A. Patel, T. K. Lindhorst
FULL PAPER
(2.10 g, 4.40 mmol) was dissolved in pyridine and the solution was
2-(tert-Butyloxycarbonylamido)ethyl 6-Deoxy-6-{[2-(methoxy-
cooled to Ϫ10 °C. Ice-cold acetic anhydride (2 mL) was then added carbonyl)ethyl]amino}-β-D-galactopyranoside (10): A mixture of the
slowly while stirring. The reaction mixture was kept at 4 °C for 12 h
and was then concentrated, and the crude product was purified by
flash chromatography (n-hexane/acetone, 2.5:1) to afford the
azide 8 (0.85 g, 2.44 mmol) and activated Pd catalyst (10% on char-
coal, 50 mg) in MeOH (10 mL) was hydrogenated under atmo-
spheric pressure for 10 h at room temp. The suspension was filtered
acetylated derivative 6 (2.57 g, 4.25 mmol, 97%) as a colorless through a short pad of Celite and the filtrate was concentrated. The
syrup. [α]D ϭ Ϫ2.7 (c ϭ 1.14 in CHCl3). 1H NMR (500 MHz, crude amino-functionalized derivative 9 thus obtained was further
CDCl3): δ ϭ 7.75 (d, J ϭ 8.4 Hz, 2 H, 2 aryl-H), 7.35 (d, J ϭ
8.6 Hz, 2 H, 2 aryl-H), 5.35 (dd, J3,4 ϭ 3.4, J4,5 ϭ 1.2 Hz, 1 H, 4-
treated with freshly distilled methyl acrylate (1.91 g, 22.23 mmol)
in dry MeOH (10 mL) at 0 °C under argon. The reaction mixture
H), 5.14 (dd, J1,2 ϭ 7.9, J2,3 ϭ 10.5 Hz, 1 H, 2-H), 4.97 (dd, J2,3 ϭ was then heated at 40 °C in darkness for 18 h. Concentration and
10.5, J3,4 ϭ 3.4 Hz, 1 H, 3-H), 4.82 (s, 1 H, NH), 4.42 (d, J1,2ϭ purification of the crude product by flash chromatography
7.9 Hz, 1 H, 1-H), 4.11 (dd, J5,6a ϭ 6.6, J6a,6b ϭ 12.8 Hz, 1 H, 6- (CH2Cl2/MeOH, 2.5:1) yielded the Michael mono-adduct 10
Ha), 4.00 (dd, J5,6b ϭ 6.3, J6a,6b ϭ 12.8 Hz, 1 H, 6-Hb), 3.93 (ddd,
(0.60 g, 1.47 mmol, 60% over two steps) as a white, hygroscopic
J5,6 ϭ 7.6, J5,6b ϭ 6.4, J4,5 ϭ 1.2 Hz, 1 H, 5-H), 3.82 (mc, 1 H, solid. [α]D ϭ Ϫ1.1 (c ϭ 1.58 in MeOH). 1H NMR (500 MHz,
OCHa), 3.58 (mc, 1 H, OCHb), 3.29 (mc, 2 H, CH2N), 2.44 (s, 3 H, [D4]MeOH): δ ϭ 4.27 (d, J1,2 ϭ 7.6 Hz, 1 H, 1-H), 3.90 (mc, 1 H,
TsCH3), 2.05, 2.03, 1.96 (each s, each 3 H, 3 COCH3), 1.43 (s, 9 OCHa), 3.81 (dd, J4,5 ϭ 1.6 Hz, 1 H, 4-H), 3.76 (mc, 1 H, 5-H),
H, tBu). 13C NMR (125.75 MHz, CDCl3): δ ϭ 170.0, 169.9, 169.6
3.71 (s, 3 H, CO2CH3), 3.62 (mc, 1 H, OCHb), 3.53Ϫ3.48 (m, 2
(3 COCH3), 156.2 (BocCO), 145.3 (aryl-Cq), 132.3 (aryl-Cq), 130.0 H, 2-H, 3-H), 3.31 (mc, 1 H, CHaNHBoc), 3.27Ϫ3.19 (m, 2 H,
(2 aryl-CH), 128.1 (2 aryl-CH), 101.5 (C-1), 80.0 [C(CH3)3], 70.7 CHbNHBoc, 6-H), 3.13 (mc, 2 H, NCH2), 3.08 (dd, J6a,6b ϭ 12.7,
(C-5), 70.5 (C-3), 69.7 (OCH2), 68.7 (C-2), 66.8 (C-4), 66.1 (C- J5,6b ϭ 3.4 Hz, 1 H, 6-Hb), 2.71 (t, J ϭ 6.6 Hz, 2 H, CH2CO),
6), 40.2 (CH2N), 28.4 [C(CH3)3], 21.7 (TsCH3), 20.53, 20.52, 20.51 1.44 (s, 9 H, tBu). 13C NMR (125.75 MHz, [D4]MeOH): δ ϭ 173.7
(3 COCH3).
(CO2CH3), 158.5 (BocCO), 105.1 (C-1), 80.2 [C(CH3)3], 74.5 (C-
3), 72.6 (C-5), 72.2 (C-2), 71.6 (C-4), 70.1 (OCH2), 52.5 (CO2CH3),
50.4 (C-6), 45.3 (NCH2), 41.5 (CH2NBoc), 32.7 (CH2CO), 28.8
[C(CH3)3]. C17H32N2O9·H2O (426.46): calcd. C 47.88, H 8.04, N
6.57, found C 48.21, H 7.95, N 6.49.
2-(tert-Butyloxycarbonylamido)ethyl 2,3,4-Tri-O-acetyl-6-azido-6-
deoxy-β-
D-galactopyranoside (7): A suspension of the acetyl-pro-
tected galactoside
6
(2.47 g, 4.09 mmol) and NaN3 (5.32 g,
81.83 mmol) in dry DMF (30 mL) was stirred at 80 °C for 24 h.
DMF was removed in vacuo and the crude product was dissolved
in ether. The organic layer was washed with water to remove inor-
ganic salts and brine. Drying with anhydrous Na2SO4, concentra-
tion, and purification by flash chromatography (n-hexane/acetone,
2.5:1) afforded the 6-deoxy-6-azido derivative 7 (1.40 g, 2.95 mmol,
72%) as a colorless syrup. [α]D ؍
Ϫ3.4 (c ϭ 1.10 in CHCl3). 1H
2-(tert-Butyloxycarbonylamido)ethyl 6-Deoxy-6-({p-[(α-
syloxy)methyl]benzoyl}[2-(methoxycarbonyl)ethyl]amino)-β-
galactopyranoside (12): The galactoside 10 (120 mg, 0.29 mmol),
the mannoside 11 (170 mg, 0.58 mmol), HATU (246 mg,
0.65 mmol), and DIPEA (0.25 mL, 1.47 mmol) were dissolved in
DMF (5 mL) under argon. The reaction mixture was stirred at 45
D-manno-
D
-
NMR (500 MHz, CDCl3): δ ϭ 5.35 (dd, J3,4 ϭ 3.5, J4,5 ϭ 1.2 Hz, °C for 6 h and DMF was then removed in vacuo. The resulting
1 H, 4-H), 5.21 (dd, J1,2 ϭ 7.9, J2,3 ϭ 10.5 Hz, 1 H, 2-H), 5.02 (dd, crude product was a pale yellow syrup, which was subjected to gel
J2,3 ϭ 10.5, J3,4 ϭ 3.4 Hz, 1 H, 3-H), 4.88 (s, 1 H, NH), 4.50 (d, permeation chromatography on Bio-gel P-2. This afforded the title
J
1,2ϭ 7.9 Hz, 1 H, 1-H), 3.93 (mc, 1 H, OCHa), 3.85 (ddd, J4,5
ϭ
compound 12 (160 mg, 0.23 mmol, 79%) as a white, hygroscopic
1.2, J5,6a ϭ 8.1, J5,6b ϭ 4.4 Hz, 1 H, 5-H), 3.64 (mc, 1 H, OCHb),
lyophilizate. [α]D ϭ ϩ37 (c ϭ 1.14 in MeOH). 1H NMR (500 MHz,
3.55 (dd, J5,6a ϭ 8.1, J6a,6b ϭ 12.9 Hz, 1 H, 6-Ha), 3.34 (mc, 2 H, [D4]MeOH): δ ϭ 7.50Ϫ7.37 (m, 4 H, 4 aryl-H), 4.84 (d, J1,2
ϭ
CH2N), 3.16 (dd, J5,6b ϭ 4.4, J6a,6b ϭ 12.9 Hz, 1 H, 6-Hb), 2.20, 1.8 Hz, 1 H, man 1-H), 4.79 (d, J ϭ 12.2 Hz, 1 H, PhCHa), 4.57
2.10, 2.00 (each s, each 3 H, 3 COCH3), 1.44 (s, 9 H, tBu). 13C (d, J ϭ 11.8 Hz, 1 H, PhCHb), 4.24 (d, J1,2 ϭ 7.8 Hz, 1 H, gal 1-
NMR (125.75 MHz, CDCl3): δ ϭ 170.2, 170.0, 169.6 (3 COCH3), H), 3.96Ϫ3.76 (m, 7 H, OCHa, man 6-Ha, NCHa, man 2-H, gal 3-
155.8 (BocCO), 101.5 (C-1), 79.4 [C(CH3)3], 72.9 (C-5), 70.7 (C-3),
H, gal 4-H, gal 5-H), 3.75Ϫ3.65 (m, 5 H, man 6-Hb, gal 6-Ha,
69.7 (OCH2), 68.8 (C-2), 67.9 (C-4), 50.5 (C-6), 40.2 (CH2N), 28.4 OCHb, NCHb, man 3-H), 3.71 (s, 3 H, CO2CH3), 3.64Ϫ3.51 (m, 3
[C(CH3)3], 20.9, 20.7, 20.6 (3 COCH3).
H, man 4-H, gal 6-Hb, man 5-H), 3.50 (mc, 1 H, gal 2-H), 3.28
(mc, 2 H, CH2NHBoc), 2.68 (mc, 2 H, CH2CO), 1.44 (s, 9 H, tBu).
13C NMR (125.84 MHz, [D4]MeOH): δ ϭ 174.8 (CO2CH3), 173.5
(NCO), 158.5 (BocCO), 141.4 (aryl-Cq), 137.7 (aryl-Cq), 129.1,
128.4, 127.8 (4 aryl-CH), 105.1 (gal C-1), 101.0 (man C-1, 1JC1,H1 ϭ
168.3 Hz), 80.2 [C(CH3)3], 75.0 (man C-5), 74.6 (gal C-2), 74.2 (gal
C-3), 72.7 (man C-3), 72.4 (gal C-5), 72.2 (man C-2), 71.0 (gal C-
4), 70.0 (OCH2), 69.4 (PhCH2), 68.7 (man C-4), 63.0 (man C-6),
52.5 (gal C-6), 52.3 (CO2CH3), 47.8 (NCH2), 41.5 (CH2NHBoc),
33.1 (CH2CO), 28.8 [C(CH3)3]. MALDI-TOF MS: m/z ϭ 727.5 [M
ϩ Na]ϩ and 743.5 [M ϩ K]ϩ found for C31H48N2O16 (calcd. 704.3).
C31H48N2O16 (704.73): calcd. C 52.83, H 6.87, N 3.98, found C
52.02, H 6.56, N 4.15.
2-(tert-Butyloxycarbonylamido)ethyl 6-Azido-6-deoxy-β-D-galactop-
yranoside (8): The acetylated galactoside 7 (1.27 g, 2.67 mmol) was
dissolved in methanol (10 mL) and a freshly prepared solution of
NaOMe in MeOH (1 , 0.5 mL) was then added at 0 °C. The
mixture was stirred at room temp. for 1 h. The basic reaction mix-
ture was neutralized with methanolic HCl solution (10%) and con-
centrated. The crude product thus obtained was purified by flash
chromatography (MeOH/CH2Cl2, 1:10) to yield triol 8 (0.91 g,
2.62 mmol, 98%) as a white hygroscopic solid. [α]D ϭ Ϫ29.5 (c ϭ
1.15 in MeOH). 1H NMR (500 MHz, [D4]MeOH): δ ϭ 4.26 (d,
J1,2 ϭ 7.5 Hz, 1 H, 1-H), 3.90 (mc, 1 H, OCHa), 3.74 (dd, J4,5
1.1, J3,4 ϭ 3.0 Hz, 1 H, 4-H), 3.69 (dd, J4,5 ϭ 1.2, J5,6b ϭ 4.8 Hz,
1 H, 5-H), 3.65Ϫ3.58 (m, 2 H, 6-Ha, OCHb), 3.55Ϫ3.48 (m, 2 H, 2-tert-Butyloxycarbonylamidoethyl
2-H, 3-H), 3.27 (mc, 2 H, CH2N), 3.22 (dd, J6a,6b ϭ 11.0, J5,6b
ϭ
6-Deoxy-6-[{p-[(α-
D-manno-
ϭ
syloxy)methyl]benzoyl}(2-propanoyl)amino]-β- -galactopyr-
D
4.2 Hz, 1 H, 6-Hb), 1.43 (s, 9 H, tBu). 13C NMR (125.75 MHz, anoside (13): The disaccharide analogue 12 (156 mg, 0.22 mmol)
[D4]MeOH): δ ϭ 158.5 (BocCO), 104.9 (C-1), 80.1 [C(CH3)3], 75.7 was dissolved in MeOH/H2O (1:2; 2 mL) and treated with
(C-5), 74.5 (C-3), 72.3 (C-2), 70.7 (C-4), 70.0 (OCH2), 52.5 (C-6), LiOH·H2O (11 mg, 0.26 mmol) at 0 °C for 12 h. The basic reaction
41.4 (CH2N), 28.8 [C(CH3)3].
mixture was then neutralized at 0 °C to a value of pH ϭ 6 by
84
Eur. J. Org. Chem. 2002, 79Ϫ86