Total synthesis of epothilone A.

Article abstract of DOI:10.1021/ol006104w

[reaction: see text]Epothilones A (1) and B (2) are potent antitumor natural products with a Taxol-like mechanism of action. A total synthesis of epothilone A (1) is reported, which utilized chiral silane-based bond construction methodology to introduce t

Full text of DOI:10.1021/ol006104w

ORGANIC
LETTERS
2000
Vol. 2, No. 17
2575-2578
Total Synthesis of Epothilone A
Bin Zhu and James S. Panek*
Department of Chemistry and the Center for Streamlined Synthesis, Metcalf Center for
Science and Engineering, Boston UniVersity, 590 Commonwealth AVenue,
Boston, Massachusetts 02215
panek@chem.bu.edu
Received May 25, 2000
ABSTRACT
Epothilones A (1) and B (2) are potent antitumor natural products with a Taxol-like mechanism of action. A total synthesis of epothilone A (1)
is reported, which utilized chiral silane-based bond construction methodology to introduce the key C-6 and C-7 stereocenters of fragment 4.
The C-15 stereocenter of fragment 5 was established by a lipase-mediated kinetic resolution. The fragments were assembled with a Suzuki
coupling reaction and an aldol condensation and cyclized with a Yamaguchi-type macrolactonization reaction.
Epothilones A (1) and B (2) are cytotoxic macrolides isolated
from the myxobacterium Sorangium cellulosum.1 These
compounds exhibit potent antitumor activity, and their
mechanism of action is found to be similar to that of Taxol
(paclitaxel).2 Both epothilones and taxanes kill tumor cells
through induction of tubulin polymerization and microtubule
stabilization. Moreover, it has been recognized that epothilones
are effective against a number of Taxol-resistant tumor cell
lines. As a consequence of their remarkable biological
activity and unique chemical structure, extensive effort
concerning the synthesis of the epothilone class of molecules
was initiated and is manifested in the large number of
publications in this area.3 However, the development of novel
and convergent synthetic routes toward these compounds
would constitute a useful contribution to this field.
We report herein a highly convergent synthesis of epothilone
A (1), which is based on the synthesis and transition metal
catalyzed cross coupling of two advanced intermediates:
polypropionate-derived fragment 4 and thiazole-containing
fragment 5. Chiral silane-based bond construction methodol-
ogy4 was utilized for the introduction of the C-6 and C-7
stereocenters of the polypropionate-derived fragment 4. The
chiral silane reagents (Figure 1) developed in our laboratory
Figure 1. Chiral crotylsilane reagents.
(1) (a) Gerth, K.; Bedorf, N.; Ho¨fle, G.; Irschik, H.; Reichenbach, H. J.
Antibiot. 1996, 49, 560-563. (b) Ho¨fle, G.; Bedorf, N.; Steinmetz, H.;
Schomburg, D.; Gerth, K.; Reichenbach, H. Angew. Chem., Int. Ed, Engl.
1996, 35, 1567-1569.
(2) 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.
have demonstrated their usefulness in a number of compli-
cated natural product syntheses.5 The chirality of these
silicon-bearing reagents is derived from a Pseudomonas AK
lipase6 mediated kinetic resolution.7 This biocatalytic process
10.1021/ol006104w CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/26/2000

is the ultimate source of enantioenriched materials used in
Scheme 2. Synthesis of Fragment 4a
our synthesis of epothilone A (1).
Scheme 1 outlines the retrosynthetic analysis of epothilone
A (1). The illustrated bond disconnection gave three frag-
Scheme 1. Retrosynthetic Analysis of Epothilone A (1)
a (a) TMSOBn, catalytic TMSOTf, CH2Cl2, -78 to -50 °C, 16
h; S-3, BF3‚Et2O, -30 °C, 24 h, 83%, syn/anti ) 15:1; (b) O3,
MeOH/CH2Cl2 (2:1), pyridine, Me2S, -78 °C to rt, 88%; (c) TiCl4,
9, CH2Cl2, -78 °C, 30 min, 83%, anti/syn ) 6:1; (d) TBSOTf,
2,6-lutidine, CH2Cl2, 0 °C, 2 h, 95%; (e) Bu4NF/AcOH (1:1), THF,
rt, 24 h, 92%; (f) (COCl)2, DMSO, Et3N, CH2Cl2, -78 °C to rt,
95%; (g) Ph3PdCHCO2Et, benzene, reflux, 4 h, 91%; (h) Me2CuLi,
TMSCl, THF, -78 °C, 4 h, 94%, anti/syn > 10:1; (i) DIBAL-H,
CH2Cl2, -78 °C, 15 min; (j) TBSCl, imidazole, DMF, 68% for
two steps; (k) CH3PPh3Br, NaN(TMS)2, THF, 0 °C, 90%.
good diastereoselectivity (syn/anti ) 15:1).8 The double bond
of 8 was oxidatively cleaved, and the resulting aldehyde was
subjected to a chelation-controlled aldol condensation with
silyl ketene acetal 9 under the catalysis of TiCl4.9 The aldol
product 10 was obtained in 83% yield and in a 6:1 ratio
favoring the desired C5-C7 anti diastereomer. The second-
ary hydroxyl group of 10 was protected as a tert-butyldi-
methylsilyl (TBS) ether, and the existing primary tert-
butyldiphenylsilyl (TBDPS) protecting group was selectively
removed using acetic acid buffered tetrabutylammonium
fluoride to give the alcohol 11. A Swern oxidation and a
Wittig olefination reaction converted 11 into the R,â-
unsaturated ester 12, which was then treated with Me2CuLi
in the presence of trimethylchlorosilane (TMSCl) at low
temperature (-78 °C, THF). The cuprate addition reaction
proceeded smoothly to give the 1,4-adduct 13 in 94% yield
with a C8-C7 anti/syn ratio greater than 10:1.10 Gratifyingly,
the two ester groups of 13 were easily differentiated by a
DIBAL-H reduction using CH2Cl2 as solvent, which cleanly
transformed the C-10 and C-3 esters to an aldehyde and a
primary hydroxyl group, respectively.11 The resulting hy-
ments, 4, 5, and 6. The 16-membered lactone was to be
assembled using an intermolecular Suzuki cross coupling of
4 and 5 and a diastereoselective aldol condensation with silyl
ketene acetal 6 followed by a Yamaguchi-type macrolac-
tonization.
The synthesis of fragment 4 is shown in Scheme 2.
Aldehyde 7 was first converted into the di-benzyl acetal
(TMSOBn, catalytic TMSOTf), which was then treated with
chiral crotylsilane reagent S-3 in the presence of BF3‚Et2O
to give the desired crotylation adduct 8 in 83% yield and
(3) (a) Nicolaou, K. C.; Roschangar, F.; Vourloumis, D. Angew. Chem.,
Int. Ed. 1998, 37, 2015-2045 and references therein. (b) Harris, C. R.;
Danishefsky, S. J. J. Org. Chem. 1999, 64, 8434-8456 and references
therein. (c) Harris, C. R.; Kuduk, S. D.; Balog, A.; Savin, K.; Glunz, P.
W.; Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121, 7050-7062. (d) White,
J. D.; Carter, R. G.; Sundermann, K. F. J. Org. Chem. 1999, 64, 684-685.
(e) White, J. D.; Sundermann, K. F.; Carter, R. G. Org. Lett. 1999, 1, 1431-
1434. (f) Sawada, D.; Shibasaki, M. Angew. Chem., Int. Ed. 2000, 39, 209-
213. (g) Zhu, B.; Panek, J. S. Tetrahedron Lett. 2000, 41, 1863-1866. (h)
Martin, H. J.; Drescher, M.; Mulzer, J. Angew. Chem., Int. Ed. 2000, 39,
581-583.
(4) Masse, C. E.; Panek, J. S. Chem. ReV. 1995, 95, 1293-1316.
(5) (a) Panek, J. S.; Xu, F. J. Am. Chem. Soc. 1995, 117, 10587-10588.
(b) Panek, J. S.; Jain, N. F. J. Org. Chem. 1998, 63, 4572-4573. (c) Hu,
T.; Panek, J. S. J. Org. Chem. 1999, 64, 3000-3001. (d) Hu, T.; Panek, J.
S. J. Am. Chem. Soc. 1999, 121, 9229-9230. (e) Liu, P.; Panek, J. S. J.
Am. Chem. Soc. 2000, 122, 1235-1236.
(8) Panek, J. S.; Yang, M. J. Org. Chem. 1991, 56, 5755-5792.
(9) For chelation-controlled addition to carbonyl see: Reetz, M. Angew.
Chem., Int. Ed. Engl. 1984, 23, 556-569.
(10) (a) Hanessian, S.; Sumi, K. Synthesis 1991, 1083-1089. (b)
Hanessian, S.; Wang, W.; Gai, Y.; Oliveier, E. J. Am. Chem. Soc. 1997,
119, 10034-10041.
(6) Pseudomonas AK lipase was purchased from Amano International
Enzyme Co. for $100/100 g.
(7) Beresis, R. T.; Solomon, J. S.; Yang, M. G.; Jain, N. F.; Panek, J. S.
Org. Synth. 1997, 75, 78-88.
2576
Org. Lett., Vol. 2, No. 17, 2000

droxy aldehyde 14 was protected as a silyl ether, and the
aldehyde moiety was subjected to a Wittig olefination
reaction to install the terminal olefin and furnish the C3-
C11 fragment 4.
the desired C12-C13 cis-olefin as a single double bond
isomer (Scheme 4).15 Compound 21 was selectively depro-
The synthesis of C12-C21 fragment 5 started with the
known aldehyde 15.12 Treatment of 15 with vinylmagnesium
bromide (-78 °C, THF) led to racemic divinyl carbinol rac-
16. An enzymatic kinetic resolution of rac-16 using
Pseudomonas AK lipase provided enantiomerically enriched
alcohol S-16 in 48% yield (50% conversion) and 90% ee (E
) 58.4),13 along with the enantiomeric acetate R-17.3g This
alcohol S-16 was then protected as its silyl ether to give 18
(TBSCl, imidazole, DMF). Selective hydroboration of the
terminal olefin of 18 with dicyclohexylborane followed by
oxidation led to alcohol 19. This intermediate was converted
into the cis-vinyl iodide 20 by a three-step sequence,
including Dess-Martin oxidation,14 Wittig olefination, and
HF-promoted desilylation. Acetylation of 20 finished the
synthesis of the C12-C21 fragment 5 (Scheme 3).
Scheme 4. Synthesis of Epothilone A (1)a
Scheme 3. Lipase Resolution and Synthesis of Fragment 5a
a (a) 4, 9-BBN, THF; then 5, Pd(dppf)Cl2, Cs2CO3, DMF, H2O,
rt, 60%; (b) HF/pyridine, THF, rt, 93%; (c) Dess-Martin perio-
dinane, CH2Cl2, 91%; (d) 6, TiCl4, CH2Cl2, -78 °C, 15 min, 87%,
syn/anti ) 9:1; (e) Bu4NF, THF, 0 °C, 10 min, 89%; (f) TBSCl,
imidazole, DMF, rt, 36 h, 91%; (g) Dess-Martin periodinane,
CH2Cl2, 93%; (h) NaOH (aq), MeOH, reflux, 1.5 h, 62%; (i) 2,4,6-
trichlorobenzoyl chloride, Et3N, THF, 0 °C, 15 min; DMAP,
toluene, rt, 30 min, 73%; (j) DDQ, CH2Cl2/H2O (4:1), rt, 82%; (k)
20% CF3CO2H in CH2Cl2, rt, 2.5 h, 90%; (l) CH3CN, H2O2 (30%
aqueous solution), KHCO3, MeOH, rt, 24 h, ca. 60% (based on
recovered starting material).
a (a) Vinylmagnesium bromide, THF, -78 °C, 90%; (b) lipase
AK (50wt %), vinyl acetate, hexane, rt, 48 to 72 h, 48%, 90% ee;
(c) TBSCl, imidazole, DMF, 95%; (d) BH3‚THF, cyclohexene,
THF, NaOH, H2O2, 90%; (e) Dess-Martin periodinane, CH2Cl2;
(f) CH2IPPh3I, NaN(TMS)2, THF; (g) HF (48% aqueous), CH3CN,
65% for three steps; (h) Ac2O, Et3N, DMAP, CH2Cl2, 95%.
In a manner similar to Danishefsky’s synthesis, an
intermolecular Suzuki coupling of fragments 4 and 5 was
successfully carried out to give the coupling product 21 with
tected at the primary position to give alcohol 22. Dess-
Martin oxidation of the primary hydroxyl group of 22
provided the corresponding aldehyde, which was then treated
(11) A possible explanation for different behavior of C3 and C10 ester
groups in DIBAL-H reduction is due to their different steric enviroment.
(12) (a) Yang, Z.; He, Y.; Vourloumis, D.; Vallberg, H.; Nicolaou, K.
C. Angew. Chem., Int. Ed. Engl. 1997, 36, 166-168. (b) Taylor, R. E.;
Haley, J. D. Tetrahedron Lett. 1997, 38, 2061-2064.
(13) The enzymatic stereoselectivity factor E was calculated according
to the method of Kagan. See: Kagan, H. B.; Fiaud, J. C. Top. Stereochem.
1988, 18, 249-330.
(14) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156.
(b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-7287.
(15) (a) Johnson, C. R.; Braun, M. P. J. Am. Chem. Soc. 1993, 115,
11014-11015. (b) Balog, A.; Meng, D.; Kamenecka, T.; Bertinato, P.; Su,
D. S.; Sorensen, E. J.; Danishefsky, S. J. Angew. Chem., Int. Ed. Engl.
1996, 2801-2803.
(16) (a) Inanaga, J.; Hirata, K.; Saeki, H.; Yamaguchi, M. Bull. Chem.
Soc. Jpn. 1979, 52, 1989. (b) Mulzer, J.; Mareski, P. A.; Buschmann, J.;
Luger, P. Synthesis 1992, 215-228.
Org. Lett., Vol. 2, No. 17, 2000
2577

with the silyl ketene acetal 6 in the presence of TiCl4. The
aldol condensation produced the desired â-hydroxy ester 23,
along with its C3 epimer in a 9:1 ratio and in 87% combined
yield. Desilylation at the C5 position followed by selective
protection of the C3 hydroxyl group afforded compound 25.
At this point, the C5 hydroxyl was oxidized to ketone 26.
Base-promoted hydrolysis of C-1 isopropyl ester and C-15
acetate of 26 furnished the hydroxy acid 27, which was
subjected to a Yamaguchi-type macrolactonization reaction
to give lactone 28.16 The protecting groups of the C7 and
C3 hydroxyls were subsequently removed by treatment of
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and tri-
fluoroacetic acid to produce the di-hydroxy lactone 30.
Finally, epoxidation of the C12-C13 cis-olefin with in situ
generated methyl peroxycarboximidic acid led to epothilone
A (1).17
Pseudomonas AK lipase was used to provide the enantio-
merically enriched thiazole subunit. Noteworthy, the materi-
als for the synthesis are not obtained from the “chiral pool”,
and the enantioenriched materials are derived from one chiral
sourcesPseudomonas AK lipase.
Acknowledgment. Financial support was obtained from
the NIH (GM 55740). We thank Professor Samuel J.
Danishefsky (The Sloan-Kettering Institute for Cancer
Research) for copies of NMR spectra of epothilone A and
several intermediates.
Supporting Information Available: Experimental details
and characterization of compounds 1, 4, 5, 7, 8, 10-13, and
16-30. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL006104W
In summary, we have successfully carried out a highly
convergent synthesis of epothilone A. Chiral silane-based
bond construction methodology was employed to install the
key C6 and C7 stereocenters. A kinetic resolution with
(17) (a) Chaudhuri, N. K.; Ball, T. J. J. Org. Chem. 1982, 47, 5196-
5198. (b) Nicolaou, K. C.; Vallberg, H.; King, N. P.; Roschangar, F.; He,
Y.; Vourloumis, D.; Nicolaou, C. G. Chem. Eur. J. 1997, 3, 1957-1970.
2578
Org. Lett., Vol. 2, No. 17, 2000