Synthesis of the Pseudohexasaccharide of T. gondii
J . Org. Chem., Vol. 66, No. 22, 2001 7439
18 (0.9 g, 1.3 mmol, 12%). TLC (petroleum ether/ethyl acetate,
2:1): Rf ) 0.60; [R]D ) -22 (c ) 2.5, CDCl3); 1H NMR (250
MHz, CDCl3): δ ) 2.52 (d, J OH,4 ) 2.1 Hz, 1H, OH), 3.81 (s,
3H, OMe), 3.78-3.95 (m, 4H, 3,5,6,6′-H), 4.03 (m, 1H, CH2-
CHdCH2), 4.13 (ddd, J OH,4 ) 2.1 Hz, J 3,4 ) J 4,5 ) 9.3 Hz, 1H,
4b-H), 4.24 (m, 1H, CH2-CHdCH2), 4.48-4.82 (m, 4H, CH2-
Ph), 5.03 (d, J 1,2 ) 1.8 Hz, 1H, 1b-H), 5.22 (dd, J cis ) 10 Hz,
J gem ) 1 Hz, 1H, CHdCHcisHtrans), 5.30 (dd, J trans ) 17 Hz, J gem
2.4 Hz, J 2,3 ) 11.0 Hz, 1H, 3-H), 4.11 (m, 1H, 5-H), 4.20 (bs,
1H, 4-H), 4.77 (m, 1H, 2-H), 6.43 (d, J NH ) 8.2 Hz, 1H, NH),
6.47 (d, J 1,2 ) 3.4 Hz, 1H, 1-H), 7.19-7.39 (m, 15H, Ph) 8.62
(s, 1H, NH). Anal. Calcd for C31H30O6Cl6N2 (739.33): C, 49.16;
H, 4.27; N, 3.70 (+H2O). Found: C, 49.44; H, 4.48; N, 3.69.
Allyl (3,4,6-Tr i-O-ben zyl-2-deoxy-2-tr ich lor oacetam ido-
â-D-ga la ctop yr a n osyl)-(1f4)-2-O-ben zoyl-3-O-ben zyl-6-O-
(4-m eth oxyben zyl)-r-D-m a n n op yr a n osid e (22). Acceptor
3 (1.3 g, 2.4 mmol) and trichloroacetimidate 4 (2 g, 2.7 mmol)
were dissolved in 30 mL of dry toluene under argon and cooled
to -40 °C. BF3‚OEt2 (30 µL) was added five times every 30
min. After 1 h, the temperature was raised to -30 °C.
Neutralization with NEt3, removal of the solvent, and flash
chromatography (petroleum ether/ethyl acetate, 6:1f5:1f2:
1) gave compound 22 (2.3 g, 2.0 mmol, 85%) as a colorless
syrup. TLC (petroleum ether/ethyl acetate, 3:1): Rf ) 0.42.
[R]D ) +4.2 (c ) 1.2, CDCl3). 1H NMR (250 MHz, CDCl3): δ )
3.31-4.08 (m, 13H; 3.75/3.74: 3H, s, OMe), 4.12-4.55 (m, 7H),
4.58-5.05 (m, 6H), 5.16-5.45 (m, 2H), 5.53-5.56 (m, 1H, 2c-
H), 5.80-5.98 (m, 1H, Allyl), 6.71 (d, J NH ) 7.4, 1H, NH), 6.79-
6.87 (m, 2H, PMB), 7.06-7.39 (m, 24H), 7.43-7.58 (m, 1H,
Bz), 7.95-7.99 (m, 2H, Bz), (2 diastereomers at amide bond);
HMQC data (13C (150.9 MHz)/1H (600 MHz) (1J CH in Hz)):
96.8/5.02 (172.4) (1c), 69.3/5.59 (2c), 75.8/4.07 (3c), 74.9/4.38
(4c), 71.2/3.94 (5c), 68.6/3.98 + 3.83 (6c), 101.2/4.41 (165.3) (1d),
61.9/3.59 (2d), 71.8/4.69 (3d), 66.2/5.19 (4d), 70.4/3.41 (5d), 60.9/
3.95 + 3.82 (6d). Anal. Calcd for C60H62O13Cl3N (1111.58): C,
64.83; H, 5.63; N, 1.26. Found: C, 64.55; H, 5.88; N, 0.96.
Allyl (3,4,6-Tr i-O-ben zyl-2-deoxy-2-tr ich lor oacetam ido-
â-D-ga la ctop yr a n osyl)-(1f4)-2-O-ben zoyl-3-O-ben zyl-r-D-
m a n n op yr a n osid e (23). Disaccharide 22 (1.69 g, 1.5 mmol)
and CAN (4.4 g, 7.5 mmol) were stirred in 85 mL of CH3CN/
toluene/H2O (91:5:4) at 0 °C for 30 min and at room temper-
ature for 1.5 h. The reaction mixture was diluted with ethyl
acetate, washed with a saturated NaHCO3 solution, dried over
Na2SO4, and evaporated. Flash chromatography (petroleum
ether/ethyl acetate, 3:1 f 2:1) afforded compound 23 (1.26 g,
1.27 mmol, 85%) as a colorless foam. TLC (petroleum ether/
ethyl acetate, 2:1): Rf ) 0.34. [R]D ) +1.3 (c ) 1.7, CDCl3). 1H
NMR (250 MHz, CDCl3): δ ) 2.16 (bs, 1H, OH), 3.32-3.51
(m, 3H), 3.68-4.15 (m, 9H), 4.19-4.29 (m, 3H), 4.35-4.53 (m,
4H, Bn), 4.70-4.78 (m, 2H, Bn), 4.90 (d, J 1,2 ) 1.8 Hz, 1H,
1c-H), 5.14 (dd, J cis ) 10 Hz, J gem ) 1 Hz, 1H, CHdCHcisHtrans),
5.17 (d, J 1,2 ) 8.1 Hz, 1H, 1d-H), 5.21 (dd, J trans ) 17 Hz, J gem
) 1 Hz, 1H, CHdCHcisHtrans), 5.61 (dd, J 1,2 ) 1.9 Hz, J 2,3
3.1 Hz, 1H, 2-H), 5.87 (ddt, J cis ) 10 Hz, J trans ) 17 Hz, J vic
)
)
5 Hz, 1H, CHdCH2), 6.84-6.90 (m, 2H, PMB), 7.16-7.44 (m,
9H, Ph), 7.52-7.59 (m, 1H, Bz), 7.97-8.07 (m, 2H, Bz); HMQC
data (13C (150.9 MHz)/1H (600 MHz) (1J CH in Hz)): 97.0/5.02
(173.5) (1), 68.3/5.6 (2), 77.7/3.93 (3), 67.3/4.12 (4), 71.4/3.86
(5), 69.5/3.8 (6). Anal. Calcd for C31H34O8 (534.65): C, 69.64;
H, 6.42. Found: C, 69.55; H, 6.38.
Th exyldim eth ylsilyl 2-Azido-3,4,6-tr i-O-ben zyl-2-deoxy-
â-D-ga la ctop yr a n osid e (20). 2-Azido-3,4,6-tri-O-benzyl-2-
deoxy-glucose (59.4 g, 125 mmol) and texyldimethylsilyl
chloride (TDS-Cl; 26.8 g, 150 mmol) were dissolved in 500
mL of dry CH2Cl2, and imidazole (10.6 g, 150 mmol) was added.
After the mixture was stirred for 1 h, the solvent was removed
and the remaining residue was subjected to flash chromatog-
raphy (petroleum ether/ethyl acetate, 6:1). Compound 20 (74.1
g, 120 mmol, 96%) was obtained as a colorless foam. TLC
(petroleum ether/ethyl acetate, 3:1): Rf ) 0.65; 1H NMR (250
MHz, CDCl3): δ ) 0.16 (s, 6H, 2 Me), 0.84-0.91 (12H, 4 Me),
1.66 (m, 1H, (H3C)2CH), 3.26 (dd, J 3,4 ) 3.0 Hz, J 2,3 ) 10.0
Hz, 1H, 3-H), 3.48 (m, 1H, 5-H), 3.52-3.63 (m, 2H, 6/6′-H),
3.71 (dd, J 1,2 ) J 2,3 ) 8.0 Hz, 1H, 2-H), 3.84 (m, 1H, 4-H), 4.40
(d, J 1,2 ) 8.0 Hz, 1H, 1-H), 4.43-4.93 (m, 6H, CH2Ph), 7.26-
7.48 (m, 15H, Ph). C35H47O5N3Si (617.94).
Th exyld im eth ylsilyl 3,4,6-Tr i-O-ben zyl-2-d eoxy-2-tr i-
ch lor oa ceta m id o-â-D-ga la ctop yr a n osid e (21). To a solu-
tion of azido compound 20 (1.36 g, 2.2 mmol) in ethanol was
added sodium borohydride (416 mg, 11 mmol) followed by the
addition of a 0.17 N solution of NiCl2‚6H2O in ethanol (1 mL,
0.17 mmol). The mixture was stirred at room temperature for
1 h, then neutralized with acetic acid, and concentrated to
dryness. The residue was titured in CH2Cl2, and the mixture
was filtered on a pad of Celite and concentrated. To a solution
of the crude amine in 20 mL of CH2Cl2 and NEt3 (1.85 mL,
13.2 mmol), trichloroacetyl chloride (490 µL, 4.4 mmol) was
added at 0 °C. The reaction mixture was stirred at room
temperature for 15 min, then diluted with CH2Cl2, washed
with water, saturated aqueous NaHCO3 solution, and water,
dried (MgSO4), and concentrated. Flash chromatography
(petroleum ether/ethyl acetate, 12:1) of the residue afforded
compound 20 (1.2 g, 1.63 mmol, 74%) as a white solid. TLC
(petroleum ether/ethyl acetate, 3:1): Rf ) 0.70; [R]D ) +5 (c )
) 1 Hz, 1H, CHdCHcisHtrans), 5.50 (dd, J 1,2 ) 2.0 Hz, J 2,3
3.1 Hz, 1H, 2c-H), 5.82 (ddt, J cis ) 10 Hz, J trans ) 17 Hz, J vic
)
)
5 Hz, 1H, CHdCH2), 6.79 (d, J NH ) 7.2 Hz, 1H, NH), 7.03-
7.31 (m, 22H, Bn + Bz), 7.41-7.47 (m, 1H, Bz), 7.91-7.95 (m,
2H, Bz). HMQC data (13C (150.9 MHz)/1H (600 MHz)): 96.7/
4.97 (1c), 68.9/5.57 (2c), 76.6/4.11 (3c), 72.3/4.32 (4c), 71.5/3.77
(5c), 61.7/3.87 + 3.83 (6c), 98.6/5.24 (1d), 56.2/3.97 (2d), 77.1/
4.12 (3d), 71.6/3.94 (4d), 73.2/3.53 (5d), 68.2/3.55 + 3.40 (6d).
Anal. Calcd for C52H54O12Cl3N (991.43): C, 62.99; H, 5.50; N,
1.41. Found: C, 63.22; H, 5.71; N, 1.28.
1
1.0, CHCl3); mp 107-108 °C; H NMR (250 MHz, CDCl3): δ
) 0.12 (s, 3H, 2 Me), 0.15 (s, 3H, Me), 0.82-0.85 (12H, 4 Me),
1.61 (m, 1H, (H3C)2CH), 3.56-3.64 (m, 3H, 5-H, 6/6′-H), 3.76
(ddd, J NH,2 ) 7.3 Hz, J 1,2 ) 7.8 Hz, J 2,3 ) 11.0 Hz, 1H, 2-H),
3.98 (m, 1H, 4-H), 4.22 (dd, J 3,4 ) 2.8 Hz, J 2,3 ) 11.0 Hz, 1H,
3-H), 4.40-4.93 (m, 6H, CH2Ph), 5.10 (d, J 1,2 ) 7.8 Hz, 1H,
1-H), 6.89 (d, J NH,2 ) 7.3 Hz, 1H, NH), 7.29-7.39 (m, 15H,
Ph). Anal. Calcd for C37H48O6Cl3NSi (737.30): C, 60.26; H,
6.56; N, 1.90. Found: C, 60.10; H, 6.55; N, 2.10.
Allyl (2-O-Acetyl-3,4,6-tr i-O-ben zyl-r-D-m a n n op yr a n o-
syl)-(1f6)-[(3,4,6-tr i-O-ben zyl-2-d eoxy-2-tr ich lor oa ceta -
m id o-â-D-ga la ctop yr a n osyl)-(1f4)]-2-O-ben zoyl-3-O-ben -
zyl-r-D-m a n n op yr a n osid e (24). Acceptor 23 (2.2 g, 2.2
mmol) and donor 5 (1.7 g, 2.67 mmol) were dissolved in 25
mL of dry diethyl ether under argon. After addition of 2 mL
of TMSOTf solution (0.1 N in dry diethyl ether), the solution
was stirred at room temperature for 10 min, neutralized with
NEt3, and concentrated. Flash chromatography (petroleum
ether/ethyl acetate, 4:1) afforded compound 24 (3.09 g, 2.1
mmol, 95%) as a colorless foam. TLC (petroleum ether/ethyl
acetate, 2:1): Rf ) 0.70. [R]D ) +15 (c ) 1.5, CDCl3). 1H NMR
(250 MHz, CDCl3): δ ) 2.14 (s, 3H, OAc), 3.32 (dd, J 5,6 ) 3.1
Hz, J 6,6′ ) 6.5 Hz, 1H, 6d-H), 3.45-3.58 (m, 2H, 5d-H, 6′d-
H), 3.68-3.72 (m, 2H, 6/6′e-H), 3.76-3.80 (m, 1H, 4d-H), 3.80-
4.02 (m, 8H, 2d-H, 3e-H, 4e-H, 5c-H, 5e-H, 6/6′c-H, 3c-H),
4.04-4.18 (m, 3H, allyl+4c-H, 3d-H), 4.20 (m, 2H, CH2Ph),
4.26-4.54 (m, 6H, CH2Ph), 4.59-4.85 (m, 6H, CH2Ph), 4.91
(d, J 1,2 ) 1.8 Hz, 1H, 1c-H), 4.96 (d, J 1,2 ) 1.7 Hz, 1H, 1e-H),
3,4,6-Tr i-O-b en zyl-2-d eoxy-2-t r ich lor oa cet a m id o-r-D-
ga la ctop yr a n osyl Tr ich lor oa cetim id a te (4). To a solution
of compound 20 (3.24 g, 4.4 mmol) in 43 mL of dry THF was
added a 1 N solution of tetrabutylammonium fluoride in THF
(4.8 mL, 4.8 mmol) at -20 °C. The mixture was stirred at 0
°C for 2 h, diluted with ethyl acetate, washed with brine and
water, dried over Na2SO4, and concentrated. A mixture of the
crude oil, trichloroacetonitrile (4.4 mL, 44 mmol), and some
drops of DBU was stirred in 32 mL of CH2Cl2 at room
temperature for 90 min and then concentrated. Flash chro-
matography (petroleum ether/ethyl acetate, 5:1, 0.1% NEt3)
gave trichloroacetimidate 21 (2.45 g, 3.3 mmol, 75%) as a
colorless foam. TLC (petroleum ether/ethyl acetate, 7:2): Rf
) 0.55. [R]D ) +42 (c ) 1.1, CHCl3). 1H NMR (250 MHz,
CDCl3): δ ) 3.59 (dd, J 5,6 ) 5.3 Hz, J 6,6′ ) 9.0 Hz, 1H, 6-H),
5.25 (d, J 1,2 ) 8.1 Hz, 1H, 1d-H), 5.18 (dd, J cis ) 10 Hz, J gem
)
3.71 (dd, J 5,6 > 1 Hz, J 6,6′ ) 8.3 Hz, 1H, 6′-H), 3.88 (dd, J 3,4
)
1 Hz, 1H, CHdCHcisHtrans), 5.27 (dd, J trans ) 17 Hz, J gem ) 1