A R T I C L E S
Liu and Gin
1
Taken collectively, all of the 13C and H NMR data thus
obtained are consistent with the reaction outlined in Scheme 5,
Path B for C2-amidoglycosylation, a process that involves: (1)
activation of the glycal donor by the 11‚Tf2O from the top (â)
face to give C2-sulfonium intermediate 33; (2) nucleophilic
attack of the amide oxygen at the C1 position of 33 to afford
C2-sulfonium glycosyl imidate 39; (3) intramolecular displace-
ment of thianthrene from C2 by imidate nitrogen at the C2-
position to provide oxazoline 37; and (4) oxazoline ring opening
by glycosyl acceptor under acidic conditions to yield the final
2-N-acylamino-2-deoxy-â-pyranoside 38.
(neat film): 3274, 2932, 2867, 1732, 1652, 1566, 1453, 1371, 1316,
1285, 1170, 1115, 1078, 1029, 985, 745, 697 cm-1. HRMS (FAB)+
m/z calcd for C54H81NO7Na (M + Na)+, 878.5911; found, 878.5914.
Method (B): Benzyl O-(2-N-Acetylamino-2-deoxy-3,4,6-tri-O-
benzyl-â-D-glucopyranosyl)-(1-4)-2,3-O-cyclohexylidene-r-L-rham-
nopyranoside (16). Trifluoromethanesulfonic anhydride (24 µL, 0.144
mmol, 2.0 equiv) was added to a solution of 3,4,6-tri-O-benzyl-D-glucal
(30 mg, 0.072 mmol, 1.0 equiv) and thianthrene-5-oxide (33.5 mg, 0.144
mmol, 2.0 equiv) in a mixture of chloroform and dichloromethane (2.4
mL; 3:1 v/v) at -78 °C. The reaction mixture was stirred at this
temperature for 12 min, then N,N-diethylaniline (45 µL, 0.29 mmol,
4.0 equiv) was added, followed by N-(TMS)acetamide (28 mg, 0.22
mmol, 3.0 equiv). The mixture was immediately warmed to 23 °C and
was stirred at this temperature for 40 min. A solution of benzyl 2,3-
O-cyclohexylidene-R-L-rhamnopyranoside (72 mg, 0.22 mmol, 3.0
equiv) in 1.0 mL of dichloromethane was added via cannula. Cam-
phorsulfonic acid (33.5 mg, 0.144 mmol, 2.0 equiv) was then added,
and the reaction was stirred for 40 h. The mixture was diluted with 40
mL of dichloromethane and washed with 40 mL of saturated aqueous
sodium bicarbonate solution and 40 mL of saturated aqueous sodium
chloride solution. The organic layer was dried over MgSO4 and
concentrated, and the residue was purified by silica gel flash column
chromatography (94:6 dichloromethane/ethyl acetate) to afford the
product (31 mg, 53% yield) as a white solid (mp 153-154 °C). Rf )
Conclusion
A one-pot C2-amidoglycosylation reaction for the synthesis
of 2-N-acylamino-2-deoxy-â-pyranosides from glycals was
developed. Both the C2-nitrogen transfer and the glycosidic bond
formation proceed stereoselectively, allowing for the introduc-
tion of both natural and nonnatural amide functionalities at C2
with concomitant anomeric bond formation in a one-pot
procedure. Tracking of the reaction by low-temperature NMR
spectroscopy employing 15N- and 18O-isotope labels suggests a
mechanism involving the formation of the C2-sulfonium gly-
cosyl imidate 39 as well as oxazoline 37 as key intermediates
in this oxidative glycosylation with glycals. These studies
provide critical insights into the pathway of nitrogen transfer
and should facilitate the development of this method for the
nitrogen transfer to electron-rich olefins in general.
25
0.07 (94:6 dichloromethane/ethyl acetate). [R]D ) -13.8 (c ) 0.55,
CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.38-7.27 (m, 18H), 7.25-
7.23 (m, 2H), 5.52 (d, 1H, J ) 8.6 Hz), 5.05 (s, 1H), 4.83 (d, 1H, J )
11.4 Hz), 4.82 (d, 1H, J ) 10.9 Hz), 4.71 (d, 1H, J ) 8.5 Hz), 4.69 (d,
1H, J ) 11.1 Hz), 4.68 (d, 1H, J ) 12.2 Hz), 4.63 (d, 1H, J ) 12.2
Hz), 4.62 (d, 1H, J ) 10.8 Hz), 4.56 (d, 1H, J ) 12.2 Hz), 4.48 (d,
1H, J ) 11.7 Hz), 4.12 (d, 1H, J ) 4.9 Hz), 4.07 (dd, 1H, J ) 7.4, 5.7
Hz), 3.86 (dt, 1H, J ) 9.8, 8.5 Hz), 3.76 (dd, 1H, J ) 11.2, 4.3 Hz),
3.73 (dd, 1H, J ) 12.0, 6.2 Hz), 3.74-3.68 (m, 2H), 3.64 (dd, 1H, J
) 9.9, 8.7 Hz), 3.46 (dd, 1H, J ) 10.0, 7.4 Hz), 3.44 (ddd, 1H, J )
9.4, 4.2, 2.2 Hz), 1.88 (s, 3H), 1.70 (q, 1H, J ) 8.3 Hz), 1.65-1.47
(m, 7H), 1.41-1.36 (m, 2H), 1.31 (d, 3H, J ) 6.3 Hz). 13C NMR (101
MHz, CDCl3): 170.2, 138.3, 138.2, 138.0, 137.0, 128.5, 128.4, 128.3,
128.3, 128.1, 128.0, 127.9, 127.8, 127.7, 127.6, 127.5, 110.0, 101.7,
96.0, 82.3, 81.7, 78.2, 77.9, 75.7, 75.4, 74.8, 74.4, 73.5, 69.1, 68.8,
64.4, 55.6, 37.8, 35.6, 28.1, 24.9, 24.1, 23.6, 23.5, 17.4. FTIR (neat
film): 3272, 3030, 2934, 1655, 1562, 1496, 1452, 1370, 1310, 1099,
1067, 1027, 936, 735, 697 cm-1. HRMS (FAB)+ m/z calcd for C48H57-
NO10Na (M + Na)+, 830.3880; found, 830.3882.
Experimental Section
Typical Procedure for C2-Amidoglycosylation. Method (A): (+)-
3-Dihydrocholesterol 3,4-Di-O-benzyl-2-N-acetylamino-2-deoxy-6-
O-dimethylpropanoyl-â-D-glucopyranoside (14). Trifluoromethane-
sulfonic anhydride (28 µL, 0.17 mmol, 2.0 equiv) was added to a
solution of 3,4-di-O-benzyl-6-O-dimethylpropanoyl-D-glucal (34 mg,
0.083 mmol, 1.0 equiv) and thianthrene-5-oxide (38.5 mg, 0.17 mmol,
2.0 equiv) in a mixture of chloroform and dichloromethane (2.4 mL;
3:1 v/v) at -78 °C. The reaction mixture was stirred at this temperature
for 11 min, then N,N-diethylaniline (53 µL, 0.33 mmol, 4.0 equiv) was
added, followed by N-(TMS)acetamide (33 mg, 0.25 mmol, 3.0 equiv).
The mixture was immediately warmed to 23 °C and stirred at this
temperature for 30 min. A solution of (+)-3-dihydrocholesterol (97
mg, 0.25 mmol, 3.0 equiv) in 1.0 mL of dichloromethane was added
via cannula. Amberlyst-15 acidic resin (66 mg) was then added, and
the reaction was stirred for 30 h. The mixture was filtered and
concentrated under vacuum, and the residue was purified by silica gel
flash column chromatography (4:1 hexane/ethyl acetate) to afford the
product (52 mg, 73% yield) as a white solid (mp 207-208 °C). Rf )
0.12 (4:1 hexane/ethyl acetate). [R]D25 ) +45.4 (c ) 0.65, CHCl3). 1H
NMR (500 MHz, CDCl3): δ 7.35-7.28 (m, 10H), 5.59 (d, 1H, J )
7.5 Hz), 5.02 (d, 1H, J ) 7.8 Hz), 4.83 (d, 1H, J ) 10.0 Hz), 4.82 (d,
1H, J ) 11.7 Hz), 4.66 (d, 1H, J ) 11.3 Hz), 4.59 (d, 1H, J ) 11.1
Hz), 4.40 (dd, 1H, J ) 11.7, 2.4 Hz), 4.28 (dd, 1H, J ) 9.8, 8.7 Hz),
4.14 (dd, 1H, J ) 12.0, 6.6 Hz), 3.65 (ddd, 1H, J ) 9.4, 6.7, 2.5 Hz),
3.53 (tt, 1H, J ) 11.1, 5.0 Hz), 3.44 (t, 1H, J ) 9.4 Hz), 3.16 (dt, 1H,
J ) 9.8, 7.8 Hz), 1.95 (dt, 1H, J ) 12.6, 3.4 Hz), 1.86 (s, 3H), 1.82-
1.77 (m, 2H), 1.70-1.61 (m, 2H), 1.57-1.40 (m, 5H), 1.37-0.95 (m,
20H), 1.20 (s, 9H), 0.89 (d, 3H, J ) 6.5 Hz), 0.86 (d, 3H, J ) 6.6 Hz),
0.85 (d, 3H, J ) 6.7 Hz), 0.76 (s, 3H), 0.63 (s, 3H), 0.58 (td, 1H, J )
11.5, 4.2 Hz). 13C NMR (126 MHz, CDCl3): 178.2, 170.5, 138.3, 137.6,
129.2, 128.6, 128.5, 128.5, 128.0, 127.9, 127.9, 127.8, 98.0, 80.2, 79.3,
79.1, 74.9, 74.7, 72.8, 63.4, 58.1, 56.4, 56.2, 54.3, 44.7, 44.3, 42.5,
40.0, 38.8, 37.0, 36.1, 35.8, 35.5, 35.4, 34.5, 32.0, 29.4, 28.7, 28.2,
28.0, 27.2, 24.2, 23.8, 23.6, 22.8, 22.5, 21.2, 18.6, 12.2, 12.0. FTIR
Method (C): Azido 3,4,6-Tri-O-benzyl-2-N-acetylamino-2-deoxy-
â-D-glucopyranoside (19). Trifluoromethanesulfonic anhydride (40 µL,
0.24 mmol, 2.0 equiv) was added to a solution of 3,4,6-tri-O-benzyl-
D-glucal (50 mg, 0.12 mmol, 1.0 equiv) and thianthrene-5-oxide (56
mg, 0.24 mmol, 2.0 equiv) in a mixture of chloroform and dichlo-
romethane (2.4 mL; 3:1 v/v) at -78 °C. The reaction mixture was stirred
at this temperature for 12 min, then N,N-diethylaniline (76 µL, 0.48
mmol, 4.0 equiv) was added, followed by N-(TMS)acetamide (47 mg,
0.36 mmol, 3.0 equiv). The mixture was immediately warmed to 23
°C and stirred at this temperature for 1 h. The solvent was quickly
removed under vacuum, and N,N-dimethylformamide (2.0 mL), sodium
azide (78 mg, 1.20 mmol, 10.0 equiv), and copper(II) trifluoromethane-
sulfonate (87 mg, 0.24 mmol, 2.0 equiv) were added, and the reaction
was stirred for 48 h. The reaction mixture was diluted with water (80
mL) and extracted four times with diethyl ether (20 mL). The combined
ether extract was then washed with saturated aqueous sodium chloride
solution (30 mL) and dried over sodium sulfate. The solution was
filtered and concentrated under vacuum, and the residue was purified
by silica gel flash column chromatography (3:1 benzene/ethyl acetate)
to afford the product (44 mg, 71% yield) as a white solid (mp 168-
25
169 °C). Rf ) 0.17 (3:1 benzene/ethyl acetate). [R]D ) +6.9 (c )
1
0.75, CHCl3). H NMR (500 MHz, CDCl3): δ 7.36-7.27 (m, 13H),
7.21-7.18 (m, 2H), 5.31 (d, 1H, J ) 7.7 Hz), 4.97 (d, 1H, J ) 8.9
9
9796 J. AM. CHEM. SOC. VOL. 124, NO. 33, 2002