A. M. Daines et al. / Bioorg. Med. Chem. 17 (2009) 5207–5218
5215
7.10–5.75 (m, 20H) 6.75 (d, J = 1.6 Hz, 1H), 6.09 (s, 2H), 5.65 (s, 2H),
5.46 (br s, 1H), 5.36 (s, 1H), 5.00–4.30 (m, 36H), 3.34 (dd, J = 4.0,
11.2 Hz, 1H), 3.16 (dd, J = 2.7, 13.0 Hz, 1H), 2.11–0.71 (m, 22H),
1.22 (s, 3H), 1.11 (s, 3H), 0.97 (s, 3H), 0.95 (s, 3H), 0.90 (s, 3H),
0.85 (s, 3H), 0.77 (s, 3H). 13C NMR (pyridine-d5) d 175.3, 143.4,
122.5, 103.5 (JCH = 172 Hz), 103.2 (JCH = 168 Hz), 101.6
(JCH = 169 Hz), 101.2 (JCH = 169 Hz), 98.0 (JCH = 167 Hz), 94.6
(JCH = 173 Hz), 82.4, 80.5, 76.1, 74.9, 74.8, 74.6, 74.5, 73.9, 72.6,
72.54, 72.51, 72.5, 71.8, 71.7, 71.5 (ꢂ2), 71.4, 69.6, 69.0, 68.7, 68.6,
66.6, 66.5, 66.2, 65.7, 62.6, 62.5 (ꢂ3), 55.1, 47.3, 46.9, 45.5, 45.4,
41.5, 41.2, 39.2, 38.0, 37.6, 36.6, 33.5 (ꢂ2), 32.5, 32.2, 30.3, 28.4,
27.4, 25.4, 23.3, 23.0, 22.9, 21.9, 18.0, 17.0, 16.3, 14.9. HRMS (FAB)
calcd for [M+Na]+ C66H109NaO33: m/z 1451.6671; found 1451.6634.
afforded title compound 23 as an amorphous white solid
(100 mg, 79%). ½a D24
ꢃ
+84.3 (c 0.48, methanol). 1H NMR (CDCl3) d
5.23 (br s, 2H), 4.94 (br s, 2H), 4.52 (br s, 2H), 3.97–3.96 (m, 1H),
3.84–3.54 (m, 11H), 2.86–2.83 (m, 1H), 2.05–0.75 (m, 28H), 1.15
(s, 3H), 1.03 (s, 3H), 0.96 (s, 3H), 0.94 (s, 3H), 0.90 (s, 3H), 0.82 (s,
3H), 0.81 (s, 3H); 13C NMR (CDCl3) d 184.8, 148.2, 126.5, 107.1,
99.4, 86.8, 84.5, 78.1, 77.9, 75.4, 75.2, 74.8, 71.9, 71.8, 66.0 (ꢂ2),
59.8, 52.0, 50.6, 50.2, 45.8, 45.7, 43.5, 42.3, 42.2, 41.1, 37.8, 37.0,
36.8, 36.5, 34.5, 32.4, 31.8, 29.3, 27.5, 27.0, 26.9, 25.9, 22.3, 20.7,
20.0, 18.9; HRMS (ESI) calcd for [MꢁH]+ C42H67O13: 779.4582;
found: 779.4595.
4.9. Allyl 3-O-[2,3,4,6-tetra-O-acetyl-
(1?2)-3,4,6-tri-O-acetyl- -mannopyranosyl-(1?2)-3,4,6-tri-
O-acetyl- -mannopyranosyl] oleanolate (24)
a-D-mannopyranosyl-
a-D
a-D
4.8. 3-O-[a-D-Mannopyranosyl-(1?2)-a-D-mannopyranosyl]
oleanolic acid (23)
Oleanolic acid (13) (103 mg, 0.207 mmol), imidate 8 (201 mg,
0.188 mmol) and flame-dried powdered 4Å molecular sieves
(1.8 g) in CH2Cl2 (20 mL) were stirred under an argon atmosphere
Allyl oleanolate (20) (145 mg, 0.291 mmol), imidate
5
(1.1 equiv, 250 mg, 0.32 mmol) and activated 4 Å molecular sieves
were suspended in CH2Cl2 (10 mL) and stirred under an Ar atmo-
sphere at room temperature for 45 min and then TBSOTf (0.1 equiv,
at room temperature for 45 min then TBSOTf (6 mg,
5 lL,
0.027 mmol) was added. When no more donor was apparent
(75 min, TLC), triethylamine (approx. 0.5 mL) was added and
the reaction mixture was filtered through Celite and concen-
trated under reduced pressure. The residue was purified by flash
silica-gel chromatography, eluting with ethyl acetate/petroleum
ether 3:7 then 1:1 to give 24 as an amorphous solid (184 mg,
70%). An analytical sample of 24 was provided following further
flash silica-gel chromatography, eluting with 1:99 methanol/
7 lL, 0.029 mmol) was added. After all donor had been consumed
(TLC, 1 h) triethylamine (0.5 mL) was added and the reaction fil-
tered through a pad of Celite. The volatiles were removed under
reduced pressure and crude product purified by flash chromatogra-
phy, eluting with a gradient of ethyl acetate/petroleum ether 3:7 to
6:4 to give 21 as a clear oil (240 mg, 74%). 1H NMR (CDCl3) d 5.95–
5.85 (m, 1H), 5.41 (dd, J = 3.3, 9.9 Hz, 1H), 5.35–5.1 8 (m, 7H), 5.09
(d, J = 2.0 Hz, 1H), 4.94 (d, J = 1.7 Hz, 1H), 4.54–4.51 (m, 2H), 4.27–
3.97 (m, 5H), 3.86 (m, 1H), 3.26–3.21 (m, 1H), 2.92–2.86 (m, 1H),
2.15 (s, 3H), 2.12 (s, 3H), 2.08 (s, 6H), 2.04 (s, 3H), 2.00 (s, 3H),
1.99–1.82 (m, 2H), 1.72–0.96 (m, 24H), 1.13 (s, 3H), 1.01 (s, 3H),
0.93 (s, 3H), 0.92 (s, 3H), 0.90 (s, 3H), 0.82 (s, 3H), 0.73 (s, 3H).
13C NMR (CDCl3) d 177.7, 171.2, 170.8, 170.7, 170.2, 170.1, 169.8
(ꢂ2), 144.2, 132.9, 122.7, 118.1, 99.1, 95.4, 84.4, 77.9, 70.6, 70.1,
69.5 (ꢂ2), 68.8, 66.9, 66.7, 65.2, 62.9, 62.8, 56.0, 48.0, 47.1, 46.2,
42.0, 41.7, 39.8, 38.7, 38.5, 37.3, 34.3, 33.4, 33.1, 32.8, 31.1, 29.1,
28.0, 26.2, 24.0, 23.8, 23.4, 22.5, 21.4, 21.2, 21.0 (ꢂ5), 18.7, 17.4,
16.9, 15.7. To a solution of glycoside 21 (190 mg, 0.170 mmol) in
CH2Cl2/methanol (1:1, 6 mL) under Ar was added Pd(0)(PPh3)4
(0.05 equiv, 10 mg, 0.008 mmol) and triphenylphosphine
(0.2 equiv, 10 mg, 0.038 mmol). The reaction was stirred for 3 h
at room temperature then an additional portion of Pd(0)(PPh3)4
(0.05 equiv, 10 mg, 0.008 mmol) and triphenylphosphine
(0.2 equiv, 10 mg, 0.038 mmol) were added. After stirring for an
addition 2 h, the solvent was removed under reduced pressure
and crude product purified by flash chromatography, eluting with
a gradient of ethyl acetate/petroleum ether 4:6 to 1:0 to afford 22
as a yellow oil (180 mg, 98%). 1H NMR (CDCl3) d 5.41 (dd, J = 9.9,
3.3 Hz, 1H), 5.32–5.25 (m, 5H), 5.09 (d, J = 1.9 Hz, 1H), 4.94 (d,
J = 1.6 Hz, 1H), 4.27–4.04 (m, 5H), 3.99–3.98 (m, 1H), 3.25–3.21
(m, 1H), 2.84–2.81 (m, 1H), 2.15 (s, 3H), 2.12 (s, 3H), 2.08 (s, 6H),
2.04 (s, 6H), 2.00 (s, 3H), 1.86–1.30 (m, 21H), 1.13 (s, 3H), 1.01 (s,
3H), 0.93 (s, 3H), 0.92 (s, 3H), 0.90 (s, 6H), 0.82 (s, 3H), 0.75 (s,
3H). 13C NMR (CDCl3) d 182.8, 170.9, 170.5, 170.3, 169.8, 169.7,
169.5 (ꢂ2), 143.8, 122.4, 98.8, 95.1, 84.1, 77.6, 70.3, 69.8, 69.2
(ꢂ2), 68.5, 66.5, 66.4, 62.6, 62.4, 55.6, 47.7, 46.5, 46.0, 41.7, 41.0,
39.4, 38.4, 38.1, 37.0, 33.8, 33.1, 32.7, 32.4, 30.7, 28.8, 27.7, 25.9,
23.6, 23.5, 23.0, 22.2, 20.7 (ꢂ7), 18.3, 17.1, 16.5, 15.3. To this oil
(22) (175 mg, 0.163 mmol) dissolved in methanol (5 mL) was
CHCl3. ½a 2D0
ꢃ
+62 (c 0.62, CHCl3). 1H NMR (CDCl3) d 5.98–5.92
(m, 1H), 5.48–4.92 (m, 13H), 4.60–4.45 (m, 2H), 4.34–3.90 (m,
11H), 3.30–3.18 (m, 1H), 2.89 (dd, J = 3.8, 13.7 Hz, 1H), 2.18–
0.66 (m, 22H), 2.15 (s, 3H), 2.13 (s, 3H), 2.11 (s, 3H), 2.08 (s,
3H), 2.07 (s, 6H), 2.06 (s, 3H), 2.04 (s, 3H), 2.02 (s, 3H), 2.00 (s,
3H), 1.26 (s, 3H), 1.14 (s, 3H), 1.01 (s, 3H), 0.93 (s, 3H), 0.92 (s,
3H), 0.90 (s, 3H), 0.80 (s, 3H). 13C NMR (CDCl3) d 177.3, 170.8
(2x), 170.5, 170.1, 170.0, 169.8, 169.7, 169.5, 169.4, 169.3,
143.8, 132.6, 122.3, 117.7, 99.2 (JCH = 172 Hz), 99.6 (JCH = 173 Hz),
95.0 (JCH = 170 Hz), 83.8, 76.7, 76.0, 69.93, 69.8, 69.8, 69.7, 69.4,
69.1, 68.5, 67.3, 66.2, 66.1, 64.8, 62.5, 62.4, 62.1, 55.7, 47.7,
46.8, 45.9, 41.7, 41.4, 39.5, 38.4, 38.1, 37.0, 33.9, 33.1, 32.8,
32.5, 30.7, 28.7, 27.7, 25.9, 23.6, 23.5, 23.1, 22.2, 20.8, 20.75,
20.74, 20.71, 20.70, 20.67 (ꢂ2), 20.65, 20.63 (ꢂ2), 18.4, 17.0,
16.5, 15.3. HRMS (ESI) calcd for [M+Na]+ C71H102O28Na1:
1425.6455, found 1425.6466. Anal. Calcd for C71H102O28
60.76; H, 7.32. Found: C, 60.31; H, 6.83;
: C,
4.10. 3-O-[a-D-Mannopyranosyl-(1?2)-a-D-mannopyranosyl-
(1?2)- -mannopyranosyl] oleanolic acid (26)
a
-D
A degassed solution of ammonium formate in dioxane (0.38 M,
2.0 mL, 0.75 mmol) was added to a round bottomed flask contain-
ing glycoside 24 (70 mg, 0.050 mmol), Pd(OAc)2 (5.6 mg,
0.025 mmol) and PPh3 (39 mg, 0.15 mmol). The mixture was stir-
red under an argon atmosphere at ambient temperature for
90 min then a further portion of PPh3 (10 mg, 0.038 mmol) was
added. After 4 h the mixture was concentrated in vacuo and par-
tially purified by flash silica-gel chromatography to give impure
acid 25 (76 mg). This material was dissolved in methanol (5 mL)
and sodium methoxide (30% w/v solution in methanol, 100 lL)
was added (pH ꢀ10). After 4 h stirring at ambient temperature
the mixture was neutralised with DowexÒ 50WX8-100 resin,
filtered, the resin washed with methanol and the crude reaction
product was pre-adsorbed onto silica. Flash silica-gel chromatogra-
phy, eluting with methanol/CHCl3/water 6:4:0.25 gave 26 as a
added sodium methoxide (30% w/v solution in methanol, 5 lL)
and the mixture stirred at room temperature under Ar for 16 h.
The reaction was neutralized with Dowex resin (H+), filtered and
solvent removed under reduced pressure. Purification by flash
chromatography, eluting with CHCl3/methanol/water 6:4:0.5
glass (41 mg, 87%).
½
a 2D0 +84 (c 0.21, methanol). 1H NMR
ꢃ