MOMO
MeOOC
MOMO
OH
HO
a, b
c
a
1
6c
Y: 91%
Y: 95%
H
H
H
(−)-pisiferin (6a) 89%
b
5c
OH
OMOM
d
OMOM
OH
H
OH
O
Scheme 2. Reagents and conditions: (a) excess CH2N2, Et2O, 0 °C
then rt; (b) MOMCl (10 equiv), K2CO3 (14 equiv), acetone, rt, 48 h;
(c) LiAlH4 (10 equiv), THF, reflux, 24 h.
e
c
H
H
(+)-pisiferanol (11) 79%
OMOM
10 99%
9 68%
Table 1. The skeletal rearrangement of (+)-O-methoxymethylpisif-
erol (5c) into icetexane regioisomers of 6c, 7c, and/or 8c
OMOM
O
HO
OH
H
H
H
O
Productb
H
Entry Reaction conditionsa
Ratio
Yield/%
6c:7c:8c
g, h
f
H
H
1
2
3
4
TsCl (4.0 equiv), pyridine, 70 °C, 24 h
TsCl (4.0 equiv), pyridine, rt, 65 h
MsCl (4.0 equiv), pyridine, 70 °C, 24 h
Tf2O (2.0 equiv), pyridine, ¹20 °C, 0.5 h
then rt, 0.5 h
90
30
95
90
67:26:7
67:33:0
67:33:0
77:23:0
13 99%; a mixture of
13a (10β-H) and
13b (10α-H) (1.0:1.0)
12 99%; a mixture of
12a (1β-OH, 10β-H) and
12b (1α-OH, 10α-H)
(1.0:1.1)
14 92%
5
6
Tf2O (2.0 equiv), DIPEA (8.0 equiv),
CH2Cl2, ¹20 °C, 0.5 h then rt, 1.5 h
Tf2O (2.0 equiv), collidine (8.0 equiv),
CH3CN, ¹20 °C, 0.5 h then rt, 4.0 h
43
65
77:15:8
33:60:7
Scheme 3. Reaction conditions: (a) 5.0 M HCl aq., THF, rt, 48 h;
(b) m-CPBA (2.5 equiv), CH2Cl2, 0 °C, 2 h; (c) LiAlH4 (4.0 equiv),
THF, reflux, 20 h; (d) 5.0 M HCl aq., THF, rt, 48 h; (e) 1.0 M BH3 in
THF (8.0 equiv), rt, 24 h, then 30% H2O2 (53 equiv), 3.0 M NaOH
(16 equiv), THF-EtOH, 50 °C, 2.0 h; (f) PCC (2.0 equiv), silica gel,
CH2Cl2, rt, 3.0 h; (g) CH3ONa, MeOH, 50 °C, 7.0 h; (h) 5.0 M HCl aq.,
THF, rt, 48 h.
aThe reaction was conducted under nitrogen. The ratio of isomers in
the product was determined by H NMR.
b
1
was chosen. Esterification of 1 with diazomethane, protection
with methoxymethyl chloride (MOMCl), and then reduction
with LiAlH4 afforded (+)-12-O-methoxymethylpisiferol (5c) in
high yield (Scheme 2). The rearrangement of 5c was examined
using several reaction conditions (Table 1). According to
Kametani’s procedure, the treatment of 5c with TsCl in pyridine
at 70 °C unfortunately gave three regioisomers 6c, 7c, and 8c
as a 67:26:7 mixture (Entry 1). When the reaction with TsCl
was carried out at room temperature, no production of 8c was
observed, but the product yield decreased in 30% yield because
of incomplete reaction (Entry 2). The treatment with methane-
sulfonyl chloride (MsCl) at 70 °C provided a mixture of 6c and
7c in high yield, but the ratio of isomers was not improved
(Entry 3). When triflic anhydride (Tf2O) was used in pyridine at
¹20 °C and then room temperature, a mixture of 6c and 7c was
obtained in a ratio of 77:23 in 90% yield (Entry 4). On the
contrary, the reaction with Tf2O using N,N-diisopropylethyl-
amine (DIPEA) or 2,4,6-collidine resulted in an unsatisfactory
yield and unfavorable ratio of isomers (Entries 5 and 6). The
conditions in Entry 4 gave the best result among all the attempts.
The mixture of isomers obtained in Entry 4 was separated by
column chromatography on 10% silver nitrate-impregnated
silica gel with hexane-toluene (2:1) to give 6c in a 64% of
isolated yield, after 7c (14% yield) had been eluted with hexane-
toluene (4:1).15 Thus, we successfully prepared 6c, though the
ratio of isomers slightly improved in comparison with that
reported by Kametani et al.
literature,12 the epoxidation of 6c with m-chloroperbenzoic acid
(m-CPBA) at 0 °C, followed by the reduction with LiAlH4 in
refluxing THF predominantly yielded 10β-hydroxy compounds
10. Deprotection of 10 using 5 M hydrochloric acid in THF at
room temperature provided the desired 11. Since no hydro-
boration of 6c with 9-borabicyclo[3.3.1]nonane took place, 6c
was treated with 1.0 M BH3 in THF at room temperature and
subsequently oxidized with H2O2 to yield an inseparable mixture
of isomers 12a and 12b in a ratio of 1.0:1.1 in 99% yield, which
was oxidized with pyridinium chlorochromate (PCC) to afford
an inseparable mixture of epimers 13a and 13b with respect
to the A/B ring junction in a ratio of 1:1 in 99% yield. The
epimerization of the mixture with sodium methoxide in meth-
anol at 50 °C predominantly gave the thermodynamically stable
trans-isomer 13a, which was deprotected with 5 M hydrochloric
acid in THF to provide 14 in 92% yield (2 steps).
Finally, the ortho-selective oxygenation of the phenols 6a,
11, and 14 was investigated. Regioselective oxygenation of
phenolic compounds with hypervalent iodine(V) reagents has
been paid much attention because of both the synthetic utility
and biological activities of products such as ortho-quinones and
ortho-hydroquinones.16 Tada et al. reported that pisiferic acid
(1) was converted into CA by oxygenation with IBX followed
by reduction with NaBH4.3 On the other hand, Ishihara et al.
recently developed a catalytic oxygenation of phenols to ortho-
quinones with Oxoneμ using the alkaline metal salt of 5-methyl-
2-iodobenzenesulfonic acid (pre-MIBS).17 These methods were
applied to the oxygenation of the phenols (Table 2). Upon
treatment of a solution of 6a, 11, and 14 in CHCl3-MeOH with
stabilized IBX (SIBX)18 (1.2 equiv) at room temperature for 3 h
followed by NaBH4 or 1.5 M sodium ascorbate aqueous solution
Next, 6c was converted into (¹)-pisiferin (6a), (+)-pisif-
eranol (11), and (+)-12-hydroxy-8,11,13-icetexatrien-1-one (14)
as follows (Scheme 3). The deprotection of 6c with 5 M
hydrochloric acid in THF at room temperature afforded 6a in
89% yield. According to a similar method described in the
© 2016 The Chemical Society of Japan | 747