Synthesis of 7beta-sulfur analogues of paclitaxel utilizing a novel epimerization of the 7alpha-thiol group.

Article abstract of DOI:10.1021/ol015727m

Paclitaxel analogues with a sulfur group at the 7beta position were required for SAR studies. Attempts to generate these compounds by displacing a 7alpha leaving group with sulfur nucleophiles were unsuccessful. Instead, these compounds were successfully

Full text of DOI:10.1021/ol015727m

ORGANIC
LETTERS
2001
Vol. 3, No. 11
1613-1615
Synthesis of 7â-Sulfur Analogues of
Paclitaxel Utilizing a Novel
Epimerization of the 7r-Thiol Group
,†
Harold Mastalerz,* Guifen Zhang,† John Kadow,† Craig Fairchild,‡
Byron Long,‡ and Dolatrai M. Vyas†
Bristol Myers-Squibb Pharmaceutical Research Institute, 5 Research Parkway,
Wallingford, Connecticut 06492, and Oncology Drug DiscoVery, Pharmaceutical
Research Institute, Bristol-Myers Squibb Co., P.O. 4000, Princeton, New Jersey 08543
harold.mastalerz@bms.com
Received February 19, 2001
ABSTRACT
Paclitaxel analogues with a sulfur group at the 7â position were required for SAR studies. Attempts to generate these compounds by displacing
a7r leaving group with sulfur nucleophiles were unsuccessful. Instead, these compounds were successfully prepared from a 7â-thiol intermediate
that was obtained by a base-catalyzed epimerization of the 7r-thiol derivative. The epimerization presumably proceeds through a thioaldehyde
intermediate and exhibits the opposite stereochemical preference of its oxygen counterpart.
The 7-methylthiomethyl analogue 1, BMS-184476,1 of
paclitaxel arose from an effort to identify taxanes with an
expanded or improved spectrum of activity in cancer patients
and is currently in Phase I clinical trials. While exploring
the SAR of this compound, we wanted to examine analogues
with sulfur substituents at the 7-position, in particular, the
transposed isomer of 1, 11. Although taxanes with hetero-
atom substituents2 other than oxygen at the 7 position have
been described, their sulfur3 counterparts have not been
reported to date. In this Letter, we report the synthesis of
7-sulfur-substituted paclitaxel analogues and a novel epimer-
ization reaction of the 7R-thiol group.
To prepare 7â-sulfur analogues of paclitaxel, we first
examined (Scheme 1) the reaction of intermediates bearing
a 7R-leaving group with sulfur nucleophiles. The 2′-acetate
derivative of the 7R-isomer of paclitaxel 3 was converted
into the known mesylate derivative 4.2a Attempts to displace
the 7R-mesylate group of 4 with the thioacetate ion only
led to the formation of the known olefin 2.2a Evidently the
displacement of a leaving group from the hindered 7R-
position is more difficult than the competing elimination
reaction. An effort to promote the displacement process by
using the more reactive 7R-triflate derivative 5 was also
† Bristol Myers-Squibb Pharmaceutical Research Institute, Wallingford,
CT.
‡ Research Institute, Bristol-Myers Squibb Co., Princeton, NJ
(1) Rose, W.; Lee, F.; Fairchild, C.; Kadow, J. Clin. Cancer Res. 2000,
6 (supplement), 6.
(2) (a) Menichincheri, M.; Botta, M.; Ceccarelli, W.; Ciomei, M.; Corelli,
F.; D’Anello, M.; Fusar-Bassini, D.; Mongelli, N.; Pesenti, E.; Pinciroli,
V.; Tafi, A.; Vanotti, E. Med. Chem. Res. 1995, 5, 534. (b) Liang, X.;
Kingston, D.; Lin, C.; Hamel, E.; Tetrahedron Lett. 1995, 36, 2901. (c)
Appendino, G.; Jakupovic, J.; Varese, M.; Belloro, E.; Danieli, B.;
Bombardelli, E. Tetrahedron Lett. 1996, 37, 7837.
(3) The current work appears in the following: Mastalerz, H.; Kadow,
J. U.S. Patent 6,017,935, 2000.
10.1021/ol015727m CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/28/2001

Scheme 1a
a (a) KSAc (5 equiv), DMF, 90 °C, 19 h (yield 54%). (b) LiSMe (2.5 equiv), DMF, -10 to 0 °C, 2 h; then TBAF (1.0 M in THF, 1.1
equiv), THF, 0 °C, 20 min (overall yield 31%). (c) KSAc (10 equiv), EtOH, rt, 45 h, (yield 89%). (d) NH3, EtOH, rt, 1 h (yield 61%). (e)
DBU (2 equiv), toluene, 95 °C (yield 69%). (f) BrCH2OMe (1.1 equiv), DBU (1.5 equiv), DCM, rt, 10 min; then TBAF (1.0 M in THF,
1.1 equiv), 0 °C, 5 min (yield 52%). (g) TBAF (1.0 M in THF, 1.1 equiv), THF, 0 °C, 5 min (yield 56%). (h) MeI (1.1 equiv), DBU (1.5
equiv), DCM, rt, 5 min (yield 79%).
explored. However, none of the desired triflate derivative
was obtained when the 7R-alcohol 3 was subjected to the
conditions (triflic anhydride with an equivalent of DMAP
in DCM at RT) that convert the isomeric 7â-alcohol into its
triflate derivative.2b Attempts to force this reaction only led
to the formation of complex product mixtures. The low
reactivity of the 7R-alcohol group has been noted previously4
and was attributed to its strong hydrogen bonding to the
4-acetate function.
Since the 7â-triflate 6 was readily available,2b it was
examined as a precursor to 7-sulfur analogues. Reaction of
6 with sulfur nucleophiles such as LiSMe5 and KSAc
afforded respectively the 7R-sulfide 7 and the 7R-thioacetate
8. The latter could be converted to the 7R-thiol 9 by selective
hydrolysis with NH3 in EtOH. In light of the facile
interconversion of paclitaxel and 7-epi-paclitaxel,6 the pos-
sibility of a related reaction of 9 was explored. It was found
that 9 underwent base-catalyzed epimerization when it was
heated in toluene at 90 °C in the presence of excess DBU.
A 9:1 mixture (HPLC determination) of the respective â and
R isomers 12 and 9 was obtained, and 12 was isolated in an
69% yield by chromatography. The isomer ratio did not
significantly change on further heating, indicating that an
equilibrium mixture had been reached. By analogy with its
oxygen counterpart, this is probably an aldol-type equilibra-
tion that proceeds through the thioaldehyde intermediate 10.
Although we are not aware of other examples of this reaction,
the intramolecular addition of an enol7 or an enolate ion8 to
a transient thioaldehyde group has been postulated in other
reactions. The observed thermodynamic preference for the
7â-thiol 12 is the opposite of what is seen with paclitaxel.
In that case, the 7-epi isomer is favored and this has been
attributed9 to the presence of a strong hydrogen bond between
the 7R-alcohol and the 4R-acetate function. The current
observations are in accord with this rationale since it is
known10 that thiols form weaker hydrogen bonds than
alcohols and therefore this stabilization is not available to
the 7R-thiol 9.
The 7â-thiol 12 could readily be S-alkylated to generate
analogues of 1. Treatment of 12 with MeOCH2Br in the
presence of DBU followed by desilylation afforded 11, the
transposed isomer of 1. Selective S-methylation of the 2′-
Table 1. In Vitro Biological Activity
compound
tubulina
HCT-116b IC50 (nM)
paclitaxel
13
7
14
11
1
1
1.8
16
0.89
1.9
1.1
4.0
13.5
13.1
0.2
0.5
2.1
a The ratio in the tubulin polymerization assay11 is the potency of the
analogue over the potency of paclitaxel. Ratios less than 1 reflect analogues
that are more potent than paclitaxel. b In vitro cytotoxicity assay against
paclitaxel sensitive human colon tumor 116 where IC50 measures the drug
concentration required for the inhibition of 50% cell proliferation after a
72 h incubation.12
(4) Chen, S.-H.; Huang, S.; Kant, J.; Fairchild, C.; Wei, J.-M.; Farina,
V. J. Org. Chem. 1993, 58, 5028.
(5) Kelly, T.; Dali, H.; Tsang, W. Tetrahedron Lett. 1977, 44, 3859.
(6) Chaudhary, A.; Rimoldi, D.; Kingston, D. J. Org. Chem. 1993, 58,
3789.
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Org. Lett., Vol. 3, No. 11, 2001

deprotected intermediate 13 gave the thioether 14 in good
yield.
The 7â-thiol 13 was found to be less effective at promoting
tubulin polymerization and at inhibiting the proliferation of
the HCT-116 cell line than paclitaxel (Table 1). For the
S-alkylated compounds, the â-isomer of the methyl sulfide
14 was significantly more cytotoxic than the R-isomer 7 and
the methoxymethyl sulfide 11 was somewhat more cytotoxic
than 1. The results of further biological evaluation of these
and additional 7-sulfur paclitaxel analogues will be reported
elsewhere.
Acknowledgment. We thank David Langley for his
helpful insights.
(7) Haynes, R.; Katsifis, A. Aust. J. Chem. 1989, 42, 1455
(8) Larsen, S.; Fisher, P.; Libby, B.; Jensen, R.; Mizsak, S.; Watt, W.;
Ronk, W.; Hill, S. J. Org. Chem. 1996, 61, 4725.
(9) (a) Kingston, D.; Samaranayake, G.; Ivey, C. J. Nat. Prod. 1990,
53, 1. (b) Fang, W.-S.; Fang, Q.-C.; Liang, X.-T. Synth. Commun. 1997,
27, 2305.
(10) Barrett, G. In Thiols; Jones, N., Ed.; Comprehensive Organic
Chemistry; Pergamon Press: 1979, Vol. 3, p 3.
(11) Swindell, C.; Krauss, N.; Horwitz, S.; Ringel, I. J. Med. Chem. 1991,
34, 1176.
(12) Scudiero, D.; Shoemaker, R.; Paull, K.; Monks, A.; Tierney, S.;
Nofziger, T.; Currens, M.; Seniff, D.; Boyd, M. Cancer Res. 1988, 48, 4827.
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 7 to 9 and
11 to 14. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL015727M
Org. Lett., Vol. 3, No. 11, 2001
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