T.P. Dang et al. / Tetrahedron 68 (2012) 5655e5667
5665
/ EtOAc / MeOH/EtOAc, 1:39) to give 19 (37.5 mg, 81%) as a 1:1
mixture of diastereomers: 1H NMR
0.14 (s, 3, Me), 0.15 (s, 3, Me),
Diazald (3.0 g, 14.0 mmol), was added dropwise to a stirred solution
of AZT (9; 200 mg, 0.75 mmol) in ethanol (15 mL) at 0 ꢁC. After 30
min, the volatiles were evaporated to give 2265 (208 mg, 99%): 1H
d
0.94 (s, 9, t-Bu), 2.31 & 2.33 (2 ꢄ s, 3, Ac), 2.34 (s, 3, Ac), 3.17 & 3.20
(2 ꢄ dd, J ¼ 6.6, 13.9 Hz,1, CH2S), 3.36 (dd, J ¼ 7.1,13.9 Hz, 0.5, CH2S),
3.37 (dd, J ¼ 6.6, 13.9 Hz, 0.5, CH2S), 3.81 (dd, J ¼ 5.4, 10.0 Hz, 0.5,
OCH2), 3.858 & 3.864 (2 ꢄ d, J ¼ 11.8 Hz, 1, H50), 3.86-3.91 (m, 1.5,
OCH2, CHS), 3.92-3.97 (m, 0.5, OCH2) 4.01 (dd, J ¼ 4.2, 10.0 Hz, 0.5,
OCH2), 4.10 & 4.11 (2 ꢄ br. d, J ¼ 11.8 Hz, 1, H500), 4.17 & 4.19 (2 ꢄ dd, J
¼ 2.5, 5.1 Hz, 1, H30), 4.27 & 4.29 (2 ꢄ “t”, J ¼ 2.7 Hz, 1, H40), 4.57 &
4.58 (2 ꢄ dd, J ¼ 2.7, 5.5 Hz, 1, H20), 5.99 ( br. s, 2, NH2), 6.15 & 6.16 (2
ꢄ d, J ¼ 2.7 Hz, 1, H10), 8.20 & 8.21 (2 ꢄ s, 1, H8), 8.33 & 8.34 (2 ꢄ s, 1,
NMR
d
1.95 (s, 3, CH3), 2.38 (ddd, J ¼ 5.4, 6.4, 13.8 Hz, 1, H20), 2.45
(dt, J ¼ 6.8,13.5 Hz,1, H2"), 3.35 (s,1, NCH3), 3.83 (dd, J ¼ 1.3,11.0 Hz,
1, H500), 3.97-4.04 (m, 2, H40,50), 4.43 (dt, J ¼ 5.0, 7.2 Hz, H30), 6.06 (t,
J ¼ 6.5 Hz, H10), 7.37 (s, 1, H6); 13C NMR
d 13.2 (CH3), 27.8 (NCH3),
37.6 (C20), 59.9 (C30), 61.8 (C50), 84.6 (C40), 86.8 (C10), 110.0 (C5),
134.6 (C6), 150.9 (C2), 163.7 (C4); HRMS m/z calcd for C11H16N5O5
[M þ H]þ 282.1197, found 282.1186.
H2); 13C NMR
d
-5.4 (Me), -5.1 (Me), 18.5 (t-Bu), 26.0 (t-Bu), 30.2,
4.1.19. 50-O-Allyl-30-azido-30-deoxy-3-N-methylthymidine
(23). KOH (78 mg, 1.39 mmol), 18-crown-6 (5 mg, 0.019 mmol) and
allyl bromide (0.12 mL, 168 mg, 1.39 mmol) were added to a stirred
solution of 22 (130 mg, 0.46 mmol) in dry THF (3 mL) at ambient
temperature. After 2 h, the volatiles were evaporated and the res-
idue was partitioned between H2O and CHCl3. The organic layer
was concentrated and purified on silica gel column (EtOAc/hexane,
30.4 (CH2S), 30.5, 30.6, 30.60 (Ac), 43.6, 43.7 (CHS), 58.7, 58.8 (C30),
61.75, 61.76 (C50), 71.79, 71.82 (OCH2), 81.9 (C40), 83.4, 83.6 (C20),
87.3, 87.4 (C10), 120.1, 120.1 (C5), 138.8, 138.9 (C8), 149.3, 149.3 (C4),
153.11, 153.12 (C2), 155.5 (C6), 194.1, 194.4, 194.52, 194.55 (SAc);
HRMS m/z calcd for C23H37N8O5S2Si [M þ H]þ 597.2092, found
597.2107.
3:7) to afford 23 (120 mg, 81%): 1H NMR
d 1.80 (s, 3, CH3), 2.31 (dt, J
4.1.16. 30-Azido-30-deoxy-20-O-[(2,3-S-diacetyl-2,3-dimercapto)pro-
pyl]adenosine (20). A solution of 19 (37.5 mg, 0.063 mmol) in TFA/
H2O (9:1, 1.0 mL) was stirred at 0 ꢁC for 1 h. Volatiles were evap-
orated and the residue was coevaporated with toluene to give 20
¼ 6.6, 13.6 Hz, 1, H20), 2.41 (ddd, J ¼ 5.1, 6.3, 13.8 Hz, 1, H2"), 3.31 (s,
3, NCH3), 3.63 (dd, J ¼ 2.5,10.8 Hz,1, H50), 3.78 (dd, J ¼ 2.5,10.8 Hz,1,
H500), 4.02 ("quint", J ¼ 2.5 Hz, 1, H40), 4.06 ("q", J ¼ 1.4 Hz, 1, OCHH),
4.08 ("q", J ¼ 1.4 Hz, 1, OCHH), 4.31 (dt, J ¼ 4.8, 6.9 Hz, 1, H30), 5.23
(dq, J ¼ 1.2, 10.4 Hz, 1, CH¼CHH), 5.29 (dq, J ¼ 1.6, 17.2 Hz, 1,
CH¼CHH), 5.90 (ddt, J ¼ 5.6, 10.4, 17.2 Hz,1, CH¼CH2), 6.27 (t, J ¼ 6.2
(30 mg, 99%) as a 1:1 mixture of diastereomers: 1H NMR
d 2.291 (s,
1.5, Ac), 2.293 (s, 1.5, Ac), 2.32 (s, 1.5, Ac), 2.33 (s, 1.5, Ac), 2.97 (dd, J
¼ 6.6, 14.1 Hz, 0.5, CHHS), 3.12 (dd, J ¼ 6.4, 14.1 Hz, 0.5, CHHS), 3.29
(dd, J ¼ 6.4, 14.1 Hz, 0.5, CHHS), 3.34 (dd, J ¼ 6.6, 14.1 Hz, 0.5, CHHS),
3.65 (dd, J ¼ 5.6, 9.6 Hz, 0.5, OCH2), 3.68-3.78 (m, 1.5, CHS, OCH2),
3.79-3.88 (m, 1, CHS, OCH2), 3.88 (d, J ¼ 12.6 Hz, 1, H50), 4.12 (d, J ¼
12.6 Hz,1, H500), 4.34-4.37 (m,1, H40), 4.37-4.40 (m,1, H30), 4.68-4.72
(m,1, H20), 6.12 & 6.17 (2 ꢄ d, J ¼ 4.8 Hz,1, H10), 8.41 (s,1, H2), 8.72 (s,
Hz, 1, H10), 7.60 (s, 1, H6); 13C NMR
d 13.3 (CH3), 27.7 (NCH3), 38.1
(C20), 60.5 (C30), 69.4 (C50), 72.4 (OCH2), 83.4 (C40), 85.5 (C10), 109.9
(C5), 117.9 (CH¼CH2), 133.4 (CH¼CH2), 133.7 (C6), 150.9 (C2), 163.6
(C4); HRMS m/z calcd for C14H20N5O4 [M þ H]þ 322.1510, found
322.1501.
0.5, H8), 8.74 (s, 0.5, H8), 8.89 (br. s, 1, OH), 9.43 (br. s, 2, NH2); 13
C
4.1.20. 30-Azido-50-O-(2,3-dibromopropyl)-30-deoxy-3-N-methyl-
NMR
d
29.9, 30.2 (CH2S), 30.3, 30.4, 30.5, 30.6 (Ac), 43.5, 43.6 (CHS),
thymidine (24). A solution of bromine (14 mL, 44 mg, 0.28 mmol) in
59.9, 60.0 (C30), 61.6 (C50), 71.9, 72.2 (OCH2), 83.3, 83.4 (C20), 84.31,
84.33 (C40), 88.7, 88.8 (C10), 119.4 (C5), 137.9 (C4), 142.9, 142.9 (C8),
145.0, 145.1 (C2), 151.7 (C6), 194.2, 194.7, 194.93, 194.94 (SAc); MS
m/z 483 [M þ H]þ).
CHCl3 (1 mL) was added dropwise to a stirred solution of 23 (90 mg,
0.28 mmol) in CHCl3 (2 mL) at -50 oC. After 40 min, the reaction
mixture was concentrated and column chromatographed (EtOAc/
hexane, 3:7) to give 24 (81 mg, 60%) as a 1:1 mixture of di-
astereomers: 1H NMR
d
1.95 (s, 3, CH3), 2.31 (ddd, J ¼ 0.9, 7.8, 13.8
4.1.17. 30-Azido-30-deoxy-20-O-(2,3-dimercaptopropyl)adenosine
(21). Saturated solution of NaOH in MeOH (2.0 mL) was added to
a stirred solution of the crude 20 (30 mg, 0.062 mmol) in MeOH (1.0
mL) at -30 oC under Ar atmosphere. The stirring was continued for
30 min until all starting material was consumed as judged by TLC.
The reaction mixture was cooled down to -50 oC, acidified with 1 M
HCl and was stirred for an additional 20 min. The resulting mixture
was extracted with CH2Cl2 (2x) and the combined organic extract
was washed with NaHCO3/H2O, brine, and was dried (Na2SO4) to
give 21 (24.5 mg, 99%; 1:1 mixture of diastereomers) as a white
Hz, 1, H20), 2.40-2.47 (m, 1, H200), 3.32 (s, 3, NCH3), 3.69-3.76 (m, 2,
H50, CHHBr), 3.80 (dd, J ¼ 4.5, 10.4 Hz, 1, CHHBr), 3.90-3.95 (m, 2,
H5", OCHH), 4.01-4.06 (m, 2, H40, OCHH), 4.26-4.32 (m, 1, CHBr),
4.36 ("dt", J ¼ 4.5, 11.5 Hz, 1, H30), 6.25 ("dt", J ¼ 6.5, 10.3 Hz, 1, H10),
7.38 (s, 0.5, H6), 7.42 (s, 0.5, H6); 13C NMR
d 13.5 (CH3), 27.8 (NCH3),
31.8 & 32.0 (CH2Br), 37.8 (C20), 48.5 & 48.6 (CHBr), 60.5 & 60.7 (C30),
70.8 (C50), 72.6 & 72.7 (OCH2), 82.97 & 82.98 (C40), 85.48 & 85.50
(C10), 110.21 & 110.24 (C5), 133.0 & 133.1 (C6), 150.91 & 150.93 (C2),
163.47 & 163.50 (C4); MS m/z 480 (48, [79Br2]), 482 (100, [79/81Br2]),
484 (52, [81Br2]). HRMS m/z calcd for C14H20 79Br2N5O4 [M þ H]þ
479.9877, found 479.9891.
foam. 1H NMR
d
1.44 (t, J ¼ 8.7 Hz, 0.5, CH2SH), 1.50 (dd, J ¼ 7.9, 9.5
Hz, 0.5, CH2SH), 1.67 (d, J ¼ 9.2 Hz, 0.5, CHSH), 1.76 (d, J ¼ 8.9 Hz, 0.5,
CHSH), 2.64-2.80 (m,1, CH2S), 2.77 (dd, J ¼ 5.7, 8.7 Hz,1, CH2S), 2.87-
2.95 (m, 0.5, CHS), 2.97-3.05 (m, 0.5, CHS), 3.41 (dd, J ¼ 6.9, 9.5 Hz,
0.5, OCHH), 3.55 (dd, J ¼ 5.2, 9.6 Hz, 0.5, OCHH), 3.70 (dd, J ¼ 6.7, 9.7
Hz, 0.5, OCHH), 3.73 (br. “d”, J ¼13 Hz, 1, H50), 3.82 (dd, J ¼ 4.7, 9.5
Hz, 0.5, OCHH), 3.98 (br. d, J ¼13.2 Hz, 1, H500), 4.24 & 4.26 (2 ꢄ “q”, J
¼ 1.0 Hz, 1, H40), 4.51 (d, J ¼ 5.4 Hz, 1, H30), 5.08 & 5.09 (2 ꢄ dd, J ¼
5.4, 7.6 Hz, 1, H20) 5.87 & 5.89 (2 ꢄ d, J ¼ 7.6 Hz, 1, H10), 6.23 (br. s, 2,
4.1.21. 30-Azido-50-O-[(2,3-S-diacetyl-2,3-dimercapto)propyl]-30-de-
oxy-3-N-methylthymidine (25). KSAc (0.18 g, 1.58 mmol) was added
to a stirred solution of 24 (75 mg, 0.156 mmol) in DMF (5 mL) at
ambient temperature under N2 atmosphere. After 24 h, the vola-
tiles were evaporated and the residue was partitioned between H2O
and CHCl3. The organic layer was concentrated and column chro-
matographed (EtOAc/hexane, 4:6) to give 25 (55 mg, 75%) as a 1:1
NH2), 6.77 (br. s, 1, OH), 7.90 & 7.91 (2 ꢄ s, 1, C8), 8.33 (s, 1, C2); 13
C
mixture of diastereomers: 1H NMR
d
1.96 (d, J ¼ 1.1 Hz, 1.5, CH3),
NMR
d
29.4, 29.7 (CH2S), 41.5, 41.7 (CHS), 62.10, 62.12 (C30), 63.36,
1.98 (d, J ¼ 1.1 Hz, 1.5, CH3), 2.27-2.38 (m, 7, 2 ꢄ Ac, H20), 2.41-2.48
(m, 1, H2"), 3.03 (dd, J ¼ 6.6,13.9 Hz, 0.5, SCHH), 3.11 (dd, J ¼ 7.1, 13.9
Hz, 0.5, SCHH), 3.34-3.43 (m, 4, NCH3, SCHH), 3.53-3.75 (m, 3, H50,
OCH2), 3.79-3.87 (m, 2, H5", CHS), 4.03 ("dt", J ¼ 2.6, 7.0 Hz, 1, H40),
4.37 (dt, J ¼ 4.4, 7.0 Hz, 0.5, H30), 4.43 (dt, J ¼ 4.1, 7.0 Hz, 0.5, H30),
6.28 ("q", J ¼ 7.0 Hz, 1, H10), 7.44 & 7.45 (2 ꢄ d, J ¼ 1.2 Hz, 1, H6); 13C
63.38 (C50), 73.5, 73.7 (OCH2), 81.3, 81.7 (C20), 85.67, 85.70 (C40),
89.29, 89.32 (C10), 121.2 (C5), 140.6 (C8), 148.4 (C4), 152.64, 152.66
(C2), 156.2 (C6); MS m/z 399 [M þ H]þ; HRMS m/z calcd for
C13H18N8NaO3S2 [M þ Na]þ 421.0835, found 421.0850.
4.1.18. 30-Azido-30-deoxy-3-N-methylthymidine (22). Freshly dis-
tilled diazomethane solution in ether (10 mL), generated from
NMR
d 13.3 & 13.4 (CH3), 27.83 & 27.85 (NCH3), 30.4, 30.5, 30.51, &
30.54 (Ac), 30.67 & 30.68 (SCH2), 37.9 (C20), 43.7 & 43.8 (SCH), 60.6