Synthesis of epothilones: Stereoselective routes to epothilone B

Article abstract of DOI:10.1055/s-1998-1794

In connection with our studies of the total syntheses of epothilones we report our efforts on the syntheses of epothilone B using a macro-lactonization and a metathesis approach. Key reaction for the solution of the acyclic stereoselection is a stereoselective aldol reaction.

Full text of DOI:10.1055/s-1998-1794

August 1998
SYNLETT
861
Synthesis of Epothilones: Stereoselective Routes to Epothilone B
Dieter Schinzer*, Armin Bauer, Jennifer Schieber
Chemisches Institut der Otto-von-Guericke-Universität Magdeburg, Universitätsplatz 2 D-39106 Magdeburg, Germany
Fax: +49-391-67-12223; E-mail: Dieter.Schinzer@chemie.uni-magdeburg.de
Received 15 May 1998
8
Abstract: In connection with our studies of the total syntheses of
epothilones we report our efforts on the syntheses of epothilone B using
a macro-lactonization and a metathesis approach. Key reaction for the
solution of the acyclic stereoselection is a stereoselective aldol reaction.
coupling of fragments 3 and 4, which were obtained by efficient routes.
In contrast to our early studies, we have used an alternative strategy to
synthesize key fragment 2, which avoids large scale borane chemistry
and offers crystalline intermediates with the possibility to obtain higher
optical purity.
In light of their powerful anti-tumor activity, epothilones, a new family
of natural products isolated by the research groups of Höfle and
Reichenbach at the Gesellschaft für Biotechnologische Forschung
(GBF), in Braunschweig, Germany, have created tremendous
1
excitement in the scientific community.
2
Due to their impressive biological profile, multiple efforts towards the
synthesis of epothilones appeared almost simultaneously in the
3
4
literature. Three groups described total syntheses of epothilone A
shortly after these initial studies, and two described total syntheses of
5
epothilone B. In addition, a flood of papers appeared presenting partial
6
solutions towards the synthesis of epothilones. Many derivatives have
7
been synthesized as well and their biological profiles have been tested.
In this report, we wish to present our recent investigations along these
lines focusing on two novel routes to approach epothilone B. The first
approach uses macro-lactonization as the ring closing step (the
4d
retrosynthetic analysis is shown in Scheme 1), and the second uses
4c,7e
metathesis for ring closure following our epothilone A strategy.
9
Zinc-mediated coupling of 6 with 3-pentanone yielded ester 7.
Subsequent transformation into aldehyde 8 and aldol coupling with
10
(S)-HYTRA [(S)-(-)-2-hydroxy-1,2,2-triphenyl acetate] yielded 9 in
very high optical purity (de = 96%). Ester cleavage, reduction,
protection, and finally, ozonolysis gave the desired ethyl ketone 2.
The alkyl fragment 4 required for our desired palladium coupling was
11
synthesized using Evans’ procedure.
As shown in Scheme 1, the two major fragments 2 and 5 are coupled by
an aldol reaction and are finally cyclized via macro-lactonization to
obtain 1. Key aldehyde 5 was obtained by a palladium-mediated

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SYNLETT
Starting from compound 11, a diastereoselective allylation gave 12
(ratio: 20:1), which was transformed into 4 by a one-pot hydroboration/
iodination sequence after cleavage of oxazolidinone from 12.
Coupling of the enolate of 2, which was preformed with LDA in THF at
low temperature, with aldehyde 5 gave the required aldol product in
94% isolated yield with the desired anti-Felkin syn isomer 20 as the
12
17
major product (9:1). Deprotection and trisilylation of the triol
The key thiazole fragments 3 and 18 were obtained by very efficient
13,14
provided compound 21 which is identical to the compound published by
reactions starting from (S)-malic acid.
4d
Nicolaou in his total synthesis of epothilone B.
14a
Starting from 14, lactone 15 was obtained after borane reduction and
acid-catalyzed cyclization. Silylation, addition of methyllithium, and
further silylation gave functionalized ketone 16, which was transformed
4c
into aldehyde 17 as previously described. Further elaborations by
15
Wittig reactions gave key intermediates 3 and 18.
16
8
Coupling of intermediates 3 and 13 by palladium catalysis gave
compound 19 in a stereochemically homogeneous form containing the
desired trisubstituted double bond moiety of epothilone B. Deprotection
and Dess Martin periodinane oxidation yielded key aldehyde 5 in high
overall yield.
Our second epothilone B synthesis is based on our epothilone A
approach using three key fragments, which were combined by an aldol
reaction that proceeds with remarkable stereocontrol, and then by ring
4c
closure via olefin metathesis. Key aldehyde 25 was also synthesized
18
using Evans’ protocol as shown in Scheme 7.

August 1998
SYNLETT
863
Ethyl ketone 2 and aldehyde 25 were coupled by an aldol reaction under
kinetically controlled conditions yielding the desired anti-Felkin syn
aldol product 26 with high facial selectivity (10:1). Following our
Bertinato, P.;. Danishefsky, S. J. J. Org. Chem. 1996, 61, 7998-
7999; d) Meng, D.; Sorensen, E. J.; Bertinato, P.; Danishefsky, S.
J. J. Org. Chem. 1996, 61, 8000-8001.
19
deprotection/protection and oxidation protocol from the epothilone A
strategy we obtained the acid 27 (4 steps, 67% from 26). Esterification
with thiazole segment 18 gave ester 28 which is identical to
(4) a) Balog, A.; Meng, D.; Kamencka, T. ; Bertinato, P.; Su, D.-S.;
Sorensen, E. J.; Danishefsky, S. J. Angew. Chem. 1996, 108,
2976-2978; Angew. Chem. Int. Ed. Engl. 1996, 35, 2801-2803;
b) Nicolaou, K. C.; He, Y.; Vourloumis, D.; Vallberg, H.; Yang, Z.
Angew. Chem. 1997, 109, 170-172; Angew. Chem. Int. Ed. Engl.
1997, 36, 166-168; c) Schinzer, D.; Limberg, A.; Bauer, A.;
Böhm, O. M.; Cordes, M. Angew. Chem. 1997, 109, 545-546;
Angew. Chem. Int. Ed. Engl. 1997, 36, 523-524; d) Nicolaou, K.
C.; Sarabia, F.; Nincovic, S.; Yang, Z. Angew. Chem. 1997, 109,
539-540; Angew. Chem. Int. Ed. Engl. 1997, 36, 525-527.
4c
Danishefsky’s key intermediate in his epothilone B synthesis based on
7e
the metathesis approach.
(5) a) Su, D.-S.; Meng, D.; Bertinanto, P.; Balog, A.; Sorensen, E. J.;
Danishefsky, S. J.; Zheng, Y.-H.; Chou, T.-C.; He, L.; Horwitz, S.
B. Angew. Chem. 1997, 109, 775-777; Angew. Chem. Int. Ed.
Engl. 1997, 36, 775-777; b) Nicolaou, K. C.; Winssinger, N.;
Pastor, J.;. Ninkovic, S.; Sarabia, F.; He, Y.; Vourloumis, D.; Yang,
Z.; Li, T.; Giannakakou, P.; Hamel, E. Nature 1997, 387, 268-272.
(6) a) Mulzer, J.; Mantoulidis, A. Tetrahedron Lett. 1996, 37, 9179-
9182; b) Claus, E.; Pahl, A.; Jones, P. G.; Meyer, H. M.;Kalesse,
M. Tetrahedron Lett. 1997, 38, 1359-1362; c) Gabriel, T.;
Wessjohann, L. Tetrahedron Lett. 1997, 38, 1363-1366;d) Taylor,
R. E.; Haley, J. D. Tetrahedron Lett. 1997, 38, 2061-2064;
e) Brabander, J. D.; Rosset, S.; Bernardinelli, G. Synlett 1997,
824-826; f) Chakraborty, T. K.; Dutta, S. Tetrahedron Lett. 1998,
39, 101-104; g) Liu, Z.-Y.; Yu, C.-Z.; Yang, J.-D. Synlett 1997,
1383-1384.
(7) a) Meng, D.; Su, D.-S.; Balog, A.; Bertinato, P.; Sorensen, E. J.;
Danishefsky, S. J.; Zheng, Y.-H.; Chou, T.-C.; He, L.; Horwitz, S.
B J. Am. Chem. Soc. 1997, 119, 2733-2734; b) Balog, A.;
Bertinato, P.; Su, D.-S.; Meng, D.; Sorensen, E.; Danishefsky, S.
J.; Zheng, Y.-H.; Chou, T.-C.; He, L.; Horwitz, S. B. Tetrahedron
Lett. 1997, 38, 4529-4532; c) Nicolaou, K. C.; Ninkovic, S.;
Sarabia, F.; Vourloumis, D.; He, Y.;Vallberg, H.; Finlay, M. R. V.;
Yang, Z. J. Am. Chem. Soc. 1997, 119, 7974-7991; d) Nicolaou,
K. C.; He, Y.; Vourloumis, D.; Vallberg, H.; Roschanger, F.;
Sarabia, F.; Ninkovic, S.; Yang, Z.; Trujillo, J. I. J. Am. Chem. Soc.
1997, 119, 7960-7973; e) Su, D.-S.; Meng, D.; Bertinato, P.;
Balog, A.; Sorensen, E. J.; Danishefsky, S. J.; Zheng, Y.-H.; Chou,
T.-C.; He, L.; Horwitz, S. B.; Angew. Chem. Int. Ed. Engl. 1997,
36, 757-759.
In summary, we have presented two formal total syntheses of epothilone
B. Our macro-lactonization approach represents the best and most
efficient solution to epothilone B to date as it provides an especially
convergent synthesis and demonstrates the power of palladium-
mediated couplings and aldol technology towards stereoselective C,C
bond formations. The acyclic stereocontrol of the configurations at C-6
and C-7 has been easily resolved using our fragments in the key aldol
reaction.
Acknowledgment. We are indebted to the Novartis Pharma AG, Basel,
for generous support.
(8) Tamaru, Y.; Ochiai, H.; Nakamura, T.; Yoshida, Z. Tetrahedron
Lett. 1986, 27, 955-958.
(9) Eilbracht, P.; Acker, M.; Rosenstock, B. Chem. Ber. 1989, 122,
151 - 158.
References and Notes
(1) a) Höfle, G.; Bedorf, N.; Steinmetz, H.; Schomburg, D.; Gerth, K.
Reichenbach, H. Angew. Chem. 1996, 108, 1671-1673; Angew.
Chem. Int. Ed. Engl. 1996, 35, 1567-69; b) Schinzer, D. Eur.
Chem. Chron. 1996, 1, 7-10; c) Wessjohann, L. Angew. Chem.
1997, 109, 739-742; Angew. Chem. Int. Ed. Engl. 1997, 36, 739-
742.
(10) Braun, M.; Waldmüller, D. Synthesis 1989, 856-858.
(11) a) Evans, D. A.; Bender, S. L .; Morris, J. J. Am. Chem. Soc. 1988,
110, 2506-2526; b) Evans, D. A.; Kaldor, S. W.; Jones, T. K.;
Clardy, J. ; Stout, T. J. J. Am. Chem. Soc. 1990
(12) Kabalka, G. W.; Gooch, E. E. J. Org. Chem. 1980, 45, 3578-3580.
(13) A similar sequence was used by Mulzer et al.: Mulzer, J.;
(2) a) Bollag, D. M.; McQueney, P. A.; Zhu, J.; Hensens, O.; Koupal,
L.; Liesch, J.; Goetz, M. E.; Lazarides, C.; Woods, M. Cancer
Res. 1995, 55, 2325-2333; b) Kowalski, R. J.; Giannakakou, P.;
Hamel, E. J. Biol. Chem. 1997, 272, 2534-2541.
Mantoulidis, A.; Öhler, E. Tetrahedron Lett. 1997, 38, 7725-7728.
(14) a) Hanessian, S.; Tehim, A.; Chen, P. J. Org. Chem. 1993, 58,
7768-7781; b) Buser, H. P.; Pugin, B.; Spindler, F.; Sutter, M.
Tetrahedron 1991, 47, 5709-5716; c) Matsuda, F.; Tamiyoshi, N.;
Yanagiya, M.; Matsumoto, M. Tetrahedron 1990, 46, 3469-3488.
(3) a) Nicolaou, K. C.; He, Y.; Vourloumis, D.; Vallberg, H.; Yang, Z.
Angew. Chem. 1996, 108, 2554-2556; Angew. Chem. Int. Ed. Engl.
1996, 35, 2399-2401; b) Schinzer, D.; Limberg, A.; Böhm, O. M.
Chem. Eur. J. 1996, 2, 1477-1482; c) Meng, D.; Sorensen, E. J.;
(15) Chen, J.; Wang, T.; Zhao, K. Tetrahedron Lett. 1994, 35, 2827-
2828.

864
LETTERS
SYNLETT
3
(16) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem.
1988, 53, 2392-2394.
3H), 1.20 (s, 3H), 1.16 - 1.05 (m, 1H), 1.09 (s, 3H), 1.02 (d, J =
t
3
7.0 Hz, 3H), 0.88 (s, 9H, -Si Bu), 0.82 (d, J = 6.8 Hz, 3H), 0.04
(s, 3H, -SiMe ), 0.00 (s, 3H, -SiMe ); C-NMR (100 MHz,
CDCl ): δ (ppm) = 222.8, 164.3, 153.3, 142.5, 136.9, 121.4,
118.7, 114.9, 98.5, 79.1, 74.7, 74.4, 59.9, 51.6, 41.3, 35.4, 35.3,
33.0, 32.4, 29.8, 25.9, 25.2, 25.2, 23.5, 21.6, 19.2, 19.0, 18.6,
13
(17) Experimental procedure for the aldol reaction: A solution of 2 (64
mg, 0.3 mmol) in THF (500 µl) was added to a freshly prepared
solution of LDA [n-BuLi (118 µl, 2.5 m solution in hexanes, 0.294
mmol, 0.98 eq) was added to a solution of diisopropylamine (41.6
µl, 0.294 mmol) in THF (500 µl) at 0 °C] dropwise at - 78 °C. The
solution was stirred for 1 h at -78 °C. A solution of 5 (65 mg, 0.15
mmol, 0.5 equiv) in THF (600 µl) was added dropwise and stirring
was continued for 20 min at -78 °C. The mixture was quenched by
2
2
3
18.2, 15.4, 13.9, 9.3, -4.7, -4.9; Anal. calcd. for C
H NO SSi
36 63 5
(650.0): C 66.46, H 9.69, N 2.15, S 4.99, found C 66.37, H 9.34, N
2.42, S 4.72.
(18) a) Limberg, A., Ph.D. thesis, Technische Universität Braun-
dropwise addition of satd. NH Cl solution (2 ml). The organic
4
schweig, 1998; b) Gage, J. R.; Evans, D. A. Org. Synth. 1989, 68,
layer was separated and the aqueous layer was extracted with
diethyl ether (3 × 5 ml). The combined organic extracts were dried
83-91.
20
(19) Spectroscopic data for compound 26: [α]
-23.3 (c = 1.0,
D
over MgSO and concentrated in vacuo. Flash column
4
20
CHCl ), [α]
-28.1 (c = 1.0, CHCl ); IR: 3508, 2969, 1685,
3
3
546
chromatography (pentane / Et O 10:1) afforded 83 mg (85 %) of
2
-1
1
1373, 1197, 1107, 971 cm ; H-NMR (400 MHz, CDCl ):δ
3
20 and 9 mg (9.5 %) of its corresponding Felkin diastereoisomer
2
3
(ppm) = 4.72 - 4.64 (m, 2H), 4.06 (dd, J = 11.8 Hz, J = 2.5 Hz,
(ratio 9:1 by HPLC).
2
3
3
20
1H), 3.96 (dt, J = 11.9 Hz, J = 2.7 Hz, 1H), 3.86 (ddd, J = 11.7
Spectroscopic data for compound 20: [α]
-2.5 (c = 1.0,
D
3
3
3
20
Hz, J = 5.4 Hz, J = 1.6 Hz, 1H), 3.50 (s, 1H, OH), 3.37 (d, J =
CHCl ), [α]
-2.7 (c = 1.0, CHCl ); IR: 3505, 2931, 1686,
3
546
3
3
3
-1
9.3 Hz, 1H), 3.29 (dq, J = 7.0 Hz, J = 1.2 Hz, 1H), 2.09 - 1.94
(m, 2H), 1.82 - 1.48 (m, 4H), 1.71 (s, 3H), 1.41 (s, 3H), 1.40 - 1.31
(m, 2H), 1.33 (s, 3H), 1.21 (s, 3H), 1.16 - 1.05 (m, 1H), 1.09 (s,
1472, 1373, 1255, 1098, 837, 777 cm ; UV (MeOH): λ
249 nm; MS (EI, 70 eV) m/z 650 (M , 3), 436(5), 282 (100); H-
= 209,
max
+
1
NMR (400 MHz, CDCl ): δ (ppm) = 6.91(s, 1H), 6.45 (s, 1H),
3
3
3
13
3
3
3
3H), 1.02 (d, J = 7.0 Hz, 3H), 0.84 (d, J = 7.0 Hz, 3H); C-
5.12 (t, J = 6.8 Hz, 1H), 4.08 (t, J = 6.2 Hz, 1H), 4.04 (dd, J =
3
2
3
NMR (100 MHz, CDCl ): δ (ppm) = 222.9, 146.2, 109.5, 98.4,
11.8 Hz, J = 2.5 Hz, 1H), 3.96 (dt, J = 11.9 Hz, J = 2.7 Hz, 1H),
3
2
3
3
74.7, 74.3, 59.8, 51.5, 41.2, 38.2, 35.3, 32.6, 29.7, 25.1, 24.7,
3.86 (ddd, J = 11.7 Hz, J = 5.4 Hz, J = 1.7 Hz, 1H), 3.49 (s br,
+
3
3
3
22.3, 21.5, 19.0, 18.5, 15.3, 9.2; MS (EI, 70 eV) m/z 354 (M , 3),
1H, -OH), 3.36 (d, J = 9.3 Hz, 1H), 3.27 (dq, J = 7.0 Hz, J = 1.4
339 (6), 296 (9), 278 (5), 214 (6), 197 (10), 185 (26), 156 (84),
141 (28), 127 (26), 123 (65), 115 (78), 82 (100); Anal. calcd. for
Hz, 1H), 2.71 (s, 3H), 2.34 -2.14 (m, 2H), 2.06 - 1.93 (m, 2H),
1.99 (d, J = 1.2 Hz, 3H), 1.82 - 1.71 (m, 1H), 1.67 (d, J = 1.1 Hz,
4
4
3H), 1.66 - 1.42 (m, 3H), 1.40 (s, 3H), 1.37 - 1.22 (m, 2H), 1.33 (s,
C H O (354.5): C 71.15, H 10.80, found C 71.21, H 10.88.
21 38 4