Efficient Synthesis of S-Linked Glycopeptides
875 887
7.5 Hz, 1H), 7.02 (brs, 1H), 5.53 (d, J=9.4 Hz, 1H), 5.18 (m, 1H), 5.09
(AB quartet, J=12.0 Hz, 2H), 4.99 (t-like, J=3.6 Hz, 1H), 4.72 (brs,
1H), 4.66 (m, 2H), 4.24 (m, 2H), 3.86 (t-like, J=8.0 Hz, 1H), 3.73 (brt,
1H), 3.66 (dd, J=14.6, 3.6 Hz, 1H), 3.62 (brs, 1H), 3.01 (dd, J=14.7,
2.8 Hz, 2H), 2.07, 2.04, 2.033, 2.030 (4s, 12H), 1.49 ppm (s, 9H);
13C NMR (CDCl3): d=171.2, 170.8, 170.4, 169.2, 168.9, 155.4, 136.1,
134.8, 128.7, 128.5, 127.7, 123.0, 122.1, 119.5, 111.2, 109.9, 87.0, 80.6, 70.8,
69.9, 67.9, 67.5, 67.0, 61.7, 55.3, 52.6, 52.0, 36.9, 28.2, 23.4, 20.8, 20.54,
20.50 ppm; MS (MALDI): m/z: 850 [M+Na]+ ; elemental analysis calcd
(%) for C40H50N4O13S (826.9): C 58.04, H 6.09, N 6.78; found: C 57.64, H
6.06, N 6.43.
53.3, 52.2, 48.1, 37.7, 34.0, 28.2, 25.1, 23.4, 20.7, 20.6, 15.4, 11.5 ppm; MS
(MALDI): m/z: 886 [M+Na]+, 902 [M+K]+ ; elemental analysis calcd
(%) for C40H57N5O14S (864.0): C 55.61, H 6.65, N 8.11; found: C 55.45, H
6.82, N 7.83.
N-tert-Butoxycarbonyl-S-(3,4,6-tri-O-acetyl-2-acetamido-2-deoxy-a-d-gal-
actopyranosyl)-l-cysteinyl-l-valinyl-l-proline tert-butyl ester (40): The
reaction procedure was identical to that described for 30 except that bro-
mide 12 was used instead of 1 and a-GalNAc thiol 26 was used instead
of 27. The crude product was purified by column chromatography using
petroleum ether/EtOAc (1:2) ! EtOAc/MeOH (100:1) as eluent to give
the S-glycotripeptide 40 as a white solid after lyophilization with dioxane
in 72% yield. Rf =0.04 (petroleum ether/EtOAc 1:2.7); [a]D =+50.2 (c=
0.5 in CHCl3); 1H NMR (250 MHz, CDCl3): d=6.98 (d, J=8.5 Hz, 1H),
6.09 (brs, 1H), 5.66 (d, J=8.4 Hz, 1H), 5.38 (m, 2H), 4.97 (dd, J=11.8,
2.9 Hz, 1H), 4.88 (dd, J=8.7, 4.9 Hz, 1H), 4.64 (dd, J=8.7, 5.6 Hz, 1H),
4.52 (t, J=6.8 Hz, 1H), 4.39 (m, 2H), 4.14 (m, 2H), 3.70 (m, 2H), 3.39
(dd, J=14.5, 4.4 Hz, 1H), 2.84 (dd, J=14.5, 5.9 Hz, 1H), 2.17, 2.11 (2s,
6H), 2.00 (s, 6H), 2.30 1.90 (m, 5H), 1.44 (s, 18H), 1.05 (d, J=6.8 Hz,
3H), 0.94 ppm (d, J=6.7 Hz, 3H); 13C NMR (CDCl3): d=171.1, 170.7,
170.5, 170.4, 170.3, 169.8, 169.7, 155.3, 87.3, 81.3, 80.6, 68.4, 67.9, 67.3,
62.0, 59.8, 55.5, 54.0, 48.0, 47.3, 35.2, 31.4, 29.1, 28.2, 27.9, 24.9, 23.2, 20.7,
19.6, 17.3 ppm; MS (MALDI): m/z: 825 [M+Na]+, 841 [M+K]+ ; elemen-
tal analysis calcd (%) for C36H58N4O14S (802.9): C 53.85, H 7.28, N 6.98;
found: C 53.64, H 7.49, N 6.51.
N-tert-Butoxycarbonyl-l-tyrosinyl-S-(3,4,6-tri-O-acetyl-2-acetamido-2-
deoxy-a-d-galactopyranosyl)-l-cysteine benzyl ester (37): The reaction
procedure was identical to that described for 30 except that bromide 6
was used instead of 1 and a-GalNAc thiol 26 was used instead of 27. The
crude product was purified by column chromatography using petroleum
ether/EtOAc (1:1!1:2) as eluent to give the title compound 37 as a
white solid after lyophilization with dioxane in 63% yield. Rf =0.10 (pe-
troleum ether/EtOAc 1:2); [a]D =+69.5 (c=1.0 in CHCl3); 1H NMR
(250 MHz, CDCl3): d=7.68 (brs, 1H), 7.36 (m, 5H), 7.27 (d, J=7.1 Hz,
1H), 6.99 (d, J=8.4 Hz, 2H), 6.75 (d, J=8.4 Hz, 2H), 5.62 (d, J=9.9 Hz,
1H), 5.17 (AB quartet, J=11.9 Hz, 2H), 5.16 (d-like, 1H), 5.00 (m, 1H),
4.82 (d-like, J=10.2 Hz, 1H), 4.62 (m, 1H), 4.60 (dd, J=11.4, 2.9 Hz,
1H), 4.46 (dd, J=10.1, 5.0 Hz, 1H), 4.31 (m, 2H), 4.03 (m, 1H), 3.83 (dd,
J=10.6, 7.9 Hz, 1H), 3.48 (dd, J=13.6, 2.4 Hz, 1H), 3.28 (dd, J=14.9,
4.2 Hz, 1H), 2.90 (dd, J=14.8, 1.6 Hz, 1H), 2.78 (dd, J=13.7, 5.9 Hz,
1H), 2.23, 2,11, 2.05, 1.99 (4s, 12H), 1.49 ppm (s, 9H); 13C NMR
(CDCl3): d=170.8, 170.7, 170.47, 170.43, 170.1, 168.9, 156.0, 155.4, 134.7,
131.0, 128.9, 128.8, 128.6, 127.3, 116.1, 88.5, 80.8, 68.9, 68.7, 67.8, 66.9,
61.6, 55.2, 53.1, 47.7, 36.7, 36.0, 28.2, 23.6, 20.7, 20.6, 20.5 ppm; MS
(MALDI): m/z: 827 [M+Na]+, 843 [M+K]+ ; elemental analysis calcd
(%) for C38H49N3O14S (803.9): C 56.78, H 6.14, N 5.23; found: C 56.56, H
6.40, N 5.05.
N-tert-Butoxycarbonyl-S-(2,3,4,6-tetra-O-acetyl-b-d-glucopyranosyl)-l-
cysteinyl-l-valinyl-l-proline tert-butyl ester (41): ApH 8.5 solution of
NaHCO3 (3 mL) followed by TBAHS (136 mg, 0.40 mmol) were added
to a solution of bromotripeptide 12 (54 mg, 0.10 mmol) and peracetyl b-
glucosyl thiol (80 mg, 0.20 mmol) in EtOAc (3 mL). The mixture was vig-
orously stirred at room temperature for 5 h, and was then diluted with
EtOAc and washed successively with saturated aqueous NaHCO3 and
brine. The organic layer was dried over MgSO4 and concentrated in
vacuo to give a residue which was purified by flash-column chromatogra-
phy (petroleum ether/EtOAc 2:1!1:1) to afford the b-thioglycoside 41
(78 mg, 96%) as a white amorphous solid. Rf =0.13 (petroleum ether/
EtOAc 1.3:1); [a]D =ꢀ50.3 (c=1.2 in CHCl3); 1H NMR (250 MHz,
CDCl3): d=7.10 (d, J=8.6 Hz, 1H), 5.66 (d, J=7.0 Hz, 1H), 5.21 (t, J=
9.2 Hz, 1H), 5.05 (t, J=9.8 Hz, 1H), 4.99 (t, J=9.3 Hz, 1H), 4.54 (m,
2H), 4.38 (m, 2H), 4.21 (m, 2H), 3.72 (m, 3H), 3.04 (dd, J=14.3, 5.9 Hz,
1H), 2.92 (dd, J=14.3, 6.5 Hz, 1H), 2.07, 2.03, 2.01, 1.98 (4s, 12H), 2.00
(m, 5H), 1.43 (s, 18H), 1.00 (d, J=6.8 Hz, 3H), 0.92 ppm (d, J=6.8 Hz,
3H); 13C NMR (CDCl3): d=171.2, 170.6, 170.1, 170.0, 169.5, 169.4, 169.3,
155.3, 83.8, 81.2, 80.4, 77.2, 76.2, 73.7, 69.4, 68.3, 62.1, 59.6, 55.7, 54.2,
47.2, 32.8, 31.4, 29.6, 29.1, 28.2, 27.9, 24.8, 20.6, 20.5, 19.4, 17.6 ppm; MS
(MALDI): m/z: 827 [M+Na]+, 843 [M+K]+ ; elemental analysis calcd
(%) for C36H57N3O15S (803.9): C 53.79, H 7.15, N 5.23; found: C 54.22, H
7.52, N 4.92.
N-tert-Butoxycarbonyl-l-alanyl-S-(3,4,6-tri-O-acetyl-2-acetamido-2-
deoxy-a-d-glucopyranosyl)-l-cysteinyl-l-proline benzyl ester (38): The
reaction procedure was identical to that described for 30 except that bro-
mide 10 was used instead of 1. The crude product was purified by column
chromatography using EtOAc/MeOH (100:1) as eluent to give the title
compound 38 as a white solid after lyophilization with dioxane in 65%
yield. Rf =0.46 (EtOAc/MeOH 20:1); [a]D =+35.3 (c=1.2 in CHCl3);
1H NMR (250 MHz, CDCl3): d=7.36 (m, 5H), 7.08 (d, J=8.2 Hz, 1H),
5.91 (d, J=8.8 Hz, 1H), 5.44 (t-like, J=5.4 Hz, 1H), 5.24 4.96 (m, 6H),
4.53 (m, 2H), 4.41 4.15 (m, 4H), 3.67 (m, 2H), 3.04 (dd, J=14.2, 3.8 Hz,
1H), 2.89 (dd, J=14.5, 7.1 Hz, 1H), 2.10 (m, 4H), 2.10, 2.04, 1.97 (3s,
12H), 1.46 (s, 9H), 1.36 ppm (d, J=7.1 Hz, 3H); 13C NMR (CDCl3): d=
172.5, 171.4, 171.3, 170.6, 170.1, 169.2, 168.3, 155.4, 135.5, 128.5, 128.3,
128.1, 86.5, 80.2, 71.4, 68.7, 67.9, 67.0, 61.6, 58.8, 52.2, 50.6, 50.2, 47.0,
34.5, 28.8, 28.2, 24.7, 23.1, 20.7, 20.64, 20.56, 17.9 ppm; MS (MALDI): m/
N-tert-Butoxycarbonyl-l-alanyl-S-(2,3,4,6-tetra-O-acetyl-b-d-glucopyra-
nosyl)-l-cysteinyl-l-serine benzyl ester (42): The reaction procedure was
identical to that described for 41 except that bromide 17 was used instead
of 12. The crude product was purified by column chromatography using
petroleum ether/EtOAc (1:1) and then EtOAc as eluent to give the S-gly-
cotripeptide 42 as a white solid after lyophilization with dioxane in 78%
yield. Rf =0.44 (EtOAc); [a]D =ꢀ10.8 (c=1.0 in CHCl3); 1H NMR
(600 MHz, CDCl3): d=7.44 (d, J=6.9 Hz, 1H), 7.38 (m, 5H), 7.19 (d,
J=7.0 Hz, 1H), 5.26 (t, J=9.3 Hz, 1H), 5.23 (q-like, 2H), 5.16 (d, J=
6.0 Hz, 1H), 5.07 (t, J=9.7 Hz, 1H), 4.99 (t, J=9.6 Hz, 1H), 4.81 (q, J=
4.9 Hz, 1H), 4.74 (d, J=10.1 Hz, 1H), 4.69 (t-like, J=3.7 Hz, 1H), 4.37
(d, J=12.1 Hz, 1H), 4.20 (dd, J=12.5, 5.1 Hz, 1H), 4.16 (t, J=6.2 Hz,
1H), 3.98 (dd, J=11.7, 3.6 Hz, 1H), 3.90 (m, 2H), 3.04 (dd, J=13.7,
3.6 Hz, 1H), 2.83 (dd, J=13.8, 8.7 Hz, 1H), 2.053, 2.048, 2.03, 2.02 (4s,
12H), 1.43 (s, 9H), 1.37 ppm (d, J=7.1 Hz, 3H); 13C NMR (CDCl3): d=
172.8, 171.4, 170.0, 169.6, 169.4, 155.3, 135.2, 128.6, 128.4, 128.3, 85.5,
80.4, 76.2, 73.7, 69.7, 68.1, 67.4, 62.8, 61.9, 55.3, 52.5, 50.5, 34.1, 28.2, 20.6,
20.5, 18.3 ppm; MS (MALDI): m/z: 822 [M+Na]+, 838 [M+K]+ ; elemen-
tal analysis calcd (%) for C35H49N3O16S (799.8): C 52.56, H 6.17, N 5.25;
found: C 52.48, H 6.31, N 5.50.
z: 831 [M+Na]+, 847 [M+K]+
; elemental analysis calcd (%) for
C37H52N4O14S (808.9): C 54.94, H 6.48, N 6.93; found: C 55.09, H 6.80, N
7.20.
N-tert-Butoxycarbonyl-l-tryptophanyl-S-(3,4,6-tri-O-acetyl-2-acetamido-
2-deoxy-a-d-galactopyranosyl)-l-cysteinyl-l-isoleucine methyl ester (39):
The reaction procedure was identical to that described for 30 except that
bromide 11 was used instead of 1 and a-GalNAc thiol 26 was used in-
stead of 27. The crude product was purified by column chromatography
using petroleum ether/EtOAc (1:2) ! EtOAc/MeOH (100:1) as eluent
to give the a-glycotripeptide 39 as a white solid after lyophilization with
dioxane in 82% yield. Rf =0.38 (EtOAc/MeOH 25:1); [a]D =+62.6 (c=
1.0 in CHCl3); 1H NMR (600 MHz, CDCl3): d=9.03 (brs, 1H), 7.69 (d,
J=7.6 Hz, 1H), 7.37 (d, J=7.8 Hz, 1H), 7.19 (t, J=7.4 Hz, 1H), 7.11
(dd, J=15.0, 7.5 Hz, 2H), 7.05 (d, J=6.5 Hz, 1H), 6.86 (d, J=6.7 Hz,
1H), 5.78 (brs, 1H), 5.21 (brs, 1H), 5.19 (d, J=8.2 Hz, 1H), 4.87 (dd,
J=11.7, 2.9 Hz, 1H), 4.72 (brs, 1H), 4.65 (d-like, J=3.9 Hz, 3H), 4.51
(dd, J=8.5, 5.0 Hz, 1H), 4.09 (brs, 1H), 3.92 (m, 1H), 3.73 (s, 3H), 3.71
(d, J=4.3 Hz, 1H), 3.49 (dd, J=14.5, 3.6 Hz, 1H), 3.12 (dd, J=14.5,
6.6 Hz, 1H), 3.04 (brd-like, J=7.6 Hz, 1H), 2.48 (d, J=10.3 Hz, 1H),
2.12, 2.04, 2.03, 2.02 (4s, 12H), 1.88 (m, 1H), 1.46 (s, 9H), 1.18 (m, 2H),
0.90 (t, J=7.3 Hz, 3H), 0.88 ppm (d, J=6.8 Hz, 3H); 13C NMR (CDCl3):
d=172.1, 171.9, 171.1, 170.5, 170.3, 170.1, 168.8, 155.4, 136.2, 127.7, 123.1,
122.3, 119.7, 119.1, 111.4, 110.0, 86.4, 80.5, 68.3, 67.9, 67.0, 61.7, 56.6, 55.3,
N-(9-Fluorenylmethoxycarbonyl)-S-(3,4,6-tri-O-acetyl-2-acetamido-2-
deoxy-b-d-glucopyranosyl)-l-cysteinyl-l-alanine benzyl ester (43):
A
pH 8.5 solution of NaHCO3 (0.8 mL) followed by H2O (1.7 mL) were
added to a solution of bromodipeptide 14 (82 mg, 0.15 mmol) and b-
885
Chem. Eur. J. 2004, 10, 875 887
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim