Synthesis, utility, and x-ray crystal structure of novel complexes of baccatin III with imidazole and 2-propanol

Article abstract of DOI:10.1021/ol006332q

(matrix presented) Baccatin III forms crystalline complexes 4 and 5 with imidazole and 2-propanol, respectively. These compounds are useful in the purification of baccatin III from mixtures of taxanes derived from plant-cell fermentation.

Full text of DOI:10.1021/ol006332q

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ORGANIC
LETTERS
2000
Vol. 2, No. 21
3269-3271
Synthesis, Utility, and X-ray Crystal
Structure of Novel Complexes of
Baccatin III with Imidazole and
2-Propanol
Frank S. Gibson,* Jianmei Wei, Purushotham Vemishetti, Qi Gao,† and
,‡
John L. Dillon*
Bristol-Myers Squibb Company, Process Exploration Labs, Technical Operations
DeVelopment, P.O. Box 4755, Syracuse, New York 13221-4755, and Analytical
Research and DeVelopment, Pharmaceutical Research Institute, 5 Research Parkway,
Wallingford, Connecticut 06492
john.dillon7@honeywell.com
Received July 14, 2000
ABSTRACT
Baccatin III forms crystalline complexes 4 and 5 with imidazole and 2-propanol, respectively. These compounds are useful in the purification
of baccatin III from mixtures of taxanes derived from plant-cell fermentation.
The baccatin III core is the central structural feature of
TAXOL® (paclitaxel) 1, a diterpenoid natural product which
has become one of the most important anticancer therapies
of recent times.1 Taxanes lacking a phenylisoserine side chain
at the C-13 position, such as 10-deacetyl baccatin III (10-
DAB) 2 and baccatin III 3, show a much lower cytotoxic
response to cancer cells and a different mechanism of action.2
These compounds are, however, useful intermediates for the
semisynthesis of paclitaxel and docetaxel.3 Since the semi-
synthesis of paclitaxel requires acetylation of the C-10
hydroxyl group, baccatin III 3 represents a more efficient
starting material than 2 for this process (Figure 1).
Figure 1. Structures of TAXOL, 10-DAB, and baccatin III.
† Wallingford, CT. To whom correspondence regarding X-ray crystal
structures should be addressed.
‡ Present address: Honeywell Co. Pharmaceutical Fine Chemicals, 20
Peabody St., Buffalo, NY 14210.
During the course of our synthetic studies with taxanes,
we have discovered that baccatin III 3 selectively forms
novel, crystalline complexes, 4 and 5, with imidazole and
2-propanol (Figure 2). These compounds allow for a simple
means of purification of 3 from complex mixtures of taxanes
derived from plant-cell fermentation. In this Letter, we report
(1) (a) Georg, G. I.; Chen. T. T.; Ojima, I.; Vyas, D. M. Taxane
Anticancer Agents, ACS Symp. Ser.; American Chemical Society: Wash-
ington, DC, 1995; p 583. (b) Kingston, D. G. I.; Molinero, A. A.; Rimoldi,
J. M. Prog. Chem. Org. Nat. Prod. 1993, 61, 1.
(2) Pengsuparp, T.; Kingston, D. G. I.; Neidigh, K. A.; Cordell, G. A.;
Pezzuto, J. M. Chem.-Biol. Interact. 1996, 101, 103.
10.1021/ol006332q CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/19/2000

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equivalent of water completes the complex with hydrogen
bonds at O-1 and O-13 of baccatin III.4
Formation of the complex was also possible in other
common organic solvents such as ethyl acetate or acetone.
The complex was found to be stable to recrystallization from
acetonitrile. Paclitaxel did not form a similar complex.
In marked contrast to the imidazole complex that involves
intermolecular interactions, recrystallization of baccatin III
with dichloromethane-2-propanol leads to the formation of
a 1:1 complex, 5, consisting of intramolecular hydrogen
bonds between baccatin III and 2-propanol (Figure 4). The
hydroxyl group of 2-propanol cross-links the C-7 hydroxyl
group, O7-H‚‚‚O(O‚‚‚O ) 2.645 Å), and the carbonyl
oxygen of the C-10 acetyl group of baccatin III, H-O‚‚‚
O10 (O‚‚‚O ) 2.734 Å). Comparison of the crystal structure
to imidazole complex 4 reveals that the two complexes are
isomorphous with the 2-propanol molecules found in infinite
linear channels along the crystallographic a-axis.5
The complexes 4 and 5 were found to have utility in
nonchromatographic purification and isolation of baccatin
III from solutions containing a myriad of other taxanes
derived from plant-cell fermentation.6 When imidazole was
added to a solution of baccatin III obtained by butyl acetate
extraction of a broth derived from plant cell fermentation,
and containing a variety of taxanes, a precipitate was formed
which was shown to be 4 of good quality. After filtration,
the solid complex was readily broken and the baccatin III
recovered in near quantitative yield by aqueous extraction
of a solution of 4 dichloromethane. In this manner the
baccatin III partitions to the dichloromethane and imidazole
to the aqueous phase. Separation of the organic layer and
removal of solvent followed by recrystallization afforded
baccatin III of high purity. Similary, concentration of the
butyl acetate extract obtained as described above to dryness
and dissolution in hot 2-propanol led to the formation of a
baccatin III-2-propanol complex of good quality.
Figure 2. Crystalline complexes of baccatin III with imidazole,
4, and 2-propanol, 5.
the preparation, utility, and X-ray crystal structure of these
compounds.
Treatment of a solution of baccatin III in dichloromethane
with imidazole produced a crystalline solid. Single-crystal
X-ray diffraction established the compound to be 4, a 1:1
polymeric complex of baccatin III and imidazole which was
isolated in 89% yield.
The intermolecular interaction involves two hydrogen
bonds (Figure 3). One H-bond is between N-1 of imidazole
and the carbonyl oxygen of the C-10 acetyl group of baccatin
III (159.0°, O‚‚‚N ) 2.643 Å, H‚‚‚N ) 1.743 Å). The second
H-bond exists between N-3 of imidazole and the C-7
hydroxyl group of another baccatin III molecule (154.0°, N‚
‚‚O ) 2.898 Å, H‚‚‚O ) 2.000 Å). One-fourth molar
Figure 3. X-ray crystal structure of baccatin III-imidazole complex, 4.
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Org. Lett., Vol. 2, No. 21, 2000

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Supporting Information Available: Experimental pro-
cedures for preparation of baccatin III-imidazole and
baccatin III-2-propanol complexes, purification of baccatin
III from plant cell fermentation broth, and X-ray crystal
coordinates for 4 and 5.
OL006332Q
(3) (a) TAXOL: Science and Applications; Suffness, M., Ed.; CRC
Press: 1995. (b) Denis, J.-N.; Greene, A. E.; Guenard, D.; Gueritte-
Voegelein, F.; Mangatal, L.; Potier, P. J. Am. Chem. Soc. 1988, 110, 5917.
(c) Holton, R. A. U.S. Patent 5,015,744, 1992. (d) Holton, R. A. U.S. Patent
5,136,060, 1992. (e) Holton, R. A. U.S. Patent 5,229,526, 1993. (f) Kingston,
D. G. I.; Chaudhary, A. G.; Guanatilaka, A. A. L.; Middleton, M. L.
Tetrahedron Lett. 1994, 35, 4483. (f) Ojima, I.; Habus, I.; Zhao, M.; Zucco,
M.; Park, Y. H.; Sun, C. M. Tetrahedron 1992, 48, 6985. (g) Ojima, I.;
Sun. C. M.; Zucco, M.; Park, Y. H.; Duclos, O.; Kuduk, S. D. Tetrahedron
1993, 4149.
(4) A crystal of 4 obtained as a colorless thick plate from acetonitrile
measuring 0.10 mm × 0.35 mm × 0.42 mm was used for X-ray diffraction
measurements. Crystal data: C31H38O11-C3H4N2‚0.25H2O, orthorhombic,
space group P21212, a ) 9.2771(4) Å, b ) 41.215(2) Å, c ) 8.5788(4) Å,
R ) â ) γ ) 90°, V ) 883.7(2) Å3, Z ) 4, dx ) 1.325 g cm-3. A total of
3894 independent reflections were measured of which 3266 were observed
with |I| g 3σ.
Figure 4. X-ray crystal structure of baccatin III-2-propanol
complex, 5.
(5) A crystal of 5 obtained as an unstable colorless plate from di-
choromethane-2-propanol measuring 0.20 mm × 0.30 mm × 0.45 mm
was used for X-ray diffraction measurements. Crystal data: C31H38O11-
C3H8O orthorhombic, space group P21212, a ) 9.3975(3) Å, b ) 41.736-
(2) Å, c ) 8.5401(3) Å, R ) â ) γ ) 90°, V ) 883.7(2) Å3, Z ) 4, dx )
1.284 g cm-3. A total of 3684 independent reflections were measured of
which 3469 were observed with |I| g 3σ. (b) The authors have deposited
atomic coordinates for structure 4 and 5 with the Cambridge Crystallographic
Data Center. The coordinates can be obtained on request from the Director,
Cambridge Crystallographic Data Center, 12 Union Road, Cambridge, CB2
IEZ, U.K.
In summary, novel complexes of baccatin III with imida-
zole and 2-propanol have been described along with their
use in the recovery and purification of baccatin III from
solutions containing other taxanes. Determination of the
ability of baccatin III to form complexes with other
compounds as well as their solution properties and reactivity
is under investigation in our laboratories.
(6) (a) Bringi, Venkataraman; Kadkade, P. G.; Kane, J. E.; Prince, C.
L.; Roach, B.; Schubmehl, B. F. U.S. Patent 5,407,816. (b) Cuside, R. M.;
Palazo, J.; Navia-Osorio, A.; Bonfil, M.; Morales, C.; Pinol, M. T. Plant
Sci. 1999, 146, 101.
Org. Lett., Vol. 2, No. 21, 2000
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