A. Thiyagarajan et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7742–7747
7747
ˇ
27. Hocek, M.; Pohl, R.; Císarová, I. Eur. J. Org. Chem. 2005, 2005, 3026.
highly active molecules, however, 6c–e was found to be moder-
ately active against HCV. The major advantages of these com-
pounds are; limited cytotoxicity (CC50 > 100 lM) and better
lipophilicity. Further synthetic exploration and biological evalua-
tion are warranted to optimize this novel lead into potential
anti-HCV nucleoside inhibitor.
28. General method for the preparation of 6a–e.
To
a mixture of appropriate 3a–e (1.5 mmol), 1 (1.57 mmol) and Ph3P
(3.75 mmol) in THF was added DIAD (3.75 mmol) dropwise at 0 °C under
nitrogen and stirring continued at rt. Completion of reaction was analyzed by
TLC, solvent evaporated under reduced pressure and crude was purified by
column chromatography on silica gel by eluting up to 30 % ethyl acetate in
hexane to give couple products in more than 80 % yield. The deprotection was
carried out by heating at 60 °C in 10
% HCl in MeOH. After completion
(monitored by TLC), the reaction mixture was neutralized by NaHCO3 and
purified by silica gel chromatography (10% methanol in DCM) to get 6a–e in
70–85% yield.
Acknowledgments
This research received funding from DST, New Delhi, India
through grant no SR/FT/CS-069/2009. A.T. and T.B. are thankful to
DST, India for JRF. AS thanks DBT, New Delhi, India for modelling
software support. A.S. & C.B. would like to dedicate this manuscript
to Professor C. K. Chu. Authors acknowledge ILS, Hyderabad for
NMR-Mass Facility and CIF, BIT Mesra for analytical support.
Data
for
(1S,2R,5R)-3-(hydroxymethyl)-5-(4-methyl-7H-pyrrolo[2,3-
d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (6a): Yield: 80 %; mp: 168–170 °C;
MS-ESI (m/z): [M++1] 261.9; ½a D21
ꢁ : ꢀ 101.70 (c 0.24, MeOH); UV (MeOH) kmax
269 nm; 1H NMR (400 MHz, DMSO-d6): d 2.64 (s, 3H), 4.12–4.17 (m, 3H), 4.44
(t, J = 5.6 Hz, 1H), 4.88–4.94 (m, 2H), 5.02 (d, J = 7.2 Hz, 1H), 5.63–5.67 (m, 2H),
6.70 (d, J = 3.6 Hz, 1H), 7.43 (d, J = 4 Hz, 1H), 8.64 (s, 1H); 13C NMR (100 MHz,
DMSO-d6): d 21.01, 58.55, 63.90, 72.31, 77.17, 99.25, 117.59, 123.98, 126.22,
149.90, 150.16, 150.54, 158.57.
Data for (1S,2R,5R)-5-(5-bromo-4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-
(hydroxymethyl)cyclopent-3-ene-1,2-diol (6d): Yield: 81 %; mp: 215–217 °C;
Supplementary data
MS-ESI (m/z): [M+] 339.8 [M++2] 341.8; ½a 2D2
ꢀ 130.39 (c 0.21 MeOH-H2O); UV
ꢁ
(MeOH) kmax 269.8 nm, 301.7 nm; 1H NMR (400 MHz, DMSO-d6) d 2.84 (s, 3H),
4.12–4.17 (m, 3H), 4.44 (t, J = 5.6 Hz, 1H), 4.88 (t, J = 5.6 Hz, 1H), 4.95 (d, J =
6 Hz, 1H), 5.06 (d, J = 7.2 Hz, 1H), 5.63 (d, J = 1.2 Hz, 1H), 5.68 (bs, 1H), 7.68 (s,
1H), 8.68 (s, 1H); 13C NMR (100 MHz, DMSO-d6) d 21.33, 59.04, 64.71, 72.74,
77.44, 87.18, 115.77, 123.93, 126.89, 149.61, 151.22, 151.60, 159.43.
29. Method for synthesis of (6f).
Supplementary data associated with this article can be found,
A suspension of 6e (0.25 mmol), Pd(PPh3)4 (0.02 mmol), CuI (0.05 mmol) and
Et3N (0.77 mmol) in anhydrous DMF was purged with nitrogen at rt.
Tributylvinyltin (2.58 mmol) was added under nitrogen and the mixture was
stirred at 50 °C. The completion of reaction was checked by TLC, solvent was
removed and residue was purified by on silica gel (100–200 mesh) column
chromatography by eluting with 10 % methanol in DCM.
References and notes
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Data for (1S,2R,5R)-3-(hydroxymethyl)-5-(4-methyl-5-vinyl-7H-pyrrolo[2,3-
d]pyrimidin-7-yl)cyclopent-3-ene-1,2-diol (6f): Yield: 72 %; mp: 148–150 °C;
MS-ESI (m/z): [M++1] 287.9; ½a D22
ꢀ 157.66 (c 0.11 MeOH-H2O); UV (MeOH)
ꢁ
kmax 269.5 nm, 310.7 nm; 1H NMR (400 MHz, DMSO-d6) d 2.75 (s, 3H), 4.13–
4.22 (m, 3H), 4.44 (t, J = 5.2 Hz, 1H), 4.92 (t, J = 5.6 Hz, 1H), 4.96 (d, J = 6.4 Hz,
1H), 5.06 (d, J = 7.2 Hz, 1H), 5.19 (d, J = 11.2 Hz, 1H) , 5.63 (bs, 1H), 5.63–5.68
(m, 1H), 5.63–5.68 (bs, 1H), 7.01–7.08 (m, 1H), 7.70 (s, 1H), 8.62 (s, 1H); 13C
NMR (100 MHz, DMSO-d6) d 22.85, 58.56, 63.77, 72.27, 77.13, 113.56, 113.81,
115.24, 122.86, 123.88, 128.46, 150.16, 150.22, 150.52, 158.89.
30. Method for synthesis of (1S,2R,5R)-5-(5-ethynyl-4-methyl-7H-pyrrolo[2,3-
d]pyrimidin-7-yl)-3-(hydroxymethyl)cyclopent-3-ene-1,2-diol (6g)
A suspension of 6e (0.25 mmol), Pd(PPh3)4 (0.02 mmol), CuI (0.05 mmol) and
Et3N (0.77 mmol) in anhydrous DMF was purged with nitrogen at rt.
Trimethylsilylacetylene (2.58 mmol) of was added under nitrogen and the
mixture was stirred at rt. The completion was checked by TLC, solvent was
removed and residue was purified on silica gel (100–200 mesh)
chromatography by eluting with 10
% methanol in DCM to give
trimethylsilyl protected compound in 80 % yield. The deprotection was done
by stirring in methanol and K2CO3 (0.1 mmol) at rt for 2 h and purified by silica
gel chromatography by eluting up to 10 % methanol in DCM to get 6g as a light
brown solid in 75 % yield.
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½
a 2D3
ꢁ
+ 28.4 (c, 1.00, CHCl3); Compound 1 ½a D29
ꢁ
+ 30.9 (c, 1.00, CHCl3).