T. Nemoto et al. / Bioorg. Med. Chem. 16 (2008) 4304–4312
4309
the next reaction (Yield, 89%). Crude compound 11 in
small amounts (300 mg) was crystallized from MeOH
to give a white solid (81 mg): mp 220–223 ꢁC; IR
organic extracts were washed with brine twice, dried
over Na SO , and evaporated. The residue was chro-
2
4
matographed
MeOH = 50:1–20:1) to give 6 (526 mg, 17%) as a
on
silica
gel
(100 g;
CHCl3/
ꢀ
KBr) cm : 3403 1705; H NMR (CDCl , 300 MHz):
3
1
1
(
ꢀ
1
d 1.56 (1H, m), 1.81 (1H, ddd, J = 2.0, 7.5, 13.5 Hz),
.93 (1H, dt, J = 5.5, 13.5 Hz), 2.04 (1H, m), 2.14 (1H,
ddd, J = 2.0, 4.5, 14.5 Hz), 2.54–2.68 (2H, m), 2.78
1H, ddd, J = 1.0, 7.0, 13.5 Hz), 2.93 (1H, d,
white amorphous residue: IR (film) cm : 3415,
1
1
1717; H NMR (CDCl , 300 MHz): d 0.03–0.17 (2H,
3
m), 0.42–0.58 (2H, m), 0.82 (1H, m), 1.34 (1H, ddd,
J = 2.0, 4.0, 13.0 Hz), 1.56 (1H, ddd, J = 2.5, 4.0,
12.0 Hz), 1.70 (1H, dt, J = 4.5, 13.0 Hz), 1.80–2.06
(4H, m), 2.25 (1H, ddd, J = 1.0, 6.5, 12.0 Hz), 2.28
(1H, dd, J = 6.5, 14.5 Hz), 2.34 (1H, dd, J = 6.5,
12.0 Hz), 2.44 (1H, m), 2.59 (1H, ddd, J = 3.0, 12.0,
19.0 Hz), 2.76–2.92 (3H, m), 3.77 (1H, dt, J = 2.0,
14.5 Hz), 5.00 (1H, d, J = 11.5 Hz), 5.06 (1H, d,
J = 11.5 Hz), 6.14 (1H, s), 6.52 (1H, d, J = 8.0 Hz),
6.74 (1H, d, J = 8.0 Hz), 7.32–7.43 (5H, m), 9.57
(1H, d, J = 1.0 Hz), one proton (OH) was not ob-
(
J = 18.0 Hz), 2.95 (1H, d, J = 13.0 Hz), 3.09 (1H, d,
J = 5.5 Hz), 3.30 (1H, ddd, J = 1.0, 5.5, 18.0 Hz), 3.83
(
6
3H, s), 3.89 (1H, dd, J = 2.0, 13.0 Hz), 4.42 (1H, s),
.57 (1H, dd, J = 1.0, 8.5 Hz), 6.67 (1H, d, J = 8.5 Hz).
MS (FAB) m/z = 304 [M+H] . HRMS (FAB) Calcd
+
+
for C H NO [M+H] : 304.1549. Found: 304.1548.
1
7
22
4
5.4. 4,14b-Dihydroxy-3-methoxy-17-methylmorphinan-6-
one (12)
+
served. MS (FAB) m/z = 448 [M+H] . HRMS (FAB)
Calcd for C H NO [M+H] : 448.2488. Found:
448.2504.
+
To a stirred solution of 11 (1.50 g, 4.95 mmol) in 2 M
AcOH (188 mL) were added anhydrous sodium acetate
2
8
34
4
(
(
2.03 g, 24.7 mmol) and 37% formaldehyde solution
1.50 mL) and 10% Pd–C (375 mg) at rt under a H2
5.6. 4,14b-Dihydroxy-3-methoxy-17-methylmorphinan-
6a-calbaldehyde (13)
atmosphere. After 22 h with stirring, the reaction mix-
ture was filtered and evaporated in vacuo. The residue
was basified (pH 9) with NH OH and the aqueous layer
Compound 13 was prepared from 12 according to the
procedure used to prepare 6. Yield, 58%. IR (film)
4
was extracted with CHCl three times. The combined or-
3
ꢀ
1
1
ganic extracts were washed with brine twice, dried over
Na SO , and evaporated. The residue was chromato-
graphed on silica gel (60 g; CHCl /MeOH = 20:1–10:1)
to give 12 (1.34 g, 85%) as an oil. Compound 12 was
crystallized from AcOEt to give a white solid (1.05 g,
cm : 3410, 1720; H NMR (300 MHz, CDCl ): d 1.34
3
(1H, ddd, J = 2.0, 4.5, 13.0 Hz), 1.56 (1H, ddd,
J = 1.5, 4.5, 14.0 Hz), 1.70 (1H, dt, J = 4.5, 13.0 Hz),
1.86 (1H, dddt, J = 1.0, 4.5, 5.0, 13.0 Hz), 1.88–2.04
(3H, m), 2.26 (1H, dd, J = 6.0, 14.0 Hz), 2.31 (3H, s),
2.36 (1H, m), 2.44 (1H, m), 2.60 (1H, d, J = 5.5 Hz),
2.82 (1H, ddd, J = 1.0, 5.5, 18.0 Hz), 2.94 (1H, d,
J = 18.0 Hz), 3.80 (1H, dt, J = 2.0, 14.0 Hz), 3.80 (3H,
s), 4.32 (1H, s), 6.08 (1H, s), 6.56 (1H, dd, J = 1.0,
8.0 Hz), 6.66 (1H, d, J = 8.0 Hz), 9.59 (1H, d,
2
4
3
ꢀ
1
1
6
7%): mp 146–148 ꢁC; IR (KBr) cm : 3415, 1712; H
NMR (CDCl , 300 MHz): d 1.57 (1H, ddd, J = 2.0,
1
1
(
(
3
3
2.0, 13.0 Hz), 1.80 (1H, ddd, J = 2.0, 7.0, 13.0 Hz),
.93 (1H, dt, J = 5.0, 13.0 Hz), 1.98–2.10 (2H, m), 2.13
1H, ddt, J = 2.0, 5.0, 13.0 Hz), 2.35 (1H, m), 2.36
3H, s), 2.70–2.88 (3H, m), 2.92 (1H, d, J = 13.5 Hz),
+
J = 1.0 Hz). MS (FAB) m/z = 332 [M+H] . HRMS
(FAB) Calcd for C H NO [M+H] : 332.1862. Found:
332.1853.
+
.08 (1H, m), 3.82 (3H, s), 3.92 (1H, dd, J = 2.0,
1
9
26
4
13.5 Hz), 4.57 (1H, s), 6.12 (1H, s), 6.57 (1H, d,
J = 8.5 Hz), 6.67 (1H, d, J = 8.5 Hz). MS (FAB)
+
m/z = 317 [M+H] . HRMS (FAB) Calcd for
5.7. 3-Benzyloxy-17-(cyclopropylmethyl)-6a-hydrox-
ymethylmorphinan-4,14b-diol (7)
+
C H NO [M+H] : 318.1705. Found: 318.1691.
1
8
24
4
5
.5. 3-Benzyloxy-17-(cyclopropylmethyl)-4,14b-
To a stirred solution of 6 (580 mg, 1.30 mmol) in MeOH
dihydroxymorphinan-6a-calbaldehyde (6)
(10 mL) was added NaBH (500 mg, 13.2 mmol) at 0 ꢁC
4
under an Ar atmosphere. After 10 min, the reaction mix-
ture was stirred at rt under an Ar atmosphere for 2 h.
After adding water and acetone, evaporated, the aque-
Methylsulfinyl carbanion was prepared from NaH
(
55% mineral oil dispersion, 2.00 g, 45.8 mmol) and
dry DMSO (18 mL) at 60 ꢁC under an Ar atmosphere
for 1.5 h. A solution of the phosphonium ylide was
prepared by the reaction of the methylsulfinyl carban-
ion (34.6 mmol) and methoxymethyltriphenylphospho-
nium chloride (12.7 g, 41.5 mmol) in DME (100 mL)
at rt for 10 min under an Ar atmosphere. To a stirred
solution of the phosphonium ylide was added drop-
wise 5 (3.00 g, 6.92 mmol) in dry DMSO (18 mL) at
rt under an Ar atmosphere. After 1.5 h with stirring,
water was added to the solution, and the aqueous
layer was extracted with benzene three times. The
combined organic extracts were extracted with 2 M
HCl three times. After the combined aqueous layer
ous layer was extracted with CHCl three times. The
3
combined organic extracts were washed with brine
twice, dried over Na SO , and evaporated. The residue
was chromatographed on silica gel (40 g; CHCl3/
2
4
MeOH = 50:1–14:1) to give 7 (365 mg, 63%) as a white
amorphous residue: IR (film) cm : 3410; H NMR
ꢀ1
1
(CDCl , 300 MHz): d 0.02–0.17 (2H, m), 0.45–0.55
3
(2H, m), 0.82 (1H, m), 1.32 (1H, ddd, J = 3.0, 4.0,
13.5 Hz), 1.42 (1H, m), 1.52 (1H, m), 1.66 (1H, dt,
J = 4.0, 13.5 Hz), 1.90–1.98 (2H, m), 2.02 (1H, m),
2.06 (1H, dd, J = 5.0, 12.5 Hz), 2.15 (1H, m), 2.27
(1H, dd, J = 6.5, 12.0 Hz), 2.35 (1H, dd, J = 6.0,
12.0 Hz), 2.56 (1H, m), 2.82–2.96 (3H, m), 3.13 (1H,
dd, J = 7.0, 11.0 Hz), 3.17 (1H, dd, J = 1.5, 12.5 Hz),
3.38 (1H, dd, J = 9.0, 11.0 Hz), 5.04 (1H, d,
was basified (pH 9) with NaHCO , the aqueous layer
3
was extracted with CHCl three times. The combined
3