for additional 45 min
allowing to warm to room temperature. The layers were
separated, the aqueous phase was extracted with Et2O, and
the combined organic solutions were dried over MgSO4,
filtered, and concentrated to give 12.3 g (60.3 mmol, 92%) of
the alcohol 17b as a colorless oil: Rf 0.6 (hexanes-EtOAc, 3:1,
EtOAc, 3:1, PMA, blue); [R]20 -6.7 (c 2.64; CHCl3); IR (film)
D
1447, 1389, 1306, 1106 cm-1
;
1H NMR (CDCl3, 400 MHz) δ
7.90 (m, 2H), 7.64 (m, 1H), 7.55 (m, 2H), 3.42 (dd, J ) 10.0,
5.0 Hz, 1H), 3.31 (dd, J ) 10.0, 6.5 Hz, 1H), 3.14 (dd, J ) 9.0,
7.0 Hz, 2H), 1.79 (m, 1H), 1.65 (mc, 1H), 1.55 (m, 1H), 0.83 (d,
J ) 6.5 Hz, 3H), 0.81 (s, 9H), -0.03 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 139.1, 133.5, 129.2, 128.1, 67.5, 54.6, 34.6, 26.4,
25.8, 18.2, 16.3, -5.5; MS (FI) m/e 343 (M+). Anal. Calcd for
C
17H30O3SSi: C, 59.6; H, 8.8. Found: C, 59.38; H, 8.72.
(-)-(3S,4E)-3-{[ter t-Bu tyl(d im eth yl)silyl]oxy}-4-m eth -
yl-5-(2-m eth yl-1,3-th ia zol-4-yl)p en t-4-en -1-ol (24b). To a
solution of 34 (31.95 g, 91.28 mmol), dried for 16 h (40 °C,
0.01 Torr), and 33b (10.1 g, 43.48 mmol) in dry THF (200 mL)
was added dropwise a solution of LiHMDS (101 mL, 1 M in
THF, 101.0 mmol) at 0 °C over a period of 40 min. After 5 min
the cooling bath was removed and the reaction mixture was
heated to 55 °C for 40 min. After recooling, the mixture was
diluted with Et2O (200 mL) and quenched by addition of
saturated aqueous NH4Cl, the phases were separated, the
aqueous phase was extracted with CH2Cl2, and the combined
organic solutions were dried over MgSO4. After filtration the
solvent was removed under reduced pressure and the residue
was subjected twice to chromatography (silica gel, elution with
hexanes-EtOAc, 5:1-3:1, and CH2Cl2-hexanes-EtOAc, 3:5:
1, respectively) to give 10.95 g (33.48 mmol, 77%) of the
E-olefin 24b. Less polar byproducts were isolated in the
following order: bissilylated E-olefin (600 mg, 3%), Z-olefin
(122 mg, <1%), recovered 33b (765 mg, 8%), and E-olefin
1
CM, blue); IR (film) 3065br, 1268, 1206, 1168, 1092 cm-1; H
NMR (CDCl3, 400 MHz) δ 3.72 (dd, J ) 10.0, 4.5 Hz, 1H), 3.61
(m, 2H), 3.53 (dd, J ) 10.0, 8.0 Hz, 1H), 2.78 (dd, J ) 6.0, 4.5
Hz, 1H), 1.93 (mc, 1H), 0.89 (s, 9H), 0.83 (d, J ) 6.5 Hz, 3H),
0.06 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 68.8, 68.3, 37.0,
25.9, 18.2, 13.1, -5.56, -5.62.
(-)-(3S)-4-{[ter t-Bu t yl(d ip h en yl)silyl]oxy}-3-m et h yl-
bu tyl P h en yl Su lfon e (18a ). To a solution of compound 17a
(6.57 g, 20 mmol) in dry pyridine (20 mL) was added tosyl
chloride (6.94 g, 40 mmol) at 0 °C, and the mixture was stirred
for 3.5 h. The reaction was quenched by addition of ice and
stirred for 1 h. The aqueous phase was extracted with Et2O (3
× 50 mL), and the combined organic solutions were washed
with saturated aqueous NaHCO3, dried over MgSO4, filtered,
and concentrated under reduced pressure. The residue was
diluted with toluene and concentrated under reduced pressure
to remove most of the pyridine by azeotropic distillation. The

Total Syntheses of Epothilones B and D
J . Org. Chem., Vol. 65, No. 22, 2000 7463
silylated at the primary hydroxy group (741 mg, 5%). 24b: Rf
NMR (CDCl3, 400 MHz) δ 6.91 (s, 1H), 6.43 (s, 1H), 5.30 (td,
J ) 8.0, 2.5 Hz, 1H), 4.13 (dd, J ) 11.0, 5.0 Hz, 1H), 4.12 (dd,
J ) 12.0, 5.0 Hz, 1H), 4.00 (dd, J ) 12.0, 6.5 Hz, 1H), 2.69 (s,
3H), 2.46 (dt, J ) 14.1, 8.0 Hz, 1H), 2.22 (m, 1H), 2.20 (t, J )
6.0 Hz, 1H), 2.00 (d, J ) 1.0 Hz, 3H), 1.79 (s, 3H), 0.88 (s,
9H), 0.04 (s, 3H), 0.02 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
164.6, 152.9, 142.2, 137.6, 124.3, 118.8, 115.2, 78.2, 61.9, 35.4,
25.8, 22.0, 19.2, 18.3, 14.2, -4.7, -4.9; MS (FI) m/e 368 (M +
H)+. Anal. Calcd for C19H33NO2SSi: C, 62.1; H, 9.0; N, 3.8.
Found: C, 61.64; H, 8.94; N, 3.79.
0.21 (hexanes-EtOAc, 3:1, CM, blue); [R]20 -31.5 (c 2.81,
D
CHCl3); IR (film) 3385 br, 1472, 1255, 1098, 1005, 978 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 6.89 (s, 1H), 6.49 (s, 1H), 4.35
(dd, J ) 7.5, 4.5 Hz, 1H), 3.71 (m, 2H), 2.67 (s, 3H), 2.28 (t, J
) 5.0 Hz, 1H), 1.98 (s, 3H), 1.90-1.73 (m, 2H), 0.88 (s, 9H),
0.07 (s, 3H), 0.01 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 164.9,
153.4, 142.0, 119.2, 115.7, 77.7, 60.6, 38.7, 26.2, 19.6, 18.5, 14.7,
-4.2, -4.8; MS (FI) m/e 327 (M+).
(-)-(2Z,5S,6E)-5-{[ter t-Bu t yl(d im et h yl)silyl]oxy}-2,6-
d im et h yl-7-(2-m et h yl-1,3-t h ia zol-4-yl)h ep t a -2,6-d ien -1-
ol (25b ). (3S,4E)-3-{[t er t -Bu t yl(d im et h yl)silyl]oxy}-4-
m eth yl-5-(2-m eth yl-1,3-th ia zol-4-yl )p en t-4-en -1-a l. To a
solution of oxalyl chloride (1.57 mL, 17.95 mmol) in CH2Cl2
(150 mL) was added dropwise DMSO (2.66 mL, 37.4 mmol) at
-78 °C. After the solution was stirred for 10 min, a solution
of alcohol 24b (4.9 g, 14.96 mmol) in CH2Cl2 (20 mL) was added
dropwise. The solution was stirred for additional 45 min before
DIPEA (74.8 mmol) was added, and stirring was continued
for 10 min at the same temperature and was then allowed to
warm to room temperature within 60 min. The reaction
mixture was diluted with Et2O (250 mL) and quenched by
addition of saturated aqueous NH4Cl (100 mL). The phases
were separated, the aqueous phase was extracted with CH2Cl2,
and the combined organic solutions were washed with satu-
rated aqueous NaHCO3 and brine and dried over MgSO4. After
filtration through a short pad of silica gel, the solvent was
removed under reduced pressure and the crude aldehyde was
subjected to the next reaction without further purification.
Eth yl (2Z,5S,6E)-5-{[ter t-Bu tyl(d im eth yl)silyl]oxy}-2,6-
d im eth yl-7-(2-m eth yl-1,3-th ia zol- 4-yl)h ep ta -2,6-d ien oa te.
To a solution of ethyl 2-[bis(2,2,2-trifluoroethyl)phosphono]-
propionate (6.73 g, 19.46 mmol) and 18-crown-6 (11.9 g, 44.9
mmol) in dry THF (200 mL) was added a solution of KHMDS
(3.62 g, 17.2 mmol) in dry THF (15 mL) at -78 °C. The cooling
bath was removed, and the mixture was stirred for 15 min.
Then a solution of the above crude aldehyde in dry THF (45
mL) was added at -78 °C over a period of 70 min, and the
reaction was stirred for 30 min. The cooling bath was removed,
and the mixture was quenched by addition of saturated
aqueous NH4Cl. The phases were separated, the aqueous
phase was extracted with Et2O, and the combined organic
solutions were washed with saturated aqueous NaHCO3 and
dried over MgSO4. After filtration through a short pad of silica
gel the solvent was removed under reduced pressure and the
residue was subjected to chromatography (silica gel, elution
with hexanes-EtOAc, 15:1-10:1) to give 5.45 g (13.31 mmol,
89%) of the unsaturated ester as a single isomer: Rf 0.46
[(4S)-2,2-Dim eth yl-5-oxo-1,3-d ioxola n -4-yl]a cetic a cid
(30).15b To a suspension of (S)-malic acid (22) (53.6 g, 0.4 mol)
in 2,2-dimethoxypropane (250 mL) was added p-TsOH (500
mg, 2.63 mmol), and the mixture was stirred for 3 h. The
solution was quenched by addition of a aqueous solution
containing NaHCO3 (220 mg, 2.63 mmol). The mixture was
diluted with CH2Cl2 and slightly acidified, the phases were
separated, the aqueous phase was extracted with CH2Cl2, and
the combined organic solutions were dried over MgSO4. After
filtration the solvent was removed under reduced pressure and
the remaining solids were purified by recrystallization
(CHCl3-CCl4, 1:1) to give 56.53 g (32.46 mmol, 79%) 30 as
1
colorless crystals: IR (film) 3268, 1766, 1130, 1104 cm-1; H
NMR (CDCl3, 400 MHz) δ 11.30 (br, ×bb1H), 4.69 (dd, J )
6.5, 3.5 Hz, 1H), 2.97 (dd, J ) 17.6, 4.0 Hz, 1H), 2.83 (dd, J )
17.6, 6.5 Hz, 1H), 1.59 (s, 3H), 1.54 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 175.1, 171.9, 111.4, 70.4, 35.9, 26.7, 25.7.
(3S)-3-Hyd r oxyd ih yd r ofu r a n -2(3H)-on e (31).15b To a
solution of 30 (41.8 g, 0.24 mol) in dry THF (250 mL) was
added dropwise borane-dimethyl sulfide complex (25 mL, 10
M in DMS, 0.25 mol) at -78 °C. After being stirred overnight,
allowing to reach room temperature, the reaction mixture was
concentrated under reduced pressure. The residue was purified
by flash chromatography (silica gel, elution with acetone), and
the volatiles were removed under reduced pressure. The
remaining oil was dissolved in toluene (500 mL), a catalytic
amount of p-TsOH was added, and the mixture was stirred
for 1 h at 65 °C. After the mixture had cooled, pyridine (1 equiv
with respect to used p-TsOH) was added and the mixture was
concentrated under reduced pressure. The residue was purified
by chromatography (silica gel, elution with hexanes-EtOAc,
2:1-1:2) and finally by Kugelrohr distillation (85 °C, 0.1 mbar)
to give 12.0 g (118 mmol, 48%) of the lactone 31 as a colorless
oil: 1H NMR (CDCl3, 400 MHz) δ 4.50 (dd, J ) 9.8, 8.4 Hz,
1H), 4.38 (ddd, J ) 10.8, 8.9, 2.0 Hz, 1H), 4.19 (ddd, J ) 10.3,
8.9, 5.9 Hz, 1H), 4.07 (br s, 1H), 2.55 (mc, 1H), 2.23 (mc, 1H);
13C NMR (100 MHz, CDCl3) δ 178.3, 67.2, 65.2, 30.7.
(-)-(3S)-3-{[ter t-Bu tyl(dim eth yl)silyl]oxy}dih ydr ofu r an -
2(3H)-on e (32b). To a solution of (S)-R-hydroxybutyrolactone
31 (3.92 g, 38.4 mmol) and imidazole (5.23 g, 76.8 mmol) in
dry DMF (50 mL) was added TBSCl (7.53 g, 49.92 mmol) at 0
°C, and the mixture was stirred for 2.5 h. The reaction was
quenched with saturated aqueous NH4Cl (100 mL), extracted
with Et2O, dried over MgSO4, filtered through a short pad of
silica gel, and concentrated under reduced pressure. Chroma-
tography (silica gel, elution with 3% Et2O in hexanes) afforded
8.27 g (38.2 mmol, 99%) of the TBS ether 32b as a colorless
oil, which crystallized at -20 °C: Rf 0.51 (hexanes-EtOAc,
(hexanes-EtOAc, 5:1, A, light blue); [R]20 -2.0 (c 3.38,
D
CH2Cl2); IR (film) 1714, 1472, 1372, 1252, 1210, 1185, 1096,
1032 cm-1; 1H NMR (CDCl3, 400 MHz) δ 6.91 (s, 1H), 6.49 (s,
1H), 5.98 (td, J ) 7.3, 1.5 Hz, 1H), 4.21 (t, J ) 5.5 Hz, 1H),
4.18 (q, J ) 7.0 Hz, 2H), 2.75 (m, 2H), 2.70 (s, 3H), 2.00 (s,
3H), 1.88 (s, 3H), 1.28 (t, J ) 7.0 Hz, 3H), 0.88 (s, 9H), 0.04 (s,
3H), 0.01 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.0, 164.4,
153.2, 141.9, 139.0, 128.3, 118.8, 115.2, 77.9, 60.1, 36.6, 26.2,
20.7, 19.2, 18.2, 14.3, 14.1, -4.7, -5.1; MS (FI) m/e 410 (M+).
Anal. Calcd for C21H35NO3SSi: C, 61.6; H, 8.6; N, 3.4. Found:
C, 61.55; H, 8.53; N, 3.39.
5:1, CM, blue); [R]20 -30.5 (c 5.82, CHCl3); IR (film) 1788,
D
Red u ction to 25b. To a solution of the above unsaturated
ester (5.43 g, 13.26 mmol) in dry THF (250 mL) was added
dropwise DIBALH (40 mL, 1 M in heptanes, 40 mmol) at 0
°C, and stirring was continued for 2.5 h at the same temper-
ature. The reaction was quenched by addition of MeOH (3 mL),
diluted with Et2O (200 mL) and saturated aqueous NaK
tartrate (200 mL), and stirred for 45 min allowing to reach
room temperature. The phases were separated, the aqueous
phase was extracted with Et2O, and the combined organic
solutions were washed with saturated aqueous NH4Cl, dried
over MgSO4, filtered, and concentrated under reduced pres-
sure. Purification by chromatography (silica gel, elution with
hexanes-EtOAc, 5:1) provided 4.75 g (12.93 mmol, 98%) of
the allylic alcohol 25b as colorless crystals: Rf 0.24 (hexanes-
EtOAc, 3:1, A, violet); [R]20D -6.8 (c 2.20; CHCl3); mp.: 58-60
1254, 1220, 1154, 1022 cm-1
;
1H NMR (CDCl3, 400 MHz) δ
4.43-4.34 (m, 2H), 4.19 (td, J ) 9.0, 6.6 Hz, 1H), 2.45 (m, 1H),
2.22 (dddd, J ) 12.8, 9.0, 9.0, 8.6 Hz, 1H), 0.91 (s, 9H), 0.017
(s, 3H), 0.014 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 175.8,
68.2, 64.7, 32.3, 25.9, 18.2, -4.2, -5.3; MS (FI) m/e 217 (M +
H)+.
(3S)-3-{[ter t-Bu tyl(d im eth yl)silyl]oxy}-5-h yd r oxyp en -
ta n -2-on e (33b). To a solution of crude 32b (5.27 g, from 24.34
mmol of (S)-R-hydroxybutyrolactone) in dry THF (100 mL) was
added dropwise MeLi (18.3 mL, 1.6 M in Et2O, 29.2 mmol) at
-78 °C, and the reaction was stirred for 90 min at the same
temperature. The cooling bath was removed, and saturated
aqueous NH4Cl was added rapidly. The mixture was diluted
with saturated aqueous NaK tartrate and Et2O, the layers
were separated, and the aqueous phase was extracted with
Et2O. The combined organic solutions were dried over MgSO4,
1
°C; IR (film) 3333br, 1472, 1441, 1253, 1100, 1006 cm-1; H

7464 J . Org. Chem., Vol. 65, No. 22, 2000
Mulzer et al.
filtered, and concentrated under reduced pressure. The residue
was subjected to chromatography (silica gel, elution with
hexanes- EtOAc, 10:1-5:1) affording 4.96 g (21.33 mmol, 88%)
of 33b as colorless crystals: Rf 0.22 (hexanes- EtOAc, 5:1, A,
green); mp 53-60 °C; IR (film) 3314 br, 1464, 1251, 1110, 1053,
1024 cm-1; MS (FI) m/e 214 (M - H2O)+. Anal. Calcd for
C11H24O3Si: C, 56.9; H, 10.4. Found: C, 57.15; H, 10.34.
Tr i-n -b u t yl[(2-m e t h yl-1,3-t h ia zol-4-yl)m e t h yl]p h os-
p h on iu m Ch lor id e (34). 4-(Ch lor om eth yl)-2-m eth yl-1,3-
th ia zole. A solution of 1,3-dichloropropan-2-one (12.7 g, 0.1
mol) and thioacetamide (7.5 g, 0.1 mol) in dry ethanol (70 mL)
was heated under Ar for 5.5 h and then concentrated under
reduced pressure. The dark crystalline residue was dissolved
in water (250 mL), and a pH ≈ 8 was achieved by addition of
solid NaHCO3. The mixture was extracted with Et2O (4 × 100
mL), and the combined organic solutions were dried over
MgSO4 and concentrated. The residue was purified by distil-
lation (bp: 55 °C, 0.05 Torr) to obtain 11.9 g (80.7 mmol, 81%)
of the thiazole as light yellow, skin-irritating oil, which was
identical in every respect with the described compound.21
of silica gel, and concentrated under reduced pressure. Flash
column chromatography (silica gel, elution with 3%-5% Et2O
in hexane) furnished 7.1 g (17.6 mmol, 96%) of the protected
ester 38 as a colorless oil: Rf 0.33 (hexanes-EtOAc, 10:1, CM,
blue); [R]20 -6.0 (c 3.91, CHCl3); IR (film) 1736, 1472, 1464,
D
1257, 1135 cm-1; H NMR (CDCl3, 400 MHz) δ 4.05 (dd, J )
1
7.5, 3.0 Hz, 1H), 3.64 (s, 3H), 3.62 (m, 2H), 1.59 (m, 2H), 1.15
(s, 3H), 1.08 (s, 3H), 0.89 (s, 9H), 0.86 (s, 9H), 0.07 (s, 3H),
0.033 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 177.6, 73.4, 60.3, 51.6, 48.3, 36.9, 26.0, 25.9, 21.7,
20.4, 18.3, -3.9, -4.3, -5.3; MS (FI) m/e 405 (M+). Anal. Calcd
for C20H44O4Si2: C, 59.4; H, 11.0. Found: C, 59.50; H, 10.74.
(4S)-4,6-Bis{[ter t-bu tyl(d im eth yl)silyl]oxy}-3,3-d im eth -
ylh exa n -2-on e (39). To a solution of 38 (1.01 g, 2.5 mmol) in
dry pentane (12 mL) was added ((trimethylsilyl)methyl)lithium
(5.5 mL, 1 M in pentane, 5.5 mmol) at 0 °C, and the mixture
was stirred for 4 h. To the suspension was added dry MeOH
(2.5 mL), and the resulting emulsion was stirred for an
additional 1 h at room temperature. The mixture was diluted
with Et2O and water, the layers were separated, and the
aqueous phase was extracted with Et2O. The combined organic
solutions were dried over NaSO4, filtered, and concentrated.
The residue was purified by flash column chromatography
(silica gel, elution with 2% Et2O in hexanes) to obtain 470 mg
(2.44 mmol, 97%) of 39 as a colorless oil: Rf 0.4 (hexanes-
To a solution of 4-chloromethyl-2-methyl-1,3-thiazole (23 g,
156.0 mmol) in dry benzene (200 mL) was added tri-n-
butylphosphane (38 mL, 156.0 mmol) under Ar, and the
reaction was heated to reflux for 8 h. The mixture was
concentrated under reduced pressure and the residue crystal-
lized with dry Et2O to give 53 g (151.5 mmol, 97%) of the title
compound as highly hygroscopic colorless crystals: mp 82-
EtOAc, 24:1, A, yellow brown); [R]20 -11.5 (c 0.71, CHCl3);
D
1H NMR (CDCl3, 400 MHz) δ 4.00 (dd, J ) 8.0, 3.0 Hz, 1H),
3.64-3.54 (m, 2H), 2.10 (s, 3H), 1.39-1.59 (m, 2H), 1.06 (s,
3H), 1.01 (s, 3H), 0.85 (s, 18H), 0.06 (s, 3H), 0.02 (s, 3H), 0.00
(s, 3H), -0.01 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 213.7,
73.7, 60.4, 53.8, 37.6, 27.1, 26.4, 26.3, 22.3, 20.4, 18.7, 18.6,
-3.6, -3.7, -4.9; MS (FI) m/e 389 (M + H)+.
1
85 °C; H NMR (CDCl3, 400 MHz) δ 7.65 (d, J ) 3.5 Hz, 1H),
4.28 (d, J ) 14.6 Hz, 2H), 2.59 (s, 3H), 2.35 (mc, 6H), 1.35-
1.50 (m, 12H), 0.86 (t, J ) 7.0 Hz, 9H); 13C NMR (100 MHz,
4
2
CDCl3) δ 166.7 (d, J ) 1.5 Hz), 142.9 (d, J ) 9.9 Hz), 119.8
(d, 3J ) 9.2 Hz), 23.7 (d, J ) 15.3 Hz), 23.4 (d, J ) 5.4 Hz),
22.6 (d, 1J ) 47.4 Hz), 19.0 (d, 1J ) 46.8 Hz), 19.0 (s), 13.2 (s).
(3R,5S)-5,7-Bis{[ter t-b u t yl(d im et h yl)silyl]oxy}-4,4-d i-
m eth ylh ep ta n -3-ol (40a ) a n d (3S,5S)-5,7-Bis{[ter t-bu tyl-
(d im eth yl)silyl]oxy}-4,4-d im eth ylh ep ta n -3-ol (40b). (3S)-
3,5-Bis{[ter t-bu tyl(d im eth yl)silyl]oxy}-2,2-d im eth ylp en -
ta n -1-ol. To a solution of 38 (4.05 g, 10 mmol) in dry toluene
(100 mL) at -20 °C was added dropwise DIBALH (30 mL, 1
M solution in hexanes, 30 mmol), and the reaction was stirred
for 2 h. At 0 °C MeOH (5 mL) was added dropwise, and the
mixture was diluted with Et2O (150 mL) and saturated
aqueous NaK tartrate (250 mL). The layers were separated,
the aqueous phase was extracted with Et2O, and the combined
organic solutions were dried over MgSO4, filtered through a
short pad of silica gel, and concentrated. Flash column
chromatography (silica gel, elution with hexanes-EtOAc, 10:
1) furnished 3.53 g (9.36 mmol, 94%) of the alcohol as a
(+)-Met h yl (3S)-5-{[ter t-Bu t yl(d im et h yl)silyl]oxy}-3-
h yd r oxy-2,2-d im eth ylp en ta n oa te (37). To a solution of
N-Ts-D-valine (1.36 g, 5.0 mmol) in dry CH2Cl2 (50 mL) was
added dropwise at room temperature a solution of BH3‚THF
(5 mL, 1 M in THF, 5.0 mmol) over a period of 30 min, and
stirring was continued for 20 min. The reaction was cooled to
-78 °C, and a solution of aldehyde 3518 (940 mg, 5.0 mmol) in
dry CH2Cl2 (5 mL) was slowly added followed by a solution of
freshly distilled ketene acetal 36 (960 mg, 5.5 mmol) in dry
CH2Cl2 (5 mL). After being stirred for 4 h at the same
temperature, the reaction mixture was quenched by addition
of phosphate buffer (35 mL, pH ) 6.9). The mixture was
extracted with CH2Cl2 (3 × 20 mL), and the combined organic
solutions were dried over MgSO4, filtered, and concentrated.
The residue was treated with cold hexane, and the precipitated
N-Ts-D-valine was recovered by filtration (96%). The solution
was again concentrated under reduced pressure and purified
by flash column chromatography (silica gel, elution with
hexanes-EtOAc, 5:1) to obtain 1.25 g (4.3 mmol, 88%) of the
â-hydroxy ester 37 as a colorless oil: Rf 0.39 (hexanes-EtOAc,
colorless oil: Rf 0.53 (hexanes-EtOAc, 5:1, CM, blue); [R]20
D
-12.4 (c 6.97, CHCl3); IR (film) 3450 br, 1473, 1464, 1389,
1256, 1103, 1043 cm-1; 1H NMR (CDCl3, 400 MHz) δ 3.66 (m,
4H), 3.28 (dd, J ) 10.5, 7.0 Hz, 1H), 2.87 (dd, J ) 7.0, 4.0 Hz,
1H), 1.90 (m, 1H), 1.62 (m, 1H), 0.98 (s, 3H), 0.883 (s, 9H),
0.878 (s, 9H),); 0.79 (s, 3H), 0.084 (s, 3H), 0.078 (s, 3H), 0.04
(s, 6H); 13C NMR (100 MHz, CDCl3) δ 76.7, 70.2, 60.7, 39.3,
36.4, 26.0, 25.9, 22.8, 22.0, 18.3, 18.2, -4.0, -4.3, -5.30, -5.33;
MS (EI) m/e 377 (M+). Anal. Calcd for C19H44O3Si2: C, 60.6;
H, 11.8. Found: C, 60.82; H, 11.70.
5:1, CM: blue); [R]20 +3.0 (c 1.88, CHCl3); IR (film) 3630 br,
D
1733, 1472, 1257, 1193, 1138, 1099, cm-1
;
1H NMR (CDCl3,
400 MHz) δ 3.92 (m, 1H), 3.87 (dd, J ) 10.0, 5.0 Hz, 1H), 3.80
(m, 1H), 3.68 (s, 3H), 3.37 (d, J ) 3.5 Hz, 1H), 1.57 (ddd, J )
11.0, 5.5, 1.0 Hz, 2H), 1.19 (s, 3H), 1.15 (s, 3H), 0.88 (s, 9H),
0.06 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 177.8, 76.0, 62.6,
51.8, 47.1, 33.7, 25.9, 21.3, 20.6, 18.2, -5.5; MS (FI) m/e 291
(M+). Anal. Calcd for C14H30O4Si: C, 57.9; H, 10.4. Found: C,
58.26; H, 10.31.
(-)-Meth yl (3S)-3,5-Bis{[ter t-bu tyl(d im eth yl)silyl]oxy}-
2,2-d im eth ylp en ta n oa te (38). To a solution of 37 (5.32 g,
18.3 mmol) in dry CH2Cl2 (100 mL) at 0 °C were added
sequentially 2,6-lutidine (6.38 mL, 55.0 mmol) and then
dropwise TBSOTf (5.05 mL, 22.0 mmol). The reaction was
stirred for 3 h and then quenched with saturated aqueous
NH4Cl (25 mL). The layers were separated, the aqueous phase
was extracted twice with CH2Cl2, and the combined organic
solutions were dried over MgSO4, filtered through a short pad
Alcoh ols 40. To a solution of the above alcohol (820 mg,
2.18 mmol) in dry CH2Cl2 (100 mL) and dry pyridine (2 mL)
was added DMP (1.21 g, 2.83 mmol), and the mixture was
stirred for 2 h. At this time, TLC (hexanes-EtOAc, 10:1)
indicated that the alcohol had been consumed and the alde-
hyde had been formed. The reaction mixture was diluted with
Et2O (100 mL) and quenched with saturated aqueous NaHCO3-
Na2S2O3 (1:1, 50 mL). The organic solution was washed with
NaHCO3-Na2S2O3 (1:1, 2 × 50 mL), dried over MgSO4, filtered
through a short pad of silica gel, and concentrated under
reduced pressure. The crude aldehyde was azeotropically dried
from toluene and then directly used in the next step.
To a solution of the above crude aldehyde in dry Et2O (10
mL) was added dropwise ethylmagnesium bromide (0.76 mL,
3 M in Et2O, 2.29 mmol) at 0 °C. The reaction was stirred for
2 h and then quenched with saturated aqueous NH4Cl (50 mL).
The layers were separated, the aqueous phase was extracted
with Et2O, and the combined organic solutions were dried over
(21) (a) Gasteiger, J .; Herzig, C. Tetrahedron 1981, 15, 2607-2611.
(b) Marzoni, G. J . Heterocycl. Chem. 1986, 23, 577-580.

Total Syntheses of Epothilones B and D
J . Org. Chem., Vol. 65, No. 22, 2000 7465
MgSO4, filtered, and concentrated under reduced pressure.
Flash column chromatography (silica gel, elution with hex-
anes-EtOAc, 25:1) furnished 530 mg (1.31 mmol, 60%) of a
diastereomeric mixture of 40a ,b, as well as 316 mg (0.84 mmol,
38.5%) of educt alcohol, resulting from reduction of the
aldehyde by the Grignard reagent. Aldehyde: Rf 0.67 (hex-
anes-EtOAc, 10:1, CM, blue). 40a : Rf 0.53 (hexanes-EtOAc,
4-[(1E,3S,5Z,8R/S,10S)-3,11-Bis{[ter t-bu tyl(d im eth yl)-
silyl]oxy}-2,6,10-tr im eth yl-8-(p h en ylsu lfon yl)u n d eca -1,5-
d ien yl]-2-m eth yl-1,3-th ia zole. To a solution of 18b (5.65 g,
12.68 mmol) and 18-crown-6 (6.7 g, 25.35 mmol) in dry THF
(350 mL) was added a solution of KHMDS (3.59 g, 17.11 mmol)
in dry THF (50 mL) at -78 °C, and the mixture was stirred
for 1 h. A solution of the above crude allylic iodide in dry THF
(60 mL) was added dropwise at -78 °C, and the reaction
mixture was stirred for 1 h. The cooling bath was removed,
and the reaction was quenched by addition of saturated
aqueous NH4Cl (250 mL) and extracted with Et2O (3 × 100
mL). The combined organic solutions were washed with
saturated aqueous Na2S2O3, dried over MgSO4, filtered through
a short pad of silica gel, and concentrated. The residue was
purified by two chromatographies (silica gel, (1) elution with
hexanes-EtOAc, 10:1-5:1; (2) elution with hexanes-EtOAc,
10:1) to give 8.19 g of the sulfones as a diastereomeric mixture
contaminated with 18b. The latter was separated by a third
chromatography (silica gel, elution with CH2Cl2): Rf 0.54
(hexanes-EtOAc, 3:1, A, violet); IR (film) 1506, 1472, 1462,
1447, 1388, 1361, 1305, 1256 cm-1; MS (FI) m/e 693 (M + H)+.
Desu lfon a t ion t o 42b . To a solution of the above dia-
stereomeric sulfones (580 mg, 0.84 mmol) and Na2HPO4 (175
mg, 1.23 mmol) in MeOH-THF (2:1, 12 mL) was added 5%
sodium-mercury amalgam (1.47 g, 3.19 mmol) at -15 °C.
After 30 min the cooling bath was removed and the mixture
was allowed to warm to room temperature over a period of 90
min. The mixture was filtered, the filter pad was washed Et2O
and water, the layers of the filtrate were separated, and the
organic phase was washed with NH4Cl. The organic solution
was dried over MgSO4, filtered through a short pad of silica
gel, and concentrated under reduced pressure. Flash column
chromatography (silica gel, elution with hexanes-EtOAc, 25:
1) gave 300 mg (543.5 mmol, 65%) 42b as a colorless oil: Rf
10:1, CM, blue); [R]20 -22.6 (c 2.32, CHCl3); IR (film) 3500
D
br, 1472, 1464, 1389, 1362, 1256, 1101, 1048, 1004 cm-1; H
1
NMR (CDCl3, 400 MHz) δ 4.29 (s, 1H), 3.71 (m, 1H), 3.63 (m,
2H), 1.92 (mc, 1H), 1.70 (mc, 1H), 1.35 (m, 2H), 1.00 (t, J )
7.0 Hz, 3H), 0.97 (s, 3H), 0.90 (s, 9H), 0.88 (s, 9H), 0.73 (s,
3H), 0.112 (s, 3H), 0.11 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 80.5, 77.4, 60.1, 40.7, 36.0, 26.1,
25.9, 24.5, 23.5, 20.5, 18.24, 18.20, 11.3, -3.9, -4.3, -5.27,
-5.31; MS (FI) m/e 405 (M+). Anal. Calcd for C21H48O3Si2: C,
62.2; H, 12.0. Found: C, 62.57; H, 11.98. 40b: Rf 0.44
(hexanes-EtOAc, 10:1, CM, blue); IR (film) 3484 br, 1472,
1
1256, 1094 cm-1; H NMR (CDCl3, 400 MHz) δ 3.75 (m, 2H),
3.68 (td, J ) 9.5, 4.5 Hz, 1H), 3.33 (ddd, J ) 10.0, 4.5, 1.5 Hz,
1H), 2.74 (dd, J ) 4.5, 1.0 Hz, 1H), 2.00 (mc, 1H), 1.49 (m,
2H), 1.29 (mc, 1H), 0.98 (t, J ) 7.0 Hz, 3H), 0.90 (s, 9H), 0.89
(s, 9H), 0.85 (s, 3H), 0.74 (s, 3H), 0.07 (s, 6H), 0.06 (s, 3H),
0.05 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 78.0, 75.5, 61.9,
42.8, 36.5, 26.1, 26.0, 24.2, 18.7, 18.5, 18.4, 18.3, 11.7, -3.6,
-4.4, -5.4; MS (FI) m/e 405 (M+).
(-)-(5S)-5,7-Bis{[ter t-bu tyl(d im eth yl)silyl]oxy}-4,4-d i-
m et h ylh ep t a n -3-on e (41). Met h od a . To a solution of 40
(495 mg, 1.22 mmol) in dry CH2Cl2 (60 mL) and pyridine (1
mL) was added DMP (778 mg, 1.84 mmol) at 0 °C, and the
suspension was stirred for 2 h. The mixture was diluted with
cold Et2O (100 mL), filtered, and washed with saturated
aqueous NaHCO3-Na2S2O3 (1:1). The organic solution was
dried over MgSO4, filtered through a short pad of silica gel,
and concentrated under reduced pressure to give 487 mg (1.21
mmol, 99%) of ketone 41 as a colorless oil.
0.74 (hexanes-EtOAc, 5:1, A, blue violet); [R]20 +8.4 (c 4.35;
D
CHCl3); IR (film) 1472, 1462, 1255, 1097 cm-1
;
1H NMR
Meth od b. To a solution of DIPA (110 µL, 0.78 mmol) in
dry THF (4 mL) was added n-BuLi (0.3 mL, 2.5 M in hexanes,
0.75 mmol) at -78 °C, and stirring was continued for 40 min
allowing to warm to room temperature. To the cooled solution
(-78 °C) of LDA was added via syringe a solution of 39 (220
mg, 0.57 mmol) in dry THF (2 mL), and the reaction was
stirred for 30 min. Then methyl iodide (0.5 mL, 9 mmol) was
added, the cooling bath was removed, and the mixture was
stirred for 90 min allowing to warm to 0 °C. The reaction was
quenched with saturated aqueous NH4Cl (10 mL), the phases
were separated, the aqueous phase was extracted with CH2Cl2,
and the combined organic solutions were dried over NaSO4,
filtered, and concentrated. Flash column chromatography
(silica gel, elution with 3% Et2O in hexanes) afforded 195 mg
(484 mmol, 85%) 41 as a colorless oil: Rf 0.44 (hexanes-
(CDCl3, 400 MHz) δ 6.90 (s, 1H), 6.44 (s, 1H), 5.12 (dd, J ≈
6.5, 6.4 Hz, 1H), 4.07 (dd, J ) 6.6, 6.5 Hz, 1H), 3.43 (dd, J )
9.5, 5.5 Hz, 1H), 3.33 (dd, J ) 9.5, 6.5 Hz, 1H), 2.70 (s, 3H),
2.24 (m, 2H), 1.99 (s, 3H), 1.97 (m, 2H), 1.65 (s, 3H), 1.39-
1.29 (m, 3H), 0.88 (s, 18H), 0.85 (d, J ) 6.5 Hz, 3H), 0.04 (s,
3H), 0.02 (s, 6H), 0.008 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
164.3, 153.3, 142.6, 136.9, 121.4, 118.7, 114.9, 79.1, 68.4, 35.8,
35.3, 33.2, 32.3, 26.0, 25.9, 25.8, 23.5, 19.2, 18.6, 16.7, 13.9,
-4.7, -5.4; MS (FI) m/e 553 (M + H)+. Anal. Calcd for C30H57
-
NO2SSi2: C, 65.3; H, 10.4; N, 2.5. Found: C, 65.51; H, 10.23;
N, 2.58.
(+)-(2S,6Z,9S,10E)-9-{[ter t-Bu t yl(d im et h yl)silyl]oxy}-
2,6,10-tr im eth yl-11-(2-m eth yl-1,3-th iazol-4-yl)u n deca-6,10-
d ien -1-ol (43b). To a solution of 42b (1.39 g, 2.51 mmol) in
MeOH-CH2Cl2 (1:1, 80 mL) was added CSA (583 mg, 2.51
mmol) at 0 °C. The mixture was stirred for 5 h allowing to
warm to 10 °C and then poured into saturated aqueous
NaHCO3 (150 mL) and extracted with Et2O. The combined
organic solutions were dried over MgSO4, filtered through a
short pad of silica gel, and concentrated under reduced
pressure. Flash column chromatography (silica gel, elution
with hexanes-EtOAc, 5:1) provided 1.1 g (2.5 mmol, 99%) of
43b as a colorless oil: Rf 0.11 (hexanes-EtOAc, 5:1, CM, blue);
[R]20D +9.5 (c 1.37; CHCl3); IR (film) 3385 br, 1461, 1449, 1253,
CH2Cl2, 1:1, A, violet blue); [R]20 -8.3 (c 2.1, CHCl3), ref 20,
D
[R]20 -7.3 (c 1.8, CHCl3); IR (film) 1472, 1462, 1255, 1097
D
1
cm-1; H NMR (CDCl3, 400 MHz) δ 4.06 (dd, J ) 7.5, 3.0 Hz,
1H), 3.62 (m, 2H), 2.51 (m, 2H), 1.50 (m, 2H), 1.10 (s, 3H),
1.04 (s, 3H), 0.99 (t, J ) 7.3 Hz, 3H), 0.88 (s, 9H), 0.87 (s, 9H),
0.08 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 215.6, 73.4, 60.1, 53.0, 37.3, 31.6, 26.1,
25.9, 22.2, 20.0, 18.3, 7.7, -4.1, -5.3; MS (FI) m/e 403 (M+).
Anal. Calcd for C21H46O3Si2: C, 62.6; H, 11.5. Found: C, 62.67;
H, 11.29.
1
1184, 1102, 1005 cm-1; H NMR (CDCl3, 400 MHz) δ 6.91 (s,
(+)-4-((1E,3S,5Z,10S)-3,11-Bis{[ter t-bu tyl(d im eth yl)si-
lyl]oxy}-2,6,10-tr im eth yl u n d eca -1,5-d ien yl)-2-m eth yl-1,3-
t h ia zole (42b ). 4-((1E,3S,5Z)-3-{[t er t -Bu t yl(d im et h yl)-
silyl]oxy}-7-iod o-2,6-d im eth ylh ep ta -1,5-d ien yl)-2-m eth yl-
1,3-th ia zole. To a solution of 25b (4.66 g, 12.68 mmol) in dry
CH3CN-diethyl ether (3:2, 100 mL) were added sequentially
Ph3P (4.33 g, 16.48 mmol), imidazole (1.16 g, 17.11 mmol), and
iodine (4.63 g, 17.75 mmol). After 60 min of stirring at room
temperature, Et2O (400 mL) was added. The precipitates were
filtered off, and the filtrate was washed with saturated
aqueous Na2S2O3, dried over MgSO4, filtered through a small
amount of silica gel, and concentrated under reduced pressure.
The crude allylic iodide was dried in high vacuo under
exclusion of light and then immediately used for the next step.
1H), 6.44 (s, 1H), 5.14 (dd, J ≈ 7.0, 6.9 Hz, 1H), 4.08 (dd, J )
6.6, 6.5 Hz, 1H), 3.43 (m, 1H), 3.39 (m, 1H), 2.69 (s, 3H), 2.24
(m, 2H), 1.98 (d, J ) 1.0 Hz, 3H), 1.96 (m, 2H), 1.66 (d, J )
1.0 Hz, 3H), 1.60 (m, 1H), 1.32-1.42 (m, 3H), 0.90 (d, J ) 6.5
Hz, 3H), 0.88 (s, 9H), 0.03 (s, 3H), -0.01 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 164.3, 153.2, 142.7, 136.8, 121.7, 118.7,
114.8, 79.2, 68.1, 35.7, 35.5, 33.1, 32.1, 25.8, 25.3, 23.4, 19.1,
18.2, 16.2, 13.9, -4.7, -4.9; MS (FI) m/e 439 (M + H)+. Anal.
Calcd for C24H43NO2SSi: C, 65.9; H, 9.9; N, 3.2. Found: C,
64.98; H, 9.79; N, 3.16.
(3S,6R,7S,8S,12Z,15S,16E)-1,3,15-Tr is{[ter t-b u t yl(d i-
m eth yl)silyl]oxy}-7-h yd r oxy-4,4,6,8,12,16-h exa m eth yl-17-
(2-methyl-1,3-thiazol-4-yl)heptadeca-12,16-dien-5-one (44b).20
(2S,6Z,9S,10E)-9-{[ter t-Bu tyl(d im eth yl)silyl]oxy}-2,6,10-

7466 J . Org. Chem., Vol. 65, No. 22, 2000
Mulzer et al.
t r im et h yl-11-(2-m et h yl-1,3-t h ia zol-4-yl)u n d eca -6,10-d i-
en a l. To a solution of 43b (983 mg, 2.25 mmol) in dry CH2Cl2
(80 mL) and dry pyridine (2 mL) was added DMP (1.24 g, 2.92
mmol) at 0 °C. The mixture was stirred for 4 h and then diluted
with Et2O (200 mL) and filtered through a short pad of silica
gel. The organic solution was washed with saturated aqueous
NaHCO3-Na2S2O3 (1:1, 100 mL), dried over MgSO4, filtered
through a short pad of silica gel, and concentrated under
reduced pressure. The crude aldehyde was azeotropically dried
from toluene and used without further purification in the next
step: aldehyde, Rf 0.26 (CH2Cl2, CM, blue); IR (film) 3385 br,
2956, 2927, 2856, 1461, 1449, 1253, 1184, 1102, 1005, 940, 888,
836, 776, 737 cm-1; 1H NMR (CDCl3, 400 MHz) δ 9.59 (d, J )
1.5 Hz, 1H), 6.91 (s, 1H), 6.44 (s, 1H), 5.15 (dd, J ≈ 6.6, 6.5
Hz, 1H), 4.07 (t, J ) 6.5 Hz, 1H), 2.69 (s, 3H), 2.18-2.33 (m,
3H), 2.06-2.00 (m, 2H), 1.99 (d, J ) 1.0 Hz, 3H), 1.72-1.64
(m, 1H), 1.65 (d, J ) 1.5 Hz, 3H), 1.43-1.30 (m, 3H), 1.07 (d,
J ) 6.5 Hz, 3H), 0.88 (s, 9H), 0.03 (s, 3H), -0.01 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 205.1, 164.3, 153.2, 142.4, 136.0,
122.1, 118.7, 115.0, 78.9, 46.3, 35.4, 31.8, 30.4, 25.8, 25.2, 23.4,
19.2, 18.2, 14.0, 13.3, -4.7, -5.0.
was removed and the reaction was quenched with saturated
aqueous NH4Cl (20 mL). The layers were separated, and the
aqueous phase was extracted with CH2Cl2. The combined
organic solutions were dried over MgSO4, filtered through a
short pad of silica gel, and concentrated under reduced
pressure. Chromatography of the residue (silica gel, elution
with hexanes-EtOAc, 25:1) provided 560 mg (588 mmol,
quantitative) of 45b as a colorless oil: Rf 0.56 (hexanes-
EtOAc, 10:1, V, blue); IR (film) 1256, 1102, 1005 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 6.90 (s, 1H), 6.44 (s, 1H), 5.12 (t, J ) 7.0
Hz, 1H), 4.07 (t, J ) 6.5 Hz, 1H), 3.87 (dd, J ) 7.5, 2.5 Hz,
1H), 3.75 (dd, J ) 7.0, 1.5 Hz, 1H), 3.66 (ddd, J ) 9.6, 9.0, 5.0
Hz, 1H), 3.56 (dd, J ) 7.5, 2.0 Hz, 1H), 3.13 (qd, J ) 6.5 Hz,
1H), 2.70 (s, 3H), 2.22 (m, 2H), 1.98 (d, J ) 1.0 Hz, 3H), 1.97-
1.90 (m, 2H), 1.64 (s, 3H), 1.40-1.30 (m, 4H), 1.28-1.24 (m,
2H), 1.21 (s, 3H), 1.03 (d, J ) 7.0 Hz, 3H), 1.01 (s, 3H), 0.89
(s, 9H), 0.88 (s, 9H), 0.875 (s, 3H), 0.876 (s, 9H), 0.871 (s, 9H),
0.08 (s, 3H), 0.053 (s, 3H), 0.047 (s, 3H), 0.03 (s, 3H), 0.02 (s,
3H), 0.017 (s, 3H), -0.01 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 218.2, 153.3, 142.5, 136.8, 121.6, 118.7, 114.9, 79.0, 77.5, 74.1,
61.0, 53.7, 45.0, 39.0, 38.1, 35.3, 32.6, 31.1, 26.2, 26.1, 26.0,
25.9, 24.9, 24.5, 23.5, 19.4, 19.2, 18.5, 18.3, 18.2, 17.5, 15.4,
13.9, -3.7, -3.8, -4.0, -4.7, -4.9, -5.3; MS (FI) m/e 953 (M+).
(3S,6R,7S,8S,12Z,15S,16E)-3,7,15-Tr is{[ter t-b u t yl(d i-
m eth yl)silyl]oxy}-1-h yd r oxy-4,4,6,8,12,16-h exa m eth yl-17-
(2-methyl-1,3-thiazol-4-yl)heptadeca-12,16-dien-5-one (46b).20
To compound 45b (540 mg, 0.57 mmol) dissolved in MeOH-
CH2Cl2 (1:1, 20 mL) was added CSA (132 mg, 0.57 mmol)
portionwise at 0 °C. The mixture was stirred for 4 h and then
diluted with CH2Cl2 (20 mL) and quenched with saturated
aqueous NaHCO3 (25 mL). The layers were separated, the
aqueous phase was extracted with CH2Cl2, and the combined
organic solutions were dried over MgSO4. The mixture was
filtered and concentrated under reduced pressure, and the
residue was subjected to flash column chromatography (silica
gel, elution with hexanes-EtOAc, 5:1) to afford 412 mg (0.49
mmol, 87%) of 46b as a colorless oil: Rf 0.32 (hexanes-EtOAc,
10:1, V, blue); IR (film) 3320 br, 1856, 1472, 1388, 1255, 1104,
1032 cm-1; 1H NMR (CDCl3, 400 MHz) δ 6.90 (s, 1H), 6.44 (s,
1H), 5.13 (t, J ) 7.5 Hz, 1H), 4.03-4.10 (m, 2H), 3.79 (dd, J )
7.1, 1.3 Hz, 1H), 3.63 (dd, J ) 6.0, 5.6 Hz, 2H), 3.12 (qd, J )
7.1, 6.7 Hz, 1H), 2.70 (s, 3H), 2.22 (m, 2H), 1.98 (d, J ) 0.9
Hz, 3H), 2.05-1.90 (m, 2H), 1.65 (s, 3H), 1.50-1.26 (m, 5H),
1.21 (s, 3H), 1.20-1.09 (m, 2H), 1.051 (s, 3H), 1.048 (d, J )
6.9 Hz, 3H), 0.92-0.86 (m, 30H), 0.10 (s, 3H), 0.06 (s, 9H),
0.03 (s, 3H), -0.01 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 218.2,
164.3, 153.3, 142.5, 136.7, 121.6, 118.7, 114.9, 79.0, 77.5, 73.1,
60.2, 17.8, 17.6, 15.6, 14.2, 13.9, -3.6, -3.8, -3.91, -3.93,
-4.7, -4.9; MS (FI) m/e 840 (M + H)+.
Ald ol 44b. To a solution of DIPA (441 mL, 3.14 mmol) in
dry THF (10 mL) was added dropwise n-BuLi (1.26 mL, 2.5 M
in hexanes, 3.14 mmol) at -78 °C, stirred for 15 min, and then
allowed to warm to room temperature over a period of 30 min.
To the cooled (-78 °C) LDA solution was added dropwise a
solution of 41 (1.27 g, 3.14 mmol) in dry THF (10 mL). The
reaction was stirred for 15 min and then allowed to warm to
-35 °C over a period of 45 min and finally cooled to -95 °C.
A solution of the above crude aldehyde in dry THF (5 mL) was
added dropwise and the reaction stirred for 90 min allowing
to warm to -80 °C. The cooling bath was removed, and the
reaction was quenched with saturated aqueous NH4Cl (50 mL)
and diluted with Et2O (50 mL). The layers were separated,
the aqueous phase was extracted with Et2O, and the combined
organic solutions were dried over MgSO4, filtered, and con-
centrated under reduced pressure. Flash column chromatog-
raphy (silica gel, elution with hexanes-EtOAc, 25:1) provided
1.31 g (1.56 mmol, 69%) of the syn aldol products as a
diastereoisomeric mixture (∼4:1), which was separated by
HPLC. 44b (desired isomer): Rf 0.14 (CH2Cl2, A, blue); IR
(film) 1472, 1463, 1444, 1389, 1366, 1257, 1198, 1132, 1075,
1006 cm-1; 1H NMR (CDCl3, 400 MHz) δ 6.90 (s, 1H), 6.44 (s,
1H), 5.12 (t, J ≈ 7.6 Hz, 1H), 4.08 (t, J ) 6.5 Hz, 1H), 3.89
(dd, J ) 7.5, 3.0 Hz, 1H), 3.66 (m, 1H), 3.59 (m, 1H), 3.29 (m,
1H), 2.70 (s, 3H), 2.23 (m, 2H), 1.98 (s, 3H), 1.90-2.02 (m, 2H),
1.77-1.69 (m, 1H), 1.65 (s, 3H), 1.67-1.57 (m, 1H), 1.53-1.43
(m, 3H), 1.35-1.24 (m, 2H), 1.20 (s, 3H), 1.08 (s, 3H), 1.01 (d,
J ) 7.0 Hz, 3H), 0.89 (s, 9H), 0.87 (s, 18H), 0.81 (d, J ) 7.0
Hz, 3H), 0.09 (s, 3H), 0.07 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H),
-0.01 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 222.2, 164.3,
153.3, 142.6, 136.9, 121.5, 118.7, 114.9, 79.1, 74.9, 74.2, 60.5,
54.0, 41.4, 37.9, 35.5, 35.3, 33.0, 32.4, 26.1, 25.9, 25.2, 23.5,
22.9, 20.5, 19.2, 18.3, 15.4, 13.9, 9.6, -3.8, -4.1, -4.7, -4.9,
-5.3. Undesired isomer: IR (film) 1472, 1462, 1255, 1183,
(3S,6R,7S,8S,12Z,15S,16E)-3,7,15-Tr is{[ter t-b u t yl(d i-
m eth yl)silyl]oxy}-4,4,6,8,12,16-h exa m eth yl-17-(2-m eth yl-
1,3-th iazol-4-yl)-5-oxoh eptadeca-12,16-dien oic acid (47b).20
To a solution 46b (389 mg, 0.46 mmol) and dry pyridine (1
mL) in dry CH2Cl2 (50 mL) was added DMP (258 mg, 0.60
mmol) at room temperature. The mixture was stirred for 2 h
and then diluted with Et2O (150 mL); the precipitate was
separated by filtration and washed with Et2O. The filtrate was
washed with saturated aqueous NaHCO3-Na2S2O3 (1:1, 100
mL), dried over MgSO4, filtered through a short pad of silica
gel, and concentrated under reduced pressure to afford the
crude aldehyde: Rf 0.56 (hexanes-EtOAc, 5:1, A and V, blue).
To a solution of the above crude aldehyde in tert-butyl
alcohol (10.3 mL) and 2,3-dimethyl-but-2-ene (10.3 mL) was
added a solution of NaClO2 (211 mg, 2.32 mmol) and NaH2-
PO4 (211 mg) in water (2.11 mL). The mixture was stirred for
40 min and then diluted with CH2Cl2/water (2:1, 150 mL) and
slightly acidified with two drops of TFA. The layers were
separated, the aqueous phase was extracted with CH2Cl2, and
the combined organic solutions were dried over MgSO4,
filtered, and concentrated under reduced pressure. The residue
was subjected to flash column chromatography (silica gel,
elution with hexanes-EtOAc, 10:1-5:1-3:1) providing 380 mg
(0.45 mmol, 96%) of the acid 47b as a viscous colorless oil: Rf
1
1104, 1032 cm-1; H NMR (CDCl3, 400 MHz) δ 6.90 (s, 1H),
6.45 (s, 1H), 5.14 (t, J ) 7.0 Hz, 1H), 4.08 (t, J ) 7.0 Hz, 1H),
4.03 (dd, J ) 7.0, 3.5 Hz, 1H), 3.69-3.58 (m, 2H), 3.47 (s, 1H),
3.40 (d, J ) 8.0 Hz, 1H), 3.22 (qd, J ) 7.0, 2.0 Hz, 1H), 2.70
(s, 3H), 2.18-2.30 (m, 2H), 1.99 (d, J ) 1.0 Hz, 3H), 2.00-
1.90 (m, 2H), 1.67 (s, 3H), 1.58 (m, 1H), 1.51 (m, 3H), 1.41-
1.29 (m, 3H), 1.14 (s, 3H), 1.10 (s, 3H), 1.05 (d, J ) 6.5 Hz,
3H), 0.97 (d, J ) 6.5 Hz, 3H), 0.88 (s, 18H), 0.87 (s, 9H), 0.81
(d, J ) 7.0 Hz, 3H), 0.10 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H),
0.03 (s, 3H), 0.02 (s, 3H), -0.01 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 221.8, 164.3, 153.2, 142.5, 136.6, 121.7, 118.7, 114.9,
79.0, 75.1, 72.7, 60.2, 54.3, 41.4, 37.8, 35.5, 35.4, 32.9, 32.3,
26.2, 25.9, 25.8, 25.2, 23.6, 22.8, 19.6, 19.2, 18.4, 15.5, 13.9,
10.8, -3.7, -4.0, -4.7, -4.9, -5.3.
(3S,6R,7S,8S,12Z,15S,16E)-1,3,7,15-Tetr a k is{[ter t-bu tyl-
(d im eth yl)silyl]oxy}-4,4,6,8,12,16-h exa m eth yl-17-(2-m eth -
yl-1,3-th ia zol-4-yl)h ep ta d eca -12,16-d ien -5-on e (45b).20 To
a solution of 44b (493 mg, 0.59 mmol) and 2,6-lutidine (250
mL, 1.76 mmol) in dry CH2Cl2 (15 mL) was added TBSOTf
(203 µL, 0.88 mmol) at 0 °C. After 3 h at 0 °C the cooling bath
0.30 (hexanes-EtOAc, 5:1, A and V, violet blue); [R]20 -3.1
D
(c 1.37; CHCl3); ref 20, -2.9 (c 0.8, CHCl3); IR (film) 1714, 1472,

Total Syntheses of Epothilones B and D
J . Org. Chem., Vol. 65, No. 22, 2000 7467
1
1255, 1102 cm-1; H NMR (CDCl3, 400 MHz) δ 6.92 (s, 1H),
(4S,7R,8S,9S,13Z,16S)-4,8-Dih yd r oxy-5,5,7,9,13-p en ta -
methyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-
oxa cycloh exa d ec-13-en e-2,6-d ion e (Ep oth ilon e D, 4). To
a solution of 49 (75 mg, 0.104 mmol) in dry THF (5 mL) and
dry pyridine (1.5 mL) was added HF‚pyridine (1.5 mL) at 0
°C allowing to warm to room temperature over 18 h. To the
mixture was added another 1 equiv of HF‚pyridine (1.5 mL)
at 0 °C and stirred for additional 18 h at room temperature.
At 0 °C the mixture was quenched by slowly adding saturated
aqueous NaHCO3, diluted with Et2O. The layers were sepa-
rated, and the aqueous phase was extracted with Et2O. The
combined organic solutions were washed with aqueous CuSO4,
dried over MgSO4, filtered, and concentrated under reduced
pressure. The residue was subjected to chromatography (silica
gel, elution with hexanes-EtOAc, 3:1) providing 49 mg (81
µmol, 78%) of a monodesilylated product (Rf 0.19, hexanes-
EtOAc, 3:1, V, blue) and 10 mg (19.6 µmol, 20%) of 4
(epothilone D). The former was again subjected to the above
conditions to obtain all together 49 mg (99.7 µmol, 96%) of
6.63 (s, 1H), 5.17 (t, J ) 7.0 Hz, 1H), 4.40 (dd, J ) 7.0, 3.5 Hz,
1H), 4.12 (m, 1H), 3.74 (dd, J ) 5.5, 2.0 Hz, 1H), 3.13 (qd, J )
7.0, 6.0 Hz, 1H), 2.70 (s, 3H), 2.43 (dd, J ) 16.6, 3.5 Hz, 1H),
2.33 (dd, J ) 16.6, 6.5 Hz, 1H), 2.22-2.12 (m, 2-3H), 1.94 (d,
J ) 1.0 Hz, 3H), 1.94-1.86 (m, 2H), 1.67 (s, 3H), 1.50-1.35
(m, 5H), 1.15 (s, 6H), 1.06 (d, J ) 7.0 Hz, 3H), 0.89 (s, 9H),
0.885 (s, 3H), 0.88 (s, 18H), 0.12 (s, 3H), 0.08 (s, 9H), 0.07 (s,
3H), 0.03 (s, 9H), 0.02 (s, 3H), -0.02 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 218.2, 174.0, 165.3, 152.7, 143.7, 137.1, 121.7,
118.1, 114.4, 79.2, 76.7, 73.1, 63.7, 54.0, 44.2, 39.9, 39.5, 35.4,
33.9, 32.5, 31.7, 26.2, 26.1, 25.8, 25.6, 24.9, 23.5, 23.4, 18.7,
18.6, 18.5, 18.3, 16.4, 15.8, 14.0, -3.9, -4.0, 4.1, -4.5, -4.7,
-5.0; MS (FI) m/e 854 (M + H)+.
(3S,6R,7S,8S,12Z,15S,16E)-3,7-Bis{[ter t-bu tyl(d im eth -
yl)silyl]oxy}-15-h yd r oxy-4,4,6,8,12,16-h exa m eth yl-17-(2-
m eth yl-1,3-th iazol-4-yl)-5-oxoh eptadeca-12,16-dien oic acid
(48b).20 To a solution of 47b (365 mg, 0.45 mmol) in dry THF
(10 mL) was added TBAF (2.23 mL, 1 M in THF, 2.23 mmol).
The reaction mixture was stirred for 10 h at room temperature
and then quenched by addition of saturated aqueous NH4Cl
(70 mL) and extracted with Et2O (4 × 25 mL). The combined
organic solutions were dried over MgSO4, filtered, and con-
centrated under reduced pressure. The residue was purified
by flash column chromatography (silica gel, elution with
CH2Cl2-hexanes-EtOAc, 6:5:1-4:3:1-2:1:1) providing 180 mg
(0.244 mmol, 55%) of 48b and 27 mg of recycled educt (47b)
as colorless oils. 48b: Rf 0.47 (hexanes-EtOAc, 1:1, A and V,
blue violet); [R]20 -10.9 (c 1.37; CHCl3), ref 20, [R]20 -10.4
epothilone D (4): Rf 0.11 (hexanes-EtOAc, 3:1, V, blue); [R]20
D
-89 (c 0.37; CHCl3), ref 20, [R]20D -91.5 (c 0.3, CHCl3); 1H NMR
(CDCl3, 400 MHz) δ 6.94 (s, 1H), 6.57 (s, 1H), 5.21 (dd, J )
10.0, 1.5 Hz, 1H), 5.13 (dd, J ) 10.0, 5.0 Hz, 1H), 4.28 (dd, J
) 11.0, 2.5 Hz, 1H), 3.71 (dd, J ) 4.0, 2.5 Hz, 1H), 3.45 (br s,
1H), 3.15 (qd, J ) 6.9, 2.5 Hz, 1H), 3.02 (br s, 1H), 2.68 (s,
3H), 2.63 (dt, J ) 15.1, 10.0 Hz, 1H), 2.45 (dd, J ) 14.6, 11.0
Hz, 1H), 2.35-2.29 (m, 1H), 2.28 (dd, J ) 14.6, 3.0 Hz, 1H),
2.22 (ddd, J ) 15.6, 3.5, 2.0 Hz, 1H), 2.06 (d, J ) 1.0 Hz, 3H),
1.89-1.83 (m, 1H), 1.78-1.68 (m, 2H), 1.65 (s, 3H), 1.33 (s,
3H), 1.31-1.24 (m, 4H), 1.18 (d, J ) 7.0 Hz, 3H), 1.06 (s, 3H),
1.01 (d, J ) 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 220.7,
170.4, 165.0, 152.0, 139.2, 138.4, 120.9, 119.2, 115.6, 78.9, 74.1,
72.3, 53.5, 41.7, 39.6, 38.4, 32.5, 31.9, 31.7, 31.6, 25.4, 22.9,
19.0, 18.0, 15.9, 15.7, 13.4.
D
D
(c 0.4, CHCl3); IR (film) 3357 br, 1696, 1472, 1387, 1255, 1186
cm-1; H NMR (CDCl3, 400 MHz) δ 6.94 (s, 1H), 6.63 (s, 1H),
1
5.17 (t, J ) 7.0 Hz, 1H), 4.40 (dd, J ) 6.0, 4.0 Hz, 1H), 4.14 (t,
J ≈ 6.5 Hz, 1H), 3.76 (dd, J ) 7.0, 2.0 Hz, 1H), 3.14 (qd, J )
7.0, 6.5 Hz, 1H), 2.70 (s, 3H), 2.435 (dd, J ) 16.6, 4.0 Hz, 1H),
2.33 (mc, 2H), 2.26 (dd, J ) 16.6, 6.0 Hz, 1H), 2.14-2.04 (m,
1H), 2.01 (d, J ) 1.0 Hz, 3H), 2.01-1.92 (m, 1H), 1.70 (s, 3H),
1.56-1.48 (mc, 3H), 1.50-1.34 (m, 2H), 1.19 (s, 3H), 1.10 (s,
3H), 1.05 (d, J ) 6.5 Hz, 3H), 0.90 (d, J ≈ 7.0 Hz, 3H), 0.89 (s,
9H), 0.865 (s, 9H), 0.10 (s, 3H), 0.07 (s, 3H), 0.055 (s, 3H), 0.04
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 217.9, 174.9, 165.0,
152.7, 142.2, 139.4, 120.3, 118.7, 115.1, 77.4, 77.3, 74.2, 53.8,
51.9, 44.8, 40.9, 39.2, 34.2, 32.5, 31.3, 26.4, 26.3, 26.2, 26.1,
23.6, 23.1, 19.9, 18.9, 18.5, 18.2, 17.1, 16.0, 14.6, 13.8, -3.8,
-3.9, -4.1, -4.7; MS (FI) m/e 739 (M + H)+.
(1S,3S,7S,10R,11S,12S,16R)-7,11-Dih yd r oxy-8,8,10,12,
16-p en ta m eth yl-3-[( E)-1-m eth yl-2-(2-m eth yl-1,3-th ia zol-
4-yl)et h en yl]-4,17-d ioxa bicyclo[14.1.0]h ep t a d eca n e-5,9-
d ion e (Ep oth ilon e B, 2). To a solution of 4 (43 mg, 87.4 µmol)
in dry CHCl3 (3.5 mL) was added m-CPBA (32.5 mg, 0.13
mmol, 70% purity) at -18 °C. The reaction mixture was stirred
for 5 h at the same temperature and then diluted with CH2Cl2
(14 mL) and quenched by the addition of saturated aqueous
NaHCO3 (15 mL). The layers were separated, the aqueous
phase was extracted with CH2Cl2, and the combined organic
solutions were dried over MgSO4, filtered, and concentrated
under reduced pressure. The residue was subjected to chro-
matography (silica gel, elution with hexanes-EtOAc, 1:1)
providing 36 mg (71 µmol, 81%) of epothilone B and its epoxide
isomer as a 4-5:1 mixture, which were separated by HPLC
(20% i-PrOH in hexanes): Rf 0.32 (hexanes-EtOAc, 3:1, A,
gray blue); [R]20 -36 (c 0.2, MeOH), ref 20, [R]20 -34.3 (c
(4S,7R,8S,9S,13Z,16S)-4,8-Bis{[ter t-bu tyl(d im eth yl)si-
lyl]oxy}-5,5,7,9,13-pen tam eth yl-16-[(E)-1-m eth yl-2-(2-m eth -
yl-1,3-t h ia zol-4-yl)et h en yl]oxa cycloh exa d ec-13-en e-2,6-
dion e (49).20 A solution of N-ethyl-N’-(3-(dimethylamino)propyl)-
carbodiimide‚HCl (EDCI, 65 mg, 0.34 mmol), DMAP (54 mg,
0.51 mmol), and DMAP‚HCl (54 mg, 0.34 mmol) in dry CHCl3
(100 mL) was warmed to reflux. A solution of 48b (125 mg,
0.17 mmol) in dry CHCl3 (8 mL) was added over a period of
17 h with a syringe pump at the same temperature. The
reaction was cooled to room temperature and quenched with
saturated aqueous NH4Cl (100 mL). The layers were sepa-
rated, the aqueous phase was extracted with CH2Cl2, and the
combined organic extracts were dried over MgSO4, filtered
through a short pad of silica gel, and concentrated under
reduced pressure. Flash column chromatography (silica gel,
elution with hexanes-EtOAc, 25:1) provided 84 mg (0.12
mmol, 69%) of the macrolactone 49 as a light yellow oil: Rf
0.37 (hexanes-EtOAc, 10:1, A and V, violet blue); [R]20D -12.5
D
D
1
0.2, MeOH); H NMR (CDCl3, 400 MHz) δ 6.96 (s, 1H), 6.58
(s, 1H), 5.41 (dd, J ) 8.0, 3.0 Hz, 1H), 4.22 (br, 2H), 3.71 (t, J
) 4.0 Hz, 1H), 3.29 (qd, J ) 7.0, 4.0 Hz, 1H), 2.80 (dd, J )
7.5, 4.5 Hz, 1H), 2.69 (s, 3H), 2.65 (br, 1H), 2.53 (dd, J ) 14.1,
10.0 Hz, 1H), 2.35 (dd, J ) 13.5, 2.5 Hz, 1H), 2.13-2.06 (m,
1H), 2.08 (s, 3H), 1.91 (dd, J ) 15.6, 8.0 Hz, 1H), 1.77-1.65
(m, 3H), 1.54-1.46 (m, 2H), 1.45-1.35 (m, 3H), 1.36 (s, 3H),
1.27 (s, 3H), 1.16 (d, J ) 7.0 Hz, 3H), 1.07 (s, 3H), 0.99 (d, J
) 7.0 Hz, 3H).
Ack n ow led gm en t. This research was supported by
the Schering AG (Berlin). We gratefully acknowledge
Dr. H. Kalchhauser for special NMR, Dr. Harry J .
Martin for technical advice, and S. Schneider for HPLC
analyses.
(c 0.9, CHCl3), ref 20, [R]20 -11.8 (c 0.8, CHCl3); 1H NMR
D
(CDCl3, 400 MHz) δ 6.95 (s, 1H), 6.55 (s, 1H), 5.15 (t, J ) 8.0
Hz, 1H), 4.96 (d, J ) 9.6 Hz, 1H), 4.02 (d, J ) 8.5 Hz, 1H),
3.88 (d, J ) 9.0 Hz, 1H), 3.01 (qd, J ) 7.0, 6.5 Hz, 1H), 2.79
(dd, J ) 16.6, 1.5 Hz, 1H), 2.69 (s, 3H), 2.71-2.62 (m, 2H),
2.49-2.41 (m, 1H), 2.09 (d, J ) 1.0 Hz, 3H), 2.08-2.02 (m,
2H), 1.77-1.66 (m, 2H), 1.66 (s, 3H), 1.61-1.47 (m, 3H), 1.18
(s, 3H), 1.13 (s, 3H), 1.09 (d, J ) 6.5 Hz, 3H), 0.97 (d, J ) 7.0
Hz, 3H), 0.93 (s, 9H), 0.83 (s, 9H), 0.10 (s, 3H), 0.095 (s, 3H),
0.07 (s, 3H), -0.12 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 215.1,
171.2, 164.5, 152.5, 140.6, 138.8, 119.4, 119.2, 115.9, 79.9, 76.3,
53.4, 39.2, 32.5, 31.9, 31.4, 29.7, 27.4, 26.4, 26.2, 25.7, 24.5,
24.3, 23.1, 19.2, 18.7, 18.6, 17.8, 15.3, -3.3, -3.69, -3.70, -5.6.
Su p p or tin g In for m a tion Ava ila ble: Text giving experi-
mental procedures and complete characterization (1H and
13C NMR and IR spectra and mass spectral data) for new
compounds not included in the Experimental Section. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O0007480