En route to a plant scale synthesis of the promising antitumor agent 12,13-desoxyepothilone B.

Article abstract of DOI:10.1021/ol0059302

[reaction--see text] Efficient and processable syntheses of key building blocks of the antitumor agent 12,13-desoxyepothilone B (dEpoB) by catalytic asymmetric induction are herein described.

Full text of DOI:10.1021/ol0059302

ORGANIC
LETTERS
2000
Vol. 2, No. 11
1633-1636
En Route to a Plant Scale Synthesis of
the Promising Antitumor Agent
12,13-Desoxyepothilone B
Mark D. Chappell,† Shawn J. Stachel,† Chul Bom Lee,† and
,†,‡
Samuel J. Danishefsky*
Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research,
1275 York AVenue, New York, New York 10021, and Department of Chemistry,
Columbia UniVersity, HaVemeyer Hall, New York, New York 10027
s-danishefsky@ski.mskcc.org
Received April 11, 2000
ABSTRACT
Efficient and processable syntheses of key building blocks of the antitumor agent 12,13-desoxyepothilone B (dEpoB) by catalytic asymmetric
induction are herein described.
Interest in the epothilone family of natural products on the
part organic chemists was incubated, no doubt, by the
promising biological profiles of the A and B isomers,
particularly the latter.1,2 These compounds seem to share a
common tubulin-centered mechanistic framework with
paclitaxel, yet offer potential advantages in terms of formu-
lability and performance in vitro toward Taxol insensitive
tumor cells.3 Likewise, the interesting and insightful structural
features of the epothilones challenge the collective ingenuity
of the science of organic synthesis. The field has benefited
from a continuing series of disclosures,2,4 seeking to improve
upon the three initial feasibility demonstrations.5-7
As early as 1997, using our then intricate (though
stereospecific) academic type synthesis,5b enough epothilone
B was garnered to show for the first time that the initial
Merck reports3 on the favorable in vitro biological profiles
of epothilones were extendable to human tumors transplanted
in murine hosts in a xenograft setting.8 However, during these
(4) For some recent total syntheses of epothilone B, see: (a) Mulzer, J.;
Mantoulidis, A.; Ohler, E. Tetrahedron Lett. 1998, 39, 8633. (b) White, J.
D.; Carter, R. G.; Sundermann, K. F. J. Org. Chem. 1999, 64, 684. (c)
May, S. A.; Grieco, P. A. Chem. Commun. 1998, 1597. (d) Sawada, D.;
Shibasaki, M. Angew. Chem., Int. Ed. 2000, 39, 209.
(5) (a) For the synthesis of epothilone A, see: Su, D. S.; Meng, D. F.;
Bertinato, P.; Balog, A.; Sorensen, E. J.; Danishefsky, S. J.; Zheng, Y.-H.;
Chou, T.-C. Angew. Chem., Int. Ed. Engl. 1996, 35, 2801. (b) For the
synthesis of epothilone B, see: Su, D. S.; Meng, D. F.; Bertinato, P.; Balog,
A.; Sorensen, E. J.; Danishefsky, S. J.; Zheng, Y.-H.; Chou, T.-C.; He, L.
F.; Horwitz, S. B. Angew. Chem., Int. Ed. Engl. 1997, 36, 757.
(6) (a) For the synthesis of epothilone A, see: Yang, Z.; He, Y.;
Vourloumis, D.; Vallberg, H.; Nicolaou, K. Angew. Chem., Int. Ed. Engl.
1997, 36, 166. (b) For the synthesis of epothilone B, see: 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.
(7) (a) For the synthesis of epothilone A, see: Schinzer, D.; Limberg,
A.; Bauer, A.; Bo¨hm, O. M.; Cordes, M. Angew. Chem., Int. Ed. Engl.
1997, 36, 523. (b) For the synthesis of epothilone B, see: Schinzer, D.;
Bauer, A.; Schieber, J. Synlett 1998, 861.
† Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for
Cancer Research, New York, NY 10021.
‡ Department of Chemistry, Columbia University, Havemeyer Hall, New
York, NY 10027.
(1) Hofle, G. H.; Bedorf, N.; Steinmetz, H.; Schomburg, D.; Gerth, K.;
Reichenbach, H. Angew. Chem., Int. Ed. Engl. 1996, 35, 1567.
(2) For extensive reviews in this field, see: (a) Nicolaou, K. C.;
Roschangar, F.; Vourloumis, D. Angew. Chem., Int. Ed. 1998, 37, 2015.
(b) Harris, C. R.; Danishefsky, S. J. J. Org. Chem. 1999, 64, 8434.
(3) 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.
10.1021/ol0059302 CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/12/2000

investigations, some potentially serious toxicity problems
were uncovered using agent 2 (Figure 1). These findings cast
Several of these maneuvers required rather sophisticated and
expensive chemistry, and prospects for serious scale-up of
these protocols were daunting. The disclosure herein now
describes new synthetic developments which render the A
fragment readily available in multigram quantities, utilizing
easily processable chemistry. These advances have major
favorable consequences for a plant-level synthesis of dEpoB.
The new route for the synthesis of the key vinyl iodide
fragment required smooth access to large quantities of
phosphine oxide 7. This subunit is in fact easily prepared in
two steps on a 100 g scale as shown in Scheme 1.17 The
Scheme 1a
Figure 1. Epothilones.
some doubt as to whether exploitable therapeutic indices
could be found with epothilone B (EpoB). During this era,
we demonstrated that much of the toxicity of EpoB could
be abrogated through the use of 12,13-desoxyepothilone B
(dEpoB, 3).9,10 Vast superiority of dEpoB relative to EpoB
and to paclitaxel has been demonstrated in a variety of
competitive in vivo settings, and the results have been
published elsewhere.2b,11 Presently, dEpoB has advanced to
toxicology and efficacy studies in dogs, en route to a full-
scale clinical evaluation.12
a (a) (i) acetone, (ii) ZnCl2, MeOH, reflux, 60%; (b) HOPPh2,
Cs2CO3, Bu4NI, CH2Cl2, 97%; (c) (i) 7, n-BuLi. THF, -78 °C, 30
min, (ii) 8, -78 °C to rt, 98%.
Since our laboratory lacks access to fermentation-derived
epothilones, total synthesis constituted our only recourse to
produce material for biological investigations. Indeed, all of
the in vivo evaluations have been conducted on fully
synthetic dEpoB. The present goal is to develop a practical
total synthesis of dEpoB which can furnish material ap-
propriate for a full scale evaluation in humans if, as expected,
findings in higher and larger animals so indicate.
In our previously described improved routes to dEpoB,13,14
three subunits were built and combined. The route to building
block C (see Figure 2) has already been shown to be
second subunit required for building the A segment is methyl
ketone 8 (vide infra). The Horner-like condensation18 be-
tween 7 and 8 is conducted in 98% yield on a multigram
scale to afford A. However, for this chemistry to be valuable,
a straightforward synthesis of 8, amenable to plant-level
scale-up, had to be accomplished.
Fortunately, two such routes have now been developed.
In the first approach (Scheme 2) following conversion of 9
(8) Su, D. S.; Balog, A.; Meng, D. F.; Bertinato, P.; Danishefsky, S. J.;
Zeng, Y. H.; Chou, T.-C.; He, L. F.; Horwitz, S. B. Angew. Chem., Int. Ed.
Engl. 1997, 36, 2093.
(9) Chou, T.-C.; Zhang, X. G.; Harris, C. R.; Kuduk, S. D.; Balog, A.;
Savin, K. A.; Bertino, J. R.; Danishefsky, S. J. Proc. Nat. Acad. Sci. 1998,
95, 15798.
(10) Chou, T.-C.; Zhang, X. G.; Balog, A.; Su, D. S.; Meng, D. F.; Savin,
K.; Bertino, J. R.; Danishefsky, S. J. Proc. Nat. Acad. Sci. 1998, 95, 9642.
(11) Harris, C.; Savin, K.; Danishefsky, S. J.; Chou, T.-C.; Zhang, X.-
G. Soc. Chim. Ther. 1999, 25, 187.
(12) This work was done in collaboration with Dr. T.-C. Chou, Dr. W.
Tong, Dr. O. O’Conner, and Dr. J. Bertino at the Sloan-Kettering Institute
for Cancer Research.
(13) Balog, A.; Harris, C.; Savin, K.; Zhang, X. G.; Chou, T. C.;
Danishefsky, S. J. Angew. Chem., Int. Ed. 1998, 37, 2675.
(14) Harris, C. R.; Kuduk, S. D.; Balog, A.; Savin, K.; Glunz, P. W.;
Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121, 7050.
(15) Lin, N.; Overman, L. E.; Rabinowitz, M. H.; Robinson, L. A.; Sharp,
M. J.; Zablocki, J. J. Am. Chem. Soc. 1996, 118, 9062.
Figure 2. Epothilone building blocks.
(16) Evans, D. A.; Bender, S. L.; Morris, J. J. Am. Chem. Soc. 1988,
110, 2506.
amenable to major scale-up. As previously described by
Overman,15 building block B was prepared by auxiliary-
mediated allylation of a suitable propionate derivative, using
methodology first promulgated by Evans and associates.16
The largest impediment to major scale-up was in the
synthesis of the A subunit, which had previously required
eight steps, exclusive of generating the required reagents.
(17) (a) For an earlier synthesis of 7 and its application to this type of
Wittig reaction, see: Bertinato, P.; Sorensen, E. J.; Meng, D. F.; Danishef-
sky, S. J. J. Org. Chem. 1996, 61, 7998. (b) Gellis, A.; Vanelle, P.;
Kaafarani, M.; Benakli, K.; Crozet, M. P. Tetrahedron Lett. 1997, 53, 5471.
(18) (a) Lythgoe, B.; Nambudiry, M. E. N.; Ruston, S.; Tideswell, J.;
Wright, P. W. Tetrahedron Lett. 1975, 40, 3863. (b) Lythgoe, B. Chem.
Soc. ReV. 1981, 449. (c) Toh, H. T.; Okamura, W. H. J. Org. Chem. 1983,
48, 1414. (d) Baggiolini, E. G.; Iacobelli, J. A.; Hennessy, B. M.; Batcho,
A. D.; Sereno, J. F.; Uskokovic, M. R. J. Org. Chem. 1986, 51, 3098.
1634
Org. Lett., Vol. 2, No. 11, 2000

dihydroxylation23 of this material, under the conditions
shown, afforded 19 (87% ee, 55% yield-two steps). Finally,
triethylsilylation of 19 completes the synthesis of ketone 8
and therefore A.
Scheme 2a
With a view to generating fragment B by strictly catalytic
asymmetric methods, its synthesis was revisited (Scheme 4).
Scheme 4a
a (a) (i) TiCl4, 0 °C, 87%, (ii) TESCl, imidazole, DMF, 84%;
(b) LHMDS, 11, -78 °C, 81%; (c) (i) HOAc:THF:H2O (3:1:1),
(ii) CH3ONHCH3, AlMe3, (iii) TESCl, DMF, 88% overall; (d)
MeMgB, 0 °C, 93%; (e) (i) RedAl, 0 °C to rt, (ii) I2, -78 °C to rt,
Et2O; (f) TMSI, CH2Cl2, 0 °C, 81%-two steps.
a (a) t-BuOH, Ti(Oi-Pr)4, (+)-DET, CH2Cl2, 98%, 82% ee; (b)
NaCNBH3, BF3‚OEt2, THF, 52%; (c) NaIO4, THF:H2O, 81%.
to 10 (84%),19,20 a highly diastereoselective alkylation of
lithio 10 with 11 produces 12 (>25:1 de) in 81% yield.19,20
As was previously reported,21 diiodide 11 is available from
2-butynol in two steps as shown. Finally, compound 12 was
advanced in three steps to 8 by recourse to the Weinreb
amide 13.22
A second route, while somewhat less selective, reaches 8
even more easily, in only four steps via asymmetric dihy-
droxylation23 (Scheme 3). This synthesis begins with the
For this purpose, we synthesized subunit 20, which is
prepared from isoprene by known chemistry.26 Asymmetric
epoxidation27 of 20 provides 21, which undergoes reductive
cleavage28 at the more substituted center to furnish diol 22.
Following periodate cleavage as shown, building block B is
in hand. While this method bypasses recourse to a chiral
auxiliary, its ultimate advantage in terms of scale-up to the
multigram levels in a plant-type setting awaits demonstration.
As previously described,13,14 a novel aldol condensation
joins fragments B and C. Subsequently, a palladium-mediated
B-alkyl Suzuki29 merger joins A with B-C. With the carbon
skeleton in place, a catalytic Noyori reduction30 provides the
desired stereochemistry at C3 and macrolactonization leads,
shortly afterward, to dEpoB.14 While we always remain open
to possibilities for still greater practicality, we are now
already confident that compound availability through total
synthesis will support a full and searching evaluation of
dEpoB and other promising epothilones at the clinical level.
Scheme 3a
(21) Gras, J.-L.; Kong Win Chan, Y.-Y.; Bertrand, M. Tetrahedron Lett.
1982, 23, 3571.
(22) (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(b) Levin, J. I.; Turos, E.; Weinreb, S. M. Synth. Commun. 1982, 12, 989.
(23) (a) Sharpless, K. B.; Amberg, W.; Beller, M.; Chen, H.; Hartung,
J.; Kawanami, Y.; Lubben, D.; Manoury, E.; Ogino, Y.; Shibata, T.; Ukita,
T. J. Org. Chem. 1991, 56, 4585. (b) Sharpless, K. B.; Amberg, W.; Bennani,
Y. L.; Crispino, G. A.; Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa,
K.; Wang, Z.-M.; Xu, D.; Zhang, X.-L. J. Org. Chem. 1992, 57, 2768 and
references therein. (c) Hashiyama, T.; Morikawa, K.; Sharpless, K. B. J.
Org. Chem. 1992, 57, 5067.
a (a) (i) I-9-BBN, hexanes, (ii) methyl vinyl ketone, hexanes,
(iii) 3 N NaOH, PhMe, 100 °C, 65%; (b) TMSI, HMDS, CH2Cl2,
-20 °C to rt; (c) 1 mol % of OsO4, AD-mix-R, MeSO2NH2,
t-BuOH:H2O (1:1), 55%-two steps; (d) TESCl, imidazole, DMF,
85%.
(24) Satoh, Y.; Serizawa, H.; Hara, S.; Suzuki, A. J. Am. Chem. Soc.
1985, 107, 5225.
(25) Quitschalle, M.; Kalesse, M. Tetrahedron Lett. 1999, 40, 7765.
(26) Babler, J. H.; Buttner, W. J. Tetrahedron Lett. 1976, 4, 239.
(27) (a) Pfenninger, A. Synthesis 1986, 89. (b) Bolitt, V.; Mioskowski,
C.; Bhatt, R. K.; Falck, J. R. J. Org. Chem. 1991, 56, 4238.
(28) Hutchins, R. O.; Taffer, I. M.; Burgoyne, W. J. Org. Chem. 1981,
46, 5214.
known reaction of propyne with B-iodo-9-BBN and methyl
vinyl ketone to produce 17,24 which reacts (in multigram
scale) with trimethylsilyl iodide to provide an 88:12 (18a:
18b) mixture of silyl enol ether isomers 18.25 Asymmetric
(29) (a) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.;
Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314. (b) Miyaura, N.; Suzuki, A.
Chem. ReV. 1995, 95, 2457. (c) Johnson, C. R.; Braun, M. P. J. Am. Chem.
Soc. 1993, 115, 11014.
(30) (a) Noyori, R. Tetrahedron 1994, 50, 4259. (b) Taber, D. F.;
Silverberg, L. J. Tetrahedron Lett. 1991, 32, 4227. (c) Taber, D. F.;
Silverberg, L. J.; Robinson, E. D. J. Am. Chem. Soc. 1991, 113, 6639.
(19) Hitherto, glycolates have been prepared by auxiliary chemistry
through hydroxylation of the alkanoate rather than through alkylation of
the glycolate: Evans, D. A.; Morrissey, M. M.; Dorow, R. L. J. Am. Chem.
Soc. 1985, 107, 4346.
(20) See however: Paterson, I.; Bower, S.; McLeod, M. D. Tetrahedron
Lett. 1995, 36, 175.
Org. Lett., Vol. 2, No. 11, 2000
1635

Acknowledgment. Postdoctoral Fellowship support is
gratefully acknowledged by M.D.C. (NIH, 1 F32 GM19972-
01), S.J.S. (NIH, 5 F32 CA81704-02; NYS, 1 F32 NYS),
and C.B.L. (US Army, DAMD 17-98-1-8155). The research
was supported by the National Institutes of Health (Grants
CA-28824 and CA-08748 to S.J.D.). Dr. George Sukenick
(NMR Core Facility, Sloan-Kettering Institute) is acknowl-
edged for NMR and mass spectral analyses.
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