Biological EValuation of Aza-C-disaccharides
J. Am. Chem. Soc., Vol. 119, No. 21, 1997 4863
66.62, 68.12, 70.79, 70.96, 71.52, 72.44, 74.25, 102.08; FAB MS for
to warm to rt, and stirring was continued for another 18 h. The reaction
was quenched at rt with CH3OH (5 mL), poured into Et2O, and washed
with 10 mL of H2O/saturated aqueous Rochelle’s salt (1:1) and finally
with brine. The aqueous layers were extracted with Et2O (3×), and
the combined organic layers were dried over MgSO4. Filtration and
concentration followed by flash chromatography on silica gel (4:1 to
2:1 to 1:1, hexanes/EtOAc) gave 877 mg (74% from 28) of olefin 29
as a clear oil: Rf 0.77 (1:1, hexanes/EtOAc); IR (neat) 2988, 2932,
2895, 1032 cm-1; [R]20D +80.0° (c 0.74, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 3.36 (m, 1 H), 3.37 (s, 3 H), 3.40 (s, 3 H), 3.41 (s, 3 H),
3.42 (s, 3 H), 3.53 (dd, 1 H, J ) 10.0, 3.5 Hz), 3.92 (t, 1 H, J ) 9.0
Hz), 4.01 (dd, 1 H, J ) 10.0, 7.0 Hz), 4.66 (d, 1 H, J ) 7.0 Hz), 4.71
(d, 1 H, J ) 6.5 Hz), 4.78 (d, 1 H, J ) 6.5 Hz), 4.79-4.84 (m, 4 H),
5.29 (ddd, 1 H, J ) 10.0, 1.5, 1.0 Hz), 5.41 (ddd, 1 H, J ) 17.0, 1.5,
1.0 Hz), 5.92 (ddd, 1 H, J ) 17.0, 10.0, 7.0 Hz); 13C NMR (125 MHz,
CDCl3) δ 55.16, 55.47, 56.20, 56.37, 71.49, 78.07, 78.98, 79.62, 97.69,
98.09, 98.35, 98.98, 118.97, 135.35; FAB MS C14H26O8 (M+) 322.1627,
found (M++H) 323 (3.8%).
Compound 30. A solution of 9-BBN-H (303 mg, 2.48 mmol) in
THF (5 mL) was added to olefin 29 (402 mg, 1.25 mmol) at rt. The
resultant solution was heated to reflux for 6 h. The reaction mixture
was cooled to rt, and 3 M aqueous K3PO4 (1.04 mL, 3.11 mmol) was
added. After 15 min, a solution of vinyl bromide 11 (556 mg, 1.09
mmol) and PdCl2(dppf) (45 mg, 0.06 mmol) in DMF (8 mL) was added
Via cannula. The dark mixture was stirred at rt for 18 h. The reaction
mixture was poured into Et2O and washed with H2O and brine. The
aqueous layers were extracted with Et2O (3×), and the combined
organic layers were dried over MgSO4. Filtration and concentration
followed by flash chromatography on silica gel (2:1 to 1:1, hexanes/
EtOAc) gave 768 mg (93%) of olefin 30 as a clear oil: Rf 0.60 (1:1,
hexanes/EtOAc); IR (neat) 3444, 3347, 2949, 2930, 2894, 1727, 1500,
1051, 1030 cm-1; [R]20D +19.50° (c 1.52, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 0.05 (s, 3 H), 0.08 (s, 3 H), 0.85 (s, 9 H), 1.32 (s, 3 H), 1.35
(s, 3 H), 1.59 (m, 1 H), 2.03 (m, 1 H), 2.15 (m, 1 H), 2.42 (m, 1 H),
3.25 (t, 1 H, J ) 9.5 Hz), 3.37 (s, 3 H), 3.38 (s, 6 H), 3.39 (s, 3 H),
3.47 (dd, 1 H, J ) 10.0, 3.5 Hz), 3.54 (td, 1 H, J ) 9.5, 2.0 Hz), 3.85
(t, 1 H, J ) 9.5 Hz), 4.19 (m, 2 H), 4.43 (d, 1 H, J ) 5.5 Hz), 4.47 (d,
1 H, J ) 8.5 Hz), 4.66 (d, 1 H, J ) 6.5 Hz), 4.70 (d, 1 H, J ) 7.0 Hz),
4.75 (d, 1 H, J ) 3.5 Hz), 4.76 (d, 1 H, J ) 6.0 Hz), 4.77 (d, 1 H, J
) 6.0 Hz), 4.81 (d, 1 H, J ) 6.0 Hz), 4.92 (d, 1 H, J ) 6.5 Hz), 4.95
(d, 1 H, J ) 9.5 Hz), 5.09 (d, 1 H, J ) 12.0 Hz), 5.12 (d, 1 H, J )
12.0 Hz), 5.25 (s, 1 H), 7.29-7.76 (m, 5 H); 13C NMR (125 MHz,
CDCl3) δ -5.03, -4.71, 17.92, 25.68, 26.72, 27.79, 28.62, 28.80, 48.10,
55.27, 55.44, 56.24, 56.47, 66.67, 69.14, 69.76, 73.20, 75.83, 78.63,
79.07, 80.08, 97.62, 98.36, 98.48, 98.77, 109.56, 122.14, 128.04, 128.47,
136.57, 137.74, 155.70; MS (EI) calcd for C37H61NO13Si (M+)
755.3912, found (M+ - C4H9) 698 (5.4%), (CI) (M+ - CH3) 740
(0.2%), (M+ - CH3O) 724 (5.0%), (M+ - C4H9) 698 (3.5%).
C14H27NO9 (M+) 353.1686, found (M+ + H) 354 (71.0%).
Methyl 6-O-(tert-Butyldiphenylsilyl)-2,3,4-tri-O-(methoxymethyl)-
r-D-glucopyranoside (27). To a cold solution (0 °C) of triol 2617 (3.96
g, 9.17 mmol) in CH2Cl2 (40 mL) was added diisopropylethylamine
(9.6 mL, 55 mmol) dropwise, followed by the addition of chloromethyl
methyl ether (6.9 mL, 91 mmol). Solid tetrabutylammonium iodide
(6.7 g, 18.3 mmol) was then added to the reaction mixture, and the
solution was allowed to warm to rt. The reaction mixture was stirred
in the dark for 20 h. The reaction mixture was cooled to 0 °C, and 20
mL of saturated aqueous NH4Cl was added. The layers were separated,
and the organic layer was washed with brine. The aqueous layer was
extracted CH2Cl2 (4×), and the combined organic layers were dried
over MgSO4. Filtration and concentration followed by flash chroma-
tography on silica gel (2:1, hexanes/EtOAc) gave 4.62 g (89%) of fully
protected sugar 27 as a clear oil: Rf 0.65 (1:1, hexanes/EtOAc); IR
(neat) 3071, 3048, 2951, 2931, 2893, 1152, 1111, 1032, 703 cm-1
;
[R]20D +43.4° (c 1.45, CHCl3); 1H NMR (500 MHz, CDCl3) δ 1.06 (s,
9 H), 3.16 (s, 3 H), 3.41 (s, 3 H), 3.42 (s, 3 H), 3.43 (s, 3 H), 3.52 (dd,
1 H, J ) 10.0, 3.5 Hz), 3.54 (t, 1 H, J ) 9.5 Hz), 3.69 (ddd, 1 H, J )
10.0, 5.5, 2.0 Hz), 3.82 (dd, 1 H, J ) 11.0, 5.5 Hz), 3.91 (m, 2 H),
4.68 (d, 1 H, J ) 6.5 Hz), 4.74 (d, 1 H, J ) 7.0 Hz), 4.80 (d, 1 H, J
) 6.5 Hz), 4.81 (d, 2 H, J ) 7.0 Hz), 4.84 (d, 1 H, J ) 6.5 Hz), 4.85
(d, 1 H, J ) 3.5 Hz), 7.35-7.44 (m, 6 H), 7.71-7.73 (m, 4 H); 13C
NMR (125 MHz, CDCl3) δ 19.28, 26.76, 54.84, 55.50, 56.23, 63.13,
71.17, 76.55, 78.64, 79.14, 97.70, 98.42, 98.67, 127.53, 127.61, 129.57,
133.44, 133.64, 135.65, 135.82.
Methyl 2,3,4-Tri-O-(methoxymethyl)-r-D-glucopyranoside (28).
A cold (0 °C) solution of silyl ether 27 (4.62 g, 8.2 mmol) in THF (41
mL) was treated with 10.6 mL of tetrabutylammonium fluoride (1.0
M in THF, 10.6 mmol). The resultant solution was then warmed to
25 °C, and stirring was continued for 18 h. The reaction mixture was
poured into EtOAc and washed with saturated aqueous NH4Cl and brine.
The aqueous layers were extracted with EtOAc, and the combined
organic layers were dried over MgSO4. Filtration and concentration
followed by flash chromatography on silica gel (1:2, hexanes/EtOAc)
gave 2.29 g (86%) of alcohol 28 as a clear oil: Rf 0.44 (1:4, hexanes/
EtOAc); IR (neat) 3489, 2932, 2896, 1152, 1108, 1037 cm-1; [R]20
D
+105.9° (c 1.18, CHCl3); 1H NMR (500 MHz, CDCl3) δ 2.60 (br s, 1
H) (OH), 3.38 (s, 3 H), 3.39 (s, 3 H), 3.40 (s, 3 H), 3.43 (s, 3 H), 3.51
(dd, 1 H, J ) 10.0, 3.5 Hz), 3.56 (t, 1 H, J ) 9.5 Hz), 3.62 (ddd, 1 H,
J ) 10.0, 3.5, 2.0 Hz), 3.77 (dd, 1 H, J ) 12.5, 2.0 Hz), 3.88 (dd, 1
H, J ) 12.5, 3.5 Hz), 3.92 (t, 1 H, J ) 9.5 Hz), 4.69 (d, 1 H, J ) 6.0
Hz), 4.70 (d, 1 H, J ) 6.5 Hz), 4.76 (d, 1 H, J ) 6.5 Hz), 4.77 (d, 1
H, J ) 6.5 Hz), 4.81 (d, 1 H, J ) 3.5 Hz), 4.82 (d, 1 H, J ) 6.0 Hz),
4.91 (d, 1 H, J ) 6.5 Hz); 13C NMR (125 MHz, CDCl3) δ 55.15, 55.46,
56.10, 56.36, 61.59, 70.35, 76.57, 78.19, 79.04, 97.64, 98.19, 98.97,
99.11; HRMS (EI) calcd for C13H26O9 (M+) 326.1576 (M+ - CH3O)
295.1393, found 295.1397.
Disaccharide 31. Olefin 30 (52.3 mg, 0.069 mmol) was subjected
to the conditions of general procedure A to provide, after flash
chromatography on silica gel (20:1, CH2Cl2/CH3OH), 28.0 mg (63%)
of disaccharide 31 as a clear oil: Rf 0.50 (10:1, CH2Cl2:CH3OH); IR
Methyl 2,3,4-Tri-O-(methoxymethyl)-6-methylene-r-D-gluco-
pyranoside (29). To a cold (-78 °C) solution of DMSO (0.52 mL,
7.4 mmol) in CH2Cl2 (15 mL) was added trifluoroacetic anhydride (0.78
mL, 5.54 mmol) in CH2Cl2 (3 mL). The mixture was stirred for 10
min. Alcohol 28 (1.20 g, 3.7 mmol) in CH2Cl2 (4 mL) was added to
the cold reaction mixture slowly Via cannula, and the resultant solution
was stirred for 30 min. Triethylamine (1.44 mL, 10.3 mmol) was added
dropwise at -78 °C. The mixture was allowed to warm to rt after 10
min, and stirring was continued for another 20 min. The mixture was
then partitioned between CH2Cl2 and H2O. The organic layer was
washed with brine. The aqueous layer was extracted with CH2Cl2 (3×),
and the combined organic layers were dried over Na2SO4. After
filtration and removal of the solvent, the resultant oil was taken up in
Et2O and filtered through Celite to remove the remaining triethylamine
hydrochloride. Upon concentration, the corresponding aldehyde was
(neat) 3493, 3310, 2929, 1034 cm-1; [R]20 +46.1° (c 0.94, CHCl3);
D
1H NMR (500 MHz, CDCl3) δ 0.05 (s, 3 H), 0.13 (s, 3 H), 0.87 (s, 9
H), 1.34 (s, 3 H), 1.49 (s, 3 H), 1.54 (m, 1 H), 1.64 (m, 1 H), 1.86 (m,
1 H), 2.07 (m, 1 H), 2.19 (br m, 2 H), 2.54 (ddd, 1 H, J ) 10.0, 7.5,
3.5 Hz), 2.88 (td, 1 H, J ) 7.5, 2.5 Hz), 3.27 (t, 1 H, J ) 9.5 Hz), 3.38
(m, 1 H), 3.38 (s, 3H), 3.39 (s, 3 H), 3.40 (s, 3 H), 3.41 (m, 1 H), 3.41
(s, 3 H), 3.49 (dd, 1 H, J ) 9.5, 3.5 Hz), 3.58 (td, 1 H, J ) 9.5, 2.5
Hz), 3.87 (t, 1 H, J ) 9.5 Hz), 3.89 (m, 2 H), 4.07 (dd, 1 H, J ) 5.0,
2.5 Hz), 4.69 (d, 1 H, J ) 6.5 Hz), 4.70 (d, 1 H, J ) 6.5 Hz), 4.75 (d,
1 H, J ) 3.5 Hz), 4.76 (d, 1 H, J ) 7.0 Hz), 4.77 (d, 1 H, J ) 6.5 Hz),
4.82 (d, 1 H, J ) 6.5 Hz), 4.93 (d, 1 H, J ) 7.0 Hz); 13C NMR (125
MHz, CDCl3) δ -5.11, -3.99, 18.07, 25.86, 26.43, 27.59, 28.16, 28.23,
55.17, 55.45, 55.77, 56.24, 56.43, 60.87, 63.23, 69.71, 73.97, 75.89,
78.70, 79.09, 80.02, 81.09, 97.62, 98.38, 98.54, 98.75, 108.84; HRMS
(EI) calcd for C29H57NO12Si (M+) 639.3650 (M+ - CH3O) 608.3466,
found 608.3457.
1
obtained as determined by H NMR. This material was used without
further purification.
Potassium bis(trimethylsilyl)amide (16.25 mL, 0.5 M toluene, 8.12
mmol) was added dropwise at rt to a suspension of methyltri-
phenylphosphonium bromide (3.04 g, 8.5 mmol) in THF (40 mL). The
resultant bright yellow solution was stirred at rt for 1 h. The ylide
solution was then cooled to -78 °C, and a solution of the crude
aldehyde (3.69 mmol) in THF (15 mL) was added slowly by cannula.
After 30 min of stirring at -78 °C, the reaction mixture was allowed
Disaccharide 7. To a solution of protected disaccharide 31 (27.4
mg, 0.043 mmol) in CH3OH (1 mL) was added aqueous 6 N HCl (0.75
mL), and the mixture was stirred at rt for 18 h. The solvents were
then removed in vacuo. The oily residue was taken up in a minimal
amount of CH3OH, and the product was precipitated with Et2O. The