Novel and facil synthesis and evaluation of antitumor activities of 6,7-bisaryl-1-(β-D-ribofuranosyl)pteridine-2,4(1H,3H)-diones

Article abstract of DOI:10.3987/COM-09-S(S)77

Novel 6,7-bisaryl-1-(β-D-ribofuranosyl)pteridine-2,4(1H,3H)-dione derivatives were synthesized by condensation of 5,6-diamino-2′,3′-O-isopropylideneuridine, which was derived from uridine, with an appropriate α,β-diketone, followed by acidic hydrolysis allowing removal of the isopropylidene group of the sugar moiety as a protecting group. Moreover, several N-3 alkyl derivatives of the 6,7-bisaryl-1-(β-D-ribofuranosyl)pteridine-2,4(1H,3H)-diones were obtained by alkylation of the 6,7-bisaryl-1-(2′,3′-O-isopropylidene-β-D-ribofuranosyl)pteridine-2,4(1H,3H)-diones with alkyl halides and by their acidic hydrolysis for deprotection. The antitumor activities of all synthesized compounds against CCRF-HSB-2 and KB cell lines were also investigated in vitro and some of the compounds showed prospective antitumor activities.

Full text of DOI:10.3987/COM-09-S(S)77

HETEROCYCLES, Vol. 80, No. 1, 2010
557
HETEROCYCLES, Vol. 80, No. 1, 2010, pp. 557ꢀ- 577. © The Japan Institute of Heterocyclic Chemistry
Received, 27th July, 2009, Accepted, 25th August, 2009, Published online, 26th August, 2009
DOI: 10.3987/COM-09-S(S)77
NOVEL AND FACIL SYNTHESIS AND EVALUATION OF ANTITUMOR
ACTIVITIES OF 6,7-BISARYL-1-(ꢀ-D-RIBOFURANOSYL)PTERIDINE-
2,4(1H,3H)-DIONES
Rafiya Khan Kandahary,a Abugafar M. L. Hossion, a Noriyuki Ashida,b and
Tomohisa Nagamatsua,*
aDepartment of Drug Discovery and Development, Division of Pharmaceutical
Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,
Okayama University, Tsushima-naka, Kita-ku, Okayama City, Okayama
b
700-8530, Japan and Biology Laboratory, Research and Development Division,
Yamasa
Shoyu
Co.,
Choshi,
Chiba
288-0056,
Japan;
Email:
nagamatsu@pheasant.pharm.okayama-u.ac.jp
Abstract – Novel 6,7-bisaryl-1-(ꢀ-D-ribofuranosyl)pteridine-2,4(1H,3H)-dione
derivatives were synthesized by condensation of 5,6-diamino-2’,3’-O-iso-
propylideneuridine, which was derived from uridine, with an appropriate ꢁ,ꢀ-
diketone, followed by acidic hydrolysis allowing removal of the isopropylidene
group of the sugar moiety as a protecting group. Moreover, several N-3 alkyl
derivatives of the 6,7-bisaryl-1-(ꢀ-D-ribofuranosyl)pteridine-2,4(1H,3H)-diones
were obtained by alkylation of the 6,7-bisaryl-1-(2’,3’-O-isopropylidene-ꢀ-D-
ribofuranosyl)pteridine-2,4(1H,3H)-diones with alkyl halides and by their acidic
hydrolysis for deprotection. The antitumor activities of all synthesized
compounds against CCRF-HSB-2 and KB cell lines were also investigated in
vitro and some of the compounds showed prospective antitumor activities.
INTRODUCTION
The development of practical and efficient route for synthesis of the drug like small molecules is of
considerable interest to medicinal chemists and chemical biologists.1,2 Nucleoside analogs have been well
established as one of the richest sources of antiviral agents despite their toxicity3,4 and the drug
resistance.5 Others are active compounds exhibiting antineoplastic,6–9 antibiotic and antifungal
properties.10–12 Recently, some nucleoside analogs (NAs) have been developed as antitumor agents, and

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HETEROCYCLES, Vol. 80, No. 1, 2010
their activities generally have been shown to result from their incorporation into DNA and/or inhibition of
DNA polymerases of cells.13,14 Some nucleoside derivatives as antimetabolite, e.g. 1-(ꢀ-D-
arabinofuranosyl)cytosine (araC), 2-chloro-2’-deoxyadenosine (CldA), 9-ꢀ-D-arabinofuranosyl-2-fluoro-
adenine 5’-monophosphate (fludarabine, FaraAMP), 2’-deoxy-2’,2’-difluorocytidine (gemcitabine, dFdC),
have been widely used not only as antileukemic agents, but also as antitumor agents against solid
tumors.15 Nevertheless, the survival rate of patients still remains low and one of the reasons is the poor
sensitivity of tumors to drugs. Therefore, the development of new agents capable of suppressing tumor
growth would contribute greatly to a better prognosis and current therapy.16 Then, several approaches of
large nucleoside analogue libraries have emerged as an important synthetic goal to chase the high
efficiency and velocity of the current biological screenings.
As a part of our ongoing project of novel antitumor agents,17–25 our recent interest is the fused pyrimidines
containing pteridine ring systems in which carbohydrate moiety is attached to pyrimidine ring.ꢀ Several
examples of similar nucleosides have been prepared by direct glycosylation into pteridine ring via the
silylation method,26 which did not serve the facile path due to containing by-products, nor did good
yield.27–31 Herein we describe the first, new and convenient synthetic route of pteridine nucleosides,
6,7-diaryl-1-(ꢀ-D-ribofuranosyl)pteridine-2,4(1H,3H)-diones (4b–g), which were derived in several steps
from uridine. Various 3-N-alkylated pteridine nucleosides (6a–l) were also prepared by alkylation of the
pteridine nucleosides (3c–f) with appropriate alkyl halides in alkali solution, followed by acidic
hydrolysis. The purpose of this work is to evaluate their antitumor activities in vitro against CCRF-HSB-2
and KB cell lines and to survey the change of biological activity of various 6,7-bisarylpteridine
nucleosides as well as the nucleosides having a different alkyl group at the N-3-position in order to
establish structure-activity relationship. Even though two nucleosides (4a and 4b) of the pteridinedione
have been previously reported by a different synthetic method,27 we wanted to include them in our study
to evaluate any differences in biological activity.
RESULTS AND DISCUSSION
The desired starting material, 6-amino-5-nitroso-2’,3’-O-isopropylideneuridine (1), was synthesized from
uridine according to the previously outlined procedure.19 Treatment of the compound (1) with Na2S2O4 in
0.5N aqueous acetic acid solution at room temperature led to the formation of requisite key intermediate
5,6-diamino-2’,3’-O-isopropylideneuridine (2) in 60% yield.32 Subsequent condensation reaction between
5,6-diamino-2’,3’-O-isopropylideneuridine (2) and appropriate ꢁ,ꢀ-diketones in ethanol at refluxing
temperature afforded the corresponding,ꢀ 1-(2’,3’-O-isopropylidene-ꢀ-D-ribofuranosyl)pteridine-2,4(1H,
3H)-dione (3a) and its diphenyl (3b) and 6,7-bisaryl derivatives (3c–g)ꢀ in 58%, 70%, and 60–65%
yields, respectively, as shown in Scheme 1 and Table 1. Then, the 1-(2’,3’-O-isopropylidene-ꢀ-D-

HETEROCYCLES, Vol. 80, No. 1, 2010
559
O
N
O
O
N
NO
NH2
N
N
R1
R1
HN
HN
HN
O
O
NH2
O
O
N
NH2
O
O
HO
HO
HO
ii
i
O
O
O
O
O
O
Me
Me
Me
Me
Me
Me
1
2
3a–g
iii
iv
O
O
O
R2
N
N
R1
R1
R2
N
N
R1
R1
N
R1
R1
HN
N
N
O
O
N
O
O
N
O
O
N
N
HO
HO
HO
HO
HO
v
OH
O
O
OH
Me
Me
4a–g
6a–l
5a–l
Compd R1
Compd R1
R2
3, 4 a
5, 6 a
PhCH2
EtOOCCH2
EtOOC(CH2)3
PhCH2
EtOOCCH2
EtOOC(CH2)3
PhCH2
EtOOCCH2
EtOOC(CH2)3
PhCH2
H
C6H5
4-Me-C6H4
4-MeO-C6H4
4-F-C6H4
4-Br-C6H4
2-Furyl
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
4-MeO-C6H4
4-MeO-C6H4
4-MeO-C6H4
4-F-C6H4
4-F-C6H4
4-F-C6H4
4-Br-C6H4
4-Br-C6H4
4-Br-C6H4
b
b
c
d
e
f
g
h
i
c
d
e
f
g
j
k
l
EtOOCCH2
EtOOC(CH2)3
Reagents and conditions: i, Na2S2O4, 0.5N AcOH (aq.), rt, 1h; ii, ꢀ,ꢁ-diketone, EtOH, reflux,
18h; iii, MeOH, 0.5N HCl, 50 °C, 2h; iv, Alkyl halide, DMF, K2CO3, 0 oC, 2h; v, MeOH,
0.5N HCl, 50 °C, 3h.
Scheme 1
ribofuranosyl)pteridine-2,4(1H,3H)-diones (3a–g) thus obtained were treated with 0.5N hydrochloric acid
in methanol solution at 50 °C to afford the corresponding deprotected 1-(ꢀ-D-ribofuranosyl)pteridine-

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HETEROCYCLES, Vol. 80, No. 1, 2010
2,4(1H,3H)-dione and its 6,7-bisaryl derivatives (4a–g) in 50–76% yields. All new compounds (3c–g and
1
4c–g) exhibited satisfactory elemental combustion analyses except for 3c and UV, IR, and H-NMR
spectral data as shown in Tables 1–3, consistent with the structures indicated in Scheme 1. The
compounds (3a,b and 4a,b) were identified with the previously reported compounds in all spectral
data.27,33 This simple and convenient preparation of the pteridine nucleosides suggested that the previous
methods26–31 by direct glycosylation via silylation of the pteridines were not expeditious. On the other
hand, synthesis of the N-3 substituted alkyl derivatives (5a–l) of 6,7-bisaryl-1-(2’,3’-O-isopropylidene-
ꢀ-D-ribofuranosyl)pteridine-2,4(1H,3H)-diones (3c–f) were accomplished by alkylation of the pteridine
nucleosides (3c–f) protected by an isopropylidene group on the sugar moiety with appropriate alkyl
halides (i.e., BrCH2Ph, BrCH2CO2C2H5, and Br(CH2)3CO2C2H5) in the presence of anhydrous K2CO3 and
dry N,N-dimethylformamide (DMF) at 0 °C in 60–70% yields as shown in Tables 4–6. Similarly, the
deprotection of 5a–l were attained by acidic hydrolysis in methanolic HCl solution to get the
corresponding N-3 substituted alkyl derivatives (6a–l) of 6,7-bisaryl-1-(ꢀ-D-ribofuranosyl)pteridine-
2,4(1H,3H)-diones (4c–f) in 60–71% yields (Tables 7–9). Specific rotation, UV, IR, and 1H-NMR spectra
and elemental analyses for 5a–l and 6a–l were also used for the structure determination of the newly
assigned compounds. The amorphous intermediates (3c and 5a,c) were characterized by UV, IR, and
1H-NMR spectra except for the micro analyses and were used for next reaction without any purification.ꢀ
In the 1H-NMR spectra for 3a–g and 5a–l in CDCl3, the presence of an isopropylidine group at the 2’ and
3’-positions of the sugar moieties indicated two singlet signals for protons of two geminal methyl groups
at ꢁ 1.38–1.40 ppm and 1.63–1.67 ppm, respectively. In contrast, the OH proton signals at the 2’ and
3’-positions of 4a–g and 6a–l in DMSO-d6 appeared as doublet at ꢁ 5.05–5.19 ppm and 4.88–4.97 ppm,
respectively. Therefore, the appearance of OH protons supported strongly the deprotected structures on
the sugar moieties. Each geminal proton of the methylene group of sugar moiety at the 5’-position
appeared as triple doublet signals in the region of ca. 3.8–3.9 ppm for 3a–g and 5a–l and ca. 3.4–3.6 ppm
for 4a–g and 6a–l with the coupling constant of 12.0–12.3 Hz between two geminal protons. Considering
the 1H-NMR spectra of the N-3 substituted alkyl derivatives (6a–l), the alkylations were characterized by
disappearance of the singlet signal of NH protons, which were assigned for the compounds (3c–f) at
ꢁ 9.0–9.4 ppm. In case of the benzyl substituted compounds of 5a, 5d, 5g, and 5j were particularly
showed each singlet signal of the geminal protons for benzylic methlene at ca. ꢁ 5.29 and 5.30 ppm,
respectively. The coupling of geminal protons bearing a coupling constant of 16.8 or 17.1 Hz was further
observed in the methylene group for the derivatives (6b, 6e, 6h, and 6k) substituted by an
ethoxycarbonylmethyl group at the 3-position. On the other hand, most of the pteridine nucleosides in
ethanol exhibited three maxima absorption bands at ca. 230–240, 270–290 and 360–380 nm in UV-vis
spectra.

HETEROCYCLES, Vol. 80, No. 1, 2010
561
BIOLOGICAL ACTIVITY
The modified34 3-(3,4-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay for cellular
growth and survival application method developed by Mosmann35 were used to determine the growth
inhibitory effects (antitumor activity) of the synthesized compounds against two human cultured tumor
cell lines, CCRF-HSB-2 (human T-cell acute lymphoblastoid leukemia) and KB (human oral epidermoid
carcinoma) cells in vitro. The antitumor agent, arabinoside cytosine (Ara-C), was used as a positive
control in this study. The results, i.e., 50% inhibitory concentration [IC50ꢀ (μg/mL)] of each compound
against both cells are summarized in Table 10. As can be seen from the table of evaluated antitumor
activities, many pteridine nucleosides (3c,d,f and 5b–e,h,i) protected by a lipophilic isopropylidene group
at the 2’ and 3’-position exhibited potential antitumor activities with IC50 value of ca. 6.0–10.0 μg/mL
against CCF-HSB-2 cells. In contrast, the deprotected pteridine nucleoside (4a–g) showed moderate
activities of ca. 30–100 μg/mL. However, the deprotected pteridine nucleoside (6a–g,j–l) having an alkyl
group such as benzyl, ethoxycarbonylmethyl, and ethoxycarbonylpropyl at the 3-position exhibited more
potential antitumor activity of 9.0–35.0 μg/mL than the compounds (4a–g). On the other hand, the
activities of the protected pteridine nucleosides (3c,f and 5b,c,h,i) against KB cell showed potential
antitumor activity with IC50 value of ca. 8.0–10.0 μg/mL, while the deprotected pteridine nucleosides
(6a,d,i–l) exhibited potential antitumor activity with IC50 value of ca. 5.0–10.0 μg/mL. Among them,
compound (6l) exhibited the best antitumor activity with IC50 value of 4.8 μg/mL against KB cell. It
seemed worthwhile to investigate that the 6,7-bis(para-substituted phenyl)pteridine nucleosides tend to
increase the activity compare to the unsubstituted and diphenyl pteridine nucleosides (3a,b and 4a,b) as
shown in Table 10.
CONCLUSION
In this study, we demonstrated a novel, facile, and general synthesis of 6,7-bisaryl-1-(ꢀ-D-
ribofuranosyl)pteridine-2,4(1H,3H)-diones (4b–g) in good yields by condensation of 5,6-diamino-2’,3’
-O-isopropylideneuridine (2) and appropriate ꢁ,ꢀ-diketones, followed by acidic hydrolysis. The N-3
substituted alkyl derivatives (6a–l) were also synthesized by alkylation of 6,7-bisaryl-1-(2’,3’-O-
isopropylideneꢂꢀ-D-ribofuranosyl)pteridine-2,4(1H,3H)-diones (3c–f) with different alkyl halides,
followed by acidic hydrolysis to remove the isopropylidene group. All synthesized compounds were
screened in vitro against two human cultured tumor cell lines, CCRF-HSB-2 and KB cell lines, and some
of the N-6 and N-7substituted pteridine nucleoside derivatives displayed prospective antitumor activities,
which can be new lead compounds as antitumor agents. Further optimization of these new compounds
can possibly lead to more active molecules against tumor cells.

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HETEROCYCLES, Vol. 80, No. 1, 2010
Table 1. Physical and analytical data for compounds 3c–g and 4c–g
Analysis (%)
Calcd (Found)
Appearance
(Shape of
crystal)
Formula
Yield
(%)a
Compd
No.
Recrystn.
solvent
(Rf)b
Mp (°C)
150–152
C
H
N
3c
3d
3e
3f
50 (62)
55 (60)
60 (65)
AcOEt
AcOEt
AcOEt
AcOEt
AcOEt
C28H28N4O6
(0.50)
pale yellow
(amorphous)
c
pale yellow
(powder)
161–162
150–152
170–171
168–170
C28H28N4O8 1/3 H2O
(0.54)
60.64
(60.86
5.21
5.34
10.10
10.11)
pale yellow
(powder)
C26H22F2N4O6 1/3 H2O
(0.56)
58.87
(58.52
4.31
4.20
10.56
10.74)
65 (65)
55 (61)
pale yellow
(powder)
C26H22Br2N4O6
(0.56)
48.32
(48.32
3.43
3.66
8.67
8.66)
3g
pale yellow
(powder)
C22H20N4O8 1/6 H2O
(0.53)
56.05
(56.47
4.35
4.54
11.88
11.49)
EtOH +
AcOEt
62.23
(62.25
5.15
5.14
11.61
11.51)
4c
40 (70)
50 (67)
colorless
(powder)
169–170
180–182
C25H24N4O6 1/3 H2O
(0.49)
C25H24N4O8 1/3 H2O
(0.48)
EtOH +
AcOEt
58.36
(58.05
4.83
4.68
10.89
10.92)
4d
pale yellow
(powder)
EtOH +
AcOEt
C23H18F2N4O6
(0.47)
57.03
3.75
3.79
11.57
4e
4f
55 (75)
55 (76)
pale yellow
(powder)
255–257
198–200
(56.88
11.57)
EtOH +
AcOEt
45.03
(44.67
3.09
2.97
9.13
9.33)
colorless
(powder)
C23H18Br2N4O6 2/5 H2O
(0.49)
EtOH +
AcOEt
51.12
(51.08
4.06
3.91
12.55
12.29)
4g
35 (50)
pale yellow
(powder)
230–231
C19H16N4O8 H2O
(0.47)
aThe yields purified by column chromatography are shown, while the yields given in parentheses show the isolated
crude products. bSolvent system for TLC is EtOAc : EtOH (4:1, v/v). cCompound 3c was used for the next step without
any purification.
Table 2. Ultraviolet spectra and specific rotation of compounds 3c–g and 4c–g
25
25
ꢁmax/nm
(log ꢂ/ dm3 mol–1 cm–1)a
[ꢀ ]D
ꢁmax/nm
(log ꢂ/ dm3 mol–1 cm–1)a
[ꢀ ]D
Compd
No.
Compd
No.
(c = 0.2, dioxane)
(c = 0.2, dioxane)
3c
3d
3e
3f
–21.8°
4c
4d
4e
4f
230 (4.80), 284
(4.62), 367 (4.57)
–75.2°
227 (4.95), 282 (4.72),
368 (4.59)
273 (4.76), 360 (4.59)
–32.0°
–16.2°
–20.6°
–30.4°
229 (4.85), 296 (4.68),
379 (4.63)
–80.4°
–61.7°
–59.4°
–83.6°
227 (4.89), 282(4.67),
370 (4.56)
223 (4.83), 274 (4.68),
361 (4.54)
273 (4.83), 360 (4.67)
230 (4.84), 281 (4.72),
361 (4.64)
274 (4.70), 294 (4.71),
393 (4.62)
273 (4.77), 311 (4.80),
392 (4.70)
4g
3g
aAll UV spectra were measured in EtOH.

HETEROCYCLES, Vol. 80, No. 1, 2010
563
Table 3. IR and 1H-NMR spectroscopic data for the compunds 3b–g and 4b–g
Compd
No.
[ꢀ max (Nujol/cm–1)]
ꢁH [300 MHz; CDCl3 for 3b–g and (CD3)2SO for 4b–g; Me4Si]
3b
3460, 1080 (OH),
3320 (NH),
1.39 and 1.63 (each 3H, each s, 2 X CH3), 2.97 (1H, br s, 5'-OH, exchangeable with
D2O), 3.81 [1H, ddd (dd after addition of D2O, J4',5'a = 3.9 Hz, Jgem = 12.3 Hz), J4',5'a
= 3.9 Hz, J5'a,OH = 8.1 Hz, Jgem = 12.3 Hz, 5'-Ha], 3.90 [1H, br d (dd after addition of
D2O, J4',5'b = 2.7 Hz, Jgem = 12.3 Hz), 5'-Hb], 4.32 (1H, ddd, J3',4' = J4',5'a = 3.9 Hz,
J4',5'b = 2.7 Hz, 4'-H), 5.10 (1H, dd, J2',3' = 6.6 Hz, J3',4' = 3.9 Hz, 3'-H), 5.42 (1H, dd,
J1',2' = 3.3 Hz, J2',3' = 6.6 Hz, 2'-H), 7.19 (1H, d, J1',2' = 3.3 Hz, 1'-H), 7.30–7.38 (5H,
m, 6-Ph-H), 7.41–7.54 (5H, m, 7-Ph-H), 8.98 (1H, s, NH, exchangeable with D2O)
1705, 1670 (C=O)
3c
3460, 1060 (OH),
3200 (NH),
1.39 and 1.64 (each 3H, each s, 2 X CH3), 2.35 (3H, s, 6-Ar-CH3), 2.38 (3H, s, 7-Ar-
CH3), 3.00 (1H, br s, 5'-OH, exchangeable with D2O), 3.78 [1H, ddd ( dd after
addition of D2O, J4',5'a = 3.9 Hz, Jgem = 12.3 Hz), J4',5'a = 3.9 Hz, J5'a,OH = 8.1 Hz,
Jgem = 12.3 Hz, 5'-Ha], 3.90 [1H, br d (dd, after addition of D2O, J4',5'b = 2.7 Hz, Jgem
= 12.3 Hz, 5'-Hb], 4.31 (1H, ddd, J3',4' = J4',5'a = 3.9 Hz, J4',5'b = 2.7 Hz, 4'-H), 5.10
(1H, dd, J2',3' = 6.3 Hz, J3',4' = 3.9 Hz, 3'-H), 5.41 (1H, dd, J1',2' = 3.3 Hz, J2',3' = 6.3
Hz, 2'-H), 7.11 (2H, JAB = 8.4 Hz, 6-Ar-mH), 7.15 (2H, JAB = 8.4 Hz, 7-Ar-mH),
7.18 (1H, d, J1',2' = 3.3 Hz, 1'-H), 7.37 (2H, d, JAB = 8.4 Hz, 6-Ar-oH), 7.43 (2H, d,
JAB = 8.4 Hz, 7-Ar-oH), 9.00 (1H, s, NH, exchangeable with D2O).
1725 (C=O)
3440, 1060 (OH),
3200 (NH),
1720 (C=O)
3d
1.39 and 1.64 (each 3H, each s, 2 X CH3), 3.08 (1H, br d, 5'-OH, exchangeable with
D2O), 3.78 [1H, m (dd after addition of D2O, Jgem = 12.3 Hz, J4',5'a = 3.9 Hz), 5'-Ha],
3.82 (3H, s, 6-Ar-OCH3), 3.84 (3H, s, 7-Ar-OCH3), 3.90 [1H, br d (dd after addition
of D2O, J4',5'b = 2.7 Hz, Jgem = 12.3 Hz), 5'-Hb], 4.32 (1H, ddd, J3',4' = J4',5'a = 3.9
Hz, J4',5'b = 2.7 Hz, 4'-H), 5.11 (1H, dd, J2',3' = 6.6 Hz, J3',4' = 3.9 Hz, 3'-H), 5.41
(1H, dd, J1',2' = 3.0 Hz, J2',3' = 6.6 Hz, 2'-H), 6.83 (2H, d, JAB = 9.0 Hz, 6-Ar-mH),
6.86 (2H, d, JAB = 9.0 Hz, 7-Ar-mH), 7.17 (1H, d, J1',2' = 3.0 Hz, 1'-H), 7.45 (2H, d,
J
AB = 9.0 Hz, 6-Ar-oH), 7.52 (2H, d, JAB = 9.0 Hz, 7-Ar-oH), 9.10 (1H, s, NH,
exchangeable with D2O).
3e
3460, 1060 (OH),
3206 (NH),
1718 (C=O)
1.39 and 1.63 (each 3H, each s, 2 X CH3), 3.08 (1H, br s, 5'-OH, exchangeable with
D2O), 3.82 [1H, ddd (dd, after addition of D2O, J4',5'a = 3.9 Hz, Jgem = 12.3 Hz),
J4',5'a = 3.9 Hz, J5'a,OH = 8.1 Hz, Jgem = 12.3 Hz, 5'-Ha], 3.92 [1H, br d (dd, after
addition of D2O, J4',5'b = 2.7 Hz, Jgem = 12.3 Hz), J = 12.3 Hz, 5'-Hb], 4.33 (1H, ddd,
J3', 4' = J4',5'a = 3.9 Hz, J4',5'b = 2.7 Hz, 4'-H), 5.10 (1H, dd, J2',3' = 6.3 Hz, J3',4' = 3.9
Hz, 3'-H), 5.40 (1H, dd, J1',2' = 3.0 Hz, J2',3' = 6.3 Hz, 2'-H), 7.01 (2H, t, JH,H = JH,F
8.7 Hz, 6-Ar-mH), 7.06 (2H, t, JH,H = JH,F = 8.7 Hz, 7-Ar-mH), 7.14 (1H, d, J1,2
=
=
3.0 Hz, 1'-H), 7.45 (2H, dd, JH,H = 8.7 Hz, JH,F = 5.1 Hz, 6-Ar-oH), 7.51 (2H, dd,
JH,H = 8.7 Hz, JH,F = 5.1 Hz, 7-Ar-oH), 9.39 (1H, s, NH, exchangeable with D2O).
3f
3475, 1076 (OH),
3199 (NH),
1718 (C=O)
1.38 and 1.63 (each 3H, each s, 2 X CH3), 3.04 (1H, br d, 5'-OH, exchangeable with
D2O), 3.82 [1H, ddd (dd, after addition of D2O, J4',5'a = 3.9 Hz, Jgem = 12.3 Hz), J4',5'a
= 3.9 Hz, J5'a,OH = 8.1 Hz, Jgem = 12.3 Hz, 5'-Ha], 3.91 [1H, br d (dd, after addition of
D2O, J4',5'b = 2.7 Hz, Jgem =12.3 Hz), J = 12.3 Hz, 5'-Hb], 4.32 (1H, ddd, J3',4' = J4',5'a
= 3.9 Hz, J4',5'b = 2.7 Hz, 4'-H), 5.09 (1H, dd, J2',3' = 6.6 Hz, J3',4' = 3.9 Hz, 3'-H),
5.39 (1H, dd, J1',2' = 3.0 Hz, J2',3' = 6.6 Hz, 2'-H), 7.12 (1H, d, J = 3.0 Hz, 1'-H), 7.34
(2H, d, JAB = 8.7 Hz, 6-Ar-mH), 7.37 (2H, d, JAB = 8.7 Hz, 7-Ar-mH), 7.46 (2H, d,
JAB = 8.7 Hz, 6-Ar-oH), 7.52 (2H, d, JAB = 8.7 Hz, 7-Ar-oH), 9.32 (1H, s, NH,
exchangeable with D2O).

564
HETEROCYCLES, Vol. 80, No. 1, 2010
Table 3. (continued)
Compd
No.
[ꢀ max (Nujol/cm–1)]
ꢁH [300 MHz; CDCl3 for 3b–g and (CD3)2SO for 4b–g; Me4Si]
3g
3400, 1075 (OH),
3200 (NH),
1716 (C=O)
1.40 and 1.67 ( each 3H, each s, 2 X CH3), 2.90 (1H, br s, 5'-OH, exchangeable with
D2O), 3.83 (1H, dd, J4',5'a = 4.2 Hz, Jgem = 12.0 Hz, 5'-Ha), 3.93 (1H, dd, J4',5'b = 2.7
Hz, Jgem = 12.0 Hz, 5'-Hb), 4.33 (1H, ddd, J3',4' = J4',5'a = 4.2 Hz, J4',5'b = 2.7 Hz 4'-
H), 5.20 (1H, dd, J2',3' = 6.6 Hz, J3',4' = 4.2 Hz, 3'-H), 5.42 (1H, dd, J1',2' = 3.0 Hz,
J
2',3' = 6.6 Hz, 2'-H), 6.58 (1H, dd, J3,4 = 3.6 Hz, J4,5 = 1.8 Hz, 4-H of 6-Furyl), 6.59
(1H, dd, J3,4 = 3.6 Hz, J4,5 = 1.8 Hz, 4-H of 7-Furyl), 6.75 (1H, dd, J3,4 = 3.6 Hz,
3,5 = 0.6 Hz, 3-H of 6-Furyl), 6.96 (1H, dd, J3,4 = 3.6 Hz, J3,5 = 0.6 Hz, 3-H of 7-
J
Furyl), 7.09 (1H, d, J1',2' = 3.0 Hz, 1'-H), 7.55 (1H, dd, J3,5 = 0.6 Hz, J4,5 = 1.8 Hz, 5-
H of 6-Furyl), 7.66 (1H, dd, J3,5 = 0.6 Hz, J4,5 = 1.8 Hz, 5-H of 7-Furyl), 9.12 (1H,
s, NH, exchangeable with D2O).
3.43 [1H, m (dd after addition of D2O, J4,5'a = 6.0 Hz, Jgem = 12.0 Hz), 5'-Ha), 3.61
[1H, m (dd after addition of D2O, J4',5'b = 4.5 Hz, Jgem = 12.0 Hz), 5'-Hb], 3.72 (1H,
br m, 4'- H), 4.17 [1H, q (t after addition of D2O, J = 6.6 Hz), J = 6.9 Hz, 3'-H], 4.65
(1H, dd, J5'a,OH = 6.0 Hz, J5'b,OH = 5.4 Hz, 5'-OH, exchangeable with D2O), 4.69
[1H, br m (dd after addition of D2O, J1',2' = 3.6 Hz, J2',3' = 6.3 Hz), 2'-H], 4.95 (1H,
d, J3',OH = 6.6 Hz, 3'-OH, exchangeable with D2O), 5.16 (1H, d, J2',OH = 5.1 Hz, 2'-
OH, exchangeable with D2O), 6.56 (1H, br s, 1'-H), 7.36–7.46 (10H, m, 6 and 7-Ph-
H), 10.41 (1H, br NH, exchangeable with D2O).
4b
3400, 1047 (OH),
3240 (NH),
1708 (C=O)
2.32 (3H, s, 6-Ar-CH3), 2.34 (3H, s, 7-Ar-CH3), 3.41 [1H, ddd (br m after addition of
D2O), J4',5'a = 5.7 Hz, J5'a,OH = 6.0 Hz, Jgem = 12. 3 Hz, 5'-Ha], 3.61 [1H, ddd (br m
after addition of D2O), J4',5'b = 4.2 Hz, J5'b,OH = 5.1 Hz, Jgem = 12. 3 Hz, 5'-Hb], 3.70
(1H, br m, 4'- H), 4.17 [1H, q (t after addition of D2O, J = 6.3 Hz), J = 6.6 Hz, 3'-H],
4.58 (1H, t, J = 5.1 Hz, 5'-OH, exchangeable with D2O), 4.67 [1H, ddd (dd after
addition D2O, J1',2' = 3.6 Hz, J2',3' = 6.0 Hz), J1',2' = 3.9 Hz, J2',3' = 6.0 Hz, J2',OH = 4.5
Hz, 2'-H], 4.88 (1H, d, J3',OH = 6.3 Hz, 3'-OH, exchangeable with D2O), 5.09 (1H, d,
4c
3425, 1048 (OH),
3200 (NH),
1716 (C=O)
J2',OH = 4.5 Hz, 2'-OH, exchangeable with D2O), 6.54 (1H, br s, 1'-H), 7.16 (2H, d,
JAB = 8.1 Hz, 6-Ar-mH), 7.20 (2H, d, JAB = 8.1 Hz, 7-Ar-mH), 7.28 (2H, d, JAB = 8.1
Hz, 6-Ar-oH), 7.35 (2H, d, JAB = 8.1 Hz, 7-Ar-oH), 12.04 (1H, s, NH, exchangeable
with D2O).
4d
3422, 1028 (OH),
3200 (NH),
3.43 [1H, ddd (dd after addition of D2O, J4',5'a = 6.0 Hz, Jgem = 12.0 Hz), J4',5'a = 6.0
Hz, J5'a,OH = 5.7 Hz, Jgem = 12.0 Hz, 5'-Ha], 3.62 [1H, ddd (dd after addition of D2O,
J4',5'b = 4.5 Hz, Jgem = 12.0 Hz), J4',5'b = 4.5 Hz, J5'b,OH = 5.4 Hz, Jgem = 12.0 Hz, 5'-
1716 (C=O)
Hb], 3.71 (1H, m, 4'-H), 3.78 (3H, s, 6-Ar-OCH3), 3.79 (3H, s, 7-Ar-OCH3), 4.18
[1H, q (t after addition of D2O, J = 6.6 Hz), J = 6.6 Hz, 3'-H], 4.61 (1H, dd, J5'a,OH
5.7 Hz, J5'b,OH = 5.4 Hz, 5'-OH, exchangeable with D2O), 4.68 [1H, ddd (dd after
addition of D2O, J1',2' = 3.6 Hz, J2',3' = 6.0 Hz), J1',2' = 3.9 Hz, J2',3' = 6.0 Hz, J2',OH
=
=
5.1 Hz, 2'-H], 4.90 (1H, d, J3',OH = 6.6 Hz, 3'-OH, exchangeable with D2O), 5.09 (1H,
d, J2',OH = 5.1 Hz, 2'-OH, exchangeable with D2O), 6.56 ( 1H, br s, 1'-H), 6.93 (2H, d,
JAB = 8.7 Hz, 6-Ar-mH), 6.96 (2H, d, JAB = 8.7 Hz, 7-Ar-mH), 7.35 (2H, d, JAB = 8.7
Hz, 6-Ar-oH), 7.43 (2H, d, JAB = 8.7 Hz, 7-Ar-oH), 12.00 (1H, s, NH, exchangeable
with D2O).
4e
3435, 1023 (OH),
3150 (NH),
1721 (C=O)
3.41 [1H, ddd (br m after addition of D2O), J4',5'a = 6.0 Hz, J5'a,OH = 5.7 Hz, Jgem =
12.0 Hz, 5'-Ha], 3.61 [1H, ddd (br m after addition of D2O), J4',5'b = 4.5 Hz, J5'b,OH
5.4 Hz, Jgem = 12.0 Hz, 5'-Hb], 3.70 (1H, m, 4'-H), 4.16 [1H, q (t after addition of
=
D2O, J = 6.6 Hz), J = 6.6 Hz, 3'-H], 4.59 (1H, dd, J5'a,OH = 5.7 Hz, J5'b,OH = 5.4 Hz,
5'-OH, exchangeable with D2O), 4.67 [1H, ddd (dd after addition of D2O, J1',2' = 4.2
Hz, J2',3' = 5.4 Hz), J1',2' = 4.2 Hz, J2',3' = 5.4 Hz, J2',OH = 4.8 Hz, 2'-H], 4.91 (1H, d,
J3',OH = 6.9 Hz, 3'-OH, exchangeable with D2O), 5.09 (1H, d, J2',OH = 4.8 Hz, 2'-OH,
exchangeable with D2O), 6.53 (1H, br s, 1'-H), 7.22 (2H, dd, JH,H = 8.7 Hz, JH,F
=
9.0 Hz, 6-Ar-mH), 7.23 (2H, dd, JH,H = 8.7 Hz, JH,F = 9.0 Hz, 7-Ar-mH), 7.43 (2H,
dd, JH,H = 8.7 Hz, JH,F = 5.4 Hz, 6-Ar-oH), 7.50 (2H, dd, JH,H = 8.7 Hz, JH,F = 5.4
Hz, 7-Ar-oH), 12.01 (1H, s, NH, exchangeable with D2O).

HETEROCYCLES, Vol. 80, No. 1, 2010
565
Table 3. (continued)
Compd
No.
[ꢀ max (Nujol/cm–1)]
ꢁH [300 MHz; CDCl3 for 3b–g and (CD3)2SO for 4b–g; Me4Si]
4f
3.41 [1H, br m (dd after addition of D2O, J4',5'a = 6.0 Hz, Jgem = 11.7 Hz), 5'-Ha], 3.61
[1H, br d (dd after addition of D2O, J4',5'b = 4.5 Hz, Jgem = 11.7 Hz), 5'-Hb], 3.69 (1H,
m, 4'-H), 4.16 [1H, q (t after addition of D2O, J = 6.6 Hz), J = 6.6 Hz, 3'-H], 4.61
(1H, br d, 5'-OH, exchangeable with D2O), 4.66 [1H, ddd (dd after addition of D2O,
3428, 1077 (OH),
3200 (NH),
1716 (C=O)
J
1',2' = 3.9 Hz, J2',3' = 6.0 Hz), J1',2' = 3.6 Hz, J2',3' = 6.3 Hz, J2',OH = 5.1 Hz, 2'-H], 4.93
(1H, d, J3',OH = 6.6 Hz, 3'-OH, exchangeable with D2O), 5.09 (1H, d, J2',OH = 5.1 Hz,
2'-OH, exchangeable with D2O), 6.51 (1H, br s, 1'-H), 7.34 (2H, d, JAB = 8.7 Hz, 6-
Ar-mH), 7.40 (2H, d, JAB = 8.7 Hz, 7-Ar-mH), 7.59 (2H, d, JAB = 8.7 Hz, 6-Ar-oH),
7.64 (2H, d, JAB = 8.7 Hz, 7-Ar-oH), 10.87 (1H, br, NH, exchangeable with D2O).
3.41 [1H, ddd (dd after addition of D2O, J4',5'a = 6.0 Hz, Jgem = 12.0 Hz), J4',5'a = 6.3
Hz, J5'a,OH = 5.7 Hz, Jgem = 12.0 Hz, 5'-Ha], 3.64 [1H, br m (dd, after addition of
D2O, J4',5'b = 4.5 Hz, Jgem = 12.0 Hz), 5'-Hb], 3.72 (1H, br m, 4'-H), 4.31 (1H, br, 3'-
H), 4.56–4.63 (2H, br m, 2'-H and 5'-OH), 4.92 (1H, d, J3',OH = 6.6 Hz, 3'-OH,
exchangeable with D2O), 5.05 (1H, d, J2',OH = 4.5 Hz, 2'-OH, exchangeable with
D2O), 6.45 (1H, br s, 1'-H), 6.57 (1H, d, J3,4 = 3.3 Hz, 4-H of 6-Furyl), 6.67 (2H, br
s, 3-H of 6-Furyl and 4-H of 7-Furyl), 6.77 (1H, d, J3,4 = 3.3 Hz, 3-H of 7-Furyl),
7.82 (1H, s, 5-H of 6-Furyl), 7.94 (1H, s, 5-H of 7-Furyl), 12.07 (1H, s, NH,
exchangeable with D2O).
4g
3446, 1077 (OH),
3100 (NH),
1724 (C=O)
EXPERIMENTAL
Mps were determined using a Yanaco micro-melting point apparatus and were uncorrected. IR spectra
were recorded using a JASCO FT/ IR-200 spectrophotometer as Nujol mulls. NMR spectra were obtained
1
with the Varian VXR 300 MHz spectrometer. The H chemical shifts are expressed in parts per million
(ppm) based on internal TMS (0.00 pm) in CDCl3 or DMSO-d6. The coupling constant, J are given in Hz.
UV spectra were recorded in EtOH with a BECKMAN DU-600 spectrophotometer. Specific rotations
were recorded in dioxane with DIP-1000 digital polarimeter. Elemental analyses were measured by a
Yanako CHN Corder MT-5 apparatus. All reagents were of commercial quality from freshly opened
containers and were used without further purification. Reaction progress was monitored by analytical thin
layer chromatography (TLC) on pre-coated glass plates (silica gel 60 F254-plate-Merck) and products were
visualized by UV light. Column chromatography was accomplished on Daisogel IR-60 (63/ 210 ꢀm,
Daiso Co.). The reaction temperatures are indicated as the temperature of the oil bath. Anhyd DMF was
stored over activated 4ꢀ molecular sieves and other all solvents were dried and freshly distilled prior to
use.

566
HETEROCYCLES, Vol. 80, No. 1, 2010
Table 4. Physical and analytical data for compounds 5a–l
Analysis (%)
Calcd (Found)
Formula
Appearance
(Shape of crystal)
Compd
No.
(Rf)c
Yield (%)a
25 (60)
C
H
N
Mp (°C)b
145–147
5a
5b
5c
5d
colorless
(amorphous)
colorless
(prisms)
colorless
(amorphous)
colorless
(powder)
C35H34N4O6
d
(0.55)
C32H34N4O8 1/2 H2O
(0.59)
C34H38N4O8
(0.61)
C35H34N4O8
(0.58)
20 (62)
21 (65)
22 (60)
148–150
150–151
134–136
62.84
(62.41
5.77
5.64
9.16
9.40)
d
65.85
(65.65
5.37
5.34
8.77
8.84)
5e
5f
25 (63)
20 (65)
22 (65)
20 (66)
20 (69)
pale yellow
(powder)
122–124
141–142
145–147
130–132
136–137
C32H34N4O10 1/3 H2O
(0.62)
59.99
(59.66
5.45
5.31
8.75
8.73)
C34H38N4O10 1/4 H2O
(0.65)
pale yellow
(powder)
61.21
(61.60
5.82
5.68
8.40
8.46)
C33H28F2N4O6 1/3 H2O
(0.51)
5g
5h
5i
colorless
(needles)
pale yellow
(powder)
63.87
(63.64
4.66
4.48
9.03
9.20)
C30H28F2N4O8 2/5 H2O
(0.56)
C32H32F2N4O8 1/3 H2O
(0.59)
58.33
(57.99
59.62
4.70
4.58
5.11 8.69
9.07
9.30)
pale yellow
(powder)
(59.72
4.92
8.99)
5j
20 (65)
22 (68)
pale yellow
(powder)
pale yellow
(powder)
144–146
139–141
C33H28Br2N4O6
(0.57)
C30H28Br2N4O8
(0.59)
53.82
(53.94
49.20
3.83
3.93
3.85
3.91 7.83)
4.24 7.37
7.61
7.83)
7.65
5k
(49.14
5l
22 (70)
pale yellow
(powder)
108-110
C32H32Br2N4O8
(0.61)
50.54
(50.13
4.25
7.55)
aThe yields purified by column chromatography are shown, while the yields given in parentheses show the isolated
crude products. bAll compounds were recrystallized from a mixture of AcOEt and n-hexane. cSolvent system for TLC
is EtOAc : EtOH (4:1, v/v). dCompounds 5a and 5c were used for the next step without any purification.
Table 5. Ultraviolet spectra and specific rotation of compounds 5a–l
25
25
ꢀmax/nm
(log ꢁ/ dm3 mol–1 cm–1)a
[ꢂ ]D
ꢀmax/nm
(log ꢁ/ dm3 mol–1 cm–1)a
[ꢂ ]D
Compd
No.
Compd
No.
(c = 0.2, dioxane)
(c = 0.2, dioxane)
5a
5b
5g
5h
–22.6°
233 (5.09), 284 (4.78),
360 (4.68)
–17.0°
227 (5.06), 283 (4.83),
369 (4.71)
–29.5°
–25.0°
227 (4.91), 282 (4.68),
370 (4.56)
232 (4.90), 274 (4.77),
360 (4.75)
5c
5d
5e
5f
5i
5j
5k
5l
–23.5°
–31.8°
–30.0°
–30.5°
–24.7°
–22.2°
–16.5°
–14.3°
228 (5.03), 282 (4.80),
370 (4.68)
253 (4.03), 299 (4.30),
384 (4.40)
294 (4.88), 394 (4.79)
236 (4.69), 283 (4.59),
365 (4.51)
233 (4.67), 282 (4.45),
360 (4.42)
226 (4.83), 282 (4.58),
368 (4.44)
235 (4.70), 282 (4.60),
369 (4.49)
237 (4.79), 285 (4.70),
363 (4.62)
aAll UV spectra were measured in EtOH.

HETEROCYCLES, Vol. 80, No. 1, 2010
567
Table 6. IR and 1H-NMR spectroscopic data for the compunds 5a–l
Compd
No.
[ꢀ max (Nujol/cm–1)]
ꢁH (300 MHz; CDCl3; Me4Si)
5a
1.38 and 1.62 (each 3H, each s, 2 X CH3), 2.35 (3H, s, 6-Ar-CH3), 2.38 (3H, s, 7-Ar-
CH3), 2.89 (1H, br s, 5'-OH, exchangeable with D2O), 3.78 [1H, ddd (dd after addition
of D2O, J4',5'a = 3.9 Hz, Jgem = 12.3 Hz), J4',5'a = 3.9 Hz, J5'a,OH = 8.7 Hz, Jgem = 12.3
Hz, 5'-Ha], 3.87 [1H, dt (dd, after addition of D2O, J4',5'b = 2.7 Hz, Jgem = 12.3 Hz),
3475, 1074 (OH),
1725, 1681 (C=O)
J4',5'b = 2.7 Hz, J5'b,OH = 5.4 Hz, Jgem = 12.3 Hz, 5'-Hb], 4.29 (1H, ddd, J3',4' = J4',5'a
=
3.9 Hz, J4',5'b = 2.7 Hz, 4'-H), 5.14 (1H, dd, J2',3' = 6.3 Hz, J3',4' = 3.9 Hz, 3'-H), 5.29
and 5.30 (each 1H, each s, each H of Bn), 5.39 (1H, dd, J1',2' = 3.0 Hz, J2',3' = 6.3 Hz,
2'-H), 7.11 (2H, JAB = 8.1 Hz, 6-Ar-mH), 7.15 (2H, JAB = 8.1 Hz, 7-Ar-mH), 7.23
(1H, d, J1',2' = 3.0 Hz, 1'-H), 7.28–7.33 (3H, m, Ph-m and pH), 7.37 (2H, d, JAB = 8.1
Hz, 6-Ar-oH), 7.41 (2H, d, JAB = 8.1 Hz, 7-Ar-oH), 7.54–7.58 (2H, m, Ph-oH).
5b
1.30 (3H, t, J = 7.2 Hz, CH3 of Et), 1.38 and 1.63 (each 3H, each s, 2 X CH3), 2.36
3493, 1030 (OH),
1730, 1683 (C=O),
1216, 1159 (C-O-C)
(3H, s, 6-Ar-CH3), 2.39 (3H, s, 7-Ar-CH3), 2.81 (1H, dd, J5'a,OH = 8.4 Hz, J5'b,OH
=
3.3 Hz, 5'-OH, exchangeable with D2O), 3.77 [1H, ddd (dd after addition of D2O,
J4',5'a = 3.9 Hz, Jgem = 12.3 Hz), J4',5'a = 3.9 Hz, J5'a,OH = 8.4 Hz, Jgem = 12.3 Hz, 5'-
Ha], 3.88 [1H, dt (dd, after addition of D2O, J4',5'b = 2.7 Hz, Jgem = 12.3 Hz), J4',5'b
2.7 Hz, J5'b,OH = 3.3 Hz, Jgem = 12.3 Hz, 5'-Hb], 4.25 (2H, q, J = 7.2 Hz, CH2 of Et),
4.29 (1H, ddd, J3',4' = J4',5'a = 3.9 Hz, J4',5'b = 2.7 Hz, 4'-H), 4.86 (2H, s, NCH2), 5.11
(1H, dd, J2',3' = 6.3 Hz, J3',4' = 3.9 Hz, 3'-H), 5.38 (1H, dd, J1',2' = 3.0 Hz, J2',3' = 6.3
Hz, 2'-H), 7.12 (2H, d, JAB = 8.1 Hz, 6-Ar-mH), 7.16 (2H, d, JAB = 8.1 Hz, 7-Ar-
mH), 7.25 (1H, d, J1',2' = 3.0 Hz, 1'-H), 7.38 ( 2H, d, JAB = 8.1 Hz, 6-Ar-oH), 7.44
(2H, d, JAB = 8.1 Hz, 7-Ar-oH).
=
1.23 (3H, t, J = 7.2 Hz, CH3 of Et), 1.39 and 1.63 (each 3H, each s, 2 X CH3), 2.07
(2H, quin, J = 7.2 Hz, NCH2CH2CH2), 2.23 (1H, br d, J = 8.4 Hz, 5'-OH,
exchangeable with D2O), 2.36 (3H, s, 6-Ar-CH3), 2.39 (3H, s, 7-Ar-CH3), 2.43 (2H,
5c
3463, 1072 (OH),
1730, 1677 (C=O),
1213, 1155 (C-O-C)
t, J = 7.2 Hz, COCH2), 3.80 [1H, m (dd after addition of D2O, J4',5'a = 3.9 Hz, Jgem
12.0 Hz), 5'-Ha], 3.90 [1H, br d (dd, after addition of D2O, J4',5'b = 2.7 Hz, Jgem
=
=
12.3 Hz), J = 12.0 Hz, 5'-Hb], 4.11 (2H, q, J = 7.2 Hz, CH2 of Et), 4.20 (2H, t, J =
6.9 Hz, NCH2), 4.31 (1H, ddd, J3',4' = J4',5'a = 3.9 Hz, J4',5'b = 2.7 Hz, 4'-H), 5.12
(1H, dd, J2',3' = 6.3 Hz, J3',4' = 3.9 Hz, 3'-H), 5.40 (1H, dd, J1',2' = 3.0 Hz, J2',3' = 6.3
Hz, 2'-H), 7.12 (2H, d, JAB = 8.1 Hz, 6-Ar-mH), 7.16 (2H, d, JAB = 8.1 Hz, 7-Ar-
mH), 7.24 (1H, d, J1',2' = 3.0 Hz, 1'-H), 7.38 (2H, d, JAB = 8.1 Hz, 6-Ar-oH), 7.43
(2H, d, JAB = 8.1 Hz, 7-Ar-oH).
1.38 and 1.62 (each 3H, each s, 2 X CH3), 2.94 (1H, br d, J = 6.6 Hz, 5'-OH,
exchangeable with D2O), 3.78 [1H, m (dd after addition of D2O, Jgem = 12.3 Hz,
5d
3400, 1029 (OH),
1724, 1680(C=O)
J
4',5'a = 3.9 Hz), 5'-Ha], 3.82 (3H, s, 6-Ar-OCH3), 3.84 (3H, s, 7-Ar-OCH3), 3.89
[1H, ddd (dd after addition of D2O, J4',5'b = 2.7 Hz, Jgem = 12.3 Hz), J4',5'b = 2.7 Hz,
5'b,OH = 3.3 Hz, Jgem = 12.3 Hz 5'-Hb], 4.30 (1H, ddd, J3',4' = J4',5'a = 3.9 Hz, J4',5'b
J
= 2.7 Hz, 4'-H), 5.16 (1H, dd, J2',3' = 6.6 Hz, J3',4' = 3.9 Hz, 3'-H), 5.29 and 5.30 (each
1H, each s, each H of Bn), 5.39 (1H, dd, J1',2' = 3.0 Hz, J2',3' = 6.6 Hz, 2'-H), 6.83
(2H, d, JAB = 9.0 Hz, 6-Ar-mH), 6.86 (2H, d, JAB = 9.0 Hz, 7-Ar-mH), 7.23 (1H, d,
J
1',2' = 3.0 Hz, 1'-H), 7.28–7.34 (3H, m, Ph-m and pH), 7.45 (2H, d, JAB = 9.0 Hz, 6-
Ar-oH), 7.51 (2H, d, JAB = 9.0 Hz, 7-Ar-oH), 7.53–7.57 (2H, m, Ph-oH).

568
HETEROCYCLES, Vol. 80, No. 1, 2010
Table 6. (continued)
Compd
No.
[ꢀ max (Nujol/cm–1)]
ꢁH (300 MHz; CDCl3; Me4Si)
5e
1.30 (3H, t, J = 7.2 Hz, CH3 of Et), 1.38 and 1.64 (each 3H, each s, 2 X CH3), 2.85
(1H, dd, J5'a,OH = 8.4 Hz, J5'b,OH = 3.3 Hz, 5'-OH, exchangeable with D2O), 3.78
[1H, m (dd after addition of D2O, J4',5'a = 3.9 Hz, Jgem = 12.3 Hz), 5'-Ha], 3.83 (3H,
s, 6-Ar-OCH3), 3.85 (3H, s, 7-Ar-OCH3), 3.88 [1H, m (dd, after addition of D2O,
3446, 1027 (OH),
1724, 1675 (C=O),
1209, 1176 (C-O-C)
J
4',5'b = 2.7 Hz, Jgem = 12.3 Hz), 5'-Hb], 4.25 (2H, q, J = 7.2 Hz, CH2 of Et), 4.30
(1H, ddd, J3',4' = J4',5'a = 3.9 Hz, J4',5'b = 2.7 Hz, 4'-H), 4.85 (2H, s, NCH2), 5.12
(1H, dd, J2',3' = 6.3 Hz, J3',4' = 3.9 Hz, 3'-H), 5.38 (1H, dd, J1',2' = 3.0 Hz, J2',3'
6.3 Hz, 2'-H), 6.85 (2H, d, JAB = 8.7 Hz, 6-Ar-mH), 6.87 (2H, d, JAB = 8.7 Hz, 7-
Ar-mH), 7.24 (1H, d, J1',2' = 3.0 Hz, 1'-H), 7.46 (2H, d, JAB = 8.7 Hz, 6-Ar-oH),
7.53 (2H, d, JAB = 8.7 Hz, 7-Ar-oH).
=
1.23 (3H, t, J = 7.2 Hz, CH3 of Et), 1.39 and 1.64 (each 3H, each s, 2 X CH3), 2.07
(2H, quin, J = 7.2 Hz, NCH2CH2CH2), 2.42 (2H, t, J = 7.2 Hz, COCH2), 3.01 (1H,
3446, 1027(OH),
1724,1675(C=O),
1253, 1176 (C-O-C)
5f
br, 5'-OH, exchangeable with D2O), 3.80 [1H, m (dd after addition of D2O, J4',5'a
=
3.9 Hz, Jgem = 12.3 Hz), 5'-Ha], 3.83 (3H, s, 6-Ar-OCH3), 3.85 (3H, s, 7-Ar-OCH3),
3.90 [1H, br d (dd, after addition of D2O, J4',5'b = 2.7 Hz, Jgem =12.3 Hz), 5'-Hb],
4.10 (2H, q, J = 7.2 Hz, CH2 of Et), 4.20 (2H, t, J = 6.9 Hz, NCH2), 4.32 (1H, ddd,
J3',4' = J4',5'a = 3.9 Hz, J4',5'b = 2.7 Hz, 4'-H), 5.13 (1H, dd, J3',4' = 3.9 Hz, J2',3' = 6.6
Hz, 3'-H), 5.40 (1H, dd, J1',2' = 3.0 Hz, J2',3' = 6.6 Hz, 2'-H), 6.84 (2H, d, JAB = 9.0
Hz, 6-Ar-mH), 6.87 (2H, d, JAB = 9.0 Hz, 7-Ar-mH), 7.24 (1H, d, J1',2' = 3.0 Hz, 1'-
H), 7.46 (2H, d, JAB = 9.0 Hz, 6-Ar-oH), 7.53 (2H, d, JAB = 9.0 Hz, 7-Ar-oH).
1.38 and 1.62 (each 3H, each s, 2 X CH3), 2.84 (1H, dd, J5'a,OH = 8.7 Hz, J5'b,OH
3.6 Hz, 5'-OH, exchangeable with D2O), 3.79 [1H, ddd (dd, after addition of D2O,
4',5'a = 3.9 Hz, Jgem = 12.3 Hz), J4',5'a = 3.9 Hz, J5'a,OH = 8.7 Hz, Jgem = 12.3 Hz, 5'-
=
5g
3500, 1073 (OH),
1726, 1682 (C=O)
J
Ha], 3.89 [1H, dt (dd, after addition of D2O, J4',5'b = 2.7 Hz, Jgem = 12.3 Hz), J4',5'b
= 2.7 Hz, J5'b,OH = 3.6 Hz, Jgem = 12.3 Hz, 5'-Hb], 4.31 (1H, ddd, J3', 4' = J4',5'a = 3.9
Hz, J4',5'b = 2.7 Hz, 4'-H), 5.15 (1H, dd, J2',3' = 6.6 Hz, J3',4' = 3.9 Hz, 3'-H), 5.30
and 5.31 (each 1H, each s, each H of Bn), 5.38 (1H, dd, J1',2' = 3.0 Hz, J2',3' = 6.6
Hz, 2'-H), 7.03 (2H, t, JH,H = JH,F = 9.0 Hz, 6-Ar-mH), 7.06 (2H, t, JH,H = JH,F
=
9.0 Hz, 7-Ar-mH), 7.20 (1H, d, J1',2' = 3.0 Hz, 1'-H), 7.27–7.35 (3H, m, Ph-m and
pH), 7.46 (2H, dd, JH,H = 9.0 Hz, JH,F = 5.4 Hz, 6-Ar-oH), 7.50 (2H, dd, JH,H = 9.0
Hz, JH,F = 5.4 Hz, 7-Ar-oH), 7.54–7.57 (2H, m, Ph-oH).
1.31 (3H, t, J = 7.2 Hz, CH3 of Et), 1.38 and 1.62 (each 3H, each s, 2 X CH3), 2.74
(1H, dd, J5'a,OH = 8.7 Hz, J5'b,OH = 3.6 Hz, 5'-OH, exchangeable with D2O), 3.79
[1H, ddd (dd, after addition of D2O, J4',5'a = 3.9 Hz, Jgem = 12.3 Hz), J4',5'a = 3.9
Hz, J5'a,OH = 8.7 Hz, Jgem = 12.3 Hz, 5'-Ha], 3.90 [1H, dt (dd, after addition of
D2O, J4',5'b = 2.7 Hz, Jgem = 12.3 Hz), J4',5'b = 2.7 Hz, J5'b,OH = 3.6 Hz, Jgem = 12.3
Hz, 5'-Hb], 4.26 (2H, q, J = 7.2 Hz, CH2 of Et), 4.31 (1H, ddd, J3',4' = J4',5'a = 3.9
5h
3493, 1030 (OH),
1730, 1683 (C=O),
1216, 1159 (C-O-C)
Hz, J4',5'b = 2.7 Hz, 4'-H), 4.86 (2H, s, NCH2), 5.11 (1H, dd, J2',3' = 6.6 Hz, J3',4'
3.9 Hz, 3'-H), 5.37 (1H, dd, J1',2' = 3.0 Hz, J2',3' = 6.6 Hz, 2'-H), 7.04 (2H, t, JH,H
=
=
JH,F = 8.7 Hz, 6-Ar-mH), 7.07 (2H, t, JH,H = JH,F = 8.7 Hz, 7-Ar-mH), 7.22 (1H, d,
J1,2 = 3.0 Hz, 1'-H), 7.47 (2H, dd, JH,H = 8.7 Hz, JH,F = 5.1 Hz, 6-Ar-oH), 7.53
(2H, dd, JH,H = 8.7 Hz, JH,F = 5.1 Hz, 7-Ar-oH).

HETEROCYCLES, Vol. 80, No. 1, 2010
569
Table 6. (continued)
Compd
No.
[ꢀ max (Nujol/cm–1)]
ꢁH (300 MHz; CDCl3; Me4Si)
5i
3485, 1072 (OH),
1727, 1681 (C=O),
1233, 1159 (C-O-C)
1.23 (3H, t, J = 7.2 Hz, CH3 of Et), 1.39 and 1.63 (each 3H, each s, 2 X CH3), 2.08
(2H, quin, J = 7.2 Hz, NCH2CH2CH2), 2.43 (2H, t, J = 7.2 Hz, COCH2), 2.91 (1H,
br, 5'-OH, exchangeable with D2O), 3.82 [1H, m (dd after addition of D2O, J4',5'a
=
3.9 Hz, Jgem = 12.3 Hz), 5'-Ha], 3.91 [1H, br d (dd, after addition of D2O, J4',5'b = 2.7
Hz, Jgem = 12.3 Hz), J = 11.7 Hz, 5'-Hb], 4.11 (2H, q, J = 7.2 Hz, CH2 of Et), 4.21
(2H, t, J = 6.9 Hz, NCH2), 4.33 (1H, ddd, J3',4' = J4',5'a = 3.9 Hz, J4',5'b = 2.7 Hz, 4'-
H), 5.12 (1H, dd, J2',3' = 6.3 Hz, J3',4' = 3.9 Hz, 3'-H), 5.39 (1H, dd, J1',2' = 3.0 Hz,
J
2',3' = 6.3 Hz, 2'-H), 7.03 (2H, t, JH,H = JH,F = 9.0 Hz, 6-Ar-mH), 7.07 (2H, t, JH,H
H,F = 9.0 Hz, 7-Ar-mH), 7.21 (1H, d, J1,2 = 3.0 Hz, 1'-H), 7.47 (2H, dd, JH,H = 9.0
=
J
Hz, JH,F = 5.4 Hz, 6-Ar-oH), 7.52 (2H, dd, JH,H = 9.0 Hz, JH,F = 5.4 Hz, 7-Ar-oH).
1.38 and 1.61 (each 3H, each s, 2 X CH3), 2.81 (1H, dd, J5'a,OH = 8.7 Hz, J5'b,OH = 3.6
Hz, 5'-OH, exchangeable with D2O), 3.79 [1H, ddd (dd after addition of D2O, J4',5'a
5j
3476, 1073 (OH),
1728, 1683 (C=O)
=
3.9 Hz, Jgem = 12.3 Hz), J4',5'a = 3.9 Hz, J5'a,OH = 8.7 Hz, Jgem = 12.3 Hz, 5'-Ha], 3.89
[1H, dt (dd, after addition of D2O, J4',5'b = 2.7 Hz, Jgem =12.3 Hz), J4',5'b = 2.7 Hz,
J5'b,OH = 3.6 Hz, Jgem =12.3 Hz, 5'-Hb], 4.30 (1H, ddd, J3',4' = J4',5'a = 3.9 Hz, J4',5'b =
2.7 Hz, 4'-H), 5.14 (1H, dd, J2',3' = 6.3 Hz, J3',4' = 3.9 Hz, 3'-H), 5.296 and 5.304
(each 1H, each s, each H of Bn), 5.37 (1H, dd, J1',2' = 3.0 Hz, J2',3' = 6.3 Hz, 2'-H),
7.17 (1H, d, J1',2' = 3.0 Hz, 1'-H), 7.28–7.32 (3H, m, Ph-m and pH), 7.35 (2H, d, JAB
= 8.7 Hz, 6-Ar-mH), 7.37 (2H, d, JAB = 8.7 Hz, 7-Ar-mH), 7.48 (2H, d, JAB = 8.7 Hz,
6-Ar-oH), 7.52 (2H, d, JAB = 8.7 Hz, 7-Ar-oH), 7.52–7.57 (2H, m, Ph-oH).
1.31 (3H, t, J = 7.2 Hz, CH3 of Et), 1.38 and 1.62 (each 3H, each s, 2 X CH3), 2.71
(1H, dd, J5'a,OH = 8.7 Hz, J5'b,OH = 3.6 Hz, 5'-OH, exchangeable with D2O), 3.79 [1H,
ddd (dd after addition of D2O, J4',5'a = 3.9 Hz, Jgem = 12.3 Hz), J4',5'a = 3.9 Hz, J5'a,OH
= 8.7 Hz, Jgem = 12.3 Hz, 5'-Ha], 3.89 [1H, dt (dd, after addition of D2O, J4',5'b = 2.7
Hz, Jgem =12.3 Hz), J4',5'b = 2.7 Hz, J5'b,OH = 3.6 Hz, Jgem =12.3 Hz, 5'-Hb], 4.26 (2H,
q, J = 7.2 Hz, CH2 of Et), 4.30 (1H, ddd, J3',4' = J4',5'a = 3.9 Hz, J4',5'b = 2.7 Hz, 4'-H),
4.86 (2H, s, NCH2), 5.11 (1H, dd, J2',3' = 6.3 Hz, J3',4' = 3.9 Hz, 3'-H), 5.36 (1H, dd,
3463, 1072 (OH),
1730, 1678 (C=O),
1213, 1158 (C-O-C)
5k
J
1',2' = 3.0 Hz, J2',3' = 6.3 Hz, 2'-H), 7.20 (1H, d, J1',2' = 3.0 Hz, 1'-H), 7.36 (2H, d,
AB = 8.7 Hz, 6-Ar-mH), 7.40 (2H, d, JAB = 8.7 Hz, 7-Ar-mH), 7.49 (2H, d, JAB = 8.7
J
Hz, 6-Ar-oH), 7.53 (2H, d, JAB = 8.7 Hz, 7-Ar-oH).
1.23 (3H, t, J = 7.2 Hz, CH3 of Et), 1.39 and 1.62 (each 3H, each s, 2 X CH3), 2.08
(2H, quin, J = 6.9 Hz, NCH2CH2CH2), 2.43 (2H, t, J = 7.2 Hz, COCH2), 2.88 (1H, dd,
5l
3491, 1073 (OH),
1727, 1681 (C=O),
1240, 1209 (C-O-C)
J
5'a,OH = 8.7 Hz, J5'b,OH = 3.6 Hz, 5'-OH, exchangeable with D2O), 3.82 [1H, ddd (dd
after addition of D2O, J4',5'a = 3.9 Hz, Jgem = 12.3 Hz), J4',5'a = 3.9 Hz, J5'a,OH = 8.7 Hz,
gem = 12.3 Hz, 5'-Ha], 3.91 [1H, dt (dd, after addition of D2O, J4',5'b = 2.7 Hz, Jgem
J
=
12.3 Hz), J4',5'b = 2.7 Hz, J5'b,OH = 3.6 Hz, Jgem = 12.3 Hz, 5'-Hb], 4.10 (2H, q, J = 7.2
Hz, CH2 of Et), 4.21 (2H, t, J = 6.9 Hz, NCH2), 4.32 (1H, ddd, J3',4' = J4',5'a = 3.9 Hz,
J
4',5'b = 2.7 Hz, 4'-H), 5.11 (1H, dd, J2',3' = 6.3 Hz, J3',4' = 3.9 Hz, 3'-H), 5.38 (1H, dd,
1',2' = 3.0 Hz, J2',3' = 6.3 Hz, 2'-H), 7.19 (1H, d, J1',2' = 3.0 Hz, 1'-H), 7.36 (2H, d, JAB
J
= 8.7 Hz, 6-Ar-mH), 7.39 (2H, d, JAB = 8.7 Hz, 7-Ar-mH), 7.49 (2H, d, JAB = 8.7 Hz,
6-Ar-oH), 7.53 (2H, d, JAB = 8.7 Hz, 7-Ar-oH).

570
HETEROCYCLES, Vol. 80, No. 1, 2010
Table 7. Physical and analytical data for compounds 6a–l
Analysis (%)
Calcd (Found)
Formula
Compd
No.
Appearance
(Shape of crystal)
(Rf)c
Mp (°C)b
250–252
Yield (%)a
25 (64)
C
H
N
6a
6b
colorless
(powder)
C32H30N4O6 1/4 H2O
(0.55)
67.30
(67.61
5.38
5.21
9.81
9.80)
22 (65)
pale yellow
(powder)
61.42
(61.10
5.42
5.28
9.88
9.84)
210–212
C29H30N4O8 1/4 H2O
(0.58)
6c
6d
6e
190–191
247–249
174–176
C31H34N4O8 1/3 H2O
(0.52)
C32H30N4O8 1/4 H2O
(0.43)
62.41
(62.16
63.73
(63.76
58.00
5.86
5.62
5.10
4.95
5.15
4.92
9.39
9.60)
9.29
9.43)
9.33
9.43)
24 (67)
21 (60)
23 (62)
pale yellow
(powder)
colorless
(powder)
pale yellow
(powder)
C29H30N4O10 1/3 H2O
(0.46)
(57.92
6f
25 (65)
20 (65)
pale yellow
(powder)
pale yellow
(powder)
178–180
230–232
C31H34N4O10 1/3 H2O
(0.48)
C30H24F2N4O6 1/4 H2O
59.23
(59.30
62.23
5.56
5.39
4.26
8.91
9.15)
9.68
6g
6h
(0.51)
(62.16
4.34
9.64)
26 (68)
24 (70)
20 (66)
pale yellow
(powder)
colorless
(powder)
pale yellow
(powder)
pale yellow
(powder)
colorless
(powder)
170–172
190–192
235–237
C27H24F2N4O8 1/3 H2O
(0.49)
C29H28F2N4O8 1/3 H2O
(0.52)
C30H24Br2N4O6
(0.48)
C27H24Br2N4O8 1/4 H2O
56.25
(56.16
4.31
4.21
4.78
4.54
3.47
3.60
3.54
3.32
3.98
3.80
9.72
9.67)
6i
6j
57.61
(57.28
51.74
(51.64
46.54
(46.41
47.95
(47.79
9.27
9.55)
8.05
7.97)
8.04
6k
6l
23 (69)
21 (71)
210–211
220–221
(0.45)
8.09)
7.71
7.85)
C29H28Br2N4O8 1/3 H2O
(0.47)
aThe yields purified by column chromatography are shown, while the yields given in parentheses show the isolated
crude products. bAll compounds were recrystallized from a mixture of EtOH and AcOEt. cSolvent system for TLC is
EtOAc : EtOH (4:1, v/v).
Table 8. Ultraviolet spectra and specific rotation of compounds 6a–l
25
25
ꢀmax/nm
(log ꢁ/ dm3 mol–1 cm–1)a
ꢀmax/nm
(log ꢁ/ dm3 mol–1 cm–1)a
[ꢂ ]D
[ꢂ ]D
Compd
No.
Compd
No.
(c = 0.2, dioxne)
(c = 0.2, dioxne)
6a
6b
6c
6d
6e
6f
6g
6h
6i
243 (4.94), 273 (4.79),
371 (4.66)
–71.3°
236 (5.09), 261 (4.90),
360 (4.69)
–74.0°
233 (4.62), 282 (4.36),
374 (4.36)
–76.2°
–64.4°
–79.8°
–68.2°
–63.6°
234 (5.13), 261 (4.90),
360 (4.70)
–62.2°
–59.6°
–47.1°
–42.9°
–63.7°
236 (5.07), 272 (4.83),
371 (4.68)
237 (4.97), 271 (4.81),
360 (4.66)
6j
234 (5.13), 292 (4.81),
385 (4.52)
231 (4.78), 275 (4.65),
369 (4.62)
6k
6l
240 (4.98), 294 (4.78),
386 (4.67)
234 (4.79), 282 (4.66)
367 (4.51)
274 (4.93), 350 (4.90)
239 (5.02), 272 (4.83),
360 (4.64)
aAll UV spectra were measured in EtOH.

HETEROCYCLES, Vol. 80, No. 1, 2010
571
Table 9. IR and 1H-NMR spectroscopic data for the compunds 6a–l
Compd
No.
[ꢀ max (Nujol/cm–1)]
ꢁH (300 MHz; (CD3)2SO; Me4Si)
6a
2.32 (3H, s, 6-Ar-CH3), 2.34 (3H, s, 7-Ar-CH3), 3.39 [1H, quin (dd after addition of
D2O, J4',5'a = 6.3 Hz, Jgem = 12. 0 Hz), J = 6.3 Hz, 5'-Ha], 3.61 [1H, ddd (dd after
addition of D2O, J4',5'b = 5.1 Hz, Jgem = 12.0 Hz), J4',5'b = 5.1 Hz, J5'b,OH = 5.4 Hz,
Jgem = 12. 0 Hz, 5'-Hb], 3.70 (1H, m, 4'- H), 4.18 [1H, q (t after addition of D2O, J =
6.9 Hz), J = 6.9 Hz, 3'-H), 4.58 (1H, t, J = 5.7 Hz, 5'-OH, exchangeable with D2O),
4.65 [1H, br m (dd after addition of D2O, J1',2' = 3.6 Hz, J2',3' = 6.3 Hz), 2'-H], 4.91
(1H, d, J3',OH = 6.9 Hz, 3'-OH, exchangeable with D2O), 5.11 (1H, d, J2',OH = 4.8 Hz,
2'-OH, exchangeable with D2O), 5.18 (2H, s, CH2 of Bn), 6.62 (1H, br s, 1'-H), 7.17
(2H, d, JAB = 8.1 Hz, 6-Ar-mH), 7.21 (2H, d, JAB = 8.1 Hz, 7-Ar-mH), 7.25–7.39 (5H,
m, Ph-H), 7.29 (2H, d, JAB = 8.1 Hz, 6-Ar-oH), 7.35 (2H, d, JAB = 8.1 Hz, 7-Ar-oH).
3422, 1070 (OH),
1723, 1673 (C=O)
1.24 (3H, t, J = 7.2 Hz, CH3 of Et), 2.33 (3H, s, 6-Ar-CH3), 2.34 (3H, s, 7-Ar-CH3),
3.40 [1H, ddd (dd after addition of D2O, J4',5'a = 6.6 Hz, Jgem = 12.0 Hz), J4',5'a = 6.3
Hz, J5'a,OH = 6.0 Hz, Jgem = 12.0 Hz, 5'-Ha], 3.61 [1H, ddd (dd after addition of D2O,
J4',5'b = 4.5 Hz, Jgem = 12. 0 Hz), J4',5'b = 4.8 Hz, J5'b,OH = 5.4 Hz, Jgem = 12. 0 Hz, 5'-
Hb], 3.72 (1H, br m, 4'- H), 4.12 (1H, m, 3'-H), 4.18 (2H, q, J = 7.2 Hz, CH2 of Et),
4.62 (1H, t, J = 5.7 Hz, 5'-OH, exchangeable with D2O), 4.66 [1H, br m (dd after
addition of D2O, J1',2' = 3.6 Hz, J2',3' = 6.6 Hz, 2'-H], 4.71 (1H, d, Jgem = 17.1 Hz, Ha
of NCH2), 4.79 (1H, d, Jgem = 17.1 Hz, Hb of NCH2), 4.93 (1H, d, J3',OH = 6.9 Hz, 3'-
OH, exchangeable with D2O), 5.17 (1H, d, J2',OH = 5.1 Hz, 2'-OH, exchangeable with
3440, 3307, 1032
(OH),
6b
1732, 1691(C=O),
1210, 1105(C-O-C)
D2O), 6.60 (1H, br s, 1'-H), 7.17 (2H, d, JAB = 8.1 Hz, 6-Ar-mH), 7.21 (2H, d, JAB
=
8.1 Hz, 7-Ar-mH), 7.30 (2H, d, JAB = 8.1 Hz, 6-Ar-oH), 7.37 (2H, d, JAB = 8.1 Hz, 7-
Ar-oH).
6c
1.18 (3H, t, J = 7.2 Hz, CH3 of Et), 1.90 (2H, quin, J = 6.9 Hz, NCH2CH2CH2), 2.33
(3H, s, 6-Ar-CH3), 2.34 (3H, s, 7-Ar-CH3), 2.40 (2H, q, J = 6.9 Hz, COCH2), 3.43 [1H,
3450, 3307, 1030
(OH),
ddd (dd after addition of D2O, J4',5'a = 6.3 Hz, Jgem = 12.0 Hz), J4',5'a = 6.3 Hz, J5'a,OH
=
1727, 1683 (C=O),
1243, 1206 (C-O-C)
5.7 Hz, Jgem = 12.0 Hz, 5'-Ha], 3.63 [1H, ddd (dd after addition of D2O, J4',5'b = 4.5 Hz,
Jgem = 12.0 Hz), J4',5'b = 4.8 Hz, J5'b,OH = 5.1 Hz, Jgem = 12. 0 Hz, 5'-Hb], 3.72 (1H, br
m, 4'-H), 4.02 (2H, t, J = 6.6 Hz, NCH2), 4.04 (2H, q, J = 7.2 Hz, CH2 of Et), 4.19 [1H,
q (t after addition of D2O, J = 6.6 Hz), J = 6.9 Hz, 3'-H], 4.60 (1H, dd, J5'a,OH = 5.7 Hz,
J5'b,OH = 5.1 Hz, 5'-OH, exchangeable with D2O), 4.65 [1H, br m (dd after addition of
D2O, J1',2' = 3.6 Hz, J2',3' = 6.6 Hz), 2'-H], 4.93 (1H, d, J3',OH = 6.6 Hz, 3'-OH,
exchangeable with D2O), 5.10 (1H, d, J2',OH = 5.1 Hz, 2'-OH, exchangeable with D2O),
6.63 (1H, br s, 1'-H), 7.18 (2H, d, JAB = 8.1 Hz, 6-Ar-mH), 7.21 (2H, d, JAB = 8.1 Hz, 7-
Ar-mH) , 7.29 (2H, d, JAB = 8.1 Hz, 6-Ar-oH), 7.35 (2H, d, JAB = 8.1 Hz, 7-Ar-oH).
3.42 [1H, ddd (dd after addition of D2O, J4',5'a = 6.6 Hz, Jgem = 11.7 Hz), J4',5'a = 6.3
Hz, J5'a,OH = 6.0 Hz, Jgem = 11.7 Hz, 5'-Ha], 3.63 [1H, ddd (br m after addition of
D2O), J4',5'b = 5.1 Hz, J5'b,OH = 5.4 Hz, Jgem = 11.7 Hz, 5'-Hb], 3.72 (1H, m, 4'-H),
3.78 (3H, s, 6-Ar-OCH3), 3.79 (3H, s, 7-Ar-OCH3), 4.19 [1H, q (t after addition of
D2O, J = 6.9 Hz), J = 6.9 Hz, 3'-H], 4.60 (1H, dd, J5'a,OH = 6.0 Hz, J5'b,OH = 5.4 Hz,
5'-OH, exchangeable with D2O), 4.66 [1H, m (dd after addition of D2O, J1',2' = 3.6
Hz, J2',3' = 6.0 Hz), 2'-H), 4.92 (1H, d, J3',OH = 6.9 Hz, 3'-OH, exchangeable with
D2O), 5.11 (1H, d, J2',OH = 4.8 Hz, 2'-OH, exchangeable with D2O), 5.177 and 5.179
(each 1H, each s, each H of Bn), 6.64 ( 1H, br s, 1'-H), 6.94 (2H, d, JAB = 9.0 Hz, 6-
Ar-mH), 6.97 (2H, d, JAB = 9.0 Hz, 7-Ar-mH), 7.25–7.38 (5H, m, Ph-H), 7.36 (2H,
d, JAB = 9.0 Hz, 6-Ar-oH), 7.44 (2H, d, JAB = 6.0 Hz, 7-Ar-oH).
3450, 3442, 1031
(OH),
6d
1717, 1669 ( C=O )

572
HETEROCYCLES, Vol. 80, No. 1, 2010
Table 9. (continued)
Compd
No.
[ꢀ max (Nujol/cm–1)]
ꢁH (300 MHz; (CD3)2SO; Me4Si)
6e
1.23 (3H, t, J = 7.2 Hz, CH3 of Et), 3.42 [1H, ddd (dd after addition of D2O, J4',5'a
6.6 Hz, Jgem = 11.7 Hz), J4',5'a = 6.6 Hz, J5'a,OH = 5.7 Hz, Jgem = 11.7 Hz, 5'-Ha],
=
3446, 1027 (OH),
1727, 1683 (C=O),
1254, 1176 (C-O-C)
3.63 [1H, ddd (dd after addition of D2O, J4',5'b = 5.1 Hz, Jgem = 11.7 Hz), J4',5'b = 5.1
Hz, J5'b,OH = 5.4 Hz, Jgem = 11.7 Hz, 5'-Hb], 3.74 (1H, br m, 4'-H), 3.78 (3H, s, 6-Ar-
OCH3), 3.80 (3H, s, 7-Ar-OCH3), 4.18 (2H, q, J = 7.2 Hz, CH2 of Et), 4.19 [1H, q (t
after addition of D2O, J = 6.9 Hz), J = 6.6 Hz, 3'-H], 4.65 (1H, dd, J5'a,OH = 5.7 Hz,
J5'b,OH =5.4 Hz, 5'-OH, exchangeable with D2O), 4.68 (1H, m, 2'-H), 4.71 (1H, d,
Jgem = 17.1 Hz, Ha of NCH2), 4.79 (1H, d, Jgem = 17.1 Hz, Hb of NCH2), 4.96 (1H,
d, J3',OH = 6.9 Hz, 3'-OH, exchangeable with D2O), 5.19 (1H, d, J2',OH = 5.1 Hz, 2'-
OH, exchangeable with D2O), 6.63 (1H, br s, 1'-H), 6.95 (2H, d, JAB = 8.7 Hz, 6-Ar-
mH), 6.97 (2H, d, JAB = 8.7 Hz, 7-Ar-mH), 7.37 (2H, d, JAB = 8.7 Hz, 6-Ar-oH),
7.46 (2H, d, JAB = 8.7 Hz, 7-Ar-oH),.
6f
1.16 (3H, t, J = 7.2 Hz, CH3 of Et), 1.88 (2H, quin, J = 6.9 Hz, NCH2CH2CH2),
3486, 1027 (OH),
1728, 1682 (C=O),
1233, 1159 (C-O-C)
2.39 (2H, q, J = 6.9 Hz, COCH2), 3.44 [1H, ddd (dd after addition of D2O, J4',5'a
6.6 Hz, Jgem = 11.7 Hz), J4',5'a = 6.3 Hz, J5'a,OH = 6.0 Hz, Jgem = 11.7 Hz, 5'-Ha],
=
3.64 [1H, ddd (dd after addition of D2O, J4',5'b = 5.1 Hz, Jgem = 11.7 Hz), J4',5'b
=
5.1 Hz, J5'b,OH = 4.8 Hz, Jgem = 11.7 Hz, 5'-Hb], 3.71 (1H, br m, 4'-H), 3.77 (3H, s,
6-Ar-OCH3), 3.78 (3H, s, 7-Ar-OCH3), 4.00 (2H, t, J = 6.6 Hz, NCH2), 4.03 (2H,
q, J = 7.2 Hz, CH2 of Et), 4.20 [1H, q (t after addition of D2O, J = 6.9 Hz), J = 6.6
Hz, 3'-H], 4.63 [2H, t, (dd after addition of D2O, J1',2' = 3.6 Hz, J2',3' = 6.0 Hz), J =
5.4 Hz, 2'-H and 5'-OH], 4.95 (1H, d, J3',OH = 6.6 Hz, 3'-OH, exchangeable with
D2O), 5.11 (1H, d, J2',OH = 4.8 Hz, 2'-OH, exchangeable with D2O), 6.64 (1H, br s,
1'-H), 6.94 (2H, d, JAB = 8.7 Hz, 6-Ar-mH), 6.97 (2H, d, JAB = 8.7 Hz, 7-Ar-mH),
7.35 (2H, d, JAB = 8.7 Hz, 6-Ar-oH), 7.42 (2H, d, JAB = 8.7 Hz, 7-Ar-oH).
3440, 3250, 1140
(OH),
6g
3.39 [1H, ddd (dd after addition of D2O, J5'a,OH = 6.3 Hz, Jgem = 11.7 Hz), J4',5'a =
J5'a,OH = 6.3 Hz, Jgem = 12.0 Hz, 5'-Ha], 3.61 [1H, br m (dd after addition of D2O,
J4',5'b = 4.5 Hz, Jgem = 12.0 Hz), 5'-Hb], 3.71 (1H, br m, 4'-H), 4.17 [1H, q (t after
addition of D2O, J = 6.9 Hz), J = 6.6 Hz, 3'-H], 4.61 (1H, dd, J5'a,OH = 6.3 Hz,
J5'b,OH = 5.4 Hz, 5'-OH, exchangeable with D2O), 4.66 [1H, br m (dd after addition
of D2O, J1',2' = 3.6 Hz, J2',3' = 6.3 Hz), 2'-H], 4.95 (1H, d, J3',OH = 7.5 Hz, 3'-OH,
exchangeable with D2O), 5.12 (1H, d, J2',OH = 4.8 Hz, 2'-OH, exchangeable with
D2O), 5.19 (2H, s, CH2 of Bn), 6.60 (1H, br s, 1'-H), 7.23 (2H, dd, JH,H = 8.7 Hz,
JH,F = 9.0 Hz, 6-Ar-oH), 7.27 (2H, dd, JH,H = 8.7 Hz, JH,F = 9.0 Hz, 7-Ar-oH), 7.30–
7.39 (5H, m, Ph-H), 7.44 (2H, dd, JH,H = 8.7 Hz, JH,F = 5.4 Hz, 6-Ar-oH), 7.50 (2H,
dd, JH,H = 8.7 Hz, JH,F = 5.4 Hz, 7-Ar-oH).
1730, 1687 ( C=O )
6h
1.24 (3H, t, J = 7.2 Hz, CH2 of Et), 3.39 [1H, q (dd after addition of D2O, J4',5'a =
3449, 1034 (OH),
1735, 1697 (C=O),
1225, 1160 (C-O-C)
6.3 Hz, Jgem = 11.7 Hz), J = 6.0 Hz, 5'-Ha], 3.60 [1H, ddd (dd after addition of D2O,
J4',5'b = 4.8 Hz, Jgem = 11.7 Hz,), J4',5'b = 4.8 Hz, J5'b,OH = 5.4 Hz, Jgem = 12.0 Hz, 5'-
Hb], 3.72 (1H, m, 4'-H), 4.15 [1H, q (t after addition of D2O, J = 6.9 Hz), J = 6.9
Hz, 3'-H], 4.19 (2H, q, J = 7.2 Hz, CH2 of Et), 4.62 (1H, t, J = 5.7 Hz, 5'-OH,
exchangeable with D2O), 4.66 (1H, m, 2'-H), 4.72 (1H, Jgem = 17.1 Hz, Ha of
NCH2), 4.80 (1H, Jgem = 17.1 Hz, Hb of NCH2), 4.96 (1H, d, J3',OH = 6.9 Hz, 3'-OH,
exchangeable with D2O), 5.17 (1H, d, J2',OH = 5.1 Hz, 2'-OH, exchangeable with
D2O), 6.59 (1H, br s, 1'-H), 7.23 (2H, t, JH,H = JH,F = 9.0 Hz, 6-Ar-mH), 7.27 (2H, t,
JH,H = JH,F = 9.0 Hz, 7-Ar-mH), 7.44 (2H, dd, JH,H = 9.0 Hz, JH,F = 5.7 Hz, 6-Ar-
oH), 7.52 (2H, dd, JH,H = 9.0 Hz, JH,F = 5.7 Hz, 7-Ar-oH).

HETEROCYCLES, Vol. 80, No. 1, 2010
573
Table 9. (continued)
Compd
No.
[ꢀ max (Nujol/cm–1)]
ꢁH (300 MHz; (CD3)2SO; Me4Si)
6i
3477, 3304, 1033
(OH),
1.18 (3H, t, J = 7.2 Hz, CH2 of Et), 1.91 (2H, quin, J = 6.9 Hz, NCH2CH2CH2), 2.40
(2H, q, J = 6.9 Hz, COCH2), 3.42 [1H, quin (dd after addition of D2O, J4',5'a = 6.6 Hz,
J
gem = 11.7 Hz), J = 6.3 Hz, 5'-Ha], 3.61 [1H, br m (dd after addition of D2O, J4',5'b = 4.5
1731, 1688 (C=O),
1225, 1160 (C-O-C)
Hz, Jgem = 11.7 Hz,), 5'-Hb], 3.72 (1H, m, 4'-H), 4.02 (2H, m NCH2), 4.04 (2H, q, J =
7.2 Hz, CH2 of Et), 4.19 [2H, q (t after addition of D2O, J = 6.9 Hz), J = 6.9 Hz, 3'-H],
4.56 (1H, dd, J5'a,OH = 5.7 Hz, J5'b,OH = 5.4 Hz, 5'-OH, exchangeable with D2O), 4.64
[1H, br m (dd after addition of D2O, J1',2' = 3.6 Hz, J2',3' = 6.6 Hz), 2'-H], 4.93 (1H, d,
J3',OH = 6.6 Hz, 3'-OH, exchangeable with D2O), 5.06 (1H, d, J2',OH = 5.1 Hz, 2'-OH,
exchangeable with D2O), 6.62 (1H, br s, 1'-H), 7.21 (2H, dd, JH,H = 8.7 Hz, JH,F = 9.0
Hz, 6-Ar-mH), 7.24 (2H, dd, JH,H = 8.7 Hz, JH,F = 9.0 Hz, 7-Ar-mH), 7.44 (2H, dd, JH,H
= 8.7 Hz, JH,F = 5.7 Hz, 6-Ar-oH), 7.50 (2H, dd, JH,H = 8.7 Hz, JH,F = 5.7 Hz, 7-Ar-oH).
3.39 [1H, ddd (dd after addition of D2O, J4',5'a = 6.9 Hz, Jgem = 11.7 Hz), J4',5'a = 6.9
Hz, J5'a,OH = 5.7 Hz, Jgem = 12.0 Hz. 5'-Ha], 3.61 [1H, ddd (dd after addition of D2O,
3460, 1083 (OH),
1718, 1670 (C=O)
6j
J4',5'b = 4.5 Hz, Jgem = 12.0 Hz), J4',5'b = 4.5 Hz, J5'b,OH = 5.4 Hz, Jgem = 12.0 Hz, 5'-
Hb], 3.70 (1H, br m, 4'-H), 4.17 [1H, q (t after addition of D2O, J = 6.9 Hz), J = 6.9
Hz, 3'-H], 4.60 (1H, dd, J5'a,OH = 5.7 Hz, J5'b,OH = 5.4 Hz, 5'-OH, exchangeable with
D2O), 4.64 [1H, m (dd after addition of D2O, J1',2' = 3.3 Hz, J2',3' = 6.0 Hz), 2'-H], 4.96
(1H, d, J3',OH = 6.9 Hz, 3'-OH, exchangeable with D2O), 5.11 (1H, d, J2',OH = 5.1 Hz,
2'-OH, exchangeable with D2O), 5.19 (2H, s, CH2 of Bn), 6.58 (1H, br s, 1'-H), 7.24–
7.36 (5H, m, Ph-H), 7.35 (2H, d, JAB = 8.4 Hz, 6-Ar-mH), 7.41 (2H, d, JAB = 8.4 Hz,
7-Ar-mH), 7.60 (2H, d, JAB = 8.4 Hz, 6-Ar-oH), 7.65 (2H, d, JAB = 8.4 Hz, 7-Ar-oH).
1.23 (3H, t, J = 7.2 Hz, CH3 of Et), 3.38 [1H, ddd (dd after addition of D2O, J4',5'a
=
3420, 3250, 1040
(OH),
6k
6.6 Hz, Jgem = 11.7 Hz), J4',5'a = 6.6 Hz, J5'a,OH = 6.0 Hz, Jgem = 12.3 Hz, 5'-Ha], 3.60
[1H, ddd (dd after addition of D2O, J4',5'b = 4.5 Hz, Jgem = 11.7 Hz), J4',5'b = 4.5 Hz,
J5'b,OH = 5.4 Hz, Jgem = 12. 3 Hz, 5'-Hb], 3.71 (1H, m, 4'-H), 4.16 [1H, q (t, after
addition of D2O, J = 6.6 Hz), J = 6.9 Hz, 3'-H], 4.18 (2H, q, J = 7.2 Hz, CH2 of Et),
4.63 (1H, dd, J5'a,OH = 6.0 Hz, J5'b,OH = 5.4 Hz, 5'-OH, exchangeable with D2O), 4.66
[1H, br s (dd after addition of D2O, J1',2' = 3.6 Hz, J2',3' = 6.0 Hz, 2'-H), 4.72 (1H, d,
Jgem = 16.8 Hz, Ha of NCH2), 4.80 (1H, d, Jgem = 16.8 Hz, Hb of NCH2), 4.97 (1H, d,
J3',OH = 6.9 Hz, 3'-OH, exchangeable with D2O), 5.17 (1H, d, J2',OH = 5.1 Hz, 2'-OH,
exchangeable with D2O), 6.57 (1H, br s, 1'-H), 7.35 (2H, d, JAB = 8.1 Hz, 6-Ar-mH),
7.42 (2H, d, JAB = 8.1 Hz, 7-Ar-mH), 7.61 (2H, d, JAB = 8.1 Hz, 6-Ar-oH), 7.65 (2H,
d, JAB = 8.1 Hz, 7-Ar-oH).
1734, 1697 (C=O),
1208, 1160 (C-O-C)
1.18 (3H, t, J = 7.2 Hz, CH3 of Et), 1.90 (2H, quin, J = 6.9 Hz, NCH2CH2CH2), 2.40
(2H, q, J = 6.9 Hz, COCH2), 3.42 [1H, ddd (dd after addition of D2O, J4',5'a = 6.0 Hz,
Jgem = 12.0 Hz), J4',5'a = 6.0 Hz, J5'a,OH = 6.3 Hz, Jgem = 12.0 Hz, 5'-Ha], 3.64 [1H, ddd
(dd after addition of D2O, J4',5'b = 4.8 Hz, Jgem = 12. 0 Hz), J4',5'b = 4.8 Hz, J5'b,OH = 5.1
Hz, Jgem = 12. 0 Hz, 5'-Hb], 3.71 (1H, br m, 4'-H), 4.02 (2H, t, J = 6.6 Hz, NCH2), 4.04
(2H, q, J = 7.2 Hz, CH2 of Et), 4.18 [1H, q (t after addition of D2O, J = 6.9 Hz), J = 6.9
Hz, 3'-H], 4.60 (1H, t, J = 5.7 Hz, 5'-OH, exchangeable with D2O), 4.64 [1H, br m (dd
after addition of D2O, J1',2' = 3.6 Hz, J2',3' = 6.0 Hz), 2'-H], 4.96 (1H, d, J3',OH = 6.9 Hz,
3'-OH, exchangeable with D2O), 5.09 (1H, d, J2',OH = 5.1 Hz, 2'-OH, exchangeable with
D2O), 6.59 (1H, br s, 1'-H), 7.36 (2H, d, JAB = 8.4 Hz, 6-Ar-mH), 7.41 (2H, d, JAB = 8.4
Hz, 7-Ar-mH), 7.61 (2H, d, JAB = 8.4 Hz, 6-Ar-oH), 7.65 (2H, d, JAB = 8.4 Hz, 7-Ar-
oH).
6l
3430, 3298, 1074
(OH),
1730, 1687 (C=O),
1240, 1204 (C-O-C)

574
HETEROCYCLES, Vol. 80, No. 1, 2010
Table 10. Evaluation of antitumor activities in vitro of the compounds 3a–g, 4a–g, 5a–l, and 6a–l
Inhibitory concentration
Inhibitory concentration
[IC50 (μg/mL)]
[IC50 (μg/mL)]
Compd
No.
Compd
No.
CCRF-HSB-2
CCRF-HSB-2
KB
>100
KB
3a
3b
3c
3d
3e
3f
5g
5h
5i
34.9
10.1
10.4
99.4
31.7
6.7
11.1
7.5
40.0
8.6
7.2
14.6
34.4
7.9
8.9
15.2
6.5
>100
5j
79.6
18.3
12.7
5k
5l
19.5
13.2
7.3
33.8
38.2
8.6
3g
4a
4b
4c
4d
4e
4f
6a
6b
6c
6d
6e
6f
56.3
26.8
47.6
44.0
61.9
99.3
27.1
>100
13.4
10.4
8.4
89.3
19.8
51.7
45.3
9.1
10.4
17.9
8.5
>100
35.1
15.7
23.6
69.0
40.5
8.9
>100
>100
43.6
>100
28.0
60.7
39.9
6g
6h
6i
4g
5a
5b
5c
5d
5e
5f
>100
41.8
8.1
6j
8.3
7.9
6k
6l
8.2
21.4
9.2
4.8
8.8
41.8
15.3
9.6
Ara-Ca
0.33
0.044
30.3
>100
aAra-C = arabinosylcytocine
5,6-Diamino-2’,3’-O-isopropylideneuridine (2)
A solution of 6-amino-2’,3’-O-isopropylidene-5-nitrosouridine (1, 0.5 g, 1.52 mmol) in 0.5N acetic acid
was stirred vigorously at rt and to it Na2S2O4 (0.5 g, 2.87 mmol) was added gradually until becomes
colorless. After the reaction was complete, the solution was neutralized with 28% aqueous ammonia.
Then, one third of the solution was evaporated and cooled in ice. The solid deposited collected by
filtration and then the filtrated solution was again subjected to evaporation under reduced pressure to
afford the second crop of 5,6-diamino-2’,3’-O-isopropylideneuridine (2) as colorless powder.
Yield: 0.3 g (60 %); mp 170 °C (from EtOH) (Lit.32); IR (Nujol) ꢀmax or ꢁmax/ cm-1: 3400 (ꢀ, OH), 3300
(ꢀas, NH2), 3200 (ꢀs, NH2), 3100 (ꢀ, NH), 1710 (ꢀ, C=O), 1620 (ꢁ, NH2), 1080 (ꢀ, OH); 1H-NMR (CDCl3)
ꢁ: 1.34 and 1.58 (each 3H, each s, 2ꢀCH3), 2.51 (2H, br s, 5-NH2, exchangeable with D2O), 3.80–3.92
(2H, m, 5’-H), 4.12 (1H, m, 4’-H), 4.88 (1H, br, 5’-OH, exchangeable with D2O), 4.98 (1H, dd, J2’,3’ = 6.9
Hz, J3’,4’ = 4.2 Hz, 3’-H), 5.14 (1H, dd, J1’,2’ = 3.9 Hz, J2’,3’ = 6.9 Hz, 2’-H), 6.13 (2H, s, 6-NH2,
exchangeable with D2O), 6.51 (1H, d, J1’,2’= 3.9 Hz, 1’-H), 9.37 (1H, br, NH, exchangeable with D2O).

HETEROCYCLES, Vol. 80, No. 1, 2010
575
General procedure for the preparation of 1-(2’,3’-O-isopropylidene-ꢀ-D-ribofuranosyl)pteridine-
2,4(1H,3H)-dione and its 6,7-bisaryl derivatives (3a–g)
A mixture of 5,6-diamino-2’,3’-O-isopropylideneuridine (2, 0.5 g, 1.59 mmol) and an appropriate
ꢁ,ꢀ-diketone (1.60 mmol) in EtOH was heated under reflux for 18 h. After the reaction was complete, the
solvent was evaporated in vacuo to yield yellow solid. The resulting solid was subjected to column
chromatography on silica gel using a mixture of EtOAc and n-hexane as eluting solvent to afford the
corresponding pure compounds (3a–g) (Table 1–3). The products of 3a and 3b were obtained in 58% and
70% yield, respectively, and were identified with the previously reported compounds in all spectral data.33
General procedure for the preparation of 1-(ꢀ-D-ribofuranosyl)pteridine-2,4(1H,3H)-dione and its
6,7-bisaryl derivatives (4a–g)
A solution one of 6,7-bisaryl-1-(2’,3’-O-isopropylidene-ꢀ-D-ribofuranosyl)pteridine-2,4(1H,3H)-dione
(3a–g, 0.5 g, 0.77–1.49 mmol) in a mixture of MeOH (25 mL) and 0.5N HCl (10 mL) was heated at
50–60 °C for 3–5 h. After cooling to rt, the solution was neutralized with triethylamine and evaporated in
vacuo. Finally, co-evaporation of the solution with EtOH to dryness was achieved. The dry residue was
treated with absolute ethanol and the insoluble material was filtered off. The filtrate was evaporated in
vacuo and the residue was purified by column chromatography on silica gel using a mixture of EtOAc
and n-hexane as eluting solvent to give the corresponding products (4a–g) (Table 1–3). The products of
4a and 4b were obtained in 51% and 75% yield, respectively, and were identified with the previously
reported compounds in all spectral data.27
General procedure for the preparation of N-3-substituted 6,7-bisaryl-1-(2’,3’-O-isopropylidene-
ꢀ-D-ribofuranosyl)pteridine-2,4(1H,3H)-diones (5a–l)
A mixture of compounds (3c–f, 0.5 g, 0.77–0.96 mmol) with anhydrous K2CO3 (1.50 mmol) in dried
DMF (4–5 mL) was cooled to 0 °C. After addition of an appropriate alkyl halide (2.56–2.90 mmol), the
mixture was stirred vigorously at 0 °C for 2–3 h. The reaction mixture was poured into water (10 mL),
and extracted with ethyl acetate (2 ꢀ 8 mL). The organic layer was dried over anhydrous MgSO4 and
evaporated to dryness under reduced pressure. The resulting solid was subjected to column
chromatography on silica gel using a mixture of EtOAc and n-hexane as eluting solvent to afford the
corresponding pure compounds (5a–l) (Table 4–6).
General procedure for the preparation of N-3-substituted 6,7-bisaryl-1-(ꢀ-D-ribofuranosyl)-
pteridine-2,4(1H,3H)-diones (6a–l)

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A solution of 5a–l (0.5 g, 0.65–0.82 mmol) in a mixture of MeOH (25 mL) and 0.5N HCl (10 mL) was
heated at 50–60 °C for 3–5 h. After cooling to rt, the solution was neutralized with triethylamine and
evaporated in vacuo. Finally, co-evaporation of the solution with EtOH to dryness was achieved. The dry
residue was treated with absolute ethanol and the insoluble material was filtered off. The filtrate was
evaporated in vacuo and the residue was purified by column chromatography on silica gel using a mixture
of EtOAc and n-hexane as eluting solvent to give the corresponding deprotected N-3 alkyl derivatives
(6a–l) (Table 7–9).
Growth inhibitory activities of compounds 3–6 against human tumor cell lines
The synthesized compounds were evaluated in vitro for the growth inhibitory effects against
CCRF-HSB-2 (human T-cell acute lymphoblastoid leukemia) and KB (human oral epidermoid
carcinoma) cells by the modified [3-(3,4-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay34
for cellular growth and survival application method developed by Mosmann.35 The results, i.e., IC50
(μg/mL) of each compound against both cells are summarized in Table 10.
ACKNOWLEDGEMENTS
The authors are indebted to the SC-NMR Laboratory of Okayama University for the NMR spectral
experiments.
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