Isonucleosides with exocyclic methylene groups

Article abstract of DOI:10.1002/1522-2675(20000705)83:7<1398::AID-HLCA1398>3.0.CO;2-I

Synthesis of isonucleosides 13, 14, 16, and 17, bearing an exocyclic methylidene group at the sugar moiety, starting from a 3-keto sugar is described. The keto compound was converted to the methylene-sugar 10b (Scheme 1), which was coupled with nucleobase

Full text of DOI:10.1002/1522-2675(20000705)83:7<1398::AID-HLCA1398>3.0.CO;2-I

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Isonucleosides with Exocyclic Methylene Groups
by Sanjib Bera and Vasu Nair*
Department of Chemistry, The University of Iowa, Iowa City, IA 52242, U.S.A. (fax:(319) 353-2621;
e-mail:vasu-nair@uiowa.edu)
Dedicated to Prof. Dr. Frank Seela on the occasion of his 60th birthday
Synthesis of isonucleosides 13, 14, 16, and 17, bearing an exocyclic methylidene group at the sugar moiety,
starting from a 3-keto sugar is described. The keto compound was converted to the methylene-sugar 10b
(Scheme 1), which was coupled with nucleobases by means of the Mitsunobu reaction. The coupling reaction
with adenine and 8-azaadenine produced both the N9- and N3-nucleosides (see 13 and 14, resp.; Scheme 2). The
structures of 13a and 14a were confirmed by single-crystal X-ray data. Synthesis of the pyrimidine compounds
was also approached from the b-amino sugar 20 that was prepared using a Gabriel-synthesis methodology
(Scheme 3).
Introduction. ± For a number of years, we have been investigating the synthesis,
enzymology, and antiviral studies of various isomeric nucleosides in our laboratory [1].
For example, (2S,4S)-4-(6-amino-9H-purin-9-yl)tetrahydrofuran-2-methanol ((S,S)-
isoddA; 1), an isomeric dideoxynucleoside synthesized by us, exhibits activity against
HIV-1 and HIV-2 [2]. Our interest in synthesizing analogs of (S,S)-isoddA (1) led us to
the design of isomeric dideoxynucleosides 3 with an exocyclic methylene group. This
synthetic design was supported by the observation of the anti-HIV and anti-HBV
activity of carbocyclic nucleoside 4 [3] and the anti-HIV activity of the dioxolanyl
compounds 5 and 6 [4]. It is likely that the antiviral activity of 4 is associated with its
ability to function as a structural analog of 2'-deoxyguanosine. The exocyclic CˆC
bond appears to act as a functional replacement for the O-atom at that position. If this
is so then our target molecules 3 (and mirror images) are related to both 4, in which the
endocyclic O-atom has replaced the exocyclic OH, and to compounds 5 and 6. This
paper reports the synthesis and antiviral studies of novel isonucleosides with exocyclic
methylene groups.
Results and Discussion. ± Synthesis of the methylene-isonucleosides was approach-
ed from the corresponding carbohydrate precursor bearing the exocyclic methylene
group. The synthesis commenced with the protected d-xylose 7 [5]. Oxidation of the 3-
OH group with DMSO and P2O5 [6] and subsequent Wittig reaction [7][8] on the
resulting ketone with NaH and (Ph3PMe)Br in DMSO produced the alkene 8. Acid-
catalyzed methanolysis [9] of the acetonide group afforded the a- and b-d-glycosides 9.
Reductive demethoxylation was carried out by refluxing 9 with hexamethyldisilazane
(HMDS) followed by treatment with Et3SiH and Me3SiOSO2CF3 [9 ± 11] in MeCN at
room temperature to give 10a. The primary OH group of 10a was selectively protected
[12] with the (tert-butyl)diphenylsilyl group to yield 10b, which was the key starting
material for the synthesis of both isodideoxypurine and pyrimidine nucleosides (Scheme 1).

Helvetica Chimica Acta ± Vol. 83 (2000)
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Scheme 1
i) DMSO, P2O5, r.t. ii) NaH, DMSO, (Ph3PMe)Br. iii) HCl, MeOH. iv) Me3SiCl, HMDS. v) Et3SiH,
t
Me3SiOSO2CF3, MeCN, r.t. vi) BuPh2SiCl, pyridine, 48.
Purine isonucleosides having adenine or 8-azaadenine bases were synthesized via
the Mitsunobu reaction [13 ± 15]. Interestingly, treatment of 10b with adenine in the
presence of DEAD (diethyl diazenedicarboxylate) and Ph3P in dioxane at room
temperature produced the N9-isomer 11a and its N3 isomer 12a (Scheme 2). Similarly,
compounds 11b and 12b were obtained when 10b was treated with 8-azaadenine under
Mitsunobu conditions. Desilylation of compounds 11 and 12 with NH4F in MeOH
afforded compounds 13 and 14, respectively. The structures of both the N9- and N3-
isomers of the coupling products were confirmed by their multinuclear NMR and HR-
MS data and particularly by their UV spectra and single-crystal X-ray data. For
example, the UV spectrum of compound 13a showed a lmax at 261 nm (e 14000),
whereas compound 14a exhibited a lmax at 275 nm (e 13300). The X-ray structure of 13a
(Fig. 1) confirmed unequivocally its structure and absolute configuration and showed
the glycosidic bond attachment of N(9) of the base, the presence of the exocyclic
methylene group, the anti-conformation about the glycosidic bond, and the endo
puckering of the sugar ring at the O-atom. The X-ray structure of compound 14a also
confirmed its structure and absolute configuration but showed the attachment of the
base at N(3) (Fig. 2). Interestingly, the crystal structure of compound 14a showed the
presence of two independent molecules in an asymmetric unit. Each formed a dimer via

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two H-bonds with a symmetry equivalent molecule of the other (i.e., molecule A was
dimerized with molecule B, and vice versa). The two molecules differ in conformation
mainly at the primary OH group of the sugar moiety.
Scheme 2
i) Ph3P, DEAD, purine base, dioxane. ii) NH4F, MeOH. iii) 3-benzoylthymine or uracil, Ph3P, DEAD, THF. iv)
i
MeONa, MeOH. v) Ac2O, pyridine. vi) Pr3SiCl, 4-(dimethylamino)pyridine, Et3N, MeCN, then NH4OH
Isodideoxypyrimidine nucleosides having an exocyclic methylene group were also
synthesized by the Mitsunobu reaction. Thus, compound 10b, on treatment with 3-
benzoyluracil or 3-benzoylthymine under Mitsunobu conditions gave the desired
products 15a,b (Scheme 2). The protecting groups of 15a,b were removed by treatment
with NH4F or by successive treatment with NH4F and NaOMe to produce 16a,b. It is
interesting to note that in the case of the uracil derivative 15b, only NH4F treatment was
required to completely deprotect to product 16b. Compound 16b was converted to the
corresponding cytosine derivative 17 according to a previously reported procedure [16].
Because of the relatively low yields obtained in the Mitsunobu coupling procedure
with pyrimidine nucleosides, we also developed an approach to these compounds from
the appropriate amino sugar 20 which was prepared from 10b (Scheme 3). When
compound 10b was treated with phthalimide under Mitsunobu-reaction conditions, no

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Fig. 1. ORTEP Plot of single-crystal X-ray structure of 13a
phthalimido derivative 19 was obtained. However, the reaction of mesylate 18,
prepared from 10b, with potassium phthalimide in DMF produced stereospecifically
the substituted product 19. It should be mentioned that treatment of mesylate 18 with
NaN3 did not give the Sn2 product but compound 22 resulting from the Sn2'
Fig. 2. ORTEP Plot of single-crystal X-ray structure of 14a

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displacement reaction by the azido group. The amino derivative 20 was obtained by the
deprotection of 19 with hydrazine [17]. Treatment of 20 with 3-methoxy-2-methylprop-
2-enoyl isocyanate [10][18][19] produced 21, which, on acid-catalyzed cyclization,
produced the thymine derivative 16a.
Scheme 3
i) MsCl, Et3N, CH2Cl2, 08. ii) Potassium phthalimide, DMF, 1108. iii) NH2NH2, EtOH, reflux. iv) 3-Methoxy-2-
methylprop-2-enoyl isocyanate, DMF, Et2O, 08 to r.t. v) 2n H2SO4, dioxane, 1008. vi) NaN3, DMF, 908.
In summary, synthesis of the methylene-isonucleosides 13, 14, 16, and 17 was
achieved starting from a 3-keto sugar prepared from inexpensive d-xylose. The keto
sugar was converted to an appropriate methylene-bearing carbohydrate precursor that
was coupled, via the Mitsunobu reaction, with nucleobases. Synthesis of the pyrimidine
compound 16a was also approached from the b-amino sugar 20 which was prepared by
means of a Gabriel-synthesis methodology. In the case of the direct coupling reaction
with adenine and 8-azaadenine, both the N9- and N3-nucleosides (see 13 and 14) were
produced. The structure of 13a and 14a was unequivocally confirmed by single-crystal
X-ray data. Preliminary antiviral evaluations suggested that the target compounds did
not show significant anti-HIV activity in vitro in infected CEM-SS cells. Further
biological studies are in progress.
We are grateful to Dr. Dale Swenson for the single-crystal X-ray structure determinations and Dr. Lynn
Teesch and Ms. Diane Herschberger for the HR-MS data. This research work was supported by the N.I.H.
(National Institute of Allergy and Infectious Diseases). We thank the National Cancer Institute for the anti-HIV
evaluations.

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Experimental Part
General. M.p.s.:uncorrected. Electrothermal-Engineering-Ltd. melting-point apparatus. UV Spectra: Cary-
3 UV-Visible spectrophotometer. 1H- and 13C-NMR Spectra: Bruker-AC-300 instrument at 300 and 75 MHz,
resp., d in ppm referenced to internal SiMe4 for 1H and to solvent CDCl3, (D6)DMSO, (D6)acetone, or CD3OD)
for 13C. Column chromatography (CC):230 ± 400 mesh silica gel. High-resolution FAB-MS: VG-ZAB-HF high-
resolution mass spectrometer.
3-Deoxy-1,2-O-isopropylidene-3-methylidene-5-O-trityl-a-d-ribofuranose (8). To a soln. of 7 [5] (4.3 g,
10 mmol) in DMSO (30 ml), P2O5 (2.6 g, 18.3 mmol) was carefully added while maintaining the temp. at 20 ±
308. The mixture was stirred at 308 for 20 h. The brown soln. was diluted with CHCl3 (120 ml) and washed with
ice-cold H2O until the washings were neutral. The org. phase was dried (Na2SO4) and evaporated and the
residue purified by CC:keto compound as white solid foam (2.9 g, 67%).
NaH (0.72 g, 15.1 mmol) was suspended in DMSO (30 ml) and the mixture heated at 758 for 45 min under
N2. After the soln. was cooled to r.t., methyltriphenylphosphonium bromide (5.8 g, 16.3 mmol) was added, and
the soln. was stirred at r.t. for 30 min. To this mixture a soln. of the keto compound in DMSO (20 ml) was added
dropwise. After the addition, the mixture was stirred for an additional 2 h and then poured into H2O (100 ml).
The aq. soln. was extracted with Et2O (3 Â 60 ml), the combined org. phase washed with H2O (2 Â 75 ml), dried
(Na2SO4), and evaporated, and the gummy residue purified by CC: 8 (2.3 g, 89%). White solid. M.p. 159 ± 1608.
1H-NMR (CDCl3):7.46 ± 7.17 ( m, 3 Ph); 5.95 (d, J ˆ 4.1, HÀC(1)); 5.34 (t, J ˆ 1.1, 1 H, ˆCH2); 5.04 (t, J ˆ 1.4,
1 H, ˆCH2); 4.94 ± 4.87 (m, HÀC(2), HÀC(4)); 3.28 (dd, J ˆ 9.9, 4.0, HaÀC(5)); 3.19 (dd, J ˆ 9.9, 4.5,
HbÀC(5)); 1.52 (s, 3 H, Me2C); 1.39 (s, 3 H, Me2C). 13C-NMR (CDCl3):147.0 (C(3)); 143.7 (Ph); 128.6, 127.7,
127.0 (Ph); 112.4 (Me2C); 111.8 (ˆCH2); 104.8 (C(1)); 86.6 (Ph3C); 81.8 (C(2)); 79.1 (C(4)); 65.8 (C(5)); 27.4,
‡
‡
27.1 (Me2C). HR-FAB-MS:451.1885 (C 28H28NaO4Si , [M ‡ Na] ; calc. 451.1885).
(3R,5S)-5-{{[(tert-Butyl)diphenylsilyl]oxy}methyl}tetrahydro-4-methylidenefuran-3-ol (10b). To a soln. of
8 (5.7 g, 13.3 mmol) in MeOH (150 ml) 4n HCl in dioxane (0.27 ml) was added, and the mixture was heated
under reflux for 2 h. The acid was neutralized with K2CO3, the suspension adsorbed on silica gel, and the mixture
purified by CC: 9 (1.66 g, 78%). Oil.
A mixture of 9 (0.54 g, 3.4 mmol) and Me3SiCl (0.25 ml) in hexamethyldisilazane (HMDS; 25 ml) was
heated under reflux for 17 h. Unreacted HMDS was evaporated to afford a pale yellow liquid. Dry MeCN was
added to the residue followed by the addition of Et3SiH (1.6 ml, 10.2 mmol) and Me3SiOSO2CF3 (1.8 ml,
10.2 mmol), and the mixture was stirred overnight at r.t. It was then quenched with H2O (5 ml), stirred for 1 h,
and then neutralized with Dowex resin (OHÀ form). The soln. was filtered, the filtrate evaporated, and the
residue purified by CC: (2S,4R)-tetrahydro-4-hydroxy-3-methylidenefuran-2-methanol (10a; 78%). Oil.
1H-NMR (CD3OD):5.29 ( t, J ˆ 2.2, 1 H, ˆCH2); 5.11 (t, J ˆ 2.0, 1 H, ˆCH2); 4.55 ± 4.48 (m, HÀC(2),
HÀC(4)); 4.04 (dd, J ˆ 9.0, 6.1, HaÀC(5)); 3.61 (dd, J ˆ 11.8, 3.5, 1 H, CH2); 3.50 (m, 2 H, HbÀC(5), CH2).
13C-NMR (CD3OD):152.2 (C(3)); 108.6 ( ˆCH2); 82.2 (C(2)); 74.2 (C(4)); 73.5 (C(5)); 65.4 (CH2).
tBuPh2SiCl (0.57 ml, 2.2 mmol) was added to a soln. of 10a (0.26 g, 2 mmol) in pyridine (20 ml) at 08. After
the addition, the mixture was stirred at 08 for 6 h and at 48 overnight. The reaction mixture was quenched with
H2O (2 ml). Pyridine was evaporated and the conc. soln. co-evaporated with toluene. The residue was purified
by CC: 10b (0.62 g, 84%). Gum. 1H-NMR (CDCl3):7.68 ± 7.38 ( m, 2 Ph); 5.34 (s, 1 H, ˆCH2); 5.08 (s, 1 H,
ˆCH2); 4.60 (m, HÀC(3), HÀC(5)); 4.1 (dd, J ˆ 9.3, 5.6, HaÀC(2)); 3.68 (m, HbÀC(2), CH2); 1.04 (s, Me3C).
13C-NMR (CDCl3):151.3 (C(4)); 135.5, 135.4, 133.2, 133.1, 129.6, 129.5, 127.5 (Ph); 108.6 ( ˆCH2); 80.6 (C(3));
‡
73.9, 72.9 (C(2), C(5)); 66.4 (CH2); 26.6 (Me3C); 19.1 (Me3C). HR-FAB-MS:391.1695 (C 22H28NaO3Si , [M ‡
‡
Na] ; calc. 391.1705).
(2S,4S)-4-(6-Amino-9H-purin-9-yl)tetrahydro-3-methylidenefuran-2-methanol (13a) and (2S,4S)-4-(6-Ami-
no-3H-purin-3-yl)tetrahydro-3-methylidenefuran-2-methanol (14a). To a suspension of 10b (0.61 g, 1.66 mmol),
Ph3P (0.65 g, 2.5 mmol), and adenine in dioxane (80 ml) at r.t., DEAD (0.4 ml, 2.6 mmol) was added dropwise.
After the addition, the mixture was stirred at r.t. for 22 h. The solvent was then evaporated and the residue
purified by CC: 11a (0.34 g, 42%) and 12a (0.15 g, 19%).
1
Data of 11a:M.p. 170 8. H-NMR (CDCl3):8.33 ( s, HÀC(8)); 7.90 (s, HÀC(2)); 7.69 ± 7.35 (m, 2 Ph); 5.87
(s, NH2); 5.64 (br. s, HÀC(4')); 5.27 (m, ˆCH2); 4.20 (dd, J ˆ 10.0, 6.0, HaÀC(5')); 4.14 (dd, J ˆ 10.0, 4.0,
HbÀC(5')); 3.93 (d, J ˆ 4.7, CH2). 13C-NMR (CDCl3):155.5 (C(6)); 152.9 (C(2)); 150.0 (C(4)); 146.9 (C(3 '));
138.9 (C(8)); 135.6, 132.9, 129.8, 127.8 (2 Ph); 119.3 (C(5)); 112.1 (ˆCH2); 81.3 (C(2')); 72.1 (C(5')); 65.6 (CH2);
56.6 (C(4')); 26.8 (Me3C); 19.2 (Me3C).
Data of 12a:M.p. 160 ± 161 8. 1H-NMR (CDCl3); 8.36 (s, HÀC(8)); 8.02 (s, HÀC(2)); 7.70 ± 7.26 (m, 2 Ph);
6.05 (br. s, HÀC(4')); 5.50 (br. s, 1 H, ˆCH2); 5.40 (br. s, 1 H, ˆCH2); 4.50 (m, HÀC(2')); 4.25 (d, J ˆ 4.0,

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2 HÀC(5')); 4.02 (dd, J ˆ 11.5, 3.9, 1 H, CH2); 3.97 (dd, J ˆ 11.4, 4.4, 1 H, CH2); 1.07 (s, Me3C). 13C-NMR
(CDCl3):154.4 (C(6)); 153.7 (C(2)); 150.6 (C(4)); 145.8 (C(3 ')); 140.8 (C(8)); 135.5, 132.8, 129.9, 127.8 (Ph);
120.5 (C(5)); 113.9 (ˆCH2); 81.5 (C(2')); 72.5 (C(5')); 64.9 (CH2); 61.3 (C(4')); 26.8 (Me3C); 19.1 (Me3C).
To a soln. of 11a (0.32 g, 0.66 mmol) in MeOH (30 ml), NH4F (0.4 g) was added and the soln. heated under
reflux for 3 h. The soln. was then adsorbed on silica gel and purified by CC: 13a (0.14 g, 85%). White solid. M.p.
1908. UV (MeOH):260.6 (14000). 1H-NMR ((D6)DMSO):8.15 (2 s, HÀC(2), HÀC(8)); 7.25 (br. s, NH2); 5.56
(t, HÀC(4')); 5.30 (br. s, 1 H, ˆCH2); 5.15 (t, J ˆ 2.0, 1 H, ˆCH2); 5.06 (t, J ˆ 5.6, OH); 4.44 (br. s, HÀC(2'));
3.73 (m, 2 HÀC(5')); 3.31 (t, J ˆ 6.7, CH2). 13C-NMR (CD3OD):157.3 (C(6)); 153.7 (C(2)); 150.5 (C(4)); 148.6
(C(3')); 141.4 (C(8)); 119.9 (C(5)); 112.7 (ˆCH2); 83.1 (C(2')); 72.9 (C(5')); 64.2 (CH2); 58.7 (C(4')). HR-FAB-
‡
‡
MS:270.0959 (C 11H13N5NaO2 , [M ‡ Na] ; calc. 270.0966).
Compound 12a was similarly deprotected to give 14a (86%). White solid. M.p. 2568. UV (MeOH):274.5
(13300). 1H-NMR (CD3OD):8.62 ( s, HÀC(8)); 7.90 (s, HÀC(2)); 5.85 (m, HÀC(4')); 5.49 (m, CH2); 4.52 (br. s,
HÀC(2')); 4.29 (dd, J ˆ 10.6, 2.7, HaÀC(5')); 4.22 (dd, J ˆ 10.6, 5.9, HbÀC(5')); 4.00 (dd, J ˆ 12.5, 2.9, 1 H, CH2);
3.90 (dd, J ˆ 12.4, 3.3, 1 H, CH2). 13C-NMR (CD3OD):156.6 (C(6)); 152.9 (C(2)); 150.5 (C(4)); 147.4 (C(3 '));
144.3 (C(8)); 120.8 (C(5)); 114.4 (ˆCH2); 83.3 (C(2')); 73.1 (C(5')); 63.7 (CH2); 63.6 (C(4')). HR-FAB-MS:
‡
‡
270.0954 (C11H13N5NaO2 , [M ‡ Na] ; calc. 270.0966).
(2S,4S)-4-(7-Amino-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)tetrahydro-3-methylidenefuran-2-methanol (13b)
and (2S,4S)-4-(7-Amino-4H-1,2,3-triazolo[4,5-d]pyrimidin-4-yl)tetrahydro-3-methylidenefuran-2-methanol (14b).
Compounds 11b and 12b were synthesized as described for 13a and 13b in 50 and 23% yield, resp.
1
Data of 11b:M.p. 168 8. H-NMR (CDCl3):8.37 ( s, HÀC(5)); 7.73 ± 7.34 (m, 2 Ph); 7.06 (br. s, NH2); 5.93
(t, J ˆ 6.3, HÀC(4')); 5.25 (s, 1 H, ˆCH2); 5.04 (s, 1 H, ˆCH2); 4.74 (t, J ˆ 5.4, HÀC(2')); 4.50 (dd, J ˆ 9.4, 6.0,
HaÀC(5')); 4.33 (dd, J ˆ 9.4, 7.2, HbÀC(5')); 4.10 (dd, J ˆ 10.8, 6.6, 1 H, CH2); 3.91 (dd, J ˆ 10.8, 5.1, 1 H, CH2);
1.07 (s, Me3C). 13C-NMR (CDCl3):156.5 (C(7)); 156.1 (C(5)); 149.1 (C(3a)); 146.2 (C(3 ')); 135.6, 133.4, 133.2,
129.6, 127.6 (2 Ph); 124.4 (C(7a)); 111.4 (ˆCH2); 81.5 (C(2')); 69.6 (C(5')); 65.8 (CH2); 60.0 (C(4')); 26.7
(Me3C); 19.1 (Me3C).
Data of 12b:M.p. 74 ± 75 8. 1H-NMR (CDCl3):8.49 ( s, HÀC(5)); 7.70 ± 7.32 (m, 2 Ph); 5.81 (m, HÀC(4'));
5.39 (s, 1 H, ˆCH2); 5.36 (s, 1 H, ˆCH2); 4.68 (m, HÀC(2')); 4.68 (dd, J ˆ 10.1, 4.0, HaÀC(5')); 4.35 (dd, J ˆ
10.1, 6.5, HbÀC(5')); 3.97 (dd, J ˆ 10.8, 6.3, 1 H, CH2); 3.85 (dd, J ˆ 15.1, 5.1, 1 H, CH2). 13C-NMR (CDCl3):
157.8 (C(7)); 156.6 (C(3a)); 156.4 (C(5)); 145.5 (C(3')); 135.5, 135.4, 133.2, 133.0, 129.6, 127.5 (2 Ph); 126.0
(C(7a)); 113.3 (ˆCH2); 81.4 (C(2')); 70.9 (C(5')); 68.9 (C(4')); 65.9 (CH2), 26.6 (Me3C); 19.0 (Me3C).
Compounds 11b and 12b were deprotected as described for 11a to give 13b and 14b in 81 and 88% yield,
resp.
Data of 13b:White solid powder. M.p. 243 8. UV (MeOH):279.5 (12400). 1H-NMR ((D6)DMSO):8.45
(br. s, 1 H, NH2); 8.29 (s, HÀC(5)); 8.11 (br. s, 1 H, NH2); 5.93 (m, HÀC(4')); 5.26 (s, 1 H, ˆCH2); 4.95 (m, 2 H,
ˆCH2, ÀOH); 4.51 (br. s, HÀC(2')); 4.38 (dd, J ˆ 9.4, 5.4, HaÀC(5')); 4.25 (dd, J ˆ 9.4, 8.2, HbÀC(5')); 3.74
(m, 1 H, CH2); 3.59 (m, 1 H, CH2). 13C-NMR ((D6)DMSO):156.7 (C(7)); 156.2 (C(5)); 148.6 (C(3a)); 147.1
(C(3')); 123.9 (C(7a)); 110.4 (ˆCH2); 81.5 (C(2')); 68.9 (C(5')); 63.4 (CH2); 59.6 (C(4')). HR-FAB-MS:
‡
‡
271.0902 (C10H12N6NaO2 , [M ‡ Na] ; calc. 271.0919).
Data of 14b:White powder. M.p. 201 8. UV (MeOH):295.3 (10900). 1H-NMR (CD3OD):8.28 ( s, HÀC(5));
5.93 (m, HÀC(4')); 5.41 (d, J ˆ 4.5, ˆCH2); 4.65 (dd, J ˆ 10.3, 3.3, HaÀC(5')); 4.58 (m, HÀC(2')); 4.33 (dd, J ˆ
10.3, 6.3, HbÀC(5')); 3.82 (dd, J ˆ 11.7, 6.7, 1 H, CH2); 3.73 (dd, J ˆ 11.7, 4.1, CH2). 13C-NMR (CD3OD):158.7
(C(7)); 158.6 (C(3a)); 157.7 (C(5)); 147.6 (C(3')); 127.1 (C(7a)); 113.6 (ˆCH2); 83.2 (C(2')); 72.1 (C(5')); 70.6
‡
‡
(C(4')); 65.1 (CH2). HR-FAB-MS:271.0919 (C 10H12N6NaO2 , [M ‡ Na] , calc. 271.0919).
3-Benzoyl-1-{(3S,5S)-5-{{[(tert-butyl)diphenylsilyl]oxy}methyl}tetrahydro-4-methylidenefuran-3-yl}-5-methyl
pyrimidine-2,4(1H,3H)-dione (15a). To a soln. of Ph3P (0.3 g, 0.92 mmol) in anh. THF (10 ml), DEAD (0.17 ml,
1.1 mmol) was added. The mixture was stirred at 08 for 30 min and then cooled to À458. To this soln., N3-
benzoylthymine (0.21 g, 0.92 mmol) and 10b (0.17 g, 0.46 mmol) in THF (10 ml) were added within 1 h. The
mixture was stirred overnight at À458. The soln. was directly adsorbed on silica gel and purified by CC: 15a
(0.08 g, 30%). Low-melting solid. 1H-NMR (CD3OD):7.92 ± 7.25 ( m, HÀC(6), 3 Ph); 5.66 (br. s, HÀC(3'));
5.34 (d, J ˆ 13.6, ˆCH2); 4.47 (br. s, HÀC(5')); 4.14 (dd, J ˆ 10.2, 6.8, 1 H); 4.04 (dd, J ˆ 11.0, 3.7, 2 H); 3.94
(dd, J ˆ 11.3, 4.5, 1 H); 1.64 (s, Me); 1.10 (s, Me3C). 13C-NMR (CDCl3):168.9 (C ˆO); 162.5 (C(4)); 150.3
(C(2)); 146.3 (C(4')); 136.8 (C(6)); 112.1 (ˆCH2); 111.6 (C(5)); 81.1 (C(5')); 71.1 (C(2')); 65.4 (CH2); 57.3
‡
‡
(C(3')); 26.9 (Me3C); 19.3 (Me3C); 12.2 (Me). HR-FAB-MS:603.2305 (C 34H36N2NaO5Si , [M ‡ Na] ; calc.
603.2291).
5-Methyl-1-[(3S,5S)-tetrahydro-5-(hydroxymethyl)-4-methylidenefuran-3-yl]pyrimidine-2,4(1H,3H)-dione (16a).
To a soln. of 15a (0.07 g, 0.13 mmol) in MeOH (10 ml), NH4F (0.065 g, 2 mmol) was added, and the soln. was

Helvetica Chimica Acta ± Vol. 83 (2000)
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heated under reflux for 3 h. The soln. was cooled to r.t., adsorbed on silica gel, and purified by CC to give the
N(3)-benzoylated derivative, which was dissolved in MeOH (5 ml) and treated with NaOMe (0.03 g). The
mixture was stirred at r.t. for 8 h, neutralized with 10% AcOH/H2O, and evaporated. The residue was taken up
in MeOH, adsorbed on silica gel, and purified by CC: 16a (0.018 g, 62% for two steps). Hygroscopic foam. UV
(MeOH):270.9 (9400). 1H-NMR ((D6)acetone):10.14 (br. s, NH); 7.62 (s, HÀC(6)); 5.56 (m, HÀC(3')); 5.36
(t, J ˆ 2.1, 1 H, ˆCH2); 5.30 (t, J ˆ 2.3, 1 H, ˆCH2); 4.40 (br. s, HÀC(5')); 4.18 ± 3.84 (m, HÀC(2'), HÀC(3),
CH2); 1.76 (s, Me). 13C-NMR (CD3OD):166.3 (C(4)); 153.2 (C(2)); 148.5 (C(4 ')); 140.3 (C(6)); 112.2 (ˆCH2);
111.6 (C(5)); 82.8 (C(5')); 72.2 (C(2')); 638 (CH2); 58.9 (C(3')); 12.3 (Me). HR-FAB-MS:261.0855
‡
‡
(C11H14N2NaO4 , [M ‡ Na] ; calc. 261.0851).
1-[(3S,5S)-Tetrahydro-5-(hydroxymethyl)-4-methylidenefuran-3-yl]pyrimidine-2,4(1H,3H)-dione (16b). To a
soln. of Ph3P (0.84 g, 3.18 mmol) in anh. THF, DEAD (0.49 ml, 3.12 mmol) was added. The mixture was then
stirred at 08 for 30 min and cooled to À708. A suspension of 3-benzoyluracil (0.54 g, 3.12 mmol) and 10b (0.46 g,
1.25 mmol) was added to the soln. within 30 min. The mixture was stirred overnight at À408 and then quenched
with H2O (1 ml) and evaporated. The gummy residue was purified by CC. The product was dissolved in MeOH
(40 ml), NH4F (0.5 g) added, and the resulting soln. heated under reflux for 3 h. The soln. was directly adsorbed
on silica gel and purified by CC: 16b (0.16 g, 57%). White solid. M.p. 1788. UV (MeOH):266.6 (11800).
1H-NMR (CD3OD):7.80 ( d, J ˆ 8.1, HÀC(6)); 5.64 (d, J ˆ 8.1, HÀC(5)); 5.57 (m, HÀC(3')); 5.35 (m, ˆCH2);
4.82 (br. s, HÀC(5')); 4.07 (dd, J ˆ 10.3, 6.5, HaÀC(2')); 4.00 (dd, J ˆ 10.2, 3.6, HbÀC(2')); 3.90 (dd, J ˆ 12.3, 2.9,
1 H, CH2); 3.80 (dd, J ˆ 12.3, 4.2, 1 H, CH2). 13C-NMR (CD3OD):166.2 (C(4)); 153.2 (C(2)); 148.5 (C(4 '));
144.6 (HÀC(6)); 112.5 (ˆCH2); 102.7 (C(5)); 82.9 (C(5')); 72.3 (C(2')); 63.9 (CH2); 59.3 (C(3')). HR-FAB-MS:
‡
‡
247.0703 (C10H12N2NaO4 , [M ‡ Na] ; calc. 247.0694).
4-Amino-1-[(3S,5S)-tetrahydro-5-(hydroxymethyl)-4-methylidenefuran-3-yl]pyrimidin-2(1H)-one (17). Ac2O
(0.25 ml, 2.65 mmol) was added to a soln. of 16b (0.12 g, 0.53 mmol) in pyridine (10 ml) at r.t. After the addition,
the mixture was stirred at r.t. overnight and then quenched with H2O (1 ml). The solvent was evaporated and the
conc. soln. co-evaporated with toluene. The residue was purified by CC to give the acetylated derivative (0.13 g,
92%) as pale yellow foamy solid. Et3N (0.1 ml) was added to a soln. of the acetylated derivative (0.09 g,
0.33 mmol) in MeCN (10 ml) containing 2,4,6-iPr3C6H2SO2Cl (0.23 g, 0.75 mmol) and 4-(dimethylamino)pyr-
idine (0.092 g, 0.75 mmol) at 08. The mixture was stirred at r.t. for 4 h. NH4OH soln. (28%, 6 ml) was added, and
the soln. was stirred at r.t. for 24 h. After evaporation, the residue was purified by CC: 17 (0.035 g, 47% in two
steps). Hygroscopic solid. UV (MeOH):276.4 (8650). 1H-NMR (CD3OD):7.80 ( d, J ˆ 7.4, HÀC(6)); 5.83
(d, J ˆ 7.5, HÀC(5)); 5.63 (m, HÀC(3')); 5.35 (t, J ˆ 2.1, 1 H, ˆCH2); 5.30 (t, J ˆ 2.2, 1 H, ˆCH2); 4.40 (br. s,
HÀC(5')); 4.08 (dd, J ˆ 10.1, 6.5, HaÀC(2')); 3.96 (dd, J ˆ 10.1, 3.6, HbÀC(2')); 3.90 (dd, J ˆ 12.3, 3.0, 1 H, CH2);
3.81 (dd, J ˆ 12.3, 4.2, 1 H, CH2). 13C-NMR (CD3OD):167.4 (C(2)); 159.2 (C(4)); 149.0 (C(4 ')); 144.8 (C(6));
112.2 (ˆCH2); 96.1 (C(5)); 83.1 (C(5')); 72.9 (C(2')); 63.9 (CH2); 60.3 (C(3')). HR-FAB-MS:224.1040
‡
‡
(C10H14N3O3 , [M ‡ H] ; calc. 224.1035).
2-{(3S,5S)-5-{{[(tert-Butyl)diphenylsilyl]oxy}methyl}tetrahydro-4-methylidenefuran-3-yl}-1H-isoindol-1,3(2H)-
dione (19). To a soln. of 10b (1.1 g, 3 mmol) in CH2Cl2 (30 ml), Et3N (1.7 ml, 12 mmol) and MsCl (0.7 ml,
9 mmol) were added at 08. After the addition, the mixture was stirred at 08 for 3 h. H2O (75 ml) was added and
extracted with CH2Cl2 (3 Â 30 ml). The combined CH2Cl2 part was washed with H2O, dried (Na2SO4), and
evaporated. The oily residue was purified by CC: 18 (1.11 g, 83%). Pale yellow low-melting solid. 1H-NMR
(CDCl3):7.70 ( m, 4 H, Ph); 7.42 (m, 6 H, Ph); 5.64 (s, 1 H, ˆCH2); 5.51 (m, HÀC(3)); 5.33 (s, 1 H, ˆCH2); 4.65
(br. s, HÀC(5)); 4.18 (dd, J ˆ 10.6, 4.8, HaÀC(2)); 4.06 (dd, J ˆ 10.6, 2.8, HbÀC(2)); 3.82 (dd, J ˆ 11.0, 3.7, 1 H,
CH2); 3.71 (dd, J ˆ 11.0, 4.6, 1 H, CH2); 3.04 (s, Me); 1.06 (s, Me3C). 13C-NMR (CDCl3):145.4 (C(4)); 114.3
(ˆCH2); 80.9, 80.2 (C(3), C(5)); 72.1 (C(2)); 66.3 (CH2); 39.2 (Me); 26.9 (Me3C); 19.3 (Me3C).
To a soln. of 18 (0.3 g, 0.67 mmol) in DMF (30 ml), potassium phthalimide (0.74 g, 4 mmol) was added, and
the mixture was heated at 1108 overnight. The soln. was cooled and filtered, and the filtrate was evaporated. The
residue was taken up in AcOEt (80 ml) and washed with H2O (2 Â 50 ml). The AcOEt part was dried (Na2SO4),
evaporated, and purified by CC: 19 (0.17 g, 51%). Low-melting solid. 1H-NMR (CDCl3):7.84 ± 7.30
(m, 14 arom. H); 5.34 (m, HÀC(3')); 5.03 (t, J ˆ 2.2, 1 H, ˆCH2); 4.87 (t, J ˆ 2.4, 1 H, ˆCH2); 4.70
(m, HÀC(5')); 4.15 (dd, J ˆ 11, 7.8, 1 H, CH2); 4.04 (d, J ˆ 8.7, 2 HÀC(2')); 3.86 (dd, J ˆ 11.1, 4.6, 1 H, CH2);
1.11 (s, Me3C). 13C-NMR (CDCl3):167.1 (C ˆO); 145.8 (C(4')); 135.7, 135.6, 134.1, 133.8, 133.5, 131.7, 129.5,
127.6, 123.3 (arom. C); 107.0 (ˆCH2); 81.8 (C(5')); 66.0, 65.9 (C(2'), CH2); 51.9 (C(3')); 26.8 (Me3C); 19.2
‡
‡
(Me3C). HR-FAB-MS:520.1930 (C 30H31NNaO4Si , [M ‡ Na] ; calc. 520.1920).
(3S,5S)-5-{{[(tert-Butyl)diphenylsilyl]oxy}methyl}tetrahydro-4-methylidenefuran-3-amine (20). To a soln.
of 19 (0.16 g, 0.32 mmol) in EtOH (20 ml), hydrazine hydrate (0.12 g) was added, and the mixture was heated
under reflux for 3 h and then allowed to cool to r.t. The white precipitate was filtered and washed with EtOH.

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Helvetica Chimica Acta ± Vol. 83 (2000)
The combined EtOH part was evaporated and the residue purified by CC: 20 (0.09 g, 77%). 1H-NMR (CDCl3):
7.71 ± 7.25 (m, 2 Ph); 5.29 (br. s, 1 H, ˆCH2); 4.48 (m, HÀC(5)); 3.99 ± 3.64 (m, 2 HÀC(2), HÀC(3), CH2); 1.06
(s, Me3C). 13C-NMR (CDCl3):153.3 (C(4)); 135.6, 133.3, 133.2, 129.6, 127.6 (Ph); 106.2 ( ˆCH2); 81.0 (C(5));
‡
74.4 (C(2)); 66.4 (CH2); 55.5 (C(3)); 26.8 (Me3C); 19.1 (Me3C). HR-FAB-MS:390.1870 (C 22H29NNaO2Si ,
‡
[M ‡ Na] ; calc. 390.1865).
5-Methyl-1-[(3S,5S)-tetrahydro-5-(hydroxymethyl)-4-methylidenefuran-3-yl}pyrimidine-2,4(1H,3H)-dione
(16a). A soln. of 3-methoxy-2-methylprop-2-enoyl isocyanate (prepared by heating the corresponding acid
chloride (0.11 g, 0.8 mmol) and silver cyanate (0.22 g) in toluene for 0.5 h) was added dropwise to a soln. of 20
(0.09 g, 0.25 mmol) in DMF (10 ml) and Et2O (5 ml) at À108. After the addition, the mixture was allowed to
warm to r.t. and stirred for 16 h. The volatile materials were evaporated. EtOH was added to the residue with
stirring and then evaporated. The gummy residue was purified by CC to give the acryloylurea derivative 21. This
compound was dissolved in dioxane (5 ml) and heated at 1008 for 4 h with 2n H2SO4 (1.0 ml). The mixture was
allowed to cool to r.t. and then neutralized with 2n aq. NaOH and evaporated. The residue was purified by CC:
16a (0.04 g, 50% in two steps), identical to the compound prepared by direct coupling and deprotection (see
above).
Single-Crystal X-Ray Structure Determination of Compounds 13a and 14a. A colorless prismatic crystal
(0.21 Â 0.24 Â 0.36 mm and 0.25 Â 0.25 Â 0.31 mm, resp.) was isolated from the sample and mounted with grease
on the tip of a glass capillary epoxied to a brass pin and placed on the diffractometer with the long crystal
dimension (a-axis and AB dimension, resp.) approximately parallel to the diffractometer f-axis. Data were
collected on an Enraf-Nonius-CAD4 diffractometer (MoKa radiation, graphite monochromator) at 200 K (cold
N2 gas cooling) using q-2q scans. Intensity standards were measured at 2 h intervals. Net intensities were
obtained by profile analysis of the 4469 and 5428 data, resp. Lorentz and polarization corrections were applied.
No change in the intensity standards was detected. Absorption was minimal and no correction was applied.
Equivalent data were averaged yielding 2018 unique data (R-int ˆ 0.023, 1926 > 4 s (F)) in the case of 13a and
3817 unique data (R-int ˆ 0.072, 3042 > 4s(F)) in the case of 14a. Based on preliminary examination of the data,
the space group P2(1)2(1)2(1) was assigned to 13a and P2(1) to 14a. The computer programs from the MoLEN
package were used for data reduction. The preliminary model of the structure was obtained with XS, a direct-
methods program. Least-squares refining of the model vs. the data was performed with the XL computer
program. Illustrations were made with the XP program, and tables were made with the XCIF program. All are in
the SHELXTL v5.0 package. Thermal ellipsoids are drawn at the 35% level unless otherwise noted. All non-H-
atoms were refined with anisotropic thermal parameters. All H-atoms were included with a riding model based
on default values. In the case of 14a, there are two independent molecules in the asymmetric unit. Each forms a
dimer via two H-bonds with a symmetry-equivalent molecule of the other (i.e., molecule A dimerizes with
molecule B, and vice versa). The two molecules differ in conformation mainly at the sugar CH2OH group.
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Received March 1, 2000