29 卷 11 期
2010. 11
结
构 化 学（JIEGOU HUAXUE）
Chinese J. Struct. Chem.
Vol. 29, No. 11
1676~1679
Synthesis and Crystal Structure of
Diisopropyl Genistein-7-yl Phosphate①
CHEN Xiao-Lana② YUAN Jin-Weib QU Zhi-Boa
YU Zhang-Qia QU Ling-Boa, b ZHAO Yu-Fena, c
a
(Department of Chemistry, Zhengzhou University, Key Laboratory of
Organic Chemistry and Chemical Biology, Zhengzhou, Henan 450052, China)
b
(Chemistry and Chemical Engineering School,
Henan University of Technology, Zhengzhou, Henan 450001, China)
c
(Department of Chemistry, Xiamen University, Xiamen 361005, China)
Diisopropyl genistein-7-yl phosphate (C21H23O8P, Mr = 434.11) has been synthe-
ABSTRACT
sized by a facile phosphorylated reaction with genistein and diisopropyl phosphite, and its structure
was determined by IR, NMR, HR MS and X-ray single-crystal diffraction. The crystal belongs to
monoclinic, space group P21/n, with a = 9.0690(18), b = 9.0412(18), c = 26.544(5) Å, β = 99.44(3)°,
V = 2147.0(7) Å3, Z = 4, Dc = 1.344 Mg/m3, µ = 0.172 mm-1, F(000) = 912, the final R = 0.0545 and
wR = 0.1352. In the crystal structure, the title compound is constructed by both intramolecular
(O–H···O=C) and intermolecular (O–H···O=P) hydrogen bonding as well as π-π stacking interaction.
Keywords: genistein, phosphate, crystal structure, hydrogen bonding, π-π stacking
activities[11, 12]. In order to obtain an efficient analo-
1 INTRODUCTION
gue to improve the biological activities of genistein,
Genistein (5,7-dihydroxy-3-(4-hydroxyphenyl)
phosphate group was introduced. Diisopropyl geni-
chromen-4-one), a major metabolite of soy, is re-
stein-7-yl phosphate was synthesized with a high
ported to have many biological activities including
yield in a facile phosphorylated reaction of genistein
[1]
[2]
[3]
anti-inflammatory , antiestrogenic , antioxidant ,
[4]
[5]
[6]
antiproliferative , antiallergic , antiviral , antibac[7]
terial effects , etc. Furthermore, genistein has de-
with diisopropyl phosphite, and its structure was
determined by IR, NMR, HR MS and X-ray singlecrystal diffraction.
[8, 9]
monstrated anticancer activities
. In recent years,
there has been growing interest in genistein as anti-
2
EXPERIMENTAL
cancer substance with high efficacy, low toxicity,
and minimum side effects[10]. However, the low
2. 1
Synthesis
absorbance of genistein in intestines results in its
IR spectra were recorded on a Shimadazu IR-408
low biological activities. It is well known that the
Fourier spectrometer (KBr pellet). High resolution
introduction of phosphate group into organic mo-
mass spectra (HR MS) were obtained on a Waters
lecules can often dramatically change their physical
Micromass Q-Tof MicroTM instrument using the ESI
and chemical properties, or improve their biological
technique. Melting points were obtained with an
Received 29 January 2010; accepted 21 April 2010 (CCDC 706726)
① Supported by the NNSFC (Nos. 20472076, 20732004, 20972130), and Henan Academic Foundation of Science and Technology (No. 0512001400)
② Corresponding author. Tel: 0371-67767051, E-mail: [email protected]
2010
Vol. 29
结
构
化
学（JIEGOU HUAXUE）Chinese J.
Struct.
Chem.
1677
XT-4 micromelting apparatus and uncorrected. NMR
gel (chloroform:ethanol = 10:1). Single crystal was
spectra were recorded on a Bruker Avance 400 MHz
obtained by slow crystallization from an ethanol
spectrometer.
1
H and
13
solution at room temperature. Yield: 81%, m.p.:
C chemical shifts were
31
quoted in parts per million downfield from TMS. P
162.5 ～ 163.5 ℃. HR MS 435.1203 [M + H]+,
chemical shifts are quoted in parts per million rela-
(calculated for C21H24O8P 435.1209). IR(KBr)
tive to an external 85% H3PO4 standard.
v(cm-1): 3250 (O–H), 2985 (CH3), 1655 (C=O),
A solution of genistein (0.3 g, 1.1 mmol) and
1244 (P=O), 1018 (P–O). 1H NMR (CDCl3) δ: 12.84
triethylamine (0.16 mL, 1.1 mmol) in ethanol (25
(s, 1H, OH-5), 7.84 (s, 1H, H-2), 7.24 (d, 3JH-H = 7.2
mL) was stirred at 0～5 ℃ for 20 min, and a mixed
Hz, 2H, H-2΄, 6΄), 6.79 (d, 4JH-H = 2.8 Hz, 1H, H-8),
solution of diisopropyl phosphite (0.2 g, 1.2 mmol)
6.75 (d, 3JH-H = 8.0 Hz, 2H, H-3΄, 5΄), 6.63 (d, 4JH-H
and tetrachloride (5 mL) was added dropwise to the
= 2.4 Hz, 1H, H-6), 4.82 (m, 2H, 2CH(CH3)2), 1.42
solution over a period of 30 min. After 1 h, the reac-
(m, 12H, 2CH(CH3)2);
tion was heated to room temperature and stirred. The
(C-4), 162.7 (C-5), 157.1 (C-4΄), 156.9 (C-7), 155.7
formation of the product was monitored by TLC.
(C-9), 153.3 (C-2), 129.5 (C-2΄, 6΄), 123.7 (C-1΄),
After completion of the reaction, the solution was
121.4 (C-3), 115.6 (C-3΄, 5΄), 108.9 (C-10), 104.0
filtered and evaporated to dryness, and the residue
(C-6), 99.3 (C-8), 74.7 (d, 2JP-C = 6.2 Hz, CH(CH3)2),
was purified by column chromatography on silica
23.6 (CH(CH3)2); 31P NMR (CDCl3) δ: –8.2.
O
HO
O
O
O
((CH3)2CHO)2PH
O
NEt3, CCl4, C2H5OH
OH
8
O
O
OH
C NMR (CDCl3) δ: 181.1
1
9 O
3
6
10
OH
1'
2'
3'
4
O
(2)
Scheme 1.
2
7
5
(1)
2. 2
P
13
4'
6'
5'
OH
Synthesis of diisopropyl genistein-7-yl phosphate (2)
Crystal data and structure determination
1/[σ2(Fo2) + (0.0734P)2 + 0.6267P], where P = (Fo2
A colorless single crystal (0.20nm × 0.18nm ×
+ 2Fc2)/3), S = 1.073, (∆/σ)max = 0.000, (∆ρ)max =
0.17nm) of compound 2 was selected and mounted
0.279 and (∆ρ)min = –0.241 e/Å3. Molecular illustra-
on the top of a glass fiber. The data were collected
tions were prepared using the XP package.
on an R-Axis-IV diffractometer equipped with a graphite-monochromatic MoKα radiation (λ = 0.71073
3 RESULTS AND DISCUSSION
Å) using an oscillation frames scan mode in the
range of 1.56<θ<25.00° at 291(2) K. A total of 6041
Compound 2 was synthesized using a facile phos-
reflections were recorded and 3491 were unique
phorylated reaction with genistein and diisopropyl
(Rint = 0.0378), among which 2736 (0≤h≤10, –10
phosphate (Scheme 1). The results showed that the
≤k≤10, –31≤l≤30) were observed. The unit cell
phosphorylation action occurred regioselectively
dimensions were obtained with the least-squares
only at the hydroxyl group of 7 position of genistein,
refinements. The structure was solved by direct
leaving the 4΄- and 5-hydroxyl groups unphosphory-
[13]
and refined
lated. For example, 13C NMR of compound 2 show-
by full-matrix least-squares method on F2 with
ed that the chemical shifts from 4΄-C and 5-C were
anisotropic thermal parameters for all non-hydrogen
nearly not variable compared to those of genistein;
methods with SHELXS-97 program
[14]
. Hydrogen atoms were
whereas, the chemical shift (δ 156.9) from 7-C of
generated geometrically. The final cycle of refine-
compound 2 was 7.4 ppm decreased related to 7-C
ment converged to R = 0.0756, wR = 0.1471 (w =
(δ 164.3) of genistein. This explains that the phos-
atoms using SHELXL-97
1678
CHEN X. L. et al.: Synthesis and Crystal Structure of Diisopropyl Genistein-7-yl Phosphate
No. 11
phorylation proceeds a regioselective attack at 7-OH
shown in Tables 1 and 2, respectively. The molecular
of genistein. X-ray crystal structure of compound 2
structure of compound 2 is depicted in Fig. 1, and
further proved this fact.
the hydrogen bonds in the crystal of 2 in Fig. 2.
The selected bond lengths and bond angles are
Table 1.
Selected Bond Lengths (Å) in the Molecule of 2
Bond
Dist.
Bond
Dist.
Bond
Dist.
P(1)–O(1)
1.459(2)
O(4)–C(3)
1.402(3)
O(3)–C(19)
1.480(4)
P(1)–O(3)
1.541(2)
O(5)–C(9)
1.352(3)
O(8)–C(13)
1.370(3)
P(1)–O(2)
1.545(2)
O(5)–C(5)
1.364(3)
C(1)–C(6)
1.414(4)
P(1)–O(4)
1.584(2)
O(6)–C(1)
1.353(3)
C(8)–C(9)
1.350(4)
O(2)–C(16)
1.488(4)
O(7)–C(7)
1.251(3)
C(8)–C(10)
1.477(4)
Table 2.
Selected Bond Angles and Torsion Angles in the Molecule of 2
o
Angle
()
Angle
(o)
Angle
(o)
O(1)–P(1)–O(3)
115.19(13)
C(9)–O(5)–C(5)
118.5(2)
O(8)–C(13)–C(14)
118.6(3)
P(1)–O(3)–C(19)
120.0(2)
O(6)–C(1)–C(2)
119.1(3)
C(21)–C(19)–O(3)
107.5(3)
P(1)–O(2)–C(16)
120.1(2)
O(5)–C(5)–C(6)
120.5(2)
C(7)–C(8)–C(10)
122.4(2)
C(3)–O(4)–P(1)
121.65(18)
O(7)–C(7)–C(6)
121.6(2)
C(8)–C(9)–O(5)
126.8(3)
O(1)–P(1)–O(2)–C(16)
45.4(3)
O(1)–P(1)–O(3)–C(19)
55.4(3)
C(2)–C(1)–C(6)–C(7)
–176.4(2)
O(1)–P(1)–O(4)–C(3)
32.5(3)
C(3)–C(4)–C(5)–O(5)
178.2(2)
C(9)–O(5)–C(5)–C(6)
3.0(4)
O(3)–P(1)–O(4)–C(3)
–92.7(2)
O(5)–C(5)–C(6)–C(7)
–1.2(4)
O(7)–C(7)–C(8)–C(10)
0.8(4)
O(2)–P(1)–O(4)–C(3)
158.8(2)
P(1)–O(2)–C(16)–C(18)
–124.1(4)
C(5)–O(5)–C(9)–C(8)
–2.8(4)
C(1)–C(2)–C(3)–C(4)
–0.7(4)
P(1)–O(3)–C(19)–C(21)
–132.0(3)
C(9)–C(8)–C(10)–C(11)
–133.4(3)
Fig. 1.
Fig. 2.
View of the molecule of diisopropyl genistein 7-yl phosphate (2)
Thermal ellipsoids are drawn at 30% probability level
Hydrogen bonds in diisopropyl genistein-7-yl phosphate (2)
X-ray single-crystal structure study revealed that
hydroxyl group at the 7 position of genistein was
phosphorylated, which is in good agreement with the
information of IR and NMR data. The P=O bond
length (1.459(2) Å) is close to those found in other
related structures[15, 16]. The P(1)−O(3) (1.541(2) Å),
2010
Vol. 29
结
构
化
学（JIEGOU HUAXUE）Chinese J.
P(1)−O(2) (1.545(2) Å) and P(1)−O(4) (1.584(2) Å)
bonds are longer than the typical P−O bond in
NaHPO3NH2 (1.51 Å)[17]. The oxygen atoms (O(2),
O(3) and O(4)) have sp2 hybridization character, and
the P(1)−O(4)−C(3), P(1)−O(3)−C(19) and P(1)−
O(2)−C(16) bond angles are 121.65(18), 120.0(2)
and 120.1(2)o, respectively. The torsion angle of
C(9)−C(8)−C(10)−C(11) is −133.4(3)o, which shows
rings B (C(10)−C(11)−C(12)−C(13)−C(14)−C(15))
and C (O(5)−C(5)−C(6)−C(7)−C(8)−C(9)) are not
coplanar. Furthermore, the C(2)−C(1)−C(6)−C(7)
and C(6)−C(5)−O(5)−C(9) torsion angles are
−176.4(2) and 3.0(4)o, respectively, so rings A
(C(1)−C(2)−C(3)−C(4)−C(5)−C(6)) and C are not
absolute planes.
In the crystal of 2 (Fig. 2), an intramolecular hydrogen bond can be observed between the hydroxyl
Table 3.
Struct.
Chem.
1679
group and the oxygen atom of carbonyl group:
O(6)−H(7)···O(7)=C(7) 1.78(4) Å. Furthermore, the
hydroxyl group at the 4΄ position of genistein forms
an intermolecular hydrogen bond with the phosphoryl group of the neighboring molecule: O(8)−
H(8)···O(1) 1.85(4) Å. The parameters of primary
hydrogen bonds are listed in Table 3. Hence, a
centrosymmetric dimmer unit is constructed by the
intermolecular hydrogen bond. Interestingly, relatively shorter centroid-to-centroid distance (Table 4)
between the rings (Cg(1) --> Cg(1)) from adjacent
molecules is also observed, implying the existence
of π-π stacking interaction in the compound. The
intramolecular and intermolecular hydrogen bonds
together with π-π stacking interaction play important
roles in stabilizing the structure.
Hydrogen Bonding Geometry in the Crystal of 2
D–H···A
d(D–H) (Å)
d(H···A) (Å)
d(D···A) (Å)
D–H···A (o)
O(6)–H(7)···O(7)
0.86(4)
1.78(4)
2.587(3)
156(4)
O(8)–H(8)···O(1)a
0.86(4)
1.85(4)
2.707(3)
177(4)
Symmetry code: a: –x, –y, –z
Table 4.
Parameters Between the Planes
Cg(I) --> Cg(J)
Distance between ring
Dihedral angle (°)
Perpendicular distance
Perpendicular distance
Cg(1) --> Cg(1)
4.103
0.000
3.466
3.466
Cg(1): O(5) --> C(1) --> C(2) --> C(3) --> C(4) --> C(5) --> C(6) --> C(7) --> C(8) --> C(9)
REFERENCES
(1)
Chacko, B. K.; Chandler, R. T.; Mundhekar, A.; Khoo, N.; Pruitt, H. M.; Kucik, D. F.; Parks, D. A.; Kevil, C. G.; Barnes, S.; Patel, R. P. Am. J.
Physiol. 2005, 289, H908–H915.
(2)
Wang, X. Y.; Clubbs, E. A.; Bomser, J. A. J. Nutr. Biochem. 2006, 17, 204–210.
(3)
Record, I. R.; Dreosti, I. E.; McInerney, J. K. J. Nutr. Biochem. 1995, 6, 481–485.
(4)
Mayr, G. W.; Windhorst, S.; Hillemeier, K. J. Biol. Chem. 2005, 280, 13229–13240.
(5)
Mastuda, H.; Morikawa, T.; Ueda, K.; Managi, H.; Yoshikawa, M. Bioorg. Med. Chem. 2002, 10, 3123–3128.
(6)
Ralph, S. J.; Wines, B. D.; Payne, M. J.; Grubb, D.; Hatzinisiriou, I.; Linnane, A. W.; Devenish, R. J. J. Immunol. 1995, 154, 2248–2256.
(7)
Ulanowska, K.; Tkaczyk, A.; Konopa, G.; Wegrayn, G. Arch. Microbiol. 2006, 184, 271–278.
(8)
Zhang, L. N.; Cao, P.; Tan, S. H.; Gu, W.; Shi, L.; Zhu, H. L. Eur. J. Med. Chem. 2008, 43, 1543–1551.
(9)
Kousidou, O. C.; Tzanakakis, G. N.; Karamanos, N. K. Mini.-Rev. Med. Chem. 2006, 6, 331–337.
(10)
Zhang, L. N.; Shi, L.; Fang, R. Q.; Zhu, H. L. Chinese J. Struct. Chem. 2008, 27, 200–204.
(11)
Yuan, J. W.; Chen, X. L.; Qu, L. B.; Qu, Z. B.; Zhou, Y. D.; Zhao, Y. F. J. Chin. Chem. Soc. 2009, 56, 51–58.
(12)
Zhang, T.; Chen, X. L.; Qu, L. B.; Wu, J. L.; Cui, R.; Zhao, Y. F. Bioorg. Med. Chem. 2004, 12, 6097–6105.
(13)
Sheldrick, G. M. SHELXS-97, Program for the Solution of Crystal Structure, University of Göttingen, Germany 1997.
(14)
Sheldrick, G. M. SHELXL-97, Program for the Crystal Structure Solution and Refinement, University of Göttingen, Germany 1997.
(15)
Gholivand, K.; Della Védova, C. O.; Erben, M. F.; Mahzouni, H. R.; Shariatinia, Z.; Amiri, S. J. Mol. Struct. 2008, 874, 178–186.
(16)
Yuan, J. W.; Chen, X. L.; Qu, L. B.; Zhu, Y.; Huang, X. Y.; Zhao, Y. F. Chinese J. Struct. Chem. 2009, 28, 498–502.
(17)
Hobbs, E.; Corbridge, D. E. C.; Raistrick, B. Acta Cryst. 1953, 6, 621–626.