Synthesis and crystal structure of 7,9-dideacetyl-1-deoxybaccatinVI

Article abstract of DOI:10.1007/s10870-006-9069-5

7,9-dideacetyl-1-deoxybaccatinVI was synthesized from 1-deoxybaccatinVI and its crystal structure was determined by X-ray crystallographic techniques. The compound (C₃₃H₄₂O₁₁·2CH₄O) crystallizes into monoclinic

Full text of DOI:10.1007/s10870-006-9069-5

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Journal of Chemical Crystallography, Vol. 36, No. 5, May 2006 ( 2006)
DOI: 10.1007/s10870-006-9069-5
Synthesis and crystal structure of
7,9-dideacetyl-1-deoxybaccatinVI
Hai-Xia. Lin,(1)∗ Na Han,(1) Jian-Min Chen,(2) and Tian-Hai Yuan(1)
Received September 13, 2005; accepted January 17, 2006
Published Online March 22, 2006
7,9-dideacetyl-1-deoxybaccatinVI was synthesized from 1-deoxybaccatinVI and its crys-
tal structure was determined by X-ray crystallographic techniques. The compound
(C33H42O11·2CH4O) crystallizes into monoclinic space group P21 with unit cell parameters:
◦
˚
˚
˚
a = 8.654(17) A, b = 16.470(5) A, c = 12.671(3) A, β = 97.63(2) , and Z = 2. The X-ray
results demonstrated that the reaction of 7,9,10-Trideacetyl-1-deoxy-baccatinVI with Ac2O
in tetrahydrofuran, using CeCl3 as catalyst, yielded monoacetylated product 7,9-dideacetyl-
1-deoxy baccatinVI In the structure, the six-membered A ring exhibits boat conformation,
the eight-membered B ring adopts boat-chair conformation, and the six-membered C ring
exhibits a sofa conformation.
KEY WORDS: Crystal structure; conformation; 7,9-dideacetyl-1-deoxybaccatinVI.
Introduction
studies suggested 1-hydroxyl group is not neces-
sary for the activity of paclitaxel.5 To explain these
A naturally occurring diterpenoid Paclitaxel
SAR, studies have focused on the determination of
the conformation of either active or inactive tax-
oids. The naturally occurring 1-deoxybaccatinVI
(1)6,7 served as precursor for the preparation of 1-
deoxypaclitaxel analog. In continuing our studies
on 1-deoxybaccatinVI,8 we focus on structural
modifications of the diterpenoid and conforma-
tional changes as an area of interest. Herein, we
report the synthesis (Scheme 1) and crystal struc-
ture of 7,9-dideacetyl-1-deoxybaccatinVI (3).
(taxol),1–3 isolated from the bark of the Pacific
yew (Taxus brevifolia), has proved to be one of
the most important new anticancer drug intro-
duced in the last decades, owing to its great po-
tential in the successful treatment of wide types
of cancer, a unique antitumor mechanism of ac-
tion, and complex molecular architecture. In or-
der to fully understand the compound’ mech-
anism of action and determine the structural
features essential for their biological activity,
extensive structure–activity relationship (SAR)
studies on taxoids have been performed.4 These
Experimental
Synthesis of 7,9,10-trideacetyl-1-deoxy-
baccatinVI (2)
(1) Department of Chemistry, Shanghai University, Shanghai 200436,
China.
(2) Department of Environmental Science and Engineering, Fudan
University, Shanghai 200433, China.
To a solution of 1 (349.4 mg, 0.5 mmol) in
methanol (20 mL) at room temperature was added
dropwise potassium carbonate (2.0 mL, 1.3 N in
∗
To whom correspondence should be addressed; e-mail: linhaixia@
online.sh.cn.
337
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1074-1542/06/0500-0337/0 2006 Springer Science+Business Media, Inc.

338
Lin, Han, Chen, and Yuan
cerium(III) chloride heptahydrate (13 mg,
0.035 mmol) and acetic anhydride (0.13 mL,
1.3 mmol) were added, and then stirred at 40◦C
for 2 h. At the end of this period, the solution was
quenched with distilled water and extracted with
ethyl acetate. The organic phase was washed with
water for three times and dried over anhydrous
magnesium sulfate, and concentrated in vacuo to
obtain a white solid. Column chromatography of
the solid on silica gel with 25% petroleum ether
in ethyl acetate solution as an eluent gave the title
compound 3 171 mg in 82% yield. IR νmaks (KBr)
cm−1: 3443.8, 1738.5, 1716.9, 1650.3, 1452.4,
1372.1, 1241.3, 969.5, 714.9.1H NMR (CDCl3,
ppm): δ 1.15 (s, 3H), 1.63–1.71 (m, 1H), 1.75 (s,
3H), 1.81 (s, 3H), 1.96 (s, 3H), 1.90–2.03 (m,
2H), 2.13 (s, 3H), 2.19 (s, 3H), 2.28 (s, 3H),
2.39–2.50 (m, 1H), 2.51–2.62 (m, 1H), 2.89 (d,
J = 8.4 Hz, 1H), 4.16 (d, J = 8.52 Hz, 1H), 4.37
(d, J = 8.24 Hz, 1H), 4.45–4.48 (m, 1H), 4.45
(d, J = 10.99 Hz, 1H), 5.00 (d, J = 8.52 Hz, 1H),
5.74 (dd, J = 5.91, 2.06 Hz, 1H), 5.94 (t, J = 9.07,
7.69 Hz, 1H), 6.16 (d, J = 10.99 Hz, 1H), 7.47
(t, J = 7.55 Hz, 2H), 7.59 (t, J = 7.42 Hz, 1H),
8.06 (d, J = 7.14 Hz, 2H).13C NMR: δ 12.6, 14.6,
21.1, 21.2, 22.7, 26.5, 26.9, 31.2, 37.9, 38.0, 44.3,
44.6, 47.0, 69.0, 71.5, 73.8, 73.9, 76.6, 77.2,
81.9, 84.0, 128.5, 129.6, 133.4, 134.7, 136.9,
165.0, 169.2, 170.6, 170.7. ESI Full MS m/z:
638, 637 (M + Na)+. The colorless single crystal
was cultured from a mixture solution of methanol
and water (9:1.v/v) by slow evaporation at room
temperature.
Scheme 1.
methanol/water), and the reaction progress was
followed by TLC until completion. After care-
ful neutralization (saturated ammonium chloride)
and removal of the methanol, the residue was
extracted with ethyl acetate and purified by col-
umn chromatography on silica gel with ethyl ac-
etate/hexane 3/2 as an eluent to give 2 (186.0 mg,
65%).1H NMR (CDCl3, ppm): δ 1.21 (s, 3H),
1.64–1.69 (m, 1H), 1.77 (s, 3H), 1.80 (s, 3H), 1.86
(s, 3H), 1.92–1.96 (m, 2H), 2.18 (s, 3H), 2.27 (s,
3H), 2.42–2.48 (m, 1H), 2.51–2.58 (m, 1H), 2.89
(d, J = 5.83 Hz,1H), 3.16 (s, 1H), 3.65 (s, 1H),
4.16 (d, J = 8.40 Hz, 1H), 4.32–4.39 (m, 3H),
4.83 (d, J = 6.95 Hz, 1H), 4.92 (d, J = 10.31 Hz,
1H), 4.99 (d, J = 8.81 Hz, 1H), 5.76 (dd, J = 2.10,
5.89 Hz, 1H), 5.97 (t, J = 8.61, 8.87 Hz, 1H),
7.47 (t, J = 7.83 Hz, 2H), 7.59 (t, J = 7.42 Hz,
1H), 8.05 (dd, J = 7.79, 1.19 Hz, 2H);13C NMR
(CDCl3): δ 12.5, 14.8, 21.2, 22.8, 26.7, 26.9, 31.7,
38.0, 38.2, 44.1, 44.3, 47.4, 69.5, 71.2, 71.8, 74.3,
76.7, 78.9, 81.9, 84.0, 128.6, 129.8, 133.5, 135.2,
137.5, 165.1, 169.3, 170.7; ESI Full MS m/z: 573
(M + H)+, 555 (M + H-H2O)+, 495, 373, 331,
313, 295.
Crystal structure determination of 3
A summary of the crystallographic informa-
tion is given in Table 1, and selected bond dis-
tances and angles are listed in Tables 2 and 3, re-
spectively. The selected crystal was mounted on a
ENRAF-NONIUS CAD4 diffractometer. Diffrac-
tion data were measured at 20◦C using graphite
monochromated Mo Kα (λ = 0.071073 nm) radi-
ation. The structure was solved by direct methods
and refined by full-matrix least squares method
Synthesis of 7,9-dideacetyl-
1-deoxybaccatinVI (3)
In a solution of anhydrous 2 (195 mg,
0.34 mmol) in dry tetrahydrofuran (7 mL),
2
on Fobs by using the SHELXTL 97 software

Synthesis and crystal structure of 7,9-dideacetyl-1-deoxybaccatinVI
339
Table 1. Crystal Data and Other Crystallographic Details
Table 3. Bond Angles (◦) of 3
–
–
–
–
–
Empirical formula
Formula weight
Temperature (K)
C33H42O11·2CH4O
678.75
292(2)
0.71073
Monoclinic
P21
C(14) C(1) C(15)
110.4(3) C(6) C(7) C(8)
114.1(3)
111.5(3)
112.7(3)
104.9(3)
113.1(3)
120.7(3)
115.2(3)
–
– –
113.9(3) C(7) C(8) C(9)
– –
113.5(3) C(19) C(8) C(3)
– –
118.9(3) C(7) C(8) C(3)
– –
112.7(3) C(9) C(8) C(3)
– –
111.4(3) C(10) C(9) C(8)
– –
114.0(3) C(11) C(10) C(9)
C(14) C(1) C(2)
–
–
C(2) C(1) C(15)
C(1) C(2) C(3)
C(4) C(3) C(2)
C(4) C(3) C(8)
˚
–
–
Wavelength (A)
–
–
Crystal system
Space group
Cell dimensions
–
–
–
–
C(2) C(3) C(8)
˚
–
–
–
– –
C(12) C(11) C(10) 119.6(3)
C(20) C(4) C(5)
85.3(3)
a (A)
8.6540(17)
16.470(5)
12.671(3)
90.00(2)
97.63(2)
90.00(2)
1790.0(8)
2
˚
–
–
–
C(20) C(4) C(3)
121.9(3) C(12) C(11) C(15) 119.3(3)
b (A)
˚
–
–
– –
118.3(3) C(10) C(11) C(15) 119.9(3)
– –
114.2(4) C(11) C(12) C(13) 118.7(3)
C(3) C(4) C(5)
c (A)
α (◦)
–
–
–
O(5) C(5) C(6)
B (◦)
–
– –
C(12) C(13) C(14) 112.9(3)
O(5) C(5) C(4)
90.4(3)
119.9(3) C(1) C(14) C(13)
ꢀ (◦)
–
–
–
–
C(6) C(5) C(4)
115.5(3)
103.7(3)
92.0(3)
3
–
–
– –
C(11) C(15) C(1)
˚
C(20) O(5) C(5)
91.4(3)
116.4(3) O(5) C(20) C(4)
Volume (A )
–
–
–
–
C(5) C(6) C(7)
Z
Density (calc.) (mg/m3)
Absorption coefficient (mm
F(0 0 0)
1.259
0.096
728
–
1
)
Crystal size (mm)
0.50 × 0.40 × 0.30
1.62–25.18
0.9719, 0.9537
− 10 ≤ h ≤ 10
− 1 ≤ k ≤ 19
− 15 ≤ l ≤ 15
7174
3594 [Rint = 0.0372]
Full-matrix least-squares
on F2
3594/1/447
1.003
R1 = 0.0404, wR2 = 0.0854
R1 = 0.0939, wR2 = 0.1024
0.138 and − 0.135
θ range for data collection (◦)
Max., Min. transmission
Index ranges
Results and discussion
The compound 3 crystallized in mono-
clinic system, space group P21. The structure
of molecule 3 with atomic labeling is shown in
Fig. 1. The crystals include two methanol mole-
cules, not shown in Fig. 1 for sake of clarity.
The cycloctane ring B adopts the most stable
boat-chair conformation, as shown by the torsion
angles with atoms C(1) and C(9) as the ends. This
Reflections collected
Independent reflections
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2σ(I)]
R indices (all data)
–
ring is transfused along the C(3) C(8) bond to
the six- membered ring C, which exhibits a chair
conformation flattened in C(4) [atoms C(7) and
Largest diff. peak and hole
−3
˚
(eA
)
CCDC deposit no.
283053
˚
˚
C(4) deviated by − 0.613 A and 0.197 A, re-
spectively, from the mean plane of the other four
atoms]. Ring A, “double-bridged” to the central
ring, exhibits the 1,3-di-planar boat conformation
package. All non-H atoms were anisotropically
refined. The hydrogen atoms were located by ge-
ometry calculation and riding on the related parent
atoms.
˚
˚
with C(11) only 0.317 A and C(15) 1.031 A fully
above the mean plane of the atoms C(13), C(12),
C(14), and C(1). The solid-state conformation of 3
is very close to that of the baccatin derivatives re-
solved by X-ray analysis: 1-deoxybaccatinVI,6 9-
dihydro-13-acetyl-baccatin III,9 10-deacetyl bac-
catin III,10 baccatin III,11 taxol12and docetaxel,13
showing that the presence of the 9-hydroxy func-
tion, removal of oxygen function at 1-position and
deacylation at 7-position and 9-position have a
minimal effect on the conformation of the taxol
skeleton. The relative orientation of the carboxyl
and benzene groups of benzoyl, which has been
the subject of discussions in some papers, deviates
˚
Table 2. Bond Lengths (A) of 3
–
–
C(1) C(14)
1.539(6)
1.549(5)
1.540(5)
1.572(5)
1.552(5)
1.574(5)
1.510(6)
1.448(5)
1.494(6)
1.432(5)
C(6) C(7)
1.514(6)
1.548(5)
1.563(5)
1.522(5)
1.512(6)
1.333(5)
1.529(5)
1.515(6)
1.536(6)
–
–
C(1) C(15)
C(7) C(8)
–
–
C(1) C(2)
C(8) C(9)
–
–
C(9) C(10)
–
C(10) C(11)
–
C(11) C(12)
–
C(11) C(15)
–
C(12) C(13)
–
C(13) C(14)
C(2) C(3)
–
C(3) C(4)
–
C(3) C(8)
–
C(4) C(20)
–
C(5) O(5)
–
C(5) C(6)
–
O(5) C(20)

340
Lin, Han, Chen, and Yuan
Fig. 1. The molecular structure and labeling scheme of 3 with 30% probability
of ellipsoids.
from coplanarity [atoms O(2) and O(1) deviated
˚
–
ing characteristics: O(6) H· · ·O(7) = 2.544 A,
˚
˚
◦
by − 0.011 A and 0.064 A, respectively, from
the plane of atoms C(21), C(22), C(23), C(24),
C(25), C(26), and C(27)]. This study, in conjunc-
tion with the earlier studies on related baccatin
derivation reveals that the benzoyl group exhibits
an unexpected conformational flexibility that may
be relevant to the bioactivity of taxanes.
˚
–
H· · ·O(7) = 1.794 A, O(6) H· · ·O(7) = 149.5 ,
and between HO(7) and O(8) with the follow-
˚
–
ing characteristics: O(7) H· · ·O(8) = 2.649 A,
◦
˚
–
H· · ·O(8) = 2.616 A, O(7) H· · ·O(8) = 83.2 [O
˚
–
(13) H· · ·O (6), 2.706 A, x − 1, y, z − 1], [O
˚
–
(7) H· · ·O (12), 2.615 A, x, y, z + 1], the
methanol molecule and the methanol molecule
Four corresponding dihedral angles differ
˚
–
[O (12) H· · ·O (13), 2.615 A] also contribute to
◦
–
–
–
–
–
by nearly 5 [C(3) C(8) C(9) C(10), C(8) C(9)
the crystal packing.
–
–
–
–
–
C(10) C(11), C(12) C(13) C(14) C(1), C◦(13)
◦
◦
◦
–
–
C(14) C(1) C(2)] (53 , − 61 , − 23 , 104 in 3
versus − 57◦, 65◦, 27◦, − 107◦ in 1). Accompa-
nying these differences are shorter bond lengths at
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–
–
–
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–
–
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˚
–
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Synthesis and crystal structure of 7,9-dideacetyl-1-deoxybaccatinVI
341
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