1324 Bull. Chem. Soc. Jpn., 74, No. 7 (2001)
Synthesis of Milbemycin Derivatives
= 6.5 Hz, C-24 CH3), 1.00 (3H, t, J = 7.4 Hz, C-25 CH2CH3),
1.15 (3H, d, J = 7.4 Hz, C-12 CH3), 1.90 (3H, s, C-4 CH3), 3.07
(1H, m, C-25 H), 3.57 (1H, m, C-2 H), 3.62 (1H, m, C-17 H), 4.02
(1H, broad s, C-7 OH), 4.80 and 4.75 (2H, ABq, J = 14.5 Hz, C-
27 H), 5.20 (1H, d, J = 7.6 Hz, C-13 H), 5.54 (1H, m, C-15 H),
6.48 (1H, t, J = 6.7 Hz, pyridine H), 6.56 (1H, s, C-3 H), 7.15
(2H, m, pyridine H), 7.72 (1H, d, J = 7.2 Hz, pyridine H). 2c: 1H
NMR δ 0.83 (3H, d, J = 6.5 Hz, C-24 CH3), 0.93 (9H, s, tBu),
0.99 (3H, t, J = 7.3 Hz, C-25 CH2CH3), 1.14 (3H, d, J = 6.5 Hz,
C-12 CH3), 1.80 (3H, s, C-4 CH3), 2.85 (1H, m, C-12 H), 3.07
(1H, m, C-25 H), 3.37 (1H, m, C-2 H), 3.60 (1H, m, C-17 H), 3.82
(1H, d, J = 5.4 Hz, C-6 H), 4.06 (1H, broad s, C-7 OH), 4.44 (1H,
m, C-5 H), 4.61 and 4.70 (2H, ABq, J = 14.5 Hz, C-27 H), 5.18
(1H, d, J = 10.6 Hz, C-13 H), 5.32 (1H, s, C-3 H), 5.38 (1H, dd, J
= 10.2 and 14.6 Hz, C-11 H), 5.53 (1H, m, C-19 H), 5.78 (1H, d,
J = 11.4 Hz, C-9 H), 5.89 (1H, dd, J = 11.4 and 14.6 Hz, C-10
H), 6.48 (1H, m, py H), 7.10 (1H, d, J = 9.6 Hz, py H), 7.17 (1H,
dd, J = 6.2 and 9.6 Hz, py H), 7.72 (1H, dd, J = 1.1 and 7.1 Hz,
py H).
perature for 20 minutes. Then the reaction mixture was diluted
with 1,2-dichloroethane and filtered. The filtrate was washed with
water, a 4% aqueous solution of NaHCO3, and with water again,
dried over Na2SO4, and evaporated in vacuo. The residue was
chromatographed on silica gel, with the eluent (ethyl
acetate:cyclohexane = 1:9) to obtain a mixture (268 mg, 65.2%
yield) of the desired 4c and undesired 5c. The ratio of 4c to 5c
was estimated at 4c:5c = 1.8:1.0 by analyzing the area ratio of
the NMR spectrum. Other derivatives, such as 4b and 5b, were
synthesized in a similar manner from 7b and also 7c (Table 2).
4b: 1H NMR δ 0.82 (3H, d, J = 6.4 Hz, C-24 CH3), 0.98 (3H, t, J
= 7.3 Hz, C-25 CH2 CH3), 1.00 (3H, d, J = 6.4 Hz, C-12 CH3),
1.38 (3H, s, C-14 CH3), 1.83 (3H, s, C-4 CH3), 2.94 (2H, t, J =
6.3 Hz, PhCH2), 3.05 (1H, m, C-25 H), 3.19 (1H, d, J = 9.8 Hz,
C-13 H), 3.26 (1H, m, C-2 H), 3.40 (1H, m, C-13 OCH), 3.50–
3.71 (2H, m, C-17 H and C-13 OCH), 3.95 (1H, d, J = 6.4 Hz, C-
6 H), 4.29 (1H, m, C-5 H), 4.70 and 4.66 (2H, ABq, J = 15.7 Hz,
C-27 H), 5.39 (1H, m, C-3 H), 7.37 (2H, d, J = 8.8 Hz, Ph H),
1
8.14 (2H, d, J = 8.8 Hz, Ph H), 5b: H NMR δ 0.82 (3H, d, J =
4a: 1H NMR δ 0.83 (3H, d, J = 6.8 Hz, C-24 CH3), 0.99 (3H, t,
J = 7.3 Hz, C-25 CH2CH3), 1.01 (3H, d, J = 6.8 Hz, C-12 CH3),
1.43 (3H, s, C-14 CH3), 1.89 (3H, s, C-4 CH3), 2.94 (2H, t, J =
6.4 Hz, PhCH2), 3.06 (1H, m, C-25 H), 3.20 (1H, d, J = 9.8 Hz,
C-13 H), 3.39 (1H, m, C-13 OCH), 3.50–3.64 (2H, m, C-13 OCH
and C-17 H), 3.55 (1H, m, C-2 H), 3.84 (1H, s, C-6 H), 3.93 (1H,
s, C-7 OH), 4.72 and 4.75 (2H, ABq, J = 15.7 Hz, C-27 H), 5.18
(1H, m, C-15 H), 5.35 (1H, dd, J = 10.2 and 13.7 Hz, C-11 H),
5.40 (1H, m, C-19 H), 5.74 (1H, dd, J = 11.2 and 13.7 Hz, C-10
H), 5.84 (1H, td, J = 1.9 and 11.2 Hz, C-9 H), 6.54 (1H, m, C-3
H), 7.37 (2H, d, J = 8.8 Hz, Ph H), 8.14 (2H, d, J = 8.8 Hz, Ph
H), 4c: 1H NMR δ 0.82 (3H, d, J = 6.4 Hz, C-24 CH3), 0.93 (9H,
s, t-Bu), 0.99 (3H, d, J = 6.4 Hz, C-12 CH3), 1.40 (3H, s, C-14
CH3), 1.79 (3H, s, C-4 CH3), 2.94 (2H, t, J = 6.3Hz, PhCH2), 3.05
(1H, m, C-25 H), 3.19 (1H, d, J = 9.8 Hz, C-13 H), 3.40 (1H, m,
C-13 OCH), 3.50–3.71 (2H, m, C-17 H and C-13 OCH), 3.87 (1H,
d, J = 5.9Hz, C-6 H), 3.98 (1H, broad s, C-7 OH), 4.42 (1H, m, C-
5 H), 4.66 and 4.58 (2H, ABq, J = 14.6 Hz, C-27 H), 5.31 (1H, m,
C-3 H), 7.33(2H, d, J = 8.8 Hz, Ph H), 8.14 (2H, d, J = 8.8 Hz,
Ph H).
6.4 Hz, C-24 CH3), 0.98 (3H, t, J = 7.3 Hz, C-25 CH2CH3), 1.07
(3H, d, J = 6.3 Hz, C-12 CH3), 1.36 (3H, s, C-14 CH3), 1.83 (3H,
s, C-4 CH3), 2.94 (2H, t, J = 6.3 Hz, PhCH2), 3.05 (1H, m, C-25
H), 3.26 (1H, m, C-2 H), 3.58 (1H, dd, J = 4.4 and 11.0 Hz, C-15
H), 4.02 (1H, d, J = 6.3 Hz, C-6 H), 4.29 (1H, m, C-5 H), 4.66
and 4.70 (2H, ABq, J = 15.7 Hz, C-27 H), 4.87 (1H, m, C-19 H),
5.10 (1H, d, J = 8.3 Hz, C-13 H), 5.45 (1H, m, C-3 H), 7.37 (2H,
d, J = 8.8 Hz, Ph H), 8.14 (2H, d, J = 8.8 Hz, Ph H); MS m/z 718
(M+1, C40H53NO10). 7b: 1H NMR δ 0.84 (3H, d, J = 6.4 Hz, C-
24 CH3), 1.03 (3H, t, J = 7.3 Hz, C-25 CH2CH3), 1.11 (3H, d, J =
6.5 Hz, C-12 CH3), 1.72 (3H, s, C-14 CH3), 1.84 (3H, s, C-4 CH3),
3.04 (1H, m, C-25 H), 3.12 (1H, m, C-12 H), 3.28 (1H, m, C-2 H),
3.45 (1H, m, C-17 H), 3.79 (1H, broad s, C-7 OH), 4.03 (1H, d, J
= 6.4 Hz, C-6 H), 4.31 (1H, d, J = 6.1 Hz, C-5 H), 4.75 and 4.67
(2H, ABq, J = 14.5 Hz, C-27 H), 4.93 (1H, m, C-19 H), 5.28 (1H,
dd, J = 10.3 and 14.4 Hz, C-11 H), 5.40–5.44 (2H, m, C-13 H and
C-15 H), 5.45 (1H, m, C-2 H), 5.74 (1H, dt, J = 11.3 and 2.3 Hz,
C-9 H), 5.84 (1H, dd, J = 11.3 and 14.4 Hz, C-10 H), 6.50 (1H,
m, py H), 7.09 (1H, d, J = 9.6 Hz, py H), 7.18 (1H, dd, J = 7.2
and 9.6 Hz, py H), 7.72 (1H, d, J = 7.2 Hz, py H). 7c: 1H NMR δ
0.82 (3H, d, J = 6.5 Hz, C-24 CH3), 0.93 (9H, s, tBu), 1.00 (3H, t,
J = 6.3Hz, C-25 CH2CH3), 1.11 (3H, d, J = 6.4 Hz, C-12 CH3),
1.62 (3H, s, C-14 CH3),1.74 (3H, s, C-4 CH3), 3.03 (1H, m, C-25
H), 3.11 (1H, m, C-12 H), 3.29 (1H, m, C-2 H), 3.51 (1H, m, C-17
H), 3.86 (1H, d, J = 5.7 Hz, C-6 H), 4.37 (1H, d, J = 5.7 Hz, C-5
H), 4.54 and 4.67 (2H, ABq, J = 14.3 Hz, C-27 H), 4.71 (1H, m,
C-19 H), 5.26 (1H, dd, J = 10.3 and 14.5 Hz, C-11 H), 5.42 (1H,
d, J = 9.8Hz, C-13 H), 5.43 (1H, m, C-15 H), 5.49 (1H, s, C-3 H),
5.66 (1H, dt, J = 11.3 and 2.3 Hz, C-9 H), 5.83 (1H, dd, J = 11.3
and 14.5 Hz, C-10 H), 6.48 (1H, m, py H), 7.10 (1H, d, J = 9.6
Hz, py H), 7.17 (1H, dd, J = 7.1 and 9.6Hz, py H), 7.72 (1H, d, J
= 7.1Hz, py H).
5a: 1H NMR δ 0.84 (3H, d, J = 6.3 Hz, C-24 CH3), 0.98 (3H, t,
J = 7.3 Hz, C-25 CH2CH3), 1.08 (3H, d, J = 6.3 Hz, C-12 CH3),
1.36 (3H, s, C-14 CH3), 1.89 (3H, s, C-4 CH3), 2.94 (2H, t, J =
8.8 Hz, PhCH2), 2.97 (1H, m, C-25 H), 3.09 (1H, m, C-12 H),
3.31 (1H, m, C-25 H), 3.40–3.60 (4H, m, C-2 H, C-15 H and C-13
OCH2), 3.52 (1H, m, C-2 H), 3.80 (1H, s, C-6 H), 3.92 (1H, s, C-7
OH), 4.72 and 4.76 (2H, ABq, J = 14.6 Hz, C-27 H), 4.91 (1H, m,
C-19 H), 5.10 (1H, d, J = 9.3 Hz, C-13 H), 5.26 (1H, m, C-11 H),
6.54 (1H, m, C-3 H), 7.38 (2H, d, J = 8.8 Hz, Ph H), 8.14 (2H, d,
J = 8.8 Hz, Ph H), 5c: 1H NMR δ 0.82 (3H, d, J = 6.6 Hz, C-24
CH3), 0.92 (9H, s, tBu), 1.07 (3H, d, J = 6.5 Hz, C-12 CH3), 1.37
(3H, s, C-14 CH3), 1.79 (3H, s, C-4 CH3), 2.93 (2H, t, J = 6.6 Hz,
PhCH2), 3.05 (1H, m, C-25 H), 3.28 (1H, m, C-17 H), 3.58 (1H,
dd, J = 4.4 and 11.0 Hz, C-15 H), 3.86 (1H, d, J = 5.8 Hz, C-6
H), 4.00 (1H, broad s, C-7 OH), 4.42 (1H, d, J = 5.1 Hz, C-5 H),
4.58 and 4.66 (2H, ABq, J = 14.6 Hz, C-27 H), 4.82 (1H, m, C-19
H), 5.08 (1H, d, J = 8.7 Hz, C-14 H), 5.32 (1H, s, C-3 H), 7.37
(2H, d, J = 8.8 Hz, Ph H), 8.14 (2H, d, J = 8.8 Hz, Ph H); MS m/
z 822 (M+1, C46H67NO10Si).
Synthesis of 4a from 3. 13-Iodomilbemycin (3) (220 mg,
0.33 mmol) was dissolved in 1,2-dichloroethane (3.0 mL). Then,
4-nitrophenethyl alcohol (251 mg, 1.5 mmol) and copper(I) triflu-
oromethanesulfonate (120 mg, 0.41 mmol) were added under ni-
trogen atmosphere. The mixture was stirred at room temperature
for 20 minutes. Then the reaction mixture was diluted with ethyl
acetate and filtered. The filtrate was washed with 1 mol dm−3 HCl
and twice with water, dried over Na2SO4, and evaporated in vacuo.
The residue was chromatographed on silica gel with the eluent
(ethyl acetate:cyclohexane = 1:4) to obtain only the desired 4a
(215 mg, 91.3% yield).
Synthesis of 4c from 7c. 15-Urethane derivative 7c (417 mg,
0.5 mmol) was dissolved in 1,2-dichloroethane (3.0 mL), then 4-
nitrophenethyl alcohol (251 mg, 1.5 mmol) and zinc triflate (218
mg, 0.6 mmol) were added. The mixture was stirred at room tem-