Highly enantioselective synthesis and potential biological activity of chiral novel nucleoside analogues containing adenine and naturally phenol derivatives

Article abstract of DOI:10.1016/j.tet.2005.06.048

This paper described an efficient synthetic strategy for chiral acyclic nucleoside analogues containing both the phenoxy components of some bioactive natural compounds and a heterocyclic base. The phenoxy components with adenine moiety were incorporated into the chiral acyclic nucleoside analogues through two key synthetic tactics. Chiron 5-(R)-menthyloxy-2(5H)-furanone 5 was obtained in good yield from the cheap starting material furfural via a valuable synthetic route. The asymmetric Michael addition of 5 with adenine and the subsequent reduction reaction afforded the key chiral intermediate, 2-(R)-(9′-adeninyl)-1,4-butanediol 8. The absolute configuration of 8 was established by X-ray crystallography. The intermolecular dehydration reaction between 2-(9′-adeninyl)-1,4-butanediol 8 and phenoxy components 9 on treatment with diethyl azodicarboxylate and triphenylphosphine was carried out to give the chiral acyclic nucleoside analogues 1a-1e. The regioselectivity of the reaction was established by NMR methods, especially through ¹³C NMR shifts and NOE effect observed in the target molecule 1c, as well as by HMBC/HMQC experiments. The target compounds were tested for inhibition of cytopathogenicity against different cancer cells and exhibited potential anticancer activity.

Full text of DOI:10.1016/j.tet.2005.06.048

Tetrahedron 65 (2005) 8505–8511
Highly enantioselective synthesis and potential biological activity
of chiral novel nucleoside analogues containing adenine and
naturally phenol derivatives
*
Lan He, Yumei Liu, Wei Zhang, Ming Li and Qinghua Chen
*
Department of Chemistry, Beijing Normal University, Beijing 100875, China
Received 21 February 2005; revised 7 June 2005; accepted 10 June 2005
Available online 15 July 2005
Abstract—This paper described an efficient synthetic strategy for chiral acyclic nucleoside analogues containing both the phenoxy
components of some bioactive natural compounds and a heterocyclic base. The phenoxy components with adenine moiety were incorporated
into the chiral acyclic nucleoside analogues through two key synthetic tactics. Chiron 5-(R)-menthyloxy-2(5H)-furanone 5 was obtained in
good yield from the cheap starting material furfural via a valuable synthetic route. The asymmetric Michael addition of 5 with adenine and
the subsequent reduction reaction afforded the key chiral intermediate, 2-(R)-(90-adeninyl)-1,4-butanediol 8. The absolute configuration of 8
was established by X-ray crystallography. The intermolecular dehydration reaction between 2-(90-adeninyl)-1,4-butanediol 8 and phenoxy
components 9 on treatment with diethyl azodicarboxylate and triphenylphosphine was carried out to give the chiral acyclic nucleoside
analogues 1a–1e. The regioselectivity of the reaction was established by NMR methods, especially through 13C NMR shifts and NOE effect
observed in the target molecule 1c, as well as by HMBC/HMQC experiments. The target compounds were tested for inhibition of
cytopathogenicity against different cancer cells and exhibited potential anticancer activity.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
incorporated into chiral acyclic nucleoside analogues
through two key synthetic tactics: (i) preparation of 2-(R)-
(90-adeninyl)-1,4-butanediol 8 by the asymmetric Michael
addition of chiron, (5)-(R)-(K)-menthyloxy-2(5H)-fura-
none 5 with adenine and subsequent reduction reaction;
and (ii) the intermolecular dehydration reaction occurring
between the 2-(90-adeninyl)-1,4-butanediol 8 and phenoxy
(acidic) components 9 on treatment with diethyl azodi-
carboxylates (DEAD) and triphenylphosphine under mild
conditions6. Herein, we report our results on the efficient
synthesis of the target chiral acyclic nucleoside analogues
containing the phenoxy components of some bioactive
natural compounds (Fig. 1).
It is well known that the phenoxy group is an important
component of some bioactive compounds for their biologic
properties.1 For example, the flavan derivatives2 as new
aromatase inhibitors have been considered as a result of the
modulation of flavonoids, which are natural products
extensively distributing in the plant kingdom. An appro-
priately fashioned hybrid drug of galdanamycin and estradiol
would offer the ability to induce a selective degradation of the
estrogen receptor (ER).3 Several adenosine nucleosides, such
as the antibiotics aristeromycin4 and neplanocin A5 (as
inhibitor S-adenosyl-L-homocyseine hydrolase), are obtained
from natural products. Despite of the progress that has been
made in this field, efficient synthesis of chiral acyclic
nucleoside analogues 1a–1e, which contains both the phenoxy
components of some bioactive natural compounds and a
heterocyclic base, has not been reported.
2. Results and discussion
The synthesis of enantiopure 5-(R)-(K)-menthyloxy-2(5H)-
furanone 5 was conveniently achieved starting from
5-hydroxy-2(5H)-furanone 3 as shown in Scheme 1. The
photooxidation of furfural 2 was probably the most suitable
method for the preparation of 3.7,8 The improved photo-
synthetic procedure using 95% C2H5OH as a the solvent at
room temperature provided 5-hydroxy-2(5H)-furanone in
good yield.7 Epimeric mixture of 5-menthyloxy-2(5H)-
furanone 4 was readily available through acetalization of the
Our approach to use a synthetic strategy in which the
phenoxy components and the adenine moiety could be
Keywords: Asymmetric synthesis; Enantiopure; Chiral acyclic nucleoside
analogue; Phenoxy and adenine components; Potential anticancer activity.
Corresponding authors. Tel.: C86 010 58802076; fax: C86 010
62206222 (Q.C.); e-mail: cqh6693@bnu.edu.cn
*
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.06.048

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L. He et al. / Tetrahedron 65 (2005) 8505–8511
of the products was another key factor. The remaining
chiron 5 was washed with petroleum, and the adduct was
extracted using acetone due to the solubility difference
between the chiron and the product. The optically pure
compound 7 was obtained in 64% yield with R98% ee by
column chromatography. The chemical structures of chiral
1
products were established by element analysis, IR, UV, H
NMR, 13C NMR, MS and X-ray crystallography.7
As outlined in Scheme 3, 5-(R)-(K)-menthyloxy-4-(R)-(90-
adeninyl)-butyrolactone 7 was reduced by LiAlH4 in a
suspension of THF to give the enantiopure functionalized
compound, 2-(R)-(90-adeninyl)-1,4-butanediol 8 in good
yield with R98% ee. The chemical structure of 8 was
readily confirmed by the spectroscopic data. The stereo-
chemistry and configuration of the molecule were further
confirmed by its X-ray crystallography as shown in Figure 2
(CCDC 273580).
Scheme 1. The synthesis of enantiomerically pure 5-(R)-(K)-menthyloxy-
2(5H)-furanone 5.
resulting 5-hydroxy-2(5H)-furanone with (K)-menthol in
refluxing benzene in the presence of a catalytic amount of
condensed sulfuric acid.7,9
Asymmetric Michael addition of heterocyclic bases with 5-
(R)-(K)-menthyloxy-2(5H)-furanone 5 was studied orig-
inally in our laboratory.7 Basic condition was one of the
most important factors for the successful reaction to acquire
the main N-9 alkylation product (Scheme 2). The reaction of
5 and adenine 6 in the presence of triethylamine afforded 5-
(R)-(K)-menthyloxy-4-(R)-(90-adeninyl)-butyrolactone 7
via the asymmetric addition. The important factor was the
selection of solvent. Because of the low solubility of
adenine, DMSO was chosen as the suitable solvent. The
base 6 was dissolved in DMSO at 40 8C, and then
triethylamine was added at room temperature. Purification
Scheme 3. The synthesis of enantiomerically pure 2-(R)-(90-adeninyl)-1,4-
butanediol 8.
Scheme 2. The synthesis of enantiomerically pure 7.
Figure 1. The structures of target molecules.

L. He et al. / Tetrahedron 65 (2005) 8505–8511
8507
compounds.10 The formation of the C–O bond in ethers can
usually be realized by the dehydration of alcohols using
sulfuric acid as the catalyst, but this process is not suitable
for the synthesis of unsymmetrical ethers partly due to the
low selectivity and strong sensitivity of the substrates. The
reaction of alcohols and acidic components such as phenoxy
group takes place easily to form the condensation products
in the presence of organic dehydrating reagents such as the
diethyl azodicarboxylate(DEAD)/triphenylphosphine(Ph3P)
system under mild conditions.6 The condensation reaction
of 2-(R)-(90-adeninyl)-1,4-butanediol 8 with different
phenoxy components 9a–9e was proceeded to afford the
corresponding chiral acyclic nucleoside analogues 1a–1e as
shown in Scheme 4. The dehydrating behavior of different
phenoxy compounds 9 with alcohol 8 could be explained on
the basis of a reaction mechanism including the phenoxy
compound as an acidic component and the alcohol contain-
ing adenine moiety 8 as a nucleophilic reagent. At first, the
adduct of DEAD and Ph3P by the protonation supported
from phenoxy compound was formed as a dipolar system
and subsequently the elimination of 1,2-dicarbethoxyhy-
drazine was easily carried out by the nucleophilic reaction
of 8 to afford a new zwitterion. Finally, the target molecules,
chiral acyclic nucleoside analogues 1a–1e were obtained
through the nucleophilic substitution of the anion of
Figure 2. ORTEP drawing of the molecule 8.
The development of mild methods for the synthesis of
phenoxy ethers has recently gained increased attention,
mainly due to their important roles in natural and unnatural
pharmacologically antibiotics and other biologically active
Scheme 4. The synthetic route to chiral acyclic nucleoside analogues 1a–1e.

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L. He et al. / Tetrahedron 65 (2005) 8505–8511
Table 1. Etherification of chiral compond 8 with phenoxy components 9 in the presence of DEAD and Ph3Pa
Entry
1 Yieldb (mg) (%)
10 Yieldb (mg) (%)
8 Recoveredb (mg)
1 (1a)
2 (1b)
3 (1c)
4 (1d)
5 (1e)
130 (43)
112 (44)
198 (52)
251 (75)
279 (53)
86 (42)
46 (22)
Tracec
—
22
56
Tracec
Tracec
Tracec
Tracec
a The etherification was carried out at room temperature for 1–3 days using 1.0 mmol of 8, 1.2 mmol of 9, 1.2 mmol of DEAD, 1.2 mmol of Ph3P in THF.
b Yield after flash chromatography based on the amount of 8.
c It was checked by TLC to show the traces of 8, 9, and 10, but did not obtain the pure compounds after the separation by flash chromatography.
phenoxy compound and elimination of triphenylphosphine
oxide. The results were summarized in Table 1. The
dehydration of alcohol 8 with 9a–9e afforded the
corresponding ethers 1a–1e in 43–75% FC yields. When
the reactions of 8 with 9a–9b were performed, the
corresponding ethers were achieved in 43–44% FC yields
(Table 1, entries 1, 2) along with the self-etherification
product 10 (Scheme 5) in 42 and 22% FC yields, as well as
recovering 22 and 56 mg of starting material 8, respectively.
The unsymmetrical etherification of 8 with 9c and 9e gave
the corresponding ethers 1c and 1e in 52 and 53% FC yields,
respectively, (Table 1, entries 3, 5). At the same time, the
traces of 8, 9 and 10 were found by checking TLC, which
were not obtained after flash chromatography. The result of
the dehydration of alcohol 8 with 9d under the same
condition gave 1d in 75% FC yield (Table 1, entry 4).
Obviously, the aim of our present study would be to propose
further groundwork for any future applications on the
unsymmetric etherification to the synthesis of more
complex molecules containing similar chiral acyclic and
cyclic nucleoside skeleton.
The stereochemistry of the nucleoside 1c was elucidated by
HMQC and HMBC experiment as shown in Figures 3, 4,
and 5 as well as Table 2. The result described that H-4 was
correlated only with C-2, C-3 and C-700, which proved the
Figure 4. The 500 MHz HMBC spectrum of compound 1c.
Scheme 5. The intramolecular dehydration of 2-(R)-(90-adeninyl)-1,4-
butanediol 8.
Figure 3. Relevant 1H/13C HMBC correlations for structural identification
of compound 1c.
Figure 5. The 500 MHz HMQC spectrum of compound 1c.

L. He et al. / Tetrahedron 65 (2005) 8505–8511
Table 2. 1H NMR, 13C NMR data and HMQC, HMBC correlations for 1ca
8509
asymmetric Michael addition of the chiron 5-(R)-(K)-
menthyloxy-2(5H)-furanone 5 with adenine and the sub-
sequent reduction reaction, which provided the key chiral
intermediate, 2-(R)-(90-adeninyl)-1,4-butanediol 8. The
other was the intermolecular dehydration reaction between
chiral 8 and phenoxy components 9 to form the target
compounds 1. The enantiopure acyclic nucleoside ana-
logues exhibited potential anticancer activity.
Position
dH
(mult. J in Hz)
dC
(mult.)
HMQC HMBC
1
3.77–3.81 (m),
388–3.94 (m)
4.73–4.75 (m)
2.40–2.42 (m),
2.47–2.51 (m)
3.88–3.94 (m),
4.07–4.11 (m)
8.08 (s)
62.9
C-1
C-3, C-2
C-1, C-3, C-4, C-80
C-1, C-2, C-4
2
3
55.3
29.8
C-2
C-3
C-2, C-3, C-700
C-40, C-50
C-10, C-7, C-4
C-50
4
65.8
C-4
20
C-20
152.5
155.1
119.5
150.2
141.0
161.8
111.6
156.4
126.8
112.8
160.6
101.7
153.8
113.6
18.6
40
C-40
50
C-50
4. Experimental
600
C-600
8.16 (s)
6.20 (s)
800
C-800
C-200
C-300
C-400
C-5
200
4.1. General
C–CH3
300
400
Infrared spectra were recorded on a Fourier 170-sx
1
C-800, C-1000
C-700, C-800
7.26 (d, 8.8)
6.82 (d, 8.8)
5
spectrophotometer. H NMR and 13C NMR spectra were
600
C-600
C-700
C-800
C-900
C-1000
C–CH3
700
recorded on a Bruker-500 MHz spectrometer and the
chemical shifts were expressed in d-values using TMS as
the internal standard. Mass spectra were determined with a
Finnegan GC2000/TRACE TM/MS mass spectrometer.
Microanalyses were performed on a Perkin-Elemer 240-C
elemental analyzer. Melting point was determined on a XT
Digital melting-point apparatus with microscope and
uncorrected. All chemical reagents were commercially
available and treated with standard methods before use.
Solvents were dried in a routine way and redistilled.
800
C-600, C-700, C-900
6.87 (s)
900
1000
CH3
OH
NH2
H-300
C-2
C-50
2.37 (s)
5.13 (t, 5.5)
7.16 (s)
a 1H NMR and 13C NMR spectra were measured at 500 and 125 MHz,
respectively. Couling constants (in parentheses) are given in Hz.
ether bond formed between C-4 and C-700. The long-range
correlations of H-2 with C-80, C-1, C-3, and C-4,
respectively, were observed and demonstrated that target
molecule 1c was the N-90 regioisomer as shown in Figure 3.
4.2. Synthesis of 2-(R)-(90-adeninyl)-1,4-butanediol (8)
To a solution of 6 mmol LiAlH4 in dry THF (20 mL) was
added 7 (2 mmol) in dry THF (40 mL) under nitrogen
atmosphere. The reaction mixture was stirred for 12–24 h
until 7 had been consumed. Saturated Na2SO4 solution was
added to decompose excess LiAlH4, followed by addition of
ethanol (20 mL). Then the mixture was filtered, washed
with ethanol. The combined organic layer was dried and
concentrated in vacuum and purified by flash chromato-
graphy to afford 368 mg (82%) of 8 as colorless crystals. Mp
181.3–181.7 8C; [a]2D0C41.6 (c 1.0, CH3OH); 1H NMR
(500 MHz, DMSO-d6) d 2.02–2.04 (1H, m, H-3), 2.09–2.15
(1H, m, H-3), 3.20–3.23 (1H, m, H-4), 3.31–3.33 (1H, m,
H-4), 3.68–3.72 (1H, m, H-1), 3.84–3.88 (1H, m, H-1),
Compounds 1a, 1b, 1c, and 1d were tested for inhibition of
cytopathogenicity against different cancer cells such as the
colon cancer HCT-8 cell, the cervical cancer HELA cell, the
pulmonary cancer A549 cell and the skin cancer A431 cell
in pharmacological primary screen model as shown in
Table 3. In comparison to the target molecules against the
different types of cancer cells, 1d exhibited higher anti-
cancer activity against skin cancer A431 cell and pulmonary
cancer A549 cell. These results probably provided a
valuable research route to look for novel types of chiral
acyclic nucleoside analogues with new biological activities.
4.60 (1H, t, JHO–CH Z5.28 Hz, OH), 4.62–4.64 (1H, m, H-2),
2
5.03 (1H, t, OH), 7.19 (2H, s, NH2), 8.11 (2H, s, H-80, 20); 13C
NMR (125 MHz, DMSO-d6) d 33.4 (C-3), 55.1 (C-2), 57.6
(C-4), 62.8 (C-1), 119.3 (C-50), 141.1 (C-80), 150.0 (C-60),
152.4 (C-20), 156.2 (C-40); IR (KBr, cmK1): 3426 (br OH),
1648, 1599, 1575, 1484. Anal. Calcd for C9H13N5O2: C,
48.42; H, 5.87; N, 31.37. Found: C, 48.37; H, 5.89; N, 31.11.
3. Conclusion
An efficient synthetic strategy for chiral acyclic nucleoside
analogues containing both the phenoxy components of some
bioactive natural compounds and a heterocyclic base was
achieved through two key synthetic tactics. One was the
Table 3. Inhibitory ratio (IR)a and corresponding inhibitory concentrations (IC50)b of chiral acyclic nucleoside analogues on the cytopathogenicity of different
cancer cells, in pharmacological primary screen model
Compound
Colon cancer HCT-8 cell
IR/IC50 (mg/mL)
Cervical cancer HELA cell
IR/IC50 (mg/mL)
Pulmonary cancer A549 cell
IR/IC50 (mg/mL)
Skin cancer A431 cell
IR/IC50 (mg/mL)
1a
1b
1c
1d
9.5/50
7.6/50
23.9/50
31.6/50
39.2/O50
82.7/16.8
58.8/4.10
78.1/12.0
42.4/53.1
80.5/5OIC50!50
23.7/50
43.5/61.7
84.9/9.5
K1.5/50
33.0/O50
79.3/16.1
a Inhibitory ratio (IR) was obtained through the use of the concentration of 50 mg/mL.
b Inhibitory concentrations (IC50) were determined through the use of an established MTTmethod11,12 and represent the average of duplicate determinations.

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L. He et al. / Tetrahedron 65 (2005) 8505–8511
4.3. General procedure for the preparation of (1a–1e)
(500 MHz, DMSO-d6) d 0.82 (3H, s, H-1800), 2.43–2.46 (2H,
m, H-3), 2.75–2.78 (2H, m, H-1600), 3.70–3.77 (2H, m, H-4),
3.87–3.91 (2H, m, H-1), 4.69–4.71 (1H, m, H-2), 5.11 (1H, t,
OH), 6.48 (1H, s, H-400), 6.57 (1H, dd, JZ2.5, 8.6 Hz, H-200),
7.11 (1H, d, JZ8.6 Hz, H-100), 7.20 (2H, s, NH2), 8.10 (1H, s,
H-20), 8.1500(1H, s, H-80); 13C NMR (125 MHz, DMSO-d6) d
14.0 (C-1800 ), 29.5 (C-3), 55.3 (C-2), 62.8 (C-1), 640.07 (C-4),
112.60(0 C-4 ), 114.6 (C-200), 119.2 (C-50), 126.6 (C-1 ), 132.3
(C-10 ), 137.8 (C-500), 141.0 (C-80), 150.1(C-60), 152.5 (C-20),
156.6 (C-40), 220.2 (C-1700); IR (KBr, cmK1): 3437 (br OH),
1732 (C]O); HRMS (FABC) m/z calcd for C27H34N5O3,
(MCH)C476.2662, found 476.2650.
To a mixture of compound 8 (1 mmol), ROH 9 (1.2 mmol),
Ph3P (1.2 mmol) in 1 mL THF, DEAD (1.2 mmol) in THF
(0.5 mL) was added dropwise. The solution was stirred at
room temperature under N2 atmosphere for 1–3 days. The
solvent was removed in vacuum and the crude product was
obtained and further purified by flash chromatography to
afford the target compounds 1a–1e.
4.3.1. 2-(R)-(90-Adeninyl)-4-(400-chlorophenoxy)-butan-
1-ol (1a). One hundred and thirty milligrams, yield 43%;
1
mp 185.7–186.3 8C; [a]2D0C80.0 (c 1.0, DMSO); H NMR
4.3.5. 2-(R)-(90-Adeninyl)-4-[400-(2000,4000,6000-trimethoxyl-
dihydrochalcony1)]-butan-1-ol (1e). Two hundred and
seventy nine milligrams, yield 53%; mp 100.1–102.0 8C;
(500 MHz, DMSO-d6) d 2.34–2.37 (1H, m, H-3), 2.44–2.49
(1H, m, H-3), 2.44–2.49 (2H, m, H-1), 3.88–3.95 (2H, m,
H-4), 4.70–4.7300(1H, m, H-2), 5.11 (1H, t, OH), 6.83 (2H, d,
JZ9.0 Hz, H-2 , 600), 7.16 (2H, s, NH2), 7.26 (2H, d, JZ
9.0 Hz, H-300, 500), 8.08 (1H, s, H-20), 8.15 (1H, s, H-80); 13C
NMR (125 MHz, DMSO-d6) d 30.0 (C-3), 55.2 (C-2), 62.8
(C-1), 65.3(C-4), 116.6 (C-200,0600), 119.4 (C-50), 124.7 (C-4000),
129.6 (C-300, 500), 141.0 (C-8 ), 150.1 (C-60), 152.5 (C-2 ),
156.3 (C-40), 157.6 (C-100); IR (KBr, cmK1): 3442 (br OH),
1678, 1605, 1492; HRMS (FABC) m/z calcd for
C15H17ClN5O2 (MCH)C334.1071, found 334.1070.
1
[a]2D0C12.0 (c 0.2, DMSO); H NMR (500 MHz, DMSO-
d6) d 2.36–2.41 (1H, m, H-3), 2.48–2.51 (1H, m, H-3), 2.74–
2.77 (2H, m, H-b), 2.88–2.91 (2H, m, H-a), 3.73 (6H, s, 2!
OCH3), 3.76 (3H, s, OCH3), 3.78–3.79 (1H, m, H-1), 3.88–
3.90 (2H, m, H-1,4), 4.03–4.06 (1H, m, H-4), 4.71–4.73
(1H, m, H-2), 5.14 (1H, t,0O0 H), 6.21 (2H, s, H-3000,5000), 6.89
(2H, d, JZ8.8 Hz, H-300,5 ), 7.18 (2H, s, NH2), 7.86 (2H, d,
JZ8.8 Hz, H-200,600), 8.08 (1H, s, 20), 8.17 (1H, s, H-80); 13C
NMR (125 MHZ, DMSO-d6) d 18.8 (C-b), 30.0 (C-3), 38.5
(C-a), 55.2 (C-2), 55.6 (OCH3), 56.1 (OCH3), 62.8 (C-1),
65.3 (C-4),0091.2 (C-3000,5000), 109.0 (C-1000), 114.7 (C-300, 5000),
129.9 (C-10 ), 130.6 (C-200, 600), 141.000(0 C-80), 150.2 (C-6 ),
152.5 (C-2 ), 156.4 (C-40), 158.7 (C-2 , 6000), 159.8 (C-4000),
162.5 (C-400), 198.8 (C]O); IR (KBr, cmK1): 3437 (br OH),
1670 (C]O); HRMS (FABC) m/z calcd for C27H32N5O6,
(MCH)C522.2353, found 522.2348.
4.3.2. 2-(R)-(90-Adeninyl)-4-(400-acetophenyl)-butan-1-ol
(1b). One hundred and twelve milligrams, yield 44%; mp
233.8–235.0 8C; [a]2D0C85.9 (c 1.0, DMSO); 1H NMR
(500 MHz, DMSO-d6) d 2.09 (3H, s, CH3), 2.37–2.40 (1H,
m, H-3), 2.50–2.51 (1H, m, H-3), 3.76–3.79 (1H, m, H-1),
3.86–3.92 (2H, m,0H-1, 4), 4.03–4.06 (1H, m, H-4), 4.72–
4.75 (1H, m, H-2 ), 5.14 (1H, t, OH), 6.89 (2H, d, JZ
8.8 Hz, H-200,600), 7.21 (2H, s, NH2), 7.86 (2H, d, JZ8.8 Hz,
H-300,500), 8.08 (1H, s, H-20), 8.17 (1H, s, H-80); 13C NMR
(125 MHz, DMSO-d6) d 26.8 (CH3), 30.0 (C-3), 55.2 (C-2),
62.80(0 C-1), 65.3 (C-4), 114.7 (C-200,600), 119.0 (C-50), 130.4
(C-40 ), 130.8 (C-300,500), 141.0 (C-80), 150.1 (C-60), 152.4
(C-2 ), 156.2 (C-40), 162.6 (C-100), 196.7 (C]O); IR (KBr,
cmK1): 3307 (br OH), 1677 (C]O). Anal. Calcd for
C17H19N5O3: C, 59.81; H, 5.61; N, 20.51. Found: C, 59.22;
H, 5.80; N, 20.02.
4.3.6. 3-(R)-(90-Adeninyl)-tetrahydrofuran(10). Mp
202.3–203.1 8C; [a]2D0K2.2 (c 1.0, CHCl3); 1H NMR
(500 MHz, DMSO-d6) d 2.29–2.30 (1H, m, H-4), 2.47–
2.50 (1H, m, H-4), 3.84–3.89 (1H, m, H-5), 3.96–3.97 (2H,
m, H-2, 5), 4.08–4.11 (1H, m, H-2), 5.15–5.19 (1H, m, H-3),
7.25 (2H, s, NH2), 8.14 (1H, s, H-20), 8.15 (1H, s, H-80); 13C
NMR (125 MHz, DMSO-d6) d 32.3 (C-4), 54.4 (C-3), 67.0
(C-5), 72.2 (C-2), 119.3 (C-50), 139.3 (C-80), 149.8 (C-60),
152.8 (C-20), 156.4 (C-40); IR (KBr, cmK1): 3341.9, 3180.9,
1652.0. Anal. Calcd for C9H11N5O: C, 52.67; H, 5.40; N,
34.13. Found: C, 52.78; H, 5.30; N, 33.59.
4.3.3. 2-(R)-(90-Adeninyl)-4-[700-(400-menthylumbelli-
feronyl)]-butan-1-ol (1c). One hundred and ninety three
milligrams, yield 52%; mp 202.3–202.4 8C; [a]2D0C85.6
(c 0.9, DMSO); 1H NMR (500 MHz, DMSO-d6) d 2.37 (3H,
s, CH3), 2.40–2.42 (1H, m, H-3), 2.47–2.51 (1H, m, H-3),
3.77–3.81 (1H, m, H-1), 3.88–3.94 (2H, m, H-1, 4), 4.07–
4.11 (1H, m, H-4), 4.73–4.75 (1H, m, H-2), 5.13 00(1H, t,
OH), 6.20 (1H, s, H-300), 6.82 (1H, d, JZ8.8 Hz, H-6 ), 6.87
(1H, s, H-800), 7.16 (2H, s, NH2), 7.26 (1H, d, JZ8.8 Hz,
H-500), 8.08 (1H, s, H-20), 8.16 (1H, s, H-80); 13C NMR
(125 MHz, DMSO-d6) d 18.6 (CH3), 29.8 (C-3), 55.3 (C-2),
62.900(C-1), 65.8 (C-4), 101.7 (C-8000), 111.6 (C-300), 112.8
(C-6 ), 113.6 (C-1000), 119.5 (C-5 ), 126.8 (C-500), 1410.0
(C-80), 150.2 (C-60), 152.5 (C-20), 153.8 (C-900), 155.1 (C-4 ),
156.4 (C-400), 160.6 (C-700), 161.8 (C-200); IR (KBr, cmK1):
3424 (br OH), 1711 (C]O); HRMS (FABC) m/z calcd for
C19H20N5O4 (MCH)C382.1515, found 382.1514.
Acknowledgements
The authors are grateful to the Key Project of Chinese
Ministry of Education (No. 03013), National Natural
Science Foundation of China (No. 20372010) and Trans-
Century Training Program Foundation for the Talents,
Ministry of Education of China, and Chinese Academy of
Medical Sciences for their help in anticancer activity
screening of our compounds.
References and notes
4.3.4. 2-(R)-(90-Adeninyl)-4-(300-estronyl)-butan-1-ol
(1d). Two hundred and fifty one milligrams, yield 75%;
mp 242.4–244.5 8C; [a]2D0C141.1 (c 0.9, DMSO); 1H NMR
1. Tietze, L. F.; Chandrasekhr, S.; Bell, H. P. Angew. Chem., Int.
Ed. 2003, 42, 3996–4028.

L. He et al. / Tetrahedron 65 (2005) 8505–8511
8511
2. Yahiaoui, S.; Pouget, C.; Fagnere, C.; Champavier, Y.;
Habrioux, G.; Chulia, A. J. Bioorg. Med. Chem. Lett. 2004,
14, 5215–5218.
8. De Jons, J. C.; Van Bolhuis, F.; Feringa, B. L. Tetrahedron:
Asymmetry 1991, 2, 1247–1262.
9. Huang, H.; Chen, Q. H. Tetrahedron: Asymmetry 1999, 10,
1295–1307.
3. Kuduk, S. D.; Zheng, F. F.; Sepp-Lorenzino, L.; Rosen, N.;
Danishefsky, S. J. Bioorg. Med. Chem. Lett. 1999, 9, 1233–1238.
4. De Clereg, E. Biochem. Pharmacol. 1987, 36, 2567–2575.
5. Borchardt, Y.; Kelleer, B. T.; Pater-Thrombre, U. J. Biol.
Chem. 1984, 256, 5353–5359.
10. Nagarajan, R. In Glycopentide Antibiotics, Drugs and the
Pharmaceutical Sciences, Vol. 63; Decker: New York, 1994.
11. Mosumann, T. J. Immunol. Methods 1983, 65, 55–63.
12. Carmichael, J.; DeGraff, W. G.; Gazdar, A. f.; Minna, J. D.;
Mitehell, J. B. Cancer Res. 1987, 47, 936–942.
6. Mitsunobu, O. Synthesis 1981, 1–28.
7. Wang, Y. H.; Chen, Q. H. Sci. China, Ser. B 1999, 42,
121–130.