L. Corcilius et al. / Bioorg. Med. Chem. 21 (2013) 3569–3581
3579
4.3.4. O-[O-(20,30,40,60-Tetra-O-acetyl-b-
[10?3]-(2-azido-4O,6O-benzylidene-2-deoxy-
galactopyranosyl)]-N-[(9H-fluoren-9-yl)-methoxycarbonyl]-
(4R)- -hydroxyproline tert-butyl ester (22)
Acceptor 20 (970 mg, 1.42 mmol), 2,3,4,6-tetra-O-acetyl-
D
-galactopyranosyl)-
(dd, 0.5H, J1 ,2 = 7.8 Hz, J2 ,3 = 5.1 Hz, 0.5H20), 5.14 (dd, 0.5H,
0
0
0
0
a-D-
J1 ,2 = 7.8 Hz, J2 ,3 = 5.1 Hz, 0.5H20), 5.04 (d, 0.5H, J1,2 = 3.7 Hz,
0.5H1), 5.03 (d, 0.5H, J1,2 = 3.7 Hz, 0.5H1), 4.98 (dd, 0.5H,
0
0
0
0
0
0
0
0
L
J3 ,4 = 3.6 Hz, 0.5H30), 4.96 (dd, 0.5H, J3 ,4 = 3.6 Hz, 0.5H30), 4.66
a
-D
-
(d, 0.5H, 0.5H10), 4.64 (d, 0.5H, 0.5H10), 4.48 (t, 0.5H, J ,b = 7.6 Hz,
a
galactopyranosyl trichloroacetimidate 21 (1.05 g, 2.13 mmol) and
activated 4 Å MS (400 mg) were combined in dry 1,2-dichloroeth-
ane (14 mL), and the resulting suspension stirred for 30 min at rt
0.5Ha), 4.46–4.42 (m, 1H, Hc), 4.41–3.70 (m, 2H, 0.5Ha, FmocCH2a,
0.5FmocCH2b), 4.35–4.30 (m, 0.5H, 0.5FmocCH2b), 4.27 (t, 0.5H,
J = 7.2, 0.5Fmoc CH), 4.19–3.99 (m, 6.5H, H6a, H6b, H60a, H60b, H3,
H5, 0.5FmocCH), 3.91–3.81 (m, 1.5H, H50, 0.5Hda), 3.77–3.76 (m,
1H, Hdb), 3.72 (dd, 0.5H, J = 4.5, 12.0, 0.5Hda), 3.61 (dd, 0.5H,
J2,3 = 10.7 Hz, 0.5H2), 3.56 (dd, 0.5H, J2,3 = 10.7 Hz, 0.5H2), 2.57–
2.46 (m, 1H, Hba), 2.25–2.12 (m, 7H, Hbb, 2CH3CO), 2.08 (s, 1.5H,
0.5CH3CO), 2.08 (s, 1.5H, 0.5CH3CO), 2.05 (s, 1.5H, 0.5CH3CO),
2.04 (s, 1.5H, 0.5CH3CO), 2.02 (s, 1.5H, 0.5CH3CO), 1.99 (s, 1.5H,
0.5CH3CO), 1.97 (s, 1.5H, 0.5CH3CO), 1.96 (s, 1.5H, 0.5CH3CO),
1.46 (s, 4.5H, 0.5tBu), 1.43 (s, 4.5H, 0.5tBu) ppm; 13C NMR
(125 MHz, CDCl3, reported as a ca. 1:1 mixture of rotational iso-
mers) d 171.5, 170.6, 170.5, 170.5, 170.4, 170.3, 170.2, 169.8,
169.7, 169.6, 154.8, 154.6, 144.2, 144.0, 144.0, 143.8, 141.4,
141.4, 141.3, 127.9, 127.9, 127.2, 127.2, 125.5, 125.3, 125.2,
125.2, 120.1, 120.1, 101.7, 98.3, 97.7, 82.2, 82.1, 77.6, 75.7, 74.6,
74.5, 70.9, 70.9, 69.5, 69.4, 68.9, 68.8, 68.4, 68.2, 68.1, 67.8, 66.9,
66.8, 63.0, 62.9, 61.1, 61.0, 59.2, 59.1, 58.9, 58.6, 52.1, 52.1, 47.4,
47.3, 37.4, 36.3, 28.1, 28.1, 20.9, 20.8, 20.8, 20.8, 20.7, 20.6 ppm;
HRMS (ESI+) m/z calcd for C48H58N4O20Na (M+Na)+ 1033.3537,
found 1033.3524.
before cooling to ꢀ20 °C. TMSOTf (27
lL, 0.15 mmol) was added
dropwise and the reaction mixture was stirred at ꢀ20 °C for 1 h.
The reaction mixture was quenched with triethylamine and fil-
tered through celite. The filtrate was concentrated under reduced
pressure and then purified by silica gel chromatography (eluent:
EtOAc:Petroleum spirit 2:3 ? 1:1 v/v), affording disaccharide 22
as a white foam (908 mg, 63%), mp: 117–120 °C. ½a D25
ꢀ70.0° (c
ꢃ
0.3, CHCl3); IR (film) mmax 2109 (N3), 1745 (C@O), 1707 (C@O),
1420, 1367, 1218, 1146, 1128, 1075, 1043 cmꢀ1
;
1H NMR
(500 MHz, CDCl3, reported as a ca. 1:1 mixture of rotational iso-
mers): d 7.79–7.75 (m, 2H ArH), 7.69–7.67 (m, 0.5H, ArH), 7.63–
7.58 (m, 1.5H, ArH), 7.54–7.51 (m, 2H, ArH), 7.43–7.29 (m, 7H,
ArH), 5.56 (s, 1H, benzylideneCH), 5.40–5.38 (m, 1H, H40), 5.28
(dd, 0.5H, J1 ,2 = 7.8 Hz, J2 ,3 = 10.2 Hz, 0.5H20), 5.26 (dd, 0.5H,
0
0
0
0
J1 ,2 = 7.8 Hz, J2 ,3 = 10.2 Hz, 0.5H20), 5.12 (d, 0.5H, J1,2 = 3.5 Hz,
0.5H1), 5.11 (d, 0.5H, J1,2 = 3.5 Hz, 0.5H1), 5.00 (dd, 0.5H,
0
0
0
0
J3 ,4 = 3.4 Hz, 0.5H30), 4.98 (dd, 0.5H, J3 ,4 = 3.4 Hz, 0.5H30), 4.73
0
0
0
0
(d, 0.5H, H10), 4.72 (d, 0.5H, H10), 4.51–4.47 (m, 1.5H, H
4.43–4.37 (m, 3H, 0.5H , FmocCH2a, 0.5FmocCH2b, H4), 4.36–4.30
c, 0.5Ha),
a
(m, 0.5H, 0.5FmocCH2b), 4.30–4.26 (m, 1.5H, H6a, 0.5FmocCH),
4.23–4.03 (m, 4.5H, 0.5FmocCH, H3, H60a, H60b, H6b), 3.94–3.73
(m, 4H, H50, H2, Hda, Hdb), 3.72 (m, 1H, H5), 2.56–2.50 (m, 0.5H,
0.5Hba), 2.49–2.43 (m, 0.5H, 0.5Hba), 2.28–2.20 (m, 0.5H, 0.5Hbb),
2.18–2.12 (m, 3.5H, 0.5Hbb, CH3CO), 2.04 (s, 1.5H, 0.5CH3CO),
2.03 (s, 1.5H, 0.5CH3CO), 2.02 (s, 1.5H, 0.5CH3CO), 1.98 (s, 1.5H,
0.5CH3CO), 1.97 (s, 1.5H, 0.5CH3CO), 1.96 (s, 1.5H, 0.5CH3CO),
1.47 (s, 4.5H, 0.5tBu), 1.44 (s, 4.5H, 0.5tBu) ppm; 13C NMR
(125 MHz, CDCl3, reported as a ca. 1:1 mixture of rotational iso-
mers) d 171.6, 171.4, 170.4, 170.3, 170.2, 169.5, 154.9, 154.7,
144.2, 144.0, 143.8, 141.4, 141.4, 141.3, 137.6, 137.6, 129.1,
128.3, 127.9, 127.2, 127.2, 127.2, 127.1, 126.2, 125.5, 125.3,
125.2, 125.2, 120.1, 120.1, 120.1, 102.7, 100.8, 100.8, 98.8, 98.2,
82.2, 82.0, 77.2, 75.9, 75.8, 75.8, 75.7, 75.4, 71.1, 70.9, 70.9, 69.2,
68.7, 68.7, 68.1, 67.9, 67.0, 67.0, 64.0, 63.9, 61.4, 61.4, 59.0, 58.8,
58.5, 58.4, 52.1, 47.4, 47.3, 37.6, 36.6, 28.1, 20.8, 20.8, 20.7,
20.6 ppm; HRMS (ESI+) m/z calcd for C51H58N4O18Na (M+Na)+
1037.3638, found 1037.3627.
4.3.6. O-[O-(20,30,40,60-Tetra-O-acetyl-b-
[10?3]-(2-acetamido-4,6-di-O-acetyl-2-deoxy-
galactopyranosyl)]-N-[(9H-fluoren-9-yl)-methoxycarbonyl]-
(4R)- -hydroxyproline tert-butyl ester (24)
Azide 23 (550 mg, 0.54 mmol) was dissolved in Ac2O/AcOH/THF
(100:17:100, v/v/v, 4.34 mL). The mixture was cooled to 0 °C before
the addition of zinc nanopowder (270 mg, 4.13 mmol). The reac-
tion mixture was stirred for 18 h at rt and then filtered through cel-
ite with additional THF. The filtrate was evaporated to dryness
under reduced pressure and the remaining solvent azeotroped
with toluene. The residue was purified by silica gel chromatogra-
phy (eluent: EtOAc:MeOH:Petroleum spirit 9:1:10 v/v/v), affording
24 as a white foam (514 mg, 92%), mp: 114–117 °C.
D-galactopyranosyl)-
a-D-
L
½
a 2D5
+16.7° (c 0.30, CHCl3); IR (film) mmax 1743 (C@O), 1705
ꢃ
(C@O), 1682 (C@O), 1423, 1368, 1218, 1152, 1125, 1046 cmꢀ1
;
1H NMR (500 MHz, CD3OD, reported as a ca. 1:1 mixture of rota-
tional isomers) d 7.89–7.80 (m, 2H, ArH), 7.69–7.60 (m, 2H, ArH),
7.42–7.39 (m, 2H, ArH), 7.33–7.31 (m, 2H, ArH), 5.42 (m, 1H, H4),
5.34 (m, 1H, H40), 5.04–4.97 (m, 2H, H20, H30), 4.93 (d, 0.5H,
J1,2 = 3.7 Hz, 0.5H1), 4.90 (d, 0.5H, J1,2 = 3.7 Hz, 0.5H1), 4.75 (d,
4.3.5. O-[O-(20,30,40,60-Tetra-O-acetyl-b-
[10?3]-(4,6-di-O-acetyl-2-azido-2-deoxy-
galactopyranosyl)]-N-[(9H-fluoren-9-yl)-methoxycarbonyl]-
(4R)- -hydroxyproline tert-butyl ester (23)
D-galactopyranosyl)-
a-D-
1H, J1 ,2 = 7.4 Hz, H10), 4.52–4.30 (m, 4.5H, FmocCH2a
0.5FmocCH2b, H , H , H2), 4.25–4.09 (m, 5.5H, 0.5FmocCH2b
,
,
0
0
a
c
L
FmocCH, H5, H60a, H60b, H6a), 4.02–3.96 (m, 3H, H6b, H50, H3),
3.75–3.73 (m, 0.5H, 0.5Hda), 3.65–3.57 (m, 1.5H, 0.5Hda, Hdb),
2.64–2.58 (m, 0.5H, 0.5Hba), 2.53–2.49 (m, 0.5H, 0.5Hba), 2.18–
2.11 (m, 7H, Hbb, 2CH3CO), 2.06 (s, 3H, CH3CO), 2.01 (s, 1.5H,
0.5CH3CO), 2.01 (s, 1.5H, 0.5CH3CO), 1.99 (s, 1.5H, 0.5CH3CO),
1.98 (s, 1.5H, 0.5CH3CO), 1.93–1.92 (m, 6H, 2CH3CO), 1.44 (s,
4.5H, 0.5tBu), 1.42 (s, 4.5H, 0.5tBu) ppm; 13C NMR (125 MHz,
CD3OD, reported as a ca. 1:1 mixture of rotational isomers) d
173.1, 173.0, 172.3, 172.0, 172.0, 172.0, 171.5, 171.1, 156.5,
156.3, 145.4, 145.2, 145.1, 144.7, 142.6, 142.6, 142.5, 129.0,
128.9, 128.3, 126.3, 126.1, 126.1, 121.1, 102.4, 102.3, 99.3, 98.7,
83.3, 83.0, 78.2, 78.0, 74.3, 74.2, 72.1, 71.8, 71.3, 71.2, 70.1, 70.1,
69.2, 68.9, 68.8, 68.6, 64.3, 62.4, 60.4, 59.8, 53.6, 52.8, 50.4, 50.3,
48.5, 48.3, 38.2, 37.3, 28.3, 22.9, 22.8, 21.0, 21.0, 20.8, 20.8, 20.7,
20.7, 20.5, 20.5, 20.5 ppm; HRMS (ESI+) m/z calcd for
Benzylidine acetal 22 (738 mg, 0.73 mmol) was dissolved in
AcOH/H2O (4:1 v/v, 20 mL) and stirred for 20 h at 50 °C. The solu-
tion was evaporated to dryness under reduced pressure and the
remaining solvent azeotroped with toluene. The residue was re-
suspended in Ac2O/Pyr (1:9 v/v, 20 mL) with a catalytic quantity
of DMAP, and the mixture stirred for 18 h at room temperature.
The solvent was removed under reduced pressure and the remain-
ing solvent azeotroped with toluene. The residue was purified by
silica gel chromatography (eluent: EtOAc:Petroleum spirit 1:1 v/
v), affording 23 as a white foam (600 mg, 81% over 2 steps), mp:
98–101 °C. ½a 2D5
ꢃ
+52.5° (c 0.2, CHCl3); IR (film) mmax 2110 (N3),
1744 (C@O), 1708 (C@O), 1452, 1420, 1368, 1219, 1150, 1125,
1050 cmꢀ1; 1H NMR (500 MHz, CDCl3, reported as a ca. 1:1 mixture
of rotational isomers) d 7.77–7.75 (m, 2H, ArH), 7.68–7.66 (m, 0.5H,
ArH), 7.62–7.57 (m, 1.5H, ArH), 7.41–7.38 (m, 2H, ArH), 7.33–7.29
(m, 2H, ArH), 5.47–5.45 (m, 1H, H4), 5.36–5.33 (m, 1H, H40), 5.16
C
50H63N2O21 (M+H)+ 1027.3918, found 1027.3917.