Total synthesis of 26-fluoro-epothilone B

Article abstract of DOI:10.1055/s-2004-817771

An efficient synthesis of the epothilone B derivative 26-fluoroepothilone B (1) was realized by early introduction of the synthetically demanding fluoromethyl epoxide function. The presence of a fluoro substituent results in a remarkable increase in the stability of the epoxide, which tolerates the wide range of reaction conditions required for the fragment coupling step and end game transformations.

Full text of DOI:10.1055/s-2004-817771

LETTER
693
Total Synthesis of 26-Fluoro-epothilone B
Total
S
ynthesis of
u
26-Fluoro-ep
i
othilon
d
e
B
o Koch,*a Olivier Loiseleur,b Karl-Heinz Altmannc
a
Novartis Institutes for Biomedical Research, WSJ-507.704, 4002 Basel, Switzerland
Fax +41(61)32442 38; E-mail: guido.koch@pharma.novartis.com
b
c
Syngenta AG, WRO-1060.5.04, 4002 Basel, Switzerland
ETH Zürich, Department of Chemistry and Applied BioSciences, Institute of Pharmaceutical Sciences, Winterthurerstr.190, 8057 Zürich,
Switzerland
Received 4 December 2003
However, we felt that the introduction of fluorine at the
very end of the synthesis could pose a significant problem
upon scale-up and we have thus devised an alternative
strategy for the synthesis of 1, which is outlined in
Abstract: An efficient synthesis of the epothilone B derivative 26-
fluoroepothilone B (1) was realized by early introduction of the syn-
thetically demanding fluoromethyl epoxide function. The presence
of a fluoro substituent results in a remarkable increase in the stabil-
ity of the epoxide, which tolerates the wide range of reaction condi- Scheme 2. Our retrosynthetic analysis of 1 is character-
tions required for the fragment coupling step and end game
transformations.
ized by three key features: a) avoidance of the late stage
fluorination step by the early introduction of the fluorine
Key words: epothilone, total synthesis, fluorine, epoxides, sub-
stituent effects
substituent, b) the diastereoselective installation of the
epoxide moiety, and c) the diastereoselective construction
of the aldol substructure (Scheme 2).
Disconnection at the ester moiety and the C6–C7 aldol
unit gives aldehyde 3 and ethyl ketone 4. The acetonide
fragment 4 has been developed by Schinzer5 for a highly
diastereoselective aldol coupling in the total synthesis of
epothilones A and B and it has also been successfully ap-
plied in the synthesis of other epothilone analogs.6 The
fluoro epoxide 3 is derived from an allylic alcohol, which
is the Wittig product formed by reaction of stabilized
ylide 5 and the known aldehyde 6.7
Epothilone compounds (e.g. epothilones A and B) repre-
sent a class of microtubule inhibitors with the remarkable
ability to inhibit the growth of multidrug-resistant human
tumor cell lines at low nanomolar or even subnanomolar
concentrations. To explore the therapeutic potential of
epothilone-type agents, natural epothilones and numerous
structural analogs thereof have been synthesized by a
multitude of research groups.1
Among those analogs, whose in vivo activity has been as-
sessed in human tumor models, 26-fluoroepothilone B
(1)2 has emerged as a promising drug candidate, which ex-
hibits high efficacy at well tolerated dose levels.
Starting from caprolactone (7), the phosphorane 5 was
prepared via a readily scalable route in 27% yield over 10
steps without the need for any chromatographic purifica-
tion (Scheme 3). Thus, caprolactone was hydrolyzed and
For further biological profiling and pharmacological eval- treated in situ with benzylchloride to give benzyl protect-
uation larger quantities of compound 1 were required. The ed hydroxy acid 8.8 Conversion of this acid to the acid
original synthesis of 1 as reported by the Nicolaou chloride and coupling to the L-phenylalanine-derived
group2b,c was based on the epoxidation of the advanced al- Evans auxiliary 10 gave imide 11. Diastereoselective
lylic alcohol 2 under Katsuki–Sharpless3 conditions and methylation and subsequent reductive removal of the aux-
subsequent fluorination with DAST4 in moderate yield iliary gave S-alcohol 13, which was obtained in 87% ee as
(Scheme 1).
determined by chiral HPLC. A two-step deprotection/pro-
tection sequence led to alcohol 15, which was converted
Scheme 1 Nicolaou synthesis of 26-fluoroepothilone B
SYNLETT 2004, No. 4, pp 0693–0697
0
9.
0
3.
2
0
0
4
Advanced online publication: 10.02.2004
DOI: 10.1055/s-2004-817771; Art ID: G33903ST
© Georg Thieme Verlag Stuttgart · New York

694
G. Koch et al.
LETTER
to the iodide 16, whose treatment with triphenylphosphine
gave the corresponding phosphonium salt. Finally ylide 5
was obtained through reaction of the phosphonium salt
with KHMDS and in situ acylation of the resulting (mono-
substituted) phosphorane with methylchloroformate.
Coupling of aldehyde 6 and fragment 5 according to ref.2c
gave a,b-unsaturated ester 17a, which was reduced to the
allylic alcohol 18a (Scheme 4). Katsuki–Sharpless epoxi-
dation of 18a gave epoxy alcohol 19a as a single dia-
stereomer in excellent yield. Subsequent fluorination with
DAST provided the desired product 20a in 26% yield, but
in addition significant amounts of the side product 21
(Figure 1) were also isolated.
Figure 1 Bis-fluoro epoxide side product 21
Formation of 21 can be rationalized by fluoride–mediated
deprotection of the primary hydroxyl group and its subse-
quent fluorination with DAST. We thus hypothesized that
competing bis-fluorination would be avoided, if the more
stable THP group was used to protect the primary alcohol
function. Gratifyingly, the implementation of this alterna-
tive protection scheme resulted in a clean and repro-
Scheme 2 Retrosynthetic analysis
Scheme 3 Reaction conditions: a) KOH/BnCl, toluene, reflux (76%); b) (COCl)2, toluene, 23 °C; c) 10, hexyl-Li, then silica gel filtration
(87%, from acid 8); d) NaHDMS, THF, –78 °C; e) MeI, –78 °C (81%); f) LiAlH4, THF, 0 °C, silica gel filtration (79%, 87% ee); g) TBDMSCl,
imidazole, DMF, 23 °C (79%); h) H2 (3.5 bar), Pd(OH)2/C, THF, 23 °C (100%); i) PPh3, imidazole, I2, CH3CN, toluene, 0 °C, (97%); j) PPh3,
100 °C; k) KHMDS, ClCO2CH3, THF, 0 °C, –78°C (quant.).
Synlett 2004, No. 4, 693–697 © Thieme Stuttgart · New York

LETTER
Total Synthesis of 26-Fluoro-epothilone B
695
Scheme 4 Reaction conditions: a) 6, Toluene, 40 °C (quant.); b) TFA, H2O, THF, 23 °C; c) dihydropyrane, PPTS, CH2Cl2, 23 °C (65%,
chromatography); d) DIBALH, THF, –78 °C–0 °C (R = TBDMS: 76% over 4 steps; R = THP: quant.); e) (+)-diethyl-L-tartrate, Ti(Oi-Pr)4,
t-BuOOH, CH2Cl2, 4 Å MS, –30 °C, 2 h (R = TBDMS, R = THP; 70%, silica gel filtration); f) DAST, CH2Cl2, 23 °C (R = TBDMS: 26%,
R = THP: 70%).
Scheme 5 Alternative fluorinating reagents
ducible fluorination protocol affording the protected enolate of 4 at low temperature gave the aldol product 24
fluoro epoxide 20b in 70% yield.
in 77% yield as a single diastereomer.
Alternative reagents for fluorine introduction were also The elaboration of 24 into 26-fluoroepothilone B 1 was
investigated. Reaction of the epoxy alcohol with the guided by the chemistry previously employed by Schinzer
Yarovenko9 or the Ishikawa10 reagents led to comparable et al. in their formal synthesis of epothilone B.11 However,
results as the reaction with DAST (Scheme 5).
it should be kept in mind that in contrast to this prior work,
all steps were carried out in the presence of the epoxide
function.
With the fluoro epoxide 20b in hand, we then investigated
the coupling of the anion of ethyl ketone 4 with aldehyde
23, which was obtained after selective removal of the THP The presence of a fluoro substituent leads to a remarkable
protecting group from intermediate 20b with PPTS and enhancement in epoxide stability towards acid and base.
subsequent Swern oxidation of the resulting alcohol The epoxide function remained unaffected by the reaction
(Scheme 6). Gratifyingly, reaction of 23 with the lithium conditions required to remove the THP, the acetonide and
TBDMS protecting groups downstream in the synthesis
Synlett 2004, No. 4, 693–697 © Thieme Stuttgart · New York

696
G. Koch et al.
LETTER
Scheme 6 Reaction conditions: a) PPTS, EtOH, 65 °C; b) (COCl)2, DMSO, Et3N, CH2Cl2, –78 °C; c) 4, LDA, –78 °C (77%, chromatography).
Scheme 7 Sensitivity of the methyl epoxide moiety in 25 toward aq HOAc. Reaction conditions: a) HOAC, THF, H2O (85%)
[conditions a) in Scheme 6, conditions a), c) and h) in for biological studies, making use of the remarkable sta-
Scheme 8]. In contrast, the methyl substituted epoxide bility of the fluoro-methyl epoxide towards a variety of re-
moiety in the model substrate 25 (Scheme 7) proved to be action conditions. As a consequence, the fluorination
labile in the presence of Brønsted and Lewis acids as well reaction, which requires harsh reaction conditions, could
as in the presence of TBAF. For example, treatment of 25 be carried out at an early stage in the synthesis on a sub-
with HOAC in addition to the expected TBDMS removal strate less sensitive than 2. In addition, all stereocenters
from the primary hydroxyl group led to rapid regioselec- were constructed using highly diastereoselective trans-
tive opening of the epoxide to give product 26. Treatment formations.
with PPTS, TFA, BF3·Et2O, or CAN all gave analogous
ring opening, which was observed even under very mild
Acknowledgment
acidic conditions (Montmorillonite K10 in CH2Cl2).12
The experimental work of D. Bixel and A. Hirni is gratefully ack-
nowledged. We thank the analytical department of the Novartis
Institutes for Biomedical Research Basel for their support. We ex-
press our gratitude to A. Schmidt for the preparation of substantial
amounts of fragments 4 and 6.
Treatment of 25 with TBAF led to a complex mixture.
In contrast, cleavage of the acetonide moiety in 24 pro-
ceeded cleanly and the corresponding diol 27a was con-
verted to the mono protected alcohol 28. Swern oxidation
afforded aldehyde 29, which was further oxidized to the
carboxylic acid 30 with sodium chlorite. The protected al-
lylic alcohol was selectively desilylated with TBAF and
the resulting seco acid 31 was subjected to Yamaguchi
macrolactonization conditions at elevated temperature as
previously reported for other epothilone derivatives.13
The macrolactone 32 was obtained in 62% yield. Final
cleavage of the remaining silyl groups required long reac-
tion times in HF·pyridine and 26-fluoroepothilone B (1)
was isolated in 45% yield.
References
(1) Reviews: (a) Altmann, K.-H. Mini-Rev. Med. Chem. 2003,
3, 149. (b) Wartmann, M.; Altmann, K.-H. Curr. Med.
Chem. 2002, 2, 123. (c) Klar, U.; Skuballa, W.; Buchmann,
B.; Schwede, W.; Bunte, T.; Hoffmann, J.; Lichtner, R. B.
ACS Symposium Series 2001, 796, 131. (d) Nicolaou, K. C.;
Ritzen, A.; Namoto, K. Chem. Commun. 2001, 1523.
(e) Harris, C. R.; Kuduk, S. D.; Danishefsky, S. J. Chemistry
for the 21st Century 2001, 8. (f) Wessjohann, L. A. Curr.
Opin Chem. Biol. 2000, 4, 303. (g) Nicolaou, K. C.;
Roschangar, F.; Vourloumis, D. Angew. Chem. Int. Ed.
1998, 37, 2014.
In conclusion, we have reported an improved total synthe-
sis of the promising epopthilone B analogue 26-fluoro-
epothilone B. This approach allowed the preparation of 1
Synlett 2004, No. 4, 693–697 © Thieme Stuttgart · New York

LETTER
Total Synthesis of 26-Fluoro-epothilone B
697
Scheme 8 Final steps; Reaction conditions: a) PPTS, EtOH, 55 °C (70%, chromatography); b) TBDMSOTf, 2,6-lutidine, CH2Cl2, –10 °C
(81%, chromatography); c) CSA, CH2Cl2, MeOH, 23 °C (89%, chromatography); d) (COCl)2, DMSO, Et3N, CH2Cl2, –78 °C (88%, chroma-
tography); e) NaClO2, 2-methyl-2-butene, NaH2PO4, t-BuOH, 23 °C (89%, chromatography); f) Bu4NF, THF, 0 °C–23 °C (88%, chromato-
graphy); g) trichloro-benzoyl chloride, Et3N, DMAP, toluene, 75 °C (62%, chromatography); h) HF–pyridine, THF, 23 °C (45%,
chromatography).
(2) (a) Newman, R. A.; Yang, J.; Finlay, M. R. V.; Cabral, F.;
Vourloumis, D.; Stephens, L. C.; Troncoso, P.; Wu, X.;
Logothetis, C. J.; Nicolaou, K. C.; Navone, N. M. Cancer
Chemother. Pharm. 2001, 48, 319. (b) Nicolaou, K. C.;
Finlay, M. R. V.; Ninkovic, S.; Sarabia, F. Tetrahedron
1998, 54, 7127. (c) Nicolaou, K. C.; Ninkovic, S.; Finlay,
M. R. V.; Sarabia, F.; Li, T. Chem. Commun. 1997, 2343.
(d) Altmann, K.-H.; Nicolaou, K. C.; Wartmann, M.;
OReilly, T. Proceedings of the American Association for
Cancer Research 2001, 42, Abstr. 1979.
(7) (a) Schinzer, D.; Limberg, A.; Bauer, A.; Boehm, O. M.;
Cordes, M. Angew. Chem. Int. Ed. 1997, 36, 523.
(b) Nicolaou, K. C.; Sarabia, F.; Ninkovic, S.; Yang, Z.
Angew. Chem. Int. Ed. 1997, 36, 525.
(8) Lermer, L.; Neeland, E.; Ounsworth, J.-P.; Sims, R. J.;
Tischler, S. A.; Weiler, L. Can. J. Chem. 1992, 70, 1427.
(9) Yarovenko, N. N.; Raksha, M. A. Zh. Obsh. Khim. 1959, 29,
215.
(10) Takaoka, A.; Iwakiri, H.; Ishikawa, N. Bull. Chem. Soc. Jpn.
1979, 52, 3377.
(3) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102,
5976.
(11) Schinzer, D.; Bauer, A.; Schieber, J. Chem.–Eur. J. 1999, 5,
2492.
(4) Review: Singh, R. P.; Shreeve, J. M. Synthesis 2002, 2561.
(5) Schinzer, D.; Limberg, A.; Boehm, O. M. Chem.–Eur. J.
1996, 2, 1477.
(6) Altmann, K.-H.; Bold, G.; Caravatti, G.; Denni, D.;
Floersheimer, A.; Schmidt, A.; Rihs, G.; Wartmann, M.
Helv. Chim. Acta 2002, 85, 4086.
(12) (a) For an analogous observation in a total synthesis of
epothilone B, see: Martin, H. J.; Drechser, M.; Mulzer, J.
Angew. Chem. Int. Ed. 2000, 39, 581. (b) For the sensitivity
of the epoxide in epothilone A and B, see: Sefkow, M.;
Kiffe, M.; Höfle, G. Bioorg. Med. Chem. Lett. 1998, 8, 3031.
(13) Nicolaou, K. C.; Namoto, K.; Ritzen, A.; Ulven, T.; Shoji,
M.; Li, J.; D’Amico, G.; Liotta, D.; French, C. T.;
Wartmann, M.; Altmann, K.-H.; Giannakakou, P. J. Am.
Chem. Soc. 2001, 123, 9313.
Synlett 2004, No. 4, 693–697 © Thieme Stuttgart · New York