Synthetic studies on Sch 202596, an antagonist of the galanin receptor subtype GalR1: An efficient synthesis of (±)-geodin, the spirocoumaranone part of Sch 202596

Article abstract of DOI:10.1016/S0040-4020(01)01250-9

An efficient and facile synthesis of (±)-geodin [(±)-2] corresponding to the spirocoumaranone part of Sch 202596 (1) was accomplished in a convergent manner. The synthetic method features (i) a coupling reaction of the aryl aldehyde 6 with the aryl lithium 7 generated in situ from the aryl bromide 8 to deliver the highly substituted diaryl methanol 24 (6+7→24) and ii) oxidative spirocyclization reaction of the benzophenone 4 to construct the requisite spirocoumaranone skeleton [4→(±)-2] as the key steps. The aromatic segments 6 and 8 were prepared from commercially available methyl 3,5-dihydroxybenzoate (9) and 5-methylresorcinol (10), respectively.

Full text of DOI:10.1016/S0040-4020(01)01250-9

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 1289±1299
Synthetic studies on Sch 202596, an antagonist of the galanin
receptor subtype GalR1: an ef®cient synthesis of (^)-geodin,
the spirocoumaranone part of Sch 202596
²
Tadashi Katoh,p Osamu Ohmori, Katsuhiko Iwasaki and Munenori Inoue
Sagami Chemical Research Center, Nishi-Ohnuma, Sagamihara, Kanagawa 229-0012, Japan
Received 16 November 2001; accepted 14 December 2001
AbstractÐAn ef®cient and facile synthesis of (^)-geodin [(^)-2] corresponding to the spirocoumaranone part of Sch 202596 (1) was
accomplished in a convergent manner. The synthetic method features (i) a coupling reaction of the aryl aldehyde 6 with the aryl lithium 7
generated in situ from the aryl bromide 8 to deliver the highly substituted diaryl methanol 24 (617!24) and ii) oxidative spirocyclization
reaction of the benzophenone 4 to construct the requisite spirocoumaranone skeleton [4!(^)-2] as the key steps. The aromatic segments 6
and 8 were prepared from commercially available methyl 3,5-dihydroxybenzoate (9) and 5-methylresorcinol (10), respectively. q 2002
Elsevier Science Ltd. All rights reserved.
1. Introduction
So far, three galanin receptor subtypes, denoted GalR1,
GalR2, and GalR3, have been cloned and characterized,
all of which contain the seven-transmembrane domain
motif typical of the G-protein coupled receptor super-
family.2a,3 Galanin has been shown to inhibit secretion of
insulin, acetylcholine, serotonin and noradrenaline, while it
stimulates prolactin and growth hormone release; therefore,
1 is anticipated to be a promising therapeutic agent
for feeding disorders involving overeating and obesity,
Alzheimer's disease, pain and depression.4
Sch 202596 (1, Fig. 1), isolated from a fungal fermentation
broth of Aspergillus sp. by the Schering±Plough research
group in 1997, is a potent antagonist of galanin receptor
subtype GalR1.1 This natural product represents the only
small non-peptidic molecule to date shown to inhibit
[
125I]-galanin binding to GalR1-containing membranes
prepared from human melanoma cells using a radioligand
competition assay (IC50ˆ1.7 mM).1,2 Galanin is a 29 amino
acid neuropeptide (30 amino acids in humans) which is
widely distributed in the central and peripheral nervous
systems in mammals.
The gross structure of 1 was revealed by extensive spectro-
scopic studies to have a novel spirocoumaranone skeleton
incorporated with a highly oxygenated cyclohexene ring via
an ether linkage.1 Since 1 belongs to the griseo¯uvin family
of compounds, the absolute con®guration of the chiral
center in the spirocoumaranone moiety was determined by
comparing its circular dichroic (CD) spectrum with that of
griseo¯uvin.1 The relative stereochemistry of the cyclo-
hexene ring moiety of 1 was revealed by analysis of 2D
NMR spectra including COSY, NOESY, HETCOR, and
HMBC experiments, while its absolute stereochemisty has
not been established.1
Its promising biological pro®les as well as unique structural
features make 1 an exceptionally intriguing and timely
target for total synthesis, which, however, has not been
achieved to date. We embarked on a project directed at
the synthesis of 1 and its congeners with the aim of explor-
ing the structure±activity relationships. As depicted in
Scheme 1, the structure of 1 can be retrosynthetically
divided into two segments, namely, the spirocoumaranone
part 2 and the cyclohexene part 3.
Figure 1. Structure of Sch 202596 (1).
Keywords: antibiotics; biomimetic reactions; coupling reactions; cycli-
zation; spiro compounds.
p
Corresponding author. Tel.: 81-427-66-4298; fax: 81-427-49-7631;
e-mail: takatoh@alles.or.jp
Graduate student from Department of Electronic Chemistry, Tokyo
Institute of Technology, Nagatsuta, Yokohama 226-8502, Japan.
²
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)01250-9

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T. Katoh et al. / Tetrahedron 58 (2002) 1289±1299
Scheme 3. Synthesis of the aryl aldehyde segment 5. (a) Zn(CN)2, HCl
(gas), AlCl3, Et2O, rt, 46%; (b) MOMCl, K2CO3, acetone, rt, 85%; (c) MeI,
Cs2CO3, DMF, rt, 95%.
endothelical cells.7 This ®nding strongly suggests that 2
may provide novel treatments for atherosclerotic cardio-
vascular diseases.7 Taking into account those mentioned
earlier, the development of a synthetic route to geodin is
of great importance from a pharmaceutical standpoint.
Recently, we communicated the total synthesis of
(^)-geodin [(^)-2],8 which, to the best of our knowledge,
represents the ®rst and only synthetic work of this natural
product. In this paper, we wish to disclose the full details of
our total synthesis of (^)-2.
Scheme 1. Synthetic strategy for Sch 202596 (1).
Incidentally, 2 is identical with the known antifungal anti-
biotic geodin,5 which was originally isolated from
Aspergillus terreus Thom.6 Quite recently, it was reported
that geodin enhances ®brinolytic activity of vascular
2. Results and discussion
2.1. Synthetic strategy
The retrosynthetic plan for (^)-geodin [(^)-2] is outlined in
Scheme 2. The most crucial stepis envisaged to be the
biogenetic-type oxidative spirocyclization reaction9 of the
benzophenone 4 to construct the requisite spirocoumara-
none skeleton in a single step[ 4!(^)-2]. Although related
oxidative phenolic coupling reactions have been previously
reported for the total synthesis of antifungal antibiotic
(^)-griseo¯uvin and its related compounds,10 to our
knowledge, the spirocyclization of the highly substituted
benzophenone derivative such as 4 to obtain (^)-2 is
unprecedented. The key spirocyclization precursor 4,
which possesses the highly sterically constrained tetra-
ortho-substituted benzophenone arrangement, is envisioned
to be elaborated through the coupling reaction of the tetra-
substituted aryl aldehyde 5 or 6 with the fully substituted
aryl lithium 7 generated in situ from the corresponding aryl
bromide 8 (5 or 617!4). Analogous coupling reaction
using less substituted substrates has been disclosed in the
synthesis of the benzophenone part of a potent protein
kinase C inhibitor balanol,11 while the coupling reaction
of 5 or 6 with 7 involves an interesting possibility at a
synthetic chemical level because all of these compounds
have much more substituted patterns. The two aryl alde-
hydes 5 and 6, in turn, could be derived from commercially
available methyl 3,5-dihydroxybenzoate (9). The aryl
bromide 8 would be accessible from commercially available
5-methylresorcinol (10).
Scheme 2. Synthetic plan for (^)-geodin [(^)-2].

T. Katoh et al. / Tetrahedron 58 (2002) 1289±1299
1291
Scheme 4. Synthesis of the aryl bromide segment 8. (a) SO2Cl2, CHCl3,
08C!rt, 59%; (b) Br2, DMF, rt, 88%; (c) MOMCl, i-Pr2EtN, CH2Cl2,
100%.
2.2. Synthesis of the aryl aldehyde segment 5
At ®rst, as shown in Scheme 3, we pursued the synthesis of
the aryl aldehyde segment 5 starting from the known
1,2,3,5-tetrasubstituted aryl aldehyde 11,12 which was
prepared from 9 according to the literature.12 Subsequent
regioselective monoprotection of 11 was carried out under
standard conditions, furnishing the methoxymethyl (MOM)
ether 12 in 85% yield. The structure of 12 was determined
by spectroscopic analysis including NOESY experiment in
Scheme 6. Synthesis of the aryl aldehyde segment 6. (a) MOMCl, i-Pr2EtN,
CH2Cl2, 08C!rt, 87%; (b) LiAlH4, Et2O, 08C!rt, 98%; (c) NBS, DMF,
08C, 93%; (d) BnBr, NaH, DMF, rt, 95%; (e) n-BuLi, Et2O, 2788C; DMF,
2788C!rt, 95%; (f) 6 M HCl, THF, rt, 94%; (g) MOMCl, K2CO3, acetone,
rt, 72%; (h) MeI, Cs2CO3, DMF, rt, 90%.
2.3. Synthesis of the aryl bromide segment 8
1
the 500 MHz H NMR spectrum; thus, clear NOE inter-
Next, the synthesis of the aryl bromide segment 8, the
coupling partner of 5, was achieved starting from the
known dichlororesorcinol 1313 (Scheme 4). Originally,
compound 13 was derived from the commercially available
5-methylresorcinol (10) by the use of tedious gaseous
chlorine as a chlorinating reagent in carbon tetrachloride.13
We carried out the preparation of 13 according to the
reported procedure13a with some improvements in the reac-
tion conditions. Thus, exposure of 10 to sulfuryl chloride
(2.1 equiv.) in chloroform at 08C!rt afforded 13 in 59%
yield. Subsequent bromination of 13 using bromine in
DMF followed by protection of the two hydroxy groups in
the resulting resorcinol 14 as its bis(MOM ether) provided
the desired aryl bromide segment 8 in 88% yield for the two
steps.
actions between the signals due to the methylene protons
(d 5.24) of the MOM protecting group and the C-6 aromatic
proton (d 7.12) were observed. In this reaction, reactivity of
the hydroxy groupadjacent to the formyl groupin 11 would
be precluded by the formation of an intramolecular
1
hydrogen bond. In the 250 MHz H NMR spectrum of 11,
a singlet signal at 12.36 ppm due to a phenolic hydroxy
proton was observed, which strongly indicates the formation
of an intramolecular hydrogen bond. Finally, methylation of
the remaining hydroxy groupin 12 was performed by
treatment with iodomethane in the presence of cesium
carbonate in N,N-dimethylformamide (DMF), giving rise
to the requisite aryl aldehyde segment 5 in 95% yield.
2.4. Initial attempts for the coupling reaction of the aryl
aldehyde segment 5 with the aryl bromide segment 8
Having obtained both the aryl aldehyde segment 5 and the
aryl bromide segment 8, we next focused our attention on
the critical coupling reaction of these two segments 5 and 8.
As depicted in Scheme 5, unfortunately, initial attempts to
realize this coupling reaction turned out to be fruitless.
When the aryl lithium 7, generated in situ from 8 by
bromine/lithium exchange with n-butyllithium at 2788C
in THF, was allowed to react with 5, none of the desired
coupling product 16 was obtained and the starting material 5
and the debrominated product 15 were recovered. We
assumed that the failure of this coupling reaction was due
to the very low reactivity of the formyl group, which may be
attributed to the steric hindrance of the methoxycarbonyl
grouppresent in 5. In order to circumvent this problem,
we decided to look at the aryl aldehyde segment 6 (see,
Scheme 5. Initial attempts for the coupling reaction of the aryl aldehyde 5
with the aryl bromide 8.

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T. Katoh et al. / Tetrahedron 58 (2002) 1289±1299
were observed. The regioselectivity observed for the mono-
bromination of 18 probably caused by the presence of the
para-directing groupsuch as MOM rpotected hydroxy
group. Conventional benzylation of the hydroxy group in
19 afforded the benzyl ether 20 in 95% yield. For intro-
ducing a formyl group, 20 was initially treated with n-butyl-
lithium at 2788C to furnish the corresponding aryl lithium,
which was then quenched with excess amount (10 equiv.) of
DMF, affording the 1,2,3,5-tetrasubstituted aryl aldehyde 21
in 95% yield. Direct conversion of 21 to the MOM ether 23
by selective deprotection of the MOM protecting groups
met with failure. Therefore, 21 was transformed to 23 via
a two-step sequence of reactions including complete depro-
tection of the two MOM groups in 21 (94%) and regio-
selective monoprotection of the resulting resorcinol 22
(72%). At last, methylation of the hydroxy groupin 23
provided the requisite aryl aldehyde segment 6 in 90% yield.
2.6. Synthesis of the substrate 4 for the key spirocycli-
zation reaction via the coupling reaction of the aryl
aldehyde segment 6 with the aryl bromide segment 8
With the aryl aldehyde segment 6 in hand, our next efforts
were directed toward the crucial coupling reaction of 6 with
the aryl bromide 8, as well as elaboration of the substrate 4
for the key spirocyclization reaction as shown in Scheme 7.
To our delight, the critical coupling reaction of 6 with 8 was
successfully achieved by initial bromine/lithium exchange
of 8 followed by reaction with 6 at 2788C!rt, which led to
the formation of the desired coupling product 24 in 86%
yield. Subsequent Dess±Martin oxidation15 of 24 furnished
the tetra-ortho-substituted benzophenone 25 in 95% yield.
After removal of the benzyl protecting group in 25 by
standard method, the resulting benzyl alcohol 26 was further
converted to the methyl ester 29 in 91% overall yield via the
aldehyde 27 and the carboxylic acid 28 by sequential two-
stepoxidation followed by methyl esteri®cation. Finally,
complete deprotection of the three MOM groups in 29
was conducted by exposure to p-toluenesulfonic acid
(p-TsOH) in re¯uxing methanol, providing the key cycli-
zation precursor 4 in 81% yield.
Scheme 7. Synthesis of the substrate 4 for the key spirocyclization. (a) 8,
n-BuLi, THF, 2788C; 6, 2788C!rt, 86%; (b) Dess±Martin periodinane,
CH2Cl2, rt, 98%; (c) H2 (1 atm), 10% Pd±C, EtOH, rt, 79%; (d) Dess±
Martin periodinane, CH2Cl2, rt, 95%; (e) NaClO2, NaH2PO4, 2-methyl-2-
butene, THF/t-BuOH/H2O (2:5:1), rt; (f) CH2N2, Et2O, 96% (2 steps);
(g) p-TsOH, MeOH, re¯ux, 81%.
Scheme 2), in which the methoxycarbonyl groupin 5 is
replaced with the synthetically equivalent O-protected
hydroxymethyl group. We anticipated that 6 would behave
as a promising substrate for the crucial coupling reaction.
Further investigations concerning the synthesis of 6 and
subsequent coupling reaction of 6 with 8 are the subjects
of the following sections.
2.7. Synthesis of (^)-geodine [(^)-2] via the key spiro-
cyclization reaction of the phenol 4
We next focused our attention on the crucial oxidative spiro-
cyclization reaction to complete the synthesis of the targeted
(^)-geodin [(^)-2]. As depicted in the scheme in Table 1,
this spirocyclization event may proceed via the phenoxo-
nium ion intermediate16,17 such as I, which would be trapped
by the inner phenolic hydroxy group to provide the requisite
spirocyclized product (^)-2. After several experiments (see,
Table 1), it was found that the desired oxidative spirocycli-
zation reaction was best achieved by applying the BuÈchi
protocol18 with some improvements of the reaction con-
ditions. Thus, the phenol 4 was treated with 3.0 equiv.
of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in
dichlorormethane/ethanol (1:1) at room temperature for
1 h, leading to the formation of the requisite (^)-2 in 57%
yield (entry 1). Despite the presence of a nucleophilic polar
protic solvent such as ethanol, none of the para-ethoxy-
substituted cyclohexadienone derivative was obtained
from this reaction. This observation strongly indicates that
2.5. Synthesis of the aryl aldehyde segment 6
The synthesis of the aryl aldehyde segment 6 was conducted
as shown in Scheme 6. Thus, the known benzyl alcohol
1811,14 could be readily prepared from 9 via the bis[methoxy-
methyl (MOM) ether] 17 according to the reported
procedure.11 Regiospeci®c monobromination of the sym-
metrical benzyl alcohol 18 was successfully carried out by
exposure to 1.0 equiv. of N-bromosuccinimide (NBS) in
DMF at 08C, providing the unsymmetrical monobromo-
benzyl alcohol 19 in 93% yield. The structure of 19 was
proven by the 500 MHz 1H NMR spectrum; thus, dis-
tinguishable two signals [d 6.82 (d, Jˆ2.7 Hz) and d 6.91
(d, Jˆ2.7 Hz)] due to the C-4 and C-6 aromatic protons

T. Katoh et al. / Tetrahedron 58 (2002) 1289±1299
1293
Table 1. The key spirocyclization reaction of 4 to (^)-geodin [(^)-2] via phenolic oxidation
Entry
Reagent (equiv.)
DDQ (3.0)
DDQ (3.0)
DDQ (2.0)
DDQ (3.0)
PhI(OCOCF3)2 (1.1)
PhI(OCOCF3)2 (1.1)
PhI (OAc)2 (1.1)
C6F5I(OCOCF3)2 (1.1)
Solvent
Temperature
Time
1 h
8 h
8 h
8 h
10 min
2 h
10 min
4 h
Isolated yield of (^)-2
1
2
3
4
5
6
7
8
CH2Cl2/EtOH (1:1)
CH2Cl2
CH2Cl2
MeCN
MeCN
CF3CH2OH
MeCN
MeCN
rt
rt
rt
rt
57%
25%
8%
25%
rt
40%
250!2308C
Decomposition
Decomposition
Decomposition
rt
rt
the phenoxonium ion intermediate I having phenolic
hydroxy groups is rapidly cyclized in an intramolecular
(10). The explored synthetic method features a coupling
reaction of the aryl aldehyde 6 with the aryl lithium 7
derived from the aryl bromide 8 as well as an oxidative
spirocyclization reaction of the benzophenone 4 to construct
the spirocoumaranone ring system. Further investigation
toward the total synthesis of 1 and analogues is now in
progress and will be reported in due course.
1
manner rather than trapped by external ethanol. The H
NMR spectrum of the synthetic material (^)-2 was identical
with that reported9a for natural (1)-geodin [(1)-(2)]. The
other experiments using DDQ as an oxidizing reagent
deserve some comments. When the reaction was carried
out in only dichloromethane, the yield of the product
decreased to 25% (entry 2); this is probably due to the
poor solubility of the substrate in the solvent. On employing
less amount of DDQ (e.g. 2.0 equiv.), lower yield (8%) of
the product was observed (entry 3). A reaction in polar
nucleophilic solvent such as acetonitrile (MeCN) gave the
product (^)-2 in 25% yield (entry 4). We further examined
the spirocyclization reaction of 4 by the use of hypervalent
iodine reagents such as phenyliodine(III) bis(tri¯uoro-
acetate) (PIFA), phenyliodine(III) diacetate (PIDA), and
penta¯uorophenyliodine(III) bis(tri¯uoroacetate) (FPIFA).
These reagents have been extensively used for various
oxidative phenolic coupling reactions.19 The results are
also summarized in Table 1 (entries 5±8). When the phenol
4 was treated with PIFA (1.1 equiv.) in MeCN at room
temperature according to the method reported by Kita et
al.16a the desired (^)-(2) was obtained in 40% yield (entry
5). In a polar and poorly nucleophilic solvent such as 2,2,2-
tri¯uoroethanol (CF3CH2OH) using the same oxidizing
reagent, the requisite cyclized product was not formed and
unidenti®ed decomposition products were generated even at
lower temperature (250!2358C) (entry 6). The use of
PIDA or FPIFA as an oxidizing reagent resulted in complete
decomposition of the products (entries 7 and 8). In all
experiments shown in Table 1, any dimerized products
generated by an intermolecular phenolic coupling reaction
of 4, were not obtained.
4. Experimental
4.1. General methods
All reactions involving air- and moisture-sensitive reagent
were carried out using oven-dried glassware and standard
syringe-septum cap techniques. Routine monitoring of
reaction were carried out using glass-supported Merck silica
gel 60 F254 TLC plates. Flash column chromatography was
performed on Kanto Chemical Silica Gel 60 N (spherical,
neutral 40±50 mm) with indicated solvents.
All solvents and reagents were used as supplied with the
following exceptions. Tetrahydrofuran (THF) and ether
were freshly distilled from sodium/benzophenone under
argon. Dichloromethane and N,N-dimethylformamide
(DMF) were distilled from calcium hydride under argon.
Melting points were taken on a Yanaco MP-3 micro melting
1
point apparatus and were uncorrected. H and 13C NMR
spectra were measured with a Brucker DRX-500 (500
MHz) spectrometer or a Brucker DRX-250 (250 MHz).
Chemical shifts were expressed in ppm using tetramethyl-
silane (dˆ0) as an internal standard. The following abbre-
viations are used: singlet (s), doublet (d), triplet (t),
multiplet (m), and broad (br). Infrared (IR) spectral
measurements were carried out with a JASCO FT/IR-5300
spectrometer. Low resolution mass (MS) spectra were taken
with a Hitachi RMU-6MG spectrometer, and high reso-
lution mass (HRMS) spectra were obtained on a Hitachi
M-80A spectrometer.
3. Conclusion
We have succeeded in developing a facile and ef®cient
synthetic pathway to (^)-geodin [(^)-2] corresponding to
the spirocoumaranone part of Sch 202596 (1) in a con-
vergent manner starting from commercially available
methyl 3,5-dihydroxybenzoate (9) and 5-methylresorcinol
4.1.1. Methyl 2-formyl-3,5-dihydroxybenzoate (11). This
preparation was carried out according to the reported

1294
T. Katoh et al. / Tetrahedron 58 (2002) 1289±1299
method.12 Anhydrous zinc cyanide (1.56 g, 13 mmol) was
added to a stirred solution of methyl 3,5-dihydroxybenzoate
(9) (1.06 g, 6.3 mmol) in dry Et2O (10 ml) at 08C, and a
solution of anhydrous aluminum chloride (1.71 g, 13
mmol) in dry Et2O (7.0 ml) was added at the same tempera-
ture. Dry hydrogen chloride (gas) was bubbled into the
mixture at 08C for 10 min, and the reaction mixture was
further stirred at room temperature for 18 h. The reaction
was quenched with water (30 ml) at 08C, and the resulting
mixture was extracted with ethyl acetate (3£50 ml). The
combined extracts were washed with brine, then dried
over MgSO4. Concentration of the solvent in vacuo afforded
a residue, which was puri®ed by column chromatography
(hexane/ethyl acetate, 2:1) to give 11 (560 mg, 46%) as a
white solid. Recrystallization from water afforded an ana-
lytical sample of 11 as colorless needles, mp169.5±171 8C
(lit.12 mp163.5 8C); 1H NMR (500 MHz, CDCl3) d 3.95 (s,
3H, OMe), 6.20 (s, 1H, C5±OH), 6.53 (d, Jˆ2.5 Hz, 1H,
C4±H), 6.97 (d, Jˆ2.5 Hz, 1H, C6±H), 10.43 (s, 1H, CHO),
12.62 (s, 1H, C3±OH); 13C NMR (125 MHz, CDCl3) d
52.64, 104.54, 109.62, 112.04, 136.30, 164.22, 164.28,
167.29, 191.52; IR (KBr) 3295, 1723, 1454, 1626, 1433,
1223, 1389, 1277, 1213, 1175, 1028, 862, 820, 783, 747,
675, 570 cm21; EI-MS (m/z) 196 (M1), 181 [(M2Me)1],
137 [(M2CO2Me)1]; Anal. calcd for C9H8O5: C, 55.11; H,
4.11. Found: C, 54.76; H, 4.09.
CDCl3) d 3.48 (s, 3H, MeOCH2), 3.91 (s, 3H, MeO), 3.92
(s, 3H, MeO), 5.23 (s, 2H, OCH2O), 6.68 (d, Jˆ1.9 Hz, 1H,
C4±H), 6.72 (d, Jˆ1.9 Hz, 1H, C6±H), 10.31 (s, 1H, CHO);
13C NMR (125 MHz, CDCl3) d 52.85, 56.05, 56.42, 94.27,
100.96, 107.68, 117.28, 136.34, 162.65, 163.07, 169.28,
187.80; IR (KBr) 2961, 1725, 1678, 1198, 1155, 1441,
1343, 1312, 1229, 1155, 1136, 1084, 1063, 1003, 936,
828 cm21; EI-MS (m/z) 254 (M1), 239 [(M2Me)1]; Anal.
calcd for C12H14O6: C, 56.69; H, 5.55. Found: C, 56.61; H,
5.59.
4.1.4. 4,6-Dichloro-5-methylresorcinol (13). Sulfuryl
chloride (6.58 ml, 82 mmol) was added to a stirred sus-
pension of 5-methylresorcinol (10) (5.00 g, 40 mmol) in
CHCl3 (200 ml) at 08C, and stirring was continued at rt
for 1.5 h. The reaction mixture was poured into water
(100 ml), which was extracted with ethyl acetate (2£
150 ml). The combined extracts were washed with saturated
aqueous NaHCO3 and brine, then dried over MgSO4.
Concentration of the solvent in vacuo afforded a residue,
which was puri®ed by column chromatography (hexane/
ethyl acetate, 4:1) to give 13 (4.59 g, 59%) as a white
solid. Recrystallization from benzene afforded an analytical
sample of 13 as colorless needles, mp170.5±171 8C (lit.13a
mp165.5±167 8C, lit.13b 163.5±1648C); 1H NMR (250 MHz,
CDCl3) d 2.45 (s, 3H, Me), 5.99 (s, 2H, OH£2), 6.63 (s, 1H,
ArH); 13C NMR (125 MHz, CD3OD) d 17.72, 101.67,
111.18, 134.47 (two carbons), 152.11 (two carbons); IR
(KBr) 3443, 1602, 1454, 1360, 1325, 1223, 1140, 1092,
1072, 835, 718, 615, 544 cm21; EI-MS (m/z) 194
[(M12)1], 192 (M1), 176 [(M122H2O)1], 174 [(M2
H2O)1], 159 [M122Cl]1], 157 [(M2Cl)1]; Anal. calcd
for C7H6Cl2O2: C, 43.56; H, 3.13. Found: C, 43.56; H, 3.11.
4.1.2. Methyl 2-formyl-3-hydroxy-5-(methoxymethoxy)-
benzoate (12). Chloromethyl methyl ether (0.32 ml,
4.0 mmol) was added to a stirred suspension of 11
(524 mg, 2.7 mmol) and potassium carbonate (630 mg,
4.5 mmol) in acetone (10 ml) at room temperature under
argon. After 6 h, the reaction mixture was diluted with
ether (50 ml). The organic layer was washed with water
and brine, then dried over MgSO4. Concentration of the
solvent in vacuo afforded a residue, which was puri®ed by
column chromatography (hexane/ethyl acetate, 2:1) to give
12 (543 mg, 85%) as a pale yellow solid. Recrystallization
from Et2O afforded an analytical sample of 12 as colorless
4.1.5. 2-Bromo-4,6-dichloro-5-methylresorcinol (14).
Bromine (0.38 M solution in CH2Cl2, 16.6 ml, 6.3 mmol)
was added dropwise to a stirred solution of 13 (1.00 g,
5.2 mmol) in dry DMF (25 ml) at room temperature. After
3 h, the reaction mixture was diluted with Et2O (200 ml).
The organic layer was washed with 10% aqueous Na2S2O3
and brine, then dried over MgSO4. Concentration of the
solvent in vacuo afforded a residue, which was puri®ed by
column chromatography (hexane/ethyl acetate, 4:1) to give
14 (1.26 g, 88%) as a white solid. Recrystallization from
hexane afforded an analytical sample of 14 as colorless
1
needles, mp81.0±82.5 8C. H NMR (500 MHz, CDCl3) d
3.48 (s, 3H, MeOCH2), 3.95 (s, 3H, MeOCO), 5.24 (2H, s,
OCH2O), 6.76 (d, Jˆ2.4 Hz, 1H, C4±H), 7.12 (d, Jˆ2.4 Hz,
1H, C6±H), 10.46 (s, 1H, CHO), 12.59 (s, 1H, OH); 13C
NMR (125 MHz, CDCl3) d 52.80, 56.49, 94.08, 106.81,
112.28, 113.43, 135.22, 162.74, 165.84, 165.93, 195.62;
IR (KBr) 2961, 1725, 1678, 1198, 1155, 1441, 1343,
1312, 1229, 1155, 1136, 1084, 1063, 1003, 936,
828 cm21; EI-MS (m/z) 240 (M1), 225 [(M2Me)1], 209
[(M2OMe)1]; Anal. calcd for C11H12O6: C, 55.00; H,
5.04. Found: C, 54.74; H, 5.06.
1
needles, mp107±108 8C; H NMR (250 MHz, CDCl3) d
2.45 (s, 3H, Me), 5.95 (s, 2H, OH£2); 13C NMR (125
MHz, CDCl3) d 17.97, 95.52, 112.78, 133.94 (two carbons),
147.95 (two carbons); IR (KBr) 3400, 1582, 1455, 1412,
1367, 1322, 1252, 1210, 1082, 743, 720, 662, 595 cm21
;
EI-MS (m/z) 274 [(M14)1], 272 [(M12)1], 270 (M1),
239 [(M122Cl)1], 237 [(M2Cl)1]; Anal. calcd for
C7H5BrCl2O2: C, 30.92; H, 1.85. Found: C, 31.11; H, 1.87.
4.1.3. Methyl 2-formyl-3-methoxy-5-(methoxymethoxy)-
benzoate (5). Iodomethane (39.0 ml, 0.63 mmol) was added
to a stirred suspension of 12 (101 mg, 0.42 mmol) and
cesium carbonate (165 mg, 0.50 mmol) in dry DMF (5 ml)
at room temperature. After 2 h, the reaction mixture was
diluted with ether (40 ml). The organic layer was washed
with water and brine, then dried over MgSO4. Concentration
of the solvent in vacuo afforded a residue, which was puri-
®ed by column chromatography (hexane/ethyl acetate, 4:1)
to give 5 (101 mg, 95%) as a white solid. Recrystallization
from Et2O/hexane (1:2) afforded an analytical sample of 5
4.1.6. 3,5-Bis(methoxymethoxy)-4-bromo-2,6-dichloro-
toluene (8). Chloromethyl methyl ether (0.74 ml,
9.7 mmol) was added dropwise to a stirred solution of 14
(1.20 g, 4.4 mmol) in CH2Cl2 (30 ml) containing N,N-diiso-
propylethylamine (2.68 ml, 15 mmol) at 08C under argon,
and stirring was continued for 1 h at room temperature. The
reaction mixture was diluted with ether (200 ml), and the
organic layer was washed with saturated aqueous NaHCO3
and brine, then dried over MgSO4. Concentration of the
1
as colorless prisms, mp 62.5±648C. H NMR (500 MHz,

T. Katoh et al. / Tetrahedron 58 (2002) 1289±1299
1295
solvent in vacuo afforded a residue, which was puri®ed by
column chromatography (hexane/ethyl acetate, 4:1) to give
8 (1.59 g, 100%) as a white solid. Recrystallization from
hexane afforded an analytical sample of 8 as colorless
needles, mp63±64 8C; 1H NMR (250 MHz, CDCl3) d
2.48 (s, 3H, ArMe), 3.71 (s, 6H, MeO£2), 5.16 (s, 4H,
OCH2O£2); 13C NMR (125 MHz, CDCl3) d 18.53, 58.38
(two carbons), 99.54 (two carbons), 112.58, 125.98, 135.62
(two carbons), 150.33 (two carbons); IR (KBr) 3452, 2950,
2905, 2840, 2098, 1775, 1655, 1542, 1478, 1460, 1412,
1398, 1375, 1340, 1304, 1212, 1177, 1098, 1042, 1005,
935, 920, 890, 760, 740, 719, 588 cm21; EI-MS (m/z) 362
[(M14)1], 360 [(M12)1], 358 (M1), 302 [(M142
MeO2OMe12H)1], 300 [(M142MeO2OMe12H)1];
Anal. calcd for C11H13BrCl2O4: C, 36.70; H, 3.60. Found:
C, 36.59; H, 3.61.
H); 13C NMR (125 MHz, CDCl3) d 52.13, 56.04 (two
carbons), 94.36 (two carbons), 109.58, 110.56 (two
carbons), 132.07, 158.03 (two carbons), 166.44; IR (neat)
3108, 2955, 2830, 2074, 2000, 1724, 1599, 1439, 1400,
1302, 1238, 1148, 1084, 1030, 923, 879, 709, 680, 553,
449 cm21; EI-MS (m/z) 256 (M1), 225 [(M2OMe)1]
HREIMS (m/z) calcd for C12H16O6 (M1): 256.0946, found
1
256.0955. The H NMR spectrum of this sample accorded
well with that reported.11,14c
4.1.9. 3,5-Bis(methoxymethoxy)benzyl alcohol (18). This
preparation was carried out according to the reported
method.11 A solution of 17 (13.0 g, 51 mmol) in dry THF
(100 ml) was added dropwise to a stirred suspension of
lithium aluminum hydride (2.89 g, 76 mmol) in dry THF
(100 ml) at 08C, and the reaction mixture was stirred at
room temperature for 2 h. Water (3 ml), 15% aqueous
NaOH (3 ml), and water (3 ml) were sequentially added to
the mixture, and stirring was continued for 1 h. The reaction
mixture was ®ltered through a pad of Celitew, and the ®ltrate
was dried over MgSO4. Concentration of the solvent in
vacuo afforded a residue, which was puri®ed by column
chromatography (hexane/ethyl acetate, 1:1) to give 18
(11.3 g, 98%) as a colorless oil. 1H NMR (500 MHz,
CDCl3) d 2,89 (br s, 1H, OH), 3.44 (s, 6H, MeO£2), 4.56
(s, 2H, ArCH2), 5.12 (s, 4H, OCH2O£2), 6.62 (br s, 1H, C4±
H), 6.68 (br s, 2H, C2±H1C6±H); 13C NMR (125 MHz,
CDCl3) d 55.86 (two carbons), 64.65, 94.21 (two carbons),
103.82, 107.77 (two carbons), 143.61, 158.19 (two
carbons); IR (neat) 3402, 2920, 2432, 2072, 2000, 1613,
1462, 1402, 1290, 1215, 1145, 1086, 1022, 924, 844,
700 cm21; EI-MS (m/z) 228 (M1), 198 [(M2CH2OH1
H)1], 168 [(M2CH2OH2OMe12H)1]; HREI-MS (m/z)
calcd for C11H16O5 (M1): 228.0096, found: 228.1000.
4.1.7. An attempt for the coupling reaction of 5 with 8.
n-BuLi (1.14 M solution in hexane, 0.29 ml, 0.34 mmol)
was added to a stirred solution of 8 (110 mg, 0.30 mmol)
in dry THF (2 ml) at 2788C under argon. After 15 min, a
solution of 5 (50.8 mg, 0.20 mmol) in THF (0.8 ml) was
added dropwise to the solution at 2788C, and the resulting
mixture was stirred for 15 min at the same temperature. The
mixture was allowed to warm upto 0 8C over 1 h, and then
stirring was continued for 1 h at 08C. After additional stir-
ring at room temperature for 1 h, the reaction was quenched
with saturated aqueous NH4Cl (0.6 ml). The mixture was
extracted with Et2O (2£40 ml), and the combined extracts
were washed with water and brine, then dried over MgSO4.
Concentration of the solvent in vacuo afforded a residue,
which was puri®ed by column chromatography (hexane/
ethyl acetate, 7:1) to give 15 (83.4 mg, 97%) along with 5
(46.7 mg, 92% recovery). Recrystallization of 15 from
hexane/CHCl3 (1:1) afforded an analytical sample as a
colorless needles, mp72±73 8C; 1H NMR (500 MHz,
CDCl3) d 2.49 (s, 3H, ArMe), 3.52 (s, 6H, MeO£2), 5.22
(s, 4H, OCH2O£2), 6.96 (s, 1H, ArH); 13C NMR (125 MHz,
CDCl3) d 18.07, 56.50 (two carbons), 95.59 (two carbons),
103.00, 118.10, 136.24 (two carbons), 151.77 (two
carbons); IR (KBr) 2966, 1581, 1479, 1452, 1402, 1323,
1226, 1163, 1095, 1041, 931, 918, 841, 742 cm21; EI-MS
(m/z) 284 [(M14)1], 282 [(M12)1], 280 (M1); Anal. calcd
for C11H14Cl2O4: C, 46.99; H, 5.02. Found: C, 46.60; H,
4.99.
4.1.10. 2-Bromo-3,5-bis(methoxymethoxy)benzyl alcohol
(19). N-Bromosuccinimide (NBS) (8.59 g, 48 mmol) was
added in small portions to a stirred solution of 18 (11.0 g,
48 mmol) in dry DMF (220 ml) at 08C. After 2 h, the reac-
tion mixture was diluted with ethyl acetate (400 ml). The
organic layer was washed successively with 10% aqueous
Na2S2O3, water, and brine, then dried over MgSO4. Concen-
tration of the solvent in vacuo afforded a residue, which was
puri®ed by column chromatography (hexane/ethyl acetate,
1:1) to give 19 (13.8 g, 93%) as a white solid. Recrystalli-
zation from i-Pr2O/hexane (1:1) afforded an analytical
1
4.1.8. Methyl 3,5-bis(methoxymethoxy)benzoate (17).
This preparation was carried out according to the reported
procedure.11 Chloromethyl methyl ether (11.3 ml, 0.15 mol)
was added dropwise to a stirred solution of methyl 3,5-di-
hydroxybenzoate (9) (10.0 g, 60 mmol) and N,N-diiso-
propylethylamine (31.0 ml, 0.18 mol) in dry CH2Cl2
(100 ml) at 08C under argon. After the solution was stirred
at room temperature for 5 h, the reaction mixture was
diluted with dichloromethane (500 ml). The organic layer
was washed successively with 3% aqueous HCl, saturated
aqueous NaHCO3, and brine, then dried over MgSO4.
Concentration of the solvent in vacuo afforded a residue,
which was puri®ed by column chromatography (hexane/
ethyl acetate, 5:1) to give 17 (13.3 g, 87%) as a colorless
sample of 19 as a white powder, mp 56±578C; H NMR
(500 MHz, CDCl3) d 2.05 (t, Jˆ6.5 Hz, 1H, OH), 3.48 (s,
3H, OMe), 3.52 (s, 3H, OMe), 4.73 (d, Jˆ6.5 Hz, 2H,
ArCH2), 5.17 (s, 1H, OCH2O), 5.23 (s, 1H, OCH2O), 6.82
(d, Jˆ2.7 Hz, 1H, C3±H or C5±H), 6.91 (d, Jˆ2.7 Hz, 1H,
C3±H or C5±H); 13C NMR (125 MHz, CDCl3) d 56.18,
56.48, 65.34, 94.57, 95.26, 104.21, 104.78, 109.48,
141.88, 154.44, 157.44; IR (KBr) 3410, 2920, 1454, 1400,
1318, 1215, 1148, 1080, 1019, 922, 853, 583 cm21; EI-MS
(m/z) 308 [(M12)1], 306 (M1); Anal. calcd for
C11H15BrO5: C, 43.02; H, 4.92. Found: C, 42.84; H, 4.95.
4.1.11.
2-Benzyloxymethyl-4,6-bis(methoxymethoxy)-
bromo benzene (20). NaH (60% dispersion in mineral oil,
1.95 g, 49 mmol) was added in small portions to a stirred
solution of 19 (10.0 g, 33 mmol) in dry DMF (50 ml) at 08C.
After 20 min, benzyl bromide (4.65 ml, 44 mmol) was
1
oil. H NMR (250 MHz, CDCl3) d 3.48 (s, 6H, MeOCH2£
2), 3.90 (s, 3H, MeOCO), 5.19 (s, 4H, OCH2O£2), 6.92 (t,
Jˆ2.3 Hz, 1H, C4±H), 7.37 (d, Jˆ2.3 Hz, 2H, C2±H1C6±

1296
T. Katoh et al. / Tetrahedron 58 (2002) 1289±1299
added dropwise to the solution at 08C, and stirring was
continued for 1 h at room temperature. The reaction was
quenched with saturated aqueous NH4Cl, and the resulting
mixture was diluted with Et2O (500 ml). The organic layer
was washed with water and brine, then dried over MgSO4.
Concentration of the solvent in vacuo afforded a residue,
which was puri®ed by column chromatography (hexane/
ethyl acetate, 7:1) to give 20 (12.2 g, 95%) as a colorless
oil. 1H NMR (500 MHz, CDCl3) d 3.46 (s, 3H, MeO), 3.50
(s, 3H, MeO), 4.60 (s, 2H, ArCH2O), 4.63 (s, 2H, ArCH2O),
5.15 (s, 2H, OCH2O), 5.22 (s, 2H, OCH2O), 6.81 (d,
Jˆ2.8 Hz, 1H, C3±H or C5±H), 6.97 (d, Jˆ2.7 Hz, 1H,
NaHCO3, and brine, then dried over MgSO4. Concentration
of the solvent in vacuo afforded a residue, which was
puri®ed by column chromatography (hexane/ethyl acetate,
1:1) to give 22 (3.77 g, 94%) as a white solid. Recrystalli-
zation from CHCl3/hexane (1:1) afforded an analytical
1
sample of 22 as a white powder, mp 130.5±131.58C; H
NMR (250 MHz, CDCl3) d 4.58 (s, 2H, ArCH2O), 4.70 (s,
2H, ArCH2O), 6.32 (d, Jˆ2.3 Hz, 1H, C3±H or C5±H), 6.41
(d, Jˆ2.3 Hz, 1H, C3±H or C5±H), 6.48 (br s, 1H, C4±OH),
7.23±7.46 (m, 5H, PhCH2O), 10.10 (s, 1H, CHO), 12.36 (s,
1H, C6±OH); 13C NMR (125 MHz, CDCl3) d 69.0, 72.6,
103.1, 110.1, 112.7, 128.0 (two carbons), 128.1, 128.6
(two carbons), 137.1, 143.8, 163.4, 166.4, 193.5; IR (KBr)
3420, 2930, 2855, 1640, 1460, 1380, 1225, 1170, 740,
700 cm21; CI-MS (m/z) 259 [(M11)1]; 167 [(M2Bn)1],
152 [(M2OBn)1]; HREIMS (m/z) calcd for C15H14O4
(M1): 258.0891, found: 258.0916.
0
C3±H or C5±H), 7.29 (t, Jˆ7.3 Hz, 1H, C4 ±H), 7.35 (t,
0
0
Jˆ7.3 Hz, 2H, C3 ±H1C5 ±H), 7.39 (d, Jˆ7.3 Hz, 2H,
C2 ±H1C6 ±H); 13C NMR (125 MHz, CDCl3) d 56.05,
56.34, 71.63, 72.72, 94.50, 95.17, 103.98, 105.02, 109.71,
127.64, 127.72 (two carbons), 128.34 (two carbons),
137.94, 139.73, 154.27, 157.18; IR (neat) 2953, 2828,
1956, 1599, 1460, 1400, 1377, 1294, 1213, 1146, 1082,
1036, 924, 847, 741, 698 cm21; EI-MS (m/z) 398 [(M1
2)1], 396 (M1), 292 [(M122OBn1H)1], 290 [(M2
OBn1H)1]; HREIMS (m/z) calcd for C18H21BrO5 (M1):
396.0561, found: 396.0566.
0
0
4.1.14. 2-Benzyloxymethyl-6-hydroxy-4-(methoxymeth-
oxy)benzaldehyde (23). Chloromethyl methyl ether
(1.04 ml, 14 mmol) was added to a stirred suspension of
22 (3.20 g, 12 mmol) and potassium carbonate (1.71g,
12 mmol) in acetone (60 ml) at room temperature under
argon. After 1 h, the reaction mixture was diluted with
ether (350 ml). The organic layer was washed with water
and brine, then dried over MgSO4. Concentration of the
solvent in vacuo afforded a residue, which was puri®ed by
column chromatography (hexane/ethyl acetate, 6:1) to give
4.1.12.
2-Benzyloxymethyl-4,6-bis(methoxymethoxy)-
benzaldehyde (21). n-BuLi (0.96 M solution in hexane,
26.6 ml, 26 mmol) was added dropwise to a stirred solution
of 20 (6.76 g, 17 mmol) in dry Et2O (70 ml) at 2788C under
argon, and stirring was continued at the same temperature
for 1 h. Dry DMF (13.2 ml, 0.17 mol) was added slowly to
the solution at 2788C, and the reaction mixture was allowed
to warm upto room temperature over 3 h. The reaction was
quenched with saturated aqueous NH4Cl (15 ml), and the
resulting mixture was diluted with Et2O (400 ml). The
organic layer was washed successively with saturated
aqueous NH4Cl, water, and brine, then dried over MgSO4.
Concentration of the solvent in vacuo afforded a residue,
which was puri®ed by column chromatography (hexane/
ethyl acetate, 4:1) to give 21 (5.60 g, 95%) as a light yellow
solid. Recrystallization from i-Pr2O/hexane (1:1) afforded
an analytical sample of 21 as a light yellow powder, mp
1
23 (2.70 g, 72%) as a colorless oil. H NMR (500 MHz,
CDCl3) d 3.47 (s, 3H, MeO), 4.57 (s, 2H, ArCH2), 4.71 (s,
2H, ArCH2), 5.20 (s, 2H, OCH2O), 6.55 (s, 2H, C3±H1C5±
H), 7.35 (m, 5H, PhCH2), 10.14 (s, 1H, CHO), 12.33 (s, 1H,
C6±OH); 13C NMR (125 MHz, CDCl3) d 56.48, 69.32, 72.61,
94.04, 103.32, 110.67, 113.35, 127.97 (two carbons), 128.04,
128.57 (two carbons), 137.33, 154.06, 163.73, 166.21,
193.92; IR (neat) 3651, 3063, 3030, 2903, 1650, 1634,
1578, 1495, 1454, 1408, 1369, 1325, 1298, 1224, 1152,
1080, 1001, 937, 854, 804, 737 cm21; CI-MS (m/z) 303
[(M11)1], 211 [(M2Bn)1], 211 [(M2OBn)1]; HREIMS
(m/z) calcd for C17H18O5 (M1): 302.1154, found: 302.1159.
1
60±60.58C; H NMR (250 MHz, CDCl3) d 3.49 (s, 3H,
4.1.15. 2-Benzyloxymethyl-6-methoxy-4-(methoxymeth-
oxy)benzaldehyde (6). Iodomethane (0.621 ml, 9.9 mmol)
was added to a stirred suspension of 23 (1.86 g, 6.2 mmol)
and cesium carbonate (2.31 g, 7.1 mmol) in dry DMF
(18 ml) at room temperature. After 1 h, the reaction mixture
was diluted with ether (250 ml). The organic layer was
washed with water and brine, then dried over MgSO4.
Concentration of the solvent in vacuo afforded a residue,
which was puri®ed by column chromatography (hexane/
ethyl acetate, 1:1) to give 6 (1.75 g, 90%) as a colorless
MeO), 3.51 (s, 3H, MeO), 4.67 (s, 2H, ArCH2O), 4.97 (s,
2H, ArCH2O), 5.23 (s, 2H, OCH2O), 5.27 (s, 2H, OCH2O),
6.77 (d, Jˆ2.1 Hz, 1H, C3±H or C5±H), 7.17 (br s, 1H, C3±
0
H or C5±H), 7.29 (t, Jˆ7.2 Hz, 1H, C4 ±H), 7.36 (t, Jˆ
0
0
0
7.4 Hz, 2H, C3 ±H1C5 ±H), 7.40 (d, Jˆ7.4 Hz, 2H, C2 ±
H1C6 ±H), 10.48 (s, 1H, CHO); 13C NMR (125 MHz,
0
CDCl3) d 56.42, 56.54, 70.33, 72.94, 94.02, 94.84,
100.80, 107.47, 116.80, 127.55, 127.61 (two carbons),
128.36 (three carbons), 138.32, 145.55, 162.76, 190.19; IR
(KBr) 3393, 2922, 1723, 1674, 1601, 1576, 1453, 1399,
1352, 1283, 1211, 1143, 1082, 1026, 925, 858, 812, 738,
698, 596 cm21; CI-MS 347 [(M11)1], 315 [(M2OMe)1],
255 [(M2Bn)1], 239 [(M2OBn)1]; Anal. calcd for
C19H22O6: C, 65.88; H, 6.40. Found: C, 65.66; H, 6.40.
1
oil. H NMR (500 MHz, CDCl3) d 3.50 (s, 3H, MeOCH2),
3.89 (s, 3H, MeOAr), 4.67 (s, 2H, ArCH2), 4.97 (s, 2H,
ArCH2), 5.25 (s, 2H, MeOCH2O), 6.55 (d, Jˆ2.2 Hz, 1H,
C3±H or C5±H), 7.11 (d, Jˆ1.3 Hz, 1H, C3±H or C5±H),
0
7.29 (br d, Jˆ7.3 Hz, 1H, C4 ±H), 7.35 (ddd, Jˆ1.7, 7.3,
0
0
0
7.3 Hz, 2H, C3 ±H1C5 ±H), 7.40 (br d, Jˆ7.2 Hz, 2H, C2 ±
H1C6 ±H), 10.45 (s, 1H, CHO); 13C NMR (125 MHz,
0
4.1.13. 2-Benzyloxymethyl-4,6-dihydroxybenzaldehyde
(22). 6 M HCl (65 ml, 0.39 mol) was added slowly to a
stirred solution of 21 (5.38 g, 16 mmol) in THF (80 ml) at
room temperature. After 2 h, the reaction mixture was
diluted with ethyl acetate (400 ml). The organic layer was
washed successively with water, saturated aqueous
CDCl3) d 55.91, 56.40, 70.40, 72.95, 94.06, 97.70,
106.16, 116.19, 127.54, 127.61 (two carbons), 128.36
(two carbons), 138.37, 145.81, 163.01, 165.08, 190.22; IR
(neat) 3063, 3030, 2940, 2903, 2787, 2612, 2000, 1728,
1672, 1601, 1456, 1437, 1408, 1350, 1267, 1233, 1198,

T. Katoh et al. / Tetrahedron 58 (2002) 1289±1299
1297
1146, 1071, 1020 cm21; CI-MS (m/z) 317 [(M11)1], 225
[(M2Bn)1], 209 [(M2OBn)1]; HRCI-MS (m/z) calcd for
C18H20O5 [(MH)1]: 317.1388, found: 317.1418.
carbons), 133.55, 136.21, 138.41, 145.61, 148.61 (two
carbons), 161.72, 162.17, 190.46; IR (neat) 3436, 2855,
1651, 1599, 1454, 1371, 1260, 1159, 1069, 1040,
922 cm21; EI-MS (m/z) 596 [(M12)1], 594 (M1), 505
[(M122Bn)1], 503 [(M2Bn)1], 490 [(M122OBn1
H)1], 488 [(M2OBn1H)1], HREIMS (m/z) calcd for
C29H32Cl2O9 (M1): 594.14234, found: 594.1411.
4.1.16. 4-{[2-Benzyloxymethyl-6-methoxy-4-(methoxy-
methoxy)phenyl]hydroxymethyl}-3,5-bis(methoxymeth-
oxy)-2,6-dichlorotoluene (24). n-BuLi (1.14 M solution in
hexane, 0.58 ml, 0.66 mmol) was added to a stirred solution
of 8 (214 mg, 0.60 mmol) in dry THF (4 ml) at 2788C under
argon. After 15 min, a solution of 6 (126 mg, 0.40 mmol) in
THF (1.5 ml) was added dropwise to the solution at 2788C,
and the resulting mixture was stirred for 15 min at the same
temperature. The mixture was allowed to warm up to 08C
over 1 h, and stirring was continued at the same temperature
for 1 h. After additional stirring at room temperature for 1 h,
the reaction was quenched with saturated aqueous NH4Cl
(1 ml). The mixture was extracted with Et2O (2£70 ml), and
the combined extracts were washed with water and brine,
then dried over MgSO4. Concentration of the solvent in
vacuo afforded a residue, which was puri®ed by column
chromatography (hexane/ethyl acetate, 7:1) to give 24
4.1.18.
2-[2,6-Bis(methoxymethoxy)-3,5-dichloro-4-
methylbenzoyl]-3-methoxy-5-(methoxymethoxy)benzyl
alcohol (26). A mixture of 25 (89.6 mg, 0.151 mmol) and
10% Pd/C (16.0 mg) in EtOH (5 ml) was stirred under H2
(1 atm) at room temperature for 1 h. The reaction mixture
was diluted with EtOH (30 ml), and the catalyst was ®ltered
off. Concentration of the ®ltrate in vacuo afforded a residue,
which was puri®ed by column chromatography (hexane/
ethyl acetate, 2:1) to give 26 (60.3 mg, 79%) as a light
1
yellow oil. H NMR (500 MHz, CDCl3) d 2.55 (s, 3H,
ArMe), 3.36 (s, 6H, MeOCH2O), 3.48 (s, 3H, MeO), 3.48
(s, 3H, MeO), 4.03 (t, Jˆ7.3 Hz, 1H, OH), 4.62 (d, Jˆ
7.0 Hz, 2H, ArCH2O), 4.92 (s, 4H, MeOCH2O£2), 5.22
(s, 2H, MeOCH2O), 6.50 (d, Jˆ2.2 Hz, 1H, C3±H or C5±
H), 6.79 (d, Jˆ2.2 Hz, 1H, C3±H or C5±H); 13C NMR
(125 MHz, CDCl3) d 18.63, 56.08, 56.39, 57.84 (two
carbons), 65.34, 94.16, 99.76, 100.22 (two carbons),
110.82, 121.59, 125.07 (two carbons), 133.13, 136.74,
146.64, 148.76 (two carbons), 162.03, 162.68, 192.40; IR
(neat) 3433, 2920, 2851, 1647, 1599, 1575, 1404, 1373,
1261, 1211, 1159, 1086, 1034, 914, 818, 606 cm21; EI-
MS (m/z) 490 [(M142H2O)1], 488 [(M122H2O)1], 486
[(M2H2O)1], 442 [(M22£OMe)1]; HREIMS (m/z) calcd
for C22H24Cl2O8 [(M2H2O)1]: 486.0848, found: 486.0826.
1
(204.1 mg, 86%) as a colorless oil. H NMR (500 MHz,
CDCl3) d 2.45 (s, 3H, ArMe), 3.47 (s, 3H, MeO), 3.51 (s,
6H, MeOCH2£2), 3.70 (s, 3H, MeO), 4.55 (s, 2H, ArCH2O),
4.63 (d, Jˆ12.3 Hz, 1H, ArCHO), 4.72 (d, Jˆ11.8 Hz, 1H,
ArCHO), 4.73 (d, Jˆ5.0 Hz, 2H, OCHH0O£2), 4.92 (d,
Jˆ5.0 Hz, 2H, OCHH0O£2), 5.14 (d, Jˆ8.3 Hz, 1H,
CHOH), 5.15 (s, 2H, MeOCH2), 6.46 (d, Jˆ8.3 Hz, 1H,
CHOH), 6.54 (d, Jˆ2.4 Hz, 1H, C3±H or C5±H), 6.81 (d,
0
Jˆ2.4 Hz, 1H, C3±H or C5±H), 7.26 (m, 1H, C4 ±H), 7.34
(m, 4H, C2 ±H1C3 ±H); 13C NMR (125 MHz, CDCl3) d
18.47, 55.67, 56.07, 57.89 (two carbons), 66.83, 70.52,
72.47, 94.49, 99.72 (two carbons), 100.11, 108.84, 122.55,
125.26 (two carbons), 127.46, 127.71 (two carbons), 128.27
(two carbons), 132.14, 135.18, 138.27, 138.65, 150.14 (two
carbons), 157.13, 158.57; IR (neat) 3436, 2938, 1605, 1454,
1383, 1333, 1213, 1153, 1082, 1032, 922, 698 cm21; EI-MS
(m/z) 598 [(M12)1], 596 (M1), 491 [(M122OBn)1], 489
[(M2OBn)1], 429 [(M122OBn22£OMe)1], 427 [(M2
OBn22£OMe)1]; HREIMS (m/z) calcd for C29H34Cl2O9
(M1): 596.1580, found: 596.1590.
0
0
4.1.19.
2-[2,6-Bis(methoxymethoxy)-3,5-dichloro-4-
methylbenzoyl]-3-methoxy-5-(methoxymethoxy)benzal-
dehyde (27). Dess±Martin periodinane (39.1 mg, 0.11
mmol) was added to a stirred solution of 26 (38.6 mg,
76 mmol) in CH2Cl2 (2 ml) at room temperature under
argon. After 1 h, the reaction mixture was diluted with
Et2O (50 ml). The organic layer was washed successively
with 5% aqueous Na2S2O3, saturated aqueous NaHCO3, and
brine, then dried over MgSO4, Concentration of the solvent
in vacuo afforded a residue, which was puri®ed by column
chromatography (hexane/ethyl acetate, 2:1) to give 27
(36.4 mg, 95%) as a white solid. Recrystallization from
i-Pr2O/hexane (1:1) afforded an analytical sample of 27 as
a white solid, mp112±113 8C; 1H NMR (500 MHz, CDCl3)
d 2.56 (s, 3H, ArMe), 3.32 (s, 6H, MeOCH2£2), 3.49 (s, 3H,
MeO), 3.56 (s, 3H, MeO), 4.97 (s, 4H, OCH2O£2), 5.25 (s,
2H, OCH2O), 6.70 (d, Jˆ2.3 Hz, 1H, C3±H or C5±H), 7.09
(d, Jˆ2.3 Hz, 1H, C3±H or C5±H), 10.12 (s, 1H, ArCHO);
13C NMR (125 MHz, CDCl3) d 18.71, 56.35, 56.51, 57.85
(two carbons), 94.31, 100.42 (two carbons), 103.84, 107.54,
121.82, 125.15 (two carbons), 134.00, 137.43, 138.77, 149.26
(two carbons), 160.30, 161.14, 172.42, 192.41; IR (KBr)
3452, 1683, 1630, 1594, 1459, 1371, 1300, 1276, 11160,
1082, 1019, 909 cm21; EI-MS (m/z) 504 [(M1 2)1], 502
(M1), 413 [(M2CHO22£OMe12H)1]; Anal. calcd for
C22H24Cl2O9: C, 52.05; H, 4.81. Found: C, 51.90; H, 4.60.
4.1.17. 20-Benzyloxymethyl-60-methoxy-2,40,6-tris(meth-
oxymethoxy)-3,5-dichloro-4-methylbenzophenone (25).
Dess±Martin periodinane (189 mg, 0.52 mmol) was added
to a stirred solution of 24 (204 mg, 0.34 mmol) in CH2Cl2
(12 ml) at room temperature under argon. After 45 min, the
reaction mixture was diluted with Et2O (60 ml). The organic
layer was washed with 5% aqueous Na2S2O3, saturated
aqueous NaHCO3, and brine, then dried over MgSO4,
Concentration of the solvent in vacuo afforded a residue,
which was puri®ed by silica gel column chromatography
(hexane/ethyl acetate, 4:1) to give 25 (199 mg, 98%) as a
1
colorless oil. H NMR (250 MHz, CDCl3) d 2.53 (s, 3H,
ArMe), 3.33 (s, 6H, MeOCH2£2), 3.48 (s, 3H, MeO), 3.49
(s, 3H, MeO), 4.67 (s, 2H, ArCH2O), 4.88 (s, 4H,
MeOCH2£2), 4.91 (s, 2H, ArCH2O), 5.22 (s, 2H,
MeOCH2), 6.46 (d, Jˆ2.3 Hz, 1H, C3±H or C5±H), 7.17
(d, Jˆ2.4 Hz, 1H, C3±H or C5±H), 7.25±7.50 (m, 5H,
ArCH2O); 13C NMR (125 MHz, CDCl3) d 18.53, 55.99,
56.34, 57.97 (two carbons), 70.59, 72.89, 94.08, 98.59,
100.16 (two carbons), 106.99, 119.81, 124.96 (two
carbons), 127.63, 127.91 (two carbons), 128.34 (two
4.1.20. Methyl 2-[2,6-bis(methoxymethoxy)-3,5-dichloro-
4-methylbenzoyl]-3-methoxy-5-(methoxymethoxy)ben-
zoate (29). Sodium hydrogenphosphate (140 mg, 0.90 mmol),

1298
T. Katoh et al. / Tetrahedron 58 (2002) 1289±1299
2-methyl-2-butene (233 ml, 2.2 mmol), and sodium chlorite
(163 mg, 1.8 mmol) were sequentially added to a stirred
solution of 27 (200 mg, 0.40 mmol) in THF/t-BuOH/H2O
(2:5:1) (8 ml) at room temperature. After 1 h, the reaction
mixture was diluted with ethyl acetate (50 ml). The organic
layer was washed with 5% aqueous Na2S2O3 and brine, then
dried over MgSO4. Concentration of the solvent in vacuo
afforded the carboxylic acid 28 (202 mg), which was
directly used for the next reaction without further puri®-
cation. CH2N2 (0.8 M solution in Et2O, 1.0 ml, 0.80
mmol) was added to a stirred solution of the crude
carboxylic acid 28 (202 mg) in MeOH (3 ml) at room
temperature. After 10 min, the reaction was quenched
with AcOH (0.1 ml). The resulting mixture was diluted
with Et2O (50 ml). The organic layer was washed with satu-
rated aqueous NaHCO3 and brine, then dried over MgSO4.
Concentration of the solvent in vacuo afforded a residue,
which was puri®ed by column chromatography (hexane/
ethyl acetate, 1:1) to give 29 (203 mg, 96%) as a colorless
oil. 1H NMR (250 MHz, CDCl3) d 2.55 (s, 3H, ArMe), 3.39
(s, 6H, MeOCH2O£2), 3.48 (s, 3H, MeO), 3.53 (s, 3H,
MeO), 3.88 (s, 3H, CO2Me), 4.96 (s, 4H, MeOCH2O£2),
5.21 (s, 2H, MeOCH2O), 6.60 (d, Jˆ2.1 Hz, 1H, C3±H or
C5±H), 6.74 (d, Jˆ2.1 Hz, 1H, C3±H or C5±H); 13C NMR
(125 MHz, CDCl3) d 18.68, 52.75, 56.32, 56.44, 57.76 (two
carbons), 94.30, 100.66 (two carbons), 101.57, 108.42,
119.82, 125.24 (two carbons), 131.85, 137.05, 138.33,
149.13 (two carbons), 161.50, 161.90, 169.85, 187.83; IR
(neat) 3649, 2951, 2831, 2361, 1778, 1734, 1655, 1597,
1456, 1373, 1329, 1240, 1215, 1157, 1067, 1040, 1015,
silica gel (ethyl acetate). Concentration of the eluent in
vacuo afforded a residue, which was puri®ed by preparative
TLC (hexane/ethyl acetate, 1:1) to give (^)-geodin [(^)-2]
(15.1 mg, 57%) as a light yellow solid. Recrystallization
from CHCl3/Et2O (1:1) afforded an analytical sample of
(^)-2 as a light yellow powder, mp 247±2498C (lit.5 227±
2318C for natural (1)-geodin [(1)-2]); 1H NMR (250 MHz,
CDCl3) d 2.58 (s, 3H, ArMe), 3.70 (s, 3H, OMe), 3.75 (s,
3H, OMe), 5.82 (s, 1H, C4±H), 7.15 (s, 1H, C6±H); 13C
NMR (125 MHz, CDCl3) d 18.58, 52.81, 57.34, 84.58,
103.58, 108.02, 118.42, 119.56, 135.61, 139.10, 141.60,
163.08, 163.63, 165.91, 170.07, 185.03, 188.97; IR (KBr)
3434, 2924, 1720, 1655, 1610, 1522, 1458, 1335,
1233 cm21; EI-MS (m/z): 400 [(M12)1], 398 (M1), 339
[(M2CO2Me)1], HREIMS (m/z) calcd for C17H12Cl2O7
1
(M1): 397.9960. Found: 397.9956. The H NMR spectrum
of this sample was identical with that reported for natural
(1)-geodin [(1)-(2)].9a
(b) Methodusing PIFA (entry 5 in Table 1). Phenyl-
iodine(III) bis(tri¯uoroacetate) (PIFA), (24.6 mg, 57
mmol) was added to a stirred solution of 4 (20.8 mg,
52 mmol) in MeCN (1.6 ml) at room temperature. After
10 min, the reaction mixture was passed through silica gel
(ethyl acetate). Concentration of the eluent in vacuo
afforded a residue, which was puri®ed by preparative TLC
(hexane/ethyl acetate, 1:1) to give (^)-geodin [(^)-2]
1
(8.3 mg, 40%) as a light yellow solid. The IR, H NMR
(250 MHz), mass spectra of this sample were identical
with those recorded in (a).
;
923 cm21 CI-MS (m/z) 533 [(M11)1], 501 [(M2
OMe)1]; HRCI-MS (m/z) calcd for C23H26Cl2O10
[(MH)1]: 532.0901, found: 532.0901.
References
4.1.21. Methyl 2-[3,5-dichloro-2,6-dihydroxy-4-methyl-
benzoyl]-5-hydroxy-3-methoxybenzoate (4). A solution
of 29 (45.1 mg, 85 mmol) and p-toluenesulfonic acid
(15.7 mg, 91 mmol) in MeOH (5 ml) was re¯uxed for 4 h.
After cooling, the reaction mixture was diluted with CH2Cl2
(40 ml). The organic layer was washed with brine, then
dried over MgSO4, Concentration of the solvent in vacuo
afforded a residue, which was puri®ed by column chromato-
graphy (hexane/acetone, 1:1) to give 4 (26.6 mg, 81%) as a
light yellow solid. Recrystallization from EtOAc/hexane
(1:1) afforded an analytical sample of 4 as a light yellow
powder, mp 227±2308C (decomposed); 1H NMR (500
MHz, CD3OD) d 2.48 (s, 3H, ArMe), 3.70 (s, 3H, OMe),
3.71 (s, 3H, OMe), 6.69 (d, Jˆ2.1 Hz, 1H, C4±H), 7.00 (d,
Jˆ2.1 Hz, 1H, C6±H); 13C NMR (125 MHz, CD3OD) d
17.48, 51.16, 55.08, 102.85, 107.48, 110.93, 112.20
(two carbons), 126.10, 128.35, 141.59, 155.41 (one or two
carbons), 157.12 (one or two carbons), 158.58 (one or two
carbons), 166.31, 200.70; IR (KBr) 3420, 3213, 2920, 1725,
1647, 1541, 1400, 1261, 1097 cm21; EI-MS (m/z) 402
[(M12)1], 400 (M1), 368 [(M2OMe2H)1], 339 [(M2
CO2Me22H)1]; Anal. calcd for C17H14Cl2O7: C, 50.89:
H, 3.52. Found: C, 50.74; H, 3.56.
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È
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quinone (DDQ) (44.8 mg, 0.20 mmol) was added to a stirred
solution of 4 (26.4 mg, 66 mmol) in CH2Cl2/EtOH (1:1)
(2 ml). After 1 h, the reaction mixture was passed through
7. Shinohara, C.; Chikanishi, T.; Nakashima, S.; Hashimoto, A.;

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