Synthesis of Milbemycins b9 and b10
1409
H-20, H2-22, H2-23, H-24, H2-31); EI-MS (m z): 556
H2-23, H-24); EI-MS (m z): 556 (M+), 538, 506;
W
W
(M+), 506; HREI-MS (m z): [M+]: calcd. for
HREI-MS
(
m z): [M+]: calcd. for C32H44O8,
W
W
C33H48O7, 556.3400; found, 556.3399.
556.3036; found, 556.3036.
5-O, 7-O-Dimethylmilbemycin A4
(ˆlm) cm„1: 2960, 2915, 2870, 1730; 1H-NMR
(200 MHz, CDCl3) : 5.67–5.91(3H, m, H-3, H-9,
H-10), 5.40(1H, dd,
4.96–5.13(2H, m, H-15, H-19), 4.65(2H, m, H2-27),
4.27(1H, d, 5.1 Hz, H-6), 3.94(1H, d, 5.1 Hz,
H-5), 3.60(1H, m, H-17), 3.48(3H, s, CH3O),
3.39(1H, m, H-2), 3.28(3H, s, CH3O), 3.05(1H, m,
H-25), 2.40–2.60(1H, m, H-12), 2.10–2.35(3H, m,
H-13, H2-16), 1.83(3H, br, H3-26), 1.55(3H, br,
(
8
): IR nmax
5-O-Formyl-27-oxomilbemicin A3 (11): IR nmax
(ˆlm) cm„1: 3450, 2960, 2915, 2870, 1755, 1725,
d
1640; 1H-NMR (200 MHz, CDCl3)
d
: 8.09(1H, s,
=
15.4, 11.4 Hz, H-10),
=
J
13.9, 9.5 Hz, H-11),
OCHO), 7.27(1H, dd, J
=
=
15.4,
6.55(1H, d,
J
11.4 Hz, H-9), 5.89(1H, dd,
J
J
=
J
=
9.9 Hz, H-11), 5.79(1H, br, H-3), 5.70(1H, d,
=
6.2 Hz, H-5), 5.50(1H, m, H-19), 5.03(1H, m,
J
=
6.2 Hz,
H-15), 4.70(1H, s, 7-OH), 4.45(1H, d,
J
=
H-6), 3.55–3.70(1H, m, H-17), 3.50(1H, dd,
J
5.1,
=
J
2.6 Hz, H-2), 3.28(1H, dd,
9.5, 6.2 Hz, H-25),
H3-29), 1.03(3H, d,
J
=
6.6 Hz, H3-28), 1.01(3H, t,
2.55–2.70(1H, m, H-12), 2.15–2.40(3H, m, H-13,
H2-16), 1.94(3H, br, H3-26), 1.54(3H, br, H3-29),
=
=
6.6 Hz, H3-30),
J
6.2 Hz, H3-32), 0.81(3H, d,
J
=
0.79–1.95(12H, m, H-13, H2-18, H2-20, H2-22,
1.15(3H, d,
J
6.2 Hz, H3-31), 1.04(3H, d,
H2-23, H-24, H2-31); EI-MS (m z): 570 (M+), 506;
J
6.6 Hz, H3-28), 0.84(3H, d,
J
6.2 Hz, H3-30),
=
=
W
HREI-MS
(
m z): [M+]: calcd. for C34H50O7,
0.83–2.05(10H, m, H-13, H2-18, H2-20, H2-22,
W
570.3557; found, 570.3554.
H2-23, H-24); EI-MS (m z): 570 (M+); HREI-MS
W
(
m z): [M+]: calcd. for C32H42O9, 570.2829; found,
W
Oxidation of
5
with CrO3 in pyridine. To stirred
570.2831.
pyridine (20 ml) in an ice bath was slowly added CrO3
(369.0 mg, 3.69 mmol) while maintaining the temper-
Oxidation of
6 with CrO3. Using the same proce-
ature at under 10
9
C. To this solution was added a
dure as that described for the preparation of 9, 6
(3.00 g, 5.40 mmol) was oxidized with CrO3 (4.69 g,
46.94 mmol) in pyridine (330 ml) to give 0.75 g
solution of 5- -methyl-milbemycin A3 (5; 200.0 mg,
O
0.37 mmol) in pyridine (2 ml). After stirring for
1 hour, the ice bath was removed, and the mixture
stirred at ambient temperature. After stirring for 6
days, the reaction mixture was poured into a mixture
of 1 N hydrochloric acid and EtOAc. After stirring
for 15 min, the insoluble material was ˆltered oŠ with
(24.4
z z
) of 10 and 0.20 g (6.5 ) of 12 as colorless
amorphous solids.
5-O-Methyl-27-oxomilbemicin A4
(ˆlm) cm„1: 3475, 2960, 2915, 2870, 1750, 1735,
1710, 1640; 1H-NMR (200 MHz, CDCl3)
: 7.28(1H,
15.0, 11.2 Hz, H-10), 6.53(1H, d,
11.2 Hz, H-9), 5.87(1H, dd, 15.0, 9.6 Hz,
(10): IR nmax
}
Celite, and the ˆltrate was extracted with EtOAc.
d
=
J
The extract was successively washed with 1 N
hydrochloric acid, water and brine, dried over mag-
dd,
=
J
J
=
nesium sulfate (MgSO4), and evaporated in vacuo
.
H-11), 5.69(1H, br, H-3), 5.40–5.55(1H, m, H-19),
4.99(1H, m, H-15), 4.67(1H, s, 7-OH), 4.34(1H, d,
The residue was puriˆed by silica gel column chro-
matography (Hex-EtOAc gradient) and preparative
J
=
5.5 Hz, H-6), 4.02(1H, d,
3.50–3.65(2H, m, H-2, H-17), 3.42(3H, s, CH3O),
3.07(1H, dt, Jt 9.2 Hz, Jd 2.3 Hz, H-25),
J 5.5 Hz, H-5),
=
HPLC (YMC-Pack ODS S-365-10, I-10
30 mm I.D. 500 mm, acetonitrile-water) to give
32.0 mg (15.6 ) of 9 and 11.6 mg (5.5 ) of 11 as
mm 120A,
×
=
=
z
z
2.50–2.70(1H, m, H-12), 2.15–2.30(3H, m, H-13,
H2-16), 1.92(3H, br, H3-26), 1.52(3H, br, H3-29),
1.02(3H, d,
colorless amorphous solids.
J 6.9 Hz, H3-28), 0.99(3H, t,
=
=
=
6.4 Hz, H3-30),
5-O-Methyl-27-oxomilbemycin A3
(
9
): IR nmax
J
6.9 Hz, H3-32), 0.82(3H, d,
J
(ˆlm) cm„1: 3465, 2960, 2915, 2870, 1755, 1730,
0.80–2.05(12H, m, H-13, H2-18, H2-20, H2-22,
1710, 1640; 1H-NMR (200 MHz, CDCl3)
d
: 7.30(1H,
H2-23, H-24, H2-31); EI-MS (m z): 570 (M+), 552,
W
dd,
J
15.0, 11.4 Hz, H-10), 6.53(1H, d,
J
520; HREI-MS (m z): [M+]: calcd. for C33H46O8,
=
=
W
11.4 Hz, H-9), 5.85(1H, dd,
J
=
15.0, 9.9 Hz, H-11),
570.3193; found, 570.3192.
5.70(1H, br, H-3), 5.50(1H, m, H-19), 5.03(1H, m,
=
H-15), 4.69(1H, s, 7-OH), 4.35(1H, d,
J
6.5 Hz,
5-O-Formyl-27-oxomilbemicin A4
(ˆlm) cm„1: 3455, 2960, 2915, 2870, 1755, 1730,
1640; 1H-NMR (200 MHz, CDCl3)
: 8.09(1H, s,
OCHO), 7.25(1H, dd, 15.1, 11.4 Hz, H-10),
(12): IR nmax
=
H-6), 4.02(1H, m, H-5), 3.65(1H, dd,
J
5.5,
2.9 Hz, H-2), 3.50–3.65(1H, m, H-17), 3.43(3H, s,
CH3O), 3.28(1H, d, 9.5, 6.2 Hz, H-25),
d
J
=
J
=
=
=
15.1,
2.55–2.75(1H, m, H-12), 2.15–2.35(3H, m, H-13,
H2-16), 1.93(3H, br, H3-26), 1.53(3H, br, H3-29),
6.56(1H, d,
10.1 Hz, H-11), 5.78(1H, br, H-3), 5.70(1H, d,
6.3 Hz, H-5), 5.40–5.60(1H, m, H-19), 5.00(1H, m,
J
11.4 Hz, H-9), 5.91(1H, dd,
J
=
J
=
6.2 Hz, H3-28), 1.03(3H, d,
1.15(3H, d,
J
=
=
=
6.3 Hz,
J
6.6 Hz, H3-31), 0.84(3H, d,
J
6.6 Hz, H3-30),
H-15), 4.70(1H, s, 7-OH), 4.45(1H, d,
H-6), 3.50–3.70(1H, m, H-17), 3.49(1H, m, H-2),
J
0.82–2.05(10H, m, H-13, H2-18, H2-20, H2-22,