Q. Huang, P. Herdewijn
FULL PAPER
J2 = 5.8 Hz, 1 H, 4Ј-Hb, major), 4.66–4.75 [m, 4 H, OCH(CH3)2, ead Sciences for financial support. We are grateful to Prof. Roger
α + β anomer], 5.99 (dd, J1 = 6.8, J2 = 5.2 Hz, 1 H, 1Ј-H, minor), Busson for assignments of 2D NMR spectra, Prof. Jef Rozenski
6.08 (dd, J1 = 6.7, J2 = 4.8 Hz, 1 H, 1Ј-H, major), 7.44 (d, J = for recording HRMS spectra, and Luc Baudemprez for running the
1.2 Hz, 1 H, T 6-H, major), 7.60 (d, J = 1.2 Hz, 1 H, T 6-H,
minor) ppm. 13C NMR (75 MHz, MeOD): δC = 12.47 (T CH3,
major), 12.56 (T CH3, minor), 24.26 (Me), 24.32 (Me), 24.36 (Me),
24.41 (Me), 25.25 (d, JP,C = 150.1 Hz, PCH2, major), 25.59 (d, JP,C
= 149.6 Hz, PCH2, minor), 39.79 (C-2Ј, minor), 39.83 (C-2Ј,
2D NMR experiments. We are grateful to the Katholieke Universit-
eit Leuven for financial support (GOA/10/13). Chantal Biernaux is
acknowledged for her excellent editorial help.
major), 43.92 (d, JP,C = 4.1 Hz, C-3Ј, major), 44.10 (d, JP, C
=
4.4 Hz, C-3Ј, minor), 73.28 [OCH(CH3)2, major], 73.37
[OCH(CH3)2, minor], the two signals of OCH(CH3)2 overlapped,
75.29 (C-4Ј, minor), 75.58 (C-4Ј, major), 87.95 (C-1Ј, minor), 88.12
(C-1Ј, major), 111.14 (T C-5, minor), 111.49 (T C-5, major), 137.86
(T C-6, major), 138.01 (T C-6, minor), 152.42 (T C-2), 166.49 (T
C-4) ppm, the signals of C-2 and C-4 of the thymine moiety were
obscured by noise. 31P NMR (121.5 MHz, MeOD): δP = 22.72,
22.84 ppm. HRMS: calcd. for C16H28N2O6PS [M + H]+ 407.1405;
found 407.1411.
[1]
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[3]
2,3-Dideoxy-3-mercapto-3-S-(phosphonomethyl)-1-(thymin-1-yl)-L-
threofuranose (1c): Iodotrimethylsilane (612 μL, 4.5 mmol) was
added to a solution of compound 20 (183 mg, 0.45 mmol) and
Et3N (3 mL, 21.64 mmol) in dry CH2Cl2 (25 mL) at 0 °C under
nitrogen. The reaction mixture was continuously stirred for 3.5 h.
The reaction was quenched with a 0.5 m TEAB solution. The mix-
ture was concentrated at room temperature in vacuo and the resi-
due was purified by chromatography on a silica gel column
(CH2Cl2/MeOH = 9:1 and CHCl3/MeOH/H2O = 5:4:1) to give
crude 1c. Purification by HPLC using a reversed-phase C18 column
(isocratic mobile phase: 1% MeCN and 99% H2O) and ion ex-
change with Dowex Na+ resin offered 1c (75 mg, 0.205 mmol) as a
colorless solid after lyophilization in 45% yield as an anomeric mix-
1
ture (α/β). H NMR (600 MHz, D2O): δH = 1.89 (s, 3 H, T CH3,
major), 1.91 (s, 3 H, T CH3, minor), 2.04 (ddd, J1 = 13.5, J2 = 6.4,
J3 = 6.4 Hz, 1 H, 2Ј-Ha, minor), 2.42 (ddd, J1 = 13.9, J2 = 6.7, J3
= 6.7 Hz, 1 H, 2Ј-Ha, major), 2.52 (ddd, J1 = 13.9, J2 = 7.2, J3 =
4.8 Hz, 1 H, 2Ј-Hb, major), 2.69 (dAB, JP,H = 14.1 Hz, 2 H, PCH2,
minor), 2.70 (dAB, JP,H = 14.3 Hz, 2 H, PCH2, major), 2.85 (ddd,
J1 = 14.4, J2 = 7.3, J3 = 7.3 Hz, 1 H, 2Ј-Hb, minor), 3.74–3.77 (m,
1 H, 3Ј-H, minor), 3.77–3.82 (m, 1 H, 3Ј-H, major), 3.91 (dd, J1 =
9.3, J2 = 5.8 Hz, 1 H, 4Ј-Ha, major), 4.07 (dd, J1 = 9.0, J2 = 6.3 Hz,
1 H, 4Ј-Ha, minor), 4.28 (dd, J1 = 9.1, J2 = 6.6 Hz, 1 H, 4Ј-Hb,
minor), 4.51 (dd, J1 = 9.3, J2 = 6.2 Hz, 1 H, 4Ј-Hb, major), 6.08
(dd, J1 = 6.5, J2 = 6.2 Hz, 1 H, 1Ј-H, minor), 6.17 (dd, J1 = 6.3,
J2 = 5.2 Hz, 1 H, 1Ј-H, major), 7.51 (s, 1 H, T 6-H, major), 7.71
(s, T 6-H, minor) ppm. 13C NMR (150 MHz, D2O): δC = 11.12 (T
CH3, major), 11.16 (T CH3, minor), 26.89 (d, JP,C = 158.3 Hz,
PCH2, major), 27.07 (d, JP,C = 158.1 Hz, PCH2, minor), 37.22 (C-
2Ј, minor), 37.34 (C-2Ј, major), 41.63 (d, JP,C = 8.4 Hz, C-3Ј,
minor), 41.91 (d, JP,C = 8.8 Hz, C-3Ј, major), 73.64 (C-4Ј, minor),
74.02 (C-4Ј, major), 86.15 (C-1Ј, minor), 86.53 (C-1Ј, major),
110.70 (two signals overlapped, T C-5), 137.23 (T C-6, major),
137.46 (T C-6, minor), 151.14 (T C-2, major), 151.23 (T C-2,
minor), 166.21 (two signals overlapped, T C-4) ppm. 31P NMR
(121.5 MHz, D2O): δP = 14.42, 14.49 ppm. HRMS: calcd. for
C10H14N2O6PS [M – H]– 321.0310; found 321.0322.
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Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra of 1–20 and HPLC spectra of 1a–
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1c.
Acknowledgments
We are indebted to Dr. Richard L. Mackman (Gilead Sciences) for
helpful discussions and for providing the antiviral data and to Gil-
3456
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