PAPER
-Anomeric Carboxylic Acid Esters from Glycosyl Donors: An Aspirin Pro-Drug Analogue
1965
H), 2.62 (dd, 1 H, 3e-H, J = 4.9, 8.4 Hz), 2.04 (dd, 1 H, 3a-H,
J = 1.3, 8.4 Hz), 2.01 (s, 3 H).
13C NMR (CD3OD, 100 MHz): = 175.0, 151.7, 146.2, 137.4,
121.0, 120.7, 99.3, 74.0, 72.5, 69.9, 67.7, 64.7, 56.5, 53.6, 50.0,
41.6, 22.9.
1H NMR (CDCl3, 400 MHz): = 7.72–7.60 (m, 5 H), 7.49–7.29 (m,
6 H), 7.15 (dd, J = 7.9 Hz, J = 1.6 Hz, 1 H), 6.95 (dd, J = 7.9, 5.1
Hz, 1 H), 5.95 (d, J1,2 = 8.1 Hz, 1 H, H-1), 4.2 (t, J3,4 = J4,5 = 2.9 Hz,
1 H, H-4), 4.05 (t, J1,2 = J2,3 = 8.1 Hz, 1 H, H-2), 4.0–3.89 (m, 2 H),
3.85 (s, 3 H, OMe), 3.83–3.72 (m, 2 H), 1.04 (s, 9 H, tert-Bu-TB-
DPSi).
13C NMR (CDCl3, 100 MHz): = 152.1 (CO-pyridyl), 143.9 (CO-
pyridyl), 136.9 (CH-pyridyl), 135.5 (4 CH-aromatic-TBDPSi),
133.2 (C4-aromatic-TBDPSi), 133.1 (C4-aromatic-TBDPSi), 129.5
(2 CH-aromatic-TBDPSi), 127.4 (4 CH-aromatic-TBDPSi), 118.5
(CH-pyridyl), 118.2 (CH-pyridyl), 96.2 (C1), 75.2 (CH-sugar), 73.9
(CH-sugar), 70.7 (CH-sugar), 68.7 (CH-sugar), 62.7 (C-6), 55.6
(OMe), 26.6 (tert-Bu-TBDPSi), 19.0 (C4-tert-Bu-TBDPSi).
HR-FABMS: m/z calcd for C18H26N2O10: 430.15875; found:
430.15684.
Methyl 2-O-Acetyl-5-N-acetyl-3,5-dideoxy- -D-glycero-D-galac-
to-2-nonulopyranosonate (22)
A mixture of sialyl MOP ( , -mixture 430 mg, 1.0 mmol), DMF
(2.0 mL) and HOAc (11 mL, 200 equiv) was stirred at r.t. for 2 h
and concentrated. Column chromatography (silica gel; CH2Cl2–
MeOH, 6:1) gave the title compound.
HR-FABMS: m/z calcd for C28H36NO7Si: 526.22614; found:
526.22520.
Yield: 290 mg (79%); amorphous mass; [ ]D –54.7 (c 0.3, MeOH).
IR (film): 3352, 1754, 1649 cm–1.
1H NMR (CD3OD, 400 MHz): = 4.04 (ddd, 1 H, J3ax,4 = 11.3 Hz,
6-O-(tert-Butyldiphenylsilyl)- -D-galactopyranosyl 1-Esters;
General Procedure
To a solution of 5 (100 mg, 190 mol, 1 equiv) in CH2Cl2 (2.4 mL,
0.08 M) and acceptor acid (1.5 equiv) at 0 °C was added methyl tri-
flate (9 L, 0.4 equiv) and the mixture was stirred for 30 min at this
temperature, then for 30 min at r.t.. The solution was diluted with
CH2Cl2 (10 mL), the organic layer washed (4 1 mL) with a cold
aq sat. NaHCO3 and dried (Na2SO4). Concentration and purification
by flash chromatography of the residue (silica gel; EtOAc–hexanes)
gave the title compound as a syrup.
J
4,5 = 10.0 Hz, J3eq,4 = 5.0 Hz, H-4), 3.96 (dd, 1 H, J5,6 = 10.0 Hz,
J6,7 = 1.0 Hz, H-6), 3.89 (dd, 1 H, H-5), 3.78 (s, 3 H, OMe), 3.76
(dd, J9a,9b = 10.0 Hz, J8,9a = 2.4 Hz, H-9a), 3.69–3.60 (m, 2 H, H-9b,
H-8), 3.50 (dd, 1 H, J7,8 = 9.0 Hz, H-7), 2.43 (dd, 1 H, J3ax,3eq = 13.4
Hz, H-3eq), 2.10 (s, 3 H, Ac), 2.02 (s, 3 H, NHAc), 1.74 (dd, 1 H,
H-3ax).
13C NMR (CD3OD, 100 MHz): = 178.5, 174.3, 174.0 (C=O),
102.4 (C2), 77.7 (C8), 75.3 (C4), 73.6 (C7), 71.4 (C6), 68.8 (C9),
57.4 (OMe), 57.3 (C5), 44.4 (C3), 26.6 (Ac), 24.3 (NHAc).
6-(tert-Butyldiphenylsilyl)- -D-galactopyranosyl 1-Acetate (25)
Purification by flash chromatography (silica gel; EtOAc–hexanes,
7:3) gave the title compound.
HR-FABMS: m/z calcd for C14H23NO10: 365.13220; found:
365.13475.
Yield: 61 mg (70%); syrup; : >50:1); [ ]D + 37.9 (c 1.5, CHCl3).
IR (film): 3402, 2932, 1744, 1428, 1229, 1113, 1091, 1010 cm–1.
Methyl 5-N-Acetyl-2-O-propionyl-3,5-dideoxy- -D-glycero-D-
galacto-2-nonulopyranosonate (23)
1H NMR (CDCl3, 400 MHz): = 7.68–7.64 (m, 5 H), 7.43–7.36 (m,
5 H), 6.22 (d, J1,2 = 3.8 Hz, 1 H, H-1), 4.17 (dd, J3,4 = 2.8 Hz, 1 H,
H-4), 4.07 (dd, J1,2 = 3.8 Hz, J2,3 = 9.9 Hz, 1 H, H-2), 3.91–3.79 (m,
5 H, H-3, H-5, H-6a, H-6b, 1 OH), 3.78–3.3 (br, 2 H, 2 OH), 2.08
(s, 3 H, Me), 1.04 (s, 9 H, tert-Bu-TBDPSi).
13C NMR (CDCl3, 100 MHz): = 170.0 (CO), 135.6 (2 CH-aromat-
ic-TBDPSi), 135.5 (2 CH-aromatic-TBDPSi), 132.8 (C4-aromatic-
TBDPSi), 132.6 (C4-aromatic-TBDPSi), 129.9 (2 CH-aromatic-
TBDPSi), 127.8 (4 CH-aromatic-TBDPSi), 92.2 (C1), 71.9 (CH-
sugar), 70.6 (CH-sugar), 69.5 (CH-sugar), 68.1 (CH-sugar), 63.3
(C6), 26.8 (tert-Bu-TBDPSi), 21 (Me), 19.1 (C4-tert-Bu-TBDPSi).
A mixture of sialyl MOP ( , -mixture 52 mg, 0.12 mmol), DMF
(0.4 mL) and propionic acid (1.4 mL, 200 equiv) was stirred at r.t.
for 2 h and concentrated. Column chromatography (silica gel;
CH2Cl2–MeOH, 6:1) gave the title compound.
Yield: 35 mg (78%), amorphous mass; [ ]D –44 (c 0.3, MeOH).
IR (film): 3352, 1754, 1654 cm–1.
1H NMR (CD3OD, 400 MHz): = 4.06 (ddd, 1 H, J3ax,4 = 11.8 Hz,
J4,5 = 10.0 Hz, J3eq,4 = 4.8 Hz, H-4), 3.95 (dd, 1 H, J5,6 = 10.0 Hz,
J6,7 = 1.0 Hz, H-6), 3.91 (dd, 1 H, H-5), 3.88 (s, 3 H, OMe), 3.76
(dd, J9a,9b = 10.0 Hz, J8,9a = 2.4 Hz, H-9a), 3.76–3.55 (m, 2 H, H-9b,
H-8), 3.49 (dd, 1H, J7,8 = 9.0 Hz, H-7), 2.45 (dd, 1 H, J3ax,3eq = 13.0
Hz, H-3eq), 2.41 (q, 2 H, J = 7.0 Hz, propionyl CH2), 2.01 (s, 3 H,
NHAc), 1.75 (dd, 1 H, H-3ax), 1.16 (t, 3 H, J = 7.0 Hz, propionyl
CH3).
13C NMR (CD3OD, 100 MHz): = 174.6, 173.8, 170.1 (C=O), 98.5
(C2), 73.8 (C8), 71.5 (C4), 69.7 (C7), 67.5 (C6), 64.9 (C9), 53.52
(OMe), 53.48 (C5), 40.6 (C3), 28.1 (propionyl CH2), 22.7 (NHAc),
9.1 (CH3).
HR-FABMS: m/z calcd for C24H32O7Si: 460.19173; found:
460.19205.
6-(tert-Butyldiphenylsilyl)- -D-galactopyranosyl 1-Pivaloate
(26)
Purification by flash chromatography (silica gel; EtOAc–hexanes,
65:35) gave the title compound.
Yield: 59 mg (62%); syrup; : = 35:1; [ ]D + 53.1 (c 1.5, CHCl3).
IR (film): 3402, 2932, 1744, 1428, 1113, 1028 cm–1.
HR-FABMS: m/z calcd for C15H25NO10: 379.14785; found:
379.14520.
1H NMR (CDCl3, 400 MHz): = 7.69–7.64 (m, 5 H), 7.41–7.37 (m,
5 H), 6.23 (d, J1,2 = 3.7 Hz, 1 H, H-1), 4.17 (d, J3,4 = 3 Hz, 1 H, H-
4), 4.09 (dd, J1,2 = 3.7 Hz, J2,3 = 9.9 Hz, 1 H, H-2), 3.94–3.82 (m, 3
H, H-5, H-6a, H-6b), 3.8 (dd, J2,3 = 9.9 Hz, J3,4 = 3 Hz, 1 H, H-3),
3.7–3.1 (br, 3 H, 3 OH), 1.20 (s, 9 H, tert-Bu), 1.05 (s, 9 H, tert-Bu-
TBDPSi).
13C NMR (CDCl3, 100 MHz): = 177.2 (CO), 135.6 (2 CH-aromat-
ic-TBDPSi), 135.5 (2 CH-aromatic-TBDPSi), 132.9 (C4-aromatic-
TBDPSi), 132.7 (C4-aromatic-TBDPSi), 129.9 (2 CH-aromatic-
TBDPSi), 127.8 (4 CH-aromatic-TBDPSi), 92 (C1), 72.3 (CH-sug-
ar), 70.8 (CH-sugar), 69.5 (CH-sugar), 68.4 (CH-sugar), 63.5 (C6),
2-(3-Methoxypyridyl) 6-(tert-Butyldiphenylsilyl)- -D-galacto-
pyranoside (5)
To 1 (1 g, 3.48 mmol) and imidazole (474 mg, 2 equiv) in DMF (7
mL, 0.5 M) was added dropwise tert-butylchlorodiphenylsilane
(1.36 mL, 1.5 equiv). The mixture was stirred overnight at r.t., then
diluted with CH2Cl2 (20 mL), washed with cold H2O (2 10 mL)
and the organic layer was dried (Na2SO4). Concentration and puri-
fication by flash chromatography of the residue (silica gel; EtOAc–
hexanes, 9:1) gave the title compound.
Yield: 1.5 g (82%); white foam; [ ]D + 28.4 (c 0.5, CHCl3).
Synthesis 2002, No. 14, 1959–1968 ISSN 0039-7881 © Thieme Stuttgart · New York