Synthesis and structure of 8-hydroxy-6-methoxy-3,7-dimethylisochromane and its analogues

Article abstract of DOI:10.1016/j.tet.2006.01.079

The title compound 1 was obtained by the reaction of alcohol 18 and triethyl orthoformate catalyzed by aluminum chloride followed by catalytic hydrogenation in good yield. Similarly, compounds 1 and 3 were obtained by intramolecular cyclization of MOM eth

Full text of DOI:10.1016/j.tet.2006.01.079

Tetrahedron 62 (2006) 3739–3751
Synthesis and structure of
8-hydroxy-6-methoxy-3,7-dimethylisochromane and its analogues
a
b
c
Tsuneo Suzuki,a, Kiyoshi Tanemura, Takaaki Horaguchi and Kimiyoshi Kaneko
*
aSchool of Dentistry at Niigata, The Nippon Dental University, Hamaura-cho 1-8, Niigata 951-8580, Japan
bDepartment of Chemistry, Faculty of Science, Niigata University, Ikarashi, Niigata 950-2181, Japan
cFaculty of Pharmaceutical Science, Niigata University of Pharmacy and Applied Life Science,
5-13-2 Kamishin’ei-cho, Niigata 950-2081, Japan
Received 27 September 2005; accepted 10 January 2006
Available online 28 February 2006
Abstract—The title compound 1 was obtained by the reaction of alcohol 18 and triethyl orthoformate catalyzed by aluminum chloride
followed by catalytic hydrogenation in good yield. Similarly, compounds 1 and 3 were obtained by intramolecular cyclization of MOM ether
19 with titanium(IV) chloride in moderate yields and isochromanes 1, 3, 26 and 27 by intramolecular cyclization of ether 20 with
titanium(IV) chloride in high yields. The structures of compounds 1–3 were elucidated by analysis of spectroscopic data and chemical
reactions. The mechanisms on the formation of 1 and 3 are discussed.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
acid.7 Methoxyethoxymethyl (MEM) ethers 8a–d were
converted to isochromanes 9a–d by intramolecular cycliza-
tion catalyzed by titanium(IV) chloride.8 Compound 10 was
obtained by catalytic hydrogenation of compound 11, which
was afforded by formylation of 12 with triethyl
orthoformate.9
Isochromane 1 is a toxic metabolite of Penicillium steckii
Zalecki1 and Penicillium corylophilum Dierckx.2 Com-
pound 1 was highly toxic to 1-day-old chickens (lethal
dose 50%: 800 mg/kg)1 and inhibited growth of etiolated
coleoptiles of wheat by 100 and 43% at 10K3 and 10K4 M,
respectively.2 Hemiacetal 2 was produced by a marine-
derived strain of P. steckii together with compound 1 and
tanzawaic acids E and F.3 Compound 1 and its regioisomer
3 were synthesized from dimethoxy isochromane 4 as
shown in Scheme 1 and the phytotoxic activity of
compounds 1 and 3 and their ethers and esters had been
investigated in detail (Fig. 1).4
Synthesis and properties of 1-hydroxyisochromanes have
been reported by several groups. These compounds were
prepared by saponification of 5-formylmellein,10 reduction
of isocoumarins with hydrides,11 reaction of benzocyclo-
butenols and aromatic aldehydes in the presence of lithium
2,2,6,6-tetramethylpiperidide,12 photo-induced hetero
Diels–Alder reaction of 2-methylbenzaldehydes,13 oxi-
dation of 2-hydroxye0thyl-5-isopropylbenzyl alcohol14 or
2-hydroxymethyl-1-(2 -hydroxyphenyl)naphthalene (13)15
with non-activated manganese dioxide or pyridinium
chlorochromate (PCC). In the case of compound 13, a
complex mixture of aldehyde 14, hemiacetal 15 and
bisacetal 16 was obtained by oxidation of 13 with PCC as
illustrated in Scheme 2 and an equilibrium between
compounds 14 and 15 was found.15 Thus, it is suggested
that compound 2 is synthetically equivalent to aldehyde 17,
which would be formed by formylation of the corresponding
alcohol 18 (Fig. 2).
Numerous methods have been developed to synthesize
isochromanes by using the C–O bond5—or the C–C
bond6—forming cyclization. Practical reactions are shown
in Scheme 1. Compound 4, which was a precursor of
isochromanes 1 and 3, was afforded by heating of 5 with
chloromethyl methyl ether and sodium hydride in tetra-
hydrofuran. Dimethyl ether 4 may be formed via methoxy-
methyl (MOM) ether of 5 under thermal conditions.4
Chloroisochromane 7 was obtained by the reaction of 6
with chloromethyl methyl ether in the presence of Lewis
In this paper, we wish to describe the synthesis of the title
compound 1 by the formylation of alcohol 18 followed by
catalytic hydrogenation and by the intramolecular cycliza-
tion of MOM ethers 19 and 20 and discuss the reaction
Keywords: Heterocycles; Mycotoxin; Isochromane; Formylation; Catalytic
reduction; Intramolecular cyclization.
*
Corresponding author. Tel.: C81 25 267 1500; fax: C81 25 267 1134;
e-mail: suzukit@ngt.ndu.ac.jp
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.01.079

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T. Suzuki et al. / Tetrahedron 62 (2006) 3739–3751
Scheme 1. Synthesis of isochromanes.
2. Results and discussion
Initially, the synthesis of isochromane 1 was examined as
shown in Scheme 3. Ketone 2116 was reduced with lithium
aluminum hydride in ether at 0 8C to give alcohol 18 in 99.0%
yield. Compound 18 was subjected to formylation with
triethyl orthoformate catalyzed by anhydrous aluminum
chloride in dry toluene at K53 to K30 8C to give aldehyde 17
and bisacetal 22 in 48.9 and 42.6% yields, respectively
(Scheme 3). The structure of aldehyde 17 was confirmed by
Figure 1.
mechanisms. The structures of compounds 1–3 were
determined by analysis of spectral data and chemical
reactions, though compounds 1–3 have been reported till
now.
1
1H NMR measurement. The H NMR spectrum showed
the two proton signals of C1–CHO and C2–OH at d 10.21

T. Suzuki et al. / Tetrahedron 62 (2006) 3739–3751
3741
Scheme 2. Syntheses of aldehyde 14, hemiacetal 15 and bisacetal 16.
159.05 and 153.67 ppm for 2 in acetone-d6, respectively.
Those NMR data were not identical with the corresponding
signals of an authentic sample obtained from P. steckii
reported in the literature3 (C1–H at 5.51 ppm; C1, C6 and C8
at 95.4, 155.1 and 155.2 ppm, respectively, in methanol-d4).
This compound must be assigned to compound 23 (Fig. 3)
because the 13C NMR peaks of C6 and C8 carbon atoms
were similar to that of 3 and the differences of chemical
shifts of C8 and C6 carbon atoms was 0.1 ppm as described
below. As shown in Scheme 4, aldehyde 17 might be
produced by hydrolysis of diethyl acetal 24, which was
obtained exclusively from 18 via intermediate A by ortho-
formylation.17 Compound 2 is formed by intramolecular
hemiacetalization of 17 and dimerized to bisacetal 22.15
Figure 2.
and 12.65, respectively. The signal for C2–OH was shifted to
downfield because of intramolecular hydrogen bonding with
C1–CHO. The structure of bisacetal 22 was determined by
the measurements of 1H NMR, Mass and IR spectra and by
1
the results of elemental analysis. The H NMR spectrum
showed the methine proton signal of C1–H at 6.10 ppm. The
mass spectrum did not show the molecular ion of 22
(MC430) but contained two ions at m/z 223 and 207, which
corresponded to the molecular formulas C12H15O4 and
C12H15O3, respectively. Furthermore, the absorption band
of formyl group was not found in the infrared absorption
spectra. Bisacetal 22 was also obtained by heating of
aldehyde 17 at 180 8C for 0.5 h.
To synthesize isochromane 1, compounds 17 and 22 were
hydrogenated as shown in Scheme 3. In the case of 17,
compounds 1 and dimethyl alcohol 25 were obtained in 98.0
and 1.4% yields, respectively, by treatment of 17 with
hydrogen in the presence of 10% palladium on charcoal in
acetone at room temperature for 4 h. When compound 22
was treated with hydrogen in the presence of 10% palladium
on charcoal in acetone at room temperature for 4 h,
compounds 1 and 25 were obtained in 97.0 and 2.0%
yields, respectively. Additionally, a crude mixture of 2, 17
and 22 in a ratio of 70:15:15, which was obtained from
the reaction of 18 with triethyl orthoformate catalyzed
by AlCl3, was stirred in acetone with 10% palladium on
charcoal under hydrogen atmosphere at room temperature
for 4 h, compounds 1 and 25 were obtained in 89.0 and
!1.0% yields, respectively. Thus, compound 1 was
obtained from 18 in good yield in two steps without
purification of the reaction products 2, 17 and 22.
Hemiacetal 2 was not obtained by the formylation of 18
with triethyl orthoformate in the presence of aluminum
chloride as described above. Compound 2 would be
converted into aldehyde 17 or bisacetal 22 during the
treatment of a reaction mixture with the usual way. For this
reasons, detection of 2 by the spectroscopic method was
1
carried out. By the H NMR measurements of the residue,
which was provided by a careful work-up of a reaction
mixture, compound 2 was detected together with 17 in a
ratio of 81:19, respectively. Hemiacetal 2 was changed
partly to aldehyde 17 when a solution of 2 and 17 in
acetone-d6 was left at room temperature for several hours.
The methine proton signal of C1–H was located at 5.64 ppm
and the C1, C6 and C8 carbon signals appeared at 96.27,
The reaction pathways for the formation of compound 1 and
25 by hydrogenation of 2, 17 and 22 with palladium on
charcoal are illustrated in Scheme 5. Hemiacetal 2, which
was formed by intramolecular hemiacetalization of 17 or by

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T. Suzuki et al. / Tetrahedron 62 (2006) 3739–3751
Scheme 3. Synthesis of isochromane 1 and dimethyl alcohol 25.
Next, intramolecular cyclization8a of MOM ether 19 was
examined to synthesize compound 1 and its regioisomer 3
and to elucidate the structures of 1 and 3, respectively,
since the 1H and 13C NMR spectra of 1, which was
obtained above, did not agree with those of an authentic
sample reported in the literature.1,4 Compounds 19 was
obtained by methoxymethylation of 18 with chloromethyl
methyl ether and N-ethyldiisopropylamine in 39.3% yields
together with ether 20 (55.9%) as shown in Scheme 6.
When MOM ether 19 was treated with 0.7 equiv of
titanium(IV) chloride at K49 8C for 15 min, a mixture of
compounds 1 and 3 was obtained in 66.1% yield (the ratio
Figure 3.
hydrolysis of 22, is a common intermediate for the
production of 1 since isochromane 1 was produced
predominantly by catalytic reduction of crude 2, 17 and
22, respectively. In the case of 22, compound 1 would be
afforded by catalytic reduction of 22. On the other hand,
dimethyl alcohol 25 must be formed by catalytic reduction
of 17.18 The structure of 1 was described below.
1
of 1 and 3 was 79:21) (Scheme 6). The H and 13C NMR
data and selected HMBC correlations for compounds 1 and
3 are summarized in Tables 1 and 2, respectively. The
1
assignment of H and 13C NMR spectra of 1 and 3 was

T. Suzuki et al. / Tetrahedron 62 (2006) 3739–3751
3743
Scheme 4. Reaction pathways for the formation of 2, 17 and 22 by the formylation of 18.
confirmed by comparison with the results of NOESY and
HMBC experiments, respectively (Figs. 4 and 5). The
signal of three protons of methoxy group was located at
3.73 ppm for 1 and at 3.61 ppm for 3. The 13C NMR
showed that the signals of C6 and C8 carbon atoms for 1
appeared at 157.68 and 151.60 ppm, respectively. Whereas,
the corresponding signals for 3 were 155.91 and
156.73 ppm, respectively. The difference of chemical
shift of C6 and C8 carbon atoms was 6.08 ppm for 1 and
that was 0.82 ppm for 3. The carbon atom bearing methoxy
group was appeared at downfield than that possessing
hydroxy group in 13C NMR spectra. The NOESY
experiments of 1 showed that three protons of methoxy
group attached at C6 carbon atom had the correlation with
aromatic hydrogen attached at C5 carbon atom (Fig. 4).
On the other hand, the correlation between three protons of
methoxy group at C8 carbon atom and two protons at C1
carbon atom for 3 was observed as shown in Figure 5. It
was indicated by HMBC spectra of 1 and 3 that three
protons of methoxy group exhibited long-range 1H/13C
correlation with C6 carbon atom for 1, while the
corresponding protons had the same correlation with C8
carbon atom for 3. Additionally, the lanthanide induced
shifts (LIS) experiments supported the structures of 1 and 3
as shown in Table 3. The large LIS values were observed
for C1–H (2.44 ppm) and C3–H (2.10 ppm) for 1. On
the other hand, in the case of 3, C5–H and C7–CH3
had large LIS values of 1.83 and 1.39 ppm, respectively.
Scheme 5. Reaction pathways for the catalytic reduction of compounds 2, 17 and 22 to isochromane 1 and dimethyl alcohol 25, respectively.

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T. Suzuki et al. / Tetrahedron 62 (2006) 3739–3751
Scheme 6. Synthesis of MOM ethers 19 and 20 and isochromanes 1, 3, 26 and 27.
Table 1. 1H and 13C NMR data and selected HMBC correlations for isochromane 1 in CD3CNa
C/H
1
13C
65.10
1H
HMBC (H/C)
0
4.50dt (15.0, 1.5, Ha )
0
4.75d (15.0, He )
3.66ddq (10.5, 3.2, 6.3)
0
2.50dd (16.0, 10.5, Ha )
3
4
71.19
36.46
C1–H
C3–CH3, C5–H
0
2.60dd (16.0, 3.2, He )
4a
5
133.18
103.74
157.68
110.20
151.60
115.67
C1–H
C4–H
6.27s
6b
7
C6–OCH3, C7–CH3
C5–H, C8–OH
C1–H, C7–CH3
C5–H, C8–OH,
C4–H, C1–H
8c
8a
C3–CH3
C6–OCH3
C7–CH3
C8–OH
21.81
56.18
8.45
1.24d (6.3)
3.73s
1.99s
d
6.02s
a NMR spectra were recorded at 500 MHz for 1H and 125 MHz for 13C. Acetonitrile-d3 was used as an internal reference instead of TMS (1H NMR: d 1.93
(CHD2CN), 13C NMR: d 1.30).
b See Ref. 1. The signal of C6 carbon atom appeared at 153.69 ppm in CDCl3.
c See Ref. 1. The signal of C8 carbon atom appeared at 152.58 ppm in CDCl3.
d See Ref. 1. The signal of three protons of methoxy group appeared at 3.66 ppm in CDCl3.

T. Suzuki et al. / Tetrahedron 62 (2006) 3739–3751
Table 2. H and 13C NMR data and selected HMBC correlations for isochromane 3 in CD3CNa
3745
1
C/H
1
13C
65.62
1H
HMBC (H/C)
0
4.57dt (14.9, 1.4, Ha )
0
4.79d (14.9, He )
3.66ddq (10.7, 3.2, 6.1)
0
2.47dd (16.4, 10.7, Ha )
3
4
72.02
36.71
C1–H
C3–CH3, C5–H
0
2.58dd (16.4, 3.2, He )
4a
5
120.82
111.93
155.91
116.68
156.73
C1–H
C4–H, C6–OH
C7–CH3
C5–H, C6–OH
C1–H, C7–CH3
C8–OCH3
C4–H
6.33s
6b
7
8c
8a
134.26
22.48
56.18
9.47
C3–CH3
C6–OH
C7–CH3
C8–OCH3
1.23d (6.1)
6.68s
2.03s
d
61.18
3.61s
a NMR spectra were recorded at 500 MHz for 1H and 125 MHz for 13C. Acetonitrile-d3 was used as an internal reference instead of TMS (1H NMR: d 1.93
(CHD2CN); 13C NMR: d 1.30).
b See Ref. 4a. The signal of C6 carbon atom appeared at 149.9 ppm in CDCl3.
c See Ref. 4a. The signal of C8 carbon atom appeared at 156.4 ppm in CDCl3.
d See Ref. 4a. The signal of three protons of methoxy group appeared at 3.79 ppm in CDCl3. Chloroform was used as an internal reference instead of TMS
(1H NMR: d 7.26).
Figure 4. The selective NOESY and HMBC correlations for 1.
Figure 5. The selective NOESY and HMBC correlations for 3.

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T. Suzuki et al. / Tetrahedron 62 (2006) 3739–3751
Table 3. Eu(dpm)3 induced shifts (ppm) of isochromanes 1 and 3a
Compound
Proton (shift value/ppm)
1
3
C1–H (2.44), C3–H (2.10), C3–CH3 (1.16), C4–H (1.09), C5–H (0.31), C6–OCH3 (0.27), C7–CH3 (0.57), C8–OH (Kb)
C1–H (0.89), C3–H (Kc), C3–CH3 (0.78), C4–H (0.40), C5–H (1.83), C6–OH (Kb), C7–CH3 (1.39), C8–OCH3 (1.17)
a Shift studies were carried out by stepwise addition of known amounts of Eu(dpm)3 to ca. 0.37–0.27 M solutions of substrates in CDCl3. The LIS data were
obtained by graphic extrapolation of the observed shifts to a 1:1 shift reagent–substrate ratio.
b Signals of hydroxyl group were disappeared by the addition of Eu(dpm)3.
c A signal of C3–H was not measured as it was week and multiple by addition of Eu(dpm)3.
Scheme 7. Plausible mechanisms for the formation of isochromanes 1 and 3 or their MOM ethers 26 and 27.
Those results indicate that the europium(III) atom is
coordinated to the oxygen of C8 hydroxy group for 1 and
to the oxygen of C6 hydroxy group for 3, respectively,
though the LIS values of phenolic protons were not obtained.
which was obtained from the metabolite of P. steckii1,3 and
P. corylophilum2 is compound 3 and the 1-hydroxyiso-
chromane, which was separated from the culture of P.
steckii3 is compound 23. Similarly, isochromanes 1 and 3,
which are shown in Scheme 1 must be corrected to
compound 3 and 1, respectively.
Compounds 1 and 3 were tried to synthesize by an alternate
route (Scheme 6). Dimethoxyisochromane 4, which was
obtained by methylation of compound 1 with MeI was
treated with sodium ethyl sulfide in N,N-dimethyformamide
(DMF) at 140 8C for 3 h to give a mixture of compounds 1
and 3 (1:3Z95:5) in 91.8% yield.4,19 Compounds 1 and 3
were identified by comparison of their spectra to those of
authentic samples obtained above. The sterically more-
hindered C8 methoxy group was selectively demethylated
though the reason is not clear.†
Finally, intramolecular cyclization of ether 20 was carried
out by using equimolecular amount of titanium(IV) chloride
as catalyst in dry dichloromethane (Scheme 6).8a Mixtures
of compounds 26 and 27 (29.0%; 26:27Z53:47) and 1 and 3
(52.6%; 1:3Z88:12) were obtained. Compound 1 or 3 must
be obtained by deprotection of MOM ether 26 or 27 with
TiCl4. The structures of 26 and 27 were identified by the
comparison of their spectra to those of authentic samples
obtained by the reaction of 1 and 3 with chloromethyl
methyl ether and N-ethyldiisopropylamine in dichloro-
methane, respectively. Plausible mechanisms for the
production of 1, 3, 26 and 27 are illustrated in Scheme 7.
In the case of 19 (RZH), the oxocarbenium intermediate B
(RZH) must be produced by the interaction of titanium(IV)
chloride with the two oxygens of MOM group and C8
hydroxyl group. On the other hand, the oxocarbenium
Although the structure of compound 1 was elucidated by the
substituent effects of hydroxy group to the 13C chemical
shifts of 1,1 above results indicated that the isochromane,
† Cutler et al.4 showed that demethylation of compound 4 with sodium
ethyl sulfide gave compound 3 because nucleophilic substitution occurred
at the less sterically hindered C6 methoxyl carbon atom (Scheme 1).

T. Suzuki et al. / Tetrahedron 62 (2006) 3739–3751
3747
intermediate D (RZH) must be formed by the interaction of
TiCl4 with the two oxygens of MOM group and C6 methoxy
group.20 By the intramolecular nucleophilic attack of
aromatic ring to the carbon atom of intermediates B and
D, compounds 1 and 3 would be afforded, respectively. In
the case of 20 (RZMOM), the oxocarbenium intermediates
C and D (RZMOM) were formed by the interactions
between TiCl4 with two oxygen atoms of two MOM groups
and MOM group and C6 methoxy group, respectively.
MOM ethers 26 and 27 were produced by the intramolecular
nucleophilic attack of aromatic ring to the carbon atom of
intermediates C and D, respectively. Compound 1 or 26
would be produced predominantly via path a, whereas
compound 3 or 27 would be produced via path b as the yield
of 1 or 1 and 26 was larger than that of 3 or 3 and 27 for the
reaction of 19 or 20 with TiCl4.21
an argon atmosphere. Ether refers to diethyl ether.
Tris (2,2,6,6-tetramethyl-3,5-heptanedionato)europium(III)
(O95%) was purchased from Tokyo Kasei Kogyo and was
used without further purification. Ketone 21 was prepared
according to the reported procedure.16
3.1.1. 1-(3-Hydroxy-5-methoxy-4-methylphenyl)-2-pro-
panol (18). To a stirred suspension of lithium aluminum
hydride (280 mg, 7.38 mmol) in dry ether (66.5 mL) was
added a solution of ketone 21 (779 mg, 4.01 mmol) in ether
(17.0 mL) dropwise at 0 8C for 32 min. After being stirred
for 30 min at 0 8C, the reaction was quenched by addition of
3 M HCl solution (60 mL). Products were extracted with
100 mL of ether twice and the combined organic layer was
washed with water and dried over anhydrous magnesium
sulfate. By evaporation of solvents in vacuo, the residue
(891 mg) was obtained. The residue was chromatographed
on silica gel (30 g, Kieselgel 60, Merck). By elution with
hexane–acetone (6/1) compound 18 (780 mg, 99.0%) was
obtained as colorless crystals, mp 84–85 8C (ether–hexane);
IR (KBr): nmax 3404 (OH), 3160 (OH), 2972, 2932, 2832,
Thus, isochromane 1 was synthesized from the reaction of
alcohol 18 with triethyl orthoformate in the presence of
AlCl3 followed by catalytic reduction of compounds 2, 17
and 22 with or without purification in good yields,
respectively. On the other hand, mixtures of 1 and 3 or of
1, 3, 26 and 27 were obtained from cyclization of MOM
ether 19 or ether 20 by treatment with TiCl4, respectively.
The structures of 1–3 were determined by chemical
1
1622, 1598, 1518, 1458, 1418, 1232, 1114, 812 cmK1; H
NMR (CD3COCD3, 500 MHz): d 1.12 (3H, d, JZ6.5 Hz,
–CH(OH)CH3), 2.01 (3H, s, C4–CH3), 2.52 (1H, dd, JZ
13.5, 6.5 Hz, –CH2CH(OH)–), 2.66 (1H, dd, JZ13.5,
6.7 Hz, –CH2CH(OH)–), 3.60 (1H, d, JZ5.0 Hz,
–CH(OH)–), 3.80 (3H, s, C5–OCH3), 3.94 (1H, m,
–CH(OH)–), 6.35 (1H, s, C2–H or C6–H), 6.38 (1H, s, C2–
H or C6–H), 8.04 (1H, s, C3–OH); 13C NMR (CD3COCD3,
125 MHz): d 8.32, 23.34, 46.89, 55.75, 69.07, 104.12,
109.89, 110.32, 138.65, 156.41, 159.38. Anal. Calcd for
C11H16O3: C, 67.32; H, 8.22. Found: C, 67.31; H, 8.22.
1
reaction, H and 13C NMR spectra and NOESY, HMBC,
and LIS experiments. The isochromane and the 1-hydro-
xyisochromanes, which were obtained from the culture
of P. steckii1,3or P. corylophilum2 were 6-hydroxy-
isochromane 3 and its 1-hydroxy compound 23, respect-
ively. The structure of demethylated compound obtained by
the reaction of 4 with sodium ethyl sulfide in DMF was
assigned to compound 1 by comparison with an authentic
sample.
3.1.2. 2-Hydroxy-6-(2-hydroxypropyl)-4-methoxy-3-
methylbenzaldehyde (17) and 1,10-oxydi(8-hydroxy-6-
methoxy-3,7-dimethylisochromane) (22). To a stirred
suspension of anhydrous aluminum chloride (302 mg,
2.15 mmol) and dry toluene (2.6 mL) at K53 8C was
added dropwise a solution of alcohol 18 (249 mg,
1.27 mmol) and triethyl orthoformate (4.2 mL,
25.34 mmol) in dry toluene (2.6 mL) over a period of
20 min. The reaction mixture was allowed to warm to
K30 8C over a period of 30 min and then stirred for another
35 min at the same temperature. After addition of 6 M HCl
solution (7 mL), cooling bath was removed and the resulting
mixture was stirred at room temperature for 5 min and then
water (10 mL) was added and stirring was continued at
room temperature for an another 10 min. The reaction
mixture was extracted with ether (100 mL) three times and
combined organic layer was washed with brine and dried
with anhydrous magnesium sulfate. Solvents were removed
by a rotary evaporator at 60 8C to gave 280.1 mg of pale
yellow crystals. The crystals were treated with a small
portion of ether and insoluble materials were removed by
filtration. By fractional recrystallization of insoluble
materials from benzene, bisacetal 22 (116 mg, 42.6%) was
obtained as colorless short needles and aldehyde 17
(24.4 mg, 8.6%) as colorless crystals, respectively. The
residue obtained by concentration of filtrate and the liquor of
fractional recrystallization was chromatographed on silica
gel (30 g). By elution with benzene–ether (volume ratio was
varied from 10/1 to 4/1) followed by recrystallization from
benzene, aldehyde 17 (114.5 mg, 40.3%) was afforded.
3. Experimental
3.1. General
Melting points were determined with a Shimadzu MM-2
micro melting point determination apparatus and are
uncorrected. IR spectra were recorded on a Hitachi
I-3000 spectrophotometer. 1H NMR spectra were measured
with a Hitachi R-24B (60 MHz), a Hitachi R-1200
(60 MHz), a Varian Unity 500plus (500 MHz), or a
JEOL ECA 500 (500 MHz) NMR spectrometer. 13C
NMR spectra were measured with a Varian Unity
500plus (125 MHz), or a JEOL ECA 500 (125 MHz)
NMR spectrometer. Tetramethylsilane was used as internal
standard unless otherwise stated. Mass spectra were
recorded on a JEOL JMS-AX505WA mass spectrometer
using electron-impact mode (70 eV). Shibata glass tube
oven model GTO-350RS was employed for heating of
aldehyde 17. Thin-layer chromatography was performed on
pre-coated Kieselgel 60 F254 plates (Merck) and spots were
visualized under UV light. Unless otherwise stated silica
gel (Wakogel C-200, Wako) was employed for the column
chromatography as the packing materials and anhydrous
sodium sulfate as the drying agent. DMF, ethanol and
toluene were dried according to the reported procedures.16
Dichloromethane was refluxed with calcium hydride,
˚
distilled and stored over molecular sieves 4 A under

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T. Suzuki et al. / Tetrahedron 62 (2006) 3739–3751
Compound 17 was transformed to bisacetal 22 by heating at
180 8C for 30 min in a glass tube oven. The IR spectrum of
heated compound was same to that of bisacetal 22 obtained
above.
3.1.4. 8-Hydroxy-6-methoxy-3,7-dimethylisochromane
(1). Method A. A mixture of aldehyde 17 (74 mg,
0.33 mmol), 10% palladium on charcoal (27 mg) and
15.0 mL of acetone was stirred under hydrogen atmosphere
at room temperature for 4 h. After removal of insoluble
materials by filtration, the filtrate was concentrated under
reduced pressure to give the residue (76.1 mg). The residue
was chromatographed on silica gel (30 g). By elution with
benzene–ether (10/1) isochromane 1 (67.7 mg, 98.0%) was
obtained as colorless cubic crystals, mp 153.0–155.3 8C
(benzene); Rf: 0.31 (hexane/etherZ2:1); IR (KBr): nmax
3324 (OH), 3004, 2972, 2928, 2844, 1622, 1594, 1504,
1470, 1456, 1336, 1274, 1256, 1224, 1204, 1130, 1070,
1052, 918, 856, 820, 756, 608, 566, 488 cmK1; MS: m/z (%)
208 (MC, 100), 207 (54), 166 (33), 165 (100). Anal. Calcd
for C12H16O3: C, 69.21; H, 7.74. Found: C, 69.27; H, 7.73.
Compound 17: colorless crystals, mp 125–127 8C (ben-
zene); IR (KBr): nmax 3260 (OH), 2980, 2956, 2924, 2904,
2856, 1630, 1574, 1494, 1416, 1404, 1364, 1304, 1256,
1
1142, 1006, 932, 910, 822, 794, 724, 566 cmK1; H NMR
(CD3COCD3, 500 MHz): d 1.22 (3H, d, JZ5.5 Hz,
CHCH3), 1.99 (3H, s, C3–CH3), 3.00 (1H, dd, JZ14.0,
5.0 Hz, Ar-CH2–), 3.09 (1H, dd, JZ14.0, 7.5 Hz, Ar-CH2–),
3.87 (1H, d, JZ4.5 Hz, –CH(OH)–, disappeared by D2O),
3.93 (3H, s, C4–OCH3), 3.99 (1H, m, –CH(OH)–), 6.56 (1H,
s, C5–H), 10.21 (1H, s, CHO), 12.65 (1H, s, C2–OH,
disappeared by D2O); 13C NMR (CD3COCD3, 125 MHz): d
7.28, 23.81, 41.78, 56.30, 69.40, 106.49, 111.24, 114.64,
145.23, 163.26, 164.67, 195.92; MS: m/z (%) 224 (MC, 49),
206 (61), 191 (58), 180 (98), 179 (100). Anal. Calcd for
C12H16O4: C, 64.27; H, 7.19. Found C, 64.41; H, 7.20.
1H and 13C NMR data of 1 are summarized at Table 1.
Next, by elution with benzene–ether (5/1) dimethyl alcohol
25 (1.0 mg, 1.4%) was obtained as colorless solid, mp 91.0–
93.5 8C; IR (KBr): nmax 3508 (OH), 3420 (OH), 2968, 2928,
2848, 1616, 1588, 1506, 1470, 1418, 1332, 1232, 1128,
Compound 22: colorless short needles from benzene, mp
258–260 8C; IR (KBr): nmax 3436 (OH), 3012, 2972, 2928,
2848, 1612, 1590, 1456, 1422, 1330, 1298, 1136, 1106, 980,
920, 876, 844, 830, 804 cmK1; 1H NMR (C6D6, 500 MHz):
d 1.33 (6H, d, JZ6.5 Hz, C3–CH3!2), 2.25–2.29 (2H, m,
1018, 934, 840, 820 cmK1
;
1H NMR (CD3COCD3,
60 MHz): d 1.13 (3H, d, JZ6.0 Hz, –CH(OH)CH3),
2.05 (3H, s, C2–CH3 or C4–CH3), 2.12 (3H, s, C2–CH3 or
C4–CH3), 2.60–2.77 (2H, m, –CH2CH(OH)–), 3.44 (1H, d,
JZ5.4 Hz, –CH(OH)–), 3.73 (3H, s, C5–OCH3), 3.94 (1H,
m, –CH(OH)–), 6.38 (1H, s, C6–H), 6.99 (1H, s, C3–OH).
Anal. Calcd for C12H18O3: C, 68.54; H, 8.63. Found C,
68.61; H, 8.70.
0
0
C4–Ha !2), 2.43–2.48 (2H, m, C4–He !2), 2.77 (6H, s, C7–
CH3!2), 3.39 (6H, s, C6–OCH3!2), 4.62–4.69 (2H, m,
C3–H!2), 6.10 (2H, s, C1–H!2), 6.16 (2H, s, C5–H!2).
MS: m/z (%) 223 (46), 207 (21), 206 (100), 191 (53), 179
(37), 163 (32), 91 (31). Anal. Calcd for C24H30O7: C, 66.96;
H, 7.02. Found: C, 67.00; H, 6.83.
Method B. A mixture of bisacetal 22 (51 mg, 0.12 mmol),
10% palladium on charcoal (18 mg) and acetone (10.0 mL)
was stirred under hydrogen atmosphere at room temperature
for 4 h. The reaction mixture was worked up in a manner
similar to that described above and isochromane 1 (47.6 mg,
97.0%) and dimethyl alcohol 25 (1.0 mg, 2.0%) were
prepared, respectively.
3.1.3. Detection of 1,8-dihydroxy-6-methoxy-3,
7-dimethylisochromane (2). Alcohol 18 (124 mg,
0.63 mmol) was formylated with triethyl orthoformate
(2.1 mL, 12.67 mmol) in the presence of 95% aluminum
chloride (156 mg, 1.11 mmol) and the reaction mixture was
worked up in a manner similar to that described above. The
extracts were concentrated by a rotary evaporator at 60 8C
until a small amount of liquor was remained and then
volatile materials were removed at room temperature in
vacuo to give the residue (152.4 mg) as oily crystals. The
residue was dissolved in acetone-d6 (1.2 mL) and insoluble
compound 22 (6.9 mg, 5.0%) was removed by filtration. A
1H NMR analysis of the filtrate showed that a ratio of 2 and
17 was 81:19, respectively. After the acetone-d6 solution in
Method C. A solution of compound 18 (124 mg, 0.63 mmol)
and triethyl orthoformate (2.1 mL, 12.67 mmol) in toluene
(1.3 mL) was added dropwise with stirring to a suspension of
aluminum chloride (157 mg, 1.12 mmol) in toluene (1.3 mL)
at K48 8C under an argon atmosphere. The reaction was
carried out similarly as described for the preparation of
compounds 17 and 22 and a reaction mixture was worked up
in a manner similar to that described for the detection of
compound 2 to give the residue (171.6 mg). A ratio of 2 and
17 (82:18) and the yield of 22 (20.5 mg, 15%) in the residue
was determined as described for the detection of 2. A ratio of
2, 17 and 23, which was calculated from the above results,
was about 70:15:15, respectively. The residue was stirred
with 10% Pd on charcoal (60 mg) for 4 h in acetone (26.0 mL)
under hydrogen atmosphere without purification. The
reaction mixture was worked up in a manner similar to that
described for the catalytic hydrogenation of 17 and
isochromane 1 (117.5 mg, 89.0%) and dimethyl alcohol 25
(1.2 mg, 0.9%) were obtained, respectively.
1
a H NMR tube was allowed to stand at room temperature
for 7.67 h, the ratio of 2 and 17 was 67:33, respectively.
Hemiacetal 2 was changed partly to 17 in acetone-d6 by
standing at room temperature.
1
Compound 2: H NMR (CD3COCD3, 500 MHz): d 1.28
(3H, d, JZ6.0 Hz, CHCH3), 2.02 (3H, s, C7–CH3), 2.49
(1H, dd, JZ16.0, 11.0 Hz, Ar-CH2–), 2.60 (1H, dd, JZ
16.0, 3.0 Hz, Ar-CH2–), 3.77 (3H, s, C6–OCH3), 4.08 (1H,
ddq, JZ11.0, 6.0, 3.0 Hz, C3–H), 5.64 (1H, s, C1–H), 6.29
(1H, s, C5–H), 6.94 (1H, s, C1–OH); 13C NMR (CD3-
COCD3, 125 MHz): d 8.31 (C7–CH3), 20.97 (C3–CH3),
36.64 (C4), 55.80 (CH3O), 64.46 (C3), 96.27 (C1), 102.48
(C5), 111.54 (C7), 114.39 (C4a or C8a), 134.22 (C4a or C8a),
153.67 (C8), 159.05 (C6).
3.1.5. 6,8-Dimethoxy-3,7-dimethylisochromane (4). A
suspension of isochromane 1 (181 mg, 0.87 mmol), 60%
sodium hydride (53 mg, 1.33 mmol) and dry DMF

T. Suzuki et al. / Tetrahedron 62 (2006) 3739–3751
3749
(12.5 mL) was stirred at 0 8C for 5 min under an argon
atmosphere and then methyl iodide (0.54 mL, 8.67 mmol)
was added by a syringe. After stirring at the same
temperature for 2 h, the reaction mixture was quenched
with 3 M HCl solution (30 mL) and extracted with
dichloromethane (50 mL) three times. The combined
organic layer was washed with brine and dried. The residue
obtained by evaporation of solvents in vacuo was
chromatographed on silica gel (35 g, Kieselgel 60,
Merck). By elution with hexane–ether (15/1) compound 4
(187.6 mg, 97.2%) was obtained as colorless columns, mp
54.5–55.3 8C (hexane) (lit.,4a 52.5–54 8C); IR (KBr): nmax
2988, 2968, 2948, 2916, 2844, 1614, 1588, 1490, 1478,
1456, 1364, 1330, 1120, 1086, 1010, 1000, 946, 830,
(1H, dd, JZ13.6, 6.0 Hz, –CH2CH(OCH2OCH3)–), 2.83
(1H, dd, JZ13.6, 6.7 Hz, –CH2CH(OCH2OCH3)–), 3.24
(3H, s, –CH(OCH2OCH3)–), 3.48 (3H, s, C3–OCH2OCH3),
3.81 (3H, s, C5–OCH3), 3.92 (1H, ddq, JZ6.7, 6.0, 6.0 Hz,
–CH(OCH2OCH3)–), 4.54 (1H, d, JZ7.0 Hz, –CH(OCH2
OCH3)–), 4.64 (1H, d, JZ7.0 Hz, –CH(OCH2CH3)–), 5.17
(2H, s, C3–OCH2OCH3), 6.42 (1H, s, C2–H or C6–H), 6.58
(1H, s, C2–H or C6–H); 13C NMR (CDCl3, 125 MHz): d 8.26,
20.36, 44.01, 55.13, 55.69, 56.01, 74.20, 94.83, 95.00,
105.79, 108.44, 113.48, 137.37, 155.75, 158.20. Anal. Calcd
for C15H24O5: C, 63.36; H, 8.51. Found: C, 63.18; H, 8.55.
Secondly, MOM ether 19 was obtained by elution with
hexane–ether (2/1) in 39.3% yield as colorless prisms, mp
52.5–53.0 8C (hexane–ether); IR (KBr): nmax 3348, 3016,
2968, 2940, 2896, 2844, 1616, 1600, 1520, 1472, 1422,
1322, 1226, 1142, 1112, 1052, 1026, 898, 826, 796, 672,
644, 608 cmK1; 1H NMR (CDCl3, 500 MHz): d 1.18 (3H, d,
JZ6.0 Hz, –CH(OCH2OCH3)CH3), 2.07 (3H, s, C4–CH3),
2.58 (1H, dd, JZ13.5, 6.0 Hz, –CH2CH(OCH2OCH3)–),
2.79 (1H, dd, JZ13.5, 7.2 Hz, –CH2CH(OCH2OCH3)–),
3.25 (3H, s, –CH(OCH2OCH3)–), 3.80 (3H, s, C5–OCH3),
3.93 (1H, ddq, JZ6.0, 6.0, 7.2 Hz, –CH(OCH2OCH3)–),
4.56 (1H, d, JZ6.8 Hz, OCH2O), 4.66 (1H, d, JZ6.8 Hz,
OCH2O), 5.34 (1H, s, OH), 6.32 (2H, s, C2–H and C6–H);
13C NMR (CDCl3, 125 MHz): d 7.85, 20.29, 43.65, 55.17,
55.71, 74.18, 94.87, 104,28, 109.10, 109.99, 137.40, 154.35,
158.48. Anal. Calcd for C13H20O4: C, 64.98; H, 8.39.
Found: C, 64.75; H, 8.44.
1
814 cmK1; H NMR (CDCl3, 60 MHz): d 1.34 (3H, d, JZ
6.0 Hz, C3–CH3), 2.11 (3H, s, C7–CH3), 2.59–2.70 (2H, m,
C4–H2), 3.69 (3H, s, C8–OCH3), 3.80 (3H, s, C6–OCH3),
4.66 and 5.00 (each 1H, d, JZ14.8 Hz, C1–H2), 6.39 (1H, s,
C5–H). Anal. Calcd for C13H18O3: C, 70.25; H, 8.16. Found:
C, 70.35; H, 8.26.
3.1.6. Demethylation of 6,8-dimethoxy-3,7-dimethyl-
isochromane (4).4,19 To a stirred suspension of 60%
sodium hydride (83 mg, 2.07 mmol) in dry DMF (2.0 mL)
was added dropwise a solution of ethanethiol (154 mL,
2.07 mmol) in dry DMF (1.0 mL) by a syringe under an
argon atmosphere and then stirring was continued for an
additional 10 min. Dimethy ether 4 (185 mg, 0.83 mmol) in
dry DMF (2.1 mL) was added dropwise to the stirred
solution by a syringe and heated at 140 8C for 3 h. After
cooling, the reaction mixture was acidified with 1 M HCl
solution (50 mL) and extracted with ether (50 mL) three
times. The combined organic layer was washed with brine,
dried and evaporated in vacuo to give the residue
(215.8 mg). The residue was chromatographed on silica
gel (30 g, Kieselgel 60, Merck). By elution with hexane–
acetone (volume ratio was varied from 30/4 to 10/3) a
mixture of compounds 1 and 3 (158.8 mg, 91.8%, 95:5) was
obtained as colorless solid. The ratio was determined by 1H
NMR spectroscopy. The structure of 1 and 3 was
determined by comparison of their spectra to that of
authentic samples obtained above.
3.1.8. The cyclization of MOM ether 19 with TiCl4. A
mixture of MOM ether 19 (47 mg, 0.19 mmol) in dry
dichloromethane (3.0 mL) was added to a solution of TiCl4
(21 mL, 0.19 mmol) in dichloromethane (3.0 mL) under
stirring at K48 8C over a period of 15 min under argon
atmosphere and stirred at the same temperature for 15 min.
Methanol (0.2 mL) was added to the reaction mixture by a
syringe and then 3 M HCl solution (4 mL) was added. After
stirring at room temperature, the reaction mixture was
extracted with dichloromethane (40 mL) three times. The
combined organic layer was washed with brine and dried.
The residue (43.8 mg) obtained by evaporation of solvents
in vacuo was chromatographed on silica gel (25 g). By
elution with hexane–ether (5/1) a mixture of compounds 1
and 3 (26.7 mg, 66.1%, 79:21) was obtained as colorless oil.
By repeating chromatography of a mixture of 1 and 3
on silica gel (Kieselgel 60, Merck) eluted with hexane–ether
(30/1)‡ and followed by recrystallization from hexane–ether
compound 3 was obtained as colorless crystals, mp 150.5–
151.5 8C (hexane–ether); Rf: 0.28 (hexane/etherZ2:1); IR
(KBr): nmax 3288 (OH), 2980, 2928, 2844, 1616, 1596,
1506, 1460, 1424, 1390, 1366, 1328, 1098, 1048, 1002, 828,
814, 662 cmK1; MS: m/z (%) 208 (MC, 71), 207 (31), 166
(23), 165 (100). Anal. Calcd for C12H16O3: C, 69.21; H,
7.74. Found: C, 69.28; H, 7.84.
3.1.7. 1-(3-Hydroxy-5-methoxy-4-methylphenyl)-2-meth-
oxymethoxypropane (19) and 1-(3-methoxy-5-methoxy-
methoxy-4-methylphenyl)-2-methoxymethoxypropane
(20). To a stirred solution of alcohol 18 (180 mg, 0.92 mmol)
and N-ethyldiisopropylamine (1.42 mL, 8.16 mmol) in dry
dichloromethane (1.0 mL) chrolomethyl methyl ether
(0.62 mL, 8.16 mmol) was added by a syringe at 0 8C and
continued stirring at room temperature for 18 h. The reaction
mixture was poured into ice water and extracted with
dichloromethane (50 mL) three times. The combined
organic layer was washed with brine and dried over
anhydrous magnesium sulfate. The residue (277.4 mg)
obtained by evaporation of solvents in vacuo was chromato-
graphed on silica gel (30 g, Kieselgel 60, Merck).
Firstly, by elution with hexane–ether (10/1) followed by
hexane–ether (5/1) ether 20 was obtained in 55.9% yield
as colorless oil; IR (KBr): nmax 2936, 1612, 1590, 1454,
1428, 1404, 1150, 1126, 1076, 1030, 920, 844, 666 cmK1; 1H
NMR (CDCl3, 500 MHz): d 1.19 (3H, d, JZ6.0 Hz,
–CH(OCH2OCH3)CH3), 2.09 (3H, s, C4–CH3), 2.62
The 1H and 13C NMR data are summarized in Table 2.
‡ As the difference of Rf values between 1 (Rf: 0.31) and 3 (Rf: 0.28) is
small, it is difficult to separate clearly 3 from 1 by column
chromatography under the given conditions.

3750
T. Suzuki et al. / Tetrahedron 62 (2006) 3739–3751
3.1.9. The cyclization of ether 20 with TiCl4. To a stirred
solution of TiCl4 (15 mL, 0.14 mmol) in dry dichloro-
methane (3.0 mL) ether 20 (55 mg, 0.19 mmol) dissolved in
dichloromethane (3.0 mL) was added dropwise at K49 8C
over a period of 15 min under an argon atmosphere and
stirred at the same temperature for 15 min. The reaction
mixture was worked up in a manner similar to the reaction
of 19 with TiCl4. The residue (42.3 mg) obtained by
evaporation of solvents in vacuo was chromatographed on
silica gel (25 g). A mixture of compounds 26 and 27
(14.1 mg, 29.0%, 53:47) was obtained by elution with
hexane–ether (volume ratio was varied from 20/1 to 10/1).
Secondly, a mixture of 1 and 3 (21.1 mg, 52.6%, 88:12) was
afforded by elution with hexane–ether (5/1). The structure
of 26 and 27 was determined by comparison of their spectra
to that of authentic samples obtained by methoxymethyla-
tion of 1 and 3, respectively, as described bellow.
(CD3COCD3, 125 MHz): d 8.99, 21.86, 36.47, 56.09,
60.28, 64.89, 71.23, 95.40, 110.87, 118.46, 122.17,
133.48, 155.76, 155.84. Anal. Calcd for C14H20O4: C,
66.65; H, 7.99. Found: C, 66.76; H, 8.11.
Acknowledgements
We thank Professor Mutsuo Okamura (Graduate school of
science and technology, Niigata University) for Mass
spectral analysis, Mr. Yoshiaki Matsuda (Faculty of science,
1
Niigata University) for H and 13C NMR measurements
(500 and 125 MHz) and the Division of Chemical Analysis,
the Institute of Physical and Chemical Research (RIKEN)
for elemental analyses, respectively.
References and notes
3.1.10. 6-Methoxy-8-methoxymethoxy-3,7-dimethyl-
isochromane (26). To a mixture of compound 1 (71 mg,
0.34 mmol), N-ethyldiisopropylamine (217 mg, 1.68 mmol)
and dry dichloromethane (1.0 mL) chloromethyl methyl
ether (135 mg, 1.68 mmol) was added by a syringe at 0 8C
under stirring. After stirring at room temperature for 18 h
45 min, water (10 mL) was added and extracted with
dichloromethane (40 mL) three times. The combined
organic layer was washed with brine and dried. The residue
(89.3 mg) obtained by evaporation of solvents in vacuo was
chromatographed on silica gel (25 g). Compound 26
(82.5 mg) was obtained in 96.7% yield by elution with
hexane–ether (10/1) followed by hexane–ether (20/1) as
colorless oil; Rf: 0.47 (hexane/etherZ2:1); IR (neat): nmax
2972, 2936, 2836, 1614, 1590, 1490, 1470, 1362, 1330,
1. Cox, R. H.; Hernandez, O.; Dorner, J. W.; Cole, R. J.;
Fennell, D. I. J. Agric. Food Chem. 1979, 27, 999.
2. Cutler, H. G.; Arrendale, R. F.; Cole, P. D.; Davis, E. E.;
Cox, R. H. Agric. Biol. Chem. 1989, 53, 1975.
3. Malmstrøm, J.; Christophersen, C.; Frisvad, J. C. Phytochem-
istry 2000, 54, 301.
4. (a) Cutler, H. G.; Majetich, G.; Tian, X.; Spearing, P. J. Agric.
Food Chem. 1997, 45, 1422 and references cited therein.
(b) Cutler, H. G.; Majetich, G.; Tian, X.; Spearing P. U.S.
Patent 5,922,889, 1999; Chem. Abstr. 1999, 131, 73559.
5. (a) Quallich, G. J.; Makowski, T. W.; Sanders, A. F.; Urban, F. J.;
Vazquez, E. J. Org. Chem. 1998, 63, 4116. (b) de Koning, C. B.;
Michael, J. P.; van Otterlo, W. A. L. Tetrahedron Lett. 1999, 40,
3037. (c) Bhide, B. H.; Shah, K. K. Indian J. Chem., Sect. B 1980,
19, 9.
1
1264, 1160, 1124, 1092, 1050, 982, 930 cmK1; H NMR
(CDCl3, 500 MHz): d 1.35 (3H, d, JZ6.0 Hz, C3–CH3),
2.11 (3H, s, C7–CH3), 2.65–2.66 (2H, m, C4–H2), 3.59 (3H,
s, OCH2OCH3), 3.75–3.79 (1H, m, C3–H), 3.80 (3H, s, C6–
OCH3), 4.73 (1H, d, JZ15.0 Hz, C1–H), 4.92 and 4.94
(each 1H, d, JZ6.0 Hz, OCH2OCH3), 5.00 (1H, d, JZ
15.0 Hz, C1–H), 6.41 (1H, s, C5–H); 13C NMR (CDCl3,
125 MHz): d 9.39, 21.53, 35.84, 55.56, 57.33, 64.99, 70.53,
99.38, 106.52, 117.10, 120.41, 132.16, 152.87, 157.12.
Anal. Calcd for C14H20O4: C, 66.65; H, 7.99. Found: C,
66.35; H, 7.96.
6. (a) Giles, R. G. F.; Rickards, R. W.; Senanayake, B. S.
¨
J. Chem. Soc., Perkin Trans. 1 1997, 3361. (b) Brase, S.
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1981, 2594.
3.1.11. 8-Methoxy-6-methoxymethoxy-3,7-dimethyl-
isochromane (27). To a stirred solution of compound 3
(20 mg, 0.10 mmol) and N-ethyldiisopropylamine (62 mg,
0.48 mmol) in dry dichloromethane (0.8 mL) chloromethyl
methyl ether (39 mg, 0.48 mmol) was added by a syringe at
0 8C under stirring and continued stirring at room
temperature for 19 h. The reaction mixture was worked up
in a manner similar to that described above and compound
27 (19.1 mg, 78.9%) was obtained as colorless oil; Rf: 0.51
(hexane/etherZ2:1); IR (neat): nmax 2932, 2852, 1614,
1590, 1486, 1450, 1362, 1324, 1262, 1154, 1118, 1086,
10. Anderson, J. R.; Edwards, R. L.; Whalley, A. J. S. J. Chem.
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11. (a) Yamato, M.; Ishikawa, T.; Nagamatsu, T.; Yoshikawa, S.;
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1
1060, 1002, 924, 854, 816 cmK1; H NMR (CD3COCD3,
15. Bringmann, G.; Breuning, M.; Endress, H.; Vitt, D.; Peters, K.;
Peters, E.-M. Tetrahedron 1998, 54, 10677.
500 MHz): d 1.25 (3H, d, JZ6.0 Hz, C3–CH3), 2.10 (3H, s,
C7–CH3), 2.52 (1H, dd, JZ16.0, 11.0 Hz, C4–H), 2.64 (1H,
dd, JZ16.0, 3.0 Hz, C4–H), 3.43 (3H, s, OCH2OCH3), 3.67
(3H, s, C6–OCH3), 3.69 (1H, m, C3–H), 4.62 and 4.83 (each
1H, d, JZ15.0 Hz, C1–H2), 5.17 and 5.19 (each 1H, d, JZ
6.0 Hz, OCH2OCH3), 6.63 (1H, s, C5–H); 13C NMR
16. Suzuki, T.; Okada, C.; Arai, K.; Awaji, A.; Shimizu, T.;
Tanemura, K.; Horaguchi, T. J. Heterocycl. Chem. 2001, 38,
1409.
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T. Suzuki et al. / Tetrahedron 62 (2006) 3739–3751
3751
´
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