Efficient transformation of 7,14-dihydroxy-ent-kaurenes to novel ent-abietanes having cis-fused α-methylene γ-lactones under Mitsunobu reaction conditions and their cytotoxicities

Article abstract of DOI:10.1016/j.tet.2014.02.082

Transformation of plant-origin 7,14-dihydroxy-ent-kaurenes to ent-abietanes having a cis-fused α-methylene γ-lactones was accomplished efficiently under the Mitsunobu reaction conditions. The yields of the desired products were apparently influenced by the steric hindrance at C-1. The cytotoxic activity on P388 murine leukemia cells of the ent-abietanes having cis-fused α-methylene γ-lactones produced were assayed.

Full text of DOI:10.1016/j.tet.2014.02.082

Tetrahedron 70 (2014) 3030e3041
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Efficient transformation of 7,14-dihydroxy-ent-kaurenes to novel
ent-abietanes having cis-fused
a-methylene g-lactones under
Mitsunobu reaction conditions and their cytotoxicities
,
b
b
b
c
Yutaka Aoyagi a , Kei Ozawa , Tatsuya Kobayashi , Tomoyo Hasuda , Ming-Yu Gui ,
*
Yong-Ri Jin c, Xu-Wen Li c, Haruhiko Fukaya b, Reiko Yano a, Yukio Hitotsuyanagi b,
Koichi Takeya b
,
*
a College of Pharmacy, Kinjo Gakuin University, 2-1723 Omori, Moriyama, Nagoya 463-8521, Japan
b School of Pharmacy, Tokyo University of Pharmacy & Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
c Department of Chemistry, Jilin University, No. 2 Xinmin Street, Changchun, Jilin 130021, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Transformation of plant-origin 7,14-dihydroxy-ent-kaurenes to ent-abietanes having a cis-fused
a-
Received 19 December 2013
Received in revised form 25 February 2014
Accepted 27 February 2014
Available online 6 March 2014
methylene
g-lactones was accomplished efficiently under the Mitsunobu reaction conditions. The yields
of the desired products were apparently influenced by the steric hindrance at C-1. The cytotoxic activity
on P388 murine leukemia cells of the ent-abietanes having cis-fused a-methylene g-lactones produced
were assayed.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
ent-Kaurene
Transformation
Cytotoxic
Diterpene
Mitsunobu reaction
1. Introduction
increase the cytotoxic activity. So, previously, we tried to prepare
7b-hydroxy-bearing ent-kaurenes of stronger cytotoxicity from
Only a limited number of ent-abietane diterpenoids have been
reported,1e14 including tetracyclic ent-abietanes jolkinolides AeF
from Euphorbia jolkini (Euphorbiaceae),7e9 helioscopinolides AeL
from Euphorbia helioscopia (Euphorbiaceae),10e13 and taibaihenryiin
protected 7 -hydroxy-bearing ent-kaurenes by the Mitsunobu re-
action. The results demonstrated, however that the reaction caused
skeletal modification to produce ent-abietane series, instead of
a
giving 7b-hydroxy-bearing ent-kaurene skeleton. By applying this
C (1), having a unique diterpene skeleton with a
d,ε-unsaturated cis-
findings, as reported in our previous communication,22 we trans-
formed 7,14-dihydroxy-ent-kaurene diterpenoids, i.e., excisanin A
(7), kamebanin (9), and kamebakaurin (10) obtained from Rabdosia
fused -methylene -lactone in the molecule, from Rabdosia henryi
a
g
(Labiatae) (Fig. 1).14 Of them, jolkinolide D (5) is known to inhibit
tumor invasion into the basement membrane tissue15,16 and to in-
duce apoptosis in tumor cells and jolkinolide B (3) is known to in-
duce neuroendocrine differentiation of human prostate LNCaP
cancer cell line.17 However, the synthetic methods reported for the
preparation of ent-abietanes are quite limited.18e20 On the other
hand, over four hundred ent-kaurene diterpenoids have been iso-
plants in moderate yield23 to ent-abietanes having a
d,ε-unsaturated
cis-fused
a-methylene g-lactone. The present paper describes
semisynthesis of pharmaceutically interesting ent-abietanes by first
protecting the hydroxyl groups of 7,14-dihydroxy-ent-kaurene
diterpenoids from Rabdosia, i.e., 7, rabdokunmin C (8), 9, and 10,
with different protective groups and then subjecting them to the
skeletal transformation under the Mitsunobu reaction. As shown in
Scheme 1, A may be derived from B under the Mitsunobu reaction
conditions: conversion of 7-hydroxyl group to an oxyphosphonium
ion intermediate, nucleophilic attack by the oxygen atom of
14-hydroxy group on the carbonyl carbon at C-15, and the elimi-
nation of triphenylphosphine oxide may occur in succession under
the Mitsunobu reaction conditions to afford the corresponding
lated from plants, of which those having an
substructure are attracting much attention as pharmaceutical lead
compounds.21 In those ent-kaurenes, 7
-hydroxy group seemed to
a,b-unsaturated ketone
b
* Corresponding authors. Tel.: þ81 52 798 0180; fax: þ81 52 798 0754 (Y.A.); tel.:
þ81 42 676 3007; fax: þ81 42 677 1436 (K.T.); e-mail addresses: yutaka@kinjo-u.ac.
jp (Y. Aoyagi), takeyak@toyaku.ac.jp (K. Takeya).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.02.082

Y. Aoyagi et al. / Tetrahedron 70 (2014) 3030e3041
3031
may be regarded as biomimetic: this view may be supported by the
fact that ent-abietane and ent-kaurene diterpenoids are often iso-
lated from the same plants.1,3 The cytotoxic activity of the ent-
abietanes thus obtained were also evaluated.
2. Results and discussion
2.1. Preparation of substrates for transformation under Mit-
sunobu reaction conditions
Substrates for the transformation were prepared from ent-
kaurenes 7, 8, 9, and 10 according to the procedures given in
Schemes 2e5, respectively. Each consisted of three steps, including
protection of 7- and 14-hydroxyls by acetalization, protection of the
other hydroxyls, and deprotection of 7-O,14-O-acetal. In the case of
excisanin A (7), after acetalization of 7,14-dihydroxy groups by the
reported manner,24,25 1- and 12-hydroxyls were protected by
acetylation,26 silylation,26 methylation, methoxymethylation, and
p-methoxyphenylmethylation. Then, deacetalization of resulting 7-
O,14-O-acetalized products 12e16, having different protecting
groups at 1-O and 12-O, were carried out in 1 N HCleTHFeMeOH or
I2 in MeOH to afford the corresponding 7,14-dihydroxy-ent-kaur-
enes 17e21, in moderate to good yields (Scheme 2).
Fig. 1. Structures of naturally occurring diterpenes having tetracyclic ent-abietane
skeletons (1e6).
ent-abietanes. In this case, usual intermolecular Mitsunobu reaction
does not take place, apparently because the steric hindrance around
C-7 makes the nucleophilic attack on C-7 by a carboxylate anion
difficult. The effect of selective protection of polyoxygenated ent-
kaurenoids (7, 8, 9, and 10) gave interesting results. In this paper, we
specifically discuss the effects of 1-, 12-, 18-substituents of ent-
kaurenes on this rearrangement reaction and demonstrated the
scope of this reaction. Since pyrophosphorylation of 7-hydoxyl
group is possible in plants, the present transformation of ent-
kaurenes to ent-abietanes under the Mitsunobu reaction conditions
Scheme 2. Preparation of protected 1,14-dihydroxy-ent-kaurenes (17e21) from ex-
cisanin A (7).
In the case of rabdokunmin C (8), its acetalization was accom-
plished by the use of acetone and PSA, because the conventional
combination of 2,2-dimethylpropane (DMP) and p-toluenesulfonic
acid (PSA) produced a complex mixture (Scheme 3). Acetylation,
methoxymethylation, and p-methoxyphenylmethylation of the
resulting acetalized product 22 was carried out in the usual manner
to give, after deacetalization, the corresponding protected 7,14-
dihydroxy-ent-kaurenes (26e28) in moderate to good yields
(Scheme 3). The protected kamebanin derivatives (33e35) were
prepared by practically the same procedure as that used in Scheme
2 for excisanin A (Scheme 4).
Scheme 1. Synthetic strategy of ent-abietanes from 1,14-dihydroxy-ent-kaurenes
(7e10).

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Y. Aoyagi et al. / Tetrahedron 70 (2014) 3030e3041
Under the other reaction conditions examined, 10 failed to
produce only 38, resulting in production of diacetonide 36 (entry 2
in Table 1) only or of a mixture of diacetonide 36 and mono-
acetonide 37 (entry 3 in Table 1). Acid-catalyzed regioselective
demonoacetalization of diacetonide 36 gave 38 in 85% yield. The
structures of 37 and 38 were determined by converting them to the
corresponding diacetates 41 and 39. In the HMBC spectral data of
41, the correlations were observed between the acetal carbon and
the hydrogens of C-20 methylene, and between the hydrogens of
7- and 14-methine and the carbon of carbonyl of acetyl groups to
show that 41 was a 1-O,20-O-acetonide. On the other hand, in those
of 39, the correlations were observed between the hydrogen of C-7
and the carbon of acetal, and the hydrogens of C-1 and C-20, and
the carbonyl carbons of acetyl groups, which implied that 39 was
the desired 7,14-acetonide. Further, the acetylation shifts at hy-
droxy group-bearing position were observed. Namely, the chemical
shifts of the methine and methylene protons bearing acetoxy
groups (
and 5.72 (14-H) in 41) appeared in the lower field than those of
methine and methylene protons not bearing acetoxy group (
(7-H) and 4.82 (14-H) in 40, and 3.61 (1-H) and 4.13 and
d 4.55 (1-H), d 4.51, and d 4.65 (20-H) in 40, and d 5.41 (7-H)
d
d
d
4.32
4.26
d
d
d
(20-H) in 41). The deacetalization of 39 gave the corresponding diol
40 in 92% (Scheme 5).
Scheme 3. Preparation of protected 1,14-dihydroxy-ent-kaurenes (26e28) from rab-
dokunmin C (8).
Scheme 4. Preparation of protected 1,14-dihydroxy-ent-kaurenes (33e35) from ka-
mebanin (9).
In the case of kamebakaurin (10), as shown in Table 1, acetali-
zation with a combination of acetone and catalytic amount of
sulfuric acid27 produced desired 38 only in a 20% yield (entry 1 in
Table 1).
Scheme 5. Preparation of protected 1,14-dihydroxy-ent-kaurenes (40) from kameba-
kaurin (10).
Table 1
2.2. Transformation of ent-kaurenes to ent-abietanes under
Acetalization of kamebakaurin (10) under several reaction conditions
Mitsunobu reaction conditions
Entries
Reaction conditions
Yields (%)a
36
37
38
The transformation of 17, 1-O,12-O-diacetylexcisanin A prepared
from 7, was studied under different reaction conditions (Table 2).
When the reaction was carried out at room temperature, p-nitro-
benzoic acid (PNB) and 3,5-dinitrobenzoic acid (3,5-DNB) gave
better yields than benzoic acid (BA) (entries 1e4 in Table 2). When
1
2
3
Me2CO/concd H2SO4/rt/3 h
DMP/p-TsOH/Me2CO/rt/0.5 h
Me2CO/p-TsOH/0 ꢀC/2 h
80
92
11
d
d
83
20
d
d
a
Isolated yields (%).

Y. Aoyagi et al. / Tetrahedron 70 (2014) 3030e3041
3033
Table 2
Transformation of 1-O,12-O-diacetylexcisanin A (17) to ent-abietane (42) under Mitsunobu reaction conditions
Entries
Equiva
Concn (mM)b
Acids (equiv)c
Reaction temperature
Reaction time (h)
Yields (%)d
1
2
3
4
5
6
7
8
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
1.1
1.1
1.0
2.2
2.2
2.2
4.5
2.2
23
23
23
23
23
12
5.8
1.0
5.8
5.8
23
PNB (2.4)
PNB (2.4)
3,5-DNB (2.4)
BA (2.4)
PNB (2.4)
PNB (2.4)
PNB (2.4)
PNB (2.4)
PNB (3.0)
PNB (3.0)
FA (2.0)
3,5-DNB(2.4)
PAA (2.4)
PNB (2.4)
PNB (2.4)
2,6-DTBP (2.4)
rt
rt
rt
rt
24
48
48
48
1
1
1
1
1
1
6
1
1
1
9
6
24
13
27
de
54
52
58
12
47
de
23
43
dh
46
dh
dh
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
9
10
11
12
13
14f
15g
16
21
5.8
5.8
5.8
5.8
a
Equivalent amount of diethyl azodicarboxylate (DEAD).
Concentration of excisanin A (7).
PNB: p-nitrobenzoic acid, 3,5-DNB: 3,5-dinitrobenzoic acid, BA: benzoic acid, FA: formic acid, PAA: p-anisic acid, 2,6-DTBP: 2,6-di-tert-butylphenol.
Isolated yields of desired product 42.
Inseparable mixture.
Benzene was used as solvent instead of THF.
DEAD on polystyrene (1.2 mmol/g) was employed instead of DEAD.
Starting material recovered.
b
c
d
e
f
g
h
the reaction was carried out under refluxing, the yield of the de-
sired 42 was generally higher than that obtained at room temper-
ature (entries 1, 2 vs 5 in Table 2). When formic acid (FA), p-anisic
acid (PAA) or 2,6-di-tert-butylphenol (2,6-DTBP) was used as
a proton source at refluxing temperature, apparently the reaction
proceeded less efficiently (entries 11, 13, and 16 in Table 2). Thus,
the best result was obtained under the following conditions
[diethyl azodicarboxylate (DEAD): 2.2 equiv; PPh3: 3.0 equiv; con-
centration of the substrate: 5.8 mM; proton source (equiv): PNB
(2.4); time and temperature: refluxing for 1 h (entry 7 in Table 2)].
The structural identification of 42 was made by the 1H and 13C NMR,
and 2D NMR spectral studies, and finally by X-ray crystallographic
analysis (Fig. 2).28 The transformation of the protected 7,14-
dihydroxy-ent-kaurenes (17e21, 26e28, 33e35, and 40) pro-
ceeded under the reaction conditions used in entry 7 in Table 2 and
the results are shown in Table 3. The electronic effect of the sub-
stituent at C-1 and C-12 did not seem to affect the results (entries 1
and 3 in Table 3), whereas the bulkiness of the substituent appar-
ently did. Namely, 18, 20, and 21 with bulky substituents at C-1 and
C-12 gave decreased yields (entries 2, 4, and 5 in Table 3). When
a bulky substituent was only at C-12, it did not seem to affect the
reaction (entries 7 and 8 in Table 3). Whereas when only one large
substituent was on C-1, it caused great decrease in the yield (entry
10 in Table 3). Consequently, the transformation of 7,14-dihydroxy-
ent-kaurenes to ent-abietanes is considered to be greatly influenced
by the steric hindrance at C-1.
Fig. 2. Ortep representation for 42.
(42e53) were tested for their cytotoxic activities on P388 murine
leukemia cells. The results are given in Table 4. All the semi-
synthetic ent-abietanes excepting for 43 and 46 showed moderate
to high cytotoxic activities of about the same levels as those of ent-
kaurenes (7e10). The low solubility of 43, a very hydrophobic an-
alogue, into the aqueous bioassay medium was seemed to be the
reason why 43 showed low cytotoxic activity. Of them, 47, having
2.3. In vitro evaluation of cytotoxic activities of ent-abietanes
Natural ent-kaurene diterpenes 7e10 and the synthesized ent-
abietanes having cis-fused a-methylene g-lactones in the molecule

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Y. Aoyagi et al. / Tetrahedron 70 (2014) 3030e3041
Table 3
Preparation of ent-abietanes (42e53) from protected 7,14-dihydroxy-ent-kaurenes (17e21, 26e28, 33e35, and 40)

Y. Aoyagi et al. / Tetrahedron 70 (2014) 3030e3041
3035
Table 4
4. Experimental section
4.1. General procedures
Cytotoxic activity of natural ent-kaurenes (7e10) and semisynthetic ent-abietanes
(42e53 and 56)
Compounds
IC50 (mg/mL)
Optical rotations were measured at 25 ꢀC. Melting points were
given uncorrected. NMR spectra were recorded in CDCl3 or pyri-
dine-d5, at frequencies of 400 MHz or 500 MHz for 1H, and at
Excisanin (7)
Rabdokunmin C (8)
Kamebanin (9)
Kamebakaurin A (10)
4.7
5.8
1.8
2.0
1.2
100 MHz or 125 MHz for 13C NMR. Chemical shifts (
d
) were given in
parts per million relative to the residual CDCl3 resonance at
7.26 ppm or the residual pyridine-d5 resonance at 7.19 ppm for 1
42
43
44
45
46
47
48
49
50
51
52
53
56
>100
3.6
3.6
17
H
NMR and to the resonance of CDCl3 at 77.0 ppm or of pyridine-d5 at
123.5 ppm for 13C NMR. IR spectra were recorded on FT-IR and
HRMS (ESI) on a spectrometer using an electrospray source in
positive mode. All procedure reagents were employed without
further purification. The ent-kaurene diterpenoids, excisanin A (7),
rabdokunmin C (8), kamebanin (9), and kamebakaurin (10) were
isolated as reported previously.23 Plant material. The leaves of
Rabdosia excisa were collected in Jingyu county, Jinlin province,
China, in September 2001. The botanical identification was made by
Prof. Hang Xie, Department of Biology, Northeast Normal Univer-
sity, China. A voucher specimen has been deposited in the herbar-
ium of Tokyo University of Pharmacy and Life Science (02JCP11).
0.81
4.6
5.5
1.4
5.3
1.6
5.4
5.4
acetoxy groups at C-12 and C-18, was the most potent. Activity
decreasing effect of bulky groups at C-1 and C-12 may be noted by
the comparison between the activities of 46 having two bulky
groups at C-1 and C-12 and those of 42, 44, and 45 having smaller
substituents at C-1 and C-12. Those having only one small sub-
stituent either at C-1 or C-12 are generally quite active (44, 47, and
52). To study the effect of the substituents at C-1 and C-12 on the
activities, compound 43 was treated with 40% hydrofluoric acid in
CH2Cl2eMeCN to give a diol 56 in quantitative yield (Scheme 6).
The results gave another evidence of the activity-decreasing effect
of bulky group at C-1 and C-12.
4.2. Acetalization of excisanin A (7) and kamebanin (9)
To a mixture of 1,14-dihydroxy-ent-kaurene 7 or 9 (2.96 mol),
2,2-DMP (21 mL, 17.8 g, 171 mmol), and dry Me2CO (200 mL), was
added p-TsOH (cat. amount). After stirring the mixture at room
temperature for 0.5 h, the solvent was evaporated in vacuo to give
an oily residue, which was purified by SiO2eMPLC
(CHCl3:Me2CO¼2:1) to give the corresponding monoacetonide.
Compound 11: quant.; the spectral and physical data were
identical to those reported.26
Compound 29: 89%; Colorless amorphous solid, mp 193e195 ꢀC;
[
a
]
25 ꢁ90.0 (c 0.40, CHCl3); 1H NMR (500 MHz, 300 K, CDCl3)
d 6.12
D
(1H, s), 5.33 (1H, s), 4.57 (1H, d, J 1.5), 4.14 (1H, dd, J 11.7, 6.5), 3.28
(1H, ddd, J 11.0, 4.7, 4.7), 3.02 (1H, br s), 2.94e2.89 (1H, m), 2.03 (1H,
dd, J 12.9, 12.9), 2.02e1.96 (2H, m), 1.78e1.73 (1H, m), 1.66 (1H, m),
1.63e1.44 (1H, m), 1.58 (3H, s), 1.40 (1H, ddd, J 13.6, 3.6, 3.6), 1.27
(1H, ddd, J 13.6, 13.6, 3.8), 1.22 (3H, s), 1.19 (1H, br s), 1.15 (3H, s),
0.88 (3H, s), 0.85 (3H, s), 0.77 (1H, dd, J 10.8, 3.3); 13C NMR
Scheme 6. Deprotection of compounds 43.
(125 MHz, 300 K, CDCl3)
d 206.7, 147.3, 116.2, 96.9, 80.5, 71.2, 70.9,
55.5, 53.6, 50.7, 44.4, 43.5, 39.2, 33.1, 32.7, 31.0, 30.7, 30.1, 27.4, 25.4,
21.2, 19.6, 13.1; IR (film) 3465 (OH), 1731 (C]O), 1651 (C]C); HRMS
(ESI): calcd for C23H34O4Na: 397.2355 (MþþNa). Found: 397.2310.
3. Conclusion
Semisynthesis of drug leads from natural products has been
a long and widely practiced strategy to generate compounds with
improved pharmaceutical properties.29 In this paper, we estab-
lished an efficient method for transformation of 7,14-dihydroxy-
ent-kaurenes to ent-abietanes under the Mitsunobu reaction con-
ditions, to enable easy preparation of ent-abietane analogues from
7,14-dihydroxy-ent-kaurenes, abundant in nature. The key reaction,
i.e., skeletal transformation of ent-kaurenes to ent-abietanes is new
and has not been described before, though the SN20 reactions of
glycals30,31 and the rearrangement of an isocaryolane sesqui-
terpenoid under the Mitsunobu reaction conditions are known.32
The yields of the reactions involved were generally moderate to
good, though the major transformation reaction of ent-kaurenes to
ent-abietanes was shown to be affected greatly by the substituent
at C-1. This report on the easy transformation found in the present
study may suggest that naturally occurring ent-abietanes are bio-
genetically derived from ent-kaurenes. The fact suggests that 1 may
have the ent-kaurenoid type absolute configuration. Those syn-
thesized ent-abietanes were shown to have about the same cyto-
toxic activities as the ent-kaurenes.
4.3. Acetalization of rabdokunmin C (8)
PSA (cat. amount) was added to a solution of rabdokunmin C (8)
(0.010 g, 0.029 mmol) in dry Me2CO (1.0 mL) at rt under an Ar at-
mosphere. The reaction mixture was stirred at rt for 3 h and then
the solvent was evaporated in vacuo to give an oily residue, which
was diluted with AcOEt (10 mL). The resulting solution was washed
with satd NaHCO3 (10 mLꢂ3), dried over MgSO4, filtered, and
evaporated in vacuo to give a brownish viscous oil, which was
purified by SiO2ePTLC (CHCl3:Me2CO¼4:1) to give acetonide 22 as
a colorless amorphous solid (0.012 g, 97%). Compound 22: 97%; the
spectral and physical data of 22 were identical to those reported.26
4.4. General procedure for acetalization of kamebakaurin
(10) under different reaction conditions
4.4.1. Method A (entry 1 in Table 1). A mixture of kamebakaurin
(10) (0.10 g, 0.285 mmol), concd H2SO4 (1 drop), and dry Me2CO
(12 mL) was stirred at rt under an Ar atmosphere for 3 h. The re-
action mixture was adjusted to pH 7.0e8.0 by adding satd NaHCO3.

3036
Y. Aoyagi et al. / Tetrahedron 70 (2014) 3030e3041
After diluting the mixture with CHCl3 (10 mL), the organic layer was
separated and the aqueous phase was extracted with CHCl3
(10 mLꢂ2). The combined organic layer was washed with H2O
(10 mLꢂ1), dried over MgSO4, filtered, and subjected to evaporation
in vacuo to give an oily residue, which was purified by SiO2eMPLC
(hexane:AcOEt¼2:1) to give acetonide 36 (0.098 g, 80%) as a color-
less amorphous solid and 38 (0.022 g, 20%) as a colorless amor-
phous solid.
3376 (OH), 1727 (C]O), 1650 (C]C) cmꢁ1; HRMS (ESI): calcd for
C
23H34O5Na: 413.2304 (MþþNa). Found: 413.2336.
4.5. General procedure for acetylation of 11, 22, 29, 37, and 38
A mixture of the alcohol 11, 22, 29, 37, or 38 (0.83 mmol), dry
pyridine (3 mL, 2.93 g, 37.1 mmol), and Ac2O (1.5 mL, 1.62 g,
15.9 mmol) was stirred at rt for 15 h. The mixture was poured into
ice-water (20 mL) and the pH was adjusted to pH 8.0 with NaHCO3.
The aqueous solution was extracted with CHCl3 (10 mLꢂ3) and the
organic phase was then washed with satd NaCl (10 mLꢂ3), dried
over MgSO4, and filtered, and the solvent was evaporated in vacuo
to give an oily residue, which was purified by SiO2eMPLC
(hexane:AcOEt¼3:1) to give the corresponding acetate.
4.4.2. Method B (entry 2 in Table 1). PSA (cat. amount) was added to
a solution of kamebakaurin (10) (0.50 g, 1.42 mmol) and DMP
(8.47 g, 81.3 mmol) in Me2CO (60 mL). The reaction mixture was
stirred at rt under an Ar atmosphere for 0.5 h. The reaction mixture
was evaporated in vacuo and to the remainings was added CHCl3
(40 mL). The organic layer was washed with satd NaHCO3
(20 mLꢂ2) and then with satd NaCl (20 mLꢂ2), dried over MgSO4,
filtered, and subjected to evaporation in vacuo to give an oily res-
idue, which was purified by SiO2eMPLC (hexane:AcOEt¼8:1) to
give acetonide 36 (0.56 g, 92%) as a colorless amorphous solid.
Compound 12: 72%; the spectral and physical data were iden-
tical to those of reported one by us.26
Compound 23: 96%; Colorless amorphous solid, mp 173e175 ꢀC;
[
a
]
25 ꢁ46 (c 0.26, CHCl3); 1H NMR (400 MHz, 300 K, CDCl3)
d 6.23
D
(1H, s), 5.53 (1H, s), 5.09 (1H, m), 4.81 (1H, d, J 1.1), 4.25 (1H, m),
3.84 (1H, d, J 11.2), 3.69 (1H, d, J 11.2), 3.17 (1H, d, J 3.5), 2.13 (3H, s),
2.08 (3H, s), 1.94 (1H, m), 1.92 (1H, m), 1.79 (1H, m), 1.70 (1H, m),
1.62e1.43 (3H, m, overlapped), 1.59 (3H, s), 1.36 (2H, m, over-
lapped),1.26e1.13 (2H, m, overlapped), 1.23 (3H, s), 1.15 (3H, s), 0.88
(3H, s), 0.71 (1H, ddd, J 12.3, 12.3, 4.0); 13C NMR (100 MHz, 300 K,
4.4.3. Method C (entry 3 in Table 1). PSA (cat. amount) was added to
a solution of kamebakaurin (10) (0.50 g, 1.42 mmol) in Me2CO
(140 mL). The reaction mixture was stirred at 0 ꢀC under an Ar
atmosphere for 2 h. After addition of satd NaHCO3 (40 mL) and H2O
(40 mL), the reaction mixture was extracted with AcOEt
(100 mLꢂ3) and the combined organic layer was washed with H2O
(100 mLꢂ1) and satd NaCl (100 mLꢂ1), dried over MgSO4, filtered,
and subjected to evaporation in vacuo to give an oily residue, which
was purified by SiO2eMPLC (hexane:AcOEt¼2:1) to give acetonide
36 (0.07 g, 11%) as a colorless amorphous solid and monoacetonide
37 (0.442 g, 83%) as a colorless amorphous solid.
CDCl3)
d 205.5, 171.0, 169.8, 143.2, 119.4, 97.4, 73.2, 71.9, 70.2, 66.6,
53.9, 52.2, 47.4, 44.8, 38.8, 37.6, 36.2, 35.4, 30.6, 27.1, 25.2, 23.0, 21.3,
20.9, 17.5, 17.3, 16.2; IR (film) 1739 (C]O), 1653 (C]C) cmꢁ1; HRMS
(ESI): calcd for C27H39O7: 475.2696 (MþþH). Found: 475.2673.
Compound 30: 95%; Colorless amorphous solid, mp
208e209 ꢀC; [
CDCl3)
a
]
25 ꢁ80.9 (c 0.23, CHCl3); 1H NMR (400 MHz, 300 K,
D
d
6.11 (1H, s), 5.33 (1H, s), 4.53 (1H, d, J 1.5), 4.47 (1H, dd, J
Compound 36: Colorless amorphous solid, mp 151e153 ꢀC;
8.0, 8.0), 4.13 (1H, dd, J 8.5, 8.5), 3.01 (1H, br s), 2.06e1.95 (4H, m),
1.98 (3H, s), 1.80e1.73 (1H, m), 1.65e1.55 (3H, m), 1.51e1.31 (3H, m),
1.57 (3H, s), 1.23 (3H, s), 1.22 (3H, s), 0.90 (3H, s), 0.87 (3H, s), 0.87
[
a
]
25 ꢁ97.9 (c 0.38, CHCl3); 1H NMR (500 MHz, 300 K, CDCl3)
d 6.11
D
(1H, s), 5.38 (1H, s), 4.58 (1H, s), 4.22 (1H, dd, J 11.3, 6.8), 4.10 (1H, d,
J 12.5), 3.95 (1H, d, J 12.5), 3.62 (1H, dd, J 3.5, 3.5), 3.06 (1H, br s),
2.51e2.46 (1H, m), 2.38e2.31 (1H, m), 2.01 (1H, ddd, J 13.3, 6.8, 1.4),
1.87e1.81 (1H, m), 1.73e1.60 (4H, m), 1.56 (1H, m), 1.488 (3H, s),
1.478 (1H, m),1.34 (3H, s),1.26 (1H, m),1.22 (3H, s), 0.99 (3H, s), 0.96
(1H, m); 13C NMR (100 MHz, 300 K, CDCl3)
d 205.8, 169.9, 147.0,
116.6, 97.0, 82.8, 71.1, 70.8, 55.2, 52.4, 51.0, 43.2, 43.1, 38.8, 33.0, 32.7,
30.9, 30.5, 27.1, 25.4, 25.2, 21.7, 21.4, 19.0, 13.8; IR (film) 1737 (C]O),
1651 (C]C) cmꢁ1; HRMS (ESI): calcd for C25H36O5Na: 439.2460
(MþþNa). Found: 439.2452.
(1H, d, J 11.7), 0.92 (3H, s); 13C NMR (125 MHz, 300 K, CDCl3)
d 206.9,
147.9, 116.7, 98.9, 97.7, 74.0, 71.7, 69.9, 60.4, 55.6, 51.3, 48.1, 42.9,
42.6, 35.3, 32.8, 31.7, 30.0, 29.0, 27.0, 26.4, 25.8, 25.6, 25.2, 24.1, 19.9;
IR (film) 1735 (C]O), 1651 (C]C) cmꢁ1; HRMS (ESI): calcd for
Compound 39: 83%; Colorless amorphous solid, mp 170e171 ꢀC;
[a
]
25 ꢁ86.3 (c 0.10, CHCl3); 1H NMR (500 MHz, 300 K, CDCl3)
d 6.14
D
(1H, s), 5.37 (1H, s), 4.60 (1H, d, J 13.1), 4.56 (1H, d, J 13.1), 4.55 (1H,
s), 4.54 (1H, dd, J 10.9, 4.5), 4.17 (1H, dd, J 12.4, 5.6), 3.01 (1H, br s),
2.26 (1H, ddd, J 12.6, 12.6, 12.6), 2.18 (3H, s), 2.05e2.00 (2H, m),
1.99e1.95 (1H, m), 1.96 (3H, s), 1.80 (1H, m), 1.78e1.72 (1H, m), 1.70
(1H, d, J 8.6), 1.68e1.61 (1H, m), 1.60e1.53 (1H, m), 1.56 (3H, s), 1.50
(1H, ddd, J 13.7, 3.6, 3.6), 1.41 (1H, ddd, J 13.7, 13.7, 4.3), 1.22 (3H, s),
1.02 (1H, dd, J 12.6, 1.3), 0.95 (3H, s), 0.91 (3H, s); 13C NMR
C
26H38O5Na: 453.2617 (MþþNa). Found: 453.2585.
Compound 37: Colorless amorphous solid, mp 227e229 ꢀC;
[a
]
D
25 ꢁ105.8 (c 0.31, CHCl3); 1H NMR (500 MHz, 300 K, CDCl3)
d 6.16
(1H, s), 5.42 (1H, s), 5.34 (1H, br s), 4.58 (1H, s), 4.34 (1H, d, J 12.1),
4.00 (1H, d, J 12.7), 3.97 (1H, d, J 12.7), 3.61 (1H, dd, J 6.3, 4.3), 3.11 (1H,
br s), 2.48 (1H, dd, J 14.4, 5.6), 2.31e2.25 (1H, m), 2.07 (1H, ddd, J 12.3,
12.3, 3.7),1.93 (1H, ddd, J 13.0, 4.1,1.8),1.71 (1H, ddd, J 12.6,12.6,12.6),
1.83e1.71 (4H, m), 1.51e1.43 (2H, m), 1.45 (3H, s), 1.35 (3H, s), 1.24
(1H, ddd, J 10.7, 4.6, 4.6), 0.98 (3H, s), 0.94 (3H, s); 13C NMR (125 MHz,
(125 MHz, 300 K, CDCl3) d 205.9, 170.4, 169.5, 147.1, 117.0, 97.2, 83.3,
71.1, 70.7, 63.2, 54.9, 51.4, 51.2, 44.2, 42.8, 39.0, 33.00, 32.95, 30.3,
30.0, 27.4, 26.0, 25.6, 21.6, 21.5, 21.3,19.4; IR (film) 1738 (C]O),1651
300 K, CDCl3)
d
207.7, 147.6, 118.0, 98.7, 75.2, 74.5, 62.0, 59.5, 54.5,
(C]C) cmꢁ1
; HRMS (ESI): calcd for C27H38O7Na: 497.2515
48.4, 46.3, 44.3, 35.1, 32.1, 31.6, 30.9, 28.4, 28.0, 27.5, 27.3, 26.2, 24.5,
(MþþNa). Found: 497.2501.
18.5; IR (film) 3334 (OH), 1726 (C]O), 1649 (C]C) cmꢁ1; HRMS
Compound 41: 83%; Colorless amorphous solid, mp 85e87 ꢀC;
(ESI): calcd for C23H34O5Na: 413.2304 (MþþNa). Found: 413.2295.
[a
]
ꢁ49 (c 0.20, CHCl3); 1H NMR (500 MHz, 300 K, CDCl3)
d 6.12
25
D
25
Compound 38: Colorless amorphous solid, mp 98e101 ꢀC; [
a]
(1H, s), 5.72 (1H, s), 5.42 (1H, s), 5.29 (1H, dd, J 10.3, 5.2), 4.26 (1H, d,
J 12.9), 4.13 (1H, d, J 12.9), 3.62 (1H, dd, J 5.3, 5.3), 3.06 (1H, br s),
2.56e2.46 (2H, m), 2.00 (3H, s), 1.94 (3H, s), 1.99e1.93 (1H, m),
1.92e1.85 (2H, m), 1.79e1.72 (2H, m), 1.71e1.68 (1H, m), 1.68e1.57
(2H, m), 1.46 (3H, s), 1.35 (3H, s), 1.26e1.21 (1H, m), 1.13 (1H, dd, J
12.6, 2.5), 0.96 (3H, s), 0.93 (3H, s); 13C NMR (125 MHz, 300 K,
D
ꢁ89.7 (c 0.29, CHCl3); 1H NMR (500 MHz, 300 K, CDCl3)
d 6.11 (1H,
s), 5.35 (1H, s), 4.64 (1H, d, J 1.4), 4.43 (1H, d, J 12.2), 4.23 (1H, dd, J
12.4, 6.4), 3.96 (1H, d, J 12.2), 3.56 (1H, dd, J 11.0, 4.5), 3.05 (1H, br s),
2.70 (1H, dd, J 14.5, 5.8), 2.58 (1H, dddd, J 12.8, 12.8, 5.8, 2.4), 1.99
(1H, ddd, J 13.2, 6.4, 2.1), 1.96e1.87 (1H, m), 1.88 (1H, ddd, J 12.9,
12.9, 12.9), 1.56 (3H, s), 1.67e1.51 (4H, m), 1.47 (1H, ddd, J 13.8, 3.6,
3.6), 1.28 (1H, ddd, J 13.8, 13.8, 3.6), 1.22 (3H, s), 0.89 (3H, s), 0.87
CDCl3)
d 204.0, 170.6, 169.5, 146.7, 117.8, 98.9, 76.5, 75.4, 72.9, 60.7,
59.3, 55.4, 48.5, 44.0, 43.8, 35.7, 32.4, 32.1, 31.8, 27.1, 26.74, 26.67,
(1H, m), 0.85 (3H, s); 13C NMR (125 MHz, 300 K, CDCl3)
d
207.6,
25.1, 24.0, 21.3, 21.2, 19.3; IR (film) 1734 (C]O), 1650 (C]C) cmꢁ1
;
147.8, 116.0, 97.0, 82.1, 71.4, 70.5, 62.2, 54.8, 53.8, 51.1, 47.0, 44.0,
38.7, 32.85, 32.79, 30.7, 30.3, 30.0, 27.5, 25.3, 21.8, 21.1; IR (film)
HRMS (ESI): calcd for C27H38O7Na: 497.2515 (MþþNa). Found:
497.2501.

Y. Aoyagi et al. / Tetrahedron 70 (2014) 3030e3041
3037
4.6. General procedure for silylation of 11 and 29
4.8. General procedure for methoxymethylation of 11 and 22
TBSOTf (0.35 mL, 0.404 g, 1.53 mmol) was added to a solution of
MOMCl (446
m
L, 331 mg, 2.56 mmol) was added to a solution of
the alcohol 11 or 29 (0.51 mmol), 2,6-lutidine (0.3 mL, 0.273 g,
diol 11 or 22 (0.12 mmol), iPr2NEt (103 mg, 96 mL, 1.28 mmol), and
CH2Cl2 (3.5 mL) at 0 ꢀC. The reaction mixture was stirred at 0 ꢀC for
1 h and then at rt for 3 h. After dilution with AcOEt (20 mL), the
reaction mixture was washed sequentially with 5% HCl (10 mLꢂ3),
satd NaHCO3 (10 mLꢂ3), and satd NaCl (10 mLꢂ3), dried over
MgSO4, filtered, and subjected to evaporation in vacuo to give an oily
residue, which was purified by SiO2eMPLC (hexane:AcOEt¼5:2) to
give the corresponding bis(methoxymethyl) ether.
2.55 mmol) in dry CH2Cl2 (10 mL). The mixture was stirred at 0 ꢀ
C
for 2 h. Satd NH4Cl (20 mL) was added to the mixture and the
aqueous solution was extracted with AcOEt (15 mLꢂ3). The com-
bined organic phase was dried over MgSO4, and filtered, and the
solvent was evaporated in vacuo to give an oily residue, which was
purified by SiO2eMPLC (hexane:AcOEt¼9:1) to give the corre-
sponding acetate.
Compound 13: 94%; the spectral and physical data were iden-
Compound 15: 91%; Colorless amorphous solid, mp 50e52 ꢀC;
tical to those of reported one by us.26
[
a
]
25 ꢁ32.2 (c 0.10, CHCl3); 1H NMR (400 MHz, 300 K, CDCl3)
d 6.13
D
Compound 31: 99%; Colorless amorphous solid, mp 67e69 ꢀC;
(1H, s), 5.40 (1H, s), 4.84 (1H, s), 4.73 (2H, s), 4.63 (1H, d, J 6.6), 4.52
(1H, d, J 6.6), 4.18 (1H, dd, J 12.0, 6.4), 3.87 (1H, br m), 3.42 (3H, s), 3.30
(3H, s), 3.15 (1H, d, J 3.1), 3.08 (1H, dd, J 11.2, 4.2), 2.85 (1H, d, J 15.1),
2.05e1.93 (2H, m, overlapped), 1.78e1.57 (5H, m, overlapped), 1.57
(3H, s),1.40 (1H, ddd, J 13.6, 3.5, 3.5),1.24 (3H,s),1.22 (3H, s), 0.88 (3H,
s), 0.86 (3H, s), 0.80 (1H, dd, J 11.2, 2.2); 13C NMR (100 MHz, 300 K,
25
[
d
a
]
ꢁ42.6 (c 0.15, CHCl3); 1H NMR (400 MHz, 300 K, CDCl3)
D
6.11 (1H, s), 5.32 (1H, s), 4.56 (1H, s), 4.11 (1H, dd, J 12.0, 5.6),
3.34 (1H, dd, J 10.5, 4.3), 3.00 (1H, br s), 2.82 (1H, dd, J 15.3, 4.0),
2.16e1.94 (3H, m, overlap), 1.75 (1H, m), 1.56 (3H, s), 1.52e1.49
(2H, m, overlapped), 1.47e1.38 (2H, m, overlapped), 1.26 (3H, s),
1.12 (3H, s), 0.91e0.89 (15H, m, overlapped), 0.77 (1H, dd, J 11.4,
2.4), 0.04 (3H, s), ꢁ0.03 (3H, s); 13C NMR (100 MHz, 300 K, CDCl3)
CDCl3) d 207.2,145.0,117.8, 97.2, 96.0, 94.6, 88.5, 76.5, 70.7, 66.9, 55.9,
55.6, 54.7, 53.3, 50.5, 48.7, 42.7, 39.3, 33.0, 32.9, 30.5, 27.1, 25.3, 25.1,
24.6, 21.4,12.3; IR (film) 1736 (C]O),1652 (C]C) cmꢁ1; HRMS (ESI):
calcd for C27H42O7Na: 501.2828 (MþþNa). Found: 501.2820.
Compound 24: 87%; Colorless amorphous solid, mp 134e136 ꢀC;
d
206.8, 147.5, 116.1, 96.9, 82.1, 71.3, 71.0, 55.7, 53.2, 50.8, 45.0,
43.4, 39.2, 33.0, 32.9, 31.0, 30.5, 29.6, 27.6, 26.0, 25.5, 21.4, 19.9,
18.1, 13.3, ꢁ2.9, ꢁ4.3; IR (film) 1728 (C]O), 1650 (C]C) cmꢁ1
;
HRMS (ESI): calcd for C29H48O4SiNa: 511.3322 (MþþNa). Found:
[a
]
25 ꢁ47.6 (c 0.15, CHCl3); 1H NMR (400 MHz, 300 K, CDCl3)
d 6.15
D
511.3322.
(1H, s), 5.40 (1H, s), 4.86 (1H, d, J 1.4), 4.75 (1H, d, J 6.9), 4.71 (1H, d, J
6.9), 4.58 (2H, s), 4.27 (1H, dd, J 11.6, 6.9), 3.93 (1H, m), 3.41 (3H, s),
3.35 (3H, s), 3.31 (1H, d, J 9.4), 3.18 (1H, d, 3.8), 2.99 (1H, d, J 9.5),
1.95e1.86 (2H, m, overlapped), 1.72e1.40 (7H, m, overlapped), 1.58
(3H, s), 1.33e1.25 (2H, m, overlapped), 1.22 (3H, s), 1.19 (3H, s), 0.82
4.7. General procedure for methylation of 11 and 29
A solution of the diol 11 or 29 (0.076 mmol) in dry THF (1.2 mL)
was added to a suspension of 60% NaH in mineral oil (18 mg,
0.46 mmol) in THF (1.2 mL) at rt under an Ar atmosphere. The re-
(3H, s), 0.72 (1H, m); 13C NMR (100 MHz, 300 K, CDCl3)
d 206.5,
144.3, 118.0, 97.3, 96.6, 95.1, 76.7, 76.4, 70.5, 66.7, 55.7, 55.2, 54.2,
53.0, 48.4, 44.4, 38.9, 37.6, 36.7, 35.6, 30.8, 27.2, 25.2, 23.6, 17.8, 17.6,
16.2; IR (film) 1736 (C]O), 1653 (C]C) cmꢁ1; HRMS (ESI): calcd for
action mixture was stirred at rt for 0.5 h and then MeI (95
mL,
216 mg, 1.52 mmol) was added to the solution. After stirring the
reaction mixture at rt overnight, ice-cooled water (10 mL) was
added to the reaction mixture carefully and the solution was
extracted with AcOEt (10 mLꢂ3). The combined organic layer was
washed with satd NaCl (10 mLꢂ3), dried over MgSO4, filtered, and
subjected to evaporation in vacuo to give a viscous oil, which was
purified by SiO2eMPLC (hexane:AcOEt¼4:1) to give the corre-
sponding dimethyl ether.
C
27H42O7Na: 501.2828 (MþþNa). Found: 501.2811.
4.9. Preparation of 21 from 11
60% NaH in mineral oil (46 mg, 1.14 mmol) was added to a so-
lution of 11 (30 mg, 0.076 mmol) in dry THF (1.2 mL) at rt under an
Ar atmosphere. After stirring at rt for 0.5 h, MPMBr (76 mg, 55 mL,
Compound 14: 97%; Colorless amorphous solid, mp 58e59 ꢀC;
0.38 mmol) was added to the solution. The reaction mixture was
further stirred at rt for 2 h and then refluxed for 1 h. After addition
of ice-cooled water (10 mL) carefully, the solution was extracted
with AcOEt (10 mLꢂ3). The combined organic layer was washed
with satd NaCl (10 mLꢂ3), dried over MgSO4, filtered, and subjected
to evaporation in vacuo to give a viscous oil, which was purified by
SiO2eMPLC (hexane:AcOEt¼3:1) to give a bis (methoxyphenyl)
ether 16 (17.4 mg), which was employed in the next reaction
without further purification. A mixture of crude 16 (10 mg), 1.0 M
HCl (0.5 mL), MeOH (0.5 mL), and THF (0.5 mL) was stirred at room
temperature for 15 h. After the reaction mixture was diluted with
H2O (10 mL), the aqueous solution was extracted with CHCl3
(10 mLꢂ3). The combined organic phase was then washed with
satd NaHCO3 (15 mLꢂ3) and satd NaCl (15 mLꢂ3), successively,
dried over MgSO4, and filtered, and the solvent was evaporated in
vacuo to give an oily residue, which was purified by SiO2eMPLC
(hexane:AcOEt¼3:2) to give 21 (7.4 mg, 29% from 11).
[
a]
25 ꢁ31.4 (c 0.10, CHCl3); 1H NMR (400 MHz, 300 K, CDCl3)
d 6.12
D
(1H, s), 5.36 (1H, s), 4.79 (1H, s), 4.17 (1H, dd, J 12.0, 6.5), 3.46 (1H,
dd, J 4.1, 4.1), 3.39 (3H, s), 3.21 (3H, s), 3.19 (1H, d, J 3.8), 2.95 (1H,
d, J 14.9), 2.64 (1H, dd, J 11.0, 4.4), 1.99 (1H, d, J 12.2), 1.95 (1H, m),
1.74 (1H, m), 1.56 (3H, s), 1.55 (1H, m), 1.52 (1H, m), 1.45 (1H, m),
1.42 (1H, m), 1.21 (3H, s), 1.21 (1H, overlapped), 1.17 (3H, s), 0.87
(3H, s), 0.84 (3H,s), 0.76 (1H, dd, J 11.6, 2.4); 13C NMR (100 MHz,
300 K, CDCl3)
d 207.5, 145.2, 117.3, 97.1, 90.9, 81.6, 70.7, 66.8, 56.2,
55.8, 54.8, 54.2, 50.6, 48.3, 42.6, 39.2, 33.1, 32.8, 30.7, 27.1, 25.3,
23.0, 22.5, 21.2, 12.2; IR (film) 1736 (C]O), 1652 (C]C) cmꢁ1
;
HRMS (ESI): calcd for C25H38O5Na: 441.2617 (MþþNa). Found:
441.2628.
Compound 32: 93%; Colorless amorphous solid, mp 145e147 ꢀC;
[
a]
25 ꢁ96.1 (c 0.10, CHCl3); 1H NMR (400 MHz, 300 K, CDCl3)
d 6.10
D
(1H, s), 5.31 (1H, s), 4.55 (1H, s), 4.10 (1H, dd, J 12.2, 6.0), 3.19 (3H, s),
3.00 (1H, br s), 2.76e2.70 (1H, m), 2.66 (1H, dd, J 10.8, 4.4),
2.04e1.90 (3H, m, overlapped), 1.78e1.71 (2H, m, overlapped), 1.55
(3H, s), 1.55e1.40 (4H, m, overlapped), 1.20 (3H, s), 1.20e1.17 (1H,
Compound 21: 29%; Colorless amorphous solid, mp 74e76 ꢀC;
[a
]
25 þ57.2 (c 0.10, CHCl3); 1H NMR (400 MHz, 300 K, CDCl3)
d 7.21
D
m), 1.12 (3H, s), 0.86 (3H, s), 0.84 (3H, s), 0.74 (1H, dd, J 11.6, 2.5); 13
C
(2H, d, J 8.6), 7.05 (2H, d, J 8.6), 6.81 (2H, d, J 8.7), 6.79 (2H, d, J 8.7),
6.12 (1H, s), 5.35 (1H, s), 5.18 (1H, s), 4.89 (1H, br s), 4.54 (1H, d, J
10.6), 4.322 (1H, d, J 11.7), 4.316 (1H, dd, J 12.2, 4.8), 4.16 (1H, d, J
10.6), 4.02 (1H, d, J 11.6), 3.79 (3H, s), 3.75 (3H, s), 3.49 (1H, dd, J 4.8,
4.8), 3.21e3.17 (2H, m, overlapped), 3.10 (1H, br s), 2.99 (1H, dd, J
10.6, 4.4), 1.94e1.76 (3H, m, overlapped), 1.69e1.59 (2H, m,
NMR (100 MHz, 300 K, CDCl3)
d 206.7, 147.5, 116.1, 96.9, 90.6, 71.3,
71.0, 56.0, 55.6, 53.6, 51.1, 44.0, 43.5, 39.1, 33.1, 32.8, 31.0, 30.7, 27.2,
25.4, 23.2, 21.3, 18.7, 13.6; IR (film) 1734 (C]O), 1652 (C]C) cmꢁ1
;
HRMS (ESI): calcd for C24H36O4Na: 411.2647 (MþþNa). Found:
411.2614.

3038
Y. Aoyagi et al. / Tetrahedron 70 (2014) 3030e3041
overlapped), 1.46 (1H, ddd, J 13.5, 3.4, 3.4), 1.42e1.34 (1H, m), 1.32
(3H, s), 1.20 (1H, ddd, J 13.9, 13.9, 3.8), 0.92e0.89 (1H, m), 0.91 (3H,
overlapped), 1.34 (3H, s), 1.00 (1H, dd, J 12.0, 1.4), 0.93 (3H, s), 0.90
(3H, s); 13C NMR (125 MHz, 300 K, CDCl3)
207.4, 170.2, 170.1, 144.1,
d
s), 0.87 (3H, s); 13C NMR (100 MHz, 300 K, CDCl3)
d
209.3, 159.0,
120.4, 82.6, 74.7, 74.0, 70.8, 61.0, 54.6, 52.0, 50.2, 42.6, 38.6, 33.1,
33.0, 27.5, 25.0, 24.3, 21.5, 21.4, 21.3, 13.3; IR (film) 3381 (OH), 1731
(C]O), 1650 (C]C) cmꢁ1; HRMS (ESI): calcd for C24H34O7Na:
457.2202 (MþþNa). Found: 457.2243.
158.8, 145.7, 130.7, 130.5, 129.4, 128.7, 118.6, 113.7, 113.5, 88.7, 79.4,
75.1, 71.1, 70.0, 69.5, 61.9, 57.0, 55.2, 52.1, 51.9, 43.8, 39.1, 33.18,
33.16, 27.7, 23.6, 23.2, 21.3, 13.5; IR (film) 3304 (OH), 1729 (C]O),
1613 (C]C) cmꢁ1; HRMS (ESI): calcd for C36H46O7Na: 613.3141
(MþþNa). Found: 613.3141.
Compound 19: 79%; Colorless amorphous solid, mp 81e83 ꢀC;
[
a
]
25 ꢁ40.6 (c 0.10, CHCl3); 1H NMR (400 MHz, 300 K, CDCl3)
d 6.14
D
(1H, s), 5.40 (1H, s), 5.11 (1H, s), 4.32 (1H, dd, J 12.2, 4.2), 3.41 (1H,
dd, J 4.2, 4.2), 3.37 (3H, s), 3.21 (3H, s), 2.98 (1H, d, J 16.6), 2.67 (1H,
dd, J 10.4, 4.2), 1.91 (1H, m), 1.81 (1H, ddd, J 12.2, 12.2, 12.2),
1.82e1.75 (1H,m, overlapped), 1.61 (1H, d, J 9.2), 1.58e1.38 (3H, m),
1.25 (3H,s), 1.25 (1H, m, overlapped), 1.17 (1H, ddd, J 13.6, 13.6, 3.5),
0.89 (1H, m, overlapped), 0.89 (3H, s), 0.86 (3H, s); 13C NMR
4.10. Preparation of 28 from 22
A solution of 22 (33 mg, 0.083 mmol) in dry THF (5 mL) was
added to a suspension of 60% NaH in mineral oil (66 mg, 1.66 mmol)
in THF (5 mL) at rt under an Ar atmosphere. After stirring at rt for
1 h, MPMBr (240
mL, 334 mg, 1.66 mmol) was added to the reaction
(100 MHz, 300 K, CDCl3) d 209.2, 145.7, 118.5, 90.7, 82.0, 75.0, 70.9,
mixture, which was then refluxed for 5 h. Ice-cooled water (20 mL)
was added carefully and the solution was extracted with AcOEt
(20 mLꢂ3). The combined organic layer was washed with satd NaCl
(20 mLꢂ3), dried over MgSO4, filtered, and subjected to evapora-
tion in vacuo to give a viscous oil, which was purified by
SiO2eMPLC (hexane:AcOEt¼15:1) to give a crude bis (methox-
yphenyl) ether 25 (40 mg). The crude product was used for the next
reaction without further purification. A mixture of crude 25
(40 mg), 1.0 M HCl (2 mL), MeOH (2 mL), and THF (2 mL) was stirred
at room temperature for 15 h. After the reaction mixture was di-
luted with H2O (15 mL), the aqueous solution was extracted with
CHCl3 (10 mLꢂ3) and the combined organic phase was then washed
with satd NaHCO3 (15 mLꢂ3) and satd NaCl (15 mLꢂ3), succes-
sively, dried over MgSO4, and filtered, and the solvent was evapo-
rated in vacuo to give an oily residue, which was purified by SiO2-
MPLC (hexane:AcOEt¼3:2) to give 28 (29 mg, 59% from 22).
61.9, 56.9, 56.0, 55.7, 52.1, 51.3, 43.5, 39.1, 33.1, 27.7, 23.1, 22.7, 21.3,
13.1; IR (film) 3308 (OH), 1730 (C]O), 1650 (C]C) cmꢁ1; HRMS
(ESI): calcd for C22H34O5Na: 401.2304 (MþþNa). Found: 401.2209.
Compound 26: 88%; Colorless amorphous solid, mp
235e237 ꢀC; [
CDCl3)
a
]
25 ꢁ46.3 (c 0.16, CHCl3); 1H NMR (400 MHz, 300 K,
D
d
6.26 (1H, s), 5.57 (1H, s), 5.39 (1H, br s), 5.11 (1H, s), 5.02
(1H, J 7.1, 3.7), 4.41 (1H, m), 3.91 (1H, d, J 11.1), 3.66 (1H, d, J 11.1),
3.19 (1H, d, J 3.1), 2.97 (1H, br s), 2.104 (3H, s), 2.095 (3H, s),1.87 (1H,
m), 1.78 (1H, ddd, J 12.0, 12.0, 12.0), 1.71 (2H, m, overlapped),
1.65e1.57 (2H, m, overlapped), 1.52e1.47 (1H, m), 1.42 (1H, dd, J 5.3,
5.3), 1.37e1.34 (2H, m, overlapped), 1.25 (1H, m), 1.21 (3H, s), 0.89
(3H, s), 0.69 (1H, m); 13C NMR (100 MHz, 300 K, CDCl3)
d 206.3,
170.3, 168.9, 142.9, 119.7, 73.7, 72.4, 71.2, 69.6, 59.8, 53.4, 49.2, 45.6,
37.7, 37.5, 35.4, 34.2, 26.9, 22.0, 20.4, 20.1, 16.6, 16.5, 15.2; IR (film)
3383 (OH), 1734 (C]O), 1646 (C]C) cmꢁ1; HRMS (ESI): calcd for
C
24H34O7Na: 457.2202 (MþþNa). Found: 457.2210.
Compound 28: 59% (two steps overall yield); Colorless amor-
Compound 33: 95%; Colorless amorphous solid, mp
25
phous solid, mp 169e171 ꢀC; [
a
]
ꢁ21.5 (c 0.12, CHCl3); 1H NMR
203e204 ꢀC; [
CDCl3)
a
]
25 ꢁ83.8 (c 0.27, CHCl3); 1H NMR (500 MHz, 300 K,
D
D
(400 MHz, 300 K, CDCl3)
d
7.27 (2H, d, J 8.7), 7.26 (2H, d, J 8.6), 6.90
d
6.13 (1H, s), 5.43 (1H, br s), 5.37 (1H, s), 4.87 (1H, s), 4.49
(2H, d, J 8.7), 6.88 (2H, d, J 8.6), 6.15 (1H, s), 5.38 (1H, s), 5.19 (1H, br
s), 5.16 (1H, s), 4.58 (1H, d, J 11.5), 4.50 (1H, d, J 11.5), 4.47 (1H, d, J
11.5), 4.38 (1H, m), 4.35 (1H, d, J 11.5), 3.81 (3H, s), 3.80 (3H, s), 3.66
(1H, dd, J 4.6, 4.6), 3.28 (1H, d, J 3.2), 3.20 (1H, d, J 9.1), 2.84 (1H, d, J
9.1), 2.72 (1H, br s), 1.78 (1H, d, J 16.5), 1.67e1.39 (9H, m, over-
lapped), 1.27e1.22 (1H, m, overlapped), 1.22 (3H, s), 0.76 (3H, s),
(1H, dd, J 9.2, 5.9), 4.29 (1H, br d, J 12.0), 3.14 (1H, br s), 3.06 (1H, s),
2.04 (1H, m), 2.01e1.96 (2H, m), 1.98 (3H, s), 1.81 (1H, ddd, J 12.6,
12.6, 12.6), 1.73e1.62 (3H, m), 1.55 (1H, d, J 8.3), 1.46e1.23 (3H, m),
1.28 (3H, s), 0.99 (1H, d, J 11.8), 0.92 (3H, s), 0.89 (3H, s); 13C NMR
(125 MHz, 300 K, CDCl3)
d 207.8, 170.0, 147.7, 117.8, 82.7, 75.1, 74.8,
62.0, 54.2, 52.2, 46.1, 44.0, 38.6, 33.1, 31.0, 27.4, 25.3, 21.7, 21.5, 19.2,
15.3; IR (film) 3314 (OH), 1732 (C]O), 1649 (C]C) cmꢁ1; HRMS
(ESI): calcd for C22H32O5Na: 399.2147 (MþþNa). Found: 399.2130.
Compound 35: 79%; Colorless amorphous solid, mp 78e80 ꢀC;
0.69 (1H, m); 13C NMR (100 MHz, 300 K, CDCl3)
d 208.4, 159.11,
159.06, 145.2, 130.8, 130.3, 129.3, 128.8, 118.7, 113.8, 113.7, 79.3, 78.3,
74.8, 72.6, 70.6, 70.3, 61.4, 55.4, 55.3, 55.2, 50.5, 45.9, 38.8, 38.4, 37.1,
35.5, 27.7, 23.0, 17.9, 17.8, 16.3; IR (film) 3255 (OH), 1724 (C]O),
1612 (C]C) cmꢁ1; HRMS (ESI): calcd for C36H46O7Na: 613.3141
(MþþNa). Found: 613.3159.
[
a
]
25 ꢁ84.0 (c 0.11, CHCl3); 1H NMR (400 MHz, 300 K, CDCl3)
d 6.12
D
(1H, s), 5.41 (br s), 5.36 (1H, s), 4.88 (1H, s), 4.27 (1H, dd, J 12.2, 3.8),
3.30 (1H, br s), 3.20 (3H, s), 3.05 (1H, br s), 2.71e2.66 (2H, m,
overlapped), 2.10e2.01 (1H, m), 1.92 (1H, ddd, J 13.0, 4.3, 2.2),
1.83e1.66 (3H, m, overlapped), 1.57e1.34 (4H, m, overlapped),
1.27e1.21 (1H, m, overlapped), 1.16 (3H, s), 0.89 (3H, s), 0.87 (3H, s),
0.89e0.87 (1H, m, overlapped); 13C NMR (100 MHz, 300 K, CDCl3)
4.11. General procedure for deacetalization
4.11.1. With 1 M HCl: preparation of diols 17, 19, 21, 26, 33, 35, 38,
and 40. A mixture of the corresponding acetonide (0.31 mmol),
1.0 M HCl (6 mL), MeOH (6 mL), and THF (6 mL) was stirred at room
temperature for 24 h. After dilution of the reaction mixture with H2O
(30 mL), the aqueous solution was extracted with CHCl3 (20 mLꢂ3).
The combined organic phase was then washed with satd NaHCO3
(10 mLꢂ3) and satd NaCl (10 mLꢂ3), successively, dried over MgSO4,
and filtered, and the solvent was evaporated in vacuo to give an oily
residue, which was purified by SiO2eMPLC (CHCl3: Me2CO¼20:1 or
hexane:AcOEt¼3:2) to give the corresponding diol.
d
208.8, 148.2,117.4, 90.5, 75.3, 74.9, 62.4, 55.9, 55.5, 52.2, 46.3, 44.9,
38.8, 33.11, 33.09, 31.3, 27.6, 23.3, 21.5, 18.9, 15.0; IR (film) 3291
(OH), 1727 (C]O), 1649 (C]C) cmꢁ1; HRMS (ESI): calcd for
C
21H32O4Na: 371.2301 (MþþNa). Found: 371.2334.
Compound 40: 92%; Colorless amorphous solid, mp 100e102 ꢀC;
[a
]
25 ꢁ87.8 (c 0.23, CHCl3); 1H NMR (500 MHz, 300 K, CDCl3)
d 6.16
D
(1H, s), 5.41 (1H, s), 5.31 (1H, br s), 4.82 (1H, d, J 0.5), 4.65 (1H, d, J
13.4), 4.55 (1H, dd, J 10.8, 4.7), 4.51 (1H, d, J 13.4), 4.32 (1H, dd, J
12.2, 4.3), 3.14 (1H, br s), 3.04 (1H, br s), 2.17 (3H, s), 2.10 (1H, ddd, J
12.5, 12.5, 12.5), 1.96 (3H, s), 2.14e1.94 (3H, m, overlapped), 1.81
(1H, m), 1.73e1.67 (3H, m, overlapped), 1.48 (2H, m), 1.40 (1H, m),
1.13 (1H, dd, J 12.4,1.9), 0.97 (3H, s), 0.91 (3H, s); 13C NMR (125 MHz,
Compound 17: 93%; Colorless amorphous solid, mp 251e253 ꢀC;
[
a
]
25 ꢁ28.4 (c 0.31, CHCl3); 1H NMR (400 MHz, 300 K, CDCl3)
d 6.21
D
(1H, s), 5.52 (1H, s), 5.36 (1H, s), 5.14 (1H, s), 4.91 (1H, dd, J 4.4, 4.4),
4.43 (1H, dd, J 10.2, 5.3), 4.39 (1H, m), 3.17 (1H, d, J 3.7), 2.90 (1H, br
s), 2.27e2.21 (1H, m), 2.14 (3H, s), 2.01e1.95 (1H, m, overlapped),
1.95 (3H, s), 1.85 (1H, ddd, J 12.3, 12.3, 12.3), 1.71e1.56 (4H, m,
overlapped), 1.42 (1H, ddd, J 13.7, 3.8, 3.8), 1.36e1.29 (1H, m,
300 K, CDCl3) d 207.9, 170.4, 169.6, 147.5, 118.3, 83.2, 75.6, 75.0, 63.2,
61.4, 53.9, 52.7, 45.8, 45.0, 38.9, 33.3, 33.1, 30.7, 28.2, 26.0, 21.6, 21.4,
19.3; IR (film) 3333 (OH), 1738 (C]O), 1650 (C]C) cmꢁ1; HRMS
(ESI): calcd for C24H34O7Na: 457.2202 (MþþNa). Found: 457.2163.

Y. Aoyagi et al. / Tetrahedron 70 (2014) 3030e3041
3039
4.11.2. With I2 in MeOH: preparation of diols 18, 20, 27, and 34. A
4.12. General procedure for transformation of ent-kaurenes
to ent-abietanes under Mitsunobu reaction conditions
mixture of the corresponding acetonide (0.104 mmol) and 1% I2 in
MeOH (5 mL) was heated at 50 ꢀC for 3 h in a sealed tube under an
Ar atmosphere. After addition of satd Na2S2O3 (5 mL), the organic
solvent was evaporated in vacuo. The remaining aqueous solution
was extracted with CHCl3 (10 mLꢂ3). The combined organic phase
was then washed with satd NaCl (10 mLꢂ3), dried over MgSO4, and
filtered, and the solvent was evaporated in vacuo to give an oily
residue, which was purified by SiO2-MPLC (hexane:AcOEt¼2:1 or
1:1) to give the corresponding diol.
DEAD (27 mL, 25.9 mg, 0.149 mmol) was added to a mixture of
PPh3 (54 mg, 0.206 mmol), protected 7,14-dihydroxy-ent-kaurene
(17e24) (0.069 mmol), and PNB (28 mg, 0.168 mmol) in dry THF
(12 mL) with stirring under an Ar atmosphere. The mixture was
refluxed for 1 h and then subjected to evaporation in vacuo to give
an oily residue, which was purified by SiO2eMPLC
(hexane:AcOEt¼2:1) and ODS-HPLC (MeCN:H2O¼55:45) to give
the corresponding ent-abietane.
Compound 18: 80%; Colorless amorphous solid, mp 265e267 ꢀC;
25
[a]
ꢁ4.2 (c 0.28, CHCl3); 1H NMR (500 MHz, 300 K, CDCl3)
d
6.12
Compound 42: 58%; Colorless needles (hexane:AcOEt), mp
D
(1H, s), 5.37 (1H, s), 5.18 (1H, br s), 5.11 (1H, s), 4.28 (1H, dd, J 12.0,
3.1), 3.93 (1H, dd, J 4.6, 4.6), 3.26 (1H, dd, J 10.8, 3.9), 3.07 (1H, br s),
2.98 (1H, d, J 3.2), 2.84 (1H, d, J 16.5), 1.89 (1H, br d), 1.80 (1H, dd, J
12.2, 12.2, 12.2), 1.71 (1H, m, overlapped), 1.65 (1H, d, J 9.6), 1.52 (1H,
ddd, J 16.0, 9.6, 5.5), 1.45 (1H, m), 1.37 (1H, ddd, J 13.6, 3.3, 3.3), 1.32
(3H, s), 1.21 (1H, dd, J 14.4, 14.4, 4.5), 0.93 (9H, s), 0.89 (3H, s), 0.87
(1H, m), 0.87 (3H, s), 0.84 (9H, s), 0.15 (3H, s), 0.07 (3H, s), 0.02 (3H, s),
207e209 ꢀC; [
CDCl3)
a
]
25 ꢁ11.4 (c 0.26, CHCl3); 1H NMR (500 MHz, 300 K,
D
d
6.18 (1H, d, J 0.9), 6.08 (1H, m), 5.65 (1H, s), 4.79 (1H, d, J
5.9), 4.65 (1H, dd, J 11.3, 4.2), 4.56 (1H, m), 2.93 (1H, dd, J 9.8, 6.0),
2.39 (1H, ddd, J 12.3, 3.5, 3.5), 2.30 (1H, br m), 2.16e2.10 (1H, m),
2.03 (3H, s), 2.02 (3H, s), 2.06e1.99 (1H, m, overlapped), 1.71e1.57
(2H, m, overlapped), 1.47e1.44 (2H, m, overlapped), 1.30 (1H, dd, J
11.8, 4.2), 1.18 (1H, ddd, J 12.0, 12.0, 12.0), 0.94 (6H, s), 0.90 (3H, s);
ꢁ0.05 (3H, s); 13C NMR (125 MHz, 300 K, CDCl3)
d
209.7, 145.6, 118.6,
13C NMR (125 MHz, 300 K, CDCl3)
d 170.4, 169.8, 169.1, 138.3, 133.7,
83.7, 75.5, 73.6, 70.9, 62.2, 56.7, 54.7, 52.2, 44.5, 39.6, 33.5, 33.3, 29.8,
28.9, 27.4, 26.3, 25.9, 21.7, 18.2, 18.0, 13.1, ꢁ3.4, ꢁ4.1, ꢁ4.3, ꢁ5.0; IR
(film) 3408 (OH), 1715 (C]O), 1648 (C]C) cmꢁ1; HRMS (ESI): calcd
for C32H59O5Si2: 579.3901 (MþþH). Found: 579.3888.
130.4,122.6, 83.5, 82.3, 73.6, 48.8, 45.31, 45.26, 39.4, 39.2, 32.9, 32.8,
31.5, 24.7, 23.3, 22.5, 21.4, 20.9, 9.4; IR (film) 1766,1738 (C]O), 1671
(C]C) cmꢁ1
; HRMS (ESI): calcd for C24H32O6Na: 439.2097
(MþþNa). Found: 439.2126.
Compound 20: 64%; Colorless amorphous solid, mp 71e74 ꢀC;
Compound 43: 31%; Colorless amorphous solid, mp 175e176 ꢀC;
[
a]
25 ꢁ41.9 (c 0.11, CHCl3); 1H NMR (400 MHz, 300 K, CDCl3)
d
6.15
[a
]
25 ꢁ50.5 (c 0.36, CHCl3); 1H NMR (500 MHz, 300 K, CDCl3)
d 6.22
D
D
(1H, s), 5.43 (1H, s), 5.15 (1H, s), 5.12 (1H, br s), 4.75 (1H, d, J 6.9),
4.72 (1H, d, J 6.9), 4.52 (1H, d, J 6.6), 4.52 (1H, d, J 6.6), 4.32 (1H, dd, J
12.2, 4.1), 3.81 (1H, dd, J 4.4, 4.4), 3.42(3H, s), 3.30 (3H, s), 3.18 (1H,
d, J 3.8), 3.10 (1H, dd, J 10.8, 4.4), 3.06 (1H, br s), 2.94 (1H,d, J 16.6),
1.92 (1H, ddd, J 12.9, 4.4, 2.0), 1.82 (1H, ddd, J 12.1, 12.1, 12.1),
1.83e1.76 (1H, m, overlapped), 1.71e1.61 (2H, m, overlapped),
1.58e1.49 (1H, m), 1.42 (1H, ddd, J 13.7, 3.6, 3.6), 1.33 (3H, s),
1.27e1.18 (1H, m), 0.90 (3H, s), 0.92e0.88 (1H, overlapped), 0.88
(1H, br s), 6.01 (1H, m), 5.66 (1H, br s), 4.76 (1H, d, J 6.1), 3.66 (1H,
ddd, J 11.6, 8.1, 3.6), 3.51 (1H, dd, J 11.0, 4.1), 2.81 (1H, dd, J 7.8, 6.3),
2.37 (1H, ddd, J 13.1, 4.9, 3.9), 2.20 (1H, m), 2.07 (1H, m), 2.02 (1H,
m), 1.62 (1H, m), 1.53 (1H, m), 1.43 (1H, d, J 3.0), 1.40 (1H, m), 1.28
(1H, dd, J 13.5, 3.5), 1.18 (1H, dd, J 11.4, 4.4), 0.90 (9H, s, overlapped),
0.90 (3H, s, overlapped), 0.874 (9H, s), 0.865 (3H, s), 0.860 (3H, s),
0.09 (3H, s), 0.08 (3H, s), 0.06 (3H, s), 0.02 (3H, s); 13C NMR
(125 MHz, 300 K, CDCl3) d 170.1, 139.1, 132.6, 131.8, 122.4, 83.7, 82.6,
(3H, s); 13C NMR (100 MHz, 300 K, CDCl3)
d
209.0, 145.4, 119.0, 95.8,
72.1, 49.4, 49.0, 45.8, 41.2, 39.7, 34.9, 33.0, 32.7, 29.2, 26.4, 25.9, 23.8,
22.5, 18.4, 18.1, 9.2, ꢁ2.9, ꢁ3.1, ꢁ3.4, ꢁ3.5; IR (film) 1763 (C]O),
1667 (C]C) cmꢁ1; HRMS (ESI): calcd for C32H57O4Si2: 561.3795
(MþþH). Found: 561.3760.
94.7, 88.2, 77.1, 75.1, 71.0, 61.8, 56.2, 56.0, 55.5, 52.2, 51.7, 43.6, 39.2,
33.3, 33.1, 27.5, 25.2, 24.7, 21.4, 13.1; IR (film) 3440 (OH), 1730 (C]
O), 1668 (C]C) cmꢁ1; HRMS (ESI): calcd for C24H38O7Na: 461.2515
(MþþNa). Found: 461.2484.
Compound 54: 37%; Colorless amorphous solid, mp 160e161 ꢀC;
Compound 27: 76%; Colorless amorphous solid, mp 58e60 ꢀC;
[a
]
25 þ125.0 (c 0.36, CHCl3); 1H NMR (500 MHz, 300 K, CDCl3)
d 6.15
D
[
a]
25 ꢁ32.2 (c 0.11, CHCl3); 1H NMR (400 MHz, 300 K, CDCl3)
d
6.14
(1H, s), 6.06 (1H, dd, J 10.0, 2.7), 5.84 (1H, dd, J 10.0, 2.8), 5.51 (1H, s),
4.53 (1H, s), 3.82 (1H, dd, J 7.6, 7.6), 3.43 (1H, dd, J 11.0, 4.3), 2.92
(1H, s), 2.36 (1H, ddd, J 14.7, 6.4, 6.4), 1.74 (1H, ddd, J 14.7, 12.8, 8.4),
1.68 (1H, br dd), 1.63 (1H, m), 1.52e1.60 (1H, m, overlapped),
1.52e1.60 (1H, m, overlapped), 1.40 (1H, ddd, J 13.6, 3.2, 3.2), 1.23
(1H, m), 0.96 (3H, s), 0.94 (3H, s), 0.92 (9H, s), 0.90 (3H, s), 0.87 (9H,
s), 0.15 (3H, s), 0.07 (3H, s), 0.05 (3H, s), 0.01 (3H, s); 13C NMR
D
(1H, s), 5.46 (1H, br s), 5.42 (1H, s), 5.11 (1H, s), 4.74 (1H, d, J 6.9),
4.67 (1H, d, J 6.9), 4.59 (1H, d, J 6.9), 4.57 (1H, d, J 6.9), 4.39 (1H, br
d), 3.82 (1H, dd, J 4.5, 4.5), 3.61 (1H, br s), 3.38 (3H, s), 3.34 (3H, s),
3.31 (1H, d, J 9.5), 3.17 (1H, d, J 3.8), 2.97 (1H, d, J 9.5), 1.86e1.83
(1H, m), 1.71 (1H, ddd, J 12.1, 12.1, 12.1), 1.69e1.43 (6H, m, over-
lapped), 1.39e1.34 (2H, m, overlapped), 1.28 (1H, m), 1.22 (3H, s),
0.80 (3H, s), 0.67 (1H, ddd, J 12.4, 12.4, 3.1); 13C NMR (100 MHz,
(125 MHz, 300 K, CDCl3) d 205.8, 145.8, 132.1, 123.1, 119.4, 81.7, 75.6,
300 K, CDCl3)
d
208.3, 145.0, 119.1, 96.6, 95.1, 77.2, 74.5, 70.6, 61.1,
70.7, 58.6, 55.2, 51.2, 50.6, 45.2, 39.0, 32.7, 32.5, 31.8, 29.4, 26.3, 25.8,
21.9, 18.3, 17.8, 9.8, ꢁ3.4, ꢁ3.1, ꢁ4.1, ꢁ4.7; IR (film) 1725 (C]O),
1646 (C]C) cmꢁ1; HRMS (ESI): calcd for C32H57O4Si2: 561.3795
(MþþH). Found: 561.3819.
55.6, 55.24, 55.16, 51.2, 46.0, 38.8, 38.4, 36.7, 35.4, 27.8, 23.7, 17.8,
17.7, 16.1, 14.1; IR (film) 3335 (OH), 1730 (C]O), 1649 (C]C) cmꢁ1
;
HRMS (ESI): calcd for C24H38O7Na: 461.2515 (MþþNa). Found:
461.2524.
Compound 55: 21%; Colorless amorphous solid, mp 217e219 ꢀC;
Compound 34: 72%; Colorless amorphous solid, mp 90e92 ꢀC;
[a
]
25 þ78.7 (c 0.26, CHCl3); 1H NMR (500 MHz, 300 K, CDCl3)
d 8.35
D
[
a]
25 ꢁ35.3 (c 0.12, CHCl3); 1H NMR (400 MHz, 300 K, CDCl3)
d
6.13
(2H, d, J 9.1), 8.32 (2H, d, J 9.1), 6.03 (1H, d, J 1.6), 6.02 (1H, s), 5.32
(1H, s), 4.83 (1H, s), 3.94 (1H, dd, J 4.2, 4.2), 3.43 (1H, dd, J 10.9, 3.9),
2.94 (1H, d, J 2.9), 2.84 (1H, d, J 16.6), 2.23 (1H, d, J 9.2), 1.88 (1H, m),
1.81 (1H, m), 1.74 (1H, m), 1.62 (1H, m), 1.57 (2H, m, overlapped),
1.50 (1H, m), 1.42 (1H, ddd, J 10.3, 3.2, 3.2), 1.36 (3H, s), 1.30 (1H, m),
0.95 (9H, s), 0.88 (9H, s), 0.86 (3H, s), 0.76 (3H, s), 0.15 (3H, s), 0.09
(3H, s), 0.08 (3H, s), 0.00 (3H, s); 13C NMR (125 MHz, 300 K, CDCl3)
D
(1H, s), 5.37 (1H, s), 5.30 (1H, br s), 4.89 (1H, s), 4.28 (1H, dd, J 12.2,
3.8), 3.37 (1H, dd, J 10.1, 4.6), 3.06 (1H, br s), 2.92 (1H, br s), 2.83 (1H,
dd, J 15.5, 5.4), 2.07e1.98 (1H, m), 1.95 (1H, ddd, J 12.6, 3.8, 1.7), 1.80
(1H, ddd, J 12.4,12.4,12.4),1.71e1.49 (4H, m, overlapped),1.42e1.20
(3H, m, overlapped), 1.16 (3H, s), 0.89 (3H, s), 0.86 (3H, s), 0.86e0.85
(1H, m, overlapped), 0.85 (9H, s), 0.04 (3H, s), ꢁ0.02 (3H, s); 13C
NMR (100 MHz, 300 K, CDCl3)
d
208.7, 148.2, 117.5, 81.9, 75.3, 75.1,
d 206.6, 164.3, 150.3, 144.9, 136.9, 130.8, 123.6, 118.6, 84.4, 74.3, 70.2,
62.6, 55.1, 52.1, 46.3, 45.9, 38.9, 33.2, 33.0, 31.1, 29.4, 27.8, 26.0, 21.6,
69.5, 58.3, 54.9, 53.8, 45.3, 44.3, 39.9, 33.2, 32.7, 29.7, 29.2, 26.3,
25.9, 24.3, 21.5, 18.2, 18.0, 12.8, ꢁ3.4, ꢁ4.0, ꢁ4.4, ꢁ4.9; IR (film)
3438(OH), 1725 (C]O), 1647 (C]C) cmꢁ1; HRMS (ESI): calcd for
19.9, 18.1, 14.9, ꢁ2.8, ꢁ4.3; IR (film) 3250 (OH), 1729 (C]O), 1650
(C]C) cmꢁ1
; HRMS (ESI): calcd for C26H44O4SiNa: 471.3009
(MþþNa). Found: 471.3012.
C
39H61NO8Si2Na: 750.3833 (MþþNa). Found: 730.3826.

3040
Y. Aoyagi et al. / Tetrahedron 70 (2014) 3030e3041
Compound 44: 57%; Colorless amorphous solid, mp 129e131 ꢀC;
Compound 49: 68%; Colorless amorphous solid, mp 134e135 ꢀC;
[
a
]
25 ꢁ58.6 (c 0.13, CHCl3); 1H NMR (500 MHz, 300 K, CDCl3)
d
6.19
[
a
]
25 ꢁ91.9 (c 0.12, CHCl3); 1H NMR (400 MHz, 300 K, CDCl3)
d 7.22
D
D
(1H, dd, J 1.3, 1.3), 6.03 (1H, m), 5.77 (1H, dd, J 0.9, 0.9), 4.76 (1H, d, J
5.8), 3.364 (3H, s), 3.60 (3H, s), 3.02 (1H, ddd, J 11.7, 9.9, 3.4),
2.93e2.89 (2H, m, overlapped), 2.71(1H, m), 2.14e1.97 (3H, m,
overlapped), 1.79 (1H, m), 1.52e1.42 (2H,m, overlapped), 1.26 (1H,
ddd, J 13.4, 13.4, 3.3), 1.19 (1H, dd, J 11.6, 4.4), 0.95 (1H, ddd, J 12.8,
12.8, 12.8), 0.92 (3H, s), 0.88 (3H,s), 0.85 (3H,s); 13C NMR (125 MHz,
(2H, d, J 8.7), 7.21 (2H, d, J 8.7), 6.89 (2H, d, J 8.6), 6.87 (2H, d, J 8.6),
6.20 (1H, br dd), 6.00 (1H, m), 5.78 (1H, br dd), 4.80 (1H, d, J 5.7),
4.56 (1H, d, J 11.0), 4.43 (1H, d, J 11.0), 4.35 (1H, d, J 6.1), 4.33 (1H, d, J
4.9), 3.81 (3H, s), 3.80 (3H, s), 3.26 (1H, m), 3.10 (1H, d, J 9.0), 2.91
(1H, d, J 9.0), 2.80 (1H, m), 2.09 (1H, ddd, J 12.1, 3.5, 3.5), 2.02e1.83
(3H, m, overlapped), 1.80 (1H, br d), 1.65 (1H, dd, J 11.2, 5.1),
1.59e1.46 (4H, m, overlapped), 1.36 (1H, m), 1.02 (1H, ddd, J 12.4,
12.4, 12.4), 0.87 (3H, s), 0.80 (3H, s); 13C NMR (100 MHz, 300 K,
300 K, CDCl3) d 170.2, 139.1, 133.3, 131.4, 122.5, 91.7, 83.2, 80.7, 57.2,
56.5, 49.0, 47.4, 47.2, 40.3, 39.8, 32.9, 32.8, 30.4, 23.5, 22.9, 22.3, 8.9;
IR (film) 1763 (C]O), 1667 (C]C) cmꢁ1; HRMS (ESI): calcd for
CDCl3) d 170.2, 159.4, 159.0, 139.0, 134.4, 130.8, 130.1, 130.0, 129.5,
C
22H32O4Na: 383.2198 (MþþNa). Found: 383.2206.
129.1, 122.8, 113.9, 113.7, 82.8, 79.1, 78.1, 72.8, 71.7, 55.294, 55.278,
47.4, 47.3, 42.9, 39.0, 37.0, 36.2, 34.8, 28.2, 24.1, 18.3, 18.0, 15.0; IR
(film) 1761 (C]O), 1612 (C]C) cmꢁ1; HRMS (ESI): calcd for
Compound 45: 36%; Colorless amorphous solid, mp 108e110 ꢀC;
[
a]
25 ꢁ88.8 (c 0.11, CHCl3); 1H NMR (400 MHz, 300 K, CDCl3)
d 6.20
D
(1H, dd, J 1.1, 1.1), 6.04 (1H, m), 5.76 (1H, dd, J 0.9, 0.9), 4.76 (1H, d, J
5.6), 4.74 (1H, d, J 6.4), 4.73 (1H, d, J 6.9), 4.65 (1H, d, J 6.4), 4.54 (1H,
d, J 6.9), 3.43 (1H, ddd, J 11.7, 9.7, 3.4), 3.35 (3H, s), 3.33 (1H, m,
overlapped), 3.31 (3H, s), 2.90 (1H, ddd, J 12.6, 3.2, 3.2), 2.78 (1H, m),
2.18 (1H, br m), 2.13e1.96 (2H, m, overlapped), 1.78 (1H, ddd, J 13.1,
7.4, 3.6),1.65e1.55 (1H, m, overlapped),1.47 (1H, ddd, J 13.7, 3.4, 3.4),
1.33 (1H, ddd, J 13.7,13.7, 3.4),1.21 (1H, dd, J 11.4, 4.6),1.08 (1H, ddd, J
12.5, 12.5, 12.5), 0.92 (3H, s), 0.90 (3H, s), 0.88 (3H, s); 13C NMR
C
36H44O6Na: 595.3036 (MþþNa). Found: 595.3036.
Compound 50: 54%; Colorless amorphous solid, mp 150e151 ꢀC;
[a
]
25 ꢁ93.7 (c 0.27, CHCl3); 1H NMR (500 MHz, 300 K, CDCl3)
d 6.11
D
(1H, d, J 1.2), 6.00 (1H, m), 5.53 (1H, d, J 1.1), 4.69e4.65 (2H, m,
overlapped), 2.90 (1H, m), 2.18e2.10 (2H, m, overlapped), 2.05e1.98
(1H, m, overlapped), 2.02 (3H, s), 1.81e1.75 (2H, m, overlapped),
1.67e1.58 (2H, m, overlapped), 1.46e1.22 (5H, m, overlapped), 0.94
(3H, s), 0.93 (3H, s), 0.89 (3H, s); 13C NMR (125 MHz, 300 K, CDCl3)
(100 MHz, 300 K, CDCl3)
d
170.0,139.3,133.3,131.3,122.4, 95.8, 95.6,
d 170.2 (overlapped), 141.7, 133.0, 131.7, 120.2, 83.1, 82.6, 49.0, 47.6,
88.3, 83.3, 76.7, 55.6, 55.5, 49.0, 47.5, 46.6, 40.1, 39.8, 33.0, 32.7, 32.5,
24.7, 23.4, 22.5, 9.2; IR (film) 1764 (C]O), 1640 (C]C) cmꢁ1; HRMS
(ESI): calcd for C24H36O6Na: 443.2410 (MþþNa). Found: 443.2400.
40.7, 39.6, 39.4, 32.747, 32.699, 29.2, 25.0, 24.4, 23.5, 22.2, 21.7, 9.2;
IR (film) 1762, 1737 (C]O), 1667 (C]C) cmꢁ1; HRMS (ESI): calcd for
C
22H30O4Na: 381.2042 (MþþNa). Found: 381.2026.
Compound 46: 32%; Colorless amorphous solid, mp
Compound 51: 19%; Colorless amorphous solid, mp 140e141 ꢀC;
25
170e172 ꢀC; [
CDCl3)
a
]
D
þ2.2 (c 0.13, CHCl3); 1H NMR (400 MHz, 300 K,
[a
]
25 ꢁ59.6 (c 0.13, CHCl3); 1H NMR (400 MHz, 300 K, CDCl3)
d 6.09
D
d
7.27 (2H, d, J 8.6), 6.97 (2H, d, J 8.6), 6.802 (2H, d, J 8.6),
(1H, d, J 0.8), 5.98 (1H, m), 5.52 (1H, d, J 0.8), 4.66 (1H, d, J 5.3), 3.47
(1H, dd, J 11.3, 3.8), 2.89 (1H, m), 2.44 (1H, m), 2.09e1.92 (3H, m,
overlapped), 1.82e1.76 (1H, m), 1.64 (1H, m), 1.48e1.23 (4H, m,
overlapped),1.18e1.09 (2H, m, overlapped), 0.90 (3H, s), 0.89 (9H, s),
0.87 (3H, s), 0.83 (3H, s), 0.07 (3H, s), 0.02 (3H, s); 13C NMR (100 MHz,
6.798 (2H, d, J 8.6), 6.17 (1H, s), 6.04 (1H, m), 5.73 (1H, s), 4.75 (1H,
d, J 5.8), 4.72 (1H, d, J 11.2), 4.30 (1H, d, J 11.2), 4.01 (1H, d, 10.4),
3.88 (1H, d, J 10.4), 3.78 (3H, s), 3.65 (3H, s), 3.25e3.16 (2H, m,
overlapped), 2.99 (1H, ddd, J 12.6, 3.2, 3.2), 2.74 (1H, dd, J 9.7, 5.7),
2.18e2.17 (1H, br m), 2.09e1.98 (2H, m, overlapped), 1.91e1.85
(1H, m), 1.64e1.50 (2H, m, overlapped), 1.55 (3H, s), 1.34e1.21 (2H,
m, overlapped), 1.02 (1H, ddd, J 12.1, 12.1, 12.1), 0.95 (3H, s), 0.90
300 K, CDCl3) d 170.6, 142.2, 132.7, 132.5, 119.7, 83.3, 83.2, 49.0, 48.1,
41.3, 41.0, 40.0, 33.1, 32.7, 29.6, 28.9, 26.0, 25.9, 23.5, 22.6, 18.1, 8.7,
ꢁ3.7, ꢁ4.3; IR (film) 1765 (C]O), 1615 (C]C) cmꢁ1; HRMS (ESI):
calcd for C26H42O3SiNa: 453.2903 (MþþNa). Found: 453.2900.
Compound 52: 52%; Colorless amorphous solid, mp 74e76 ꢀC;
(3H, s); 13C NMR (100 MHz, 300 K, CDCl3)
d 170.3, 159.2, 158.9,
139.2, 133.3, 131.5, 131.2, 130.2, 129.4, 128.5, 122.5, 113.8, 113.7,
89.9, 83.4, 78.9, 71.0, 70.3, 55.3, 55.0, 49.2, 47.2, 47.1, 40.5, 39.9,
33.0, 32.9, 31.6, 23.5, 23.3, 22.5, 9.3; IR (film) 1761 (C]O), 1614
[
a
]
25 ꢁ85.3 (c 0.10, CHCl3); 1H NMR (400 MHz, 300 K, CDCl3)
d 6.11
D
(1H, d, J 1.2), 5.98 (1H, m), 5.54 (1H, d, J 1.2), 4.69 (1H, d, J 5.5), 3.31
(3H, s), 2.94e2.88 (2H, m, overlapped), 2.26 (1H, m), 2.17e2.09 (1H,
m), 2.07e1.94 (2H, m, overlapped), 1.86e1.75 (2H, m, overlapped),
1.50e1.25 (5H, m, overlapped), 1.20 (1H, dd, J 11.6, 4.6), 0.91 (3H, s),
(C]C) cmꢁ1
; HRMS (ESI): calcd for C36H44O6Na: 595.3060
(MþþNa). Found: 595.3036.
Compound 47: 79%; Colorless amorphous solid, mp 156e157 ꢀC;
[
a
]
25 ꢁ70.9 (c 0.14, CHCl3); 1H NMR (400 MHz, 300 K, CDCl3)
d
6.19
0.87 (3H, s), 0.83 (3H, s); 13C NMR (100 MHz, 300 K, CDCl3)
d 170.6,
D
(1H, s), 6.07 (1H, m), 5.66 (1H, s), 4.85 (1H, d, J 5.7), 4.68 (1H, ddd, J
11.1, 11.1, 3.4), 3.80 (1H, dd, J 11.0), 3.67 (1H, dd, J 11.0), 2.94 (1H, m),
2.19 (1H, br d), 2.12e1.94 (2H, m, overlapped), 2.08 (3H, s), 2.06 (3H,
s), 1.79 (1H, br m), 1.58e1.51 (4H, m, overlapped), 1.41e1.38 (2H, m,
overlapped), 1.16 (1H, ddd, J 12.0, 12.0, 12.0), 1.15e1.04 (1H, m), 0.93
142.2, 132.7, 132.2, 119.9, 91.4, 83.1, 56.5, 49.2, 48.6, 41.1, 40.5, 39.8,
32.921, 32.865, 29.7, 24.8, 23.5, 23.0, 22.2, 8.8; IR (film) 1761 (C]O),
1667 (C]C) cmꢁ1; HRMS (ESI): calcd for C21H30O3Na: 353.2093
(MþþNa). Found: 353.2090.
Compound 53: 50%; Colorless amorphous solid, mp 166e167 ꢀC;
(3H, s), 0.82 (3H, s); 13C NMR (100 MHz, 300 K, CDCl3)
d
171.3, 170.0,
[
a
]
25 ꢁ89.1 (c 0.10, CHCl3); 1H NMR (500 MHz, 300 K, CDCl3)
d 6.12
D
169.3, 138.3, 134.4, 129.5, 122.7, 82.0, 72.8, 72.1, 46.9, 45.7, 42.8, 38.7,
36.2, 35.7, 34.8, 28.4, 23.9, 21.1, 20.9, 18.0, 17.7, 14.8; IR (film) 1766,
1738 (C]O), 1612 (C]C) cmꢁ1; HRMS (ESI): calcd for C24H32O6Na:
439.2097 (MþþNa). Found: 439.2082.
(1H, d, J 0.9), 6.06 (1H, dd, J 2.3, 2.3), 5.55 (1H, br s), 4.74 (1H, dd, J
11.4, 4.8), 4.70 (1H, d, J 5.4), 4.51 (1H, d, J 13.2), 4.48 (1H, d, J 13.2),
2.93 (1H, ddd, J 9.7, 6.2, 6.2), 2.31 (1H, m), 2.27e2.14 (2H, m, over-
lapped), 2.02 (3H, s), 2.01 (3H, s), 1.94e1.90 (1H, m), 1.86e1.83 (1H,
m),1.74e1.66 (2H, m),1.55e1.47 (3H, m, overlapped),1.38e1.32 (2H,
m, overlapped), 0.99 (3H, s), 0.94 (3H, s); 13C NMR (125 MHz, 300 K,
Compound 48: 64%; Colorless amorphous solid, mp 75e76 ꢀC;
[
a
]
25 ꢁ88.8 (c 0.05, CHCl3); 1H NMR (400 MHz, 300 K, CDCl3)
d 6.21
D
(1H, br dd), 6.05 (1H, m), 5.76 (1H, br dd), 4.79 (1H, d, J 5.6), 4.73
(1H, d, J 6.8), 4.58 (1H, d, 6.5), 4.57 (1H, d, 6.8), 4.57 (1H, d, J 6.5),
3.42 (1H, m), 3.33 (3H, s), 3.32 (3H, s), 3.25 (1H, d, J 9.7), 3.01 (1H, d,
J 9.7), 2.79 (1H, m), 2.14e1.91 (3H, m, overlapped), 1.82 (1H, br d),
1.66 (1H, dd, J 11.6, 4.5), 1.63e1.46 (4H, m, overlapped),1.35 (1H, m),
1.12e1.02 (2H, m, overlapped), 0.89 (3H, s), 0.82 (3H, s); 13C NMR
CDCl3) d 170.7, 170.1, 169.9, 141.6, 133.6, 131.7, 120.3, 82.6, 82.3, 63.0,
49.2, 46.5, 41.8, 40.9, 39.4, 33.0, 32.7, 29.4, 25.6, 25.1, 24.5, 21.8, 21.5,
21.2; IR (film) 1761, 1738 (C]O), 1667 (C]C); HRMS (ESI): calcd for
C
24H32O6Na: 439.2097 (MþþNa). Found: 439.2098.
4.13. Preparation of 56
(100 MHz, 300 K, CDCl3) d 170.0, 139.1, 134.2,130.0, 122.7, 96.6, 95.9,
82.7, 76.8, 76.4, 55.7, 55.3, 47.5, 47.2, 42.6, 39.0, 36.6, 36.0, 34.8, 29.2,
24.0, 18.3, 18.0, 14.9; IR (film) 1763 (C]O), 1615 (C]C) cmꢁ1; HRMS
(ESI): calcd for C24H36O6Na: 443.2410 (MþþNa). Found: 443.2404.
40% HF (0.34 mL) was added to a solution of TBS-protected 7,14-
dihydroxy-ent-abietane 43 (10 mg, 0.017 mmol) in MeCN (2.2 mL)
and CH2Cl2 (1.1 mL) at 0 ꢀC under an Ar atmosphere. The mixture

Y. Aoyagi et al. / Tetrahedron 70 (2014) 3030e3041
3041
was stirred at 0 ꢀC for 1 h and then at rt for 3 h. After dilution with
References and notes
AcOEt (10 mL), sat NaHCO3 (10 mL) was added. The organic layer
was separated and the aqueous phase was extracted with AcOEt
(10 mLꢂ2). The combined organic phase was dried over MgSO4,
filtered, and subjected to evaporation in vacuo to give an oily res-
idue, which was purified by ODS-HPLC (MeOH:H2O¼60:40) to give
56 in quantitative yield (6.1 mg).
1. Liu, X.; Zhan, R.; Wang, W.-G.; Du, X.; Li, X.-N.; Yang, J.-H.; Zhang, P.; Li, Y.; Pu, J.-
X.; Wu, J.-Z.; Sun, H.-D. Chem. Pharm. Bull. 2013, 61, 90.
2. He, S.-l.; Yan, R.-y.; Zuo, L.; Chen, R.-y. Planta Med. 2009, 75, 641.
3. Huang, S.-X.; Pu, J.-X.; Xiao, W.-L.; Li, L.-M.; Weng, Z.-Y.; Zhou, Y.; Han, Q.-B.;
Peng, S.-L.; Ding, L.-S.; Lou, L.-G.; Sun, H.-D. Phytochemistry (Elsevier) 2007, 68,
616.
4. Lee, C.; Hong, S. S.; Han, X. H.; Jin, Q.; Li, D.; Kim, T. O.; Kim, H.-K.; Lee, J.;
Kwon, S. H.; Kim, Y.-B.; Lee, M. K.; Hwang, B. Y. Arch. Pharmacol. Res. 2008,
31, 1381.
Compound 56: quant.; Colorless amorphous solid, mp
201e203 ꢀC; [
pyridine-d5)
a
]
25 ꢁ44.9 (c 0.19, CHCl3); 1H NMR (500 MHz, 300 K,
D
5. Valente, C.; Pedro, M.; Duarte, A.; Nascimento, M. S. J.; Abreu, P. M.; Ferreira, M.-
J. U. J. Nat. Prod. 2004, 67, 902.
d
6.89 (1H, d, J 4.8), 6.38 (1H, s), 6.08 (1H, br s), 6.00
(1H, d, J 5.1), 5.98 (1H, s), 4.92 (1H, br s, overlapped), 3.91 (1H, m),
3.67 (1H, ddd, J 12.4, 3.4, 3.4), 3.63 (1H, ddd, J 11.6, 4.5, 4.5), 2.47
(1H, m), 1.98e2.01 (2H, m, overlapped), 1.87 (1H, ddd, J 11.9, 11.9,
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m
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Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Re-
search from the Ministry of Education, Culture, Sports, Science and
Technology (To Y.A.).