Synthesis of phosphoryl amino acids chrysin esters

Article abstract of DOI:10.1080/10426500701793204

The N-phosphoryl amino acids are coupled with chrysin to form phosphoryl amino acids chrysin esters. Five of its new analogs have been synthesized. The structures of all the newly synthesized chrysin derivatives were confirmed by ESI-MS, NMR and IR. Copyr

Full text of DOI:10.1080/10426500701793204

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Phosphorus, Sulfur, and Silicon
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Synthesis of Phosphoryl Amino
Acids Chrysin Esters
Xiaolan Chen a , Lingbo Qu a b , Wenfeng Li c , Jinwei
Yuan a & Yufen Zhao a
a Department of Chemistry , Zhengzhou University ,
Zhengzhou, P. R. China
b Henan University of Technology , Henan Province,
Zhengzhou, P. R. China
c Institute of Chemistry , Academy of Science of
Henan Province , Zhengzhou, P. R. China
Published online: 20 Jun 2008.
To cite this article: Xiaolan Chen , Lingbo Qu , Wenfeng Li , Jinwei Yuan & Yufen Zhao
(2008) Synthesis of Phosphoryl Amino Acids Chrysin Esters, Phosphorus, Sulfur, and
Silicon and the Related Elements, 183:2-3, 603-609, DOI: 10.1080/10426500701793204
To link to this article: http://dx.doi.org/10.1080/10426500701793204
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Phosphorus, Sulfur, and Silicon, 183:603–609, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701793204
Synthesis of Phosphoryl Amino Acids Chrysin Esters
Xiaolan Chen,1 Lingbo Qu,2,1 Wenfeng Li,3 Jinwei Yuan,1
and Yufen Zhao1
1Department of Chemistry, Zhengzhou University, Zhengzhou,
P. R. China
2Henan University of Technology, Henan Province, Zhengzhou,
P. R. China
3Institute of Chemistry, Academy of Science of Henan Province,
Zhengzhou, P. R. China
The N-phosphoryl amino acids are coupled with chrysin to form phosphoryl amino
acids chrysin esters. Five of its new analogs have been synthesized. The structures
of all the newly synthesized chrysin derivatives were confirmed by ESI-MS, NMR
and IR.
Keywords 5,7-dihydroxyflavone; N-phosphoamino acids; phosphoryl amino acids
chrysin esters
INTRODUCTION
Chrysin, 5,7-dihydroxyflavone, extensively distributed in plants,was
reported to have many biological activities, including antioxidant,1
antibacterial,2 anticancery,3 anti-inflammatory,4 antiallergic,5 and
anxiolytic6 antivities. Though chrysin has extensively pharmaceutical
values in clinics, there are still some flaws to confine its pharmaceutical
application, for example, low solubility. Efforts to improve the biolog-
ical activity of chrysin have led to the development of its derivatives
by appropriate modification of chrysin as mentioned in some published
papers. Ester and amides of phosphoric acid play a vital role in many
biological process and could be hydrolyzed into the parents compound
in living organism. The studies from C.B. Xue, H. Fu, and C.X. Lin
indicate that N-phosphoamino acids are important to explain some liv-
ing phenomena and probe into living origin, e.g., N-phospho-α-amino
The authors thank the Chinese National Natural Science Foundation (No. 20472076)
and Henan Excellent Youth Grant (No. 0512001400).
Address correspondence to Xiaolan Chen, Department of Chemistry, Zhengzhou Uni-
versity, Zhengzhou 450052 P. R. China. E-mail:chenxl@zzu.edu.cn
603

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X. L. Chen et al.
acids could self-activated to give N-phosphoryl peptides, N-phospho-
α-amino acid esters, ester-exchanged products on phosphorus, and an
intramolecular phosphoryl group migration from nitrogen to oxygen,
which suggest that N-phosphoamino acids might be prebiotic precur-
sors of oligopeptides. At the same time, they have application fore-
ground in the fields of biology technology, medicine and so on.7−9 Within
the pharmaceutical industry, phosphate esters are often used as pro-
drugs to increase the water solubility and hence bio-availability of the
agent.10 In the work described in this article, N-phosphoamino acids
were introduced to modification of crysin. The N-phosphated amino
acids are coupled with chrysin to form phosphoryl amino acids chrysin
esters. Five chrysin new analogs were synthesized. The structures of all
the newly synthesized chrysin derivatives were elucidated by ESI-MS
(Scheme 2), NMR, and IR.
EXPERIMENTAL
IR spectra were recorded on a Shimadazuir-408 1H and 31P NMR
spectra were on a Bruker-DTX-400. Chemical shifts are expressed in
parts per million positive values downfield form internal TMS (1H) and
externa 85% H3PO4(31P). Coupling constants are expressed in Hertz.
TLC was performed on silica gel plates and preparative chromatograph
on columns of silica gel (200–300 mesh). MS were recorded on Bruker
Esquire-3000.
SCHEME 1

Phosphoryl Amino Acids
605
Compound P1. C24H28NO8P
0.5404 g chrysin and 0.5398 g N-phosphoryl L-Alanine were added to a
solution of 40 ml THF. The mixture was stirred until chrysin was dis-
solved and then a solution of DCC and DMAP (0.5936 g DCC + 0.0530 g
DMAP) was added with vigorous stirring in ice-water bath. The reaction
proceeded for 12 h at 5–10◦C. The solution was removed by distillation.
The product was further purified by column chromatography (ethyl ac-
etate:petroleum ether:ethanol = 50:40:1). The yield of yellow product
1
is 62%. m.p. 155–156◦C. H NMR (400 MHz, DMSO) δ: 8.10 (d, 2H,
J = 7.40, 2ꢀ-H, 6ꢀ-H), 7.62 (m, 3H, 3ꢀ-H, 4ꢀ-H, 5ꢀ-H), 7.13 (s, 1H, 3-H),
7.09 (d, 1H, J = 1.1, 6-H), 6.60 (s, 1H, J = 1.2, 8-H), 4.51 (m, 2H, 2ꢀꢀꢀ-H),
4.05 (m, 1H, 2ꢀꢀ-H), 2.53 (1H, N-H), 1.47 (m, 3H, 1ꢀꢀ-H), 1.28 (m, 12H,
1ꢀꢀꢀ-H). 13C NMR δ: 182.82 (s, 1C, 4-C), 172.21 (s, 1C, 3ꢀꢀ-C), 164.57 (s, 1C,
5-C), 160.88 (s, 1C, 2-C), 156.69 (s, 1C, 9-C), 156.22 (s, 1C, 7-C), 132.80
(s, 1C, 1ꢀ-C), 130.63 (s, 2C, 3ꢀ-C, 5ꢀ-C), 129.57 (s, 1C, 4ꢀ-C), 126.83 (d, 2C,
J = 98,2ꢀ-C, 6ꢀ-C), 108.66 (s, 1C, 10-C), 106.11 (s, 1C, 6-C), 105.31 (s, 1C,
3-C), 101.84 (s, 1C, 8-C), 70.34 (m, 1C, 2ꢀꢀꢀ-C), 50.68 (s, C, 2ꢀꢀ-C), 23.89 (d,
1C, J = 17.6, 1ꢀꢀꢀ-C), 19.67 (d, 1C, J = 26.4, 1ꢀꢀ-C). 31P NMR (400 MHz,
D2O): δ: 6.243. ESI-MS/MS: m/z: 490[M + H]+, 978 [2M], 1001 [2M
+ Na]+. IR 1265 (PO). A molecular formula of C24H28NO8P was de-
termined from the molecular ion peak at 490.1639.1130 m/z [M+H]+
(calcd. 490.1631 for C24H28NO8P ) obtained by ESIQ-TOF.
Compound P2. C26H32NO8P
0.4678 g chrysin and 0.5895 g phosphoryl L-valine was added to a solu-
tion of 40 ml THF. The mixture was stirred until chrysin was dissolved
and then a solution of DCC and DMAP (0.5216 g DCC + 0.0568 g DMAP)
was added dropwise with vigorous stirring in ice-water bath. The reac-
tion proceeded for 12 h at 5–10◦C. The solution was removed by distilla-
tion. The product was further purified by column chromatography (ethyl
acetate:petroleum ester:ethanol = 50:40:1). The yield of yellow prod-
1
uct is 60%. m.p. 176–178. H NMR (400 MHz, DMSO): δ: 8.14 (d, 2H,
J = 7.20, 2ꢀ-H, 6ꢀ-H), 7.62 (m, 3H, 3ꢀ-H, 4ꢀ-H, 5ꢀ-H), 7.16 (s, 1H, 3-H),
7.09 (d, 1H, J = 0.8, 6-H), 6.60 (s, 1H, 8-H), 4.49 (m, 2H, 2ꢀꢀꢀ-H), 3.67 (m,
1H, 3ꢀꢀ-H), 2.52 (1H, N-H), 2.13 (m, 1H, 2ꢀꢀ-H), 1.24 (m, 12H, 1ꢀꢀꢀ-H),
1.03 (m, 6H, 1ꢀꢀ-H). 13C NMR δ:182.84 (s, 1C, 4-C), 171.30 (s, 1C, 4ꢀꢀ-C),
164.57 (s, 1C, 5-C), 160.87 (s, 1C, 2-C), 156.73 (s, 1C, 9-C), 155.93 (s,
1C, 7-C), 132.82 (s, 1C, 1ꢀ-C), 130.63 (s, 2C, 3ꢀ-C, 5ꢀ-C), 129.55 (s, 1C,
4ꢀ-C), 126.99 (d, 2C, J = 98, 2ꢀ-C, 6ꢀ-C), 108.72 (s, 1C, 10-C), 106.13 (s,
1C, 6-C), 105.12 (s, 1C, 3-C), 101.82 (s, 1C, 8-C), 70.45 (d, 1C, J = 55.6,
2ꢀꢀꢀ-C), 60.91 (s, 1C, 3ꢀꢀ-C), 31.53 (s, 1C, 2ꢀꢀ-C), 19.05 (d, 1C, J = 27,

606
X. L. Chen et al.
1ꢀꢀ-C).31P NMR (400 MHz, D2O): δ 7.01. ESI-MS/MS: m/z: 518 [M+H]+,
1057 [2M+Na]+. IR 1266 (PO). A molecular formula of C26H32NO8P
was determined from the molecular ion peak at 518.1940 m/z [M+H]+
(calcd. 518.1944 for C26H32NO8P) obtained by ESI-Q-TOF.
Compound P3. C27H34NO8P
0.6202 g chrysin and 0.6649 g phosphoryl L-leucine was added to a
solution 40 ml THF. The mixture was stirred until chrysin was dis-
solved and then a solution of DCC and DMAP (0.5665 g DCC + 0.0593
g DMAP) was added dropwise with vigorous stirring in ice-water bath.
The reaction proceed for 12 h at 5–10◦C. The solution was removed by
distillation. The product was futher purified by comumn chromatog-
raphy (ethyl acetate:petroleum ether:ethanol = 50:40:1).The yield of
yellow productis 64%. m.p. 157–159. 1H NMR(400 MHz, DMSO) δ: 8.13
(d, 2H, J = 7.20, 2ꢀ-H, 6ꢀ-H), 7.62 (m, 3H, 3ꢀ-H, 4ꢀ-H, 5ꢀ-H), 7.14 (s, 1H,
3-H), 7.10 (d, 1H,J = 0.8, 6-H), 6.63 (d, 1H, J = 1.78, 8-H), 4.48 (m, 2H,
2ꢀꢀꢀ-H), 3.91 (m, 1H, 4ꢀꢀ-H), 2.52 (1H, N-H), 1.85 (m, 1H, 2ꢀꢀ-H), 1.68 (m,
2H, 3ꢀꢀ-H), 1.21 (m, 12H, 1ꢀꢀꢀ-H), 0.92 (m, 6H, 1ꢀꢀ-H). 13C NMR δ: 182.93
(s, 1C, 4-C), 172.34 (s, 1C, 5ꢀꢀ-C), 164.63 (s, 1C, 5-C), 160.96 (s, 1C, 2-C),
156.81 (s, 1C, 9-C), 155.19 (s, 1C, 7-C), 132.90 (s, 1C, 1ꢀ-C), 130.73 (s,
2C, 3ꢀ-C, 5ꢀ-C), 129.65 (s, 1C, 4ꢀ-C), 127.07 (s, 2C, 2ꢀ-C, 6ꢀ-C), 108.79 (s,
1C, 10-C), 106.22 (s, 1C, 6-C), 105.32 (s, 1C, 3-C), 101.93 (s, 1C, 8-C),
70.45 (m, 1C, ,2ꢀꢀꢀ-C), 53.35 (s, 1C, 4ꢀꢀ-C), 42.00 (d, 1C, J = 31.20, 3ꢀꢀ-C),
24.20 (d, 1C, J = 167.6, 1ꢀꢀꢀ-C) 23.19 (s, 2C, 1ꢀꢀ-C), 21.74 (s, 1C, 2ꢀꢀ-C). 31
P
NMR (400 MHz, D2O) δ: 6.899 . . . ESI-MS/MS: m/z: 532 [M+H]+. IR
1267 (PO). A molecular formula of C27H34NO8P was determined from
the molecular ion peak at 532.2104 m/z [M+H]+ (calc. 532.2100 for
C27H34NO8P) obtained by ESI-Q-TOF.
Compound P4. C27H34NO8P
0.5035 g chrysin and 0.6487 g phosphoryl L-isoleucine was added to
a solution 40 ml THF. The mixture was stirred until chrysin was dis-
solved and then a solution of DCC and DMAP (0.5665 g DCC + 0.0435 g
DMAP) was added dropwise with vigorous stirring in ice-water bath.
The reaction proceed for 12 h at 5–10◦C. The solution was removed
by distillation. The product was further purified by column chromatog-
raphy (ethyl acetate:petroleum ether:ethanol = 50:40:1). The yield of
1
yellow product is 63%. m.p. 158–160. H NMR (400 MHz, DMSO): δ:
8.14 (m, 2H, 2ꢀ-H, 6ꢀ-H), 7.63 (m, 3H, 3ꢀ-H, 4ꢀ-H5ꢀ-H), 7.16 (s, 1H, 3-H),
7.09 (d, 1H, J = 1.98, 6-H), 6.60 (d, 1H, J = 1.97, 8-H), 4.49 (m, 2H,
2ꢀꢀꢀ-H), 3.73 (m, 1H, 4ꢀꢀ-H), 2.52 (1H, N-H), 1.89 (m, 1H, 3ꢀꢀ-H), 1.62 (m,

Phosphoryl Amino Acids
607
2H, 2ꢀꢀ-H), 1.26 (m, 12H, 1ꢀꢀꢀ-H), 1.00 (m, 3H, 6ꢀꢀ-H), 0.92 (m, 3H, 1ꢀꢀ-H).
13C NMR δ: 182.84 (s, 1C, 4-C), 171.26 (s, 1C, 5ꢀꢀ-C), 164.57 (s, 1C, 5-C),
160.87 (s, 1C, 2-C), 156.74 (s, 1C, 9-C), 155.90 (s, 1C, 7-C), 132.82 (s,
1C, 1ꢀ-C), 130.62 (s, 2C, 3ꢀ-C, 5ꢀ-C), 129.55 (s, 1C, 4ꢀ-C), 127.00 (s, 2C,
SCHEME 2 Positive ion ESI mass spectral fragmentation pathway of proto-
nated compound P4.

608
X. L. Chen et al.
2ꢀ-C, 6ꢀ-C), 108.72 (s, 1C, 10-C), 106.13 (s, 1C, 6-C), 105.15 (s, 1C, 3-C),
101.81 (s, 1C, 8-C), 70.39 (m, 1C, 2ꢀꢀꢀ-C), 59.53 (s, 1C, 4ꢀꢀ-C), 37.86 (d, 1C,
J = 31.20, 3ꢀꢀ-C), 24.97 (s, 1C, 2ꢀꢀ-C) , 23.89 (d, 1C, J = 18.4, 1ꢀꢀꢀ-C), 15.69
(s, 1C, 6ꢀꢀ-C), 11.20 (s, 1C, 1ꢀꢀ-C). 1P NMR (400MHz, D2O) δ: 4.59 δ: 7.30.
ESI-MS/MS: m/z: 532 [M+H]+, 1062 [2M]+. IR 1267 (PO). A molecular
formula of C27H34NO8P was determined from the molecular ion peak
at 532.2103 m/z [M+H]+ (calcd. 532.2100 for C27H34NO8P) obtained by
ESI-Q-TOF.
Compound P5. C26H30NO8P
0.4715 chrysin and 0.4335 g phosphoryl L-isoleucine was added to a
solution 40 ml THF. The mixture was stirred until chrysin was dis-
solved and then a solution of DCC and DMAP (0.4821 g DCC + 0.0439
g DMAP) was added dropwise with vigorous stirring in ice-water bath.
The reaction proceed for 12 h at 5–10◦C. The solution was removed by
distillation. The product was futher purified by comumn chromatog-
raphy (ethyl acetate:petroleum ether:ethanol = 50:40:1). The yield of
1
yellow product is 63%. m.p. 163–164◦C. H NMR (400 MHz, DMSO):
8.12 (m, 2H, 6ꢀ-H, 2ꢀ-H), 7.63 (m, 3H, 3ꢀ-H, 5ꢀ-H, 4ꢀ-H), 7.14 (s. 1H, 3-H),
7.12 (d, 1H, J = 1.92, 6-H), 6.67 (d, 1H, J = 1.92, 8-H), 4.50 (m, 2H,
2ꢀꢀꢀ-H), 4.39 (d, 1H, J = 4.28, 4ꢀꢀ-H), 3.19 (m, 2H, 1ꢀꢀ-H), 2.26 (m, 2H,
3ꢀꢀ-H), 1.95 (m, 2H, 2ꢀꢀ-H), 1.26 (m, 12H, 1ꢀꢀꢀ-H). 13C NMR δ:182.94 (s,
1C, 4-C), 172.35 (s, 1C, 5ꢀꢀ-C), 164.63 (s, 1C, 5-C), 160.96 (s, 1C, 2-C),
156.76 (s, 1C, 9-C), 156.22 (s, 1C, 7-C), 132.89 (s, 1C, 1ꢀ-C), 130.72 (s, 2C,
3ꢀ-C, 5ꢀ-C), 129.65 (s, 2C, 2ꢀ-C, 6ꢀ-C), 126.93 (s, 1C, 4ꢀ-C), 108.76 (s, 1C,
10-C),106.19 (s, 1C, 6-C), 105.46 (s, 1C, 3-C), 102.01 (s, 1C, 8-C), 70.37
(m, 1C, 2ꢀꢀꢀ-C), 60.60 (d, 1C, J = 27.2 4ꢀꢀ-C), 47.22 (s, 1C, 1ꢀꢀ-C), 31.26 (d,
1C, J = 32.40, 3ꢀꢀ-C), 25.64 (d, 1C, J = 33.6, 2ꢀꢀ-C), 23.95 (m, 1C, 1ꢀꢀꢀ-C).
31P NMR (400 MHz, D2O) δ: 4.59. ESI-MS/MS: m/z: 516[M+H]+. IR
1267 (PO). A molecular formula of C17H27Cl2N2O3P was determined
from the molecular ion peak at 516.1792 m/z [M+H]+ (calc. 516.1787
for C17H27Cl2N2O3P) obtained by ESI-Q-TOF.
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