540
E. Nishimura et al. / Tetrahedron Letters 56 (2015) 539–541
DIBAL (3 eq.)
toluene,5 °C, 0.5 h
then 3N HCl,
O
OH
1) (COCl2) (2 eq.)
toluene,90 °C
30 min
OMe
O
n-pentyl
R
O
R
70 °C, 1 h
6
O
O
HO
OH
69%
2) NaOMe (3 eq.)
MeOH, 45 °C,18 h
75% in 2 steps
O
OH
5
6
phloroglucinol (
)
R = n-Pentyl
10
11
1-Me-AZADO (5 mol%)
KBr (1.4 eq.), NaOCl
DCM/10% NaHCO3 aq.
5 °C, 1 h
O
O
n-pentyl
HO
OsO4 (1.5 eq.)
pyridine,5 °C,
1 h
R
O
n-pentyl
HO
n-pentyl OH
O
α-ketol
rearrangement
O
quant.
HO
O
quant.
12
Scheme 3. Conversion of 6 to ( )-triumphalone (1).
1
HO
O
HO
O
1
( )-triumphalone ( )
proposed structure of
isotriumphalone (2)
No reaction: CDCl3, DMSO-d6, C6D6, D2O
Reaction profile in CD3OD: See below.
Scheme 1. Synthetic route to 1 and 2.
sovlent
O
n-pentyl
HO
room temperature
O
OH
OH
isotriumphalone
O
n-pentyl
HO
O
O
1
synthetic
O
O
HO
OH
alkylation
5
6
7
O
(1.01 eq.)
Cl
NaBH3CN (2.5 eq.)
AcOH, rt, 18 h
41%
BF3.OEt2 (3.0 eq.)
rt, 33 h 82%
n-Bu OH
MeI (7 eq.)
n-Bu OH
NaOMe (5.0 eq.)
O
MeOH, reflux, 15 h
O
O
O
76%
HO
OH
9
8
Scheme 2. Conversion of 5–6.
Figure 2. Rearrangement reaction of 1 in CD3OD at room temperature. The reaction
was monitored for 117 h. The conversion was calculated by the relative integration
ratio of the methine protons [( )-1 (3.72, s, 1H); ( )-isotriumphalone (4.68, s, 1H)].
(7 equiv) in the presence of NaOMe (5 equiv) to afford 9 in 76%
yield.4a Chemoselective reduction of the carbonyl group on the acyl
side chain was achieved by the modified Smith’s condition.6 Treat-
ment of 9 with NaBH3CN in acetic acid gave 6 in 41% yield.
Triketone 6 was successfully transformed to ( )-triumphalone
(1) in 5 steps (Scheme 3). Treatment of 6 with (COCl)2 provided
O
OH
OH
the corresponding b-chloro-a,b-unsaturated ketone which
O
HO
smoothly reacted with MeONa to afford 10 in 75% yield in 2 steps.
Reduction of 10 with DIBAL, followed by hydrolysis of the enol
intermediate with HCl gave 11 in 69% yield. Alcohol 11 was oxi-
dized by the AZADO oxidation7 to provide ketone 12. The cis-diol
moiety of 1 was installed in a stereoselective manner using OsO4
(1.5 equiv) to give ( )-triumphalone (1), quantitatively. Spectral
data of ( )-1 were identical to those of the natural product (see
Supplementary material).
HO
O
O
proposed structure of
isotriumphalone (2)
ORTEP view of
synthetic isotriumphalone (4)
revised structure of
isotriumphalone (4)
Figure 3. Ortep view of ( )-isotriumphalone (4).
Having ( )-triumphalone (1) in hand, the key
a-ketol rearrange-
moiety.8 Thus, the proposed structure of isotriumphalone is
revised as 4.
ment reaction was examined in five solvents (Fig. 2). ( )-Triumph-
alone (1) was dissolved in CDCl3, DMSO-d6, C6D6, or CD3OD to give
a homogenous solution. Addition of ( )-1 to D2O gave a suspension.
We next explored the reactivity of 1 at the elevated tempera-
ture because isotriumphalone (4) was obtained by steam distilla-
tion. Each solution was heated at 70 °C for 112 h (Fig. 4). The
reaction profiles were plotted in Figure 4. In all solutions, signifi-
cant rate acceleration effects were observed. Among them, the
reactions in CD3OD and D2O were found to be much faster than
those in C6D6, CDCl3, and DMSO-d6. In contrast, ( )-4 did not
change at all under the same reaction conditions. These results
indicated a probability that 4 would be produced during steam
distillation.
The rearrangement reaction in each solution was monitored by 1
H
NMR at room temperature. No reactions were observed in CDCl3,
DMSO-d6, C6D6 or D2O. In contrast, a new set of proton signals
which were identical to those of the isotriumphalone reported in
the literature1 slowly appeared in CD3OD (Fig. 2). After 117 h,
60% of ( )-1 changed to isotriumphalone. In contrast, the purified
isotriumphalone did not undergo the rearrangement reaction in
all solvents to recover the starting material.
To confirm the proposed structure of isotriumphalone (2), we
examined X-ray analysis of the synthetic ( )-isotriumphalone in
which the 1H NMR data were identical to that of the reported data
(Fig. 3). To our surprise, the crystallographic data did not support
the proposed structure, but cyclopentanone 4 with a cis-1,2-diol
Naturally occurring triumphalone (1) was purified by a C18
reverse-phase HPLC column chromatograph (eluent: 0.05% TFA/
H2O, 0.05% TFA/CH3CN).1 It has been reported that the
a-ketol rear-
rangement reaction was promoted under the acidic and basic reac-
tion conditions.9 We tested the feasibility of the acid-catalyzed