N-Acetylneuraminic Acid-Based Rotavirus Inhibitors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 6 1319
Hz, 1H, H-6), 2.90 (dd, J 6′,6 ) 13.9, J 6′,5 ) 7.3 Hz, 1H, H-6′),
3.35 (dd, J 2,3 ) 9.8, J 2,1 ) 7.9 Hz, 1H, H-2), 3.44 (s, 3H, OMe),
3.48 (dd, J 3,2 ) 9.8, J 3,4 ) 3.3 Hz, 1H, H-3), 3.62-3.66 (m, 1H,
H-5), 3.87 (d, J 4,3 ) 3.3 Hz, 1H, H-4), 4.15 (d, J 1,2 ) 7.9 Hz,
1H, H-1); 13C NMR29 (D2O) Neu5Ac unit-δ 25.2 (NC(O)Me),
43.3 (C-3), 54.7 (C-5), 65.9 (C-9), 70.9 (C-4), 71.1 (C-6), 74.6
(C-7), 78.1 (C-8), 86.8 (C-2), 175.6 (C-1), 178.1 (NC(O)Me); Gal
unit-δ 32.3 (C-6), 60.3 (OMe), 72.2 (C-4), 73.5 (C-2), 75.9
(C-3), 76.9 (C-5), 107.0 (C-1); FABMS 524 ((M + 1)+, 9), 502
(32), 469 (12), 292 (50), 277 (33), 274 (51), 257 (25), 201 (100).
Anal. (C18H30NO13SNa) C, H, N.
S -(5-Ace t a m id o-9-O-a ce t yl-3,5-d id e oxy-D-glycer o-r-D-
ga la cto-2-n on u lop yr a n osylon a t e)-(2f6)-6-t h io-r-D-glu -
cop yr a n osid e (21). To a solution of 14 (300 mg, 0.57 mmol)
in DMSO (2 mL) at room temperature under nitrogen was
added trimethyl orthoacetate (750 µL, 5.8 mmol) and p-Ts-
OH‚H2O (10 mg). The solution was stirred at room temper-
ature for 2 h and then applied to a column (7 × 1 cm) of Dowex
1-X4 (HCO2-) ion exchange resin (100-200 mesh). The
column was washed with water (50 mL) and then eluted with
formic acid (1 N, 100 mL). The eluant was concentrated under
reduced pressure and then purified by HPLC (H2O) to give 21
(230 mg, 74%) as a white solid: mp 151-154 °C; [R]D +112.9°
(c 0.72, H2O); IR 3420 (br), 1728, 1620, 1578, 1377, 1119, 1038
cm-1; 1H NMR28 (D2O) Neu5Ac unit-δ 1.74 (dd, J 3a,3e ) 12.4,
J 3a,4 ) 11.7 Hz, 1H, H-3a), 1.97 (s, 3H, AcN), 2.07 (s, 3H, OAc),
2.74 (dd, J 3e,3a ) 12.4, J 3e,4 ) 4.3 Hz, 1H, H-3e), 3.53-3.58 (m,
1H, H-7), 3.61-3.69 (m, 1H, H-4), 3.77 (dd, J 5,6 ) J 5,4 ) 10.1
Hz, 1H, H-5), 3.78 (dd, J 6,5 ) 10.1, J 6,7 ) 2.4 Hz, 1H, H-6),
4.01 (ddd, J 8,7 ) 8.7, J 8,9 ) 6.0, J 8,9′ ) 1.8 Hz, 1H, H-8), 4.12
(dd, J 9,9′ ) 11.7, J 9,8 ) 6.0 Hz, 1H, H-9), 4.35 (dd, J 9′,9 ) 11.7,
J 9′,8 ) 1.8 Hz, 1H, H-9′); Glc unit-δ 2.80 (dd, J 6,6′ ) 13.6, J 6,5
) 8.7 Hz, 1H, H-6), 3.20 (dd, J 4,3 ) 10.7, J 4,5 ) 3.4 Hz, 1H,
H-4), 3.26 (dd, J 6′,6 ) 13.6, J 6′,5 ) 3.1 Hz, 1H, H-6′), 3.35 (s,
3H, OMe), 3.50 (dd, J 2,3 ) 9.7, J 2,1 ) 3.7 Hz, 1H, H-2), 3.53-
3.58 (m, 1H, H-3), 3.61-3.69 (m, 1H, H-5), 4.68 (d, J 1,2 ) 3.7
Hz, 1H, H-1); 13C NMR29 (D2O) Neu5Ac unit-δ 23.0 (OC(O)-
Me), 24.8 (NC(O)Me), 43.5 (C-3), 54.4 (C-5), 68.3 (C-9), 71.0
(C-4), 72.1 (C-8), 73.1 (C-6), 77.1 (C-7), 87.2 (C-2), 177.1 (C-1),
177.7 (NC(O)Me/OC(O)Me); Glc unit-δ 32.9 (C-6), 57.8 (OMe),
71.2 (C-5), 74.0 (C-2), 75.5 (C-4), 75.6 (C-3), 101.8 (C-1);
FABMS 582 ((M + K)+, 18), 566 ((M + Na)+, 25), 315 (15),
Sodiu m 5-acetam ido-3,5-dideoxy-D-glycer o-r-D-ga la cto-
2-n on u lop yr a n osylon a t e-(2f6)-1,2-O-isop r op ylid en e-6-
th io-r-D-glu cofu r a n ose (17) was prepared in 72% yield after
HPLC (H2O) as an amorphous mass: mp 120-124 °C; [R]D
+10.3° (c 0.77, H2O); IR 3460 (br), 1712, 1620, 1378, 1214, 1070
1
cm-1; H NMR (D2O) Neu5Ac unit-δ 1.75 (dd, J 3a,3e ) 12.7,
J 3a,4 ) 11.2 Hz, 1H, H-3a), 1.90 (s, 3H, AcN), 2.68 (dd, J 3e,3a
)
12.7, J 3e,4 ) 4.5 Hz, 1H, H-3e), 3.42 (d, J 6,5 ) 9.8 Hz, 1H, H-6),
3.52 (dd, J 9,9′ ) 11.5, J 9,8 ) 5.8 Hz, 1H, H-9), 3.56 (dd, J 5,6
)
J 5,4 ) 9.8 Hz, 1H, H-5), 3.63 (ddd, J 4,3a ) 11.2, J 4,5 ) 9.8, J 4,3e
) 4.5 Hz, 1H, H-4), 3.73 (dd, J 9′,9 ) 11.5, J 9′,8 ) 2.7 Hz, 1H,
H-9′), 3.83-3.89 (m, 2H, H-7/H-8); Glc unit-δ 1.22, 1.39, (2 ×
s, 2 × 3H, 2 × (RO)2CMe), 2.79 (dd, J 6,6′ ) 13.3, J 6,5 ) 6.9 Hz,
1H, H-6), 3.11 (dd, J 6′,6 ) 13.3, J 6′,5 ) 2.1 Hz, 1H, H-6′), 3.71-
3.79 (m, 2H, H-4/H-5), 4.17 (d, J 3,4 ) 2.3 Hz, 1H, H-3), 4.55 (d,
J 2,1 ) 3.6 Hz, 1H, H-2), 5.88 (d, J 1,2 ) 3.6 Hz, 1H, H-1); 13C
NMR (D2O) Neu5Ac unit-δ 24.6 (NC(O)Me), 44.6 (C-3), 55.5
(C-5), 66.3 (C-9), 70.8 (C-4), 72.3 (C-8), 75.5 (C-6), 78.4 (C-7),
88.6 (C-2), 176.3 (C-1), 177.7 (NC(O)Me); Glc unit-δ 28.9, 29.3
(2 × (RO)2CMe), 37.3 (C-6), 71.9 (C-4), 77.3 (C-3), 85.6 (C-5),
88.2 (C-2), 108.3 (C-1), 116.3 ((RO)2CMe2); FABMS 572 ((M +
Na+, 8), 550 (16), 223 (25), 131 (60), 115 (100).
283 (47), 239 (30), 223 (98), 207 (95), 185 (100). Anal. (C20H33
-
NO14S‚2H2O) C, H, N.
The following were prepared in a similar manner.
Meth yl S-(sod iu m 5-a ceta m id o-3,5-d id eoxy-D-glycer o-
r-D-ga la cto-2-n on u lop yr a n osylon a t e)-(2f5)-5-t h io-D-r i-
bofu r a n osid e (18) was prepared in 74% yield after HPLC
(H2O) as an amorphous white solid: mp 120-125 °C; [R]D
+14.7° (c 0.97, H2O); IR 3385 (br), 1705, 1632, 1440, 1374,
1122, 1024 cm-1; 1H NMR (D2O) Neu5Ac unit-δ 1.78 (dd, J 3a,3e
) 12.7, J 3a,4 ) 11.9 Hz, 1H, H-3a), 1.94 (s, 3H, AcN), 2.72 (dd,
J 3e,3a ) 12.7, J 3e,4 ) 4.2 Hz, 1H, H-3e), 3.47 (d, J 6,5 ) 9.6 Hz,
1H, H-6), 3.52-3.59 (m, 2H, H-5/H-9), 3.65 (ddd, J 4,3a ) 11.9,
J 4,5 ) 10.0, J 4,3e ) 4.2 Hz, 1H, H-4), 3.74-3.83 (m, 3H, H-7/
H-8/H-9′); Rib unit-δ 2.91 (dd, J 5,5′ ) 13.7, J 5,4 ) 6.6 Hz, 1H,
H-5), 3.00 (dd, J 5′,5 ) 13.7, J 5′,4 ) 5.1 Hz, 1H, H-5′), 3.30 (s,
Meth yl S-(5-a ceta m id o-9-O-a cetyl-3,5-d id eoxy-D-glyc-
er o-r-D-ga la cto-2-n on u lop yr a n osylon a te)-(2f6)-2-a ceta -
m id o-2-d eoxy-6-th io-r-D-glu cop yr a n osid e (22) was pre-
pared in 78% yield after HPLC (H2O) as an amorphous white
solid: mp 166-170 °C; [R]D +101.6° (c 0.52, H2O); IR 3395
(br), 1720, 1640, 1548, 1438, 1378, 1266, 1126, 1040 cm-1; 1H
NMR28 (D2O) Neu5Ac unit-δ 1.83 (dd, J 3a,3e ) 12.4, J 3a,4
)
11.6 Hz, 1H, H-3a), 2.10 (s, 3H, OAc), 2.77 (dd, J 3e,3a ) 12.4,
J 3e,4 ) 4.5 Hz, 1H, H-3e), 3.57 (dd, J 7,8 ) 8.7, J 7,6 ) 1.4 Hz,
1H, H-7), 3.62-3.72 (m, 2H, H-4/H-6), 3.83 (dd, J 5,6 ) J 5,4
)
10.1 Hz, 1H, H-5), 4.05 (ddd, J 8,7 ) 8.7, J 8,9 ) 6.0, J 8,9′ ) 2.0
Hz, 1H, H-8), 4.15 (dd, J 9,9′ ) 11.6, J 9,8 ) 6.0 Hz, 1H, H-9),
4.38 (dd, J 9′,9 ) 11.6, J 9′,8 ) 2.0 Hz, 1H, H-9′); GlcNAc unit-δ
3H, OMe), 3.97 (d, J 2,3 ) 4.6 Hz, 1H, H-2), 4.02 (ddd, J 4,5
)
6.6, J 4,3 ) 6.0, J 4,5′ ) 5.1 Hz, 1H, H-4), 4.13 (dd, J 3,4 ) 6.0, J 3,2
) 4.6 Hz, 1H, H-3), 4.78 (s, 1H, H-1). 13C NMR (D2O) Neu5Ac
unit-δ 24.7 (NC(O)Me), 43.1 (C-3), 54.3 (C-5), 65.4 (C-9), 74.1,
76.1, 77.0, 77.5 (C-4/C-6/C-7/C-8), 86.8 (C-2), 175.8 (C-1), 177.6
(NC(O)Me); Rib unit-δ 35.3 (C-5), 57.8 (OMe), 70.8, 70.9
(C-2/C-3), 83.8 (C-4), 110.6 (C-1); FABMS 472 ((M - Na)+, 5),
292 (10), 277 (34), 257 (20), 215 (27), 201 (100).
2.87 (dd, J 6,6′ ) 13.8, J 6,5 ) 8.8 Hz, 1H, H-6), 3.29 (dd, J 6′,6
)
13.8, J 6′,5 ) 2.6 Hz, 1H, H-6′), 3.33-3.37 (m, 1H, H-4), 3.34 (s,
3H, OMe), 3.58-3.72 (m, 2H, H-3/H-5), 3.89 (dd, J 2,3 ) 10.4,
J 2,1 ) 3.6 Hz, 1H, H-2), 4.66 (d, J 1,2 ) 3.6 Hz, 1H, H-1);
others-δ 1.99, 2.00 (2 × s, 2 × 3H, 2 × AcN); 13C NMR29 (D2O)
Neu5Ac unit-δ 22.8 (OC(O)Me), 42.6 (C-3), 54.1 (C-5), 68.5
(C-9), 70.3 (C-4), 70.9 (C-7), 71.1 (C-8), 77.0 (C-6), 84.5 (C-2),
174.8 (C-1), 177.3 (OC(O)Me); GlcNAc unit-δ 32.4 (C-6), 56.1
(C-2), 57.6 (OMe), 72.6 (C-5), 73.4 (C-3), 75.5 (C-4), 100.4
(C-1); others-δ 24.4, 24.6 (2 × NC(O)Me), 176.8 (2 × NC(O)-
Me); FABMS 585 ((M + 1)+, 75), 334 (47), 316 (68), 252 (51),
220 (73), 201 (68), 185 (100). Anal. (C22H35N2O14SNa‚2H2O)
C, H, N.
Meth yl S-(sod iu m 5-a ceta m id o-3,5-d id eoxy-D-glycer o-
r-D-ga la cto-2-n on u lop yr a n osylon a t e)-(2f4)-4-t h io-â-D-
glu cop yr a n osid e (19) was prepared in 77% yield after HPLC
(H2O) as an amorphous white solid: mp 140-145 °C; [R]D
+189.6° (c 1.10, H2O); IR 3430 (br), 1710, 1640, 1552, 1376,
1275, 1058 cm-1 1H NMR28 (D2O) Neu5Ac unit-δ 1.83 (dd,
;
J 3a,3e ) 12.1, J 3a,4 ) 11.9 Hz, 1H, H-3a), 1.97 (s, 3H, AcN), 2.80
(dd, J 3e,3a ) 12.1, J 3e,4 ) 4.2 Hz, 1H, H-3e), 3.48-3.53 (m, 1H,
H-7), 3.55 (dd, J 9,9′ ) 12.3, J 9,8 ) 5.8 Hz, 1H, H-9), 3.62 (d, J 6,5
Met h yl
S-(5-a cet a m id o-9-O-a cet yl-3,5-d id eoxy-D-
glycer o-r-D-ga la cto-2-n on u lop yr a n osylon a te)-(2f6)-4-O-
a cetyl-6-th io-â-D-ga la ctop yr a n osid e (23) was prepared in
63% yield after HPLC (H2O) as an amorphous white solid: mp
164-167 °C; [R]D +57.5° (c 0.71, H2O); IR 3455 (br), 1726, 1640,
1552, 1376, 1246, 1062 cm-1; 1H NMR28 (D2O) Neu5Ac unit-δ
1.80 (dd, J 3a,3e ) 12.1, J 3a,4 ) 11.4 Hz, 1H, H-3a), 2.00 (s, 3H,
AcN), 2.76 (dd, J 3e,3a ) 12.1, J 3e,4 ) 4.3 Hz, 1H, H-3e), 3.59
(dd, J 7,8 ) 8.2, J 7,6 ) 1.5 Hz, 1H, H-7), 3.62 (dd, J 6,5 ) 10.2,
J 6,7 ) 1.5 Hz, 1H, H-6), 3.72 (ddd, J 4,3a ) 11.4, J 4,5 ) 10.2,
J 4,3e ) 4.3 Hz, 1H, H-4), 3.80-3.84 (m, 1H, H-5), 3.96 (ddd,
) 10.2 Hz, 1H, H-6), 3.68 (ddd, J 4,3a ) 11.9, J 4,5 ) 10.2, J 4,3e
)
4.2 Hz, 1H, H-4), 3.79-3.86 (m, 3H, H-5/H-8/H-9); Gal unit-δ
2.82 (dd, J 4,3 ) J 4,5 ) 10.2 Hz, 1H, H-4), 3.22 (dd, J 2,3 ) 9.2,
J 2,1 ) 8.0 Hz, 1H, H-2), 3.47 (dd, J 3,4 ) 10.2, J 3,2 ) 9.2 Hz, 1H,
H-3), 3.49-3.53 (m, 1H, H-5), 3.50 (s, 3H, OMe), 3.73 (dd, J 6,6′
) 12.2, J 6,5 ) 6.5 Hz, 1H, H-6), 4.15 (dd, J 6′,6 ) 12.2, J 6′,5
)
1.8 Hz, 1H, H-6′), 4.27 (d, J 1,2 ) 8.0 Hz, 1H, H-1); 13C NMR29
(D2O) Neu5Ac unit-δ 24.6 (NC(O)Me), 43.1 (C-3), 54.1 (C-5),
65.5 (C-9), 70.4 (C-4), 70.8 (C-7), 73.4 (C-6), 77.5 (C-8), 86.5
(C-2), 174.7 (C-1), 177.5 (NC(O)Me); Glc unit-δ 49.5 (C-4), 59.5
(OMe), 64.5 (C-6), 76.6 (2 ×) (C-2/C-3), 78.3 (C-5), 105.5 (C-1);
FABMS 524 ((M + 1)+, 4), 502 (25), 470 (13), 292 (74), 274
(73), 201 (32), 185 (100). Anal. (C18H30NO13SNa) C, H, N.
(iv) Syn th esis of 9-O-Acetyl Der iva tives of r-(2f6)-
Th ioglycosid es of N-Acetyln eu r a m in ic Acid . Meth yl
J 8,7 ) 8.2, J 8,9 ) 6.5, J 8,9′ ) 2.1 Hz, 1H, H-8), 4.14 (dd, J 9,9′
)
11.7, J 9,8 ) 6.5 Hz, 1H, H-9), 4.39 (dd, J 9′,9 ) 11.7, J 9′,8 ) 2.1
Hz, 1H, H-9′); Gal unit-δ 2.78 (dd, J 6,6′ ) 14.0, J 6,5 ) 6.2 Hz,
1H, H-6), 2.88 (dd, J 6′,6 ) 14.0, J 6′,5 ) 7.2 Hz, 1H, H-6′), 3.46
(dd, J 2,3 ) 9.7, J 2,1 ) 7.9 Hz, 1H, H-2), 3.54 (s, 3H, OMe), 3.80-
3.84 (m, 1H, H-3), 3.90 (dd, J 5,6′ ) 7.2, J 5,6 ) 6.2 Hz, 1H, H-5),