The olefin metathesis approach to epothilone A and its analogues

Article abstract of DOI:10.1021/ja971109i

The olefin metathesis approach to epothilone A (1) and several analogues (39-41, 42-44, 51-57, 58-60, 64-65, and 67-69) is described. Key building blocks 6-8 were constructed in optically active form and were coupled and elaborated to olefin metathesis pr

Full text of DOI:10.1021/ja971109i

7960
J. Am. Chem. Soc. 1997, 119, 7960-7973
The Olefin Metathesis Approach to Epothilone A and Its
Analogues
K. C. Nicolaou,* Y. He, D. Vourloumis, H. Vallberg, F. Roschangar, F. Sarabia,
S. Ninkovic, Z. Yang, and J. I. Trujillo
Contribution from the Department of Chemistry and The Skaggs Institute for Chemical Biology
and 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 olefin metathesis approach to epothilone A (1) and several analogues (39-41, 42-44, 51-57, 58-
60, 64-65, and 67-69) is described. Key building blocks 6-8 were constructed in optically active form and were
coupled and elaborated to olefin metathesis precursor 4 via an aldol reaction and an esterification coupling. Olefin
metathesis of compound 4, under the catalytic influence of RuCl2(dCHPh)(PCy3)2, furnished cis- and trans-cyclic
olefins 3 and 48. Epoxidation of 49 gave epothilone A (1) and several analogues, whereas epoxidation of 50 resulted
in additional epothilones. Similar elaboration of isomeric as well as simpler intermediates resulted in yet another
series of epothilone analogues and model systems.
1. Introduction
The epothilones (A: 1 and B: 2, Figure 1)1-4 represent a
new class of natural products with potent microtubule binding
and stabilizing abilities and selective antitumor properties.3,4 In
their action as inducers of tubulin polymerization and micro-
tubule stabilization, the epothilones resemble Taxol,5,6 which
they do not only mimic but also displace on the microtubules.3,4
Significantly, these new antitumor agents exhibit selective
cytotoxicity and are particularly effective against certain drug-
resistant tumor cell lines, even in cases where Taxol fails.3,4
Epothilones A (1) and B (2) were originally isolated by Ho¨fle
et al. from myxobacteria (Sorangium cellulosum strain 90)1,2
and independently by a group at Merck.4a Their novel molecular
architecture has been fully characterized by spectroscopic and
X-ray crystallographic techniques.2 Their structural appeal
combined with their important biological activities3,4 and
intriguing mechanism of action4 defines exciting opportunities
for synthetic chemists, biologists, and clinicians.7-12 Our
interest focused initially on developing strategies for the total
Figure 1. Structure and numbering of epothilones A (1) and B (2).
synthesis of these natural substances and of designed epothilones
for chemical and biological studies.7a,10,11 In this article, we
describe the details of our olefin metathesis approach to
epothilone A (1) and its application to the synthesis of several
of its analogues. Similar strategies leading to total syntheses
of epothilone A (1) and several of its congeners were indepen-
dently pursued by the Danishefsky9 and the Schinzer groups.12
The first total synthesis of epothilone A was achieved via an
intramolecular ester enolate-aldehyde condensation by the
Danishefsky group.8
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, G.;
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.
2. Retrosynthetic Analysis and Strategy
The structure of epothilone A (1) is characterized by a 16-
membered macrocyclic lactone carrying a cis-epoxide moiety,
two hydroxyl groups, two secondary methyl groups, and a gem
dimethyl group, as well as a side chain consisting of a
trisubstituted double bond and a thiazole moiety. With its seven
stereocenters and two geometrical elements, epothilone A (1)
presents a considerable challenge as a synthetic target, particu-
larly with regard to stereochemistry and functional group
(8) 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.
(9) Meng, D.; Su, D.-S.; Balog, A.; Bertinato, P.; Sorensen, E. J.;
Danishefsky, S. D.; Zheng, Y.-H.; Chou, T.-C.; He, L.; Horwitz, S. B. J.
Am. Chem. Soc. 1997, 119, 2733-2734.
(10) Yang, Z.; He, Y.; Vourloumis, D.; Vallberg, H.; Nicolaou, K. C.
Angew. Chem., Int. Ed. Engl. 1997, 36, 166-168.
(11) Nicolaou, K. C.; Sarabia, F.; Ninkovic, S.; Yang, Z. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 525-527.
(12) Schinzer, D.; Limberg, A.; Bauer, A.; Bo¨hm, O. M.; Cordes, M.
Angew. Chem., Int. Ed. Engl. 1997, 36, 523-524.
S0002-7863(97)01109-8 CCC: $14.00 © 1997 American Chemical Society

Olefin Metathesis Approach to Epothilone A
J. Am. Chem. Soc., Vol. 119, No. 34, 1997 7961
sensitivity. In search for a suitable synthetic strategy, we sought
to apply new principles of organic synthesis and, at the same
time, retain optimum flexibility for structural diversity and
construction of libraries.
Scheme 1. Retrosynthetic Analysis of Epothilone A (1)
In recent years, the olefin metathesis reaction has become a
powerful tool for organic synthesis.13 In particular, a number
of publications report application of this chemistry to the
construction of macrocycles.14
Inspection of the structure of epothilone A (1) revealed the
intriguing possibility of applying the olefin metathesis reaction
to bis(terminal) olefin 4 to yield the cis-olefin-containing
macrocyclic lactone 3, which could be converted to the natural
product by simple epoxidation, as retrosynthetically outlined
in Scheme 1. Daring as it was, this strategy had the potential
of delivering both the cis- and trans-cyclic olefins corresponding
to 4 for structural variation. Proceeding with the retrosynthetic
analysis, an esterification reaction was identified as a means to
permit disconnection of 4 to its components, carboxylic acid 5
and secondary alcohol 6. The aldol moiety in 5 allowed the
indicated disconnection, defining aldehyde 7 and keto acid 8
as potential intermediates. Carboxylic acid 8 could then be
traced to intermediate 9, whose asymmetric synthesis via
allylboration of the known keto aldehyde 12 was straightforward.
An asymmetric allylboration could also be envisioned as a
method to construct alcohol 6, leading to precursor 10, which
could be derived from the known thiazole derivative 11. This
retrosynthetic analysis led to a highly convergent and flexible
synthetic strategy, the execution of which proved to be highly
rewarding in terms of delivering epothilone A (1) and a series
of analogues of this naturally occurring substance for biological
screening.
3. Construction of Key Building Blocks and Model
Studies
As a prelude to the total synthesis, a number of building
blocks were synthesized and utilized in model studies. Thus,
fragments 7, 18a,b, and 21 (Schemes 2-4) were targeted for
synthesis. Aldehyde 7 was constructed by two different routes,
one of which is summarized in Scheme 2.15 Thus, Oppolzer’s
acylated sultam derivative 1316 was alkylated with 5-iodo-1-
pentene in the presence of sodium bis(trimethylsilyl)amide
(NaHMDS) to furnish compound 14 as a single diastereoisomer
Scheme 2. Synthesis of Aldehyde 7a
1
(by H NMR). Lithium aluminum hydride reduction of 14
produced alcohol 1514d in 60% overall yield from sultam 13.
Oxidation of 15 with tetrapropylammonium perruthenate(VII)
(13) For the development of the olefin metathesis as a ring forming
reaction, see: (a) Zuercher, W. J.; Hashimoto, M.; Grubbs, R. H. J. Am.
Chem. Soc. 1996, 118, 6634-6640. (b) Schwab, P. R.; Grubbs, H.; Ziller,
J. W. J. Am. Chem. Soc. 1996, 118, 100-110. (c) Grubbs, R. H.; Miller, S.
J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446-452 and references therein.
(d) Tsuji, J.; Hashiguchi, S. Tetrahedron Lett. 1980, 21, 2955-2959. For
some earlier pioneering studies on this reaction, see: (e) Katz, T. J.; Lee,
S. J.; Acton, N. Tetrahedron Lett. 1976, 4247-4250. (f) Katz, T. J.; Acton,
N. Tetrahedron Lett. 1976, 4241-4254. (g) Katz, T. J.; McGinnis, J.; Altus,
C. J. Am. Chem. Soc. 1976, 98, 606-608. (h) Katz, T. J. AdV. Organomet.
Chem. 1977, 16, 283-317.
(14) For a number of applications of the olefin metathesis reaction in
medium and large ring synthesis, see: (a) Borer, B. C.; Deerenberg, S.;
Biera¨ugel, H.; Pandit, U. K. Tetrahedron Lett. 1994, 35, 3191-3194. (b)
Clark, T. D.; Ghadiri, M. R. J. Am. Chem. Soc. 1995, 117, 12364-12365.
(c) Houri, A. F.; Xu, Z.; Cogan, D. A.; Hoveyda, A. H. J. Am. Chem. Soc.
1995, 117, 2943-2944. (d) Fu¨rstner, A.; Langemann, K. J. Org. Chem.
1996, 61, 3942-3943. (e) Martin, S. F.; Chen, H.-J.; Courtney, A. K.; Liao,
Y.; Pa¨tzel, M.; Ramser, M. N.; Wagman, A. S. Tetrahedron 1996, 52, 7251-
7264. (f) Xu, Z.; Johannes, C. W.; Salman, S. S.; Hoveyda, A. H. J. Am.
Chem. Soc. 1996, 118, 10926-10927.
a Reagents and conditions: (a) 1.05 equiv of NaHMDS, 2.0 equiv
of n-C5H9I, 3.0 equiv HMPA, -78 f 25 °C, 5 h; (b) 1.1 equiv of
LiAlH4, THF, -78 °C, 15 min, 60% (two steps); (c) 1.5 equiv of NMO,
5 mol % of TPAP, CH2Cl2, 4 Å MS, 25 °C, 0.5 h, 95%. NaHMDS )
sodium bis(trimethylsilyl)amide; HMPA ) hexamethylphosphoramide,
NMO ) 4-methylmorpholine N-oxide; TPAP ) tetrapropylammonium
perruthenate.
(15) For the other route to 7, see ref 7a.
(TPAP)17 and 4-methylmorpholine N-oxide (NMO) provided
the desired aldehyde 7 in 95% yield.
(16) (a) Oppolzer, W.; Moretti, R.; Thomi, S. Tetrahedron Lett. 1989,
30, 5603-1989. (b) Oppolzer, W. Pure Appl. Chem. 1990, 62, 1241-1250.

7962 J. Am. Chem. Soc., Vol. 119, No. 34, 1997
Scheme 3. Synthesis of Alcohols 18a,ba
Nicolaou et al.
Scheme 5. Synthesis of the Epothilone Cyclic Framework
via Olefin Metathesis: the 15S Seriesa
a Reagents and conditions: (a) 1.3 equiv of TPSCl, 2.0 equiv of
imidazole, DMF, 0 f 25 °C, 1.5 h (90% of 17a, 94% of 74b); (b)
1.25 equiv of tetravinyltin, 5.0 equiv of n-BuLi, THF, -78 °C, 45 min,
then 2.5 equiv of CuCN in THF, -78 f -30 °C; then 17a or 17b in
t
THF, -30 °C, 1 h, 18a (86%), 18b (83%). TPS ) SiPh2 Bu.
Scheme 4. Synthesis of Ketoacid 21a
a Reagents and conditions: (a) 1.2 equiv of 19, 1.6 equiv of NaH,
THF, 0 f 25 °C, 1 h, 99%; (b) CF3COOH (TFA):CH2Cl2 (1:1), 25
°C, 0.5 h, 99%.
The synthesis of the two antipodal alcohols 18a,b is outlined
in Scheme 3. Thus, glycidols 16a and 16b were converted to
the corresponding tert-butyldiphenylsilyl ethers (OTPS) 17a
(90% yield) and 17b (94% yield), respectively, by a standard
procedure (TPSCl, imidazole), and then to homoallylic alcohols
18a (86% yield) and 18b (83% yield) by reaction with the vinyl
cuprate reagent derived from copper(I) cyanide and vinyl-
lithium.18
Scheme 4 summarizes the synthesis of the third required
building block, keto acid 21, starting with the known and readily
available keto aldehyde 12.19 Condensation of 12 with the
sodium salt of phosphonate 19 produced R,â-unsaturated ester
20 in 99% yield. Cleavage of the tert-butyl ester with CF3-
COOH (TFA) in CH2Cl2 resulted in a 99% yield of carboxylic
acid 21.
a Reagents and conditions: (a) 1.2 equiv of EDC, 0.1 equiv of
4-DMAP, CH2Cl2, 0 f 25 °C, 12 h, 86%; (b) 21, 1.2 equiv of LDA,
-78 °C f 40 °C, THF, 45 min; then 1.6 equiv of 7 in THF, -78 f
-40 °C, 0.5 h, 23 (42%), 24 (33%); (c) 0.1 equiv of RuCl2-
(dCHPh)(PCy3)2, CH2Cl2, 25 °C, 12 h, 25 (85%), 26 (79%); (d) 2.0
equiv of TBAF, 5.0 equiv of AcOH, 25 °C, 36 h, 27 (92%), 28 (95%).
EDC ) 1-ethyl-3-(3-(dimethylamino)propyl-3-carbodiimide hydro-
chloride. 4-DMAP ) 4-dimethylaminopyridine. LDA ) lithium
diisopropylamide. TBAF ) tetrabutylammonium fluoride.
With the requisite fragments in hand, we turned our attention
to a feasibility study of the olefin metathesis strategy. Scheme
5 summarizes the results of our initial work in this field. Thus,
coupling of fragments 18a and 21, mediated by the action of
1-ethyl-(3-(dimethylamino)propyl)-3-carbodiimide hydrochlo-
ride (EDC) and 4-dimethylaminopyridine (4-DMAP), led to
ester 22a in 86% yield. Aldol condensation of the lithium
enolate of keto ester 22a (generated by the action of lithium
diisopropylamide (LDA)) and aldehyde 7 resulted in the
formation of aldols 23 and 24 in ca. 4:3 ratio (1H NMR).
Chromatographic separation allowed the isolation of pure 23
(42% yield) and 24 (33% yield). The stereochemical assign-
ments of compounds 23 and 24 were based on an X-ray
crystallographic analysis of a subsequent intermediate as will
be described below. Returning to Scheme 5, exposure of 23 to
the RuCl2(dCHPh)(PCy3)2 catalyst in CH2Cl2 solution under
high-dilution conditions at 25 °C for 12 h resulted in clean
formation of single trans-macrocyclic olefin 25 (J12,13 ) 15.5
Hz) in 85% yield. Similar treatment of 24 generated the
diastereomeric trans-olefin 26 (J12,13 ) 15.2 Hz) as the sole
product in 79% yield. Desilylation of 25 and 26 with tetrabu-
Figure 2. ORTEP drawing of compound 28.
tylammonium fluoride (TBAF) and AcOH in THF at 25 °C
furnished dihydroxy lactones 27 (92% yield) and 28 (95% yield,
mp 128-129 °C, EtOAc-hexanes), respectively.
X-ray crystallographic analysis of macrocyclic diol 28
revealed the trans nature of the double bond and defined the
stereochemistry of all stereogenic centers (see ORTEP drawing
of compound 28, Figure 2). Comparison of the 1H NMR spectra
of 26 and 28 with those of 25 (J12,13 ) 15.5 Hz), 27, 31 (J12,13
) 15.7 Hz) and 32 (vide infra) supported the trans geometry
(17) Griffith, W. P.; Ley, S. V. Aldrichim. Acta 1990, 23, 13-19.
(18) Lipshuzt, B. H.; Kozlowski, J. A. J. Org. Chem. 1984, 49, 1147-
1149.
(19) Inuka, T.; Yoshizawa, R. J. Org. Chem. 1967, 32, 404-407.

Olefin Metathesis Approach to Epothilone A
J. Am. Chem. Soc., Vol. 119, No. 34, 1997 7963
Scheme 6. Synthesis of the Epothilone Cyclic Framework
via Olefin Metathesis: the 15R Seriesa
Scheme 7. Metathesis and Epoxidation in the Presence of
Thiazole: Synthesis of Epothilone Analogues 39-44a
a Reagents and conditions: (a) 1.4 equiv of DCC, 1.4 equiv of
4-DMAP, toluene, 25 °C, 12 h, 95%; (b) 21, 1.2 equiv of LDA, -78
°C f -40 °C, THF, 45 min; then 1.6 equiv of 7 in THF, -78 f -40
°C, 0.5 h, 29 (54%), 30 (24%); (c) 0.1 equiv of RuCl2(dCHPh)(PCy3)2,
CH2Cl2, 25 °C, 12 h, 31 (80%), 32 (81%). DCC ) 1,3 dicyclohexyl-
carbodiimide.
of the double bond generated by the olefin metathesis and the
C6-C7 stereochemistry. Therefore, the original assignment7a
of the cis geometry for this double bond and the C6-C7
stereochemistry of the aldol products in these model systems
should now be revised as shown. Ironically, it was this
erroneous, but encouraging, assignment that led us to embark
on the final plan to synthesize epothilone A by the olefin
metathesis approach. As events unfolded (vide infra), the real
system produced both the cis- and the trans-cyclic olefins and
the metathesis approach turned out to be fruitful.
For the purposes of analogue synthesis, the 15R-fragment 18b
was also utilized in these studies, as shown in Scheme 6.
Coupling of 18b and 21 with 1,3-dicyclohexylcarbodiimide
(DCC) and 4-DMAP led to a 95% yield of ester 22b, the
enantiomer of 22a. LDA-mediated aldol condensation of 22b
with aldehyde 7 furnished aldols 29 (54% yield) and 30 (24%
yield), which are diastereomeric with 23 and 24 of Scheme 5.
Olefin metathesis of 29 and 30 with the RuCl2(dCHPh)(PCy3)2
catalyst led to cyclic systems 31 (J12,13 ) 15.7 Hz) (80% yield)
and 32 (J12,13 ) 15.4 Hz) (81% yield), respectively. Compounds
27, 28, 31, and 32 may serve as suitable precursors for the
construction of a series of designed epothilones for biological
investigations. At this juncture, however, it was considered
more urgent to investigate the compatibility of the thiazole side
chain with the conditions of olefin metathesis and epoxidation.
a Reagents and conditions: (a) 21, 2.3 equiv of LDA, -78 f -30
°C, THF, 1.5 h; then 1.6 equiv of 7 in THF, -78 f -40 °C, 1 h
(33:34, 2:3); (b) ca. 2.0 equiv of 6, ca. 1.2 equiv of EDC, ca. 0.1 equiv
of 4-DMAP, CH2Cl2, 0 f 25 °C, 12 h, 35 (29%), 6 (44%) (two steps);
(c) 0.1 equiv of RuCl2(dCHPh)(PCy3)2, CH2Cl2, 25 °C, 12 h, 37 (86%),
38 (66%); (d) 0.991.2 equiv of mCPBA, CHCl3, -20 f 0 °C, 12 h,
37 f 39 (or 40) (40%), 40 (or 39) (25%), 41 (18%); 38 f 42 (or 43)
(22%), 43 (or 42) (11%), 44 (7%); (e) excess of CF3COCH3, 8.0 equiv
of NaHCO3, 5.0 equiv of Oxone, CH3CN/Na2EDTA (2:1), 0 °C, 37 f
39 (or 40) (45%), 40 (or 39) (28%); 38 f 42 (or 43) (60%), 43 (or 42)
(15%). mCPBA ) 3-chloroperoxybenzoic acid. Oxone ) potassium
peroxymonosulfate. Na2EDTA ) ethylenediaminetetraacetic acid
disodium salt.
To this end, the chemistry shown in Scheme 7 was studied.
The enolate of keto acid 21 (2.3 equiv of LDA, THF, -78 f
-30 °C) reacted with aldehyde 7 to afford hydroxy acids 33
620 in the presence of EDC and 4-DMAP to afford two
diastereomeric esters 35 and 36 (29% and 44% yield, respec-
tively, for two steps). Both products, 35 and 36, were subjected
to the olefin metathesis reaction, and we were delighted to
1
and 34 as a mixture of C6-C7 diastereomers (ca. 2:3 by H
NMR) in good yield. This mixture was coupled with alcohol

7964 J. Am. Chem. Soc., Vol. 119, No. 34, 1997
Scheme 8. Coupling of Building Blocks 6-8a
Nicolaou et al.
Scheme 9. Epoxidation of Epothilone Framework: Total
Synthesis of Epothilone A (1) and Analogues 51-57a
a Reagents and conditions: (a) 8, 2.3 equiv of LDA, -78 f -30
°C, THF, 1.5 h; then 1.6 equiv of 7 in THF, -78 f -40 °C, 1 h
(45:46, 3:2); (b) ca. 2.0 equiv of 6, ca. 1.2 equiv of EDC, ca. 0.1 equiv
of 4-DMAP, CH2Cl2, 0 f 25 °C, 12 h, 4 (52%), 47 (31%) (two steps).
observe a smooth ring closure leading to trans-macrocycles 37
(J12,13 ) 15.5 Hz) (86%) and 38 (J12,13 ) 15.0 Hz) (66%). With
cyclized products 37 and 38 in hand, we then proceeded to
demonstrate the feasibility of epoxidizing the C12-C13 double
bond in the presence of the thiazole and olefin functionalities
in the side chain. Thus, treatment of both 37 and 38 with 0.9-
1.2 equiv of 3-chloroperoxybenzoic acid (mCPBA) in CHCl3
at 0 °C resulted in the formation of epoxides 39 (or 40) (40%),
40 (or 39) (25%),22 and 41 (18%), as well as 42 (or 43) (22%),
43 (or 42) (11%), and 44 (7%) along with some unidentified
side products. The use of methyl(trifluoromethyl)dioxirane21
(CH3CN, ethylenediaminetetraacetic acid disodium salt [Na2-
(EDTA), NaHCO3, potassium peroxymonosulfate (Oxone), 0
°C] resulted in improved yields and regio- and stereoselectivities
compared to mCPBA and dimethyldioxirane.8,12,23 Thus, olefins
37 and 38 were converted to epoxides 39 (or 40) (45%) and 40
(or 39) (28%) and epoxides 42 (or 43) (60%) and 43 (or 42)
(15%), respectively. No side-chain epoxidation was observed
in either case. These results paved the way for the final drive
toward epothilone A (1).
4. Total Synthesis of Epothilone A and Analogues
Encouraged by the results of the model studies described
above, we proceeded to assemble epothilone A (1). Scheme 8
shows the initial stages of the construction beyond the key
building blocks 6-8. Thus, aldol condensation of 820 (2.3 equiv
of LDA) with aldehyde 7 afforded diastereomeric products 45
a (a) 0.1 equiv of RuCl2(dCHPh)(PCy3)2, CH2Cl2, 25 °C, 20 h, 3
(46%), 48 (39%); (b) 20% CF3COOH (TFA) in CH2Cl2, 0 °C, 3 h, 3
f 49 (90%); 48 f 50 (92%); (c) 0.8-1.2 equiv of mCPBA, CHCl3,
-20 f 0 °C, 12 h, 49 f 1 (35%); 51 (13%), 52 (or 53) (9%), 53 (or
52 (7%), 54 (or 55) (5%), 55 (or 54) (5%); 1 f 54 (or 55) (35%), 55
(or 54) (33%), 57 (6%); (d) 1.3-2.0 equiv of mCPBA, CHCl3, -20 f
0 °C, 12 h, 1 (15%), 51 (10%), 52 (or 53) (10%), 53 (or 52) (8%), 54
(or 55) (8%), 55 (or 54) (7%), 56 (5%), 57 (5%); (e) 1.0 equiv of
dimethyldioxirane, CH2Cl2/acetone, 0 °C, 1 (50%), 51 (15%), 52 (or
53) (5%), 53 (or 52) (5%); (f) excess of CF3COCH3, 8.0 equiv of
NaHCO3, 5.0 equiv of Oxone, CH3CN/Na2EDTA (2:1), 0 °C, 1 (62%),
51 (13%).
1
and 46 (ca. 3:2 ratio by H NMR), which as a mixture were
coupled with homoallylic alcohol 620 in the presence of EDC
and 4-DMAP to afford, after chromatographic purification, pure
esters 4 (52% overall yield from 8) and 43 (31% overall yield
from 8).
(20) Nicolaou, K. C.; Ninkovic, S.; Sarabia F.; Vourloumis, D.; He, Y.;
Vallberg, H.; Finlay, M. R. V.; Yang, Z. J. Am. Chem. Soc. 1997, 119,
7974-7991 (accompanying paper).
(21) Yang, D.; Wong, M.-K.; Yip, Y.-C. J. Org. Chem. 1995, 60, 3887-
3889.
The olefin metathesis reaction of 4 (6R,7S stereochemistry
as proven by conversion to epothilone A) proceeded smoothly
in the presence of the RuCl2(dCHPh)(PCy3)2 catalyst, as shown
in Scheme 9, to afford cyclic systems 3 (J12,13 ) 10.5 Hz) (46%)
and 48 (J12,13 ) 15.0 Hz) (39%). The silyl ethers from 3 and
(22) Preliminary biological experiments indicated that compounds 39 and
40, 52-55, 64, and 65, 67, and 68 did not induce significant tubulin
polymerization, and therefore, the determination of their stereochemistry
at the position of the epoxide was not pursued further: Nicolaou, K. C.; et
al. Unpublished results.
(23) Murray, R. W.; Jeyaraman, R. J. Org. Chem. 1985, 50, 2847-2853.

Olefin Metathesis Approach to Epothilone A
J. Am. Chem. Soc., Vol. 119, No. 34, 1997 7965
Scheme 10. Synthesis of Epothilones 58-60a
a Reagents and conditions: (a) 0.9-1.3 equiv of mCPBA, CHCl3,
-20 f 0 °C, 12 h, 58 (or 59) (5%), 59 (or 58) (5%), 60 (60%); (b) 1.0
equiv of dimethyldioxirane, CH2Cl2/acetone, 0 °C, 58 (or 59) (10%),
59 (or 58) (10%), 60 (40%); (c) excess of CF3COCH3, 8.0 equiv of
NaHCO3, 5.0 equiv of Oxone, MeCN/Na2EDTA (2:1), 0 °C, 58 (or
59) (45%), 59 (or 58) (35%).
48 were removed by exposure to CF3COOH in CH2Cl2,
affording dihydroxy compounds 49 (90%) and 50 (92%),
respectively.
The cis-olefin 49 was converted to epothilone A (1) by the
action of mCPBA (0.8-1.2 equiv) in a reaction that, in addition
to 1 (35%), produced the isomeric epoxides 51 (13%), 52 (or
53) (9%), and 53 (or 52) (7%),22 as well as bis(epoxides) 54
(or 55) and 55 (or 54) (10% total yield).22 Reaction of olefin
49 with excess mCPBA (1.3-2.0 equiv) resulted in a different
product distribution: 1 (15%), 51 (10%), 52 (or 53) (10%), 53
(or 52) (8%), 54 (or 55) (8%), 55 (or 54) (7%), 56 (5%), and
57 (5%). The action of dimethyldioxirane8,12,23 (CH2Cl2, 0 °C)
on 49 gave mainly 1 (50%) and 51 (15%), together with small
amounts of 53 (or 54) and 54 (or 53) (10% total yield).
However, we found that the preferred procedure for this
epoxidation was the one employing methyl(trifluoromethyl)-
dioxirane,21 a method that furnished epothilone A (1) in 62%
yield, together with smaller amount of its R-epoxide epimer 51
(13% yield). Chromatographically purified synthetic epothilone
A (1) exhibited properties identical to those of an authentic
Figure 3. Computer-generated minimized structures of epothilones
58 (trans-12S,13S-epothilone A) and 59 (trans-12R,13R-epothilone A).
1H-1H NOESY derived NOE’s between protons (intensity, distance):
For 58: H17-H3 (weak, 6.21 Å), H17-H8 (none, 8.13 Å), H17-H12
(none, 4.18 Å), H17-H13 (none, 5.30 Å). For 59: H17-H3 (strong, 2.28
Å), H17-H6 (strong, 2.57 Å), H17-H12 (weak, 3.78 Å), H17-H13 (strong,
2.87 Å). The epothilone atoms are colored according to the following
code: carbon, green; hydrogen, white; oxygen, red; nitrogen, blue;
sulfur, yellow. Molecular dynamics and minimization calculations (CV
Force Field) were performed on a SGI Indigo-2 workstation using
Insight II (Biosym Technologies, Inc., San Diego, CA). Pictures were
created using AVS (AVS Inc., Waltham, MA) and locally developed
modules running on a DEC Alpha 3000/500 with a Kubota Pacific
Denali graphics card.
1
sample (TLC, HPLC, [R]D, IR, H and 13C NMR, and mass
spectroscopy).24 Further oxidation of pure epothilone A (1) with
mCPBA (0.8-1.1 equiv) resulted in the formation of bis-
(epoxides) 54 (or 55) (35%) and 55 (or 54) (32%) along with
sulfoxide 57 (6%), confirming the C12-C13 stereochemical
assignments shown in Scheme 9. Under similar conditions,
R-isomeric epoxide 51 was recovered unreacted.
The trans-olefinic compound 50 gave rise to another series
of epothilones A (58-60) as shown in Scheme 10. Thus,
epoxidation of 50 with 1.0 equiv of mCPBA furnished com-
pounds 58 (5%), 59 (5%), and 60 (60%, stereochemistry
unassigned). Similarly, epoxidation of 50 with 1.0 equiv of
dimethyldioxirane8,12,23 resulted in the formation of 58 (10%),
59 (10%), and 60 (40%). Interestingly, however, the action of
methyl(trifluoromethyl)dioxirane21 led only to 58 (45%) and 59
(35%) in a much cleaner fashion.
of the side chain and the macrolactone. In the (12S,13S)-
epoxide 58, these two subunits assume remote spacial orienta-
tions, while in the (12R,13R)-epoxide 59, the side chain and
the large ring take up overlapping positions (see Figure 3). These
calculated conformations were supported by the 2D NMR
experiments showing, in the case of 59, NOE's between H-17
and several of the macrocyclic protons (H17-H3, H17-H6, H17-
H12, H17-H13), whereas similar experiments with 58 revealed
NOE's between H17-H3 but not between H17-H6, H17-H12,
and H17-H13.
To expand the epothilone A library, we utilized the 6S,7R-
stereoisomer 61 (obtained from 47 by CF3COOH-induced
desilylation in 90% yield) in the olefin metathesis reaction to
afford cyclic compounds 62 (J12,13 ) 9.8 Hz) (20%) and 63
(J12,13 ) 15.0 Hz) (69%) (Scheme 11). Epoxidation of the
dihydroxy macrocycle 62 with mCPBA (0.8-1.2 equiv) in
CHCl3 at -20 f 0 °C gave isomeric epoxides 64 (or 65) (25%)
and 65 (or 64) (23%).22 Side-chain epoxide 66 was not isolated
in this case. Similarly, diol 63 furnished 67 (or 68) (24%), 68
(or 67) (19%),22 and 69 (31%) under the same reaction
conditions. Again, epoxidation of compounds 62 and 63 using
methyl(trifluoromethyl)dioxirane21 resulted in cleaner formation
The stereochemistry of 58 and 59 was tentatively assigned
on the basis of 1H-1H NOESY and 1H-1H COSY experiments
and computer modeling. Thus, molecular dynamics calculations
revealed significant differences between the structures of the
two epimeric epoxides with regard to the spacial arrangements
(24) We thank Dr. G. Ho¨fle for a sample of natural epothilone A (1).

7966 J. Am. Chem. Soc., Vol. 119, No. 34, 1997
Scheme 11. Synthesis of Epothilones 64-69a
Nicolaou et al.
Experimental Section
General Techniques. All reactions were carried out under an argon
atmosphere with dry, freshly distilled solvents under anhydrous
conditions, unless otherwise noted. Tetrahydrofuran (THF), toluene,
and ethyl ether (ether) were distilled from sodium-benzophenone, and
methylene chloride (CH2Cl2), from calcium hydride. Anhydrous
solvents were also obtained by passing them through commercially
available alumina column. Yields refer to chromatographically and
spectroscopically (1H NMR) homogeneous materials, unless otherwise
stated. Reagents were purchased at highest commercial quality and
used without further purification unless otherwise stated. Reactions
were monitored by thin-layer chromatography carried out on 0.25 mm
E. Merck silica gel plates (60F-254) using UV light as visualizing agent
and 7% ethanolic phosphomolybdic acid or p-anisaldehyde solution
and heat as developing agents. E. Merck silica gel (60, particle size
0.040-0.063 mm) was used for flash column chromatography.
Preparative thin-layer chromatography (PTLC) separations were carried
out on 0.25, 0.50, or 1 mm E. Merck silica gel plates (60F-254). NMR
spectra were recorded on Bruker DMX-600 or AMX-500 instruments
and calibrated using residual undeuterated solvent as an internal
reference. The following abbreviations were used to explain the
multiplicities: s ) singlet, d ) doublet, t ) triplet, q ) quartet, m )
multiplet, b ) broad. IR spectra were recorded on a Perkin-Elmer
1600 series FT-IR spectrometer. Optical rotations were recorded on a
Perkin-Elmer 241 polarimeter. High-resolution mass spectra (HRMS)
were recorded on a VG ZAB-ZSE mass spectrometer under fast atom
bombardment (FAB) conditions with NBA as the matrix. Melting
points (mp) are uncorrected and were recorded on a Thomas-Hoover
Unimelt capillary melting point apparatus.
Sultam 14. Sodium-Mediated Alkylation of N-Acylsultam 13.
A solution of sodium bis(trimethylsilyl)amide (NaHMDS, 236 mL, 1
M in THF, 1.05 equiv) was added over 30 min at -78 °C to a solution
of N-acylsultam 13 (61.0 g, 0.225 mol) in THF (1.1 L, 0.2 M). After
the resulting sodium enolate solution was stirred at -78 °C for 1 h,
freshly distilled 5-iodo-1-pentene (58 mL, 0.45 mol, 2.0 equiv) in
hexamethylphosphoramide (HMPA, 117 mL, 0.675 mol, 3.0 equiv) was
added. The reaction mixture was allowed to slowly warm to 25 °C,
quenched with water (1.5 L), and extracted with ether (3 × 500 mL).
Drying (MgSO4) and evaporation of the solvents gave crude sultam
14 (76.3 g), which was used without further purification. A pure sample
of 14 was obtained by preparative thin-layer chromatography (250 µm
silica gel plate, 10% EtOAc in hexanes): Rf ) 0.57 (silica gel, 20%
EtOAc in hexanes); [R]22D -50.5 (c 2.00, CHCl3); IR (film) νmax 2939,
1694, 1331, 1216, 1131, 540 cm-1; H NMR (500 MHz, CDCl3) δ
1
a (a) 20% CF3COOH in CH2Cl2, 0 °C, 3 h, 90%; (b) 0.1 equiv of
RuCl2(dCHPh)(PCy3)2, CH2Cl2, 25 °C, 20 h, 62 (20%), 63 (69%); (c)
0.8-1.2 equiv of mCPBA, CHCl3, -20 f 0 °C, 12 h, 62 f 64 (or
65) (25%), 65 (or 64) (23%); 63 f 67 (or 68) (24%), 68 (or 67) (19%),
69 (31%); (d) excess of CF3COCH3, 8.0 equiv of NaHCO3, 5.0 equiv
of Oxone, CH3CN/Na2EDTA (2:1), 0 °C, 62 f 64 (or 65) (58%), 65
(or 64) (29%); 63 f 67 (or 68) (44%), 68 (or 67) (21%).
5.79-7.72 (m, 1 H, CH2CHdCH2), 5.00-4.90 (m, 2 H, CH2CHdCH2),
3.89 (dd, J ) 7.5, 5.5 Hz, 1 H, CH2CHN), 3.50 (d, J ) 14.0 Hz, 1 H,
CH2SO2), 3.43 (d, J ) 14.0 Hz, 1 H, CH2SO2), 3.15-3.06 (m, 1 H,
(OdC)CH(CH3)), 2.10-2.00 (m, 3 H), 1.96-1.84 (m, 2 H), 1.78-
1.68 (m, 1 H), 1.50-1.30 (m, 6 H), 1.16 (s, 3 H, C(CH3)2), 1.15 (d, J
) 7.5 Hz, 3 H, CHCH3), 0.97 (s, 3 H, C(CH3)2); 13C NMR (125.7
MHz, CDCl3) δ 176.4, 138.2, 114.5, 65.1, 53.0, 48.1, 47.6, 44.5, 39.5,
38.5, 34.7, 33,2, 32.7, 26.3, 26.0, 20.7, 19,8, 16.5; HRMS (FAB) calcd
for C18H30NO3S (M + H+) 340.1946, found 340.1942.
of epoxides 64 (or 65) (58%) and 65 (or 64) (29%) and in
epoxides 67 (or 68) (44%) and 68 (or 67) (21%), respectively.
Alcohol 15. Reductive Cleavage of Sultam 14. A solution of crude
sultam 14 (76.0 g, 0.224 mol) in ether (200 mL) was added to a stirred
suspension of lithium aluminum hydride (LAH, 9.84 g, 0.246 mol, 1.1
equiv) in ether (900 mL) at -78 °C. The reaction mixture was stirred
at -78 °C for 15 min, quenched by addition of water (9.8 mL), and
warmed to 0 °C. Sequential addition of 15% aqueous sodium hydroxide
solution (9.8 mL) and water (29.4 mL) was followed by warming the
reaction mixture to 25 °C. After the mixture was stirred for 5 h, the
aluminum salts were removed by filtration through Celite, the filtrate
was dried (MgSO4), and the solvent was removed by distillation under
atmospheric pressure. Vacuum distillation (bp 85 °C at 8 mmHg)
furnished pure alcohol 15 as a colorless oil (17.1 g, 60% from sultam
5. Conclusion
In this article, we describe studies culminating in the total
synthesis of epothilone A (1) and several of its analogues by
an olefin metathesis approach, which was also the basis of
independently initiated studies by Danishefsky,9 Schinzer,12 and
Taylor.7h Not only did we explore the scope and limitations of
this new reaction in total synthesis, but we also succeeded in
the production of a series of epothilone A models and analogues
for biological investigations and further chemical explorations.
The high convergence and relative simplicity of the chemistry
involved in this construction make this strategy amenable to
combinatorial synthesis25 for the generation of large libraries
of these structures. This goal as well as improvements and
modifications of the sequences described are currently being
pursued in these laboratories.
14): Rf ) 0.40 (silica gel, 20% EtOAc in hexanes); [R]22 -11.1 (c
D
1.41, CHCl3); IR (film) νmax 3344, 2956, 2927, 2873, 1641, 1460, 1033,
1
910, 803 cm-1; H NMR (500 MHz, CDCl3) δ 5.85-5.77 (m, 1 H,
(25) 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.

Olefin Metathesis Approach to Epothilone A
J. Am. Chem. Soc., Vol. 119, No. 34, 1997 7967
CH2CHdCH2), 5.03-4.93 (m, 2 H, CH2CHdCH2), 3.53-3.49 (dd, J
) 10.5, 6.0 Hz, 1 H, CH2OH), 3.44-3.41 (dd, J ) 10.5, 6.5 Hz, 1 H,
CH2OH), 2.09-2.01 (m, 2 H), 1.67-1.58 (m, 1 H, HOCH2CH(CH3))
1.51-1.34 (m, 3 H), 1.17-1.08 (m, 1 H) 0.92 (d, J ) 6.5 Hz, 3 H,
CH3); 13C NMR (125.7 MHz, CDCl3) δ 138.8, 114.2, 68.0, 35.5, 33.9,
32.5, 26.2, 16.4.
135.6, 135.4, 134.3, 134.3, 133.1, 129.9, 129.7, 127.8, 127.6, 117.4,
71.2, 67.3, 37.5, 26.8, 19.2; HRMS (FAB) calcd for C21H28NaO2Si (M
+ Na+) 363.1756, found 363.1773.
Alcohol 18b. Opening of Epoxide 17b with Vinyl Cuprate. By
following the procedure described for the synthesis of alcohol 18a,
epoxide 17b (1.97 g, 6.3 mmol) yielded alcohol 18b (1.78 g, 83%).
Keto Ester 20. Horner-Wadsworth-Emmons Reaction of
Aldehyde 12 with Phosphonate 19. A solution of phosphonate 19
(23.6 g, 94 mmol, 1.2 equiv) in THF (100 mL) was transferred Via
cannula to a suspension of sodium hydride (60% dispersion in mineral
oil, 5.0 g, 125 mmol, 1.6 equiv) in THF (200 mL) at 25 °C. After
being stirred for 15 min, the reaction mixture was cooled to 0 °C, a
solution of aldehyde 12 (10.0 g, 78 mmol) in THF (20 mL) was added
via cannula, and the ice bath was removed. After 1 h at 25 °C, TLC
indicated the disappearance of aldehyde 12. The mixture was then
separated between water (320 mL) and hexanes (100 mL). The aqueous
layer was extracted with hexanes (100 mL), and the combined organic
layers were successively washed with water (200 mL) and saturated
aqueous NaCl solution (200 mL). Drying (MgSO4), concentration
under reduced pressure, and purification by flash column chromatog-
raphy (silica gel, 10% EtOAc in hexanes) yielded keto ester 20 (17.4
g, 99%) as a yellow oil. Rf ) 0.58 (silica gel, 20% EtOAc in hexanes);
Aldehyde 7. Oxidation of Alcohol 15. To a solution of alcohol
15 (0.768 g, 6.0 mmol) in CH2Cl2 (30 mL, 0.2 M) were added powdered
4 Å molecular sieves (1.54 g), 4-methylmorpholine N-oxide (NMO,
1.06 g, 9.0 mmol, 1.5 equiv), and tetrapropylammonium perruthenate
(TPAP, 0.105 g, 0.3 mmol, 0.05 equiv) at room temperature. After
the mixture was stirred for 30 min, the disappearance of starting material
was indicated by TLC. Celite was added (1.54 g), and the suspension
was filtered through silica gel and eluted with CH2Cl2. The solvent
was carefully distilled off under atmospheric pressure to yield aldehyde
7 (0.721 g, 95%) as a colorless oil: Rf ) 0.69 (silica gel, 20% EtOAc
in hexanes); [R]22D +18.3 (c 2.35, CHCl3); IR (film) νmax 2934, 1707,
1
1463, 1238, 912 cm-1; H NMR (500 MHz, CDCl3) δ 9.58 (d, 1 H,
CHO), 5.80-5.71 (m, 1 H, CH2CHdCH2), 5.00-4.90 (m, 2 H, CH2-
CHdCH2), 2.36-2.27 (m, 1 H), 2.10-2.00 (m, 2 H), 1.73-1.65 (m,
1 H), 1.42-1.30 (m, 3 H), 1.06 (d, J ) 7.0 Hz, 3 H, CH3); 13C NMR
(125.7 MHz, CDCl3) δ 204.9, 138.0, 114.7, 46.0, 33.5, 29.7, 26.0, 13.1.
Silyl Ether 17a. Silylation of Alcohol 16a. Alcohol 16a (5.0 g,
0.068 mol) was dissolved in DMF (70 mL, 1.0 M), the solution was
cooled to 0 °C, and imidazole (9.2 g, 0.135 mol, 2.0 equiv) was added.
After the mixture was stirred for 10 min, tert-butylchlorodiphenylsilane
(TPSCl, 24 mL, 0.088 mol, 1.3 equiv) was added and the reaction
mixture was allowed to stir for 30 min at 0 °C and for 1 h at 25 °C.
Ether (70 mL) was added, followed by saturated aqueous NaHCO3
solution (70 mL). The organic phase was separated, and the aqueous
layer was extracted with ether (50 mL) and washed with water (2 ×
120 mL) and saturated aqueous NaCl solution (120 mL). The organic
extract was dried (MgSO4) and filtered through Celite, and the solvents
were removed under reduced pressure. Flash column chromatography
(silica gel, 5% EtOAc in hexanes) provided silyl ether 17a (18.9 g,
90%): Rf ) 0.28 (5% EtOAc in hexanes); [R]22D -1.8 (c 1.14, CHCl3);
IR (film) νmax 2957, 2930, 2857, 1471, 1427, 1111, 824, 703 cm-1; 1H
NMR (500 MHz, CDCl3) δ 7.72-7.67 (m, 4 H, SiC(CH3)3(C6H5)2),
7.47-7.38 (m, 6 H, SiC(CH3)3(C6H5)2), 3.86 (dd, J ) 12.0, 3.0 Hz, 1
H, CH2OTPS), 3.72 (dd, J ) 12.0, 4.5 Hz, 1 H, CH2OTPS), 3.16-
3.12 (m, 1 H, CH2-O(epoxide)CH, 2.76 (dd, J ) 5.0, 4.0, 1 H, CH2-
O(epoxide)CH), 2.62 (dd, J ) 5.0, 3.0, 1 H, CH2-O(epoxide)CH),
1.08 (s, 9 H, SiC(CH3)3(C6H5)2); 13C NMR (125.7 MHz, CDCl3) δ
135.5, 133.2, 129.7, 127.6, 64.2, 52.2, 44.3, 26.7, 19.1.
1
IR (film) νmax 2977, 1714, 1645, 1318, 1297, 1158 cm-1; H NMR
(500 MHz, CDCl3) δ 6.91 (d, J ) 15.5 Hz, 1 H, CHdCHCOO), 5.77
(d, J ) 15.5 Hz, 1 H, CHdCHCOO), 2.47 (q, J ) 7.0 Hz, 2 H, CH2-
CH3), 1.47 (s, 9 H, C(CH3)3), 1.25 (s, 6 H, C(CH3)2), 0.99 (t, J ) 7.0
Hz, 3 H, CH2CH3); 13C NMR (125.7 MHz, CDCl3) δ 211.7, 165.5,
150.3, 122.2, 80.5, 50.2, 31.2, 28.0, 23.5, 7.9; HRMS (FAB) calcd for
C13H23O3 (M + H+) 227.1647, found 227.1656.
Keto Acid 21. Hydrolysis of Keto Ester 20. Keto ester 20 (17.4
g, 77 mmol) in CH2Cl2 (39 mL, 2 M) was treated with trifluoroacetic
acid (TFA, 39 mL, 2 M) at 25 °C. Within 30 min TLC indicated
disappearance of the ester. The mixture was concentrated under reduced
pressure, dissolved in saturated aqueous NaHCO3 solution (20 mL),
and washed with ether (2 × 20 mL). The aqueous phase was then
acidified to pH ∼ 2 with 4 N HCl, saturated with NaCl, and extracted
with EtOAc (6 × 20 mL). The organic layer was dried (MgSO4) and
concentrated under reduced pressure to give pure keto acid 21 (13.0 g,
99%) as a clear oil, which solidified on standing: Rf ) 0.20 (silica
gel, 2% TFA in CH2Cl2); mp 56-57 °C (EtOAc); IR (film) νmax 2979,
1712, 1647, 1300, 1201 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.18 (d,
J ) 16.0 Hz, 1 H, CHdCHCOOH), 5.89 (d, J ) 16.0 Hz, 1 H,
CHdCHCOOH), 2.50 (q, J ) 7.0 Hz, 2 H, CH2CH3), 1.31 (s, 6 H,
C(CH3)2), 1.03 (t, J ) 7.0 Hz, 3 H, CH2CH3); 13C NMR (125.7 MHz,
CDCl3) δ 211.8, 171.3, 154.3, 119.6, 50.4, 31.2, 23.2, 7.7; HRMS
(FAB) calcd for C9H14NaO3 (M + Na+) 193.0841, found 193.0846.
Keto Ester 22a. EDC Coupling of Alcohol 18a with Keto Acid
21. A solution of keto acid 21 (2.43 g, 14.3 mmol, 1.2 equiv),
4-(dimethylamino)pyridine (4-DMAP, 0.145 g, 1.2 mmol, 0.1 equiv),
and alcohol 18a (4.048 g, 11.9 mmol, 1.0 equiv) in CH2Cl2 (40 mL,
Silyl Ether 17b. Silylation of Alcohol 16b. By following the
procedure described for the synthesis of silyl ether 17a, alcohol 16b
(5.0 g, 0.068 mol) in DMF (70 mL, 1.0 M) was treated with imidazole
(9.2 g, 0.135 mol, 2.0 equiv) and tert-butylchlorodiphenylsilane (24
mL, 0.088 mol, 1.3 equiv) to yield silyl ether 17b (19.8 g, 94%).
Alcohol 18a. Opening of Epoxide 17a with Vinyl Cuprate. To
a solution of tetravinyltin (3.02 mL, 16.6 mmol, 1.25 equiv) in THF
(44 mL) was added n-butyllithium (41.5 mL, 1.6 M in hexanes, 5.0
equiv) at -78 °C, and the reaction mixture was stirred for 45 min.
The resulting solution of vinyllithium was transferred via cannula to a
solution of azeotropically dried (2 × 5 mL toluene) copper(I) cyanide
(2.97 g, 33.2 mmol, 2.5 equiv) in THF (44 mL) at -78 °C, and the
mixture was allowed to warm to -30 °C. Epoxide 17a (4.14 g, 13.3
mmol) in THF (44 mL) was transferred via cannula to this vinyl cuprate
solution, and the mixture was stirred at -30 °C for 1 h. The reaction
mixture was quenched with saturated aqueous NH4Cl solution (150
mL), filtered through Celite, extracted with ether (2 × 100 mL), and
dried (MgSO4). After removal of the solvents under reduced pressure,
flash column chromatography (silica gel, 3% EtOAc in hexanes)
furnished alcohol 18a (5.01 g, 86%) as a pale yellow oil: Rf ) 0.33
0.3 M) was cooled to
0 °C and then treated with 1-ethyl-
3-((dimethylamino)propyl)carbodiimide hydrochloride (EDC, 2.74 g,
14.3 mmol, 1.2 equiv). The reaction mixture was stirred at 0 °C for 2
h and then at 25 °C for 12 h. The solution was concentrated to dryness
in vacuo, and the residue was taken up in EtOAc (10 mL) and water
(10 mL). The organic layer was separated, washed with saturated NH4-
Cl solution (10 mL) and water (10 mL), and dried (MgSO4).
Evaporation of the solvents followed by flash column chromatography
(silica gel, 4% EtOAc in hexanes) resulted in pure keto ester 22a (5.037
g, 86%): Rf ) 0.41 (silica gel, 10% EtOAc in hexanes); [R]22 -6.1
D
(c 1.22, CHCl3); IR (film) νmax 3072, 2960, 2933, 2858, 1715, 1645,
1470, 1428, 1295, 1181, 1112, 704 cm-1; 1H NMR (500 MHz, CDCl3)
δ 7.66-7.64 (m, 4 H, SiC(CH3)3(C6H5)2), 7.44-7.36 (m, 6 H, SiC-
(CH3)3(C6H5)2), 7.05 (d, 1 H, J )16.0 Hz, CHdCHCOO), 5.86 (d, J
)16.0 Hz, 1 H, CHdCHCOO), 5.79-5.70 (m, 1 H, CH2CHdCH2),
5.15-5.04 (m, 3 H, CH2CHdCH2 and CO2CH), 3.76-3.70 (m, 2 H,
CH2OTPS), 2.53-2.36 (m, 4 H), 1.29 (s, 6 H, C(CH3)2), 1.04 (s, 9 H,
SiC(CH3)3(C6H5)2), 1.01 (t, J ) 7.0 Hz, 3 H, CH3CH2CdO); 13C NMR
(125.7 MHz, CDCl3) δ 211.4, 165.7, 151.7, 135.5, 135.4, 133.2, 129.6,
127.6, 120.6, 117.9, 73.6, 64.3, 50.4, 35.0, 31.3, 26.6, 23.6, 23.5, 19.2,
7.9; HRMS (FAB) calcd for C30H40CsO4Si (M + Cs+) 625.1750, found
625.1765.
(silica gel, 10% EtOAc in hexanes); [R]22 -2.0 (c 2.20, CHCl3); IR
D
1
(film) νmax 3071, 2930, 2858, 1428, 1111, 703 cm-1; H NMR (500
MHz, CDCl3) δ 7.70-7.65 (m, 4 H, SiC(CH3)3(C6H5)2), 7.47-7.38
(m, 6 H, SiC(CH3)3(C6H5)2), 5.84-5.75 (m, 1 H, CH2CHdCH2), 5.11-
5.04 (m, 2 H, CH2CHdCH2), 3.82-3.76 (m, 1 H, CHOH), 3.67 (dd,
J ) 10.5, 3.5 Hz, 1 H, CH2OTPS), 3.56 (dd, J ) 10.5, 7.0 Hz, 1 H,
CH2OTPS), 2.27-2.22 (m, 2 H, CH2CHdCH2), 2.17 (bs, 1 H, OH),
1.08 (s, 9 H, SiC(CH3)3(C6H5)2); 13C NMR (125.7 MHz, CDCl3) δ

7968 J. Am. Chem. Soc., Vol. 119, No. 34, 1997
Nicolaou et al.
Trienes 23 and 24. Aldol Condensation of Ester 22a with
Aldehyde 7. A solution of keto ester 22a (1.79 g, 3.63 mmol, 1.0
equiv) in THF (15 mL) was added via cannula to a freshly prepared
solution of lithium diisopropylamide [LDA; formed by addition of
n-BuLi (2.83 mL, 1.6 M solution in hexanes, 4.58 mmol, 1.25 equiv)
to a solution of diisopropylamine (0.61 mL, 4.36 mmol, 1.2 equiv) in
THF (30 mL) at -10 °C and stirring for 30 min] at -78 °C. After 15
min, the reaction mixture was allowed to warm to -40 °C and was
stirred for 45 min. The reaction mixture was cooled to -78 °C, and
a solution of aldehyde 7 (0.740 g, 5.8 mmol, 1.6 equiv) in THF (15
mL) was added dropwise. The resulting mixture was stirred for 15
min, then warmed to -40 °C for 30 min, cooled back to -78 °C, and
then quenched by slow addition of saturated aqueous NH4Cl solution
(10 mL). The reaction mixture was warmed to 25 °C and diluted with
EtOAc (10 mL), and the aqueous phase was extracted with EtOAc (3
× 10 mL). The combined organic layers were dried (MgSO4),
concentrated under reduced pressure, and subjected to flash chromato-
graphic purification (silica gel, 5 f 20% EtOAc in hexanes) to afford
a mixture of aldol products 23 (926 mg, 42%) and 24 (724 mg, 33%),
along with unreacted starting keto ester 22a (178 mg, 10%). 23: Rf )
0.40 (silica gel, 18% EtOAc in hexanes); [R]22D -11.4 (c 1.00, CHCl3);
IR (film) νmax 3518, 2962, 2932, 2858, 1722, 1644, 1294, 1182, 1114,
cm-1; 1H NMR (500 MHz, CDCl3) δ 7.69-7.64 (m, 4 H, SiC(CH3)3-
(C6H5)2), 7.46-7.36 (m, 6 H, SiC(CH3)3(C6H5)2), 6.78 (d, J ) 15.5
Hz, 1 H, CHdCHCOO), 5.98 (d, J ) 15.5 Hz, 1 H, CHdCHCOO),
5.40 (ddd, J ) 15.5, 8.5, 4.0 Hz, 1 H, CHdCHCH2), 5.38 (ddd, J )
15.5, 8.5, 4.5 Hz, 1 H, CHdCHCH2), 5.22-5.16 (m, 1 H, CO2CH),
3.75 (dd, J ) 10.5, 6.0 Hz, 1 H, CH2OTPS), 3.70 (dd, J ) 10.5, 5.0
Hz, 1 H, CH2OTPS), 3.58 (bs, 1 H, CHOH(CHCH3)), 3.05 (qd, J )
6.5, 5.5 Hz, 1 H, CH3CH(CdO)), 2.42 (d, J ) 14.0 Hz, 1 H), 2.24-
2.16 (m, 2 H), 2.12-2.04 (m, 1 H), 2.03-1.94 (m, 1 H), 1.55-1.40
(m, 2 H), 1.37 (s, 3 H, C(CH3)2), 1.28-1.04 (m, 3 H), 1.20 (s, 3 H,
C(CH3)2), 1.15 (d, J ) 7.0 Hz, 3 H, CH3CH(CdO)), 1.05 (s, 9 H,
SiC(CH3)3(C6H5)2), 0.93 (d, J ) 7.0 Hz, 3 H, CH3CHCH2); 13C NMR
(125.7 MHz, CDCl3) δ 214.8, 164.9, 149.6, 135.5, 135.4, 133.2, 133.2,
132.7, 129.6, 129.6, 127.6, 127.6, 126.3, 122.5, 75.7, 73.2, 65.6, 52.2,
42.1, 38.2, 34.8, 33.2, 30.3, 27.2, 26.9, 23.4, 23.2, 19.4, 16.3, 14.6;
HRMS (FAB) calcd for C36H50O5CsSi (M + Cs+) 723.2482, found
723.2508.
Hydroxy Lactone 26. Olefin Metathesis of Diene 24. By
following the procedure described above for the synthesis of hydroxy
lactone 25, a solution of diene 24 (0.197 g, 0.32 mmol) in CH2Cl2
(100 mL, 0.003 M) was treated with bis(tricyclohexylphosphine)-
benzylideneruthenium dichloride ((RuCl2(dCHPh)(PCy3)2, 26 mg,
0.032 mol, 0.1 equiv) to produce, after flash chromatography (silica
gel, 18 f 25% EtOAc in hexanes), trans-hydroxy lactone 26 (150 mg,
1
989, 702 cm-1; H NMR (600 MHz, CDCl3) δ 7.67-7.63 (m, 4 H,
SiC(CH3)3(C6H5)2), 7.45-7.40 (m, 2 H, SiC(CH3)3(C6H5)22), 7.40-
7.35 (m, 4 H, SiC(CH3)3(C6H5)2), 7.03 (d, 1 H, J )15.8 Hz,
CHdCHCOO), 5.92 (d, J ) 15.8 Hz, 1 H, CHdCHCOO), 5.84-5.76
(m, 1 H, CH2CHdCH2), 5.76-5.68 (m, 1 H, CH2CHdCH2), 5.14-
5.09 (m, 1 H, CO2CH), 5.08 (d, J ) 17.2 Hz, 1 H, CH2CHdCH2),
5.04 (d, J )10.1 Hz, 1 H, CH2CHdCH2), 4.99 (d, J )18.9 Hz, 1 H,
CH2CHdCH2), 4.92 (d, J ) 10.2 Hz, 1 H, CH2CHdCH2), 3.76-3.69
(m, 2 H, CH2OTPS), 3.29 (d, J ) 8.9 Hz, 1 H, CHOH(CHCH3)), 3.16
(s, 1 H, CHOH(CHCH3)), 3.13 (qd, J )7.0, 1.8 Hz, 1 H, CH3CH(CdO)),
2.52-2.45 (m, 1 H), 2.42-2.35 (m, 1 H), 2.09-1.97 (m, 2 H), 1.76-
1.68 (m, 1 H), 1.52-1.43 (m, 2 H), 1.30 (s, 3 H, C(CH3)2), 1.30 (s, 3
H, C(CH3)2), 1.30-1.25 (m, 1 H), 1.12-1.00 (m, 1 H), 1.03 (s, 9 H,
SiC(CH3)3(C6H5)2), 1.01 (d, J ) 7.1 Hz, 3 H, CH3CH(CdO), 0.77 (d,
J ) 6.8 Hz, 3 H, CH3CHCH2; 13C NMR (150.9 MHz, CDCl3) δ 217.0,
165.2, 150.1, 138.9, 135.4, 135.4, 135.4, 133.1, 133.1, 129.6, 129.6,
127.6, 127.5, 121.5, 117.9, 114.2, 74.9, 73.8, 64.4, 51.6, 41.5, 35.5,
35.2, 34.3, 32.2, 26.8, 26.2, 23.3, 23.3, 19.4, 15.6, 10.4; HRMS (FAB)
calcd for C38H54CsO5Si (M + Cs+) 751.2795, found 751.2766. 24:
79%): Rf ) 0.3 (silica gel, 18% EtOAc in hexanes); [R]22 -3.00 (c
D
) 0.40, CHCl3); IR (film) νmax 3522, 2961, 2931, 2857, 1718, 1698,
1
1646, 1294, 1182, 1113, 702 cm-1; H NMR (600 MHz, CDCl3): δ
7.67-7.63 (m, 4 H, SiC(CH3)3(C6H5)2), 7.45-7.41 (m, 2 H, SiC(CH3)3-
(C6H5)2), 7.40-7.36 (m, 4 H, SiC(CH3)3(C6H5)2), 7.07 (d, J ) 16.0
Hz, 1 H, CHdCHCOO), 5.86 (d, J ) 16.0 Hz, 1 H, CHdCHCOO),
5.30 (ddd, J ) 15.2, 7.4, 4.2 Hz, 1 H, CHdCHCH2), 5.28 (ddd, J )
15.2, 7.5, 4.2 Hz, 1 H, CHdCHCH2), 5.26-5.21 (m, 1 H, CO2CH),
3.77 (dd, J ) 10.7, 6.3 Hz, 1 H, CH2OTPS), 3.70 (dd, 1 H, J ) 10.7,
5.2 Hz, CH2OTPS), 3.27 (d, J ) 9.0, 1 H, CHOH(CHCH3)), 3.13 (q,
J ) 6.9 Hz, 1 H, CH3CH(CdO)), 2.87 (bs, 1 H, CHOH(CHCH3)),
2.52-2.45 (m, 1 H), 2.34-2.26 (m, 1 H), 2.15-2.08 (m, 1 H), 1.97-
1.89 (m, 1 H), 1.52-1.44 (m, 1 H), 1.40-1.31 (m, 1 H), 1.31 (s, 3 H,
C(CH3)2), 1.30-1.20 (m, 1 H), 1.24 (s, 3 H, C(CH3)2), 1.12-1.00 (m,
1 H), 1.04 (s, 9 H, SiC(CH3)3(C6H5)2), 1.01 (d, 3 H, J ) 6.9 Hz, CH3-
CH(CdO)), 0.96 (d, 3 H, J ) 6.6 Hz, CH3CHCH2), 0.93 (m, 1 H); 13
C
NMR (150.9 MHz, CDCl3) δ 217.8, 165.3, 151.1, 135.5, 135.4, 133.3,
133.2, 133.1, 129.6, 129.6, 127.6, 127.6, 125.6, 121.5, 75.0, 73.4, 64.9,
51.0, 43.6, 35.6, 34.2, 32.7, 32.0, 26.9, 25.6, 25.2, 24.0, 19.4, 16.0,
7.0; HRMS (FAB) calcd for C36H50O5CsSi (M + Cs+) 723.2482, found
723.2506.
Rf ) 0.30 (silica gel, 18% EtOAc in hexanes); [R]22 -1.33 (c 0.60,
D
CHCl3); IR (film) νmax 3521, 2962, 2932, 2858, 1722, 1644, 1294, 1182,
1113, 988, 702 cm-1; 1H NMR (600 MHz, CDCl3) δ 7.68-7.63 (m, 4
H, SiPh2), 7.45-7.40 (m, 2 H, SiC(CH3)3(C6H5)2), 7.40-7.35 (m, 4
H, SiC(CH3)3(C6H5)2), 7.03 (d, 1 H, J ) 15.8 Hz, CHdCHCOO), 5.90
(d, J ) 15.8 Hz, 1 H, CHdCHCOO), 5.82-5.68 (m, 2 H, 2 ×
CH2CHdCH2), 5.14-5.08 (m, 1 H, CO2CH), 5.09 (d, J ) 16.9 Hz, 1
H, CH2CHdCH2), 5.05 (d, J ) 10.1 Hz, 1 H, CH2CHdCH2), 4.99 (d,
J ) 17.1 Hz, 1 H, CH2CHdCH2), 4.95 (d, J ) 10.1 Hz, 1 H, CH2-
CHdCH2), 3.76-3.69 (m, 2 H, CH2OTPS), 3.44 (dd, J ) 6.6, 3.9 Hz,
1 H, CHOH(CHCH3)), 3.13-3.08 (m, 1 H, CH3CH(CdO)), 2.69 (bs,
1 H, CHOH(CHCH3)), 2.53-2.47 (m, 1 H), 2.43-2.37 (m, 1 H), 2.07-
1.95 (m, 2 H), 1.48-1.25 (m, 5 H), 1.31 (s, 3 H, C(CH3)2), 1.29 (s, 3
H, C(CH3)2), 1.05 (d, J ) 7.0 Hz, 3 H, CH3CH(CdO)), 1.03 (s, 9 H,
SiC(CH3)3(C6H5)2), 0.92 (d, J ) 6.6 Hz, 3 H, CH3CHCH2); 13C NMR
(150.9 MHz, CDCl3) δ 216.1, 165.2, 150.3, 138.5, 135.5, 135.4, 135.4,
133.1, 133.1, 129.6, 129.6, 127.6, 127.6, 121.4, 117.9, 114.6, 75.1,
73.8, 64.4, 51.5, 42.6, 35.5, 35.1, 33.9, 32.6, 26.8, 26.0, 23.6, 23.3,
19.4, 15.0, 12.3; HRMS (FAB), calcd for C38H54CsO5Si (M + Cs+)
751.2795, found 751.2771.
Diol 27. Desilylation of TPS Ether 25. A solution of TPS ether
25 (145 mg, 0.23 mmol) in THF (4.7 mL, 0.05 M) was treated with
glacial acetic acid (70 µL, 1.15 mmol, 5.0 equiv) and tetrabutylam-
monium fluoride (TBAF, 490 µL, 1 M solution in THF, 0.46 mmol,
2.0 equiv) at 25 °C. After the mixture was stirred for 36 h, no starting
material was detected by TLC and the reaction mixture was quenched
by addition of saturated aqueous NH4Cl (10 mL). Extractions with
ether (3 × 10 mL), drying (MgSO4), and concentration was followed
by flash chromatographic purification (silica gel, 50% EtOAc in
hexanes) to provide diol 27 (78 mg, 92%): Rf ) 0.30 (silica gel, ether),
[R]22D +144.5 (c 0.51, CHCl3); IR (film) νmax 3440, 2933, 1706, 1646,
1
1293, 1183, 982 cm-1; H NMR (600 MHz, CDCl3) δ 6.82 (d, J )
16.0 Hz, 1 H, CHdCHCOO), 6.08 (d, J ) 16.0 Hz, 1 H, CHdCHCOO),
5.42 (ddd, J ) 15.5, 8.0, 4.5 Hz, 1 H, CHdCHCH2), 5.40 (ddd, J )
15.5, 8.5, 4.5 Hz, 1 H, CHdCHCH2), 5.20-5.14 (m, 1 H, CO2CH),
3.76 (dd, J ) 12.0, 4.0 Hz, 1 H, CH2OH), 3.72 (dd, J ) 12.0, 6.5 Hz,
1 H, CH2OH), 3.58 (dd, J ) 5.0, 2.5 Hz, 1 H, CHOH(CHCH3)), 3.06
(qd, J ) 7.0, 6.0 Hz, 1 H, CH3CH(CdO)), 2.38-2.34 (m, 1 H), 2.28-
2.20 (m, 1 H), 2.12-2.03 (m, 1 H), 2.03-1.95 (m, 1 H), 1.55-1.42
(m, 2 H), 1.40 (s, 3 H, C(CH3)2), 1.22-1.08 (m, 2 H), 1.22 (s, 3 H,
C(CH3)2), 1.15 (d, J ) 7.0 Hz, 3 H, CH3CH(CdO)), 1.08-0.86 (m, 1
H), 0.94 (d, J ) 7.0 Hz, 3 H, CH3CHCH2); 13C NMR (125.7 MHz,
CDCl3) δ 214.8, 165.3, 150.4, 133.0, 126.0, 122.1, 75.5, 73.7, 64.9,
52.1, 41.9, 38.0, 34.4, 33.0, 30.1, 26.9, 23.2, 22.7, 16.1, 14.6; HRMS
(FAB), calcd for C20H33O5 (M + H+) 353.2328, found 353.2319.
Hydroxy Lactone 25. Olefin Metathesis of Diene 23. To a
solution of diene 23 (0.186 g, 0.3 mmol) in CH2Cl2 (100 mL, 0.003
M) was added bis(tricyclohexylphosphine)benzylideneruthenium dichlo-
ride (RuCl2(dCHPh)(PCy3)2, 25 mg, 0.03 mol, 0.1 equiv), and the
reaction mixture was allowed to stir at 25 °C for 12 h. After the
completion of the reaction was established by TLC, the solvent was
removed under reduced pressure and the crude product was purified
by flash chromatography (silica gel, 30% EtOAc in hexanes) to give
trans-hydroxy lactone 25 (151 mg, 85%): Rf ) 0.50 (silica gel, 30%
EtOAc in hexanes); [R]22D +65.9 (c 0.80, CHCl3); IR (film) νmax 3520,
2960, 2932, 2858, 1711, 1705, 1646, 1292, 1183, 1114, 982, 702, 505
Diol 28. Desilylation of TPS Ether 26. In accordance with the
procedure describing the desilylation of TPS ether 25, a solution of

Olefin Metathesis Approach to Epothilone A
J. Am. Chem. Soc., Vol. 119, No. 34, 1997 7969
TPS ether 26 (31 mg, 0.05 mmol) in THF (1.0 mL, 0.05 M) was treated
with glacial acetic acid (15 µL, 0.25 mmol, 5.0 equiv) and tetrabuty-
lammonium fluoride (TBAF, 105 µL, 1 M solution in THF, 0.10 mmol,
2.0 equiv) to yield diol 28 (17 mg, 95%) as a crystalline solid: Rf )
0.15 (silica gel, 50% EtOAc in hexanes); mp 128-129 °C (EtOAc-
through a short plug of silica gel, and concentration afforded, in high
yield, a mixture of aldol products 33 and 34 along with unreacted
starting acid 21 in a 35:50:15 ratio (1H NMR). This crude material
was used without further purification: 1H NMR (500 MHz, CDCl3;
only signals for 33 and 34 are reported) δ 7.16 (d, J ) 16.0 Hz, 1 H,
CHdCHCOOH), 5.95 (d, J ) 16.0 Hz, 1 H, CHdCHCOOH), 5.86-
5.73 (m, 1 H, CH2CHdCH2), 5.02-4.91 (m, 2 H, CH2CHdCH2),
hexanes); [R]22 +45.6 (c 0.80, CHCl3); IR (film) νmax 3442, 2932,
D
1
1702, 1647, 1296, 1184, 974 cm-1; H NMR (600 MHz, CDCl3) δ
7.14 (d, J ) 16.0 Hz, 1 H, CHdCHCOO), 5.94 (d, J ) 16.0 Hz, 1 H,
CHdCHCOO), 5.34 (ddd, J ) 15.4, 7.6, 4.2 Hz, 1 H, CHdCHCH2),
5.32 (ddd, J ) 15.4, 7.6, 4.2 Hz, 1 H, CHdCHCH2), 5.20-5.16 (m, 1
H, CO2CH), 3.75-3.73 (m, 2 H, CH2OH), 3.28 (dd, J ) 9.0, 1.2 Hz,
1 H, CHOH(CHCH3)), 3.13 (qd, J ) 7.0, 1.2 Hz, 1 H, CH3CH(CdO)),
2.81 (bs, 1 H, CHOH(CHCH3)), 2.46-2.42 (m, 1 H), 2.36-2.30 (m,
1 H), 2.17-2.13 (m, 1 H), 1.97-1.92 (m, 1 H), 1.86 (bs, 1 H, CH2OH),
1.51-1.46 (m, 1 H), 1.40-1.22 (m, 2H), 1.33 (s, 3 H, C(CH3)2), 1.27
(s, 3 H, C(CH3)2), 1.12-0.89 (m, 2 H) 1.01 (d, J ) 7.0 Hz, 3 H, CH3-
CH(CdO)), 0.96 (d, J ) 6.6 Hz, 3 H, CH3CHCH2); 13C NMR (125.7
MHz, CDCl3) δ 217.4, 165.8, 151.9, 133.6, 125.3, 121.2, 75.0, 74.4,
64.7, 51.0, 43.8, 35.6, 34.3, 32.7, 32.0, 25.5, 25.3, 24.0, 16.0, 9.9;
HRMS (FAB) calcd for C20H33O5 (M + H+) 353.2328, found 353.2323.
Ester 22b. DCC Coupling of Alcohol 18b with Keto Acid 21.
To a solution of alcohol 18b (1.000 g, 2.94 mmol, 1.0 equiv), 1,3-
dicyclohexylcarbodiimide (DCC, 0.836 g, 4.06 mmol, 1.4 equiv), and
4-dimethylaminopyridine (4-DMAP, 0.496 g, 4.06 mmol, 1.4 equiv)
in toluene (30 mL, 0.1 M) was added keto acid 21 (0.638 g, 3.75 mmol,
1.2 equiv) at 25 °C. After 12 h the reaction was complete, as indicated
by TLC. The reaction mixture was then passed through a short plug
of silica gel, eluted with toluene, and concentrated under reduced
pressure. The crude material was submitted to flash column chroma-
tography (silica gel, 5% EtOAc in hexanes) to yield pure 22b (1.38 g,
95%).
Dienes 29 and 30. Aldol Condensation of Ester 22b with
Aldehyde 7. In accordance with the procedure described for the
preparation of dienes 23 and 24, keto ester 22b (0.702 g, 1.43 mmol,
1.0 equiv) in THF (8.0 mL) was treated with lithium diisopropylamide
[LDA; freshly prepared from n-butyllithium (1.12 mL, 1.6 M solution
in hexanes, 1.79 mmol, 1.25 equiv) and diisopropylamine (241 µL,
1.72 mmol, 1.2 equiv) in THF (16 mL)] and aldehyde 7 (289 mg, 2.29
mmol, 1.6 equiv) in THF (3.0 mL) tï afford a mixture of aldol products
29 (0.478 g, 54%) and 30 (0.210 g, 24%) along with unreacted starting
material 22b (79 mg, 11%).
3.46-3.32 (m, 1 H, CHOH(CHCH3)), 3.17-3.11 (m, 1 H,
CH3CH(CdO)), 2.09-1.98 (m, 2 H, CH2CHdCH2), 1.72-1.24 (m, 9
H), 1.14-1.02 (m, 5 H), 0.95-0.81 (m, 3 H); HRMS (FAB) calcd for
C17H29O4 (M + H+) 297.2066, found 297.2074.
Esters 35 and 36. EDC Coupling of Alcohol 6 with Keto Acids
33 and 34. By analogy to the procedure described above for the
synthesis of ester 22a, a solution of keto acids 33 and 34 (1.034 g
crude), 4-(dimethylamino)pyridine (4-DMAP, 43 mg, 0.35 mmol), and
alcohol 6 (1.1 g, 5.24 mmol) in CH2Cl2 (4 mL) was treated with 1-ethyl-
3-((dimethylamino)propyl)carbodiimide hydrochloride (EDC, 1.00 g,
5.24 mmol) to provide, after column chromatography (silica gel, 20%
EtOAc in hexanes), ester 35 (0.567 g, 29% from keto acid 21) and
ester 36 (0.863 g, 44% from keto acid 21). 35: Rf ) 0.27 (silica gel,
20% EtOAc in hexanes); [R]22 -7.3 (c 2.90, CHCl3); IR (film) νmax
D
3510, 2973, 2932, 1719, 1703, 1641, 1459, 1293, 1179, 985 cm-1; 1H
NMR (500 MHz, CDCl3) δ 7.03 (d, J ) 16.0 Hz, 1 H, CHdCHCOO),
6.95 (s, 1 H, ArH), 6.53 (s, 1 H, ArCHdCCH3), 5.95 (d, J ) 16.0 Hz,
1 H, CHdCHCOO), 5.80-5.69 (m, 2 H, 2 x CH2CHdCH2), 5.39 (t,
J ) 6.5 Hz, 1 H, CO2CH), 5.10 (d, J ) 17.5 Hz, 1 H, CH2CHdCH2),
5.05 (d, J ) 10.5 Hz, 1 H, CH2CHdCH2), 4.97 (d, J ) 17.0 Hz, 1 H,
CH2CHdCH2), 4.93 (d, J ) 10.0 Hz, 1 H, CH2CHdCH2), 3.43 (dd, J
) 6.5, 4.0 Hz, 1 H, CHOH(CHCH3)), 3.11 (qd, J ) 7.0, 4.0 Hz, 1 H,
CH3CH(CdO)), 2.76 (bs, 1 H, CHOH(CHCH3)), 2.69 (s, 3 H, CH3-
Ar), 2.57-2.47 (m, 2 H, CH2CHdCH2), 2.08 (d, J ) 1.0 Hz, 3 H,
ArCHdCCH3), 2.07-1.93 (m, 2 H, CH2CHdCH2), 1.47-1.28 (m, 4
H), 1.30 (s, 3 H, C(CH3)2), 1.28 (s, 3 H, C(CH3)2), 1.05 (d, J ) 7.0
Hz, 3 H, CH3CH(CdO)), 1.05-0.98 (m, 1 H), 0.91 (d, J ) 6.5 Hz, 3
H, CH3CHCH2); 13C NMR (125.7 MHz, CDCl3) δ 216.3, 165.0, 164.7,
152.2, 150.5, 138.6, 136.9, 133.2, 121.4, 120.8, 117.8, 116.4, 114.6,
78.4, 75.0, 51.5, 42.6, 37.5, 35.3, 33.7, 32.5, 25.9, 23.2, 23.2, 19.1,
14.8, 12.2; HRMS (FAB) calcd for C28H42NO4S (M + H+) 488.2835,
found 488.2843. 36: Rf ) 0.34 (silica gel, 20% EtOAc in hexanes);
[R]22 -9.2 (c 1.00, CHCl3); IR (film) νmax 3519, 2930, 1716, 1641,
D
1
1457, 1293, 1179, 986 cm-1; H NMR (500 MHz, CDCl3) δ 7.04 (d,
J ) 16.0 Hz, 1 H, CHdCHCOO), 6.95 (s, 1 H, ArH), 6.54 (s, 1 H,
ArCHdCCH3), 5.96 (d, J ) 15.5 Hz, 1 H, CHdCHCOO), 5.84-5.69
(m, 2 H, 2 x CH2CHdCH2), 5.40 (t, J ) 6.5 Hz, 1 H, CO2CH), 5.10
(d, J ) 17.0 Hz, 1 H, CH2CHdCH2), 5.05 (d, J ) 10.5 Hz, 1 H, CH2-
CHdCH2), 4.98 (d, J ) 17.5 Hz, 1 H, CH2CHdCH2), 4.92 (d, J ) 9.0
Hz, 1 H, CH2CHdCH2), 3.30 (dd, J ) 8.5, 1.5 Hz, 1 H, CHOH-
(CHCH3)), 3.13 (qd, J ) 7.0, 2.0 Hz, 1 H, CH3CH(CdO)), 2.70 (s, 3
H, CH3Ar), 2.57-2.49 (m, 2 H, CH2CHdCH2), 2.09 (s, 3 H,
ArCHdCCH3), 2.09-1.96 (m, 2 H, CH2CHdCH2), 1.74-1.68 (m, 1
H), 1.52-1.43 (m, 2 H), 1.32 (s, 3 H, C(CH3)2), 1.30 (s, 3 H, C(CH3)2),
1.30-1.01 (m, 2 H), 1.02 (d, J ) 7.0 Hz, 3 H, CH3CH(CdO)), 0.79
(d, J ) 6.5 Hz, 3 H, CH3CHCH2); 13C NMR (125.7 MHz, CDCl3) δ
217.3, 165.1, 164.7, 152.4, 150.4, 139.0, 136.8, 133.2, 121.6, 121.0,
117.8, 116.4, 114.3, 78.5, 74.9, 51.5, 41.5, 37.5, 35.4, 34.1, 32.1, 26.0,
23.2, 23.0, 19.2, 15.5, 14.7, 10.2; HRMS (FAB) calcd for C28H41-
CsNO4S (M + Cs+) 620.1811, found 620.1838.
Hydroxy Lactone 37. Olefin Metathesis of Diene 35. A solution
of diene 35 (58 mg, 0.12 mmol) in CH2Cl2 (129 mL, 0.001 M) was
treated with bis(tricyclohexylphosphine)benzylideneruthenium dichlo-
ride (RuCl2(dCHPh)(PCy3)2, 10 mg, 0.0012 mmol, 0.1 equiv), in
accordance with the procedure described for the synthesis of hydroxy
lactone 25, to furnish, after column chromatography (silica gel, 15%
EtOAc in hexanes) hydroxy lactone 37 (48 mg, 86%).
Hydroxy Lactone 31. Olefin Metathesis of Diene 29. A solution
of diene 29 (104 mg, 0.17 mmol) in CH2Cl2 (25 mL, 0.007 M) was
treated with bis(tricyclohexylphosphine)benzylideneruthenium dichlo-
ride ((RuCl2(dCHPh)(PCy3)2, 14 mg, 0.017 mmol, 0.1 equiv), in
accordance with the procedure described for the preparation of hydroxy
lactone 25, to furnish, after flash column chromatography (silica gel,
5 f 17% EtOAc in hexanes), hydroxy lactone 31 (79 mg, 80%).
Hydroxy Lactone 32. Olefin Metathesis of Diene 30. A solution
of diene 30 (20 mg, 0.03 mmol) in CH2Cl2 (10 mL, 0.003 M) was
treated with bis(tricyclohexylphosphine)benzylideneruthenium dichlo-
ride (RuCl2(dCHPh)(PCy3)2, 2.5 mg, 0.003 mmol, 0.1 equiv), in
accordance with the procedure described for the preparation of hydroxy
lactone 25, to produce after preparative thin-layer chromatography (250
µm silica gel plate, 10% EtOAc in hexanes) hydroxy lactone 32 (15
mg, 81%).
Hydroxy Acids 33 and 34. Aldol Condensation of Acid 21 with
Aldehyde 7. A solution of keto acid 21 (752 mg, 4.42 mmol, 1.0
equiv) in THF (22 mL) was added dropwise at -78 °C to a freshly
prepared solution of LDA [formed by addition of n-BuLi (6.49 mL,
1.6 M solution in hexanes, 10.4 mmol, 2.35 equiv) to a solution of
diisopropylamine (1.43 mL, 10.2 mmol, 2.3 equiv) in THF (44 mL) at
-10 °C and stirring for 30 min]. After being stirred for 15 min, the
reaction mixture was allowed to warm to -30 °C and stirred at that
temperature for 1.5 h. The reaction mixture was cooled back to -78
°C and a solution of aldehyde 7 (0.891 g, 7.07 mmol, 1.6 equiv) in
THF (22 mL) was added via cannula. The resulting mixture was stirred
for 15 min at -78 °C, then warmed to -40 °C, stirred for 1 h, cooled
to -78 °C, and quenched by slow addition of saturated aqueous NH4-
Cl (10 mL) solution. The reaction mixture was warmed to 0 °C, and
acetic acid (1.26 mL, 22.1 mmol, 5.0 equiv) was added, followed by
warming to 25 °C. Extractions with EtOAc (6 × 15 mL), filtration
Hydroxy Lactone 38. Olefin Metathesis of Diene 36. A solution
of diene 36 (167 mg, 0.34 mmol) in CH2Cl2 (340 mL, 0.001 M) was
treated with bis(tricyclohexylphosphine)benzylideneruthenium dichlo-
ride (RuCl2(dCHPh)(PCy3)2, 28 mg, 0.034 mmol, 0.1 equiv), in
accordance with the procedure described for the synthesis of hydroxy
lactone 25, to furnish, after column chromatography (silica gel, 20%
EtOAc in hexanes), hydroxy lactone 38 (103 mg, 66%): Rf ) 0.38
(silica gel, 30% EtOAc in hexanes); [R]22D +70.4 (c 1.60, CHCl3); IR

7970 J. Am. Chem. Soc., Vol. 119, No. 34, 1997
Nicolaou et al.
1
(film) νmax 2933, 1703, 1640, 1292, 1179, 982 cm-1; H NMR (500
23.0, 22.1, 19.3, 18.1, 14.9, 14.5; HRMS (FAB) calcd for C26H37NO5S
MHz, CDCl3) δ 6.99 (d, J ) 16.0 Hz, 1 H, CHdCHCOO), 6.97 (s, 1
H, ArH), 6.55 (s, 1 H, ArCHdCCH3), 6.02 (d, J ) 16.0 Hz, 1 H,
CHdCHCOO), 5.51 (dd, J ) 8.0, 2.5 Hz, 1 H, CO2CH), 5.47 (ddd, J
) 15.0, 7.5, 7.5 Hz, 1 H, CHdCHCH2), 5.38 (ddd, J ) 15.0, 7.5, 7.5
Hz, 1 H, CHdCHCH2), 3.60 (d, J ) 6.8 Hz, 1 H, CHOH(CHCH3)),
3.14 (dq, J ) 7.0, 7.0 Hz, 1 H, CH3CH(CdO)), 2.70 (s, 3 H, CH3Ar),
2.48-2.37 (m, 2 H, CHdCHCH2), 2.21-2.12 (m, 1 H, CHdCHCH2),
2.08 (s, 3 H, ArCHdCCH3), 1.98-1.90 (m, 1 H, CHdCHCH2), 1.62-
1.52 (m, 1 H), 1.41-1.32 (m, 2H), 1.36 (s, 3 H, C(CH3)2), 1.21 (s, 3
H, C(CH3)2), 1.17-1.07 (m, 1H), 1.14 (d, J ) 7.0 Hz, 3 H, CH3CH-
(CdO)), 0.98-0.87 (m, 1H), 0.97 (d, J ) 7.0 Hz, 3 H, CH3CHCH2);
13C NMR (125.7 MHz, CDCl3) δ 215.5, 165.0, 164.6, 152.2, 150.9,
137.4, 133.6, 126.0, 121.9, 119.4, 115.6, 76.6, 76.2, 51.6, 44.1, 37.9,
36.2, 33.3, 29.6, 27.1, 24.0, 23.0, 18.9, 17.0, 15.9, 15.4; HRMS (FAB)
calcd for C26H38NO4S (M + H+) 460.2522, found 460.2534.
Epothilones 39-41. Epoxidation of trans-Hydroxy Lactone 37.
Procedure A: A solution of trans-hydroxy lactone 37 (20 mg, 0.06
mmol) in CHCl3 (1 mL, 0.06 M) was treated with 3-chloroperoxyben-
zoic acid (mCPBA, 57-86%, 15 mg, 0.05-0.07 mol, 0.9-1.2 equiv)
at -20 °C, and the reaction mixture was allowed to warm to 0 °C.
After 12 h, disappearance of starting material was detected by TLC,
and the reaction mixture was treated with saturated aqueous NaHCO3
solution (2 mL). The aqueous phase was then extracted with EtOAc
(3 × 2 mL). The combined organic layer was dried (MgSO4), filtered,
and concentrated. Purification by preparative thin-layer chromatography
(250 µm silica gel plate, 30% EtOAc in hexanes) furnished epothilones
39 (or 40) (12 mg, 40%), 40 (or 39) (7.5 mg, 25%), and 41 (5.4 mg,
18%). Procedure B: To a solution of trans-hydroxy lactone 37 (32
mg, 0.07 mmol) in acetonitrile (1.0 mL) was added a 0.0004 M aqueous
solution of disodium salt of ethylenediaminetetraacetic acid (Na2EDTA,
0.5 mL), and the reaction mixture was cooled to 0 °C. Excess of 1,1,1-
trifluoroacetone (0.2 mL) was added, followed by a portionwise addition
of Oxone (200 mg, 0.35 mmol, 5.0 equiv) and NaHCO3 (50 mg, 0.56
mmol, 8.0 equiv) with stirring, until the disappearance of starting
material was detected by TLC. The reaction mixture was then treated
with excess dimethyl sulfide (150 µL) and water (1.0 mL) and extracted
with EtOAc (4 × 2 mL). The combined organic layer was dried
(MgSO4), filtered, and concentrated. Purification by preparative thin-
layer chromatography (250 µm silica gel plate, 70% EtOAc in hexanes)
provided a mixture of diastereomeric epoxides, epoxide 39 (or 40) (15
mg, 45%) and R-isomeric epoxide 40 (or 39) (9.2 mg, 28%).
(M + H+) 476.2471, found 476.2485. 43 (or 42): Rf ) 0.64 (silica
gel, ether); [R]22 +38.0 (c 0.20, CHCl3); IR (film) νmax 3479, 2926,
D
2855, 1721, 1702, 1643, 1455, 1174 cm-1; 1H NMR (500 MHz, CDCl3)
δ 7.08 (d, J ) 16.0 Hz, 1 H, CHdCHCOO), 7.01 (s, 1 H, ArH), 6.63
(s, 1 H, ArCHdCCH3), 6.05 (d, J ) 16.0 Hz, 1 H, CHdCHCOO),
5.47 (dd, J ) 7.6, 2.6 Hz, 1 H, CO2CH), 3.65 (dd, J ) 6.5, 3.5 Hz, 1
H, CHOH(CHCH3)), 3.19 (dq, J ) 6.8, 6.8 Hz, 1 H, CH3CH(CdO)),
2.85-2.80 (m, 1 H), 2.78-2.72 (m, 1 H), 2.73 (s, 3 H, CH3Ar), 2.52
(ddd, J ) 15.0, 8.5, 4.0 Hz, 1 H), 2.10 (s, 3 H, ArCHdCCH3), 1.73
(ddd, J ) 15.0, 7.5, 3.5 Hz, 1 H), 1.65-0.80 (m, 7 H), 1.43 (s, 3 H,
C(CH3)2), 1.26 (s, 3 H, C(CH3)2), 1.15 (d, J ) 6.8 Hz, 3 H, CH3CH-
(CdO)), 0.99 (d, J ) 7.0 Hz, 3 H, CH3CHCH2); 13C NMR (150.9 MHz,
CDCl3) δ 215.1, 165.5, 164.7, 152.1, 152.0, 130.9, 128.8, 120.9, 115.9,
75.7, 75.2, 57.6, 55.6, 51.7, 44.3, 37.5, 34.4, 32.3, 31.1, 23.9, 23.3,
22.8, 18.8, 17.2, 15.8, 14.6; HRMS (FAB) calcd for C26H37NO5S (M
+ H+) 476.2471, found 476.2489. 44: Rf ) 0.60 (silica gel, ether);
[R]22 +23.3 (c 0.06, CHCl3); IR (film) νmax 3443, 2924, 1731, 1462,
D
1260 cm-1; 1H NMR (500 MHz, CDCl3) δ 6.97 (s, 1 H, ArH), 6.84 (d,
J ) 16.0 Hz, 1 H, CHdCHCOO), 6.04 (d, J ) 16.0 Hz, 1 H,
CHdCHCOO), 5.51-5.43 (m, 1H, CHdCHCH2), 5.42-5.35 (m, 1H,
CHdCHCH2), 5.05 (dd, J ) 10.0, 2.5 Hz, 1 H, CO2CH), 4.18 (s, 1H,
ArCH-O(epoxide)CCH3), 3.60-3.57 (m, 1 H, CHOH(CHCH3)), 3.06
(dq, J ) 7.0, 7.0 Hz, 1 H, CH3CH(CdO)), 2.72 (s, 3 H, CH3Ar), 2.56-
2.50 (m, 1 H), 2.40-2.32 (m, 1 H), 2.30-2.22 (m, 1 H), 2.14-1.96
(m, 2 H), 1.60-0.98 (m, 4 H), 1.38 (s, 3H, ArCH-O(epoxide)CCH3),
1.30 (s, 3 H, C(CH3)2), 1.22 (s, 3 H, C(CH3)2), 1.14 (d, J ) 7.0 Hz, 3
H, CH3CH(CdO)), 0.95 (d, J ) 7.0 Hz, 3 H, CH3CHCH2); HRMS
(FAB) calcd for C26H38NO5S (M + H+) 476.2471, found 476.2492.
Hydroxy Keto Acids 45 and 46. Aldol Condensation of Keto
Acid 8 and Aldehyde 7. In accordance with the procedure described
for the synthesis of keto acids 33 and 34, keto acid 8 (0.896 g, 2.97
mmol, 1.0 equiv) in THF (10 mL) was treated with lithium diisopro-
pylamide [LDA; freshly prepared from n-BuLi (4.36 mL, 1.6 M solution
in hexanes, 7.41 mmol, 2.5 equiv) and diisopropylamine (960 µL, 6.83
mmol, 2.3 equiv) in THF (30 mL)] and aldehyde 7 (0.68 g, 5.3 mmol,
1.8 equiv) in THF (30 mL) tï afford a mixture of aldol products 45
and 46 in high yield and in a ca. 3:2 ratio (1H NMR), along with
unreacted keto acid 8 (5%): Rf ) 0.20 (silica gel, 50% EtOAc in
1
hexanes); H NMR (500 MHz, CDCl3; only signals for 45 and 46 are
reported) δ 5.88-5.73 (m, 1 H, CH2CHdCH2), 5.04-4.92 (m, 2 H,
CH2CHdCH2), 4.51-4.47 (m, 0.4 H, (CH3)2CCH(OTBS)), 4.44-4.40
(m, 0.6 H, (CH3)2CCH(OTBS)), 3.42 (d, J ) 8.0 Hz, 0.4 H, CHOH-
(CHCH3)), 3.32 (d, J ) 9.0 Hz, 0.6 H, CHOH(CHCH3)), 3.30-3.20
(m, 1 H, CH3CH(CdO), 2.51-2.45 (m, 1 H, CH2COOH), 2.38 (dd, J
) 16.5, 6.5 Hz, 0.4 H, CH2COOH), 2.35 (dd, J ) 16.5, 6.5 Hz, 0.6 H,
CH2COOH), 2.11-1.98 (m, 2 H), 1.80-1.21 (m, 5 H), 1.20 (s, 1.8 H,
C(CH3)2), 1.19 (s, 1.2 H, C(CH3)2), 1.16 (s, 1.8 H, C(CH3)2), 1.14 (s,
1.2 H, C(CH3)2), 1.06 (d, J ) 6.5 Hz, 1.2 H), 1.05 (d, J ) 6.5 Hz, 1.8
H), 1.00 (d, J ) 6.5 Hz, 1.2 H), 0.89 (s, 5.4 H, SiC(CH3)3(CH3)2),
0.87 (s, 3.6 H, SiC(CH3)3(CH3)2), 0.85 (d, J )7.0 Hz, 1.8 H), 0.11 (s,
1.8 H, SiC(CH3)3(CH3)2), 0.09 (s, 1.2 H, SiC(CH3)3(CH3)2), 0.08 (s,
1.2 H, SiC(CH3)3(CH3)2), 0.07 (s, 1.8 H, SiC(CH3)3(CH3)2); HRMS
(FAB) calcd for C23H44NaO5Si (M + Na+) 451.2856, found 451.2867.
Epothilones 42-44. Epoxidation of trans-Hydroxy Lactone 38.
Procedure A: A solution of trans-hydroxy lactone 38 (32 mg, 0.07
mmol) in CHCl3 (1.4 mL) was reacted with 3-chloroperoxybenzoic acid
(mCPBA, 57-86%, 17.8 mg, 0.06-0.09 mmol, 0.9-1.3 equiv),
according to procedure A described for the epoxidation of 37, resulting
in the isolation of epoxides 42 (or 43) (7.3 mg, 22%), 43 (or 42) (3.7
mg, 11%), and 44 (2.2 mg, 7%) (stereochemistry unassigned for all
compounds), along with unreacted starting material (3.5 mg, 11%), after
two consecutive preparative thin-layer chromatographic purifications
(250 µm silica gel plate, ether). Procedure B: As described in
procedure B for the epoxidation of trans-hydroxy lactone 37, cis-
hydroxy lactone 38 (24 mg, 0.05 mmol) in MeCN (800 µL) was treated
with a 0.0004 M aqueous solution of disodium salt of ethylenediamine-
tetraacetic acid (Na2EDTA, 380 µL), 1,1,1-trifluoroacetone (150 µL),
Oxone (144 mg, 0.25 mmol, 5.0 equiv), and NaHCO3 (36 mg, 0.40
mmol, 8.0 equiv), to yield, after purification by preparative thin-layer
chromatography (250 µm silica gel plate, ether), epoxides 42 (or 43)
(15 mg, 60%) and 43 (or 42) (3.8 mg, 15%). 42 (or 43): Rf ) 0.60
Hydroxy Esters 4 and 47. EDC Coupling of Carboxylic Acids
45 and 46 and Alcohol 6. The crude mixture of keto acids 45 and 46
(1.30 g), 4-dimethylaminopyridine (4-DMAP, 0.037 g, 0.3 mmol), and
alcohol 6 (1.90 g, 9.0 mmol) in CH2Cl2 (5 mL) was treated with 1-ethyl-
3-((dimethylamino)propyl)carbodiimide hydrochloride (EDC, 0.7 g, 3.6
mmol), according to the procedure described for the synthesis of keto
ester 22a, producing pure hydroxy esters 4 (0.940 g, 52% from keto
acid 8) and 47 (0.569 g, 31% from keto acid 8) after flash column
chromatography (silica gel, 18% EtOAc in hexanes). 4: Rf ) 0.30
(silica gel, 18% EtOAc in hexanes); [R]22D -53.4 (c 1.00, MeOH); IR
(silica gel, ether); [R]22 +78.5 (c 0.94, CHCl3); IR (film) νmax 3500,
D
2929, 1714, 1644, 1462, 1293, 1179, 982 cm-1; H NMR (500 MHz,
1
CDCl3) δ 6.98 (s, 1 H, ArH), 6.89 (d, J ) 16.0 Hz, 1 H, CHdCHCOO),
6.58 (s, 1 H, ArCHdCCH3), 6.06 (d, J ) 16.0 Hz, 1 H, CHdCHCOO),
5.69 (d, J ) 11.0 Hz, 1 H, CO2CH), 3.80-3.73 (m, 1 H, CHOH-
(CHCH3)), 3.11 (dq, J ) 7.0, 7.0 Hz, 1 H, CH3CH(CdO)), 2.82-2.74
(m, 2 H), 2.71 (s, 3 H, CH3Ar), 2.43 (d, J ) 14.5 Hz, 1 H), 2.11 (s, 3
H, ArCHdCCH3), 1.93-1.85 (m, 1 H), 1.60-0.98 (m, 7 H), 1.46 (s,
3 H, C(CH3)2), 1.24 (s, 3 H, C(CH3)2), 1.14 (d, J ) 7.0 Hz, 3 H, CH3-
CH(CdO)), 1.01 (d, J ) 7.0 Hz, 3 H, CH3CHCH2); 13C NMR (150.9
MHz, CDCl3) δ 212.7, 165.0, 164.7, 152.0, 151.7, 137.0, 121.1, 120.6,
116.7, 76.2, 75.7, 58.7, 57.7, 52.2, 44.4, 37.3, 36.1, 33.5, 30.0, 24.2,
1
(film) νmax 3508, 2932, 1737, 1690, 1650, 1178, 1088, 835 cm-1; H
NMR (500 MHz, CDCl3): δ 6.93 (s, 1 H, ArH), 6.47 (s, 1 H,
ArCHdCCH3), 5.81-5.73 (m, 1 H, CH2CHdCH2), 5.73-5.65 (m, 1
H, CH2CHdCH2), 5.27 (dd, J ) 7.0, 6.5 Hz, 1 H, CO2CH), 5.09 (d, J
) 17.5 Hz, 1 H, CH2CHdCH2), 5.03 (d, J ) 10.0 Hz, 1 H,
CH2CHdCH2), 4.96 (d, J ) 17.0 Hz, 1 H, CH2CHdCH2), 4.89 (d, J
) 10.5 Hz, 1 H, CH2CHdCH2), 4.39 (dd, J ) 6.0, 4.0 Hz, 1 H, (CH3)2-
CCH(OTBS)), 3.42 (bs, 1 H, CHOH(CHCH3)), 3.28 (q, J ) 7.0 Hz, 1

Olefin Metathesis Approach to Epothilone A
J. Am. Chem. Soc., Vol. 119, No. 34, 1997 7971
H, CH3CH(CdO)), 3.24 (d, J ) 9.5 Hz, 1 H, CHOH(CHCH3)), 2.67
(s, 3 H, CH3Ar), 2.54-2.43 (m, 2 H), 2.43 (dd, J ) 10.0, 4.0 Hz, 1 H,
CH2COO), 2.31 (dd, J ) 10.0, 6.0 Hz, 1 H, CH2COO), 2.04 (s, 3 H,
ArCHdCCH3), 2.03-1.90 (m, 2 H, CH2CHdCH2), 1.75-1.65 (m, 1
H), 1.48-1.43 (m, 1 H), 1.43-1.36 (m, 1 H), 1.22-1.10 (m, 2 H),
1.17 (s, 3 H, C(CH3)2), 1.09 (s, 3 H, C(CH3)2), 1.01 (d, J ) 6.5 Hz, 3
H, CH3CH(CdO)), 0.86 (s, 9 H, SiC(CH3)3(CH3)2), 0.81 (d, J ) 7.0
Hz, 3 H, CH3CHCH2), 0.09 (s, 3 H, SiC(CH3)3(CH3)2), 0.04 (s, 3 H,
SiC(CH3)3(CH3)2); 13C NMR (125.7 MHz, CDCl3) δ 221.8, 170.9,
164.6, 152.4, 139.0, 136.6, 133.2, 121.0, 117.8, 116.4, 114.1, 78.8,
74.5, 73.4, 53.9, 41.2, 40.1, 37.4, 35.4, 34.1, 32.3, 26.0, 25.9, 21.9,
19.9, 19.2, 18.1, 15.2, 14.6, 9.7, -4.3, -4.9; HRMS (FAB) calcd for
C34H57CsNO5SSi (M + Cs+) 752.2781, found 752.2760. 47: Rf ) 0.20
(silica gel, 18% EtOAc in hexanes); [R]22D -27.3 (c 1.00, CHCl3); IR
(film) νmax 3509, 2932, 2857, 1737, 1691, 1465, 1381, 1292, 1253,
CH3CHCH2), 0.86 (s, 9 H, SiC(CH3)3(CH3)2), 0.08 (s, 3 H, SiC(CH3)3-
(CH3)2), 0.00 (s, 3 H, SiC(CH3)3(CH3)2); 13C NMR (150.9 MHz, CDCl3)
δ 217.9, 169.9, 164.7, 152.1, 136.3, 134.5, 124.9, 119.4, 115.4, 77.4,
75.1, 74.1, 54.1, 43.9, 41.0, 38.5, 35.3, 33.0, 30.9, 27.0, 26.2, 23.8,
21.7, 19.1, 18.5, 17.0, 16.1, 14.8, -3.8, -4.2; HRMS (FAB) calcd for
C32H53CsNO5SSi (M + Cs+) 724.2468, found 724.2479.
cis-Dihydroxy Lactone 49. Desilylation of Compound 3. Silyl
ether 3 (30 mg, 0.05 mmol) was treated with a freshly prepared solution
of 20% (v/v) trifluoroacetic acid-CH2Cl2 (0.3 mL, 0.17 M) at 0 °C.
The reaction mixture was stirred at 0 °C for 3 h (completion of the
reaction by TLC), and the solvents were evaporated under reduced
pressure. The crude reaction mixture was purified by preparative thin-
layer chromatography (0.5 mm silica gel plate, 50% EtOAc in hexanes)
to obtain cis-dihydroxy lactone 49 (22 mg, 90%): Rf ) 0.30 (silica
gel, 50% EtOAc in hexanes); [R]22 -80.2 (c 1.36, CHCl3); IR (thin
D
1
1177, 1088, 984, 835 cm-1; H NMR (500 MHz, CDCl3) δ 6.95 (s, 1
1
film) νmax 3453, 2929, 1733, 1686, 1506, 1464, 1250, 978 cm-1; H
H, ArH), 6.49 (s, 1 H, ArCHdCCH3), 5.83-5.69 (m, 2 H, 2 x
CH2CHdCH2), 5.29 (dd, J ) 6.5, 6.5 Hz, 1 H, CO2CH), 5.11 (d, J )
17.0 Hz, 1 H, CH2CHdCH2), 5.05 (d, J ) 10.0 Hz, 1 H, CH2CHdCH2),
5.01 (d, J ) 17.0 Hz, 1 H, CH2CHdCH2), 4.95 01 (d, J ) 10.5 Hz, 1
H, CH2CHdCH2), 4.50 (dd, J ) 6.5, 4.0 Hz, 1 H, (CH3)2CCH(OTBS)),
3.42 (dd, J ) 8.0, 1.5 Hz, 1 H, CHOH(CHCH3)), 3.21 (qd, J ) 7.0,
2.0 Hz, 1 H, CH3CH(CdO)), 2.70 (s, 3 H, CH3Ar), 2.54-2.33 (m, 4
H), 2.11-1.98 (m, 2 H), 2.07 (s, 3 H, ArCHdCCH3), 1.53-0.98 (m,
5 H), 1.15 (s, 3 H, C(CH3)2), 1.11 (s, 3 H, C(CH3)2), 1.01 (d, J ) 7
Hz, 3 H, CH3CH(CdO)), 0.99 (d, J ) 6.5 Hz, 3 H, CH3CHCH2), 0.86
(s, 9 H, SiC(CH3)3(CH3)2), 0.08 (s, 3 H, SiC(CH3)3(CH3)2), 0.07 08 (s,
3 H, SiC(CH3)3(CH3)2); 13C NMR (125.7 MHz, CDCl3) δ 220.8, 170.9,
164.4, 152.2, 138.6, 136.6, 133.1, 120.9, 117.8, 116.3, 114.5, 78.8,
74.8, 72.5, 53.9, 41.3, 40.1, 37.4, 35.2, 33.7, 32.0, 25.9, 25.8, 21.7,
19.6, 19.1, 18.1, 15.4, 14.5, 10.5, -4.4, -4.8; HRMS (FAB) calcd for
C34H58NO5SSi (M + H+) 620.3805, found 620.3813.
NMR (400 MHz, CDCl3) δ 6.95 (s, 1 H, ArH), 6.59 (s, 1 H, ArCHdC-
(CH3)), 5.44 (ddd, J ) 10.5, 10.5, 4.5 Hz, 1 H, CHdCHCH2), 5.36
(ddd, J ) 10.5, 10.5, 5.0 Hz, 1 H, CHdCHCH2), 5.28 (d, J ) 9.4 Hz,
1 H, CO2CH), 4.23 (d, J ) 11.1 Hz, 1 H, (CH3)2CCH(OH)), 3.72 (m,
1 H, CHOH(CHCH3)), 3.43-3.37 (m, 1 H, OH), 3.14 (q, J ) 6.7 Hz,
1 H, CH3CH(CdO)), 3.05 (bs, 1 H, OH), 2.72-2.63 (m, 1 H), 2.69 (s,
3 H, CH3Ar), 2.48 (dd, J ) 14.8, 11.3 Hz, 1 H, CH2COO), 2.33 (dd,
J ) 14.8, 2.0 Hz, 1H, CH2COO), 2.30-2.13 (m, 2 H) 2.07 (s, 3 H,
ArCHdCCH3), 2.07-1.98 (m, 1 H), 1.80-1.60 (m, 2H), 1.32 (s, 3 H,
C(CH3)2), 1.36-1.13 (m, 3 H), 1.17 (d, J ) 6.8 Hz, 3 H, CH3CH-
(CdO)), 1.06 (s, 3 H, C(CH3)2), 0.99 (d, J ) 7.0 Hz, 3 H, CH3CHCH2);
13C NMR (150.9 MHz, CDCl3) δ 220.6, 170.4, 165.0 151.9, 138.7,
133.4, 125.0, 119.4, 115.8, 78.4, 74.1, 72.3, 53.3, 41.7, 39.2, 38.5, 32.4,
31.7, 27.6, 27.4, 22.7, 19.0, 18.6, 15.9, 15.5, 13.5; HRMS (FAB) calcd
for C26H39CsNO5S (M + Cs+) 610.1603, found 610.1580.
trans-Dihydroxy Lactone 50. Desilylation of Compound 48. Silyl
ether 48 (32 mg, 0.05 mmol) was treated with a freshly prepared
solution of 20% (v/v) trifluoroacetic acid (TFA)-CH2Cl2 (0.3 mL, 0.17
M), according to the procedure described for cis-dihydroxy lactone 49,
to yield, after preparative thin-layer chromatography (0.5 mm silica
gel plate, 50% EtOAc in hexanes), trans-dihydroxy ester 50 (24 mg,
92%): Rf ) 0.15 (silica gel, 50% EtOAc in hexanes); [R]22D -62.7 (c
1.65, CHCl3); IR (film) νmax 3428, 2932, 1730, 1692, 1468, 1253, 976
cm-1; 1H NMR (500 MHz, CDCl3) δ 6.97 (s, 1 H, ArH), 6.56 (s, 1 H,
ArCHdCCH3), 5.49 (ddd, J ) 15.0, 4.7, 4.7 Hz, 1 H, CHdCHCH2),
5.38 (dd, J ) 5.7, 5.7 Hz, 1 H, CO2CH), 5.37 (ddd, J ) 15.0, 6.5, 6.5
Hz, 1 H, CHdCHCH2), 4.18 (d, J ) 10.5 Hz, 1 H, (CH3)2CCH(OH)),
3.73 (m, 1 H, CHOH(CHCH3)), 3.27-3.20 (m, 2 H, CH3CH(CdO)
and OH), 2.82 (bs, 1 H, OH), 2.70 (s, 3 H, CH3Ar), 2.55 (dd, J )
15.5, 10.5 Hz, 1 H, CH2COO), 2.48-2.43 (m, 3 H), 2.18-2.12 (m, 1
H), 2.07 (s, 3 H, ArCHdCCH3), 1.98-1.91 (m, 1 H), 1.63-1.55 (m,
2 H), 1.46 (dddd, J ) 12.5, 12.5, 4.0, 4.0 Hz, 1 H), 1.27 (s, 3 H,
C(CH3)2), 1.23-1.14 (m, 2 H), 1.17 (d, J ) 6.5 Hz, 3 H, CH3CH-
(CdO)), 1.06 (s, 3 H, C(CH3)2), 0.97 (d, J ) 6.5 Hz, 3 H, CH3CHCH2);
13C NMR (125.7 MHz, CDCl3) δ 219.8, 170.4, 164.9, 151.9, 137.1,
134.2, 125.6, 119.6, 115.9, 77.5, 75.7, 72.2, 52.5, 43.5, 38.8, 37.6, 36.1,
32.3, 31.2, 26.9, 21.3, 21.1, 19.1, 17.0, 15.7, 14.3; HRMS (FAB) calcd
for C26H40NO5S (M + H+) 478.2627, found 478.2612.
Hydroxy Lactones 3 and 48. Cyclization of Triene 4 Wia Olefin
Metathesis. A solution of diene 4 (0.186 g, 0.3 mmol) in CH2Cl2 (200
mL, 0.0015 M) was treated with bis(tricyclohexylphosphine)ben-
zylideneruthenium dichloride (RuCl2(dCHPh)(PCy3)2, 25 mg, 0.03 mol,
0.1 equiv), for 20 h, in accordance with the procedure described for
the synthesis of hydroxy lactone 25, producing hydroxy lactones 3 (83
mg, 46%) and 48 (70 mg, 39%) after flash chromatography (7 f 25%
EtOAc in hexanes). 3: Rf ) 0.18 (silica, 20% EtOAc in hexanes);
[R]22 -79.5 (c 1.00, CHCl3); IR (film) νmax 3422, 2930, 1739, 1688,
D
1
1255, 1180, 1090, 598 cm-1; H NMR (500 MHz, CDCl3) δ 6.96 (s,
1 H, ArH), 6.55 (s, 1 H, ArCHdCCH3), 5.45 (ddd, J ) 10.5, 10.5, 3.0
Hz, 1 H, CHdCHCH2), 5.35 (ddd, J ) 10.5, 10.5, 5.5 Hz, 1 H,
CHdCHCH2), 5.03 (d, J ) 10.0 Hz, 1 H, CO2CH), 4.06 (t, J )6.0
Hz, 1 H, (CH3)2CCH(OTBS)), 3.94 (bs, 1 H, CHOH(CHCH3)), 3.05
(qd,
J )6.5, 3.5 Hz, 1 H, CH3CH(CdO)), 3.00 (bs, 1 H,
CHOH(CHCH3)), 2.80 (d, J ) 6.0 Hz, 2 H, CH2COO), 2.78-2.69 (m,
1 H), 2.70 (s, 3 H, CH3Ar), 2.40-2.30 (m, 1 H), 2.10 (s, 3 H,
ArCHdCCH3), 2.12-2.03 (m, 1 H), 2.00-1.93 (m, 1 H), 1.80-1.74
(m, 1 H), 1.70-1.58 (m, 1 H), 1.50-1.43 (m, 1 H), 1.30-1.15 (m, 2
H), 1.17 (s, 6 H, C(CH3)2), 1.14 (d, 3 H, J ) 5.0 Hz, CH3CH(CdO)),
1.02 (d, 3 H, J ) 5.0 Hz, CH3CHCH2), 0.82 (s, 9 H, SiC(CH3)3(CH3)2),
0.12 (s, 3 H, SiC(CH3)3(CH3)2), -0.05 (s, 3 H, SiC(CH3)3(CH3)2); 13
C
NMR (150.9 MHz, CDCl3) δ 217.7, 170.7, 164.4, 152.2, 138.1, 134.5,
124.0, 119.5, 116.0, 79.0, 76.3, 73.2, 53.6, 43.1, 39.1, 38.9, 33.7, 32.0,
28.5, 28.0, 26.3, 24.9, 23.0, 19.3, 18.7, 16.6, 15.4, 14.3, -3.4, -5.3;
HRMS (FAB) calcd for C32H53CsNO5SSi (M + Cs+) 724.2468, found
724.2466. 48: Rf ) 0.40 (silica, 20% EtOAc in hexanes); [R]22D -71.5
(c 0.80, CHCl3); IR (film) νmax 3381, 2958, 2928, 1727, 1273, 1122,
1072 cm-1; 1H NMR (600 MHz, CDCl3) δ 7.00 (s, 1 H, ArH), 6.62 (s,
1 H, ArCHdCCH3), 5.36 (ddd, J ) 15.0, 7.3, 7.3 Hz, 1 H,
CHdCHCH2), 5.27 (ddd, J ) 15.0, 7.3, 7.3 Hz, 1 H, CHdCHCH2),
5.19 (dd, J ) 6.5, 3.6 Hz, 1 H, CO2CH), 4.43 (dd, J ) 8.6, 2.7 Hz, 1
H, (CH3)2CCH(OTBS)), 3.87-3.83 (m, 1 H, CHOH(CHCH3)), 3.29
(bs, 1 H, CHOH(CHCH3)), 3.19 (qd, J ) 6.9, 5.4 Hz, 1 H,
CH3CH(CdO)), 2.71 (s, 3 H, CH3Ar), 2.72-2.67 (m, 1 H), 2.65 (dd,
J ) 15.4, 8.6 Hz, 1 H, CH2COO), 2.59 (dd, J ) 15.4, 2.7 Hz, 1 H,
CH2COO), 2.45-2.37 (m, 1 H), 2.20-2.12 (m, 1 H), 2.08 (s, 3 H,
ArCHdCCH3), 2.00-1.93 (m, 1 H), 1.65-1.44 (m, 4 H), 1.22 (d, 3
H, J ) 6.9 Hz, CH3CH(CdO)), 1.2-1.12 (m, 1 H), 1.15 (s, 3 H,
C(CH3)2), 1.09 (s, 3 H, C(CH3)2), 1.03 (d, 3 H, J ) 6.9 Hz,
Epothilones A (1) and 51-57. Epoxidation of cis-Dihydroxy
Lactone 49. Procedure A: A solution of cis-dihydroxy lactone 49
(24 mg, 0.05 mmol) in CHCl3 (4.0 mL) was reacted with 3-chlorop-
eroxybenzoic acid (mCPBA, 57-86%, 13.0 mg, 0.04-0.06 mmol, 0.8-
1.2 equiv), at -20 f 0 °C, according to the procedure described for
the epoxidation of 37, resulting in the isolation of epothilone A (1)
(8.6 mg, 35%), its isomeric R-epoxide 51 (2.8 mg, 13%), and
compounds 52 (or 53) (1.6 mg, 9%), 53 (or 52) (1.5 mg, 7%), 54 (or
55) (1.0 mg, 5%), and 55 (or 54) (1.0 mg, 5%) (stereochemistry
unassigned for 52 and 53 and for 54 and 55), after two consecutive
preparative thin-layer chromatographic purifications (250 µm silica gel
plate, 5% MeOH in CH2Cl2 and 70% EtOAc in hexanes). Procedure
B: To a solution of cis-dihydroxy lactone 49 (15 mg, 0.03 mmol) in
CH2Cl2 (1.0 mL) at 0 °C was added dropwise a solution of dimethyl-
dioxirane in acetone (ca. 0.1 M, 0.3 mL, ca. 1.0 equiv) until no starting
lactone was detectable by TLC. The solution was then concentrated
in vacuo and the crude product was subjected to two consecutive
preparative thin-layer chromatographic purifications (250 µm silica gel

7972 J. Am. Chem. Soc., Vol. 119, No. 34, 1997
Nicolaou et al.
plate, 5% MeOH in CH2Cl2 and 70% EtOAc in hexanes), to obtain
pure epothilone A (1) (7.4 mg, 50%), its isomeric R-epoxide 51 (2.3
mg, 15%), and epothilones 52 (or 53) (0.8 mg, 5%) and 53 (or 52)
(0.8 mg, 5%) (stereochemistry unassigned for 52 and 53. Procedure
C: As described in procedure B for the epoxidation of trans-hydroxy
lactone 37, cis-dihydroxy lactone 49 (10.0 mg, 0.02 mmol) in MeCN
(200 µL) was treated with a 0.0004 M aqueous solution of disodium
salt of ethylenediaminetetraacetic acid (Na2EDTA, 120 µL), excess
1,1,1-trifluoroacetone (100 µL), Oxone (61 mg, 0.10 mmol, 5.0 equiv),
and NaHCO3 (14 mg, 0.16 mmol, 8.0 equiv), to yield, after purification
by preparative thin-layer chromatography (250 µm silica gel plate,
ether), a mixture of diastereomeric epoxides, epothilones A (1) (6.4
mg, 62%) and R-isomeric epoxide 51 (1.3 mg, 13%). Procedure D:
A solution of cis-dihydroxy lactone 49 (18 mg, 0.037 mmol) in CHCl3
(1.0 mL) was treated with 3-chloroperoxybenzoic acid (mCPBA, 57-
86%, 15 mg, 0.049-0.074 mmol, 1.3-2.0 equiv), according to the
procedure described for the epoxidation of 37, furnishing compounds
1 (2.7 mg, 15%), 51 (1.8 mg, 10%), 52 (or 53) (1.8 mg, 10%), 53 (or
52) (1.4 mg, 8%), 54 (or 55) (1.4 mg, 8%), 55 (or 54) (1.26 mg, 7%),
56 (0.9 mg, 5%), and 57 (0.9 mg, 5%) (stereochemistry unassigned
for 52-57), after two consecutive preparative thin-layer chromato-
graphic purifications (250 µm silica gel plate, 5% MeOH in CH2Cl2
and 70% EtOAc in hexanes). Epothilone A (1): Rf ) 0.23 (silica gel,
33% MeOH-CH2Cl2); HPLC (Watman EOC, C-18, 4 µ, 108 × 4.6
mm column, solvent gradient: 0 f 20 min, 30 f 80% MeOH in H2O)
Rt ) 14.8 min; [R]D ) -45.0 (c 0.02, MeOH); IR (film) νmax 3476,
2974, 1738, 1692 cm-1; 1H NMR (600 MHz, C6D6) δ ) 6.71 (s, 1 H,
ArCHdCCH3), 6.45 (s, 1 H, ArH), 5.45 (dd, 1 H, J ) 8.2, 2.3 Hz,
CO2CH), 4.15 (dd, 1 H, J ) 10.8, 2.9 Hz, (CH3)2CCH(OH)), 3.81-
3.78 (m, 1 H, CHOH(CHCH3)), 3.65 (bs, 1 H, OH), 3.03 (qd, J ) 6.9,
6.5 Hz, 1 H, CH3CH(CdO)), 2.77 (ddd, J ) 7.9, 4.0, 4.0 Hz, 1 H,
CH2CH-O(epoxide)CH), 2.62-2.58 (m, 1 H, CH2CH-O(epoxide)CH),
2.40 (dd, J ) 14.4, 10.8 Hz, 1 H, CH2COO), 2.26 (bs, 1 H, OH), 2.21
(s, 3 H, CH3Ar), 2.19 (dd, J ) 14.4, 2.9 Hz, 1 H, CH2COO), 2.05 (s,
3 H, ArCHdCCH3), 1.86 (ddd, J ) 15.2, 2.5, 2.5 Hz, 1 H, CH2CH-
O(epoxide)CH), 1.81-1.74 (m, 1 H, CH2CH-O(epoxide)CH), 1.68
(ddd, J ) 15.2, 7.6, 7.6 Hz, 1 H, CH2CH-O(epoxide)CH), 1.53-1.49
(m, 1 H, CH2CH-O(epoxide)CH), 1.40-1.15 (m, 5 H), 1.06 (d, 3 H,
J ) 7.0 Hz, CH3CH(CdO)), 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, CH3CHCH2); 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. 51: Rf ) 0.35 (silica
gel, 70% EtOAc in hexanes); [R]22D -23.0 (c 0.10, CHCl3); IR (film)
(mCPBA, 57-86%, 11.0 mg, 0.036-0.054 mmol, 0.9-1.3 equiv) at
-20 f 0 °C, according to the procedure described for the epoxidation
of compound 37, to give a epothilones 58 (1.0 mg, 5%), 59 (1.0 mg,
5%), and 60 (12 mg, 60%) (stereochemistry unassigned for all three),
after preparative thin-layer chromatography (250 µm silica gel plate,
70% EtOAc in hexanes). Procedure B: According to procedure B for
the epoxidation of cis-dihydroxy lactone 49, a solution of trans-
dihydroxy lactone 50 (10.0 mg, 0.02 mmol) in CH2Cl2 (1.0 mL) was
reacted with a solution of dimethyldioxirane (ca. 0.1 M, 0.2 mL, ca.
1.0 equiv) in acetone at 0 °C, and after preparative thin-layer
chromatography (250 µm silica gel plate, 70% EtOAc in hexanes),
epothilones 58 (1.0 mg, 10%), 59 (1.0 mg, 10%), and 60 (4.0 mg, 40%)
were obtained. Procedure C: As described in procedure B for the
epoxidation of trans-hydroxy lactone 37, trans-dihydroxy lactone 50
(5.1 mg, 0.01 mol) in MeCN (100 µL) was treated with a 0.0004 M
aqueous solution of disodium salt of ethylenediaminetetraacetic acid
(Na2EDTA, 60 µL), excess 1,1,1-trifluoroacetone (100 µL), Oxone (32
mg, 0.05 mmol, 5.0 equiv), and NaHCO3 (7.0 mg, 0.08 mmol, 8.0
equiv), to yield, after purification by preparative thin-layer chroma-
tography (250 µm silica gel plate, ether), epothilones 58 (2.3 mg, 45%)
and 59 (1.8 mg, 35%). 58: Rf ) 0.15 (silica gel, ether); [R]22D -23.3
(c 0.40, CHCl3); IR (film) νmax 3454, 2926, 2856, 1731, 1690, 1464,
1
1376, 1259, 1151, 980 cm-1; H NMR (500 MHz, C6D6) δ 6.73 (s, 1
H, ArCHdC(CH3)), 6.53 (s, 1 H, ArH), 5.54 (dd, J ) 8.0, 2.0 Hz, 1
H, CO2CH), 4.18 (d, J ) 10.0 Hz, 1 H, (CH3)2CCH(OH)), 3.87 (dd, J
) 4.5, 2.0 Hz, 1 H, CHOH(CHCH3)), 3.43 (bs, 1 H), 3.13 (dq, J )
7.0, 7.0 Hz, 1 H, CH3CH(CdO)), 2.74-2.72 (m, 1 H), 2.63-2.60 (m,
1 H), 2.45 (dd, J ) 15.0, 10.5 Hz, 1 H, CH2COO), 2.33 (dd, J ) 15.0,
3.0 Hz, 1 H, CH2COO), 2.32-2.24 (m, 1 H), 2.28 (s, 3 H, CH3Ar),
2.12 (s, 3 H, ArCHdCCH3), 2.00 (ddd, J ) 15.0, 3.0, 2.5 Hz, 1 H),
1.75-1.65 (m, 3 H), 1.60-0.98 (m, 4 H), 1.18 (d, J ) 7.0 Hz, 3 H,
CH3CH(CdO)), 1.10 (s, 3 H, C(CH3)2), 1.05 (s, 3 H, C(CH3)2), 0.97
(d, J ) 7.0 Hz, 3 H, CH3CHCH2); 13C NMR (125.7 MHz, C6D6) δ
217.2, 170.3, 164.6, 153.2, 137.0, 120.4, 116.9, 76.7, 75.6, 72.8, 58.0,
56.0, 53.0, 44.7, 38.8, 36.5, 35.8, 32.0, 30.3, 30.1, 22.6, 21.0, 20.9,
17.1, 15.3, 14.9; HRMS (FAB) calcd for C26H39CsNO6S (M + Cs+)
626.1552, found 626.1538. 59: Rf ) 0.20 (silica gel, ether); [R]22
D
-25.3 (c 0.30, CHCl3); IR (film) νmax 3419, 2923, 1732, 1691, 1464,
1259 cm-1 1H NMR (500 MHz, C6D6) δ 6.82 (s, 1 H, ArCHdC-
;
(CH3)), 6.56 (s, 1 H, ArH), 5.53 (dd, J ) 7.5, 3.5 Hz, 1 H, CO2CH),
4.47 (d, J ) 8.5 Hz, 1 H, (CH3)2CCH(OH)), 3.94 (bs, 1 H, CHOH-
(CHCH3)), 3.65-3.58 (m, 1 H), 3.35 (dq, J ) 6.5, 6.5 Hz, 1 H,
CH3CH(CdO)), 2.73-2.65 (m, 1 H), 2.65-2.61 (m, 1 H), 2.52-2.46
(m, 1 H), 2.41 (dd, J ) 14.0, 9.5 Hz, 1 H, CH2
COO), 2.33 (dd, J )
1
νmax 3416, 2925, 2855, 1732, 1688, 1457 1258, 1150 cm-1; H NMR
14.0, 4.0 Hz, 1 H, CH2COO), 2.31 (s, 3 H, CH3Ar), 2.03 (s, 3 H,
ArCHdCCH3), 1.91-1.81 (m, 2 H), 1.78-1.53 (m, 4 H), 1.41-1.32
(m, 2 H), 1.22 (d, J ) 7.0 Hz, 3 H, CH3CH(CdO)), 1.21 (s, 3 H,
C(CH3)2), 1.08 (d, J ) 7.0 Hz, 3 H, CH3CHCH2), 1.05 (s, 3 H,
C(CH3)2); 13C NMR (150.9 MHz, C6D6) δ 215.7, 167.6, 161.7, 149.8,
133.8, 116.6, 113.4, 73.8, 73.2, 70.1, 55.2, 52.4, 49.9, 41.7, 36.4, 34.0,
32.3, 28.0, 27.8, 27.4, 19.9, 17.8, 15.8, 14.6, 13.0, 12.3; HRMS (FAB)
calcd for C26H39CsNO6S (M + Cs+) 626.1552, found 626.1531. 60:
(500 MHz, C6D6) δ 6.79 (s, 1 H, ArCHdCCH3), 6.57 (s, 1 H, ArH),
5.82 (d, J ) 8.0 Hz, 1 H, CO2CH), 4.31 (dd, J ) 10.5, 2.5 Hz, 1 H,
(CH3)2CCH(OH)), 4.19-4.15 (m, 1 H, CHOH(CHCH3)), 3.78 (bs, 1
H), 3.31 (qd, J ) 7.0, 3.0 Hz, 1 H, CH3CH(CdO)), 2.82 (ddd, J )
10.0, 4.2, 4.2 Hz, 1 H, CH2CH-O(epoxide)CH), 2.76 (bs, 1 H), 2.55
(ddd, J ) 9.0, 9.0, 4.5 Hz, 1 H, CH2CH-O(epoxide)CH), 2.40 (dd, J )
13.0, 10.5, 1 H, CH2COO), 2.33 (dd, J ) 13.0, 2.5 Hz, 1 H, CH2-
COO), 2.31 (s, 3 H, CH3Ar), 2.20 (s, 3 H, ArCHdCCH3), 1.97-1.92
(m, 1 H), 1.72 (ddd, J ) 15.0, 8.5, 8.5 Hz, 1 H), 1.56 (ddd, J ) 15.0,
4.5, 2.0 Hz, 1 H), 1.54-1.28 (m, 6 H), 1.17 (d, J ) 7.0 Hz, 3 H,
CH3CH(CdO)), 1.13 (s, 3 H, C(CH3)2), 1.06 (d, J ) 7.0 Hz, 3 H,
CH3CHCH2), 0.97 (s, 3 H, C(CH3)2); 13C NMR (150.9 MHz, C6D6) δ
221.7, 171.0, 165.5, 154.2, 138.3, 120.7, 117.6, 77.0, 74.8, 73.2, 57.7,
56.8, 52.4, 43.5, 39.5, 38.5, 33.0, 31.4, 28.3, 24.6, 21.6, 19.5, 19.2,
17.0, 15.7, 13.9; HRMS (FAB) calcd for C26H40NO6S (M + H+)
494.2576, found 494.2558.
Rf ) 0.6 (silica gel, 70% EtOAc in hexanes); [R]22 -28.3 (c 0.30,
D
1
CHCl3); IR (film) νmax 3472, 2928, 1735, 1691, 1466 cm-1; H NMR
(500 MHz, C6D6) δ 6.67 (s, 1 H, ArH), 5.48-5.41 (m, 1 H,
CHdCHCH2), 5.36-5.23 (m, 2 H, CHdCHCH2 and CO2CH), 4.36-
4.30 (m, 1 H, (CH3)2CCH(OH)), 3.79-3.73 (m, 1 H), 3.63-3.58 (m,
1 H), 3.17-3.10 (m, 1 H, CH3CH(CdO)), 2.81 (bs, 1 H), 2.53 (dd, J
) 15.0, 10.5 Hz, 1 H, CH2COO), 2.40-2.29 (m, 2 H), 2.26-2.19 (m,
2 H), 2.25 (s, 3 H, CH3Ar), 2.20-1.95 (m, 1 H), 1.80-1.72 (m, 1 H),
1.62-1.53 (m, 1 H), 1.46-1.33 (m, 2 H), 1.20 (d, J ) 6.5 Hz, 3 H,
CH3CH(CdO)), 1.13 (s, 3 H, C(CH3)2), 1.10 (s, 3 H, C(CH3)2), 1.08
(d, J ) 7.0 Hz, 3 H, CH3CHCH2), 1.06 (s, 3 H, ArCH-O(epoxide)-
CCH3); 13C NMR (125.7 MHz, C6D6) δ 219.7, 169.6, 166.9, 151.3,
135.4, 124.6, 115.8, 78.3, 72.8, 72.6, 64.2, 59.1, 53.3, 43.4, 40.2, 38.8,
34.3, 33.1, 31.4, 27.5, 21.8, 19.8, 18.9, 16.5, 15.3, 14.0; HRMS (FAB)
calcd for C26H40NO6S (M + H+) 494.2576, found 494.2587.
Oxidation of Epothilone A (1) with mCPBA. A solution of
epothilone A (1) (3.0 mg, 0.006 mmol) in CHCl3 (120 µL, 0.05 M)
was reacted with 3-chloroperoxybenzoic acid (mCPBA, 57-86%, 1.1
mg, 0.0023-0.0032 mmol, 0.8-1.1 equiv), at -20 f 0 °C, according
to the procedure described for the epoxidation of 37, resulting in the
formation of bis(epoxides) 54 (or 55) (1.1 mg, 35%) and 55 (or 54)
(1.0 mg, 32%) along with sulfoxide 57 (0.2 mg, 6%).
Dihydroxy Ester 61. Desilylation of Compound 47. Silyl ether
47 (48 mg, 0.079 mmol) was treated with a freshly prepared solution
of 20% (v/v) trifluoroacetic acid (TFA)-CH2Cl2 (1.6 mL, 0.05 M),
according to the procedure described for the desilylation of compound
Epothilones 58-60. Epoxidation of trans-Dihydroxy Lactone 50.
Procedure A: A solution of trans-dihydroxy lactone 50 (20 mg, 0.042
mmol) in CHCl3 (4.0 mL) was treated with 3-chloroperoxybenzoic acid

Olefin Metathesis Approach to Epothilone A
J. Am. Chem. Soc., Vol. 119, No. 34, 1997 7973
3, to yield, after flash column chromatography (silica gel, 5% f 50%
EtOAc in hexanes), dihydroxy ester 61 (35 mg, 90%).
(250 µm silica gel plate, 70% EtOAc in hexanes), epothilones 67 (or
68) (4.2 mg, 24%), 68 (or 67) (3.3 mg, 19%), and 69 (5.4 mg, 31%)
(stereochemistry unassigned for all three). Procedure B: As described
in procedure C for the epoxidation of cis-lactone 49, trans-dihydroxy
lactone 63 (6.0 mg, 0.0126 mmol) in MeCN (240 µL) was treated with
a 0.0004 M aqueous solution of disodium salt of ethylenediaminetet-
raacetic acid (Na2EDTA, 90 µL), 1,1,1-trifluoroacetone (90 µL), Oxone
(40 mg, 0.063 mmol, 5.0 equiv), and NaHCO3 (8.4 mg, 0.100 mmol,
8.0 equiv), to yield, after purification by preparative thin-layer
chromatography (250 µm silica gel plate, ether), epothilones 67 (or
68) (2.7 mg, 44%) and 68 (or 67) (1.3 mg, 21%).
Dihydroxy Lactones 62 and 63. Olefin Metathesis of Dihydroxy
Ester 61. A solution of compound 61 (48 mg, 0.095 mmol) in CH2-
Cl2 (20 mL, 0.005 M) was treated with bis(tricyclohexylphosphine)-
benzylideneruthenium dichloride (RuCl2(dCHPh)(PCy3)2, 16 mg, 0.019
mmol, 0.2 equiv), according to the procedure described for the
cyclization of 25, producing dihydroxy lactones 62 (9.1 mg, 20%) and
63 (32 mg, 69%), after preparative thin-layer chromatograpy (0.5 mm
silica gel plate, 33% EtOAc in hexanes).
Epothilones 64-65. Epoxidation of cis-Dihydroxy Lactone 62.
Procedure A: A solution of cis-dihydroxy lactone 62 (10.0 mg, 0.021
mmol) in CHCl3 (210 µL) was treated with 3-chloroperoxybenzoic acid
(mCPBA, 57-86%, 5.0 mg, 0.0165-0.0252 mmol, 0.8-1.2 equiv) at
-20 f 0 °C, according to the procedure described for the epoxidation
of compound 37, to produce, after preparative thin-layer chromatog-
raphy (250 µm silica gel plate, 70% EtOAc in hexanes), epothilones
64 (or 65)(2.6 mg, 25%) and 65 (or 64) (2.4 mg, 23%) (stereochemistry
unassigned for all three). Procedure B: As described in procedure B
for the epoxidation of trans-hydroxy lactone 37, cis-dihydroxy lactone
62 (10.0 mg, 0.021 mmol) in MeCN (400 µL) was treated with a 0.0004
M aqueous solution of disodium salt of ethylenediaminetetraacetic acid
(Na2EDTA, 200 µL), excess 1,1,1-trifluoroacetone (150 µL), Oxone
(65 mg, 0.105 mmol, 5.0 equiv), and NaHCO3 (14 mg, 0.168 mmol,
8.0 equiv), to yield, after purification by preparative thin-layer
chromatography (250 µm silica gel plate, ether), epothilones 64 (or
65) (6.0 mg, 58%) and 65 (or 64) (3.0 mg, 29%).
Acknowledgment. We thank Dr. G. Ho¨fle for an authentic
sample of natural epothilone A (1) and Drs. Raj Chada, Dee H.
Huang, and Gary Siuzdak for their superb X-ray crystal-
lographic, NMR, and mass spectroscopic assistance, respec-
tively. This work was financially supported by The Skaggs
Institute for Chemical Biology, the National Institutes of Health
USA, fellowships from Novartis (D.V.), the Deutsche Fors-
chungsgemeinschaft (DFG) (F.R.), the Fundacio´n Ramo´n Areces
(F.S.), and the National Science Foundation (NSF) (J.I.T.), and
grants from Amgen, DuPont-Merck, Hoffmann La Roche,
Merck, Schering-Plough, and CaPCURE.
Supporting Information Available: Selected physical
properties for compounds of 17b, 18b, 22b, 29-32, 37, 39-
41, 52-57, and 61-69, X-ray crystallographic parameters for
Epothilones 67-69. Epoxidation of trans-Dihydroxy Lactone 63.
Procedure A: A solution of trans-dihydroxy lactone 63 (17.0 mg, 0.033
mmol) in CHCl3 (2.0 mL) was treated with 3-chloroperoxybenzoic acid
(mCPBA, 57-86%, 8.9 mg, 0.029-0.044 mmol, 0.9-1.3 equiv) at
-20 f 0 °C, according to the procedure described for the synthesis of
epoxide 37, to produce, after preparative thin-layer chromatography
1
1
compound 28, and H-1H NOESY and H-1H COSY NMR
spectra for 58 and 59 (39 pages). See any current masthead
page for ordering and Internet access instructions.
JA971109I