Synthesis and antiviral evaluation of novel 4′-hydroxymethyl branched apiosyl nucleosides

Article abstract of DOI:10.1080/15257770500379173

Novel 4′-hydroxymethyl branched apiosyl nucleosides were synthesized in this study. The introduction of a hydroxymethyl group in the 4′-position was accomplished by a [3, 3]-sigmatropic rearrangement. Apiosyl sugar moiety was constructed by sequential ozo

Full text of DOI:10.1080/15257770500379173

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Synthesis and Antiviral Evaluation of
Novel 4′-Hydroxymethyl Branched
Apiosyl Nucleosides
Jin Woo Kim a & Joon Hee Hong a
a College of Pharmacy , Chosun University , Kwangju, Republic of
Korea
Published online: 20 Aug 2006.
To cite this article: Jin Woo Kim & Joon Hee Hong (2006) Synthesis and Antiviral Evaluation of Novel
4′-Hydroxymethyl Branched Apiosyl Nucleosides, Nucleosides, Nucleotides and Nucleic Acids, 25:1,
109-117
To link to this article: http://dx.doi.org/10.1080/15257770500379173
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Nucleosides, Nucleotides, and Nucleic Acids, 25:109–117, 2006
Copyright ꢀ Taylor & Francis Group, LLC
C
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770500379173
SYNTHESIS AND ANTIVIRAL EVALUATION OF NOVEL
4ꢀ-HYDROXYMETHYL BRANCHED APIOSYL NUCLEOSIDES
Jin Woo Kim and Joon Hee Hong
College of Pharmacy, Chosun University,
2
Kwangju, Republic of Korea
Novel 4ꢁ-hydroxymethyl branched apiosyl nucleosides were synthesized in this study. The in-
2
troduction of a hydroxymethyl group in the 4ꢁ-position was accomplished by a [3,3]-sigmatropic
rearrangement. Apiosyl sugar moiety was constructed by sequential ozonolysis and reductions. The
natural bases (uracil, thymine, cytosine, and adenine) were efficiently coupled by a classical glycosyl
condensation procedure (persilyated base and TMSOTf ). The antiviral activities of the synthesized
compounds were evaluated against HIV-1, HSV-1, HSV-2, and HCMV. Compound 18 displayed
moderate anti-HCMV activity (EC = 20.1 µg/mL) without exhibiting any cytotoxicity up to
50
100 µM.
Keywords Antiviral agents; Branched nucleoside; Apiosyl nucleoside; Claisen rear-
rangement; Ozonolysis
INTRODUCTION
The discovery of novel nucleosides as antiviral and anticancer agents has
been the goal of nucleoside chemists for a several decades. In particular,
since the emergence of the HIV pandemic, extensive efforts have been con-
centrated on various modifications in the sugar moiety of nucleosides, result-
ing in FDA approved anti-HIV agents such as AZT,[1] ddC,[2] ddI,[3] d4T,[4]
3TC,[5] and abacavir.[6] However, side effects and the emergence of drug-
resistant mutants continue to be a problem with these antiviral agents. It is
now clear that judicious combination therapy is the optimum way to improve
the survival of patients infected with HIV-1. Therefore, the development of
structurally new nucleoside derivatives, which have potent antiviral activities
and low toxicity as well as novel resistant profiles, are urgently needed to pro-
vide better choices for combination chemotherapy. Recently, the compounds
synthesized (Figure 1), 4ꢁ-cyanothymidine 1,[7] 4ꢁ-azidothymidine 2,[8] and 4ꢁ-
hydroxymethythymidine 3[9] are of particular interest as they represent a new
Received 4 January 2005; accepted 1 August 2005.
Address correspondence to Dr. Joon Hee Hong, College of Pharmacy, Chosun University, Kwangju
501-759, Republic of Korea. E-mail: hongjh@chosun.ac.kr
109

110
J. W. Kim and J. H. Hong
FIGURE 1 Structures of potent 4ꢁ-branched nucleosides, and target nucleosides.
class of compounds and exhibit significant biological activity. Furthermore,
more fundamental modifications of the pentofuranose moiety, such as isonu-
cleosides and apionucleosides, have been reported to be compatible with
antiviral activities. In attempts to find new lead compounds with improved
biological activity, we have synthesized novel 4ꢁ-hydroxymethyl branched api-
onucleosides. Previously, we reported an efficient synthetic method[10] of
producing quaternary carbon useful for target molecules using the Claisen
rearrangement reaction.
RESULTS AND DISCUSSION
As shown in Scheme 1, the γ ,δ-unsaturated ester derivative 5, which
was readily synthesized from 1,3-dihydroxy acetone by a previously reported
method[10] (Scheme 1), was selected as the starting compound for the synthe-
sis of the 4ꢁ-hydroxymethyl branched apiosyl nucleosides. Ester 5 was treated
with ozone in methylene chloride at −78◦C, followed by decomposition of
the ozonide by dimethylsulfide (DMS) to give the aldehyde 6 and subse-
quently reduced using DIBAL-H in toluene at −78◦C to give lactol 7 in 71%
yield. The apiose lactol 7 was acetylated in pyridine to furnish the key inter-
mediate 8 as glycosyl donor (Scheme 1). For the preparation of the uracil and
thymine nucleosides, compound 8 was condensed with corresponding per-
O-silylated bases using trimethylsilyl trifluoromethanesulfonate (TMSOTf)
as the catalyst in 1,2-dichloroethane (DCE) to give protected nucleosides 9
and 10, respectively. Cytosine nucleoside 17 was prepared from the corre-
sponding N4-benzoyl cytosine nucleoside analogue 11, which was prepared

Synthesis of Branched Apiosyl Nucleosides
111
SCHEME 1 Synthesis of apiosyl acetate.
from corresponding N4-benzoyl cytosine in a similar method described for 9
and 10. The synthesis of adenine nucleoside was carried out by condensation
of compound 8 with silylated 6-chloropurine using TMSOTf as a catalyst in
DCE to give protected 6-chloropurine derivative 12, which was treated with
ammonia in methanol in a steel bomb at 90–100◦C followed by desilylation
to give final nucleoside 18 (Scheme 2).
The synthesized compounds 13, 14, 17, and 18 were tested against several
viruses such as HIV (MT-4 cells), HSV-1 (CCL81 cells), HSV-2 (CCL-81 cells),
and HCMV (AD-169, Davis cells). All the compounds synthesized showed
neither excellent antiviral activity nor any cytotoxicity when tested up to
100 µg/mL. However, the adenine analogue 18 did show moderate antiviral
activity against HIV-1 (Table 1), indicating that this virus might allow the
sugar moiety for phosphorylation as well as for DNA polymerase, which is
different from other viruses.
In summary, a novel synthetic method for 4ꢁ-branched apiosyl nucleo-
sides from a simple 1,3-dihydroxy acetone derivative was developed. When
TABLE 1 The Antiviral Activities of the Synthesized Compounds
HIV-1
HSV-1
HSV-2
HCMV
Cytotoxicity
Compound EC50 (µg/mL) EC50 (µg/mL) EC50 (µg/mL) EC50 (µg/mL) IC50 (µg/mL)
13
14
17
18
>100
51.0
>100
20.1
0.0008
ND
ND
>100
>100
>100
>100
ND
>100
>100
>100
>100
ND
>100
>100
>100
>100
ND
>100
>100
>100
>100
2.01
AZT
Ganciclovir
Ribavirin
1.9
ND
1.9
ND
ND
10.5
>10
300.00
ND: Not determined.

112
J. W. Kim and J. H. Hong
SCHEME 2 Synthesis of target apiosyl nucleosides.
the synthesized compounds were tested against several viruses such as HIV-1,
HSV-1, HSV-2, and HCMV, only the adenosine analogue 18 exhibited weak
antiviral activity against the HIV-1. The lack of antiviral activity of these
racemic compounds is presumably associated with their unfavorable con-
formations for the phosphorylation step occurring during the nucleotide
activation process. However, the information obtained in the present study
will be useful for the development of a novel apiosyl nucleoside. Studies
toward this end and to clarify the mechanism are underway.
EXPERIMENTAL
All the chemicals were of reagent grade and were used without further
purification. All the moisture-sensitive reactions were performed in an
inert atmosphere with either N2 or Ar using distilled dry solvents. The
melting points were determined using a Mel-temp II laboratory device and
were uncorrected. The NMR spectra were recorded on a JEOL JNM-LA
300 spectrometer. The chemical shifts are reported in parts per million
(δ) and the signals are quoted as s (singlet), d (doublet), t (triplet), q
(quartet), m (multiplet), and dd (doublet of doublets). The UV spectra

Synthesis of Branched Apiosyl Nucleosides
113
were obtained using a Beckman DU-7 spectrophotometer. The elemental
analyses were performed using an Elemental Analyzer System (EA1112).
TLC was performed on Uniplates (silica gel) purchased from Analtech Co.
The dry THF was obtained by distillation from Na and benzophenone when
the solution became purple.
Ethyl-3,3ꢁ-bis-(t-butyldimethylsilyloxymethyl)-4-oxobutyrate (6).
A so-
lution of compound 5 (10 g, 23.9 mmol) in anhydrous CH2Cl2 (200 mL)
was cooled down to −78◦C, and ozone gas was then bubbled into the reac-
tion mixture until a blue color persisted for an additional 5 min. The reaction
mixture was degassed with nitrogen, and methyl sulfide (8.7 mL, 119 mmol)
was slowly added at −78◦C. The mixture was stirred for 2 h at rt under nitro-
gen. The mixture was concentrated under reduced pressure, and the residue
was purified by silica gel column chromatography (EtOAc/hexane, 1:30) to
give compound 6 (8.7 g, 87%) as a colorless oil: 1H NMR (CDCl3, 300 MHz)
δ 9.66 (s, 1H), 4.05 (q, J = 7.2 Hz, 2H), 3.84–3.64 (m, 4H), 2.36 (s, 2H), 1.19
(t, J = 7.2 Hz, 3H), 0.83 (s, 18H), 0.06 (s, 6H), 0.03 (s, 6H); 13C NMR (CDCl3,
75 MHz) δ 204.41, 171.06, 65.40, 60.22, 55.11, 25.48, 18.22, 14.10, −5.72.
(
) - 4,4 - bis-(tert - Butyldimethylsilanyloxymethyl )tetrahydrofuran-2-ol
To a solution of compound 6 (4.5 g, 10.7 mmol) in anhydrous
(7).
toluene (100 mL), 1.5 M solution of DIBAL-H (14.9 mL, 22.47 mmol) in
toluene was added dropwise at −78◦C under nitrogen, and the mixture was
then stirred for 20 min at −78◦C. The reaction mixture was quenched by
MeOH (23 mL), and the temperature was elevated to rt. After stirring at rt
for 2 h, the resulting solid was removed by Celite filtration, and the filtrate
was concentrated under reduced pressure. The residue was purified by silica
gel column chromatography (EtOAc/hexane, 1:15) to give compound 7
1
(2.86 g, 71%) as a colorless oil: H NMR (CDCl3, 300 MHz) δ 5.24 (dd,
J = 9.3, 4.5 Hz, 1H), 3.73 (d, J = 9.3 Hz, 1H), 3.66 (d, J = 9.3 Hz, 1H), 3.54
(dd, J = 14.4, 9.3 Hz, 2H), 1.77 (dd, J = 13.5, 5.1 Hz, 1H), 1.62 (d, J = 13.5
Hz, 1H), 0.81 (s, 9H), 0.75 (s, 9H), 0.04 (s, 6H), 0.01 (s, 6H); 13C NMR
(CDCl3, 75 MHz) δ98.63, 70.38, 67.08, 66.39, 49.30, 40.87, 25.83, 18.13,
−5.62; Anal calc for C18H40O4Si2: C, 57.39; H, 10.70. Found: C, 57.55; H,
10.54.
( )-Acetic Acid 4,4-bis-(tert-Butyldimethylsilanyloxymethyl)tetrahydro-
furan-2-yl Ester (8).
To a solution of compound 7 (3.5 g, 9.34 mmol)
in anhydrous pyridine (50 mL), Ac2O (1.42 g, 14.0 mmol) was slowly added,
and the mixture was stirred overnight under nitrogen. The pyridine was evap-
orated under reduced pressure and co-evaporated with toluene. The residue
was extracted with EtOAc/H2O, dried over MgSO4 and filtered. The filtrate
was concentrated under reduced pressure. The residue was purified by silica

114
J. W. Kim and J. H. Hong
gel column chromatography (EtOAc/hexane, 1:15) to give compound 8 (3.5
g, 90%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 6.20 (d, J = 5.4 Hz,
1H), 3.72 (s, 2H), 3.59 (s, 2H), 3.46 (dd, J = 13.5, 9.6 Hz, 2H), 1.98 (s, 3H),
1.93 (dd, J = 14.1, 6.0 Hz, 1H), 1.82 (d, J = 14.1 Hz, 1H), 0.84 (s, 9H), 0.82
(s, 9H), 0.03 (s, 6H), 0.01 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ 170.41,
99.62, 73.17, 64.27, 63.78, 49.95, 37.34, 25.64, 21.36, 18.22, −5.61; Anal calc
for C20H42O5Si2: C, 57.37; H, 10.11. Found: C, 57.52; H, 10.20.
(
)-1-[4,4-bis-(tert-Butyldimethylsilanyloxymethyl)tetrahydrofuran-2-
yl]-uracil (9). Uracil (300 mg, 2.67 mmol), anhydrous HMDS (20 mL),
and a catalytic amount of ammonium sulfate were refluxed to a clear
solution, and the solvent was distilled under anhydrous conditions. The
residue was dissolved in anhydrous 1,2-dichloroethane (DCE). To this
mixture, a solution of 8 (559 mg, 1.335 mmol) in dry DCE (10 mL) and
TMSOTf (0.48 mL, 2.67 mmol) was added, and the resulting mixture was
stirred at rt for 2 h. The reaction mixture was quenched with 5 mL of
saturated NaHCO3 and stirred for 10 min. The resulting solid was filtered
through a celite pad, and the filtrate was extracted twice with CH2Cl2. The
combined organic layers were dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by silica gel
column chromatography (EtOAc/hexane, 2:1) to give compound 9 (414
mg, 66%): 1H NMR (CDCl3, 300 MHz) δ 8.27 (br s, 1H), 7.44 (d, J = 7.8 Hz,
1H), 6.00 (t, J = 5.4 Hz, 1H), 5.67 (d, J = 7.8 Hz, 1H), 4.07 (dd, J = 13.5,
6.6 Hz, 2H), 3.89 (d, J = 8.7 Hz, 1H), 3.78 (d, J = 8.7 Hz, 1H), 3.49 (d, J =
7.5 Hz, 2H), 2.25 (dd, J = 14.1, 6.6 Hz, 1H), 1.83 (dd, J = 14.4, 5.4 Hz, 1H),
0.82 (s, 18H), 0.03 (s, 12H); 13C NMR (CDCl3, 75 MHz) δ 165.02, 151.78,
141.49, 102,25, 86.83, 72.90, 64.65, 63.93, 50.91, 37.30, 25.79, 18.23, −5.57;
Anal calc for C22H42N2O5Si2: C, 56.13; H, 8.99; N, 5.95. Found: C, 56.30; H,
8.78; N, 5.82.
( )-1- [4,4-bis-(tert-Butyldimethylsilanyloxymethyl)tetrahydrofuran-2-
yl] Thymine (10).
Compound 10 was prepared from thymine using the
similar method as described for 9: yield 56%; 1H NMR (CDCl3, 300 MHz) δ
8.48 (br s, 1H), 7.48 (s, 1H), 6.02 (t, J = 7.5 Hz, 1H), 4.20 (dd, J = 8.4, 3.9
Hz, 1H), 3.91 (dd, J = 13.5, 6.8 Hz, 1H), 3.85 (d, J = 8.7 Hz, 1H), 3.76 (d,
J = 8.7 Hz, 1H), 3.54 (d, J = 12.9 Hz, 1H), 3.44 (d, J = 12.9 Hz, 1H), 2.17
(dd, J = 13.5, 6.4 Hz, 1H), 1.80 (dd, J = 14.0, 5.6 Hz, 1H), 1.26 (s, 3H),
0.88 (s, 18H), 0.04 (s, 12H); 13C NMR (CDCl3, 75 MHz) δ 164.44, 151.48,
135.79, 106.98, 89.11, 72.44, 64.29, 63.42, 50.62, 36.74, 25.53, 17.95, 12.48,
−5.89; Anal calc for C23H44N2O5Si2: C, 56.98; H, 9.15; N, 5.78. Found: C,
56.82; H, 9.30; N, 5.82.
( )-N4-Benzoyl-1-[4,4-bis-(tert-Butyldimethylsilanyloxymethyl)tetrahyd-
rofuran-2-yl]cytosine (11).
cytosine using the method as described for 9: yield 65%; H NMR (CDCl3,
Compound 11 was prepared from N4-benzoyl
1

Synthesis of Branched Apiosyl Nucleosides
115
300 MHz) δ 7.97–7.54 (m, 7H), 5.99 (s, 1H), 4.16 (dd, J = 10.5, 6.9 Hz,
2H), 3.81 (dd, J = 13.5, 6.8 Hz, 2H), 3.66 (dd, J = 14.0, 8.7 Hz, 2H), 2.23
(d, J = 7.2 Hz, 1H), 2.10 (s, 1H), 0.89 (s, 9H), 0.76 (s, 9H), 0.04 (s, 6H),
0.02 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ 191.02, 161.79, 133.06, 128.98,
127.53, 69.12, 64.73, 62.59, 54.85, 30.16, 25,77, 18.12, −5.55; Anal calc for
C29H47N3O5Si2: C, 60.69; H, 8.26; N, 7.32. Found: C, 60.49; H, 8.08; N, 7.21.
( )-6-Chloro-9-[4,4-bis-(tert-butyldimethylsilanyloxymethyl)tetrahydro-
furan-2-yl]purine (12).
Compound 12 was prepared from 6-Cl-purine
1
using the similar method as described for 9: yield 60%; H NMR (CDCl3,
300 MHz) δ 8.59 (s, 1H), 8.04 (s, 1H), 6.02 (s, 1H), 4.04 (dd, J = 14.4, 6.6
Hz, 2H), 3.66 (dd, J = 16.2, 10.2 Hz, 2H), 3.34 (d, J = 10.5 Hz, 1H), 3.22 (d,
J = 10.5 Hz, 1H), 2.11 (d, J = 8.1 Hz, 1H), 1.93 (s, 1H), 0.80 (s, 9H), 0.56 (s,
9H), 0.05 (s, 6H), 0.01 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ 155.75, 152.67,
148.44, 147.89, 129.54, 69.17, 63.64, 62.24, 55.11, 29.55, 25.65, 18.21, 18.02,
−5.44, −5.99; Anal calc for C23H41ClN4O3Si2: C, 53.83; H, 8.05; N, 10.92.
Found: C, 53.78; H, 8.15; N, 10.80.
( )-1-(4,4-bis-Hydroxymethyltetrahydrofuran-2-yl)uracil (13).
To a so-
lution of 9 (180 mg, 0.382 mmol) in tetrahydrofurane (10 mL), tetrabuty-
lammonium fluoride (1.15 mL, 1.0 M solution in THF) was added at 0◦C.
The mixture was stirred for 6 h at rt, and concentrated under reduced
pressure. The residue was purified by silica gel column chromatography
(MeOH/CH2Cl2, 1:5) to give compound 13 (66 mg, 72%): mp 168–169◦C;
UV (H2O) λmax 261.0 nm; 1H NMR (DMSO-d6, 300 MHz) δ 11.23 (br s, 1H),
7.62 (d, J = 8.0 Hz, 1H), 6.01 (t, J = 6.6 Hz, 1H), 5.65 (d, J = 8.0 Hz, 1H)
4.97 (t, J = 5.4 Hz, 1H), 4.76 (t, J = 5.6 Hz, 1H), 3.90 (d, J = 9.3 Hz, 1H),
3.77 (d, J = 9.3 Hz, 1H), 3.52 (m, 4H), 2.27 (dd, J = 14.4, 6.9 Hz, 1H),
1.82 (dd, J = 14.4, 6.3 Hz, 1H); 13C NMR (DMSO-d6, 75 MHz) δ 165.34,
153.45, 140.67, 99.31, 78.22, 72.97, 65.25, 64.12, 51.78, 30.21; Anal calc
for C10H14N2O5: C, 49.58; H, 5.83; N, 11.56. Found: C, 49.77; H, 5.81; N,
11.40.
( )-1-(4,4-bis-Hydroxymethyltetrahydrofuran-2-yl)thymine (14). Com-
pound 14 was synthesized from 10 with use of similar procedure as de-
scribed for 13: yield 78%; mp 166–168◦C; UV (H2O) λmax 265.5 nm; 1H NMR
(DMSO-d6, 300 MHz) δ 11.45 (br s, 1H), 7.23 (s, 1H), 6.00 (t, J = 7.2 Hz, 1H),
4.12 (d, J = 7.8 Hz, 1H), 3.93 (dd, J = 6.8, 1H), 3.88 (d, J = 8.6 Hz, 1H),
3.72 (d, J = 8.6 Hz, 1H), 3.55 (d, J = 13.5 Hz, 1H), 3.31 (d, J = 13.5 Hz,
1H), 2.15 (dd, J = 12.5, 6.8 Hz, 1H), 1.82 (dd, J = 12.0, 5.4 Hz, 1H), 1.26
(s, 3H); 13C NMR (DMSO-d6, 75 MHz) δ 164.76, 151.51, 135.12, 103.34,
89.11, 74.12, 64.67, 62.98, 49.87, 35.76, 11.87; Anal calc for C11H16N2O5: C,
51.56; H, 6.29; N, 10.93. Found: C, 51.79; H, 6.09; N, 10.78.

116
J. W. Kim and J. H. Hong
(
)-1-[4,4-bis -(tert -Butyldimethylsilanyloxymethyl)tetrahydrofuran-
2-yl]cytosine (15).
Compound 11 (200 mg, 0.348 mmol) was treated with
saturated methanolic ammonia overnight at rt. The solvent was evaporated
under reduced pressure. The residue was purified by silica gel column
chromatography (MeOH/CH2Cl2, 1:10) to give compound 15 (140 mg,
86%): 1H NMR (CDCl3, 300 MHz) δ 7.46 (d, J = 7.5 Hz, 1H), 5.90 (s, 1H),
5.72 (d, J = 7.5 Hz, 1H), 4.27 (dd, J = 14.7, 9.0 Hz, 1H), 4.06 (dd, J = 14.7,
6.6 Hz, 1H), 3.80 (d, J = 9.9 Hz, 1H), 3.73 (d, J = 9.9 Hz, 1H), 3.65 (d, J =
10.2 Hz, 1H), 3.56 (d, J = 10.2 Hz, 1H), 2.13 (m, 2H), 0.94 (s, 9H), 0.87 (s,
9H), 0.12 (d, J = 6.0 Hz, 6H), 0.01 (d, J = 7.8 Hz, 6H); 13C NMR (CDCl3,
75 MHz) δ 165.50, 156.12, 142.55, 93.14, 90.49, 68.76, 64.94, 62.70, 54.40,
30.78, 25.81, 18.14, −5.67; Anal calc for C22H43N3O4Si2: C, 56.25; H, 9.23;
N, 8.94. Found: C, 56.11; H, 9.13; N, 8.81.
( )-9-[4,4-bis-(tert -Butyldimethylsilanyloxymethyl)tetrahydrofuran-2-
yl]adenine (16).
Compound 12 (150 mg, 0.29 mmol) was treated with
saturated methanolic ammonia for 15 h at 90–100◦C in a steel bomb.
After removal of the solvent, the residue was purified by silica gel column
chromatography (MeOH/CH2Cl2, 1:10) to give compound 16 (101 mg,
70%): 1H NMR (CDCl3, 300 MHz) δ 8.22 (s, 1H), 7.73 (s, 1H), 5.91 (s, 1H),
4.37 (dd, J = 14.0, 8.1 Hz, 1H), 4.02 (dd, J = 14.2, 7.8 Hz, 1H), 3.71 (d,
J = 9.6 Hz, 1H), 3.63 (d, J = 9.6 Hz, 1H), 3.34 (d, J = 10.2 Hz, 1H), 3.23
(d, J = 10.2 Hz, 1H), 2.07 (m, 2H), 0.89 (s, 9H), 0.52 (s, 9H), 0.03 (s, 6H),
0.01 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ 155.45, 152.81, 140.44, 88.99,
68.99, 63.01, 61.95, 55.01, 29.61, 25.83, 18.21, −5.56, −6.01; Anal calc for
C23H43N5O3Si2: C, 55.94; H, 8.78; N, 14.18. Found: C, 55.81; H, 8.60; N,
14.02.
(
)-1-(4,4-bis -Hydroxymethyltetrahydrofuran-2-yl)cytosine (17).
Compound 17 was prepared from 15 by the similar method as described for
13: yield 56%; mp 171–173◦C; UV (H2O) λmax 270.5 nm; 1H NMR (DMSO-
d6, 300 MHz) δ 7.47 (d, J = 7.5 Hz, 1H), 7.21 (br d, 2H), 5.77 (d, J = 8.7 Hz,
1H), 5.73 (d, J = 7.5 Hz, 1H), 4.92 (t, J = 5.6 Hz, 1H), 4.64 (t, J = 5.7 Hz,
1H), 4.20 (dd, J = 14.1, 6.6 Hz, 1H), 3.90 (dd, J = 15.9, 8.1 Hz, 1H), 3.27
(d, J = 10.2 Hz, 1H), 3.21 (d, J = 10.2 Hz, 1H), 3.16 (d, J = 11.1, 1H), 3.13
(d, J = 11.1 Hz, 1H), 1.86 (d, J = 6.9 Hz, 1H), 1.81 (d, J = 12.6 Hz, 1H);
13C NMR (DMSO-d6, 75 MHz) δ 165.65, 156.12, 141.80, 93.63, 67.77, 62.84,
60,55, 54.91, 54.03, 29.94; Anal calc for C10H15N3O4: C, 49.79; H, 6.27; N,
17.42. Found: C, 49.52; H, 6.38; N, 17.29.
(
)-9-(4,4-bis -Hydroxymethyltetrahydrofuran-2-yl)adenine (18).
Compound 18 was synthesized from 16 using the similar procedure as de-
scribed for 13: yield 60%; mp 180–183◦C; UV (H2O) λmax 260.0 nm; 1H NMR

Synthesis of Branched Apiosyl Nucleosides
117
(DMSO-d6, 300 MHz) δ 8.41 (s, 1H), 8.25 (s, 1H), 7.35 (br s, 2H), 6.01 (s,
1H), 5.01 (t, J = 5.8 Hz, 1H), 4.78 (t, J = 5.8 Hz, 1H), 4.21 (dd, J = 13.5, 8.2
Hz, 2H), 3.81 (d, J = 9.2 Hz, 1H), 3.60 (d, J = 9.2 Hz, 1H), 3.24 (d, J = 10.4 Hz,
1H), 3.19 (d, J = 10.2 Hz, 1H), 2.01 (s, 1H), 1.92 (s, 1H); 13C NMR (DMSO-
d6, 75 MHz) δ 155.61, 152.78, 140.12, 87.34, 69.76, 63.12, 61.67, 54.67, 30.21;
Anal calc for C11H15N5O3: C, 49.81; H, 5.70; N, 26.40. Found: C, 49.72; H,
5.55; N, 26.19.
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