Total Synthesis of Ganglioside GalNAc-GD1a
FULL PAPER
were extracted with CHCl3, and the organic layer was washed with satu-
rated aqueous Na2CO3, dried (Na2SO4), and concentrated. The residue
was purified by column chromatography on silica gel (acetone/hexane
1:5) to give 28 (36 mg, 72%). [a]D =ꢀ16.18 (c=0.7, CHCl3); 1H NMR
(500 MHz, CDCl3): d=5.80 (m, 1H; H-5Cer), 5.72 (d, J2,NH =9.8 Hz, 1H;
NH), 5.30 (m, 2H; H-3Cer, H-4Cer), 4.95 (t, J2,3 =J3,4 =8.3 Hz, 1H; H-3a),
4.88 (t, J1,2 =7.5 Hz, 1H; H-2a), 4.47 (m, 2H; H-1a, H-6a), 4.32 (m, 1H;
7.6 Hz, 1H; H-1b), 4.67 (dd, J5,6 =6.6 Hz, Jgem =11.3 Hz, 1H; H-6b), 4.42
(dd, J2,3 =10.3 Hz, J3,4 =2.8 Hz, 1H; H-3b), 4.33 (m, 2H; H-1a, H-6’b),
4.27 (m, 3H; H-6a, H-9c, H-2Cer), 4.14 (near d, 1H; H-6’a), 4.03–3.95 (m,
4H; H-9’c, H-6d, H-6’d, H-5d), 3.89 (m, 2H; H-5b, H-5c), 3.83–3.78 (m,
5H; H-4b, H-6c, COOCH3), 3.74–3.67 (m, 4H; H-4a, H-2d, H-1Cer, H-
1’Cer), 3.49 (near t, 1H; H-5a), 2.61–2.48 (m, 5H; OCOCH2CH2COO, H-
3ceq), 2.16–1.82 (11ꢂs, 33H; 11ꢂAc), 2.13–1.84 (m, 5H; H-3cax, H-6Cer
,
H-2Cer), 4.27 (dd, J5,6’ =2.3 Hz, Jgem =12.0 Hz, 1H; H-6’a), 3.87 (dd, J1,2
=
H-6’Cer, NHCOCH2), 1.57 (m, 2H; NHCOCH2CH2), 1.23 (m, 50H; 25ꢂ
CH2), 0.88 ppm (2ꢂt, 6H; 2ꢂCH3); 13C NMR (150 MHz, CDCl3): d=
172.7, 171.3, 170.6, 170.3, 170.3, 170.2, 170.2, 170.1, 169.9, 169.4, 168.2,
165.8, 164.6, 137.6, 133.4, 133.3, 130.2, 129.8, 129.5, 129.2, 128.6, 128.5,
124.5, 100.7, 100.1, 99.3, 98.0, 76.7, 74.3, 73.4, 73.3, 73.1, 72.2, 72.0, 71.8,
71.7, 70.5, 70.1, 69.4, 68.7, 67.3, 66.9, 66.5, 66.3, 63.0, 62.7, 62.3, 61.4, 53.0,
52.4, 50.0, 49.1, 36.7, 36.4, 32.2, 31.9, 29.7, 29.6, 29.5, 29.4, 29.3, 29.3, 29.2,
28.8, 25.6, 23.4, 23.1, 22.6, 21.2, 20.8, 20.7, 20.6, 20.4, 20.3, 14.1 ppm;
HRMS: m/z calcd for C104H151N3O39Na+: 2088.9818 [M+Na]+; found:
2088.9817.
4.9 Hz, Jgem =10.0 Hz, 1H; H-1Cer), 3.77 (dd, J1ꢄ,2 =4.0 Hz, 1H; H-1’Cer),
3.62 (m, 2H; H-4a, H-5a), 2.83 (d, J4,OH =4.6 Hz, 1H; OH), 2.73–2.56 (m,
4H; OCOCH2CH2COO), 2.16 (m, 2H; NHCOCH2), 2.12 (s, 3H; Ac),
,
2.05 (s, 3H; Ac), 1.96 (m, 2H; H-6Cer H-6’Cer), 1.59 (m, 2H;
NHCOCH2CH2), 1.25 (m, 50H; 25ꢂCH2), 0.88 ppm (2ꢂt, 6H; 2ꢂCH3);
13C NMR (125 MHz, CDCl3): d=172.8, 172.0, 171.9, 170.4, 169.4, 138.0,
124.5, 99.6, 76.6, 73.5, 71.2, 70.4, 66.4, 63.7, 50.0, 36.8, 32.3, 31.9, 29.7,
29.7, 29.5, 29.5, 29.4, 29.2, 28.9, 25.7, 22.7, 20.9, 20.8, 14.1 ppm; HRMS:
m/z calcd for C50H87NO12Na+: 916.6121 [M+Na]+; found: 916.6120.
Compound 30: Molecular sieves (AW-300, 4 ꢃ, 200 mg) were added to a
solution of 25 (25.0 mg, 24 mmol) and 13 (32.0 mg, 24 mmol) in CHCl3
(800 mL). The suspension was stirred for 1 h at RT, after which TMSOTf
(0.4 mL, 1.9 mmol) was added at 08C. Stirring was continued for 2 h at
08C (completion of the reaction was confirmed by TLC, toluene/EtOAc/
MeOH 5:5:1). The reaction mixture was filtered through Celite and the
removed molecular sieves were washed with CHCl3. The combined fil-
trate and washings were extracted with CHCl3, and the organic layer was
washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), and
concentrated. The residue was purified by column chromatography on
silica gel (toluene/EtOAc/MeOH 10:10:1) to give 30 (37 mg, 70%).
[a]D =+1.88 (c=0.8, CHCl3); 1H NMR (600 MHz, CDCl3): d=8.10–7.43
(m, 15H; 3ꢂPh), 7.20–6.70 (2ꢂd, 4H; Ar), 6.04 (d, JNH,2 =8.2 Hz, 1H;
NHd), 5.73 (m, 1H; H-5Cer), 5.58 (d, JNH,2 =9.6 Hz, 1H; NHCer), 5.40 (m,
3H; H-3d, H-2b, H-8c), 5.34 (m, 1H; H-4d), 5.26–5.11 (m, 5H; H-7c,
NHc, H-2a, H-3Cer, H-4Cer), 5.07 (m, 1H; H-4c), 5.02 (d, J1,2 =8.3 Hz, 1H;
H-1d), 4.84 (d, Jgem =11.0 Hz, 1H; ArCH2), 4.82 (d, J1,2 =8.2 Hz, 1H; H-
Compound 32: Molecular sieves (AW-300, 4 ꢃ, 200 mg) were added to a
solution of 29 (39 mg, 41.1 mmol) and 13 (55 mg, 41.1 mmol) in CHCl3
(820 mL). The suspension was stirred for 30 min at RT, after which
TMSOTf (0.8 mL, 4.11 mmol) was added at 08C. Stirring was continued
for 1 h at 08C (completion of the reaction was confirmed by TLC, ace-
tone/hexane 1:1). The reaction mixture was filtered through Celite and
the removed molecular sieves were washed with CHCl3. The combined
filtrate and washings were extracted with CHCl3, and the organic layer
was washed with saturated aqueous NaHCO3, dried (Na2SO4), and con-
centrated. The residue was purified by column chromatography on silica
gel (acetone/hexane 1:1) to give 32 (24 mg, 28%). [a]D =ꢀ3.58 (c=1.0,
CHCl3); 1H NMR (600 MHz, CDCl3): d=8.09–7.39 (m, 15H; 3ꢂPh),
6.40 (d, 1H; J2,NH =7.5 Hz, NHd), 5.85–5.79 (m, 2H; H-3d, H-5Cer), 5.70
(d, J2,NH =9.6 Hz, 1H; NHCer), 5.52–5.41 (m, 3H; H-8c, H-3Cer, H-4Cer),
5.35 (d, J3,4 =3.5 Hz, 1H; H-4d), 5.29–5.24 (m, 2H; H-2b, H-7c), 5.21 (d,
J
J
1,2 =8.3 Hz, 1H; H-1d), 5.13 (t, J2,3 =J3,4 =9.3 Hz, 1H; H-3a), 4.99 (d,
5,NH =9.6 Hz, 1H; NHc), 4.89–4.82 (m, 2H; H-2a, H-4c), 4.70 (d, J1,2
=
1b), 4.69 (dd,
J
gem =11.7 Hz,
J
5,6 =6.2 Hz, 1H; H-6b), 4.64 (d, 1H;
8.2 Hz, 1H; H-1b), 4.65 (dd, J5,6 =6.2 Hz, Jgem =11.0 Hz, 1H; H-6b), 4.42
(m, 1H; H-2Cer), 4.39 (dd, J2,3 =10.3 Hz, J3,4 =2.1 Hz, 1H; H-3b), 4.35–
4.32 (m, 2H; H-1a, H-6’b), 4.31 (dd, J8,9 =2.4 Hz, Jgem =12.7 Hz, 1H; H-
9c), 4.09–3.90 (m, 7H; H-6a, H-6’a, H-9’c, H-5d, H-6d, H-6’d, H-1Cer),
3.88–3.81 (m, 3H; H-4a, H-5b, H-5c), 3.78 (s, 3H; COOCH3), 3.77–3.75
(m, 2H; H-4b, H-6c), 3.59–3.53 (m, 2H; H-2d, H-1’Cer), 3.35 (m, 1H; H-
5a), 2.61 (dd, J3eq,4 =4.9 Hz, Jgem =13.0 Hz, 1H; H-3ceq), 2.15, 2.14, and
2.13 (3ꢂs, 9H; 3ꢂAc), 2.12–2.08 (m, 4H; NHCOCH2), 2.06–1.98 (m,
17H; H-6Cer, H-6’Cer, 5 Ac), 1.96 and 1.88 (2ꢂs, 6H; 2ꢂAc), 1.82–1.78 (m,
7H; H-3cax, 2 Ac), 1.57 (m, 2H; NHCOCH2CH2), 1.30–1.22 (m, 50H;
25ꢂCH2), 0.88 ppm (2ꢂt, J=6.6 Hz, 6H; 2ꢂCH2CH3); 13C NMR
(150 MHz, CDCl3): d=172.7, 171.5, 170.7, 170.4, 170.4, 170.2, 170.2,
170.1, 170.1, 169.8, 169.6, 168.3, 165.9, 165.2, 164.6, 137.4, 133.5, 133.3,
130.0, 130.2, 130.2, 129.7, 129.6, 129.5, 129.2, 128.7, 128.5, 128.3, 124.6,
100.5, 100.2, 99.6, 97.8, 74.5, 74.2, 73.5, 73.4, 72.7, 72.6, 71.9, 71.6, 71.4,
70.6, 70.1, 69.0, 68.8, 67.3, 66.9, 66.2, 62.8, 61.9, 61.8, 61.4, 52.9, 52.8, 50.7,
49.2, 36.8, 36.6, 32.3, 31.9, 29.7, 29.7, 29.6, 29.5, 29.5, 29.4, 29.3, 29.2, 28.9,
25.7, 23.4, 23.1, 22.7, 21.3, 20.9, 20.7, 20.7, 20.7, 20.5, 20.4, 20.3, 14.1 ppm;
HRMS: m/z calcd for 1= (C104H151N3O39)+Na+: 1088.0011 [1= M+Na]+;
ArCH2), 4.45 (d, J1,2 =6.9 Hz, 1H; H-1a), 4.33 (dd, J2,3 =10.3 Hz, J3,4
=
2.8 Hz, 1H; H-3b), 4.25–4.03 (m, 9H; H-2d, H-6d, H-6’d, H-5d, H-6’a, H-
9c, H-9’c, H-6’b, H-2Cer), 4.02–3.74 (m, 11H; OMe, H-4b, H-5b, H-6a, H-
5a, H-4a, H-5c, H-6c, H-1Cer), 3.64 (s, 3H; OMe), 3.54 (near t, 1H; H-3a),
3.50 (dd, Jgem =9.6 Hz, J1ꢄ,2 =3.4 Hz, 1H; H-1’Cer), 2.55–2.35 (m, 4H;
OCOCH2CH2COO), 2.25 (dd, Jgem =13.1 Hz, J3eq,4 =4.8 Hz, 1H; H-3ceq),
2.15–1.84 (m, 32H; 9ꢂAc, H-3cax, H-6Cer, H-6’Cer, NHCOCH2), 1.45 (m,
2H; NHCOCH2CH2), 1.25 (m, 50H; 25ꢂCH2), 0.88 ppm (t, 6H; 2ꢂ
CH3); 13C NMR (150 MHz, CDCl3): d=172.6, 171.1, 170.8, 170.5, 170.3,
170.2, 169.9, 169.7, 168.1, 165.9, 165.1, 164.3, 158.9, 138.2, 133.3, 133.1,
130.5, 130.1, 129.9, 129.7, 129.6, 129.5, 129.4, 129.2, 128.4, 124.9, 113.5,
101.5, 101.2, 99.5, 98.6, 80.5, 79.0, 76.5, 74.1, 73.9, 73.3, 73.0, 72.3, 72.0,
70.9, 70.7, 70.1, 68.7, 67.4, 67.0, 66.6, 66.5, 63.5, 63.1, 62.1, 61.4, 55.0, 53.2,
51.3, 49.9, 49.3, 36.6, 36.4, 35.9, 32.2, 31.9, 29.7, 29.7, 29.5, 29.5, 29.4, 29.3,
29.3, 28.9, 25.5, 23.3, 23.2, 22.7, 21.1, 20.8, 20.7, 20.6, 20.5, 20.4, 14.1 ppm;
HRMS: m/z calcd for C115H159N3O39Na+: 2229.0448 [M+Na]+; found:
2229.0448.
2
2
Compound 31: Molecular sieves (AW-300, 4 ꢃ, 300 mg) were added to a
solution of 28 (40 mg, 44.8 mmol) and 13 (60 mg, 44.8 mmol) in CHCl3
(448 mL). The suspension was stirred for 1 h at RT, after which TMSOTf
(0.8 mL, 4.48 mmol) was added at 08C. Stirring was continued for 1 h at
08C (completion of the reaction was confirmed by TLC, acetone/hexane
1:1). TFA (224 mL) was added to the reaction mixture. Stirring was con-
tinued for 2 h at 08C. The reaction mixture was filtered through Celite
and the removed molecular sieves were washed with CHCl3. The com-
bined filtrate and washings were extracted with CHCl3, and the organic
layer was washed with saturated aqueous Na2CO3, dried (Na2SO4), and
concentrated. The residue was purified by column chromatography on
silica gel (acetone/hexane 2:3) to give 31 (45 mg, 48%). [a]D =ꢀ13.78
found: 1088.0014.
Compound 33: Molecular sieves (AW-300, 4 ꢃ, 100 mg) were added to a
solution of 25 (20.0 mg, 20 mmol) and 17 (48.0 mg, 20 mmol) in CHCl3
(0.96 mL). The suspension was stirred for 1 h at RT, after which TMSOTf
(0.7 mL, 3.9 mmol) was added at 08C. Stirring was continued for 2 h at RT
(completion of the reaction was confirmed by TLC, CHCl3/EtOAc/
MeOH 3:3:1). The reaction mixture was filtered through Celite and the
removed molecular sieves were washed with CHCl3. The combined fil-
trate and washings were extracted with CHCl3, and the organic layer was
washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), and
concentrated. The residue was purified by column chromatography on
silica gel (CHCl3/EtOAc/MeOH 8:8:1) to give 33 (39 mg, 60%). [a]D =
+3.58 (c=0.2, CHCl3); 1H NMR (600 MHz, CDCl3): d=8.15–7.35 (m,
25H; 5ꢂPh), 7.10–6.64 (2ꢂd, 4H; Ar), 6.41 (d, JNH,5 =7.6 Hz, 1H; NHf),
5.65 (m, 5H; H-5Cer, NHCer, H-8f, NHg, NHd), 5.41 (m, 2H; H-4d, H-8c),
5.33 (m, 1H; H-4g), 5.29 (m, 2H; H-2b, H-2e), 5.19 (m, 4H; H-3Cer, H-
1
(c=0.7, CHCl3); H NMR (600 MHz, CDCl3): d=8.11–7.43 (m, 10H; 2ꢂ
Ph), 6.42 (d, J2,NH =7.6 Hz, 1H; NHd), 5.75 (m, 2H; H-5Cer, H-3d), 5.67
(d, J2,NH =9.6 Hz, 1H; NHCer), 5.53 (m, 1H; H-8c), 5.33 (m, 2H; H-4d, H-
2b), 5.24 (m, 3H; H-3Cer, H-4Cer, H-7c), 5.14 (m, 3H; H-1d, H-3a, NHc),
4.88 (m, 1H; H-4c), 4.82 (t, J1,2 =J2,3 =7.6 Hz, 1H; H-2a), 4.73 (d, J1,2
=
Chem. Eur. J. 2011, 17, 5641 – 5651
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5649