The first enantioselective total synthesis of lantalucratin C and determination of its absolute configuration

Article abstract of DOI:10.1016/j.tet.2015.07.050

Described here is the first enantioselective total synthesis of lantalucratin C, which was isolated from the rainforest plant Lantana involucrata, and which possesses anti-tumor activity. The OH group on the aromatic ring was systematically introduced by

Full text of DOI:10.1016/j.tet.2015.07.050

Tetrahedron 71 (2015) 6672e6680
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The first enantioselective total synthesis of lantalucratin C and
determination of its absolute configuration
,
Tokutaro Ogata y, Manami Tanaka, Momoe Ishigaki, Maki Shimizu, Arisa Nishiuchi,
*
*
Kiyofumi Inamoto, Tetsutaro Kimachi
School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women’s University, 11-68 Koshien Kyu-bancho, Nishinomiya, 663-8179, Hyogo, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 May 2015
Received in revised form 15 July 2015
Accepted 16 July 2015
Available online 22 July 2015
Described here is the first enantioselective total synthesis of lantalucratin C, which was isolated from the
rainforest plant Lantana involucrata, and which possesses anti-tumor activity. The OH group on the ar-
omatic ring was systematically introduced by an appropriate management of the OH protecting groups.
The alkyl side chain connected to a chiral carbon center was incorporated by directed ortho-lithiation of
naphthalenes followed by asymmetric epoxidation. The furano-1,2-naphthoquinone skeleton was con-
structed from 3-hydroxyalkylnaphthalene by CAN-mediated oxidative cyclization. The absolute stereo-
chemistry at the C2 carbon was assigned the R-configuration by the KusumieMosher method.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Naphthoquinone
Natural product
Total synthesis
Asymmetric epoxidation
Oxidative cyclization
1. Introduction
Lantalucratin C (4), which was isolated from the rainforest plant
Lantana involucrata in 2004, displays cytotoxic activity against
previous work
various human tumor cell lines with IC50 values of 4.7e6.3 m
M.1
O
O
This compound has a central 1,2-naphthoquinone framework in-
volving a fused tricyclic core, a C7-hydroxy group, and an iso-
propenyl group linked to the C2 chiral carbon (Fig. 1). To the best of
our knowledge, there is no report on the chemical synthesis of 4
and the absolute configuration at the C2 chiral carbon has not been
identified yet. Synthesis of the related compound 1 was reported
previously, and the absolute configuration at the C2 position was
found to be R (Fig. 1).2a In case of lantalucratins, although there may
be the same R configurations as compound 1, this must be con-
firmed by synthesizing the respective natural products in order to
obtain accurate information. We thought that the method2a,2b for
the syntheses of natural products 1e3 have a large potential to
access for a series of enantiomerically pure natural products. The
major point to overcome in the syntheses of lantalucratins is de-
termining the most appropriate stage at which to introduce the OH
groups present on the aromatic ring C. Specific considerations
O
O
O
R
O
dehydroiso-β-lapachone (1)
(±)-lantalucratin A (2: R=OCH )
(±)-lantalucratin B (3: R=OH)
3
present work
O
B
functionalization
A
absolute config.
determination
C
HO
O
O
lantalucratin C (4)
future goals
O
O
O
HO
O
HO
O
O
OH NH
trypethelone (5)
cereoaldomine (6)
* Corresponding authors. E-mail addresses: t-ogata@hokuriku-u.ac.jp (T. Ogata),
tkimachi@mukogawa-u.ac.jp (T. Kimachi).
Fig. 1. Biologically active furo-ortho-naphthoquinone derivatives.
y
Present address: Faculty of Pharmaceutical Sciences, Hokuriku University,
Kanagawa-machi, Kanazawa, 920-1181, Ishikawa, Japan.
http://dx.doi.org/10.1016/j.tet.2015.07.050
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

T. Ogata et al. / Tetrahedron 71 (2015) 6672e6680
6673
include: whether the OH group should be introduced directly to
compound 1, whether a starting material including the OH group
should be chosen, and whether it is possible to introduce the OH
group during the synthesis.
The method described in this article would be applicable for the
synthesis of structurally more complicated compounds, such as
trypethelone (5) and cereoaldomine (6) (Fig. 1).3 Herein we de-
scribe the first asymmetric total synthesis of lantalucratin C.
isomers (11a,b) were easily separated by silica gel column chro-
matography. Naphthalenes including the O-TBS group at the 2- and
7-positions cannot be utilized for this reaction probably because
the retro-[1,3]-Brook type rearrangement will occur in the presence
of n-BuLi.2d
Since the alkenyl side chain was successfully incorporated, we
next prepared the substrate for asymmetric epoxidation of alkenes.
Previously, we demonstrated a similar reaction using 1,2,4-tri-
substituted-3-prenylnaphthalene as a substrate without the sub-
stituent on the B ring.2a Clearly in this case, the TBS group effi-
ciently acts as a bulky substituent and can induce enantioselectivity
up to 82% ee. Therefore, the TBS group was chosen for the OH
protection, and the results are shown in Scheme 3. After acidic
cleavage of the MOM group, compound 12 was treated with TBSCl
and imidazole giving no desired product 13. Compound 15 was
obtained as the sole product (condition A). The yield of 15 was
estimated as the sum of the following reactions due to its own la-
bility (see Experimental section for details). The reaction was per-
formed using N,N-dimethyl-4-aminopyridine (4-DMAP) as
a catalyst to accelerate the double OH protection. As expected,
2. Results and discussion
Retrosynthetic analysis of target compound 4 was carried out as
illustrated in Scheme 1. The fused 2,3-dihydrofuran ring of 4 can be
constructed by diammonium cerium(IV) nitrate (CAN)-mediated
oxidative cyclization from chiral secondary alcohol (I). The syn-
thetic intermediate I will be also useful to determine the absolute
C2 stereochemistry. The alkyl side chain containing chiral alcohol is
incorporated by directed ortho-lithiation4 of 1,2,4,7-tetra-
substituted naphthalene followed by asymmetric epoxidation of
internal alkene. Naphthoquinone (II) containing a C7 oxo-sub-
stituent group is selected as a synthon because of the difficulty in
introducing the oxo-substituent group without any directing
groups on the aromatic ring.
OCH
OCH
3
3
A) TBSCl, Imid
RO
OR
TBSO
OTBS
B) TBSCl, Imid
4-DMAP
OCH
OCH
+
3
13 (A: 0%)
13 (B: 65%)
3
11a: R=MOM
12: R=H
Br
HCl/i-PrOH
OCH3
+
O
12 (A: 39%: recovered)
C) SEMCl, i-Pr NEt
MS3A, DMF
2
12 (B: 0%)
O
O
+
OH
OR
OCH
3
OCH
3
RO
HO
O
OCH3
O
HO
OH
SEMO
16 (44%)
OSEM
HO
OTBS
I
II
4
OCH
+
OCH
+
14 (A: 0%)
14 (B: 0%)
3
3
Scheme 1. Retrosynthetic analysis of lantalucratin C (4).
OCH
OCH
3
3
The synthetic approach toward compound 4 was begun using
a known synthetic intermediate 85 (Scheme 2). In demethylation of
the methoxy group, the yield was dramatically increased from
36%5e78% by extending the reaction time and improving the work-
up procedure. This provided 8 on the scale of dozens grams (see
Experimental section for details).
HO
17 (38%) OCH
OSEM
TBSO
OH
15 (A: 33%) OCH
15 (B: 29%)
3
3
Scheme 3. Regioselective OH-protection.
O
O
1) t-BuOK, O
t-BuOH
MOMCl, i-Pr NEt
MS3A, DMF
1) Pd/C, H , THF
2
2
2
2) NaH, (CH ) SO
3 2 4
2) AlCl , 180 °C
3
10min
78%
rt, 1 h
74%
89%
CH O
3
HO
OH
MOMO
OMOM
O
O
O
7
8
9
OCH
OCH
OCH
OCH
OCH
3
3
3
n-BuLi, THF
-80 to -40 °C, 2 h
+
then
prenyl bromide
rt, 0.5 h
MOMO
OMOM
MOMO
OMOM
MOMO
OMOM
OCH
3
3
3
10
11a (66%)
11b (18%)
Scheme 2. Synthesis of prochiral alkene 11a.
Naphthalene derivative 10 was obtained by OH protection, and
subsequent reductive methylation of 9. The following regiose-
lective prenylation by directed ortho-lithiation alkylation was
supposed to be challenging because the four pendant directing
groups were on the naphthalene ring. Namely, compound 10 has
potentially three ‘reactive sites’ beside the methoxymethyl groups.
Fortunately, the regioselectivity could be moderately controlled by
precise regulation of the reaction temperature and time. The
compound 13 was obtained in moderate yield (condition B). Al-
though the amount of TBSCl that was used in condition B
(3.0 equiv) are different from condition A (1.5 equiv), the catalyst
ability was well demonstrated.
Compound 13 has relatively poor solubility in many polar or-
ganic solvents that resulting in reduced reactivity and enantiose-
lectivity in asymmetric epoxidation. Thus, we expanded the scope
onto other protecting groups having appropriate steric hindrance

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T. Ogata et al. / Tetrahedron 71 (2015) 6672e6680
with good affinity in common solvents. The solubility was even-
tually improved by utilizing the SEM group; interestingly, ether-
ification occurred quickly at the C2eOH position in contrast to the
reaction with TBSCl.
H2O mixed solvent system was applied instead of the original
CH3CN/H2O solvent system because of the low solubility of 20. By
exposure of 20 to aqueous CAN solution, 5-endo cyclization oc-
curred specifically at the C4 position, and the TBS ether 24 was
immediately deprotected by tetra-n-butylammonium fluoride to
afford the final compound 4 with retention of its configuration.
Finally, optically pure 4 was obtained by recrystallization from ethyl
acetate and hexane, and all measured analytical data, such as 1H
and 13C NMR (Table 2), IR, LR/MS, HR/MS, optical rotation value, and
melting point were identical with the compound isolated from the
natural plant.
Since two types of alkene (13 and 16) were obtained, their
asymmetric epoxidation was examined as summarized in Table 1.
The asymmetric Shi epoxidation is known as one of the most
powerful methods for creating the epoxy ring stereospecifically on
tri-substituted trans-alkenes.6 Generally, as the Shi epoxidation is
conducted in a polar solvent system including aqueous basic buffer,
the low solubility of alkenes in these solvents often becomes a se-
rious problem. In our cases, the reaction of 13 did not proceed at all
in a mixed solvent of acetonitrile and dimethoxymethane (DMM),
which is used as a standard Shi condition (entry 2). It is true that the
solubility was improved by introducing O-SEM group (16) instead
of O-TBS group (13), but conversion yield did not reached within an
acceptable level (entry 8). In order to obtain adequate solubility of
13, many solvents and conditions were achieved (entries 3e7). The
best result was observed when the reaction was performed using
a mixed solvent system (CH3CN:EtOH:toluene¼1:1:2), with H2O2
as an oxidant7 and a stoichiometric amount of Shi catalyst (entry 7).
The reaction on a larger scale with substoichiometric amount of Shi
catalyst led to a slight increase of the yield with a small decrease of
the ee (entry 5). Shi epoxidation reaction often suffers from a po-
tential catalyst deactivation sequence via Baeyer-Villiger oxidation,
and the side-reaction proceeds as extending the time. In entry 5,
the diketal catalyst was added portionwise into the reaction mix-
ture to suppress the effect of catalyst deactivation. The ee increased
when the reaction was performed under lower temperature though
the chemical yield drastically fell to 4% (entry 6). Thus, the
reaction condition of entry 5 in Table 1 was selected for the syn-
thesis of (ꢀ)-4.
CH3O
OH
TBSO
3
18
20
(S)- or (R)-MTPA
WSCD·HCl
4-DMAP
rt, 24 h
1) CAN, H2O, THF
0 °C, 0.5 h
R
O
(S)-MTPA-20
2) TBAF, THF
0 °C, 2 h
HO
O
or
3) recrystallization
40%
(R)-MTPA-20
O
4
Scheme 4. Total synthesis of (R)-(ꢀ)-4.
Table 2
1H and 13C NMR Data for synthetic (synth-4) and natural compound (nat-4)1c
Position
1H
13C
Synth-4
Nat-4
Synth-4
Nat-4
2
3
3a
4
5
5a
6
7
8
9
9a
9b
10
11
12
OH
5.57
2.81, 3.21
5.61
2.83, 3.24
90.3
31.7
90.2
31.6
Table 1
Stereoselective epoxidation of alkenesa
113.5
175.8
181.9
134.0
117.1
161.9
121.4
127.3
120.0
170.5
144.0
113.4
16.9
113.3
175.5
181.6
133.8
116.9
161.8
121.2
127.2
119.8
170.2
143.8
113.3
16.9
OCH3
OCH3
Oxone or H2O2
O
O
RO
OR
RO
OR
O
O
OCH3
OCH3
7.44
7.46
O
O
13: R=TBS
16: R=SEM
18: R=TBS
19: R=SEM
O
7.16
7.57
7.19
7.60
Entry
R
Method Solvent (ratio)
Temp (ꢁC) Yield (%) ee (%)
1
2
3
4
5
6
7
8
TBS
TBS
TBS
TBS
A
B
B
C
CH2Cl2
CH3CN:DMM (1:2)
1,4-dioxane
CH3CN:EtOH:toluene (1:1:2) 25
CH3CN:EtOH:toluene (1:1:2) 25
25
ꢀ10
25
93
0
25
60
72
4
d
d
69
78
74
84
79
64
5.00, 5.16
1.81
9.45
5.02, 5.17
1.82
TBS Cb
TBS
TBS Cc
SEM
C
CH3CN:EtOH:toluene (1:1:2)
CH3CN:EtOH:toluene (1:1:2) 25
CH3CN:DMM (1:2)
ꢀ10
0
60
21
B
a
Reaction conditions: A) 13 (0.28 mmol), m-CPBA (1.6 equiv), 0.5 h. B) 13
(0.28 mmol) or 16 (0.1 mmol), Oxone (1.5e2.5 equiv), Shi diketal catalyst
(0.3 equiv), K2CO3 (6e11 equiv), n-Bu4NHSO4 (0.04e0.09 equiv), buffer (0.05M
Na2B4O7/Na2EDTA aq; 1e3 mL), solvent (1.5e13.5 mL), 3 h. C) 13 (0.28 mmol), H2O2
In order to determine the absolute configuration at the C2 car-
bon, KusumieMosher ester analysis9 was applied to the chiral
secondary alcohol 20. Esterification of 20 was conducted with (S)-
(30 v/v%, 8.6 equiv), Shi diketal catalyst (0.6 equiv), buffer (2.0M K2CO3/4.0ꢂ10-4
M
or (R)-a-methoxy-a-trifluoromethylphenylacetic acid (MTPA) in
EDTA aq; 0.42 mL), solvent (1.6 mL), 6e72 h.
b
1.5 mmol of 13 was used, and Shi diketal catalyst was added in 13 portions for 3
the presence of water-soluble carbodiimide hydrochloride
(WSCD$HCl) and 4-DMAP to give the corresponding esters (S)-
MTPA-20 or (R)-MTPA-20, respectively (Scheme 4). The Dd values of
these compounds observed in the 1H NMR (400 MHz) spectrum are
illustrated in Fig. 2. The assignment of each proton was confirmed
by 2D NMR and comparison with the related fully assigned com-
pound. The chirality of 18 is considered to be maintained as the
same configuration until 4 is formed. Thus, the absolute configu-
ration at the C2 carbon is assigned as R. This result is consistent
with the configuration of similar analogs, such as compound 3, and
the absolute configuration of other lantalucratins can be assumed
to be R.
days.
c
1.0 equiv of Shi diketal catalyst was used.
In the last stage of the synthesis, we investigated the con-
struction of the dihydrofuran ring (A ring) and assignment of the
orientation of the C2 asymmetric center in 4 (Scheme 4). The acid-
catalyzed ring opening of epoxide 18 was carried out using para-
toluenesulfonic acid and 1,3-dimethyl-2-imidazolidinone (DMI) to
yield the secondary alcohol 20 in high yield.8 The intramolecular
cyclization of 20 was attempted by our previous method.2 The THF/

T. Ogata et al. / Tetrahedron 71 (2015) 6672e6680
6675
(24.8 g, 186.4 mmol) and sodium chloride (5.8 g, 100 mmol), and
which was heated to 180 ꢁC (oil bath temp) until these solids were
completely melted. A fine powder of 21 (4.08 g, 20 mmol) was
added to the flask, and heating was continued for 15 min at the
same temperature. After cooling to about 100 ꢁC, conc. HCl in
crushed ice (170 mL) was carefully added to the flask, and the
mixture was filtered through a CeliteÒ pad to remove the insoluble
black materials. The filtrate was extracted with ethyl acetate (ꢂ3),
and the rest of the target compound was extracted by Soxhlet ex-
traction using ethyl acetate from the insoluble materials. The
combined organic extracts were dried over Na2SO4, filtered and
concentrated to give a reddish brown solid which was then com-
pletely dried at 60 ꢁC under reduced pressure to give 3.16 g of 8 in
97% yield. In the larger scale reaction using 21 (8.16 g, 40 mmol),
85% (6.45 g) of 8 was obtained. On this scale, the reaction was
conducted in two batches and the following work-up process was
conducted at once on the combined reaction mixture. This com-
pound was used directly for the next reaction. 1H NMR (DMSO-d6)
H
2
δ
δ
Δδ = (S)-MTPA-20 - (R)-MTPA-
Fig. 2. Determination of the absolute configuration of 20.
3. Conclusion
In summary, we have achieved the first asymmetric total syn-
thesis of lantalucratin C in seven steps with 7% overall yield from
the known intermediate 10. The absolute stereochemistry at the C2
carbon was determined to be the R-configuration. Further appli-
cation for other natural products, such as 5 and 6, is in progress.
4. Experimental
4.1. General
d: 6.04 (1H, s, AreH), 7.14 (1H, dd, J¼2.6, 8.4, AreH), 7.31 (1H, d,
J¼2.6, AreH), 7.80 (1H, d, J¼8.4, AreH), 10.7 (1H, br s, OH).
4.4. 2,7-Bis(methoxymethoxy)-1,4-naphthoquinone (9)
All materials not explicitly mentioned were purchased from
Wako Pure Chemical Products Co., Kanto Chemical Co., TCI Labo-
ratory Chemical Co., Nacalai Tesque Co. and Aldrich Chemical Co.
MS3A was activated by heating to dryness under reduced pressure
for a few hours. 1H NMR spectra were recorded on a JEOL JNM-
ECP400 or JNM-ECP500 spectrometer using tetramethylsilane
(TMS) as an internal standard. Chemical shifts are recorded in parts
per million (ppm) relative to TMS. Coupling constants are shown in
Hertz. Abbreviations are as follows: s, singlet; d, doublet; t, triplet;
q, quartet; m, multiplet; br, broad. 13C NMR spectra were proton
decoupled and recorded on a JEOL JNM-ECP400 or JNM-ECP500
spectrometer using the carbon signal of the deuterated solvent as
the internal standard. IR spectra were recorded on a SHIMADZU IR
Affinity-1. Mass spectra (MS) were obtained on JEOL JMS-700 in-
struments. Melting points were measured on a Yanaco micro
melting point apparatus and are uncorrected. Flash chromatogra-
phy was performed with silica gel utilizing Wakosil C-200 obtained
from Wako Pure Chemical Products Co. or Silica gel 60 N (spherical,
neutral) obtained from Kanto Chemical Co. Analytical thin layer
chromatography was performed on Merck Silica Gel 60 F254 alu-
minum sheets and the visualization was done using a UV lamp.
An eggplant-shaped flame-dried flask was charged with 8
(4.94 g, 26 mmol) and activated MS3A (6.5 g) and then filled with
argon gas. Anhydrous N,N-dimethylformamide (26 mL) was added,
and the mixture was stirred at rt for 1 h to completely remove
moisture. After addition of N,N-diisopropylethylamine (10.1 g,
78 mmol) at 0 ꢁC, the reaction mixture was stirred at rt for 15 min
followed by addition of chloromethyl methyl ether (6.24 g,
78 mmol), and stirring was continued for 1 h. The reaction mixture
was poured onto ice water. The reaction mixture was diluted with
ethyl acetate and the solution was filtered through a CeliteÒ pad.
The filtrate was separated, and the aqueous layer was extracted
with ethyl acetate. The combined organic layer was successively
washed with water (ꢂ3), brine (ꢂ1) and then dried over Na2SO4.
Filtration and concentration under reduced pressure gave a dark
brown crude oil, which was purified by flash column chromatog-
raphy by eluting with toluene and acetone in a 10/1 ratio to give
5.33 g (74%) of 9 as a yellow solid of mp 106.6e108.2 ꢁC. IR (KBr):
1684,1645,1613,1597,1491,1348,1317,1304,1271,1236,1200,1165,
1090 cmꢀ1. 1H NMR (CDCl3)
d: 3.50 (3H, s, OCH3), 3.52 (3H, s, OCH3),
5.28 (2H, s, OCH2), 5.29 (2H, s, OCH2), 6.41 (1H, s, CH), 7.33 (1H, dd,
J¼2.6, 8.4, AreH), 7.71 (1H, d, J¼2.6, AreH), 8.02 (1H, d, J¼8.4,
4.2. 2-Hydroxy-7-methoxy-1,4-naphthoquinone (21)5
AreH). 13C NMR (CDCl3)
d: 56.4 (CH3), 57.1 (CH3), 94.2 (CH2), 94.8
(CH2), 113.0 (CH), 113.2 (CH), 121.8 (CH), 126.1 (C), 128.5 (CH), 132.9
(C), 157.7 (C), 161.3 (C), 180.1 (C), 184.3 (C). EIMS m/z: 278 (Mþ).
HRMS-EI m/z: (Mþ) calcd for C14H14O6, 278.0790; found, 278.0787.
According to the literature procedure,5 a solution of potassium
tert-butoxide (8.8 g, 78 mmol) in tert-butanol (88 mL) was vigorously
stirred for 1 h in the flask equipped with an O2 gas balloon. To the
reaction mixture was added 7-methoxy-1-tetralone (7; 1.76 g,
10 mmol) with stirring at rt for 1 day. The resulting red color sus-
pension was poured into ice water, and then acidified with 1M HCl to
form yellow solid which was collected by vacuum filtration. The fil-
trate was extracted with chloroform (ꢂ3), the organic layer and yel-
low solid was combined and basified with 1M NaOH to form a red
solution. The red aqueous layer was washed with chloroform (ꢂ2),
and the separated aqueous layer was acidified with conc. HCl to form
a yellow solid which was collected by vacuum filtration. After com-
plete dryingof the solid at80ꢁC under reduced pressure,1.63 g, 80% of
the title compound was obtained as a yellow solid. In a larger scale
reaction using 7 (52.8 g, 300 mmol), 63% (38.3 g) of 21 was obtained.
4.5. 1,4-Dimethoxy-2,7-bis(methoxymethoxy)naphthalene
(10)
To a 1 L three-neck round-bottom flask was added 10% wet-Pd/C
(10.4 g) followed by addition of 9 (10.4 g, 37.4 mmol) in THF
(374 mL). After the flask was fully purged with hydrogen gas, the
reaction mixture was vigorously stirred at rt overnight, equipped
with a hydrogen gas balloon. To the reaction mixture was added
sodium hydride at 60% dispersion in mineral oil (3.74 g, 93.5 mmol)
and dimethyl sulfate (17.7 g, 187 mmol) under hydrogen gas at-
mosphere. After stirring for 1 h, sodium hydride (93.5 mmol) and
dimethyl sulfate (187 mmol) were added to the reaction mixture,
and stirring was continued for about 1 h at the same temperature
until 9 was fully converted to 10 based on the results of TLC anal-
ysis. The catalyst was filtered off by using CeliteÒ and then thor-
oughly washed with ether. To the filtrate was added 10w/v% NaOH
(1.15 L) with vigorous stirring for 4 h to destroy any excess dimethyl
4.3. 2,7-Dihydroxy-1,4-naphthoquinone (8)5
According to the literature procedure,5 to a 300 mL of Erlen-
meyer flask was added finely grounded aluminum trichloride

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T. Ogata et al. / Tetrahedron 71 (2015) 6672e6680
sulfate. The reaction mixture was separated and the aqueous layer
was extracted with ether (ꢂ2). The combined ethereal layer was
successively washed with water (ꢂ1), brine (ꢂ1) and then dried
over Na2SO4. Filtration and concentration under reduced pressure
gave a pale yellow oil, which was then purified by flash column
chromatography by eluting with hexane and ethyl acetate in 5/1
ratio to give 10.2 g (89%) of 6 as a white solid of mp 49.4e52.2 ꢁC. IR
(KBr): 2928, 2830, 1630, 1620, 1603, 1593, 1466, 1445, 1362, 1352,
4.7. 7-(tert-Butyldimethylsilanyloxy)-1,4-dimethoxy-3-(3-
methylbuten-2-yl)naphthalen-2-ol (15)
Method A: i) To a solution of 11a (188 mg, 0.5 mmol) in anhy-
drous THF (2.5 mL) was added satd hydrogen chloride in 2-
propanol solution (2.5 mL) at 0 ꢁC. After stirring at rt for 45 min,
the reaction mixture was diluted with an ample amount of water
under ice bath cooling, and was extracted with ethyl acetate (ꢂ1).
The separated organic layer was successively washed with water
(ꢂ1) and brine (ꢂ1), dried over Na2SO4, filtered and concentrated in
vacuo to give 1,4-dimethoxy-3-(3-methylbuten-2-yl)naphthalene-
2,7-diol (12), which was immediately used for the next reaction
1260,1223,1196,1153,1076,1034 cmꢀ1. 1H NMR (CDCl3)
d: 3.52 (3H,
s, OCH3), 3.58 (3H, s, OCH3), 3.92 (3H, s, OCH3), 3.95 (3H, s, OCH3),
5.29 (2H, s, OCH2), 5.31 (2H, s, OCH2), 6.64 (1H, s, C3-H), 7.10 (1H,
dd, J¼2.6, 9.2, C6-H), 7.55 (1H, d, J¼2.6, C8-H), 8.08 (1H, d, J¼9.2, C5-
H). 13C NMR (CDCl3)
d
: 55.7 (CH3), 56.1 (CH3), 56.4 (CH3), 61.1 (CH3),
without any purification because of its lability. 1H NMR (CDCl3)
d:
94.5 (CH2), 96.4 (CH), 96.5 (CH2), 104.1 (CH), 116.4 (CH), 118.3 (C),
124.0 (CH), 130.6 (C), 137.4 (C), 146.6 (C), 152.5 (C), 156.3 (C). EIMS
m/z: 308 (Mþ). HRMS-EI m/z: (Mþ) calcd for C16H20O6, 308.1260;
found, 308.1262.
1.70 (3H, s, CH3),1.83 (3H, s, CH3), 3.53 (2H, d, J¼7.0, CH2), 3.876 (3H,
s, OCH3), 3.880 (3H, s, OCH3), 5.28e5.31 (1H, m, CH), 5.40 (1H, br s,
OH), 5.90 (1H, br s, OH), 6.93 (1H, dd, J¼2.6, 9.2, C6-H), 7.20 (1H, d,
J¼2.6, C8-H), 7.91 (1H, d, J¼9.2, C5-H).
ii) To a 30 mL flame-dried eggplant-shaped flask was added
imidazole (41 mg, 0.6 mmol) under an argon atmosphere, and the
crude diol (12) in anhydrous CH2Cl2 (1.5 mL) was added at 0 ꢁC.
After stirring for 10 min, tert-butyldimethylsilyl chloride (91 mg,
0.6 mmol) in anhydrous CH2Cl2 (1 mL) was added dropwise to the
reaction mixture, and stirring was continued at rt for 3 h. Additional
tert-butyldimethylsilyl chloride (23 mg, 0.15 mmol) in anhydrous
CH2Cl2 (0.5 mL) was added dropwise to the reaction mixture, and
stirring was continued for 1 day. The reaction was quenched with
satd NH4Cl aq under ice bath cooling followed by extraction with
CHCl3 (ꢂ3). The combined organic extracts were successively
washed with water (ꢂ1) and brine (ꢂ1), dried over Na2SO4, filtered
and concentrated. A pale yellow oil of crude 12 and 15 was used for
the next reaction without further purification because it was un-
stable. IR (neat): 3402, 2955, 2932, 2859, 1628, 1605, 1499, 1466,
1447, 1423, 1385, 1344, 1294, 1261, 1227, 1171, 1107, 1051 cmꢀ1. 1H
4.6. 1,4-Dimethoxy-3,6-bis(methoxymethoxy)-2-(3-
methylbuten-2-yl)naphthalene (11a)
To a solution of 10 (3.08 g, 10 mmol) in anhydrous THF (50 mL)
was added dropwise 1.6 M n-butyllithium in hexane solution
(7.52 mL, 12 mmol) at ꢀ80 ꢁC under an argon atmosphere. The
reaction mixture was warmed to ꢀ40 ꢁC, and then was stirred for
2 h. The reaction mixture was cooled back to ꢀ80 ꢁC, and prenyl
bromide (4.47 g, 30 mmol) was added dropwise. The reaction
mixture was warmed to rt and stirred for 30 min. The reaction was
quenched with satd NH4Cl aq under ice bath cooling, and the entire
mixture was extracted with ethyl acetate (ꢂ3). The organic layer
was successively washed with 1w/v% Na2S2O3 aq (ꢂ1), water (ꢂ1)
and brine (ꢂ1), dried over Na2SO4, filtered and concentrated in
vacuo. The residue was purified by flash column chromatography
by eluting with hexane and ethyl acetate in 20/1 ratio to obtain
2.41 g (66%) of 11a as a colorless oil. A mixture of a side product;
1,4-dimethoxy-2,7-bis(methoxymethoxy)-6-(3-methylbuten-2-yl)
naphthalene (11b) and the recovered starting material 10 was also
obtained as 1.03 g of a pale yellow oil. The structure of 11b was
surmised by comparison with related compounds such as 11a, 13,
etc., and the yield was calculated by 1H NMR analysis. 11a: IR (neat):
2990, 2934, 2828, 1626, 1597, 1501, 1456, 1445, 1395, 1373, 1341,
1263, 1223, 1196, 1153, 1101, 1082, 1051, 1009 cmꢀ1. 1H NMR (CDCl3)
NMR (CDCl3)
d
: 0.25 (6H, s, 2ꢂCH3), 1.02 (9H, s, t-Bu), 1.70 (3H, s,
CH3), 1.83 (3H, s, CH3), 3.53 (2H, d, J¼7.0, CH2), 3.88 (3H, s, OCH3),
3.91 (3H, s, OCH3), 5.28e5.32 (1H, m, CH), 5.85 (1H, s, OH), 6.91 (1H,
dd, J¼2.2, 8.8, C6-H), 7.22 (1H, d, J¼2.2, C8-H), 7.88 (1H, d, J¼8.8, C5-
H). 13C NMR (CDCl3)
d: ꢀ4.3 (CH3), 17.9 (CH3), 23.7 (CH2), 25.7 (CH3),
25.8 (CH3), 61.3 (CH3), 62.3 (CH3), 108.0 (CH), 119.1 (C), 119.3 (CH),
119.5 (C), 122.7(CH), 124.3 (CH), 128.1 (C), 132.0 (C), 135.5 (C), 145.4
(C), 150.9 (C), 154.0 (C). FABMS m/z: 402 (Mþ). HRMS-FAB m/z: (Mþ)
calcd for C23H34O4Si, 402.2226; found, 402.2220.
d
: 1.69 (3H, d, J¼1.1, CH3), 1.82 (3H, s, CH3), 3.52 (3H, s, OCH3), 3.55
(2H, d, J¼6.9, CH2), 3.60 (3H, s, OCH3), 3.87 (3H, s, OCH3), 3.91 (3H, s,
OCH3), 5.24 (2H, s, OCH2), 5.26e5.29 (3H, m), 7.15 (1H, dd, J¼2.2,
4.8. Structural assignment of 15 by OH group protection with
MOMCl
8.8, C6-H), 7.58 (1H, d, J¼2.2, C8-H), 7.92 (1H, d, J¼8.8, C5-H). 13
C
NMR (CDCl3) d: 18.0 (CH3), 24.1 (CH2), 25.7 (CH3), 56.1 (CH3), 57.6
OCH
OCH
+
R O
OR
TBSO
OMOM
OCH
OCH
OCH
OCH
MOMCl, i-Pr NEt
MS3A, DMF
OCH
22
23a: R =H, R =MOM
23b: R =MOM, R =H
OCH
+
rt, 24 h
HO
OH
TBSO
OH
OCH
MOMO
OMOM
12
15
OCH
11a
(CH3), 60.8 (CH3), 62.2 (CH3), 94.6 (CH2), 99.5 (CH2), 104.5 (CH),
117.8 (CH),121.8 (C),123.5 (CH),124.1 (CH),125.2 (C),129.2 (C), 131.4
(C), 142.8 (C), 146.4 (C), 150.5 (C), 155.4 (C). FABMS m/z: 376 (Mþ).
HRMS-FAB m/z: (Mþ) calcd for C21H28O6, 376.1886; found, 376.1884.
4.8.1. tert-Butyl[5,8-dimethoxy-7-methoxymethoxy-6-(3-
methylbuten-2-yl)naphthalen-2-yloxy]dimethylsilane (22). The re-
action was conducted by the same method as that for preparing of 9
as a colorless oil. IR (neat): 2955, 2930, 2857, 1624, 1597, 1497, 1456,
1395, 1371, 1337, 1263, 1231, 1217, 1161, 1051 cmꢀ1. 1H NMR (CDCl3)
11b: 1H NMR (CDCl3)
d: 1.74 (3H, s, CH3), 1.76 (3H, s, CH3), 3.51 (3H,
s, OCH3), 3.57 (3H, s, OCH3), 3.91 (3H, s, OCH3), 3.94 (3H, s, OCH3),
5.27e5.31 (3H, m), 5.35 (2H, s, OCH2), 6.61 (1H, s, C3-H), 7.50 (1H, s,
C5-H or C8-H), 7.90 (1H, s, C5-H or C8-H).
d
: 0.25 (6H, s, 2ꢂCH3), 1.02 (9H, s, t-Bu), 1.69 (3H, s, CH3), 1.82 (3H, s,
CH3), 3.55 (2H, d, J¼7.0, CH2), 3.61 (3H, s, OCH3), 3.87 (3H, s, OCH3),
3.89 (3H, s, OCH3), 5.25 (2H, s, OCH2), 5.27e5.31 (1H, m, CH), 7.00

T. Ogata et al. / Tetrahedron 71 (2015) 6672e6680
6677
(1H, dd, J¼2.2, 8.8, C3-H), 7.38 (1H, d, J¼2.2, C1-H), 7.88 (1H, d,
gas. Anhydrous N,N-dimethylformamide (0.5 mL) was added and
the mixture was stirred at rt for 1 h to complete absorption of the
moisture. After addition of N,N-diisopropylethylamine (194 mg,
1.5 mmol) at 0 ꢁC, the reaction mixture was stirred at rt for 10 min
followed by addition of chloromethyl 2-trimethylsilylethyl ether
(251 mg, 1.5 mmol), and stirring was continued for 1 h. The reaction
mixture was poured onto ice water. The reaction mixture was di-
luted with ether and the solution was filtered through a CeliteÒ pad.
The filtrate was separated, and the aqueous layer was extracted
with ether. The combined ethereal layer was successively washed
with water (ꢂ3), brine (ꢂ1) and then dried over Na2SO4. Filtration
and concentration under reduced pressure gave 289 mg of crude
oil, which was purified by flash column chromatography by eluting
with hexane and ethyl acetate in 10/1 to 2/1 ratio to give 121 mg
(44%) of 16 as a colorless oil. IR (neat): 2953, 2895, 1626, 1597, 1501,
1458,1445,1373,1341,1248,1209,1094,1055 cmꢀ1. 1H NMR (CDCl3)
J¼8.8, C4-H). 13C NMR (CDCl3)
: ꢀ4.3 (CH3), 18.0 (CH3), 18.3 (C),
d
24.1 (CH2), 25.7 (CH3), 25.8 (CH3), 57.6 (CH3), 60.8 (CH3), 62.2 (CH3),
99.6 (CH2), 109.1 (CH), 121.0 (CH), 121.5 (C), 123.6 (CH), 123.9 (CH),
124.8 (C), 129.4 (C), 131.3 (C), 142.5 (C), 146.2 (C), 150.5 (C), 153.9 (C).
FABMS m/z: 446 (Mþ). HRMS-FAB m/z: (Mþ) calcd for C25H38O5Si,
446.2489; found, 446.2487.
4.8.2. Compound 23. The geometry of the MOM group in com-
pound 23 (23a or 23b) was not specifically assigned because the
compound is not stable enough to measure some types of spectral
data. 1H NMR (CDCl3)
d: 1.71 (3H, s, CH3), 1.83 (3H, s, CH3), 3.52 (3H,
s, OCH3), 3.54e3.55 (2H, m, CH2), 3.88 (3H, s, OCH3), 3.92 (3H, s,
OCH3), 5.28e5.32 (3H, m), 5.88 (1H, s, OH), 7.08 (1H, dd, J¼2.6, 9.2,
AreH), 7.42 (1H, d, J¼2.6, AreH), 7.94 (1H, d, J¼9.2, AreH).
d
: ꢀ0.02 (9H, s, Si(CH3)3), ꢀ0.01 (9H, s, Si(CH3)3), 0.92e1.01 (4H, m),
CH O
H
H
1.67 (3H, s, CH3), 1.80 (3H, s, CH3), 3.53 (2H, d, J¼6.2, CH2),
3.58e3.87 (4H, m), 3.84 (3H, s, OCH3), 3.88 (3H, s, OCH3), 5.26 (2H,
s, OCH2), 5.32 (2H, s, OCH2), 7.13 (1H, dd, J¼2.2, 9.2, C7-H), 7.56 (1H,
H
O
H C
3
H
H
t-Bu
Si
O
OCH
CH
3
H
OCH
22
d, J¼2.2, C5-H), 7.90 (1H, d, J¼9.2, C8-H). 13C NMR (CDCl3)
: ꢀ1.42
d
(CH3), ꢀ1.41 (CH3), 18.0 (CH3), 18.1 (CH3), 18.3 (CH2), 24.1 (CH2), 25.7
(CH2), 60.7 (CH3), 62.2 (CH3), 65.7 (CH2), 66.3 (CH2), 67.5 (CH2), 97.7
(CH2), 104.4 (CH), 117.7 (CH), 121.6 (C), 123.6(CH), 123.9 (CH), 125.1
(C), 129.2 (C), 131.2 (C), 142.8 (C), 146.3 (C), 150.4 (C), 155.5 (C). EIMS
m/z: 548 (Mþ). HRMS-EI m/z: (Mþ) calcd for C29H48O6Si2, 548.2989;
found, 548.2990. 79 mg (38%) of 5,8-dimethoxy-6-(3-methylbuten-
2-yl)-7-(2-trimethylsilanylethoxymethoxy)naphthalen-2-ol (17)
was also obtained as reddish-brown oil. IR (neat): 3377, 2953, 1738,
1711, 1630, 1601, 1505, 1460, 1443, 1370, 1252, 1223, 1086,
4.8.3. Structural determination of 22. Key NOESY correlations of
compound 22 were observed as shown above, and this result
supported the structure of 22. Hence, the structure of 15 was found
to be correct.
4.9. 3,6-Bis(tert-butyldimethylsilanyloxy)-1,4-dimethoxy-2-
(3-methylbuten-2-yl)naphthalene (13)
1051 cmꢀ1. 1H NMR (CDCl3)
d: 0.02 (9H, s, Si(CH3)3), 0.98e1.03 (2H,
Method B: i) The preparation of 12 was described above. ii) To
a mixture of imidazole (102 mg, 1.5 mmol) and N,N-dimethyl-4-
aminopyridine (24.4 mg, 0.2 mmol) was added the crude 12 in
anhydrous CH2Cl2 (1 mL) under an argon atmosphere. After stirring
for 10 min at rt, tert-butyldimethylsilyl chloride (225 mg, 1.5 mmol)
in anhydrous CH2Cl2 (1 mL) was added dropwise to the reaction
mixture, and stirring was continued for 1 day at the same tem-
perature. The reaction was quenched with satd NH4Cl aq under ice
bath cooling followed by extraction with CHCl3 (ꢂ3). The combined
organic extracts were successively washed with water (ꢂ1) and
brine (ꢂ1), dried over Na2SO4, filtered and concentrated. This re-
action (ii) was repeated two times to increase the yield. The yield
did not improve whether the reaction time was extended or ad-
ditional reagent was added. The residue was purified by flash col-
umn chromatography by eluting with hexane and ethyl acetate in
100/1 ratio to give 168 mg (65%) of 13 as a white solid of mp
99.5e105.3 ꢁC. IR (KBr): 2963, 2859, 1622, 1616, 1597, 1497, 1460,
m), 1.69 (3H, s, CH3), 1.82 (3H, s, CH3), 3.54 (2H, d, J¼6.6, CH2),
3.85e3.89 (8H, m), 4.93 (1H, s, OH), 5.28 (2H, s, OCH2), 7.02 (1H, dd,
J¼2.6, 8.8, C6-H), 7.35 (1H, d, J¼2.6, C8-H), 7.91 (1H, d, J¼8.8, C5-H).
13C NMR (CDCl3)
d
: ꢀ1.5 (CH3), 18.0 (CH3), 18.2 (CH3), 24.0 (CH2),
25.7 (CH2), 60.7 (CH3), 62.2 (CH3), 67.5 (CH2), 97.7 (CH2), 103.8 (CH),
116.7 (CH), 121.1 (C), 123.6 (CH), 124.3 (CH), 124.5 (C), 129.5 (C),
131.2 (C), 142.4 (C), 146.4 (C), 150.5 (C), 154.0 (C). EIMS m/z: 418
(Mþ). HRMS-EI m/z: (Mþ) calcd for C23H34O5Si, 418.2176; found,
418.2173.
H
H
H
CH
3
H
H
HO
O
O
H
Si
3
17
Key NOESY correlations of compound 17 were observed as
shown above, and this result supported the structure of 17.
1450, 1416, 1371, 1341, 1261, 1217, 1182, 1109, 1061, 1001 cmꢀ1
.
1H
NMR (CDCl3)
d
: 0.25 (6H, s, 2ꢂCH3), 0.26 (6H, s, 2ꢂCH3), 1.03 (18H,
s, 2ꢂt-Bu), 1.67 (3H, s, CH3), 1.78 (3H, s, CH3), 3.49 (2H, d, J¼6.6,
CH2), 3.78 (3H, s, OCH3), 3.85 (3H, s, OCH3), 5.26 (1H, t, J¼6.6, CH),
6.94 (1H, dd, J¼2.2, 8.8, C7-H), 7.33 (1H, d, J¼2.2, C5-H), 7.85 (1H, d,
4.11. ( )-3-[3,6-Bis(tert-butyldimethylsilanyloxy)-1,4-
dimethoxynaphthalen-2-ylmethyl]-2,2-dimethyloxirane (18)
J¼8.8, C8-H). 13C NMR (CDCl3)
d: ꢀ4.3 (CH3), ꢀ4.0 (CH3), 18.0 (CH3),
Method A: To a solution of 13 (48.4 mg, 0.1 mmol) in CH2Cl2
(0.3 mL) was added m-chloroperoxybenzoic acid, wet, 75% purity
(26 mg, 0.11 mmol) at 0 ꢁC, and the reaction mixture was warmed
to rt and stirred for 1 h. The reaction was quenched with water with
ice bath cooling, and the mixture was extracted with CHCl3 (ꢂ3).
The combined organic layer was successively washed with 1w/v%
Na2S2O3 aq (ꢂ1) and brine (ꢂ1), dried over Na2SO4, filtered and
concentrated in vacuo. The residue was purified by flash column
chromatography by eluting with hexane and ethyl acetate in 20/1
18.3 (C), 18.8 (C), 24.2 (CH2), 25.6 (CH3), 25.8 (CH3), 26.2 (CH3), 60.6
(CH3), 62.0 (CH3), 108.9 (CH), 119.8 (CH), 120.1 (C), 123.7 (CH), 123.9
(CH), 124.3 (C), 129.2 (C), 130.9 (C), 140.5 (C), 144.6 (C), 150.6 (C),
153.7 (C). EIMS m/z: 516 (Mþ). HRMS-EI m/z: (Mþ) calcd for
C
29H48O4Si2, 516.3091; found, 516.3090.
4.10. 1,4-Dimethoxy-2-(3-methylbut-2-enyl)-3,6-bis(2-
trimethylsilanyloxyethoxy)naphthalene (16)
ratio to give 46 mg (92%) of 18 as
a white solid of mp
i) The preparation of 12 was described above. ii) To an eggplant
shaped flame-dried flask was added 12 (144 mg, 0.5 mmol) and
activated MS3A (125 mg), and then the flask was filled with argon
105.3e108.2 ꢁC. IR (KBr): 2965, 2889, 2857, 1622, 1599, 1499, 1466,
1452, 1422, 1387, 1339, 1244, 1175, 1125, 1059 cmꢀ1. 1H NMR (CDCl3)
d: 0.22 (3H, s, CH3), 0.27 (6H, s, 2ꢂCH3), 0.29 (3H, s, CH3), 1.03 (9H, s,

6678
T. Ogata et al. / Tetrahedron 71 (2015) 6672e6680
t-Bu), 1.05 (9H, s, t-Bu), 1.29 (3H, s, CH3), 1.43 (3H, s, CH3), 3.04 (1H,
d, J¼1.5), 3.05 (1H, br s), 3.10 (1H, dd, J¼1.5, 5.9), 3.78 (3H, s, OCH3),
3.90 (3H, s, OCH3), 6.96 (1H, dd, J¼2.6, 8.8, C7-H), 7.34 (1H, d, J¼2.2,
aq (0.65 mL) were added dropwise separately using a syringe pump
over a period of 3 h at ꢀ10 ꢁC. After stirring for 1 h, the mixture was
quenched by addition of water and CHCl3. The mixture was
extracted with CHCl3 (ꢂ2), washed with water (ꢂ1), dried over
Na2SO4, filtered and concentrated in vacuo. The residue was puri-
fied by flash chromatography by eluting with hexane and ethyl
acetate in 10/1 to give 12 mg, 21% of enantioenriched (R)-19 as
a colorless oil. This material showed analytical and spectroscopic
C5-H), 7.87 (1H, d, J¼8.8, C8-H). 13C NMR (CDCl3)
: ꢀ4.3 (CH3), ꢀ4.2
d
(CH3), ꢀ3.9 (CH3), 18.3 (C), 18.8 (C), 19.0 (CH3), 24.8 (CH3), 25.3
(CH3), 25.8 (CH2), 26.2 (CH3), 58.7 (C), 60.6 (CH), 62.5 (CH3), 63.9
(CH3), 109.0 (CH), 120.04 (CH), 120.07 (C), 120.8 (C), 124.0 (CH),
129.7 (C), 140.5 (C), 144.4 (C), 151.4 (C), 153.9 (C). FABMS m/z: 532
(Mþ). HRMS-FAB m/z: (Mþ) calcd for C29H48O5Si2, 532.3040; found,
532.3036.
data consistent with those of 19 in all aspects except the enantio-
21
meric purity. [
a
]
ꢀ11.5 (c 0.33, CHCl3). The enantiomeric excess
D
was found to be 64% and was obtained by HPLC on a Chiralpak IB
column (250ꢂ4.6 mm, i.d.) from Daicel Co., using hexane/2-
propanol¼99.5/0.5 as an eluent (flow rate: 1.0 mL/min) at
230 nm. The major enantiomer was eluted after 8.98 min, and the
minor enantiomer was eluted after 19.55 min.
4.12. (R)-3-[3,6-Bis(tert-butyldimethylsilanyloxy)-1,4-
dimethoxynaphthalen-2-ylmethyl]-2,2-dimethyloxirane ((R)-
18)
Method C: To a solution of 13 (776 mg, 1.5 mmol) in acetonitrile/
ethanol/toluene¼1/1/2 (8 mL) was added 2.1 mL of buffer (2M
K2CO3/4.0ꢂ10ꢀ4 M EDTA aq) followed by addition of Shi epoxida-
tion diketal catalyst (232 mg, 0.9 mmol) and 30% H2O2 (1.0 mL,
9 mmol) separately in 13 portions over 3 days at rt. The reaction
was quenched with water, and the reaction mixture was extracted
with ether (ꢂ2) and the combined ethereal layer was successively
washed with 1w/v% Na2S2O3 aq (ꢂ1), water (ꢂ1) and brine (ꢂ1),
dried over Na2SO4, filtered and concentrated in vacuo. The residue
was purified by flash column chromatography by eluting with
hexane and ethyl acetate in 20/1 ratio to obtain 575 mg (72%) of
enantioenriched (R)-18 as a white solid of mp 62.0e68.4 ꢁC. This
material showed analytical and spectroscopic data consistent with
4.15. ( )-1-[3,6-Bis(tert-butyldimethylsilanyloxy)-1,4-
dimethoxynaphthalen-2-yl]-3-methyl-3-buten-2-ol (20)
According to the literature procedure,10 to a solution of 18
(154 mg, 0.29 mmol) in CH2Cl2 (1.45 mL) was added 1,3-
dimethylimidazolidin-2-one (66 mg, 0.58 mmol) and p-toluene-
sulfonic acid monohydrate (27.6 mg, 0.145 mmol), and the solution
was stirred at rt for 2 h. The reaction was quenched with water, and
the reaction mixture was extracted with CH2Cl2 (ꢂ2). The com-
bined organic layer was successively washed with water (ꢂ1) and
brine (ꢂ1), dried over Na2SO4, filtered and concentrated in vacuo.
The residue was purified by flash column chromatography using
neutral silica gel by eluting with hexane and ethyl acetate in 25/1
ratio to give 135 mg (87%) of 20 as a white solid of mp 90.2e92.5 ꢁC.
IR (KBr): 3551, 2955, 2934, 2891, 2859, 1624, 1595, 1497, 1456, 1416,
1381, 1341, 1260, 1221, 1190, 1174, 1113, 1061 cmꢀ1. 1H NMR (CDCl3)
those of 18 in all aspects except the enantiomeric purity. [
a
]
D
23 ꢀ14.4
(c 0.30, CHCl3). The enantiomeric excess was found to be 74% and
was obtained by HPLC on a Chiralpak IA column (250ꢂ4.6 mm, i.d.)
from Daicel Co., using hexane/2-propanol¼99.5/0.5 as an eluent
(flow rate: 0.5 mL/min) at 254 nm. The major enantiomer was
eluted after 8.72 min, and the minor enantiomer was eluted after
9.63 min.
d
: 0.25 (3H, s, CH3), 0.266 (6H, s, 2ꢂCH3), 0.270 (3H, s, CH3), 1.03
(18H, s, 2ꢂt-Bu), 1.86 (3H, s, CH3), 2.92 (1H, d, J¼4.0, OH), 3.01 (1H,
dd, J¼4.0, 13.9, C1-Ha), 3.16 (1H, dd, J¼3.3, 13.9, C1-Hb), 3.77 (3H, s,
OCH3), 3.92 (3H, s, OCH3), 4.29e4.33 (1H, m, C2-H), 4.84 (1H, br s,
C4-Ha), 5.03 (1H, br s, C4-Hb), 6.97 (1H, dd, J¼2.2, 8.8, C7-H), 7.34
4.13. ( )-3-[1,4-Dimethoxy-3,6-bis(2-
trimethylsilanylethoxymethoxy)-naphthalen-2-ylmethyl]-2,2-
dimethyloxirane (19)
(1H, d, J¼2.2, C5-H), 7.86 (1H, d, J¼8.8, C8-H). 13C NMR (CDCl3)
d:
ꢀ4.3 (CH3), ꢀ3.9 (CH3), ꢀ3.8 (CH3), 18.0 (CH3), 18.3 (C), 18.7 (C), 25.8
(CH2), 26.2 (CH3), 31.7 (CH3), 60.7 (CH3), 62.1 (CH3), 76.3 (CH), 109.1
(CH), 110.7 (CH2), 120.1 (C), 120.3 (CH), 121.1 (C), 124.0 (CH), 129.7
(C), 140.8 (C), 144.4 (C), 147.7 (C), 151.2 (C), 154.1 (C). FABMS m/z:
532 (Mþ). HRMS-FAB m/z: (Mþ) calcd for C29H48O5Si2, 532.3040;
found, 532.3039.
The reaction was conducted by the same method as that for
the preparation of 18, and 46% of 19 was obtained as a colorless
oil. IR (neat): 2953, 2897, 1626, 1599, 1501, 1458, 1375, 1342, 1261,
1248, 1209, 1152, 1092, 1055, 1009 cmꢀ1 1H NMR (CDCl3)
. d: 0.01
(18H, s, 2ꢂSi(CH3)3), 0.96e1.00 (4H, m), 3.04e3.14 (3H, m),
3.78e3.87 (4H, m), 3.90 (6H, s, 2ꢂOCH3), 5.29e5.34 (4H, m), 7.16
(1H, dd, J¼2.6, 9.2, C7-H), 7.59 (1H, d, J¼2.6, C5-H), 7.93 (1H, d,
4.16. (R)-1-[3,6-Bis(tert-butyldimethylsilanyloxy)-1,4-
dimethoxynaphthalen-2-yl]-3-methyl-3-buten-2-ol ((R)-20)
J¼9.2, C8-H). 13C NMR (CDCl3)
: ꢀ1.42 (CH3), ꢀ1.40 (CH3), 18.1
d
(CH3), 18.3 (CH3), 19.1 (CH2), 24.8 (CH2), 25.1 (CH2), 58.9 (C), 60.7
(CH3), 62.5 (CH3), 64.0 (CH), 66.4 (CH2), 67.7 (CH2), 93.1 (CH2),
97.8 (CH2), 104.4 (CH), 117.9 (CH), 121.50 (C), 121.54 (C), 124.1
(CH), 129.8 (C), 142.7 (C), 146.4 (C), 151.2 (C), 155.8 (C). FABMS m/
z: 564 (Mþ). HRMS-FAB m/z: (Mþ) calcd for C29H48O7Si2,
564.2939; found, 564.2942.
74% ee of (R)-18 was used as substrate. A white solid of mp
86.4e92.0 ꢁC showed analytical and spectroscopic data consistent
with those of 20 in all aspects except the enantiomeric purity.
[
a
]
24 þ31.0 (c 0.30, CHCl3). The enantiomeric excess was found to
D
be 74% by HPLC on a Chiralpak IA column (250ꢂ4.6 mm, i.d.) from
Daicel Co., using hexane/2-propanol¼99.5/0.5 as an eluent (flow
rate: 0.5 mL/min) at 254 nm. The major enantiomer was eluted
after 17.38 min, and the minor enantiomer was eluted after
18.67 min.
4.14. (R)-3-[1,4-Dimethoxy-3,6-bis(2-
trimethylsilanylethoxymethoxy)-naphthalen-2-ylmethyl]-2,2-
dimethyloxirane ((R)-19)
4.17. ( )-7-Hydroxy-2-isopropenyl-2,3-dihydronaphtho[1,2-b]
Method B: To a solution of 16 (55 mg, 0.1 mmol) in acetonitrile
and dimetoxymethane in 1/2 (1.5 mL) was successively added
buffer [1 mL, 0.05 M solution of Na2B4O7$10H2O in 4ꢂ10ꢀ4M Na2
(EDTA) aq], tetra-n-butylammonium hydrogen sulfate (1.4 mg,
0.004 mmol) and Shi epoxidation diketal catalyst (7.8 mg,
0.03 mmol) at ꢀ10 ꢁC with stirring. A solution of Oxone (85 mg,
0.138 mmol) in 4ꢂ10ꢀ4M Na2(EDTA) aq (0.65 mL) and 0.83 M K2CO3
furan-4,5-dione (racemic lantalucratin C: 4)
According to our reported method,2 to a solution of 20 (129 mg,
0.24 mmol) in THF containing BHT as a stabilizer (4.0 mL) was
gently added diammonium celium nitrate (328 mg, 0.6 mmol) in
1.44 mL of water at 0 ꢁC. The reaction mixture was warmed to rt and
stirred for 2 h while the color in the solution changed into a dark

T. Ogata et al. / Tetrahedron 71 (2015) 6672e6680
6679
red. The reaction mixture was diluted with water and CH2Cl2, and
the entire mixture was extracted with CH2Cl2 (ꢂ3). The combined
organic layer was successively washed with water (ꢂ1) and brine
(ꢂ1), dried over Na2SO4, filtered and concentrated in vacuo to give
137 mg of a crude dark red gum which was immediately used for
the next reaction without further purification. For analysis, another
batch of the reaction was subjected to purification by flash column
chromatography using neutral silica gel by eluting with hexane and
ethyl acetate in 25/1 ratio, only a small amount of (ꢃ)-7-(tert-
butyldimethylsilanyloxy)-2-isopropenyl-2,3-dihydronaphtho[1,2-
b]furan-4,5-dione (24) was obtained as a red solid. 1H NMR (CDCl3)
Na2SO4, filtered and concentrated in vacuo. The residue was puri-
fied by flash column chromatography using neutral silica gel by
eluting with hexane and ethyl acetate in 5/1 ratio to give 35 mg
(93%) of (S)-MTPA-20 including inseparable minor isomer as a col-
orless oil. 1H NMR (CDCl3)
d
: 0.22 (3H, s, 2ꢂCH3), 0.29 (3H, s,
2ꢂCH3), 1.02 (9H, s, t-Bu), 1.05 (9H, s, t-Bu), 1.75 (3H, s, CH3), 3.00
(1H, dd, J¼4.4, 13.9, C1-Ha), 3.15 (3H, br-d, J¼0.7, OCH3), 3.46 (1H,
dd, J¼10.6, 13.9, C1-Hb), 3.60 (3H, s, OCH3), 3.81 (3H, s, OCH3), 4.94
(1H, t, J¼1.5, C4-Ha), 5.06 (1H, br s, C4-Hb), 6.07 (1H, q, J¼4.4, C2-H),
6.83e6.87 (2H, m, PheH), 6.99 (1H, dd, J¼2.6, 8.8, C7-H), 7.01e7.16
(3H, m, PheH), 7.35 (1H, d, J¼2.6, C5-H), 7.86 (1H, d, J¼8.8, C8-H).
d
: 0.26 (6H, s, 2ꢂCH3), 1.00 (9H, s, t-Bu), 1.80 (3H, s, CH3), 2.93 (1H,
13C NMR (CDCl3)
d: ꢀ4.2 (CH3), ꢀ3.9 (CH3), 17.7 (CH3), 18.3 (C), 18.7
dd, J¼7.7,15.4, C3-Ha), 3.27 (1H, dd, J¼10.3,15.4, C3-Hb), 5.01 (1H, br
s, C11-Ha), 5.13 (1H, br s, C11-Hb), 5.45 (1H, dd, J¼7.7, 10.3, C2-H),
7.05 (1H, dd, J¼2.6, 8.5, C8-H), 7.52 (1H, d, J¼2.6, C6-H), 7.56 (1H, d,
J¼8.5, C9-H).
(C), 25.8 (CH2), 26.2 (CH3), 29.0 (CH3), 55.0 (CH3), 60.5 (CH3), 61.9
(CH3), 79.0 (CH), 109.0 (CH), 114.5 (CH2), 119.2 (C), 120.0 (C), 120.2
(CH), 124.2 (CH), 127.1 (CH), 128.0 (CH), 129.1 (CH), 130.0 (C), 132.6
(C), 140.8 (C), 142.5 (C), 142.8 (C), 144.7 (C), 151.8 (C), 154.2 (C), 165.8
(C). (One quaternary carbon signal was overlapped.) EIMS m/z: 748
(Mþ). HRMS-EI m/z: (Mþ) calcd for C39H55F3O7Si2, 748.3438; found,
748.3435.
To a crude solution of 24 (137 mg) in THF containing BHT as
a stabilizer (2.4 mL) was added a solid tetra-n-butylammonium
fluoride (227 mg, 0.72 mmol) under ice bath cooling. The reaction
was completed in a moment when the color changed to a dark
purple, and the reaction mixture was poured onto ice water. The
resulting red solution was extracted with ethyl acetate (ꢂ2), and
the combined organic layer was successively washed with water
(ꢂ1) and brine (ꢂ1), dried over Na2SO4, filtered and concentrated in
vacuo. The residue was purified by flash column chromatography
using neutral silica gel by eluting with hexane and ethyl acetate in
2/1 ratio to give 41 mg (67%) of 4 as a purple solid of mp
199.5e200.3 ꢁC. IR (KBr): 3117, 2972, 2930, 1697, 1640, 1601, 1551,
1505, 1425, 1366, 1304, 1229, 1182, 1159, 1094, 1022 cmꢀ1. 1H NMR
4.19.2. (R)-MTPA-20. According to the literature procedure,11 to
a solution of 20 (26.6 mg, 0.05 mmol) in anhydrous CH2Cl2 (1 mL)
was added water soluble carbodiimide hydrochloride (86 mg,
0.45 mmol), N,N-dimethyl-4-aminopyridine (54.9 mg, 0.45 mmol)
and
(R)-(ꢀ)-
a-methoxy-a-(trifluoromethyl)phenylacetic
acid
(70.2 mg, 0.3 mmol) in CH2Cl2 (0.5 mL), which was then stirred at rt
for 1 day. After complete consumption of 20 as judged by TLC
analysis, the reaction mixture was diluted with CHCl3 and water.
The entire solution was then extracted with CHCl3 (ꢂ3), and the
combined organic layer was washed with brine (ꢂ1), dried over
Na2SO4, filtered and concentrated in vacuo. The residue was puri-
fied by flash column chromatography using neutral silica gel by
eluting with hexane and ethyl acetate in 5/1 ratio to give 36 mg
(96%) of (R)-MTPA-20 including inseparable minor isomer as a col-
(acetone-d6)
d
: 1.81 (3H, s, CH3), 2.81 (1H, dd, J¼7.7, 15.0, C3-Ha),
3.21 (1H, dd, J¼10.2, 15.0, C3-Hb), 5.00 (1H, s, C11-Ha), 5.16 (1H, s,
C11-Hb), 5.57 (1H, dd, J¼7.7, 10.2, C2-H), 7.16 (1H, dd, J¼2.6, 8.1, C8-
H), 7.44 (1H, d, J¼2.6, C6-H), 7.57 (1H, d, J¼8.1, C9-H), 9.45 (1H, br s,
OH). 13C NMR (acetone-d6)
d: 16.9 (CH3), 31.7 (CH2), 90.3 (CH), 113.4
(CH2), 113.5 (C), 117.1 (CH), 120.0 (C), 121.4 (CH), 127.3 (CH), 134.0
(C), 144.0 (C), 161.9 (C), 170.5 (C), 175.8 (C), 181.9 (C). EIMS m/z: 256
(Mþ). HRMS-EI m/z: (Mþ) calcd for C15H12O4, 256.0736; found,
256.0735.
orless oil. 1H NMR (CDCl3)
d: 0.18 (3H, s, CH3), 0.24 (3H, s, CH3), 0.29
(6H, s, 2ꢂCH3), 1.02 (9H, s, t-Bu), 1.05 (9H, s, t-Bu), 1.85 (3H, s, CH3),
3.00 (1H, dd, J¼5.1, 13.9, C1-Ha), 3.34 (3H, br-d, J¼1.1, OCH3), 3.40
(1H, dd, J¼9.9, 13.9, C1-Hb), 3.60 (3H, s, OCH3), 3.69 (3H, s, OCH3),
4.96 (1H, t, J¼1.4, C4-Ha), 5.13 (1H, br s, C4-Hb), 6.25 (1H, q, J¼5.1,
C2-H), 6.82e6.86 (2H, m, PheH), 6.94 (1H, dd, J¼2.6, 8.8, C7-H),
7.03e7.07 (3H, m, PheH), 7.34 (1H, d, J¼2.6, C5-H), 7.72 (1H, d,
4.18. (R)-7-Hydroxy-2-isopropenyl-2,3-dihydronaphtho[1,2-
b]furan-4,5-dione (lantalucratin C: (R)-4)
J¼8.8, C8-H). 13C NMR (CDCl3)
: ꢀ5.2 (CH3), ꢀ4.9 (CH3), 16.9 (CH3),
d
Optically pure (R)-4 was obtained by recrystallization from
hexane and ethyl acetate as a purple solid of mp 191.8e193.8 ꢁC
(Lit. mp 199 ꢁC)1c. This material showed analytical and spectro-
scopic data consistent with those of 4 in all aspects except the
17.4 (C), 18.8 (C), 24.9 (CH2), 25.3 (CH3), 27.8 (CH3), 54.2 (CH3), 59.6
(CH3), 60.7 (CH3), 77.1 (CH), 107.9 (CH), 114.4 (CH2), 117.8 (C), 119.0
(CH), 119.2 (C), 123.4 (CH), 126.2 (CH), 127.0 (CH), 128.1 (CH), 129.0
(C),131.3 (C),139.7 (C),141.6 (C),141.8 (C),143.7 (C),150.6 (C),150.72
(C), 150.76 (C), 153.2 (C). EIMS m/z: 748 (Mþ). HRMS-EI m/z: (Mþ)
calcd for C39H55F3O7Si2, 748.3438; found, 748.3434.
enantiomeric purity. ½a D25
ꢀ411.3 (c 0.002, CHCl3). Lit (natural
ꢄ
material): [
a
]
ꢀ420.3 (c 0.07, CHCl3)1c. The enantiomeric excess
D
was found to be >99% by HPLC on a Chiralpak IA column
(250ꢂ4.6 mm, i.d.) from Daicel Co., using hexane/ethanol¼98/2 as
an eluent (flow rate: 1.0 mL/min) at 270 nm. The major enantio-
mer was eluted after 5.43 min, and the minor enantiomer was
eluted after 4.89 min.
Acknowledgements
We thank for the Instrumental Analysis Center of MWU Phar-
maceutical Sciences.
4.19. Determination of the absolute configuration of 4 (20)
Supplementary data
4.19.1. (S)-MTPA-20. According to the literature procedure,11 to
a solution of 20 (26.6 mg, 0.05 mmol) in anhydrous CH2Cl2 (1 mL)
was added water-soluble carbodiimide hydrochloride (86 mg,
0.45 mmol), N,N-dimethyl-4-aminopyridine (54.9 mg, 0.45 mmol)
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2015.07.050.
and
(S)-(ꢀ)-
a
-methoxy-
a
-(trifluoromethyl)phenylacetic
acid
References and notes
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combined organic layer was washed with brine (ꢂ1), dried over
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6680
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