Unusual, chemoselective etherification of 2-hydroxy-1,4-naphthoquinone derivatives utilizing alkoxymethyl chlorides: Scope, mechanism and application to the synthesis of biologically active natural product (±)-lantalucratin C

Article abstract of DOI:10.1016/j.tet.2016.01.040

A novel etherification of 2-hydroxy-1,4-naphthoquinone derivatives with alkoxyalkyl chlorides and hydride bases is described. Precise study of the conditions and substrate scope suggested that the reaction occurs specifically in the molecule having a 2-hydroxy-1,4-benzoquinone skeleton. A chemoselective O-methylation reaction was achieved to afford a synthetically important intermediate, which offered easy access to a natural product possessing anti-tumor activity.

Full text of DOI:10.1016/j.tet.2016.01.040

Tetrahedron xxx (2016) 1e10
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Unusual, chemoselective etherification of 2-hydroxy-1,4-
naphthoquinone derivatives utilizing alkoxymethyl chlorides: scope,
mechanism and application to the synthesis of biologically active
natural product (ꢀ)-lantalucratin C
,
Tokutaro Ogata y, Tomoyo Yoshida, Maki Shimizu, Manami Tanaka, Chie Fukuhara,
*
*
Junko Ishii, 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:
A novel etherification of 2-hydroxy-1,4-naphthoquinone derivatives with alkoxyalkyl chlorides and hy-
dride bases is described. Precise study of the conditions and substrate scope suggested that the reaction
occurs specifically in the molecule having a 2-hydroxy-1,4-benzoquinone skeleton. A chemoselective O-
methylation reaction was achieved to afford a synthetically important intermediate, which offered easy
access to a natural product possessing anti-tumor activity.
Received 5 October 2015
Received in revised form 21 January 2016
Accepted 22 January 2016
Available online xxx
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Naphthoquinone
Etherification
Protecting group
Chemoselective
Total synthesis
1. Introduction
leads an unusual etherification reaction giving methyl ether 3a
(Scheme 1).6
A large number of biologically active compounds containing the
1,4-naphthoquinone skeleton have been found over the past cen-
tury.1 Among the 1,4-naphthoquinone derivatives, 2-hydroxy-1,4-
naphthoquinone (1a: lawsone) has been used as a dye for color-
ing hair and skin since ancient times. Today, 1a and its analogs are
recognized as synthetically valuable building blocks for synthe-
sizing dyes,2 agrochemicals3 and drugs.4 From the viewpoint of
drug discovery, 1a is an interesting pharmacophore due to its redox
potential at the quinone moiety.
Over the past few years, our research interest has been directed
toward the synthesis of naturally occurring naphthoquinones
possessing biological activities such as anti-tumor activity.5 These
compounds are accessible from 2-hydroxy-1,4-naphthoquinones
as a common synthon (Fig. 1). Recently, we found that the re-
action of 1a with chloromethyl methyl ether (MOMCl) and NaH
1a was treated with excess of MOMCl and NaH to give methyl
ether 3a in 59% yield along with methoxymethyl ether 2a (34%).
Although MOMCl is frequently used to protect alcohol groups in
synthetic organic chemistry, to the best of our knowledge, there
is no example of its use for the production of O-methyl ether
using the MOMCl/NaH reagent system. This extraordinary phe-
nomenon prompted us to continue our study of it. Here we
describe
a full detail of the study in the reaction scope,
limitations, mechanism and application of this phenomenon to
the synthesis of biologically active natural product (ꢀ)-lantalu-
cratin C.
2. Results and discussion
Our study began with a thorough investigation of the reaction
conditions as summarized in Table 1. First, 1a was treated with
excess amounts of NaH and MOMCl in DMF at rt, which is a com-
mon OH protection method. The unusual O-methylation pro-
ceeded, and methyl ether 3a was obtained in moderate yield (Table
1, entry 1). However, reproducibility was poor. Therefore, we tried
the reaction under various conditions and found that the water
* Corresponding authors. E-mail addresses: t-ogata@hokuriku-u.ac.jp (T. Ogata),
tkimachi@mukogawa-u.ac.jp (T. Kimachi).
y
Present address: Faculty of Pharmaceutical Sciences, Hokuriku University,
Kanagawa-machi, Kanazawa, 920-1181, Ishikawa, Japan.
http://dx.doi.org/10.1016/j.tet.2016.01.040
0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.
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2
T. Ogata et al. / Tetrahedron xxx (2016) 1e10
Fig. 1. 2-Hydroxy-1,4-naphthoquinones as useful synthetic building blocks toward various biologically active natural products.
both NaH and MOMCl (Table 2, entries 1e4). Interestingly, the
transformation of 3a into 2a did not proceed under anhydrous
condition but did occur under wet condition, indicating that the
water in the reaction may promote degradation by hydrolysis of 3a
(Table 2, entries7 and 8). On the other hand, the alkoxide is
Scheme 1. Unusual O-alkylation of 2-hydroxy-1,4-naphthoquinone with MOMCl and
NaH.
Table 1
Scope of the reaction conditionsa
content of the reaction mixture strongly affects the product yield.
Without moisture control, the yield of 3a decreased (Table 1, entry
1 vs 2). In addition, the formation of 3a markedly decreased when
the reaction was performed with a small volume of water (Table 1,
entry 1 vs 3).
Entry Base (equiv) MOMCl Solvent
(equiv) (mol/L)
Time (h) Product
Finally, we found that using activated molecular sieves 3A gave
reproducible results (Table 1, entry 4). Thus, further examinations
were carried out with moisture control. Extended reaction time
resulted in improvement of the yield of 3a although excess reaction
time caused a slight decrease (Table 1, entries 4 vs 5, 10 vs 12).
Controlling the amount of reagent and concentration of the re-
action solution was also effective for improving results. The product
ratio of 3a increased with use of a larger amount of base and
MOMCl although excess use of these reagents caused a decrease
(Table 1, entries 6e9). The selectivity could be completely regulated
by using 1 or 3 equiv of the reagent against 1a (Table 1, entries 6, 8
and 9). These results indirectly indicated that the rate of formation
of 2a was faster than that of 3a, and the formation of 3a went
through the production of 2a. Good selectivity of 3a was observed
at higher solution concentrations (Table 1, entries 10 and 11).
Various kinds of organic and inorganic bases were tested, and
the results indicated that a base of appropriate basicity and mo-
lecular size is needed to obtain the methyl ether 3a (Table 1, entries
13e19). Using a weaker base afforded 2a in good to excellent yield
with complete selectivity. This result implied that there is
a deprotonation sequence during the transformation of 2a into 3a
(see Scheme 2).
The choice of solvent also affected the ratio of the product. On
examining polar aprotic solvents, we found that a solvent including
an amide function was crucial for efficient production of 3a (Table 1,
entries 20e26). The absence of significant impurities such as
methanol in MOMCl was confirmed by 1H NMR analysis.
In order to elucidate the route of the generation of methyl ether
3a, the isolated compound 2a or 3a was treated using the NaH/
MOMCl reagent system (Table 2). As expected, we found that 3a
was generated from 2a, and this molecular conversion requires
2a (%)
3a (%)
1b
2c
3d
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19e
20
21
22
23
24
25
26
NaH (2.0)
NaH (2.0)
NaH (2.0)
NaH (2.0)
NaH (2.0)
NaH (1.0)
NaH (2.0)
NaH (3.0)
NaH (3.0)
NaH (2.0)
NaH (2.0)
NaH (2.0)
LiH (2.0)
KH (2.0)
K2CO3 (2.0)
iPr2NEt (2.0) 2.0
KOtBu (2.0) 2.0
NaOMe (2.0) 2.0
NaOH (2.0)
NaH (2.0)
NaH (2.0)
NaH (2.0)
NaH (2.0)
NaH (2.0)
NaH (2.0)
NaH (2.0)
3.0
3.0
3.0
3.0
3.0
1.0
2.0
3.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
DMF (0.2)
DMF (0.2)
DMF (0.2)
DMF (0.2)
DMF (0.2)
DMF (0.2)
DMF (0.2)
DMF (0.2)
DMF (0.2)
DMF (1.0)
DMF (0.05)
DMF (1.0)
DMF (1.0)
DMF (1.0)
DMF (1.0)
DMF (1.0)
DMF (1.0)
DMF (1.0)
DMF (1.0)
THF (1.0)
0.25
0.25
0.25
0.25
1
1
1
1
34
69
76
43
29
85
14
0
59
23
10
44
61
0
83
47
31
73
69
63
0
40
0
0
10
0
0
1
0
1
5
1
5
1
1
1
1
1
2
1
1
1
1
1
1
13
Trace
82
20
75
90
50
64
Trace
24
44
53
11
2
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
0
5
13
74
80
52
MeCN (1.0)
DMSO (1.0)
NMPf (1.0)
DMAg (1.0)
TMUh (1.0)
Pyridine (1.0)
1
45
1
Complex mixture
a
The reaction was carried out using a flame-dried round bottom flask filled with
argon gas. 1a (2 mmol) and activated MS3A (500 mg) were stirred at rt.
b
The reaction was conducted without MS3A.
The reaction was carried out without moisture control.
The reaction was carried out with addition of water (1 drop).
Most of the 1a was recovered.
N-methyl pyrrolidone.
N,N-dimethylacetamide.
Tetramethylurea.
c
d
e
f
g
h
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T. Ogata et al. / Tetrahedron xxx (2016) 1e10
3
Scheme 2. Postulated reaction pathway for formation of 2 and 3.
considered to be one of the degradation fragments at the MOM
group and is thought to act as an O-nucleophile to yield 3a. How-
ever, only a small amount of methyl ether 3a was obtained using
sodium methoxide as a base, and most of the 2a was recovered
(Table 2, entry 9). The radical reduction and/or radical chain re-
action pathway is unlikely as the major route because the O-
methylation was not inhibited in the presence of dibutylhydrox-
ytoluene (BHT) as a free radical scavenger (Table 2, entry 6).
Instead of MOMCl, other alkoxyalkyl halides were used for the
reaction of 1a (Table 3). The reaction using benzyloxymethyl or
ethoxymethyl chloride with NaH proceeded smoothly, and the
corresponding alkyl ether 3bec was obtained together with
alkoxymethyl ether 2bec (Table 3, entries 1 and 3). In both cases, 3a
was not obtained, strongly suggesting that the methyl group of 3a
did not originate from the methylene moiety of 2a but from the
terminal methyl moiety in the reaction of 1a with NaH and MOMCl.
On the other hand, extending one carbon at the methylene position
caused no reaction even when the reaction was conducted at higher
temperature over a longer period of time (Table 3, entry 4). Bromide
also acted similarly to chloride, giving the corresponding ethers at
different yields (Table 3, entry 5).
Some of the 2-hydroxy-1,4-naphthoquinones and related com-
pounds were prepared and examined for the O-alkylation reactions
to evaluate the substrate scope and limitations (Table 4). Methyl
ethers (3e,f) were obtained from 2-hydroxy-1,4-naphthoquinones
(1e,f), respectively, which contained substituent groups at the 3-
position (Table 4, entries 1 and 2). These findings clearly showed
that deprotonation at the 3-position by strong base and subsequent
migration did not occur during the alkyl ether (3) formation. The O-
alkylation reaction was also applicable for anthraquinone de-
rivatives (Table 4, entry 3). Normal O-methoxymethylation oc-
curred when cyclic or acyclic 1,3-diketone was used as a substrate,
the alkyl ether was not obtained at all (Table 4, entries 4 and 5). As
expected, only the normal O-methoxymethylation occurred in the
case of 1-naphthol (Table 4, entry 6). The reaction of 2-amino-1,4-
naphthoquinone with NaH and MOMCl afforded tertiary amine as
the sole product (Table 4, entry 7). Interestingly, the reaction con-
ducted using weaker LiH to repress the formation of tertiary amine
led to accumulation of the secondary amine (Table 4, entry 8). The
reaction of monocyclic compound 1m with NaH and MOMCl pro-
vided the O-methylated product (Table 4, entry 9). These results
indicated that the substrate involving the 2-hydroxy-1,4-
benzoquinone skeleton is thought to be essential for the unusual
O-alkylation reaction.7 In other words, this reaction system can
specifically and sensitively recognize the 2-hydroxy-1,4-
benzoquinone structure. We hope that it can be used for the de-
velopment of novel chemical sensors in the future.
Table 2
Molecular conversion between 2a and 3a in the presence of NaH and MOMCla
Entry Substrate Base (equiv) MOMCl (equiv) Time (h) Product (recovered)
2a (%)
3a (%)
1
2
3
4
2a
2a
2a
2a
2a
2a
3a
3a
2a
NaH (1.0)
None
NaH (1.0)
None
NaH (1.0)
NaH (1.0)
NaH (1.0)
NaH (1.0)
1.0
1.0
None
None
1.0
1.0
1.0
1.0
1
1
1
24
1
1
1
1
2
39
91
21
0
0
<26b
Quant
69
0
5c
6d
7
11
36
88
33
4
61
0
36
90
Based on experimental results, the proposed reaction pathway
is illustrated in Scheme 2. The transformation of compound 2,
which was obtained by simple SN2 reaction from compound 1, can
be explained by two pathways. In route A, deprotonation at the
methylene carbon by strong base such as NaH generates a six-
membered chelate complex,6 and this reacts with MOMCl to give
intermediate I. The intramolecular oxa-Michael addition provides
8c
9
NaOMe (1.0) 1.0
a
The reaction was carried out using a flame-dried round bottom flask filled with
argon gas. In this flask, 0.5 mmol of substrate (2a or 3a), anhydrous DMF (0.5 mL)
and activated MS3A (125 mg) were placed with stirring at rt.
b
Unidentified compounds were also obtained.
A drop of water was added to the reaction mixture.
0.6 mmol of BHT (dibutylhydroxytoluene) was added.
c
d
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4
T. Ogata et al. / Tetrahedron xxx (2016) 1e10
Table 3
Reaction of 1a with various alkoxyalkyl halidesa
Entry
1
Base (equiv)
NaH (2.0)
R1OR2X (equiv)
BnOCH2Cl (2.0)
Product 2bed
Yield (%)
44
Product 3bed
Yield (%)
53
2
K2CO3 (1.5)
NaH (2.0)
NaH (2.0)
BnOCH2Cl (3.0)
EtOCH2Cl (2.0)
Quant
0
51
0
3
32
4b
CH3OCH2CH2Cl (2.0)
0c
48
5
NaH (2.0)
MOMBr (2.0)
27
a
The reaction was carried out using a flame-dried round bottom flask and filled with argon gas. 1a (2 mmol), anhydrous DMF (2 mL) and activated MS3A (500 mg) were
stirred at rt for 1 h.
b
The reaction was carried out at 100 ꢂC for 24 h.
1a was recovered quantitatively.
c
a five-membered spiro-ketal II, and finally compound 3 is ob-
tained by release of the methyl acetate from intermediate III. On
the other hand, in route B, 1,3-dioxetane intermediate IV8 is
generated directly by oxa-Michael addition of 2, and subsequent
removal of formaldehyde gives 3. From the results presented in
Table 2, the transformation of 2 into 3 seems to require both NaH
and MOMCl, which supports route A because those reagents are
not included in the transformation in route B. The reverse re-
action from 3 into 2 is considered to occur by the following
processes. A Michael addition between sodium hydroxide, which
is generated from NaH and water, and 3 occurs first, and sub-
sequent elimination yields 1. The formation of 2 occurs in the
same way as explained above.
As part of our study on the application of the unusual O-alkyl-
ation reaction, we designed 2,7-dihydroxy-1,4-naphthoquinone
(1n) in an attempt to realize a chemoselective O-methylation re-
action (Table 5). As expected, the reaction of 1n with NaH and
MOMCl gave the desired product 6 but the selectivity and yield
were not satisfactory. The reaction was accelerated when a large
excess of the reagents was used to afford 6, with some unidentified
products (Table 5, entry 2). The concentration of the reaction so-
lution strongly affected the ratio and yield of the product (Table 5,
entries 1e4). Fortunately, the selectivity and yield of 6 dramatically
improved when DMA was selected as the solvent (Table 5, entry 5).
On the other hand, the reaction utilizing a weaker base gave
compound 5 by the usual O-methoxymethylation (Table 5, entry 6).
Thus, we were able to successfully demonstrate the chemoselective
O-methylation, with compound 6 being obtained as the sole
product in good yield.
Compound 6 is an important synthetic intermediate for the
synthesis of biologically active natural products. As the last part of
the study, we tried to synthesize (ꢀ)-lantalucratin C9 (12) to
demonstrate the utility of compound 6. Recently, we reported the
first example of stereoselective synthesis of R-(ꢁ)-lantalucratin C in
7% overall yield.5e We thought that the overall yield could be im-
proved by using compound 6 although 12 would obtain as a race-
mic mixture. The actual synthetic route is summarized in Fig. 2.
Compound 6 was first converted to tetra-substituted naphthalene 8
by reductive methylation, and the prenyl side chain was introduced
by ortho-lithiation-alkylation reaction to afford 9. The precursor 11
for cyclization was afforded by olefin epoxidation and subsequent
epoxy-ring opening reaction in the presence of acid catalyst. The
target compound was successfully obtained by diammonium cer-
ium(IV) nitrate (CAN) oxidative cyclization followed by depro-
tection of the MOM group. Thus, the total synthesis of (ꢀ)-12 was
achieved in six steps from the known compound 1n with 22%
overall yield.
3. Conclusion
In summary, we have developed a novel etherification of 2-
hydroxy-1,4-naphthoquinone derivatives with alkoxyalkyl chlo-
rides and hydride bases. Precise study of the conditions and sub-
strate scope suggested that the reaction occurred specifically in the
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T. Ogata et al. / Tetrahedron xxx (2016) 1e10
5
Table 4
Substrate scopea
Entry
Substrate (1)
Product (2)
Yield (%)
Product (3)
Yield (%)
1
2
e: R¼CH3
f: R¼Bn
65
51
19
45
3
4
35
44
32
0
5
6
17
0
0
Quant
7
40
0
8b
32
43
0
16
9
a
The reaction was carried out using a flame-dried round bottom flask and filled with argon gas. 1a (2.0 mmol), NaH (2 equiv), MOMCl (2 equiv) and activated MS3A (500 mg)
were stirred at rt for 1 h.
b
LiH was used instead of NaH.
molecule having a 2-hydroxy-1,4-benzoquinone skeleton. In addi-
tion, chemoselective O-methylation reaction was achieved to afford
the synthetically important intermediate 6. Use of 6 for the syn-
thesis of 12 resulted in significant improvement of the overall yield.
Further study of the applicability of this process is in progress.
shown in Hertz. Abbreviations are as follows: s, singlet; d, doublet;
t, triplet; q, quartet; quint, quintet; m, multiplet; br, broad. IR
spectra were recorded on an SHIMADZU IR Affinity-1. Mass spectra
(MS) were obtained on JEOL JMS-700 instruments. Melting points
were measured on a Yanaco micro melting point apparatus and are
uncorrected. Flash chromatography was performed with silica gel
(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 aluminum sheets and the visualization was ac-
companied by UV lamp.
4. Experimental
4.1. General
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.
Activated MS3A was prepared by heating to dryness under reduced
pressure for a few hours. Activated NaHSO4∙SiO2 was prepared by
heating at 120 ꢂC in a drying oven for 2 days. 1H NMR (400 MHz)
and 13C NMR (100 MHz) were recorded on a JEOL JNM-ECP400
spectrometer. Chemical shift values were expressed in ppm rela-
tive to an internal reference of tetramethylsilane (0 ppm) in 1H
NMR and CDCl3 (77.0 ppm) in 13C NMR. Coupling constants are
4.2. Typical procedure for O-alkylation of 2-hydroxy-1,4-
naphthoquinones (example for the reaction in Table 1, entry
10)
To a flame-dried round bottom flask was added 2-hydroxy-1,4-
naphthoquinone (348 mg, 2 mmol) and activated MS3A (500 mg)
followed by filling with argon gas. Anhydrous DMF (2.0 mL) was
added and the mixture was stirred at rt for 1 h to allow complete
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6
T. Ogata et al. / Tetrahedron xxx (2016) 1e10
Table 5
Stirring of the reaction mixture was continued at rt overnight. The
Reaction of 1n with NaH and MOMCla
resulting yellow suspension was cooled to 0 ꢂC and yellow solid was
collected by vacuum filtration. The filtrate was concentrated in
vacuo and ethyl acetate was added to obtain a yellow suspension,
and, which was collected by vacuum filtration. The obtained yellow
solid was combined and dried by heating at 60 ꢂC under reduced
pressure for 2 days to obtain 26.4 g (82%) of yellow powder.
4.4. 2-Benzyloxymethoxy-1,4-naphthoquinone (2b)
Entry
Base (equiv)
MOMCl
(equiv)
DMF
(mol/L)
Product (isolated yield)
5 (%)
6 (%)
7 (%)
A yellow solid of mp 98.2e98.8 ꢂC. IR (KBr): 1678, 1655, 1613,
1
2
3
4
5
6
NaH (3.0)
NaH (5.0)
NaH (3.0)
NaH (5.0)
NaH (5.0)
iPr2NEt (3.0)
3.0
5.0
3.0
5.0
5.0
3.0
1.0
1.0
0.2
0.2
0.2b
1.0
6
0
59
16
0
36
32
23
40
69
0
6
0
9
1593, 1578, 1499, 1331, 1262, 1231, 1196, 1167, 1107, 1082, 1034 cmꢁ1
.
1H NMR (CDCl3)
CH), 7.27e7.36 (5H, m, Ph-H), 7.69e7.77 (2H, m, AreH), 8.07e8.15
(2H, m, AreH). 13C NMR (CDCl3)
: 71.4 (CH2), 92.7 (CH2), 113.4 (CH),
d: 4.76 (2H, s, OCH2), 5.42 (2H, s, OCH2), 6.53 (1H, s,
Trace
0
2
d
74
126.1 (CH), 126.6 (CH), 128.0 (CH), 128.2 (CH), 128.5 (CH), 131.1 (C),
131.9 (C), 133.3 (CH), 134.2 (CH), 136.2 (C), 157.9 (C), 180.2 (C), 184.9
(C). FABMS m/z: 295 (MþþH). HRMS-FAB m/z: (MþþH) calcd for
a
The reaction was carried out using a flame-dried round bottom flask and filled
with argon gas. 1n (0.5 mmol) and activated MS3A (125 mg) were used.
b
DMA was used instead of DMF.
C18H15O4, 295.0970; found, 295.0970.
4.4.1. 2-Benzyloxy-1,4-naphthoquinone (3b).12 1H NMR (CDCl3)
d:
5.14 (2H, s, OCH2), 6.23 (1H, s, CH), 7.35e7.45 (5H, m, Ph-H),
7.68e7.76 (2H, m, AreH), 8.06e8.15 (2H, m, AreH).
absorption of the moisture. After stirring for 10 min by adding so-
dium hydride 60% dispersion in mineral oil (160 mg, 4 mmol) in one
portion, methoxymethyl chloride (320 mg, 4 mmol) was added
dropwise. The reaction mixture was warmed up to rt and stirred for
1 h. After complete consumption of the substrate confirmed by TLC
analysis, the reaction mixture was poured onto ice water. The re-
action 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 or-
ganic layer was successively washed with water (ꢃ3), brine (ꢃ1)
and then dried over Na2SO4. Filtration and concentration under
reduced pressure gave a dark brown crude oil, which was purified
by flash column chromatography eluting with hexane and ethyl
acetate in 5/1 to 1/1 ratio to obtain a mixture of 2a and 3a as
a yellow solid. The product yield was calculated based on 1H NMR
analysis results.
4.5. 2-Ethoxymethoxy-1,4-naphthoquinone (2c)
A yellow solid of mp 129.3e129.7 ꢂC. IR (KBr): 1684, 1647, 1603,
1337, 1302, 1267, 1233, 1202, 1117 cmꢁ1. 1H NMR (CDCl3)
d: 1.24 (3H,
t, J¼7.0, CH3), 3.77 (2H, q, J¼7.0, CH2), 5.35 (2H, s, OCH2O), 6.50 (1H,
s, CH), 7.69e7.76 (2H, m, AreH), 8.06e8.13 (2H, m, AreH). 13C NMR
(CDCl3) d: 14.9 (CH3), 65.7 (CH2), 93.6 (CH2), 113.2 (CH), 126.1 (CH),
126.6 (CH), 131.1 (C), 131.9 (C), 133.3 (CH), 134.2 (CH), 158.0 (C),
180.3 (C), 185.0 (C). EIMS m/z: 232 (Mþ). HRMS-EI m/z: (Mþ) calcd
for C13H12O4, 232.0736; found, 232.0735.
4.5.1. 2-Ethoxy-1,4-naphthoquinone (3c).13 1H NMR (CDCl3)
d: 1.24
(3H, t, J¼7.0, CH3), 3.77 (2H, q, J¼7.0, eOCH2), 6.15 (1H, s, CH),
4.2.1. 2-Methoxymethoxy-1,4-naphthoquinone (2a).10 1H NMR
(CDCl3) d: 3.53 (3H, s, OCH3), 5.30 (2H, s, CH2), 6.47 (1H, s, CH),
7.68e7.75 (2H, m, AreH), 8.06e8.14 (2H, m, AreH).
7.69e7.77 (2H, m, AreH), 8.07e8.15 (2H, m, AreH).
4.6. Preparation of 2-hydroxy-3-methyl-1,4-naphthoquinone
(1e)14
4.2.2. 2-Methoxy-1,4-naphthoquinone (3a).11 1H NMR (CDCl3)
d:
3.91 (3H, s, OCH3), 6.18 (1H, s, CH), 7.69e7.77 (2H, m, AreH),
8.08e8.15 (2H, m, AreH).
According to a literature procedure,14 to an ice-cooled suspen-
sion of 3-methyl-1,4-naphthoquinone (757 mg, 4.4 mmol) in eth-
anol (3 mL) was added 30% H2O2 (1.5 mL), Na2CO3 (60 mg,
0.57 mmol) and water (0.6 mL). After stirring for 1.5 h at rt, water
(20 mL) was added and then the reaction mixture was extracted
with CHCl3 (ꢃ3). The combined organic layer was dried over
Na2SO4, filtered and concentrated in vacuo to give epoxide. To the
epoxide was then added conc. H2SO4 (5 mL) and stirred for 1 h. The
4.3. Alternative method for the synthesis of 3a
To a solution of lawsone (30 g, 172 mmol) in methanol (1 l) was
added conc. HCl (100 mL), and the mixture was gently warmed
with stirring until all of the substrate had completely dissolved.
Fig. 2. Synthetic application of compound 6 toward the biologically active natural product (ꢀ)-lantalucratin C.
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T. Ogata et al. / Tetrahedron xxx (2016) 1e10
7
reaction mixture was carefully added to ice water, and the whole
mixture was extracted with CHCl3 (ꢃ3). The combined organic
layer was dried over Na2SO4, filtered and concentrated in vacuo to
give a crude product, which was purified by flash column chro-
matography by eluting with hexane and ethyl acetate in 2/1 ratio to
yield 551 mg (67%) of the target product as a yellow solid. 1H NMR
7.58e7.66 (2H, m), 8.08e8.14 (2H, m), 8.36 (1H, s), 8.41
(1H, s).
4.10.1. 2-Methoxymethoxyanthracene-1,4-dione (2g). A yellow solid
of mp 144.3e145.6 ꢂC. IR (KBr): 1680, 1649, 1613, 1601, 1458, 1289,
1242, 1155, 1061 cmꢁ1. 1H NMR (CDCl3)
d
: 3.56 (3H, s, OCH3), 5.34
(2H, s, OCH2), 6.58 (1H, s, AreH), 7.64e7.70 (2H, m, AreH),
8.03e8.06 (2H, m, AreH), 8.58 (1H, s, AreH), 8.66 (1H, s, AreH). 13
NMR (CDCl3) : 57.2 (CH3), 94.9 (CH2), 114.9 (CH), 127.8 (C), 128.2
(CDCl3) d: 2.11 (3H, s, CH3), 7.28 (1H, s, OH), 7.66e7.77 (2H, m,
AreH), 8.07e8.14 (2H, m, AreH).
C
d
4.7. 2-Methoxymethoxy-3-methyl-1,4-naphthoquinone (2e)
(CH), 128.3 (C), 129.29 (CH), 129.32 (CH), 129.7 (CH), 130.1 (CH),
130.2 (CH),134.6 (C),135.1 (C),159.1 (C),179.9 (C),184.6 (C). EIMS m/
z: 268 (Mþ). HRMS-EI m/z: (Mþ) calcd for C16H12O4, 268.0736;
found, 268.0732.
A yellow solid of mp 52.3e53.9 ꢂC. IR (KBr): 1674, 1659, 1622,
1593, 1333, 1298, 1263, 1225, 1173, 1156, 1092, 1071 cmꢁ1. 1H NMR
(CDCl3)
7.66e7.72 (2H, m, AreH), 8.03e8.10 (2H, m, AreH). 13C NMR
(CDCl3) : 9.5 (CH3), 57.5 (CH3), 98.3 (CH2), 126.2 (CH), 126.3 (CH),
d: 2.17 (3H, s, CH3), 3.56 (3H, s, OCH3), 5.45 (2H, s, OCH2),
4.11. 2-Methoxyanthracene-1,4-dione (3g)19
d
131.4 (C), 132.1 (C), 133.1 (C), 133.3 (CH), 133.8 (CH), 155.5 (C), 181.2
1H NMR (CDCl3)
d: 3.94 (3H, s, OCH3), 6.29 (1H, s, AreH),
7.64e7.71 (2H, m, AreH), 8.04e8.06 (2H, m, AreH), 8.60 (1H, s,
AreH), 8.68 (1H, s, AreH).
(C), 185.5 (C). EIMS m/z: 232 (Mþ). HRMS-EI m/z: (Mþ) calcd for
C
13H12O4, 232.0736; found, 232.0734.
4.7.1. 2-Methoxy-3-methyl-1,4-naphthoquinone (3e).15 1H NMR
4.12. 3-Methoxymethoxycyclohex-2-enone (2h)20
(CDCl3) : 2.11 (3H, s, CH3), 4.12 (3H, s, OCH3), 7.68e7.70 (2H, m,
AreH), 8.04e8.08 (2H, m, AreH).
d
1H NMR (CDCl3)
d
: 2.00 (2H, quint, J¼6.2, CH2), 2.35 (2H, t, J¼6.2,
CH2), 2.43 (2H, t, J¼6.2, CH2), 3.47 (3H, s, OCH3), 5.06 (2H, s, OCH2),
4.8. Preparation of 2-benzyl-3-hydroxy-1,4-naphthoquinone
(1f)16
5.49 (1H, s, CH).
4.13. 3-Methoxymethoxy-1,3-diphenylpropenone (2i)
According to a literature procedure,16 a mixture of lawsone
(348 mg, 2 mmol) and potassium carbonate (312 mg, 2.26 mmol) in
anhydrous DMF (10 mL) was stirred at rt for 15 min under argon gas
atmosphere. The resulting red suspension was combined with po-
tassium iodide (349 mg, 2.1 mmol), and then benzyl bromide
(360 mg, 2.1 mmol) in anhydrous DMF (2 mL) was added dropwise.
The mixture was heated to 150 ꢂC and stirred for 2 h. The reaction
mixture was cooled to rt, and then poured into ice water. The
resulting dark reddish violet solution was washed with hexane
(ꢃ1), and the aqueous layer was acidified with 10% HCl to become
a yellow suspension, which was extracted with ethyl acetate (ꢃ2).
The organic layer was dried over Na2SO4, filtered and concentrated
in vacuo gave a yellow crude solid, which was purified by flash
column chromatography eluting with hexane and ethyl acetate in
5/1 ratio to obtain 228 mg, 43% yield of the target compound as
As a pale yellow oil. IR (neat): 1651, 1591, 1564, 1491, 1449, 1408,
1354, 1302, 1271, 1213, 1157, 1069, 1003 cmꢁ1 1H NMR (CDCl3)
. d:
3.53 (3H, s, OCH3), 5.19 (2H, s, OCH2), 6.63 (1H, s, CH), 7.41e7.56 (6H,
m, AreH), 7.71e7.73 (2H, m, AreH), 7.97 (2H, d, J¼7.3, AreH). 13
C
NMR (CDCl3) d: 57.6 (CH3), 99.1 (CH2), 105.0 (CH), 127.6 (CH), 128.2
(CH), 128.4 (CH), 128.6 (CH), 130.7 (CH), 132.4 (CH), 135.4 (C), 139.3
(C), 165.6 (C), 189.2 (C). EIMS m/z: 268 (Mþ). HRMS-EI m/z: (Mþ)
calcd for C17H16O3, 268.1099; found, 268.1099.
4.14. 1-Methoxymethoxynaphthalene (2j)21
1H NMR (CDCl3)
d: 3.55 (3H, s, OCH3), 5.39 (2H, s, OCH2), 7.09
(1H, d, J¼7.7, AreH), 7.37 (1H, t, J¼7.7, AreH), 7.47e7.49 (3H, m,
AreH), 7.79e7.82 (1H, m, AreH), 8.26e8.28 (1H, m, AreH).
a yellow solid. 1H NMR (CDCl3)
d: 3.95 (2H, s, CH2), 7.14e7.27 (2H, m,
PheH), 7.36e7.39 (3H, m, PheH), 7.64e7.76 (2H, m, AreH),
8.05e8.13 (2H, m, AreH).
4.15. Preparation of 2-amino-1,4-naphthoquinone (1k)22
According to a literature procedure,22a to a solution of 1,4-
naphthoquinone (2.5 g, 15.8 mmol) in glacial acetic acid (25 mL)
was added sodium azide (1.7 g, 26.2 mmol) in water (5 mL) drop-
wise at 40 ꢂC, and then stirred for 1.5 h at the same temperature.
The reaction was quenched with large volume of water, and basi-
fied with satd aqueous sodium bicarbonate. The reaction mixture
was extracted with ethyl acetate (ꢃ2), and the organic layer was
dried over Na2SO4, filtered and concentrated in vacuo. The residue
was purified by flash column chromatography eluting with hexane
and ethyl acetate in 10/1 ratio to obtain 1.14 g, 42% of the target
4.9. 2-Benzyl-3-methoxymethoxy-1,4-naphthoquinone (2f)
A yellow solid of mp 90.5e90.9 ꢂC. IR (KBr): 1663, 1601, 1491,
1445, 1335,1300,1217,1169, 1032 cmꢁ1. 1H NMR (CDCl3)
d: 3.49 (3H,
s, OCH3), 4.02 (2H, s, CH2), 5.52 (2H, s, OCH2), 7.14e7.27 (3H, m,
PheH), 7.35 (2H, d, J¼7.3, PheH), 7.66e7.71 (2H, m, AreH),
8.03e8.07 (2H, m, AreH). 13C NMR (CDCl3)
d: 29.6 (CH2), 57.7 (CH3),
98.6 (CH2), 126.26 (CH), 126.30 (CH), 126.4 (CH), 128.4 (CH), 129.1
(CH), 131.4 (C), 131.9 (C), 133.3 (CH), 133.9 (CH), 134.4 (C), 138.8 (C),
155.5 (C), 181.8 (C), 184.9 (C). EIMS m/z: 308 (Mþ). HRMS-EI m/z:
(Mþ) calcd for C19H16O4, 308.1049; found, 308.1041.
compound as an orange solid. 1H NMR (CDCl3)
d: 5.12 (2H, br-s,
NH2), 6.00 (1H, s, CH), 7.63 (1H, ddd, J¼1.5, 7.3, 7.7, AreH), 7.72
(1H, ddd, J¼1.5, 7.3, 7.7, AreH), 8.05e8.09 (2H, m, AreH).
4.9.1. 2-Benzyl-3-methoxy-1,4-naphthoquinone (3f).17 1H NMR
(CDCl3)
d
: 3.94 (2H, s, CH2), 4.13 (3H, s, OCH3), 7.14e7.34 (5H, m,
4.16. 2-(Bismethoxymethylamino)-1,4-naphthoquinone (2k)
PheH), 7.63e7.71 (2H, m, AreH), 8.02e8.08 (2H, m, AreH).
4.10. Preparation of 2-hydroxyanthracene-1,4-dione (1g)18
The reaction was performed in the same manner as shown
As a dark brown oil. IR (CHCl3): 1676, 1640, 1595, 1568, 1470,
1397,1331,1302,1260,1217,1119,1076 cmꢁ1. 1H NMR (CDCl3)
d
: 3.38
(6H, s, 2ꢃOCH3), 4.89 (4H, s, 2ꢃCH2), 6.42 (1H, s, CH), 7.64e7.72
(2H, m, AreH), 8.02e8.04 (2H, m, AreH). 13C NMR (CDCl3)
: 55.8
(CH3), 82.6 (CH2), 114.7 (CH), 125.5 (CH), 126.7 (CH), 131.9 (C), 132.6
d
above (preparation of 1e). 1H NMR (DMSO-d6)
d
: 5.59 (1H, s),
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8
T. Ogata et al. / Tetrahedron xxx (2016) 1e10
(CH), 132.7 (C), 133.8 (CH), 150.6 (C),182.7 (C), 184.3 (C). FABMS m/z:
262 (MþþH). HRMS-FAB m/z: (MþþH) calcd for C14H16NO4,
262.1079; found, 262.1079.
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, AreH). 13C NMR
(CDCl3) d: 56.4 (CH3), 57.1 (CH3), 94.2 (CH2), 94.8 (CH2), 113.0 (CH),
4.17. 2-(Methoxymethylamino)-1,4-naphthoquinone (2l)23
113.2 (CH), 121.8 (CH), 126.1 (C), 128.5 (CH), 132.9 (CH), 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.
1H NMR (CDCl3)
d
: 3.35 (3H, s, OCH3), 4.70 (2H, d, J¼6.6, CH2),
6.09 (1H, s, CH), 6.46 (1H, br-s, NH), 7.64 (1H, ddd, J¼1.5, 7.3, 7.7,
AreH), 7.73 (1H, ddd, J¼1.5, 7.3, 7.7, AreH), 8.06 (1H, dd, J¼1.5, 7.7,
4.22. 2-Methoxy-7-methoxymethoxy-1,4-naphthoquinone (6)
AreH), 8.09 (1H, dd, J¼1.5, 7.7, AreH). 13C NMR (CDCl3)
d: 55.4
(CH3), 74.6 (CH2), 104.6 (CH), 126.20 (CH), 126.24 (CH), 130.5 (C),
132.3 (CH), 133.1 (C), 134.7 (CH), 147.3 (C), 181.7 (C), 183.5 (C).
As a yellow solid of mp 137.0e137.5 ꢂC. IR (KBr): 1682, 1647,
1601, 1489, 1441, 1350, 1304, 1275, 1246, 1206, 1167, 1084,
1038 cmꢁ1. 1H NMR (CDCl3)
d: 3.50 (3H, s, OCH3), 3.89 (3H, s, OCH3),
4.18. 2,5-Bismethoxymethoxy-1,4-benzoquinone (2m)
5.29 (2H, s, OCH2), 6.11 (1H, s, CH), 7.33 (1H, dd, J¼2.6, 8.4, AreH),
7.71 (1H, d, J¼2.6, AreH), 8.03 (1H, d, J¼8.4, AreH). 13C NMR (CDCl3)
As a yellow solid of mp 160.4e160.9 ꢂC. IR (KBr): 3447, 3071,
d: 56.3 (CH3), 56.4 (CH3), 94.3 (CH2), 109.8 (CH), 113.1 (CH), 121.8
2969, 2949, 2914, 1668, 1595, 1364, 1221, 1186, 1150, 1090 cmꢁ1. 1H
(CH), 126.3 (C), 128.5 (CH), 132.9 (CH), 160.3 (C), 161.3 (C), 180.0 (C),
NMR (CDCl3)
d
: 3.49 (6H, s, 2ꢃOCH3), 5.23 (4H, s, 2ꢃOCH2), 6.17
184.1 (C). EIMS m/z: 248 (Mþ). HRMS-EI m/z: (Mþ) calcd for
(2H, s, CH). 13C NMR (CDCl3)
d
: 57.2 (CH3), 95.0 (CH2), 109.0 (CH),
C13H12O5, 248.0685; found, 248.0681.
156.5 (C), 182.1 (C). EIMS m/z: 228 (Mþ). HRMS-EI m/z: (Mþ) calcd
for C10H12O6, 228.0634; found, 228.0627.
4.23. 7-Hydroxy-2-methoxymethoxy-1,4-naphthoquinone (7)
4.19. 2,5-Dimethoxy-1,4-benzoquinone (3m)24
As a yellowish green solid of mp 169.0e170.1 ꢂC. The position of
the methoxymethyl substituent group was determined by NOE
measurement and analysis. IR (KBr): 3190, 1690, 1634, 1559, 1468,
1H NMR (CDCl3)
d
: 3.84 (6H, s, 2ꢃOCH3), 5.87 (2H, s, AreH).
1343, 1308, 1233, 1173, 1084, 1022 cmꢁ1.1H NMR (DMSO-d6)
d: 3.41
4.20. Preparation of 2,7-dihydroxy-1,4-naphthoquinone
(1n)25
(3H, s, OCH3), 5.28 (2H, s, OCH2), 6.24 (1H, s, CH), 7.14 (1H, dd, J¼2.6,
8.4, AreH), 7.29 (1H, d, J¼2.6, AreH), 7.81 (1H, d, J¼8.4, AreH), 10.8
(1H, br-s, OH). 13C NMR (CDCl3)
d: 56.7 (CH3), 94.7 (CH2), 111.9 (CH),
According to the literature procedure,24 a solution of potassium
tert-butoxide (8.8 g, 78 mmol) in tert-butanol (88 mL) was vigor-
ously stirred for 1 h in a flask equipped with an O2 gas balloon. To
the reaction mixture was added 7-methoxy-1-tetralone (1.76 g,
10 mmol), and stirring was continued at rt overnight. The resulting
red color suspension was poured into ice water, and then acidified
with 1M HCl to form a yellow solid, which was collected by vacuum
filtration. The filtrate was extracted with chloroform (ꢃ3), and the
organic layer and the yellow solid were combined and basified with
1M NaOH to form a red solution. The red aqueous layer was washed
with chloroform (ꢃ2), and separated aqueous layer was acidified
with conc. HCl to form a yellow solid again, which was collected by
vacuum filtration. After completely drying the solid at 80 ꢂC under
reduced pressure, 1.57 g, 76% of 2-hydroxy-7-methoxy-1,4-
naphthoquinone was obtained as a yellow solid. A 100 mL of
Erlenmeyer flask was charged with finely grounded anhydrous
aluminum trichloride (6.2 g, 46.6 mmol) and sodium chloride
(1.45 g, 25 mmol), and heated to 180 ꢂC (oil bath temp) until these
solids melted completely. A fine powder of 2-hydroxy-7-methoxy-
1,4-naphthoquinone was added to the flask, and heating was con-
tinued for 15 min at the same temperature. After cooling to about
100 ꢂC, conc. HCl in crushed ice (40 mL) was carefully added to the
flask, and the mixture was filtered through a CeliteÒ pad to remove
insoluble black materials. The filtrate was extracted with ether
(ꢃ3), and the rest of the target compound was extracted by Soxhlet
extraction using ether from the insoluble materials. The combined
organic extracts were dried over Na2SO4, filtered and concentrated
to obtain a yellow solid, which was then completely dried at 60 ꢂC
under reduced pressure to furnish the target compound 930 mg in
112.2 (CH), 120.9 (CH), 123.4 (C), 128.3 (CH), 132.8 (C), 157.1 (C),
162.2 (C), 179.7 (C), 183.6 (C). EIMS m/z: 234 (Mþ). HRMS-EI m/z:
(Mþ) calcd for C12H10O5, 234.0528; found, 234.0529.
4.24. 1,2,4-Trimethoxy-7-methoxymethoxynaphthalene (8)
To a 100 mL round-bottom flask was added 10% wet-Pd/C
(620 mg) in THF (25 mL) followed by addition of 6 (620 mg,
2.5 mmol). After the flask had been fully purged with hydrogen
gas, the reaction mixture was vigorously stirred at rt overnight,
with the flask being equipped with a hydrogen gas balloon. To
the reaction mixture was added sodium hydride at 60% disper-
sion in mineral oil (250 mg, 6.25 mmol) and dimethyl sulfate
(1.58 g, 12.5 mmol) under hydrogen gas atmosphere. After stir-
ring for 1 h, sodium hydride (6.25 mmol) and dimethyl sulfate
(12.5 mmol) were added to the reaction mixture, and stirring
was continued for about 1 h at the same temperature until 6 was
fully converted to 8 as confirmed by the results of TLC analysis.
The catalyst was filtered off by using CeliteÒ followed by thor-
ough washing with ether. To the filtrate was added 10w/v%
NaOH (75 mL) with vigorous stirring for 4 h to destroy any ex-
cess dimethyl sulfate. The reaction mixture was separated and
the aqueous layer was extracted with ether (ꢃ2). The combined
ethereal layer was successively washed with water (ꢃ1), brine
(ꢃ1) 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 obtain 605 mg (87%) of 8 as
a white solid of mp 53.2e53.5 ꢂC. IR (KBr): 2959, 2903, 2841,
1630, 1603, 1516, 1466, 1445, 1356, 1262, 1221, 1194, 1157, 1105,
98% yield. 1H NMR (DMSO-d6)
d
: 6.04 (1H, s, CH), 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
1084, 1059, 1009 cmꢁ1 1H NMR (CDCl3)
. d: 3.52 (3H, s, OCH3),
(1H, br-s, OH).
3.90 (3H, s, OCH3), 3.96 (3H, s, OCH3), 3.99 (3H, s, OCH3), 5.31
(2H, s, OCH2), 6.51 (1H, s, C3eH), 7.07 (1H, dd, J¼2.6, 9.2, C6eH),
7.54 (1H, d, J¼2.6, C8eH), 8.07 (1H, d, J¼9.2, C5eH). 13C NMR
4.21. 2,7-Bismethoxymethoxy-1,4-naphthoquinone (5)
(CDCl3)
d: 55.7 (CH3), 56.1 (CH3), 57.3 (CH3), 61.0 (CH3), 93.9
As a yellow solid of mp 106.6e108.2 ꢂC. IR (KBr): 1684, 1645,
(CH2), 94.5 (CH), 103.8 (CH), 116.0 (CH), 117.4 (C), 124.0 (CH),
130.7 (C), 136.4 (C), 149.0 (C), 152.6 (C), 156.3 (C). EIMS m/z: 278
1613, 1597, 1491, 1348,1317, 1304, 1271, 1236, 1200,1165, 1090 cmꢁ1
.
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T. Ogata et al. / Tetrahedron xxx (2016) 1e10
9
(Mþ). HRMS-EI m/z: (Mþ) calcd for C15H18O5, 278.1154; found,
278.1157.
organic layer was successively washed with water (ꢃ1) and brine
(ꢃ1), dried over Na2SO4, filtered and concentrated in vacuo. The
residue was purified by flash column chromatography by eluting
with hexane and ethyl acetate in 5/1 to 2/1 ratio to give 1.092 g
(81%) of 11 as a colorless oil. IR (neat): 3489, 2938, 2839, 1626, 1599,
1503, 1451, 1404, 1379, 1343, 1265, 1223, 1196, 1152, 1111, 1080, 1067,
4.25. 1,3,4-Trimethoxy-6-methoxymethoxy-2-(3-methyl-2-
butenyl)naphthalene (9)
To a solution of 8 (1.30 g, 4.68 mmol) in anhydrous THF (23 mL)
was added dropwise 1.6 M n-butyllithium in hexane solution
(8.8 mL, 14.0 mmol) at ꢁ80 ꢂC under an argon atmosphere. The
reaction mixture was warmed to ꢁ40 ꢂC, and then was stirred for
2 h. The reaction mixture was cooled to ꢁ80 ꢂC, and prenyl bromide
(2.09 g, 14.0 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 (ꢃ3). The organic layer was suc-
cessively washed with 1w/v% Na2S2O3 aq (ꢃ1), water (ꢃ1) and
brine (ꢃ1), dried over Na2SO4, filtered and concentrated in vacuo.
The residue was purified by flash column chromatography by
eluting with hexane and ethyl acetate in 10/1 to 5/1 ratio to obtain
1.25 g (77%) of 9 as a colorless oil with recovery of starting material
8 (21%). IR (neat): 2934, 1626, 1597, 1501, 1449, 1404, 1379, 1343,
1003 cmꢁ1. 1H NMR (CDCl3)
d
: 1.88 (3H, s, CH3), 2.94 (1H, dd, J¼4.4,
13.9, C1eHa), 2.97 (1H, d, J¼4.4, OH), 3.16 (1H, dd, J¼3.3, 13.9,
C1eHb), 3.53 (3H, s, OCH3), 3.92 (3H, s, OCH3), 3.95 (3H, s, OCH3),
4.00 (3H, s, OCH3), 4.28e4.32 (1H, m, C2eH), 4.85 (1H, d, J¼1.4,
C4eHa), 5.04 (1H, d, J¼1.4, C4eHb), 5.31 (2H, s, OCH2), 7.18 (1H, dd,
J¼2.6, 9.2, C7eH), 7.62 (1H, d, J¼2.6, C5eH), 7.93 (1H, d, J¼9.2,
C8eH). 13C NMR (CDCl3)
d: 18.1 (CH3), 31.7 (CH2), 56.1 (CH3), 60.65
(CH3), 60.70 (CH3), 62.1 (CH3), 76.3 (CH), 94.5 (CH2), 104.4 (CH),
110.2 (CH2), 117.9 (CH), 121.2 (C), 121.8 (C), 124.0 (CH), 129.9 (C),
143.0 (C), 147.8 (C), 148.6 (C), 150.8 (C), 155.5 (C). EIMS m/z: 362
(Mþ). HRMS-EI m/z: (Mþ) calcd for C20H26O6, 362.1729; found,
362.1727.
4.28. ( )-7-Hydroxy-2-isopropenyl-2,3-dihydronaphtho[1,2-
b]furan-4,5-dione (racemic lantalucratin C: 12)5e
1263, 1223, 1192, 1152, 1111, 1080, 1063 cmꢁ1 1H NMR (CDCl3)
. d:
According to our reported method,5 to a solution of 11 (109 mg,
0.3 mmol) in MeCN (5.0 mL) was gently added diammonium ce-
rium nitrate (411 mg, 0.75 mmol) in 1.8 mL of water at 0 ꢂC. The
reaction mixture was stirred at 0 ꢂC for 0.5 h while the color of the
solution changed to a dark red. The reaction mixture was diluted
with water and CHCl3, and the entire mixture was extracted with
CHCl3 (ꢃ3). The combined organic layer was successively washed
with water (ꢃ1) and brine (ꢃ1), dried over Na2SO4, filtered and
concentrated in vacuo to give 104 mg of a crude dark red gum.
According to the literature procedure,27 to a solution of crude in
anhydrous CH2Cl2 (6 mL) was added pre-activated NaHSO4∙SiO2
(120 mg) and the mixture was stirred at rt for 5 h. The resulting
purple solution was filtered in vacuo and the filtrate was evapo-
rated. The residue was purified by flash column chromatography
using neutral silica gel by eluting with hexane and ethyl acetate in
5/1 to 1/1 ratio to obtain 49 mg (64%) of 12 as a purple solid. 1H
1.70 (3H, d, J¼1.1, CH3), 1.83 (3H, s, CH3), 3.50 (2H, d, J¼7.0, CH2),
3.52 (3H, s, OCH3), 3.87 (3H, s, OCH3), 3.95 (6H, s, 2ꢃOCH3),
5.21e5.25 (1H, m, CH), 5.30 (2H, s, OCH2), 7.15 (1H, dd, J¼2.6, 9.2,
C7eH), 7.60 (1H, d, J¼2.6, C5eH), 7.93 (1H, d, J¼9.2, C8eH). 13C NMR
(CDCl3) d: 17.9 (CH2), 23.9 (CH3), 25.7 (CH3), 56.1 (CH3), 60.6 (CH3),
62.2 (CH3), 94.6 (CH2), 104.4 (CH), 117.6 (CH), 121.5 (C), 123.6 (CH),
123.9 (CH), 125.0 (C), 129.4 (C), 131.3 (C), 143.1 (C), 149.1 (C), 150.1
(C), 155.2 (C). EIMS m/z: 346 (Mþ). HRMS-EI m/z: (Mþ) calcd for
C
20H26O5, 346.1780; found, 346.1780.
4.26. 2,2-Dimethyl-3-(1,3,4-trimethoxy-6-methoxymethoxy-
2-naphthalenylmethyl)oxirane (10)
To a solution of 9 (1.67 g, 4.82 mmol) in CH2Cl2 (15 mL) was
added m-chloroperoxybenzoic acid, wet, 75% purity (1.22 g,
5.30 mmol) at 0 ꢂC, 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 (ꢃ3). The
combined organic layer was successively washed with 1w/v%
Na2S2O3 aq (ꢃ1) and brine (ꢃ1), dried over Na2SO4, filtered and
concentrated in vacuo. The residue was purified by flash column
chromatography by eluting with hexane and ethyl acetate in 5/1 to
2/1 ratio to give 1.61 g (92%) of 10 as a colorless oil. IR (neat): 2938,
2839, 1738, 1626, 1599, 1503, 1451, 1404, 1381, 1343, 1265, 1246,
NMR (acetone-d6)
d
: 1.81 (3H, s, CH3), 2.81 (1H, dd, J¼7.7, 15.0,
C3eHa), 3.21 (1H, dd, J¼10.2, 15.0, C3eHb), 5.00 (1H, s, C11eHa),
5.16 (1H, s, C11eHb), 5.57 (1H, dd, J¼7.7, 10.2, C2eH), 7.16 (1H, dd,
J¼2.6, 8.1, C8eH), 7.44 (1H, d, J¼2.6, C6eH), 7.57 (1H, d, J¼8.1,
C9eH), 9.45 (1H, br-s, OH).
Acknowledgements
1223,1196,1152,1117,1082,1061,1005 cmꢁ1. 1H NMR (CDCl3)
d: 1.31
We thank for the Instrumental Analysis Center of MWU Phar-
maceutical Sciences.
(3H, s, CH3), 1.46 (3H, s, CH3), 2.96e3.11 (3H, m), 3.53 (3H, s, OCH3),
3.91 (3H, s, OCH3), 3.95 (3H, s, OCH3), 4.00 (3H, s, OCH3), 5.31 (2H, s,
OCH2), 7.17 (1H, dd, J¼2.6, 9.2, C7eH), 7.62 (1H, d, J¼2.6, C5eH),
Supplementary data
7.94 (1H, d, J¼9.2, C8eH). 13C NMR (CDCl3)
d: 19.0 (CH2), 24.7 (CH3),
24.8 (CH3), 56.1 (CH3), 59.0 (C), 60.61 (CH3), 60.64 (CH3), 62.4 (CH3),
64.1 (CH), 94.5 (CH2), 104.4 (CH), 117.7 (CH), 121.27 (C), 121.30 (C),
124.1 (CH), 129.9 (C), 142.9 (C), 149.0 (C), 150.9 (C), 155.5 (C). EIMS
m/z: 362 (Mþ). HRMS-EI m/z: (Mþ) calcd for C20H26O6, 362.1729;
found, 362.1729.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2016.01.040.
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