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S. Hanessian et al. / Tetrahedron 62 (2006) 5201–5214
ꢁ
for 3 h, warmed to 0 C, and quenched by adding satd
ꢀ78 C under argon atmosphere. The mixture was stirred
NMR (400 MHz, CDCl3, ppm): d 1.30 (s, 9H, PivO–);
3.28 (m, 1H, H-6); 3.37 (s, 3H, –OMe); 3.63 (d, 1H,
J¼12.0 Hz, H-5), 3.73 (d, 1H, J ¼10.0, J¼4.3 Hz, H-3a);
3.98 (d, 1H, J¼12.0 Hz, H-5); 4.42 (m, 2H, H-7 and H-
7a); 5.69 (t, 1H, J¼4.3 Hz, H-3); 5.82 (d. 1H, J¼4.3 Hz,
H-2), 7.24–7.51 (m, 5H, Ph–); 13C NMR (100 MHz,
CDCl3, ppm): d 26.9, 39.2, 56.6, 58.5, 65.0, 70.5, 73.5,
73.6, 76.9, 89.9, 126.9, 128.9, 130.5, 134.8, 176.8; FABMS
m/z: 408 (M+H+, 20), 298 (M+ꢀPhS, 100); HRMS (FAB)
calcd for C19H26N3O5S (M+H+) 408.1593; found 408.1601.
ꢁ
NaHCO3. The mixture was extracted with CH2Cl2
(30 mLꢂ3), and the combined organic layer was washed
with satd NaHCO3 and brine, dried over anhydrous
Na2SO4, filtered, and concentrated. Purification by flash sil-
ica chromatography (hexanes/EtOAc, 5:1) afforded the di-
thioacetal 30 as a colorless oil (473 mg, 0.88 mmol, 80%);
[a]D +41.0 (c 0.56, CHCl3); IR (neat): l 2918, 2109, 1723,
1439, 1268 cmꢀ1 1H NMR (400 MHz, CDCl3, ppm):
;
d 2.54 (d, 1H, J¼5.6 Hz, –OH); 3.35 (s, 3H, –OMe); 3.40
(m, 1H, H-5); 3.49 (dd, 1H, J¼12.5, J¼3.5 Hz, H-6), 3.56
(dd, 1H, J¼12.5, J¼2.4 Hz, H-6); 3.94 (t, 1H, J¼4.2 Hz,
H-4); 4.07 (m, 1H, H-3); 4.18 (t, 1H, J¼7.6 Hz, H-7), 4.95
(d, 1H, J¼2.5 Hz, H-20); 5.73 (dd, 1H, J¼7.6, J¼2.5 Hz,
H-10); 7.25–8.08 (m, 15H, Ph–); 13C NMR (100 MHz,
CDCl3, ppm): d 57.1, 61.5, 62.3, 63.6, 67.9, 74.6, 74.7,
76.7, 127.7, 128.3, 128.33, 128.9, 129.0, 129.3, 130.1,
132.3, 133.3, 133.7, 134.5, 166.2; FABMS m/z (relative
intensity): 537 (M+, 3), 428 (M+ꢀPhS, 16); HRMS (FAB)
calcd for C27H28N3O5S2 (M+H+) 538.1470; found
538.1453.
4.1.17. (2R, 3R, 3aR, 6R, 7R, 7aR)-7-Azido-2-(20,40-dioxo-
30,40-dihydro-2H-pyrimidin-10-yl)-6-methoxy-3-pivaloyl-
oxy-hexahydrofuro[3,2-b]pyran and (2R, 3R, 3aR, 6R,
7R, 7aR)-7-azido-2-(50-iodo-20,40-dioxo-30,40-dihydro-
2H-pyrimidin-10-yl)-6-methoxy-3-pivaloyloxy-hexahy-
drofuro [3,2-b]pyran (32, 33). To a solution of 31 (41 mg,
0.1 mmol), bis-TMS-uracil (40 mg, 0.16 mmol) and NIS
(45 mg, 0.2 mmol) in 4 mL dry CH2Cl2 was added TfOH
(10 mL) over several minutes. After stirring for 5 h, the mix-
ture was quenched by adding satd Na2S2O3, and extracted
with CH2Cl2 (30 mLꢂ3). The combined organic layer was
washed with satd NaHCO3, dried over anhydrous Na2SO4,
filtered, and concentrated. Purification by flash silica
chromatography (CH2Cl2/MeOH, 10:1) afforded the 32
(20 mg) and iodonucleoside 33 (8 mg) as colorless oils,
the combined yield was 80% based on recovered starting
material (10 mg). For 32: [a]D +114.5 (c 1.6, CHCl3); IR
4.1.16. (2R, 3R, 3aS, 6R, 7R, 7aR)-7-Azido-6-methoxy-2-
phenylsulfanyl-hexahydrofuro[3,2-b]pyran-3-ol (31). To
a solution of 30 (420 mg, 0.78 mmol) in 10 mL MeOH
was added anhydrous K2CO3 (5 mg) at room temperature
and the mixture was stirred for 30 min. The mixture was
evaporated under vacuum and the residue was purified by
flash silica chromatography (hexanes/EtOAc, 3:1) to afford
diol as a colorless oil (335 mg, 0.77 mmol). To a solution
of above diol in 10 mL dry CH2Cl2 was added NBS
(205 mg, 1.16 mmol) at room temperature under argon
atmosphere. After stirring for 30 min, the reaction was
quenched by adding satd Na2S2O3 (10 mL), and the mixture
was extracted with CH2Cl2 (20 mLꢂ3). The combined or-
ganic layer was washed with satd NaHCO3 and brine, dried
over anhydrous Na2SO4, filtered, and concentrated. Purifica-
tion by flash silica chromatography (hexanes/EtOAc, 10:1)
afforded alcohol as a colorless oil (190 mg, 0.59 mmol,
77%); [a]D +150.5 (c 0.54, CHCl3); IR (neat): 3402, 2918,
(neat): 2971, 2106, 1695, 1458, 1147 cmꢀ1 1H NMR
.
(400 MHz, CDCl3, ppm): d 1.25 (s, 9H, PivO–); 3.39 (m,
1H, H-6); 3.40 (s, 3H, –OMe); 3.68 (d, 1H, J¼13.4 Hz, H-
5); 3.80 (dd, 1H, J¼9.8, J¼5.1 Hz, H-7a); 4.08 (d, 1H,
J¼13.4 Hz, H-5); 4.21 (dd, 1H, J¼9.8, J¼3.0 Hz, H-3a);
4.45 (m, 1H, H-7); 5.30 (d, 1H, J¼3.0 Hz, H-3); 5.79 (d,
1H, J¼8.1 Hz, H-50); 5.85 (s, 1H, H-1); 7.44 (d, 1H,
J¼8.1 Hz, H-60); 8.29 (s, 1H, –NH); 13C NMR (100 MHz,
CDCl3, ppm): d 26.9, 38.8, 56.8, 59.2, 65.2, 71.9, 73.0,
74.4, 76.6, 89.6, 102.9, 139.4, 149.4, 162.5, 176.9; FABMS
m/z (relative intensity): 410 (M+H+, 10), 391 (M+ꢀH2O,
16), 298 (M+ꢀuracilyl, 16); HRMS (FAB) calcd for
C17H24N5O7 (M+H+) 410.1675; found 410.1662. For 33:
[a]D +123.4 (c 0.87, CHCl3); IR (neat): 2978, 2104, 1691,
2103, 1584, 1482, 1069 cmꢀ1
.
1H NMR (400 MHz,
CDCl3, ppm): d 2.59 (d, 1H, J¼2.0 Hz, –OH); 3.31 (dd,
1H, J¼2.4, J¼1.3 Hz, H-6); 3.73 (m, 1H, H-7); 3.78 (dd,
1H, J¼12.9, J¼1.6 Hz, H-5); 4.06 (d, 1H, J¼12.9 Hz, H-
5); 4.46 (m, 2H, H-3a and H-7a), 4.58 (m, 1H, H-3); 5.77
(d, 1H, J¼4.0 Hz, H-2); 13C NMR (100 MHz, CDCl3,
ppm): d 57.6, 58.7, 66.7, 70.6, 70.61, 73.4, 74.7, 92.8,
127.3, 129.4, 130.8, 132.5; FABMS m/z (relative intensity):
323 (M+, 25); HRMS (FAB) calcd for C14H18N3O4S
(M+H+) 324.1018; found 324.1012.
1611, 1136 cmꢀ1 1H NMR (400 MHz, CDCl3, ppm):
;
d 1.25 (s, 9H, PivO–); 3.40 (s, 3H, –OMe); 3.42 (m, 1H,
H-6); 3.72 (d, 1H, J¼13.1 Hz, H-5); 3.79 (dd, 1H, J¼10.1,
5.0 Hz, H-3a); 4.08 (d, 1H, J¼13.1, H-5); 4.25 (dd, 1H,
J¼10.1, J¼2.4 Hz, H-7a); 4.47 (s, 1H, H-7); 5.36 (d, 1H,
J¼5.0 Hz, H-3); 5.80 (s, 1H, H-2); 8.03 (s, 1H, H-60); 8.59
(s, 1H, –NH); 13C NMR (100 MHz, CDCl3, ppm): d 27.5,
39.4, 57.4, 59.9, 65.8, 68.8, 72.2, 73.4, 75.4, 77.3, 90.3,
144.7, 149.5, 159.8, 177.2; FABMS m/z (relative intensity):
536 (M+H+, 10), 298 (M+ꢀiodouracilyl, 26); HRMS (FAB)
calcd for C17H23N5O7I (M+) 536.0642; found 536.0664.
To a solution of 31 (170 mg, 0.53 mmol) in 5 mL dry pyri-
dine was added DMAP (200 mg), then pivaloyl chloride
(0.2 mL) at room temperature under argon atmosphere.
The mixture was stirred overnight and pyridine was removed
under reduced pressure. The residue was dissolved with
50 mL CH2Cl2, washed with satd NaHCO3, brine, dried
over anhydrous Na2SO4, filtered, and concentrated. Purifica-
tion by flash silica chromatography (hexanes/EtOAc, 5:1)
afforded the pivalate ester 31 as a colorless oil (214 mg,
0.53 mmol, quant.); [a]D +149.6 (c 0.51, CHCl3); IR
4.1.18. (2R, 3R, 3aS, 6S, 7R, 7aR)-[2-(20,40-Dioxo-30,40-
dihyro-2H-pyrimidin-10-yl)-3-hydroxyl-6-methoxy-
hexahydrofuro[3,2-b]pyran-7-yl]-urea (6-epi-N-
malayamycin) (34). To a solution of 32 (37 mg, 0.09 mmol)
in 4 mL anhydrous THF was added Me3P (1 M in toluene)
(250 mL, 0.25 mmol) at room temperature under argon at-
mosphere. After stirring for 30 min, 10 mL of H2O was
added, and the resulting mixture was refluxed for 40 min,
then evaporated. The residue was dried under reduced
(neat): 2977, 2931, 2104, 1742, 1480, 1146 cmꢀ1 1H
;