Total syntheses of epothilones B and D

Article abstract of DOI:10.1021/jo048742o

A convergent, total synthesis of epothilones B (2) and D (4) is described. The key steps are Normant coupling to establish the desired (Z)-stereochemistry at C12-C13, Wadsworth-Emmons olefination of methyl ketone 28 with the phosphonate ester 8, diastereoselective aldol condensation of aldehyde 5 with the enolate of keto acid derivatives to form the C6-C7 bond, selective deprotection of acid 52, and macrolactonization.

Full text of DOI:10.1021/jo048742o

Total Syntheses of Epothilones B and D
Jae-Chul Jung, Rajashaker Kache, Kimberly K. Vines, Yan-Song Zheng, Panicker Bijoy,
Muralikrishna Valluri, and Mitchell A. Avery*,†
Department of Medicinal Chemistry, School of Pharmacy, Department of Chemistry, and
National Center for Natural Products Research, University of Mississippi, P.O. Box 1848,
University, Mississippi 38677-1848
mavery@olemiss.edu
Received July 22, 2004
A convergent, total synthesis of epothilones B (2) and D (4) is described. The key steps are Normant
coupling to establish the desired (Z)-stereochemistry at C12-C13, Wadsworth-Emmons olefination
of methyl ketone 28 with the phosphonate ester 8, diastereoselective aldol condensation of aldehyde
5 with the enolate of keto acid derivatives to form the C6-C7 bond, selective deprotection of acid
52, and macrolactonization.
Introduction
The naturally occurring macrolactones, epothilones A
(1) and B (2), first isolated and characterized by Ho¨fle et
al. from the myxobacterium Sorangium cellulosum, have
evoked a great deal of interest in recent years due to their
novel molecular architecture and taxol-like, antitumor
mechanism of action.1 Both the taxanes and the epo-
thilones exert their therapeutic effects by promoting
tubulin polymerization and the formation of stable mi-
crotubules, thereby causing cell death through disruption
of the normal microtubule dynamics. Since the discovery
of the epothilones in 1993, more than 500 reports have
been published,2,3 further indicating the interest in this
class of compounds. Taxol (paclitaxel) is currently used
in the chemotherapy of a broad range of tumor types
including breast, ovarian, lung, head, neck, and AIDS-
related cancers (Karposi’s sarcoma). Taxol also has
activity in malignancies that are refractory to conven-
tional chemotherapy, including previously treated lym-
phoma and small-cell lung cancers. Unfortunately, the
effectiveness of taxol has been hampered by the emer-
gence of multidrug resistance and by side effects4 (hy-
persensitivity, neurotoxicity, and hematological toxicity).
Furthermore, the development of multidrug resistance
in patients treated with Taxol fuels the need for the
development of additional chemotherapeutics which pos-
sess potency equal to or greater than Taxol without the
associated undesirable characteristics. Most significantly,
epothilones, unlike paclitaxel (Taxol), are equally active
FIGURE 1. Structures of epothilones A-D (1-4).
against drug-sensitive and multidrug-resistant cancer
cell lines in vitro and epothilone B has shown potent in
vivo antitumor activity in Taxol-resistant human tumor
models. Epothilone B is currently undergoing phase II
clinical trials.5
Epothilone B is superior to Taxol in the areas of
solubility, potency, and effectiveness against Taxol-
resistant cancer cell lines. Our interest in the epothilones
(3) (a) Meng, D.; Bertinato, P.; Balog, A.; Su, D. S.; Kamenecka, T.;
Sorensen, E.; Danishefsky, S. J. J. Am. Chem. Soc. 1997, 119, 10073-
10092. (b) Nicolaou, K. C.; He, Y.; Vourloumis, D.; Vallberg, H.;
Roschanger, F.; Sarabia, F.; Ninkovic, S.; Yang Z.; Trujillo, J. I. J. Am.
Chem. Soc. 1997, 119, 7960-7973. (c) 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. (d) Schinzer, D.;
Limberg, A.; Bauer, A.; Boehm, O. M.; Cordes, M. Angew. Chem., Int.
Ed. Engl. 1997, 36, 523-524. (e) Schinzer, D.; Bauer, A.; Scieber, J.
Synlett 1998, 861-864. (f) May, S. A.; Grieco, P. A. Chem. Commun.
1998, 1597-1598. (g) White, J. D.; Carter, R. G.; Sundermann, K. F.;
Wartmann, M. J. Am. Chem. Soc. 2001, 123, 5407-5413. (h) Martin,
H. J.; Drescher, M.; Mulzer, J. Angew. Chem., Int. Ed. 2000, 39, 581-
583. (i) Sawada, D.; Shibasaki, M. Angew. Chem., Int. Ed. 2000, 39,
209-213. (j) Mulzer, J.; Mantoulidis, A.; O¨ hler, E. J. Org. Chem. 2000,
65, 7456-7467. (k) Bode, J. W.; Carreira, E. M. J. Am. Chem. Soc.
2001, 123, 3611-3612. (l) Sun, J.; Sinha, S. C. Angew. Chem., Int. Ed.
2002, 41, 1381-1383. (m) Liu, Z. Y.; Chen, Z. C.; Yu, C. Z.; Wang, R.
F.; Zhang, R. Z.; Huang, C. S.; Yan, Z.; Cao, D. R.; Sun, J. B.; Li, G.
Chem. Eur. J. 2002, 8, 3747-3756. (n) Altmann, K. H.; Bold, G.;
Caravatti, G.; Denni, D.; Flo¨rsheimer, A.; Schmidt, A.; Rihs, G.;
Wartmann, M. Helv. Chim. Acta 2002, 85, 4086-4110.
† Department of Medicinal Chemistry, School of Pharmacy, Depart-
ment of Chemistry, and National Center for Natural Products Re-
search.
(1) (a) Ho¨fle, G.; Bedorf, N.; Steinmetz, H.; Schomburg, D.; Gerth,
K.; Reichenbach, H. Angew. Chem. 1996, 108, 1671-16773; Angew.
Chem., Int. Ed. Engl. 1996, 35, 1567-1569. (b) Gerth, K.; Bedorf, N.;
Ho¨fle, G.; Irschik, H.; Reichenbach, H. J. Antibiot. 1996, 49, 560-563.
(c) Hardt, I. H.; Steinmetz, H.; Gerth, K.; Sasse, F.; Reichenbach, H.;
Ho¨fle, G. J. Nat. Prod. 2001, 64, 847-856.
(2) Reviews: (a) Nicolaou, K. C.; Roschanar, F.; Vourloumis, D.
Angew. Chem. 1998, 110, 2121-2153. (b) Mulzer, J. J. Chem. Mon.
2000, 131, 205-238.
(4) (a) Mekhail, T. M.; Markman, M. Expert Opin. Pharmacother.
2002, 3, 755-766. (b) 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.
10.1021/jo048742o CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/18/2004
J. Org. Chem. 2004, 69, 9269-9284
9269

Jung et al.
FIGURE 2. General synthetic approaches of epothilone B (2).
stems from a desire to perform SAR (structure activity
relationship) studies with respect to the C3 and C7
positions. Therefore, a practical synthetic route of
epothilones B (2) and D (4) was needed. The major
approaches to the syntheses of epothilones B (2) and D
(4) fall into three categories (Figure 2). Key steps in the
first approach include an aldol reaction of acetate B and
aldehyde C to construct the C2-C3 bond of A followed
by ring-closing olefin metathesis to furnish the C12-C13
olefin of epothilone B (2).3a Another strategy employed
an aldol reaction between aldehyde E and keto acid F to
provide the C6-C7 bond of acid D, which could then
undergo ring closure via macrolactonization to give
epothilone B (2).3b,c,e,j,n In an alternative approach, Cas-
tro-Stephens coupling of allylic halide H with terminal
alkyne I generated the C10-C11 bond of dienyne G,
which was converted to epothilone B (2) via macro-
lactonization.3g In a preliminary communication,6 we
reported the total synthesis of epothilone B (2). Key steps
include an aldol reaction to establish the C6-C7 bond
and macrolactonization to afford epothilone B (2) (Scheme
1). Herein, we describe the details of the total synthesis
of epothilones B (2) and D (4) and improvements made
to our previous route.
Results and Discussion
Retrosynthetic analysis of epothilones B (2) and D (4)
reveals a convergent, two-step sequence involving a
double-diastereoselective aldol condensation of aldehyde
5 and keto acid 9 (derived from acetyl sultam 10 and keto
aldehyde 11), followed by Yamaguchi macrolactonization7
to give the target framework (Scheme 1). The (Z)-olefin,
an essential feature of the epothilones, has traditionally
been prepared by Wittig olefination methods or ring-
closing metathesis approaches. We envisioned utilizing
the classic Normant alkyne cupration reaction and elec-
trophile trapping to not only establish the necessary (Z)-
stereochemistry of olefin 5 but also fix the stereochem-
istry at C9 (5) in a single step. Organocuprate 7, propyne,
and PMB-protected epoxy alcohol 6 could be coupled to
accomplish this goal. Furthermore, the resulting Nor-
(5) (a) Grever, M. R.; Schepartz, S. A.; Chabner, B. A. Semin. Oncol.
1992, 19, 622-638. (b) Bollag, D. M.; McQueney, P. A.; Zhu, J.;
Hensens, O.; Koupal, L.; Liesch, J.; Goetz, M.; Lazarides, E.; Woods,
C. M. Cancer Res. 1995, 55, 2325-2333. (c) Kowalski, R. J.; Gianna-
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Wartmann, M.; Altmann, K.-H. Curr. Med. Chem.: Anti-Cancer Agents
2002, 2, 123-148.
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56, 7859-7868. (b) Hindupur, R. M.; Panicker, B.; Valluri, M.; Avery,
M. A. Tetrahedron Lett. 2001, 42, 7341-7344. (c) Valluri, M.; Hindu-
pur, R. M.; Bijoy, P.; Labadie, G.; Jung, J. C.; Avery, M. A. Org. Lett.
2001, 3 (23), 3607-3609.
(7) Iranaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. Jpn. 1979, 52, 1989-1993.
9270 J. Org. Chem., Vol. 69, No. 26, 2004

Total Syntheses of Epothilones B and D
SCHEME 1. Retrosynthetic Analysis of Epothilone B (2)
SCHEME 2. Synthesis of Epoxide 6a
SCHEME 3. Synthesis of Bromide 18a
a Reagents and conditions: (a) D-(-)-DIPT, molecular sieves
(powdered, 4 Å), tert-butyl hydroperoxide, Ti(Oi-Pr)4, CH2Cl2, -23
°C, 2 d, 37%; (b) 4-methoxybenzyl bromide, NaH (60%), Bu4NI,
THF, 0 °C, 6 h, 86%.
a Reagents and conditions: (a) CH3C(OEt)3/propionic acid, 170
°C, 1 h (quantitative yield); (b) LiAlH4, ether, -5 °C to 0 °C, 2 h,
then rt 3 h, 70%; (c) p-TsCl, TEA, CH2Cl2, 0 °C, 30 min, then rt 3
h, 73%; (d) LiBr, acetone, reflux, 2 h, 69%.
mant alkyne cupration product would provide easy access
to fragment 5 through a reaction sequence involving
deprotection, oxidation, and Wadsworth-Horner-Em-
mons condensation.
SCHEME 4. Synthesis of Phosphonate 8a
Preparation of Aldehyde 5. Synthesis of fragment
5 first required the development of a suitable method for
preparing PMB-protected alcohol 6 (Scheme 2). This was
accomplished by subjecting commercially available ra-
cemic 3-buten-2-ol (12) to Sharpless asymmetric epoxi-
dation.8 The crude product was purified first by vacuum
distillation followed by column chromatography to give
pure (2S,3R)-epoxy alcohol 13. Compound 13 was pro-
tected as the PMB ether with freshly prepared 4-meth-
oxybenzyl bromide [prepared by treating 4-methoxy-
benzyl alcohol in ether with phosphorus tribromide at 0
°C for 2 h]9 in the presence of sodium hydride to give 6
in 86% yield.
Bromide 18, also required for the Normant coupling
reaction, was easily prepared as shown in Scheme 3.
Commercially available alcohol 14 underwent Claisen
rearrangement to afford ethyl ester 15.10 Without further
purification, 15 was reduced with LiAlH4 in ether to yield
volatile alcohol 16 in 70% yield. Tosylation of 16 (73%)
followed by displacement of the tosylate of 17 gave
bromide 18 in 69% yield.11 The synthesis of phosphonate
8, the third fragment required for the Normant reaction,
a Reagents and conditions: (a) ethyl bromopyruvate, EtOH, rt,
20 h, 70%; (b) LiAlH4, ether, -78 °C, 3 h, 84%; (c) Ph3P, CBr4,
CCl4, rt, 3 h, 85%; (d) 1,3-dichloroacetone, rt to 50 °C, 20 h, 93%;
(e) P(OEt)3, 160 °C, 3 h, 86%.
was accomplished by using two known synthetic methods
(Scheme 4). In the original approach, thioacetamide (19)
was treated with ethyl bromopyruvate to afford thiazole
20 (70%). Reduction of 20 with LiAlH4 afforded alcohol
21 in 84% yield. Bromination of 21 with CBr4/PPh3 gave
bromide 22 (85%), which was smoothly converted to
diethyl (2-methylthiazol-4-yl)methanephosphonate (8) in
86% yield following treatment with triethyl phosphite.12
In the current approach, phosphonate 8 is formed in a
two-step reaction by treating thioacetamide (19) with 1,3-
dichloroacetone to give thiazole 23.13,3j The crude product
was treated with triethyl phosphite to yield 8 (80%, two
(8) (a) Gao, Y.; Hanson, R. H.; Klunder, J. M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780. (b)
White, J. D.; Kang, M. C.; Sheldon, B. G. Tetrahedron Lett. 1983, 24
(42), 4539-4542.
(9) Charlton, J. L.; Alauddin, M. M. J. Org. Chem. 1986, 51, 3490-
3493.
(10) Gen, A. V. D.; Wiedhaup, K.; Swoboda, J. J.; Dunathan, H. C.;
Johnson, W. S. J. Am. Chem. Soc. 1973, 95, 2656-2663.
(11) Mazzocchi, P. H.; Wilson, P.; Khachik, F.; Klingler, L.; Minami-
kawa, S. J. Org. Chem. 1983, 48, 2981-2989.
(12) Schnizer, D.; Limberg, A.; Bo¨hm, O. M. Chem. Eur. J. 1996,
11, 1477-1482.
J. Org. Chem, Vol. 69, No. 26, 2004 9271

Jung et al.
SCHEME 5. Synthesis of Aldehyde 5a
a Reagents and conditions: (a) (i) Mg, ether, rt to reflux, 1 h; (ii) CuBr-DMS, ether, DMS, -45 °C, 2 h; (iii) propyne, -23 °C, 4 h, then
lithiohexyne, -78 °C, 1 h; (b) 6, -78 °C, 3 h; -25 °C, 14 h, 75%; (c) SEM-Cl, DIPEA, CH2Cl2, 0 °C; then rt, 6 h, 92%; (d) DDQ, CH2Cl2/H2O
(8:2), rt, 3 h, 91%; (e) DMSO, (COCl)2, TEA, CH2Cl2, -78 °C, 2 h, 85%; (f) 8, n-BuLi, THF, -78 °C, 1 h; then rt, 12 h, 86%; (g) (i-PC)2BH,
THF, rt, 30 min; then LiOH(aq), NaBO3(aq), rt, 2 h, 78%; (h) DMSO, (COCl)2, TEA, CH2Cl2, -78 °C, 1 h, (94%); or TPAP (5 mol %), NMO,
molecular sieves (powdered, 4 Å), CH2Cl2, 0 °C, 15 min, 72%; or Dess-Martin periodinane, CH2Cl2, rt, 30 min, 92%.
steps). The latter method is superior in that it allows
access to the desired phosphonate in only two steps and
in significantly higher yield.
followed by oxidative workup with aqueous lithium
hydroxide/sodium perborate furnished 30 (78%).
Swern oxidation of alcohol 30 gave the enantiomeri-
cally pure aldehyde 5 in 94% yield. Oxidation of 30 was
also accomplished by using Dess-Martin periodinane
(DMP)16 and tetrapropylammonium perruthenate (TPAP)/
NMO conditions.17 Although these latter conditions were
more convenient for scale-up due to shorter reaction time
and ease of handing, Swern oxidation afforded a superior
yield. With the completion of the synthesis of aldehyde
5, we had assembled the northern hemisphere of
epothilones B (2) and D (4).
Preparation of Enolizable Substrates. The next
key step in our synthesis involved the aldol coupling of
an enolizable substrate with fragment 5. Obtaining
maximum diastereoselectivity is the primary goal in a
reaction of this type. Therefore, we sought to determine
the conditions necessary to achieve this goal by varying
the enolizable substrate and the reaction conditions for
the aldol condensation (Table 1). In our original report,6b,c
keto acid 9 was used as the enolizable substrate resulting
in a 2:1 diastereomeric ratio of 44a:44b. Several deriva-
tives of keto acid 9 including sultam 34, Weinreb amide
35, TBS ether 41, OBO ester 42, and ABO ester 43 were
prepared to investigate the effect of steric bulk on the
diastereoselectivity of the aldol reaction.
Having completed the syntheses of fragments 6, 8, and
18 we could proceed with the assembly of aldehyde 5 via
the Normant olefination reaction14 (Scheme 5). The
Grignard reagent of bromide 18 was transmetalated by
using copper(I) bromide-dimethyl sulfide (CuBr-DMS)
at -23 °C, followed by chain elongation via the stepwise
addition of propyne and freshly prepared lithiohexyne
[1-hexyne treated with n-butyllithium and hexameth-
ylphosphoramide (HMPA) in ether at -78 °C for 1 h] in
ether at -78 °C to form the intermediate 24, which when
treated with 6 led to epoxide opening to provide (Z)-
alkene 25 in 75% yield.
Protection of the resulting hydroxyl of 25 with SEM-
Cl in the presence of DIPEA gave SEM ether 26 (92%).
Subsequent removal of the adjacent PMB protecting
group with DDQ gave alcohol 27 in 91% yield. Oxidation
of alcohol 27 was accomplished by using Swern conditions
to generate methyl ketone 28, which was subjected to
Wadsworth-Horner-Emmons olefination12 with phos-
phonate ester 8 to afford the (E)-olefin 29 in 86% yield.
Finally, asymmetric hydroboration of triene 29 with
freshly prepared bis(isopinocampheyl)borane [(i-PC)2BH]15
(13) (a) Ermolenko, M. S.; Potier, P. Tetrahedron Lett. 2002, 43,
2895-2898. (b) Arbuzov, B. A.; Lugovkin, B. P. Zh. Obshch. Khim.
1951, 21, 1869; Chem. Abstr. 1952, 46, 6122e. (c) Marzoni, G. J.
Heterocycl. Chem. 1986, 23, 577-580. (d) Gasteiger, J.; Herzig, C.
Tetrahedron 1981, 15, 2607-2611.
(14) (a) Normant, J. F. Synthesis 1972, 63-80. (b) Marfat, M.;
McGuirk, P.; Helquist, P. J. Org. Chem. 1979, 44, 3888-3092.
(15) (a) Wifely, G.; Ayyangar, N. R.; Takashi, M.; Brown, H. C. J.
Am. Chem. Soc. 1964, 86, 1076-1078. (b) Brown, H. C.; Joshi, N. N.
J. Am. Chem. Soc. 1988, 110, 4059-4061.
(16) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156.
(17) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639-666.
9272 J. Org. Chem., Vol. 69, No. 26, 2004

Total Syntheses of Epothilones B and D
TABLE 1. Effect of Structure of the Enolizable Substrate on Diastereoselectivity
a dr ) diastereoselective ratio; diastereoselectivity was determined based on isolation (substrates 9, 42, and 43) and HPLC (substrates
34, 35, and 41). b Isolated total yield. c Based on recovered starting material.
As shown in Scheme 6, sultam 34 was prepared in a
six-step reaction sequence. (+)-Camphor-10-sulfonic acid
31 was treated with thionyl chloride to afford the acid
chloride, which was subsequently treated with am-
monium hydroxide to give imine sultam in quantitative
yield. The imine sultam was reduced with sodium boro-
hydride to afford 2-camphorsultam 32 (66%) followed by
N-acetylation with acetyl chloride in the presence of
sodium hydride in toluene to give acetyl sultam 10 (62%
yield, four steps). Aldol condensation of acetyl sultam 10
with freshly prepared aldehyde 11 (Scheme 6) [isobutyl
aldehyde was treated with morpholine in benzene to
afford enamine, which was reacted with propionyl chlo-
ride in ether, 34% two steps yield]18 resulted in sultam-
3-ol 33 (88%). Compound 33 was protected with TBSOTf/
2,6-lutidine in dichloromethane to give 34 in 95% yield.3n
Enolizable substrate keto acid 9 could be prepared from
sultam 34 via hydrolysis with lithium hydroxide and
hydrogen peroxide in 76% yield.19 Weinreb amide 35 was
obtained from keto acid 9 in 88% yield with use of N,O-
dimethylhydroxylamine hydrochloride/DMAP/DCC. Gen-
eration of TBS ether 4120 was accomplished with two
routes. In the first method, treatment of sultam 34 with
LiBH4 resulted in reduction of both the amide and ketone
functionalities to give a diol 36. Selective silylation of the
primary C1 hydroxyl group resulted in TBS ether 37
(57% yield, two steps). Dess-Martin oxidation of the
secondary alcohol of 37 yielded 41 (80%). In an alternate
method,3n keto acid 9 was readily reduced with B(OMe)3/
BH3‚DMS to give primary alcohol 40. The C1 hydroxyl
of 40 was silylated with TBSCl/imidazole to afford TBS
ether 41 (51% yield, two steps).
The ortho esters 42 and 43 were prepared in two
steps.21 Reaction of keto acid 9 with 3-methoxy-3-oxet-
(19) (a) Inukai, T.; Yoshizwa, R. J. Org. Chem. 1967, 32, 404-407.
(b) Capet, M.; David, F.; Bertin, L.; Hardy, J. C. Synth. Commun. 1995,
25 (21), 3323-3327. (c) Oppolzer, W.; Moretti, R.; Thomi, S. Tetra-
hedron Lett. 1989, 30 (46), 5603-5606.
(20) Kalesse, M.; Quitschalle, M.; Claus, E.; Gerlach, K.; Pahl, A.;
Meyer, H. H. Eur. J. Org. Chem. 1999, 2817-2823.
(21) Suh, Y. G.; Jung, J. K.; Seo, S. Y.; Min, K. H.; Shin, D. Y.; Lee,
Y. S.; Kim, S. H.; Park, H. J. J. Org. Chem. 2002, 67, 4127-4137.
(18) Brabander, J.; Rosset, S.; Bernardinelli, G. Synlett 1997, 824-
826.
J. Org. Chem, Vol. 69, No. 26, 2004 9273

Jung et al.
SCHEME 6. Synthesis of Enolizable Substratesa
a Reagents and conditions: (a) (i) SOCl2, DMF (cat.), rt, 3 h, 99%; (ii) NH4OH/1,4-dioxane, rt, 2 h, then 95 °C, 4 h, 100%; (b) NaBH4,
MeOH/H2O, 5 °C, 1 h, 66%; (c) CH3COCl, NaH (60%)/toluene, rt, 16 h, 95%; (d) 11, Bu2BOTf, DIPEA/CH2Cl2, -78 °C, 1 h, 88%; (e)
TBSOTf, 2,6-lutidine/CH2Cl2, 0 °C, 1 h, 95%; (f) LiOH, H2O2, THF/H2O, 0 °C to rt, 4 h, 76%; (g) CH3ONHCH3‚HCl, DMAP, DCC/CH2Cl2,
rt, 1 h, 88%; (h) LiBH4/THF, rt, 20 h; (i) BH3‚Me2S, B(OMe)3/THF, 0 °C, 3 h; 15 °C, 6 h, 71%; (j) 3-methoxy-3-oxetanemethanol, DMAP,
DCC/CH2Cl2, rt, 1 h, 95%; (k) 2-methyloxiraneethanol, DMAP, DCC/CH2Cl2, rt, 1 h, 96%; (l) TBSCl, 2,6-lutidine/CH2Cl2, 0 °C, 1 h (57%,
two steps); (m) Dess-Martin periodinane, pyridine/CH2Cl2, 0 °C to rt, 2 h, 80%; (n) TBSCl, imidazole/CH2Cl2, 0 °C, 3 h, 72%; (o) BF3‚Et2O/
CH2Cl2, 20 °C, 3 h, 73%; (p) BF3‚Et2O/CH2Cl2, 10 °C, 1 h, 75%; or Cp2ZrCl2, AgClO4/CH2Cl2, 0 °C, 15 min, 93%.
anemethanol or 2-methyloxiraneethanol22 in the presence
of DMAP/DCC gave acyloxetane intermediates 38 and
39 in 95% and 96% yields, respectively. Acyloxetane
intermediates 38 and 39 underwent rearrangement when
treated with BF3‚Et2O or Cp2ZrCl2 (10 mol %) and AgClO4
(2 mol %) to afford OBO (2,6,7-trioxabicyclo[2.2.2]octyl)
ester 42 in 73% yield and ABO (2,7,8-trioxabicyclo[3.2.1]-
octyl) ester 43 in 75% yield.23
Diastereoselectivity of the Aldol Condensation.
The stereocontrolled aldol reaction to generate the C6-
C7 bond is one of the important strategic steps in the
construction of the epothilone framework. In our previous
report,6c a diastereomeric ratio of 2:1 was obtained with
keto acid 9 as the enolizable substrate. A recent report24
demonstrated that the diastereomeric ratio may be
greatly enhanced by increasing steric bulk on the eno-
lizable substrate six carbons removed from the reaction
site. The diastereoselectivity of the aldol condensation
is also sensitive to changes in reaction conditions (Table
1). As previously reported, the optimal conditions for the
aldol condensation of the parent keto acid 9 required
dilithiation [LDA (-78 to -40 °C) in THF] followed by
transmetalation with ZnCl2 at -78 °C.25 The diastereo-
meric mixture of the aldol products was cleanly separated
by flash column chromatography to give (6R,7S)-44a and
(6S,7R)-44b (2.3:1 ratio 44a:44b, 85% combined yield).
Aldol condensation of TBS ether 41 and aldehyde 5
afforded improved diastereoselectivity (3.2:1 ratio of
47a:47b, 72% combined yield).3j Although diastereo-
(24) Koch, G.; Loiseleur, O.; Fuentes, D.; Jantsch, A.; Altmann, K.
H. Org. Lett. 2002, 4 (22), 3811-3814.
(25) Nicolaou, K. C.; Winssinger, N.; Pastor, J.; Ninkovic, F.;
Sarabia, F.; He, Y.; Vourloumis, D.; Yang, Z.; Li, T.; Giannakaku, P.;
Hamel, E. Nature 1997, 387, 268-272.
(22) Srinivasan, R.; Chandrasekharam, M.; Vani, P. V. S. N.; Chida,
A. S.; Singh, A. K. Synth. Commun. 2002, 32 (12), 1853-1858.
(23) Wipf, P.; Xu, W.; Kim, H.; Takahashi, H. Tetrahedron 1997,
53 (48), 16575-16596.
9274 J. Org. Chem., Vol. 69, No. 26, 2004

Total Syntheses of Epothilones B and D
SCHEME 7. Protection of the C7 Hydroxyl of 44a as a Troc Ethera
a Reagents and conditions: (a) TBSCl (1.2 equiv), pyridine (10.0 equiv), CH2Cl2, 0 °C, 1 h; (b) Troc-Cl, CH2Cl2, rt, 5 h; (c) AcOH,
THF/H2O (8:2), 0 °C, 3 h, 36% yield for 52, 12% yield for 53, three steps; (d) 2,4,6-trichlorobenzoyl chloride (6.0 equiv), Et3N (10.0 equiv),
DMAP (10.0 equiv), CH2Cl2, -5 °C, 30 min, 90%.
selectivity was enhanced, the reaction failed to go to
completion. Aldol reactions with the Weinreb amide 35
and ortho esters 42 and 43 failed to enhance the dia-
stereoselectivity. The greatest enhancement in dia-
stereoselectivity was achieved with the titanium enolate
of sultam 34 (10:1 ratio of 45a:45b, 60% combined yield).
The enhancement in diastereoselectivity was not suf-
ficient to compensate for the low yields in both the aldol
condensation (60% yield) and the hydrolysis of the
resulting sultam 45a (23% yield). We have found that
our original reaction conditions using the dilithio deriva-
tive of keto acid 9 followed by transmetalation with ZnCl2
provided acceptable selectivity and yield for preparation
of the epothilones B (2) and D (4).
Protecting Group Strategies. Following the aldol
condensation, it was necessary to protect the C1 acid and
the resulting C7 hydroxyl of 44a (Scheme 7). The C1 acid
was protected as the TBS ester (50) and the C7 hydroxyl
as a trichloroethyl (Troc) carbonate (51). Surprisingly,
attempted acid-catalyzed cleavage of the C1 TBS ester
of 51 with acetic acid yielded the desired product 52 (36%)
as well as an eight-membered lactone 53 (12%). Obvi-
ously, C1 TBS ester hydrolysis was accompanied by
cleavage of the C7 Troc group as well. We believe that
the C1 acid may have formed an unstable Troc anhydride,
which facilitated attack by the nucleophilic unprotected
C7 hydroxyl thus accounting for the formation of the
undesired eight-membered lactone 53.
Not surprisingly, attempted Yamaguchi macrolacton-
ization directly from the C7-hydroxyl acid 44a (2,4,6-
trichlorobenzoyl chloride in dichloromethane) resulted
exclusively in the formation of the undesired eight-
membered lactone 53 (90%). Therefore, selective removal
of the C15 SEM protecting group of 52 was required prior
to macrolactonization, which proved to be more difficult
than expected. Because of these complications, a system-
atic study was undertaken to optimize the conditions
required for selective deprotection of the C15 SEM ether
of 52 in the presence of both the C3 TBS and C7 Troc
protecting groups (Table 2).
Numerous deprotecting conditions were investigated,
including TFA/CH2Cl2,26 TBAF/CH2Cl2,27 BF3‚Et2O/THF,28
CBr4/MeOH,29 MgBr2/Et2O,30 ZnBr2/CH2Cl2,31 InF3/CH2-
(26) Jansson, K.; Frejd, T.; Kihlberg, J.; Magnusson, G. Tetrahedron
Lett. 1988, 29 (3), 361-362.
(27) (a) Kan, T.; Hashimoto, M.; Yanagiya, M.; Shirahama, H.
Tetrahedron Lett. 1988, 29 (42), 5417-5418. (b) Lipshutz, B.; Miller,
T. A. Tetrahedron Lett. 1989, 30 (51), 7149-7152. (c) Berkowitz, D.
B.; Choi, S.; Maeng J. H. J. Org. Chem. 2000, 65, 847-860.
(28) Wincott, F. E.; Usman, N. Tetrahedron Lett. 1994, 35 (37),
6827-6830.
(29) Chen, M. Y.; Lee, A. S. Y. J. Org. Chem. 2002, 67 (4), 1384-
1387.
(30) (a) Kim, S.; Park, Y. H.; Kee, I. S. Tetrahedron Lett. 1991, 32
(26), 3099-3100. (b) Chen, W. C.; Vera, M. D.; Joullie´, M. M.
Tetrahedron Lett. 1997, 38 (23), 4025-4028. (c) Vakalopoulos, A.;
Hoffmann, H. M. R. Org. Lett. 2000, 2 (10), 1447-1450.
(31) Vakalopoulos, A.; Hoffmann, H. M. R.Org. Lett. 2001, 3 (14),
2185-2188.
J. Org. Chem, Vol. 69, No. 26, 2004 9275

Jung et al.
TABLE 2. Selective Cleavage of the SEM Ether of 52 in the Presence of TBS and Troc Groups
entry
reagent
temp (°C)
solvent
time (h)
yield (%)a
1
2
TFA
-30 to rt
-30 to rt
-30 to rt
reflux
-30 to tr
rt
-45 to rt
-45 to rt
-20 to rt
-10 to rt
-10 to rt
CH2Cl2
THF
2
16
16
5
42
b
TBAF
3
BF3‚Et2O
CBr4
MgBr2
MgBr2, n-BuSH
ZnBr2
InF3
LiBF4
1.5% HCl
DAST
CH2Cl2
MeOH
Et2O
c
4
33
56
72
48
d
d
22
c
5
3
6
Et2O
1
7
CH2Cl2
CH2Cl2
CH3CN
MeOH
CH2Cl2
2
8
2
9
2
10
11
3
1
a Isolated yield. b Complex mixture. c Decomposed product. d No reaction.
SCHEME 8. Summary of Assembly of Epothilones B (2) and D (4) from Aldehyde 5a
a Reagents and conditions: (a) LDA, -5 °C, 20 min; then 9 (1.2 equiv), THF, -78 °C, 15 min; then -40 °C, 1 h; ZnCl2 (2.5 equiv), -78
°C, 30 min; then 5 (1.0 equiv), THF, -78 °C, 15 min, (85%, combined yield); (b) (i) TBSCl (1.2 equiv), pyridine (10.0 equiv), CH2Cl2, 0 °C,
1 h; then Troc-Cl, CH2Cl2, rt, 5 h; (ii) AcOH, THF/H2O (8:2), 0 °C, 3 h, 36%; (c) MgBr2 (6.0 equiv), MeNO2 (6.0 equiv), n-BuSH (3.0 equiv),
Et2O, rt, 1 h; (d) 2,4,6-trichlorobenzoyl chloride (3.0 equiv), Et3N (3.6 equiv), THF, 0 °C, 1 h; then toluene, added to DMAP (6.0 equiv) in
toluene, rt, 4 h (38%, three steps); (e) Zn, NH4Cl, MeOH, reflux, 20 min, 92%; (f) HF-Py, THF, rt, 16 h, 95%; (g) m-CPBA (2.0 equiv),
CHCl3, -10 to 0 °C, 5 h, 30%; or 3,3-dimethyldioxirane, CH2Cl2, -78 °C; then -50 °C, 2 h, 53%.
Cl2, LiBF4/CH3CN,32 1.5% HCl/MeOH,33 and DAST/
CH2Cl2. However, these reactions failed to selectively
remove the SEM group in the presence of the TBS and
Troc protecting groups, giving mixtures of diols and/or
the triol in poor yields. Among the various protocols
summarized in Table 2, selective removal of the SEM
group of 52 was achieved with MgBr2, MeNO2, and
n-BuSH34 in ether to give the C15 hydroxy acid 54 in 72%
yield. Carboxylic acid 54 was then subjected to macro-
lactonization under Yamaguchi conditions7 to give the
lactone 55 (38% yield, three steps) (Scheme 8).
To complete our synthesis, selective removal of the Troc
group of 55 at the C7 position was effected by using Zn/
NH4Cl in methanol to afford lactone 56 (92%). The C3
TBS protecting group of 56 was removed with HF-
pyridine to provide epothilone D (4).35 Epoxidation of the
C12-C13 double bond of 4 with Prilezhaev conditions (m-
CPBA) resulted in a diastereomeric mixture with the
desired â-epoxy diastereomer as the major product 2
(2.8:1 ratio of â:R epoxides, 30% combined yield). Dra-
matic enhancements in both diastereoselectivity and
yield were observed with 3,3-dimethyldioxirane36 (DMDO)
(9.5:1 ratio of â:R epoxides, 53% combined yield) (Scheme
(32) Lipshutz, B. H.; Pegram, J. J.; Morey, M. C. Tetrahedron Lett.
1981, 22 (46), 4603-4606.
(35) Yang, D.; Wong, M.-K.; Yip, Y.-C. J. Org. Chem. 1995, 60, 3887-
3889.
(36) (a) Murray, R. W.; Jeyaraman, R. J. Org. Chem. 1985, 50,
2847-2853. (b) Stachel, S. J.; Danishefsky, S. J. Tetrahedron Lett.
2001, 42, 6785-6787.
(33) Pinto, B. M.; Buiting, M. M. W.; Reimer, K. B. J. Org. Chem.
1990, 55, 2177-2181.
(34) Kim, S.; Kee, I. S.; Park, Y. H.; Park, J. H. Synlett 1991, 183-
184.
9276 J. Org. Chem., Vol. 69, No. 26, 2004

Total Syntheses of Epothilones B and D
δ 164.6, 145.4, 115.2, 61.5, 29.3, 27.9, 18.3, 15.9; HRMS calcd
for C9H17O3PNS 250.0661 [M + H]+, found 250.0624.
8). The properties of 2 and 4 were identical with the
reported spectral and physical data for the these
compounds.3c,36
(3S)-3-(tert-Butyldimethylsilyloxy)-4,4-dimethyl-5-oxo-
heptanoic Acid (9). To a solution of sultam 34 (35.0 g, 70.0
mmol) in THF:H2O (350 mL:150 mL) was added lithium
hydroxide (5.90 g, 140.6 mmol) followed by H2O2 (56 mL, 490.0
mmol, 30% aqueous solution) at 0 °C. The resulting mixture
was stirred at room temperature for 4 h. The mixture was
diluted with water (200 mL) and washed with ether (100 mL).
The aqueous phase was cooled to 0 °C, neutralized (pH 7.0)
with aqueous 2 N HCl, and extracted with ethyl acetate (3 ×
300 mL). The combined ethyl acetate layers were dried
(anhydrous Na2SO4), filtered, and concentrated in vacuo. The
crude residue was purified by flash silica chromatography (50%
ether/hexanes) to afford keto acid 9 (16.2 g, 53.6 mmol, 76%)
as a viscous, colorless oil. Rf 0.2 (50% ethyl acetate/hexanes);
[R]22D -17.6 (c 1.0, CHCl3); IR (neat, NaCl) 3032, 2956, 2858,
Conclusion
We have developed efficient and scalable syntheses of
epothilone fragments 5, 6, 7, and 9, which were subse-
quently employed in the total syntheses of epothilone B
(2) and epothilone D (4). We have explored the effects of
steric bulk in the enolizable substrate on the diastereo-
meric ratio of the aldol condensation. Through an exten-
sive study of deprotection conditions for the C15 SEM
group, the optimal reaction conditions were discovered
that would selectively cleave the C15 SEM ether in the
presence of C3 TBS and C7 Troc protecting groups in
acceptable yields. In addition, the diastereoselectivity of
the epoxidation of epothilone D (4) to give epothilone B
(2) was greatly improved resulting in a 3-fold increase
in diastereoselectivity. Collectively, these improvements
provide a practical route for the syntheses of epothilones
B (2) and D (4).
1713, 1471, 1254, 1092 cm-1 1H NMR (CDCl3, 500 MHz) δ
;
9.63 (br s, 1H, COOH), 4.50 (q, J ) 3.6 Hz, 1H, CHOSi), 2,-
57-2.50 (m, 3H, CH2CH3, CH2COOH), 2.35 (dd, J ) 6.9 Hz, J
) 2.3 Hz, 1H, CH2COOH), 1.15 (s, 3H, C(CH3)2), 1.10 (s, 3H,
C(CH3)2), 1.02 (t, J ) 7.1 Hz, 3H, CH3CH2), 0.89 (s, 9H,
(CH3)3C), 0.07 (s, 3H, Si(CH3)2), 0.06 (s, 3H, Si(CH3)2); 13C NMR
(CDCl3, 125 MHz) δ 215.4, 178.4, 73.9, 53.00, 39.7, 32.1, 26.3,
21.4, 20.9, 18.5, 8.1, -4.0, -4.5; HRMS calcd for C15H31O4Si
303.1986 [M + H]+, found 303.1971.
5-Bromo-2-methyl-1-pentene (18). To a stirred solution
of tosylate 17 (23.3 g, 91.7 mmol) in acetone (1 L) was added
lithium bromide (9.5 g, 109.4 mmol) in portions at ambient
temperature. The reaction mixture was heated to reflux for 2
h and cooled to room temperature. After 3 h at room temper-
ature, the reaction mixture was poured over ice (100 g), and
the product was extracted with ether (3 × 500 mL). The
combined ether layers were then washed with brine (500 mL),
dried over anhydrous Na2SO4, filtered, and evaporated under
reduced pressure to give the crude bromide, which was purified
by flash column chromatography (silica gel, 1% ethyl acetate/
hexanes), followed by vacuum distillation (68-70 °C/30 mmHg)
to yield 18 (10.2 g, 69%) as a colorless oil. Rf 0.6 (1% ethyl
acetate in hexanes); IR (neat, NaCl) 2967, 1651, 1438, 1244,
892 cm-1; 1H NMR10 (CDCl3, 300 MHz) δ 4.74 (d, J ) 12.6 Hz,
2H), 3.40 (t, J ) 6.6 Hz, 2H), 2.16 (t, J ) 6.6 Hz, 2H), 2.04-
1.91 (m, 2H), 1.72 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 143.9,
111.0, 36.1, 33.3, 30.6, 22.3.
Experimental Section
(2S,3R)-3-(4-Methoxybenzyloxy)-1,2-epoxybutane (6).
To a suspension of NaH (10.0 g, 248.2 mmol, 60% dispersion
in mineral oil) in dry THF (200 mL) was added dropwise
(2S,3R)-1,2-epoxybutanol (13,18.20 g, 206.8 mmol) in THF (60
mL) at 0 °C, and the mixture was stirred at 0 °C for 1 h.
Tetrabutylammonium iodide (4.60 g, 12.4 mmol) was added,
and the mixture was stirred at 0 °C for 15 min. Freshly
prepared 4-methoxybenzyl bromide (49.6 g, 248 mmol) [pre-
pared by treating 4-methoxybenzyl alcohol (36.7 g, 260 mmol)
in ether (420 mL) with phosphorus tribromide (36.3 g, 130
mmol) at 0 °C]9 in dry THF (50 mL) was added dropwise, and
the resulting mixture was stirred at 0 °C for 6 h. The reaction
mixture was quenched at 0 °C by slow addition of water (50
mL) and extracted with ethyl acetate (120 mL). The organic
layer was separated, and the aqueous phase was extracted
with ethyl acetate (2 × 30 mL). The combined organic solution
was dried over anhydrous MgSO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash
column chromatography (silica gel, 15% ethyl acetate/hexanes)
to give 6 (36.8 g, 176.9 mmol, 86%) as a colorless oil. Rf 0.3
(-)-(2R,3S,5Z)-2-(4-Methoxybenzyloxy)-6,10-dimeth-
ylundeca-5,10-dien-3-ol (25). To a solution of copper(I)
bromide-dimethyl sulfide complex (22.6 g, 110.0 mmol) in dry
ether (110 mL) and dimethyl sulfide (100 mL) was added
dropwise freshly prepared 4-methyl-4-pentenylmagnesium
bromide [4-methyl-4-pentenyl bromide (22.0 g, 134.9 mmol)
in ether (100 mL) was treated with magnesium (3.9 g, 162.5
mmol)] at -45 °C, and the mixture was stirred at this
temperature for 2 h. A solution of condensed propyne (6.6 g,
165.0 mmol) in ether (20 mL) was added, and the resulting
mixture was stirred at -23 °C for 4 h. The dark green solution
was cooled to -78 °C, and a freshly prepared solution of
lithiohexyne [1-hexyne (9.0, 109.8 mmol) was treated with
n-butyllithium (7.1 g, 110.0 mmol; 1.6 M solution in hexanes)
and HMPA (18.5 g, 109.3 mmol) in ether (200 mL) at -78 °C
for 1 h] was added slowly, and the mixture was stirred at -78
°C for 1 h. (2S,3R)-3-(4-Methoxybenzyloxy)-1,2-epoxybutane
(6, 23.1 g, 109. 6 mmol) was added dropwise, and the resulting
mixture was stirred at -78 °C for 3 h and an additional 14 h
at -25 °C. The reaction mixture was quenched with aqueous
saturated NH4Cl solution (adjusted to pH 8 with NH3‚H2O)
and extracted with ether. The organic layer was separated,
dried (anhydrous Na2SO4), and concentrated under reduced
pressure. The residue was purified by flash silica chromatog-
raphy (15% ethyl acetate/hexanes) to give alcohol 25 (27.3 g,
82.2 mmol, 75%) as a colorless oil. Rf 0.6 (silica gel, 25% ethyl
(15% ethyl acetate/hexanes); [R]22 -6.8 (c 1.8, CHCl3); IR
D
(neat, NaCl) 2983, 2836, 1737, 1612, 1513, 1247 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 7.28 (d, J ) 5.8 Hz, 2H, aromaticΗ), 6.90
(d, J ) 8.6 Hz, 2H, aromaticΗ), 4.54 (dd, J ) 11.4 Hz, J )
11.4 Hz, 2H, CH2OCH), 3.83 (s, 3H, OCH3), 3.42 (dq, J ) 5.5
Hz, J ) 6.1 Hz, 1H, CH3CHCH), 2.96-2.94 (m, 1H, CH2-
OCHCH), 2.81 (dd, J ) 4.0 Hz, J ) 3.9 Hz, 1H, CH2OCHCH),
2.71 (dd, J ) 2.6 Hz, J ) 2.6 Hz, 1H, CH2OCHCH), 1.31 (d, J
) 6.4 Hz, 3H, CH3CHO); 13C NMR (CDCl3, 100 MHz) δ 159.6,
131.0, 129.6, 114.2, 74.4, 71.5, 55.7, 54.8, 46.2, 18.0; HRMS
calcd for C12H16O3Na 231.0997 [M + Na]+, found 231.1029.
Diethyl (2-Methylthiazol-4-yl)methanephosphonate (8).
A mixture of chloromethyl-2-methylthiazole (23, 50.0 g, 340
mmol) and triethyl phosphite (112.5 g, 677.0 mmol) was heated
at 160 °C for 6 h. The mixture was cooled, and excess triethyl
phosphite was distilled under reduced pressure. The residue
was purified by flash silica chromatography (5% methanol/
ether) to afford phosphonate 8 (72.80 g, 292.4 mmol, 86%) as
a pale yellow oil. Rf 0.3 (60% ethyl acetate/hexanes); IR (neat,
NaCl) 3506, 2983, 2903, 1735, 1521, 1442, 1247, 1016, 953
1
cm-1; H NMR (CDCl3, 300 MHz) δ 7.03 (d, J ) 3.3 Hz, 1H,
SCHOC), 4.08 (dq, J ) 14.7 Hz, J ) 7.2 Hz, 4H, 2 × OCH2-
CH3), 3.32 (d, J ) 21.0 Hz, 2H, POCH2C), 2.66 (s, 3Η, CH3),
1.27 (t, J ) 7.0 Hz, 6H, 2 × CH3); 13C NMR (CDCl3, 100 MHz)
acetate/hexanes); [R]24 -22.8 (c 2.3, CHCl3); IR (neat, NaCl)
D
3462, 2936, 2864, 1613, 1513, 1456, 1249, 1036 cm-1; 1H NMR
J. Org. Chem, Vol. 69, No. 26, 2004 9277

Jung et al.
(CDCl3, 500 MHz) δ 7.28 (d, J ) 8.0 Hz, 2H, aromatic Η), 6.90
(d, J ) 8.0 Hz, 2H, aromatic Η), 5.20 (t, J ) 7.0 Hz, 1H,
CH2CHdC(CH3)CH2), 4.72 (d, J ) 15.0 Hz, 2H, CH2dC(CH3)-
CH2), 4.56 (d, J ) 11.5 Hz, 1H, OCH2), 4.47 (d, J ) 11.5 Hz,
1H, OCH2), 3.82 (s, 3H, OCH3), 3.73 (d, J ) 3.5 Hz, 1H,
CH2CH(OH)CH), 3.53 (t, J ) 3.9 Hz, 1H, CH2OCHCH), 2.56
(br s, 1H, OH), 2.21 (dd, J ) 6.4 Hz, J ) 6.4 Hz, 2H, CHCH2-
CHOH), 2.08-2.00 (m, 4Η), 1.74 (s, 6H, CHdCHCH3, CH2-
(CH3)CdCH), 1.58-1.51 (m, 2H), 1.20 (d, J ) 6.0 Hz, 3H,
CH3CHOCH2); 13C NMR (CDCl3, 125 MHz) δ158.9, 145.6,
138.0, 130.6, 129.1, 120.7, 113.8, 109.9, 73.5, 70.6, 55.5, 37.9,
31.9, 31.3, 26.2, 23.9, 22.8, 14.2; HRMS calcd for C21H33O3
333.2424 [M + H]+, found 333.2429.
22.7, 18.4, 17.5, -1.0; HRMS calcd for C19H39O3Si 343.2663
[M + H]+, found 343.2668.
(-)-(3S,5Z)-3-(Trimethylsilylethoxymethoxy)-6,10-di-
methylundeca-5,10-dien-2-one (28). To a solution of oxalyl
chloride (12.8 g, 100.8 mmol) in dichloromethane (300 mL) was
added DMSO (15.8 g, 202.2 mmol) dropwise at -78 °C, and
the mixture was stirred at this temperature for 15 min. 3-SEM
alcohol 27 (23.0 g, 67.2 mmol) in dichloromethane (30 mL) was
added dropwise at -78 °C, and the resulting mixture was
stirred for 2 h. The reaction mixture was quenched by slow
addition of triethylamine (40.7 g, 402.6 mmol) at -78 °C. The
reaction mixture was allowed to warm to 0 °C. After 10 min,
ethyl acetate (220 mL) was added followed by saturated
aqueous NH4Cl solution (200 mL). The organic layer was
separated, dried over anhydrous Na2SO4, filtered, and con-
centrated under reduced pressure. The residue was purified
by flash column chromatography (silica gel, 10% ethyl acetate/
hexanes) to afford ketone 28 (19.4 g, 57.1 mmol, 85%) as a
colorless oil. Rf 0.6 (15% ethyl acetate/hexanes); [R]24D -6.6 (c
2.4, CHCl3); IR (neat, NaCl) 2953, 2892, 1717, 1456, 1376,
(-)-(2R,3S,5Z)-2-(4-Methoxybenzyloxy)-3-(trimethyl-
silylethoxymethoxy)-6,10-dimethylundeca-5,10-diene (26).
To a stirred solution of alcohol 25 (25.0 g, 75.3 mmol) and
DIPEA (14.5 g, 112.2 mmol) in dichloromethane (300 mL) was
added SEM-Cl (15.0 g, 90.0 mL) dropwise at 0 °C. The mixture
was warmed to room temperature and stirred for 6 h. The
reaction was quenched with saturated aqueous NH4Cl solution
(120 mL) and extracted with ethyl acetate (200 mL). The
organic layer was separated, dried over anhydrous Na2SO4,
and concentrated under reduced pressure to give the desired
product, which was purified by flash column chromatography
(silica gel, 10% ethyl acetate/hexanes) to afford 3-SEM diene
26 (32.0 g, 69.2 mmol, 92%) as a colorless oil. Rf 0.6 (15% ethyl
1
1249, 1107, 1029 cm-1; H NMR (CDCl3, 500 MHz) δ 5.12 (t,
J ) 6.5 Hz, 1H, CH2CHdC(CH3)CH2), 4.68 (d, J ) 7.0 Hz, 2H,
CH2dC(CH3)CH2), 4.64 (d, J ) 5.5 Hz, 2H, OCH2O), 3.98 (t, J
) 6.0 Hz, 1H, CH2CH(OH)CH), 3.60 (q, J ) 7.5 Hz, 2H, OCH2-
Si), 2.38-3.36 (m, 2H), 2.14 (s, 3H, COCH3), 2.00-1.95 (m,
4H), 1.69 (s, 3H, CHdCHCH3), 1.67 (s, 3Η, CH2(CH3)CdCH),
1.48 (dd, J ) 7.0 Hz, J ) 7.0 Hz, 2H, CH2CH2CH2), 0.88 (dd,
J ) 8.0 Hz, J ) 8.0 Hz, 2H, CH2Si(CH3)3), -0.01 (s, 9H, Si-
(CH3)3); 13C NMR (CDCl3, 125 MHz) δ 209.2, 145.4, 138.5,
118.8, 109.9, 94.4, 82.5, 65.9, 37.9, 31.8, 30.8, 26.6, 26.1, 23.7,
22.7, 18.3, -1.0; HRMS calcd for C19H36O3SiNa 363.5710 [M
+ Na]+, found 363.2321.
acetate/hexanes); [R]24 -13.2 (c 2.5, CHCl3); IR (neat, NaCl)
D
2953, 2893, 1613, 1513, 1457, 1376, 1249, 1171, 1030 cm-1
;
1H NMR (CDCl3, 500 MHz) δ 7.28 (d, J ) 8.0 Hz, 2H, aromatic
Η), 6.90 (d, J ) 8.0 Hz, 2H, aromatic Η), 5.21 (t, J ) 6.5 Hz,
1H, CH2CHdC(CH3)CH2), 4.81 (d, J ) 8.5 Hz, 1H, CH2d
C(CH3)CH2), 4.75 (d, J ) 7.0 Hz, 1H, CH2dC(CH3)CH2), 4.71
(d, J ) 15.0 Hz, 2H, OCH2O), 4.51 (dd, J ) 11.5 Hz, J ) 11.5
Hz, 2H, OCH2), 3.81 (s, 3H, OCH3), 3.76-3.66 (m, 3Η), 3.56
(dd, J ) 4.0 Hz, J ) 3.5 Hz, 1H, CH3CH(OCH2)CH), 2.32 (q,
J ) 6.0 Hz, 1H, CHCH2CHOH), 2.24 (d, J ) 6.5 Hz, 1H,
CHCH2CHOH), 2.05-1.99 (m, 4H), 1.73 (s, 3H, CHdCHCH3),
1.72 (s, 3H, CH2(CH3)CdCH), 1.53 (dd, J ) 6.5 Hz, J ) 7.0
Hz, 2H, CH2CH2CH2), 1.21 (d, J ) 6.0 Hz, 3H, CH3CHOCH2),
0.97 (dd, J ) 7.0 Hz, J ) 8.5 Hz, 2H, CH2Si(CH3)3), 0.03 (s,
9H, Si(CH3)3); 13C NMR (CDCl3, 125 MHz) δ 159.0, 145.6,
136.8, 130.8, 129.0, 121.1, 113.6, 109.8, 94.3, 79.2, 76.1, 70.6,
65.3, 55.4, 38.0, 31.9, 29.9, 26.2, 23.9, 22.8, 18.5, 15.5, -0.9;
HRMS calcd for C27H47O4Si 463.3238 [M + H]+, found 463.3258.
(-)-(1E,3S,5Z)-1-(2-Methyl-1,3-thiazol-4-yl)-3-trimeth-
ylsilylethoxymethoxy-2,6,10-trimethylundeca-1,5,10-
triene (29). To a solution of diethyl (2-methyl-1,3-thiazol-4-
yl)methyl phosphonate (8, 13.2 g, 52.8 mmol) in THF (150 mL)
was added dropwise n-butyllithium (3.4 g, 53.1 mmol, 1.6 M
solution in hexanes) at -78 °C, and the mixture was stirred
for 1 h. Ketone 28 (12.2 g, 35.8 mmol) was added slowly at
-78 °C, and the resulting mixture was warmed to room
temperature over a period of 12 h. The reaction mixture was
quenched with saturated aqueous NH4Cl solution (60 mL) and
extracted with ethyl acetate (120 mL). The organic layer was
separated, and the aqueous phase was extracted with ethyl
acetate (2 × 40 mL). The combined organic phases were
washed with brine (150 mL), dried over anhydrous Na2SO4,
and concentrated under reduced pressure to give the diene,
which was purified by flash column chromatography (silica gel,
10% ethyl acetate/hexanes) to afford triene 29 (12.6 g, 30.9
mmol, 86%) as a colorless oil. Rf 0.81 (25% ethyl acetate/
(+)-(2R,3S,5Z)-3-(Trimethylsilylethoxymethoxy)-6,10-
dimethylundeca-5,10-dien-2-ol (27). To a mixture of 26 (40
g, 86.5 mmol) in dichloromethane (400 mL) and water (80 mL)
was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (23.6 g,
103.9 mmol) portionwise at room temperature. The resulting
mixture was stirred for 3 h and extracted with dichlo-
romethane (200 mL). The organic layer was separated, dried
over anhydrous Na2SO4, and concentrated under reduced
pressure to give the deprotected alcohol, which was purified
by flash column chromatography (silica gel, 10% ethyl acetate/
hexanes) to afford 3-SEM alcohol 27 (26.9 g, 78.7 mmol, 91%)
hexanes); [R]24 -66.8 (c 2.5, CHCl3); IR (neat, NaCl) 2954,
D
2892, 1507, 1248, 1102, 1024 cm-1; 1H NMR (CDCl3, 500 MHz)
δ 6.93 (s, 1H, SCHdC), 6.48 (s, 1H, CHdCCH3), 5.18 (t, J )
5.5 Hz, 1H, CH2CHdCCH3), 4.68 (d, J ) 6.5 Hz, 1H, CH2d
C(CH3)CH2), 4.65 (d, J ) 7.0 Hz, 2H, OCH2O), 4.60 (d, J ) 6.5
Hz, 1H, CH2dC(CH3)CH2), 4.07 (t, J ) 6.5 Hz, 1H, CCHOCH2),
3.76 (dd, J ) 8.0 Hz, J ) 8.0 Hz, 1H, OCH2CH2Si), 3.51 (dd,
J ) 8.0 Hz, J ) 8.0 Hz, 1H, OCH2CH2Si), 2.69 (s, 3Η,
NdC(S)CH3), 2.37 (dd, J ) 7.0 Hz, J ) 7.0 Hz, 1H, CHCH2-
CHO), 2.30 (dd, J ) 6.5 Hz, J ) 6.5 Hz, 1H, CHCH2CHO),
2.03-1.97 (m, 7H), 1.70 (s, 3H, CHdCCH3), 1.68 (s, 3H, CH2-
CHdCCH3), 1.53-1.48 (m, 2H), 0.93 (dd, J ) 7.0 Hz, J ) 8.0
Hz, 2H, CH2Si(CH3)3), 0.01 (s, 9H, Si(CH3)3); 13C NMR (CDCl3,
125 MHz) δ 164.1, 152.6, 145.5, 138.7, 136.9, 121.1, 120.9,
115.6, 109.8, 92.0, 81.9, 65.3, 37.9, 32.9, 31.9, 26.2, 23.8, 22.7,
19.5, 18.4, 14.2, -0.9; HRMS calcd for C24H42NO2SSi 436.2700
[M + H]+, found 436.2685.
as a colorless oil. Rf 0.7 (25% ethyl acetate/hexanes); [R]24
D
+29.8 (c 1.7, CHCl3); IR (neat, NaCl) 3478, 2953, 2891, 1625,
1454, 1376, 1250, 1102, 1033 cm-1; 1H NMR (CDCl3, 500 MHz)
δ 5.17 (t, J ) 6.0 Hz, 1Η, CH2CHdC(CH3)CH2), 4.80 (d, J )
7.0 Hz, 1H, CH2dC(CH3)CH2), 4.72 (d, J ) 7.0 Hz, 1H, CH2d
C(CH3)CH2), 4.67 (d, J ) 7.0 Hz, 2H, OCH2O), 3.77 (dd, J )
6.5 Hz, J ) 6.5 Hz, 2H, OCH2Si), 3.60 (dd, J ) 10.0 Hz, J )
10.0 Hz, 1H, CH2CH(OH)CH), 3.54 (dd, J ) 5.5 Hz, J ) 5.0
Hz 1H, CH2CH(OH)CH), 3.20 (br s, 1H, OH), 2.34 (q, J ) 7.5
Hz, 1H, CHCH2CHOH), 2.14 (dd, J ) 8.0 Hz, J ) 8.0 Hz, 1H,
CHCH2CHOH), 2.04-1.99 (m, 4Η), 1.72 (s, 3H, CHdCHCH3),
1.71 (s, 3H, CH2(CH3)CdCH), 1.53 (dd, J ) 6.5 Hz, J ) 6.5
Hz, 2H, CH2CH2CH2), 1.16 (d, J ) 6.5 Hz, 3H, CH3CHOCH2),
0.97 (dd, J ) 7.0 Hz, J ) 8.0 Hz, 2H, CH2Si(CH3)3), 0.03 (s,
9H, Si(CH3)3); 13C NMR (CDCl3, 125 MHz) δ 145.5, 137.3,
120.7, 109.8, 95.5, 85.0, 68.9, 65.8, 37.9, 31.9, 30.1, 26.1, 23.8,
(-)-(2S,6Z,9S,10E)-11-(2-Methyl-1,3-thiazol-4-yl)-9-tri-
methylsilylethoxymethoxy-2,6,10-trimethylundeca-6,10-
dien-1-ol (30). To a solution of freshly prepared (i-PC)2BH
(7.0 g, 24.5 mmol) [(1R)-(+)-pinene in THF was treated with
BH3‚DMS in THF (100 mL)] was added diene 29 (10.0 g, 24.5
9278 J. Org. Chem., Vol. 69, No. 26, 2004

Total Syntheses of Epothilones B and D
mmol) slowly at 0 °C, and the resulting mixture was stirred
at room temperature for 30 min. Aqueous lithium hydroxide
(3.1 g, 73.5 mmol, in 25 mL of water) and sodium perborate
(11.3 g, 73.5 mmol) were added, and the resulting mixture was
stirred at room temperature for 2 h. The reaction mixture was
extracted with ethyl acetate (100 mL), and the organic layer
was separated, dried over anhydrous Na2SO4, and evaporated
under reduced pressure to give the alcohol, which was purified
by flash column chromatography (silica gel, 15% ethyl acetate/
hexanes) to afford trienol 30 (8.1 g, 19.0 mmol, 78%) as a
periodinane (1.4 g, 3.3 mmol) at room temperature, and the
resulting mixture was stirred for 30 min. The reaction mixture
was quenched by slow addition of saturated aqueous Na2S2O3
solution (3 mL) and saturated aqueous NaHCO3 solution (5
mL). The organic layer was separated, and the aqueous phase
was extracted with ether (2 × 10 mL). The combined organic
phases were dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure to give the aldehyde,
which was purified by flash column chromatography (silica gel,
10% ethyl acetate/hexanes) to afford aldehyde 5 (0.92 g, 2.0
mmol, 92%) as a colorless oil.
colorless oil. Rf 0.3 (25% ethyl acetate/hexanes); [R]24 -64.7
D
(c 1.9, CHCl3); IR (neat, NaCl) 2953, 2893, 1455, 1377, 1249,
(-)-(3S)-3-(tert-Butyldimethylsilyloxy)-4,4-dimethyl-5-
oxoheptanoic Acid 3-Methoxymethyl Amide (35). To a
stirred suspension of the keto acid 9 (1.0 g, 3.3 mmol), DMAP
(0.46 g, 3.6 mmol), and DCC (0.75 g, 3.6 mmol) in dichlo-
romethane (12 mL) at ambient temperature was added N,O-
dimethylhydroxylamine hydrochloride (0.34 g, 3.5 mmol) at 5
°C. The reaction mixture was stirred at room temperature for
1 h and diluted with ethyl acetate (10 mL). The resulting
mixture was filtered through a pad of Celite and concentrated
under reduced pressure. The residue was purified by column
chromatography (20% ethyl acetate/hexanes) to afford pure
amide 35 (1.0 g, 88%) as a colorless oil. Rf 0.5 (15% ethyl
1100, 1025 cm-1 1H NMR (CDCl3, 500 MHz) δ 6.94 (s, 1H,
;
SCHdC), 6.48 (s, 1H, CHdCCH3), 5.17 (t, J ) 6.5 Hz, 1H,
CH2CHdCCH3), 4.62 (dd, J ) 6.5 Hz, J ) 6.5 Hz, 2H, OCH2O),
4.07 (t, J ) 6.0 Hz, 1H, CCHOCH2), 3.78-3.69 (m, 1H, CH2-
OH), 3.48 (ddd, J ) 7.5, Hz, J ) 6.0 Hz, J ) 6.0 Hz, 2H, OCH2-
CH2Si), 3.40 (dd, J ) 7.0 Hz, J ) 7.5 Hz, 1H, CH2OH), 2.69
(s, 3H, NdC(S)CH3), 3.00 (br s, 1H, OH), 2.36 (dd, J ) 7.0 Hz,
J ) 7.0 Hz, 1H, CHCH2CHO), 2.30 (dd, J ) 6.5 Hz, J ) 6.5
Hz, 1H, CHCH2CHO), 2.04-2.00 (m, 2H), 1.99 (s, 3H, CHd
CCH3), 1.67 (s, 3H, CH2CHdCCH3), 1.61-1.58 (m, 1H), 1.46-
1.31 (m, 4H), 0.93 (dd, J ) 7.0 Hz, J ) 8.0 Hz, 2H,
CH2Si(CH3)3), 0.89 (d, J ) 6.0 Hz, 3H, CH3CHOCH2), 0.03 (s,
9H, Si(CH3)3); 13C NMR (CDCl3, 125 MHz) δ 164.4, 152.1,
138.8, 137.1, 121.1, 120.8, 115.5, 92.0, 82.1, 68.1, 65.3, 36.0,
33.3, 33.0, 32.4, 25.5, 23.8, 19.4, 18.4, 17.0, 14.2, -1.0; HRMS
calcd for C24H44NO3SSi 454.2805 [M + H]+, found 454.2781.
acetate/hexanes); [R]22 -12.6 (c 1.0, CHCl3); IR (neat, NaCl)
D
2937, 2857, 1705, 1667, 1471, 1388, 1254, 1089, 836 cm-1; 1H
NMR (CDCl3, 300 MHz) δ 4.55 (t, J ) 6.5 Hz, 1H), 3.66 (s,
3H), 3.13 (s, 3H), 2.65-2.42 (m, 3H), 2.37 (dd, J ) 6.0 Hz, J )
6.5 Hz, 1H), 1.10 (s, 6H), 0.97 (t, J ) 7.5 Hz, 3H), 0.84 (s, 9H),
0.08 (s, 3H), -0.01 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 215.6,
172.6, 73.5, 61.6, 53.2, 37.0, 33.5, 32.0, 26.3, 22.3, 20.5, 18.5,
8.1, -3.9, -4.5; HRMS calcd for C17H35NO4SiNa 368.2233 [M
+ Na]+, found 368.2276.
(+)-(2S,6Z,9S,10E)-2,6,10-Trimethyl-11-(2-methyl-1,3-
thiazol-4-yl)-9-(2-trimethylsilylethoxymethoxy)undeca-
6,10-dienal (5). Method A: To a solution of oxalyl chloride
(0.3 g, 2.6 mmol) in dichloromethane (20 mL) was added
DMSO (0.4 g, 5.3 mmol) dropwise at -78 °C, and the mixture
was stirred for 15 min. Trienol 30 (1.0 g, 2.2 mmol) in
dichloromethane (3 mL) was added dropwise at -78 °C, and
the resulting mixture was stirred for 1 h. The reaction mixture
was quenched by slow addition of triethylamine (1.1 g, 10.6
mmol) at -78 °C, and the reaction mixture was allowed to
warm to 0 °C. After 10 min, ether (30 mL) was added followed
by saturated aqueous NH4Cl solution (30 mL). The organic
layer was separated, and the aqueous phase was extracted
with ether (20 mL). The combined organic phases were washed
with brine (30 mL), dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure to give the aldehyde,
which was purified by flash column chromatography (silica gel,
10% ethyl acetate/hexanes) to afford aldehyde 5 (0.94 g, 2.1
mmol, 94%) as a colorless oil. Rf 0.6 (20% ethyl acetate/
(-)-(3S)-3-(tert-Butyldimethylsilyloxy)-4,4-dimethyl-5-
oxoheptanoic Acid 3-Methyloxetan-3-ylmethyl Ester (38).
To a stirred solution of the keto acid 9 (2.0 g, 6.6 mmol) in
dichloromethane (20 mL) at ambient temperature was added
oxetanemethanol (0.75 g, 7.3 mmol), DMAP (0.24 g, 2.0 mmol),
and DCC (1.50 g, 7.3 mmol). The reaction mixture was stirred
at room temperature for 1 h, and diluted with ethyl acetate
(18 mL). The resulting mixture was filtered through a pad of
Celite, and concentrated under reduced pressure. The residue
was purified by column chromatography (20% ethyl acetate/
hexanes) to afford methyl ester 38 (2.4 g, 95%) as a colorless
oil. Rf 0.5 (20% ethyl acetate/hexanes); [R]22 -20.0 (c 1.0,
D
CHCl3); IR (neat, NaCl) 2957, 2859, 1740, 1705, 1471, 1253,
1177, 1090, 836 cm-1; 1H NMR (CDCl3, 500 MHz) δ 4.48 (d, J
) 4.0 Hz, 3H), 4.36 (d, J ) 6.0 Hz, 2H), 4.13 (q, J ) 11.0 Hz,
2H), 2.56-2.44 (m, 3H), 2.32 (dd, J ) 6.5 Hz, J ) 7.0 Hz, 1H),
1.32 (s, 3H), 1.11 (s, 3H), 1.07 (s, 3H), 0.98 (t, J ) 6.5 Hz, 3H),
0.83 (s, 9H), 0.05 (s, 3H), 0.00 (s, 3H); 13C NMR (CDCl3, 125
MHz) δ 214.4, 171.8, 79.6, 73.8, 69.2, 52.7, 39.6, 39.2, 32.0,
26.2, 21.5, 20.8, 18.4, 8.1, -4.0, -4.5; HRMS calcd for C20H38O5-
SiNa 409.2381 [M + Na]+, found 409.2372.
hexanes); [R]26 -51.2 (c 0.5, CHCl3); IR (neat, NaCl) 2955,
D
2857, 1711, 1470, 1250, 1097, 836 cm-1; 1H NMR (CDCl3, 500
MHz) δ 9.61 (d, J ) 0.8 Hz, 1H, CHO), 6.96 (s, 1Η, SCHdC),
6.50 (s, 1Η, CHdCCH3), 5.21 (t, J ) 6.9 Hz, 1Η, CH2CHd
CCH3), 4.64 (dd, J ) 6.9 Hz, J ) 6.9 Hz, 2Η, OCH2O), 4.09 (t,
J ) 7.0 Hz, 1Η, CCHO), 3.77 (dd, J ) 9.7 Hz, J ) 9.3 Hz, 1Η,
OCH2CH2), 3.52 (dd, J ) 9.3 Hz, J ) 10.0 Hz, 1Η, OCH2CH2),
2.72 (s, 3Η, NdC(S)CH3), 2.41-2.30 (m, 3Η), 2.08-2.05 (m,
2H), 2.02 (s, 3Η, CHdCCH3), 1.72-1.70 (m, 1H), 1.68 (s, 3Η,
CH2CHdCCH3), 1.46-1.31 (m, 3H), 1.09 (d, J ) 7.0 Hz, 3Η,
CH3CH), 0.96-0.89 (m, 2Η), 0.03 (s, 9Η, Si(CH3)3); 13C NMR
(CDCl3, 125 MHz) δ 205.4, 165.0, 153.2, 139.3, 137.0, 121.8,
121.6, 116.2, 92.5, 82.2, 65.6, 46.6, 33.1, 32.5, 30.7, 25.6, 23.8,
19.6, 18.5, 14.3, 13.7, -1.0; HRMS calcd for C24H42NO3SSi
452.2649 [M + H]+, found 452.2610.
(-)-(3S)-3-(tert-Butyldimethylsilyloxy)-4,4-dimethyl-5-
oxoheptanoic Acid 2-(2-Methyloxiranyl) Ethyl Ester (39).
To a stirred solution of the keto acid 9 (2.0 g, 6.6 mmol) in
dichloromethane (20 mL) at ambient temperature was added
freshly prepared [3-methyl-3-buten-1-ol (4.4 g, 50.0 mmol) in
dichloromethane was treated with m-CPBA (13.2 g, 52.7 mmol,
70% purity) at -78 °C for 4 h in 58% yield]22 2-methyloxira-
neethanol (0.68 g, 6.6 mmol), DMAP (0.24 g, 2.0 mmol), and
DCC (1.5 g, 7.3 mmol). The reaction mixture was stirred at
room temperature for 1 h, and diluted with ethyl acetate (10
mL). The resulting mixture was filtered through a pad of Celite
and concentrated under reduced pressure. The residue was
purified by column chromatography (15% ethyl acetate/hex-
anes) to afford ethyl ester 39 (2.5 g, 96%) as a colorless oil. Rf
Method B: To a solution of trienol 30 (1.0 g, 2.2 mmol) in
dichloromethane (20 mL) were added molecular sieves (1.0 g,
4 Å, powdered) and 4-methylmorpholine N-oxide (0.4 g, 3.3
mmol) followed by addition of tetrapropylammonium perru-
thenate (38.7 mg, 0.11 mmol) at 0 °C. The resulting mixture
was stirred for 15 min. The reaction mixture was filtered
through a short pad of silica (10% ethyl acetate/hexanes) to
give aldehyde 5 (0.72 g, 1.6 mmol, 72%) as a colorless oil.
0.4 (15% ethyl acetate/hexanes); [R]22 -13.9 (c 1.3, CHCl3);
D
IR (neat, NaCl) 2958, 2933, 2857, 1737, 1705, 1472, 1254, 1090,
1
835 cm-1; H NMR (CDCl3, 400 MHz) δ 4.42 (d, J ) 4.5 Hz,
Method C: To a stirred solution of trienol 30 (1.0 g, 2.2
mmol) in dichloromethane (20 mL) was added Dess-Martin
1H), 4.19-4.01 (m, 2H), 2.61-2.30 (m, 5H), 2.23 (dd, J ) 8.0
Hz, J ) 9.0 Hz, 1H), 1.89 (tq, J ) 8.0 Hz, J ) 7.5 Hz 1H), 1.80
J. Org. Chem, Vol. 69, No. 26, 2004 9279

Jung et al.
(tq, J ) 8.5 Hz, J ) 9.0 Hz 1H), 1.30 (s, 3H), 1.07 (s, 3H), 1.01
(s, 3H), 0.94 (t, J ) 8.5 Hz, 3H), 0.79 (s, 9H), 0.01 (s, 3H),
-0.04 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 215.2, 172.2, 74.0,
61.4, 55.1, 53.9, 52.9, 39.8, 35.8, 32.1, 26.2, 21.6, 21.4, 18.4,
8.0, -4.1, -4.6; HRMS calcd for C20H38O5SiNa 409.2410 [M +
Na]+, found 409.2407.
droxy-4,4-dimethylheptan-3-one (40, 0.68 g, 71%) as a colorless
oil. Rf 0.5 (20% ethyl acetate/hexanes); [R]24 +33.2 (c 0.5,
D
CHCl3); IR (neat, NaCl) 3459, 2956, 2884, 2859, 1706, 1471,
1
1259, 1077, 835 cm-1; H NMR (CDCl3, 400 MHz) δ 6.00 (dd,
J ) 14.0 Hz, J ) 14.0 Hz, 1Η), 4.18-4.00 (m, 1H), 3.73-3.54
(m, 2H), 2.23-2.04 (m, 1H), 1.72-1.33 (m, 3H), 1.07 (s, 3H),
1.00 (s, 6H), 0.94 (s, 9H), 0.11 (s, 3H), 0.06 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ 101.4, 54.8, 39.9, 29.2, 28.0, 25.7, 23.0,
17.8, 5.9, -3.9, -4.4; HRMS calcd for C15H32O3SiNa 311.2018
[M + Na]+, found 311.2135.
(-)-(5S)-5,7-Bis(tert-butyldimethylsilyloxy)-4,4-dime-
thylheptan-3-one (41). Method A: To a stirred solution of
sultam 34 (0.1 g, 0.2 mmol) in THF (2 mL) was added LiBH4
(4.3 mg, 0.2 mmol) at 0 °C, and the mixture was stirred at
room temperature for 20 h. The reaction mixture was quenched
by addition of saturated aqueous NH4Cl solution (2 mL) and
the aqueous phase was extracted with ethyl acetate (5 mL).
The combined organic layers were washed with brine (6 mL),
dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure to afford the diol, which was treated with
dry DMF (2 mL), triethylamine (0.024 g, 0.24 mmol), and
DMAP (3.0 mg, 0.024 mmol) at 0 °C, followed by TBSCl (0.036
g, 0.24 mmol). The reaction mixture was stirred at room
temperature for 1 h and diluted with ethyl acetate (4 mL).
The mixture was washed with water (4 mL) and brine (4 mL).
The organic phase was separated, dried over anhydrous Na2-
SO4, filtered, and concentrated under reduced pressure. The
crude mixture was purified by column chromatography (20%
ethyl acetate/hexanes) to afford (-)-(5S)-5,7-bis(tert-butyldim-
ethylsilyloxy)-4,4-dimethylheptan-3-ol (37, 0.046 g, 57%) as a
To a stirred solution of the alcohol 40 (1.1 g, 3.8 mmol) and
imidazole (0.4 g, 5.8 mmol) in dichloromethane (50 mL) at 0
°C was added TBSCl (0.7 g, 4.6 mmol), and the reaction
mixture was stirred at 0 °C for 3 h. The mixture was quenched
by addition of saturated aqueous NH4Cl solution (20 mL), and
the aqueous phase was extracted with dichloromethane (25
mL). The combined organic layers were washed with brine (30
mL), dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure to give the ketone, which was purified
by flash column chromatography (silica gel, 10% ethyl acetate/
hexanes) to afford pure ketone 41 (1.1 g, 72%) as a colorless
oil.
(-)-(5S)-5-(tert-Butyldimethylsilyloxy)-4,4-dimethyl-6-
(4-methyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)hexan-3-one
(42). To a stirred solution of methyl ester 38 (2.2 g, 5.7 mmol)
in dichloromethane (10 mL) at -10 °C was added boron
trifluoride etherate (165 µL, 1.3 mmol). The reaction mixture
was stirred for 20 min and warmed to 20 °C over 1 h. After
being stirred for 3 h, the mixture was quenched by addition
of triethylamine (0.8 mL, 5.7 mmol) at 0 °C. The resulting
mixture was diluted with ethyl acetate (12 mL), filtered
through a pad of Celite, and concentrated under reduced
pressure. The residue was purified by column chromatography
(10% ethyl acetate/hexanes) to afford OBO ester 42 (1.6 g, 73%)
as a colorless oil. Rf 0.6 (15% ethyl acetate/hexanes); [R]22D -3.2
(c 1.5, CHCl3); IR (neat, NaCl) 2958, 2932, 2879, 1706, 1471,
1251, 1106, 1053, 837 cm-1; 1H NMR (CDCl3, 500 MHz) δ 4.33
(s, 1H), 3.86 (s, 6H), 2.51 (q, J ) 6.5 Hz, 2H), 1.92 (dd, J ) 3.8
Hz, J ) 3.8 Hz, 1H), 1.71 (dd, J ) 4.5 Hz, J ) 4.5 Hz, 1H),
1.33 (s, 3H), 1.00 (s, 3H), 0.99 (s, 3H), 0.83 (s, 9H), 0.80 (s,
3H), 0.10 (s, 3H), 0.04 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ
214.5, 108.5, 72.4, 72.3, 53.5, 41.8, 31.4, 30.6, 26.4, 21.2, 20.7,
18.7, 14.9, 8.2, -3.7, -4.4; HRMS calcd for C20H39O5Si
387.2489 [M + H]+, found 387.2573.
colorless oil. Rf 0.4 (15% ethyl acetate/hexanes); [R]22 -13.1
D
(c 1.2, CHCl3); IR (neat, NaCl) 3721, 2955, 2927, 2851, 1473,
1258, 1087, 837 cm-1; 1H NMR (CDCl3, 400 MHz) δ 3.76-3.64
(m, 3H), 3.33 (d, J ) 10.4 Hz, 1H), 2.80 (br s, 1H), 2.02-1.98
(m, 1H), 1.53-1.46 (m, 2H), 1.36-1.25 (m, 1H), 0.98 (t, J )
7.2 Hz, 3H), 0.90 (s, 3H), 0.89 (s, 9H), 0.85 (s, 9H), 0.74 (s,
3H), 0.04-0.07 (m, 12H); 13C NMR (CDCl3, 100 MHz) δ 78.4,
75.9, 62.3, 43.2, 36.9, 26.5, 26.4, 24.6, 19.1, 19.0, 18.8, 18.7,
12.1, -3.2, -4.0, -5.0; MS (ESI) (m/z) C21H49O3Si, 405 [M +
H]+.
To a stirred solution of the alcohol 37 (0.025 g, 0.06 mmol)
in dry dichloromethane (2 mL) and pyridine (0.1 mL) at 0 °C
was added Dess-Martin periodinane (0.039 g, 0.09 mmol). The
reaction mixture was stirred at room temperature for 2 h. The
mixture was diluted with cold ether (4 mL), filtered, and
washed with saturated aqueous NaHCO3-Na2S2O3 (3 mL, 1:1,
v/v). The organic solution was dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure to give the
ketone, which was purified by flash column chromatography
(silica gel, 10% ethyl acetate/hexanes) to afford pure ketone
41 (0.02 g, 80%) as a colorless oil. Rf 0.7 (10% ethyl acetate/
hexanes); [R]22D -8.1 (c 1.2, CHCl3); IR (neat, NaCl) 2959, 2927,
(-)-(5S)-5-(tert-Butyldimethylsilyloxy)-4,4-dimethyl-6-
(5-methyl-2,7,8-trioxabicyclo[3.2.1]oct-1-yl)hexan-3-one
(43). A stirred solution of ethyl ester 39 (0.37 g, 0.96 mmol)
in dry dichloromethane (5 mL) was treated at 0 °C with bis-
(cyclopentadienyl)zirconium dichloride (0.03 g, 0.096 mmol)
and silver perchlorate (0.01 g, 0.048 mmol), and the reaction
mixture was stirred at 0 °C for 15 min. The mixture was
warmed to 5 °C over 30 min and quenched by addition of
saturated aqueous NaHCO3 solution (3 mL). The mixture was
separated, and the aqueous phase was washed with dichlo-
romethane (5 mL). The combined organic solution was dried
over anhydrous MgSO4, filtered, and concentrated under
reduced pressure. The residue was purified by column chro-
matography (10% ethyl acetate/hexanes) to afford ABO ester
43 (0.35 g, 93%) as a colorless oil. Rf 0.4 (10% ethyl acetate/
1
2851, 1699, 1469, 1389, 1258, 1099, 944, 835 cm-1; H NMR
(CDCl3, 500 MHz) δ 4.07 (dd, J ) 7.5 Hz, J ) 3.0 Hz, 1H),
3.65-3.57 (m, 2H), 2.58-2.42 (m, 2H), 1.57-1.45 (m, 2H), 1.11
(s, 3H), 1.04 (s, 3H), 0.99 (t, J ) 7.0 Hz, 3H), 0.89 (s, 9H), 0.88
(s, 9H), 0.09 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H); 13
C
NMR (CDCl3, 125 MHz) δ 214.8, 73.5, 60.2, 53.2, 37.5, 31.8,
26.4, 26.2, 22.4, 20.3, 18.7, 18.5, 8.1, -3.6, -4.9; HRMS calcd
for C21H47O3Si2 403.3053 [M + H]+, found 403.3053.
Method B: To a stirred solution of the keto acid 9 (1.0 g,
3.3 mmol) in THF (5 mL) was added dropwise trimethyl borate
(1.4 g, 13.2 mmol) at 10 °C within 5 min, followed by borane-
methyl sulfide complex (0.75 g, 9.9 mmol). The reaction
mixture was stirred at 0 °C for 3 h, warmed to 15 °C, and
stirred for 6 h. The reaction mixture was cooled to -5 °C, ice
water (2.6 g) was added portionwise, and the resulting mixture
was stirred at room temperature for 30 min. The solvents were
removed by evaporation, and ether (10 mL) and hexane (40
mL) were added to the milky residue followed by water (1.0
g) and Na2SO4 (1.3 g). The resulting mixture was stirred at
room temperature for 1 h and filtered through a pad of Celite.
The residue was dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. The crude mixture was
purified by column chromatography (20% ethyl acetate/hex-
anes) to afford (-)-(5S)-5-(tert-butyldimethylsilyloxy)-5-hy-
hexanes); [R]22 -13.6 (c 1.6, CHCl3); IR (neat, NaCl) 2936,
D
2858, 1734, 1706, 1471, 1379, 1254, 1090, 837 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 4.38 (t, J ) 6.5 Hz, 1H), 3.97 (t, J ) 11.0
Hz, 1H), 3.83 (t, J ) 8.5 Hz, 2H), 3.67 (d, J ) 12.5 Hz, 1H),
2.56-2.40 (m, 3H), 2.36-2.28 (m, 1H), 2.21 (dd, J ) 5.5 Hz, J
) 5.5 Hz, 1H), 1.99-1.90 (m, 1H), 1.56 (s, 3H), 1.06 (s, 3H),
1.02 (s, 3H), 0.94 (t, J ) 9.0 Hz, 3H), 0.80 (s, 9H), 0.02 (s, 3H),
0.00 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 215.3, 172.7, 87.3,
73.7, 67.5, 53.0, 40.6, 39.8, 32.2, 26.2, 22.6, 21.2, 21.1, 18.4,
8.1, -3.8, -4.5; HRMS calcd for C20H38O5SiNa 409.2410 [M +
Na]+, found 409.2464.
(3S,6R,7S,8S,12Z,15S,16E)-3-(tert-Butyldimethylsilyl-
oxy)-7-hydroxy-15-(2-trimethylsilylethoxymethoxy)-
9280 J. Org. Chem., Vol. 69, No. 26, 2004

Total Syntheses of Epothilones B and D
4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-
oxoheptadeca-12,16-dienoic Acid/(3S,6S,7R,8S,12Z,15S,-
16E)-3-(tert-Butyldimethylsilyloxy)-7-hydroxy-15-(2-tri-
methylsilyl ethoxymethoxy)-4,4,6,8,12,16-hexamethyl-17-
(2-methyl-1,3-thiazol-4-yl)-5-oxoheptadeca-12,16-
dienoic Acid (44a/44b). A solution of keto acid 9 (2.3 g, 7.6
mmol) in THF (10 mL) was added dropwise to a freshly
prepared solution of LDA [diisopropylamine (2.6 mL, 18.0
mmol) was added to n-BuLi (16.5 mL, 1.6 M solution in
hexanes, 18.0 mmol) in 30 mL of THF at -5 °C] at -78 °C.
The reaction mixture was stirred at -78 °C for 15 min,
warmed to -40 °C, and stirred for 1 h. The temperature was
reduced to -78 °C, and ZnCl2 (18 mL, 1.0 M solution in ether,
15.0 mmol) was added dropwise over 30 min. A solution of
aldehyde 5 (2.7 g, 6.0 mmol) was added dropwise, and the
resulting mixture was stirred for 15 min and quenched by slow
addition of saturated aqueous NH4Cl solution (30 mL). The
mixture was warmed to 0 °C, and AcOH (2.1 mL, 36.0 mmol)
was added, followed by addition of ethyl acetate (20 mL). The
organic phase was separated, and the aqueous layer was
extracted with ethyl acetate (3 × 20 mL). The combined
organic phases were dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure to give the aldol products
as a diastereomeric mixture (2.3:1), which was purified by
column chromatography (silica gel; 600 g, ethyl acetate/
hexanes/methanol, 15:80:5) to give 7-hydroxy acids 44a (2.6
g, 3.5 mmol, 59%) and 44b (1.2 g, 1.6 mmol, 26%) as colorless
oils.
-3.8, -4.3; HRMS calcd for C39H72NO7SSi2 754.4562 [M + H]+,
found 754.4640.
(3S,6R,7S,8S,12Z,15S,16E)-3-(tert-Butyldimethylsil-
yloxy)-1-[(S)-10,10-dimethyl-3,3-dioxothia-4-aza-tricyclo-
[5.2.1.0]dec-4-yl]-7-hydroxy-15-(2-trimethylsilylethoxy-
methoxy)-4,4,6,8,12,16-hexa methyl-17-(2-methyl-1,3-thia-
zol-4-yl)-5-oxoheptadeca-12,16-dienoic Ester (45a). To a
stirred solution of sultam 34 (0.5 g, 1.0 mmol) in dichloro-
methane (4.0 mL) was added TiCl4 (1.1 g, 1.0 M solution in
dichloromethane, 1.1 mmol) dropwise followed by DIPEA (0.14
mg, 1.1 mmol) at -78 °C, and the reaction mixture was stirred
for 1 h. A solution of aldehyde 5 (0.45 g, 1.0 mmol) in
dichloromethane was added dropwise to the mixture at -78
°C. The reaction mixture was stirred for 30 min and then
allowed to warm to -40 °C over a period of 1 h. The resulting
mixture was quenched by slow addition of phosphate buffer
solution (3.7 mL, pH 7.0) and extracted with dichloromethane
(10 mL). The aqueous layer was extracted with dichlo-
romethane (2 × 5 mL). The combined organic solution was
washed with saturated NaHCO3 solution (10 mL) and brine
(10 mL). The organic phase was dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure to give the
aldol products as a diastereomeric mixture (10:1), which was
purified by column chromatography (20% ethyl acetate/hex-
anes) to give aldol product 45a (0.57 g, 60%) as a colorless oil.
Rf 0.4 (20% ethyl acetate/hexanes); [R]24D -95.0 (c 0.2, CHCl3);
IR (neat, NaCl) 3509, 2956, 2858, 1696, 1471, 1333, 1218, 1095,
1
837 cm-1; H NMR (CDCl3, 500 MHz) δ 6.92 (s, 1H), 6.48 (s,
1H), 5.14 (t, J ) 6.6 Hz, 1H), 4.62 (d, J ) 6.6 Hz, 1H), 4.56
(dd, J ) 7.2 Hz, J ) 4.2 Hz, 1H), 4.05 (q, J ) 7.2 Hz, 1H), 3.84
(dd, J ) 4.2 Hz, J ) 4.2 Hz, 1H)), 3.73 (q, J ) 8.4 Hz, 1H),
3.50 (q, J ) 7.8 Hz, 1H), 3.46 (d, J ) 3.0 Hz, 1H), 3.44 (br s,
1H), 3.41-3.36 (m, 1H), 3.27 (d, J ) 9.0 Hz, 1H), 3.20 (q, J )
6.6 Hz, 1H), 2.92 (dd, J ) 5.4 Hz, J ) 4.8 Hz, 1H), 2.69 (s,
3H), 2.61 (dd, J ) 3.6 Hz, J ) 3.6 Hz, 1H), 2.36-2.16 (m, 3H),
2.07 (dd, J ) 8.4 Hz, J ) 7.8 Hz, 1H), 2.03-1.91 (m, 2H), 1.98
(s, 3H), 1.91-1.75 (m, 4H), 1.63 (s, 3H), 1.58-1.46 (m, 2H),
1.34 (dd, J ) 9.0 Hz, J ) 7.8 Hz, 1H), 1.31-1.22 (m, 2H), 1.19
(s, 3H), 1.14 (s, 3H), 1.13 (s, 3H), 1.00 (d, J ) 6.6 Hz, 3H),
0.91 (d, J ) 7.8 Hz, 3H), 0.95 (s, 3H), 0.86 (s, 9H), 0.81 (dd, J
) 7.2 Hz, J ) 7.2 Hz, 2H), 0.09 (s, 3H), 0.07 (s, 3H), 0.00 (s,
9H); 13C NMR (CDCl3, 125 MHz) δ 222.4, 170.1, 164.7, 153.0,
139.5, 137.7, 121.2, 120.8, 115.8, 92.3, 82.1, 75.1, 72.3, 65.4,
60.6, 54.6, 53.2, 48.7, 47.9, 44.9, 41.7, 41.2, 38.5, 35.6, 33.2,
32.8, 32.7, 26.7, 26.2, 26.1, 25.2, 23.7, 22.7, 21.0, 20.1, 19.3,
18.3, 18.2, 15.6, 14.1, 9.8, -4.0, -4.1, -4.7, -4.8; HRMS calcd
for C49H87N2O8S2Si2 951.5442 [M + H]+, found 951.5413.
General Procedure for the Aldol Condensation of
Aldehyde 5 with Various Keto Acid Derivatives (46a-
49a). A solution of the appropriate keto acid derivative (41-
43) (0.37 mmol) in THF (1 mL) was added dropwise to a freshly
prepared solution of LDA [diisopropylamine (140 µL) was
added to n-BuLi (0.7 mL, 1.6 M solution in hexanes) in 1 mL
of THF at -5 °C] at -78 °C. The reaction mixture was stirred
at -78 °C for 15 min and warmed to -40 °C for 30 min. A
solution of aldehyde 5 (0.33 mmol) in THF (1 mL) was added
dropwise at -78 °C, and the resulting mixture was stirred for
10 min and quenched by slow addition of saturated aqueous
NH4Cl solution (1.5 mL). The mixture was warmed to 0 °C,
and ethyl acetate (2 mL) was added to the mixture. The organic
phase was separated, and the aqueous layer was extracted
with ethyl acetate (3 × 3 mL). The combined organic phases
were dried over anhydrous MgSO4, filtered, and concentrated
under reduced pressure to give the aldol products, which were
purified by flash column chromatography.
For 44a: Rf 0.42 (ethyl acetate/hexanes/methanol; 15:80:
5); [R]22 -40.7 (c 1.8, CHCl3); IR (neat, NaCl) 3484, 3110,
D
2953, 2895, 1714, 1693, 1470, 1250, 1096 cm-1
;
1H NMR
(CDCl3, 500 MHz) δ 6.97 (s, 1Η, SCHdC), 6.50 (s, 1Η, CHd
CCH3), 5.25 (t, J ) 7.0 Hz, 1Η, CH2CHdCCH3), 4.69 (dd, J )
7.0 Hz, J ) 7.0 Hz, 1Η, OCH2O), 4.54 (d, J ) 7.0 Hz, 1Η, CH2-
COOCHCH2), 4.45 (br s, 1Η, OH), 4.08 (dd, J ) 5.5 Hz, J )
5.5 Hz, 1Η, CHOCOOCCH2), 3.83 (dd, J ) 8.0 Hz, J ) 7.5 Hz,
1Η), 3.76 (t, J ) 8.5 Hz, 1Η), 3.62-3.57 (m, 1Η), 3.46 (dd, J )
8.0 Hz, J ) 7.5 Hz, 1Η, CHOSi), 3.35 (q, J ) 7.0 Hz, 1Η,
COCHCH3), 2.78 (s, 3Η, NdCCH3), 2.72 (d, J ) 2.0 Hz, 1Η,
CH2COOCH), 2.34-2.22 (m, 5Η), 2.16-2.11 (m, 1Η), 2.06-
2.00 (m, 2Η), 1.95 (s, 3Η, CHdC(CH3)), 1.70 (s, 3Η, CH2C-
(CH3)dCH), 1.57-1.53 (m, 3Η), 1.40-1.34 (m, 1Η), 1.22 (s,
3Η, C(CH3)2), 1.09 (d, J ) 4.5 Hz, 3Η, CH(CH3)), 1.07 (d, J )
7.0 Hz, 3Η, CH(CH3)), 0.93 (s, 3Η, C(CH3)2), 0.91 (s, 9Η, SiC-
(CH3)3), 0.15 (s, 3Η, Si(CH3)2), 0.08 (s, 3Η, Si(CH3)2), 0.05 (s,
9Η, Si(CH3)3); 13C NMR (CDCl3, 125 MHz) δ 213.7, 173.9,
165.0, 152.1, 138.6, 137.1, 121.4, 121.0, 115.0, 91.5, 82.5, 73.6,
72.5, 65.4, 60.4, 55.2, 41.4, 40.4, 36.3, 33.3, 33.2, 32.4, 26.4,
25.1, 23.8, 23.3, 19.1, 18.6, 18.4, 15.7, 14.1, 10.4, -1.0, -3.8,
-4.3; HRMS calcd for C39H72NO7SSi2 754.4562 [M + H]+,
found 754.4554.
For 44b: Rf 0.40 (ethyl acetate/hexanes/methanol; 15:80:
5); [R]22 -35.7 (c 1.6, CHCl3); IR (neat, NaCl) 3491, 3106,
D
2953, 2896, 1730, 1713, 1470, 1251, 1097 cm-1
;
1H NMR
(CDCl3, 500 MHz) δ 6.92 (s, 1Η, SCHdC), 6.48 (s, 1Η, CHd
CCH3), 5.16 (t, J ) 6.5 Hz, 1Η, CH2CHdCCH3), 4.61 (dd, J )
7.0 Hz, J ) 7.0 Hz, 1Η, OCH2O), 4.40 (q, J ) 3.5 Hz, 1Η, CH2-
COOCHCH2), 4.07 (dd, J ) 6.0 Hz, J ) 6.0 Hz, 1Η, CHOCOOC-
CH2), 3.74 (dd, J ) 8.3 Hz, J ) 9.0 Hz, 1Η), 3.67 (dd, J ) 7.0
Hz, J ) 6.5 Hz, 1Η), 3.52 (t, J ) 8.5 Hz, 1Η), 3.46 (dd, J ) 7.0
Hz, J ) 7.0 Hz, 1Η), 3.41 (dd, J ) 3.0 Hz, J ) 3.0 Hz, 1Η),
3.25 (q, J ) 3.5 Hz, 1Η), 2.69 (s, 3Η, NdCCH3), 2.62 (d, J )
1.0 Hz, 1Η, CH2COOCH), 2.50-2.40 (m, 2Η), 2.31-2.25 (m,
3Η), 2.03-1.98 (m, 2Η), 1.96 (s, 3Η, CHdC(CH3), 1.83 (br s,
1Η, OH), 1.68 (s, 3Η, CH2C(CH3)dCH), 1.22-1.17 (m, 4Η),
1.12 (d, J ) 1.5 Hz, 3Η, CH(CH3)), 1.06 (d, J ) 7.0 Hz, 3Η,
CH(CH3)), 0.95 (s, 3Η, C(CH3)2), 0.87 (s, 9Η, SiC(CH3)3), 0.82
(s, 3Η, C(CH3)2), 0.11 (s, 3Η, Si(CH3)2), 0.06 (s, 3Η, Si(CH3)2),
0.01 (s, 9Η, Si(CH3)3); 13C NMR (CDCl3, 125 MHz) δ 214.5,
175.5, 164.7, 152.2, 139.0, 136.9, 122.2, 120.9, 115.4, 92.0, 82.0,
75.0, 73.5, 65.9, 58.1, 54.0, 42.3, 40.2, 35.9, 33.4, 33.0, 32.5,
26.3, 25.4, 23.9, 22.8, 19.2, 18.5, 18.4, 15.5, 14.2, 11.8, -0.9,
(3S,6R,7S,8S,12Z,15S,16E)-1,3-Bis(tert-butyldimethyl-
silyloxy)-7-hydroxy-15-(2-trimethyl silylethoxymethoxy)-
4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-
heptadeca-12,16-dien-5-one (47a). Rf 0.6 (ethyl acetate/
hexanes/methanol; 15:80:5); [R]22 -56.5 (c 0.4, CHCl3); IR
D
(neat, NaCl) 3503, 2884, 2857, 1683, 1471, 1251, 1100, 836
1
cm-1; H NMR (CDCl3, 500 MHz) δ 6.96 (s, 1H), 6.50 (s, 1H),
J. Org. Chem, Vol. 69, No. 26, 2004 9281

Jung et al.
5.18 (t, J ) 7.0 Hz, 1H), 4.64 (dd, J ) 6.5 Hz, J ) 6.5 Hz, 2H),
4.09 (dd, J ) 6.5 Hz, J ) 6.0 Hz, 1H), 3.90 (d, J ) 7.0 Hz, 1H),
3.77 (q, J ) 8.0 Hz, 1H), 3.68 (dd, J ) 6.0 Hz, J ) 6.0 Hz, 1H),
3.62 (dd, J ) 7.8 Hz, J ) 7.8 Hz, 1H), 3.51 (dd, J ) 11.0 Hz,
J ) 11.0 Hz, 2H), 3.32 (d, J ) 8.0 Hz, 1H), 2.72 (s, 3H), 2.42-
2.19 (m, 2H), 2.07-2.03 (m, 2H), 2.02 (s, 3H), 1.80-1.73 (m,
2H), 1.69 (s, 3H), 1.66-1.61 (m, 1H), 1.59-1.44 (m, 4H), 1.36-
1.28 (m, 2H), 1.22 (s, 3H), 1.11 (s, 3H), 1.04 (d, J ) 7.0 Hz,
3H), 0.92 (s, 9H), 0.90 (s, 9H), 0.84 (d, J ) 7.0 Hz, 3H), 0.12
(s, 3H), 0.10 (s, 3H), 0.05 (s, 6H), 0.01 (s, 9H); 13C NMR (CDCl3,
125 MHz) δ 217.5, 174.9, 166.1, 152.8, 142.8, 137.2, 120.5,
118.6, 115.3, 92.2, 74.3, 65.4, 53.9, 45.1, 39.4, 33.0, 32.9, 31.5,
26.5, 26.4, 26.2, 26.0, 23.9, 21.4, 18.9, 18.6, 18.5, 17.6, 16.2,
14.4, 1.5, -0.9, -3.1, -3.3, -3.4, -3.7, -3.9, -4.1, -4.4; HRMS
calcd for C45H88NO6SSi3 854.5640 [M + H]+, found 854.5611.
layers were washed with brine (20 mL), dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure.
Acetic acid (2.2 mL) was added to a solution of the protected
acid 51 in THF:H2O (20 mL, 8:2) at 0 °C and the mixture was
stirred for 3 h. The reaction mixture was evaporated under
reduced pressure, and the residue was dissolved in ethyl
acetate (30 mL). The organic phase was washed with water
(20 mL) and brine (20 mL), dried over anhydrous MgSO
,
4
filtered, and concentrated under reduced pressure. The crude
residue was purified by column chromatography (silica gel,
ethyl acetate/hexanes/methanol, 15:80:5) to give acid 52 (0.67
g, 0.72 mmol, 36%) as a colorless oil. Rf 0.3 (ethyl acetate/
hexanes/methanol; 15:80:5); [R]22 -35.8 (c 1.0, CHCl3); IR
D
(neat, NaCl) 2954, 2859, 1732, 1715, 1472, 1383, 1251, 1100,
837 cm-1; 1H NMR (CDCl3, 500 MHz) δ 6.92 (s, 1Η, SCHdC),
6.48 (s, 1Η, CHdCCH3), 5.16 (t, J ) 7.50 Hz, 1Η, CH2CHd
CCH3), 4.83 (d, J ) 11.0 Hz, 1Η), 4.75 (d, J ) 8.7 Hz, 2Η,
OCH2CCl3), 4.67 (d, J ) 7.1 Hz, 1Η), 4.62 (dd, J ) 7.5 Hz, J
) 7.5 Hz, 2Η, OCH2O), 4.35 (q, J ) 3.0 Hz, 1Η, CH2-
COOCHCH2), 4.00 (d, J ) 6.2 Hz, 1Η, CHOCOOCCH2), 3.76
(dd, J ) 8.1 Hz, J ) 8.1 Hz, 1Η), 3.52 (dd, J ) 8.1 Hz, J ) 8.1
Hz, 1Η), 3.42 (q, J ) 3.0 Hz, 1Η), 2.70 (s, 3Η, NdCCH3), 2.59
(d, J ) 1.2 Hz, 1Η, CH2COOCH), 2.33-2.23 (m, 3Η), 2.04-
1.93 (m, 5Η), 1.75-1.68 (m, 1Η), 1.64 (s, 3Η, CH2C(CH3)dCH),
1.46-1.1.38 (m, 2Η), 1.21 (s, 3Η), 1.10 (d, J ) 2.8 Hz, 3Η, CH-
(CH3)), 1.07 (d, J ) 3.7 Hz, 3Η, CH(CH3)), 0.93 (s, 3Η, C(CH3)2),
0.87 (s, 9Η, SiC(CH3)3), 0.84 (s, 3Η, C(CH3)2), 0.12 (s, 3Η, Si-
(CH3)2), 0.05 (s, 3Η, Si(CH3)2), 0.00 (s, 9Η, Si(CH3)3); 13C NMR
(CDCl3, 125 MHz) δ 214.5, 175.8, 164.5, 153.9, 152.5, 139.3,
136.6, 121.6, 115.8, 94.8, 92.2, 82.6, 82.0, 74.3, 73.9, 65.7, 60.5,
54.7, 41.6, 40.3, 39.5, 35.2, 33.0, 32.5, 32.2, 26.3, 26.2, 23.8,
23.3, 19.4, 18.6, 14.1, -0.9, -1.0, -3.8, -4.2; HRMS calcd for
C42H73Cl3NO9SSi2 928.3605 [M + H]+, found 928.3620.
(2S,5R,6S,7S,11Z,14S,15E)-2-(tert-Butyldimethylsil-
yloxy)-1-(4-methyl-2,6,7-trioxabicyclo[2.2.2]octyl)-6-hydroxy-14-
(2-trimethylsilylethoxymethoxy)-3,3,5,7,11,15-hexamethyl-
16-(2-methyl-1,3-thiazol-4-yl)hexadeca-11,15-dien-4-one
(48a). Rf 0.6 (20% ethyl acetate in hexanes); [R]22 -24.5 (c
D
0.4, CHCl3); IR (neat, NaCl) 3500, 2954, 2930, 1685, 1471,
1249, 1102, 1055, 836 cm-1; 1H NMR (CDCl3, 500 MHz) δ 6.96
(s, 1H), 6.50 (s, 1H), 5.20 (t, J ) 7.0 Hz, 1H), 4.63 (dd, J ) 6.5
Hz, J ) 6.5 Hz, 2H), 4.19 (s, 1H), 4.08 (t, J ) 6.5 Hz 1H), 3.86
(s, 6H), 3.77 (q, J ) 8.0 Hz, 1H), 3.64-3.48 (m, 2H), 3.35 (d, J
) 9.5 Hz, 1H), 3.27 (q, J ) 7.0 Hz, 1H), 2.71 (s, 3H), 2.42-
2.28 (m, 2H), 2.08-2.02 (m, 2H), 2.01 (s, 3H), 1.95-1.84 (m,
1H), 1.81-1.73 (m, 2H), 1.68 (s, 3H), 1.58-1.43 (m, 3H), 1.37-
1.25 (m, 3H), 1.14 (s, 3H), 1.10 (s, 3H), 1.03 (d, J ) 7.0 Hz,
3H), 0.94 (t, J ) 8.5 Hz, 3H), 0.88 (s, 9H), 0.79 (s, 3H), 0.13 (s,
3H), 0.09 (s, 3H), 0.02 (s, 9H); 13C NMR (CDCl3, 125 MHz) δ
213.7, 173.9, 165.0, 152.1, 138.6, 137.1, 121.4, 121.0, 115.0,
91.5, 82.5, 73.6, 72.5, 65.4, 60.4, 55.2, 41.4, 40.4, 36.3, 33.3,
33.2, 32.4, 26.4, 25.1, 23.8, 23.3, 19.1, 18.6, 18.4, 15.7, 14.1,
10.4, -1.0, -3.8, -4.3; HRMS calcd for C44H80NO8SSi2 838.5143
[M + H]+, found 838.5118.
(4S,7S,8S,5Z,9E)-4-(tert-Butyldimethylsilyloxy)-5,5,7-
trimethyl-8-[1,5,9-trimethyl-10-(2-methylthiazol-4-yl)-8-
(2-trimethylsilanylethoxymethoxy)-deca-5,9-dienyl]oxo-
cane-2,6-dione (53). To a stirred solution of acid 44a (0.3 g,
0.4 mmol) in dichloromethane (10 mL) was added triethyl-
amine (0.4 g, 4.0 mmol) and DMAP (0.5 g, 4.0 mmol) followed
by 2,4,6-trichlorobenzoyl chloride (0.6 g, 2.4 mmol) at -5 °C.
The mixture was stirred at 0 °C for 30 min. The mixture was
quenched by addition of saturated aqueous NH4Cl solution (2
mL) and diluted with dichloromethane (5 mL). The mixture
was separated, and the aqueous phase was washed with
dichloromethane (5 mL). The combined organic solution was
dried over anhydrous MgSO4, filtered, and concentrated under
reduced pressure. The residue was purified by column chro-
matography (10% ethyl acetate/hexanes) to afford eight-
membered lactone 53 (0.26 g, 90%) as a colorless oil. Rf 0.3
(2S,5R,6S,7S,11Z,14S,15E)-2-(tert-Butyldimethylsil-
yloxy)-1-(5-methyl-2,7,8-trioxabicyclo [3.2.1]octyl)-6-hy-
droxy-14-(2-trimethylsilylethoxymethoxy)-3,3,5,7,11,15-
hexamethyl-16-(2-methyl-1,3-thiazol-4-yl)hexadeca-11,-
15-dien-4-one (49a). Rf 0.7 (20% ethyl acetate in hexanes);
[R]22D -31.0 (c 0.2, CHCl3); IR (neat, NaCl) 3447, 2958, 2924,
1717, 1559, 1458, 1293, 1101, 1028, 836 cm-1; 1H NMR (CDCl3,
600 MHz) δ 6.97 (s, 1H), 6.50 (s, 1H), 5.19 (t, J ) 6.5 Hz, 1H),
4.65 (dd, J ) 8.5 Hz, J ) 8.5 Hz, 2H), 4.22-4.15 (m, 1H), 4.10-
4.04 (m, 2H), 3.95-3.86 (m, 4H), 3.79-3.72 (m, 3H), 3.51 (q,
J ) 7.0 Hz, 1H), 2.73 (s, 3H), 2.69 (d, J ) 8.0 Hz, 1H), 2.44-
2.27 (m, 3H), 2.10-2.03 (m, 2H), 2.02 (s, 3H), 1.95-1.79 (m,
3H), 1.70 (s, 3H), 1.60-1.44 (m, 2H), 1.36-1.23 (m, 4H), 1.13
(s, 3H), 1.10 (s, 3H), 1.00 (d, J ) 7.5 Hz, 3H), 0.96 (t, J ) 8.0
Hz, 3H), 0.89 (s, 9H), 0.81 (s, 3H), 0.12 (s, 3H), 0.10 (s, 3H),
0.01 (s, 9H); 13C NMR (CDCl3, 150 MHz) δ 214.3, 170.8, 162.2,
155.0, 140.4, 136.5, 127.5, 124.4, 115.3, 92.7, 83.6, 71.1, 65.5,
61.6, 60.4, 56.6, 55.7, 43.8, 40.7, 36.3, 35.9, 34.1, 33.9, 31.1,
30.0, 26.5, 22.9, 22.4, 21.9, 19.1, 18.7, 18.3, 16.5, 15.6, 14.4,
9.8, -1.2, -3.6, -4.9; HRMS calcd for C44H80NO8SSi2 838.5143
[M + H]+, found 838.5112.
(3S,6R,7S,8S,12Z,15S,16E)-3-(tert-Butyldimethylsil-
yloxy)-7-[(2,2,2-trichloroethoxycarbonyl)oxy]-15-(2-trimeth-
ylsilylethoxymethoxy)-4,4,6,8,12,16-hexamethyl-17-
(2-methyl-1,3-thiazol-4-yl)-5-oxoheptadeca-12,16-dieno-
ic Acid (52). To a stirred solution of acid 44a (1.5 g, 2.0 mmol)
in dichloromethane (20 mL) were sequentially added pyridine
(1.6 g, 20.0 mmol) and tert-butyldimethylsilyl chloride (0.37
g, 2.4 mmol) at 0 °C, and the reaction mixture was stirred for
1 h. To the solution was added 2,2,2-trichloroethyl chloro-
formate (2.2 g, 10.0 mmol) dropwise at 0 °C, and the resulting
mixture was stirred at room temperature for 5 h. After
completion of the reaction, water (20 mL) was slowly added
followed by addition of dichloromethane (20 mL). The organic
layer was separated, and the aqueous phase was extracted
with dichloromethane (2 × 10 mL). The combined organic
(5% ethyl acetate/hexanes); [R]22 -37.7 (c 1.2, CHCl3); IR
D
(neat, NaCl) 2954, 2929, 2859, 1735, 1704, 1472, 1384, 1251,
1021, 838 cm-1; 1H NMR (CDCl3, 500 MHz) δ 6.95 (s, 1H), 6.45
(s, 1H), 5.16 (t, J ) 6.5 Hz, 1H), 4.81 (d, J ) 12.0 Hz, 1H),
4.70 (d, J ) 8.5 Hz, 1H), 4.60 (dd, J ) 6.5 Hz, J ) 7.0 Hz, 2H),
4.01 (d, J ) 7.0 Hz, 1H), 3.70 (tq, J ) 7.0 Hz, J ) 8.5 Hz, 4H),
3.52-3.43 (m, 3H), 2.70 (s, 3H), 2.45-2.22 (m, 4H), 2.10-2.02
(m, 2H), 1.99 (s, 3H), 1.65 (s, 3H), 1.48-1.39 (m, 1H), 1.33 (s,
3H), 1.25 (s, 3H), 1.20 (s, 3H), 1.17 (s, 3H), 1.22-1.07 (m, 2H),
0.90 (s, 9H), 1.13 (s, 3H), 0.07 (s, 3H), 0.00 (s, 9H); 13C NMR
(CDCl3, 125 MHz) δ 210.2, 170.0, 164.2, 152.6, 138.7, 136.7,
121.0, 115.7, 94.7, 92.0, 81.9, 74.2, 65.3, 53.5, 51.9, 41.22, 39.0,
34.9, 32.9, 32.5, 31.9, 26.0, 25.0, 23.8, 19.5, 18.5, 15.8, 14.3,
12.4, 11.4, -1.2, -3.6, -4.6; MS (ESI) (m/z) 736 [M + H]+;
HRMS calcd for C39H70NO6SSi2 736.4462 [M + H]+, found
736.4434.
(4S,7R,8S,9S,13Z,16S)-4-(tert-Butyldimethylsilyloxy)-
8-[(2,2,2-trichloroethoxycarbonyl)oxy]-5,5,7,9,13-penta-
methyl-16-[(E)-1-methyl-(2-methyl-1,3-thiazol-4-yl)ethen-
yl]oxacyclohexadec-13-ene-2,6-dione (55). To a stirred sus-
pension of magnesium bromide (0.56 g, 3.0 mmol) in ether (10
mL) were added nitromethane (0.19 g, 3.0 mmol) and 1-bu-
tanethiol (0.14 g, 1.5 mmol) at room temperature, and the
9282 J. Org. Chem., Vol. 69, No. 26, 2004

Total Syntheses of Epothilones B and D
mixture was stirred for 20 min. The resulting solution was
added to a stirred solution of acid 52 (0.46 g, 0.5 mmol) in
ether (10 mL) at room temperature, and the mixture was
stirred for 1 h. The reaction mixture was diluted with ether
(30 mL) and dichloromethane (10 mL) and washed with water
(25 mL). The organic layer was separated, and the aqueous
phase was extracted with ether (30 mL) and dichloromethane
(10 mL). The combined organic phases were dried over
anhydrous MgSO4, filtered, and concentrated under reduced
pressure to give the acid 54, which was used in the next
reaction without further purification.
(s, 9Η, SiC(CH3)3), 0.14 (s, 3Η, Si(CH3)2), -0.04 (s, 3Η,
Si(CH3)2); 13C NMR (CDCl3, 125 MHz) δ 218.2, 171.3, 165.0,
153.0, 139.8, 138.9, 120.7, 119.9, 116.4, 79.9, 73.9, 60.8, 53.9,
43.8, 39.7, 39.4, 33.4, 32.9, 31.7, 26.9, 26.5, 24.9, 23.4, 23.1,
21.4, 19.6, 19.0, 17.3, 15.7, 14.6, -3.5, -5.1; HRMS calcd for
C33H56NO5SSi 606.3643 [M + H]+, found 606.3632.
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-5,5,7,9,13-penta-
methyl-16[(E)-1-methyl(2-methyl-1,3-thiazol-4-yl)ethen-
yl]oxacyclohexadec-13-ene-2,6-dione (Epothilone D, 4).
To a solution of 7-OH lactone 56 (0.12 g, 0.2 mmol) in THF
(10 mL) was added dropwise hydrogen fluoride-pyridine (2.2
mL) at 0 °C. After being stirred at room temperature for 16 h,
the mixture was diluted with ether (10 mL) and quenched at
0 °C by slow addition of saturated aqueous NaHCO3 solution
until CO2 evolution ceased. The organic layer was separated,
and the aqueous phase was extracted with ether (8 mL). The
combined organic phases were washed with saturated aqueous
CuSO4 solution (10 mL), water (10 mL), and brine (10 mL).
The organic layer was separated, dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure. The residue
was purified by column chromatography (silica gel, ethyl
acetate/hexanes/methanol, 20:70:10) to afford epothilone D (4,
0.093 g, 0.19 mmol, 95%) as a colorless oil. Rf 0.5 (ethyl acetate/
To a stirred solution of 54 (0.27 g, 0.3 mmol) in THF (12
mL) was added triethylamine (0.18 g, 1.8 mmol) followed by
2,4,6-trichlorobenzoyl chloride (0.36 g, 1.5 mmol) at -5 °C. The
mixture was stirred at 0 °C for 1 h. The solution was added
dropwise to a solution of DMAP (0.37 g, 3.0 mmol) in toluene
(120 mL) at room temperature, and the resulting mixture was
stirred for 4 h. The mixture was concentrated under reduced
pressure to a small volume and filtered through silica gel. The
residue was washed with 40% ether in n-hexanes. The result-
ing solution was evaporated under reduced pressure. The
residue was purified by column chromatography (silica gel,
15% ethyl acetate/hexanes) to give lactone 55 (0.14 g, 0.36
mmol, 38%) as a colorless oil. Rf 0.5 (20% ethyl acetate/
hexanes/methanol; 20:70:10, v/v); [R]22 -56.2 (c 0.3, CHCl3);
D
hexanes); [R]22 -16.9 (c 1.4, CHCl3); IR (neat, NaCl) 2957,
IR (neat, NaCl) 3506, 2960, 2930, 2874, 1730, 1688, 1464, 1377,
D
1
1272, 1146, 977 cm-1; H NMR (CDCl3, 500 MHz) δ 6.97 (s,
2858, 1759, 1740, 1698, 1385, 1249, 1097 cm-1
;
1H NMR
1Η, SCHdC), 6.61 (s, 1Η, CHdCCH3), 5.24 (d, J ) 10.0 Hz,
1Η, CH2COOH), 5.16(d, J ) 4.5 Hz, 1Η, CH3CdCHCH2), 4.31
(d, J ) 11.0 Hz, 1Η, (CH3)2CCHOH), 3.74 (s, 1Η, CHOH), 3.50
(q, J ) 7.0 Hz, 1Η, COCHCH3), 3.18 (d, J ) 6.5 Hz, 1Η,
COCHCH3), 3.05 (br s, 1Η, OH), 2.71 (s, 3Η, NdCCH3), 2.65
(ddd, J ) 5.0 Hz, J ) 5.5 Hz, J ) 11.0 Hz, 1Η, CH2CHdCCH3),
2.48 (dd, J ) 11.5 Hz, J ) 11.0 Hz, 1Η, CH2COOCH), 2.39-
2.24 (m, 3Η), 2.09 (s, 3Η, CHdCCH3), 1.96-1.87 (m, 1Η),
1.77-1.72 (m, 1Η), 1.68 (s, 3Η, CH2C(CH3)dCH), 1.36 (s, 3Η,
C(CH3)2), 1.34-1.28 (m, 4Η), 1.21 (d, J ) 7.0 Hz, 3Η,
CH(CH3)), 1.09 (s, 3Η, C(CH3)2), 1.04 (d, J ) 7.0 Hz, 3Η, CH-
(CH3)); 13C NMR (CDCl3, 150 MHz) δ 221.4, 170.6, 168.0, 149.2,
143.7, 138.6, 121.0, 115.4, 115.2, 78.3, 74.5, 71.3, 60.6, 54.2,
41.3, 39.6, 39.2, 32.1, 31.7, 25.4, 23.0, 22.9, 17.7, 17.0, 15.4,
14.4, 13.6; HRMS calcd for C27H42NO5S 492.2784 [M + H]+,
found 492.2777.
(CDCl3, 500 MHz) δ 6.99 (s, 1Η, SCHdC), 6.56 (s, 1Η, CHd
CCH3), 5.22 (d, J ) 10.3 Hz, 1Η, CH2CHdCCH3), 5.21 (d, J )
15.9 Hz, 1Η, CH2COOCHCH2), 5.00 (d, J ) 10.4 Hz, 1Η,
CHOCOOCCH2), 4.90 (d, J ) 11.9 Hz, 1Η, CH2CCl3), 4.80 (d,
J ) 11.9 Hz, 1Η, CH2CCl3), 4.06 (d, J ) 10.3 Hz, 1Η, CHOSi),
3.34 (q, J ) 6.7 Hz, 1Η, COCHCH3), 2.84 (d, J ) 16.1 Hz, 1Η,
CH2COOCH), 2.73 (s, 3Η, NdCCH3), 2.71-2.66 (m, 1Η, CH2-
COOCH), 2.56-2.52 (m, 1Η), 2.14 (s, 3Η, CHdC(CH3)), 2.09-
2.03 (m, 2Η), 1.80-1.74 (m, 3Η), 1.70 (s, 3Η, CH2C(CH3)dCH),
1.38 (d, J ) 9.3 Hz, 1Η), 1.29 (d, J ) 8.4 Hz, 2Η), 1.24 (s, 3Η,
C(CH3)2), 1.20 (s, 3Η, C(CH3)2), 1.15 (d, J ) 6.7 Hz, 3Η, CH-
(CH3)), 1.05 (d, J ) 6.9 Hz, 3Η, CH(CH3)), 0.88 (s, 9Η, SiC-
(CH3)3), 0.14 (s, 3Η, Si(CH3)2), 0.09 (s, 3Η, Si(CH3)2); 13C NMR
(CDCl3, 125 MHz) δ 212.9, 172.3, 165.0, 155.0, 152.9, 140.8,
138.9, 120.2, 119.7, 116.7, 95.3, 86.9, 80.8, 76.7, 53.9, 46.2, 39.4,
35.8, 32.8, 32.1, 31.7, 28.0, 26.6, 25.1, 24.3, 23.4, 19.6, 19.3,
19.1, 16.7, 15.2, -3.2, -5.3; HRMS calcd for C36H57Cl3NO7SSi
780.2691 [M + H]+, found 780.2668.
(4S,7R,8S,9S,13Z,16S)-4-(tert-Butyldimethylsilyloxy)-
8-hydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-(2-
methyl-1,3-thiazol-4-yl)ethenyl]oxacyclohexadec-13-ene-
2,6-dione (56). To a solution of lactone 55 (0.25 g, 0.32 mmol)
in methanol (18 mL) was added ammonium chloride (0.42 g,
6.4 mmol) and zinc dust (0.43 g, 8.0 mmol). The mixture was
heated to reflux for 20 min. The reaction mixture was diluted
with ethyl acetate (16 mL) and filtered through Celite. The
filtrate was concentrated under reduced pressure, and the
residue was dissolved in ethyl acetate (40 mL) and washed
with water (15 mL) and brine (15 mL). The organic layer was
dried over anhydrous MgSO4, filtered, and concentrated under
reduced pressure to give the lactone, which was purified by
column chromatography (silica gel, 25% ethyl acetate/hexanes)
to yield lactone 56 (0.18 g, 0.30 mmol, 92%) as a colorless oil.
Rf 0.3 (20% ethyl acetate/hexanes); [R]22D -52.6 (c 0.3, CHCl3);
IR (neat, NaCl) 3487, 2958, 1736, 1684, 1468, 1245, 1113, 842
cm-1; 1H NMR (CDCl3, 500 MHz) δ 6.98 (s, 1Η, SCHdC), 6.57
(s, 1Η, CHdCCH3), 5.17 (dd, J ) 6.1 Hz, J ) 5.9 Hz, 1Η,
CH2CHdCCH3), 5.00 (d, J ) 10.4 Hz, 1Η, CH2COOCHCH2),
4.08 (dd, J ) 3.7 Hz, J ) 3.9 Hz, 1Η, CHOCOOCCH2), 3.95 (t,
J ) 3.1 Hz, 1Η, CHOSi), 3.08 (dd, J ) 3.6 Hz, J ) 3.6 Hz, 1Η,
COCHCH3), 2.93 (br s, 1Η, OH), 2.80-2.79 (m, 2Η), 2.73 (s,
3Η, NdCCH3), 2.71-2.68 (m, 2Η), 2.52-2.49 (m, 1Η), 2.12 (s,
3Η, CHdC(CH3)), 1.86-1.78 (m, 3Η), 1.73-1.71 (m, 1Η), 1.68
(s, 3Η, CH2C(CH3)dCH), 1.47-1.42 (m, 1Η), 1.25-1.22 (m,
1Η), 1.20 (s, 3Η, C(CH3)2), 1.18 (s, 3Η, C(CH3)2), 1.17 (d, J )
6.7 Hz, 3Η, CH(CH3)), 1.05 (d, J ) 7.0 Hz, 3Η, CH(CH3)), 0.85
(1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,-
16-pentamethyl-3-[(E)-1-methyl-(2-methyl-1,3-thiazol-4-
yl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-di-
one (Epothilone B, 2). Method A: To a stirred solution of
epothilone D (4, 30.0 mg, 0.061 mmol) in dry chloroform (3
mL) was added m-CPBA (30.0 mg, 0.12 mmol, 70% purity) at
-12 °C, and the reaction mixture was stirred at -10 to 0 °C
for 5 h. The mixture was diluted with dichloromethane (12
mL) and quenched by slow addition of saturated aqueous
NaHCO3 solution (10 mL). The organic layer was separated,
and the aqueous phase was extracted with dichloromethane
(10 mL). The combined organic phases were washed with 5%
NaOH solution (10 mL), and the aqueous phase was back-
extracted with dichloromethane (10 mL). The combined or-
ganic phases were dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified
by flash column chromatography (silica gel, 5% methanol/
dichloromethane) to provide a mixture of epothilone B (2) and
its epoxy diastereoisomer (28 mg, 0.11 mmol, ca. 2.8:1 ratio
by HPLC), which was purified by preparative HPLC (grad.
50% AcCN/H2O, v/v) to give pure epothilone B (2, 9 mg, 30%)
as colorless crystals. Rf 0.3 (ethyl acetate/hexanes/methanol;
20:70:10); mp 117-118 °C (124-125 °C);37 [R]22D -74.4 (c 0.5,
CHCl3); IR (film, NaCl) 3481, 2963, 2931, 1734, 1686, 1457,
1
1378, 1293, 1259, 1187, 1148, 1054, 1008, 978, 752 cm-1; H
NMR (CDCl3, 600 MHz) δ 6.96 (s, 1Η, SCHdC), 6.58 (s, 1Η,
CHdCCH3), 5.40 (dd, J ) 7.8 Hz, J ) 2.4 Hz 1Η, CH2COOH),
(37) Hofmann, H.; Mahnke, M.; Memmert, K.; Petersen, F.; Schupp,
T.; KU¨ sters, E.; Mutz, M. WO 99/42602, August 26, 1999.
J. Org. Chem, Vol. 69, No. 26, 2004 9283

Jung et al.
4.22 (br s, 1H), 4.21 (br s, 1H), 3.75 (t, J ) 3.0 Hz, 1H, CHOH),
3.28 (dq, J ) 6.9 Hz, J ) 4.8 Hz 1Η, (CO)CHCH3), 2.79 (dd, J
) 7.2 Hz, J ) 4.8 Hz 1Η, CHOCCH3), 2.68 (s, 3H, NdCCH3),
2.52 (dd, J ) 10.2 Hz, J ) 10.2 Hz, 1Η, CH2COOH), 2.34 (dd,
J ) 3.0 Hz, J ) 3.0 Hz, 1Η, CH2COOCH), 2.10 (td, J ) 3.6
Hz, J ) 3.6 Hz, 1H, CH3COCHCH2CHO), 2.07 (s, 3Η, CHd
CCH3), 1.90 (ddd, J ) 15.0, J ) 7.8 Hz, J ) 7.2 Hz, 1H,
(CH3)COCHCH2CHO), 1.76-1.67 (m, 3Η), 1.52-1.42 (m, 2H),
1.41-1.37 (m, 2Η), 1.36 (s, 3Η, C(CH3)OCHCH2), 1.26 (s, 3Η,
C(CH3)2), 1.15 (d, J ) 6.6 Hz, 3Η, CH(CH3)), 1.06 (s, 3Η,
C(CH3)2), 0.99 (d, J ) 7.2 Hz, 3Η, CH(CH3)); 13C NMR (CDCl3,
150 MHz) δ 220.8, 170.8, 165.4, 151.9, 137.9, 119.8, 116.3, 76.9,
74.3, 73.0, 61.9, 61.6, 53.3, 43.1, 39.4, 36.6, 32.6, 32.3, 31.0,
23.0, 22.6, 21.7, 19.8, 19.3, 17.3, 16.1, 13.8; HRMS calcd for
C27H42NO6S 508.2733 [M + H]+, found 508.2757.
Method B: To a stirred solution of epothilone D (4, 30.0
mg, 0.061 mmol) in dichloromethane (3 mL) was added
dropwise DMDO (0.1 M in acetone, 1.4 mL, 1.4 mmol;
precooled to -78 °C) at -78 °C, and the reaction mixture was
warmed to -50 °C and stirred for 2 h. The excess DMDO was
quenched by the addition of dimethyl sulfide (0.3 mL). The
solvent was removed under reduced pressure. The residue was
purified by flash column chromatography (silica gel, acetate/
hexanes/methanol; 20:70:10) to provide a mixture that was
crystallized by the addition of ether (1 mL). The solid was
filtered and washed with ether (1 mL) to give a mixture of
epothilone B (2) and its epoxy diastereoisomer (20 mg, 67%;
ca. 9.5:1 ratio by HPLC), which was purified by preparative
HPLC (grad. 50% AcCN/H2O, v/v) to give pure epothilone B
(2, 16 mg, 53%) as colorless crystals.
Acknowledgment. The authors wish to express
their gratitude to Dr. Tilak Raj for early attempts at
the Normant olefination reaction and to Drs. E. Blake
Watkins and R. M. Hindupur for helpful contributions.
Early funding for this work was provided by the Elsie
M. Pardee Foundation. Subsequent funding was pro-
vided by the University of Mississippi. More recently,
funding has been provided by Tapestry Pharmaceuti-
cals, Inc. (formerly Napro Biotherapeutics, Inc.).
Supporting Information Available: NMR spectra (1H,
13C, DEPT-135, 2D) and HPLC chromatograms of selected
intermediates and Epothilones B and D. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO048742O
9284 J. Org. Chem., Vol. 69, No. 26, 2004