Synthesis of the novel phosphoramidate derivatives of Chrysin

Article abstract of DOI:10.1080/10426500902772858

A novel type of phosphoramidate derivatives of chrysin were synthesized by a facile phosphorylation reaction. The structures of all the newly synthesized chrysin derivatives were confirmed by ESI MS, HR MS, NMR, and IR.

Full text of DOI:10.1080/10426500902772858

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Phosphorus, Sulfur, and Silicon and the
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Synthesis of the Novel Phosphoramidate
Derivatives of Chrysin
Xiaolan Chen a , Jinwei Yuan a , Shouren Zhang a , Lingbo Qu a b
Yufen Zhao a c
a Key Laboratory of Organic Chemistry and Chemical Biology,
&
Henan Province, Department of Chemistry , Zhengzhou University ,
Zhengzhou, P. R. China
b Henan University of Technology, Henan Province , Zhengzhou, P. R.
China
c Key Laboratory for Bioorganic Phosphorus Chemistry and Chemical
Biology, Ministry of Education, Department of Chemistry, School of
Life Sciences and Engineering , Tsinghua University , Beijing, P. R.
China
Published online: 03 Feb 2010.
To cite this article: Xiaolan Chen , Jinwei Yuan , Shouren Zhang , Lingbo Qu & Yufen Zhao (2010)
Synthesis of the Novel Phosphoramidate Derivatives of Chrysin, Phosphorus, Sulfur, and Silicon and the
Related Elements, 185:2, 274-278
To link to this article: http://dx.doi.org/10.1080/10426500902772858
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Phosphorus, Sulfur, and Silicon, 185:274–278, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500902772858
SYNTHESIS OF THE NOVEL PHOSPHORAMIDATE
DERIVATIVES OF CHRYSIN
Xiaolan Chen,1 Jinwei Yuan,1 Shouren Zhang,1 Lingbo Qu,1,2
and Yufen Zhao1,3
1Key Laboratory of Organic Chemistry and Chemical Biology, Henan Province,
Department of Chemistry, Zhengzhou University, Zhengzhou, P. R. China
2Henan University of Technology, Henan Province, Zhengzhou, P. R. China
3Key Laboratory for Bioorganic Phosphorus Chemistry and Chemical Biology,
Ministry of Education, Department of Chemistry, School of Life Sciences and
Engineering, Tsinghua University, Beijing, P. R. China
A novel type of phosphoramidate derivatives of chrysin were synthesized by a facile phos-
phorylation reaction. The structures of all the newly synthesized chrysin derivatives were
confirmed by ESI MS, HR MS, NMR, and IR.
Keywords 5,7-Dihydroxyflavone; phosphoramidates; phosphorylation
INTRODUCTION
5,7-Dihydroxyflavone (chrysin), extensively distributed in plants, has been reported
to have many biological activities, including antioxidant, antibacterial, anticancer, anti-
inflammatory, anti-allergenic, and anxiolytic antivities.1–6 Efforts to improve the biological
activity of chrysin have led to the development of its derivatives by appropriate modification
of chrysin as mentioned in some previously published articles.7,8 The introduction of
a phosphate group essentially changes the physical and chemical properties of the parent
molecule, resulting in changes to the polarization and intermolecular bonding characteristics
of that molecule.9–11 Moreover, phosphates and phosphoramidates were widely used as
pro-drug moieties to enhance water solubility and have proven to be exceedingly important
agents for anticancer and antiviral therapy.12–17
Given the importance of this functional group to these properties and potential bi-
ological activities, arylalkoxy-amino acid phosphorochloridates are coupled with chrysin
to provide the target compounds, aryl phosphoramidates of chrysin, in order to change the
physical and chemical properties of the parent molecule and enhance its bio-availability. A
novel type of phosphoramidate derivatives of chrysin was synthesized by a facile phospho-
rylated reaction (Scheme 1) for the first time. The structures of all the newly synthesized
chrysin derivatives were elucidated by ESI MS, HR MS, NMR, and IR.
Received 18 September 2008; accepted 21 January 2009.
Address correspondence to Xiaolan Chen and Lingbo Qu, Key Laboratory of Organic Chemistry and
Chemical Biology, Henan Province, Department of Chemistry, Zhengzhou University, Zhengzhou, 450052, P. R.
China. E-mail: chenxl@zzu.edu.cn
274

PHOSPHORAMIDATE DERIVATIVES OF CHRYSIN
275
R2
O
P
O
POCl3
-78
HCl NH2CHCOOR1
NEt3, -78
OH
Cl
O
P
Cl
O
NEt3,
NHCHCOOR1
Cl
R2
2a-e
1
O
H
C
R2
O
C
OR1
HO
O
O
3'
2''
6''
3''
2'
NH
4'
5'
1
O
8
P
O
4''
9
2
OH
3
1"
7
6
O
6'
5''
4
5
NEt3, r.t.
3
10
O
OH
4a-e
2, 4
R1
a
b
C
d
e
C2H5
CH3
CH3
C2H5
CH3
H
C2H5
H
R2
CH2CH(CH3)2 CH2CH(CH3)2
Scheme 1 Synthesis of phosphoramidates of chrysin.
RESULTS AND DISCUSSION
In the synthesis of phosphoramidate derivatives of chrysin (4) (Scheme 1), phenol
was first reacted with phosphorus oxychloride at low temperature in the presence of triethy-
lamine to give phenyl dichlorophosphates (1). Then phenyl dichlorophosphates (1) were
coupled to different L-amino acid ester hydrochloride salts to achieve phenyl aminophos-
phorochloridates (2), which were not further purified by chromatography. Chrysin (3)
was reacted with phenyl aminophosphorochloridates (2) in THF to form phosphoramidate
derivatives of chrysin (4) in the presence of triethylamine at room temperature. The struc-
tures of all the newly synthesized chrysin derivatives were confirmed by ESI MS, HR MS,
NMR, and IR.
Phenyl aminophosphorochloridates (2) could react at two different reaction positions
(7-OH and 5-OH) of chrysin (3). The results showed that the phosphorylation occurred
chemselectively only at the 7-OH of chrysin and not at 5-OH. This conclusion was confirmed
by the 13C NMR of compound 4d. For example, 13C NMR of compound 4d showed that the
signals from 7-C at δ 155.83 (J = 6.3), 6-C at δ 104.01 (J = 6.4), and 8-C at δ 99.36 (J =
4.6) were split into doublets by the single phosphorus atom nearby, respectively. Whereas,
the singles from 5-C at δ 162.17 and 10-C at δ 108.43 were not split, and only a singlet was
observed. These facts explain that the phosphorylation proceeds chemselectively favoring
attack at 7-OH of chrysin. The reason why the phosphorylation occurred at the 7-OH of
chrysin may be due to the hydrogen bonding of 5-OH group with the carbonyl group.
Due to the stereochemistry at the chiral phosphorus center, the products 4a–4c were
isolated as mixtures of diastereoisomers, which were not easily separated by column chro-
matography, but are readily distinguished by 31P NMR. These diastereoisomers displayed

276
X. CHEN ET AL.
two closely spaced signals by 31P NMR (e.g., 4a, δ −2.98, −3.00). Moreover, the presence
of phosphate diastereoisomers was also apparent in the 1H NMR and 13C NMR spectra.
EXPERIMENTAL
All experiments involving water-sensitive compounds were conducted under scrupu-
lously dry conditions. The solvents were dried by appropriate methods. IR spectra were
recorded on a Shimadazu IR-408. 1H, 13C, and 31P NMR spectra were recorded on a Bruker
Avance DPX spectrometer operating at 400.13, 100.61, and 161.98 MHz, respectively,
with 13C and 31P spectra being recorded proton-decoupled. All NMR spectra were recorded
1
in CDCl3 at room temperature (20◦C 3◦C). H and 13C chemical shifts are quoted in
parts per million downfield from TMS. 31P chemical shifts are quoted in parts per million
relative to an external 85% H3PO4 standard. J values refer to coupling constants, and signal
splitting patterns are described as singlet (s), broad singlet (bs), doublet (d), triplet (t),
quartet (q), multiplet (m), or combinations thereof. TLC was performed on silica gel plates
and preparative chromatograph on columns of silica gel (200–300 mesh). HR MS were
recorded on Q-Tof Micro.
General Procedure for the Synthesis of Phosphoramidates of Chrysin
A solutionofphenol(50.0g, 0.53mol)inphosphorus oxychloride(48.7mL, 0.53mol)
and anhydrous diethylether (200 mL) was stirred at −78◦C. Anhydrous triethylamine (76
mL, 0.54 mol) was added dropwise to this solution for 30 min. The reaction mixture
was then allowed to warm up to room temperature and stirred for 16 h. The precipitated
triethylamine hydrochloride salt was filtered off, and the filtrate was evaporated to dryness
under reduced pressure. The crude product of phosphorodichloridate (1) was obtained as a
clear liquid.18
Phosphodichloridate (1) (1.05 g, 5.0 mmol) and the appropriate amino acid esters
hydrochloric salt (5.0 mmol) were suspended in anhydrous dichloromethane. Anhydrous
triethylamine was added dropwise at −78◦C during 1 h, and then the reaction was left to
warm to room temperature. After 5 h, the solvent was removed under reduced pressure, and
the residue was washed with anhydrous ether and was filtered. The filtrate was evaporated
to dryness under reduced pressure. The crude phosphochloridate (2) was obtained and used
without further purification by the chromatography.18
Anhydrous triethylamine was added dropwise to a solution of the appropriate phos-
phorochloridate (2) (0.02–0.03 mol) and chrysin (3) (2.54 g, 0.01 mol) in anhydrous
tetrahydrofuran at room temperature, and the reaction mixture was stirred for 6–10 h. The
precipitated triethylamine hydrochloride salt was filtered off, and the filtrate was evapo-
rated to dryness under reduced pressure. The crude product (4) was purified by column
chromatography on silica gel (CH2Cl2/ CH3OH = 1:10).
1
Compound 4a (C26H24NO8P). Yield (56%); mp 157–158◦C. H NMR (400.13
MHz, CDCl3) δ: 12.74, 12.73 (s, 1H, 5-H), 7.88–7.86 (m, 2H, 2ꢁ,6ꢁ-H), 7.57–7.49 (m,
3H, C-3ꢁ, 4ꢁ, 5ꢁ), 7.38–7.18 (m, 5H, H-2ꢁꢁ, 3ꢁꢁ, 4ꢁꢁ, 5ꢁꢁ, 6ꢁꢁ), 7.05 (s, 1H, 8-H), 6.71 (s, 1H,
3-H), 6.66, 6.63 (d, 1H, J = 2.0, 6-H), 4.20–4.11 (m, 3H, OCH2, CH-NH), 4.09–4.03
(m, 1H, NH), 1.43, 1.42 (d, 3H, J = 2.2, CH3-CH), 1.27–1.23 (m, 3H, OCH2CH3). 13C
NMR (100.61 MHz, CDCl3) δ: 182.74 (C-4), 173.01 (d, J = 8.0, C O), 164.67, 164.65
(C-2), 162.15, 162.12 (C-5), 157.02 (C-9), 156.01, 155.93 (d, J = 6.5, C-7), 150.41, 150.34

PHOSPHORAMIDATE DERIVATIVES OF CHRYSIN
277
(d, J = 6.2, C-1ꢁꢁ), 132.15 (C-3ꢁ, 5ꢁ), 130.87 (C-1ꢁ), 129.83 (C-3ꢁꢁ, 5ꢁꢁ), 129.14 (C-4ꢁ),
126.40 (C-2ꢁ, 6ꢁ), 125.39 (C-4ꢁꢁ), 120.18, 120.13 (d, J = 4.7, C-2ꢁꢁ, 6ꢁꢁ), 108.34 (C-10),
106.03 (C-3), 104.05, 104.00 (d, J = 3.7, C-6), 99.37, 99.28 (d, J = 4.6, C-8). 61.79,
61.77 (OCH2), 50.49 (CH-NH), 21.00 (CH3), 14.07 (OCH2CH3). 31P NMR (CDCl3) δ:
−2.98, −3.00. IR(KBr) νmax(cm−1): 1257 (P O), 3200 (NH). ESI MS m/z: 532 [M +
Na]+. A molecular formula of C26H24NO8P was determined from the molecular ion peak
at 510.1318 m/z [M + H]+ (calc. 510.1318 for C26H24NO8PH) obtained by HR MS.
1
Compound 4b (C28H28NO8P). Yield (59%); mp 149–150◦C. H NMR (400.13
MHz, CDCl3) δ: 12.77 (s, 1H, 5-H), 7.83 (d, 2H, J = 7.4, 2ꢁ, 6ꢁ-H), 7.52–7.45 (m, 3H, C-3ꢁ,
4ꢁ, 5ꢁ), 7.37–7.27 (m, 4H, H-2ꢁꢁ, 3ꢁꢁ, 5ꢁꢁ, 6ꢁꢁ), 7.20–7.16 (m, 1H, H-4ꢁꢁ), 7.05 (s, 1H, 8-H),
6.70 (s, 1H, 3-H), 6.67, 6.62 (d, 1H, J = 2.0, 6-H), 4.38–4.33 (m, 1H, NH), 4.14–4.08
(m, 1H, NH CH), 3.68, 3.65 (s, 3H, OCH3), 1.73–1.65 (m, 1H, CH-(CH3)2), 1.65–1.52
(m, 2H, CH2 CH (CH3)2), 0.90, 0.88 (d, 6H, J = 3.7, CH-(CH3)2). 13C NMR (100.61
MHz, CDCl3) δ: 182.69, 182.69 (C-4), 173.75, 173.69 (d, J = 4.0, C O), 164.56, 164.54
(C-2), 162.05, 162.02 (C-5), 156.93 (C-9), 156.09, 156.04 (d, J = 3.7, C-7), 150.49, 150.43
(C-1ꢁꢁ), 132.12 (C-3ꢁ, 5ꢁ), 130.73 (C-1ꢁ), 129.75, 129.80 (C-3ꢁꢁ, 5ꢁꢁ), 129.09 (C-4ꢁ), 126.32
(C-2ꢁ, 6ꢁ), 125.30 (C-4ꢁꢁ), 120.18, 120.09 (d, J = 5.0, C-2ꢁꢁ, 6ꢁꢁ), 108.21 (C-10), 105.90
(C-3), 104.02, 103.95 (C-6), 99.34, 99.27 (d, J = 4.5, C-8), 53.38, 53.35 (NH-CH), 52.33,
52.28 (OCH3), 43.57, 43.51 (d, J = 1.3, CH2-CH-(CH3)2), 24.35, 24.28 (CH-(CH3)2),
22.68, 21.75 (CH (CH3)2). 31P NMR (CDCl3) δ: −2.23, −2.41. IR(KBr) νmax(cm−1):
1253(P O), 3184(NH). ESI MS: m/z: 538[M + H]+, 1097[2M + Na]+. A molecular
formula of C28H28NO8P was determined from the molecular ion peak at 538.1639 m/z [M
+ H]+ (calc.538.1631 for C28H28NO8PH) obtained by HR MS.
1
Compound 4c (C29H30NO8P). Yield (54%); mp 129–130◦C. H NMR (400.13
MHz, CDCl3) δ: 12.71, 12.71 (s, 1H, 5-H), 7.83 (d, 2H, J = 7.0, 2ꢁ, 6ꢁ-H), 7.52–7.45 (m, 3H,
C-3ꢁ, 4ꢁ, 5ꢁ), 7.36–7.27 (m, 4H, 3ꢁꢁ, 2ꢁꢁ, 5ꢁꢁ, 6ꢁꢁ-H), 7.20–7.18 (m, 1H, 4ꢁꢁ-H), 7.05 (d, 1H, J =
1.36, 8-H), 6.70 (s, 1H, 3-H), 6.67, 6.63 (d, 1H, J = 1.68, 6-H), 4.30 (d, 1H, J = 3.7, NH),
4.15–4.08 (m, 3H, NH CH, OCH2), 1.59–1.53 (m, 2H, CH2 CH (CH3)2), 1.26–1.19
(m, 3H, OCH2CH3), 0.91, 0.89 (d, 6H, J = 4.0, CH-(CH3)2). 13C NMR (100.61 MHz,
CDCl3) δ: 182.7 (C-4), 173.3, 173.2 (d, J = 4.1, C O), 164.5 (C-2), 162.1, 162.0 (C-5),
156.9(C-9), 156.1 (d, J = 6, C-7), 150.5 (d, J = 1.7, C-1ꢁꢁ), 132.1 (C-3ꢁ, 5ꢁ), 130.8 (C-1ꢁ),
129.8, 129.7 (C-3ꢁꢁ, 5ꢁꢁ), 129.1 (C-4ꢁ), 126.3 (C-2ꢁ, 6ꢁ), 125.3 (C-4ꢁꢁ), 120.2, 120.1 (d, J =
5.0, C-2ꢁꢁ, 6ꢁꢁ), 108.2 (C-10), 105.9 (C-3), 104.1, 103.1 (d, J = 3.4, C-6), 99.4, 99.3 (d, J =
4.5, C-8), 61.4, 61.5 (OCH2), 53.5, 53.4 (NH CH), 43.7, 43.6 (CH2 CH (CH3)2), 24.4,
24.3 (CH (CH3)2), 22.7, 21.8 (C CH (CH3)2). 31P NMR (CDCl3) δ: −2.16, −2.34.
IR(KBr) νmax(cm−1): 1252 (P O), 3188 (NH). ESI MS m/z: 574 [M + Na]+, 1125 [2M +
Na]+. A molecular formula of C28H28NO8P was determined from the molecular ion peak
at 552.1782 m/z [M + H]+ (calc. 552.1787 for C29H30NO8PH) obtained by HR MS.
1
Compound 4d (C24H20NO8P). Yield (58%); mp 156–157◦C. H NMR (400.13
MHz, CDCl3) δ: 12.75 (s, 1H, 5-H), 7.88–7.86 (m, 2H, 2ꢁ, 6ꢁ-H), 7.56–7.50 (m, 3H, C-3ꢁ,
4ꢁ, 5ꢁ), 7.39–7.26 (m, 4H, H-2ꢁꢁ, 3ꢁꢁ, 5ꢁꢁ, 6ꢁꢁ), 7.23–7.19 (m, 1H, H-4ꢁꢁ), 7.06, 7.06 (d d, 1H,
J = 2.1, J = 1.0, 8-H), 6.71 (s, 1H, 3-H), 6.66, 6.65 (d d, 1H, J = 2.0, J = 0.6, 6-H),
3.92 (d, 2H, J = 9.8, CH2-NH), 3.75 (s, 3H, OCH3). 13C NMR (100.61 MHz, CDCl3) δ:
182.76 (C-4), 170.40 (d, J = 9.0, C O), 164.71 (C-2), 162.17 (C-5), 157.05 (C-9), 155.83
(d, J = 6.3, C-7), 150.28 (d, J = 7.0, C-1ꢁꢁ), 132.19 (C-3ꢁ, 5ꢁ), 130.84 (C-1ꢁ), 129.91 (C-2ꢁꢁ,
6ꢁꢁ), 129.16 (C-4ꢁ), 126.42 (C-2ꢁ, 6ꢁ), 125.51 (C-4ꢁꢁ), 120.14 (d, J = 4.7, C-3ꢁꢁ, 5ꢁꢁ), 108.43
(C-10), 106.04 (C-3), 104.01 (d, J = 6.4, C-6), 99.36 (d, J = 4.6, C-8). 52.65 (OCH3), 42.98

278
X. CHEN ET AL.
(CH2-NH). 31P NMR (CDCl3) δ: -2.77. IR(KBr) νmax(cm−1): 1252 (P O), 3220 (NH). ESI
MS: m/z: 504.0[M + Na]+. A molecular formula of C24H20NO8P was determined from
the molecular ion peak at 482.1008 m/z [M + H]+ (calc. 482.1005 for C24H20NO8PH)
obtained by HR MS.
1
Compound 4e (C25H22NO8P). Yield (56%); mp 139–140◦C. H NMR (400.13
MHz, CDCl3) δ: 12.75 (s, 1H, 5-H), 7.88 (d, 2H, J = 6.9, 2ꢁ, 6ꢁ-H), 7.57–7.51 (m, 3H, H-3ꢁ,
4ꢁ, 5ꢁ), 7.39–7.19 (m, 4H, H-2ꢁꢁ, 3ꢁꢁ, 5ꢁꢁ, 6ꢁꢁ), 7.07 (d, 1H, J = 0.92, 8-H), 6.72 (s, 1H, 3-H),
6.66 (s, 1H, 6-H), 4.24–4.19 (m, 1H, CH2 NH), 4.09 (d, 2H, J = 6.7, CH2 NH), 3.89
(d d, 2H, J = 9.2, 5.7, OCH2), 1.27 (t, 3H, J = 7.2, CH3). 13C NMR (100.61 MHz, CDCl3)
δ: 182.77 (C-4), 170.00 (d, J = 7.9, C O), 164.73 (C-2), 162.21 (C-5), 157.08 (C-9),
155.95 (d, J = 6.1, C-7), 132.19 (C-3ꢁ, 5ꢁ), 130.90 (C-1ꢁ), 129.80 (C-2ꢁꢁ, 6ꢁꢁ), 129.17 (C-4ꢁ),
126.43 (C-2ꢁ, 6ꢁ), 125.49 (C-4ꢁꢁ), 120.15 (d, J = 5.0, C-3ꢁꢁ, 5ꢁꢁ), 108.46 (C-10), 106.08
(C-3), 104.02 (d, J = 6.6, C-6), 99.36 (d, J = 4.6, C-8), 61.93 (OCH2), 43.13 (CH2-NH),
14.12 (CH3). 31P NMR (CDCl3) δ: −2.42. IR(KBr) νmax(cm−1): 1252 (P O), 3194 (NH).
ESI MS: m/z: 496 [M + H]+, 518 [M + Na]+. A molecular formula of C25H22NO8P was
determined from the molecular ion peak at 496.1163 m/z [M + H]+ (calc. 496.1161 for
C25H22NO8PH) obtained by HR MS.
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