Total Synthesis of the Mucin-Related F1R Antigen
J. Am. Chem. Soc., Vol. 120, No. 31, 1998 7767
The reaction mixture was stirred at 0 °C for 5 h. After filtration through
a pad of Celite, the organic layer was submitted to aqueous workup.
The EtOAc extract was dried over Na2SO4. After evaporation of the
solvent, the residue was separated by chromatography on silica gel to
give 21R (59 mg, 6%) and 21â (910 mg, 84%). 21R: IR (film) 3020,
3000, 2860, 1480, 1450 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.83 (d,
J ) 7.5 Hz, 2H), 7.12-7.46 (m, 33H), 6.36 (d, J ) 6.2 Hz, 1H), 5.11
(d, J ) 8.9 Hz, 1H), 4.98 (d, J ) 10.9 Hz, 1H), 4.93 (d, J ) 11.6 Hz,
1H), 4.83 (d, J ) 8.1 Hz, 1H), 4.80 (d, J ) 11.6 Hz, 1H), 4.68-4.73
(m, 4H), 4.50-4.58 (m, 3H), 4.27-4.32 (m, 4H), 4.27 (d, J ) 6.2 Hz,
1H), 4.05 (m, 1H), 3.97 (m, 2H), 3.83 (m, 2H), 3.70 (m, 2H), 3.58 (m,
2H), 3.24-3.49 (m, 4H), 1.52 (s, 3H), 1.41 (s, 3H); HRMS (FAB)
calcd for C69H75O15NSNa [M + Na+] 1212.4756, found 1212.4720.
8.67 (s, 1H), 7.78 (d, J ) 7.4 Hz, 2H), 7.15-7.42 (m, 43H), 6.26 (d,
J ) 3.3 Hz, 1H), 4.91-4.93 (m, 2H), 4.83 (d, J ) 11.0 Hz, 1H), 4.73-
4.80 (m, 3H), 4.65-4.70 (m, 5H), 4.53 (d, J ) 11.5 Hz, 1H), 4.47 (d,
J ) 11.2 Hz, 1H), 4.27-4.42 (m, 6H), 4.10-4.14 (m, 2H), 3.96 (m,
2H), 3.86-3.90 (m, 2H), 3.69-3.79 (m, 3H), 3.33-3.56 (m, 9H); 13
C
NMR (75 MHz, CDCl3) δ 161.2, 141.7, 138.8, 138.5, 138.3, 138.2,
138.1, 138.0, 137.2, 132.1, 128.5, 128.4, 128.3, 128.2, 128.0, 127.9,
127.7, 127.6, 127.5, 127.4, 127.1, 103.0, 101.5, 95.9, 91.0, 82.2, 79.7,
79.0, 75.8, 75.4, 74.8, 74.6, 73.4, 73.2, 73.0, 72.6, 72.3, 71.8, 68.4,
68.1, 66.4, 59.0, 58.1; HRMS (FAB) calcd for C82H84O16N5Cl3SK [M
+ K+] 1570.4336, found 1570.4399.
1
23â: FT-IR (film) 3303, 3025, 2867, 2113, 1670, 1447 cm-1; H
NMR (500 MHz, CDCl3) δ 8.32 (s, 1H), 7.86 (d, J ) 7.5 Hz, 2H),
7.10-7.44 (m, 43H), 6.10 (d, J ) 9.3 Hz, 1H), 5.25 (d, J ) 8.3 Hz,
1H), 4.92 (d, J ) 11.5 Hz, 1H), 4.86 (d, J ) 11.5 Hz, 1H), 4.66-4.82
(m, 8H), 4.61 (d, J ) 11.5 Hz, 1H), 4.51-4.55 (m, 2H), 4.41 (d, J )
8.5 Hz, 1H), 4.32-4.37 (m, 3H), 4.25 (d, J ) 11.8 Hz, 1H), 3.98-
4.04 (m, 2H), 3.78-3.87 (m, 3H), 3.71 (dd, J ) 9.6, 7.8 Hz, 1H),
3.59-3.64 (m, 2H), 3.55 (d, J ) 2.3 Hz, 1H), 3.40-3.45 (m, 2H),
3.27-3.35 (m, 4H), 3.18 (m, 1H), 3.12 (dd, J ) 9.5, 8.5 Hz, 1H), 3.07
(d, J ) 6.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 162.9, 143.3, 139.0,
138.5, 138.4, 138.1, 138.0, 137.4, 137.2, 131.6, 128.6, 128.5, 128.3,
128.2, 128.1, 127.9, 127.8, 127.6, 127.5, 127.4, 127.2, 102.6, 102.1,
97.7, 90.4, 82.2, 80.0, 79.7, 76.2, 75.1, 74.5, 74.3, 73.3, 73.0, 72.7,
72.4, 72.0, 68.9, 68.0, 62.7, 58.9; HRMS (FAB) calcd for C82H84O16N5-
Cl3SK [M + K+] 1570.4336, found 1570.4298.
Preparation of Trisaccharide Donor 24. To a solution of
trisaccharide glycal 22 (225 mg, 0.264 mmol) in 2 mL of anhydrous
CH3CN at -15 °C were added NaN3 (26 mg, 0.40 mmol) and CAN
(436 mg, 0.794 mmol). The mixture was stirred at -15 °C overnight.
After aqueous workup, the organic layer was dried over Na2SO4. The
solvent was evaporated, and the residue was separated by chromatog-
raphy on silica gel to give a mixture of azidonitrate derivatives (130
mg, 51%). This azidonitrate mixture was hydrolyzed under reductive
conditions. The azidonitrates (125 mg, 0.129 mmol) were dissolved
in 5 mL of anhydrous CH3CN at room temperature. EtN(i-Pr)2 (25
µL, 0.147 mmol) and PhSH (45 µL, 0.441 mmol) were added. After
15 min, the reaction was complete and the solvent was evaporated at
room temperature. The hemiacetal derivative (92 mg, 77%) was
obtained after chromatography on silica gel. This hemiacetal (80 mg,
0.087 mmol) was dissolved in 5 mL of anhydrous CH2Cl2. To this
solution were added 0.9 mL of CCl3CN and 0.12 g of K2CO3 at room
temperature. The reaction was run overnight. After filtration through
a pad of Celite, the organic solvent was evaporated and the residue
was separated by chromatography on silica gel to give a mixture of
the R and â isomers of 24 (71 mg, 77%, R:â 3:1). 24: 1H NMR (300
MHz, CDCl3) δ 9.55 (s, 1H, NH of â isomer), 8.71 (s, 1H, NH of R
isomer), 6.54 (d, J ) 3.6 Hz, amomeric H of R isomer). Compound
24 decomposes quickly at room temperature.
1
21â: IR (film) 3020, 3000, 2860, 1480, 1450 cm-1; H NMR (300
MHz, CDCl3) δ (7.87 (d, J ) 7.2 Hz, 2H), 7.19-7.45 (m, 33H), 6.35
(d, J ) 6.2 Hz, 1H), 4.98 (d, J ) 8.9 Hz, 1H), 4.95 (d, J ) 11.6 Hz,
1H), 4.78 (m, 4H), 4.67 (m, 3H), 4.56 (m, 2H), 4.50 (d, J ) 12.0 Hz,
1H), 4.43 (d, J ) 6.2 Hz, 1H), 4.27-4.39 (m, 4H), 4.04 (d, J ) 6.2
Hz, 1H), 3.97 (t, J ) 7.2 Hz, 1H), 3.90 (d, J ) 2.5 Hz, 1H), 3.73-
3.82 (m, 3H), 3.48-3.66 (m, 6H), 3.35-3.42 (m, 3H), 1.43 (s, 3H),
1.30 (s, 3H); HRMS (FAB) calcd for C69H75O15NSNa [M + Na+]
1212.4755, found 1212.4780.
Preparation of Trisaccharide 22. In a flame-dried flask was
condensed 30 mL of anhydrous NH3 at -78 °C. To this liquid NH3
was added sodium metal (320 mg, 13.95 mmol) in one portion. After
15 min, the dry ice-ethanol bath was removed and the dark blue
solution was refluxed for 20 min. It was cooled to -78 °C again, and
a solution of trisaccharide 20 (619 mg, 0.47 mmol) in 6 mL of
anhydrous THF was added slowly. The reaction mixture was refluxed
at -30 °C for 30 min and quenched with 10 mL of MeOH. After
evaporation of the NH3, the basic solution was neutralized with Dowex
resin. The organic solution was filtered and evaporated to give the
crude product which was submitted to acetylation. The crude product
was dissolved in 3.0 mL of pyridine and 2.0 mL of Ac2O in the presence
of 10 mg of DMAP at 0 °C. The reaction mixture was stirred from 0
°C to room temperature overnight. After aqueous workup, the organic
layer was dried over Na2SO4. The solvent was evaporated, and the
residue was separated by chromatography on silica gel to give
peracetylated trisaccharide 22 (233 mg, 59%). 22: [R]20D -19.77° (c
1.04, CHCl3); IR (film) 1740, 1360 cm-1, 1H NMR (300 MHz, CDCl3)
δ 6.46 (dd, J ) 6.2, 1.5 Hz, 1H), 5.64 (d, J ) 9.1 Hz, 1H), 5.54 (d, J
) 2.0 Hz, 1H), 5.40 (d, J ) 4.5 Hz, 1H), 5.36 (d, J ) 2.9 Hz, 1H),
5.12 (m, 2H), 4.98 (dd, J ) 10.4, 3.4 Hz, 1H), 4.70 (d, J ) 6.2 Hz,
1H), 4.58 (d, J ) 7.3 Hz, 1H), 4.50 (m, 2H), 4.26 (t, J ) 5.0 Hz, 1H),
4.12 (m, 3H), 3.89 (m, 2H), 3.78 (m, 2H), 3.64 (m, 1H), 2.16 (s, 3H),
2.13 (s, 3H), 2.12 (s, 3H), 2.09 (s, 3H), 2.07 (s, 3H), 2.06 (s, 3H), 2.05
(s, 3H), 2.02 (s, 3H), 1.98 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 170.29,
170.14, 169.24, 145.34, 128.20, 100.85, 100.72, 88.86, 75.58, 74.26,
72.58, 72.06, 70.71, 70.61, 68.98, 66.77, 66.55, 64.19, 63.53, 62.09,
60.70, 52.97, 23.05, 20.72, 20.56; HRMS (FAB) calcd for C36H49O22-
NNa [M + Na+] 870.2645, found 870.2644.
Preparation of Trisaccharide Donor 25. The azidonitrate deriva-
tives (100 mg, 0.103 mmol) from peracetylated trisaccharide 22 were
dissolved in 0.5 mL of anhydrous CH3CN at room temperature. To
this solution was added anhydrous LiBr (45 mg, 0.52 mmol). The
mixture was stirred for 3 h. After aqueous workup, the solvent was
evaporated and the residue was separated by chromatography on silica
gel to give compound 25 (91 mg, 90%). 25: 1H NMR (300 MHz,
CDCl3) δ 6.04 (d, J ) 3.6 Hz, 1H, anomeric H). The low stability of
this compound prevented further characterization.
Preparation of Trisaccharide Donor 23. To a solution of
trisaccharide glycal 20 (460 mg, 0.346 mmol) in 3 mL of anhydrous
CH3CN at -25 °C were added NaN3 (34 mg, 0.519 mmol) and CAN
(569 mg, 1.4 mmol). The mixture was stirred at -25 °C for 8 h. After
aqueous workup, the organic layer was dried over Na2SO4. The solvent
was evaporated, and the residue was separated by chromatography on
silica gel to give a mixture of azidonitrate derivatives (134 mg, 27%).
This azidonitrate mixture was hydrolyzed under reductive conditions.
The azidonitrates were dissolved in 2 mL of anhydrous CH3CN at room
temperature. EtN(i-Pr)2 (16 µL, 0.091 mmol) and PhSH (28 µL, 0.272
mmol) were added. After 15 min, the reaction was complete and the
solvent was evaporated at room temperature. The hemiacetal derivative
(103 mg, 74%) was obtained after chromatography on silica gel. This
hemiacetal (95 mg, 0.068 mmol) was dissolved in 2 mL of anhydrous
CH2Cl2. To this solution were added 1 mL of CCl3CN and 0.5 g of
K2CO3 at room temperature. The reaction was run overnight. After
filtration through a pad of Celite, the organic solvent was evaporated
and the residue was separated by chromatography on silica gel to give
23R (18 mg, 17%) and 23â (70 mg, 67%). 23R: FT-IR (film) 3322,
Preparation of Trisaccharide Donor 26. The trisaccharide donor
25 (91 mg, 0.093 mmol) was dissolved in 2 mL of anhydrous THF at
0 °C. To this solution was added LiSPh (100 mL, 0.103 mmol). The
reaction was run at 0 °C for 30 min. The solvent was removed, and
the residue was separated by chromatography on silica gel to give
compound 26 (61 mg, 66%). 26: IR (film) 3000, 2100, 1750, 1680,
1
1500 cm-1; H NMR (300 MHz, CDCl3) δ 7.61 (m, 2H), 7.39 (m,
3H), 5.50 (d, J ) 9.1 Hz, 1H), 5.35 (m, 2H), 5.11 (m, 2H), 4.96 (dt,
J ) 10.5, 3.5 Hz, 1H), 4.84 (dd, J ) 10.2, 3.0 Hz, 1H), 4.50 (m, 4H),
4.16 (m, 3H), 3.59-3.90 (m, 8H), 2.15 (s, 3H), 2.10 (s, 3H), 2.08 (s,
3H), 2.06 (s, 6H), 2.05 (s, 3H), 2.04 (s, 3H), 1.97 (s, 3H), 1.87 (s, 3H).
HRMS (FAB) calcd for C42H54N4O22SNa [M + Na+] 1021.8620, found
1021.8612.
1
3025, 2867, 2113, 1670, 1452 cm-1; H NMR (500 MHz, CDCl3) δ