K. C. Nicolaou et al.
FULL PAPER
saturated aqueous NaHCO3 (20 mL) and brine (20 mL). The organic layer
was dried (Na2SO4), the solvents were removed under reduced pressure,
and the residue was purified by flash column chromatography (silica gel,
0 ! 80% Et2O in hexanes) to afford A1BC alcohol 73 (1.17 g, 81%) as a
white foam. 73: Rf 0.24 (70% Et2O in hexanes); [a]2D2 12.0 (c 0.20,
CHCl3); IR (thin film): nÄ 3425, 2931, 2884, 1731, 1614, 1544, 1438, 1326,
4.67, 4.66 (brd, J 8.4 Hz, 2H, B1), 4.62 ± 4.59 (m, 1H, C1b), 4.02 (dq, J
6.0 Hz, 1H, C5), 3.90 ± 3.82 (m, 4H, B3, B3, C3, C3), 3.87 (s, 3H, OMe),
3.85 (s, 3H, OMe), 3.75 ± 3.73 (m, 3H, B5, C2, C2), 3.72 (t, J 8.8 Hz, 1H,
C4), 3.65 (d, J 9.3 Hz, 2H, A4), 3.51 ± 3.35 (m, 5H, A5, A5, B5, C4, C5),
3.36 (s, 3H, OMe), 3.07 (brs, 1H, OH), 2.87 (brs, 1H, OH), 2.47 (dd, J
13.9, 4.7 Hz, 2H, A2), 2.39, 2.38 (s, 3H, Me (A1)), 2.35 ± 2.30 (m, 2H, B2),
2.02 (dd, J 13.7, 2.1 Hz, 2H, A2), 1.72 ± 1.67 (m, 2H, B2), 1.43 (s, 6H, Me
(A3)), 1.32 (d, J 5.9 Hz, 6H, C6), 1.27 (d, J 6.2 Hz, 6H, B6), 0.84 (d, J
6.2 Hz, 6H, A6); 13C NMR (150 MHz, CDCl3): d 165.6, 153.3, 153.2,
138.7, 135.8, 134.7, 128.6, 128.5, 128.5, 128.4, 127.8, 127.8, 127.7, 127.7, 126.4,
126.0, 126.0, 125.5, 99.8, 96.3, 92.5, 91.8, 89.9, 84.2, 82.6, 82.1, 82.0, 80.3, 76.2,
76.1, 75.3, 75.0, 74.9, 74.9, 72.4, 72.4, 72.2, 71.4, 71.4, 67.1, 66.2, 62.0, 60.8,
60.4, 40.0, 36.4, 30.3, 19.4, 18.3, 18.0, 17.9, 17.6, 14.2; HRMS (FAB): calcd for
1302, 1249, 1120, 1073, 938, 820, 749 cmÀ1 1H NMR (500 MHz, CDCl3):
;
d 7.57 (d, J 6.9 Hz, 2H, ArH), 7.43 ± 7.28 (m, 10H, ArH, PMB), 7.16 (d,
J 8.6 Hz, 2H, PMB), 6.88 (d, J 8.6 Hz, 2H, PMB), 6.79 (d, J 8.6 Hz,
2H, PMB), 5.03 (brs, 2H, CH2Ar), 4.93, 4.83 (AB, J 10.9 Hz, 2H,
CH2Ar), 4.88, 4.59 (AB, J 11.5 Hz, 2H, CH2Ar), 4.81, 4.59 (AB, J 11.5 Hz,
2H, CH2Ar), 4.78 (t, J 9.4 Hz, 1H, B4), 4.74 (dd, J 9.7, 1.8 Hz, 1H, B1),
4.47 (d, J 7.9 Hz, 1H, C1), 3.87 (s, 3H, OMe), 3.85 ± 3.72 (m, 1H, B3), 3.81
(s, 3H, OMe), 3.78 (s, 3H, OMe), 3.55 (brt, J 9.0 Hz, 1H, C3), 3.43 (dd,
J 9.0, 7.9 Hz, 1H, C2), 3.41 ± 3.36 (m, 2H, C4, C5), 3.33 (dq, J 9.4,
6.2 Hz, 1H, B5), 2.66 (d, J 4.4 Hz, 1H, OH), 2.36 (s, 3H, Me (A1)), 2.40 ±
2.30 (m, 1H, B2), 1.72 (dt, J 12.2, 9.7 Hz, 1H, B2), 1.35 (d, J 5.3 Hz, 3H,
C6), 1.23 (d, J 6.2 Hz, 3H, B6); 13C NMR (125 MHz, CDCl3): d 166.4,
159.3, 159.1, 153.0, 151.8, 139.0, 138.9, 133.2, 130.5, 130.1, 129.8, 129.7, 129.6,
129.5, 129.2, 128.5, 128.2, 127.5, 127.3, 126.4, 125.5, 121.4, 113.8, 113.6, 102.2,
100.3, 84.2, 82.9, 81.9, 79.5, 75.3, 74.9, 74.5, 70.9, 70.8, 69.8, 69.6, 65.8, 62.4,
55.2, 39.3, 34.2, 30.3, 29.5, 21.1, 18.0, 17.6, 17.4, 15.2; HRMS (FAB): calcd for
C43H53Cl2NO15Cs [MCs] : 1026.1847, found 1026.1809.
A1B(A)C bis-acetate 76: Ac2O (0.010 mL, 0.10 mmol) was added to a
solution of A1B(A)C diol 75 (0.036 g, 0.040 mmol), Et3N (0.022 mL,
0.16 mmol), and 4-DMAP (1 mg, 0.01 mmol) in CH2Cl2 (0.5 mL) at 08C
and the resulting mixture was warmed to 258C and stirred for 1 h. The
reaction mixture was diluted with CH2Cl2 (100 mL) and washed with
saturated aqueous NaHCO3 (10 mL) and brine (10 mL). The organic layer
was dried (Na2SO4) and the solvents were removed under reduced
pressure. The residue was purified by flash column chromatography (silica
gel, 0 ! 100% Et2O in hexanes) to afford A1B(A)C bis-acetate 76 (0.038 g,
97%) as a white foam. 76: Rf 0.61 (100% Et2O); IR (thin film): nÄ 2938,
C51H56Cl2O13Na [MNa] : 969.2995, found 969.2998.
A1B(A)C trisaccharide 74: Ring A glycosyl fluoride 9 (0.025 g, 0.11 mmol)
and A1BC alcohol 73 (0.060 g, 0.063 mmol) were azeotroped with benzene
(1 mL) and then dried under high vacuum for 1 h. The residue was
dissolved in Et2O/CH2Cl2 (1:1, 1 mL), 4 MS were added, and the mixture
was cooled to 08C and stirred for 5 min. SnCl2 (0.019 g, 0.10 mmol) was
added to the reaction mixture in one portion and the resulting mixture was
warmed to 258C and stirred for 1 h. The reaction mixture was quenched by
the addition of Et3N (1 mL), diluted with CH2Cl2 (100 mL) and washed
with saturated aqueous NaHCO3 (10 mL) and brine (10 mL). The organic
layer was dried (Na2SO4) and the solvents were removed under reduced
pressure. The residue was purified by flash column chromatography (silica
gel, 0 ! 100% Et2O in hexanes) to afford A1B(A)C trisaccharide 74
(0.055 g, 77%) as a white foam. 74: Rf 0.12 (70% Et2O in hexanes);
[a]2D2 À20.7 (c 0.28, CHCl3); IR (thin film): nÄ 2931, 2872, 1731, 1549,
1750, 1542, 1456, 1371, 1247, 1129, 1036, 737 cmÀ1 1H NMR (600 MHz,
;
CDCl3, a:b ca. 1:1): d 7.57 ± 7.21 (m, 20H, ArH), 6.19 (d, J 3.6 Hz, 1H,
C1a), 5.59 (d, J 8.3 Hz, 1H, C1b), 5.06 (t, J 9.2 Hz, 1H, C2b), 5.04, 5.02
(AB, J 9.9 Hz, 4H, CH2Ar), 4.99 (dd, J 10.0, 3.6 Hz, 1H, C2a), 4.97, 4.71
(AB, J 11.6 Hz, 2H, CH2Ar), 4.93, 4.63 (AB, J 11.8 Hz, 2H, CH2Ar),
4.95 ± 4.94 (m, 2H, A1), 4.89 (t, J 9.4 Hz, 2H, B4), 4.70, 4.67 (dd, J 10.1,
1.9 Hz, 2H, B1), 3.93 ± 3.81 (m, 4H, B3, B3, C3, C4), 3.85, 3.84 (2 Â s, 3 H,
OMe), 3.65 (d, J 9.5 Hz, 2H, A4), 3.61 (t, J 10.0 Hz, 1H, C3), 3.53 ± 3.32
(m, 7H, A5, A5, B5, B5, C4, C5, C5), 3.37 (s, 6H, OMe), 2.46 (dd, J 13.8,
4.8 Hz, 2H, A2), 2.38, 2.27 (s, 3H, Me (A1)), 2.31 ± 2.28 (m, 2H, B2), 2.13 (s,
3H, OAc), 2.08 (s, 3H, OAc), 2.01 (dd, J 13.8, 1.5 Hz, 2H, A2), 1.72 ± 1.67
(m, 2H, B2), 1.95 (s, 3H, OAc), 1.91 (s, 3H, OAc), 1.43 (s, 6H, Me (A3)),
1.29 ± 1.22 (m, 12H, B6, C6), 0.84 (d, J 6.2 Hz, 6H, A6); 13C NMR
(150 MHz, CDCl3): d 169.9, 169.2, 165.6, 153.3, 153.1, 138.7, 135.9, 134.8,
129.5, 128.6, 128.5, 128.3, 128.2, 127.7, 127.6, 127.2, 125.9, 125.5, 121.7, 113.8,
100.3, 92.5, 92.0, 89.9, 89.5, 84.2, 82.3, 80.9, 78.3, 75.1, 74.8, 72.1, 71.6, 71.1,
69.1, 66.3, 62.0, 60.8, 40.0, 36.5, 30.2, 29.7, 20.9, 20.7, 19.4, 18.2, 18.0, 17.6;
1
1455, 1390, 1237, 1090, 744 cmÀ1; H NMR (600 MHz, CDCl3): d 7.58 (d,
J 7.0 Hz, 2H, ArH), 7.44 ± 7.28 (m, 10H, ArH, PMB), 7.17 (d, J 8.6 Hz,
2H, PMB), 6.89 (d, J 8.6 Hz, 2H, PMB), 6.80 (d, J 8.6 Hz, 2H, PMB),
5.05, 5.02 (AB, J 8.1 Hz, 2H, CH2Ar), 5.03, 4.90 (AB, J 9.7 Hz, 2H,
CH2Ar), 4.93 (brd, J 5.1 Hz, 1H, A1), 4.89, 4.63 (AB, J 10.6 Hz, 2H,
CH2Ar), 4.87 (t, J 9.1 Hz, 1H, B4), 4.83, 4.60 (AB, J 10.4 Hz, 2H,
CH2Ar), 4.70 (brd, J 9.6 Hz, 1H, B1), 4.48 (d, J 7.7 Hz, 1H, C1), 3.92 ±
3.75 (m, 2H, B3, C3), 3.84 (s, 3H, OMe), 3.82 (s, 3H, OMe), 3.79 (s, 3H,
OMe), 3.65 (d, J 9.4 Hz, 1H, A4), 3.57 ± 3.29 (m, 5H, A5, B5, C2, C4, C5),
3.36 (s, 3H, OMe), 2.45 (dd, J 13.7, 5.0 Hz, 1H, A2), 2.39 (s, 3H, Me (A1)),
2.29 ± 2.28 (m, 1H, B2), 2.01 (dd, J 13.7, 1.6 Hz, 1H, A2), 1.69 ± 1.64 (m,
1H, B2), 1.44 (s, 3H, Me (A3)), 1.36 (d, J 5.3 Hz, 3H, C6), 1.29 (d, J
6.2 Hz, 3H, B6), 0.84 (d, J 6.2 Hz, 3H, A6); 13C NMR (150 MHz, CDCl3):
d 165.5, 159.3, 159.1, 153.2, 153.1, 139.0, 138.8, 134.8, 130.5, 130.2, 130.1,
129.8, 129.6, 129.5, 129.4, 128.6, 128.5, 128.1, 127.5, 127.4, 126.3, 126.0, 125.5,
121.7, 113.8, 113.6, 102.2, 99.8, 92.4, 89.9, 84.2, 83.1, 82.1, 81.9, 76.1, 75.1,
74.9, 74.5, 72.4, 71.1, 70.9, 70.8, 68.6, 66.2, 61.9, 60.7, 55.2, 40.1, 36.4, 31.5,
30.3, 29.7, 22.6, 19.3, 18.2, 18.1, 18.0, 17.6; HRMS (FAB): calcd for
HRMS (FAB): calcd for C47H57Cl2NO17Cs [MCs] : 1110.2058, found
1110.2017.
A1BC TIPS ether 77: TIPSOTf (0.37 mL, 1.39 mmol) was added to a
solution of A1BC alcohol 73 (1.10 g, 1.16 mmol) and 2,6-lutidine (0.20 mL,
1.74 mmol) in CH2Cl2 (6 mL) at 08C and the resulting mixture was warmed
to 258C and stirred for 1 h. The reaction mixture was quenched by the
addition of MeOH (1 mL), diluted with CH2Cl2 (200 mL), and washed with
saturated aqueous NaHCO3 (10 mL) and brine (10 mL). The organic layer
was dried (Na2SO4) and the solvents were removed under reduced
pressure. The residue was purified by flash column chromatography (silica
gel, 0 ! 80% Et2O in hexanes) to afford A1BC TIPS ether 77 (1.19 g, 93%)
as a white foam. 77: Rf 0.60 (50% Et2O in hexanes); IR (thin film): nÄ
2943, 2872, 1731, 1614, 1508, 1461, 1384, 1249, 1094, 1061, 908, 744 cmÀ1
;
1H NMR (400 MHz, CDCl3, a:b ca. 1:10): d 7.57 (d, J 7.1 Hz, 2H, ArH),
7.44 ± 7.27 (m, 10H, ArH, PMB), 7.18 (d, J 8.6 Hz, 2H, PMB), 6.88 (d, J
8.6 Hz, 2H, PMB), 6.80 (d, J 8.6 Hz, 2H, PMB), 5.05 (brs, 2H, CH2Ar),
4.93, 4.89 (AB, J 10.8 Hz, 2H, CH2Ar), 4.88 (t, J 8.9 Hz, 1H, B4), 4.88,
4.63 (AB, J 11.3 Hz, 2H, CH2Ar), 4.81, 4.58 (AB, J 12.0 Hz, 2H,
CH2Ar), 4.69 (brd, J 8.2 Hz, 1H, B1), 4.48 (d, J 7.7 Hz, 1H, C1), 3.95 ±
3.86 (m, 1H, B3), 3.83 (s, 3H, OMe), 3.82 (s, 3H, OMe), 3.79 (s, 3H, OMe),
3.56 (brt, J 8.8 Hz, 1H, C3), 3.51 ± 3.28 (m, 4H, C2, C4, C5, B5), 2.37 (s,
3H, Me (A1)), 2.33 (dd, J 12.2, 6.0 Hz, 1H, B2), 1.74 (dt, J 11.7, 11.7 Hz,
1H, B2), 1.34 (d, J 6.0 Hz, 3H, B6), 1.32 (d, J 5.8 Hz, 3H, C6), 1.01 (s,
21H, iPr3Si); 13C NMR (100 MHz, CDCl3): d 165.7, 159.3, 159.1, 152.9,
152.7, 139.2, 138.9, 135.9, 134.3, 130.5, 130.0, 129.9, 129.6, 129.5, 129.4, 128.5,
128.1, 127.7, 126.7, 126.1, 121.5, 113.7, 113.6, 102.2, 99.8, 94.7, 83.1, 82.2, 81.8,
80.3, 79.3, 70.0, 68.6, 66.2, 61.9, 55.2, 41.0, 18.0, 17.8, 12.8; HRMS (FAB):
C59H69Cl2NO17Cs [MCs] : 1266.2997, found 1266.3051.
A1B(A)C diol 75: BF3 ´ Et2O (0.024 mL, 0.194 mmol) was added to a
solution of A1B(A)C trisaccharide 74 (0.055 g, 0.048 mmol) and PhSH
(0.040 mL, 0.39 mmol) in CH2Cl2 (1 mL) at À358C and the resulting
mixture was stirred for 2 h. The reaction mixture was quenched by the
addition of Et3N (1 mL), diluted with CH2Cl2 (100 mL) and washed with
saturated aqueous NaHCO3 (10 mL) and brine (10 mL). The organic layer
was dried (Na2SO4) and the solvents were removed under reduced
pressure. The residue was purified by flash column chromatography (silica
gel, 0 ! 100% EtOAc in hexanes) to afford A1B(A)C diol 75 (0.036 g,
83%) as a white foam. 75: Rf 0.17 (100% Et2O); IR (thin film): nÄ 3416,
2978, 2931, 2872, 1731, 1537, 1449, 1384, 1249, 1090, 1032, 908, 738 cmÀ1
;
1H NMR (600 MHz, CDCl3, a:b ca. 1:1): d 7.57 (d, J 7.1 Hz, 2H, ArH),
7.43 ± 7.29 (m, 8H, ArH), 5.21 (brs, 1H, C1a), 5.05, 5.02 (AB, J 11.8 Hz,
4H, CH2Ar), 5.02, 4.78 (AB, J 11.3 Hz, 2H, CH2Ar), 5.02, 4.74 (AB, J
11.3 Hz, 2H, CH2Ar), 4.97 (brs, 2H, A1), 4.91, 4.89 (t, J 9.4 Hz, 2H, B4),
calcd for C60H76Cl2O13SiCs [MCs] : 1235.3489, found 1235.3427.
A1BC diol 78: BF3 ´ Et2O (0.46 mL, 3.62 mmol) was added to a solution of
A1BC TIPS ether 77 (1.00 g, 0.91 mmol) and PhSH (0.74 mL, 7.24 mmol) in
3112
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Chem. Eur. J. 2000, 6, No. 17