Ring-expanded analogues of natural oxetanocin

Article abstract of DOI:10.1016/j.tet.2004.08.087

Synthesis of ring-expanded analogs of the natural compound, oxetanocin is described. The starting material for the synthesis of the series, 4-7, was d-glucosamine and introduction of the base moiety was done through the stereochemically appropriate epoxid

Full text of DOI:10.1016/j.tet.2004.08.087

Tetrahedron 60 (2004) 10261–10268
Ring-expanded analogues of natural oxetanocin
b
a
Vasu Nair,a,b, Byoung-Kwon Chun and Jean John Vadakkan
*
aDepartment of Pharmaceutical and Biomedical Sciences, University of Georgia, Room 320A, R. C. Wilson PH, Athens, GA 30602, USA
bDepartment of Chemistry, University of Iowa, Iowa City, IA 52242, USA
Received 10 June 2004; revised 19 August 2004; accepted 26 August 2004
Abstract—Synthesis of ring-expanded analogs of the natural compound, oxetanocin is described. The starting material for the synthesis of
the series, 4–7, was D-glucosamine and introduction of the base moiety was done through the stereochemically appropriate epoxide. For the
enantiomeric series, 8–11, the starting material was D-glucose and preparation of the key intermediate involved a rearrangement reaction. The
structures of the target molecules were established by NMR, HRMS, optical rotation and UV data. Single-crystal X-ray data confirmed the
enantiomeric structural assignments.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Oxetanocin (1), a natural nucleoside with a surrogate
carbohydrate moiety isolated from bacterial sources,
exhibits anti-HIV activity.1 In designing ring-expanded
analogs of oxetanocin that would have the potential for
antiviral activity, we envisaged that a combination of the
structural features of the surrogate carbohydrate moiety of
oxetanocin with the sugar component of another antiviral
compound, 4(S)-(adenin-9-yl)-2(S)-hydroxymethyltetra-
hydrofuran [(S,S)-isoddA] (2) (Fig. 1) would be of
interest.2–5 Earlier work in our laboratory had led to the
discovery of (S,S)-isoddA which exhibits potent anti-HIV
activity against HIV-1, HIV-2, and HIV-resistant strains.
(S,S)-IsoddA triphosphate is among the strongest known
inhibitors of HIV reverse transcriptase.2 In addition, another
Figure 1. Structures of oxetanocin, (S,S)-IsoddA and an analog of
oxetanocin.
isomeric nucleoside related to oxetanocin, compound 3,
shows antiviral activity against HSV-1 (KOS) and HSV-2
(186).6 Our design of novel nucleosides included the
enantiomeric purine isonucleosides 4 and 8 and the
pyrimidine counterparts 5–7 and 9–11 (Fig. 2).
gave the key precursor 13 in 89% yield (Scheme 1). An SN2-
type condensation of 13 with the sodium salt of adenine in
DMF at 120 8C5 gave an inseparable diastereomeric mixture
of 14 and 15 in 49% yield (14:15 ratioZ3:1). The ratio of
products reflects the higher steric hindrance to nucleophilic
attack that is inherent on one of the two carbon centers of
epoxide 13. This product mixture was converted to the
deoxygenated compounds 16 and 17 using the Barton
deoxygenation.9 Separation of the diastereoisomers by
preparative silica gel TLC was possible at this stage to
give 16 and 17 in 52 and 17% yield, respectively.
Deprotection of 16 and 17 using 80% acetic acid gave the
target compound 4 (74%) and its diastereoisomer 18 (72%).
2. Results and discussion
In order to synthesize target compounds (4–7), epoxide 13
was prepared from D-glucosamine using a known method.7,8
The ditrityl derivative, 12, under Mitsunobu conditions,
Keywords: Oxetanocin; Stereochemical synthesis; Glucosamine; Epoxide;
Rearrangement reaction; Enantiomers; NMR; X-ray.
* Corresponding author. Tel.: C1-706-542-6293; fax: C1-706-583-8283;
e-mail: vnair@rx.uga.edu
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.08.087

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sequential treatment with 2,4,6-triisopropylbenzenesulfonyl
chloride and ammonium hydroxide.10 Finally, uridine and
cytidine analogues, 5 and 6, were prepared from the
intermediates 23 and 24, by deprotection with acetic acid
respectively in 67 and 65% yield. Thymidine analogue 7
was similarly obtained from compound 13 via intermediates
21 and 25 (Scheme 2).
For the synthesis of the corresponding enantiomers (8–11), a
different synthetic strategy was employed where starting
material 26 was prepared from diacetone D-glucose using
known procedures (Scheme 3).11,12 To prepare key
intermediate 28, an acid-catalyzed rearrangement of 2613
was carried out to produce an aldehyde intermediate which,
was under the conditions of the reaction, was transformed to
the cyclic acetal 27. Selective tritylation of the primary
hydroxyl functionality (82%) followed by mesylation of the
remaining hydroxyl group (89%) of 27 gave intermediate
28. Coupling of 28 with the sodium salt of adenine in N,N-
dimethylformamide at 80–85 8C gave the protected adeno-
sine analogue 29 in 56% yield. The cyclic acetal of
compound 29 was hydrolyzed with trifluoroacetic acid–HCl
and the resulting aldehyde was reduced with NaBH4 to the
isoadenosine target 8 in 64% yield. Its structure was
confirmed by single crystal X-ray data (Fig. 3). While its 1H
and 13C NMR spectra were identical to that of its
enantiomer, the dextrorotatory compound 4, compound 8
was laevorotatory and the magnitude of its optical rotation
was close to that for 4. Thus, the spectroscopic data, the
Figure 2. Ring-expanded analogs of oxetanocin.
For the preparation of pyrimidine derivatives, the key
intermediate 13 was coupled with the sodium salt of uracil,
under conditions similar to the preparation of adenosine
analogue 14, to give two products, 19 and 20 (Scheme 2).
The major product 19 was deoxygenated to 23 (40% yield)
and then aminated to cytidine analogue 24 (73% yield) by
Scheme 1.

V. Nair et al. / Tetrahedron 60 (2004) 10261–10268
10263
Scheme 2.
Scheme 3.
crystal structure data, and the optical rotation data
confirmed the structures of both 4 and 8.
converted to the target thymidine 9 in 67% yield (Scheme 4).
Because of the low yield for the direct coupling, the
synthesis of uracil and cytosine analogues utilized a base
construction methodology from the amino intermediate 31
prepared in high yield from 28 through azide displacement
and catalytic reduction. The amine 31 was treated with
3-methoxyacryloyl isocyanate,14 freshly prepared from
For the preparation of thymidine analogue 9, the key
intermediate 28 was treated with sodium salt of thymine in
N,N-dimethylformamide at elevated temperatures to give
protected thymidine analogue 30 (20%) which was

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V. Nair et al. / Tetrahedron 60 (2004) 10261–10268
In summary, new enantiomeric isonucleoside analogs
related to natural oxetanocin have been synthesized from
D-glucose and D-glucosamine. The structures of the target
compounds and intermediates were confirmed by NMR,
HRMS, UV, single crystal X-ray and optical rotation data.
These compounds are undergoing comprehensive antiviral
testing against various viral infected cell lines and those
results will be reported elsewhere.
3. Experimental
3.1. General
Melting points reported are uncorrected and were deter-
mined on an Electrothermal Engineering Ltd. melting point
apparatus. Nuclear magnetic resonance spectra were
recorded on Bruker Model AC300 and WM 360 systems.
High-resolution mass spectral data were determined at the
Nebraska Center for Mass Spectrometry. Ultraviolet spectra
were recorded on a Varian Cary Model 3 spectro-
photometer. Purities of intermediates and final products
were determined by a combination of HPLC analyses, 13C
NMR spectra, HRMS data and quantitative UV data.
Figure 3. Ortep plot of single-crystal X-ray structure of compound 8.
3-methoxyacryloyl chloride and silver cyanate, to give an
acryloylurea intermediate which was cyclized to 32 (66%)
under catalysis with ammonium hydroxide at 100 8C in a
steel bomb. The isouridine analogue 10 was obtained from
32 in 67% yield by deprotection with trifluoroacetic acid
and HCl followed by reduction with NaBH4. Similarly, the
final target cytidine analogue 11 was prepared from 10 in
three steps in 36% yield (Scheme 4).
3.1.1. 2,5:3,4-Dianhydro-1,6-di-O-trityl-D-altritol (13).
To a mixture of compound 12 (9.8 g, 15.11 mmol) and
triphenylphosphine (7.9 g, 30.12 mmol) in anhydrous 1,4-
dioxane (50 mL) was cooled to 0 8C and DEAD (4.8 mL,
Scheme 4.

V. Nair et al. / Tetrahedron 60 (2004) 10261–10268
10265
1
30.48 mmol) in 8 mL anhydrous 1,4-dioxane was added
with stirring under nitrogen atmosphere. The reaction
mixture was allowed to come to room temperature and
stirred for 2 h at 70 8C. The solvent was removed under
vacuum and the residue obtained was separated by silica gel
column chromatography (chloroform) to give compound
(MeOH); H NMR (CDCl3) d (ppm) 8.23 (s, 1H), 7.68 (s,
1H), 7.51–7.14 (m, 30H), 5.63 (s, 2H), 4.65 (m, 1H), 4.57
(m, 1H), 3.26 (d, 2H, JZ4.8 Hz), 3.13 (dd, 1H, JZ4.8,
9.6 Hz), 2.67 (dd,1H, JZ7.4, 9.6 Hz), 2.48 (dt, 1H, JZ7.4,
12.1 Hz), 2.35 (dd 2H, JZ8.1, 12.0 Hz); 13C NMR (CDCl3)
d (ppm) 155.5, 153.1, 150.4, 144.1, 143.5, 139.6, 129.3,
128.8, 128.2, 127.9, 127.4, 127.2, 87.2, 79.9, 77.4, 66.5,
61.9, 55.7, 35.5; HRFABMS: calcd mass 750.3444 for
C49H44N5O3, found 750.3434 (MCH)C.
1
1315 as a white solid (8.5 g, 89%). Mp 166–168 8C; H
NMR (CDCl3) d (ppm) 7.57–7.23 (m, 30H), 4.35 (t, 1H, JZ
6.3 Hz), 4.24 (t, 1H, JZ4.2 Hz), 4.02 (d, 1H, JZ3.0 Hz),
3.75 (d, 1H, JZ3.0 Hz), 3.45–3.32 (m, 3H), 3.19 (dd, 1H,
JZ3.6, 9.9 Hz); 13C NMR (CDCl3) d (ppm) 144.0, 143.7,
128.8, 128.7, 128.0, 127.9, 127.2, 127.1, 87.0, 86.9, 77.5,
76.9, 64.2, 62.7, 58.3, 57.5; FABMS: 653 (MCNa)C.
3.1.4. 3(R)-(Adenin-9-yl)-2(S),5(S)-di(hydroxymethyl)
tetrahydrofuran (4). Compound 16 (200 mg, 0.27 mmol)
in 80% acetic acid (13 mL) was heated at 60 8C for 12 h and
concentrated to give a white solid that was purified by silica
gel column chromatography (chloroform–methanolZ10:1)
to give compound 4 (53 mg, 74%) as a white solid. Mp 189–
191 8C; [a]2D0ZC27.08 (c 0.6 MeOH). UV lmax 260 nm (3
12,695, MeOH); 1H NMR (D2O) d (ppm) 8.30 (s, 1H), 8.20
(s, 1H), 5.11 (dd, 1H, JZ1.5, 8.3 Hz), 4.45 (m, 2H), 3.88–
3.65 (m, 4H), 2.72 (m, 1H), 2.37 (m, 1H); 13C NMR (D2OC
DMSO-d6) d (ppm) 157.08, 154.01, 150.04, 142.13, 120.12,
83.64, 80.39, 64.57, 62.40, 56.91, 34.97; HRFABMS: calcd
mass 266.1253 for C11H16N5O3, found 266.1258 (MCH)C.
3.1.2. 4(R)-(Adenin-9-yl)-2(R),5(S)-di(trityloxymethyl)-
3(R)-hydroxytetrahydrofuran (14) and 4(S)-(adenin-9-
yl)-2(R),5(S)-di(trityloxymethyl)-3(S)-hydroxytetra-
hydrofuran (15). A mixture of adenine (936 mg,
6.93 mmol) and 60% sodium hydride (277 mg,
6.93 mmol) in anhydrous N,N-dimethylformamide
(20 mL) was heated at 110 8C for 2 h and compound 13
(1.46 g, 2.31 mmol) in N,N-dimethylformamide (5 mL) was
added under nitrogen atmosphere. The resulting reaction
mixture was heated at 110–120 8C for 21 h. After removal
of solvent under reduced pressure, the residue was separated
by silica gel column chromatography (chloroform–metha-
nolZ49:1) to give a mixture of compound 14 and 15 (14:15
3.1.5. 3(S)-(Adenin-9-yl)-2(S),5(S)-di(hydroxymethyl)
tetrahydrofuran (18). Using the same procedure for 4,
compound 18 (21 mg, 72%) was obtained as a white solid
from compound 17 (80 mg, 0.11 mmol). Mp 189–192 8C;
[a]2D0ZC85.08 (c 0.5 MeOH). UV lmax 261 nm (3 12 863,
MeOH); 1H NMR (D2O) d (ppm) 8.21 (s, 1H), 8.12 (s, 1H),
5.31 (m, 1H), 4.71 (m, 1H), 4.36 (m, 1H), 3.71 (m, 2H), 3.35
(dd, 1H, JZ6.0, 16.0 Hz), 3.15 (dd, 1H, JZ8.8, 16.0 Hz),
2.54 (m, 2H); 13C NMR (D2OCDMSO-d6) d (ppm) 157.11,
154.25, 150.76, 142.23, 120.24, 81.91, 80.15, 65.00, 61.22,
57.28, 35.02; HRFABMS: calcd mass 266.1253 for
C11H16N5O3, found 266.1257 (MCH)C.
1
ratioZ3:1 by H NMR) as a white solid (866 mg, 49%).
Data given for 14/15 mixture. UV lmax 262 nm (MeOH);
HRFABMS: calcd mass 766.3393 for C49H44N5O4, found
766.3413 (MCH)C.
3.1.3. 3(R)-(Adenin-9-yl)-2(S),5(S)-di(trityloxymethyl)
tetrahydrofuran (16) and 3(S)-(adenin-9-yl)-2(S),5(S)-
di(trityloxymethyl)tetrahydrofuran (17). To a solution
of the mixture of 14 and 15 (760 mg, 0.99 mmol) and
4-dimethyl-aminopyridine (242 mg, 1.98 mmol) in
anhydrous CH2Cl2 (20 mL) was added phenyl chloro-
thionoformate (0.22 mL, 1.98 mmol) slowly at K10 8C
over 10 min under nitrogen atmosphere. The resulting
mixture was stirred at K10 8C for 6 h and the reaction was
quenched with water (2 mL). After dilution with EtOAc
(200 mL), the reaction mixture was washed with brine (3!
15 mL), dried on sodium sulfate, and concentrated. The
resulting residue was purified by silica gel column
chromatography (EtOAc) to give a xanthate intermediate
(640 mg, 0.71 mmol, 71%), which was dried under high
vacuum and dissolved in benzene (30 mL). To this solution,
Bu3SnH (1.47 mL, 5.46 mmol) and AIBN (70 mg,
0.41 mmol) were added and the resulting mixture was
heated under reflux for 1.5 h and cooled to rt. Upon
concentration, the residue was separated by preparative
silica gel TLC (chloroform–methanolZ40:1) to afford
compound 16 (268 mg, 52%) and compound 17 (88 mg,
17%) as oils. Compound 16. UV lmax 261 nm (MeOH); 1H
NMR (CDCl3) d (ppm) 8.29 (s, 1H), 7.78 (s, 1H), 7.50–7.20
(m, 30H), 5.70 (s, 2H), 5.14 (q, 1H, JZ7.9 Hz), 4.48 (m,
2H), 3.33 (d, 4H, JZ4.5 Hz), 2.61 (dt, 1H, JZ7.2, 13.4 Hz),
2.46 (m, 1H); 13C NMR (CDCl3) d (ppm) 155.2, 152.7,
150.0, 143.9, 143.6, 138.8, 129.6, 128.7, 128.6, 127.9,
127.8, 127.1, 127.0, 87.0, 86.8, 81.2, 77.7, 65.9, 64.2, 56.7,
35.3; HRFABMS: calcd mass 750.3444 for C49H44N5O3,
found 750.3464 (MCH)C. Compound 17. UV lmax 261 nm
3.1.6. 2(S),5(S)-Di(hydroxymethyl)-3(R)-(uracil-1-yl)
tetrahydrofuran (5). A mixture of uracil (1.99 g,
17.75 mmol) and 60% sodium hydride (710 mg,
17.75 mmol) in anhydrous N,N-dimethylformamide
(150 mL) was heated at 110 8C for 2 h and then compound
13 (2.80 g, 4.44 mmol) in anhydrous N,N-dimethylforma-
mide (10 mL) was added. The reaction mixture was heated
at 150–160 8C for 48 h and concentrated under reduced
pressure. The residue was separated by silica gel column,
chromatography (chloroform–methanolZ60:1) to give
compound 19 (800 mg, 24%) and 20 (200 mg, 6%) as
1
oils. Compound 19. UV lmax 266 nm (MeOH); H NMR
(CDCl3) d (ppm) 9.35 (s, 1H), 7.45–7.15 (m, 31H), 5.52 (d,
1H, JZ8.0 Hz), 4.84 (t, 1H, JZ6.0 Hz), 4.37 (t, 1H, JZ
6.1 Hz), 4.20 (dd, 1H, JZ5.2, 11.1 Hz), 4.07 (m, 1H), 3.44
(dd, 1H, JZ4.7, 10.3 Hz), 3.38 (dd, 1H, JZ5.3, 10.2 Hz),
3.32 (m, 2H); 13C NMR (CDCl3) d 163.2, 151.0, 143.6,
143.5, 142.0, 128.8, 128.6, 128.0, 127.9, 127.2, 103.0, 87.2,
87.2, 82.6, 79.1, 76.9, 66.4, 64.3, 64.1. Compound 20. UV
1
lmax 266 nm (MeOH); H NMR (CDCl3) d (ppm) 8.63 (s,
1H), 7.59–7.18 (m, 31H), 5.39 (d, 1H, JZ8.1 Hz), 5.27 (t,
1H, JZ6.7 Hz), 4.96 (dd, 1H, JZ7.6, 15.0 Hz), 4.78 (m,
1H), 4.59 (m, 1H), 3.69 (dd, 1H, JZ4.2, 10.5 Hz), 3.34–
3.25 (m, 2H), 2.88 (dd, 1H, JZ2.7, 10.8 Hz); 13C NMR
(CDCl3) d (ppm) 167.7, 151.0, 143.2, 143.1, 141.8, 128.5,
128.4, 128.2, 128.0, 127.4, 127.3, 101.7, 87.8, 87.7, 77.9,

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V. Nair et al. / Tetrahedron 60 (2004) 10261–10268
76.4, 74.6, 64.3, 63.6, 62.4. Compound 23 (234 mg, 40%)
was obtained from compound 19 (600 mg, 0.81 mmol)
using the same method as described for compound 16. UV
as oils. Compound 21. UV lmax 270 nm (MeOH); 1H NMR
(CDCl3) d (ppm) 9.50 (s, 1H), 7.46–7.04 (m, 30H), 7.04 (s,
1H), 4.88 (t, 1H, JZ6.1 Hz), 4.42 (t, 1H, JZ4.2 Hz), 4.22
(q, 1H, JZ5.8 Hz), 4.05 (m, 1H), 3.67 (bs, 1H), 3.42 (m,
2H), 3.30 (m, 2H), 1.69 (s, 3H); 13C NMR (CDCl3) d (ppm)
163.7, 151.3, 143.7, 143.6, 137.5, 128.7, 128.6, 127.9,
127.9, 127.2, 127.1, 111.6, 87.2, 87.1, 82.4, 79.0, 77.2, 65.8,
64.2, 64.0, 12.4. Compound 22. UV lmax 270 nm (MeOH);
1H NMR (CDCl3) d (ppm) 8.57 (s, 1H), 7.71–7.09 (m, 30H),
7.08 (s, 1H), 5.23 (t, 1H, JZ6.7 Hz), 5.00 (q, 1H, JZ
7.2 Hz), 4.79 (m, 1H), 4.60 (dt, 1H, JZ4.0, 7.2 Hz), 3.68
(dd, 1H, JZ4.3, 10.5 Hz), 3.35–3.24 (m, 3H), 2.87 (dd, 1H,
JZ3.0, 10.6 Hz), 1.56 (s, 3H); 13C NMR (CDCl3) d (ppm)
163.4, 151.2, 143.2, 138.0, 128.5, 128.4, 128.2, 127.4,
127.3, 109.7, 89.8, 87.5, 78.0, 76.4, 74.5, 64.3, 63.5, 62.7,
12.2. Compound 25 (393 mg, 51%) was obtained from
compound 21 (750 mg, 0.99 mmol) using the same method
for compound 16. UV lmax 270 nm (MeOH); 1H NMR
(CDCl3) d (ppm) 8.65 (s, 1H), 7.48–7.17 (m, 31H), 5.13 (m,
1H), 4.33 (m, 1H), 4.19 (q, 1H, JZ5.2 Hz), 3.38 (m, 2H),
3.20 (m, 2H), 2.44 (m, 1H), 1.94 (m, 1H), 1.73 (m, 3H); 13C
NMR (CDCl3) d (ppm) 163.4, 150.7, 143.7, 143.6, 129.0,
128.7, 128.6, 127.9, 127.9, 127.2, 127.1, 111.8, 87.2, 86.9,
81.2, 77.5, 65.6, 64.6, 57.0, 34.1, 12.5.
1
lmax 266 nm (MeOH); H NMR (CDCl3) d (ppm) 8.76 (s,
1H), 7.46–7.19 (m, 31H), 5.55 (d, 1H, JZ8.1 Hz), 4.32 (m,
1H), 4.28 (m, 1H), 3.43 (dd, 1H, JZ3.7, 10.2 Hz), 3.35 (dd,
1H, JZ4.1, 9.3 Hz), 3.19 (m, 2H), 2.46 (m, 1H), 1.86 (m,
1H); 13C NMR (CDCl3) d (ppm) 162.8, 150.6, 143.6, 141.3,
128.8, 128.6, 127.9, 127.3, 127.2, 103.2, 87.3, 87.2, 81.7,
77.7, 65.4, 64.7, 57.3, 34.2.
Compound 5 (10 mg, 67%) was obtained from compound
23 (45 mg, 0.062 mmol) using the same method for
compound 4. Mp 200–202 8C; [a]2D0ZC328; (c 0.24,
1
MeOH). UV lmax 266 nm (3 10 076, MeOH); H NMR
(D2O) d (ppm) 7.81 (d, 1H, JZ8.1 Hz), 5.92 (d, 1H, JZ
8.0 Hz), 5.08 (dt, 1H, JZ6.3, 8.6 Hz), 4.34 (m, 1H), 4.23
(dt, 1H, JZ3.9, 6.0 Hz), 3.83 (dd, 1H, JZ3.1, 12.4 Hz),
3.75–3.65 (m, 3H), 2.54 (m, 1H), 2.08 (dt, 1H, JZ8.9,
13.1 Hz); 13C NMR (D2OCDMSO-d6) d (ppm) 167.8,
153.8, 145.4, 104.1, 83.0, 80.3, 64.4, 62.6, 58.4, 33.6;
HRFABMS: calcd mass 243.0980 for C10H15N2O5, found
243.0984 (MCH)C.
3.1.7. 3(R)-(Cytosin-1-yl)-2(S),5(S)-di(hydroxymethyl)
tetrahydrofuran (6). To a mixture of compound 23
(230 mg, 0.32 mmol) and 4-dimethylaminopyridine
(114 mg, 0.93 mmol) in anhydrous acetonitrile (15 mL)
was added 2,4,6-triisopropylbenzenesulfonyl chloride
(282 mg, 0.93 mmol) and triethylamine (1.3 mL) at 0 8C.
The resulting reaction mixture was stirred at rt for 3 h.
Ammonium hydroxide (29%, 8 mL) was added to the
reaction mixture, which was then stirred for additional 2 h.
After removal of solvent, the residue was separated by silica
gel column chromatography (chloroform–methanolZ30:1)
to give compound 24 (170 mg, 76%) as an oil. UV lmax
276 nm (MeOH); 1H NMR (CDCl3) d (ppm) 7.58–7.21 (m,
31H), 5.54 (d, 1H, JZ10.0 Hz), 5.31 (m, 1H), 4.38 (m, 1H),
4.28 (m, 1H), 3.43–3.22 (m, 4H), 2.55 (m, 1H), 1.89 (m, 1H)
1.76 (bs, 2H); 13C NMR (CDCl3) d (ppm) 164.7, 156.0,
143.8, 143.7, 142.7, 128.8, 128.7, 127.7, 127.1, 127.0, 94.8,
87.1, 86.9, 82.2, 77.6, 65.6, 64.7, 57.8, 35.1. Compound 6
(20 mg, 65%) was obtained as a hygroscopic white solid
from compound 24 (93 mg, 0.128 mmol) using the same
method for compound 4. [a]2D0ZC298 (c 0.24, MeOH). UV
Compound 7 (50 mg, 72%) was obtained from compound
25 (200 mg, 0.27 mmol) using the same method for
compound 4. Compound 7. Mp 199–202 8C; [a]2D0ZC308
1
(c 0.23, MeOH). UV lmax 270 nm (3 10 100, MeOH); H
NMR (D2O) d (ppm) 7.64 (s, 1H), 5.08 (dt, 1H, JZ6.5,
8.6 Hz), 4.32 (m, 1H), 4.23 (dt, 1H, JZ3.8, 6.0 Hz), 3.84
(dd, 1H, JZ3.0, 12.3 Hz), 3.73–3.64 (m, 3H), 2.52 (ddd,
1H, JZ6.6, 8.5, 13.0 Hz), 2.06 (t, 1H, JZ9.1, 12.9 Hz),
1.92 (s, 3H); 13C NMR (D2O–DMSO-d6) d (ppm) 167.6,
153.1, 140.4, 112.7, 82.7, 79.9, 64.7, 62.5, 57.7, 33.5, 13.1;
HRFABMS: calcd mass 279.0957 for C11H16N2O5Na,
found 279.0950 (MCNa)C.
3.1.9. 3(S)-(Adenin-9-yl)-2(R),5(R)-di(hydroxymethyl)
tetrahydrofuran (8). A mixture of compound 26 (1.88 g,
3.58 mmol), prepared by known methodology,11,12 ethylene
glycol (1.6 mL, 28.69 mmol), p-toluenesulfonic acid
(330 mg, 1.73 mmol) in benzene (140 mL) containing
N,N-dimethylformamide (3 mL) was refluxed with (Dean–
Stark apparatus, for 24 h), neutralized with saturated
aqueous sodium bicarbonate, and concentrated under
reduced pressure. The residue obtained was separated by
silica gel column chromatography (chloroform–methanolZ
30:1) to give 2,5-anhydro-3-deoxy-L-talose ethylene acetal
(27) (500 mg, 73%) as a syrup; [a]2D0ZC17.118 (c 0.45,
MeOH); 1H NMR (CDCl3) d (ppm) 4.87 (d, 1H, JZ4.1 Hz),
4.53 (m, 1H), 4.29 (dt, 1H, JZ4.1, 7.8 Hz), 4.04–3.89 (m,
6H), 3.17 (m, 1H), 2.07 (m, 2H); 13C NMR (CDCl3) d (ppm)
104.8, 81.8, 78.1, 73.6, 65.5, 65.3, 61.5, 36.8. A solution of
compound 27 (1.76 g, 9.25 mmol) in anhydrous pyridine
(20 mL) was treated with trityl chloride (3.25 g, 12.02 mmol)
at rt. The resulting reaction mixture was stirred for 24 h,
quenched with cold water, and concentrated. The residue
was separated by silica gel column chromatography
(hexanes–ethylacetateZ5:1 to 1:1) to give 2,5-anhydro-3-
1
lmax 276 nm (3 10 405, MeOH); H NMR (D2O) d (ppm)
7.77 (d, 1H, JZ7.5 Hz), 6.08 (d, 1H, JZ7.5 Hz), 5.12 (m,
1H), 4.35 (m, 1H), 4.23 (m, 1H), 3.82 (m, 1H), 3.70 (m, 3H),
2.54 (m, 1H), 2.05 (m, 1H); 13C NMR (D2OCDMSO-d6) d
(ppm) 166.0, 158.5, 143.6, 96.9, 82.2, 78.9, 63.1, 61.4, 57.5,
32.8; HRFABMS: calcd mass 242.1140 for C10H16N3O4,
found 242.1141 (MCH)C.
3.1.8. 2(S),5(S)-Di(hydroxymethyl)-3(R)-(thymin-1-yl)-
tetrahydrofuran (7). A mixture of thymine (1.90 g,
15.06 mmol) and 60% sodium hydride (608 mg,
15.20 mmol) in anhydrous N,N-dimethylformamide
(10 mL) was heated at 110 8C for 2 h and then compound
13 (2.40 g, 3.80 mmol) was added. The resulting reaction
mixture was heated at 150–160 8C for 48 h and concentrated
under reduced pressure. The residue was separated by silica
gel column chromatography (chloroform–methanolZ1:1)
to give compound 21 (807 mg, 28%) and 22 (168 mg, 6%)
1
deoxy-6-O-trityl-L-talose ethylene acetal (3.28 g, 82%); H
NMR (CDCl3) d (ppm) 7.44–7.21(m, 15H), 4.86 (d, 1H, JZ
4.1 Hz), 4.57 (m, 1H), 4.25 (dt, 1H, JZ4.1, 7.5 Hz), 4.17

V. Nair et al. / Tetrahedron 60 (2004) 10261–10268
10267
(m, 1H), 3.99–3.97 (m, 2H), 3.90–3.87 (m, 2H), 3.48 (dd,
1H, JZ4.6, 9.5 Hz), 3.29 (dd, 1H, JZ7.5, 9.5 Hz), 2.43 (s,
1H), 2.09–2.06 (m, 2H); FABMS: 455 (MCNa)C, 450
(MCNH4)C. To a solution of the trityl compound (2.45 g,
5.66 mmol) in anhydrous methylene chloride (80 mL)
containing triethylamine (6 mL) was added methane-
sulfonyl chloride (1.75 mL, 22.61 mmol) at 0 8C over
10 min and the resulting reaction mixture was stirred at rt
for 1 h and then quenched with cold water. The reaction
mixture was diluted with methylene chloride (50 mL),
washed with water (30 mL), dried with sodium sulfate, and
concentrated to give a residue, which was then purified by
silica gel column chromatography (hexanes–ethylacetateZ
10:1 to 1:1) to give 2,5-anhydro-3-deoxy-4-O-methane-
sulfonyl-6-O-trityl-L-talose ethylene acetal (28) (2.57 g,
concentrated in vacuo, and separated by silica gel column
chromatography (hexanes–ethylacetateZ2:1) to give com-
pound 30 (248 mg, 20%) as a syrup; H NMR (CDCl3) d
1
(ppm) 8.38 (s 1H), 7.41–7.20 (m, 16H), 5.16 (m, 1H), 5.04
(d, 1H, JZ2.9 Hz), 4.28 (dt, 1H, JZ2.9, 7.8 Hz), 4.13 (dd,
1H, JZ5.2, 10.5 Hz), 4.06–3.96 (m, 4H), 3.35 (dd, 1H, JZ
5.0, 10.0 Hz), 3.19 (dd, 1H, JZ5.5, 10.0 Hz), 2.55 (dt, 1H,
JZ9.2, 13.7 Hz), 1.98 (dt, 1H, JZ7.1, 13.6 Hz), 1.95 (s,
3H); 13C NMR (CDCl3) d (ppm) 163.3, 150.6, 143.6, 137.4,
128.6, 127.9, 127.2, 111.4, 104.0, 87.2, 81.6, 78.4, 65.6,
65.3, 64.6, 57.0, 32.2, 12.6. Using the procedure for 29 to 8,
compound 9 was obtained from compound 30 in 67% yield
as a white solid. Mp 197–200 8C; [a]2D0ZK278; (c 0.4,
MeOH). UV lmax 270 nm (9,100, MeOH); 1H NMR (D2O) d
(ppm) 7.64 (s, 1H), 5.08 (dt, 1H, JZ6.5, 8.6 Hz), 4.32 (m,
1H), 4.23 (dt, 1H, JZ3.8, 6.0 Hz), 3.84 (dd, 1H, JZ3.0,
12.3 Hz), 3.73–3.64 (m, 3H), 2.52 (ddd, 1H, JZ6.6, 8.5,
13.0 Hz), 2.06 (dt, 1H, JZ9.1 Hz, 12.9 Hz), 1.92 (s, 3H);
13C NMR (D2OCDMSO-d6) d (ppm) 167.6, 153.1, 140.4,
112.6, 82.7, 79.9, 64.7, 62.5, 57.7, 33.5, 13.1; HRFABMS:
calcd mass 279.0957 for C11H16N2O5Na, found 279.0975
(MCNa)C.
1
89%) as an oil; H NMR (CDCl3) d (ppm) 7.43–7.21 (m,
15H), 5.38 (m, 1H), 4.91 (d, 1H, JZ3.5 Hz), 4.29–4.26 (m,
2H), 4.12–3.88 (m, 4H), 3.52 (dd, 1H, JZ5.2, 9.3 Hz), 3.19
(dd, 1H, JZ7.8, 9.2 Hz), 2.72 (s, 3H), 2.47 (m, 1H), 2.25
(m, 1H). A mixture of adenine (1.99 g, 14.72 mmol) and
sodium hydride (60% in oil) in anhydrous N,N-dimethyl-
formamide (120 mL) was heated at 100 8C for 1 h and
cooled to 85 8C. Compound 28 (1.88 g, 3.68 mmol) in
anhydrous N,N-dimethylformamide (20 mL) was then
added. The resulting reaction mixture was heated at 85 8C
for 3 days and concentrated under reduced pressure to give a
residue which was separated by silica gel column chroma-
tography (chloroform–methanolZ30:1) to give compound
29 (1.13 g, 56%) as white foam. UV lmax 265 nm (MeOH);
1H NMR (CDCl3) d (ppm) 8.32 (s, 1H), 8.02 (s, 1H), 7.32–
7.17 (m, 15H), 5.60 (s, 2H), 5.21 (m, 1H), 5.07 (d, 1H, JZ
3.5 Hz), 4.46 (m, 1H), 4.34 (t, 1H, JZ3.5, 7.6 Hz), 4.04–
3.95 (m, 4H), 3.34 (dd, 1H, JZ4.7, 10.0 Hz), 3.27 (dd, 1H,
JZ5.6, 10.0 Hz), 2.71 (dt, 1H, JZ8.9, 13.3 Hz), 2.40 (dt,
1H, JZ7.4, 13.4 Hz); 13C NMR (CDCl3) d (ppm) 155.3,
152.9, 150.1, 143.5, 139.1, 128.6, 127.8, 127.1, 119.6,
104.2, 87.0, 82.2, 78.7, 65.7, 65.3, 64.1, 56.3, 33.5.
Compound 29 (550 mg, 1.00 mmol) was dissolved in
tetrahydrofuran (4 mL) containing trifluoroacetic acid
(2 mL) and conc. HCl (0.3 mL) heated at 80 8C for 8 h,
neutralized with saturated aqueous sodium bicarbonate and
concentrated. The obtained residue was dissolved in
methanol (10 mL) and NaBH4 (100 mg, 2.64 mmol) was
added at 0 8C. The resulting reaction mixture was stirred at
rt for 8 h and concentrated to give a residue, which was
separated by silica gel column chromatography (chloro-
form–methanolZ10:1) to give compound 8 (170 mg, 64%)
as a white solid. Mp 189–190 8C. UV lmax 260 nm (3 12
286, MeOH); [a]2D0ZK258 (c 3.0, MeOH); 1H NMR (D2O)
d (ppm) 8.30 (s, 1H), 8.20 (s, 1H), 5.11 (dd, 1H, JZ1.5,
8.3 Hz), 4.45 (m, 2H), 3.98–3.65 (m, 4H), 2.72 (m, 1H),
2.37 (m, 1H); 13C NMR (D2OCDMSO-d6) d (ppm) 157.0,
154.0, 150.0, 142.1, 120.1, 83.7, 80.5, 64.7, 63.4, 56.9, 35.0;
HRFABMS: calcd mass 288.1072 for C11H15N5O3Na,
found 288.1068 (MCNa)C.
3.1.11. 2(R),5(R)-Di(hydroxymethyl)-3(S)-(uracil-1-yl)-
tetrahydrofuran (10). A mixture of compound 28
(710 mg, 1.39 mmol) and sodium azide (452 mg,
6.95 mmol) in anhydrous N,N-dimethylformamide
(15 mL) was heated at 85 8C for 24 h, concentrated in
vacuo, and purified by silica gel column chromatography
(hexanes–ethylacetateZ5:1) to give an azide as a white
foam (502 mg, 79%); 1H NMR (CDCl3) d (ppm) 7.48–7.22
(m, 15H), 4.94 (d, 1H, JZ5.1 Hz), 4.16–3.91 (m, 7H), 3.24
(dd, 1H, JZ4.8, 10.1 Hz), 3.17 (dd, 1H, JZ3.7, 10.1 Hz),
2.43 (m, 1H), 2.02 (m, 1H); 13C NMR (CDCl3) d (ppm)
143.7, 128.7, 127.9, 127.1, 104.3, 83.0, 79.2, 77.3, 65.5,
65.3, 63.9, 62.5, 32.4. A mixture of the azide (650 mg,
1.42 mmol) and 10 wt% Pd/C (170 mg) in ethyl acetate–
ethanol (1:1, 20 mL) was stirred at 30 psi in the presence of
hydrogen gas for 4 h at rt. The catalyst was filtered and the
filtrate was concentrated and purified by silica gel column
chromatography (hexanes–ethylacetateZ5:1) to give com-
pound 31 as a white foam (600 mg, 98%); 1H NMR (CDCl3)
d (ppm) 7.45–7.20 (m, 15H), 4.93 (d, 1H, JZ3.9 Hz), 4.08
(dt, 1H, JZ3.9, 7.5 Hz), 4.02 (m, 2H), 3.90 (m, 2H), 3.80
(dd, 1H, JZ5.9, 10.5 Hz), 3.39 (dd, 1H, JZ7.4, 13.4 Hz),
3.29 (dd, 1H, JZ4.5, 9.6 Hz), 3.12 (dd, 1H, JZ6.1, 9.6 Hz),
2.31 (dt, 1H, JZ7.5, 12.7 Hz), 1.69 (dt, 1H, JZ7.4,
12.7 Hz), 1.60 (bs, 2H); 13C NMR (CDCl3) d (ppm)
143.9, 128.6, 127.8, 127.0, 104.8, 86.8, 85.9, 78.5, 65.5,
65.2, 65.0, 55.2, 36.1. A mixture of b-methoxyacryloyl
chloride (800 mg, 6.64 mmol) and silver cyanate (1.79 g,
11.94 mmol) in anhydrous toluene (40 mL) was heated
under reflux for 30 min and cooled, and then the supernatant
was added to compound 31 (680 mg, 1.58 mmol) in
anhydrous toluene (20 mL) at 0 8C. The reaction mixture
was stirred at 0 8C for 30 min at rt for 1 h. The reaction
mixture was poured onto saturated aqueous sodium
bicarbonate solution (50 mL) and extracted with ethyl
acetate (2!50 mL). After concentration of the organic
layer, the residue was purified by silica gel column
chromatography (hexanes–ethylacetateZ2:1) and the pro-
duct (800 mg, 88%) was dissolved in ethanol (40 mL) and
29% ammonium hydroxide solution (5 mL) was added. The
3.1.10. 2(R),5(R)-Di(hydroxymethyl)-3(S)-(thymin-1-yl)-
tetrahydrofuran (9). A mixture of 60% sodium hydride
(230 mg, 9.20 mmol) and thymine (1.16 g, 9.19 mmol) in
anhydrous N,N-dimethylformamide (15 mL) was heated at
95 8C for 1 h and then compound 28 (1.17 g, 2.29 mmol) in
anhydrous N,N-dimethylformamide (5 mL) was introduced.
The reaction mixture was stirred at 100 8C for 4 days,

10268
V. Nair et al. / Tetrahedron 60 (2004) 10261–10268
resulting reaction mixture was heated at 100 8C for 18 h in a
steel bomb. After concentration, the residue was purified by
silica gel column chromatography (hexanes–ethylacetateZ
1:1) to give compound 32 (546 mg, 66% from 31) as a white
foam. UV lmax 266 nm (MeOH); 1H NMR (CDCl3) d (ppm)
8.31 (s, 1H), 7.54 (d, 1H, JZ8.1 Hz), 7.40–7.20 (m, 15H),
5.75 (dd, 1H, JZ2.2, 8.1 Hz), 5.17 (m, 1H), 5.02 (d, 1H, JZ
2.7 Hz), 4.29 (dt, 1H, JZ2.7, 7.7 Hz), 4.12 (m, 1H), 4.07–
3.93 (m, 4H), 3.35 (dd, 1H, JZ4.8, 10.0 Hz), 3.18 (dd, 1H,
JZ5.8, 9.9 Hz), 2.25 (dt, 1H, JZ8.5, 13.6 Hz), 1.97 (dt, 1H,
JZ6.9, 13.7 Hz); 13C NMR (CDCl3) d (ppm) 162.6, 150.5,
143.5, 141.5, 128.6, 127.9, 127.2, 103.9, 102.9, 87.3, 81.5,
78.4, 65.7, 65.3, 64.6, 57.2, 32.2. Compound 10: (62 mg,
67%) was obtained from compound 32 (200 mg,
0.38 mmol) using the same method for compound 9.
Compound 10. Mp 200–202 8C; [a]2D0ZK308 (c 0.5,
3.2. X-ray crystallographic data
Crystallographic data (excluding structure factors) for
compound 8 described in this paper have been deposited
with the Cambridge Crystallographic Data Center as
supplementary publication number CCDC 230719. Copies
of the data can be obtained, free of charge, on application to
the CCDC (deposit@ccdc.cam.ac.uk).
Acknowledgements
The project described was supported by Grant Number AI
32851 from the National Institutes of Health. Its contents are
solely the responsibility of the authors and do not
necessarily represent the official views of the NIH. We
thank Dr. Dale Swenson for help with the single crystal
X-ray structural data.
1
MeOH). UV lmax 266 nm (3 11 200, MeOH); H NMR
(D2O) d (ppm) 7.81 (d, 1H, JZ8.1 Hz), 5.92 (d, 1H, JZ
8.0 Hz), 5.08 (dt, 1H, JZ6.3, 8.6 Hz), 4.34 (m, 1H), 4.23
(dt, 1H, JZ3.9, 6.0 Hz), 3.83 (dd, 1H, JZ3.1, 12.4 Hz),
3.75–3.65 (m, 3H), 2.54 (m, 1H), 2.08 (dt, 1H, JZ8.9,
13.1 Hz); 13C NMR (D2OCDMSO-d6) d (ppm) 167.8,
153.8, 145.4, 104.1, 83.0, 80.3, 64.4, 62.6, 58.4, 33.6;
HRFABMS: calcd mass 243.0980 for C10H15N2O5, found
243.0983 (MCH)C.
References and notes
1. Hoshino, H.; Shimizu, N.; Shimada, N.; Takita, T.; Takeuchi,
T. J. Antibiot. 1987, 40, 1077–1078.
2. Nair, V.; St. Clair, M.; Reardon, J. E.; Krasny, H. C.; Hazen,
R. J.; Paff, M. T.; Boone, L. R.; Tisdale, M.; Najera, I.;
Dornsife, R. E.; Everett, D. R.; Borroto-Esoda, K.; Yale,
J. L.; Zimmerman, T. P.; Rideout, J. L. Antimicrob. Agents
Chemother. 1995, 39, 1993–1999.
3.1.12. 3(S)-(Cytosin-1-yl)-2(R),5(R)-di(hydroxymethyl)
tetrahydrofuran (11). To a solution of compound 10
(460 mg, 1.90 mmol) in anhydrous acetonitrile (20 mL)
containing triethylamine (10 mL) was added acetic
anhydride (3.6 mL, 38.15 mmol) at 0 8C. The resulting
reaction mixture was stirred at rt for 3 h, cooled to 0 8C,
treated with water (5 mL), stirred for 4 h, diluted with
ethylacetate (50 mL), and then washed with water (3!
10 mL). The organic layer was concentrated and the residue
was purified by silica gel chromatography (hexanes–
ethylacetateZ1:2) to give a diacetate as a syrup (489 mg,
79%); 1H NMR (CDCl3) d (ppm) 9.05 (s, 1H), 7.43 (d, 1H,
JZ8.1 Hz), 5.78 (d, 1H, JZ8.1 Hz), 5.14 (m, 1H), 4.42 (m,
1H), 4.33 (m, 1H), 4.23–4.13 (m, 4H), 2.61 (m, 1H), 2.11 (s,
3H), 2.09 (s, 3H), 1.94 (m, 1H); 13C NMR (CDCl3) d (ppm)
170.6, 170.6, 162.9, 150.8, 140.7, 103.7, 79.9, 76.2, 65.0,
63.5, 56.8, 33.7, 20.9, 20.8. To a solution of the diacetate
(142 mg, 0.44 mmol) in anhydrous acetonitrile (20 mL)
containing 4-dimethylaminopyridine (54 mg, 0.44 mmol)
and triethylamine (1 mL) was added 2,4,6-triisopropyl-
benzenesulfonyl chloride (133 mg, 0.44 mmol) at 0 8C. The
resulting reaction mixture was stirred at rt for 4 h, treated
with ammonium hydroxide (29%, 3.5 mL) for an additional
2 h and then concentrated. The resulting residue was
separated by silica gel column chromatography (chloro-
form–methanolZ10:1 to 5:1) to give compound 11 (23 mg,
3. Nair, V.; Jahnke, T. S. Antimicrob. Agents Chemother. 1995,
39, 1017–1029.
4. Nair, V. Recent Advances in Nucleosides: Chemistry and
Chemotherapy; Chu, C. K., Ed.; Elsevier: Amsterdam,
Netherlands, 2002; pp 149–166.
5. (a) Nair, V.; Nuesca, Z. M. J. Am. Chem. Soc. 1992, 114,
7951–7953. (b) Bolon, P. S.; Sells, T. B.; Nuesca, Z. M.;
Purdy, D. F.; Nair, V. Tetrahedron 1994, 50, 7747–7764.
6. Tino, J. A.; Clark, J. M.; Field, A. K.; Jacobs, G. A.; Lis,
K. A.; Michalik, T. L.; McGeever-Rubin, B.; Slusarchyk,
W. A.; Spergel, S. H.; Sundeen, J. E.; Tuomari, A. V.; Weaver,
E. R.; Young, M. G.; Zahler, R. J. Med. Chem. 1993, 36,
1221–1229.
7. Horton, D.; Philips, K. D. Carbohydr. Res. 1973, 30, 367–374.
8. Guthrie, R.-D.; Jenkins, I.-D.; Walter, J. J.; Wright,
M. W.; Yamasaki, R. Aust. J. Chem. 1982, 35, 2169–2173.
9. Nair, V.; Buenger, G. S. J. Am. Chem. Soc. 1989, 111,
8502–8504.
10. Kakefuda, A.; Shuto, S.; Nagahata, T.; Seki, J.-I.; Sasaki, T.;
Matsuda, A. Tetrahedron 1994, 50, 10167–10182.
11. Rokach, J.; Khanapure, S. P.; Hwang, S.-W.; Adiyaman, M.;
Schio, L.; FitzGerald, G. A. Synthesis 1998, 569–580.
12. Bolon, P. J.; Jahnke, T. S.; Nair, V. Tetrahedron 1995, 51,
10443–10452.
1
45%) as a white solid. Mp 200–201 8C; H NMR (D2O) d
(ppm) 7.7 (d, 1H, JZ7.5 Hz), 6.08 (d, 1H, JZ7.5 Hz), 5.12
(m, 1H), 4.35 (m, 1H), 4.23 (m, 1H), 3.82 (m, 1H), 3.70 (m,
3H), 2.54 (m, 1H), 2.05 (m, 1H); 13C NMR (D2OCDMSO-
d6) d (ppm) 166.0, 158.5, 143.6, 96.9, 82.2, 78.9, 63.1, 61.4,
57.5, 37.8; HRFABMS: calcd mass 264.0960 for
C10H15N3O4Na, found 265.0971 (MCNa)C.
13. Defaye, J.; Horton, D.; Musser, M. Carbohydr. Res. 1971, 20,
305–318.
14. Purdy, D. F.; Zintek, L.; Nair, V. Nucleosides Nucleotides
1994, 13, 109–126.
15. Lei, Z.; Min, J. M.; Zhang, L. H. Tetrahedron: Asymmetry
2000, 11, 2899–2906.