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DOI: 10.1055/s-2008-1078265
SO2-Extrusion Reactions of Sulfonylated Nucleosides: A Novel Strategy for the Synthesis of Exocyclic Olefinic Thymidines
Publication History
Publication Date:
21 August 2008 (online)
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Abstract
Analogues of 3′-C-methylidene-2′,3′-dideoxy-5-methyluridine have been synthesized from the 3′-deoxy-3′-sulfonylated derivatives of thymidine using sulfur dioxide extrusion reaction.
Key words
nucleosides - sulfones - olefination - antiviral agents - carbohydrates
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References and Notes
Reactions of 1-(5′-O-benzoyl-3′-C-methyl-2′-deoxy-β-d-threo-pentofuranosy1)thymine with SOCl2 produced 3′-C-methylidene-2′,3′dideoxy-5methyluridine in 11% yield.²a
12Synthesis of Compound 8 Dibromodifluoromethane (1 mL) was dropwise added to a vigorously stirred mixture of the sulfone 6 (0.2 g, 0.33 mmol), alumina-supported KOH (2 g),¹¹ t-BuOH (10 mL) and CH2Cl2 (10 mL) kept at 0 ˚C. The reaction mixture was stirred at r.t. for an additional 1 h after which the solid catalyst was removed by suction filtration through a Celite bed. The filtrate was evaporated to dryness. The filter cake was washed thoroughly with CH2Cl2 and the washes were combined with the residue from the first filtrate. The resultant organic solution was washed with brine and H2O, dried, and evaporated. The residue was purified on silica gel to obtain compound 8 (0.127 g, 71%); EtOAc-PE (1:4) as eluent; white solid; mp 96 ˚C; [α]D ²9.² +44.9 (c 0.13, CHCl3). ¹H NMR (400 MHz, CDCl3): δ = 3.33 (t, J = 9.6 Hz, 1 H), 3.41 (s, 3 H), 3.56-3.59 (m, 1 H), 4.04 (t, J = 9.2 Hz, 1 H), 4.23-4.27 (m, 1 H), 4.59-4.63 (m, 2 H), 4.69 (d, J = 12.0 Hz, 1 H), 4.76-4.88 (m, 3 H), 4.98 (d, J = 10.8 Hz, 1 H), 6.16 (dd, J = 5.4, 16.0 Hz, 1 H), 6.71 (d, J = 16.0 Hz, 1 H), 7.23-7.44 (m, 20 H). ¹³C NMR (100 MHz, CDCl3): δ = 55.3, 71.4, 73.4 (CH2), 75.2 (CH2), 75.9 (CH2), 79.8, 81.7, 82.2, 98.2, 126.3, 126.5, 127.6, 127.7, 127.8, 127.9, 128.0, 128.1, 128.2, 128.3, 128.4, 128.5, 128.6, 133.2, 136.5, 137.9, 138.2, 138.7. HRMS (ES+): m/z calcd for C35H36O5Na: 559.2460 [M + Na+]; found: 559.2454.
14Compound 12a (0.2 g, 0.37 mmol) was converted into compound 13 (0.055 g, 31%) following the procedure described for the synthesis of compound 8.
15Compound 12b (0.2 g, 0.35 mmol) was converted into 14 (0.062 g, 35%) following the procedure described for the synthesis of compound 8.
16
Compound 11c
White
solid; mp 78 ˚C. ¹H NMR (400
MHz, CDCl3): δ = 1.15 (d, J = 6.8 Hz,
3 H), 1.24 (d, J = 6.6
Hz, 3 H), 1.43 (d, J = 1
Hz, 3 H), 2.39-2.56 (m, 2 H), 2.73-2.86 (m, 1
H), 3.35 (dd, J = 3.6,
10.8 Hz, 1 H), 3.57-3.69 (m, 2 H), 3.89-3.96 (m,
1 H), 6.15 (dd, J = 3.6,
6.6 Hz, 1 H), 7.23-7.37 (m, 9 H), 7.41-7.46 (m,
6 H), 7.81 (d, J = 1.2
Hz, 1 H), 8.51 (br s, 1 H). ¹³C NMR
(100 MHz, CDCl3): δ = 11.9, 23.4, 24.0,
35.4, 39.2, 41.6 (CH2), 61.8 (CH2), 84.9,
85.8, 87.1, 110.6, 127.4, 127.9, 128.6, 135.5, 143.2, 150.2, 164.4.
HRMS (ES+): m/z calcd
for C32H34N2O4SNa: 565.2137 [M + Na]+;
found: 565.2112.
Compound 12c
White
solid; mp 102 ˚C. ¹H NMR (400
MHz, CDCl3): δ = 1.25 (d, J = 6.8 Hz,
3 H), 1.31 (d, J = 6.8
Hz, 3 H), 1.53 (s, 3 H), 2.39-2.54 (m, 1 H), 2.90-3.06
(m, 2 H), 3.34 (dd, J = 2.6,
10.9 Hz, 1 H), 3.74 (dd, J = 2.2,
10.9 Hz, 1 H), 4.02-4.09 (m, 1 H), 4.61-4.64 (m,
1 H), 6.24 (t, J = 6.4
Hz, 1 H), 7.14-7.47 (m, 15 H), 7.63 (s, 1 H), 8.63 (s,
1 H). ¹³C NMR (100 MHz, CDCl3): δ = 11.9,
15.0, 15.1, 33.8 (CH2), 52.4, 56.3, 63.5 (CH2),
78.1, 85.3, 87.4, 111.4, 127.5, 128.1, 128.4, 135.2, 142.9, 149.8,
163.4. HRMS (ES+): m/z calcd for
C32H34N2O6SNa: 597.2035 [M + Na]+;
found: 597.2027.
Compound 15
Compound 12c (0.2 g, 0.34 mmol) was converted into compound 15 (0.06 g, 34%) following the
procedure described for the synthesis of compound 8.
Glassy liquid. ¹H NMR (400 MHz, CDCl3): δ = 1.33
(s, 3 H), 1.55 (d, J = 1.3 Hz,
3 H), 1.84 (s, 3 H), 2.77-2.81 (m, 1 H), 3.15-3.23
(m, 2 H), 3.37-3.44 (m, 1 H), 4.73 (br s, 1 H), 6.16 (dd, J = 5.8, 8.7 Hz,
1 H), 7.20-7.34 (m, 9 H), 7.39-7.47 (m, 6 H),
7.86 (d, J = 0.9
Hz, 1 H), 8.88 (br s, 1 H). ¹³C NMR
(100 MHz, CDCl3): δ = 11.6, 19.9, 22.0,
37.0 (CH2), 65.7 (CH2), 79.6, 84.2, 87.2,
110.9, 126.4, 127.2, 127.9, 128.4, 128.6, 136.2, 143.5, 150.4, 163.9.
HRMS (ES+): m/z calcd
for C32H32N2O4Na: 531.2260 [M + Na]+;
found: 531.2237.
Compound 11d
White
solid; mp 82 ˚C. ¹H NMR (400
MHz, CDCl3): δ = 1.39 (s, 3 H), 2.38-2.45
(m, 2 H), 3.28-3.34 (m, 1 H), 3.48-3.56 (m, 2
H), 3.67-3.68 (m, 2 H), 3.93-3.96 (m, 1 H), 6.17 (t, J = 6.4 Hz,
1 H), 7.16-7.43 (m, 20 H), 7.63 (s, 1 H), 8.59 (s, 1 H). ¹³C
NMR (100 MHz, CDCl3): δ = 11.8, 36.1
(CH2), 40.3, 40.5 (CH2), 62.2 (CH2),
84.7, 84.9, 87.2, 110.7, 127.3, 127.9, 128.7, 135.4, 137.3, 143.2,
150.2, 163.8. HRMS (ES+): m/z calcd
for C36H34N2O4SNa: 613.2137 [M + Na]+; found:
613.2134.
Compound 12d
White
solid; mp 106 ˚C. ¹H NMR (400
MHz, CDCl3): δ = 1.34 (s, 3 H), 2.30-2.40
(m, 1 H), 2.86-2.96 (m, 1 H), 3.27 (dd, J = 2.2,
10.8 Hz, 1 H), 3.55-3.60 (m, 1 H), 3.85-3.95 (m,
1 H), 4.21 (s, 2 H), 4.57-4.60 (m, 1 H), 6.24 (t, J = 6.6 Hz,
1 H), 7.11-7.49 (m, 20 H), 7.57 (s, 1 H), 8.65 (br s, 1
H). ¹³C NMR (100 MHz, CDCl3): δ = 11.8,
34.2 (CH2), 57.6, 59.0 (CH2), 63.5 (CH2),
77.2, 84.9, 87.3, 111.4, 127.2, 127.4, 128.0, 128.4, 129.2, 129.3,
130.5, 135.1, 142.9, 150.3, 164.6. HRMS (ES+): m/z calcd for C36H34N2O6SNa: 645.2035 [M + Na]+;
645.2025.
Compound 16
Compound 12d (0.2 g, 0.32 mmol) was converted into compound 16 (0.085 g, 47%) following the
procedure described for the synthesis of compound 8.
White solid; mp 78 ˚C. ¹H
NMR (400 MHz, CDCl3): δ = 1.44 (s,
3 H), 3.04-3.08 (m, 1 H), 3.44-3.49 (m, 3 H),
4.78 (br s, 1 H), 6.29 (t, J = 7.2
Hz, 1 H), 6.37 (s, 1 H), 7.22-7.31 (m, 12 H), 7.37-7.41
(m, 2 H), 7.44-7.46 (m, 6 H), 7.72 (s, 1 H), 8.13 (br s, 1
H). ¹³C NMR (100 MHz, CDCl3): δ = 11.8,
37.4 (CH2), 66.5 (CH2), 82.2, 84.5, 87.2 (C),
111.3 (C), 123.5,127.3, 127.4, 127.9, 128.3, 128.5, 128.6, 135.6,
136.3, 136.8, 143.4, 150.5, 164.1. HRMS (ES+): m/z calcd for C36H32N2O4Na:
579.2260 [M + Na]+;
found: 579.2247.
Compound 17
A
mixture of compound 16 (0.05 g, 0.09 mmol),
10% Pd/C (0.01 g) and ammonium formate (catalytic
amount) in MeOH (15 mL) was heated under reflux under H2 atmosphere.
After 1 h, the reaction mixture was brought to r.t. The suspension
was filtered through a Celite bed, and the bed was washed with MeOH.
The filtrate was evaporated under vacuum to afford a thick viscous
liquid. The residue was dissolved in H2O, and the water
layer was washed with CHCl3. The CHCl3 layers
were pooled together, dried over anhyd Na2SO4,
filtered, and the filtrate was evaporated to dryness. The residue
was purified over silica gel to afford compound 17 (0.01
g, 35%). Glassy liquid. ¹H NMR (400 MHz,
CDCl3): δ = 1.93 (s, 3 H, CH3),
1.97-2.05 (m, 1 H, H-2′′), 2.14-2.20
(m, 1 H, H-2′), 2.42 (br s, 1 H, OH), 2.80-2.88
(m, 2 H, H-3′, one of benzyl CH2), 2.91-3.00
(m, 1 H, one of benzyl CH2), 3.82-3.85 (m, 1
H, H-5′′), 3.95-3.98 (m, 1 H, H-5′),
4.21-4.23 (m, 1 H, H-4′), 5.98 (dd, J = 5.2, 8.8 Hz,
1 H, H-1′), 7.17-7.23 (m, 3 H, arom.), 7.26-7.31
(m, 2 H, arom.), 7.65 (s, 1 H, H-6), 8.58 (br s, 1 H, NH). ¹³C
NMR (100 MHz, CDCl3): δ = 12.6 (CH3),
34.9 (benzyl CH2), 36.6 (C-2′), 42.0 (C-2′),
63.1 (C-5′), 80.8 (C-4′), 86.1 (C-1′), 110.8
(C), 126.4 (arom.), 128.4 (arom.), 128.6 (arom.), 136.6 (C-6), 139.7
(C), 150.4 (CO), 164.4 (CO). HRMS (ES+): m/z calcd for C17H21N2O4:
317.1501 [M + Na]+; found:
317.1510.
The stereochemistry at C-3′ of 17 was confirmed from NOESY experiments. Thus, NOESY correlations were observed between H-3′ (δ = 2.80-2.88) and H-4′ (δ = 4.21-4.23), but no correlation was observed for H-3′ (δ = 2.80-2.88) and H-5′ (δ = 3.95-3.98)/H-5′′ (δ = 3.82-3.85), suggesting H-3′ and H-4′ were in cis relationship and H-3′ was away from H-5′, H-5′′. This observation was further supported by NOESY correlation between benzyl CH2 protons (δ = 2.80-2.88 and δ = 2.91-3.00) and H-5′′ (δ = 3.82-3.85).