7516
C. Gauthier et al. / Tetrahedron 57 02001) 7513±7517
[a]D 213.45 .c 0.29, CHCl3); 1H NMR .300 MHz,
CDCl3): d1.15±1.60 .m, 10H, CH2), 2.05 .s, 3H), 2.45
.d, J2.2 Hz, 1H, H5), 3.98 .dd, J5.3, 9.0 Hz, 1H, H1),
4.10 .dd, J6.4 and 9.0 Hz, 1H, H1), 4.27 .ddd, J5.3, 6.4
and 7.5 Hz, 1H, H2), 5.38 .dd, J2.2 and 7.5 Hz, 1H, H3);
13C NMR .75 MHz, CDCl3): d23.67, 23.80, 24.93, 29.60,
34.76, 36.05, 65.06, 65.72, 74.87, 75.71, 77.15, 111.33,
169.54; IR .KBr, neat): 2924, 2852, 1746, 1454, 1368,
1226, 1098 cm21; C13H18O4 .238.28): calcd C 65.55, H
7.56; found C 65.49, H 7.82.
4.52 .dd, J4.9 and 6.4 Hz, 0.4H, H1, 8b), 4.55 .dd, J3.8
and 7.8 Hz, 0.6H, H1, 8a); IR .KBr, neat): 2971, 2929, 2859,
2101, 1443, 1381, 1348, 1124, 1073 cm21; MS .EI, 70 eV);
m/z .rel. int.): 285 .8) [M1], 242 .7) [M12HN3], 222 .2),
199 .6), 156 .8), 141 .38), 127 .80), 113 .38), 75 .90), 55
.100). C13H23O4N3 .285.34): calcd C 54.74, H 8.07; found C
55.06, H 8.18.
20
1.3. AZT: 30a-Azido-30-deoxy-b-thymidine )1a)
Under argon, silylated thymine nucleobase 9 .0.23 g,
0.85 mmol, 1.40 equiv.)7 was added to .4R)-3-azido-1,1-
1.2.5. 4,5-O-Cyclohexylidene-2,3-dideoxy-3-azido-alde-
hydo-d-glycero-pentanose )7). According to a previously
reported procedure,1j conjugated aldehyde 4 .0.94 g,
4.80 mmol, 1.00 equiv.) in acetic acid .10 mL, 80%) was
added to NaN3 .0.71 g, 10.92 mmol, 2.30 equiv.) in acetic
acid .35 mL, 80%). The mixture, stirred for 3 h at room
temperature, was treated with H2O .60 mL) and extracted
with CH2Cl2 .3£45 mL). The combined extracts were
washed with cooled aqueous saturated NaHCO3 .160 mL)
and H2O .2£45 mL), dried over MgSO4 and concentrated to
give azido derivative 7 .1.14 g, colourless oil) in 99% yield
as a mixture of two stereomers 7a and 7b; the ratio was
dimethoxy-4,5-O-cyclohexylidene pentane
8
.0.17 g,
0.60 mmol, 1.00 equiv.) in anhydrous CH3CN .5 mL). A
solution of trimethylsilyltri¯ate .0.14 mL, 0.63 mmol,
1.05 equiv.) in CH3CN .0.5 mL) was added dropwise to
the above mixture maintained at 2308C. The mixture was
stirred for 2 h 30 min at 2308C, 2 h at 2208C then 36 h at
room temperature before addition of CH2Cl2 .20 mL) and
treatment by aqueous saturated NaHCO3 until basic
medium. The aqueous phase was extracted with CH2Cl2.
The combined extracts were dried over MgSO4 and concen-
trated to give an oil containing the four diastereomers 1a±d
and the non cyclisated derivative .4R)-3-azido-1-methoxy-
1-thyminyl-4,5-O-cyclohexylidene pentane 10 .1a±d/
1
determined by GC analysis and by H NMR spectroscopy
20
1
.7a/7b60:40); [a]D 225.20 .c 2.52, C6H6); H NMR
.300 MHz, CDCl3): d1.30±1.70 .m, 10H, CH2, 7a, 7b),
2.50±2.80 .m, 2H, H2, 7a, 7b), 3.72 .dd, J6.1 and 8.4 Hz,
0.4H, H5, 7b), 3.80 .m, 1H, H3, 7b, H5, 7a), 3.85±4.01 .m,
1.8H, H5, 7b, H3, 7a, H4, 7a, H5, 7a), 4.14 .dd, J6.0 and
12.0 Hz, 0.4H, H4, 7b), 9.80 .m, 1H, H1, 7a, 7b); 13C NMR
.75 MHz, CDCl3): d.7a, 7b): 23.58, 23.80, 23.83, 24.90,
24.93, 34.30, 34.37, 35.78, 35.98, .7a): 44.98 C2, 58.06 C3,
65.95 C5, 76.45 C4, 110.68 Cacet., 198.60 C1, .7b): 44.03 C2,
57.12 C3, 65.46 C5, 76.78 C4, 110.72 Cacet., 198.46 C1; IR
.KBr, neat): 3106, 3036, 2949, 2887, 2110, 1731, 1701,
1482, 1461, 1377, 1268, 1153, 1103 cm21; MS .EI,
70 eV); m/z .rel. int.): 239 .9) [M1], 205 .4), 196 .12)
[M12HN3], 169 .3), 152 .20), 141 .31), 81 .100), 54 .17).
1
1088:12; ratios were determined by H NMR spectro-
scopy analysis). By silica gel column chromatography
.CHCl3/CH3OH95:5) we have succeeded to isolate and
identify the pure AZT .1a) .0.060 g) as a white solid in
38% yield, the different diastereomers 1b±d .1b/1c/
1d25:13:12, respectively, 0.040, 0.021 and 0.019 g) and
the .4R)-3-azido-1-methoxy-1-thyminyl-4,5-O-cyclohexyl-
idene pentane 10 .0.030 g) in 12% yield. The analytical
data of 1a were consistent with those published and with
the ones obtained from a commercial available sample.
1.3.1. 30a-Azido-30-desoxy-a-thymidine )1b). White solid;
mp 73±748C; 1H NMR .300 MHz, CDCl3): d1.55 .s, 1H,
0
H6 ), 1.95 .d, J1.1 Hz, 3H, CH3), 2.16 .dt, J4.2 and
0
14.7 Hz, 1H, H2 b), 2.84 .ddd, J6.8, 6.9 and 14.7 Hz,
1.2.6. 4,5-O-Cyclohexylidene-2,3-dideoxy-3-azido-1,1-di-
methoxy-d-glycero-pentanose )8). Under argon, a solution
of TiCl4 .1.34 mL of a 1 M solution in CH2Cl2, 1.34 mmol,
0.17 equiv.) was added dropwise to .4R)-3-azido-4,5-O-
cyclohexylidene pentanal .7) .1.88 g, 7.87 mmol,
1.00 equiv.) in anhydrous CH3OH .17 mL) cooled to 08C.
The mixture was stirred at 08C for 1 h then at room tempera-
ture for 3 h. Et3N .0.19 mL, 1.39 mmol, 0.18 equiv.) was
added and the mixture was stirred at 08C for 10 min before
treatment with H2O .60 mL). After extraction with CH2Cl2,
the organic layer was washed with H2O .60 mL) dried over
MgSO4. Evaporation has given an oil, which was puri®ed by
¯orisil column chromatography .pentane/Et2O80:20) to
afford 8 .1.46 g) in 65% yield as a mixture of two stereo-
mers 8a and 8b .8a/8b60:40), the ratio was determined by
GC analysis and by 1H NMR spectroscopy. 1H NMR
.300 MHz, CDCl3): d1.30±1.70 .m, 10H, CH2, 8a, 8b),
1.50±1.70 .m, 0.8H, H2, 8b), 1.60 .m, 0.6H, H2, 8a), 1.88
.ddd, J3.4, 7.8 and 14.3 Hz, 0.6H, H2, 8a), 3.30 .s, 1.2H,
CH3, 8b), 3.35 .s, 1.2H, CH3, 8b), 3.38 .s, 1.8H, CH3, 8a),
3.40 .s, 1.8H, CH3, 8a), 3.40 .m, 0.4H, H3, 8b), 3.65 .m,
0.6H, H3, 8a), 3.72 .dd, J6.6 and 8.0 Hz, 0.4H, H5, 8b),
3.82 .dd, J5.5 and 7.7 Hz, 0.6H, H5, 8a), 4.00 .m, 0.4H,
H5, 8b), 4.02 .m, 1.2H, H4,5, 8a), 4.08 .m, 0.4H, H4, 8b),
0
0
1H, H2 a), 3.65 .dd, J3.4 and 12.1 Hz, 1H, H5 ), 3.71 .m,
0
0
1H, H4 ), 3.85 .dd, J3.0 and 12.1 Hz, 1H, H5 ), 4.20±4.30
0
0
.m, 1H, H3 ), 6.22 .dd, J4.2 and 6.9 Hz, 1H, H1 ), 7.27 .d,
J1.1 Hz, 1H, H6), 8.10±8.20 .s, 1H, H3); 13C NMR
0
0
.75 MHz, CDCl3): d12.59 CH3, 38.15 C2 , 60.60 C3 ,
0
0
0
62.55 C5 , 85.92 C4 , 85.74 C1 , 110.99 C5, 135.04 C6,
150.12 C4, 163.33 C2; IR .KBr, neat): 3390, 3197, 3062,
1694, 1472, 1270, 1100 cm21; C10H13O4N5 .267.24 g):
calcd C 44.94, H 4.87; found: C 44.88, H 5.05.
1.3.2. 30b-Azido-30-desoxy-b-thymidine )1c). Colourless
0
1
oil; H NMR .300 MHz, CDCl3): d1.50 .s, 1H, H6 ),
1.90 .d, J0.8 Hz, 3H, CH3), 2.50 .dt, J6.5 and 14.3 Hz,
0
0
1H, H2 b), 2.67 .ddd, J2.3, 6.5 and 14.3 Hz, 1H, H2 a), 3.88
0
0
.m, 2H0, H5 ), 4.42 .m, 1H, H3 ), 4.47 .dt, J4.9 and 10.6 Hz,
0
1H, H4 ), 6.04 .t, J6.5 Hz, 1H, H1 ), 7.07 .d, J0.8 Hz, 1H,
0
H6); 13C NMR .75 MHz, CDCl3): d12.59 CH3, 38.25 C2 ,
0
0
0
0
61.47 C5 , 61.90 C3 , 83.66 C4 , 87.43 C1 , 111.06 C5, 135.11
C6, 150.28 C4, 163.59 C2; IR .KBr, neat): 3400, 3100, 1694,
1652, 1470, 1270, 1056.
1.3.3. 30b-Azido-30-desoxy-a-thymidine )1d). Colourless
0
oil; 1H NMR .300 MHz, CDCl3): d1.60 .s, 1H, H6 ), 1.95