Total syntheses of epothilones A and B via a macrolactonization-based strategy

Article abstract of DOI:10.1021/ja971110h

The total syntheses of epothilones A (1) and B (2) and several analogues thereof are described. The reported strategy relies on a macrolactonization approach and features selective epoxidation of the macrocycle double bond in precursors 3 and 4 (Scheme 1), respectively, as well as high convergency and flexibility. Building blocks 9-12 and 15 were constructed by asymmetric processes and coupled via Wittig, aldol, and macrolactonization reactions to afford the basic skeleton of epothilones and that of several of their analogues by a relatively short route. The utilization ofintermediate 14, obtained via a stereoselective Wittig reaction and its Enders coupling to SAMP hydrazone 13 (Scheme 8), in combination with a stereoselective aldol reaction with the modified substrate 69 (Scheme 10) improved the stereoselectivity and efficiency of the total synthesis of these new and highly potent microtubule binding antitumor agents.

Full text of DOI:10.1021/ja971110h

7974
J. Am. Chem. Soc. 1997, 119, 7974-7991
Total Syntheses of Epothilones A and B via a
Macrolactonization-Based Strategy
K. C. Nicolaou,* S. Ninkovic, F. Sarabia, D. Vourloumis, Y. He, H. Vallberg,
M. R. V. Finlay, and Z. Yang
Contribution from the Department of Chemistry and The Skaggs Institute for Chemical Biology,
The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, and
Department of Chemistry and Biochemistry, UniVersity of California, San Diego, 9500 Gilman
DriVe, La Jolla, California 92093
ReceiVed April 7, 1997X
Abstract: The total syntheses of epothilones A (1) and B (2) and several analogues thereof are described. The
reported strategy relies on a macrolactonization approach and features selective epoxidation of the macrocycle double
bond in precursors 3 and 4 (Scheme 1), respectively, as well as high convergency and flexibility. Building blocks
9-12 and 15 were constructed by asymmetric processes and coupled via Wittig, aldol, and macrolactonization reactions
to afford the basic skeleton of epothilones and that of several of their analogues by a relatively short route. The
utilization of intermediate 14, obtained via a stereoselective Wittig reaction and its Enders coupling to SAMP hydrazone
13 (Scheme 8), in combination with a stereoselective aldol reaction with the modified substrate 69 (Scheme 10)
improved the stereoselectivity and efficiency of the total synthesis of these new and highly potent microtubule binding
antitumor agents.
1. Introduction
analogues has also been reported first by Danishefsky12 and then
by us13 in preliminary communications. Here, we report the
details of the total synthesis of both epothilones A (1) and B
(2) and of a number of analogues of these compounds by our
macrolactonization strategy.10
Epothilones A (1) and B (2) are two architecturally novel
natural products recently isolated from the myxobacteria Sor-
angium cellulosum strain 901,2 and possess impressive micro-
tubule binding affinities and antitumor properties.1-4 Their
molecular structures have been secured by a combination of
spectroscopic and X-ray crystallographic techniques.1,2 Interest-
ingly, and despite their structural difference from Taxol, the
epothilones were found to bind to the same region on micro-
tubules4 and to displace Taxol from its binding site.5,6 The
higher potency of these new compounds, and their effectiveness
against certain drug-resistant tumor cell lines,3,4 generated a great
deal of excitement among chemists,7 biologists, and clinicians.
At least five total syntheses8-11 of epothilone A (1) have already
been achieved. The two from these laboratories were based on
an olefin metathesis approach9 and a macrolactonization ap-
proach.10 The total synthesis of epothilone B (2) and its
2. Retrosynthetic Analysis
Scheme 1 outlines the macrolactonization-based retrosynthetic
analysis of epothilones A (1) and B (2). Thus, retrosynthetic
removal of the epoxide oxygen from 1 and 2 reveals the
corresponding Z-olefins, 3 and 4, as potential precursors,
respectively. The second major retrosynthetic step along this
route is the disconnection of the macrocyclic ring at the lactone
site, leading to hydroxy acids 5 and 6 as possible key
intermediates. Moving further along the retrosynthetic path,
an aldol-type disconnection allows the generation of keto acid
9 as a common intermediate and aldehydes 7 and 8 as reasonable
building blocks for 5 and 6, respectively. Keto acid 9 can be
envisioned to arise from an asymmetric allylboration14 of the
corresponding aldehyde, followed by appropriate elaboration
of the terminal olefin. The larger intermediates, 7 and 8, can
be disconnected by two slightly different ways. The first
X Abstract published in AdVance ACS Abstracts, August 1, 1997.
(1) (a) Ho¨fle, G.; Bedorf, N.; Gerth, K.; Reichenbach, H. (GBF) DE-
4138042, 1993 (Chem. Abstr. 1993, 120, 52841). (b) Gerth, K.; Bedorf,
N.; Ho¨fle, G.; Irschik, H.; Reichenbach, H. J. Antibiot. 1996, 49, 560-
563.
(2) Ho¨fle, G.; Bedorf, N.; Steinmetz, H.; Schomburg, D.; Gerth, K.;
Reichenbach, H. Angew. Chem., Int. Ed. Engl. 1996, 35, 1567-1569.
(3) Grever, M. R.; Schepartz, S. A.; Chabner, B. A. Semin. Oncol. 1992,
19, 622-638.
(4) (a) 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. (b) Kowalski, R. J.; Giannakakou, P.; Hamel, E. J. Biol.
Chem. 1997, 272, 2534-2541.
(5) Horwitz, S. B.; Fant, J.; Schiff, P. B. Nature 1979, 277, 665-667.
(6) Nicolaou, K. C.; Dai, W.-M., Guy, R. K. Angew. Chem., Int. Ed.
Engl. 1994, 33, 15-44.
(7) (a) Nicolaou, K. C.; He, Y.; Vourloumis, D.; Vallberg, H.; Yang, Z.
Angew. Chem., Int. Ed. Engl. 1996, 35, 2399-2401. (b) Meng, D.; Sorensen,
E. J.; Bertinato, P.; Danishefsky, S. J. J. Org. Chem. 1996, 61, 7998-
7999. (c) Bertinato, P.; Sorensen, E. J.; Meng, D.; Danishefsky, S. J. J.
Org. Chem. 1996, 61, 8000-8001. (d) Schinzer, D.; Limberg, A.; Bo¨hm,
O. M. Chem. Eur. J. 1996, 2, 1477-1482. (e) Mulzer, J.; Mantoulidis, A.
Tetrahedron Lett. 1996, 37, 9179-9182. (f) Claus, E.; Pahl, A.; Jones, P.
G.; Meyer, H. M.; Kalesse, M. Tetrahedron Lett. 1997, 38, 1359-1362.
(g) Gabriel, T.; Wessjohann, L. Tetrahedron Lett. 1997, 38, 1363-1366.
(h) Taylor, R. E.; Haley, J. D. Tetrahedron Lett. 1997, 38, 2061-2064.
(8) (a) Balog, A.; Meng, D.; Kamenecka, T.; Bertinato, P.; Su, D.-S.;
Sorensen, E. J.; Danishefsky, S. J. Angew. Chem., Int. Ed. Engl. 1996, 35,
2801-2803. (b) Meng, D.; Su, D.-S.; Balog, A.; Bertinato, P.; Sorensen,
E. J.; Danishefsky, S.; Zheng, Y.-H.; Chou, T.-C.; He, L.; Horwitz, S. B.
J. Am. Chem. Soc. 1997, 119, 2733-2734.
(9) Yang, Z.; He, Y.; Vourloumis, D.; Vallberg, H.; Nicolaou, K. C.
Angew. Chem., Int. Ed. Engl. 1997, 36, 166-168.
(10) Nicolaou, K. C.; Sarabia, F.; Ninkovic, S.; Yang, Z. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 525-527.
(11) Schinzer, D.; Limberg, A.; Bauer, A.; Bo¨hm, O. M.; Cordes, M.
Angew. Chem., Int. Ed. Engl. 1997, 36, 523-524.
(12) Su, D.-S.; Meng, D.; Bertinato, P.; Balog, A.; Sorensen, E. J.;
Danishefsky, S. J.; Zheng, Y.-H.; Chou, T.-C.; He, L.; Horwitz, S. B. Angew.
Chem., Int. Ed. Engl. 1997, 36, 757-759.
(13) Nicolaou, K. C.; Winssinger, N.; Pastor, J. A.; Ninkovic, S.; Sarabia
F.; He, Y.; Vourloumis, D.; Yang, Z.; Li, T.; Giannakakou, P.; Hamel, E.
Nature 1997, 387, 268-272.
(14) (a) Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56, 401-
404. (b) Jadhav, P. K.; Bhat, K. S.; Perumal, P. T.; Brown, H. C. J. Org.
Chem. 1967, 32, 404-407.
S0002-7863(97)01110-4 CCC: $14.00 © 1997 American Chemical Society

Total Synthesis of Epothilones A and B
J. Am. Chem. Soc., Vol. 119, No. 34, 1997 7975
Scheme 2. Synthesis of Keto Acid 9a
Scheme 1. Molecular Structures and Retrosynthetic
Analysis of Epothilones A (1) and B (2)
a Reagents and conditions: (a) 1.2 equiv of (+)-Ipc2B(allyl), Et2O,
-100 °C, 0.5 h, 74% (ee >98% by Mosher ester analysis); (b) 1.1
equiv of TBSOTf, 1.2 equiv of 2,6 lutidine, CH2Cl2, 25 °C, 98%; (c)
O3, CH2Cl2, -78 °C, 0.5 h; then 1.2 equiv Ph3P, -78 f 25 °C, 1 h,
90%; (d) 3.0 equiv of NaClO2, 4.0 equiv of 2-methyl-2-butene, 1.5
t
equiv of NaH2PO4, BuOH:H2O (5:1), 25 °C, 2 h, 93%.
Scheme 3. Synthesis of Phosphonium Salt 12 and Aldehyde
15a
a Reagents and conditions: (a) 1.6 equiv of DIBAL, CH2Cl2, -78
°C, 2 h, 90%; (b) Ph3PdC(CH3)CHO, benzene, reflux, 98%; (c) 1.5
equiv of (+)-Ipc2B(allyl), Et2O, -100 °C, 0.5 h, 96% (ee >97% by
Mosher ester analysis); (d) 1.2 equiv TBSCl, 1.5 equiv of imidazole,
DMF, 0 f 25 °C, 2 h, 99%; (e) i. 1.0 mol % OsO4, 1.1 equiv of
4-methylmorpholine N-oxide (NMO), THF:tBuOH:H2O (1:1:0.1), 0 f
25 °C, 12 h, 95%; ii. 1.3 equiv of Pb(OAc)4, EtOAc, 0 °C, 0.5 h, 98%,
(f) 2.5 equiv of NaBH4, MeOH, 0 °C, 15 min, 96%; (g) 1.5 equiv of
I2, 3.0 equiv of imidazole, 1.5 equiv of Ph3P, Et2O:MeCN (3:1), 0 °C,
0.5 h, 89%; (h) 1.1 equiv Ph3P, neat, 100 °C, 2 h, 98%.
3. Total Synthesis
a. Construction of Building Blocks. The strategy derived
from the retrosynthetic analysis discussed above (Scheme 1)
required building blocks 9-12, 15, and related compounds.
Their construction in optically active form proceeded as follows.
Scheme 2 summarizes the synthesis of keto acid 9 starting with
the known keto aldehyde 17.16 Thus, addition of (+)-Ipc2B-
(allyl)14 to 17 in ether at -100 °C resulted in the formation of
enantiomerically enriched alcohol 18 (74% yield, ee > 98%
by Mosher ester determination).17 Silylation of 18 with tert-
butyldimethylsilyl triflate (TBSOTf) furnished, in 98% yield,
silyl ether 19. The conversion of terminal olefin 19 to
carboxylic acid 9 was carried out in two steps: (i) ozonolysis
in CH2Cl2 at -78 °C followed by exposure to Ph3P to give
aldehyde 20 (90% yield) and (ii) oxidation of 20 with NaClO2
in the presence of 2-methyl-2-butene and NaH2PO4 in tBuOH-
H2O (5:1) (93% yield).
disconnection (route a) involves a retro-Wittig type reaction
accompanied by a number of functional group interchanges,
leading to compounds 10-12. The second disconnection,
specifically sought for its potential to address the geometry issue
of the trisubstituted double bond of epothilone B (2) (route b),
involves (i) a retro-Enders alkylation,15 leading to hydrazone
13 and iodide 14, and (ii) a retro-Wittig type disconnection of
the latter intermediate (14) to reveal aldehyde 15 and stabilized
ylide 16 as potential building segments. An asymmetric
allylboration of 15 then points to Brown’s chiral allylborane14
and an aldehyde carrying the required thiazole moiety as
potential starting points.
The synthesis of the thiazole-containing fragments 15 and
12 was accomplished as shown in Scheme 3. Thus, the known
thiazole derivative 2118 was reduced with DIBAL (1.6 equiv,
CH2Cl2, -78 °C) to aldehyde 22 (90% yield), which reacted
(16) Inuka, T.; Yoshizawa, R. J. Org. Chem. 1967, 32, 404-407.
(17) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512-
519. (b) Kusumi, T.; Ohtani, I.; Inouye, Y.; Kakisawa, H. Tetrahedron Lett.
1988, 29, 4731-4734. (c) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa,
H. J. Am. Chem. Soc. 1991, 113, 4092-4096.
(18) Bredenkamp, M. W.; Holzapfel, C. W.; van Zyl, W. J. Synth.
Commun. 1990, 20, 2235-2249.
(15) (a) Enders, D. Asymmetric Synth. 1984, 3, 275-339. (b) Enders,
D.; Klatt, M. Synthesis 1996, 1403-1418.

7976 J. Am. Chem. Soc., Vol. 119, No. 34, 1997
Scheme 4 Synthesis of Aldehyde 10 and Ketone 11a
Nicolaou et al.
TBSCl in CH2Cl2 in the presence of Et3N and 4-DMAP to afford
silyl ether 31 in 95% yield. Cleavage of the benzyl ether in 31
by hydrogenolysis [H2, Pd(OH)2 cat., THF, 50 psi] gave primary
alcohol 32 (95% yield), which was smoothly oxidized to the
desired aldehyde 10 under Swern conditions22 [(COCl)2, DMSO,
Et3N, 98% yield]. Addition of MeMgBr to 10 proceeded in
84% yield and was followed by TPAP-NMO oxidation23 of
the resulting secondary alcohol (33) to give the other required
building block, ketone 11, in 96% yield.
With the appropriate building blocks at hand, the convergent
approach to epothilones A (1) and B (2) could now enter its
second phase.
b. Total Synthesis of Epothilone A. The couplings of
building blocks 9, 10, and 12 and the total synthesis of
epothilone A (1) and its 6S,7R-diastereoisomers (44 and 45)
are shown in Scheme 5. Thus, generation of the ylide from
phosphonium salt 12 with sodium bis(trimethylsilyl)amide
(NaHMDS), followed by reaction with aldehyde 10 resulted in
the formation of the desired Z-olefin 34 (J12,13 ) 10.8 Hz,
obtained from decoupling experiments) as the predominant
product in 77% yield [Z:E ca. 9:1; the minor isomer (E) was
removed chromatographically in subsequent steps]. Parentheti-
cally, key intermediate 34 was also prepared by Wittig coupling
of phosphonium salt 47 and aldehyde 15 in a reversal of the
reacting functionalities of the two fragments as shown in Scheme
6. Thus, alcohol 32 was directly converted to iodide 46 by the
action of I2, imidazole, and Ph3P (91% yield) and then to
phosphonium salt 47 by heating with Ph3P (91% yield).
Generation of the ylide from 47 with equimolar amounts of
NaHMDS in THF, followed by reaction with aldehyde 15
yielded Z-olefin 34 in 69% and in ca. 9:1 ratio with its E-isomer.
Returning to Scheme 5, selective desilylation of the primary
hydroxyl group from 34 was achieved by the action of
camphorsulfonic acid (CSA) in MeOH:CH2Cl2 (1:1),24 leading
to hydroxy compound 35 in 86% yield. Oxidation of 35 to
aldehyde 7 was then carried out using SO3‚pyr., DMSO, and
Et3N (94% yield).25 With the availability of 7, we were then
in a position to investigate its aldol condensation with keto acid
9. It was found that the optimum conditions for this coupling
reaction required generation of the dilithio derivative of 9 (1.2
equiv) with 3.0 equiv of lithium diisopropylamide (LDA) in
THF (-78 f -40 °C), followed by addition of aldehyde 7
(1.0 equiv), resulting in the formation of a mixture of the desired
product 36a and its 6S,7R-diastereoisomer 36b in ca. 1:1 ratio
and in high yield. Despite the lack of stereoselectivity in this
reaction, the result was welcome at least with regard to the
prospect it provided for the construction of the 6S,7R-diaste-
reoisomer of epothilones A and B. This mixture was then
carried through to the stage of carboxylic acids 38 and 39
(Scheme 5), where it was chromatographically separated to its
components. Thus, exposure of 36a,b to excess of TBSOTf
and 2,6-lutidine furnished a mixture of tetra-silylated products
37a,b, which was then briefly treated with K2CO3 in MeOH26
to afford, after silica gel flash or preparative layer chromatog-
raphy, carboxylic acids 38 (31% overall yield from 7) and 39
(30% overall yield from 7) (38: Rf ) 0.61; 39: Rf ) 0.70,
silica gel, 5% MeOH in CH2Cl2). The indicated stereochemistry
at C7 and C6 in compounds 38 and 39 was assigned later and
was based on the successful conversion of 38 to epothilone A
(1) as described below.
a Reagents and conditions: (a) 1.1 equiv of LDA, THF, 0 °C, 8 h;
then 1.5 equiv of 4-iodo-1-(benzyloxy)butane in THF, at -100 f 0
°C, 6 h, 92% (de > 98% by 1H NMR); (b) O3, CH2Cl2, -78 °C, 77%
or MeI, 60 °C, 5 h; then 3 N aqueous HCl, n-pentane, 25 °C, 1 h,
86%; (c) 3.0 equiv of NaBH4, MeOH, 0 °C, 15 min, 98%; (d) 1.5
equiv of TBSCl, 2.0 equiv of Et3N, CH2Cl2, 0 f 25 °C, 12 h, 95%;
(e) H2, Pd(OH)2 cat., THF, 50 psi, 25 °C, 15 min, 95%; (f) 2.0 equiv
of (COCl)2, 4.0 equiv of DMSO, 6.0 equiv of Et3N, CH2Cl2, -78 f
0 °C, 1.5 h, 98%; (g) 1.5 equiv of MeMgBr, THF, 0 °C, 15 min, 84%;
(h) 1.5 equiv of NMO, 0.05 equiv of tetrapropylammonium perruthenate
(TPAP), 4 Å MS, CH2Cl2, 25 °C, 45 min, 96%.
with the appropriate stabilized ylide [Ph3PdC(Me)CHO] in
benzene at 80 °C to afford the required (E)-R,â-unsaturated-
aldehyde 237a,b,h,9 in 98% yield. Addition of (+)-Ipc2B(allyl)14
to 23 in ether/pentane at -100 °C gave allylic alcohol 24 in
96% yield (>97% ee by Mosher ester analysis).17 Protection
of the hydroxyl group in 24 as a TBS ether (TBSCl, imidazole,
DMF, 99% yield), followed by chemoselective dihydroxylation
(OsO4 cat., NMO)19 of the terminal olefin (95% yield) and Pb-
(OAc)4 cleavage of the resulting diol (98% yield), furnished
aldehyde 15 via intermediate 25. Finally, NaBH4 reduction of
15 (96% yield), followed by iodination (I2, imidazole, Ph3P,
89% yield) and phosphonium salt formation (Ph3P, neat, 100
°C, 98% yield) gave the requisite fragment 12 via the interme-
diacy of alcohol 26 and iodide 27.
The construction of aldehyde 10 and ketone 11 proceeded
from SAMP hydrazone 13 as shown in Scheme 4. Thus,
reaction of propionaldehyde with SAMP20 furnished 13, which
upon sequential treatment with LDA (THF, 0 °C) and 4-iodo-
1-(benzyloxy)butane (THF, -100 f 0 °C) led to compound
28 in 92% yield and >98% de (1H NMR). Cleavage of the
hydrazone moiety by exposure to ozone (CH2Cl2, -78 °C, 77%
yield) or by treatment with MeI at 60 °C followed by acidic
workup (aqueous HCl, 86% yield),21 followed by NaBH4
reduction of the resulting aldehyde (29), furnished alcohol 30
in 98% yield. The latter compound (30) was then silylated with
(19) (a) Schneider, W. P.; McIntosh, A. V. U.S. Patent 2,769,824,
November 6, 1956. (b) VanRheenen, V.; Kelly, R. C.; Cha, D. Y.
Tetrahedron Lett. 1976, 1973-1976. (c) Kolb, H. C.; VanNieuwenhze, M.
S.; Sharpless, K. B. Chem. ReV. 1994, 94, 2483-2547.
(20) (a) Enders, D.; Eichenauer, H. Chem. Ber. 1979, 112, 2933-2960.
(b) Enders, D.; Tiebes, J.; De Kimpe, N.; Keppens, M.; Stevens, C.;
Smagghe, G.; Betz, O. J. Org. Chem. 1993, 58, 4881-4884. (c) Enders,
D.; Plant, A.; Backhaus, D.; Reinhold, U. Tetrahedron 1995, 51, 10699-
10714. We thank Prof. Enders for a generous gift of SAMP.
(22) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43,
2480-2482.
(23) Griffith, W. P.; Ley, S. V. Aldrichim. Acta 1990, 23, 13-19.
(24) Nelson, T. D; Crouch, R. D. Synthesis 1996, 1031-1069.
(25) Parikh, J. R.; von Doering, W. E. J. Am. Chem. Soc. 1967, 89, 5505-
5507.
(21) Davenport, K. G.; Eichenauer, H.; Enders, D.; Newcomb, M.;
Bergbreiter, D. E. J. Am. Chem. Soc. 1979, 101, 5654-5659.
(26) Morton, D. R.; Thompson, J. L. J. Org. Chem. 1978, 43, 2102-
2106.

Total Synthesis of Epothilones A and B
J. Am. Chem. Soc., Vol. 119, No. 34, 1997 7977
Scheme 6. Synthesis of Compound 34a
Scheme 5. Total Synthesis of Epothilone A (1) and Its
6S,7R-Diastereoisomers (44 and 45)a
a Reagents and conditions: (a) 1.5 equiv of I2, 3.0 equiv of imidazole,
1.5 equiv of Ph3P, Et2O:MeCN (3:1), 0 °C, 0.5 h, 91%; (b) 1.1 equiv
of Ph3P, neat, 100 °C, 2 h, 91%; (c) 1.2 equiv of 47, 1.2 equiv of
NaHMDS, THF, 0 °C, 15 min; then add 1.0 equiv of aldehyde 15, 0
°C, 15 min, 69% (Z:E ca. 9:1).
groups from 41 (CF3COOH, CH2Cl2, 0 °C) furnished diol 3 in
92% yield. Finally, treatment of 3 with methyl(trifluoromethyl)-
dioxirane28 led cleanly to epothilone A (1) (62% yield) and its
R-epoxide epimer (13% yield). The reaction of macrocyclic
olefin 3 with mCPBA gave a number of other products as
described in detailed in the preceding article.29 Synthetic
epothilone A (1) was chromatographically purified (preparative
thin-layer chromatography, silica gel) and exhibited properties
identical to those of an authentic sample (TLC, HPLC, [R]D,
1
IR, H and 13C NMR, and HRMS).30
A similar sequence was followed for the synthesis of the
6S,7R-diastereoisomers 44 and 45 of epothilone A (1) from
compound 39 (Scheme 5) via intermediates 40 (82% yield from
39), 42 (85% yield from 40), and 43 (95% yield from 42).
Epothilone 44 was obtained as the major product, together with
its R-epoxide epimer 45 (87% total yield, ca. 2:1 ratio), from
olefinic precursor 43 by methyl(trifluoromethyl)dioxirane ep-
oxidation.28 The epoxide stereochemistry assignments in 44 and
45 are tentative.
c. Total Synthesis of Epothilone B. The first approach to
epothilone B (2) was designed with the aim of delivering not
only the natural substance but also its 12S-diastereoisomer 58
(Scheme 7), which in turn required the generation of both 12Z-
and 12E-olefins. To this end, the ylide generated from
phosphonium salt 12 with equimolar amounts of NaHMDS in
THF was reacted with ketone 11 to afford a mixture of Z- and
E-olefins 48 (ca. 1:1 ratio) in 73% total yield. This mixture
was carried through the sequence to the stage of carboxylic acids
52′ and 53′ (see Scheme 7 for details), which were chromato-
graphically separable. Carboxylic acid 53′ (mixture of geo-
metrical isomers) with the wrong stereochemistry at C6 and
C7 (6S,7R) was abandoned at this stage, whereas the mixture
of Z- and E-isomers 52′ with the correct stereochemistry at C6
and C7 (6R,7S) was taken to the macrolactone stage (compounds
54 and 55) via hydroxy acid 6′, by (i) selective desilylation of
the C15 hydroxyl group (TBAF, THF, 75% yield) and (ii)
Yamaguchi cyclization (37% yield of 54, plus 40% of 55).27
Deprotection of bis(silyl ether) 54 by treatment with CF3COOH
in CH2Cl2 afforded diol 4 in 91% yield. Finally, epoxidation
of 4 with mCPBA in benzene at 3 °C gave epothilone B (2)
together with its R-epoxide epimer 57 in 66% total yield and
a Reagents and conditions: (a) 1.2 equiv of 12, 1.2 equiv of
NaHMDS, THF, 0 °C, 15 min, then add 1.0 equiv of aldehyde 10, 0
°C, 15 min, 77% (Z:E ca. 9:1); (b) 1.0 equiv of CSA portionwise over
1 h, CH2Cl2:MeOH (1:1), 0 f 25 °C, 0.5 h, 86%; (c) 2.0 equiv of
SO3‚pyr., 10.0 equiv of DMSO, 5.0 equiv of Et3N, CH2Cl2, 25 °C, 0.5
h, 94%; (d) 3.0 equiv of LDA, THF, 0 °C, 15 min; then 1.2 equiv of
9 in THF, -78 f -40 °C, 0.5 h; then 1.0 equiv of 7 in THF at -78
°C, high yield of 36a and its 6S,7R-diastereoisomer 36b (ca. 1:1 ratio);
(e) 3.0 equiv of TBSOTf, 5.0 equiv of 2,6-lutidine, CH2Cl2, 0 °C, 2 h;
(f) 2.0 equiv of K2CO3, MeOH, 25 °C, 15 min, 31% of 38 and 30% of
6S,7R-diastereoisomer 39 from 7; (g) 6.0 equiv of TBAF, THF, 25 °C,
8 h, 78%; (h) same as g, 82%; (i) 5.0 equiv of 2,4,6-trichlorobenzoyl-
chloride, 6.0 equiv of Et3N, THF, 25 °C, 15 min; then add to a solution
of 10.0 equiv of 4-DMAP in toluene (0.002 M based on 5), 25 °C, 0.5
h, 90%; (j) same as i, 85%; (k) 20% CF3COOH (by volume) in CH2Cl2,
0 °C, 1 h, 92%; (l) same as k, 95%; (m) methyl(trifluoromethyl)diox-
irane, MeCN, 0 °C, 75% (ca. 5:1 ratio of diastereoisomers), see ref
27); (n) same as m, 87% (44:45 ca. 2:1 ratio of diastereoisomers,
tentative stereochemistry).
(27) (a) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. Jpn. 1979, 52, 1989. (b) Mulzer, J.; Mareski, P. A.;
Buschmann, J.; Luger, P. Synthesis 1992, 215-228. (c) Nicolaou, K. C.;
Patron, A. P.; Ajito, K.; Richter, P. K.; Khatuya, H.; Bertinato, P.; Miller,
R. A.; Tomaszewski, M. J. Chem. Eur. J. 1996, 2, 847-868.
(28) Yang, D.; Wong, M.-K.; Yip, Y.-C. J. Org. Chem. 1995, 60, 3887-
3889.
(29) Nicolaou, K. C.; He, Y.; Vourloumis, D.; Vallberg, H.; Roschangar,
F.; Sarabia, F.; Ninkovic, S.; Yang, Z.; Trujillo, J. I. J. Am. Chem. Soc.
1997, 119, 7960-7973 (preceding paper).
(30) We thank Dr. G. Ho¨fle for samples of natural epothilones A (1)
and B (2).
At this stage, it was necessary to selectively remove the TBS
group from the allylic hydroxyl group of 38, so as to allow
macrolactonization of the seco-acid substrate (5). This goal was
achieved by treatment of 38 with tetra-n-butylammonium
fluoride (TBAF) in THF at 25 °C, generating the desired
hydroxy acid 5 in 78% yield. The key macrolactonization
reaction of 5 was carried out using the Yamaguchi method27
(2,4,6-trichlorobenzoyl chloride, Et3N, 4-DMAP) at 25 °C,
affording compound 41 in 90% yield. Removal of both TBS

7978 J. Am. Chem. Soc., Vol. 119, No. 34, 1997
Nicolaou et al.
Scheme 7. Total Synthesis of Epothilone B (2) and
Scheme 8. Stereoselective Synthesis of Aldehyde 8 for
Analoguesa
Epothilone B (2)a
a Reagents and conditions: (a) 1.5 equiv of 16, benzene, reflux 5 h,
95%; (b) 3.0 equiv of DIBAL, THF, -78 °C, 2 h, 98%; (c) 2.0 equiv
of Ph3P, CCl4, reflux, 24 h, 83%. (d) 2.0 equiv of LiEt3BH, THF, 0
°C, 1 h, 99%; (e) 1.2 equiv of 9-BBN, THF, 0 °C, 2 h, 91%; (f) 1.5
equiv of I2, 3.0 equiv of imidazole, 1.5 equiv of Ph3P, Et2O:MeCN
(3:1) 0 °C, 0.5 h, 92%; (g) 1.5 equiv of 13, 1.5 equiv of LDA, THF,
0 °C, 8 h; then 1.0 equiv of 14 in THF, -100 f -20 °C, 10 h, 70%;
(h) 2.5 equiv of monoperoxyphthalic acid, magnesium salt (MMPP),
MeOH:phosphate buffer pH7 (1:1), 0 °C, 1 h, 80%; (i) 2.0 equiv of
DIBAL, toluene, -78 °C, 1 h, 82%.
ca. 5:1 ratio (1H NMR), while the use of dimethyldioxirane,31
first reported by Danishefsky,8a,12 gave 2 and 27 in 75% total
yield in the same ratio (ca. 5:1 in favor of 2). Epoxidation of
4 with methyl(trifluoromethyl)dioxirane28 in CH3CN at 0 °C
improved the yield of epothilone B (2) and its R-epimer 57 to
85% but did not significantly change the diastereoselectivity
of the reaction. Epothilone B (2) was purified by silica gel
preparative layer chromatography and exhibited identical prop-
1
erties (TLC, HPLC, [R]D, IR, H and 13C NMR, and HRMS)
with those of an authentic sample.30
a Reagents and conditions: (a) 1.5 equiv of 12, 1.5 equiv of
NaHMDS, THF, 0 °C, 15 min, then add 1.0 equiv of ketone 11, -20
°C, 12 h, 73% (Z:E ca. 1:1); (b) 1.0 equiv of CSA portionwise over 1
h, CH2Cl2:MeOH (1:1), 0 °C; then 25 °C, 0.5 h, 97%; (c) 2.0 equiv of
SO3‚pyr., 10.0 equiv of DMSO, 5.0 equiv of Et3N, CH2Cl2, 25 °C, 0.5
h, 95%; (d) 3.0 equiv of LDA, THF, 0 °C, 15 min; then 1.2 equiv of
9 in THF, -78 f -40 °C, 0.5 h; then 1.0 equiv of 8' in THF at -78
°C, high yield of 50a' and its 6S,7R-diastereoisomer 50b' (ca. 1:1 ratio);
(e) 3.0 equiv of TBSOTf, 5.0 equiv of 2,6-lutidine, CH2Cl2, 0 °C, 2 h;
(f) 2.0 equiv of K2CO3, MeOH, 25 °C, 15 min, 31% of 52' and 30%
of 6S,7R-diastereoisomer 53' from 8'; (g) 6.0 equiv of TBAF, THF,
25 °C, 8 h, 75%; (h) 1.3 equiv of 2,4,6-trichlorobenzoylchloride, 2.2
equiv of Et3N, THF, 0 °C, 1 h; then add to a solution of 10.0 equiv of
4-DMAP in toluene (0.002 M based on 6'), 25 °C, 12 h, 37% of 54;
and 40% of 55; (i) 20% CF3COOH (by volume) in CH2Cl2 -10 f 0
°C, 1 h, 91%; (j) same as i, 89%; (k) dimethyldioxirane, CH2Cl2, -50
°C, 75% (2:57 ca. 5:1 ratio of diastereoisomers) or 1.5 equiv of mCPBA,
benzene, 3 °C, 2 h, 66% (2:57 ca. 5:1 ratio of diastereoisomers) or
methyltrifluoromethyl)dioxirane, MeCN, 0 °C, 85% (2:57 ca. 5:1 ratio
of diastereoisomers); (l) 1.5 equiv of mCPBA, benzene, 3 °C, 2 h, 73%
(58:59 ca. 1:4 ratio of stereoisomers) or methyl(trifluoromethyl)diox-
irane, MeCN, 0 °C, 86% (58:59 ca. 1:1 ratio of diastereoisomers).
By the same sequence, and in similar yields, the macrocycle
55 containing the E-endocyclic double bond (Scheme 7) was
converted to the 12S-epimeric epothilone B 58 and its R-epoxy
epimer 59 via dihydroxy macrocyclic compound 56 [epoxidation
with methyl(trifluoromethyl)dioxirane].28 The stereochemistry
of epoxides 58 and 59 was tentatively assigned by comparisons
with the corresponding epothilone A epoxides whose stereo-
chemistry was determined by NMR spectroscopy and molecular
dynamics computations and molecular modeling as described
in the preceding article29 (see also Supporting Information for
1
1H-1H NOESY and H-1H COSY).
To improve the efficiency of the route to epothilone B (2), a
more stereoselective total synthesis was devised and executed
as follows. Scheme 8 addresses the stereoselective construction
of intermediate 8 with the 12Z-geometry. Thus, condensation
of the stabilized ylide 16 [obtained from 4-bromo-1-butene by
(i) phosphonium salt formation, (ii) anion formation with
(31) Murray, R. W.; Jeyaraman, R. J. Org. Chem. 1985, 50, 2847-2853.

Total Synthesis of Epothilones A and B
J. Am. Chem. Soc., Vol. 119, No. 34, 1997 7979
NaHMDS, and (iii) quenching with MeOC(O)Cl]32 with alde-
hyde 15 proceeded smoothly to afford olefinic compound 60
in 95% yield and as a single isomer. Reduction of the methyl
ester in 60 with DIBAL resulted in the formation of allylic
alcohol 61 (98% yield), which was deoxygenated by first
reacting it with Ph3P-CCl4 and then with LiEt3BH,33 to afford
the desired trisubstituted 12Z-olefin 63, via chloride 62, in 82%
overall yield. The latter compound 63 was regioselectively
hydroborated with 9-BBN and converted to the primary alcohol
64 (91%), which was then treated with I2-imidazole-Ph3P to
afford iodide 14 (92% yield). This iodide was then used in an
Enders alkylation reaction with SAMP hydrazone 13 to give
compound 65 as a single isomer (1H NMR) and in 70% yield.
Treatment of hydrazone 65 with monoperoxyphthalic acid
magnesium salt (MMPP) in MeOH:phosphate pH 7 buffer (1:
1)20c,34 resulted in clean conversion to nitrile 66 (80% yield),
which formed aldehyde 8 (82% yield) upon exposure to DIBAL
at -78 °C in toluene solution.
Scheme 9. First Stereoselective Total Synthesis of
Epothilone B (2)a
The homogeneous aldehyde 8 was converted to epothilone
B (2) by the sequence depicted in Scheme 9. Thus, condensa-
tion of the dianion of 9 with 8 as before (Scheme 7), produced
two diastereoisomers, 50a (6R,7S stereoisomer) and 50b (6S,7R
stereoisomer), in high yield and in ca. 1.3:1.0 ratio (50a:50b).
This mixture was carried through the indicated sequence to
carboxylic acids 52 (32% overall yield from 8) and 53 (28%
overall yield from 8), which were separated by silica gel
preparative layer or flash column chromatography and taken
individually further along the sequence as described for the
corresponding stereoisomeric mixtures shown in Scheme 7.
Thus, 52 was selectively deprotected with TBAF to afford
hydroxy acid 6 (73% yield), which was then cyclized to
macrolactone 54 in 77% yield by the Yamaguchi method.27 The
conversion of 54 to epothilone B (2) and its R-epoxide epimer
57 has already been described above (Scheme 7).
a Reagents and conditions: (a) 3.0 equiv of LDA, THF, 0 °C, 15
min; then 1.2 equiv of 9 in THF, -78 f -40 °C, 0.5 h, then 1.0
equiv of 8 in THF at -78 °C, high yield of 50a and 6S,7R-
diastereoisomer 50b (ca. 1.3:1.0 ratio of diastereoisomers); (b) 3.0 equiv
of TBSOTf, 5.0 equiv of 2,6-lutidine, CH2Cl2, 0 °C, 2 h; (c) 2.0 equiv
of K2CO3, MeOH, 25 °C, 15 min, 32% of 52 and 28% of 6S,7R-
diastereoisomer 53 from 8; (d) 6.0 equiv of TBAF, THF, 25 °C, 8 h,
73%; (e) same as d, 71%; (f) 5.0 equiv of 2,4,6-trichlorobenzoyl
chloride, 6.0 equiv of Et3N, THF, 25 °C, 15 min, then add to a solution
of 10.0 equiv of 4-DMAP in toluene (0.002 M based on 6), 25 °C, 12
h, 77%; (g) same as f, 76%; (h) 20% CF3COOH (by volume) in CH2Cl2,
0 °C, 1 h, 91%; (i) see Scheme 7.
In an effort to improve the diastereoselectivity of the aldol
condensation between C1-C6 and C7-C15 fragments, the
following chemistry was explored (Scheme 10). Thus, ketone
69 [prepared from ketone 20 (Scheme 2) by selective reduction,
followed by silylation] was converted to its enolate with
stoichiometric amounts of LDA and reacted with aldehyde 8
(Z-isomer), affording coupling products 70 and 71 in 85% total
yield and ca. 3:1 ratio, with the desired compound 70 predomi-
nating as proven by its conversion to 52 and epothilone B (2).
Thus, chromatographic purification (silica gel, 20% ether in
hexanes) led to 70, which was efficiently transformed to the
previously synthesized intermediate 52 (Scheme 9) as follows.
The newly generated hydroxyl group in 70 was silylated with
TBSOTf-2,6-lutidine to furnish 72 (96% yield), which was then
selectively desilylated at the primary position by the mild action
of camphorsulfonic acid (CSA) in MeOH-CH2Cl2, leading to
73 (85%). Finally, sequential oxidation of the primary alcohol
with (COCl)2-DMSO-Et3N (95% yield) and NaClO2-NaH2-
PO4 (90% yield) led to hydroxy acid 52 via aldehyde 74. The
conversion of 52 to 2 has already been described above (Scheme
9). This sequence represents a stereoselective and highly
efficient synthesis of epothilone B (2) and opens the way for
the construction of further analogues within this important family
of microtubule binding agents.
4. Conclusion
The chemistry described in this article defines a concise
strategy for the construction of epothilones A (1) and B (2)
based on a macrolactonization strategy, and which enjoys
convergency and flexibility for structural diversity. It is
expected that the numerous intermediates and structural ana-
logues included herein, as well as several new ones currently
under construction, will play a crucial role in elucidating
structure-activity relationships of these new substances and in
determining their relevance to cancer chemotherapy. Indeed,
independent reports from the Danishefsky8b,12 and from these
laboratories13 demonstrated impressive tubulin binding affinities
and cytotoxicities for some of these compounds. Further details
on the biological actions of these and other compounds will be
published elsewhere.
Experimental Section
General Techniques. See preceding paper.29
Alcohol 18. Allylboration of Keto Aldehyde 17. Aldehyde 1716
(16.0 g, 0.125 mol) was dissolved in ether (400 mL) and cooled to
-100 °C. To this solution was added (+)-diisopinocampheylallylbo-
rane (800 mL, 0.15 M in pentane, 0.125 mol, 1.0 equiv) by cannulation
during 45 min. [(+)-Diisopinocampheylallylborane in pentane was
typically prepared by the adaptation of the original method reported
by Brown.14 Allyllmagnesium bromide (66.0 mL, 1 M solution in ether,
(32) (a) Marshall, J. A.; DeHoff, B. S.; Cleary, D. G. J. Org. Chem.
1986, 51, 1735-1741. (b) Bestmann, H. J. Angew. Chem., Int. Ed. Engl.
1965, 645-660.
(33) Heissler, D.; Jenn, T.; Nagano, H. Tetrahedron Lett. 1991, 32, 7587-
7590.
(34) Enders, D.; Backhaus, D.; Runsink, J. Tetrahedron 1996, 52, 1503-
1528.

7980 J. Am. Chem. Soc., Vol. 119, No. 34, 1997
Nicolaou et al.
reaction mixture was allowed to stir at -78 °C for 45 min, after which
time no starting material was detected by TLC. Saturated aqueous NH4-
Cl solution (30 mL) was added, and the reaction mixture was allowed
to warm to room temperature. The organic phase was separated, and
the aqueous layer was extracted with ether (3 × 20 mL). The combined
organic extracts were dried (MgSO4) and filtered through Celite, and
the solvents were removed under reduced pressure. Purification by
flash column chromatography (silica gel, 2 f 10% ether in hexanes)
gave pure 19 (18.0 g, 98%): Rf ) 0.75 (silica gel, 20% ether in
Scheme 10. Second Stereoselective Synthesis of Epothilone
B (2)a
hexanes); [R]22 +2.6 (c 0.8, CHCl3); IR (thin film) νmax 2935, 1705,
D
1
1467, 1362, 1254, 1089, 911, 836, 775 cm-1; H NMR (600 MHz,
CDCl3) δ 5.78-5.71 (m, 1 H, CHdCH2), 5.01-4.94 (m, 2 H,
CHdCH2), 3.97 (dd, J ) 6.2, 5.2 Hz, 1 H, CHOSi), 2.54 (dq, J )
14.3, 7.2 Hz, 1 H, CH2CH3), 2.44 (dq, J ) 14.2, 7.1 Hz, 1 H, CH2-
CH3), 2.21-2.16 (m, 1 H, CH2CHdCH2), 2.14-2.08 (m, 1 H, CH2-
CHdCH2), 1.10 (s, 3 H, C(CH3)2), 1.07 (s, 3 H, C(CH3)2), 0.98 (t, J )
7.1 Hz, 3 H, CH3CH2), 0.87 (s, 9 H, SiC(CH3)3), 0.05 (s, 3 H, Si-
(CH3)2), 0.01 (s, 3 H, Si(CH3)2); 13C NMR (150.9 MHz, CDCl3) δ 215.9,
136.2, 116.5, 76.7, 52.9, 39.0, 31.9, 26.0, 22.4, 20.1, 18.2, 7.7, -3.6,
-4.4.
Keto Aldehyde 20. Ozonolysis of Ketone 19. Alkene 19 (2.84 g,
10 mmol) was dissolved in CH2Cl2 (25 mL, 0.4 M), and the solution
was cooled to -78 °C. Oxygen was bubbled through for 2 min, after
which time ozone was passed through until the reaction mixture adopted
a blue color (ca. 30 min). The solution was then purged with oxygen
for 2 min at -78 °C (disappearance of blue color) and Ph3P (3.16 g,
12.0 mmol, 1.2 equiv) was added. The cooling bath was removed,
and the reaction mixture was allowed to reach room temperature and
stirred for an additional 1 h. The solvent was removed under reduced
pressure, and the mixture was purified by flash column chromatography
(silica gel, 25% ether in hexanes) to provide pure keto aldehyde 20
a Reagents and conditions: (a) 1.2 equiv of LDA, THF, 0 °C, 15
min; then 1.2 equiv of 69 in THF, -78 f -40 °C, 1 h; then 1.0 equiv
of 8 in THF at -78 °C, 85% of 70 and 6S,7R-diastereoisomer 71 (ca.
3:1 ratio); (b) 1.2 equiv of TBSOTf, 2.0 equiv of 2,6-lutidine, CH2Cl2,
0 °C, 2 h, 96%; (c) 1.0 equiv of CSA portionwise over 1 h, CH2Cl2:
MeOH (1:1), 0 f 25 °C, 0.5 h, 85%; (d) 2.0 equiv of (COCl)2, 4.0
equiv of DMSO, 6.0 equiv of Et3N, CH2Cl2, -78 f 0 °C, 1.5 h, 95%;
(e) 3.0 equiv of NaClO2, 4.0 equiv of 2-methyl-2-butene, 1.5 equiv of
(2.57 g, 90%): Rf ) 0.45 (silica gel, 20% ether in hexanes); [R]22
D
-1.9 (c 4.0, CHCl3); IR (thin film) νmax 2935, 2858, 1707, 1467, 1388,
1255, 1093, 1004, 837, 777 cm-1; 1H NMR (500 MHz, CDCl3) δ 9.78
(dd, J ) 2.1, 2.0 Hz, CHO), 4.55 (dd, J ) 6.0, 4.5 Hz, 1 H, CHOSi),
2.59-2.44 (m, 4 H, CH2CH3, CH2CHdO), 1.13 (s, 3 H, C(CH3)2),
1.09 (s, 3 H, C(CH3)2), 1.00 (t, J ) 7.0 Hz, 3 H, CH3CH2), 0.85 (s, 9
H, (CH3)3C), 0.06 (s, 3 H, Si(CH3)2), 0.03 (s, 3 H, Si(CH3)2); 13C NMR
(125.7 MHz, CDCl3) δ 215.3, 200.9, 71.3, 52.3, 48.5, 31.9, 25.8, 21.3,
20.4, 18.0, 7.5, -4.4, -4.9; FAB HRMS (NBA/NaI) m/e 309.1854,
M + Na+ calcd for C15H30O3Si 309.1862.
Keto Acid 9. Oxidation of Keto Aldehyde 20. Aldehyde 20 (2.86
g, 10 mmol), tBuOH (50 mL, 0.2 M), isobutylene (20 mL, 2 M solution
in THF, 40 mmol, 4.0 equiv), H2O (10 mL), NaClO2 (2.71 g, 30.0
mmol, 3.0 equiv), and NaH2PO4 (1.80 g, 15.0 mmol, 1.5 equiv) were
combined and stirred at room temperature for 4 h. The reaction mixture
was concentrated under reduced pressure, and the residue was subjected
to flash column chromatography (silica gel, 50% ether in hexanes) to
produce pure keto acid 9 (2.81 g, 93%): Rf ) 0.12 (silica gel, 20%
ether in hexanes); [R]22D +16.1 (c 1.0, CHCl3); IR (thin film) νmax 2934,
2858, 1710, 1467, 1254, 1093, 834 cm-1; 1H NMR (600 MHz, CDCl3)
δ 4.46 (dd, J ) 7.0, 3.6 Hz, 1 H, CHOSi), 2.64-2.34 (m, 3 H, CH2-
CH3, CH2COOH), 2.32 (q, J ) 7.0 Hz, 1 H, CH2CH3), 1.13 (s, 3 H,
C(CH3)2), 1.11 (s, 3 H, C(CH3)2), 0.99 (t, J ) 7.0 Hz, 3 H, CH3CH2),
0.83 (s, 9 H, (CH3)3C), 0.04 (s, 3 H, Si(CH3)2), 0.03 (s, 3 H, Si(CH3)2);
13C NMR (125.7 MHz, CDCl3) δ 215.1, 178.2, 73.4, 52.4, 39.2, 31.6,
25.8, 20.8, 20.5, 18.0, 7.6, -4.5, -5.0; FAB HRMS (NBA) m/e
303.1996, M + H+ calcd for C15H30O3Si 303.1992.
Aldehyde 22. Reduction of Ester 21. Ethyl ester 2118 (52.5 g,
0.306 mol) was dissolved in CH2Cl2 (1 L) and cooled to -78 °C.
DIBAL (490.0 mL, 1 M solution in CH2Cl2, 0.4896 mol, 1.6 equiv)
was added dropwise via a cannula while the temperature of the reaction
mixture was maintained at -78 °C. After the addition was complete,
the reaction mixture was stirred at the same temperature until its
completion was verified by TLC (ca. 1 h). Methanol (100 mL) was
added at -78 °C and was followed by addition of EtOAc (1 L) and
saturated aqueous NH4Cl solution (300 mL). The quenched reaction
mixture was allowed to warm to room temperature and stirred for 12
h. The organic layer was separated, and the aqueous phase was
extracted with EtOAc (3 × 200 mL). The combined organic phase
was dried over MgSO4, filtered, and concentrated under reduced
pressure. Flash column chromatography (silica gel, 10 f 90% ether
in hexanes) furnished the desired aldehyde 22 (33.6 g, 90%): Rf )
t
NaH2PO4, BuOH:H2O (5:1), 25 °C, 2 h, 90%.
0.066 mol) was added dropwise to a well-stirred solution of (-)-B-
methoxydiisopinocampheylborane (20.9 g, 0.066 mol) in ether (400
mL) at 0 °C. After the completion of the addition, the reaction mixture
was stirred at room temperature for 1 h and the solvent was removed
under reduced pressure. The residue was extracted with pentane (3 ×
400 mL) under argon, and stirring was discontinued to allow precipita-
tion of the magnesium salts. The clear pentane solution was cannulated
into another flask using a double-ended needle through a Kramer filter
and used without further purification. After the addition was complete,
the mixture was stirred at the same temperature for 30 min. Methanol
(20 mL) was added at -100 °C, and the reaction mixture was allowed
to reach room temperature. To this solution was added saturated
aqueous NaHCO3 solution (200 mL), followed by H2O2 (80 mL of
50% solution in H2O), and the reaction mixture was allowed to stir at
room temperature for 12 h. The reaction mixture was extracted with
EtOAc (3 × 200 mL), and the organic extracts were combined, washed
with saturated aqueous NH4Cl solution (100 mL), and dried (Na2SO4).
Evaporation of the solvents followed by flash column chromatography
(silica gel, 3% acetone in CH2Cl2) resulted in pure alcohol 18 (14.6 g,
74%). 18: colorless oil; Rf ) 0.20 (silica gel, 3% acetone in CH2Cl2);
[R]22D -4.0 (c 1.5, CHCl3); IR (thin film) νmax 3492, 2976, 2939, 1699,
1
1641, 1469, 1379, 1087, 1020, 990, 973, 914 cm-1; H NMR (600
MHz, CDCl3) δ 5.85-5.80 (m, 1 H, CHdCH2), 5.11-5.07 (m, 2 H,
CHdCH2), 3.73 (dd, J ) 10.5, 2.0 Hz, 1 H, CHOH), 2.54-2.40 (m,
3 H), 2.25-2.18 (m, 1 H), 2.03-1.96 (m, 1 H), 1.14 (s, 3 H, C(CH3)2),
1.10 (s, 3 H, C(CH3)2), 0.99 (t, J ) 7.0 Hz, 3 H, CH3CH2); 13C NMR
(150.9 MHz, CDCl3) δ 217.2, 135.6, 117.7, 75.5, 51.2, 36.4, 31.3, 21.8,
19.5, 7.8; FAB HRMS (NBA/NaI) m/e 193.1200, M + Na+ calcd for
C10H18O2 193.1204.
Ketone 19. Silylation of Alcohol 18. Alcohol 18 (11.0 g, 0.0647
mol) was dissolved in CH2Cl2 (200 mL), the solution was cooled at
-78 °C, and 2,6-lutidine (10.5 mL, 0.0906 mol, 1.4 equiv) was added.
After being stirred for 5 min at that temperature, tert-butyldimethylsilyl
triflate (19.3 mL, 0.0841 mol, 1.3 equiv) was added dropwise and the

Total Synthesis of Epothilones A and B
J. Am. Chem. Soc., Vol. 119, No. 34, 1997 7981
0.68 (silica gel, ether); IR (thin film) νmax 3095, 2828, 1695, 1485,
1437, 1378, 1334, 1178, 1129, 1011 cm-1; 1H NMR (500 MHz, CDCl3)
δ 9.96 (s, 1 H, CHO), 8.0 (s, 1 H, SCHdC), 2.77 (s, 3 H, NdC(S)-
CH3); 13C NMR (125.7 MHz, CDCl3) δ 184.2, 167.5, 154.8, 128.0,
19.1; FAB HRMS (NBA/NaI) m/e 149.9992, M + Na+ calcd for C5H5-
NOS 149.9990.
Aldehyde 15. Dihydroxylation of Olefin 25 and 1,2 Glycol
Cleavage. Olefin 25 (16.7 g, 51.6 mmol) was dissolved in THF/t-
BuOH (1:1, 500 mL) and H2O (50 mL). 4-Methylmorpholine N-oxide
(NMO) (7.3 g, 61.9 mmol, 1.2 equiv) was added at 0 °C, followed by
t
OsO4 (5.2 mL, solution in BuOH 1.0 mol %, 2.5% by weight). The
mixture was vigorously stirred for 2.5 h at 0 °C and then for 12 h at
25 °C. After completion of the reaction, Na2SO3 (5.0 g) was added at
0 °C, followed by H2O (100 mL). Stirring was continued for another
30 min, and then ether (1 L) was added, followed by saturated aqueous
NaCl solution (2 × 100 mL). The organic phase was separated, and
the aqueous phase was extracted with ether (2 × 100 mL). The
combined organic extracts were dried (MgSO4) and filtered, and the
solvents were removed under reduced pressure. Flash column chro-
matography (silica gel, ether f EtOAc) provided 17.54 g (95%) of
the expected 1,2-diol as a 1:1 mixture of diastereoisomers: Rf ) 0.55
(silica gel, EtOAc); IR (thin film) νmax 3380, 2931, 2856, 1656, 1505,
Aldehyde 23. Aromatic aldehyde 22 (31.1 g, 0.245 mol) was
dissolved in benzene (500 mL), and 2-(triphenylphosphoranilidenyl)-
propionaldehyde (90.0 g, 0.282 mol, 1.15 equiv) was added. The
reaction mixture was heated at reflux until the reaction was complete
as judged by TLC (ca. 2 h). Evaporation of the solvent under reduced
pressure followed by flash column chromatography (10 f 90% ether
in hexanes) produced the desired aldehyde 23 (40.08 g, 98%): Rf )
0.78 (silica gel, ether); IR (thin film) νmax 3089, 1675, 1624, 1190,
1
1141, 1029, 947.6, 881 cm-1; H NMR (500 MHz, CDCl3) δ 9.57 (s,
1 H, CHO), 7.46 (s, 1 H), 7.26 (s, 1 H), 2.77 (s, 3 H, NdC(S)CH3),
2.20 (s, 3 H, CHdC(CHO)CH3); 13C NMR (125.7 MHz, CDCl3) δ
195.3, 165.7, 151.9, 140.9, 138.2, 122.6, 19.2, 10.9; FAB HRMS (NBA)
m/e 168.0481, M + H+ calcd for C8H9NOS 168.0483.
1
1465, 1460, 1254, 1187, 1073, 908, 837, 777 cm-1; H NMR (500
MHz, CDCl3) δ 6.90 and 6.88 (singlets, 1 H total, SCHdC), 6.52 and
6.47 (singlets, 1 H total, CHdCCH3), 4.44-4.39 (m, 1 H), 3.95-3.84
(m, 1 H), 3.81-3.72 and 3.63-3.34 (m, 4 H total), 2.66 and 2.65
(singlets, 3 H total, NdC(S)CH3), 1.96 and 1.95 (singlets, 3 H total),
1.82-1.75 and 1.69-1.56 (m, 2 H total), 0.87 and 0.86 (singlets, 9 H
total, SiC(CH3)3), 0.08 and -0.01 (singlets, 3 H total, Si(CH3)2), 0.07
and 0.10 (singlets, 3 H total, Si(CH3)2); 13C NMR (125.7 MHz, CDCl3)
δ 164.6, 164.5, 152.8, 152.4, 141.6, 141.5, 119.4, 118.4, 115.3, 115.2,
78.0, 75.4, 70.4, 68.8, 66.8, 66.5, 38.9, 38.7, 25.7, 19.0, 18.9, 18.0,
17.9, 14.6, 13.5, -4.6, -4.8, -5.2, -5.4; FAB HRMS (NBA/NaI) m/e
380.1699, M + Na+ calcd for C17H31NO3SSi 380.1692.
Alcohol 24. Allylboration of Aldehyde 23. Aldehyde 23 (20.0 g,
0.120 mol) was dissolved in anhydrous ether (400 mL), and the solution
was cooled to -100 °C. (+)-Diisopinocampheylallylborane (1.5 equiv
in pentane, prepared from 60.0 g of (-)-Ipc2BOMe and 1.0 equiv of
allylmagnesium bromide according to the method described for the
synthesis of alcohol 18),14 was added dropwise under vigorous stirring,
and the reaction mixture was allowed to stir for 1 h at the same
temperature. Methanol (40 mL) was added at -100 °C, and the reaction
mixture was allowed to warm to room temperature. Aminoethanol
(72.43 mL, 1.2 mol, 10.0 equiv) was added, and stirring was continued
for 15 h. The workup procedure was completed by the addition of
saturated aqueous NH4Cl solution (200 mL), extraction with EtOAc
(4 × 100 mL), and drying of the combined organic layers with MgSO4.
Filtration followed by evaporation of the solvents under reduced
pressure and flash column chromatography (silica gel, 35% ether in
hexanes for several fractions until all the boron complexes were
removed; then 70% ether in hexanes) provided alcohol 24 (24.09 g,
96%): Rf ) 0.37 (60% ether in hexanes); [R]22D -20.2 (c 1.0, CHCl3);
IR (thin film) νmax 3357, 2923, 1642, 1505, 1437, 1322, 1186, 1018,
914, 878 cm-1; 1H NMR (600 MHz, CDCl3) δ 6.81 (s, 1 H, SCHdC),
6.46 (s, 1 H, CHdCCH3), 5.87-5.79 (m, 1 H, CHdCH2), 5.02 (d, J
) 17.1 Hz, 1 H, CHdCH2), 4.97 (d, J ) 10.3 Hz, 1 H, CHdCH2),
4.12 (dd, J ) 7.8, 5.0 Hz, 1 H, CHOH), 3.8 (bs, 1 H, OH), 2.59 (s, 3
H, NdC(S)CH3), 2.31 (dd, J ) 7.0, 6.5 Hz, 2 H, CH2dCHCH2), 1.91
(s, 3 H, CHdCCH3); 13C NMR (150.9 MHz, CDCl3) δ 164.5, 152.5,
141.8, 134.8, 118.7, 117.1, 115.1, 76.3, 39.8, 18.8, 14.1; FAB HRMS
(NBA) m/e 210.0956, M + H+ calcd for C11H15NOS 210.0953.
The diol obtained from 25 as described above (5.2 g, 14.5 mmol)
was dissolved in EtOAc (150 mL) and cooled to 0 °C. Pb(OAc)4 (8.1
g, 95% purity, 18.3 mmol, 1.2 equiv) was then added portionwise over
10 min, and the mixture was vigorously stirred for 15 min at 0 °C.
After completion of the reaction, the mixture was filtered through silica
gel and washed with 60% ether in hexanes. The solvents were then
removed under reduced pressure providing pure aldehyde 15 (4.7 g,
98%): Rf ) 0.76 (silica gel, 60% ether in hexanes); [R]22 -20.3 (c
D
1.4, CHCl3); IR (thin film) νmax 2931, 2856, 1726, 1504, 1466, 1389,
1254, 1182, 1087, 999, 839, 784 cm-1; 1H NMR (500 MHz, CDCl3) δ
9.69 (dd, J ) 2.7, 2.2 Hz, 1 H, CHO), 6.86 (s, 1 H, SCHdC), 6.48 (s,
1 H, CHdCCH3), 4.60 (dd, J ) 8.2, 3.9 Hz, 1 H, CHOSi), 2.64 (ddd,
J ) 15.5, 8.3, 2.9 Hz, 1 H, CHOCH2), 2.59 (s, 3 H, NdC(S)CH3),
2.41 (ddd, J ) 15.5, 4.0, 2.0 Hz, 1 H, CHOCH2), 1.95 (s, 3 H,
CHdCCH3), 0.79 (s, 9 H, SiC(CH3)3), 0.00 (s, 3 H, Si(CH3)2), -0.06
(s, 3 H, Si(CH3)2); 13C NMR (125.7 MHz, CDCl3) δ 201.0, 164.5, 152.4,
140.3, 119.0, 115.8, 73.7, 49.9, 25.6, 18.9, 17.9, 13.9, -4.8, -5.4;
FAB HRMS (NBA) m/e 326.1615, M + H+ calcd for C16H27NO2SSi
326.1610.
Compound 25. Silylation of Alcohol 24. Alcohol 24 (7.0 g, 0.033
mol) was dissolved in DMF (35 mL, 1.0 M), the solution was cooled
to 0 °C, and imidazole (3.5 g, 0.050 mol, 1.5 equiv) was added. After
stirring for 5 min, tert-butyldimethylsilyl chloride (6.02 g, 0.040 mol,
1.2 equiv) was added portionwise and the reaction mixture was allowed
to stir at 0 °C for 45 min, and then at 25 °C for 2.5 h, after which time
no starting alcohol was detected by TLC. Methanol (2 mL) was added
at 0 °C, and the solvent was removed under reduced pressure. Ether
(100 mL) was added followed by saturated aqueous NH4Cl solution
(20 mL), the organic phase was separated, and the aqueous phase was
extracted with ether (2 × 20 mL). The combined organic solution
was dried (MgSO4) and filtered over Celite, and the solvents were
removed under reduced pressure. Flash column chromatography (silica
gel, 10 f 20% ether in hexanes) provided pure 25 (10.8 g, 99%): Rf
) 0.70 (40% ether in hexanes); [R]22D +1.39 (c 3.0, CHCl3); IR (thin
film) νmax 2931, 2060, 1496, 1460, 1249, 1173, 1073, 908, 837, 779
Alcohol 26. Reduction of Aldehyde 15. A solution of aldehyde
15 (440 mg, 1.35 mmol) in MeOH (13 mL) was treated with NaBH4
(74 mg, 2.0 mmol, 1.5 equiv) at 0 °C for 15 min. The solution was
diluted with ether (100 mL), and then saturated aqueous NH4Cl solution
(5 mL) was carefully added. The organic phase was washed with brine
(10 mL), dried (MgSO4), and concentrated. Flash column chromatog-
raphy (silica gel, 60% ether in hexanes) gave alcohol 26 (425 mg, 96%)
as a colorless oil. 26: Rf ) 0.52 (silica gel, 60% ether in hexanes);
[R]22 -29.4 (c 0.8, CHCl3); IR (thin film) νmax 3362, 2950, 2856,
D
1
1656, 1505, 1466, 1362, 1254, 1186, 1075, 839, 777 cm-1; H NMR
(500 MHz, CDCl3) δ 6.86 (s, 1 H, SCHdC), 6.40 (s, 1 H, CHdCCH3),
4.30 (dd, J ) 7.6, 5.3 Hz, 1 H, CHOSi), 3.69-3.59 (m, 2 H, CH2OH),
3.15 (s, 1 H, OH), 2.61 (s, 3 H, NdC(S)CH3), 1.92 (s, 3 H, CHdCCH3),
1.82-1.76 (m, 1 H, CH2CH2OH), 1.73-1.67 (m, 1 H, CH2CH2OH),
0.82 (s, 9 H, SiC(CH3)3), 0.02 (s, 3 H, Si(CH3)2), -0.05 (s, 3 H, Si-
(CH3)2); 13C NMR (150.9 MHz, CDCl3) δ 164.3, 152.7, 141.6, 118.5,
115.1, 76.6, 59.6, 38.3, 25.8, 18.9, 18.0, 14.0, -4.8, -5.4; FAB HRMS
(NBA/CsI) m/e 460.0727, M + Cs+ calcd for C16H29NO2SSi 460.0743.
Iodide 27. Iodination of Alcohol 26. A solution of alcohol 26
(14.0 g, 42.7 mmol) in ether: MeCN (3:1, 250 mL) was cooled to 0
°C. Imidazole (8.7 g, 128.1 mmol, 3.0 equiv), Ph3P (16.8 g, 64.1 mmol,
1.5 equiv), and iodine (16.3 g, 64.1 mmol, 1.5 equiv) were sequentially
added, and the mixture was stirred for 0.5 h at 0 °C. A saturated
aqueous solution of Na2S2O3 (50 mL) was added, followed by the
addition of ether (600 mL). The organic phase was washed with brine
(50 mL) and dried (MgSO4), and the solvents were removed under
1
cm-1; H NMR (600 MHz, CDCl3) δ 6.91 (s, 1 H, SCHdC), 6.45 (s,
1 H, CHdCCH3), 5.80-5.75 (m, 1 H, CHdCH2), 5.03 (ddd, J ) 17.1,
3.5, 1.5 Hz, 1 H, CHdCH2), 4.99 (ddd, J ) 10.2, 2.1, 0.9 Hz, 1 H,
CHdCH2), 4.14 (dd, J ) 6.6, 6.1 Hz, 1 H, CHOH), 2.69 (s, 3 H, NdC-
(S)CH3), 2.37-2.32 (m, 1 H, CH2dCHCH2), 2.31-2.25 (m, 1 H,
CH2dCHCH2), 1.99 (s, 3 H, CHdCCH3), 0.88 (s, 9 H, SiC(CH3)3),
0.05 (s, 3 H, Si(CH3)2), 0.00 (s, 3 H, Si(CH3)2); 13C NMR (150.9 MHz,
CDCl3) δ 165.2, 153.9, 142.9, 136.2, 119.7, 117.4, 115.9, 79.3, 42.1,
26.7, 20.1, 19.0, 14.8, -3.8, -4.1; FAB HRMS (NBA) m/e 324.1804,
M + H+ calcd for C17H29NOSSi 324.1817.

7982 J. Am. Chem. Soc., Vol. 119, No. 34, 1997
Nicolaou et al.
vacuum. Flash column chromatography (silica gel, 15% ether in
(500 MHz, CDCl3) δ 9.60 (d, J ) 2.0 Hz, 1 H, CHO), 7.34 (s, 5 H,
Ph), 4.50 (s, 2 H, CH2Ph), 3.47 (t, J ) 6.5 Hz, 2 H, CH2OBn), 2.33
(m, 1 H, CH(CH3)CO), 1.75-1.69 (m, 1 H), 1.65-1.61 (m, 2 H), 1.49-
1.34 (m, 3 H), 1.08 (d, J ) 7.0 Hz, 3 H, CHCH3); 13C NMR (125.7
MHz, CDCl3) δ 205.0, 138.4, 128.2, 127.5, 127.4, 72.8, 69.9, 46.1,
30.1, 29.6, 23.6, 13.2; FAB HRMS (NBA) m/e 221.1538, M + H+
calcd for C14H20O2 221.1542.
hexanes) gave pure iodide 27 (16.6 g, 89%) as a colorless oil: Rf )
0.40 (silica gel, 10% ether in hexanes); [R]22 +11.0 (c 1.0, CHCl3);
D
IR (thin film) νmax 2951, 2856, 1503, 1466, 1253, 1179, 1081, 936,
884, 836, 777 cm-1 1H NMR (600 MHz, CDCl3) δ 6.90 (s, 1 H,
;
SCHdC), 6.53 (s, 1 H, CHdCCH3), 4.19 (dd, J ) 7.7, 4.5 Hz, 1 H,
CHOSi), 3.18 (t, J ) 7.3 Hz, 2 H, CH2I), 2.67 (s, 3 H, NdC(S)CH3),
2.10-2.05 (m, 1 H, CH2CH2I), 2.01-1.95 (m, 1 H, CH2CH2I), 1.99
(s, 3 H, CHdCCH3), 0.87 (s, 9 H, SiC(CH3)3), 0.09 (s, 3 H, Si(CH3)2),
0.00 (s, 3 H, Si(CH3)2); 13C NMR (150.9 MHz, CDCl3) δ 164.4, 152.7,
140.9, 119.3, 115.4, 78.0, 40.2, 25.8, 19.2, 18.1, 13.9, 3.1, -4.6, -5.0;
FAB HRMS (NBA) m/e 438.0768, M + H+ calcd for C16H28INOSSi
438.0784.
Alcohol 30. Reduction of Aldehyde 29. A solution of aldehyde
29 (17.0 g, 77.0 mmol) in MeOH (200 mL) was treated with NaBH4
(8.6 g, 228 mmol, 3.0 equiv) at 0 °C for 15 min. The solution was
then diluted with ether (400 mL), and saturated aqueous NH4Cl solution
(50 mL) was carefully added. The organic phase was washed with
brine (50 mL), dried (MgSO4), and concentrated. The crude product
was purified by flash column chromatography (silica gel, 40% ether
in hexanes) to give alcohol 30 (16.8 g, 98%) as a colorless oil: Rf )
0.23 (silica gel, 50% ether in hexanes); [R]22D -5.1 (c 1.9, CHCl3); IR
(thin film) νmax 3401, 2931, 2860, 1455, 1361, 1267, 1202, 1102, 1037,
937, 732, 697 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.35 (s, 5 H, Ph),
4.51 (s, 2 H, CH2Ph), 3.50 (dd, J ) 11.0, 6.0 Hz, 1 H, CH2OH), 3.48
(t, J ) 6.5 Hz, 2 H, CH2OBn), 3.42 (dd, J ) 11.0, 6.5 Hz, 1 H, CH2-
OH), 1.65-1.59 (m, 2 H), 1.47-1.34 (m, 4 H), 1.15-1.12 (m, 1 H),
0.91 (d, J ) 6.7 Hz, 3 H, CHCH3); 13C NMR (125.7 MHz, CDCl3) δ
138.6, 128.2, 127.6, 127.3, 72.9, 70.3, 68.1, 35.7, 32.9, 30.1, 23.6, 14.1;
FAB HRMS (NBA) m/e 223.1705, M + H+ calcd for C14H22O2
223.1698.
Phosphonium Salt 12. A mixture of iodide 27 (16.5 g, 37.7 mmol)
and Ph3P (10.9 g, 41.5 mmol, 1.1 equiv) was heated neat at 100 °C for
2 h. Purification by flash column chromatography (silica gel, CH2Cl2;
then 7% MeOH in CH2Cl2) provided phosphonium salt 12 (25.9 g,
98%) as a white solid: Rf ) 0.50 (silica gel, 7% MeOH in CH2Cl2);
[R]22D +3.7 (c 0.7, CHCl3); IR (thin film) νmax 2951, 2856, 1503, 1466,
1253, 1179, 1081, 936, 884, 836, 777 cm-1 1H NMR (600 MHz,
;
CDCl3) δ 7.78-7.28 (m, 15 H, aromatic), 6.97 (s, 1 H, SCHdC), 6.57
(s, 1 H, CHdCCH3), 4.48 (dd, J ) 6.3, 4.8 Hz, 1 H, CHOSi), 3.72-
3.65 (m, 1 H, CH2P), 3.31-3.25 (m, 1 H, CH2P), 2.61 (s, 3 H, NdC-
(S)CH3), 1.91 (s, 3 H, CHdCCH3), 1.95-1.86 (m, 1 H, CH2CH2P),
1.82-1.74 (m, 1 H, CH2CH2 P), 0.83 (s, 9 H, SiC(CH3)3), 0.07 (s, 3
H, Si(CH3)2), -0.02 (s, 3 H, Si(CH3)2); 13C NMR (150.9 MHz, CDCl3)
δ 164.4, 152.3, 139.4, 135.1, 133.3, 133.2, 130.5, 130.4, 128.1, 119.8,
117.9, 117.3, 116.5, 76.0, 28.9, 25.7, 19.1, 18.4, 17.9, 14.5, -4.8.
Silyl Ether 31. Silylation of Alcohol 30. Alcohol 30 (17.0 g, 76.0
mmol) was dissolved in CH2Cl2 (350 mL), the solution was cooled to
0 °C and Et3N (21.2 mL, 152.0 mmol, 2.0 equiv) and 4-DMAP (185
mg, 1.52 mmol, 0.05 equiv) were added. After the mixture was stirred
for 5 min, tert-butyldimethylsilyl chloride (17.3 g, 115 mmol, 1.5 equiv)
was added portionwise and the reaction mixture was allowed to stir at
0 °C for 2 h and then at 25 °C for 10 h. Methanol (20 mL) was added
at 0 °C, and the solvents were removed under reduced pressure. Ether
(200 mL) and saturated aqueous NH4Cl solution (30 mL) were
sequentially added, and the organic phase was separated. The aqueous
phase was extracted with ether (2 × 100 mL), and the combined organic
layer was dried (MgSO4), filtered, and concentrated under reduced
pressure. Purification by flash column chromatography (silica gel, 5%
ether in hexanes) provided pure silyl ether 31 (24.4 g, 95%): Rf ) 0.54
(silica gel, 10% ether in hexanes); [R]22D -2.3 (c 1.1, CHCl3); IR (thin
Hydrazone 28. Alkylation of Hydrazone 13. Hydrazone 1315
(20.0 g, 117.0 mmol, 1.0 equiv), dissolved in THF (80 mL), was added
to a freshly prepared solution of LDA [19.75 mL of diisopropylamine
(141.0 mmol, 1.2 equiv) was added to a solution of 88.1 mL of 1.6 M
solution of n-BuLi in hexanes (141 mmol, 1.2 equiv) in 160 mL of
THF at 0 °C] at 0 °C. After the mixture was stirred at this temperature
for 8 h, the resulting yellow solution was cooled to -100 °C and a
solution of 4-iodo-1-(benzyloxy)butane (36.0 g, 124.0 mmol, 1.2 equiv)
in THF (40 mL) was added dropwise over a period of 30 min. The
mixture was allowed to warm to room temperature over 8 h and was
then poured into saturated aqueous NH4Cl solution (40 mL) and
extracted with ether (3 × 200 mL). The combined organic extracts
were dried (MgSO4), filtered, and evaporated. Purification by flash
column chromatography on silica gel (20% ether in hexanes) provided
film) νmax 2931, 2860, 1461, 1361, 1249, 1091, 839, 773, 738 cm-1
;
1H NMR (500 MHz, CDCl3) δ 7.35 (s, 5 H, Ph), 4.51 (s, 2 H, CH2Ph),
3.48 (t, J ) 6.5 Hz, 2 H, CH2OBn), 3.43 (dd, J ) 10.5, 6.0 Hz, 1 H,
CH2OSi), 3.36 (dd, J ) 10.5, 6.5 Hz, 1 H, CH2OSi), 1.64-1.60 (m, 3
H), 1.47-1.29 (m, 3 H), 1.15-1.05 (m, 1 H), 0.90 (s, 9 H, SiC(CH3)3),
0.87 (d, J ) 6.8 Hz, 3 H, CHCH3), 0.043 (s, 3 H, Si(CH3)2), 0.041 (s,
3 H, Si(CH3)2); 13C NMR (125.7 MHz, CDCl3) δ 138.6, 128.2, 127.5,
127.3, 72.7, 70.3, 68.3, 35.6, 32.9, 30.0, 25.8, 23.5, 18.1, 16.6, -5.5;
FAB HRMS (NBA) m/e 337.2553, M + H+ calcd for C20H36O2Si
337.2563.
1
hydrazone 28 as a yellow oil (35.8 g, 92%, de > 98% by H NMR):
Rf ) 0.45 (silica gel, 50% ether in hexanes); [R]22 -55.0 (c 1.2,
D
CHCl3); IR (thin film) νmax 2929, 2862, 1603, 1455, 1362, 1198, 1108,
737, 698 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.33 (s, 5 H, Ph), 6.48
(d, J ) 6.5 Hz, 1 H, CHdNN), 4.46 (s, 2 H, CH2Ph), 3.54 (dd, J )
9.0, 3.8 Hz, 1 H, CH2OCH3), 3.44 (t, J ) 6.5 Hz, 2 H, CH2OBn), 3.40
(dd, J ) 9.0, 6.8 Hz, 1 H, CH2OCH3), 3.33 (s, 3 H, OCH3), 2.65 (m,
1 H, CHCH2OCH3), 2.29 (m, 1 H, CH(CH3)CdN), 1.94-1.76 (m, 4
H), 1.61 (m, 2 H), 1.45-1.36 (m, 6 H), 1.01 (d, J ) 6.8 Hz, 3 H,
CHCH3); 13C NMR (125.7 MHz, CDCl3) δ 144.6, 138.6, 128.2, 127.5,
127.3, 74.7, 72.7, 70.2, 63.4, 59.1, 50.4, 37.0, 35.2, 29.7, 26.4, 23.7,
22.0, 18.9; FAB HRMS (NBA) m/e 333.2552, M + H+ calcd for
C20H32N2O2 333.2542.
Alcohol 32. Hydrogenolysis of Benzyl Ether 31. To a solution
of benzyl ether 31 (21.0 g, 62.5 mmol) in THF (200 mL) was added
10% Pd(OH)2/C (1.0 g). The reaction was allowed to proceed under
an atmosphere of H2 at a pressure of 50 psi and at 25 °C (Parr
hydrogenetor apparatus). After 15 min, no starting benzyl ether was
detected by TLC and the mixture was filtered through Celite. The
clear solution was concentrated under reduced pressure, and the resulting
crude product was purified by flash column chromatography (silica
gel, 40% ether in hexanes) to give alcohol 32 (14.7 g, 95%) as a
colorless oil: Rf ) 0.32 (silica gel, 50% ether in hexanes); [R]22D -3.6
(c 3.6, CHCl3); IR (thin film) νmax 3342, 2931, 2860, 1467, 1384, 1249,
1085, 838, 773, 667 cm-1; 1H NMR (500 MHz, CDCl3) δ 3.63 (t, J )
7.0 Hz, 2 H, CH2OH), 3.42 (dd, J ) 11.0, 6.0 Hz, 1 H, CH2OSi), 3.35
(dd, J ) 11.0, 7.0 Hz, 1 H, CH2OSi), 1.57-1.53 (m, 3 H), 1.42-1.39
(m, 3 H), 1.16-1.06 (m, 1 H), 0.88 (s, 9 H, SiC(CH3)3), 0.85 (d, J )
6.5 Hz, 3 H, CHCH3), 0.03 (s, 3 H, Si(CH3)2), 0.02 (s, 3 H, Si(CH3)2);
13C NMR (125.7 MHz, CDCl3) δ 68.2, 62.7, 35.6, 32.9, 32.8, 25.7,
23.0, 18.2, 16.5, -5.5; FAB HRMS (NBA) m/e 247.2097, M + H+
calcd for C13H30O2Si 247.2093.
Aldehyde 29. Cleavage of Hydrazone 28. Procedure A: A
solution of hydrazone 28 (13.0 g, 39.1 mmol) in CH2Cl2 (50 mL) was
treated with ozone at -78 °C until the solution turned blue-green. The
solution was purged with oxygen for 2 min at -78 °C, allowed to
warm to room temperature, and then concentrated. The crude mixture
so obtained was purified by flash column chromatography (silica gel,
10% ether in hexanes) to give aldehyde 29 (6.6 g, 77%) as a colorless
oil. Procedure B: A solution of hydrazone 28 (30 g, 90.3 mmol) in
MeI (100 mL) was heated at 60 °C. After 5 h, the reaction was
complete (TLC) and the mixture was concentrated. The resulting crude
product was suspended in n-pentane (360 mL) and was treated with 3
N aqueous HCl (360 mL). The two-phase system was vigorously stirred
for 1 h, and the aqueous phase was extracted with n-pentane (3 × 200
mL). The combined organic solution was dried (MgSO4), concentrated,
and purified by flash column chromatography (silica gel, 10% ether in
hexanes) to give 29 (17.1 g, 86%): Rf ) 0.49 (silica gel, 50% ether in
Aldehyde 10. Oxidation of Alcohol 32. To a solution of oxalyl
chloride (5.6 mL, 65.0 mmol, 2.0 equiv) in CH2Cl2 (250 mL) was added
dropwise DMSO (9.2 mL, 130 mmol, 4.0 equiv) at -78 °C. After the
mixture was stirred for 15 min, a solution of alcohol 32 (8.0 g, 32.0
hexanes); [R]22D +11.6 (c 1.7, CHCl3); IR (thin film) νmax 2932, 2856,
1
1715, 1450, 1361, 1272, 1202, 1102, 920, 732, 697 cm-1
;
H NMR

Total Synthesis of Epothilones A and B
J. Am. Chem. Soc., Vol. 119, No. 34, 1997 7983
mmol, 1.0 equiv) in CH2Cl2 (50 mL) was added dropwise at -78 °C
over a 15 min period. The solution was stirred for a further 30 min at
-78 °C, and Et3N (27.1 mL, 194 mmol, 6.0 equiv) was added at the
same temperature. The reaction mixture was allowed to warm to 0 °C
over 30 min, and then ether (400 mL) was added, followed by saturated
aqueous NH4Cl solution (100 mL). The organic phase was separated,
and the aqueous phase was extracted with ether (2 × 300 mL). The
combined organic solution was dried (MgSO4), filtered, and concen-
trated under reduced pressure. Purification by flash column chroma-
tography (silica gel, 20% ether in hexanes) provided aldehyde 10 (7.9
g, 98%) as a colorless oil: Rf ) 0.64 (silica gel, 50% ether in hexanes);
[R]22D -5.1 (c 0.7, CHCl3); IR (thin film) νmax 2952, 2858, 1728, 1466,
1389, 1254, 1095, 841, 776 cm-1; 1H NMR (500 MHz, CDCl3) δ 9.74
(t, J ) 1.5 Hz, 1 H, CHO), 3.39 (dd, J ) 9.8, 6.1 Hz, 1 H, CH2OSi),
3.36 (dd, J ) 9.8, 6.3 Hz, 1 H, CH2OSi), 2.39 (m, 2 H, CH2CHO),
171-1.64 (m, 1 H), 1.61-1.53 (m, 2 H), 1.44-1.38 (m, 1 H), 1.11-
1.05 (m, 1 H), 0.87 (s, 9 H, SiC(CH3)3), 0.85 (d, J ) 6.5 Hz, 3 H,
CHCH3), 0.019 (s, 3 H, Si(CH3)2), 0.004 (s, 3 H, Si(CH3)2); 13C NMR
(125.7 MHz, CDCl3) δ 202.7, 68.9, 44.1, 35.5, 32.6, 25.8, 23.0, 18.2,
16.5, -5.5; FAB HRMS (NBA) m/e 245.1932, M + H+ calcd for
C13H28O2Si 245.1937.
OSi), 3.19 (t, J ) 7.0 Hz, 2 H, CH2I), 1.85-1.78 (m, 2 H), 1.61-1.55
(m, 1 H), 1.47-1.33 (m, 3 H), 1.10-1.02 (m, 1 H, CH2), 0.89 (s, 9 H,
SiC(CH3)3), 0.87 (d, J ) 6.7 Hz, 3 H, CHCH3), 0.04 (s, 6 H, Si(CH3)2);
13C NMR (125.7 MHz, CDCl3) δ 68.1, 35.4, 33.7, 31.8, 27.8, 25.8,
18.2, 16.5, 7.1, -5.5; FAB HRMS (NBA) m/e 229.1983, M - I- calcd
for C13H39IOSi 229.1988.
Phosphonium Salt 47. A mixture of iodide 46 (4.7 g, 13.1 mmol)
and Ph3P (3.8 g, 14.4 mmol, 1.1 equiv) was heated neat at 100 °C for
2 h. Purification by flash column chromatography (silica gel, CH2Cl2
f 7% MeOH in CH2Cl2) provided phosphonium salt 47 (7.4 g, 91%)
as a white solid: Rf ) 0.42 (silica gel, 5% MeOH in CH2Cl2); [R]22
D
-7.3 (c 1.5, CHCl3); IR (thin film) νmax 2931, 2849, 1578, 1461, 1431,
1
1243, 1184, 1102, 997, 914, 838, 720, 685, 532, 503 cm-1; H NMR
(500 MHz, CDCl3) δ 7.82-7.77 (m, 9 H, Ph), 7.74-7.68 (m, 6 H,
Ph), 3.62 (dt, J ) 12.5, 8.0 Hz, 2 H, CH2P), 3.34 (dd, J ) 9.5, 6.5 Hz,
1 H, CH2OSi), 3.30 (dd, J ) 9.5, 6.5 Hz, 1 H, CH2OSi), 1.69-1.55
(m, 4 H), 1.50-1.46 (m, 1 H), 1.39-1.32 (m, 1 H), 1.10-1.01 (m, 1
H), 0.83 (s, 9 H, SiC(CH3)3), 0.79 (d, J ) 6.6 Hz, 3 H, CHCH3), -0.04
(s, 6 H, Si(CH3)2); 13C NMR (125.7 MHz, CDCl3) δ 135.0, 133.6, 133.5,
133.2, 130.5, 130.4, 68.0, 35.2, 32.4, 27.8, 25.8, 23.2, 22.7, 18.2, 16.4,
-5.5.
Alcohol 33. To a cold (0 °C) solution of aldehyde 10 (7.8 g, 32.0
mmol) in THF (300 mL) was slowly added MeMgBr (1.0 M solution
in THF, 48.0 mL, 48.0 mmol, 1.5 equiv). The reaction mixture was
stirred for 15 min at 0 °C, and then it was diluted with ether (500 mL)
and quenched by carefull addition of saturated aqueous NH4Cl solution
(100 mL). The organic phase was washed with brine (100 mL), dried
(MgSO4), and concentrated. The crude product so obtained was purified
by flash column chromatography (silica gel, 30% ether in hexanes) to
give alcohol 33 (7.0 g, 84%) as a colorless oil: Rf ) 0.38 (silica gel,
50% ether in hexanes); IR (thin film) νmax 3352, 2931, 2858, 1465,
1384, 1253, 1096, 839, 775 cm-1; 1H NMR (500 MHz, CDCl3) δ 3.79
(m, 1 H, CH(CH3)OH), 3.43 (dd, J ) 9.8, 6.0 Hz, 1 H, CH2OSi), 3.36
(dd, J ) 9.8, 6.8 Hz, 1 H, CH2OSi), 1.61-1.57 (m, 1 H), 1.47-1.35
(m, 4 H), 1.30-1.26 (m, 1 H), 1.19 (d, J ) 6.1 Hz, 3 H, CH(OH)-
CH3), 1.09-1.05 (m, 1 H), 0.89 (s, 9 H, SiC(CH3)3), 0.86 (d, J ) 6.7
Hz, 3 H, CHCH3), 0.04 (s, 6 H, Si(CH3)2); 13C NMR (125.7 MHz,
CDCl3) δ 68.2, 67.9, 39.5, 35.6, 33.0, 25.9, 23.4, 23.1, 18.2, 16.6, -5.4;
FAB HRMS (NBA) m/e 261.2256, M + H+ calcd for C14H32O2Si
261.2250.
Olefin 34. Method A. From Phosphonium Salt 12 and Aldehyde
10: Phosphonium salt 12 (13.60 g, 19.4 mmol, 1.2 equiv) was dissolved
in THF (80 mL, 0.2 M), and the solution was cooled to 0 °C. Sodium
hexamethyldisilylamide (NaHMDS, 19.4 mL, 19.4 mmol, 1.0 M
solution in THF, 1.2 equiv) was slowly added, and the resulting mixture
was stirred for 15 min before aldehyde 10 (3.96 g, 16.2 mmol, 1.0
equiv, in 10 mL of THF) was added at the same temperature. Stirring
was continued for another 15 min at 0 °C, and then, the reaction mixture
was quenched with saturated aqueous NH4Cl solution (25 mL). Ether
(250 mL) was added, and the organic phase was separated and washed
with brine (2 × 40 mL), dried (MgSO4), and concentrated under Vacuo.
The crude product was purified by flash column chromatography (silica
gel, 10% ether in hexane) to afford olefin 34 (6.70 g, 77%) as a mixture
of Z- and E-isomers (ca. 9:1 by 1H NMR). Method B. From
Phosphonium Salt 47 and Aldehyde 15: Phosphonium salt 47 (7.40
g, 11.96 mmol, 1.2 equiv) was dissolved in THF (120 mL, 0.1 M),
and the solution was cooled to 0 °C. Sodium hexamethyldisilylamide
(NaHMDS, 11.96 mL, 11.96 mmol, 1.0 M solution in THF, 1.2 equiv)
was slowly added at the same temperature, and the resulting mixture
was stirred for 15 min, before aldehyde 15 (3.20 g, 9.83 mmol, 1.0
equiv, in 20 mL of THF) was slowly added. Stirring was continued
for another 15 min at 0 °C, and then the mixture was quenched with
saturated aqueous NH4Cl solution (150 mL). Ether (200 mL) was
added, and the organic phase was separated and washed with brine (2
× 150 mL), dried (MgSO4), and concentrated under reduced pressure
to afford the crude product. Flash column chromatography (silica gel,
10% ether in hexane) furnished olefin 34 (3.65 g, 69% yield) as a
Ketone 11. Oxidation of Alcohol 33. To a solution of alcohol 33
(7.0 g, 27.0 mmol) in CH2Cl2 (250 mL) were added molecular sieves
(4 Å, 6.0 g), 4-methylmorpholine N-oxide (NMO) (4.73 g, 40.0 mmol,
1.5 equiv), and tetrapropylammonium perruthenate (TPAP) (189 mg,
0.54 mmol, 0.02 equiv) at room temperature. After being stirred for
45 min (depletion of starting material, TLC), the reaction mixture was
filtered through Celite and the solvent was removed under reduced
pressure. The crude product was purified by flash column chroma-
tography (silica gel, 20% ether in hexanes) to give ketone 11 (6.6 g,
96%) as a colorless oil: Rf ) 0.67 (silica gel, 50% ether in hexanes);
[R]22D -4.5 (c 1.1, CHCl3); IR (thin film) νmax 2931, 2849, 1713, 1461,
1
mixture of Z- and E-isomers (ca. 9:1 by H NMR): Rf ) 0.75 (silica
gel, 50% ether in hexane); [R]22 +4.0 (c 0.5, CHCl3); IR (thin film)
D
1
νmax 2930, 2856, 1465, 1388, 1253, 1089, 939, 838 cm-1; H NMR
1
1355, 1249, 1161, 1091, 838, 773, 667 cm-1; H NMR (500 MHz,
(500 MHz, CDCl3) (signals for the Z-isomer (34) only reported) δ 6.92
(s, 1 H, SCHdC), 6.46 (s, 1 H, CHdCCH3), 5.49-5.31 (m, 2 H,
CHdCH), 4.12 (dd, J ) 6.5, 6.4 Hz, 1 H, CHOSi), 3.44 (dd, J ) 9.8,
5.8 Hz, 1 H, CH2OSi), 3.34 (dd, J ) 9.8, 6.8 Hz, 1 H, CH2OSi), 2.71
(s, 3 H, NdC(S)CH3), 2.39-2.24 (m, 2 H, CH2CHOSi), 2.00 (s, 3 H,
CHdCCH3), 2.05-1.96 (m, 2 H), 1.59-1.51 (m, 1 H), 1.42-1.23 (m,
3 H), 1.10-0.98 (m, 1 H), 0.89 (s, 18 H, SiC(CH3)3), 0.85 (d, J ) 6.8
Hz, 3 H, CH3CH), 0.06 (s, 3 H, Si(CH3)2), 0.04 (s, 6 H, Si(CH3)2),
0.01 (s, 3 H, Si(CH3)2); 13C NMR (150.9 MHz, CDCl3) δ 164.3, 153.1,
142.2, 131.4, 125.7, 118.8, 114.9, 78.7, 68.3, 35.7, 34.6, 32.9, 27.8,
27.1, 25.9, 25.8, 19.2, 18.3, 18.2, 16.7, 13.9, -4.7, -4.9, -5.4; FAB
HRMS (NBA) m/e 538.3582, M + H+ calcd for C29H55NO2SSi2
538.3570.
CDCl3) δ 3.41 (dd, J ) 9.8, 6.0 Hz, 1 H, CH2OSi), 3.36 (dd, J ) 9.8,
6.3 Hz, 1 H, CH2OSi), 2.41 (m, 2 H, CH2COCH3), 2.13 (s, 3 H,
COCH3), 168-1.48 (m, 3 H), 1.42-1.35 (m, 1 H), 1.09-1.00 (m, 1
H), 0.88 (s, 9 H, SiC(CH3)3), 0.86 (d, J ) 6.7 Hz, 3 H, CHCH3), 0.03
(s, 6 H, Si(CH3)2); 13C NMR (125.7 MHz, CDCl3) δ 209.8, 68.0, 43.9,
35.5, 32.6, 29.7, 25.8, 21.2, 18.2, 16.4, -5.5; FAB HRMS (NBA) m/e
259.2097, M + H+ calcd for C14H30O2Si 259.2093.
Iodide 46. Iodination of Alcohol 32. A solution of alcohol 32
(3.8 g, 15.0 mmol) in ether:MeCN, 3:1 (150 mL), was cooled to 0 °C.
Imidazole (3.1 g, 45.0 mmol, 3.0 equiv), Ph3P (5.9 g, 22.5 mmol, 1.5
equiv), and iodine (5.7 g, 22.5 mmol, 1.5 equiv) were sequentially
added, and the reaction mixture was stirred at 0 °C for 0.5 h.
A
saturated aqueous solution of Na2S2O3 (200 mL) was added followed
with ether (200 mL). The organic phase was washed with brine (200
mL) and dried (MgSO4), and the solvents were removed under vacuum.
The crude product was purified by flash column chromatography (silica
gel, 10% ether in hexanes) to give pure iodide 46 (4.9 g, 91%) as a
colorless oil: Rf ) 0.68 (silica gel, 10% ether in hexanes); [R]22D -4.3
(c 1.2, CHCl3); IR (thin film) νmax 2929, 2860, 1461, 1386, 1248, 1090,
Alcohol 35. Compound 34 (1.77 g, 3.29 mmol) was dissolved in
CH2Cl2:MeOH (1:1, 66 mL), the solution was cooled to 0 °C, and CSA
(764 mg, 3.29 mmol, 1.0 equiv) was added over a 5 min period. The
mixture was stirred for 30 min at 0 °C and then for 1 h at 25 °C. Et3N
(2.0 mL) was added, and the solvents were removed under reduced
pressure. Flash column chromatography (silica gel, 50% ether in
hexanes) furnished the desired alcohol 35 (1.2 g, 86%): Rf ) 0.72
(silica gel, 80% ether in hexanes); [R]22D +1.1 (c 1.0, CHCl3); IR (thin
film) νmax 3370, 2923, 2857, 1464, 1384, 1253, 1185, 1074, 836, 776
1
836, 774, 664 cm-1; H NMR (500 MHz, CDCl3) δ 3.42 (dd, J )
10.0, 6.5 Hz, 1 H, CH2OSi), 3.38 (dd, J ) 10.0, 6.0 Hz, 1 H, CH2-

7984 J. Am. Chem. Soc., Vol. 119, No. 34, 1997
Nicolaou et al.
1
1
cm-1; H NMR (500 MHz, CDCl3) δ 6.91 (s, 1 H, SCHdC), 6.44 (s,
νmax 2931, 2856, 1712, 1466, 1254, 1083, 836 cm-1; H NMR (600
1 H, CHdCCH3), 5.45-5.32 (m, 2 H, CHdCH), 4.12 (dd, J ) 6.5,
6.4 Hz, 1 H, CHOSi), 3.46 (dd, J ) 10.5, 5.9 Hz, 1 H, CH2OH), 3.37
(dd, J ) 10.5, 6.5 Hz, 1 H, CH2OH), 2.68 (s, 3 H, NdC(S)CH3), 2.39-
2.21 (m, 2 H, CH2CHOSi), 2.21 (s, 1 H, OH), 1.98 (s, 3 H, CHdCCH3),
2.05-1.95 (m, 2 H), 1.59-1.51 (m, 1 H), 1.42-1.23 (m, 3 H), 1.10-
0.98 (m, 1 H), 0.88 (d, J ) 6.5 Hz, 3 H, CH3CH), 0.87 (s, 9 H, SiC-
(CH3)3), 0.05 (s, 3 H, Si(CH3)2), -0.01 (s, 3 H, Si(CH3)2); 13C NMR
(125.7 MHz, CDCl3) δ 164.4, 152.9, 142.2, 131.2, 125.8, 118.7, 114.8,
78.6, 67.9, 35.5, 34.6, 32.7, 27.5, 26.9, 25.8, 25.7, 18.9, 16.5, 13.7,
-4.8, -5.1; FAB HRMS (NBA/NaI) m/e 446.2534, M + Na+ calcd
for C23H41NO2SSi 446.2525.
MHz, CDCl3) δ 6.94 (s, 1 H, SCHdC), 6.61 (s, 1 H, CHdCCH3),
5.44-5.41 (m, 2 H, CHdCH), 4.40 (dd, J ) 6.5, 3.2 Hz, 1 H, (CH3)2-
CCHOSi), 4.11 (dd, J ) 6.5, 5.9 Hz, 1 H, CH2CHOSi), 3.75 (dd, J )
6.5, 3.0 Hz, 1 H, CH(CH3)CHOSi), 3.12 (dq, J ) 7.0, 6.5 Hz, 1 H,
C(O)CH(CH3)), 2.69 (s, 3 H, NdC(CH3)S), 2.48 (dd, J ) 16.0, 3.2
Hz, 1 H, CH2COOH), 2.35 (dd, J ) 16.0, 6.7 Hz, 1 H, CH2COOH),
2.39-2.28 (m, 2 H, CH2CHdCH), 2.10-1.92 (m, 2 H, CHdCHCH2),
1.95 (s, 3 H, CHdC(CH3)), 1.42-1.30 (m, 5 H, CH(CH3), 2 x CH2),
1.18 (s, 3 H, C(CH3)2), 1.10 (s, 3 H, C(CH3)2), 1.06 (d, J ) 7.0 Hz, 3
H, CH(CH3)), 0.90-0.85 (m, 30 H, CH(CH3), 3 x SiC(CH3)3), 0.12 (s,
3 H, Si(CH3)2), 0.09 (s, 3 H, Si(CH3)2), 0.07 (s, 3 H, Si(CH3)2), 0.05
(s, 3 H, Si(CH3)2), 0.04 (s, 3 H, Si(CH3)2), 0.03 (s, 3 H, Si(CH3)2); 13
C
Aldehyde 7. Oxidation of Alcohol 35. Alcohol 35 (1.9 g, 4.5
mmol) was dissolved in CH2Cl2 (45 mL, 0.1 M). DMSO (13.5 mL),
Et3N (3.0 mL, 22.4 mmol, 5.0 equiv), and SO3‚pyr (1.43 g, 8.98 mmol,
2.0 equiv) were added at 25 °C, and the resulting mixture was stirred
for 30 min. Saturated aqueous NH4Cl solution (100 mL) and ether
(200 mL) were added sequentially. The organic phase was washed
with brine (2 × 30 mL) and dried (MgSO4), and the solvents were
removed under reduced pressure. Flash column chromatography (silica
gel, 30% ether in hexanes) furnished aldehyde 7 (1.79 g, 94%): Rf )
NMR (150.9 MHz, CDCl3) δ 218.1, 176.7, 164.8, 152.8, 142.6, 131.3,
125.9, 118.6, 114.7, 78.6, 77.4, 73.4, 53.5, 44.9, 40.1, 38.8, 34.6, 30.7,
28.0, 27.8, 26.2, 26.0, 25.8, 23.6, 19.1, 18.8, 18.5, 18.2, 17.4, 15.7,
13.8, -3.7, -3.8, -4.2, -4.6, -4.7, -4.9; FAB HRMS (NBA/CsI)
m/e 970.4318, M + Cs+ calcd for C44H83NO6SSi3 970.4303. 39: Rf
) 0.70 (silica gel, 5% MeOH in CH2Cl2); [R]22D +2.2 (c 3.5, CHCl3);
IR (thin film) νmax 2929, 2856, 1713, 1470, 1386, 1254, 1082, 988,
836, 776 cm-1; 1H NMR (600 MHz, CDCl3) δ 6.91 (s, 1 H, SCHdC),
6.45 (s, 1 H, CHdCCH3), 5.44-5.38 (m, 1 H, CHdCH), 5.37-5.32
(m, 1 H, CHdCH), 4.55 (dd, J ) 6.7, 3.7 Hz, 1 H, (CH3)2CCHOSi),
4.11 (dd, J ) 6.7, 6.2 Hz, 1 H, CH2CHOSi), 3.83 (d, J ) 8.4, 1 H,
CH(CH3)CHOSi), 3.09 (dq, J ) 7.0, 6.9 Hz, 1 H, C(O)CH(CH3)), 2.73
(s, 3 H, NdC(CH3)S), 2.40 (dd, J ) 16.3, 3.8 Hz, 1 H, CH2COOH),
2.35-2.22 (m, 3 H, CH2COOH, CH2CHdCH), 1.98-1.94 (m, 2 H,
CHdCHCH2), 1.92 (s, 3 H, CHdC(CH3)), 1.34-1.21 (m, 5 H,
CH(CH3), 2 x CH2), 1.18 (s, 3 H, C(CH3)2), 1.07 (s, 3 H, C(CH3)2),
1.05 (d, J ) 7.0 Hz, 3 H, CH(CH3)), 0.89 (s, 9 H, SiC(CH3)3), 0.88 (s,
9 H, SiC(CH3)3), 0.85 (s, 9 H, SiC(CH3)3), 0.82 (d, J ) 6.9 Hz, 3 H,
CH(CH3)), 0.07 (s, 6 H, 2 x Si(CH3)2), 0.06 (s, 3 H, Si(CH3)2), 0.05 (s,
3 H, Si(CH3)2), 0.04 (s, 3 H, Si(CH3)2), 0.01 (s, 3 H, Si(CH3)2); 13C
NMR (150.9 MHz, CDCl3) δ 217.7, 175.3, 165.4, 152.4, 143.1, 131.3,
125.9, 118.3, 114.6, 78.6, 76.7, 72.3, 53.8, 45.7, 40.1, 37.9, 34.9, 34.6,
27.7, 27.3, 26.3, 26.2, 26.0, 25.8, 22.4, 19.0, 18.6, 18.2, 18.1, 16.8,
13.9, 13.5, -3.4, -3.6, -4.3, -4.6, -4.7, -4.9; FAB HRMS (NBA/
CsI) m/e 970.4331, M + Cs+ calcd for C44H83NO6SSi3 970.4303.
0.55 (silica gel, 40% ether in hexanes); [R]22 +13.3 (c 0.7, CHCl3);
D
IR (thin film) νmax 2930, 2856, 1725, 1504, 1462, 1385, 1253, 1182,
1
1076, 938, 836, 776 cm-1; H NMR (600 MHz, CDCl3) δ 9.57, (d, J
) 1.8 Hz, 1 H, CHO), 6.91 (s, 1 H, SCHdC), 6.44 (s, 1 H, CHdCCH3),
5.45-5.35 (m, 2 H, CHdCH), 4.11 (dd, J ) 6.6, 6.3 Hz, 1 H, CHOSi),
2.69 (s, 3 H, NdC(S)CH3), 2.34-2.24 (m, 3 H), 2.05-2.01 (m, 2 H),
1.98 (s, 3 H, CHdCCH3), 1.71-1.64 (m, 1 H), 1.41-1.29 (m, 3 H),
1.05 (d, J ) 7.0 Hz, 3 H, CH3CH), 0.87 (s, 9 H, SiC(CH3)3), 0.04 (s,
3 H, Si(CH3)2), -0.01 (s, 3 H, Si(CH3)2); 13C NMR (150.9 MHz,
CDCl3) δ 205.2, 164.4, 153.0, 142.0, 130.6, 126.4, 118.8, 115.0, 78.7,
46.2, 34.7, 30.0, 27.3, 26.9, 25.8, 19.2, 18.2, 13.9, 13.2, -4.7, -5.0;
FAB HRMS (NBA) m/e 422.2559, M + H+ calcd for C23H39NO2SSi
422.2549.
Aldol Reaction of Keto Acid 9 with Aldehyde 7. A solution of
keto acid 9 (1.52 g, 5.10 mmol, 1.2 equiv) in THF (10 mL) was added
dropwise to a freshly prepared solution of LDA [diisopropylamine (1.78
mL, 12.78 mmol) was added to n-BuLi (7.95 mL, 1.6 M solution in
hexanes, 12.78 mmol) in 20 mL of THF at 0 °C] at -78 °C. After
being stirred for 15 min, the solution was allowed to warm to -40 °C,
Hydroxy Acid 5. Selective Desilylation of Tris(silyl ether) 38.
A solution of tris(silyl ether) 38 (300 mg, 0.36 mmol) in THF (7.0
mL) at 25 °C was treated with TBAF (2.2 mL, 1 M solution in THF,
2.2 mmol, 6.0 equiv). After being stirred for 8 h, the reaction mixture
was diluted with EtOAc (10 mL) and washed with aqueous HCl (10
mL, 1 N solution). The aqueous solution was extracted with EtOAc
(4 × 10 mL), and the combined organic phase was washed with brine
(10 mL), dried (MgSO4), and concentrated. The crude mixture was
purified by flash column chromatography (silica gel, 5% MeOH in CH2-
Cl2) to provide hydroxy acid 5 (203 mg, 78%) as a yellow oil: Rf )
and after 0.5 h at that temperature, it was recooled to -78 °C.
A
solution of aldehyde 7 (1.79 g, 4.24 mmol, 1.0 equiv) was added
dropwise, and the resulting mixture was stirred for 15 min and then
quenched at -78 °C by slow addition of saturated aqueous NH4Cl
solution (20 mL). The reaction mixture was warmed to 0 °C, and
AcOH (2.03 mL, 26.84 mmol, 6.3 equiv) was added, followed by
addition of EtOAc (50 mL). The organic layer was separated, and the
aqueous phase was extracted with EtOAc (3 × 25 mL). The combined
organic solution was dried over MgSO4 and concentrated under vacuum
to afford a mixture of aldol products 36a:36b in a ca. 1:1 ratio (1H
NMR) and unreacted keto acid 9. The mixture was dissolved in CH2-
Cl2 (50 mL) and treated, at 0 °C, with 2,6-lutidine (3.2 mL, 27.36 mmol)
and tert-butyldimethylsilyl trifluoromethanesulfonate (4.2 mL, 18.24
mmol). After stirring for 2 h (complete reaction by TLC), aqueous
HCl (20 mL, 10% solution) was added and the resulting biphasic
mixture was separated. The aqueous phase was extracted with CH2-
Cl2 (3 × 20 mL), and the combined organic solution was washed with
brine (50 mL), dried (MgSO4), and concentrated under reduced pressure
to give a mixture of the tetra-tert-butyldimethylsilyl ethers 37a,b. The
crude product was dissolved in MeOH (50 mL), and K2CO3 (1.40 g,
10.20 mmol) was added at 25 °C. The reaction mixture was vigorously
stirred for 15 min and then filtered. The residue was washed with
MeOH (20 mL), and the solution was acidified with ion-exchange resin
(DOWEX 50WX8-200) to pH 4-5 and filtered again. The solvent
was removed under reduced pressure, and the resulting residue was
dissolved in EtOAc (50 mL) and washed with saturated aqueous NH4-
Cl solution (50 mL). The aqueous phase was extracted with EtOAc
(4 × 25 mL), and the combined organic solution was dried (MgSO4),
filtered, and concentrated to furnish a mixture of carboxylic acids 38,
39, and 9. Purification by preparative thin-layer chromatography (silica
gel, 5% MeOH in CH2Cl2) gave pure acids 38 (1.1 g, 31% from 7)
and 39 (1.0 g, 30% from 7) as colorless oils. 38: Rf ) 0.61 (silica
gel, 5% MeOH in CH2Cl2); [R]22D -8.8 (c 0.8, CHCl3); IR (thin film)
0.40 (silica gel, 5% MeOH in CH2Cl2); [R]22 -19.2 (c 0.1, CHCl3);
D
IR (thin film) νmax 3358, 2932, 2857, 1701, 1466, 1254, 1088, 988,
835 cm-1; 1H NMR (600 MHz, CDCl3) δ 6.95 (s, 1 H SCHdC), 6.67
(s, 1 H, CHdCCH3), 5.58-5.54 (m, 1 H, CHdCH), 5.43-5.39 (m, 1
H, CHdCH), 4.39 (dd, J ) 6.7, 3.9 Hz, 1 H, (CH3)2CCHOSi), 4.18
(dd, J ) 7.5, 5.0 Hz, 1 H, CH2CHOH), 3.78 (dd, J ) 6.9, 1.0 Hz, 1 H,
CH(CH3)CHOSi), 3.11 (dq, J ) 6.9, 6.7 Hz, 1 H, C(O)CHCH3), 2.70
(s, 3 H, NdC(CH3)S), 2.43 (dd, J ) 16.2, 3.9 Hz, 1 H, CH2COOH),
2.40-2.35 (m, 2 H, CH2CHdCH), 2.35 (dd, J ) 16.2, 6.7 Hz, 1 H,
CH2COOH), 2.15-2.10 (m, 1 H, CHdCHCH2), 2.00 (s, 3 H, CHdC-
(CH3)), 1.99-1.95 (m, 1 H, CHdCHCH2), 1.48-1.30 (m, 5 H,
CH(CH3), 2 x CH2), 1.18 (s, 3 H, C(CH3)2), 1.08 (s, 3 H, C(CH3)2),
1.05 (d, J ) 6.7 Hz, 3 H, CH(CH3)), 0.89-0.84 (m, 21 H, CH(CH3),
SiC(CH3)3), 0.09 (s, 3 H, Si(CH3)2), 0.05 (s, 3 H, Si(CH3)2), 0.04 (s, 3
H, Si(CH3)2), 0.03 (s, 3 H, Si(CH3)2); 13C NMR (150.9 MHz, CDCl3)
δ 218.9, 175.4, 166.3, 152.8, 143.5, 134.4, 125.7, 119.5, 115.9, 74.4,
54.7, 45.5, 40.9, 40.0, 34.3, 31.9, 30.6, 28.9, 28.8, 27.0, 26.8, 26.7,
24.4, 20.0, 19.6, 19.3, 19.1, 17.9, 17.1, 15.5, -2.9, -3.1, -3.3, -3.8;
FAB HRMS (NBA/CsI) m/e 856.3459, M + Cs+ calcd for C38H69-
NO6SSi2 856.3439.
Hydroxy Acid 40. Selective Desilylation of Tris(silyl ether) 39.
Carboxylic acid 39 (150 mg, 0.18 mmol) was converted to hydroxy
acid 40 (107 mg, 82%) according to the procedure described above
for 5. 40: yellow oil; Rf ) 0.45 (silica gel, 5% MeOH in CH2Cl2);
[R]22D -8.0 (c 0.2, CHCl3); IR (thin film) νmax 3225, 2943, 2860, 1719,

Total Synthesis of Epothilones A and B
J. Am. Chem. Soc., Vol. 119, No. 34, 1997 7985
1690, 1461, 1384, 1296, 1250, 1190, 1085, 985, 832, 761, 667 cm-1
;
25.8, 19.7, 19.2, 19.0, 18.8, 17.7, 15.9, 14.1, -3.0, -3.3, -3.7, -4.3;
FAB HRMS (NBA) m/e 706.4333, M + H+ calcd for C38H67NO5SSi2
706.4357.
1H NMR (600 MHz, CDCl3) δ 6.93 (s, 1 H SCHdC), 6.60 (s, 1 H,
CHdCCH3), 5.54-5.50 (m, 1 H, CHdCH), 5.40-5.34 (m, 1 H,
CHdCH), 4.54 (dd, J ) 6.4, 3.7 Hz, 1 H, (CH3)2CCHOSi), 4.15 (dd,
J ) 6.5, 6.3 Hz, 1 H, CH2CHOH), 3.82 (d, J ) 7.6 Hz, 1 H, CH-
(CH3)CHOSi), 3.09 (dq, J ) 6.9, 6.5 Hz, 1 H, C(O)CHCH3), 2.71 (s,
3 H, NdC(CH3)S), 2.37-2.32 (m, 3 H, CH2CHdCH, CH2COOH),
2.30 (dd, J ) 16.3, 6.4 Hz, 1 H, CH2COOH), 2.15-2.10 (m, 2 H,
CHdCHCH2), 1.97 (s, 3 H, CHdC(CH3)), 1.36-1.18 (m, 5 H,
CH(CH3), 2 x CH2), 1.17 (s, 3 H, C(CH3)2), 1.07 (s, 3 H, C(CH3)2),
1.05 (d, J ) 6.8 Hz, 3 H, CH(CH3)), 0.88 (s, 9 H, SiC(CH3)3), 0.85-
0.82 (m, 12 H, CH(CH3), SiC(CH3)3), 0.07 (s, 3 H, Si(CH3)2), 0.06 (s,
3 H, Si(CH3)2), 0.05 (s, 6 H, Si(CH3)2); 13C NMR (150.9 MHz, CDCl3)
δ 218.2, 175.4, 165.4, 152.2, 142.0, 133.1, 124.9, 118.6, 115.1, 74.4,
53.8, 45.8, 40.2, 38.9, 37.7, 34.8, 33.2, 27.9, 27.5, 27.1, 26.2, 26.1,
26.0, 22.6, 21.4, 18.8, 18.6, 16.9, 14.5, 13.3, -3.4, -3.6, -4.3, -4.6;
FAB HRMS (NBA/CsI) m/e 856.3402, M + Cs+ calcd for C38H69-
NO6SSi2 856.3439.
Dihydroxy Lactone 3. To lactone 41 (50 mg, 0.071 mmol), cooled
to -20 °C, was added a freshly prepared 20% (v/v) CF3COOH solution
in CH2Cl2 (400 µL). The reaction mixture was allowed to reach 0 °C
and was stirred for 1 h at that temperature. The solvents were
evaporated under reduced pressure, and the crude product was purified
by preparative thin-layer chromatography (silica gel, 6% MeOH in CH2-
Cl2) to afford pure dihydroxy lactone 3 (31 mg, 92%): Rf ) 0.38 (silica
gel, 5% MeOH in CH2Cl2); [R]22D -80.2 (c 1.7, CHCl3); IR (thin film)
νmax 3470, 2929, 1733, 1686, 1464, 1380, 1250, 1182, 1045, 978, 732
cm-1; 1H NMR (500 MHz, C6D6) δ 6.83 (s, 1 H, SCHdC), 6.56 (s, 1
H, CHdCCH3), 5.48 (dd, J ) 7.0, 3.0 Hz, 1 H, OdCOCH), 5.43-
5.41 (m, 2 H, CHdCH), 4.21 (d, J ) 11.5 Hz, 1 H, CHOH), 3.77 (bs,
1 H, CHOH), 3.13 (bs, 1 H, OH), 3.01 (bs, 1 H, OH), 2.95 (m, 1 H,
C(O)CHCH3), 2.70-2.62 (m, 1 H, CH2COO), 2.47 (ddd, J ) 14.6,
11.5 Hz, 1 H, CH2COO), 2.27 (s, 3 H, NdC(CH3)S), 2.18-2.12 (m,
2 H, CHdCHCH2), 2.15 (s, 3 H, CHdC(CH3)), 1.97-1.83 (m, 2H,
CH2CHdCH), 1.56-1.50 (m, 1 H, CH(CH3)), 1.41-1.22 (m, 4 H, 2
x CH2), 1.15 (d, J ) 7.0 Hz, 3 H, CH(CH3)), 1.07 (d, J ) 6.0 Hz, 3 H,
CH(CH3)), 1.07 (s, 3 H, C(CH3)2), 1.06 (s, 3 H, C(CH3)2); 13C NMR
(150.9 MHz, C6D6) δ 220.2, 170.6, 165.4, 153.8, 139.2, 134.1, 126.1,
120.4, 116.9, 79.2, 74.9, 73.2, 54.2, 42.5, 40.3, 39.5, 32.9, 32.6, 28.6,
28.4, 23.3, 19.3, 19.1, 16.4, 16.3, 14.4; FAB HRMS (NBA/CsI) m/e
610.1580, M + Cs+ calcd for C26H39NO5S 610.1603.
Lactone 41. Macrolactonization of Hydroxy Acid 5. A solution
of hydroxy acid 5 (200 mg, 0.28 mmol) in THF (4 mL) was treated at
0 °C with Et3N (0.23 mL, 1.68 mmol, 6.0 equiv) and 2,4,6-
trichlorobenzoyl chloride (0.22 mL, 1.40 mmol, 5.0 equiv). The
reaction mixture was stirred at 0 °C for 15 min and then added to a
solution of 4-DMAP (342 mg, 2.80 mmol, 10.0 equiv) in toluene (140
mL) at 25 °C and stirred at that temperature for 0.5 h. The reaction
mixture was concentrated under reduced pressure to a small volume
and filtered through silica gel. The residue was washed with 40% ether
in hexanes, and the resulting solution was concentrated. Purification
by flash column chromatography (silica gel, 2% MeOH in CH2Cl2)
furnished lactone 41 (178 mg, 90%) as a colorless oil: Rf ) 0.37 (silica
gel, 30% ether in hexanes); [R]22D -22.9 (c 0.3, CHCl3); IR (thin film)
νmax 2925, 2854, 1734, 1693, 1464, 1381, 1252, 1187, 1158, 1099,
Dihydroxy Lactone 43. Lactone 42 (38.0 mg, 0.054 mmol) was
treated with CF3COOH in exactly the same way as described above
for 3, yielding dihydroxy lactone 43 (24.5 mg, 95%): Rf ) 0.30 (silica
gel, 6% MeOH in CH2Cl2); [R]22D -93.1 (c 0.1, CHCl3); IR (thin film)
ν
max 3450, 2929, 1735, 1685, 1464, 1380, 1250, 1182, 1045, 978, 732
1
cm-1; H NMR (600 MHz, CDCl3) δ 6.96 (s, 1 H, SCHdC), 6.51 (s,
1 H, CHdCCH3), 5.60-5.50 (m, 2 H, CHdCH), 5.40-5.32 (m, 1 H,
OdCOCH), 4.25 (d, J ) 9.5 Hz, 1 H, CHOH), 3.55 (d, J ) 9.6 Hz, 1
H, CHOH), 3.39 (bs, 1 H, OH), 3.31 (dq, J ) 6.9, 6.7 Hz, 1 H, C(O)-
CHCH3), 2.99 (bs, 1 H, OH), 2.71 (s, 3 H, NdC(CH3)S), 2.69-2.61
(m, 1 H, CHdCHCH2), 2.59 (d, J ) 16.3 Hz, 1 H, CH2COO), 2.45-
2.35 (m, 2 H, CH2COO, CHdCHCH2), 2.20-2.10 (m, 1 H, CH2-
CHdCH), 2.08 (s, 3 H, CHdC(CH3)), 1.98-1.90 (m, 1 H, CH2-
CHdCH), 1.59-1.50 (m, 1 H, CH(CH3)), 1.49-1.30 (m, 4 H, 2 x
CH2), 1.17 (s, 3 H, C(CH3)2), 1.11 (d, J ) 6.9 Hz, 3 H, CH(CH3)),
1.03 (s, 3 H, C(CH3)2), 1.01 (d, J ) 7.0 Hz, 3 H, CH(CH3)); 13C NMR
(150.9 MHz, CDCl3) δ 222.2, 171.1, 165.2, 153.5, 139.5, 133.2, 125.1,
120.0, 116.7, 78.4, 74.1, 72.9, 52.5, 40.7, 39.5, 37.9, 34.5, 32.7, 31.3,
27.6, 24.7, 22.2, 18.9, 17.5, 15.5, 15.3; FAB HRMS (NBA) m/e
478.2610, M + H+ calcd for C26H39NO5S 478.2627.
988, 829, 758 cm-1 1H NMR (600 MHz, CDCl3) δ 6.98 (s, 1 H,
;
SCHdC), 6.58 (s, 1 H, CHdCCH3), 5.53 (m, 1 H, CHdCH), 5.43-
5.34 (m, 1 H, CHdCH), 5.00 (d, J ) 10.2 Hz, 1 H, OdCOCH), 4.03
(d, J ) 10.5 Hz, 1 H, CHOSi), 3.89 (d, J ) 9.0 Hz, 1 H, CHOSi), 2.98
(dq, J ) 6.9, 6.7 Hz, 1 H, C(O)CHCH3), 2.85 (d, J ) 16.7 Hz, 1 H,
CH2COO), 2.72 (s, 3 H, NdC(CH3)S), 2.66 (dd, J ) 16.7, 10.7 Hz, 1
H, CH2COO), 2.40-2.30 (m, 1 H, CHdCHCH2), 2.11 (s, 3 H, CHdC-
(CH3)), 2.10-2.04 (m, 2 H, CH2CHdCH), 1.92-1.83 (m, 1 H,
CHdCHCH2), 1.66-1.38 (m, 5 H, CH(CH3), 2 x CH2), 1.17 (s, 3 H,
C(CH3)2), 1.13 (s, 3 H, C(CH3)2), 1.06 (d, J ) 7.0 Hz, 3 H, CH(CH3)),
0.94 (d, J ) 7.0 Hz, 3 H, CH(CH3)), 0.92 (s, 9 H, SiC(CH3)3), 0.83 (s,
9 H, SiC(CH3)3), 0.09 (s, 3 H, Si(CH3)2), 0.07 (s, 3 H, Si(CH3)2), 0.05
(s, 3 H, Si(CH3)2), -0.12 (s, 3 H, Si(CH3)2); 13C NMR (150.9 MHz,
CDCl3) δ 215.0, 171.3, 165.4, 135.7, 135.1, 125.8, 122.7, 119.9, 115.9,
79.5, 76.4, 53.3, 48.0, 38.8, 31.7, 31.3, 29.7, 29.2, 28.4, 26.4, 26.2,
26.1, 25.9, 24.2, 19.1, 18.7, 18.6, 17.7, 15.3, -3.1, -3.2, -3.7, -5.8;
FAB HRMS (NBA) m/e 706.4382, M + H+ calcd for C38H67NO5SSi2
706.4357.
Epothilone A (1). Epoxidation of Lactone 3 with Methyl-
(trifluoromethyl)dioxirane. To a solution of 3 (10 mg, 21.0 µmol)
in MeCN (200 µL) was added 4 × 10-4 M aqueous solution of disodium
ethylenediaminetetraacetate (Na2EDTA, 120 µL), and the reaction
mixture was cooled to 0 °C. 1,1,1-Trifluoroacetone (200 µL) was added
followed by a mixture of Oxone (61 mg, 0.10 mmol, 5.0 equiv) and
NaHCO3 (14.0 mg, 0.17 mmol, 8.0 equiv) with stirring until completion
of the reaction was revealed by TLC. The reaction mixture was treated
with excess Me2S (100 µL) and water (500 µL) and was then extracted
with EtOAc (4 × 2 mL). The combined organic phase was dried
(MgSO4), filtered, and concentrated. Purification by preparative thin-
layer chromatography (silica gel, 5% MeOH in CH2Cl2) gave a mixture
of epothilones A (1) and its R-epoxide epimer (8.6 mg, 78% total yield).
A second preparative thin-layer chromatography (silica gel, 70% EtOAc
in hexanes) furnished pure epothilone A (1) (6.4 mg, 65%) as a white
solid. For a more extensive study of the epoxidation of 3 and isolation
of a number of epothilone A analogues, see ref 29. 1: Rf ) 0.23 (silica
Lactone 42. Macrolactonization of Hydroxy Acid 40. The
cyclization of hydroxy acid 40 (100 mg, 0.14 mmol) was carried out
exactly as described for 41 above and yielded lactone 42 (84 mg, 85%)
as a colorless oil: Rf ) 0.40 (silica gel, 30% ether in hexanes); [R]22
D
-40.5 (c 0.2, CHCl3); IR (thin film) νmax 2929, 2855, 1739, 1690, 1469,
1
1384, 1253, 1180, 1089, 1053, 985, 835, 775 cm-1; H NMR (600
MHz, CDCl3) δ 6.94 (s, 1 H, SCHdC), 6.53 (s, 1 H, CHdCCH3),
5.55-5.46 (m, 1 H, CHdCH), 5.39-5.30 (m, 1 H, CHdCH), 5.32
(dd, J ) 7.0, 3.0 Hz, 1 H, OdCOCH), 4.43 (dd, J ) 7.5, 2.9 Hz, 1 H,
CHOSi), 3.99 (d, J ) 7.1 Hz, 1 H, CHOSi), 3.20 (dq, J ) 7.3, 7.1 Hz,
1 H, C(O)CHCH3), 2.71 (s, 3 H, NdC(CH3)S), 2.59 (m, 1 H,
CHdCHCH2), 2.21 (dd, J ) 14.6, 3.2 Hz, 1 H, CH2COO), 2.20 (dd,
J ) 14.6, 7.6 Hz, 1 H, CH2COO), 2.16 (s, 3 H, CHdC(CH3)), 2.15-
1.95 (m, 3 H, CHdCHCH2, CH2CHdCH), 1.60-1.50 (m, 3 H,
CH(CH3), 2 x CH2), 1.47-1.35 (m, 2 H, CH(CH3), 2 x CH2), 1.24 (s,
3 H, C(CH3)2), 1.11 (d, J ) 7.2 Hz, 3 H, CH(CH3)), 1.09 (s, 3 H,
C(CH3)2), 0.90 (s, 9 H, SiC(CH3)3), 0.86 (s, 9 H, SiC(CH3)3), 0.83 (d,
J ) 6.7 Hz, 3 H, CH(CH3)), 0.09 (s, 6 H, 2 x Si(CH3)2), 0.01 (s, 3 H,
Si(CH3)2), -0.05 (s, 3 H, Si(CH3)2); 13C NMR (150.9 MHz, CDCl3) δ
221.2, 171.6, 165.8, 134.9, 134.1, 125.7, 125.2, 120.7, 117.1, 78.8,
75.2, 74.5, 54.3, 48.1, 42.5, 37.9, 33.7, 32.4, 26.8, 26.7, 26.5, 26.2,
gel, 5% MeOH in CH2Cl2); [R]22 -45.0 (c 0.02, MeOH); IR (thin
D
film) νmax 3476, 2974, 1738, 1692 cm-1; 1H NMR (600 MHz, C6D6) δ
6.71 (s, 1 H, CHdCCH3), 6.45 (s, 1 H, SCHdC), 5.45 (dd, J ) 8.2,
2.3 Hz, 1 H, OdCOCH), 4.15 (dd, J ) 10.8, 2.9 Hz, 1 H, CHOH),
3.81-3.78 (m, 1 H, CHOH), 3.65 (bs, 1 H, OH), 3.03 (dq, J ) 6.9,
6.5 Hz, 1 H, C(O)CHCH3), 2.77 (ddd, J ) 7.9, 4.0, 4.0 Hz, 1 H,
CH2CHO), 2.62-2.58 (m, 1 H, CH2CHO), 2.40 (dd, J ) 14.4, 10.8
Hz, 1 H, CH2COO), 2.26 (bs, 1 H, OH), 2.21 (s, 3 H, NdC(CH3)S),
2.19 (dd, J ) 14.4, 2.9 Hz, 1 H, CH2COO), 2.05 (s, 3 H, CHdC-
(CH3)), 1.86 (ddd, J ) 15.2, 2.5, 2.5 Hz, 1 H, CH2CHO), 1.81-1.74

7986 J. Am. Chem. Soc., Vol. 119, No. 34, 1997
Nicolaou et al.
(m, 1 H, CH2CHO), 1.68 (ddd, J ) 15.2, 7.6, 7.6 Hz, 1 H, CH2CHO),
1.53-1.49 (m, 1 H, CH2CHO), 1.40-1.15 (m, 5 H, CH(CH3), 2 x CH2),
1.06 (d, J ) 7.0 Hz, 3 H, CH(CH3)), 1.03 (s, 3 H, C(CH3)2), 0.97 (s,
3 H, C(CH3)2), 0.95 (d, J ) 6.9 Hz, 3 H, CH(CH3)); 13C NMR (150.9
MHz, C6D6) δ 219.0, 170.2, 164.7, 153.0, 137.5, 119.9, 116.6, 76.6,
75.2, 73.5, 57.2, 54.2, 52.9, 43.8, 39.1, 36.3, 31.7, 30.3, 27.3, 23.9,
21.1, 20.6, 18.7, 17.4, 15.7, 14.6; HRMS (FAB), calcd for C26H39-
CsNO6S (M + Cs+) 626.1552, found 626.1531.
Tris(silyl ethers) 52′ and 53′. Aldol Reaction of Keto Acid 9
with Aldehyde 8′. A solution of keto acid 9 (773 mg, 2.56 mmol, 1.2
equiv) in THF (7.0 mL) was reacted with aldehyde 8′ (930 mg, mixture
of Z:E olefins, ca. 1:1, 2.13 mmol, 1.0 equiv) according to the same
procedure as described above for the condensation of 9 and 7, to afford,
after similar processing, pure carboxylic acids 52′ (564 mg, mixture
of Z and E isomers, ca. 1:1, 31% from 8′) and 53′ (545 mg, mixture of
Z and E isomers, ca. 1:1, 30% from 8′) as colorless oils and recovered
keto acid 9 (125 mg).
6S,7R-Epothilones 44 and 45. Epoxidation of Lactone 43. To a
solution of lactone 43 (9.0 mg, 18.8 µmol) in MeCN (0.5 mL) were
Hydroxy Acid 6′. Selective Desilylation of 52′. Carboxylic acid
52′ (300 mg, mixture of Z and E isomers, ca. 1:1, 0.35 mmol) was
converted to hydroxy acid 6′ (194 mg, mixture of Z and E isomers, ca.
1:1, 75%) according to the same procedure described above for hydroxy
acid 5.
added disodium ethylenediaminetetraacetate (Na2EDTA, 4 × 10-4
M
aqueous solution, 200 µL) and 1,1,1-trifluoroacetone (200 µL) at 0 °C.
The resulting solution was stirred at 0 °C, while a mixture of solid
Oxone (58 mg, 94.0 mmol, 5.0 equiv) and NaHCO3 (14.0 mg, 0.17
mmol, 8.8 equiv) was added portionwise until completion of the reaction
was established by TLC). The reaction mixture was treated with excess
Me2S (100 µL) and water (500 µL) and was extracted with EtOAc (4
× 2 mL). The combined organic phase was dried (MgSO4), filtered,
and concentrated. Purification by preparative thin-layer chromatography
(silica gel, 5% MeOH in CH2Cl2) gave a mixture of epothilones 44
and 45 (8.1 mg, 87% total yield, ca. 2:1 ratio by 1H NMR). The major
diastereoisomer (44, stereochemistry unassigned) was isolated by
preparative thin-layer chromatography (silica gel, 70% EtOAc in
hexanes) (5.4 mg, 58%) and exhibited the following properties: Rf )
Lactones 54 and 55. Macrolactonization of Hydroxy Acid 6′.
A solution of hydroxy acid 6′ (140 mg, mixture of Z and E isomers,
ca. 1:1, 0.189 mmol) in THF (2.6 mL) was treated at 0 °C with Et3N
(58 µL, 0.416 mmol, 2.2 equiv) and 2,4,6-trichlorobenzoyl chloride
(29.4 µL, 0.246 mmol, 1.3 equiv). The reaction mixture was stirred at
0 °C for 1 h and then added to a solution of 4-DMAP (233 mg, 1.896
mmol, 10.0 equiv) in toluene (90 mL, 0.002 M) at 25 °C and stirred at
that temperature for 10 h. The solvents were removed in vacuo, and
the crude product obtained was suspended in 40% ether in hexanes
and filtered through silica gel. Concentration followed by preparative
thin-layer chromatography (silica gel, 5% MeOH in CH2Cl2) gave pure
lactones 54 (50 mg, 37%) and 55 (54 mg, 40%) as colorless oils. 54:
0.23 (silica gel, 6% MeOH in CH2Cl2); [R]22 -20.0 (c 0.2, CHCl3);
D
IR (thin film) νmax 3448, 2919, 1725, 1684, 1455, 1378, 1284, 1149,
1
1061, 1020, 973, 750 cm-1; H NMR (500 MHz, CHCl3) δ 6.99 (s, 1
Rf ) 0.40 (silica gel, 1% MeOH in CH2Cl2); [R]22 -11.8 (c 0.8,
D
H, SCHdC), 6.68 (s, 1 H, CHdCCH3), 5.64-5.61 (m, 1 H, OdCOCH),
4.43 (d, J ) 2.1 Hz, 1 H, OH), 4.29 (ddd, J ) 7.6, 2.5, 2.5 Hz, 1 H,
CHOH), 3.82 (d, J ) 8.2 Hz, 1 H, CHOH), 3.35 (bs, 1 H, OH), 3.22
(q, J ) 7.0 Hz, 1 H, C(O)CHCH3), 3.14 (ddd, J ) 10.3, 4.1, 3.2 Hz,
1 H, CH2CHO), 2.90 (ddd, J ) 10.3, 4.3, 2.3 Hz, 1 H, CH2CHO), 2.71
(s, 3 H, NdC(CH3)S), 2.54 (dd, J ) 13.7, 7.6 Hz, 1 H, CH2COO),
2.51 (dd, J ) 13.7, 2.5 Hz, 1 H, CH2COO), 2.21-2.19 (m, 1 H, CH2-
CHO), 2.18 (s, 3 H, CHdC(CH3)), 1.94 (ddd, J ) 15.3, 10.3, 3.7 Hz,
1 H, CH2CHO), 1.77-1.69 (m, 2 H, CH2CHO), 1.60-1.00 (m, 5 H,
CH(CH3), 2 x CH2), 1.15 (s, 3 H, C(CH3)2), 1.14 (d, J ) 6.9 Hz, 3 H,
CH(CH3)), 1.06 (s, 3 H, C(CH3)2), 1.02 (d, J ) 7.0 Hz, 3 H, CH-
(CH3)); 13C NMR (150.9 MHz, CHCl3) δ 221.8, 172.1, 165.1, 152.6,
134.7, 119.8, 116.8, 76.0, 74.4, 72.8, 56.4, 53.8, 53.0, 40.2, 39.1, 34.1,
32.7, 29.4, 27.8, 22.7, 20.9, 19.0, 16.1, 15.9, 15.0, 11.8; FAB HRMS
(NBA) m/e 494.2587, M + H+ calcd for C26H39NO6S 494.2576.
CHCl3); IR (thin film) νmax 2931, 2848, 1737, 1690, 1461, 1378, 1249,
1
1184, 1158, 1097, 1020, 984, 835, 775 cm-1; H NMR (600 MHz,
CDCl3) δ 6.95 (s, 1 H, SCHdC), 6.56 (s, 1 H, CHdCCH3), 5.16 (dd,
J ) 8.4, 7.5 Hz, 1 H, CH3CdCHCH2), 4.96 (d, J ) 10.1 Hz, 1 H,
CH2COOCH), 4.02 (d, J ) 9.9 Hz, 1 H, CHOSi), 3.88 (d, J ) 8.9 Hz,
1 H, CHOSi), 3.02 (dq, J ) 6.9, 6.7 Hz, 1 H, C(O)CHCH3), 2.79 (d,
J ) 15.6 Hz, 1 H, CH2COOCH), 2.70 (s, 3 H, NdC(CH3)S), 2.70-
2.65 (m, 2 H), 2.48-2.40 (m, 1 H), 2.10 (s, 3 H, CHdC(CH3)), 2.10-
2.04 (m, 2 H), 1.75-1.69 (m, 2 H), 1.67 (s, 3 H, CH2C(CH3)dCH),
1.66-1.45 (m, 3 H), 1.18 (s, 3 H, C(CH3)2), 1.13 (s, 3 H, C(CH3)2),
1.09 (d, J ) 6.8 Hz, 3 H, CH(CH3)), 0.97 (d, J ) 6.8 Hz, 3 H, CH-
(CH3)), 0.94 (s, 9 H, SiC(CH3)3), 0.84 (s, 9 H, SiC(CH3)3), 0.10 (s, 3
H, Si(CH3)2), 0.09 (s, 3 H, Si(CH3)2), 0.07 (s, 3 H, Si(CH3)2), -0.12
(s, 3 H, Si(CH3)2); 13C NMR (150.9 MHz, CDCl3) δ 215.1, 171.2, 164.6,
152.5, 140.6, 138.8, 119.3, 119.1, 115.9, 79.9, 76.3, 53.4, 39.1, 32.4,
31.9, 31.4, 29.7, 27.4, 26.4, 26.1, 26.0, 24.5, 24.3, 23.1, 19.2, 18.7,
18.6, 17.8, 15.3, -3.3, -3.7, -5.7; FAB HRMS (NBA) m/e 720.4534,
M + H+ calcd for C39H69NO5SSi2 720.4513. 55: Rf ) 0.50 (silica gel,
Olefinic Compound 48. Phosphonium salt 12 (9.0 g, 12.93 mmol,
1.5 equiv) was dissolved in THF (90 mL), and the solution was cooled
to 0 °C. Sodium bis(trimethylsilyl)amide (NaHMDS, 1.0 M solution
in THF, 12.84 mL, 12.84 mmol, 1.48 equiv) was slowly added, and
the resulting mixture was stirred at 0 °C for 15 min. The reaction
mixture was then cooled to -20 °C before ketone 11 (2.23 g, 8.62
mmol, 1.0 equiv) in THF (10 mL) was added, and the reaction mixture
was stirred at the same temperature for 12 h. Saturated aqueous NH4-
Cl solution (50 mL) was added, and the mixture was extracted with
ether (200 mL). The organic phase was washed with brine (2 × 100
mL), dried (MgSO4), and concentrated to afford, after flash column
chromatography (silica gel, 2% ether in hexanes), olefins 48 (3.8 g,
1% MeOH in CH2Cl2); [R]22 -22.7 (c 0.6, CHCl3); IR (thin film)
D
νmax 2931, 2860, 1731, 1696, 1461, 1378, 1249, 1179, 1079, 985, 832,
773 cm-1; 1H NMR (600 MHz, CDCl3) δ 6.92 (s, 1 H, SCHdC), 6.53
(s, 1 H, CHdCCH3), 5.27 (dd, J ) 8.0, 2.7 Hz, 1 H, CH2COOCH),
5.16 (dd, J ) 6.9, 6.6 Hz, 1 H, CH3CdCHCH2), 4.47 (t, J ) 5.1 Hz,
1 H, CHOSi), 3.89 (dd, J ) 4.5, 1.0 Hz, 1 H, CHOSi), 3.05 (dq, J )
6.7, 6.2 Hz, 1 H, C(O)CHCH3), 2.70 (s, 3 H, NdC(CH3)S), 2.60 (dd,
J ) 15.8, 5.8 Hz, 1 H, CH2COOCH), 2.55 (m, 1 H, CH3CdCHCH2),
2.51-2.47 (m, 2 H, CH2COOCH, CH3CdCHCH2), 2.13 (s, 3 H,
CHdC(CH3)), 2.10-2.05 (m, 1 H, CH2C(CH3)dCH), 1.91 (m, 1 H,
CH2C(CH3)dCH), 1.68-1.45 (m, 4 H), 1.57 (s, 3 H, CH2C(CH3)dCH),
1.27-1.23 (m, 1 H), 1.17 (s, 3 H, C(CH3)2), 1.04 (d, J ) 6.8 Hz, 3 H,
CH(CH3)), 1.07 (s, 3 H, C(CH3)2), 0.93 (d, J ) 6.9 Hz, 3 H, CH-
(CH3)), 0.88 (s, 9 H, SiC(CH3)3), 0.86 (s, 9 H, SiC(CH3)3), 0.07 (s, 6
H, Si(CH3)2), 0.06 (s, 3 H, Si(CH3)2), 0.05 (s, 3 H, Si(CH3)2); 13C NMR
(150.9 MHz, CDCl3) δ 217.2, 171.3, 165.5, 153.6, 139.0, 138.3, 120.9,
120.2, 117.0, 80.1, 77.2, 73.9, 54.8, 44.9, 42.7, 41.1, 40.2, 32.8, 26.9,
26.8, 25.6, 23.5, 21.1, 20.1, 19.2, 19.1, 17.7, 16.8, 16.6, 16.3, -2.7,
-3.1, -3.4, -3.6; FAB HRMS (NBA) m/e 720.4533, M + H+ calcd
for C39H69NO5SSi2 720.4513.
1
73%, Z:E ca. 1:1 by H NMR).
Hydroxy Olefins 49. Desilylation of Silyl Ether 48. Silyl ether
48 (3.80 g, 6.88 mmol) was dissolved in CH2Cl2:MeOH (1:1, 70 mL),
and the solution was cooled to 0 °C prior to addition of CSA (1.68 g,
7.23 mmol, 1.05 equiv) during a 5 min period. The resulting mixture
was stirred for 30 min at 0 °C and then for 1 h at 25 °C. Et3N (1.57
mL, 7.23 mmol, 1.05 equiv) was added, and the solvents were removed
under reduced pressure. Flash column chromatography (silica gel, 50%
ether in hexanes) furnished pure hydroxy compound 49 (2.9 g, 97%).
Aldehyde 8′. Oxidation of Alcohol 49. Alcohol 49 (mixtures of
Z and E geometrical isomers, 4.60 g, 10.64 mmol) was dissolved in
CH2Cl2 (105 mL, 0.1 M). DMSO (35 mL), Et3N (7.4 mL, 53.20 mmol,
5.0 equiv), and SO3‚pyr (3.4 g, 21.28 mmol, 2.0 equiv) were added at
25 °C, and the resulting mixture was stirred for 30 min. Saturated
aqueous NH4Cl solution (50 mL) and ether (300 mL) were added, and
the organic phase was separated and washed with brine (2 × 30 mL),
dried (MgSO4), and concentrated under reduced pressure. Flash column
chromatography (silica gel, 20% ether in hexanes) furnished aldehyde
8′ (4.40 g, mixture of Z:E isomers, ca. 1:1, 95%).
Dihydroxy Lactone 4. Dihydroxy lactone 4 was prepared from
bis(silyl ether) lactone 54 (13.3 mg, 0.018 mmol) by treatment with
CF3COOH according to the same procedure described above for the
preparation of 3, to obtain pure lactone 4 (8.4 mg, 91%) as a colorless
oil. 4: Rf ) 0.21 (silica gel, 4% MeOH in CH2Cl2); [R]22 -91.5 (c
D
0.3, CHCl3); IR (thin film) νmax 3460, 2954, 2919, 1725, 1684, 1455,
1
1379, 1290, 1249, 1184, 1143, 1043, 1008, 973, 750 cm-1; H NMR
(600 MHz, CDCl3) δ 6.94 (s, 1 H, SCHdC), 6.57 (s, 1 H, CHdCCH3),

Total Synthesis of Epothilones A and B
J. Am. Chem. Soc., Vol. 119, No. 34, 1997 7987
5.20 (d, J ) 9.7 Hz, 1 H, CH2COOCH), 5.13 (dd, J ) 9.6, 4.6 Hz, 1
H, CH3CdCHCH2), 4.28 (d, J ) 9.7 Hz, 1 H, (CH3)2CCHOH), 3.71
(s, 1 H, CHOH), 3.47 (bs, 1 H, OH), 3.15 (q, J ) 6.8 Hz, 1 H, C(O)-
CHCH3), 3.04 (bs, 1 H, OH), 2.68 (s, 3 H, NdC(CH3)S), 2.62 (ddd, J
) 15.0, 10.2, 10.1 Hz, 1 H, CH2CHdCCH3), 2.45 (dd, J ) 14.7, 11.1
Hz, 1 H, CH2COOCH), 2.38-2.24 (m, 1 H), 2.28 (dd, J ) 14.8, 2.2
Hz, CH2COOCH), 2.22 (d, J ) 14.9 Hz, 1 H, CH2C(CH3)dCHCH2),
2.06 (s, 3 H, CHdCCH3), 1.90-1.84 (m, 1 H), 1.76-1.69 (m, 1 H),
1.65 (s, 3 H, CH2C(CH3)dCH), 1.33 (s, 3 H, C(CH3)2), 1.32-1.22
(m, 4 H), 1.19 (d, J ) 6.8 Hz, 3 H, CH(CH3)), 1.06 (s, 3 H, C(CH3)2),
1.00 (d, J ) 7.0 Hz, 3 H, CH(CH3)); 13C NMR (150.9 MHz, CDCl3)
δ 220.4, 170.2, 164.9, 151.8, 139.1, 138.3, 120.8, 119.1, 115.5, 78.9,
74.1, 72.3, 53.6, 41.7, 39.7, 32.6, 31.8, 31.7, 25.4, 23.0, 19.1, 18.1,
16.0, 15.8, 13.5; FAB HRMS (NBA) m/e 492.2795, M + H+ calcd for
C27H41NO5S 492.2784.
CHCH3), 2.80 (dd, J ) 7.6, 4.7 Hz, 1 H, CHOCCH3), 2.70 (s, 3 H,
NdC(CH3)S), 2.64 (bs, 1 H, OH), 2.54 (dd, J ) 14.0, 10.2 Hz, 1 H,
CH2COOCH), 2.36 (d, J ) 14.0, 2.9 Hz, 1 H, CH2COOCH), 2.12 (dd,
J ) 4.7, 2.8 Hz, 1 H, (CH3)COCHCH2CHO), 2.08 (s, 3 H, CHdCCH3),
1.91 (ddd, J ) 15.4, 7.8, 7.6 Hz, 1 H, (CH3)COCHCH2CHO), 1.77-
1.68 (m, 3 H), 1.53-1.46 (m, 2 H), 1.43-1.37 (m, 2 H), 1.36 (s, 3 H,
C(CH3)OCHCH2), 1.27 (s, 3 H, C(CH3)2), 1.16 (d, J ) 6.9 Hz, 3 H,
CH(CH3)), 1.08 (s, 3 H, C(CH3)2), 1.00 (d, J ) 7.0 Hz, 3 H, CH-
(CH3)); 1H NMR (600 MHz, DMSO-d6) δ 7.34 (s, 1 H, SCHdC), 6.49
(s, 1 H, CHdCCH3), 5.27 (dd, J ) 9.0, 2.0 Hz, 1 H, CH2COOCH),
5.07 (d, J ) 6.9 Hz, 1 H, OH), 4.45 (bs, 1 H, OH), 4.08 (m, 1 H,
(CH3)2CCHOH), 3.47 (d, J ) 7.4 Hz, 1 H, CHOH), 3.10 (dq, J ) 6.8,
6.5 Hz, 1 H, C(O)CHCH3), 2.81 (dd, J ) 9.5, 3.3 Hz, 1 H, CHOCCH3),
2.64 (s, 3 H, NdC(CH3)S), 2.40-2.30 (m, 2 H, CH2COOCH), 2.08
(s, 3 H, CHdCCH3), 2.05 (ddd, J ) 15.0, 2.6, 1.0 Hz, 1 H,
(CH3)COCHCH2CHO), 1.83 (ddd, J ) 15.0, 9.3, 9.1 Hz, 1 H,
(CH3)COCHCH2CHO), 1.61 (m, 1 H), 1.45-1.35 (m, 3 H), 1.35-
1.25 (m, 3 H), 1.17 (s, 6 H, C(CH3)OCHCH2, C(CH3)2), 1.05 (d, J )
6.6 Hz, 3 H, CH(CH3)), 0.87 (d, J ) 7.0 Hz, 3 H, CH(CH3)), 0.86 (s,
3 H, C(CH3)2); 13C NMR (150.9 MHz, DMSO-d6) δ 218.1, 170.7, 164.8,
152.5, 137.6, 119.5, 118.0, 76.7, 75.7, 70.7, 61.6, 61.1, 53.3, 44.9, 35.6,
33.0, 32.1, 29.6, 23.0, 22.4, 22.0, 19.7, 18.8, 18.4, 16.4, 14.1; FAB
HRMS (NBA/CsI) m/e 640.1725, M + Cs+ calcd for C27H41NO6S
640.1709. A natural sample30 of epothilone B (2) exhibited properties
identical to those reported above.
Dihydroxy Lactone 56. Dihydroxy lactone 56 was prepared from
bis(silyl ether) lactone 55 (40.0 mg, 0.055 mmol) by treatment with
CF3COOH according to the same procedure described above for the
preparation of 3. Obtained pure 56 (24.3 mg, 89%): Rf ) 0.19 (silica
gel, 4% MeOH in CH2Cl2); [R]22D -61.0 (c 0.2, CHCl3); IR (thin film)
νmax 3418, 2932, 1731, 1691, 1466, 1381, 1252, 1159, 1067, 1044,
1
1012, 978, 755 cm-1; H NMR (600 MHz, CDCl3) δ 6.99 (s, 1 H,
SCHdC), 6.54 (s, 1 H, CHdCCH3), 5.38 (dd, J ) 6.7, 3.8 Hz, 1 H,
CH2COOCH), 5.08 (t, J ) 6.9 Hz, 1 H, CH3CdCHCH2), 4.32 (dd, J
) 10.0, 2.4 Hz, 1 H, (CH3)2CCHOH), 3.65 (t, J ) 3.4 Hz, 1 H, CHOH),
3.25 (dq, J ) 6.7, 3.9 Hz, 1 H, C(O)CHCH3), 2.68 (s, 3 H,
NdC(CH3)S), 2.55-2.43 (m, 3 H, CH2COOCH, C(CH3)dCHCH2),
2.40 (dd, J ) 15.3, 2.5 Hz, 1 H, CH2COOCH), 2.17-2.10 (m, 1 H,
CH2C(CH3)dCH), 2.05 (s, 3 H, CHdCCH3), 1.95 (ddd, J ) 13.4, 10.0,
3.3 Hz, 1 H, CH2C(CH3)dCH), 1.70-1.57 (m, 3 H), 1.57 (s, 3 H,
CH2C(CH3)dCH), 1.50-1.35 (m, 2 H), 1.33 (s, 3 H, C(CH3)2), 1.15
(d, J ) 6.8 Hz, 3 H, CH(CH3)), 1.03 (s, 3 H, C(CH3)2), 0.97 (d, J )
7.0 Hz, 3 H, CH(CH3)); 13C NMR (150.9 MHz, CDCl3) δ 220.7, 170.7,
165.3, 152.3, 138.5, 137.4, 119.6, 119.4, 115.7, 77.7, 76.2, 71.6, 52.7,
42.7, 39.4, 39.0, 37.3, 30.7, 24.5, 20.5, 19.7, 18.7, 15.9, 15.8, 15.5,
14.3; FAB HRMS (NBA) m/e 492.2772, M + H+ calcd for C27H41-
NO5S 492.2784.
Epothilone 58 and 59. Epoxidation of Lactone 56. Procedure
A: Compound 56 (5.0 mg, 10.2 µmol) was epoxidized with mCPBA
according to procedure A described above for 2 to yield a mixture of
12S-epi-epothilone B (58) and its R-epoxy diastereoisomer 59 (3.7 mg,
73% total yield, ca. 1:4 by 1H NMR). Purification by preparative thin-
layer chromatography (silica gel, 5% MeOH in CH2Cl2) gave pure 12R-
epothilone 59 (2.5 mg, 49%) as a white solid. Procedure B: The
epoxidation of 56 (3.0 mg, 6.1 µmol) according to the procedure
described above for 1 led to epothilones 58 and its R-epoxy diastere-
oisomer 59 (2.6 mg, 86% total yield, ca. 1:1 ratio by 1H NMR).
Preparative thin-layer chromatography (silica gel, 5% MeOH in CH2-
Cl2) furnished pure epothilone 58 (1.3 mg, 43%) and its R-epoxy
diastereoisomer 59 (1.3 mg, 43%). 58: Rf ) 0.52 (silica gel, 5% MeOH
Epothilone B (2) and Its r-Epoxide Epimer 57. Epoxidation of
Lactone 4. Procedure A: To a solution of lactone 4 (3.0 mg, 6.1
µmol) in benzene (0.2 mL) at -10 °C was added m-chloroperbenzoic
acid (2.9 mg, 50-60% purity, 8.4-10.1 µmol, 1.4-1.6 equiv), and
the reaction mixture was stirred at that temperature for 2 h, at which
time TLC indicated completion of the reaction. The reaction mixture
was diluted with EtOAc (5 mL) and washed with saturated aqueous
NaHCO3 solution (2 mL), and the aqueous phase was extracted with
EtOAc (3 × 2 mL). The combined organic layer was dried (MgSO4),
filtered, and concentrated. Purification by preparative thin-layer
chromatography (silica gel, 5% MeOH in CH2Cl2) provided a mixture
of epothilone B (2) and its R-epoxy diastereoisomer 57 (2.0 mg, 66%,
1
in CH2Cl2); [R]22 -33.1 (c 0.1, CHCl3); H NMR (600 MHz, C6D6)
D
δ 6.62 (s, 1 H, CHdCCH3), 6.44 (s, 1 H, SCHdC), 5.46 (dd, J ) 7.2,
5.1 Hz, 1 H, CH2COOCH), 4.22 (dd, J ) 8.3, 3.0 Hz, 1 H, (CH3)2-
CCHOH), 3.71 (dd, J ) 4.2, 3.6 Hz, 1 H, CHOH), 3.10 (dq, J ) 8.6,
3.7 Hz, 1 H, C(O)CHCH3), 2.95 (bs, 1 H, OH), 2.86 (dd, J ) 5.8, 5.7
Hz, 1 H, CHOCCH3), 2.82 (bs, 1 H, OH), 2.30 (dd, J ) 14.8, 10.1 Hz,
1 H, CH2COOCH), 2.24 (dd, J ) 14.8, 3.5 Hz, 1 H, CH2COOCH),
2.19 (s, 3 H, NdC(CH3)S), 1.99 (s, 3 H, CHdCCH3), 1.79-1.75 (m,
2 H), 1.74-1.70 (m, 1 H, (CH3)COCHCH2CHO), 1.60-1.55 (m, 1
H), 1.37-1.20 (m, 3 H), 1.18-1.11 (m, 1 H), 1.05 (d, J ) 6.9 Hz, 3
H, CH(CH3)), 1.04 (s, 6 H, C(CH3)OCHCH2), C(CH3)2), 0.92 (s, 3 H,
C(CH3)2), 0.85 (d, J ) 7.1 Hz, 3 H, CH(CH3)); 13C NMR (150.9 MHz,
CDCl3) δ 220.3, 170.8, 134.0, 133.8, 132.3, 128.7, 116.3, 73.7, 72.2,
61.5, 59.7, 53.0, 42.5, 38.7, 38.4, 36.7, 32.4, 32.1, 22.5, 21.4, 19.5,
17.8, 15.7, 15.4, 13.9, 12.5. 59: Rf ) 0.55 (silica gel, 5% MeOH in
CH2Cl2); [R]22D -34.5 (c 0.1, CHCl3); IR (thin film) νmax 3440, 2929,
1
ca. 5:1 ratio by H NMR), which was separated to its components by
a second preparative thin-layer chromatography (silica gel, 70% EtOAc
in hexanes) furnishing pure epothilone B (2) (1.6 mg, 52%) as a white
solid. Procedure B: To a solution of lactone 4 (5.0 mg, 10.2 µmol)
in CH2Cl2 (0.5 mL) at -50 °C was added dropwise a solution of
dimethyldioxirane in acetone untill the starting material disappeared
(TLC). The resulting solution was concentrated, and the crude product
was subjected to preparative thin-layer chromatography (silica gel, 5%
MeOH in CH2Cl2) to give epothilone B (2) and its R-epoxy diastere-
oisomer 57 in ca. 5:1 ratio (3.9 mg, 75%). Pure epothilone B (2) was
obtained (3.1 mg, 60%) by preparative thin-layer chromatography as
described above. Procedure C: Lactone 4 (3.0 mg, 6.1 µmol) was
epoxidized with methyl(trifluoromethyl)dioxirane according to the
procedure described above for the epoxidation of 3, to yield a mixture
1
1731, 1693, 1467, 1384, 1294, 1257, 1151, 1050, 977, 755 cm-1; H
NMR (600 MHz, CDCl3) δ 6.97 (s, 1 H, SCHdC), 6.60 (s, 1 H,
CHdCCH3), 5.50 (dd, J ) 8.0, 4.0 Hz, 1 H, CH2COOCH), 4.25 (dd,
J ) 10.1, 3.2 Hz, 1 H, (CH3)2CCHOH), 3.80 (bs, 1 H, OH), 3.75 (dd,
J ) 5.5, 3.6 Hz, 1 H, CHOH), 3.31 (dq, J ) 6.7, 6.3 Hz, 1 H, C(O)-
CHCH3), 2.88 (dd, J ) 6.3, 4.5 Hz, 1 H, CHOCCH3), 2.69 (s, 3 H,
NdC(CH3)S), 2.59 (bs, 1 H, OH), 2.55 (dd, J ) 13.5, 10.4 Hz, 1 H,
CH2COOCH), 2.45 (dd, J ) 13.5, 3.7 Hz, 1 H, CH2COOCH), 2.08 (s,
3 H, CHdCCH3), 2.05-1.97 (m, 3 H), 1.95-1.90 (m, 1 H,
(CH3)COCHCH2CHO), 1.75-1.70 (m, 2 H), 1.51-1.45 (m, 3 H), 1.37
(s, 3 H, C(CH3)OCHCH2), 1.27 (s, 3 H, C(CH3)2), 1.14 (d, J ) 6.9
Hz, 3 H, CH(CH3)), 1.04 (s, 3 H, C(CH3)2), 0.95 (d, J ) 6.9 Hz, 3 H,
CH(CH3)); 13C NMR (150.9 MHz, CDCl3) δ 219.6, 170.7, 164.9, 152.1,
136.6, 119.8, 116.4, 77.6, 75.9, 73.3, 61.3, 59.9, 52.9, 44.2, 38.8, 37.2,
36.4, 32.9, 31.3, 21.9, 21.3, 19.8, 19.4, 17.9, 17.4, 14.8; FAB HRMS
(NBA/CsI) m/e 640.1686, M + Cs+ calcd for C27H41NO6S 640.1709.
1
of 2 and its R-epoxy diastereoisomer 57 in ca. 5:1 ratio by H NMR
(2.6 mg, 85% yield). The major diastereoisomer, epothilone B (2),
was isolated as described above (2.1 mg, 69%). 2: colorless crystals;
mp 93 °C (crystallized in CH2Cl2/petroleum ether); Rf ) 0.24 (silica
gel, 4% MeOH in CH2Cl2); [R]22D -34.3 (c 0.2, MeOH); IR (thin film)
νmax 3436, 2954, 2931, 1731, 1684, 1455, 1373, 1290, 1249, 1184,
1143, 1043, 1049, 973, 750 cm-1; 1H NMR (600 MHz, CDCl3) δ 6.97
(s, 1 H, SCHdC), 6.59 (s, 1 H, CHdCCH3), 5.41 (dd, J ) 7.8, 2.8
Hz, 1 H, CH2COOCH), 4.22 (bs, 2 H, (CH3)2CCHOH, OH), 3.77 (dd,
J ) 4.3, 4.2 Hz, 1 H, CHOH), 3.30 (dq, J ) 6.8, 4.1 Hz, 1 H, C(O)-
r,â-Unsaturated Ester 60. A mixture of aldehyde 15 (5.17 g, 15.9
mmol) and stabilized ylide 16 (8.92 g, 24.0 mmol, 1.5 equiv, prepared
from 4-bromo-1-butene by (i) phosphonium salt formation, (ii) anion

7988 J. Am. Chem. Soc., Vol. 119, No. 34, 1997
Nicolaou et al.
formation with NaHMDS, and (iii) quenching with MeOC(O)Cl)32) in
benzene (300 mL, 0.05 M) was heated at reflux for 3 h. After being
cooled to 25 °C, the solvent was removed under reduced pressure and
the residue was subjected to flash column chromatography (silica gel,
30% ether in hexanes) to afford R,â-unsaturated ester 60 (7.15 g,
(silica gel, 20% ether in hexanes) furnished pure 63 (2.38 g, 99%): Rf
) 0.60 (silica gel, 15% ether in hexanes); [R]22D +17.1 (c 0.7, CHCl3);
IR (thin film) νmax 2928, 2856, 1637, 1505, 1464, 1253, 1181, 1075,
946, 836, 776 cm-1 1H NMR (600 MHz, CDCl3) δ 6.91 (s, 1 H,
;
SCHdC), 6.45 (s, 1 H, CHdCCH3), 5.77-5.68 (m, 1 H, CHdCH2),
5.22 (dd, J ) 7.3, 7.0 Hz, 1 H, CH2CHdCCH3), 5.01 (dd, J ) 17.1,
3.2 Hz, 1 H, CHdCH2), 4.96 (dd, J ) 10.1, 3.3 Hz, 1 H, CHdCH2),
4.09 (dd, J ) 7.2, 5.9 Hz, 1 H, CHOSi), 2.80 (dd, J ) 14.5, 6.5 Hz,
1 H, CH2CHdCH2), 2.73-2.68 (m, 1 H, CH2CHdCH2), 2.70 (s, 3 H,
NdC(S)CH3), 2.32-2.19 (m, 2 H, CH2CHOSi), 1.99 (s, 3 H,
CHdCCH3), 1.66 (s, 3 H, CH2CHdCCH3), 0.88 (s, 9 H, SiC(CH3)3),
0.04 (s, 3 H, Si(CH3)2), -0.01 (s, 3 H, Si(CH3)2); 13C NMR (150.9
MHz, CDCl3) δ 164.3, 153.2, 142.5, 136.0, 134.4, 122.5, 118.7, 115.1,
114.9, 78.9, 36.6, 35.3, 25.8, 23.5, 19.2, 18.2, 13.9, -4.8, -5.0; FAB
HRMS (NBA) m/e 378.2279, M + H+ calcd for C21H35NOSSi
378.2287.
95%): Rf ) 0.65 (silica gel, 40% ether in hexanes); [R]22 +10.4 (c
D
1.4, CHCl3); IR (thin film) νmax 2939, 2856, 1715, 1644, 1504, 1464,
1
1437, 1365, 1284, 1252, 1209, 1076, 955, 836, 776 cm-1; H NMR
(500 MHz, CDCl3) δ 6.91 (s, 1 H, SCHdC), 6.87 (d, J ) 7.4 Hz, 1 H,
CHdCCOOCH3), 6.47 (s, 1 H, CHdCCH3), 5.83-5.71 (m, 1 H,
CHdCH2), 5.01-4.92 (m, 2 H, CHdCH2), 4.19 (dd, J ) 7.7, 4.9 Hz,
1 H, CHOSi), 3.69 (s, 3 H, COOCH3), 3.05 (d, J ) 6.0 Hz, 2 H, CH2-
CHdCH2), 2.67 (s, 3 H, NdC(S)CH3), 2.46 (ddd, J ) 15.1, 7.7, 7.4
Hz, 1 H, CH2CHOSi), 2.39 (ddd, J ) 15.0, 7.5, 5.0 Hz, 1 H, CH2-
CHOSi), 1.99 (s, 3 H, CHdCCH3), 0.86 (s, 9 H, SiC(CH3)3), 0.03 (s,
3 H, Si(CH3)2), -0.02 (s, 3 H, Si(CH3)2); 13C NMR (125.7 MHz,
CDCl3) δ 167.8, 164.4, 152.8, 141.5, 140.6, 135.3, 130.7, 119.1, 115.5,
115.1, 77.6, 51.7, 36.1, 30.9, 25.7, 19.2, 18.1, 13.9, -4.7, -5.1; FAB
HRMS (NBA/CsI) m/e 554.1168, M + Cs+ calcd for C22H35NO3SSi
554.1161.
Primary Alcohol 64. Selective Hydroboration of Olefinic Com-
pound 63. Compound 63 (1.1 g, 2.91 mmol) was dissolved in THF
(3.0 mL, 1.0 M), and the solution was cooled to 0 °C. 9-BBN (7.0
mL, 0.5 M solution in THF, 3.5 mmol, 1.2 equiv) was added, and the
reaction mixture was stirred for 2 h at 0 °C. Aqueous NaOH (7.0 mL,
3 N solution, 21.0 mmol, 7.2 equiv) was added with stirring, followed
by H2O2 (2.4 mL, 30%, aqueous solution). Stirring was continued for
0.5 h at 0 °C, after which time the reaction mixture was diluted with
ether (30 mL). The organic solution was separated, and the aqueous
phase was extracted with ether (2 × 15 mL). The combined organic
layer was washed with brine (2 × 5 mL), dried (Na2SO4), and
concentrated in vacuo. Flash column chromatography (silica gel, 50
f 80% ether in hexanes) furnished primary alcohol 64 (1.0 g, 91%):
Rf ) 0.17 (silica gel, 50% ether in hexanes); [R]22D +3.6 (c 0.2, CHCl3);
IR (thin film) νmax 3381, 2953, 2929, 2856, 1723, 1660, 1469, 1444,
Allylic Alcohol 61. Methyl ester 60 (6.1 g, 14.4 mmol) was
dissolved in THF (80 mL) and cooled to -78 °C. DIBAL (44.0 mL,
1 M solution in CH2Cl2, 44.0 mmol, 3.0 equiv) was added dropwise at
-78 °C, and the reaction mixture was stirred for 3 h. The reaction
mixture was quenched with MeOH (1.0 mL) at -78 °C, and then ether
(100 mL) was added, followed by saturated aqueous sodium-potasium
tartrate solution (10 mL). The resulting mixture was allowed to warm
to room temperature, where it was stirred for 3 h. The organic layer
was separated, and the aqueous phase was extracted with ether (2 ×
50 mL). The combined organic phase was dried (MgSO4), filtered,
and concentrated under reduced pressure. Flash column chromatog-
raphy (silica gel, 40 f 80% ether in hexanes) furnished alcohol 61
1
1376, 1253, 1185, 1073, 941, 837, 776 cm-1; H NMR (600 MHz,
(5.58 g, 98%): Rf ) 0.18 (silica gel, 40% ether in hexanes); [R]22
CDCl3) δ 6.91 (s, 1 H, SCHdC), 6.44 (s, 1 H, CHdCCH3), 5.17 (dd,
J ) 7.0, 6.9 Hz, 1 H, CH2CHdCCH3), 4.11 (dd, J ) 7.1, 5.7 Hz, 1 H,
CHOSi), 3.59 (dd, J ) 6.5, 6.4 Hz, 2 H, CH2OH), 2.70 (s, 3 H, NdC-
(S)CH3), 2.35-2.28 (m, 1 H, CH2CHOSi), 2.27-2.20 (m, 1 H, CH2-
CHOSi), 2.10 (dd, J ) 7.6, 7.5 Hz, 2 H CH2CH2CH2OH), 1.98 (s, 3
H, CHdCCH3), 1.67 (s, 3 H, CH2CHdCCH3), 1.67-1.58 (m, 2 H,
CH2CH2OH), 0.88 (s, 9 H, SiC(CH3)3), 0.04 (s, 3 H, Si(CH3)2), -0.01
(s, 3 H, Si(CH3)2); 13C NMR (150.9 MHz, CDCl3) δ 164.5, 153.0, 142.7,
136.2, 122.2, 118.5, 115.0, 78.9, 62.4, 35.4, 30.7, 28.0, 25.8, 23.3, 19.2,
18.3, 14.0, -4.7, -5.0; FAB HRMS (NBA) m/e 396.2382, M + H+
calcd for C21H37NO2SSi 396.2393.
D
+6.6 (c 1.1, CHCl3); IR (thin film) νmax 3380, 2928, 2855, 1637, 1505,
1
1464, 1386, 1253, 1185, 1074, 836, 776 cm-1; H NMR (600 MHz,
CDCl3) δ 6.88 (s, 1 H, SCHdC), 6.41 (s, 1 H, CHdCCH3), 5.77-
5.69 (m, 1 H, CHdCH2), 5.48 (dd, J ) 7.3, 7.2 Hz, 1 H, CHdCCH2-
OH), 5.00 (dd, J ) 15.5, 3.3 Hz, 1 H, CHdCH2), 4.93 (dd, J ) 10.0,
3.3 Hz, 1 H, CHdCH2), 4.12 (dd, J ) 6.5, 6.4 Hz, 1 H, CHOSi), 3.97
(s, 2 H, CH2OH), 2.86-2.76 (m, 2 H, CH2CHdCH2), 2.65 (s, 3 H,
NdC(S)CH3), 2.53 (bs, 1 H, OH), 2.36-2.24 (m, 2 H, CH2CHOSi),
1.94 (s, 3 H, CHdCCH3), 0.86 (s, 9 H, SiC(CH3)3), 0.02 (s, 3 H, Si-
(CH3)2), -0.02 (s, 3 H, Si(CH3)2); 13C NMR (150.9 MHz, CDCl3) δ
164.5, 152.8, 142.0, 138.1, 123.7, 118.7, 115.2, 114.9, 78.3, 66.6, 34.7,
32.4, 25.7, 19.0, 18.1, 13.7, -4.8, -5.0; FAB HRMS (NBA) m/e
394.2232, M + H+ calcd for C21H35NO2SSi 394.2236.
Iodide 14. Iodide 14 (1.18 g, 92%) was prepared from alcohol 64
(1.0 g, 2.53 mmol) according to the procedure described above for 27.
14: Colorless oil; Rf ) 0.65 (silica gel, 20% ether in hexanes); [R]22
D
Compound 62. Chlorination of Alcohol 61. Alcohol 61 (3.00 g,
7.60 mmol) was dissolved in CCl4 (75 mL, 0.1 M), and Ph3P (4.00 g,
15.2 mmol, 2.0 equiv) was added. The reaction mixture was stirred at
100 °C for 24 h and cooled to room temperature, and the solvent was
removed under reduced pressure. Flash column chromatography (silica
gel, 10% ether in hexanes) furnished pure 62 (2.6 g, 83%): Rf ) 0.50
+7.5 (c 0.8, CHCl3); IR (thin film) νmax 2955, 2930, 2855, 1504, 1462,
1
1444, 1376, 1360, 1253, 1183, 1074, 942, 837, 776 cm-1; H NMR
(500 MHz, CDCl3) δ 6.91 (s, 1 H, SCHdC), 6.46 (s, 1 H, CHdCCH3),
5.20 (dd, J ) 7.3, 7.1 Hz, 1 H, CH2CHdCCH3), 4.09 (dd, J ) 7.4, 5.5
Hz, 1 H, CHOSi), 3.14 (dd, J ) 7.1, 7.0 Hz, 2 H, CH2I), 2.69 (s, 3 H,
NdC(S)CH3), 2.34-2.27 (m, 1 H, CH2CHOSi), 2.26-2.19 (m, 1 H,
CH2CHOSi), 2.17-2.03 (m, 2 H), 2.00 (s, 3 H, CHdCCH3), 1.93-
1.86 (m, 2 H), 1.67 (s, 3 H, CH2CHdCCH3) 0.88 (s, 9 H, SiC(CH3)3),
0.04 (s, 3 H, Si(CH3)2), -0.01 (s, 3 H, Si(CH3)2); 13C NMR (125.7
MHz, CDCl3) δ 164.2, 153.1, 142.3, 134.6, 123.1, 118.6, 115.0, 78.8,
35.4, 32.6, 31.9, 25.8, 23.4, 19.2, 18.2, 14.0, 6.5, -4.7, -5.0; FAB
HRMS (NBA) m/e 506.1422, M + H+ calcd for C21H36INOSSi
506.1410.
(silica gel, 15% ether in hexanes); [R]22 +13.7 (c 1.0, CHCl3); IR
D
(thin film) νmax 2953, 2928, 2855, 1637, 1504, 1470, 1439, 1387, 1254,
1
1182, 1075, 953, 917, 836, 776 cm-1; H NMR (600 MHz, CDCl3) δ
6.93 (s, 1 H, SCHdC), 6.47 (s, 1 H, CHdCCH3), 5.77-5.69 (m, 1 H,
CHdCH2), 5.66 (dd, J ) 7.5, 7.2 Hz, 1 H, CH2CHdCCH2Cl), 5.07
(dd, J ) 17.1, 1.6 Hz, 1 H, CHdCH2), 5.02 (dd, J ) 10.1, 1.4 Hz, 1
H, CHdCH2), 4.14 (dd, J ) 7.2, 5.5 Hz, 1 H, CHOSi), 4.02 (s, 2 H,
CH2Cl), 2.99-2.89 (m, 2 H, CH2CHdCH2), 2.71 (s, 3 H, NdC(S)CH3),
2.52-2.27 (m, 2 H, CH2CHOSi), 1.99 (s, 3 H, CHdCCH3), 0.88 (s, 9
H, SiC(CH3)3), 0.05 (s, 3 H, Si(CH3)2), 0.00 (s, 3 H, Si(CH3)2); 13C
NMR (150.9 MHz, CDCl3) δ 164.3, 152.9, 141.8, 134.9, 134.7, 128.9,
119.0, 116.2, 115.2, 78.1, 49.9, 35.3, 32.3, 25.8, 19.2, 18.2, 13.9, -4.7,
-5.0; FAB HRMS (NBA) m/e 412.1884, M + H+ calcd for C21H34-
ClNOSSi 412.1897.
Hydrazone 65. Alkylation of SAMP Hydrazone 13 with Iodide
14. SAMP hydrazone 1315 (337 mg, 0.2 mmol, 2.0 equiv) in THF
(2.5 mL) was added to a freshly prepared solution of LDA at 0 °C
[diisopropylamine (277 µL, 0.20 mmol, 2.0 equiv) was added to n-BuLi
(1.39 mL, 1.42 M solution in hexanes, 0.20 mmol. 2.0 equiv) in 2.5
mL of THF at 0 °C] at 0 °C. After being stirred at that temperature
for 8 h, the resulting yellow solution was cooled to -100 °C and a
solution of iodide 14 (0.5 g, 0.99 mmol, 1.0 equiv) in THF (3 mL)
was added dropwise over a period of 5 min. The mixture was allowed
to warm to -20 °C over 10 h and then poured into saturated aqueous
NH4Cl solution (5 mL) and extracted with ether (3 × 25 mL). The
combined organic extracts were dried (MgSO4), filtered, and evaporated.
Purification by flash column chromatography on silica gel (20 f 40%
ether in hexanes) provided hydrazone 65 (380 mg, 70%, de > 98% by
Compound 63. Reduction of 62. Compound 62 (2.60 g, 6.30
mmol) was dissolved in THF (60 mL, 0.1 M) and cooled to 0 °C. LiEt3-
BH (12.6 mL, 1.0 M solution in THF, 12.6 mmol, 2.0 equiv) was added
dropwise, and the reaction mixture was stirred at 0 °C for 1 h. Aqueous
NaOH (1.0 mL, 3.0 N) solution was added followed by addition of
Et20 (150 mL). The organic phase was washed with brine (2 × 20
mL), dried (MgSO4) and concentrated. Flash column chromatography

Total Synthesis of Epothilones A and B
J. Am. Chem. Soc., Vol. 119, No. 34, 1997 7989
1H NMR) as a yellow oil: Rf ) 0.17 (silica gel, 20% ether in hexanes);
processing, geometrically pure 12Z-carboxylic acids 52 (207 mg, 32%)
and 53 (181 mg, 28%) and recovered 9. 12Z-Carboxylic acid 52: Rf
) 0.56 (silica gel, 5% MeOH in CH2Cl2); [R]22D -2.9 (c 0.8, CHCl3);
IR (thin film) νmax 2933, 2854, 1708, 1464, 1385, 1249, 1187, 1079,
[R]22 -27.8 (c 2.6, CHCl3); IR (thin film) νmax 2931, 2861, 1724,
D
1653, 1599, 1499, 1451, 1374, 1249, 1178, 1077, 940, 834, 774, 727,
673 cm-1; 1H NMR (500 MHz, CDCl3) δ 6.91 (s, 1 H, SCHdC), 6.48
(d, J ) 6.6 Hz, 1 H, CNH), 6.44 (s, 1 H, CHdCCH3), 5.12 (dd, J )
7.1, 6.9 Hz, 1 H, CH2CHdCCH3), 4.07 (dd, J ) 6.8, 6.2 Hz, 1 H,
CHOSi), 3.55 (dd, J ) 9.1, 3.7 Hz, 1 H, CH2OCH3), 3.41 (dd, J )
9.1, 6.9 Hz, 1 H, CH2OCH3), 3.36 (s, 3 H, CH2OCH3), 3.35-3.32 (m,
2 H, CH2N), 2.70 (s, 3 H, NdC(S)CH3), 2.69-2.62 (m, 1 H), 2.31-
2.17 (m, 3 H), 2.04-1.84 (m, 5 H), 1.99 (s, 3 H, CHdCCH3), 1.79-
1.72 (m, 1 H), 1.64 (s, 3 H, CH2CHdCCH3) 1.41-1.22 (m, 4 H), 1.01
(d, J ) 6.9 Hz, CHCH3), 0.88 (s, 9 H, SiC(CH3)3), 0.04 (s, 3 H, Si-
(CH3)2), -0.01 (s, 3 H, Si(CH3)2); 13C NMR (125.7 MHz, CDCl3) δ
164.2, 153.1, 144.3, 142.4, 136.6, 121.5, 118.5, 114.8, 78.9, 74.7, 63.4,
59.1, 50.4, 37.0, 35.3, 35.2, 31.8, 26.4, 25.7, 25.4, 23.3, 22.0, 19.1,
18.9, 18.1, 13.8, -4.8, -5.0; FAB HRMS (NBA) m/e 548.3728, M +
H+ calcd for C30H53N3O2SSi 548.3706.
983, 830, 773 cm-1 1H NMR (500 MHz, CDCl3) δ 6.92 (s, 1 H,
;
SCHdC), 6.58 (s, 1 H, CHdCCH3), 5.15 (dd, J ) 7.4, 7.1 Hz, 1 H,
(CH3)CdCHCH2), 4.39 (dd, J ) 6.7, 3.0 Hz, 1 H, (CH3)2CCHOSi),
4.11 (dd, J ) 7.3, 5.7 Hz, 1 H, CH2CHOSi), 3.74 (dd, J ) 6.1, 1.8 Hz,
1 H, CH(CH3)CHOSi), 3.13 (dq, J ) 7.0, 6.5 Hz, 1 H, C(O)CH(CH3)),
2.70 (s, 3 H, NdC(CH3)S), 2.44 (dd, J ) 16.4, 3.1 Hz, 1 H, CH2-
COOH), 2.31 (dd, J ) 16.4, 6.8 Hz, 1 H, CH2COOH), 2.28-2.04 (m,
3 H, CH2C(CH3)dCH, CH2C(CH3)dCHCH2), 1.94 (s, 3 H, CHdC-
(CH3)), 1.96-1.86 (m, 1 H), 1.66 (s, 3 H, CH2C(CH3)dCH), 1.47-
1.31 (m, 4 H), 1.17 (s, 3 H, C(CH3)2), 1.12 (s, 3 H, C(CH3)2), 1.21-
1.09 (m, 1 H), 1.08 (d, J ) 6.8 Hz, 3 H, CH(CH3)), 0.90-0.85 (m, 30
H, CH(CH3), 3 x SiC(CH3)3), 0.10 (s, 3 H, Si(CH3)2), 0.06 (s, 3 H,
Si(CH3)2), 0.05 (s, 3 H, Si(CH3)2), 0.03 (s, 3 H, Si(CH3)2), 0.02 (s, 3
H, Si(CH3)2), -0.02 (s, 3 H, Si(CH3)2); 13C NMR (125.7 MHz, CDCl3)
δ 218.2, 175.5, 165.0, 152.8, 143.4, 137.0, 121.6, 118.2, 114.5, 79.1,
73.1, 53.8, 44.4, 40.0, 39.2, 35.3, 32.4, 31.4, 26.2, 26.0, 25.8, 25.7,
23.5, 23.4, 18.8, 18.7, 18.4, 18.2, 16.8, 15.8, 13.9, -3.9, -4.0, -4.1,
-4.6, -4.7, -5.0; FAB HRMS (NBA/CsI) m/e 984.4427, M + Cs+
calcd for C45H85NO6SSi3 984.4460. 12Z-Carboxylic acid 53: Rf )
0.65 (silica gel, 5% MeOH in CH2Cl2); [R]22D +6.2 (c 0.6, CHCl3); IR
(thin film) νmax 2933, 2854, 1708, 1459, 1386, 1249, 1074, 988, 830,
773 cm-1; 1H NMR (500 MHz, CDCl3) δ 6.91 (s, 1 H, SCHdC), 6.45
(s, 1 H, CHdCCH3), 5.12 (dd, J ) 7.4, 6.9 Hz, 1 H, (CH3)CdCHCH2),
4.56 (dd, J ) 6.1, 5.6 Hz, 1 H, (CH3)2CCHOSi), 4.07 (dd, J ) 7.6, 5.6
Hz, 1 H, CH2CHOSi), 3.85 (d, J ) 8.4 Hz, 1 H, CH(CH3)CHOSi),
3.10 (dq, J ) 7.1, 7.0 Hz, 1 H, C(O)CH(CH3)), 2.75 (s, 3 H, NdC-
(CH3)S), 2.43-2.10 (m, 4 H), 1.96-1.88 (m, 2 H), 1.91 (s, 3 H, CHdC-
(CH3)), 1.66 (s, 3 H, CH2C(CH3)dCH), 1.35-1.02 (m, 14 H, CH(CH3),
2 x CH2, C(CH3)2, C(CH3)2, CH(CH3)), 0.92-0.80 (m, 30 H, 3 x SiC-
(CH3)3, CH(CH3)), 0.09-0.01 (m, 18 H, 3 x Si(CH3)2); 13C NMR (125.7
MHz, CDCl3) δ 218.1, 174.2, 165.4, 152.3, 143.7, 137.1, 121.6, 117.9,
114.4, 78.9, 72.4, 53.8, 45.8, 40.4, 38.3, 35.6, 35.3, 32.3, 26.7, 26.3,
26.2, 26.0, 25.8, 25.7, 23.9, 23.3, 18.6, 18.5, 18.4, 17.1, 13.9, 13.4,
-3.4, -3.6, -4.3, -4.6, -4.7, -4.9; FAB HRMS (NBA/CsI) m/e
984.4430, M + Cs+ calcd for C45H85NO6SSi3 984.4460.
Nitrile 66. Monoperoxyphthalic acid magnesium salt (MMPP‚6H2O,
233 mg, 0.38 mmol, 2.5 equiv) was suspended in a rapidly stirred
mixture of MeOH and pH 7 phosphate buffer (1:1, 3.0 mL) at 0 °C.
Hydrazone 65 (83 mg, 0.15 mmol, 1.0 equiv) in MeOH (1.0 mL) was
added dropwise, and the mixture was stirred at 0 °C until the reaction
was complete by TLC (ca. 1 h). The resulting suspension was placed
in a separating funnel along with ether (15 mL) and saturated aqueous
NaHCO3 solution (5 mL). The organic layer was separated, and the
aqueous phase was extracted with ether (10 mL). The combined organic
solution was washed with water (5 mL) and brine (5 mL), dried
(MgSO4), and concentrated. Flash column chromatography (silica gel,
50% ether in hexanes) afforded nitrile 66 (53 mg, 80%) as a colorless
oil: Rf ) 0.44 (silica gel, 50% ether in hexanes); [R]22D +10.3 (c 3.2,
CHCl3); IR (thin film) νmax 2926, 2855, 1503, 1457, 1381, 1250, 1179,
1
1072, 935, 833, 773, cm-1; H NMR (500 MHz, CDCl3) δ 6.92 (s, 1
H, SCHdC), 6.45 (s, 1 H, CHdCCH3), 5.18 (dd, J ) 7.0, 6.5 Hz, 1
H, CH2CHdCCH3), 4.08 (dd, J ) 6.5, 6.0 Hz, 1 H, CHOSi), 2.70 (s,
3 H, NdC(S)CH3), 2.60-2.53 (m, 1 H), 2.30-2.18 (m, 2 H), 2.11-
1.97 (m, 2 H), 1.99 (s, 3 H, CHdCCH3), 1.67 (s, 3 H, CH2CHdCCH3)
1.67-1.45 (m, 4 H), 1.29 (d, J ) 6.9 Hz, CHCH3), 0.88 (s, 9 H, SiC-
(CH3)3), 0.04 (s, 3 H, Si(CH3)2), -0.01 (s, 3 H, Si(CH3)2); 13C NMR
(125.7 MHz, CDCl3) δ 164.3, 153.0, 142.3, 135.5, 122.8, 122.4, 118.6,
114.9, 78.4, 35.3, 33.6, 31.1, 25.7, 25.4, 25.1, 23.2, 19.1, 18.1, 17.9,
13.9, -4.8, -5.1; FAB HRMS (NBA) m/e 433.2720, M + H+ calcd
for C24H40N2OSSi 433.2709.
12Z-Hydroxy Acid 6. 12Z-Carboxylic acid 52 (400 mg, 0.47 mmol)
was converted to 12Z-hydroxy acid 6 (253 mg, 73% yield) according
to the same procedure described above for 5. 6: yellow oil; Rf ) 0.41
(silica gel, 5% MeOH in CH2Cl2); [R]22 -10.4 (c 0.4, CHCl3); IR
Aldehyde 8. Nitrile 66 (53 mg, 0.12 mmol) was dissolved in toluene
(2.0 mL) and cooled to -78 °C. DIBAL (245 µL, 1 M solution in
toluene, 0.22 mmol, 2.0 equiv) was added dropwise at -78 °C, and
the reaction mixture was stirred at that temperature until its completion
was verified by TLC (ca. 1 h). Methanol (150 µL) and aqueous HCl
(150 µL, 1 N solution) were sequentially added, and the resulting
mixture was brought up to 0 °C and stirred at that temperature for 30
min. Ether (5 mL) and water (2 mL) were added, and the organic
layer was separated. The aqueous phase was extracted with ether (2
× 5 mL), and the combined organic solution was washed with brine
(5 mL), dried (MgSO4), filtered, and concentrated under reduced
pressure. Flash column chromatography (silica gel, 15% ether in
hexanes) furnished pure aldehyde 8 (44 mg, 82%): Rf ) 0.48 (silica
gel, 50% ether in hexanes); [R]22D +14.7 (c 1.7, CHCl3); IR (thin film)
D
(thin film) νmax 3227, 2933, 2852, 1711, 1696, 1468, 1387, 1245, 1189,
1087, 986, 834, 773 cm-1; 1H NMR (500 MHz, CDCl3) δ 6.95 (s, 1 H
SCHdC), 6.67 (s, 1 H, CHdCCH3), 5.19 (dd, 1 H, J ) 7.5, 7.0 Hz,
CH3CdCHCH2), 4.41 (dd, J ) 6.0, 3.5 Hz, 1 H, (CH3)2CCHOSi), 4.16
(dd, J ) 6.6, 6.5 Hz, 1 H, CH2CHOH), 3.78 (d, J ) 6.9 Hz, 1 H,
CH(CH3)CHOSi), 3.13 (dq, J ) 6.9, 6.6 Hz, 1 H, C(O)CHCH3), 2.72
(s, 3 H, NdC(CH3)S), 2.47 (dd, J ) 16.2, 3.9 Hz, 1 H, CH2COOH),
2.40-2.35 (m, 3 H, CH2C(CH3)dCH, CH2COOH), 2.17-2.10 (m, 1
H, C(CH3)dCHCH2), 2.00 (s, 3 H, CHdC(CH3)), 1.99-1.93 (m, 1 H,
C(CH3)dCHCH2), 1.72 (s, 3 H, CH2C(CH3)dCH), 1.53-1.35 (m, 5
H), 1.19 (s, 3 H, C(CH3)2), 1.14 (s, 3 H, C(CH3)2), 1.07 (d, J ) 6.7
Hz, 3 H, CH(CH3)), 0.94-0.84 (m, 21 H, CH(CH3), SiC(CH3)3), 0.11
(s, 3 H, Si(CH3)2), 0.07 (s, 6 H, Si(CH3)2), 0.05 (s, 3 H, Si(CH3)2); 13
C
NMR (125.7 MHz, CDCl3) δ 217.9, 174.8, 165.1, 152.3, 142.1, 139.4,
120.2, 118.5, 115.0, 73.2, 53.8, 44.5, 40.0, 39.1, 34.1, 32.4, 31.2, 26.2,
26.1, 25.9, 23.5, 23.3, 18.9, 18.6, 18.3, 18.1, 16.8, 16.0, 14.6, -3.9,
-4.1, -4.2, -4.7; FAB HRMS (NBA/CsI) m/e 870.3632, M + Cs+
calcd for C39H71NO6SSi2 870.3595.
ν
max 2915, 2859, 1721, 1500, 1455, 1381, 1251, 1183, 1070, 940, 832,
770 cm-1; H NMR (500 MHz, CDCl3) δ 9.60 (d, J ) 1.9 Hz, 1 H,
CHO), 6.92 (s, 1 H, SCHdC), 6.45 (s, 1 H, CHdCCH3), 5.16 (dd, J
) 7.1, 7.0 Hz, 1 H, CH2CHdCCH3), 4.08 (dd, J ) 7.0, 5.5 Hz, 1 H,
CHOSi), 2.70 (s, 3 H, NdC(S)CH3), 2.36-2.18 (m, 3 H), 2.07-2.01
(m, 2H), 1.99 (s, 3 H, CHdCCH3), 1.71-1.64 (m, 1 H), 1.66 (d, J )
1.0 Hz, 3 H, CH2CHdCCH3), 1.43-1.29 (m, 3 H), 1.08 (d, J ) 7.0
Hz, 3 H, CH3CH), 0.88 (s, 9 H, SiC(CH3)3), 0.04 (s, 3 H, Si(CH3)2),
-0.01 (s, 3 H, Si(CH3)2); 13C NMR (125.7 MHz, CDCl3) δ 205.0, 164.4,
153.1, 142.3, 135.9, 122.0, 118.6, 114.9, 78.8, 46.1, 35.3, 31.7, 30.2,
25.7, 25.1, 23.3, 19.1, 18.2, 13.8, 13.2, -4.8, -5.1; FAB HRMS (NBA)
m/e 436.2717, M + H+ calcd for C24H41NO2SSi 436.2706.
1
Hydroxy Acid 67. 12Z-Carboxylic acid 53 (200 mg, 0.24 mmol)
was converted to 12Z-hydroxy acid 67 (123 mg, 71% yield) according
to the procedure described above for 5. 67: yellow oil; Rf ) 0.45
(silica gel, 5% MeOH in CH2Cl2); [R]22D -8.1 (c 0.3, CHCl3); IR (thin
film) νmax 3227, 2933, 2862, 1711, 1691, 1463, 1382, 1250, 1189, 1082,
986, 834, 773 cm-1 1H NMR (500 MHz, CDCl3) δ 6.96 (s, 1 H
;
SCHdC), 6.61 (s, 1 H, CHdCCH3), 5.15 (dd, 1 H, J ) 7.5, 7.0 Hz,
CH3CdCHCH2), 4.55 (dd, J ) 6.1, 3.5 Hz, 1 H, (CH3)2CCHOSi), 4.12
(dd, J ) 8.0, 4.5 Hz, 1 H, CH2CHOH), 3.86 (d, J ) 8.2 Hz, 1 H,
CH(CH3)CHOSi), 3.12 (dq, J ) 7.2, 7.0 Hz, 1 H, C(O)CHCH3), 2.75
(s, 3 H, NdC(CH3)S), 2.37-2.30 (m, 5 H, CH2C(CH3)dCH, CH2-
COOH, C(CH3)dCHCH2), 1.98 (s, 3 H, CHdC(CH3)), 1.94-1.89 (m,
12Z-Carboxylic Acids 52 and 53. Aldol Reaction of Keto Acid
9 with 12Z-Aldehyde 8. A solution of keto acid 9 (365 mg, 1.21
mmol, 1.6 equiv) in THF (5.0 mL) was reacted with 12Z-aldehyde 8
(330 mg, 0.76 mmol, 1.0 equiv) according to the same procedure as
described above for the condensation of 9 and 8 to afford, after similar

7990 J. Am. Chem. Soc., Vol. 119, No. 34, 1997
Nicolaou et al.
1 H), 1.72 (s, 3 H, CH2C(CH3)dCH), 1.39-1.04 (m, 14 H, CH(CH3),
CH(CH3), 2 x CH2, C(CH3)2), 0.95-0.84 (m, 21 H, SiC(CH3)3, CH-
(CH3)), 0.09 (s, 3 H, Si(CH3)2), 0.08 (s, 3 H, Si(CH3)2), 0.07 (s, 6 H,
Si(CH3)2); 13C NMR (125.7 MHz, CDCl3) δ 218.6, 174.0, 165.6, 152.0,
142.4, 139.4, 120.1, 118.0, 114.7, 72.4, 53.8, 45.8, 40.4, 38.4, 35.5,
34.0, 32.1, 26.4, 26.2, 26.0, 25.9, 23.8, 23.6, 18.5, 18.4, 18.2, 17.2,
14.9, 13.2, -3.5, -3.7, -4.4, -4.8; FAB HRMS (NBA/CsI) m/e
870.3574, M + Cs+ calcd for C39H71NO6SSi2 870.3595.
The reaction mixture was cooled to -78 °C, and a solution of aldehyde
8 (244 mg, 0.56 mmol, 1.0 equiv) in THF (1.0 mL) was added dropwise.
The resulting mixture was stirred for 15 min at -78 °C and then
quenched by dropwise addition of saturated aqueous NH4Cl solution
(2 mL). The aqueous phase was extracted with ether (3 × 5 mL), and
the combined organic layer was dried (MgSO4) and concentrated.
Purification by flash column chromatography (silica gel, 20% ether in
hexanes) provided a mixture of aldol products 70:71 (354 mg (85%)
of ca. 3:1 by 1H NMR). Separation of these diastereoisomers was
carried out by preparative thin-layer chromatography (silica gel, 20%
ether in hexanes), leading to pure 70 (270 mg, 64%) and 71 (84 mg,
20%). 70: colorless oil; Rf ) 0.40 (silica gel, 20% ether in hexanes);
Lactone 54. Macrolactonization of 12Z-Hydroxy Acid 6. 12Z-
Hydroxy acid 6 (8.1 mg, 0.011 mmol) was cyclized according to the
procedure described above for 6′ to afford lactone 54 (6.1 mg, 77%).
Lactone 68. Macrolactonization of 12Z-Hydroxy Acid 67. The
macrolactonization of 12Z-hydroxy acid 67 (5.0 mg, 0.007 mmol) to
lactone 68 (3.7 mg, 76%) was carried out according to the procedure
described above for 6′. 68: colorless oil; Rf ) 0.83 (silica gel, 2%
[R]22 -17.5 (c 0.5, CHCl3); IR (thin film) νmax 3490, 2932, 2873,
D
1
1683, 1463, 1385, 1249, 1089, 840, 775 cm-1; H NMR (500 MHz,
CDCl3) δ 6.89 (s, 1 H, SCHdC), 6.44 (s, 1 H, CHdCCH3), 5.12 (dd,
J ) 7.1, 7.0 Hz , 1 H, C(CH3)dCHCH2), 4.08 (dd, J ) 6.8, 6.5 Hz, 1
H, (CH3)2CCHOSi), 3.89 (dd, J ) 7.6, 2.7 Hz, 1 H, CH2CHOSi), 3.69-
3.65 (m, 1 H, CH(CH3)CHOH), 3.59 (t, J ) 7.5 Hz, 2 H, CH2OSi),
3.32-3.27 (m, 1 H, C(O)CH(CH3)), 2.68 (s, 3 H, NdC(CH3)S), 2.30-
2.19 (m, 2 H, C(CH3)dCHCH2), 2.10-1.90 (m, 2 H, CH2C(CH3)dCH),
1.98 (s, 3 H, CHdC(CH3)), 1.65 (s, 3 H, C(CH3)dCHCH2), 1.80-
1.46 (m, 5 H), 1.34-1.25 (m, 2 H), 1.19 (s, 3 H, C(CH3)2), 1.07 (s, 3
H, C(CH3)2), 1.01 (d, J ) 6.8 Hz, 3 H, CH(CH3)), 0.89 (s, 18 H, 2 x
SiC(CH3)3), 0.87 (s, 9 H, SiC(CH3)3), 0.81 (d, J ) 6.8 Hz, 3 H, CH-
(CH3)), 0.10 (s, 3 H, Si(CH3)2), 0.08 (s, 3 H, Si(CH3)2), 0.03 (s, 3 H,
Si(CH3)2), 0.02 (s, 6 H, Si(CH3)2), -0.01 (s, 3 H, Si(CH3)2); 13C NMR
(125.7 MHz, CDCl3) δ 222.0, 164.1, 153.1, 142.4, 136.7, 121.3, 118.5,
114.7, 78.9, 74.7, 74.0, 60.3, 53.8, 41.2, 37.7, 35.9, 32.8, 32.5, 32.2,
26.0, 25.9, 25.8, 25.0, 24.9, 23.5, 22.8, 20.4, 19.0, 18.2, 18.1, 18.0,
15.2, 13.8, 9.5, -3.8, -4.2, -4.8, -5.1, -5.4; FAB HRMS (NBA/
CsI) m/e 970.4620, M + Cs+ calcd for C45H87NO5SSi3 970.4667. 71:
colorless oil; Rf ) 0.33 (silica gel, 20% ether in hexanes); IR (thin
film) νmax 3490, 2932, 2873, 1683, 1463, 1385, 1249, 1089, 840, 775
MeOH in CH2Cl2); [R]22 -31.8 (c 0.1, CHCl3); IR (thin film) νmax
D
2931, 2860, 1736, 1690, 1461, 1384, 1360, 1296, 1249, 1084, 985,
832, 773 cm-1; 1H NMR (600 MHz, CDCl3) δ 6.98 (s, 1 H, SCHdC),
6.45 (s, 1 H, CHdCCH3), 5.07-5.21 (m, 2 H, CH3CdCHCH2, CH2-
COOCH), 4.32 (dd, J ) 6.8, 5.0 Hz, 1 H, CHOSi), 4.05 (d, J ) 5.7
Hz, 1 H, CHOSi), 3.17 (dq, J ) 7.0, 6.8 Hz, 1 H, C(O)CHCH3), 2.70
(s, 3 H, NdC(CH3)S), 2.57-2.52 (m, 1 H), 2.29 (dd, J ) 14.4, 4.6
Hz, 1 H, CH2COOCH), 2.27-2.13 (m, 1 H), 2.25 (dd, J ) 14.5, 7.0
Hz, 1 H, CH2COO), 2.20-2.15 (m, 1 H), 2.14 (s, 3 H, CHdC(CH3)),
1.88-1.82 (m, 1 H), 1.57-1.52 (m, 2 H), 1.47-1.38 (m, 3 H), 1.30
(s, 3 H, C(CH3)2), 1.11 (d, J ) 7.2 Hz, 3 H, CH(CH3)), 1.08 (s, 3 H,
C(CH3)2), 0.91 (s, 9 H, SiC(CH3)3), 0.89-0.82 (bs, 12 H, SiC(CH3)3,
CH(CH3)), 0.11 (s, 3 H, Si(CH3)2), 0.09 (s, 3 H, Si(CH3)2), 0.06 (s, 3
H, Si(CH3)2), -0.03 (s, 3 H, Si(CH3)2); 13C NMR (150.9 MHz, CDCl3)
δ 220.2, 170.9, 164.8, 153.1, 140.0, 137.6, 120.2, 118.9, 116.3, 79.3,
74.0, 53.3, 48.0, 41.2, 39.7, 34.9, 31.4, 31.3, 26.6, 26.1, 25.9, 25.3,
23.9, 19.0, 18.5, 18.4, 18.1, 16.2, 14.9, 13.8, -3.9, -4.4, -4.6, -4.9;
FAB HRMS (NBA/CsI) m/e 852.3451, M + Cs+ calcd for C39H69-
NO5SSi2 852.3489.
1
cm-1; H NMR (500 MHz, CDCl3) δ 6.90 (s, 1 H, SCHdC), 6.44 (s,
1 H, CHdCCH3), 5.16-5.12 (m, 1 H, C(CH3)dCHCH2), 4.09-4.05
(m, 1 H, (CH3)2CCHOSi), 3.65-3.58 (m, 3 H, CH2CHOSi, CH2OSi),
3.42-3.38 (m, 1 H, CH(CH3)CHOH), 3.24-3.19 (m, 1 H, C(O)-
Ketone 69. To a solution of aldehyde 20 (1.3 g, 4.53 mol) in THF
(20 mL) at -78 °C was added dropwise lithium tri-tert-butoxyalumi-
nohydride (4.98 mL, 1.0 M solution in THF, 4.98 mmol, 1.1 equiv).
After 5 min, the reaction mixture was brought up to 0 °C and stirred
at that temperature for 15 min, before quenching with saturated aqueous
solution of sodium-potasium tartrate (25 mL). The aqueous phase
was extracted with ether (3 × 20 mL), and the combined organic layer
was dried (MgSO4), filtered, and concentrated. The crude primary
alcohol so obtained was dissolved in CH2Cl2 (25 mL) and cooled to 0
°C. Et3N (2.5 mL, 15.85 mmol, 3.5 equiv), 4-DMAP (60 mg, 0.09
mmol, 0.02 equiv), and tert-butyldimethylsilyl chloride (2.0 g, 13.59
mmol, 3.0 equiv) were added. The reaction mixture was allowed to
stir at 0 °C for 2 h, then at 25 °C for 10 h. MeOH (5 mL) was added,
and the solvents were removed under reduced pressure. Ether (100
mL) was added followed by saturated aqueous NH4Cl solution (25 mL),
and the organic phase was separated. The aqueous phase was extracted
with ether (2 × 50 mL), and the combined organic solution was dried
(MgSO4), filtered, and concentrated under reduced pressure. Purifica-
tion by flash column chromatography (silica gel, 5% ether in hexanes)
provided pure bis(silyl ether) 69 (1.26 g, 70% yield from 20): Rf )
0.67 (silica gel, 20% ether in hexanes); [R]22D -7.3 (c 1.8, CHCl3); IR
(thin film) νmax 2941, 2856, 1701, 1466, 1388, 1252, 1095, 1024, 946,
CH(CH3)), 2.69 (s,
3 H, NdC(CH3)S), 2.31-2.18 (m, 2 H,
C(CH3)dCHCH2), 1.98 (s, 3 H, CHdC(CH3)), 1.99-1.88 (m, 2 H,
CH2C(CH3)dCH), 1.67 (s, 3 H, C(CH3)dCHCH2), 1.55-1.40 (m, 5
H), 1.35-1.25 (m, 2 H), 1.20 (s, 3 H, C(CH3)2), 1.13 (s, 3 H, C(CH3)2),
1.09 (d, J ) 7.0 Hz, 3 H, CH(CH3)), 0.95 (d, J ) 7.0 Hz, 3 H, CH-
(CH3)), 0.88 (s, 18 H, 2 x SiC(CH3)3), 0.87 (s, 9 H, SiC(CH3)3), 0.10
(s, 3 H, Si(CH3)2), 0.05 (s, 3 H, Si(CH3)2), 0.04 (s, 3 H, Si(CH3)2),
0.03 (s, 6 H, Si(CH3)2), -0.01 (s, 3 H, Si(CH3)2); FAB HRMS (NBA)
m/e 838.5653, M + Cs+ calcd for C45H87NO5SSi3 838.5691.
Tetrakis(silyl ether) 72. Compound 70 (275 mg, 0.33 mmol) was
dissolved in CH2Cl2 (5.0 mL), cooled to 0 °C, and treated with 2,6-
lutidine (76 µL, 0.66 mmol, 2.0 equiv) and tert-butyldimethylsilyl
trifluoromethanesulfonate (88 µL, 0.39 mmol, 1.2 equiv). After being
stirred for 2 h at 0 °C, the reaction mixture was quenched with aqueous
HCl (5 mL, 1.0 N solution) and the aqueous phase was extracted with
CH2Cl2 (3 × 5 mL). The combined organic solution was washed with
brine (5 mL), dried (MgSO4), and concentrated under reduced pressure.
Purification by flash column chromatography (silica gel, 3% ether in
hexanes) provided tetrakis(silyl ether) 72 (300 mg, 96%) as a colorless
1
832, 775 cm-1; H NMR (500 MHz, CDCl3) δ 4.06 (dd, J ) 8.0, 3.0
oil. 72: Rf ) 0.56 (silica gel, 10% ether in hexanes); [R]22 -10.8 (c
D
Hz, 1 H, CHOSi), 3.65-3.56 (m, 2 H, CH2OSi), 2.56 (dq, J ) 18.5,
7.0 Hz, 1 H, CH2CH3), 2.46 (dq, J ) 18.5, 7.0 Hz, 1 H, CH2CH3),
1.56-1.43 (m, 2 H, CH2CH2OSi), 1.11 (s, 3 H, C(CH3)2), 1.04 (s, 3
H, C(CH3)2), 0.98 (t, J ) 7.0 Hz, 3 H, CH3CH2), 0.88 (s, 9 H, SiC-
(CH3)3), 0.87 (s, 9 H, SiC(CH3)3), 0.09 (s, 3 H, Si(CH3)2), 0.04 (s, 3
H, Si(CH3)2), 0.03 (s, 3 H, Si(CH3)2), 0.02 (s, 3 H, Si(CH3)2); 13C NMR
(125.7 MHz, CDCl3) δ 215.5, 73.2, 59.9, 52.9, 37.1, 31.4, 25.9, 25.7,
22.0, 19.8, 18.2, 18.1, 7.6, -4.1, -4.2, -5.4, -5.5; FAB HRMS (NBA)
m/e 403.3075, M + H+ calcd for C21H46O3Si2 403.3064.
Tris(silyl ethers) 70 and 71. Aldol Reaction of Ketone 69 with
Aldehyde 8. A solution of ketone 68 (270 mg, 0.67 mmol, 1.2 equiv)
in THF (1.5 mL) was added dropwise to a freshly prepared solution of
LDA [diisopropylamine (94 µL, 0.67 mmol) was added to n-BuLi (0.43
mL, 1.6 M solution in hexanes, 0.67 mmol) in 2.5 mL of THF at 0 °C]
in THF (2.5 mL) at -78 °C. After being stirred for 15 min at -78
°C, the solution was allowed to warm to -40 °C over a period of 1 h.
0.5, CHCl3); IR (thin film) νmax 2919, 2872, 1690, 1461, 1384, 1361,
1249, 1085, 985, 838, 773, 732, 667 cm-1; 1H NMR (500 MHz, CDCl3)
δ 6.88 (s, 1 H, SCHdC), 6.43 (s, 1 H, CHdCCH3), 5.13 (dd, J ) 7.1,
7.0 Hz, 1 H, C(CH3)dCHCH2), 4.08 (dd, J ) 6.8, 6.7 Hz, 1 H, (CH3)2-
CCHOSi), 3.89 (dd, J ) 7.6, 2.7 Hz, 1 H, CH2CHOSi), 3.77 (dd, J )
6.7, 1.0 Hz, 1 H, CH(CH3)CHOSi), 3.67-3.62 (m, 1 H, CH2OSi),
3.58-3.53 (m, 1 H, CH2OSi), 3.14 (dd, J ) 6.8, 6.7 Hz, 1 H, C(O)-
CH(CH3)), 2.68 (s,
3 H, NdC(CH3)S), 2.29-2.17 (m, 2 H,
C(CH3)dCHCH2), 1.98 (s, 3 H, CHdC(CH3)), 1.97-1.89 (m, 2 H,
CH2C(CH3)dCH), 1.64 (s, 3 H, C(CH3)dCHCH2) 1.50-1.45 (m, 5
H), 1.34-1.23 (m, 2 H), 1.20 (s, 3 H, C(CH3)2), 1.02 (d, J ) 6.8 Hz,
3 H, CH(CH3)), 1.00 (s, 3 H, C(CH3)2), 0.88-0.86 (m, 39 H, CH-
(CH3), 4 x SiC(CH3)3), 0.08 (s, 3 H, Si(CH3)2), 0.07 (s, 3 H, Si(CH3)2),
0.04 (s, 3 H, Si(CH3)2), 0.03 (s, 3 H, Si(CH3)2), 0.02 (s, 6 H, Si(CH3)2),
0.01 (s, 3 H, Si(CH3)2), -0.02 (s, 3 H, Si(CH3)2); 13C NMR (125.7
MHz, CDCl3) δ 218.2, 164.2, 153.2, 142.4, 136.6, 121.5, 118.5, 114.9,

Total Synthesis of Epothilones A and B
J. Am. Chem. Soc., Vol. 119, No. 34, 1997 7991
78.8, 77.3, 73.9, 60.9, 53.6, 44.9, 38.8, 37.9, 35.2, 32.4, 30.9, 26.2,
26.1, 25.9, 24.4, 23.4, 19.2, 19.1, 18.5, 18.3, 18.2, 18.1, 17.5, 13.9,
-3.7, -3.8, -4.0, -4.7, -4.9, -5.2, -5.3; FAB HRMS (NBA) m/e
952.6515, M + H+ calcd for C51H101NO5SSi4 952.6556.
C(CH3)dCHCH2), 4.48-4.44 (m, 1 H, (CH3)2CCHOSi), 4.07 (dd, J
) 6.1, 5.3 Hz, 1 H, CH2CHOSi), 3.75 (dd, J ) 7.4, 1.0 Hz, 1 H, CH-
(CH3)CHOSi), 3.11 (dd, J ) 7.0, 6.7 Hz, 1 H, C(O)CH(CH3)), 2.69 (s,
3 H, NdC(CH3)S), 2.50 (ddd, J ) 16.6, 4.5, 1.0 Hz, 1 H, CH2CHO),
2.37 (ddd, J ) 16.6, 3.2, 1.0 Hz, 1 H, CH2CHO), 2.28-2.16 (m, 2 H,
C(CH3)dCHCH2), 1.97 (s, 3 H, CHdC(CH3)), 1.97-1.89 (m, 2 H,
CH2C(CH3)dCH), 1.64 (s, 3 H, C(CH3)dCHCH2), 1.50-1.25 (m, 5
H), 1.22 (s, 3 H, C(CH3)2), 1.05 (s, 3 H, C(CH3)2), 1.01 (d, J ) 6.9
Hz, 3 H, CH(CH3)), 0.89-0.84 (m, 30 H, CH(CH3), 3 x SiC(CH3)3),
0.08 (s, 3 H, Si(CH3)2), 0.04 (s, 6 H, Si(CH3)2), 0.03 (s, 3 H, Si(CH3)2),
0.02 (s, 3 H, Si(CH3)2), -0.02 (s, 3 H, Si(CH3)2); 13C NMR (125.7
MHz, CDCl3) δ 218.5, 201.0, 164.3, 153.2, 142.7, 136.7, 121.5, 118.5,
114.8, 78.9, 77.7, 71.3, 53.4, 45.1, 38.7, 35.3, 32.5, 30.7, 26.2, 25.9,
25.8, 24.1, 23.5, 19.1, 18.7, 18.6, 18.5, 17.7, 15.6, 13.9, -3.6, -3.7,
-4.1, -4.5, -4.7, -5.0; FAB HRMS (NBA) m/e 836.5500, M + H+
calcd for C45H85NO5SSi3 836.5535.
Alcohol 73. Alcohol 73 (200 mg, 85%) was obtained from
compound 72 (264 mg, 0.28 mmol) according to the procedure
described above for 35. 73: colorless oil; Rf ) 0.25 (silica gel, 20%
ether in hexanes); [R]22D -9.3 (c 0.2, CHCl3); IR (thin film) νmax 3392,
2939, 2865, 1689, 1463, 1378, 1357, 1252, 1083, 988, 867, 835, 772,
730 cm-1; 1H NMR (500 MHz, CDCl3) δ 6.90 (s, 1 H, SCHdC), 6.44
(s, 1 H, CHdCCH3), 5.14 (dd, J ) 7.0, 6.9 Hz , 1 H, C(CH3)dCHCH2),
4.10-4.05 (m, 2 H, (CH3)2CCHOSi, CH2CHOSi), 3.78 (dd, J ) 7.0,
1.0 Hz, 1 H, CH(CH3)CHOSi), 3.63 (t, J ) 7.0 Hz , 2 H, CH2OH),
3.11 (dd, J ) 7.0, 6.8 Hz, 1 H, C(O)CH(CH3)), 2.70 (s, 3 H, NdC-
(CH3)S), 2.27-2.19 (m, 2 H, C(CH3)dCHCH2), 1.99 (d, J ) 1.0 Hz,
3 H, CHdC(CH3)), 2.10-1.90 (m, 2 H, CH2C(CH3)dCH), 1.65 (s, 3
H, C(CH3)dCHCH2), 1.50-1.39 (m, 2 H), 1.36-1.29 (m, 3 H), 1.21
(s, 3 H, C(CH3)2), 1.20-1.10 (m, 2 H), 1.05 (s, 3 H, C(CH3)2), 1.04
(d, J ) 6.8 Hz, 3 H, CH(CH3)), 0.91-0.87 (m, 30 H, CH(CH3), 3 x
SiC(CH3)3), 0.11 (s, 3 H, Si(CH3)2), 0.07 (s, 3 H, Si(CH3)2), 0.06 (s, 6
H, Si(CH3)2), 0.04 (s, 3 H , Si(CH3)2), -0.01 (s, 3 H, Si(CH3)2); 13C
NMR (125.7 MHz, CDCl3) δ 219.5, 164.2, 153.1, 142.4, 136.6, 121.5,
118.5, 114.8, 78.8, 77.4, 72.9, 60.1, 53.6, 45.8, 44.9, 38.6, 38.2, 35.2,
32.4, 30.6, 26.1, 25.9, 24.7, 23.4, 19.1, 18.4, 18.1, 18.0, 17.6, 15.5,
13.8, -3.7, -3.8, -4.0, -4.7, -5.1; FAB HRMS (NBA/CsI) m/e
970.4694, M + Cs+ calcd for C45H87NO5SSi3 970.4667.
Carboxylic Acid 52. Oxidation of Aldehyde 74. Aldehyde 74
t
(224 mg, 0.29 mmol), BuOH (5.0 mL), isobutylene (5.0 mL, 2 M
solution in THF, 10.0 mmol), H2O (1.0 mL), NaClO2 (90 mg, 0.86
mmol, 3.0 equiv), and NaH2PO4 (60 mg, 0.43 mmol, 1.5 equiv) were
combined and stirred at room temperature for 1 h. The reaction mixture
was concentrated under reduced pressure, and the residue was subjected
to flash column chromatography (silica gel, 6% MeOH in CH2Cl2) to
afford carboxylic acid 52 (220 mg, 90%) whose spectroscopic data
were identical with those exhibited by 52 obtained above.
Aldehyde 74. Oxidation of Alcohol 73. To a solution of oxalyl
chloride (54 µL, 0.61 mmol, 2.0 equiv) in CH2Cl2 (5.0 mL) was added
dropwise DMSO (86 µL, 1.21 mmol, 4.0 equiv) at -78 °C. After the
mixture was stirred for 15 min at -78 °C, a solution of alcohol 73
(255 mg, 0.305 mmol, 1.0 equiv) in CH2Cl2 (2.0 mL) was added
dropwise at -78 °C over a period of 5 min. The solution was stirred
at -78 °C for 30 min, and then Et3N (250 µL, 1.82 mmol, 6.0 equiv)
was added. The reaction mixture was allowed to warm to 0 °C over
a period of 30 min, and then ether (20 mL) was added, followed by
saturated aqueous NH4Cl solution (10 mL). The organic phase was
separated, and the aqueous phase was extracted with ether (2 × 10
mL). The combined organic solution was dried (MgSO4), filtered, and
concentrated under reduced pressure. Purification by flash column
chromatography (silica gel, 20% ether in hexanes) provided aldehyde
74 (241 mg, 95%) as a colorless oil. 74: Rf ) 0.47 (silica gel, 20%
ether in hexanes); [R]22D -12.0 (c 0.1, CHCl3); IR (thin film) νmax 2943,
Acknowledgment. We thank Dr. G. Ho¨fle for a generous
gift of authentic samples of natural epothilones A (1) and B (2)
and Drs. Dee H. Huang and Gary Siuzdak for NMR and mass
spectroscopic assistance, respectively. This work was financially
supported by The Skaggs Institute for Chemical Biology, the
National Institutes of Health USA, fellowships from the
Fundacio´n Ramo´n Areces (F.S.), Novartis (D.V.) and Fulbright
Commission (M.R.V.F.), and grants from CaPCURE, Amgen,
Merck, DuPont-Merck, Hoffmann LaRoche, and Schering-
Plough.
Supporting Information Available: Selected physical data
for compounds 48, 49, 8′, 52′, 53′, and 6′ and 1H-1H NOESY
1
and H-1H COSY spectra for epoxides 58 and 59 (8 pages).
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1
2849, 1725, 1690, 1461, 1384, 1249, 1079, 985, 832, 773 cm-1; H
NMR (500 MHz, CDCl3) δ 9.74 (m, 1 H, CHO), 6.89 (s, 1 H, SCHdC),
6.43 (s, 1 H, CHdCCH3), 5.14 (dd, J ) 7.1, 7.0 Hz, 1 H,
JA971110H