4284 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 22
Marwood et al.
3.57 (0.6 H, dd, J ) 3.7 Hz, 10.0 Hz, H-2R), 3.64 (0.4 H, ddd,
J ) 4.2 Hz, 4.2 Hz, 10.3 Hz, H-5â), 4.18 (0.6 H, ddd, J ) 3.9
Hz, 3.9 Hz, 10.2 Hz, H-5R), 4.41-4.64 (3.6 H, m, OCH2Ar), 4.74
(0.4 H, d, J ) 7.8 Hz, H-1R), 4.85 (0.4 H, AB, J AB ) 11.7 Hz,
OCH2Ar), 4.93 (0.4 H, dd, J ) 10.3 Hz, 10.3 Hz, H-4â), 5.01
(0.6 H, dd, J ) 9.8 Hz, 9.8 Hz, H-4R), 5.12 (0.4 H, dd, J ) 9.3
Hz, 9.3 Hz, H-3â), 5.25 (0.6 H, d, J ) 3.4 Hz, H-1R), 5.45 (0.6
H, dd, J ) 9.8 Hz, 9.8 Hz, H-3R), 7,23-7.33 (10 H, m, ArCH);
13C NMR (CDCl3, 100.4 MHz) δC 20.61, 20.65, 20.72, 20.84 (4
q, 2 × CH3COR and â), 68.07, 68.64 (2 t, C-6R and â), 68.07, 69.22,
69.38, 72.02, 72.73, 73.99 (6 d, C-5R and â, C-4R and â, C-3R and â),
72.90, 73.43, 73.48, 74.19 (4 t, 2 × OCH2ArR and â), 76.88, 79.57
127.80, 127.98, 128.33 (6 d, ArCH), 137.49, 137.80, 138.80 (3
s, 3 × C-1 of Bn rings), 169.68, 170.23 (2 s, 2 × CH3CO); MS
m/z (+ve ion FAB) 729 [(M + Na)+, 8%], 91 (100). Anal.
(C39H46O12) C, H.
3′,4′-Di-O-acetyl-2′,5,6′-tr i-O-ben zyl-3-O-r-D-glu copyr an -
osyl-D-r ibofu r a n ose (21). Compound 20 (672 mg, 0.95 mmol)
was heated at reflux for 15 min in a mixture of acetic acid/
water/ethylene glycol (14/6/3, v/v/v, 25 mL). After cooling, the
reaction mixture was slowly poured into saturated NaHCO3
(75 mL). This aqueous suspension was extracted with di-
chloromethane (3 × 75 mL) and the resulting organic layers
were combined, dried (MgSO4), filtered and concentrated
repeatedly from toluene to give a yellow oil which was
subjected to flash chromatography (eluent ethyl acetate/hexane
1:1) to give the title compound (477 mg, 0.71 mmol, 75%): Rf
0.45 (ethyl acetate/hexane 1:1); mp 126-128 °C (from ether);
(2 d, C-2R
â), 90.76, 97.27 (2 d, C-1R
â), 127.72, 127.78,
and
and
127.89, 127.98, 128.03, 128.33, 128.36, 128.42, 128.51 (9 d,
ArCH), 137.27, 137.40 (2 s, 2 × C-1 of Bn ring), 169.86, 169.91,
170.33, 170.41 (4 s, 2 × CH3COR
â), R and â subscripts
and
20
1
denote signals arising from R and â anomers, respectively; MS
m/z (-ve ion FAB) 443 [(M - H)-, 97%], 597 (100). Anal.
(C24H28O8) C, H.
[R]D 116.5 (c ) 0.2, CHCl3); H NMR (CDCl3, 400 MHz) δH
1.88, 1.89, 1.99, 2.00 (6 H, 4 s, 2 × CH3COR, 2 × CH3COâ),
3.27-3.36 (2 H, m, H-6′A, H-6′B), 3.44 (0.4 H, d, J ) 6.8 Hz,
D2O exch, OHâ-1), 3.52-3.67 (3 H, m, H-5A, H-5B, H-2′), 3.72
(0.4 H, d, J ) 6.3 Hz, D2O exch, OHâ-2), 3.82 (0.6 H, d, J ) 9.3
Hz, D2O exch, OHR-1), 3.90 (1 H, ddd, J ) 3.4 Hz, 3.4 Hz, 10.3
Hz, H-5′), 4.00-4.02 (0.4 H, m, H-4â), 4.12-4.17 (1.2 H, m,
H-2R, H-3R), 4.24-4.29 (1 H, m, H-2â, H-4R), 4.32-4.72 (6.8 H,
m, 3 × OCH2Ar, H-3â, H-1′â), 4.98 (0.6 H, d, J ) 3.9 Hz, H-1′R),
5.01-5.08 (1 H, m, H-4′), 5.26-5.31 (1 H, m, H-1), 5.33-5.42
(1 H, m, H-3′), 7.22-7.38 (15 H, m, ArCH); 13C NMR (CDCl3,
100.4 MHz) δC 20.61, 20.87 (2 q, CH3CO), 67.36 (t, C-6′R), 67.46
(t, C-6′â), 68.67 (d, C-4′), 69.17 (d, C-5′R), 69.22 (d, C-5′â), 69.70
(t, C-5R), 70.10 (t, C-5â), 70.57 (d, C-2R or C-3R), 72.44 (d, C-3′â),
72.57 (d, C-3′R), 73.46, 73.53, 73.59,74.21 (4 t, 2 × OCH2ArR
and â), 74.63 (d, C-4â), 75.88 (d, C-2′â), 76.01 (d, C-2′R), 77.54 (d,
C-2R or C-3R), 78.55 (d, C-3â), 79.83, 80.56 (2d, C-2â and C-4R),
96.98 (d, C-1â), 97.53 (d, C-1′â), 97.86 (d, C-1′R), 102.47 (d, C-1R),
127.54, 127.67, 127.79, 127.82, 127.94, 128.00, 128.27, 128.33,
128.38, 128.51, 128.73, 128.77 (12 d, ArCH), 136.69, 136.74,
3,4-Di-O-a cet yl-2,6-d i-O-b en zyl-D-glu cop yr a n osyl d i-
m eth yl p h osp h ite (19). Bis(methoxy)(diethylamino)phos-
phine (966 mg, 5.86 mmol) was added to a mixture of
1H-tetrazole (477 mg, 6.76 mmol) and 18 in dichloromethane
(20 mL). TLC (ethyl acetate/hexane 2:3) after 30 min indicated
complete conversion to product (Rf 0.65). The reaction mixture
was partitioned between ether (100 mL) and water (80 mL).
The ethereal layer was washed with saturated NaCl (80 mL),
dried (MgSO4), filtered and concentrated, to give a clear oil of
sufficient purity to use in the next step: 1H NMR (CDCl3, 400
MHz) δH 1.88, 1.89, 1.90, 2.01 (6 H, 4 s, 2 × CH3COR, 2 ×
2
3
CH3COâ), 3.47 (0.5 H, ABX, J AB ) 11.0 Hz, J AX ) 3.9 Hz,
H-6Aâ), 3.50-3.59 (8 H, m, H-2â, H-6AR, H-6B, 2 × POCH3), 3.62
(0.5 H, dd, J ) 3.2 Hz, 10.0 Hz, H-2R), 3.68-3.73 (0.5 H, m,
H-5â), 4.14 (0.5 H, ddd, J ) 3.9 Hz, 3.9 Hz, 10.3 Hz, H-5R),
4.42-4.66 (3.5 H, m, OCH2Ar), 4.84 (0.5 H, AB, J AB ) 11.7
Hz, OCHHAr), 4.98-5.05 (1 H, m, H-1â, H-4â), 5.11 (0.5 H,
dd, J ) 9.8 Hz, 9.8 Hz, H-4R), 5.17 (0.5 H, dd, J ) 9.8 Hz, 9.8
Hz, H-3â), 5.45 (0.5 H, dd, J ) 9.3 Hz, 9.3 Hz, H-3R), 5.56 (0.5
H, dd, J H-P ) 8.3 Hz, 3.4 Hz, H-1R), 7.26-7.34 (10 H, m,
ArCH); 31P NMR (CD3OD, 161.7 MHz, 1H decoupled) δP 138.54
OPâ(OMe)2, 139.58 OPR(OMe)2.
137.20, 137.42, 137.86 (5 s, C-1 of Bn ringsR
â), 169.69,
and
170.19 (2 s, 2 × CH3CO), R and â subscripts denote signals
arising from R and â anomers, respectively; MS m/z (+ve ion
FAB) 689 [(M + Na)+, 12%], 91 (100). Anal. (C36H42O12) C, H.
1,2,3′,4′-Tetr a -O-a cetyl-2′,5,6′-tr i-O-ben zyl-3-O-r-D-glu -
cop yr a n osyl-D-r ibofu r a n ose (9). Diol 21 (635 mg, 0.95
mmol) was stirred in a mixture of acetic anhydride (0.5 mL)
and pyridine (5 mL) for 20 h. The solution was concentrated
repeatedly from toluene to give a runny clear oil which was
subjected to flash chromatography (eluent ethyl acetate/hexane
3:7) to yield the title compound (587 mg, 0.78 mmol, 82%): Rf
0.29 (ethyl acetate/hexane 3:7); mp 105-107 °C (from ethyl
acetate/hexane); [R]D20 98.2 (c ) 0.2, CHCl3); 1H NMR (CDCl3,
400 MHz) δH 1.86, 1.87, 1.93, 1.96 (12 H, 4 s, CH3CO), 3.29,
3′,4′-Di-O-acetyl-2′,5,6′-tr i-O-ben zyl-3-O-r-D-glu copyr an -
osyl-1,2-O-isop r op ylid en e-r-D-r ibofu r a n ose (20). A mix-
ture of 15 (1.51 g, 5.41 mmol), 19 (3.62 g, 6.76 mmol) and 4 Å
molecular sieves (6.00 g) in dioxane (36 mL) and toluene (12
mL) was stirred for 2 h, after which time zinc chloride (1.10
g, 8.11 mmol) and silver perchlorate (3.36 g, 16.22 mmol) were
added. The flask was wrapped in foil and the reaction mixture
stirred for 20 h whereupon TLC (ethyl acetate/hexane 3:7)
indicated loss of donor (Rf 0.55) and acceptor (Rf 0.24) and
appearance of product (Rf 0.24). Sodium bicarbonate (3.00 g);
ethyl acetate (100 mL) and water (75 mL) were added and the
mixture stirred for 30 min before being filtered through Celite.
The organic layer was washed with saturated NaCl (100 mL),
dried (MgSO4), filtered and concentrated to a clear oil that was
subjected to flash chromatography to yield the title compound
(3.08 g, 4.38 mmol, 81% based on acceptor): mp 125-127 °C
(from diisopropyl ether); [R]D20 101.6 (c ) 1.6, CHCl3); 1H NMR
(CDCl3, 400 MHz) δH 1.36, 1.53 (6 H, 2 s, 2 × isopropylidene
2
3
3
3.36 (2 H, ABX, J AB ) 10.7 Hz, J AX ) 3.9 Hz, J BX ) 2.4 Hz,
H-6′A, H-6′B), 3.56 (1 H, J ) 9.8 Hz, 3.4 Hz, H-2′), 3.63, 3.72 (2
2
3
3
H, ABX, J AB ) 11.2 Hz, J AX ) 3.9 Hz, J BX ) 2.9 Hz, H-5A,
H-5B), 3.88 (1 H, ddd, J ) 2.9 Hz, 2.9 Hz, 10.3 Hz, H-5′), 4.29
(1 H, AB, J AB ) 12.2 Hz, OCHHAr), 4.37-4.40 (1 H, m, H-4),
4.47-4.57 (4 H, m, 2 × OCH2Ar), 4.63-4.64 (2 H, m, H-3,
OCHHAr), 5.03-5.08 (2 H, m, H-1′, H-4′), 5.33 (1 H, d, J )
4.9 Hz, H-2), 5.38 (1 H, dd, J ) 9.3 Hz, 9.3 Hz, H-3′), 6.12 (1
H, s, H-1), 7.23-7.34 (15 H, m, ArCH); 13C NMR (CDCl3, 100.4
MHz) δC 20.45, 20.56, 20.63, 20.74, 20.83, 20.94, 21.05, 21.16
(8 q, 2 × CH3COR, 2 × CH3COâ), 67.52 (t, C-6′), 68.85 (d, C-5′),
69.00, 69.28 (2 t, C-5R and â), 71.89, 72.02 (2 d, C-3′R and â), 73.02
(d, C-2), 73.17, 73.26, 73.35, 73.41, 73.48, 73.55 (4 t and 2 d,
C-3R and â, 3 × OCH2ArR and â), 76.59, 76.76 (2d, C-2′R and â), 81.27
2
CH3), 1.88, 2.03 (6 H, 2s, CH3CO), 3.28, 3.34 (2 H, ABX, J AB
3
3
) 10.7 Hz, J AX ) 3.9 Hz, J BX ) 2.4 Hz, H-6′A, H-6′B), 3.61 (1
2
H, dd, J ) 3.7 Hz, 10.0 Hz, H-2′), 3.72 (1 H, ABX, J AB ) 11.5
Hz, J AX ) 3.7 Hz, H-5A), 3.79-3.84 (2H, m, H-5B, H-5′), 4.16
3
(1 H, dd, J ) 4.4 Hz, 9.3 Hz, H-3), 4.29-4.32 (2 H, m,
OCHHAr, H-4), 4.48-4.71 (6 H, m, 5 × OCHHAr, H-2), 5.10
(1 H, dd, J ) 10.0 Hz, 10.0 Hz, H-4′), 5.20 (1 H, d, J ) 3.9 Hz,
H-1′), 5.38 (1 H, dd, J ) 9.8 Hz, 9.8 Hz, H-3′), 5.83 (1 H, d, J
) 3.9 Hz, H-1), 7.23-7.31 (15 H, m, ArCH); 13C NMR (CDCl3,
100.4 MHz) δC 20.68, 20.89 (2 q, 2 × CH3CO), 26.66, 26.72 (2
q, 2 × isopropylidene CH3), 67.23 (t, C-6′), 67.78 (t, C-5), 68.49
(d, C-5′), 68.84, (d, C-4′), 71.51 (t, OCH2Ar), 72.06 (d, C-3′),
72.71 (d, C-3), 73.39, 73.59 (2 t, 2 × OCH2Ar), 75.62 (d, C-2′),
76.21 (d, C-2), 77.56 (d, C-4), 94.31 (d, C-1′), 104.32 (d, C-1),
113.04 (s, isopropylidene C(CH3)2), 127.58, 127.69, 127.74,
(d, C-4), 96.28, 96.47 (2d, C-1′R
â), 98.46, 98.50 (d, C-1R
and
and
â), 127.32, 127.61, 127.74, 127.91, 128.02, 128.36, 128.46 (7 d,
ArCH), 137.51, 137.76, 138.11 (3 s, 3 × C-1 of Bn rings),
169.35, 169.69, 170.17, 170.28 (4 s, 4 × CH3CO), R and â
subscripts denote signals arising from R and â anomers,
respectively; MS m/z (+ve ion FAB) 750 (M+, 1%), 91 (100).
Anal. (C40H46O14) C, H.
2′,3′′,4′′-Tr i-O-a cetyl-2′′,5′,6′′-tr i-O-ben zyl-3′-O-r-D-glu -
cop yr a n osyl-1-â-D-r ibofu r a n osid oim id a zole (22). A solu-
tion of 9 (412 mg, 0.55 mmol) in 1,2-dichloroethane (8 mL)