SO₂-Extrusion Reactions of Sulfonylated Nucleosides: A Novel Strategy for the Synthesis of Exocyclic Olefinic Thymidines

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.

nucleosides - sulfones - olefination - antiviral agents - carbohydrates

References and Notes

1 Len C. Mackenzie G. Tetrahedron  2006,  62:  9085 

2a Fedorov II. Kazmina EM. Novicov NA. Gurskaya GV. Bochkarev AV. Jasko MV. Viktorova LS. Kukhanova MK. Balzarini J. De Clercq E. Krayevsky AA. J. Med. Chem.  1992,  35:  4567 

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6 Serafinowski PJ. Barnes CL. Synthesis  1997,  225 

7

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

For reviews on the formation of a wide range of products from vinyl sulfone modified carbohydrates, see:

8a Pathak T. Tetrahedron  2008,  64:  3605 

8b Pathak T. Bhattacharya R. Carbohydr. Res.  2008,  343:  1980 

For reviews, see:

9a Taylor RJK. Chem. Commun.  1999,  217 

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11 Tze-Lock C. Sun F. Yu L. Tim-On M. Chi-Duen P. J. Chem. Soc., Chem. Commun.  1994,  1771 

12

Synthesis 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.

Compounds 11a and 12a are reported in the literature, see:

13a Mansuri MM. Wos JA. Martin JC. Nucleosides Nucleotides  1989,  8:  1463 

13b Herdewijn P. De Bruyn A. Wigerinck P. Hendrix C. Kerremans L. Rozenski J. Busson R. J. Chem. Soc., Perkin Trans. 1  1994,  249 

14

Compound 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.

15

Compound 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.

17

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.

18

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.

19

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).

20 Pathak T. Chem. Rev.  2002,  102:  1623 

21 Contreras ML. Gonzalez FD. Munoz VC. Rozas R. Bol. Soc. Chil. Quim.  1995,  40:  279 ; Chem. Abstr. 1995, 123, 305993