Synthesis and biological evaluation of glycosylated psoralen derivatives

Article abstract of DOI:10.1016/j.tet.2012.01.090

A novel route for the efficient synthesis of a target psoralen moiety, 4,4′-dimethylxanthotoxol, has been developed, which need only four steps using cheap pyrogallol as a starting material. Subsequently, a range of new glycosylated psoralen derivatives w

Full text of DOI:10.1016/j.tet.2012.01.090

Tetrahedron 68 (2012) 2598e2606
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Synthesis and biological evaluation of glycosylated psoralen derivatives
,
d
b
a,c,
*
Chao-Yue Chen a, Jian-Guo Sun b, Fei-Yan Liu b , Kwok-Pui Fung , Ping Wu , Zhi-Zhen Huang
*
a School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, PR China
b Research Centre of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zijinggang Campus, Zhejiang University, Hangzhou 310058, PR China
c Department of Chemistry, Zhejiang University, Hangzhou 310028, PR China
d Department of Biochemistry, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, PR China
a r t i c l e i n f o
a b s t r a c t
A novel route for the efficient synthesis of a target psoralen moiety, 4,40-dimethylxanthotoxol, has been
developed, which need only four steps using cheap pyrogallol as a starting material. Subsequently,
a range of new glycosylated psoralen derivatives were synthesized in good yields with simple procedures
and mild reaction conditions. The experiment of biological activity shows that some of the glycosylated
psoralen derivatives have antiproliferative activities against human cancer cell lines. A strong photo-
induced antiproliferative effects were found under UVA. All of the glycosylated psoralen derivatives
exhibited antioxidant activities against the oxidation of DNA induced by Cu2þ/glutathione (GSH). Further
experiment also demonstrates that the introduction of sugar moieties in some glycosylated psoralen
derivatives can improve their antioxidant activities significantly.
Article history:
Received 15 November 2011
Received in revised form 18 January 2012
Accepted 31 January 2012
Available online 3 February 2012
Keywords:
Glycosylated psoralen derivatives
Synthesis
Antiproliferative activity
Antioxidant activity
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
the substitution of glucopyranosyl bromide with xanthotoxol.19
Atal et al. prepared five glycosylated psoralen derivatives in-
Psoralen derivatives are linear furocoumarins existed widely in
plants, which have been shown to possess a wide spectrum of bi-
ological activities spanning from cytotoxic, phytotoxic, photo-
sensitizing, insecticidal, and antibacterial to antifungal effects.1,2
Furthermore, some of them have been applied medicinally for the
treatment of skin disorders, cutaneous T-cell lymphoma and au-
toimmune diseases.2e4 Recently, many new psoralen derivatives
containing sugar moieties were isolated and identified from dif-
ferent plants, some of which possess interesting biological activities
(Scheme 1).1,5e18 For example, glycosidic psoralen derivatives 1, 2,5
in which glucosidic moiety attached to 8- or 5-position of xan-
thotoxol, and feronielloside 4,5 in which glucosidic moiety attached
to 5-position through a linker, were found to be able to inhibit
acetylcholinesterase with IC50 values of 24.5, 41.6, and 24.7 mM,
respectively. Aviprin-300-O-glucoside 5,1 in which glucosidic moiety
attached to 8-position of xanthotoxol through a linker, exhibited
phytotoxic activity with IC50 value of 0.575 mg/mL. Citrusoside B 66
containing a glucosidic moiety attached to 5-position of xantho-
toxol through a linker, showed cholinesterase inhibitory activity
cluding 9-b-D-arabinopyranosyl psoralen 3 and found that it caused
dose dependent inhibition of spontaneous motor activity, pro-
longation of hexabarbitone, pentobarbitone, and ether hypnosis.20
Considering that introducing sugar moieties into pharmaco-
phores, natural products or prodrugs can improve their anticancer
activities,22e30 we embarked on the design and synthesis of gly-
cosylated psoralen derivatives and the evaluation of their
with IC50 value of 339ꢀ3
mM. However, only a few literature dis-
closed the synthesis of glycosylated psoralen derivatives.19e21
Hwang et al. synthesized glycosylated psoralen derivative 1 by
* Corresponding authors. Tel.: þ86 0571 88206287; fax: þ86 025 83686240;
Scheme 1. Structures of some glycosidic psoralen derivatives.
e-mail addresses: liuf64@zju.edu.cn (F.-Y. Liu), huangzz@nju.edu.cn (Z.-Z. Huang).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.01.090

C.-Y. Chen et al. / Tetrahedron 68 (2012) 2598e2606
2599
antiproliferative activities against several human tumor cell lines
and antioxidant activities.
HO
O
O
K2CO3 , acetone
O
O
O
8
aldol condensation
2. Results and discussion
2.1. Chemistry
14
8
1M NaOH,Isopropanol
9
retrograde aldol condensation
Due to its concise synthetic route, 4,40-dimethylxanthotoxol 10
was chosen as a target psoralen moiety (Scheme 2). Initially, cheap
pyrogallol was employed as a starting material to undergo Pech-
mann reaction with ethylacetoacetate in the solution of 12 M sul-
furic acid, giving the desired coumarin derivative 7 in 81% yield.31 7
was then etherated with 1-chloroacetone in acetone to give cou-
marin derivative 8 in 24% yield and by-product 1432 in 51% yield,
which was resulted from the intramolecular aldol condensation of
8 (Scheme 3). It was found that 14 could also be transformed into 9
through retrograde aldol condensation followed by cyclization in
aqueous solution of 1 M NaOH/isopropanol. So the mixture after
the O-dialkylation reaction was used directly into the cyclization
reaction of 8 without separation, affording the desired psoralen
derivative 9 in one pot with 43% overall yield. Among the cleavage
reagents, such as aluminum chloride, p-toluenesulfonic acid, tri-
fluoroacetic acid, sodium amide, pyridine hydrochlorides, and
magnesium iodide,33,34 magnesium iodide was found to be the
most suitable to undergo the dealkylation of 9 to give 4,40-dime-
thylxanthotoxol 10 in 89% yield. It should be noted that the known
method for the synthesis of dimethylxanthotoxol 10 using 8-acetyl-
7-hydroxy-4-methyl coumarin as starting material needs six steps
with 29.6% overall yield.35 Our method for the synthesis of dime-
thylxanthotoxol 10 needs only four steps and employs cheap py-
rogallol as a starting material.
Scheme 3.
derivatives 12aed in 53e73% yield. The deacetylation of 12 using
catalytic amount of NaOMe in anhydrous methanol at room tem-
perature gave glycosylated psoralen derivatives 13aed in 83e94%
yields. Thus,
D
D-glucose and
D-galactose as the monosaccharides, and
-lactose and
D-maltose as disaccharides were introduced to 8-
position of dimethylxanthotoxol 10 successfully.
Moreover, we also introduced sugar moieties into dime-
thylxanthotoxol 10 via ester linkers, vanillate, and salicylate
(Scheme 4). Reaction of vanillin with peracetylglycosyl bromide 11
using Bu4NBr as a phase transfer catalyst and NaOH as a base in
CH2Cl2/H2O, which was similar to the method for 12, gave 15 in
48e72% yields. Subsequent oxidation with potassium permanga-
nate in water afforded aromatic acid 16 in 80e92% yields. In the
presence of the N,N0-diisopropylcarbodiimide (DIC), dimethylxan-
thotoxol 10 underwent esterification smoothly with 16 under the
catalysis of 4-dimethylaminopyridine (DMAP), giving glycosylated
psoralen derivatives 17aed in 66e83% yields. The introduction of
sugar moieties using salicylate as a linker were conducted by
a similar protocol to that for 17 using vanillate as a linker, furnishing
glycosylated psoralen derivatives 20aed in 65e79% yields.
O
O
O
OH
OH
O
O
HO
OH
HO
O
O
O
O
O
O
Cl
OEt
1 M NaOH
12 M H2SO4
K2CO3 , acetone
Isopropanol
8
7
O
O
R1
O
OAc
O
R2
O
OH
R1
R2
AcO
AcO
O
AcO
OAc
O
O
O
Br
O
O
O
MgI2
11a-d
O
TBAB, NaOH
AcO
12a-d
O
9
10
11a, 12a: R1 = H, R2 = OAc 11b, 12b: R1 = OAc, R2 = H
O
O
OAc
OAc
O
R3
11c, 12c: R1 = H, R2
=
O
AcO
AcO
OH
O
AcO
OAc
NaOMe
MeOH
R4
O
HO
O
11d, 12d: R1 = H, R2
=
HO
13a-d
AcO
O
AcO
O
13a: R3 = H, R4 = OH
OH
13b: R3 = OH, R4 = H
OH
O
OH
O
13d: R3 = H, R4
13c: R3 = H, R4
=
HO
=
O
HO
HO
HO
HO
O
Scheme 2. Synthesis of glycosylated psoralen derivatives 12 and 13.
The direct O-glycosylation of 10 was performed with per-
acetylglycosyl bromide 11 in a biphasic media (CH2Cl2/H2O) using
tetrabutylammonium bromide (TBAB) as phase transfer catalyst
and NaOH as a base, affording the desired glycosylated psoralen
2.2. Biology
2.2.1. Antiproliferative activity. The antiproliferative activities of all
the synthesized psoralen derivatives 10, 12, 13, 17, and 20 were

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C.-Y. Chen et al. / Tetrahedron 68 (2012) 2598e2606
Scheme 4. Synthesis of glycosylated psoralen derivatives 17 and 20.
evaluated in vitro against four cancer cell lines including human
hepatoma HepG2 cells, human squamous cell carcinoma cell line
A431, human cervical cancer cell HeLa and human uterine sarcoma
cell SA using the MTT cell viability assay and expressed as IC50
values. With reference to the reports that many psoralen de-
rivatives showed a photo-induced antiproliferative effect,2,36e38
experiments were performed both in dark and under UVA light
following previously established procedures.2
Our experiment (Table 1) showed that the antiproliferative po-
tency of the glycosylated psoralen derivatives varied strongly
depending on both their structure and the type of cell lines. Many
glycosylated psoralen derivatives exhibited antiproliferative activ-
ities against human cancer cell lines, their IC50 values were lower
increase in cytotoxic activities, which was particularly striking for
12a and 12b against SA cell line, and 20c and 20d against A431 cell
line. The IC50 values of 12a, 12b, 20c, and 20d tested under UVA
irradiation were about six times lower than IC50 values tested in
dark. These results showed that the glycosylated psoralen de-
rivatives had strong photo-induced antiproliferative effects, which
was in agreement with those disclosed in the literature.2,36e38
The results also demonstrated that glycosylated psoralen de-
rivatives 12a and 12b were much potent antiproliferative against
HepG2, A431, and SA than their deacetylated counterparts 13a and
13d under UVA. The lipophilic property of acetylated sugar moiety
in these compounds might facilitate antiproliferative potency24,30
against HepG2, A431, and SA under UVA. Among glycosylated
psoralen derivatives 17 with vanillate as a linker, only 17a displayed
than 200
mM. Under UVA irradiation, some of them showed an
Table 1
In vitro antiproliferative activities (IC50 mM) of glycosylated psoralen derivatives against HeLa, HepG2, A431, and SA
Compd
HeLa
Dark
HepG2
Dark
A431
Dark
SA
UV
UV
UV
Dark
UV
12a
12b
12c
12d
13a
13b
13c
13d
17a
17b
17c
17d
20a
20b
20c
20d
10a
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
53.67ꢀ8.15
117.39ꢀ5.78
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
55.64ꢀ0.76
57.76ꢀ0.30
114.75ꢀ2.01
>200
>200
>200
30.51ꢀ2.50
28.53ꢀ1.37
>200
>200
>200
>200
>200
>200
>200
>200
>200
172.97ꢀ5.42
64.90ꢀ1.66
>200
91.80ꢀ2.40
>200
>200
166.52ꢀ4.91
>200
>200
>200
>200
71.74ꢀ2.95
>200
>200
>200
169.42ꢀ3.22
195.67ꢀ2.19
>200
>200
>200
>200
196.81ꢀ6.14
>200
>200
>200
>200
>200
>200
>200
164.50ꢀ0.78
151.13ꢀ2.67
>200
>200
47.79ꢀ5.63
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
182.27ꢀ8.46
92.72ꢀ1.79
>200
28.30ꢀ2.89
32.78ꢀ1.67
>200
78.08ꢀ1.21
61.50ꢀ1.55
75.05ꢀ4.21
75.83ꢀ1.23
29.07ꢀ0.98
>200
>200
>200
>200
>200
>200
>200
>200
1.02ꢀ0.03
>200
>200
>200
>200
53.56ꢀ0.92
31.00ꢀ3.13
>200
0.68ꢀ0.01
>200
>200
>200
>200
167.65ꢀ15.63
>200
91.13ꢀ4.90
49.12ꢀ2.57
95.55ꢀ0.64
168.93ꢀ2.17
Dox.b
1.03ꢀ0.06
0.28ꢀ0.04
0.21ꢀ0.02
0.71ꢀ0.03
0.18ꢀ0.02
0.22ꢀ0.04
a
The parent psoralen dimethylxanthotoxol 10 was selected as a reference compound.
b
Doxorubicin (dox.) was selected as a positive control.

C.-Y. Chen et al. / Tetrahedron 68 (2012) 2598e2606
2601
antiproliferative effect against SA with IC50 value of 47.79ꢀ5.63
m
M
4. Experimental section
4.1. Chemistry
in dark. For the glycosylated psoralen derivatives 20 with salicylate
as a linker, it is notable that 20a showed the highest and broadest
spectrum antiproliferative effect on all the four tumor cells both in
the dark and under UVA light, except against HeLa under UVA. 20a
was approximately 2.6-, 1.5-, 2.7-, and 3.3-fold more potent than
the reference psoralen derivative 10 against HeLa, HepG2, A431,
and SA cancer cells in dark, respectively. Glycosylated psoralen
derivatives 20c and 20d exhibited higher activities against A431
cell line as compared to the reference psoralen derivative 10 both in
the dark and under UVA, while they exhibited no antiproliferative
activities against HeLa, HepG2, and SA.
4.1.1. Synthesis of 7,8-dihydroxy-4-methylcoumarin 7. 7,8-Dihy-
droxy-4-methylcoumarin 7 was prepared as a white solid according
to the method described in literature31 (81% yield), mp: 241e243 ꢁC
(lit. 242e244 ꢁC31). 1H NMR (300 MHz, DMSO-d6)
d (ppm): 10.06
(br s, 1H), 9.29 (br s, 1H), 7.07 (d, J¼8.7 Hz, 1H), 6.80 (d, J¼8.7 Hz,
1H), 6.11 (s, 1H), 2.34 (s, 3H).
4.1.2. Synthesis of 7,8-diacetonyloxy-4-methylcoumarin 8. A mix-
ture of 7,8-dihydroxy-4-methylcoumarin 7 (7.22 g, 37.6 mmol),
chloroacetone (10.45 g, 112.8 mmol), and anhydrous K2CO3 (15.60 g,
112.8 mmol) in dry acetone (120 mL) was refluxed for 12 h. After
filtration, the residue was washed with dry acetone, and the filtrate
was evaporated under reduced pressure. The crude products con-
taining coumarin derivatives 8 and 14 were employed in the next
reaction for 9 without further purification. 8 and 14 can be isolated by
flash chromatography (silica gel, hexane/ethyl acetate¼1:1 aseluent).
2.2.2. Antioxidant activities. In recent years, psoralens have
attracted much attention as naturally occurring anti-
oxidants.35,39e43 However, the antioxidant activities of glycosylated
psoralen derivatives were not reported to the best of our knowl-
edge. Here we report the antioxidant effects of glycosylated psor-
alen derivatives 12, 13a,b,d, 17aec, 20 on protecting DNA against
the oxidation induced by Cu2+/glutathione (GSH). As shown in
Fig. 1, all the fifteen compounds 10, 12, 13a,b,d, 17aec, 20 exhibited
antioxidant activities against the oxidation induced by Cu2+/gluta-
thione (GSH) comparing with the control experiment. Antioxidant
activities of 12c, 13a,b, 17a,c, 20b, and 20c were higher than their
parental compound 10. Glycosylated psoralen derivatives 17a, 20b,
and 13b possessed highest antioxidant activities.
4.1.2.1. 8-Diacetonyloxy-4-methylcoumarin 8.32 White solid,
mp: 122e124 ꢁC. 1H NMR (300 MHz, CDCl3)
d (ppm): 7.28 (d,
J¼8.9 Hz, 1H), 6.74 (d, J¼8.9 Hz, 1H), 6.18 (d, J¼1.1 Hz, 1H), 4.742 (s,
2H), 4.737 (s, 2H), 2.41 (s, 3H), 2.39 (s, 3H), 2.28 (s, 3H). 13C NMR
(75 MHz, CDCl3)
d (ppm): 205.5, 203.4, 160.0, 152.8, 152.6, 147.4,
135.0, 119.9, 115.6, 112.9, 109.6, 77.8, 73.6, 26.7, 26.4, 18.8. MS (ESI,
negative) m/z calcd for C16H15O6: 303.09 [MꢂH]ꢂ; found: 303.10.
HRMS (ESI, positive) m/z calcd for C16H17O6: 305.1025 [M+H]+;
found: 305.1009.
535 nm absorbance
1.40
1.30
1.20
4.1.2.2. Coumarin derivative 14.32 White solid, mp: 194e196 ꢁC.
1H NMR (300 MHz, DMSO-d6)
d
(ppm): 7.29 (d, J¼9.0 Hz, 1H), 7.05
(d, J¼9.0 Hz,1H), 6.26 (d, J¼1.2 Hz,1H), 5.51 (s,1H), 4.49 (s,1H), 4.32
(d, J¼11.4 Hz, 1H), 4.01 (d, J¼11.4 Hz,1H), 2.36 (d, J¼1.2 Hz, 3H), 2.33
1.10
1.00
0.90
0.80
0.70
0.60
l
(s, 3H), 1.40 (s, 3H). 13C NMR (75 MHz, DMSO-d6)
d (ppm): 206.2,
159.9, 153.8, 151.1, 144.9, 137.8, 118.5, 117.1, 116.3, 112.8, 91.9, 78.8,
73.8, 29.0, 23.5, 18.8. MS (ESI, negative) m/z calcd for C16H15O6:
303.09 [MꢂH]ꢂ; found: 303.05.
10
ro
t
12c
17c
20c
12a 12b
12d 13a 13b 13d 17a 17b
20a 20b
20d
4.1.3. Synthesis of 8-acetonyloxy-4,40-dimethylpsoralen 9. The mix-
ture of 8 and 14 (or pure 8) was refluxed in the mixed solvent of
1.0 M NaOH (100 mL) and isopropanol (100 mL) for 12 h under N2.
Then, the most of isopropanol in the mixture was evaporated under
reduced pressure. The residue was diluted with water and then
acidified with 2.0 M HCl. The precipitate formed was collected,
washed with water, and purified by flash chromatography (silica
gel, hexane/ethyl acetate¼1:1 as eluent) to give 8-acetonyloxy-4,40-
dimethylpsoralen 9 (43% for two steps) as a white solid. Mp:
n
co
Fig. 1. The variety of the absorbance of TBARS in the oxidation of DNA (2.0 mg/mL)
induced by 5.0 mM Cu2þ and 3.0 mM GSH in the presence of glycosylated psoralen
derivatives. (Experiments were performed following the method of a previous report35
and were measured by detecting thiobarbituric acid (TBA) reactive substances
(TBARS)).
3. Conclusions
We have developed a concise route for the efficient synthesis of
a target psoralen moiety, 4,40-dimethylxanthotoxol 10, which needs
only four steps using cheap pyrogallol as a starting material. Then,
a range of new glycosylated psoralen derivatives 12, 13, 17, 20 were
synthesized in good yields with simple procedures and mild re-
action conditions. The experiment of their antiproliferative activi-
ties against four human cancer cell lines shows that some
glycosylated psoralen derivatives are moderately active. Among
them, 20a has highest and broadest spectrum antiproliferative
activities, while 20c and 20d exhibit selective antiproliferative ac-
tivities against A431 cell line. A strong photo-induced anti-
proliferative activities of 12a, 12b, 20c, and 20d were found under
UVA. All the glycosylated psoralen derivatives have antioxidant
activities against the oxidation of DNA induced by Cu2+/glutathione
(GSH). Our experiment also demonstrates that the introduction of
sugar moieties in 12c, 13a,b, 17ac, 20b, and 20c can improve their
antioxidant activities significantly.
136e138 ꢁC. 1H NMR (300 MHz, CDCl3)
d
(ppm): 7.44 (d, J¼1.2 Hz,
1H), 7.36 (s, 1H), 6.24 (d, J¼0.9 Hz, 1H), 5.00 (s, 2H), 2.50 (d,
J¼0.9 Hz, 3H), 2.38 (s, 3H), 2.26 (d, J¼1.2 Hz, 3H). 13C NMR (75 MHz,
CDCl3)
d (ppm): 205.1, 160.3, 153.1, 146.9, 143.0, 142.3, 130.8, 127.4,
117.3, 116.1, 113.3, 108.4, 77.0, 26.4, 19.4, 7.8. MS (ESI, positive) m/z
calcd for C16H14O5Na: 309.07 [M+Na]+; found: 308.85; calcd for
C32H28O10Na: 595.16 [2M+Na]+; found: 595.05. HRMS (ESI, positive)
m/z calcd for C16H15O5: 287.0919 [M+H]+; found: 287.0908.
4.1.4. Synthesis of 4,40-dimethylxanthotoxol 10.33,34 To a suspension
of MgI2 (5.56 g, 20.0 mmol) in the mixed solvent of Et2O/C6H6
(120 mL, v/v¼3:4) was added a solution of 8-acetonyloxy-4,40-
dimethylpsoralen 9 (2.86 g, 10.0 mmol) in dry benzene (50 mL).
After the mixture was blended sufficiently, the solvent was re-
moved in vacuo, and the residue was evaporated in vacuo at 130 ꢁC.
Then the reaction mixture was kept at 160e165 ꢁC (bath temper-
ature) for 1.5e2 h. After reaction, the solid was pulverized and

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C.-Y. Chen et al. / Tetrahedron 68 (2012) 2598e2606
hydrolyzed with dilute sulfuric acid. After filtration, the residue was
washed with water, aqueous NaHSO3 to disappearance of iodine
brown, and with water again. Finally, crystallized from alcohol led
to 4,40-dimethylxanthotoxol 10 as a pale powder (2.03 g, 89%). Mp:
CDCl3) d (ppm): 170.4, 170.23, 170.19, 170.0, 169.84, 169.80, 169.2,
159.9, 152.8, 148.2, 143.5, 143.2, 128.2, 127.2, 117.1, 116.0, 113.4, 110.1,
101.0, 100.4, 75.9, 73.0, 72.7, 72.0, 71.0, 70.6, 69.1, 66.8, 61.9, 60.9,
20.81, 20.76, 20.6, 20.5, 19.3, 7.7. MS (ESI, positive) m/z calcd for
C39H44O21Na: 871.23 [MþNa]þ; found: 871.33. HRMS (ESI, positive)
m/z calcd for C39H46O22: 866.2481 [MþH2O]þ; found: 866.2489.
>250 ꢁC (lit. >250 ꢁC35). 1H NMR (300 MHz, DMSO-d6)
d
(ppm):
10.50 (s, 1H), 7.85 (s, 1H), 7.43 (s, 1H), 6.31 (s, 1H), 2.51 (s, 3H), 2.24
(s, 3H). 13C NMR (75 MHz, DMSO-d6)
(ppm): 160.4, 154.7, 145.9,
d
143.9, 140.2, 130.4, 126.9, 117.2, 116.3, 112.8, 105.8, 19.3, 8.0. MS (ESI,
4.1.6.4. 4,40-Dimethyl-8-O-(200,300,600,2000,3000,4000,6000-hepta-O-ace-
negative) m/z calcd for C13H9O4: 229.05 [MꢂH]ꢂ; found: 229.17.
tyl-
b
-
D
-maltosyl)xanthotoxol 12d. Yield 53%; light yellow solid, mp:
172e175 ꢁC. 1H NMR (300 MHz, CDCl3)
d
(ppm): 7.46(d, J¼1.2 Hz,
4.1.5. Synthesis of peracetylglycosyl bromide 11. 2,3,4,6-Tetra-O-
1H), 7.45 (s, 1H), 6.23 (d, J¼1.2 Hz, 1H), 5.47e5.42 (m, 2H),
5.38e5.24 (m, 4H), 5.03(t, J¼9.6 Hz, 1H), 4.84 (dd, J¼10.5, 3.9 Hz,
1H), 4.20 (dd, J¼12.3, 3.0 Hz, 1H), 4.27e4.17 (m, 4H), 4.03 (dd,
J¼12.3, 2.1 Hz, 1H), 3.97e3.93 (m, 1H), 3.77e3.70 (m, 1H), 2.49 (d,
J¼0.9 Hz, 3H), 2.26 (d, J¼1.2 Hz, 3H), 2.14 (s, 3H), 2.08 (s, 3H), 2.05 (s,
3H), 2.03 (s, 3H), 2.00 (s, 3H), 1.99 (s, 3H), 1.98 (s, 3H). 13C NMR
acetyl-
D
a-D a-
-glucopyranosyl bromide 11a,44 2,3,4,6-tetra-O-acetyl-
-galactopyranosyl bromide 11b,44 2,3,6,20,30,40,60-hepta-O-acetyl-
a-D a-D-
-lactosyl bromide 11c,44 and 2,3,6,20,30,40,60-hepta-O-acetyl-
maltosyl bromide 11d45 were prepared according to literature
methods.
(75 MHz, CDCl3)
d (ppm): 170.60, 170.56, 170.3, 170.2, 170.02,
4.1.6. General procedure of glycosylation for glycosylated psoralen
derivatives 12aed. 4,40-Dimethylxanthotoxol 10 (1.38 g, 6.0 mmol),
peracetylglucosyl bromide 11aed (7.5 mmol), and tetrabuty-
lammonium bromide (2.58 g, 8.0 mmol) were dissolved in
dichloromethane (30 mL) and warmed to 35 ꢁC. A solution of so-
dium hydroxide (5%, 10.0 mL) was added, and the reaction mixture
was refluxed for 8 h. The mixture was cooled to room temperature
and diluted with CHCl3 (30 mL), which was then washed with cold
1 N HCl solution and brine, dried over anhydrous Na2SO4, and
concentrated. The residue was purified by column chromatography
(silica gel, EtOAc/hexane¼1:2 as eluent) to afford glycosylated
psoralen derivatives 12aed (53e73%).
169.96, 169.4, 159.9, 152.6, 148.4, 143.5, 143.3, 128.3, 127.2, 117.2,
115.9, 113.6, 110.2, 100.9, 95.5, 90.0, 75.2, 72.6, 72.4, 72.3, 70.0, 69.4,
68.5, 68.1, 62.5, 61.4, 20.93, 20.86, 20.74, 20.69, 20.65, 20.59, 19.4,
7.8. MS (ESI, positive) m/z calcd for C39H44O21Na: 871.23 [MþNa]þ;
found: 871.25. HRMS (ESI, positive) m/z calcd for C39H46O22
866.2481 [MþH2O]þ; found: 866.2493.
:
4.1.7. General procedure of deacetylation for glycosylated psoralen
derivatives 13aed. A solution of glycosylated psoralen derivatives
12aed (1.2 g) in dry methanol (25 mL) was chilled to 0 ꢁC with
stirring under nitrogen. A solution of NaOMe in methanol (1.2 mL,
1.0 M, 1.2 mmol) was added, and the mixture was stirred at room
temperature for 3 h. The mixture was neutralized with Dowex Hþ
ion-exchange resin. The resin was filtered off and washed with
methanol several times. The collected filtrate was concentrated in
vacuum to afford glycosylated psoralen derivatives 13aed
(83e93%).
4.1.6.1. 4,40-Dimethyl-8-O-(200,300,400,600-tetra-O-acetyl-
pyranosyl)xanthotoxol 12a. Yield 73%; white solid, mp: 118e120 ꢁC.
1H NMR (300 MHz, CDCl3)
b-D-gluco-
d
(ppm): 7.48(d, J¼1.2 Hz, 1H), 7.47 (s,
1H), 6.25 (d, J¼1.2 Hz, 1H), 5.45e5.21 (m, 4H), 4.26 (dd, J¼12.0,
4.5 Hz, 2H), 4.08 (dd, J¼12.0, 3.9 Hz, 2H), 3.75 (ddd, J¼9.9, 4.8,
2.1 Hz, 2H), 2.51 (d, J¼0.9 Hz, 3H), 2.27 (d, J¼1.2 Hz, 3H), 2.19 (s, 3H),
2.05 (s, 3H), 2.02 (s, 3H), 1.97 (s, 3H). 13C NMR (75 MHz, CDCl3)
4.1.7.1. 4,40-Dimethyl-8-O-
eld 94%; white solid, mp: 137e140 ꢁC. 1H NMR (300 MHz, DMSO-d6)
b-D-glucopyranosyl xanthotoxol 13a. Yi-
d
(ppm): 170.6, 170.3, 169.8, 169.4, 159.9, 152.7, 148.6, 143.4, 128.5,
d
(ppm): 7.87 (d, J¼1.2 Hz, 1H), 7.64 (s, 1H), 6.35 (s, 1H), 5.60 (d,
127.2, 117.2, 115.9, 113.5, 110.3, 101.6, 72.8, 72.1, 71.4, 68.5, 61.8, 30.9,
20.8, 20.65, 20.60, 19.4, 7.8. MS (ESI, positive) m/z calcd for
C27H28O13Na: 583.14 [MþNa]þ; found: 583.25. HRMS (ESI, positive)
m/z calcd for C27H29O13: 561.1608 [MþH]þ; found: 561.1617.
J¼7.5 Hz, 1H), 3.54e3.16 (m, 10H), 2.49 (s, 3H), 2.24 (s, 3H). 13C NMR
(75 MHz, DMSO-d6)
d (ppm): 160.2, 154.5, 146.6, 144.2, 142.5, 129.1,
127.5,117.3,116.1, 113.1,109.7,102.2, 78.0, 77.2, 74.3, 70.1, 60.9,19.3, 7.9.
MS (ESI, positive) m/z calcd for C19H20O9Na: 415.10 [MþNa]þ; found:
415.25. HRMS (ESI, positive) m/z calcd for C19H21O9: 393.1186
[MþH]þ; found: 393.1180.
4.1.6.2. 4,40-Dimethyl-8-O-(200,300,400,600-tetra-O-acetyl-
actopyranosyl)xanthotoxol 12b. Yield 71%; white solid, mp:
156e158 ꢁC. 1H NMR (300 MHz, CDCl3)
b-D-gal-
d
(ppm): 7.48(d, J¼1.5 Hz,
4.1.7.2. 4,40-Dimethyl-8-O-
13b. Yield 92%; white solid, mp: 206e209 ꢁC. 1H NMR (300 MHz,
DMSO-d6) (ppm): 7.86 (s, 1H), 7.62 (s, 1H), 6.33 (s, 1H), 5.54 (d,
J¼7.5 Hz, 1H), 5.34 (d, J¼4.8 Hz, 1H), 4.88 (d, J¼5.4 Hz, 1H), 4.56 (d,
J¼3.6 Hz, 1H), 4.46e4.43 (m, 1H), 3.70e3.64 (m, 2H), 3.49e3.38 (m,
3H), 3.33e3.25 (m, 1H), 2.49 (s, 3H), 2.23 (s, 3H). 13C NMR (75 MHz,
b
-D
-galactopyranosyl
xanthotoxol
1H), 7.47 (s, 1H), 6.24 (d, J¼1.5 Hz, 1H), 5.63 (dd, J¼10.2, 7.8 Hz, 1H),
5.43 (dd, J¼3.3, 0.9 Hz, 1H), 5.29 (d, J¼8.1 Hz, 3H), 5.14 (dd, J¼10.5,
3.3 Hz, 1H), 4.16e4.07 (m, 2H),3.90(dt, J¼6.9, 0.9 Hz, 1H), 2.50 (d,
J¼0.9 Hz, 3H), 2.27 (d, J¼1.2 Hz, 3H), 2.22 (s, 3H), 2.21 (s, 3H), 2.02
d
(s, 3H), 1.91 (s, 3H). 13C NMR (75 MHz, CDCl3)
d (ppm): 170.4, 170.3,
170.14, 170.09, 160.0, 152.8, 148.8, 143.5, 143.4, 128.7, 127.2, 117.2,
115.9, 113.5, 110.4, 102.5, 71.1, 70.9, 68.8, 66.8, 61.0, 20.9, 20.8, 20.6,
20.5, 19.4, 7.8. MS (ESI, positive) m/z calcd for C27H28O13Na: 583.14
[MþNa]þ; found: 583.33. HRMS (ESI, positive) m/z calcd for
C27H29O13: 561.1608 [MþH]þ; found: 561.1617.
DMSO-d6) d (ppm): 160.2, 154.4, 146.7, 144.2, 142.6, 129.2, 127.5,
117.3, 116.1, 113.1, 109.7, 102.9, 76.4, 73.8, 71.4, 68.4, 60.5, 19.3, 7.9.
MS (ESI, positive) m/z calcd for C19H20O9Na: 415.10 [MþNa]þ;
found: 415.33. HRMS (ESI, positive) m/z calcd for C19H21O9:
393.1186 [MþH]þ; found: 393.1175.
4.1.6.3. 4,40-Dimethyl-8-O-(200,300,600,2000,3000,4000,6000-hepta-O-ace-
4.1.7.3. 4,40-Dimethyl-8-O-
88%; white solid, mp: 226e229 ꢁC. 1H NMR (300 MHz, DMSO-d6)
(ppm): 7.86 (s, 1H), 7.63 (s, 1H), 6.34 (s, 1H), 5.69e5.63 (m, 2H),
b-D-lactosyl xanthotoxol 13c. Yield
tyl-
b
-
D
-lactosyl)xanthotoxol 12c. Yield 57%; white solid, mp:
175e178 ꢁC. 1H NMR (300 MHz, CDCl3)
d
(ppm): 7.46 (s, 2H), 6.25 (d,
d
J¼0.9 Hz, 1H), 5.54 (d, J¼6.6 Hz, 1H), 5.37e5.25 (m, 3H), 5.12 (dd,
J¼10.2, 8.1 Hz, 1H), 4.98 (dd, J¼10.2, 3.3 Hz, 1H), 4.60 (d, J¼8.1 Hz,
1H), 4.41 (dd, J¼12.0,1.5 Hz, 1H), 4.26 (t, J¼9.0 Hz, 1H), 4.13e4.04
(m, 4H), 3.97 (t, J¼6.9 Hz, 1H), 3.74 (ddd, J¼9.6, 4.8, 2.1 Hz, 1H), 2.51
(s, 3H), 2.27 (d, J¼0.9 Hz, 3H), 2.16 (s, 3H), 2.15 (s, 3H), 2.10 (s, 3H),
2.05 (s, 3H), 2.03 (s, 3H), 2.02 (s, 3H), 1.95 (s, 3H). 13C NMR (75 MHz,
5.08 (d, J¼3.3 Hz, 1H), 4.83e4.79 (m, 2H), 4.70e4.67 (m, 1H), 4.53
(d, J¼4.5 Hz, 1H), 4.43 (t, J¼5.4 Hz, 1H), 4.23 (d, J¼6.3 Hz, 1H),
3.61e3.31 (m, 12H), 2.49 (s, 3H), 2.23 (s, 3H). 13C NMR (75 MHz,
DMSO-d6)
d (ppm): 160.1, 154.4, 146.5, 144.3, 142.4, 128.9, 127.5,
117.3, 116.1, 113.1, 109.8, 104.3, 101.9, 80.7, 76.0, 75.9, 75.5, 74.0, 73.7,
71.0, 68.6, 60.9, 60.4, 19.3, 7.9. MS (ESI, positive) m/z calcd for

C.-Y. Chen et al. / Tetrahedron 68 (2012) 2598e2606
2603
C25H30O14Na: 577.15 [MþNa]þ; found: 577.33. HRMS (ESI, positive)
m/z calcd for C25H31O14: 555.1714 [MþH]þ; found: 555.1703.
61.5, 56.0, 20.8, 20.6, 20.5, 20.4. MS (ESI, negative) m/z calcd for
C
34H41O20: 769.22 [MꢂH]ꢂ; found: 769.20.
4.1.7.4. 4,40-Dimethyl-8-O-
83%; sticky yellow liquid. 1H NMR (300 MHz, DMSO-d6)
7.87 (s, 1H), 7.67 (s, 1H), 6.36 (s, 1H), 5.65e5.61 (m, 2H),
5.46e5.43 (m, 2H), 5.08e4.87 (m, 4H), 4.51(s, 2H), 4.36e4.29 (m,
1H), 3.70e3.03 (m, 10H), 2.51 (s, 3H), 2.24 (s, 3H). 13C NMR
b
-D
-maltosyl xanthotoxol 13d. Yield
4.1.8.5. 2-(20,30,40,60-Tetra-O-acetyl-
benzaldehyde 18a. Yield 71%; white solid, mp: 140e142 ꢁC (lit.
142 ꢁC49). 1H NMR (300 MHz, CDCl3)
(ppm): 10.35 (s, 1H),
7.88e7.85 (m, 1H), 7.58e7.54 (m, 1H), 7.21e7.19 (m, 1H), 7.13e7.11
(m, 1H), 5.38e5.31 (m, 2H), 5.22e5.18 (m, 2H), 4.30 (dd, J¼12.3,
5.1 Hz, 1H), 4.20 (dd, J¼12.3, 2.1 Hz, 1H), 3.94e3.89 (m, 1H), 2.08 (s,
3H), 2.07 (s, 6H), 2.06 (s, 6H), 2.05 (s, 3H). 13C NMR (75 MHz, CDCl3)
b-D-glucopyranosyl-oxy)
d
(ppm):
d
(75 MHz, DMSO-d6)
d (ppm): 160.2, 154.6, 146.4, 144.2, 142.2,
128.9, 127.6, 117.3, 116.1, 113.0, 109.7, 101.2, 97.2, 92.5, 80.2, 76.9,
75.4, 74.8, 73.8, 72.8, 70.7, 70.3, 61.3, 19.3, 7.8. MS (ESI, positive)
m/z calcd for C25H30O14Na: 577.15 [MþNa]þ; found: 577.33.
HRMS (ESI, positive) m/z calcd for C25H31O14: 555.1714 [MþH]þ;
found: 555.1701.
d
(ppm): 189.1, 170.4, 170.1, 169.3, 169.2, 158.8, 135.7, 128.3, 126.2,
123.6, 116.0, 99.0, 72.4, 72.2, 70.9, 68.2, 61.8, 20.63, 20.56. MS (ESI,
positive) m/z calcd for C21H24O11Na: 475.12 [MþNa]þ; found:
475.00.
4.1.8. General procedure for synthesis of glycosides of 15aed or
18aed. Acetylated glycosides of 15aed or 18aed were prepared by
the similar procedure to that for 12aed but using vanillin or sali-
cylaldehyde as a reactant.
4.1.8.6. 2-(20,30,40,60-Tetra-O-acetyl-
benzaldehyde 18b. Yield 62%; white solid, mp: 92e94 ꢁC. 1H NMR
(300 MHz, CDCl3)
b-D-galactopyranosyl-oxy)
d
(ppm): 10.36 (s, 1H), 7.86 (dd, J¼7.8, 1.5 Hz, 1H),
7.57e7.53 (m, 1H), 7.21e7.11 (m, 2H), 5.59 (dd, J¼10.5, 7.8 Hz, 1H),
5.48 (d, J¼2.7 Hz, 1H), 5.17e5.12 (m, 2H), 4.28e4.08 (m, 3H), 2.20 (s,
4.1.8.1. 3-Methoxy-4-(20,30,40,60-tetra-O-acetyl-
anosyloxy)benzaldehyde 15a.46 Yield 72%; white solid, mp:
125e128 ꢁC. 1H NMR (300 MHz, CDCl3)
(ppm): 9.88(s, 1H), 7.42 (s,
b
-
D
-glucopyr-
3H), 2.06 (s, 6H), 2.02 (s, 3H). 13C NMR (75 MHz, CDCl3)
d (ppm):
189.2,170.3,170.1,170.0,169.3,158.8,135.7,128.2,126.0,123.4,115.7,
99.4, 71.3, 70.6, 68.4, 66.8, 61.3, 20.63, 20.60, 20.5. MS (ESI, positive)
m/z calcd for C21H24O11Na: 475.12 [MþNa]þ; found: 475.00. HRMS
(ESI, positive) m/z calcd for C21H26O12: 470.1424 [MþH2O]þ; found:
470.1440.
d
1H), 7.42e7.39 (m, 1H), 7.20 (d, J¼8.7 Hz, 1H), 5.32e5.29 (m, 2H),
5.20e5.13 (m, 1H), 5.11e5.09 (m, 1H), 4.26 (dd, J¼12.3, 5.4 Hz, 1H),
4.17 (dd, J¼12.3, 2.4 Hz, 1H), 3.88 (s, 3H), 3.88e3.82 (m, 1H), 2.061
(s, 3H), 2.059 (s, 3H), 2.04 (s, 3H), 2.03 (s, 3H). 13C NMR (75 MHz,
CDCl3)
d
(ppm): 190.9, 170.4, 170.2, 169.4, 169.2, 151.1, 150.9, 132.8,
4.1.8.7. 2-(20,30,60,200,300,400,600-Hepta-O-acetyl-
benzaldehyde 18c. Yield 51%; white solid, mp: 125e127 ꢁC (lit.
125e126 ꢁC49). 1H NMR (300 MHz, CDCl3)
(ppm): 10.33 (s, 1H),
b-D-lactosyloxy)
125.3, 118.1, 110.8, 99.7, 72.4, 72.2, 71.0, 68.2, 61.9, 56.1, 20.65, 20.56.
MS (ESI, positive) m/z calcd for C22H26O12Na: 505.13 [MþNa]þ;
found: 505.05.
d
7.85 (dd, J¼7.8, 1.5 Hz, 1H), 7.58e7.52 (m, 1H), 7.20e7.15 (m, 1H),
7.12 (d, J¼8.1 Hz, 1H), 5.36 (d, J¼3.0 Hz, 1H), 5.32e5.24 (m, 2H),
5.19e5.10 (m, 2H),4.97 (dd, J¼10.2, 3.3 Hz, 1H), 4.52 (d, J¼8.1 Hz,
2H), 4.18e4.06 (m, 3H), 3.97e3.80 (m, 3H), 2.16 (s, 3H), 2.09 (s, 3H),
2.07 (s, 3H), 2.06 (s, 3H), 2.05 (s, 6H), 1.97 (s, 3H). 13C NMR (75 MHz,
4.1.8.2. 3-Methoxy-4-(20,30,40,60-tetra-O-acetyl-
anosyloxy)benzaldehyde 15b.47 Yield 59%; white solid, mp:
121e123 ꢁC. (lit. 123e124 ꢁC47). 1H NMR (300 MHz, CDCl3)
(ppm):
b-D-galactopyr-
d
9.68 (s, 1H), 7.28e7.24 (m, 2H), 7.08 (d, J¼8.1 Hz, 1H), 5.37e5.20 (m,
4H), 5.02e4.90 (m, 3H), 4.05e3.87 (m, 6H), 3.70 (s, 3H), 1.89 (s, 3H),
1.86 (s, 3H), 1.83 (s, 3H), 1.82 (s, 3H). 13C NMR (75 MHz, CDCl3):
CDCl3) d (ppm): 189.1, 170.4, 170.2, 170.1, 170.0, 169.7, 169.5, 169.1,
158.7, 135.8, 128.3, 126.1, 123.5, 115.9, 101.2, 98.5, 76.1, 72.9, 72.6,
71.2, 70.9, 70.8, 69.0, 66.6, 61.8, 60.9, 20.8, 20.7, 20.6, 20.5. MS (ESI,
positive) m/z calcd for C33H40O19Na: 763.21 [MþNa]þ; found:
763.15.
d
(ppm): 191.1, 170.3, 170.2, 170.0, 169.3, 151.2, 150.5, 132.3, 125.1,
117.3, 110.8, 99.8, 71.0, 70.4, 68.4, 66.9, 61.3, 55.9, 20.5, 20.33, 20.26.
MS (ESI, positive) m/z calcd for C22H26O12Na: 505.13 [MþNa]þ;
found: 505.05.
4.1.8.8. 2-(20,30,60,200,300,400,600-Hepta-O-acetyl-
benzaldehyde 18d. Yield 57%; white solid, mp: 140e143 ꢁC (lit.
141e143 ꢁC49). 1H NMR (300 MHz, CDCl3)
(ppm): 10.32 (s, 1H),
b-D-maltosyloxy)
4.1.8.3. 3-Methoxy-4-(20,30,60,200,300,400,600-hepta-O-acetyl-
syloxy)benzaldehyde 15c.46 Yield 55%; white solid, mp: 121e124 ꢁC.
1H NMR (300 MHz, CDCl3)
(ppm): 9.89 (s, 1H), 7.42e7.39 (m, 2H),
b
-lacto-
d
7.85 (dd, J¼7.5, 1.5 Hz, 1H), 7.57 (ddd, J¼8.4, 7.8, 1.8 Hz, 1H),
7.21e7.16 (m, 1H), 7.12 (d, J¼8.1 Hz, 1H), 5.43 (d, J¼4.2 Hz, 1H),
5.42e5.32 (m, 2H), 5.23 (d, J¼6.9 Hz, 1H), 5.20 (d, J¼8.1 Hz, 1H),
5.05(t, J¼10.2 Hz, 1H), 4.89e4.82 (m, 1H), 4.50 (dd, J¼12.3, 3.0 Hz,
1H), 4.35 (dd, J¼5.7, 3.9 Hz, 1H), 4.29e4.19 (m, 1H), 4.09e3.88 (m,
3H), 2.10 (3H), 2.07 (3H), 2.05 (6H), 2.04 (3H), 2.03(3H), 2.00 (3H).
d
7.18 (d, J¼7.8 Hz, 1H), 5.36 (d, J¼3.6 Hz, 1H), 5.33e5.20 (m, 2H),
5.16e5.07 (m, 2H), 4.97 (dd, J¼10.5, 3.6 Hz, 1H), 4.56e4.51 (m, 2H),
4.16e4.06 (m, 3H), 3.94e3.88 (m, 2H), 3.88 (s, 3H), 3.80e3.74 (m,
1H), 2.16 (s, 3H), 2.08 (s, 6H), 2.07 (s, 6H), 2.05 (s, 3H), 1.97 (s, 3H).
13C NMR (75 MHz, CDCl3)
d
(ppm): 190.9,170.4,170.2,170.14,170.07,
13C NMR (75 MHz, CDCl3)
d (ppm): 189.0, 170.5, 170.28, 170.25,
169.7, 169.5, 169.1, 151.1, 150.9, 132.7, 125.4, 117.8, 110.7, 101.1, 99.3,
76.1, 73.0, 72.4, 71.3, 70.9, 70.7, 69.1, 66.6, 61.8, 60.8, 56.1, 20.9, 20.8,
20.6, 20.5. MS (ESI, negative) m/z calcd for C34H41O20: 769.22
[MꢂH]ꢂ; found: 769.20.
170.1, 170.0, 169.5, 169.4, 158.7, 135.8, 128.3, 126.2, 123.6, 116.1, 98.5,
95.7, 74.6, 75.0, 72.6, 72.5, 71.7, 70.0, 69.3, 68.7, 68.0, 62.6, 61.6, 20.9,
20.7, 20.5. MS (ESI, positive) m/z calcd for C33H40O19Na: 763.21
[MþNa]þ; found: 763.15.
4.1.8.4. 3-Methoxy-4-(20,30,60,200,300,400,600-hepta-O-acetyl-
tosyloxy)benzaldehyde 15d.48 Yield 48%; white solid, mp:
129e131 ꢁC. 1H NMR (300 MHz, CDCl3)
(ppm): 9.76 (s, 1H),
b
-mal-
4.1.9. General procedure for synthesis of glycosides 16aed or
19aed. To a stirred mixture of acetylated glycosides of vanillin
15aed or salicylaldehyde 18aed (7.0 mmol) in water (20 mL) was
added a solution of potassium permanganate (1.26 g, 8.0 mmol) in
water (40 mL) dropwise during a period of 20 min at 70e80 ꢁC. The
reaction mixture was stirred at this temperature for 1 h. The warm
mixture was filtered and the residue was washed twice with hot
water. The filtrate was evaporated under reduced pressure to
remove approximately 30 mL water. After acidification with 2 N
hydrochloric acid, white precipitate formed immediately. The crude
d
7.33e7.30 (m, 2H), 7.09 (d, J¼8.7 Hz, 1H), 5.33e5.20 (m, 4H),
5.10e4.90 (m, 3H), 4.75 (dd, J¼10.5, 3.9 Hz, 1H), 4.40 (dd, J¼12.0,
2.4 Hz, 1H), 4.18e4.11 (m, 2H), 4.00e3.87 (m, 2H), 3.81e3.76 (m,
1H), 3.76 (s, 1H), 1.97 (s, 3H), 1.94 (s, 3H), 1.96 (s, 3H), 1.93 (s, 6H),
1.91 (s, 3H), 1.89 (s, 3H). 13C NMR (75 MHz, CDCl3)
d (ppm): 190.8,
170.3,170.1,170.0,169.8,169.4,169.3,150.9, 150.8,132.6,125.2,117.7,
110.7, 98.8, 95.6, 74.7, 72.7, 72.4, 71.7, 70.0, 69.2, 68.5, 68.0, 62.6,

2604
C.-Y. Chen et al. / Tetrahedron 68 (2012) 2598e2606
product was collected by filtration, washed with ice-cold water, and
dried in air, affording desired glycosides 16aed or 19aed.
70.8, 68.5, 62.1, 20.95, 20.86, 20.84, 20.76. MS (ESI, negative) m/z
calcd for C21H23O12: 467.12 [MꢂH]ꢂ; found: 467.10.
4.1.9.1. 3-Methoxy-4-[(20,30,40,60-tetra-O-acetyl-
anosyl)oxy]benzoic acid 16a. Yield 89%; white solid, mp:
165e168 ꢁC. 1H NMR (300 MHz, DMSO-d6)
(ppm): 7.53 (d,
b
-
D
-glucopyr-
4.1.9.6. 2-[(20,30,40,60-Tetra-O-acetyl-
benzoic acid 19b. Yield 94%; white solid, mp: 71e74 ꢁC. 1H NMR
(300 MHz, DMSO-d6)
b-D-galactopyranosyl) oxy]
d
d
(ppm): 7.57 (dd, J¼7.5, 1.5 Hz, 1H), 7.50 (t,
J¼8.1 Hz, 1H), 7.49 (s, 1H), 7.18 (d, J¼8.1 Hz, 1H), 5.53 (d, J¼8.1 Hz,
1H), 5.38 (t, J¼9.6 Hz, 1H), 5.09e4.96 (m, 2H), 4.25e4.16 (m, 2H),
4.06 (d, J¼9.9 Hz, 1H), 3.78 (s, 3H), 2.00 (s, 3H), 1.99 (s, 6H), 1.95 (s,
J¼7.5 Hz, 1H), 7.19 (d, J¼8.1 Hz, 1H), 7.11 (t, J¼7.5 Hz, 1H), 5.44e5.42
(m, 1H), 4.40e4.33 (m, 1H), 5.40 (d, J¼0.9 Hz, 1H), 5.26e5.24 (m,
2H), 4.47e4.43 (m, 1H), 4.18e4.08 (m, 2H), 2.14 (s, 3H), 2.02 (s, 6H),
3H). 13C NMR (75 MHz, DMSO-d6)
d
(ppm): 170.5, 170.1, 169.8, 169.5,
1.97 (s, 3H), 1.92 (s, 3H). 13C NMR (75 MHz, DMSO-d6)
d (ppm):
167.3, 149.7, 149.6, 126.6, 123.0, 117.0, 113.7, 98.3, 72.3, 71.4, 71.1,
68.4, 62.1, 56.4, 20.94, 20.88, 20.79. MS (ESI, negative) m/z calcd for
C22H25O13: 497.13 [MꢂH]ꢂ; found: 497.15. HRMS (ESI, positive) m/z
calcd for C22H28O14: 516.1479 [MþH2O]þ; found: 516.1489.
170.4, 170.3, 170.0,169.4, 167.7,155.1, 132.8, 130.4, 124.0,123.0, 116.7,
98.9, 70.9, 70.7, 68.3, 67.8, 61.8, 20.9, 20.84, 20.79. MS (ESI, negative)
m/z calcd for C21H23O12: 467.12 [MꢂH]ꢂ; found: 467.10. HRMS (ESI,
positive) m/z calcd for C21H26O13: 486.1373 [MþH2O]þ; found:
486.1379.
4.1.9.2. 3-Methoxy-4-[(20,30,40,60-tetra-O-acetyl-
anosyl)oxy]benzoic acid 16b. Yield 92%; white solid, mp: 81e83 ꢁC.
1H NMR (300 MHz, DMSO-d6)
(ppm): 7.55e7.52 (m, 2H), 7.15 (d,
b-D-galactopyr-
4.1.9.7. 2-[(20,30,60,200,300,400,600-Hepta-O-acetyl-
benzoic acid (19c). Yield 82%; white solid, mp: 105e108 ꢁC. 1H NMR
(300 MHz, DMSO-d6)
b-D-lacto-syl)oxy]
d
J¼8.4 Hz, 1H), 5.41e5.23 (m, 4H), 4.39 (t, J¼6.3 Hz, 1H), 4.11e4.09
d
(ppm): 12.75 (s, 1H),7.56 (d, J¼7.5 Hz, 1H),
(m, 2H), 3.78 (s, 3H), 2.14 (s, 3H), 2.01 (s, 3H), 1.99 (s, 3H), 1.93 (s,
7.51e7.46 (m, 1H), 7.17 (d, J¼8.4 Hz, 1H), 7.10 (t, J¼7.5 Hz, 1H), 5.45
(d, J¼8.1 Hz, 1H), 5.29e5.14 (m, 3H), 4.98 (dd, J¼9.3, 8.1 Hz, 1H),
4.88e4.77 (m, 2H), 4.40e4.33 (m, 1H), 4.25e4.20 (m, 1H),
4.15e4.09 (m, 2H), 4.01 (d, J¼6.0 Hz, 1H), 3.89 (t, J¼8.7 Hz, 1H), 2.09
(s, 4H), 2.07 (s, 4H), 2.02 (s, 4H), 2.00 (s, 4H),1.97 (s, 4H),1.95 (s, 4H),
3H). 13C NMR (75 MHz, DMSO-d6)
d (ppm): 170.4,170.3,170.0,169.6,
168.0, 149.6, 149.4, 128.2, 122.9, 117.1, 113.9, 99.1, 70.9, 70.6, 68.8,
67.7, 61.8, 56.4, 20.91, 20.88, 20.86, 20.80. MS (ESI, negative) m/z
calcd for C22H25O13: 497.13 [MꢂH]ꢂ; found: 497.15. HRMS (ESI,
positive) m/z calcd for C22H28O14: 516.1479 [MþH2O]þ; found:
516.1491.
1.89 (s, 4H). 13C NMR (75 MHz, DMSO-d6)
d (ppm): 170.6, 170.4,
170.0, 169.8, 169.55, 169.46, 167.5, 155.2, 132.9, 130.5, 123.5, 122.9,
116.6, 100.4, 98.0, 76.7, 72.8, 72.3, 71.0, 70.8, 70.2, 69.4, 67.5, 65.4,
4.1.9.3. 3-Methoxy-4-[(20,30,60,200,300,400,600-hepta-O-acetyl-
syl)oxy]benzoic acid 16c. Yield 80%; white solid, mp: 146e149 ꢁC.
1H NMR (300 MHz, DMSO-d6)
(ppm): 7.52e7.47 (m, 2H), 7.12 (d,
b
-lacto-
61.3, 21.1, 20.9, 20.8. MS (ESI, negative) m/z calcd for C33H39O20:
755.20 [MꢂH]ꢂ; found: 755.20. HRMS (ESI, positive) m/z calcd for
d
C33H42O21: 774.2219 [MþH2O]þ; found: 774.2227.
J¼8.1 Hz, 1H), 5.46 (d, J¼8.1 Hz, 1H), 5.29e5.21 (m, 2H), 5.16 (d,
J¼9.9, 3.6 Hz, 1H), 4.97 (dd, J¼9.6, 8.1 Hz, 1H), 4.87e4.75 (m, 2H),
4.33 (d, J¼10.5 Hz, 1H), 4.25e4.20 (m, 1H), 4.13e4.00 (m, 4H), 3.88
(t, J¼9.0 Hz, 1H), 3.76 (s, 3H), 3.15 (s, 1H), 2.09 (s, 1H), 2.05 (s, 1H),
2.01 (s,1H), 2.00 (s,1H),1.98 (s,1H),1.97 (s,1H),1.89 (s, 3H). 13C NMR
4.1.9.8. 2-[(20,30,60,200,300,400,600-Hepta-O-acetyl-
benzoic acid (19d). Yield 80%; white solid, mp: 180e183 ꢁC. 1H NMR
(300 MHz, CDCl3)
b-D-malto-syl)oxy]
d
(ppm): 8.09 (d, J¼7.8, 1H), 7.58e7.53 (m, 1H),
7.26e7.18 (m, 2H), 5.44 (m,1H), 5.37e5.30 (m, 2H), 5.20e5.15 (m,
1H), 5.06 (t, J¼9.9, 1H), 4.87 (dd, J¼10.5, 3.9 Hz, 1H), 4.53 (dd,
J¼12.3, 2.4 Hz, 2H), 4.28e4.04 (m, 5H), 3.99e3.95 (m, 1H), 2.10 (s,
3H), 2.09 (s, 3H), 2.08 (s, 3H), 2.06 (s, 6H), 2.03 (s, 3H), 2.01 (s, 3H).
(75 MHz, DMSO-d6) d (ppm): 170.6, 170.4, 170.0, 169.8, 169.6, 167.8,
149.5, 149.4, 127.3, 122.9, 116.5, 113.7, 100.4, 98.0, 76.6, 72.6, 72.4,
71.3, 70.8, 70.2, 69.3, 67.5, 62.5, 61.3, 56.3, 21.0, 20.9, 20.8. MS (ESI,
negative) m/z calcd for C34H41O21: 785.21 [MꢂH]ꢂ; found: 785.20.
HRMS (ESI, positive) m/z calcd for C34H44O22: 804.2324 [MþH2O]þ;
found: 804.2332.
13C NMR (75 MHz, CDCl3)
d (ppm): 170.6, 170.5, 170.4, 170.2, 170.0,
169.8, 169.5, 166.9, 155.7, 134.6, 133.0, 123.8, 120.2, 116.5, 98.8, 95.7,
74.8, 72.5, 71.5, 70.0, 69.3, 68.6, 68.0, 62.5, 61.5, 20.9, 20.7, 20.6. MS
(ESI, negative) m/z calcd for C33H39O20: 755.20 [MꢂH]ꢂ; found:
755.20. HRMS (ESI, positive) m/z calcd for C33H42O21: 774.2219
[MþH2O]þ; found: 774.2214.
4.1.9.4. 3-Methoxy-4-[(20,30,60,200,300,400,600-hepta-O-acetyl-
tosyl)oxy]benzoic acid 16d. Yield 83%; white solid, mp: 90e93 ꢁC.
1H NMR (300 MHz, DMSO-d6)
(ppm): 12.85 (s, 1H), 7.53 (dd,
b-mal-
d
J¼8.1, 2.1 Hz, 1H), 7.48 (d, J¼2.1 Hz, 3H), 7.14 (d, J¼8.1 Hz, 1H), 5.52
(d, J¼8.1 Hz, 1H), 5.42 (t, J¼9.3 Hz, 1H), 5.29 (d, J¼3.6 Hz, 1H), 5.22
(t, J¼9.6 Hz, 1H), 5.01e4.94 (m, 2H), 4.88 (dd, J¼10.2, 3.9 Hz, 1H),
4.44e4.37 (m, 1H), 4.24e4.13 (m, 3H), 4.06e3.96 (m, 3H), 3.77 (s,
3H), 2.04 (s, 3H), 2.01 (s, 3H), 1.983 (s, 3H), 1.977 (s, 3H), 1.96 (s,
4.1.10. General procedure for synthesis of glycosylated psoralen de-
rivatives 17aed or 20aed. To a stirred solution of 16aed or 19aed
(0.8 mmol) and 4,40-dimethylxanthotoxol (10) (0.23 g, 1.0 mmol) in
anhydrous dichloromethane (25 mL) was added N,N0-diisopro-
pylcarbodiimide (0.15 g, 1.2 mmol) and 4-dimethylamiopryidine
(0.05 g, 0.4 mmol). The reaction mixture was stirred at room
temperature for 12 h. After reaction, the mixture was filtered. The
filtrate was washed with 0.5 N HCl and brine, dried over anhydrous
sodium sulfate. After evaporation, the residue was subjected to
column chromatography (silica gel, ethyl acetate/petroleum
ether¼1:2) to give glycosylated psoralen derivatives 17aed or
20aed.
6H), 1.94 (s, 3H). 13C NMR (75 MHz, DMSO-d6)
d (ppm): 170.5,
170.3, 170.1, 170.0, 169.7, 167.2, 159.3, 149.8, 149.6, 126.3, 123.0,
116.7, 113.7, 97.8, 96.0, 74.5, 74.1, 72.1, 71.8, 69.9, 69.3, 68.6, 68.2,
63.2, 61.9, 56.4, 21.0, 20.9, 20.82, 20.75. MS (ESI, positive) m/z calcd
for C34H42O21Na: 809.21 [MþNa]þ; found: 809.50. HRMS (ESI,
positive) m/z calcd for C34H44O22: 804.2324 [MþH2O]þ; found:
804.2341.
4.1.9.5. 2-[(20,30,40,60-Tetra-O-acetyl-
benzoic acid 19a. Yield 90%; white solid, mp: 164e165 ꢁC (lit.
168e169 ꢁC50) 1H NMR (300 MHz, CDCl3)
b
-
D
-glucopyranosyl)-oxy]
4.1.10.1. Glycosylated psoralen derivative 17a. Yield 83%; white
solid, mp: 198e201 ꢁC. 1H NMR (300 MHz, CDCl3)
d (ppm): 7.89 (d,
d
(ppm): 8.09 (dd, J¼7.5,
J¼6.6 Hz, 1H), 7.78 (s, 1H), 7.60 (s, 1H), 7.45 (s, 1H), 7.21 (d, J¼7.8 Hz,
1H), 6.25 (s, 1H), 5.35e5.32 (m, 2H), 5.21e5.15 (m, 1H), 5.12e5.09
(m, 1H), 4.24 (dd, J¼12.3, 5.1 Hz, 2H), 4.18 (dd, J¼12.1, 2.1 Hz, 2H),
3.91 (s, 3H), 3.89e3.83 (m,1H), 2.52 (s, 3H), 2.28 (s, 3H), 2.09 (s, 6H),
1.2 Hz, 1H), 7.58e7.52 (m, 1H), 7.27e7.17 (m, 2H), 5.37e5.34 (m,
2H), 5.31e5.18 (m, 2H), 4.24 (qd, J¼12.3, 4.8 Hz, 2H), 3.93 (ddd,
J¼9.9, 5.1, 2.7 Hz, 1H), 2.10 (s, 3H), 2.07 (s, 6H), 2.059 (s, 3H), 2.056
(s, 3H). 13C NMR (75 MHz, DMSO-d6)
d
(ppm): 170.5, 170.0, 169.8,
2.04 (s, 6H). 13C NMR (75 MHz, CDCl3)
d
(ppm): 170.6, 170.3, 169.5,
169.3, 167.5, 155.2, 133.0, 130.6, 123.7, 123.0, 116.7, 98.3, 72.5, 71.3,
169.4, 163.1, 160.0, 152.9, 150.8, 150.4, 143.7, 143.6, 127.2, 124.5,

C.-Y. Chen et al. / Tetrahedron 68 (2012) 2598e2606
2605
124.1, 118.4, 117.1, 116.2, 114.4, 113.5, 112.1, 100.0, 72.5, 72.3, 71.1,
68.3, 61.9, 56.3, 20.8, 20.6, 19.4, 7.8. MS (ESI, positive) m/z calcd for
C35H34O16Na: 733.17 [MþNa]þ; found: 733.17. HRMS (ESI, positive)
m/z calcd for C35H35O16: 711.1925 [MþH]þ; found: 711.1931.
4.1.10.6. Glycosylated psoralen derivative 20b. Yield 79%; light
yellow solid, mp: 121e124 ꢁC. 1H NMR (300 MHz, CDCl3)
(ppm):
d
8.23 (dd, J¼7.5, 1.5 Hz, 1H), 7.60 (s, 1H), 7.57e7.54 (m, 1H), 7.47 (s,
1H), 7.32e7.22 (m, 2H), 6.26 (s, 1H), 5.53 (dd, J¼10.5, 8.4 Hz, 1H),
5.44 (d, J¼3.3 Hz, 1H), 5.24 (d, J¼7.8 Hz, 1H), 5.12 (dd, J¼10.5, 3.3 Hz,
1H), 4.26e4.07 (m, 3H), 2.54 (s, 3H), 2.29 (s, 3H), 2.19 (s, 3H), 2.15 (s,
3H), 2.05 (s, 3H), 1.93 (s, 3H), 1.70 (s, 3H). 13C NMR (75 MHz, CDCl3)
4.1.10.2. Glycosylated psoralen derivative 17b. Yield 77%; white
solid, mp: 130e133 ꢁC. 1H NMR (300 MHz, CDCl3)
d (ppm): 7.91 (dd,
J¼8.7, 1.5 Hz, 1H), 7.79 (d, J¼1.5 Hz, 1H), 7.62 (d, J¼1.2 Hz, 1H), 7.47
(s, 1H), 7.23 (d, J¼8.4 Hz, 1H), 6.27 (s, 1H), 5.58 (dd, J¼10.2, 7.8 Hz,
1H), 5.47 (d, J¼2.7 Hz, 1H), 5.14 (dd, J¼10.5, 3.3 Hz, 1H), 5.06 (d,
J¼7.8 Hz, 1H), 4.25e4.19 (m, 2H), 4.07 (t, J¼6.6 Hz, 1H), 3.92 (s, 3H),
2.54 (s, 3H), 2.30 (s, 3H), 2.19 (s, 3H), 2.11 (s, 3H), 2.07 (s, 3H), 2.03 (s,
d (ppm): 170.4, 170.3, 170.0, 169.4, 161.5, 160.0, 156.9, 152.9, 148.8,
143.7, 143.5, 134.6, 132.9, 127.2, 123.6, 123.1, 119.8, 119.2, 117.0, 116.2,
113.4, 111.9, 100.1, 71.1, 70.9, 68.3, 67.1, 61.4, 20.7, 20.6, 20.4, 19.4, 7.8.
MS (ESI, positive) m/z calcd for C34H32O15Na: 703.16 [MþNa]þ;
found: 703.10. HRMS (ESI, positive) m/z calcd for C34H33O15
681.1819 [MþH]þ; found: 681.1814.
:
3H). 13C NMR (75 MHz, CDCl3)
d (ppm): 170.4, 170.3, 170.2169.5,
163.1,160.0,152.9,151.0,150.3,148.7,143.7,143.6,127.2,124.5,124.0,
123.1, 118.1, 117.2, 116.2, 114.4, 113.5, 112.0, 100.6, 71.3, 70.7, 68.5,
66.9, 61.4, 56.3, 20.8, 20.72, 20.67, 20.63, 19.38, 7.8. MS (ESI, posi-
tive) m/z calcd for C35H34O16Na: 733.17 [MþNa]þ; found: 733.17.
HRMS (ESI, positive) m/z calcd for C35H35O16: 711.1925 [MþH]þ;
found: 711.1929.
4.1.10.7. Glycosylated psoralen derivative 20c. Yield 65%; white
solid, mp: 169e172 ꢁC. 1H NMR (300 MHz, CDCl3)
(ppm): 8.20 (dd,
d
J¼8.1, 1.8 Hz, 1H), 7.61e7.54 (m, 2H), 7.49 (d, J¼1.2 Hz, 1H), 7.25e7.20
(m, 2H), 6.29 (s, 1H), 5.34e5.20 (m, 4H), 5.12 (dd, J¼10.5, 8.1 Hz, 1H),
4.96 (dd, J¼10.5, 3.6 Hz, 1H), 4.56e4.50 (m, 2H), 4.16 (dd, J¼11.7,
5.7 Hz, 1H), 4.07e3.98 (m, 3H), 3.90e3.86 (m, 2H), 2.55 (s, 3H), 2.30
(s, 3H), 2.14 (s, 3H), 2.04 (s, 6H), 2.02 (s, 3H), 1.96 (s, 3H), 1.94 (s, 3H),
4.1.10.3. Glycosylated psoralen derivative 17c. Yield 79%; light
yellow solid, mp: 149e152 ꢁC. 1H NMR (300 MHz, CDCl3)
d
(ppm):
1.72 (s, 3H). 13C NMR (75 MHz, CDCl3)
d (ppm): 170.35, 170.30, 170.1,
7.89 (dd, J¼8.4,1.8 Hz,1H), 7.78 (d, J¼1.8 Hz,1H), 7.62 (s,1H), 7.46 (d,
J¼1.2 Hz, 1H), 7.18 (d, J¼8.7 Hz, 1H), 6.27 (s, 1H), 5.37e5.22 (m, 3H),
5.16e5.07 (m, 2H), 4.97 (dd, J¼10.2, 3.3 Hz, 1H), 4.55e4.51 (m, 2H),
4.19e4.09 (m, 3H), 3.94e3.88 (m, 2H), 3.91 (s, 3H), 3.81e3.75 (m,
1H), 2.54 (s, 3H), 2.30 (s, 3H), 2.30 (s, 3H), 2.16 (s, 3H), 2.11 (s, 3H),
2.093 (s, 3H), 2.090 (s, 3H), 2.07 (s, 3H), 2.06 (s, 3H), 1.97 (s, 3H). 13C
170.0, 169.7, 169.5, 169.1, 161.7, 159.9, 156.7, 152.9, 148.7, 143.7, 143.5,
134.6, 132.8, 127.1, 123.3, 123.0, 119.7, 118.3, 117.0, 116.2, 113.5, 111.9,
100.7, 98.9, 76.1, 72.74, 72.69, 71.4, 71.0, 70.6, 69.1, 66.7, 62.1, 60.8,
20.7, 20.6, 20.5, 20.3, 19.3, 7.8. MS (ESI, positive) m/z calcd for
C46H48O23Na: 991.25 [MþNa]þ; found: 991.42. HRMS (ESI, positive)
m/z calcd for C46H49O23: 969.2665 [MþH]þ; found: 969.2675.
NMR (75 MHz, CDCl3)
d (ppm): 170.41, 170.36, 170.2, 170.1, 169.8,
169.6, 169.1, 163.1, 160.0, 152.9, 150.8, 150.3, 148.7, 143.7, 143.6,
124.4, 127.2, 124.0, 123.1, 118.1, 117.1, 116.2, 114.3, 113.5, 112.1, 101.1,
99.6, 76.1, 73.0, 72.5, 71.3, 71.0, 70.7, 69.1, 66.7, 61.9, 60.9, 56.2, 20.8,
20.7, 20.5, 19.4, 7.8. MS (ESI, positive) m/z calcd for C47H50O24Na:
1021.26 [MþNa]þ; found: 1021.25. HRMS (ESI, positive) m/z calcd
for C47H51O24: 999.2770 [MþH]þ; found: 999.2758.
4.1.10.8. Glycosylated psoralen derivative 20d. Yield 70%; light
yellow solid, mp: 131e134 ꢁC. 1H NMR (300 MHz, CDCl3)
d (ppm):
8.20 (dd, J¼8.1, 1.8 Hz, 1H), 7.62e7.57 (m, 2H), 7.48 (d, J¼1.2 Hz, 1H),
7.24e7.21 (m, 2H), 6.26 (d, J¼1.2 Hz, 1H), 6.26 (d, J¼3.6 Hz, 1H),
5.37e5.28 (m, 3H), 5.18 (dd, J¼9.0, 7.5 Hz, 1H), 5.04 (t, J¼9.6 Hz, 1H),
4.85 (dd, J¼10.5, 3.9 Hz, 1H), 4.51 (dd, J¼12.0, 3.0 Hz, 1H), 4.32e4.23
(m, 2H), 4.17e4.11 (m, 1H), 4.07e3.90 (m, 3H), 2.54 (s, 3H), 2.30 (d,
J¼0.9 Hz, 3H), 2.10 (s, 3H), 2.09 (s, 3H), 2.03 (s, 6H), 2.00 (s, 3H), 1.91
4.1.10.4. Glycosylated psoralen derivative 17d. Yield 66%; white
solid, mp: 129e132 ꢁC. 1H NMR (300 MHz, CDCl3)
d
(ppm): 7.91 (dd,
(s, 3H), 1.73 (s, 3H). 13C NMR (75 MHz, CDCl3)
d (ppm): 170.6, 170.5,
J¼8.4, 2.1 Hz, 1H), 7.77 (d, J¼1.8 Hz, 1H), 7.61 (s, 1H), 7.46 (d,
J¼1.5 Hz, 1H), 7.18 (d, J¼8.1 Hz, 1H), 6.26 (d, J¼1.2 Hz, 1H), 5.44 (d,
J¼3.9 Hz, 1H), 5.40e5.33 (m, 2H), 5.18e5.16 (m, 2H), 5.05 (t,
J¼10.2 Hz, 1H), 4.87 (dd, J¼10.2, 3.6 Hz, 1H), 4.51 (dd, J¼12.3, 3.0 Hz,
1H), 4.26 (dt, J¼12.3, 4.2 Hz, 2H), 4.14e3.95 (m, 3H), 3.90 (s, 3H),
3.88e3.84 (m, 1H), 2.53 (s, 3H), 2.29 (s, 3H), 2.12 (s, 3H), 2.10 (s, 3H),
2.07 (s, 3H), 2.054 (s, 3H), 2.048 (s, 3H), 2.02 (s, 3H), 2.00 (s, 3H). 13C
170.4, 170.1, 169.9, 169.6, 169.5, 161.7, 159.5, 156.7, 152.8, 148.7, 143.6,
143.5, 134.7, 132.8, 127.1, 123.3, 119.7, 117.9, 117.0, 116.1, 113.4, 111.9,
98.8, 95.6, 75.2, 72.7, 72.4, 71.7, 70.0, 69.4, 68.5, 68.1, 62.8, 61.6, 20.8,
20.73, 20.67, 20.59, 20.56, 20.3, 19.3, 7.8. MS (ESI, positive) m/z calcd
for C46H48O23Na: 991.25 [MþNa]þ; found: 991.33. HRMS (ESI, posi-
tive) m/z calcd for C46H49O23: 969.2665 [MþH]þ; found: 969.2662.
NMR (75 MHz, CDCl3)
d
(ppm): 170.6, 170.4, 170.2, 170.0, 169.7,
4.2. Biology
163.1, 160.0, 152.9, 150.6, 150.3, 148.6, 143.7, 143.6, 127.2, 124.5,
124.0, 123.1, 118.1, 117.1, 116.2, 114.3, 113.5, 112.1, 99.2, 95.7, 75.0,
72.7, 72.5, 71.9, 70.0, 69.3, 68.6, 68.0, 62.7, 61.6, 56.2, 20.9, 20.8, 20.7,
20.6, 19.4, 7.8. MS (ESI, positive) m/z calcd for C47H50O24Na: 1021.26
[MþNa]þ; found: 1021.25. HRMS (ESI, positive) m/z calcd for
C47H51O24: 999.2770 [MþH]þ; found: 999.2761.
4.2.1. Cell viability assay (MTT). HepG2, A431, HeLa, and SA cells
(7000 cells/well) were seeded in each well of a 96-well plate for
24 h. New medium was added to give final concentrations of
0e200 mM of our glycosylated psoralen derivatives. The cells were
cultured in dark immediately or exposed to UVA light for 30 min
without lids. All irradiations were performed with a UVGL 58 lamp
emitting mainly at 365 nm. The total UVA dose was 0.3ꢀ0.06 J/cm2
and the plates were then moved to incubator with lids. After 48 h
4.1.10.5. Glycosylated psoralen derivative 20a. Yield 74%; white
solid, mp: 177e180 ꢁC. 1H NMR (300 MHz, CDCl3)
d (ppm): 8.20 (dd,
J¼7.8, 1.5 Hz, 1H), 7.59 (s, 1H), 7.57e7.54 (m, 1H), 7.48 (d, J¼1.2 Hz,
1H), 7.28e7.22 (m, 2H), 6.26 (s, 1H), 5.33e5.25 (m, 3H), 5.20e5.14
(m, 1H), 4.30 (dd, J¼12.3, 5.4 Hz, 1H), 4.17 (dd, J¼12.3, 2.4 Hz, 1H),
3.90 (ddd, J¼9.6, 5.1, 2.1 Hz, 1H), 2.53 (s, 3H), 2.29 (d, J¼0.9 Hz, 1H),
2.06 (s, 3H), 2.03 (s, 6H), 1.94 (s, 3H), 1.68 (s, 3H). 13C NMR (75 MHz,
the medium was discarded and 50 mL of 1 mg/mL 3-(4,5-
dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT, Sig-
maeAldrich Chemical) was added to each well and incubated for
4 h at 37 ꢁC. The purple formazan formed was then solubilized by
DMSO. Absorbance at 570 nm was read by a microplate reader
(Molecular Devices).
CDCl3)
d (ppm): 170.6, 170.1, 169.5, 169.3, 161.7, 160.0, 156.6, 153.0,
148.7,143.6,134.6,132.8,127.2,123.6,123.0,120.0,119.0,117.0,116.2,
113.4, 112.0, 99.6, 72.8, 72.0, 70.9, 68.3, 62.0, 20.7, 20.62, 20.57, 20.2,
19.4, 7.8. MS (ESI, positive) m/z calcd for C34H32O15Na: 703.16
[MþNa]þ; found: 703.10. HRMS (ESI, positive) m/z calcd for
C34H33O15: 681.1819 [MþH]þ; found: 681.1826.
4.2.2. Effects of compounds on the oxidation of DNA mediated by
Cu2þ/GSH. Cu2þ/GSH-mediated oxidation of DNA was performed
according to the reference.35 Aqueous solution of CuSO4 was mixed
with the phosphate buffered solutions (6.1 mM Na2HPO4, 3.9 mM

2606
C.-Y. Chen et al. / Tetrahedron 68 (2012) 2598e2606
13. Jia, X. D.; Feng, X.; Zhao, X. Z.; Dong, Y. F.; Zhao, Y. Y.; Sun, H. Chem. Nat. Compd.
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NaH2PO4) of DNA and GSH, in which the final concentration for
DNA, Cu2þ, and GSH were 2.0 mg/mL, 5.0 mM, and 3.0 mM, re-
spectively. Then, the solution of our glycosylated psoralen de-
rivatives in dimethyl sulfoxide (DMSO) was added with the final
concentration of their IC50. The above mixture was dispensed into
test tubes, each one contained 1.0 mL. The test tubes were in-
cubated in a water bath (37 ꢁC) to initiate the oxidation of DNA.
Tubes were taken out after 30 min and cooled immediately, to
which 0.5 mL of PBS solution of EDTA (30.0 mM as the final con-
centration) was added to chelate Cu2þ. Then 0.5 mL of thio-
barbituric acid (TBA) solution (1.00 g TBA and 0.40 g NaOH
dissolved in 100 mL of PBS) and 0.5 mL of 3.0% trichloroacetic acid
aqueous solution were added, followed by heating in boiling water
for 30 min. After the mixture in the test tube was cooled to room
temperature, 0.75 mL of n-butanol was added and shaken vigor-
ously to extract TBA reactive substance (TBARS). The absorbance of
n-butanol layer was measured at 535 nm, and plotted versus in-
cubation time.
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Financial supports from National High Technology Research and
Development Program of China (No. 2007AA021504), MOST of
China (973 program 2011CB808600) and NSFC (No. 20872059 and
21072091) are gratefully acknowledged. We thank Dr. Yin Ding
(State Key Laboratory of Analytical Chemistry for Life Science, De-
partment of Chemistry, Nanjing University, Nanjing 210093, P.R.
China) for the determination of HRMS.
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Supplementary data related to this article can be found online at
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