Synthesis, structure, and conformation of 2′,3′-fused oxathiane and thiomorpholine uridines

Article abstract of DOI:10.1002/hlca.200790199

The syntheses of two 2′,3′-fused bicyclic nucleoside analogues, i.e., 1-[4aR,5R,7R,7aS)-hexahydro-S-(hydroxymethyl)-4,4-dioxidofuro[3,4-b][1,4] oxathiin-7-yl]pyrimidine-2,4(1H,3H)-dione (1a) and 1-[(4aS,5R,7R,7aS)-hexahydro- 7-(hydroxymethyl)-1,1-dioxido-

Full text of DOI:10.1002/hlca.200790199

Helvetica Chimica Acta – Vol. 90 (2007)
1917
Synthesis, Structure, and Conformation of 2’,3’-Fused Oxathiane and
Thiomorpholine Uridines
by Jingbo Sun, Jinchang Wu*, and Hua Yang
Chemistry College, Jilin University, Changchun 130012, P. R. China
(phone: þ 86-0-135-1102-1737; fax: þ 86-431-8519-5516; e-mail:jcwu@jlu.edu.cn)
The syntheses of two 2’,3’-fused bicyclic nucleoside analogues, i.e., 1-[(4aR,5R,7R,7aS)-hexahydro-5-
(hydroxymethyl)-4,4-dioxidofuro[3,4-b][1,4]oxathiin-7-yl]pyrimidine-2,4(1H,3H)-dione (1a) and 1-
[(4aS,5R,7R,7aS)-hexahydro-7-(hydroxymethyl)-1,1-dioxido-2H-furo[3,4-b][1,4]thiazin-5-yl]pyrimidine-
2,4(1H,3H)-dione (1b), are described, the key step being an intramolecular hetero-Michael addition.
Their structures and conformations, previously solved by X-ray crystallography, were analyzed in more
detail, using 1D- and 2D-NMR as well as HR-MS analyses.
Introduction. – 2’,3’-Dideoxy nucleosides, including, e.g., 3’-azido-3’-deoxythymi-
dine (AZT; zidovudine) [1], 2’,3’-dideoxycytidine (ddC, zalcitabine) [2], 2’,3’-dideoxy-
inosine (ddI, didanosine) [3], and 2’,3’-didehydro-2’,3’-dideoxythymidine (d4T,
stavudine) [4], are an important class of antiviral drugs. The mechanism of action of
these nucleosides requires their conversion by host cellular kinases into the
corresponding triphosphate forms, which then serve as competitive inhibitors for
HIV reverse transcriptase and/or as chain terminators due to the lack of a 3’-OH
functionality for viral cDNA synthesis [5]. Therefore, a highly potent and selective
nucleoside drug candidate should be structurally adaptable to the active sites of both
the kinases and the reverse transcriptase, but display minimum affinity to cellular
polymerases.
It is known that ribonucleosides predominantly exist in the N-type (C(3’)-endo)
sugar conformation, while deoxyribonucleosides have S-type (C(3’)-exo) puckering
(Scheme 1) [6]. A large number of 2’,3’-modified nucleosides have been synthesized
and evaluated for their biological activities, revealing that the conformational
equilibrium of the sugar moiety is a key factor in terms of biological effects [7]. 2’,3’-
Fused bicyclic nucleosides as conformationally restricted sugar-ring analogues have
Scheme 1
ꢀ 2007 Verlag Helvetica Chimica Acta AG, Zürich

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Helvetica Chimica Acta – Vol. 90 (2007)
been used to probe the conformational requirement of the key enzymes to maximize
the therapeutic index of nucleoside-based antiviral agents [7][8].
In our research on the structure – activity relationship of sugar-modified nucleo-
sides, we decided to synthesize and investigate the S,S-dioxo-1,4-oxathiane- and S,S-
dioxothiomorpholine-fused nucleosides 1a and 1b, respectively. In these compounds,
the 5’-OH group and the nucleobase are intact for phosphorylation and recognition,
respectively. The conformation of the nucleoside moiety should be restricted by fusion
at the 2’- and 3’-positions of the furanose ring, especially in the case of an additional six-
membered ring (in chair conformation), which could result in a proper balance
between the rigidity and flexibility of the sugar puckering. Compound 1b, with an
amino group linked to the 2’-position of the furanose moiety, would be an interesting
building block for the synthesis and evaluation of conformationally restricted 2’,5’-
linked oligonucleotides in antisense therapy [9].
Many methods have been applied for the synthesis of bicyclic nucleosides such as
intramolecular nucleophilic substitution [10], ring-closing metathesis [11], 1,3-dipolar
addition [12], aldol reaction [13], or Michael addition. This latter method (Michael
addition) has been developed by Chattopadhyaya et al. as a powerful means for the
synthesis of a large variety of modified nucleosides, including bicyclic nucleosides [14].
Recently, Pathak et al. [15] reported the synthesis of 1,4-thiazinane (thiomorpholine)-
fused uridine derivatives in 2’,3’-position via Michael addition of amines to bisvinyl-
sulfonyl uridine. Intramolecular Michael addition has been employed to construct
cyclic structures of natural and synthetic compounds, but no such application has been
elaborated in the field of nucleoside chemistry [16].
Herein we report the synthesis and conformational properties of the uridine target
compounds 1 prepared via intramolecular hetero-Michael addition to olefinic sulfones.
Results and Discussion. – The synthesis of 1a is outlined in Scheme 2 (series a).
Thus, ꢁ2’,3’-O-anhydro-5’-O-trityl-lyxo-uridineꢂ (2) [17] was reacted with 2-{[tert-
butyl(dimethyl)silyl]oxy}ethane-1-thiol (TBSOCH2CH2SH) in the presence of 1,1,3,3-
tetramethylguanidine (TMG) to generate a mixture of the substituted xylo- and
arabino-configured uridines 3a and 4a, respectively, which were separated chromato-
graphically to afford the pure compounds in 26 and 57% yield1). Next, oxidation of the
sulfide 4a with ꢁmeta-chloroperpenzoic acidꢂ (MCPBA) in the presence of 10%
NaHCO3 as buffer afforded the corresponding sulfone 5a. Subsequently, elimination of
the 2’-OH group was effected by mesylation and, after workup, heating at 408 in
pyridine, which resulted in the desired vinylsulfonyl uridine 6a in 62% yield (over two
1
)
When the OH group of 2-mercaptoethanol was not protected, the regioisomeric products from the
ring opening of the epoxide 2 could not be separated [14].

Helvetica Chimica Acta – Vol. 90 (2007)
1919
Scheme 2
a) For series a:TBSOCH 2CH2SH, DMF, 1,1,3,3-tetramethylguanidine (TMG), 408, 5 h; 26% of 3a, 57%
of 4a; for series b:BocNHCH 2CH2SH, DMF, TMG, 408, 5 h; 23% of 3b, 52% of 4b. b) MCPBA, 10%
aq. NaHCO3, CH2Cl2, 08, 2 h; 84% of 5a, 87% of 5b. c) 1. MsCl, pyridine, 08, 6 h; 2. pyridine, 408, 3 h;
62% of 6a, 66% of 6b (two steps). d) For 8a:TBAF, THF, r.t., 1 h; 89%; for series b:20% TFA in
CH2Cl2, r.t., 4 h. e) For 1b: K2CO3, MeOH, r.t., 3 h; 64% (two steps). f) 80% AcOH, r.t., 3 h; 67%.
steps). Deprotection of the TBS group by treatment with Bu4NþFÀ (TBAF) in THF led
to compound 7a, which underwent in situ cyclization via intramolecular Michael
addition to afford directly 8a. Finally, detritylation with 80% aqueous AcOH provided
the bicyclic target nucleoside 1a in 67% yield.
The synthesis of 1b was performed similarly (Scheme 2, series b). Thus, 2 was
attacked by BocNHCH2CH2SH in the presence of TMG to afford 3b and 4b in 23 and
52% yield, respectively. Compound 4b was oxidized with MCPBA to give the sulfone
5b, which was mesylated and eliminated to afford the vinylsulfonyl uridine 6b. The tert-
butoxycarbonyl (Boc) and triphenylmethyl (trityl; Tr) protecting groups were then
removed simultaneously by treatment with 20% CF3COOH (TFA) in CH2Cl2 to afford
the crude product 7b, which was cyclized in the presence of K2CO3 to afford 1b in 64%
yield (over two steps).
1
The structures of 1a and 1b were determined by H- and 13C-NMR as well as by
HR-ESI-MS studies (see Exper. Part), which confirmed the previously reported single-

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Helvetica Chimica Acta – Vol. 90 (2007)
crystal X-ray-diffraction analyses [18]. The configuration of the six-membered, fused
rings were determined by 1D- and 2D-NMR experiments. Based on the NOESY cross-
peaks shown in the Figure, the two rings in 1 are cis-fused and in a-position. Further, as
previously reported, both bicyclic nucleoside analogues adopt the 4’-exo,3’-endo
conformation [18]. Selected torsion angles and other conformational parameters of the
sugar moiety are presented in the Table, based on the X-ray results [18].
Figure. Selected NOE correlations for compounds 1a and 1b
Table. Selected Conformational Parameters Determined from the X-Ray Structures of 1a and 1ba) [18].
All values in degrees (8).
Parameter
1a
1b
C(4’)ÀOÀC(1’)ÀC(2’)
OÀC(1’)ÀC(2’)ÀC(3’)
C(1’)ÀC(2’)ÀC(3’)ÀC(4’)
C(2’)ÀC(3’)ÀC(4’)ÀO
C(3’)ÀC(4’)ÀOÀC(1’)
C(3’)ÀC(4’)ÀC(5’)ÀO
OÀC(3’)ÀC(4’)ÀC(5’)
OÀC(1’)ÀN(1)ÀC(2)
À 6.1(3)
27.8(2)
38.0(2)
À 4.4(3)
28.0(3)
39.9(2)
À 35.3(2)
À 38.2(2)
18.5(3)
21.5(3)
À 169.8(2)
82.3(2)
51.9(4)
77.6(3)
À 163.2(1)
À 160.2(2)
Pb)
36.8(2)
36.9(2)
c
nm
)
47.5(3)
49.9(3)
a) The crystallographic data of 1a and 1b have been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication numbers CCDC-636232 and -636249, resp. Copies of the data can be
obtained, free of charge, at http://www.ccdc.cam.ac.uk/data_request/cif. b) Pseudorotational phase angle.
c) Puckering amplitude.
In conclusion, we have demonstrated that the intramolecular Michael addition of
vinylsulfonyl nucleosides is a versatile method for the construction of 2’,3’-fused
bicyclic nucleosides. The two target nucleosides 1a and 1b adopt the 4’-exo,3’-endo
conformation, which shows, to some extent, a deviation from the classical N- or S-type
conformations found in the majority of nucleosides in the solid state. The antiviral
activities of the two novel compounds are currently investigated and will be reported
elsewhere.

Helvetica Chimica Acta – Vol. 90 (2007)
1921
Experimental Part
General. All reactions were carried out under N2 atmosphere. CH2Cl2 was dried over anh. CaCl2.
Compound 2 was prepared as described in [17]. All other reagents were commercially available and used
as received. Melting points (m.p.) are uncorrected. Anal. TLC was performed with silica gel GF 254
(0.25 cm) plates. Column chromatography (CC) was performed on silica gel G (200 – 300 mesh; Qingdao
1
Haiyang Chemical Co., China). H- and 13C-NMR (1H-decoupled) Spectra2) were recorded at 300 and
75 MHz, resp., in CDCl3 or (D6)DMSO; chemical shifts d in ppm rel. to Me4Si, coupling constants J in
Hz. High-resolution mass spectrometry (HR-MS) was carried out on an IonSpec 7.0 T Actively Shielded
FT Ion-Cyclotron-Resonance mass spectrometer equipped with an electrospray-ionization (ESI) source.
Other mass spectra were recorded on an Applied Biosystems ABI Q-Trap mass spectrometer equipped
with an atmospheric-pressure chemical-ionization (APCI) source.
1-[2-S-(2-{[(1,1-Dimethylethyl)dimethylsilyl]oxy}ethyl)-2-thio-5-O-(triphenylmethyl)-b-d-xylofura-
nosyl]pyrimidine-2,4(1H,3H)-dione (3a) and 1-[3-S-[2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]ethyl]-3-
thio-5-O-(triphenylmethyl)-b-d-arabinofuranosyl]pyrimidine-2,4(1H,3H)-dione (4a). A mixture of 2-
{[(tert-butyl(dimethyl)silyl]oxy}ethane-1-thiol (TBSOCH2CH2OH; 17.3 g, 0.09 mol), 1,1,3,3-tetrame-
thylguanidine (TMG; 22.6 ml, 0.18 mol), and 2 (14.6 g, 0.03 mol) in anh. DMF (150 ml) was heated to
45 – 508 for 5 h. The mixture was cooled to r.t., poured on cold sat. aq. NH4Cl soln. (300 ml), and
extracted with AcOEt (3 Â 200 ml). The combined org. phase was washed with brine (2 Â 300 ml), dried
(Na2SO4) , filtered, and concentrated. The residue was purified by CC (SiO2; 0 ! 5% MeOH in CH2Cl2)
to afford 3a (5.6 g, 28%) and 4a (8.2 g, 41%).
Data of 3a. M.p. 96 – 1008. 1H-NMR (CDCl3):7.91 ( s, HÀN(3)); 7.72 (d, J ¼ 8.1, HÀC(6)); 7.49 – 7.20
(m, 15 arom. H); 6.01 (s, HÀC(1’)); 5.52 (d, J ¼ 8.1, HÀC(5)); 4.44 (s, HÀC(3’)); 4.20 (s, 3’-OH); 3.84 (t,
J ¼ 6.0, CH2(6’)); 3.58 – 3.54 (m, HÀC(4’)); 3.41 – 3.36 (m, HÀC(4’)); 2.90 – 2.87 (m, CH2(5’)), CH2(7)’));
0.88 (s, t-Bu)); 0.06 (s, Me2Si). 13C-NMR (CDCl3):163.97; 162.49; 150.25; 143.30; 141.19; 128.46; 127.72;
126.98; 100.98; 91.45; 87.03; 82.74; 75.95; 62.71; 62.13; 56.24; 36.31; 34.24; 31.26; 25.72; 18.12; À 5.48.
APCI-MS:659.5 ([ M À H]À), C36H43N2O6SSiÀ; calc. 659.26).
Data of 4a. M.p. 99 – 1038. 1H-NMR (CDCl3):8.09 ( d, J ¼ 8.1, HÀC(6)); 7.43 – 7.25 (m, 15 arom. H);
6.15 (d, J ¼ 5.7, HÀC(1’)); 5.34 (d, J ¼ 8.1, HÀC(5)); 4.49 (m, HÀC(2’)); 3.84 (s, 2’-OH); 3.82 – 3.76 (m,
CH2(6’), HÀC(4’)); 3.59 – 3.44 (m, CH2(5’), HÀC(3’)); 2.88 – 2.68 (m, CH2(7’)); 0.88 (s, t-Bu)); 0.06 (s,
Me2Si). 13C-NMR (CDCl3):164.00; 151.24; 143.35; 141.78; 128.94; 128.30; 127.69; 101.68; 87.79; 85.34;
81.72; 78.53; 63.76; 61.69; 48.05; 34.42; 26.18; 18.62; À 5.2. APCI-MS:659.5 ([ M À H]À),
C36H43N2O6SSiÀ; calc. 659.26).
1-[2-S-(2-{[(1,1-Dimethylethoxy)carbonyl]amino}ethyl)-2-thio-5-O-(triphenylmethyl)-b-d-xylofura-
nosyl]pyrimidine-2,4(1H,3H)-dione (3b) and 1-[3-S-(2-{[(1,1-Dimethylethoxy)carbonyl]amino}ethyl)-3-
thio-5-O-(triphenylmethyl)-b-d-arabinofuranosyl]pyrimidine-2,4(1H,3H)-dione (4b). A mixture of tert-
butyl 2-mercaptoethylcarbamate (15.5 g, 0.09 mol), TMG (22.6 ml, 0.18 mol), and 2 (14.6 g, 0.03 mol) in
anh. DMF (150 ml) was heated at 35 – 408 for 3 h. The mixture was cooled to r.t., poured on cold sat. aq.
NH4Cl soln. (300 ml), and extracted with AcOEt (3 Â 200 ml). The combined org. layers were washed
with brine (2 Â 300 ml), dried (Na2SO4), filtered, and concentrated. The residue was purified by CC
(SiO2; 0 ! 5% MeOH in CH2Cl2) to afford 3b (4.8 g, 25%) and 4b (5.1 g, 26%).
Data of 3b. M.p. 109 – 1118. 1H-NMR (CDCl3):7.68 ( d, J ¼ 8.1, HÀC(6)); 7.48 – 7.23 (m, 15 arom. H);
5.97 (s, HÀC(1’)); 5.45 (d, J ¼ 8.1, HÀC(5)); 5.14 – 5.12 (m, HÀC(3’)); 4.42 (s, 3’-OH); 4.19 (s,
HÀC(2’)); 6.38 – 3.62 (m, HÀC(4’)); 3.48 – 3.38 (m, CH2(6’)); 2.96 – 2.99 (m, HaÀC(5’)); 2.79 – 2.72 (m,
HbÀC(5’)); 1.98 – 1.80 (m, CH2(7’)); 1.42 (s, t-Bu)). 13C-NMR (CDCl3):163.9; 156.2; 150.4; 143.4; 141.1;
128.7; 128.0; 127.3; 109.8; 100.9; 91.7; 87.4; 83.1; 79.8; 76.2; 62.2; 55.5; 39.6; 31.8; 29.7; 28.4. APCI-MS:
644.5 ([M À H]À), C36H40N2O7SÀ; calc. 644.26).
Data of 4b. M.p. 112 – 1158. 1H-NMR (CDCl3):10.25 ( s, HÀN(3)); 8.14 (d, J ¼ 8.1, HÀC(6)); 7.41 –
7.30 (m, 15 arom. H); 6.17 (s, HÀC(1’)); 5.36 (d, J ¼ 8.1, HÀC(5)); 5.11 (s, 3’-OH); 4.53 (s, HÀC(2’)));
3.80 (d, J ¼ 9.3, HÀC(3’)) 3.61 – 3.31 (m, HÀC(4’)), CH2(5’), CH2(6’)); 2.75 – 2.64 (m, CH2(7’)); 1.40 (s, t-
2
)
Arbitrary atom numbering (see Figure).

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Helvetica Chimica Acta – Vol. 90 (2007)
Bu). 13C-NMR (CDCl3):164.26; 155.94; 143.00; 141.84; 128.60; 127.93; 127.31; 101.44; 87.24; 84.80; 81.20;
78.37; 77.84; 61.28; 46.95; 40.10; 31.95; 28.27. APCI-MS:644.5 ([ M À H]À), C36H40N2O7SÀ; calc. 644.26).
1-{3-Deoxy-3-[(2-{[(1,1-dimethylethyl)dimethylsilyl]oxy}ethyl)sulfonyl]-5-O-(triphenylmethyl)-b-d-
arabinofuranosyl}pyrimidine-2,4(1H,3H)-dione (5a). 10% aq. NaHCO3 (46 ml, 0.05 mmol) was added to
a soln. of 4a (6.61 g, 0.01 mol) in CH2Cl2 (100 ml), and the mixture was cooled to 08. MCPBA (6.09 g,
0.03 mol) was added slowly, and the mixture was stirred in an ice bath for 2 h. Then, cold sat. aq. NaHCO3
soln. (100 ml) and CH2Cl2 (100 ml) were added, the org. layer was separated, washed with brine, dried
(Na2SO4), filtered, and concentrated. The resulting residue was purified by CC (SiO2; 0 ! 8% MeOH in
CH2Cl2). Yield. 5.82 g (84%). M.p. 112 – 1148. 1H-NMR (CDCl3):11.11 (br. s, HÀN(3)); 7.67 (d, J ¼ 8.1,
HÀC(6)); 7.50 – 7.19 (m, 15 arom. H); 6.06 (m, HÀC(1’)); 3.37 (d, J ¼ 8.1, HÀC(5)); 5.11 (s, 2’-OH); 4.85
(m, CH2(6’)); 4.13 (m, HÀC(2’)); 4.15 – 3.86 (m, HÀC(4’), CH2(7’)); 3.51 – 3.43 (m, CH2(5’)); 3.22 (m,
HÀC(3’)); 0.84 (s, t-Bu)); 0.01 (s, Me2Si). 13C-NMR (CDCl3):165.97; 149.99; 143.51; 142.98; 128.69;
127.86; 127.15; 100.47; 87.79; 87.03; 74.53; 70.71; 69.46; 65.43; 57.36; 54.89; 25.81; 18.21; À 5.57. APCI-MS:
691.5 ([M À H]À, C36H43N2O8SSiÀ; calc. 691.25).
1-{(2R,5R)-4-[(2-{[(1,1-Dimethylethyl)dimethylsilyl]oxy}ethyl)sulfonyl]-2,5-dihydro-5-[(triphenyl-
methoxy)methyl]furan-2-yl}pyrimidine-2,4(1H,3H)-dione (6a). Compound 4a (8.31 g, 12 mmol) was
added to anh. pyridine (60 ml), and the soln. was cooled to 08. Then, methanesulfonyl chloride (MsCl;
2.80 ml, 36 mmol) was slowly added, and the mixture was stirred at 08 for 24 h. Then, H2O (4.8 ml) was
added, and the mixture was heated to 40 – 508 for 2 h. Then, the mixture was poured into ice-water
(500 ml), and the precipitate was filtered off, dried, and purified by CC (SiO2; 0 ! 3% MeOH in
1
CH2Cl2). Yield:5.01 g (62%, two steps). M.p. 103 – 107 8. H-NMR (CDCl3):8.63 ( s, HÀN(3)); 7.89 (d,
J ¼ 8.1, HÀC(6)); 7.39 – 7.28 (m, 15 arom. H); 7.09 – 7.07 (m, HÀC(2’)); 6.76 (d, J ¼ 1.8, HÀC(1’)); 5.18 –
5.20 (m, HÀC(4’)); 4.74 – 4.78 (m, HÀC(5)); 3.99 – 4.03 (m, CH2(6’)); 3.77 – 3.71 (m, CH2(7’)); 3.13 – 3.38
(m, CH2(5’)); 0.85 (s, t-Bu); 0.04 (s, Me2Si). 13C-NMR (CDCl3):162.57; 150.04; 147.94; 142.41; 140.89;
136.94; 129.03; 128.01; 127.62; 102.75; 88.33; 87.36; 84.37; 62.67; 58.35; 56.90; 25.78; 18.27; À 5.52. APCI-
MS:673.5 ([ M À H]À, C36H41N2O7SSiÀ; calc. 673.24).
1-{(4aR,5R,7R,7aS)-Hexahydro-4,4-dioxido-5-[(trityloxy)methyl]furo[3,4-b][1,4]oxathiin-7-yl}pyri-
midine-2,4(1H,3H)-dione (8a). Compound 6a (4.5 g, 6.7 mmol) was added to 1m TBAF soln. in THF
(65 ml), and the mixture was stirred at r.t. for 5 h. Then, H2O (60 ml) and AcOEt (50 ml) were added, the
layers were separated, and the aq. phase was re-extracted with AcOEt (3 Â 50 ml). The combined org.
layers were washed with brine (2 Â 50 ml), dried (Na2SO4), filtered, and concentrated. The residue was
purified by CC (SiO2; 0 ! 5% MeOH in CH2Cl2). Yield:3.33 g (89%). M.p. 162 – 166 8. 1H-NMR
(CDCl3):8.41 ( s, HÀN(3)); 8.08 (d, J ¼ 8.1, HÀC(6)); 7.43 – 7.28 (m, 15 arom. H); 5.87 (s, HÀC(1’)); 5.06
(d, J ¼ 8.1, HÀC(5)); 4.63 (d, J ¼ 3.6, HÀC(2’)); 4.55 (d, J ¼ 11.1, HÀC(4’)); 4.34 – 4.37 (m, HaxÀC(6’));
4.15 (d, J ¼ 12.0, HeqÀC(6’)); 3.99 – 3.94 (m, HÀC(3’)); 3.87 (m, HaÀC(5’)); 3.64 (d, J ¼ 11.4, HbÀC(5’));
3.29 – 3.23 (m, HaxÀC(7’)); 3.06 (m, HeqÀC(7’)). 13C-NMR (CDCl3):162.42; 149.71; 142.72; 139.44;
130.91; 128.66; 128.18; 127.61; 102.05; 89.18; 88.20; 83.65; 79.38; 64.94; 60.81; 59.22; 49.74; 19.16. APCI-
MS:559.4 ([ M À H]À), C30H27N2O7SÀ; calc. 559.15).
1-[(4aR,5R,7R,7aS)-Hexahydro-5-(hydroxymethyl)-4,4-dioxidofuro[3,4-b][1,4]oxathiin-7-yl]pyri-
midine-2,4(1H,3H)-dione (1a). Compound 8a (2.0 g, 3.6 mmol) was added to 80% AcOH (40 ml), and
the mixture was stirred at r.t. for 2 h. The solvent was evaporated, and the residue was washed with
AcOEt and CHCl3 to afford the title compound. Yield:0.76 g (67%). Colorless powder. M.p. 303 – 310 8
(dec.). 1H-NMR ((D6)DMSO):11.33 ( s, HÀN(3)); 8.08 (d, J ¼ 8.1, HÀC(6)); 5.72 (s, HÀC(1’)); 5.57 (d,
J ¼ 8.1, HÀC(5)); 5.51 (t, J ¼ 4.5, 5’-OH); 4.68 (d, J ¼ 3.6, HÀC(2’)); 4.61 (d, J ¼ 10.5, HÀC(4’)); 4.34 (d,
J ¼ 12.9, HaxÀC(6’)); 3.91 (t, J ¼ 12.0, HeqÀC(6’)), HaÀC(5’)); 3.73 (m, HÀC(3’), HbÀC(5’)); 3.67 – 3.57
(m, HaxÀC(7’)); 3.31 (d, J ¼ 14.7, HeqÀC(7’)). 13C-NMR ((D6)DMSO):172.02; 163.31; 150.27; 140.17;
101.98; 89.04; 82.56; 79.95; 64.54; 59.38; 58.07; 48.83. HR-ESI-MS:317.04469 ([ M À H]À, C11H13N2O7SÀ;
calc. 317.04435).
1-{3-Deoxy-3-[(2-{[(1,1-dimethylethoxy)carbonyl]amino}ethyl)sulfonyl]-5-O-(triphenylmethyl)-b-
d-arabinofuranosyl}pyrimidine-2,4(1H,3H)-dione (5b). Prepared in analogy to 5a. Yield:3.7 g (87%).
M.p. 128 – 1328. 1H-NMR (CDCl3):7.93 ( d, J ¼ 8.1, HÀN(3)); 7.47 – 7.23 (m, 15 arom. H); 6.11 (d, J ¼ 4.5,
HÀC(1’)); 5.33 (m, HÀC(5), 2’-OH)); 5.11 (s, HÀC(2’)); 4.58 (s, HÀC(3’)); 4.02 – 3.99 (m, HÀC(4’));
3.68 – 3.54 (m, CH2(5’), CH2(6’)); 3.49 – 3.45 (m, CH2(7’)); 1.43 (s, t-Bu)). 13C-NMR (CDCl3):164.89;

Helvetica Chimica Acta – Vol. 90 (2007)
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155.79; 150.60; 143.22; 142.27; 128.69; 128.05; 127.41; 101.27; 87.55; 85.93; 80.16; 74.60; 72.24; 66.04;
63.20; 53.06; 34.02; 29.69; 28.33. APCI-MS:676.4 ([ M À H]À, C35H38N3O9SÀ; calc. 676.23).
1-{(2R,5R)-4-[(2-{[(1,1-Dimethylethoxy)carbonyl]amino}ethyl)sulfonyl]-2,5-dihydro-5-[(triphenyl-
methoxy)methyl]-2-furanyl}pyrimidine-2,4(1H,3H)-dione (6b). Prepared in analogy to 6a. Yield:2.8 g
(66%, two steps). M.p. 91 – 938. 1H-NMR (CDCl3):7.91 ( d, J ¼ 8.1, HÀC(6)); 7.31 – 7.25 (m, 15 arom. H);
7.11 (m, HÀC(2’)); 6.84 (s, HÀC(1’)); 5.16 (d, J ¼ 1.8, HÀC(4’)); 5.08 (s, HÀN(3)); 4.87 (d, J ¼ 8.1,
HÀC(5)); 3.79 – 3.65 (m, CH2(7’)); 3.49 – 3.46 (m, CH2(6’)); 3.35 – 3.32 (m, HaÀC(5’)); 3.10 – 3.03 (m,
HbÀC(5’)); 1.43 (s, t-Bu)). 13C-NMR (CDCl3):163.02; 155.53; 150.29; 146.51; 142.19; 140.72; 138.58;
128.91; 128.05; 127.73; 102.99; 88.31; 87.59; 83.98; 80.30; 62.50; 54.52; 34.11; 28.28. APCI-MS:658.9
([M À H]À), C35H36N3O8SÀ; calc. 658.22).
1-[(4aS,5R,7R,7aS)-Hexahydro-7-(hydroxymethyl)-1,1-dioxido-2H-furo[3,4-b][1,4]thiazin-5-yl]-
pyrimidine-2,4(1H,3H)-dione (1b). To compound 6b (2 g, 3.0 mmol), 20% TFA in CH2Cl2 (40 ml) was
added, and the mixture was stirred at r.t. for 3 h. The solvent was evaporated, the residue was dissolved in
MeOH (50 ml), and K2CO3 (0.83 g, 6.0 mmol) was added. The mixture was stirred at r.t. for 2 h, and then
concentrated in vacuo. The residue was purified by CC (SiO2; 5 ! 10% MeOH in CH2Cl2). Yield:0.61 g
1
(64%, two steps). M.p. 283 – 2878 (dec.). H-NMR ((D6)DMSO):11.35 ( s, HÀN(3)); 7.95 (d, J ¼ 8.1,
HÀC(6)); 5.94 (d, J ¼ 5.7, HÀC(1’)); 5.64 (d, J ¼ 8.1, HÀC(5)); 5.48 (s, 5’-OH)); 4.55 (m, HÀC(4’)); 3.91
(m, HÀC(2’)); 3.80 (d, J ¼ 12.0, HaÀC(5’)); 3.64 (d, J ¼ 12.0, HbÀC(5’)); 3.57 (m, HÀC(3’)); 3.25 – 3.05
(m, CH2(6’)), CH2(7’), 2’-NH). 13C-NMR ((D6)DMSO):163.03; 150.66; 139.99; 101.69; 84.20; 76.60;
62.20; 61.74; 59.43; 49.91; 41.12. HR-ESI-MS:316.06107 ([ M – H]À, C11H14N3O6SÀ; calc. 316.06033).
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Received May 30, 2007