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1-[20-deoxy-b-D-lyxofuranosyl]thymine (2). To a solution of 1
RSC Advances
0.37 mmol) in 1 : 1 mixture of THF/H2O (1.5 mL) NaHCO3
(93.3 mg, 1.11 mmol) and Boc2O (96.9 mg, 0.44 mmol) were
(1.57 g, 2.9 mmol) in DCM (30 mL) was added triuoroacetic
acid (TFA; 0.3 mL). The reaction mixture was stirred at RT for
2 h followed by concentration in vacuo. The residue was puried
by silica gel column chromatography (DCM : MeOH, 97 : 3, v/v)
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added consecutively at 0 C. Aer 1 h at 0 C, the solution was
stirred at RT for 2 h. Aer which time it was ltered and
concentrated in vacuo. The residue was puried by silica gel
column chromatography with 100% EtOAc to provide the
product (80 mg, 64%) as a white solid. 1H NMR (400 MHz,
DMSO-d6) d 11.22 (s, 1H, NH), 7.79 (m, 1H, H-6), 6.89 (t, J ¼
6.0 Hz, 1H, NH-Boc), 6.03 (dd, J ¼ 8.4, 2.4 Hz, 1H, H-10), 5.26 (d, J
¼ 3.3 Hz, 1H, 30-OH), 4.17 (dt, J ¼ 6.2, 3.2 Hz, 1H, H-30), 3.79 (td,
J ¼ 6.4, 3.0 Hz, 1H, H-40), 3.25 (t, J ¼ 5.9 Hz, 2H, H-50, H-500), 2.57
(ddd, J ¼ 14.2, 8.5, 5.4 Hz, 1H, H-20), 1.87 (dd, J ¼ 14.8, 2.5 Hz,
1H, H-200), 1.77 (d, J ¼ 1.2 Hz, 3H, 5-CH3), 1.38 (s, 9H, boc). 13C
NMR (101 MHz, DMSO-d6) d 163.81 (CO-4), 155.95 (CO-Boc),
150.53 (CO-2), 137.12 (CH-6), 108.68 (C-5), 83.53 (CH-40), 82.49
(CH-10), 77.97 (C-Boc), 68.55 (CH-30), 40.31 (CH2-50), 39.20 (CH2-
20), 28.21 (CH3-Boc), 12.44 (5-CH3). HRMS (ESI) ¼ 342.1671 (M +
H)+. Calc. for C15H24N3O6: 342.1665.
1-[50-amino-50-N-(-t-butoxycarbonyl-)-50-deoxy-20-deoxy-30-O-
(4-nitrobenzenesulfonyl)-b-D-lyxofuranosyl]thymine (6). The
solid 5 (70 mg, 0.21 mmol) was dissolved in anhydrous pyridine
(3 mL) at RT then the 4-nitrobenzenesulfonyl chloride (57.6 mg,
0.26 mmol) was added, followed by silver tri-
uoromethanesulfonate ꢂ(66.8 mg, 0.26 mmol). The reaction
mixture was stirred at 0 C for 0.5 h and then RT for 2 h, aer
which time it was diluted with EtOAc (10 mL) and the precipi-
tate (AgCl) that was formed, was ltered. The ltrate was
extracted with brine (15 mL) and water (15 mL). The organic
layer was dried with anhydrous Na2SO4 and concentrated in
vacuo. The residue was puried by silica gel column chroma-
tography with 100% EtOAc to give product (65 mg, 60%) as
a yellow solid. 1H NMR (400 MHz, DMSO-d6) d 11.26 (s, 1H, NH),
8.58–8.33 (m, 2H, H-Ph), 8.30–8.09 (m, 2H, H-Ph), 7.38 (m, 1H,
H-6), 7.00 (t, J ¼ 5.8 Hz, 1H, NH-Boc), 5.96 (dd, J ¼ 7.7, 2.6 Hz,
1H, H-10), 5.33 (dd, J ¼ 4.9, 3.4 Hz, 1H, H-30), 4.12 (dt, J ¼ 8.0,
3.9 Hz, 1H, H-40), 3.30–3.07 (m, 2H, H-50, H-500), 2.78 (ddd, J ¼
15.7, 7.7, 5.1 Hz, 1H, H-20), 2.32–2.16 (m, 1H, H-200), 1.72 (d, J ¼
1.2 Hz, 3H, 5-CH3), 1.36 (s, 9H, boc). 13C NMR (101 MHz, DMSO-
d6) d 163.59 (CO-4), 155.58 (CO-Boc), 150.76 (CO-2), 150.16 (C-
Ph), 140.78 (C-Ph), 135.13(CH-6), 129.21 (CH-Ph), 124.99 (CH-
Ph), 109.01 (C-5), 83.58 (CH-40), 81.43 (CH-10), 80.68 (CH-30),
77.99 (C-Boc), 39.07 (CH2-50), 38.40 (CH2-20), 28.14 (CH3-Boc),
12.21 (5-CH3). HRMS (ESI) ¼ 527.1461 (M + H)+. Calc. for
1
to afford the product (560 mg, 80%) as a white solid. H NMR
(400 MHz, DMSO-d6) d 11.21 (s, 1H, NH), 7.80 (q, J ¼ 1.1 Hz, 1H,
H-6), 6.06 (dd, J ¼ 8.4, 2.6 Hz, 1H, H-10), 5.23 (d, J ¼ 3.5 Hz, 1H,
30-OH), 4.67 (t, J ¼ 5.7 Hz, 1H, 50-OH), 4.31–4.17 (m, 1H, H-30),
3.88–3.55 (m, 3H, H-40, H-50, H-500), 2.62–2.50 (m, 1H, H-20), 1.85
(ddd, J ¼ 14.7, 2.7, 1.0 Hz, 1H, H-200), 1.76 (d, J ¼ 1.2 Hz, 3H, 5-
CH3). 13C NMR (101 MHz, DMSO-d6) d 163.81 (CO-4), 150.56
(CO-2), 137.17 (CH-6), 108.64 (C-5), 84.77 (CH-40), 83.44 (CH-10),
68.64 (CH-30), 59.57 (CH2-50), 40.67 (CH2-20), 12.46 (5-CH3).
HRMS (ESI) ¼ 243.0977 (M + H)+. Calc. for C10H15N2O5:
243.0981.
1-[5-N-(4,5,6,7-tetrachloroisoindole-1,3-dione)50-deoxy-20-
deoxy-b-D-lyxofuranosyl]thymine (3). To a mixture of 2 (466 mg,
1.9 mmol), triphenylphosphine (TPP, 629 mg, 2.4 mmol) and
tetrachlorophtalimide (TCP-NH, 683 mg, 2.4 mmol) anhydrous
THF (50 mL) was added. The white slurry was stirred vigorously
under N2 at RT. Diisopropyl azodicarboxylate (DIAD, 473 mL, 2.4
mmol) was added drop wise by a syringe and the reaction
mixture, a yellow clear solution, was stirred at RT for 4 days. The
resulting precipitate was collected by suction ltration and
washed with THF to give the product (506 mg, 52%) as a white
solid. 1H NMR (400 MHz, DMSO-d6) d 11.24 (s, 1H, NH), 7.85 (m,
1H, H-6), 5.93 (dd, J ¼ 8.0, 2.4 Hz, 1H, H-10), 5.50 (d, J ¼ 3.4 Hz, 1H,
30-OH), 4.33 (q, J ¼ 4.2 Hz, 1H, H-30), 4.24–4.05 (m, 2H, H-40, H-50),
3.79 (dd, J ¼ 14.1, 2.9 Hz, 1H, H-500), 2.57 (ddd, J ¼ 14.6, 8.0, 5.2 Hz,
1H, H-20), 1.97 (ddd, J ¼ 14.5, 2.5, 1.1 Hz, 1H, H-200), 1.85 (d, J ¼
1.2 Hz, 3H, 5-CH3). 13C NMR (101 MHz, DMSO-d6) d 163.84 (CO),
163.38 (CO), 150.39 (CO-2), 138.32 (CH-6), 136.84 (C), 128.17 (C),
128.13 (C), 108.33 (C-5), 84.23 (CH-40), 80.45 (CH-10), 68.60 (CH-30),
40.81 (CH2-50), 38.37 (CH2-20), 12.49 (5-CH3). HRMS (ESI) ¼
505.9489 (M ꢁ H)ꢁ. Calc for C18H12N3O6Cl4: 505.9480.
1-[50-amino-50-deoxy-20-deoxy-b-D-lyxofuranosyl]thymine (4).
Synthesised by adapting a literature procedure.32 To a solution
of compound 3 (270 mg, 0.53 mmol) in CH3CN/THF/EtOH
(2 : 1 : 1 v/v, 40 mL) was added dropwise ethylenediamine (159
mL, 2.4 mmol). The reaction mixture was stirred rst at 60 ꢂC for
1 h, then at 45 ꢂC for 2 h, aer which it was concentrated in
vacuo. The resulting material was puried by silica gel column
chromatography (EtOAc : MeOH : TEA, 7 : 3 : 0.1) to provide the
product (126 mg, 98%) as a pale yellow solid. 1H NMR (400 MHz,
deuterium oxide) d 7.79 (q, J ¼ 1.2 Hz, 1H, H-6), 6.17 (dd, J ¼ 8.4,
2.9 Hz, 1H, H-10), 4.52 (ddd, J ¼ 5.6, 3.3, 1.0 Hz, 1H, H-30), 4.08
(td, J ¼ 6.1, 3.3 Hz, 1H, H-40), 3.17 (d, J ¼ 6.1 Hz, 2H, H-50, H-500),
2.78 (ddd, J ¼ 15.4, 8.4, 5.6 Hz, 1H, H-20), 2.14 (ddd, J ¼ 15.4, 3.0,
1.0 Hz, 1H, H-200), 1.91 (d, J ¼ 1.2 Hz, 3H, 5-CH3). 13C NMR (101
MHz, deuterium oxide) d 168.67 (CO-4), 153.34 (CO-2), 138.19
(CH-6), 111.05 (C-5), 85.20 (CH-40), 83.20 (CH-10), 69.74 (CH-30),
39.98 (CH2-50), 39.33 (CH2-20), 11.83 (5-CH3). HRMS (ESI) ¼
242.1140 (M + H)+. Calc. for C10H16N3O4: 242.1141.
C
21H27N4O10S: 527.1448.
50-N-(4,5,6,7-tetrachloroisoindole-1,3-dione)-50,30-deoxy-30-
uoro-thymidine (8). To a mixture of alcohol (350 mg, 1.43
mmol), triphenylphosphine (TPP, 466 mg, 1.78 mmol) and tet-
rachlorophtalimide (TCP-NH, 507 mg, 1.78 mmol) anhydrous
THF (20 mL) was added. The mixture, white slurry, was stirred
vigorously under N2 at RT. Diisopropyl azodicarboxylate (DIAD,
350 mL, 1.78 mmol) was added by a syringe, and the reaction
mixture, yellow clear solution, was stirred at RT for 4 days. The
reaction mixture was concentrated in vacuo. The resulting
precipitate was washed with acetone to give the product
(585 mg, 80%) as a white solid. 1H NMR (400 MHz, DMSO)
d 11.34 (s, 1H, NH), 7.57 (d, J ¼ 1.5 Hz, 1H, H-6), 6.14 (dd, J ¼ 9.0,
5.7 Hz, 1H, H-10), 5.58–5.12 (m, 1H, H-30), 4.52–4.22 (m, 1H, H-
1-[50-amino-50-N-(-t-butoxycarbonyl-)-50-deoxy-20-deoxy-b-D-
lyxofuranosyl]thymine (5). To a solution of free amine 4 (88 mg,
© 2021 The Author(s). Published by the Royal Society of Chemistry
RSC Adv., 2021, 11, 12423–12433 | 12429