Enantioselective syntheses of the assigned structures of the helibisabonols A and B

Article abstract of DOI:10.1016/j.tet.2011.03.064

The enantioselective syntheses of the compounds with the assigned structures of the helibisabonols A and B have been accomplished. Using an enzymatic desymmetrization of the σ-symmetrical diol (route a) and a diastereoselective conjugate addition of the m

Full text of DOI:10.1016/j.tet.2011.03.064

Tetrahedron 67 (2011) 6753e6761
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Enantioselective syntheses of the assigned structures of the helibisabonols A and B
*
Akari Miyawaki, Mayu Osaka, Makoto Kanematsu, Masahiro Yoshida, Kozo Shishido
Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78-1 Sho-machi, Tokushima 770-8505, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 March 2011
Received in revised form 21 March 2011
Accepted 22 March 2011
Available online 11 April 2011
The enantioselective syntheses of the compounds with the assigned structures of the helibisabonols A
and B have been accomplished. Using an enzymatic desymmetrization of the s-symmetrical diol (route
a) and a diastereoselective conjugate addition of the methyl to the enone with a chiral auxiliary (route b)
we constructed the key tertiary stereogenic center at the benzylic position (C7) and then used an
asymmetric dihydroxylation for assembling the C10 stereogenic center. In addition, possible di-
astereoisomers of the natural products were prepared and detailed comparisons of the 1H and 13C NMR
spectra were conducted. As a result, the structure originally assigned to helibisabonol A may be revised to
(7R,10R)-1. In the case of helibisabonol B, the (7R,10R)-2 would be reasonable based on a comparison of
the NMR data and the biogenetic parallelism with helibisabonol A.
Keywords:
Total synthesis
Enantioselective synthesis
Sesquiterpene
Desymmetrization
Lipase
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
The sesquiterpenes helibisabonols A (1) and B (2) were isolated
from the extracts of dried leaves of Helianthus annuus L. cv.
PeredovickÒ by Macías et al.1 The structures were elucidated on the
basis of extensive NMR and theoretical studies and it was revealed
that both are aromatic bisabolene sesquiterpenes with a hydroqui-
none moiety and two tertiary stereogenic centers at the C7 and C10
positions. The relative stereochemistries of the two chiral centers
10
HO
Me
HO
Me
OH
OH
7
8
OH
OH
OH
OH
Helibisabonol
A (1)
Helibisabonol
B
(2)
Fig. 1. Structures of the helibisabonols A and B.
were deduced to be (7R
*
,10S
*
) and (7R
*
,10R ), respectively, based on
*
a comparison of the coupling constants between the experimental
and the theoretical values. Helibisabonol A (1) has been reported to
exhibit inhibitory activity against the growth of etiolated wheat
coleoptiles, which is called allelopathic activity. Since the heli-
bisabonols are believed to represent the biogenetic precursor of
helianane sesquiterpenes (e.g., heliannuols2 and heliespirones3),
the development of an efficient and practical synthetic route to
both natural products would be valuable. Although both a racemic
and an enantioselective synthesis of 1 have been reported by
Macías4 and Sirat,5 respectively, the synthesis of helibisabonol B (2)
has never been accomplished. We describe herein the enantiose-
lective syntheses of the assigned structures of the helibisabonols A
(1) and B (2) and the structure elucidation of the natural products
by extensive comparisons of the NMR spectra (Fig. 1).
2. Results and discussion
2.1. Enantioselective synthesis of helibisabonol A (1)
For the enantioselective synthesis, the (7R,10S)-1 was initially
targeted since the absolute configuration at C7 of the biogenetically
paralleled heliannuols had been established to be R.6a Our retro-
synthetic analysis of 1 is shown in Scheme 1. We envisaged the C10-
S stereogenic center of 1 being assembled by dihydroxylation using
AD-mix-a. For the preparation of 3 with the C7-R configuration, we
planned to examine the two strategies that we have already de-
veloped; route a: the enzymatic desymmetrization7 of a
s-sym-
metrical 2-aryl-1,3-propanediol 46,8 followed by the Julia allylation
with prenyl bromide, and route b: the diastereoselective conjugate
addition of the methyl to the substrate 59 with a chiral auxiliary
followed by Wittig olefination (Scheme 1).
Enzymatic desymmetrization of the prochiral diol 4, derived
from 4-iodo-2,5-dimethoxytoluene via two steps,6 using PPL (Por-
cine Pancreatic Lipase) provided the optically active monoacetate
* Corresponding author. Tel.: þ81 88 6337287; fax: þ81 88 6339575; e-mail
address: shishido@ph.tokushima-u.ac.jp (K. Shishido).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.03.064

6754
A. Miyawaki et al. / Tetrahedron 67 (2011) 6753e6761
(a) desymmetrization using Lipase
O
O
O
O
(b) diastereoselective conjugate addition
MeO
Me
Br
MeO
Me
a
AD
N
g
O
N
O
+
OMe
OMe
OMe
Ph
MeO
HO
Me
Ph
OH
12
13
5
OH
Me
OMe
OH
helibisabonol A (1)
(b) Wittig
O
O
3
(a) Julia allylation
MeO
Me
R
MeO
c
b
N
O
3
(b)
(a)
Me
OMe
Ph
Ar=2,5-dimethoxy-4-methylphenyl
Ar
O
OH
O
14
15: R=CH2OH
d
e
f
16: R=CHO
OH
N
O
17: R=CH=CHOMe
18: R=CH2CHO
Ar
5
4
Ph
Scheme 3. Preparation of 3 via route b. Reagents and conditions: (a) Pd(OAc)2, (o-
tol)3P, Et3N, CH3CN/H2O (10/1), 80 ꢁC, 2 h, 81%; (b) MeMgBr, CuBr$SMe2, THF, ꢀ20 ꢁC,
0.5 h, 71% (recrystallized from AcOEt/n-hexane); (c) NaBH4, THF/H2O (3/1), 50 ꢁC, 3.5 h,
80%; (d) PCC, CH2Cl2, rt, 3 h; (e) (Ph3PþCH2OCH3)Clꢀ, NaHMDS, THF, rt, 1 h; (f) 2 N HCl
(aq), THF, rt, 6 h, 71% (three steps); (g) [Ph3PþCH(CH3)2]Iꢀ, tBuOK, THF, rt, 0.5 h, quant.
Scheme 1. Synthetic strategy of 1.
R-68a with 84% ee (HPLC, Chiralcel AD), which was converted to the
alcohol 8 by tosylation, NaBH4 reduction, and hydrolysis. At this
stage, recrystallization rendered
8 optically pure. Phenyl-
(7R,10S)-helibisabonol A (1) in 51% yield for the two steps. Although
sulfenylation followed by m-CPBA oxidation of the resulting sulfide
9 produced the sulfone 10, which was treated with nBuLi and prenyl
bromide in THF/HMPA at ꢀ78 ꢁC to give 11. Finally, desulfonylation
using Na/Hg provided 3 in 8% overall yield for nine steps from 4-
iodo-2,5-dimethoxytoluene (Scheme 2).
the optical rotation of the synthetic 1 {[
a
]
2D9 ꢀ38.9 (c 0.68, acetone)}
25
was in close accord with the reported values {[
a
]
ꢀ44.9 (c 0.1,
D
acetone);1 [
a]
D ꢀ31.5 (c 0.3, MeOH)5}, the 1H and 13C NMR spectra
were not identical with those of the natural product (Tables 1 and
2). Notably, the chemical shift of the methine proton H10 at
exhibits a distinctive difference (Δ
¼0.36 ppm) and the chemical
shift differences (Δ ) of the three protons at H7, H8, and H10 are
d 3.30
d
OH
OH
OH
OAc
d
>0.05 ppm. In addition, five of the fifteen carbons showed large
differences (>0.5 ppm) in the 13C NMR. Therefore, it was deduced
that the configuration at C10, which has been elucidated by an
ambiguous method,1 was actually R. Thus, we examined the prep-
aration of the 10R-diastereoisomer. Treatment of 3 with AD-mix-
MeO
Me
MeO
Me
a
d
b
OMe
OMe
4
6
R1
MeO
R
MeO
OR2
b
at 0 ꢁC provided quantitatively the (7R,10R)-diol 21 as a single
f
product (1H NMR) and it was similarly converted to (7R,10R)-1
Me
e
OMe
Me
c
OMe
7: R1=OTs, R2=Ac
8: R1=R2=H
29
{[
a]
ꢀ6.9 (c 0.33, acetone)}15 in 69% yield for the two steps
D
9: R=SPh
(Scheme 4). The chemical shifts of the 1H NMR were in good accord
with those of the natural product except for H10. The chemical
shifts in the 13C NMR were identical with those of the natural
product except for those of the C7, C9, and C13 carbons, which were
10: R=SO2Ph
MeO
R
11: R=SO2Ph
3: R=H
g
Me
OMe
Table 1
Comparison of 1H and 13C NMR chemical shifts of the natural helibisabonol A with
Scheme 2. Preparation of 3 via route a. Reagents and conditions: (a) PPL, vinyl acetate,
Et2O, rt, 34 h, 34% (98% based on recovered 4), 84% ee (HPLC, Chiralcel AD); (b) TsCl,
Et3N, 4-DMAP, CH2Cl2, rt, 2 h, 98%; (c) NaBH4, DMSO, 60 ꢁC, 1.5 h then K2CO3, MeOH,
H2O, rt, 3 h, 51% (after recrystallization from n-hexane), >99% ee (HPLC, Chiralcel OD);
(d) PhSSPh, nBu3P, pyridine, rt, 1 h; (e) m-CPBA, KHCO3, CH2Cl2, rt, 4 h, 94% (two steps);
synthetic (7R,10S)- and (7R,10R)-1. The chemical shift difference (Δ
parenthesis. Differences Δ
>0.05/0.5 ppm (1H/13C) are marked in bold. Assignments
in 1H NMR are supported by 500 MHz H/H-COSY
d) is indicated in
d
14
12
n
(f) prenyl bromide, BuLi, HMPA, THF, ꢀ78 ꢁC, 0.5 h, 76%; (g) Na/Hg, Na2HPO4, MeOH,
HO
Me
10
1
2
HO
Me
sonication, rt, 8 h, 86%.
OH
7
OH
OH
OH
OH
Although we could obtain the desired 3, this route contains two
low-yielding steps, 4/6 and the preparation of optically pure 8.
Therefore, we tried to find a more efficient route. Substrate 5 for the
key diastereoselective conjugate addition was synthesized in 81%
yield by the Heck reaction10,11 of the aryl bromide 1212 and the
optically active enone 1313 with catalytic Pd(OAc)2 and (o-tol)3P in
the presence of Et3N. Treatment of a solution of 5 in THF with
MeMgBr and CuBr$SMe2 at ꢀ20 ꢁC produced the methylated
product 14 as an inseparable mixture of diastereoisomers (12:1
from 1H NMR in C6D6), which was recrystallized immediately from
AcOEt and n-hexane to give the diastereomerically pure 14 in 71%
yield. Reductive removal of the chiral auxiliary with NaBH4 fol-
lowed by PCC oxidation provided the aldehyde 16, which was
converted to 18 by a standard one-carbon homologation procedure.
It was then subjected to the Wittig reaction to produce 3 in 33%
overall yield for seven steps from 12 (Scheme 3).
OH
(7R,10R)-1
(7R,10S)-1
H
Natural Synthetic
C
Natural Synthetic
(7R,10S)-1
(7R,10R)-1
(7R,10S)-1
(7R,10R)-1
3
6
7
8
6.51
6.59
3.06
1.74
6.55 (þ0.04) 6.55 (þ0.04) 1 132.1 132.2 (þ0.1) 132.4 (þ0.3)
6.59 (0)
6.60 (þ0.01) 2 147.5 148.0 (þ0.5) 147.8 (þ0.3)
3.12 (þ0.06) 3.11 (þ0.05) 3 117.9 118.2 (þ0.3) 118.3 (þ0.4)
1.86 (þ0.12) 1.78 (þ0.04) 4 121.9 122.2 (þ0.3) 122.2 (þ0.3)
1.54 (ꢀ0.01) 1.58 (þ0.03) 5 148.8 149.1 (þ0.3) 149.1 (þ0.3)
1.47 (þ0.02) 1.50 (þ0.05) 6 113.3 113.9 (þ0.6) 113.7 (þ0.4)
80 1.55
1.45
9
90 1.23
10 3.66
12 1.04
13 1.03
14 1.09
15 2.04
C10eOH
C11eOH
1.18 (ꢀ0.05) 1.27 (þ0.04)
3.30 (ꢀ0.36) 3.27 (ꢀ0.39)
1.05 (þ0.01) 1.06 (þ0.02)
7
8
9
29.8a
35.4
32.3 (þ2.5) 32.3 (þ2.5)
35.2 (ꢀ0.2) 35.8 (þ0.4)
30.0 (þ5.6) 30.0 (þ5.6)
78.9 (ꢀ0.3) 79.5 (þ0.3)
72.8 (þ0.4) 72.7 (þ0.3)
26.0 (þ0.5) 25.8 (þ0.3)
24.7 (ꢀ4.3) 24.7 (ꢀ4.3)
22.0 (þ0.9) 21.4 (þ0.3)
15.8 (þ0.4) 15.7 (þ0.3)
24.4b
1.03 (0)
1.06 (þ0.03) 10 79.2
1.13 (þ0.04) 1.14 (þ0.05) 11 72.4
2.08 (þ0.04) 2.08 (þ0.04) 12 25.5
3.40
3.21
3.59
3.27
13 29.0b
14 21.1
15 15.4
Sharpless dihydroxylation14 of 3 with AD-mix-
a provided the
diol 19 with the 10S configuration in 91% yield with 93% de (1H
a
NMR). Sequential oxidation with cerium ammonium nitrate (CAN)
and reduction of the resulting quinone 20 with Na2S2O4 gave
This may be due to impurity.
These assignments may be reversed.
6
b

A. Miyawaki et al. / Tetrahedron 67 (2011) 6753e6761
6755
Table 2
MeO
Me
SO2Ar
Comparison of the selected J values (Hz) of the natural helibisabonol A with syn-
thetic (7R,10S)- and (7R,10R)-1
8
10
HO
Me
OMe
H
Natural
Synthetic
OH
7
23
OH
(7R,10S)-1
(7R,10R)-1
OH
OHC
7e8
7.0
7.6
1.4
4.9a
d
7.0
7.0
2.0
10.0
5.0
7.0
7.0
2.0
10.0
5.0
helibisabonol B (2)
7e80
O
O
9e10
90e10
10-OH
25
24
Scheme 5. Synthetic strategy of 2.
a
This may be the J between H10 and C10eOH.
reductive workup produced the right hand segment S-aldehyde 24.16
We next examined the Julia coupling19 for the installation of the E-
alkene. The reaction of 10 with 24 using the three-step sequence (1.
nBuLi, THF, ꢀ78 ꢁC; 2. BzCl, 4-DMAP, THF, rt; 3. Na/Hg, Na2HPO4,
MeOH, rt) produced the alkene 31 as an inseparable mixture of E/Z
isomers (4.4:1) in 17% yield. Higher yield was obtained using the
modified Julia olefination;20 treatment of the sulfone 30, prepared
from 8 by sequential sulfenylation with benzo[d]thiazole-2-thiol (28)
and oxidation of the resulting 29 with ammonium heptamolybdate
tetrahydrate/H2O2, with24 inthepresenceofNaHMDSprovided31 as
a 3:1 mixture of E and Z isomers in 60% yield. Cleavage of methyl
ethers on the aryl ring was realized via a two-step sequence.6 Oxi-
dation of 31 with CAN produced the quinone 32 quantitatively. At this
stage, E and Z isomers could be separated by HPLC. The acetonide
MeO
a
b
OH
7
3
OH
Me
OMe
19
14
12
10
O
1
2
HO
Me
c
OH
OH
OH
OH
Me
O
OH
20
(7R,10S)-1
[ ]D –38.9 (c 0.68, acetone)
lit.1 [ ]D –44.9 (c 0.1, acetone)
lit.5 [ ]D –31.5 (c 0.3, MeOH)
moiety of the E-isomer was hydrolyzed and the resulting diol 33 was
MeO
Me
d
b
27
OH
reduced with Na2S2O4 to give the (7R,10R)-helibisabonol B (2), {[
a]
3
D
þ0.9 (c 0.47, acetone), lit.1 [
a]
25 ꢀ7.2 (c 0.1, acetone)}, which is the
OH
D
OMe
assigned structure1 (Scheme 6).
21
O
HO
Me
c
X
OH
OH
OH
OH
a
b
Me
O
OH
O
O
25
22
(7R,10R)-1
HO
OH
26
27: X=C(CH3)2
24: X=O
[ ]D –6.90 (c 0.33, acetone)
c
+0.048
H
+0.004
Scheme 4. Syntheses of (7R,10S)-1 and (7R,10R)-1. Reagents and conditions: (a) AD-
t
mix-
0.5 h, 62% for 20, 85% for 22; (c) Na2S2O4, THF, H2O, rt, 10 min, 82% for (7R,10S)-1, 81%
a
, CH3SO2NH2, BuOH, H2O, 0 ꢁC, 23 h, 91%, 93% de; (b) CAN, CH3CN, H2O, 0 ꢁC,
–0.068
–0.058
OH
MTPA
t
for (7R,10R)-1; (d) AD-mix-b
, CH3SO2NH2, BuOH, H2O, 0 ꢁC, 21 h, quant, >99% de.
+0.033
²
O
also different in the (7R,10S) isomer. We also compared the selected
coupling constants between the natural product and the two syn-
thetic compounds (Table 2). The observed H90eH10 coupling con-
stant (J¼4.9 Hz) was quite similar to the coupling (J¼5.0 Hz)
between H10 and OH for the synthetic 1. Therefore, it was thought
=
–
(S)
(R)
N
MeO
X
N
f
d
+
8
SH
S
d
3.66 in the 1H NMR of the natural
S
Me
e
OMe
that the chemical shift at
product is not that of H10 but rather that of C10eOH. In our case,
the signals of the C10eOH were observed at 3.40 (doublet,
3.59
28
29: X=S
30: X=SO2
d
J¼5.0 Hz, D2O exchangeable) for the (7R,10S)-1 and at
d
MeO
Me
O
(doublet, J¼5.0 Hz, D2O exchangeable) for the (7R,10R)-1, re-
spectively. From these data, one may conclude that the structure of
helibisabonol A is (7R,10R)-1 (Tables 1 and 2).
g
OR2
O
O
OR1
OMe
31
Me
O
32: R1+R2=C(CH3)2
h
i
33: R1=R2=H
(7R,10R)-2
2.2. Enantioselective synthesis of helibisabonol B (2)
Scheme 6. Synthesis of (7R,10R)-helibisabonol B (2). Reagents and conditions: (a) AD-
t
mix-b
, CH3SO2NH2, BuOH, H2O, 0 ꢁC, 20 h, 79%, 93% ee; (b) (CH3O)2C(CH3)2, p-TsOH,
Our retrosynthesis of helibisabonol B (2), illustrated in Scheme 5,
proposes a convergent strategy employing the Julia coupling of the
two chiral building blocks 23 and 24.16 The left hand segment 23
would be prepared from the optically active alcohol 8. The right half
aldehyde 24 could be accessed from a commercially available 2,5-
dimethylhexa-2,4-diene (25) (Scheme 5).
acetone, rt, 8 h, quant.; (c) O3 then Me2S, CH2Cl2, ꢀ78 ꢁC, 68%; (d) diisopropyl azodi-
carboxylate, Ph3P, THF, rt, 2.5 h, 91%; (e) ammonium heptamolybdate tetrahydrate, 30%
H2O2 (aq), EtOH, rt, 4 h, 93%; (f) NaHMDS, S-24, THF, ꢀ78 ꢁC, 1 h, 60%. E/Z¼3/1; (g) CAN,
CH3CN, H2O, rt, 0.5 h, quant; (h) 10% HCl (aq), MeOH, rt, 5 h, 98%; (i) Na2S2O4, THF, H2O,
rt, 0.5 h, 95%.
Asymmetric dihydroxylation of 25 with AD-mix-b provided the
diol 2617 in 79% yield with 93% ee (1H NMR of the MTPA ester). The
configuration of a newly generated stereogenic center was confirmed
to be R by the KusumieMosher method18 as shownin Scheme 6. After
protection of the diol as an acetonide, ozonolysis followed by
As in the case of helibisabonol A, we also prepared the di-
astereomeric (7R,10S)-2 for comparison purposes. According to the
procedure described above, 30 was condensed with R-24, prepared
by using AD-mix-a for the asymmetric dihydroxylation, to give

6756
A. Miyawaki et al. / Tetrahedron 67 (2011) 6753e6761
Table 4
a 6:1 mixture of the E/Z isomers of 34, which were separated by
HPLC, in 61% yield. The desired E-isomer of 34 was then converted
Comparison of the selected J values (Hz) of the natural helibisabonol B with syn-
thetic (7R,10R)- and (7R,10S)-2
to (7R,10S)-2, {[
a
]
D ꢀ23.1 (c 0.66, acetone)}, via the same three-step
H
Natural
Synthetic
sequence (Scheme 7).
(7R,10R)-2
(7R,10S)-2
7e8
7e14
8e9
9e10
10-OH
6.6
6.6
15.5
7.7
d
6.5
7.0
15.5
7.0
6.0
7.0
15.5
7.0
OHC
NaHMDS, THF
–78 °C, 2 h
MeO
Me
O
+
30
O
O
O
61%, E/Z=6/1
OMe
OH
4.0
4.0
34
R-24
HO
Me
diastereoisomers for both natural products and made a detailed
comparison of the NMR data. As a result, it would be reasonable
that the structure of helibisabonol A is (7R,10R)-1 and that of hel-
ibisabonol B is (7R,10R)-2.
3 steps (88%)
OH
OH
(7R,10S)-2
Scheme 7. Synthesis of (7R,10S)-helibisabonol B (2).
4. Experimental
4.1. General
Comparison of the 1H and 13C NMR chemical shifts between the
natural helibisabonol B and the two synthetic diastereoisomers
(7R,10R)- and (7R,10S)-2 is shown in Table 3. They showed similar
chemical shift differences (Δd
) both in the 1H and 13C NMR, except
All nonaqueous reactions were carried out under a positive at-
mosphere of argon in dried glassware unless otherwise indicated.
Materials were obtained from commercial suppliers and used
without further purification except when otherwise noted. Solvents
were dried and distilled according to standard protocols. The phrase
‘residue upon workup’ refers to the residue obtained when the or-
ganic layer was separated and dried over anhydrous MgSO4, and the
solvent was evaporated under reduced pressure. Column chroma-
tography was performed on silica gel, and flash column chroma-
tography was performed on silica gel using the indicated solvent.
for the C7 and C10 chemical shifts in the 13C NMR, which may be
due to impurities. The J values for the selected protons of the nat-
ural and synthetic compounds were also similar (Table 4). Although
it was difficult to determine the structure of helibisabonol B from
these data, the (7R,10R)-2, which was originally assigned to the
natural product, would be a more reasonable structure from the
point of view of biogenetic parallelism with the helibisabonol A
(Tables 3 and 4).
Table 3
Comparison of 1H and 13C NMR chemical shifts of the natural helibisabonol B with synthetic (7R,10R)- and (7R,10S)-2. Assignments in 1H NMR are supported by 500 MHz
H/H-COSY
14
12
10
OH
1
2
HO
Me
HO
Me
7
OH
OH
OH
OH
OH
(7R,10R)-2
(7R,10S)-2
H
Natural
Synthetic
C
Natural
Synthetic
(7R,10R)-2
(7R,10S)-2
(7R,10R)-2
(7R,10S)-2
3
6
7
8
6.52
6.49
3.70
5.81
5.46
3.78
1.07
1.02
1.26
2.10
6.58 (þ0.06)
6.57 (þ0.08)
3.79 (þ0.09)
5.85 (þ0.04)
5.55 (þ0.09)
3.80 (þ0.02)
1.09 (þ0.02)
1.07 (þ0.05)
1.24 (ꢀ0.02)
2.08 (ꢀ0.02)
6.57 (þ0.05)
6.57 (þ0.08)
3.79 (þ0.09)
5.87 (þ0.06)
5.54 (þ0.08)
3.79 (þ0.01)
1.11 (þ0.04)
1.08 (þ0.06)
1.24 (ꢀ0.02)
2.08 (ꢀ0.02)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
132.1
147.5
117.9
121.9
148.8
113.3
28.9a
138.2
127.7
31.9a
72.4
130.8 (ꢀ1.3)
147.7 (þ0.2)
118.2 (þ0.3)
122.7 (þ0.8)
149.1 (þ0.3)
114.6 (þ1.3)
35.4 (þ6.5)
137.4 (ꢀ0.8)
128.9 (þ1.2)
80.1 (þ48.2)
72.7 (þ0.3)
24.7 (ꢀ1.6)
26.3 (ꢀ0.2)
20.4 (ꢀ0.4)
15.8 (þ0.4)
130.6 (ꢀ1.5)
147.5 (0)
118.1 (þ0.2)
122.7 (þ0.8)
148.9 (þ0.1)
114.5 (þ1.2)
35.4 (þ6.5)
137.5 (ꢀ0.7)
128.6 (þ0.9)
80.0 (þ48.1)
72.6 (þ0.2)
24.6 (ꢀ1.7)
26.2 (ꢀ0.3)
20.3 (ꢀ0.5)
15.7 (þ0.3)
9
10
12
13
14
15
26.3
26.5
20.8
15.4
a
These may be due to impurities.
3. Conclusion
4.1.1. (R)-2-(2,5-Dimethoxy-4-methylphenyl)-3-hydroxypropyl ace-
tate (6). To a stirred solution of diol 4 (3.35 g, 14.8 mmol) in Et2O
(70 mL) were added PPL (6.70 g) and vinyl acetate (2.73 mL,
29.6 mmol) at rt. After stirring was continued for 34 h at the same
temperature, the reaction mixture was filtered through a pad of
Celite. The resulting solution was evaporated in vacuo, the residue
was chromatographed on silica gel with hexane/AcOEt (2:1 v/v) as
eluent to give monoacetate 6 (1.30 g, 34%, 84% ee) as a yellow oil
In conclusion, we have completed the enantioselective total
syntheses of the assigned structures of the helibisabonols A and B
using two key reactions, lipase-mediated desymmetrization and
diastereoselective conjugate addition, for the construction of the
tertiary carbon stereogenic center at the benzylic position (C7). In
addition, we also have prepared two corresponding

A. Miyawaki et al. / Tetrahedron 67 (2011) 6753e6761
6757
and some starting material was recovered (2.12 g, 64%); ½a D25
ꢂ
þ12.9
extracts were washed with brine. The residue upon workup was
chromatographed on silica gel with hexane/AcOEt (7:3 v/v) as el-
uent to give sulfone 10 (113 mg, 94% two steps) as a colorless oil;
(c 1.0 in CHCl3); IR (neat): 3457, 1738, 1211, 1045 cmꢀ1
;
1H NMR
(400 MHz, CDCl3) d 1.89 (1H, s, D2O exchangeable), 2.05 (3H, s), 2.21
(3H, s), 3.53 (1H, quint, J¼5.9 Hz), 3.78 (6H, s), 3.85 (2H, d,
½
a 2D5
ꢂ
ꢀ6.6 (c 1.2 in CHCl3); IR (neat): 1365, 1177, 1050 cmꢀ1; 1H NMR
J¼6.0 Hz), 4.42 (1H, dd, J¼7.7 and 10.9 Hz), 4.36 (1H, dd, J¼5.9 and
(400 MHz, CDCl3)
d
1.42 (3H, d, J¼7.3 Hz), 2.13 (3H, s), 3.31 (1H, m),
10.9 Hz), 6.72 (2H, s); 13C NMR (100 MHz, CDCl3)
d
16.2 (CH3), 21.0
3.51 (1H, m), 3.58 (3H, s), 3.64 (1H, m), 3.74 (3H, s), 6.45 (1H, s), 6.53
(CH3), 41.1 (CH), 56.1 (CH3), 56.2 (CH3), 63.2 (CH2), 64.5 (CH2), 111.4
(CH), 114.3 (CH), 124.8 (Cq), 126.2 (Cq), 151.2 (Cq), 151.8 (Cq), 171.4
(Cq); MS (EI) m/z 268 [M]þ; HRMS (EI) m/z calcd for C14H20O5 [M]þ
268.1311, found 268.1317. Enantiomeric excess was determined by
HPLC analysis [Chiralcel AD, 3% isopropanol/hexane, 1.0 mL/min,
(1H, s), 7.44 (2H, m), 7.75 (1H, m), 7.77 (2H, d, J¼7.3 Hz); 13C NMR
(100 MHz, CDCl3) d 16.0 (CH3), 19.9 (CH3), 31.2 (CH), 55.5 (CH3), 56.1
(CH3), 61.6 (CH2), 111.1 (CH), 113.9 (CH), 125.8 (Cq), 127.9 (CH), 128.7
(CH), 128.9 (Cq), 133.0 (CH), 139.9 (Cq), 150.3 (Cq), 151.6 (Cq); MS
(EI) m/z 334 [M]þ; HRMS (EI) m/z calcd for C18H22O4S [M]þ
334.1239, found 334.1259.
l¼254 nm, retention times 27.1 min (S) and 31.9 min (R)].
4.1.2. (S)-2-(2,5-Dimethoxy-4-methylphenyl)-3-(tosyloxy)propyl ac-
etate (7). To a stirred solution of monoacetate 6 (1.84 g, 6.87 mmol)
in CH2Cl2 (30 mL) were added NEt3 (4.79 mL, 34.4 mmol), TsCl
(3.93 g, 20.6 mmol), and catalytic amount of 4-DMAP at rt. After
stirring was continued for 2 h at the same temperature, the reaction
mixture was quenched with saturated aqueous NH4Cl and extrac-
ted with CH2Cl2. The combined extracts were washed with brine.
The residue upon workup was chromatographed on silica gel with
hexane/AcOEt (1:1 v/v) as eluent to give tosylate 7 (2.84 g, 98%) as
4.1.5. (S)-1,4-Dimethoxy-2-methyl-5-[6-methyl-3-(phenylsulfonyl)
hept-5-en-2-yl]benzene (11). To a stirred solution of sulfone 10
(70.5 mg, 0.21 mmol) in THF (1.5 mL) and HMPA (0.3 mL) was added
dropwise 1.43 M solution of nBuLi in hexane (0.22 mL, 0.32 mmol) at
ꢀ78 ꢁC. After stirring was continued for 20 min at the same temper-
ature and further 30 min at 0 ꢁC, prenyl bromide (0.073 mL,
0.63 mmol) was added dropwise and stirring was continued for
30 min at ꢀ78 ꢁC. The reaction mixture was quenched with saturated
aqueous NH4Cl and extracted with CH2Cl2. The combined extracts
were washed with brine. The residue upon workup was chromato-
graphed on silica gel with hexane/AcOEt (9:1 v/v) as eluent to give
a yellow oil; ½a 2D7
ꢂ
þ4.6 (c 0.8 in CHCl3); IR (neat): 1741, 1365, 1177,
1045 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 1.98 (3H, s), 2.19 (3H, s),
2.43 (3H, s), 3.62 (1H, m), 3.67 (3H, s), 3.72 (3H, s), 4.28 (4H, m), 6.53
sulfone 11 (64.5 mg, 76%) as a colorless oil; IR (neat): 1211,1049 cmꢀ1
;
(1H, s), 6.60 (1H, s), 7.26 (2H, d, J¼8.2 Hz), 7.65 (2H, d, J¼8.2 Hz); 13C
1H NMR (400 MHz, CDCl3)
d
1.25 (3H, s), 1.38 (1.5H, s), 1.41 (1.5H, s),
NMR (100 MHz, CDCl3)
d
16.2 (CH3), 20.8 (CH3), 21.6 (CH3), 38.3
1.43 (1.5H, d, J¼7.2 Hz),1.57 (1.5H, d, J¼7.2 Hz), 2.16 (3H, s), 2.22 (0.5H,
m), 2.37 (1H, m), 2.68 (0.5H, m), 3.59(1H, m), 3.61 (1.5H, s), 3.69(1.5H,
s), 3.75 (1.5H, s), 3.77 (1.5H, s), 3.80 (1H, m), 4.71 (0.5H, m), 4.90 (0.5H,
s), 6.52 (0.5H, s), 6.54 (0.5H, s), 6.63 (0.5H, s), 6.66 (0.5H, s), 7.58 (3H,
m), 7.81 (1H, d, J¼7.3 Hz), 7.85 (1H, d, J¼7.3 Hz); MS (EI) m/z 402 [M]þ;
HRMS (EI) m/z calcd for C23H30O4S [M]þ 402.1865, found 402.1888.
(CH), 55.9 (CH3), 56.0 (CH3), 63.4 (CH2), 69.7 (CH2), 111.4 (CH), 114.0
(CH), 122.5 (Cq), 126.6 (Cq), 127.9 (CH), 129.6 (CH), 132.9 (Cq), 144.6
(Cq), 150.8 (Cq), 151.6 (Cq), 170.7 (Cq); MS (EI) m/z 422 [M]þ; HRMS
(EI) m/z calcd for C21H26O7S [M]þ 422.1399, found 422.1410.
4.1.3. (S)-2-(2,5-Dimethoxy-4-methylphenyl)propan-1-ol
(8). To
a stirred solution of tosylate 7 (1.90 g, 4.49 mmol) in DMSO (10 mL)
was added NaBH4 (0.68 g, 18.0 mmol) at rt, and stirring was con-
tinued for 1.5 h at 60 ꢁC. The reaction mixture was diluted with
water and extracted with CH2Cl2. The combined extracts were
washed with brine. The residue upon workup was dissolved in
MeOH/H2O (5:1, 18 mL) and added K2CO3 (1.24 g, 8.98 mmol) at rt.
After stirring was continued for 3 h at the same temperature, the
reaction mixture was extracted with AcOEt. The combined extracts
were washed with brine. The residue upon workup was recrystal-
lized from hexane to give alcohol 8 (0.48 g, 51%, >99% ee, two steps)
as colorless crystals; mp 78.0e79.5 ꢁC (recrystallized from hexane);
4.1.6. (R)-1,4-Dimethoxy-2-methyl-5-(6-methylhept-5-en-2-yl)ben-
zene (3). To a stirred solution of sulfone 11 (24.3 mg, 0.06 mmol) in
MeOH (0.2 mL) were added Na2HPO4 (34.3 mg, 0.24 mmol) and Na/
Hg (364.5 mg) at rt and sonicated for 8 h. The reaction mixture was
filtered through a pad of Celite and the resulting solution was
extracted with AcOEt. The combined extracts were washed with
brine. The residue upon workup was chromatographed on silica gel
with hexane/AcOEt (9:1 v/v) as eluent to give alkene 3 (13.6 mg,
86%) as a colorless oil; ½a D25
ꢀ29.3 (c 1.0 in CHCl3); IR (neat): 1209,
ꢂ
105 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
1.18 (3H, d, J¼6.8 Hz), 1.51
(1H, m), 1.54 (3H, s), 1.63 (1H, m), 1.67 (3H, s), 1.89 (2H, m), 2.20 (3H,
½
a 2D5
ꢂ
ꢀ12.7 (c 1.0 in CHCl3); IR (neat): 3274,1209,1043 cmꢀ1; 1H NMR
s), 3.14 (1H, sext, J¼7.3 Hz), 3.76 (3H, s), 3.78 (3H, s), 5.12 (1H, m),
(400 MHz, CDCl3)
d
1.26 (3H, d, J¼6.8 Hz), 1.54 (1H, s, D2O ex-
6.67 (2H, s); 13C NMR (100 MHz, CDCl3)
d 16.1 (CH3), 17.6 (CH3), 21.3
changeable), 2.21 (3H, s), 3.42 (1H, m), 3.69 (2H, d, J¼6.8 Hz), 3.78
(CH3), 25.7 (CH3), 26.4 (CH2), 31.9 (CH), 37.3 (CH2), 56.1 (CH3), 56.4
(CH3), 109.8 (CH), 114.4 (CH), 124.2 (Cq), 124.9 (CH), 131.1 (Cq), 134.0
(Cq), 150.9 (Cq), 151.9 (Cq); MS (EI) m/z 262 [M]þ; HRMS (EI) m/z
calcd for C17H26O2 [M]þ 262.1933, found 262.1933.
(3H, s), 3.80 (3H, s), 6.70 (1H, s), 6.71 (1H, s); 13C NMR (100 MHz,
CDCl3) d 16.1 (CH3),16.7 (CH3), 35.5 (CH), 56.1 (CH3), 56.3 (CH3), 68.0
(CH2), 110.3 (CH), 114.4 (CH), 125.3 (Cq), 129.8 (Cq), 151.1 (Cq), 152.0
(Cq); MS (EI) m/z 210 [M]þ; HRMS (EI) m/z calcd for C12H18O3 [M]þ
210.1256, found 210.1245. Enantiomeric excess was determined by
HPLC analysis [Chiralcel OD, 1% isopropanol/hexane, 0.5 mL/min,
4.1.7. (R,E)-3-[3-(2,5-Dimethoxy-4-methylphenyl)acryloyl]-4-phe-
nyloxazolidin-2-one (5). To
a stirred solution of 1-bromo-
l
¼254 nm, retention times 57.2 min (S) and 52.5 min (R)].
2,5-dimethoxy-4-methylbenzene (12) (1.98 g, 8.58 mmol) and
(R)-3-acryloyl-4-phenyloxazolidin-2-one (13) (1.86 g, 8.58 mmol)
in MeCN/H2O (10:1, 40 mL) were added Pd(OAc)2 (192.58 mg,
0.86 mmol), (o-tol)3P (522 mg, 1.7 mmol), and Et3N (2.391 mL,
0.017 mmol) at rt, and allowed to warm to 80 ꢁC. After being stirred
at the same temperature for 2 h, the resultant mixture was added
water and CH2Cl2 and then extracted with CH2Cl2. The combined
extracts were washed with brine, the residue upon workup was
chromatographed on silica gel with hexane/AcOEt (4:1 v/v) as
4.1.4. (S)-1,4-Dimethoxy-2-methyl-5-[1-(phenylsulfonyl)propan-2-
yl]benzene (10). To a stirred solution of alcohol 8 (75.7 mg,
0.36 mmol) in pyridine (1.5 mL) were added PhSSPh (236 mg,
1.08 mmol) and nBu3P (0.27 mL, 1.08 mmol) at rt, and stirring was
continued for 1 h at the same temperature. The reaction mixture
was diluted with Et2O and washed with 15% aqueous NaOH, 10%
aqueous HCl and brine. The residue upon workup was dissolved in
CH2Cl2 (1.5 mL) and added KHCO3 (22 mg, 0.22 mg) and m-CPBA
(216 mg, 0.81 mmol) at rt. After stirring was continued for 4 h at the
same temperature, the reaction mixture was quenched with satu-
rated aqueous NH4Cl and extracted with CH2Cl2. The combined
a eluent to give a enone 5 (2.564 g, 81%) as a yellow solid; ½a D29
ꢂ
ꢀ5.17 (c 0.95 in CHCl3); mp 55.5e59.5 ꢁC; IR (neat) 2958,1781,1705,
1505,1465,1384,1209,1045 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 2.24
(3H, s), 3.82 (3H, s), 3.82 (3H, s), 4.31 (1H, dd, J¼8.8 and 4.0 Hz), 4.73

6758
A. Miyawaki et al. / Tetrahedron 67 (2011) 6753e6761
(1H, t, J¼8.8 Hz), 5.57 (1H, dd, J¼8.8 and 4.0 Hz), 6.72 (1H, s), 7.02
(1H, s), 7.30e7.39 (5H, m), 7.93 (1H, d, J¼16.0 Hz), 8.12 (1H, d,
eluent to give methylenolether 17 (1.6 g) as a colorless oil; IR (neat)
2933, 1654, 1506, 1466, 1398, 1208, 1048 cmꢀ1; 1H NMR (400 MHz,
J¼16.0 Hz); 13C NMR (100 MHz, CDCl3)
d
16.7 (CH3), 55.8 (CH3), 56.0
CDCl3)
d
2.02 (3H, d, J¼7.2 Hz), 2.04e2.11 (0.55H, m), 2.20 (3H, s),
(CH3), 57.8 (CH3), 69.8 (CH2), 109.8 (CH), 114.4 (CH), 115.7 (CH), 121.1
(Cq), 125.9 (CH), 128.5 (CH), 129.0 (CH), 131.8 (Cq), 139.3 (Cq), 142.0
(CH), 151.7 (Cq), 153.0 (Cq), 153.9 (Cq), 165.2 (Cq); HRMS (ESI) calcd
for C21H21NO5Na [MþNa]þ 390.1317, found 390.1310.
2.19e2.27 (0.45H, m), 2.31e2.37 (1H, m), 3.15 (1H, sext, J¼7.2 Hz),
3.47 (1.65H, s), 3.56 (1.35H, s), 3.77 (3H, s), 3.79 (3H, s), 4.28 (0.45H,
q, J¼6.4 Hz), 4.68 (0.55H, dt, J¼12.8 and 7.2 Hz), 5.86 (0.45H, d,
J¼6.4 Hz), 6.27 (0.55H, d, J¼12.8 Hz), 6.66 (0.55H, s), 6.68 (1H, s),
6.72 (0.45H, s); HRMS (ESI) calcd for C15H22O3Na [MþNa]þ
273.1467, found 273.1466.
4.1.8. (R)-3-[(R)-3-(2,5-Dimethoxy-4-methylphenyl)butanoyl]-4-
phenyloxazolidin-2-one (14). To a stirred solution of CuBr$SMe2
(5.67 g, 27.6 mmol) in THF/Me2S (2.5:1, 43 mL) was added dropwise
1.06 M solution of MeMgBr in THF (27.1 mL, 28.7 mmol) at ꢀ4 ꢁC.
After being stirred at the same temperature for 10 min, the resultant
mixture was cooled to ꢀ20 ꢁC. To the reaction mixture was added
dropwise a solution of enone 5 (3.4 g, 9.45 mmol) in THF at the same
temperature and the stirring was continued for 30 min. The re-
sultant mixture was quenched with pH 7 phosphate buffer and
extracted with hexane/AcOEt (1:1 v/v). The combined extracts were
washed with brine, the residue upon workup was recrystallized
4.1.11. (R)-4-(2,5-Dimethoxy-4-methylphenyl)pentanal (18). To a sti-
rred solution of methylenolether 17 (1.6 g) inTHF (15 mL) was added
2 N aqueous HCl (3 mL) at 0 ꢁC. After stirring was continued for 6 h at
rt, the reaction mixture was quenched with saturated aqueous
NaHCO3 and extracted with AcOEt. The combined extracts were
washed with brine. The residue uponworkup was chromatographed
on silica gel with hexane/AcOEt (95:5 v/v) as eluent to give aldehyde
18 (0.75 g, 71% three steps) as a colorless oil; ½a D28
ꢀ11.7 (c 0.63 in
ꢂ
CHCl3); IR (neat) 2930, 2360,1718,1506,1457,1398,1209,1046 cmꢀ1
;
from hexane/AcOEt to give a 14 (2.52 g, 71%) as a colorless solid; ½a D26
ꢂ
1H NMR (400 MHz, CDCl3)
d
1.23 (3H, d, J¼6.8 Hz),1.81e1.96 (2H, m),
ꢀ72.89 (c 0.81 in CHCl3); mp 116.1e116.5 ꢁC; IR (neat) 2958, 1781,
2.20 (3H, s), 2.22e2.43 (2H, m), 3.18 (1H, sext, J¼6.8 Hz), 3.75 (3H, s),
1705,1505,1465,1384,1209,1045 cmꢀ1; 1H NMR (400 MHz, CDCl3,)
3.79 (3H, s), 6.64 (1H, s), 6.68 (1H, s), 9.69 (1H, t, J¼1.6 Hz); 13C NMR
d
1.20 (3H, d, J¼7.2 Hz), 2.19 (3H, s), 3.17 (1H, dd, J¼16.8 and 7.6 Hz),
(100 MHz, CDCl3) d 16.1 (CH3) 21.0 (CH3), 29.5 (CH2), 31.5 (CH), 42.1
3.42 (1H, dd, J¼16.8 and 7.6 Hz), 3.64e3.72 (1H, m), 3.76 (3H, s), 3.76
(3H, s), 4.22 (1H, dd, J¼8.8 and 3.6 Hz), 4.59 (1H, t, J¼8.8 Hz), 5.36
(1H, dd, J¼8.8 and 3.6 Hz), 6.66 (1H, s), 6.68 (1H, s), 7.23e7.37 (5H,
(CH2), 56.1 (CH3), 56.2 (CH3),109.6 (CH),114.2 (CH),124.8 (Cq),132.0
(Cq), 150.8 (Cq), 151.9 (Cq), 202.9 (CH); HRMS (ESI) calcd for
C14H20O3Na [MþNa]þ 259.1310, found 259.1310.
m); 13C NMR (100 MHz, CDCl3)
d 16.0 (CH3), 20.7 (CH3), 29.9 (CH),
41.5 (CH2), 56.1 (CH3), 56.2 (CH3), 57.6 (CH), 69.8 (CH2), 110.3 (CH),
114.4 (CH), 124.8 (Cq), 125.8 (CH), 128.5 (CH), 129.0 (CH), 131.6 (Cq),
139.1 (Cq), 150.6 (Cq), 151.6 (Cq), 153.7 (Cq), 171.7 (Cq); HRMS (ESI)
calcd for C22H25NO5Na [MþNa]þ 406.1630, found 406.1622.
4.1.12. (R)-1,4-Dimethoxy-2-methyl-5-(6-methylhept-5-en-2-yl)ben-
zene (3). To a stirred solution of isopropyltriphenylphosphonium io-
t
dide (4.01 g, 9.28 mmol) in THF (12 mL) was added BuOK (1.04 g,
9.28 mmol) at 0 ꢁC. After stirring was continued for 15 min, aldehyde
18 (0.73 g, 3.09 mmol) in THF (3 mL) was dropwise at the same tem-
perature. After stirring was continued for 0.5 h at rt, the reaction
mixture was quenched with saturated aqueous NH4Cl and extracted
with AcOEt. The combined extracts were washed with brine. The
residueuponworkupwas chromatographed onsilica gelwithhexane/
AcOEt(98:2v/v)aseluenttogivealkene3(0.82 g, quant.)asacolorless
oil. Spectra data coincides with those of the described above.
4.1.9. (R)-3-(2,5-Dimethoxy-4-methylphenyl)butan-1-ol
(15). To
a stirred solution of oxazolidinone 14 (3.73 g, 9.74 mmol) in THF/H2O
(3:1, 40 mL) was added NaBH4 (1.84 g, 48.7 mmol) at rt. After stirring
was continued for 3.5 h at 50 ꢁC, the reaction mixture was quenched
with saturated aqueous NH4Cl and extracted with AcOEt. The com-
bined extracts were washed with brine, the residue uponworkup was
chromatographed on silica gel with hexane/AcOEt (7:3 v/v) as eluent
to give alcohol 15 (1.74 g, 80%) as a colorless oil; ½a D28
ꢂ
ꢀ39.0 (c 1.34 in
4.1.13. (3S,6R)-6-(2,5-Dimethoxy-4-methylphenyl)-2-methyl-
CHCl3); IR (neat) 3735, 2956, 2360,1506,1457,1397,1208,1045 cmꢀ1
;
heptane-2,3-diol (19). To a stirred solution of AD-mix-a (295 mg,
1H NMR (400 MHz, CDCl3)
exchangeable), 1.56e1.65 (1H, m), 1.88e1.96 (1H, m), 2.21 (3H, s),
3.33e3.40 (2H, m), 3.50e3.56 (1H, m), 3.79 (3H, s), 3.80 (3H, s), 6.67
d
1.27 (3H, d, J¼7.2 Hz), 1.59 (1H, br, D2O
0.38 mmol) and CH3SO2NH2 (18.0 mg, 0.19 mmol) in BuOH/H2O
(1:1, 1 mL) was added alkene 3 (49.4 mg, 0.19 mmol) at 0 ꢁC. After
stirring was continued for 23 h at the same temperature, the re-
action mixture was quenched with saturated aqueous Na2SO3 and
stirred for 1 h at 0 ꢁC. After further stirring was continued for 1 h at
rt, the reaction mixture was extracted with CHCl3. The combined
extracts were washed with brine. The residue upon workup was
chromatographed on silica gel with hexane/AcOEt (6:4 v/v) as eluent
t
(1H, s), 6.70(1H, s); 13CNMR(100 MHz,CDCl3)
d16.0 (CH3), 21.2(CH3),
27.6 (CH), 41.0 (CH2), 56.0 (CH3), 56.5 (CH3), 60.9 (CH2), 109.3 (CH),
114.2 (CH), 124.7 (Cq), 132.3 (Cq), 150.4 (Cq), 152.2 (Cq); HRMS (ESI)
calcd for C13H20O3Na [MþNa]þ 247.1310, found 247.1315.
4.1.10. (R)-1,4-Dimethoxy-2-(5-methoxypent-4-en-2-yl)-5-methyl-
benzene (17). To a stirred solution of alcohol 15 (1.00 g, 4.46 mmol)
in CH2Cl2 (18 mL) was added PCC (1.44 g, 6.69 mmol) at 0 ꢁC and
stirring was continued for 3 h at rt. The reaction mixture was
treated with silica gel, and filtered through a pad of Celite. The
resulting solution was evaporated in vacuo to give crude aldehyde
16 (0.97 g) as a brown oil, which was used to the next reaction
without further purification.
to give diol 19 (51.1 mg, 91%, 93% de) as a colorless oil; ½a D26
ꢀ40.9 (c
ꢂ
1.3 in CHCl3); IR (neat): 3418, 2955, 1504, 1466, 1399, 1208 cmꢀ1; 1H
NMR (400 MHz, CDCl3)
d 1.01 (3H, s), 1.13 (3H, s), 1.21 (3H, d,
J¼6.8 Hz), 1.15e1.28 (1H, m), 1.38e1.46 (1H, m), 1.58e1.67 (1H, m),
1.81e1.90 (1H, m), 2.00e2.20 (2H, br, D2O exchangeable), 2.20 (3H,
s), 3.15e3.24 (1H, m), 3.39 (1H, dd, J¼10.4 and 1.6 Hz), 3.76 (3H, s),
3.79 (3H, s), 6.67 (1H, s), 6.68 (1H, s); 13C NMR (100 MHz, CDCl3)
d
16.1 (CH3), 21.6 (CH3), 23.2 (CH2), 26.4 (CH3), 29.6 (CH3), 31.6 (CH),
To a stirred solution of methoxymethyltriphenylphosphonium
chloride (4.53 g, 13.4 mmol) in THF (16 mL) was added dropwise
1.09 M solution of NaHMDS in THF (12.3 mL, 13.4 mmol) at 0 ꢁC.
After stirring was continued for 15 min, crude aldehyde 16 (0.97 g)
in THF (2 mL) was dropwise at the same temperature. After further
stirring was continued for 1 h at rt, the reaction mixture was
quenched with brine and extracted with AcOEt. The combined
extracts were washed with brine. The residue upon workup was
chromatographed on silica gel with hexane/AcOEt (95:5 v/v) as
34.1 (CH2), 56.1 (CH3), 56.3 (CH3), 73.1 (Cq), 78.4 (CH), 109.7 (CH),
114.2 (CH), 124.4 (Cq), 133.2 (Cq), 150.7 (Cq), 151.9 (Cq); HRMS (ESI)
m/z calcd for C17H29O4 [MþH]þ 297.2066, found 297.2066.
4.1.14. 2-[(2R,5S)-5,6-Dihydroxy-6-methylheptan-2-yl]-5-methyl-
cyclohexa-2,5-diene-1,4-dione (20). To a stirred solution of diol 19
(25.8 mg, 0.09 mmol) in CH3CN/H2O (4:1, 0.4 mL) was added CAN
(95.5 mg, 0.17 mmol) at 0 ꢁC, and stirring was continued for 30 min
at the same temperature. The resulting solution was diluted with

A. Miyawaki et al. / Tetrahedron 67 (2011) 6753e6761
6759
water and extracted with Et2O. The combined extracts were
washed with brine. The residue upon workup was chromato-
graphed on silica gel with hexane/AcOEt (1:1 v/v) as eluent to give
described for 7R,10S-1, 7R,10R-1 was prepared from 22: yield 81%;
colorless oil; ½a D29
ꢂ
ꢀ6.9 (c 0.33 in acetone); IR (neat): 3367, 2963,
1703,1419,1193 cmꢀ1; 1H NMR (500 MHz, CD3COCD3)
d
1.06 (6H, s),
quinone 20 (14.4 mg, 62%) as a yellow oil; ½a D28
ꢂ
ꢀ26.9 (c 0.77 in
1.14 (3H, d, J¼7.0 Hz), 1.22e1.31 (1H, m), 1.50 (1H, dddd, J¼15.5,
10.0, 5.5 and 2.0 Hz), 1.58 (1H, dddd, J¼13.5, 10.0, 7.5 and 5.5 Hz),
1.78 (1H, dddd, J¼13.5, 10.0, 7.0 and 5.5 Hz), 2.08 (3H, s), 3.11 (1H,
sext, J¼7.0 Hz), 3.27 (1H, s, D2O exchangeable), 3.27 (1H, ddd,
J¼10.0, 5.0 and 2.0 Hz), 3.59 (1H, d, J¼5.0 Hz, D2O exchangeable),
6.55 (1H, s), 6.60 (1H, s), 7.26 (1H, s, D2O exchangeable), 7.36 (1H, s,
CHCl3); IR (neat): 3434, 2969, 1654 cmꢀ1
;
1H NMR (400 MHz,
CDCl3)
d
1.13 (3H, s), 1.15 (3H, d, J¼6.8 Hz), 1.20 (3H, s), 1.20e1.27
(1H, m), 1.43e1.52 (2H, m), 1.77e1.87 (1H, m), 1.87 (1H, br s, D2O
exchangeable), 2.04 (3H, d, J¼2.0 Hz), 2.28 (1H, br s, D2O ex-
changeable), 2.96 (1H, sext, J¼6.8 Hz), 3.34 (1H, dd, J¼10.4 and
2.0 Hz), 6.54 (1H, s), 6.60 (1H, d, J¼2.0 Hz); 13C NMR (100 MHz,
D2O exchangeable); 13C NMR (125 MHz, CD3COCD3)
d 15.7 (CH3),
CDCl3)
d
15.4 (CH3), 19.8 (CH3), 23.2 (CH3), 26.5 (CH3), 29.2 (CH2),
21.4 (CH3), 24.7 (CH3), 25.8 (CH3), 30.0 (CH2), 32.3 (CH), 35.8 (CH2),
72.7 (Cq), 79.5 (CH), 113.7 (CH), 118.3 (CH), 122.2 (Cq), 132.4 (Cq),
147.8 (Cq), 149.1 (Cq); HRMS (ESI) m/z calcd for C15H25O4 [MþH]þ
269.1753, found 269.1758.
31.4 (CH), 33.1 (CH2), 73.1 (Cq), 78.5 (CH), 131.3 (CH), 133.7 (CH),
145.3 (Cq), 153.8 (Cq), 187.5 (Cq), 188.5 (Cq); HRMS (ESI) m/z calcd
for C15H23O4 [MþH]þ 267.1596, found 267.1604.
4.1.15. 2-[(2R,5S)-5,6-Dihydroxy-6-methylheptan-2-yl]-5-methyl-
benzene-1,4-diol (7R,10S-1). To a stirred solution of quinone 20
(14.4 mg, 0.05 mmol) in THF (0.2 mL) were added Na2S2O4
(28.3 mg, 0.16 mmol) in H2O (0.1 mL) at 0 ꢁC, and stirring was
continued for 10 min at rt. The resulting solution was diluted with
water and extracted with AcOEt. The combined extracts were
washed with brine. The residue upon workup was chromato-
graphed on silica gel with hexane/AcOEt (3:7 v/v) as eluent to give
4.1.19. (S)-2-[2-(2,5-Dimethoxy-4-methylphenyl)propylthio]benzo[d]
thiazole (29). Toastirredsolutionof alcohol8 (264 mg,1.25 mmol)in
THF (10 mL) were added 2-benzothiazolethiol 28 (251 mg,
1.50 mmol) and Ph3P (393 mg,1.50 mmol) atrt. Afterthe solutionwas
cooled to 0 ꢁC, DIAD (0.32 mL, 1.63 mmol) was added dropwise and
the mixture was stirred for 2.5 h at rt. The reaction mixture was
quenched with 1 N aqueous NaOH and extracted with Et2O. The
combined extracts were washed with brine. The residue upon
workup was chromatographed on silica gel with hexane/AcOEt (95:5
tetraol 7R,10S-1 (11.9 mg, 82%) as a colorless oil; ½a D29
ꢂ
ꢀ38.9 (c 0.68
in acetone); IR (neat): 3373, 2967, 1703, 1420, 1195 cmꢀ1
;
1H NMR
v/v) as eluent to give sulfide 29 (409 mg, 91%) as a colorless oil; ½a D29
ꢂ
(500 MHz, CD3COCD3)
d 1.03 (3H, s), 1.05 (3H, s), 1.13 (3H, d,
ꢀ31.8 (c 0.87 in CHCl3); IR (neat): 2931, 2829, 1504, 1462, 1427, 1398,
J¼7.0 Hz), 1.16e1.21 (1H, m), 1.45e1.50 (1H, m), 1.51e1.57 (1H, m),
1.82e1.90 (1H, m), 2.08 (3H, s), 3.12 (1H, sext, J¼7.0 Hz), 3.21 (1H, s,
D2O exchangeable), 3.30 (1H, ddd, J¼10.0, 5.0 and 2.0 Hz), 3.40 (1H,
d, J¼5.0 Hz, D2O exchangeable), 6.55 (1H, s), 6.59 (1H, s), 7.27 (1H, s,
D2O exchangeable), 7.28 (1H, s, D2O exchangeable); 13C NMR
1209, 756 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
1.42 (3H, d, J¼6.8 Hz),
2.20 (3H, s), 3.56e3.63 (2H, m), 3.66e3.70 (1H, m), 3.77 (3H, s), 3.78
(3H, s), 6.69 (1H, s), 6.70 (1H, s), 7.27 (1H, td, J¼8.0 and 1.2 Hz), 7.39
(1H, td, J¼8.0 and 1.2 Hz), 7.72 (1H, dd, J¼8.0 and 1.2 Hz), 7.85 (1H, dd,
J¼8.0 and 1.2 Hz); 13C NMR (100 MHz, CDCl3)
d 16.1 (CH3),19.6 (CH3),
(125 MHz, CD3COCD3)
d 15.8 (CH3), 22.0 (CH3), 24.7 (CH3), 26.0
33.4 (CH), 40.1 (CH2), 56.1 (CH3ꢃ2),110.2 (CH),114.2 (CH),120.8 (CH),
121.3 (CH), 124.0 (CH), 125.5 (Cq), 125.9 (CH), 130.2 (Cq), 135.2 (Cq),
150.8 (Cq), 151.7 (Cq), 153.3 (Cq), 167.7 (Cq); HRMS (ESI) m/z calcd for
C19H22NO2S2 [MþH]þ 360.1092, found 360.1102.
(CH3), 30.0 (CH2), 32.3 (CH), 35.2 (CH2), 72.8 (Cq), 78.9 (CH), 113.9
(CH), 118.2 (CH), 122.2 (Cq), 132.2 (Cq), 148.0 (Cq), 149.1 (Cq); HRMS
(ESI) m/z calcd for C15H25O4 [MþH]þ 269.1753, found 269.1757.
4.1.16. (3R,6R)-6-(2,5-Dimethoxy-4-methylphenyl)-2-methyl-
4.1.20. (S)-2-[2-(2,5-Dimethoxy-4-methylphenyl)propylsulfonyl]
benzo[d]thiazole (30). To a stirred solution of sulfide 29 (163 mg,
0.45 mmol) in EtOH (2 mL) was added dropwise solution of am-
monium heptamolybdate tetrahydrate (56.0 mg, 0.045 mmol) in
30% aqueous H2O2 (0.44 mL, 4.54 mmol) at rt, and stirring was
continued for 4 h at the same temperature. The resulting mixture
was diluted with water and extracted with Et2O. The combined
extracts were washed with brine. The residue upon workup was
chromatographed on silica gel with hexane/AcOEt (8:2 v/v) as el-
heptane-2,3-diol (21). By following the same procedure described
for 19, diol 21 was prepared from alkene 3 with AD-mix-
b
: quanti-
tative yield, >99% de; colorless oil; ½a D26
ꢂ
ꢀ6.89 (c 1.2 in CHCl3); IR
(neat): 3422, 2956,1504,1466,1398,1208 cmꢀ1; 1H NMR (400 MHz,
CDCl3)
d
1.11 (3H, s),1.15 (3H, s),1.21 (3H, d, J¼6.8 Hz),1.22e1.37 (1H,
m), 1.37e1.49 (1H, m), 1.56e1.70 (1H, m), 1.70e1.83 (1H, m), 2.20
(3H, s), 2.39 (1H, br, D2O exchangeable), 2.67 (1H, br, D2O ex-
changeable), 3.15e3.20 (1H, m), 3.36 (1H, d, J¼9.6 Hz), 3.77 (3H, s),
3.78 (3H, s), 6.67 (1H, s), 6.68 (1H, s); 13C NMR (100 MHz, CDCl3)
uent to give sulfone 30 (164 mg, 93%) as a colorless oil; ½a D28
ꢀ0.55
ꢂ
d
16.0 (CH3), 20.8 (CH3), 23.0 (CH2), 26.3 (CH3), 29.5 (CH3), 31.4 (CH),
(c 0.62 in CHCl3); IR (neat): 2934, 1505, 1469, 1401, 1329, 1211, 1143,
34.6 (CH2), 56.1 (CH3), 56.4 (CH3), 73.0 (Cq), 78.6 (CH), 109.4 (CH),
114.3 (CH), 124.4 (Cq), 133.6 (Cq), 150.3 (Cq), 151.9 (Cq); HRMS (ESI)
m/z calcd for C17H29O4 [MþH]þ 297.2066, found 297.2075.
1045, 762 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
1.46 (3H, d, J¼6.8 Hz),
1.95 (3H, s), 3.59 (3H, s), 3.61e3.69 (2H, m), 3.73 (3H, s), 4.22e4.30
(1H, m), 6.24 (1H, s), 6.54 (1H, s), 7.55 (1H, ddd, J¼8.1, 7.0 and
1.2 Hz), 7.60 (1H, ddd, J¼8.1, 7.2 and 1.2 Hz), 7.92 (1H, dd, J¼7.0 and
1.2 Hz), 8.13 (1H, dd, J¼7.2 and 1.2 Hz); 13C NMR (100 MHz, CDCl3)
4.1.17. 2-[(2R,5R)-5,6-Dihydroxy-6-methylheptan-2-yl]-5-methyl-
cyclohexa-2,5-diene-1,4-dione (22). By following the same pro-
cedure described for 20, quinone 22 was prepared from 21: yield
d
15.9 (CH3), 19.9 (CH3), 31.9 (CH), 55.4 (CH3), 56.0 (CH3), 60.0 (CH2),
85%; yellow oil; ½a D25
þ10.8 (c 0.58 in CHCl3); IR (neat): 3421, 2970,
ꢂ
111.6 (CH), 113.4 (CH), 122.0 (CH), 125.1 (CH), 126.0 (Cq), 127.3 (CH),
127.5 (Cq), 127.6 (CH), 137.2 (Cq), 150.3 (Cq), 151.3 (Cq), 152.5 (Cq),
166.3 (Cq); HRMS (ESI) m/z calcd for C19H22NO4S2 [MþH]þ
392.0990, found 392.0973.
1654 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
1.13 (3H, d, J¼6.8 Hz), 1.15
(3H, s), 1.20 (3H, s), 1.34e1.49 (2H, m), 1.57e1.64 (2H, m), 1.96 (1H,
br s, D2O exchangeable), 2.04 (3H, d, J¼1.6 Hz), 2.46 (1H, br s, D2O
exchangeable), 2.96 (1H, sext, J¼6.8 Hz), 3.39 (1H, d, J¼10.0 Hz),
6.53 (1H, s), 6.60 (1H, d, J¼1.6 Hz); 13C NMR (100 MHz, CDCl3)
d 15.4
4.1.21. (R)-5-[(R,E)-3-(2,5-Dimethoxy-4-methylphenyl)but-1-enyl]-
2,2,4,4-tetramethyl-1,3-dioxolane (31). To a stirred solution of sul-
fone 30 (105 mg, 0.26 mmol) in THF (1.0 mL) was added dropwise
1.1 M solution of NaHMDS in THF (0.35 ml, 0.39 mmol) at ꢀ78 ꢁC.
After stirring was continued for 15 min, a solution of (S)-2,2,5,5-
tetramethyl-1,3-dioxolane-4-carbaldehyde S-24 (62 mg, 0.39 mmol)
in THF (0.5 mL) was added dropwise to this reaction mixture at the
same temperature, and stirring was continued for 1 h at rt. The
(CH3), 18.7 (CH3), 23.3 (CH3), 26.6 (CH3), 29.0 (CH2), 30.9 (CH), 32.9
(CH2), 73.0 (Cq), 77.9 (CH), 131.1 (CH), 133.8 (CH), 145.4 (Cq), 153.9
(Cq), 187.7 (Cq), 188.4 (Cq); HRMS (ESI) m/z calcd for C15H23O4
[MþH]þ 267.1596, found 267.1588.
4.1.18. 2-[(2R,5R)-5,6-Dihydroxy-6-methylheptan-2-yl]-5-methyl-
benzene-1,4-diol (7R,10R-1). By following the same procedure

6760
A. Miyawaki et al. / Tetrahedron 67 (2011) 6753e6761
reaction mixture was quenched with saturated aqueous NH4Cl and
extracted with Et2O. The combined extracts were washed with brine.
The residue upon workup was chromatographed on silica gel with
hexane/AcOEt (95:5 v/v) as eluent to give E- and Z-alkene 31
(52.3 mg, 60%, E/Z¼3:1) as a colorless oil; IR (neat): 2979, 1504, 1208,
þ0.9 (c 0.47 in acetone); IR (neat): 3367, 2972, 1703, 1418 cmꢀ1; 1H
NMR (500 MHz, CD3COCD3)
d 1.07 (3H, s), 1.09 (3H, s), 1.24 (3H, d,
J¼7.0 Hz), 2.08 (3H, s), 3.22 (1H, s, D2O exchangeable), 3.71 (1H, d,
J¼4.0 Hz, D2O exchangeable), 3.76e3.81 (1H, m), 3.80 (1H, dd, J¼7.0
and 2.0 Hz), 5.55 (1H, ddd, J¼15.5, 7.0, and 1.5 Hz), 5.85 (1H, ddd,
J¼15.5, 6.5 and 1.0 Hz), 6.57 (1H, s), 6.58 (1H, s), 7.33 (1H, s, D2O
exchangeable), 7.37 (1H, s, D2O exchangeable); 13C NMR (125 MHz,
1048 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 1.09 (2.25H, s), 1.14 (0.75H,
s), 1.22 (2.25H, s), 1.30 (0.75H, s), 1.33 (2.25H, d, J¼6.0 Hz), 1.35
(0.75H, d, J¼6.0 Hz), 1.36 (2.25H, s), 1.38 (0.75H, s), 1.46 (3H, s), 2.19
(0.75H, s), 2.20 (2.25H, s), 3.76 (2.25H, s), 3.77 (2.25H, s), 3.79 (0.75H,
s), 3.80 (0.75H, s), 3.92 (1H, dq, J¼6.0 and 2.0 Hz), 4.17 (0.75H, dd,
J¼8.0 and 0.8 Hz), 4.82 (0.25H, d, J¼8.8 Hz), 5.32 (0.25H, dd, J¼11.2
and 8.8 Hz), 5.50 (0.75H, ddd, J¼15.6, 8.0 and 2.0 Hz), 5.70 (0.25H, dd,
J¼11.2 Hz), 5.98 (0.75H, ddd, J¼15.6, 6.0 and 0.8 Hz), 6.64 (0.75H, s),
6.67 (0.25H, s), 6.68 (0.75H, s), 6.71 (0.25H, s); HRMS (ESI) m/z calcd
for C20H31O4 [MþH]þ 335.2222, found 335.2216.
CD3COCD3) d 15.8 (CH3), 20.4 (CH3), 24.7 (CH3), 26.3 (CH3), 35.4 (CH),
72.7 (Cq), 80.1 (CH), 114.6 (CH), 118.2 (CH), 122.7 (Cq), 128.9 (CH),
130.8 (Cq),137.4 (CH),147.7 (Cq),149.1 (Cq); HRMS (ESI) m/z calcd for
C15H23O4 [MþH]þ 267.1596, found 267.1591.
4.1.25. (S)-5-[(R,E)-3-(2,5-Dimethoxy-4-methylphenyl)but-1-enyl]-
2,2,4,4-tetramethyl-1,3-dioxolane (34). By following the same pro-
cedure described for 31, alkene 34 was prepared from 30 and R-24:
yield 61%, E/Z¼6:1; colorless oil. The E, Z isomer of 34 were partially
separated with HPLC column (Mightysil, 8% AcOEt/hexane, 10 mL/
4.1.22. 2-Methyl-5-[(R,E)-4-((R)-2,2,5,5-tetramethyl-1,3-dioxolan-4-
yl)but-3-en-2-yl]cyclohexa-2,5-diene-1,4-dione (32). To
a
stirred
min,
l
¼254 nm); E-alkene: ½a D25
ꢂ
þ29.8 (c 0.67 in CHCl3); IR (neat):
solution of alkene 31 (45.8 mg, 0.14 mmol) in CH3CN/H2O (4:1,
0.5 mL) was added CAN (150 mg, 0.27 mmol) at 0 ꢁC, and stirring
was continued for 30 min at the same temperature. The resulting
solution was diluted with water and extracted with Et2O. The
combined extracts were washed with brine. The residue upon
workup was chromatographed on silica gel with hexane/AcOEt (9:1
v/v) as eluent to give quinone 32 (43.0 mg, quant.) as a yellow oil.
The E, Z isomer of 32 were partially separated with HPLC column
2979, 1504, 1398, 1376, 1209, 1043, 989 cmꢀ1 1H NMR (400 MHz,
;
CDCl3)
d
1.13 (3H, s), 1.25 (3H, s), 1.32 (3H, d, J¼6.8 Hz), 1.36 (3H, s),
1.46 (3H, s), 2.20 (3H, s), 3.76 (3H, s), 3.78 (3H, s), 3.93 (1H, dquint,
J¼6.8 and 1.2 Hz), 4.19 (1H, d, J¼8.4 Hz), 5.48 (1H, ddd, J¼15.6, 8.4
and 1.2 Hz), 6.03 (1H, dd, J¼15.6 and 6.8 Hz), 6.59 (1H, s), 6.69 (1H, s);
13C NMR (100 MHz, CDCl3)
d 16.1 (CH3), 19.7 (CH3), 23.6 (CH3), 25.8
(CH3), 27.0 (CH3), 28.5 (CH3), 34.6 (CH), 56.0 (CH3), 56.2 (CH3), 80.9
(Cq), 85.0 (CH), 107.2 (Cq), 110.2 (CH), 114.1 (CH), 123.1 (CH), 124.9
(Cq), 131.3 (Cq), 140.2 (CH), 150.4 (Cq), 151.7 (Cq); HRMS (ESI) m/z
calcd for C20H31O4 [MþH]þ 335.2222, found 335.2232. Z-Alkene:
(Mightysil, 10% AcOEt/hexane, 10 mL/min,
l
¼254 nm); ½a 2D3
þ6.6 (c
ꢂ
0.91 in CHCl3); IR (neat): 2979,1656,1369 cmꢀ1; 1H NMR (400 MHz,
CDCl3)
d
1.08 (3H, s), 1.22 (3H, s), 1.26 (3H, d, J¼6.8 Hz), 1.36 (3H, s),
½
a 2D8
ꢂ
ꢀ93.0 (c 0.28 in CHCl3); IR (neat): 2979, 1504, 1466, 1397, 1369,
1.46 (3H, s), 2.04 (3H, d, J¼1.2 Hz), 3.68 (1H, quint, J¼6.8 Hz), 4.14
(1H, d, J¼7.6 Hz), 5.58 (1H, dd, J¼15.6 and 7.6 Hz), 5.80 (1H, dd,
J¼15.6 and 6.8 Hz), 6.54 (1H, s), 6.60 (1H, d, J¼1.2 Hz); 13C NMR
1208, 1048 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 0.99 (3H, s), 1.07 (3H,
s),1.32 (3H, dd, J¼6.8 and 1.2 Hz),1.41 (3H, s),1.46 (3H, s), 2.19 (3H, s),
3.77 (3H, s), 3.78 (3H, s), 4.22e4.26 (1H, m), 4.68 (1H, dd, J¼9.8 and
0.8 Hz), 5.38 (1H, ddd, J¼10.8, 9.8 and 1.2 Hz), 5.97 (1H, ddd, J¼10.8,
6.8 and 0.8 Hz), 6.66 (1H, s), 6.68 (1H, s); 13C NMR (100 MHz, CDCl3)
(100 MHz, CDCl3)
d 15.4 (CH3), 18.5 (CH3), 23.6 (CH3), 25.8 (CH3),
27.0 (CH3), 28.4 (CH3), 34.4 (CH), 80.9 (Cq), 84.3 (CH), 107.4 (Cq),
126.3 (CH), 131.5 (CH), 133.7 (CH), 135.7 (CH), 145.4 (Cq), 151.7 (Cq),
186.8 (Cq), 188.3 (Cq); HRMS (ESI) m/z calcd for C18H25O4 [MþH]þ
305.1753, found 305.1763.
d
16.1 (CH3), 22.4 (CH3), 23.5 (CH3), 25.5 (CH3), 27.2 (CH3), 28.6 (CH3),
31.3 (CH), 55.9 (CH3), 56.2 (CH3), 79.0 (Cq), 81.2 (CH),107.3 (Cq),110.3
(CH), 114.0 (CH), 123.3 (CH), 124.8 (Cq), 132.6 (Cq), 140.9 (CH), 149.9
(Cq), 151.8 (Cq); HRMS (ESI) m/z calcd for C20H31O4 [MþH]þ
335.2222, found 335.2233.
4.1.23. 2-[(2R,5R,E)-5,6-Dihydroxy-6-methylhept-3-en-2-yl]-5-
methylcyclohexa-2,5-diene-1,4-dione (33). To a stirred solution of
quinone 32 (9.8 mg, 0.03 mmol) in MeOH (0.2 mL) was added 10%
aqueous HCl (0.2 mL) at rt, and stirring was continued for 5 h at the
same temperature. The resulting solution was diluted with water
and extracted with AcOEt. The combined extracts were washed
with brine. The residue upon workup was chromatographed on
silica gel with hexane/AcOEt (1:1 v/v) as eluent to give diol 33
4.1.26. 2-Methyl-5-[(R,E)-4-((S)-2,2,5,5-tetramethyl-1,3-dioxolan-4-
yl)but-3-en-2-yl]cyclohexa-2,5-diene-1,4-dione (7R,10S-32). By fol-
lowing the same procedure described for 32, 7R,10S-32 was pre-
pared from 34: 92% yield; yellow oil; ½a D26
ꢂ
þ20.8 (c 0.82 in CHCl3);
IR (neat): 2979, 1656, 1369, 913 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
1.05 (3H, s), 1.25 (3H, s), 1.26 (3H, d, J¼6.8 Hz), 1.35 (3H, s), 1.44
(7.8 mg, 98%) as a yellow oil; ½a D26
ꢂ
þ23.9 (c 0.66 in CHCl3); IR (neat):
(3H, s), 2.04 (3H, d, J¼1.6 Hz), 3.68 (1H, dquint, J¼6.8 and 0.8 Hz),
4.15 (1H, d, J¼7.6 Hz), 5.52 (1H, ddd, J¼15.6, 7.6, and 0.8 Hz), 5.85
(1H, dd, J¼15.6 and 6.8 Hz), 6.51 (1H, s), 6.60 (1H, d, J¼1.6 Hz); 13C
3426, 2973, 2360, 1654 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
1.13 (3H,
s), 1.18 (3H, s), 1.25 (3H, d, J¼7.2 Hz), 1.96 (1H, br s, D2O exchange-
able), 2.04 (3H, d, J¼1.2 Hz), 2.14 (1H, br s, D2O exchangeable), 3.65
(1H, dq, J¼7.2 and 6.8 Hz), 3.78 (1H, d, J¼7.2 Hz), 5.61 (1H, dd,
J¼15.6 and 7.2 Hz), 5.74 (1H, dd, J¼15.6 and 6.8 Hz), 6.52 (1H, s),
NMR (100 MHz, CDCl3)
d 15.4 (CH3), 18.8 (CH3), 23.6 (CH3), 25.8
(CH3), 27.0 (CH3), 28.4 (CH3), 34.4 (CH), 80.9 (Cq), 84.2 (CH), 107.4
(Cq), 126.0 (CH), 131.7 (CH), 133.6 (CH), 135.9 (CH), 145.4 (Cq), 151.7
(Cq), 186.8 (Cq), 188.3 (Cq); HRMS (ESI) m/z calcd for C18H25O4
[MþH]þ 305.1753, found 305.1765.
6.59 (1H, d, J¼1.2 Hz); 13C NMR (100 MHz, CDCl3)
d 15.4 (CH3), 18.7
(CH3), 23.7 (CH3), 26.4 (CH3), 34.5 (CH), 72.8 (Cq), 79.2 (Cq), 129.8
(CH), 131.5 (CH), 133.7 (CH), 134.9 (CH), 145.4 (Cq), 151.8 (Cq), 186.9
(Cq), 188.3 (Cq); HRMS (ESI) m/z calcd for C15H21O4 [MþH]þ
265.1440, found 265.1431.
4.1.27. 2-[(2R,5S,E)-5,6-Dihydroxy-6-methylhept-3-en-2-yl]-5-
methylcyclohexa-2,5-diene-1,4-dione (7R,10S-33). By following the
same procedure described for 33, 7R,10S-33 was prepared from
4.1.24. 2-[(2R,5R,E)-5,6-Dihydroxy-6-methylhept-3-en-2-yl]-5-
methylbenzene-1,4-diol (7R,10R-2). To a stirred solution of diol 33
(3.9 mg, 0.01 mmol) in THF (0.2 mL) were added Na2S2O4 in H2O
(0.1 mL) at 0 ꢁC, and stirring was continued for 30 min at rt. The
resulting solution was diluted with water and extracted with AcOEt.
The combined extracts were washed with brine. The residue upon
workup was chromatographed on silica gel with hexane/AcOEt (3:7
7R,10S-32: yield 96%; yellow oil; ½a D25
ꢂ
þ1.4 (c 0.70 in CHCl3); IR
(neat): 3419, 2974,1653,1026 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
1.12
(3H, s),1.21 (3H, s),1.24 (3H, d, J¼6.8 Hz), 2.06 (3H, d, J¼1.6 Hz), 2.43
(1H, br s, D2O exchangeable), 2.44 (1H, br s, D2O exchangeable), 3.65
(1H, dquint, J¼6.8 and 1.2 Hz), 3.89 (1H, d, J¼6.8 Hz), 5.61 (1H, ddd,
J¼15.6, 6.8, and 1.2 Hz), 5.75 (1H, dd, J¼15.6 and 6.8 Hz), 6.52 (1H, s),
6.60 (1H, d, J¼1.6 Hz); 13C NMR (100 MHz, CDCl3)
d 15.4 (CH3), 18.8
(CH3), 23.8 (CH3), 26.5 (CH3), 34.5 (CH), 72.8 (Cq), 79.2 (Cq), 129.6
v/v) as eluent to give 7R,10R-2 (3.8 mg, 95%) as a colorless oil; ½a D27
ꢂ

A. Miyawaki et al. / Tetrahedron 67 (2011) 6753e6761
6761
(CH), 131.6 (CH), 133.7 (CH), 134.9 (CH), 145.5 (Cq), 151.8 (Cq), 187.0
References and notes
(Cq), 188.3 (Cq); HRMS (ESI) m/z calcd for C15H21O4 [MþH]þ
ꢀ
1. Macías, F. A.; Torres, A.; Galindo, J. L. G.; Varela, R. M.; Alvarez, J. A.; Molinillo,
J. M. G. Phytochemistry 2002, 61, 687e692.
265.1440, found 265.1440.
2. For a review, see: Vyvyan, J. R. Tetrahedron 2002, 58, 1631e1646.
3. (a) Macías, F. A.; Varela, R. M.; Torres, A.; Molinillo, J. M. G. Tetrahedron Lett.
1998, 39, 427e430; (b) Macías, F. A.; Galindo, J. L. G.; Valela, R. M.; Torres, A.;
Molinillo, J. M. G.; Fronczek, F. R. Org. Lett. 2006, 8, 4513e4516.
4. Macías, F. A.; Marín, D.; Chinchilla, D.; Molinillo, J. M. G. Tetrahedron Lett. 2002,
43, 6417e6420.
5. Sirat, H. M.; Hong, N. M.; Jauri, M. H. Tetrahedron Lett. 2007, 48, 457e460.
6. (a) Takabatake, K.; Nishi, I.; Shindo, M.; Shishido, K. J. Chem. Soc., Perkin Trans. 1
2000, 1807e1808; (b) Yoshimura, T.; Kishuku, H.; Kamei, T.; Takabatake, K.;
Shindo, M.; Shishido, K. ARKIVOC 2003, 8, 247e255.
7. For reviews, see: (a) Shishido, K.; Bando, T. J. Mol. Catal. B: Enzym. 1998, 5,
183e186; (b) Shishido, K. Chem. Ind. 2004, 55, 623e633; (c) Kamei, T.; Mor-
imoto, S.; Shishido, K. J. Synth. Org. Chem. Jpn. 2006, 64, 1021e1031.
8. (a) Kishuku, H.; Shindo, M.; Shishido, K. Chem. Commun. 2003, 350e351; (b)
Morimoto, S.; Shindo, M.; Shishido, K. Heterocycles 2005, 66, 69e73; (c)
Morimoto, S.; Shindo, M.; Yoshida, M.; Shishido, K. Tetrahedron Lett. 2006, 47,
7353e7356.
4.1.28. 2-[(2R,5S,E)-5,6-Dihydroxy-6-methylhept-3-en-2-yl]-5-
methylbenzene-1,4-diol (7R,10S-2). By following the same pro-
cedure described for 7R,10R-2, 7R,10S-2 was prepared from 7R,
10S-33: quantitative yield; colorless oil; ½a D27
ꢂ
ꢀ23.1 (c 0.66 in ace-
tone); IR (neat): 3373, 2973, 1703, 1193 cmꢀ1
;
1H NMR (500 MHz,
CD3COCD3)
d
1.08 (3H, s),1.11 (3H, s),1.24 (3H, d, J¼7.0 Hz), 2.08 (3H,
s), 3.21 (1H, s, D2O exchangeable), 3.72 (1H, d, J¼4.0 Hz, D2O ex-
changeable), 3.77e3.82 (1H, m), 3.79 (1H, dd, J¼7.5 and 7.5 Hz),
5.54 (1H, ddd, J¼15.5, 7.0, and 1.5 Hz), 5.87 (1H, ddd, J¼15.5, 6.0,
and 1.0 Hz), 6.57 (2H, s), 7.33 (1H, s, D2O exchangeable), 7.37 (1H, s,
D2O exchangeable); 13C NMR (125 MHz, CD3COCD3)
d 15.7 (CH3),
20.3 (CH3), 24.6 (CH3), 26.2 (CH3), 35.4 (CH), 72.6 (Cq), 80.0 (CH),
114.5 (CH), 118.1 (CH), 122.7 (Cq), 128.6 (CH), 130.6 (Cq), 137.4 (CH),
147.5 (Cq), 148.9 (Cq); HRMS (ESI) m/z calcd for C15H23O4 [MþH]þ
267.1596, found 267.1602.
9. Osaka, M.; Kanematsu, M.; Yoshida, M.; Shishido, K. Tetrahedron: Asymmetry
2010, 21, 2319e2320 and references are cited therein.
10. (a) Burke, T. R.; Liu, D. G.; Gao, Y. J. Org. Chem. 2000, 65, 6288e6292; (b) Gao, Y.;
Wei, C.; Burke, T. R. Org. Lett. 2001, 3, 1617e1620.
11. For a review, see: Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100,
3009e3066.
Acknowledgements
12. Yoshida, M.; Shoji, Y.; Shishido, K. Org. Lett. 2009, 11, 1441e1443.
13. Kise, N.; Mimura, R. Tetrahedron: Asymmetry 2007, 18, 988e993.
14. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94,
2483e3547.
We thank Dr. Takashi Ooi of the University of Tokushima for
NMR analyses. This work was supported financially by a Grant-in-
Aid for the Promotion of Basic and Applied Research for Innovations
in the Bio-oriented Industry (BRAIN).
15. The synthesis of (7R,10R)-1 was reported by Sirat et al.,5 however the optical
rotation was not mentioned in the literature.
16. Krief, A.; Froidbise, A. Tetrahedron 2004, 60, 7637e7658.
17. Xu, D.; Crispino, G. A.; Sharpless, K. B. J. Am. Chem. Soc. 1992, 114,
7570e7571.
18. Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113,
4092e4096.
19. Julia, M.; Paris, J. M. Tetrahedron Lett. 1973, 16, 4833e4836.
20. (a) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron Lett. 1991, 32,
1175e1178; (b) For a review, see: Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1
2002, 2563e2585.
Supplementary data
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2011.03.064.