Simple synthesis of benzofuranoid neolignans from Myristica fragrans

Article abstract of DOI:10.1021/np990327h

The total synthesis of four neolignans - fragnasols A (1), B (2), and C (3) and dehydrodiisoeugenol (4) - starting from the readily available phenol derivative isoeugenol (5) was accomplished. The key step of the synthesis of these natural products is a n

Full text of DOI:10.1021/np990327h

866
J . Nat. Prod. 2000, 63, 866-870
Sim p le Syn th esis of Ben zofu r a n oid Neolign a n s fr om Myr istica fr a gr a n s
La´szlo´ J uha´sz, La´szlo´ Ku¨rti, and Sa´ndor Antus*
Department of Organic Chemistry, Lajos Kossuth University, P.O. Box 20, H-4010 Debrecen, Hungary
Received J uly 2, 1999
The total synthesis of four neolignanssfragnasols A (1), B (2), and C (3) and dehydrodiisoeugenol
(4)sstarting from the readily available phenol derivative isoeugenol (5) was accomplished. The key step
of the synthesis of these natural products is a novel type of dimerization of 5 into 4 with iodobenzene
diacetate.
Sch em e 1. Mechanism of the Dimerization of Isoeugenol (5)
by IDA
Neolignans possessing a 2,3-dihydrobenzo[b]furan skel-
eton are a prominent subgroup of the naturally occurring
O-heterocycles owing to their complex biological activities.1-5
The mace of Myristica fragrans Houtt. (Myristicaceae) is
a commonly used spice and has been applied as a remedy
for strengthening the stomach and expelling the “wind-evil”
in Chinese medicine. Its methanolic extract has also been
found to be useful for preventing dental caries due to its
antibacterial activity against Streptococcus mutans.6 From
this source fragnasols A (1), B (2),7 and (-) C (3)8 have been
isolated, along with dehydrodiisoeugenol (4), which is
known as one of the major and most active phenolic
constituents of this plant.
In a continuation of our study on the synthesis of
benzofuranoid-type neolignans with potential biological
activity,9-11 herein we report the total synthesis of frag-
nasols A (1), B (2), and C (3) and dehydrodiisoeugenol (4),
starting from the commercially available isoeugenol (5),
using the hypervalent iodine reagent, iodobenzene diac-
etate (IDA).12 In a previous paper13 we reported that the
oxidation of o- or p-substituted phenols to the correspond-
ing semi-quinol derivatives by IDA in nucleophilic solvents
such as alcohols occurred via a phenoxenium ion interme-
diate. Therefore, it seemed to be obvious to suppose that
the phenoxenium ion 6a (stabilized in its quinone-methide
form, 6b) can also be generated from isoeugenol (5) with
IDA in dry dichloromethane as depicted in Scheme 1.
Moreover, in the absence of nucleophilic solvent, the latter
intermediate presumably reacts smoothly with 5, owing to
its high electrophilic character, to form the C-C bond of
the 2,3-dihydrobenzo[b]furan skeleton of 4. The resulting
quinone-methide-type intermediate 7 could then be trans-
formed into dehydrodiisoeugenol (4) by the thermodynami-
cally controlled addition of its phenolic hydroxyl group at
the quinone-methide moiety.
In full accordance with the above-mentioned assumption,
transformation of isoeugenol (5) with IDA in dry dichlo-
romethane at room temperature resulted only in one
product, accompanied by some polymerization based on
TLC monitoring of the reaction mixture. Isolation of this
product in crystalline form (mp, 129-132 °C) was executed
by flash chromatography on Si gel in a moderate yield
* To whom correspondence should be addressed. Tel.: 0036-52-512-900/
2471. Fax: 0036-52-453-836. E-mail: antuss@tigris.klte.hu.
10.1021/np990327h CCC: $19.00
© 2000 American Chemical Society and American Society of Pharmacognosy
Published on Web 04/19/2000

Notes
J ournal of Natural Products, 2000, Vol. 63, No. 6 867
Sch em e 3. Synthesis of rac-Fragnasol B (2)
Sch em e 2. Synthesis of rac-Fragnasol A (1)
(35%) and its structure was proved to be identical with that
1
of dehydrodiisoeugenol (4) by means of H and 13C NMR
measurements. The coupling constant for C-2H and C-3H
(J ) 9.45 Hz) clearly showed that the adjacent 2-aryl and
3-methyl substituents are trans oriented. It is to be noted
that 4 has been isolated also from Magnolia kachira-
chiari,14 and prepared15 from 5 via the corresponding
quinone-methide radical intermediate generated by FeCl3.
The synthesis of fragnasol A (1) could be achieved in two
steps starting from dehydrodiisoeugenol (4) (Scheme 2). In
the first step its unsaturated side-chain of E-geometry was
hydroxylated with OsO4 in dioxane at room temperature
to give the corresponding threo-diol derivative 8 in a
satisfactory yield (49%), due to the well-known stereospe-
cific syn addition of this reagent16 at the double bond of 4.
The benzylic hydroxyl group of 8 was susceptible to
solvolysis, with inversion of configuration in the presence
of methanol/boron trifluoride etherate at room tempera-
ture, to afford fragnasol A (1). The spectroscopic data (1H
and 13C NMR) of our synthetic product (isolated by
preparative TLC) were found to be identical with those of
the natural substance.
Dehydrodiisoeugenol (4) served as a suitable starting
material for the synthesis of fragnasol B (2), as well
(Scheme 3). According to our previous observations,17 the
phenolic hydroxyl group of 4 required protection prior to
the oxidative cleavage at the side-chain. Thus, 4 was
benzylated with benzyl chloride in the presence of potas-
sium carbonate in dry DMF to result in 9 with 61% yield,
and subsequently oxidized to 10 with sodium metaperio-
date in the presence of a catalytic amount of OsO4. To
introduce a hydroxymethyl group at the aldehyde func-
tional group of 10, and thus to construct the side-chain of
2, the methyl vinyl ether derivative 11 was prepared by
the Wittig reaction of 10 with methoxymethyltriphenylphos-
phonium chloride18 in THF at 0 °C in the presence of
potassium tert-butoxide. As expected, the Wittig reaction
furnished a 2:3 mixture of the cis/trans vinyl ethers (11)
according to the 1H NMR spectrum of the products isolated
by means of flash chromatography.
16) under mild acidic condition in methanol did not result
in 12 directly. Spontaneous decarboxylation of the â-oxo-
carboxylic acid derivative 16 furnished the dimethyl acetal
(17). Hydrolysis of 17 in the absence of methanol under
mild conditions (10% HCl-CH2Cl2, room temperature)
afforded the aldehyde 12 in high yield. The dimethyl acetal
14 could not be directly transformed into 12 under basic
conditions (14 f 15 f 16 f 12). Only the first step of this
process occurred, even though cleavage of the dimethyl-
acetal of aldehydes carrying an active hydrogen at R-posi-
tion is well-documented.21 In this case, however, the
stability of the dimethylacetal function of 14 can be
explained by the lack of an electron-withdrawing effect
caused by a very rapid hydrolysis of the ester group to the
sodium salt of 15.
Finally, transformation of 12 into fragnasol B (2) could
be achieved by means of a good-yielding (67%) two-step
procedure involving reduction of the aldehyde to the
corresponding alcohol (12 f 18) and its catalytic hydroge-
nation to remove the benzyl protecting group (15 f 2). The
spectroscopic data of our synthetic product were identical
with those of fragnasol B (2) reported by Hattori et al.7
Starting from 4, the synthesis of racemic fragnasol C (3)
could also be accomplished in four steps (Scheme 4). First,
4 was methylated with dimethyl sulfate in the presence of
potassium carbonate in dry acetone, giving 19 (85%). The
side-chain of 19 was cleaved with NaIO4-OsO4 in a good
yield (80%) as described for 10. The resulting aldehyde 20
was transformed into 21 with the Wittig methodology (see
Experimental Section).
The hydrolysis of the enol ether of 11 was readily
achieved by treatment with hydrochloric acid in dichlo-
romethane to give quantitative conversion to the corre-
sponding phenylacetaldehyde derivative 12, which could
also be synthesized from 10 in a five-step method described
below.
First, 10 was transformed into 13 by Wittig reaction with
methyl carboxymethylene-triphenylphosphorane19 in a good
yield (63%). Rearrangement of 13 with thallium(III) nitrate
(TTN) under the conditions described by McKillop et al.20
furnished the dimethylacetal (14) in 54% yield. Saponifica-
tion of 14 with sodium hydroxide in methanol (14 f 15),
followed by hydrolysis of the dimethyl acetal group (15 f
Reduction of the R,â-unsaturated ester function of 21 to
the allyl alcohol moiety of 3 preserving the trans-geometry
at the side-chain, could be accomplished with lithium
aluminum hydride in dry THF at room temperature.
Identification of our synthetic product with fragnasol C (3)
was accomplished by comparison of spectroscopic data.

868 J ournal of Natural Products, 2000, Vol. 63, No. 6
Sch em e 4. Synthesis of rac-Fragnasol C (3)
Notes
C-2 OH), 3.47 (1H, m, J 2,3 ) 9.59, J 3,Me ) 6.29, H-3), 3.88 (3H,
s, OMe), 3.89 (3H, s, OMe), 3.89 (1H, m; J 2′′,3′′ ) 6.77, J 2′′,1′′
7.49, H-2′′), 4.34 (1H, d, J 2′′,1′′ ) 7.49, H-1′′), 5.11 (1H, d, J 2,3
)
)
9.59, H-2), 5.68 (1H, br s, C-4′ OH), 6.70-7.10 (5H, m, Ar-
H), 13C NMR* δ 16.83 (Me), 18.22 (C-3′′), 44.85 (C-3), 55.28
(OCH3), 55.38 (OCH3), 71.59 (C-2′′), 78.98 (C-1′′), 93.12 (C-2),
108.24 (C-6), 109.67 (C-6′), 113.44 (C-3,C-4), 119.22 (C-2′),
131.21 (C-1′,C-5), 132.61 (C-7), 133.92 (C-3a), 143.47 (C-7a),
145.15 (C-4′), 145.97 (C-3′); HRMS m/z 360.1569 (calcd for
C
20H24O6, 360.1573).
(()-er yth r o-1-[2-(4-Hyd r oxy-3-m eth oxyp h en yl)-3-m eth -
yl-7-m eth oxy-2,3-d ih yd r oben zo[b]fu r a n -5-yl]-1-m eth oxy-
2-p r op a n ol, r a c-fr a gn a sol A (1). To a stirred solution of 8
(110 mg, 0.35 mmol) in dry methanol (5 mL) was added 0.1
mL of BF3‚OEt2 at room temperature. After 12 h, the mixture
was diluted with 5 mL of water, and the product was extracted
with dichloromethane (2 × 10 mL) and dried. Evaporation of
the solvent gave an oil (50 mg), which was purified by
preparative TLC (toluene-ethyl acetate, 1:1) to obtain 1 (15
mg, 13%) as a colorless oil: 1H NMR δ 1.01 (3H, d, J ) 5.58,
H-3′′), 1.39 (3H, dd, J ) 2.63, J 2,3 ) 6.89, C-3-Me), 3.27 (3H,
s, C-1′′ OMe), 3.48 (1H, m, H-3), 3.9 (6H, s, OMe), 3.9 (1H, m,
H-2′′), 4.0 (1H, d, J 1′′,2′′ ) 5.25, H-1′′), 5.12 (1H, d, J 2,3 ) 9.52,
H-2), 5.67 (1H, br s, C-4′ OH), 6.6-7.1 (5H, m, Ar-H); 13C
NMR δ 17.37 (C-3-Me), 18.14 (C-3′′), 45.57 (C-3), 56.0 (OMe),
56.6 (OMe), 71.5 (C-2′′), 88.0 (C-1′′), 93.9 (C-2), 108.9 (C-2′),
110.7 (C-6), 114.0 (C-5′), 115.0 (C-4), 119.9 (C-6′), 131.8 (C-5),
133.2 (C-3a, C-1′), 144.2 (C-7), 145.8 (C-4′), 146.7 (C-3′), 147.3
(C-7a); HRMS m/z 374.1731 (calcd for C21H26O6, 374.1729).
(()-2-(4-Ben zyloxy-3-m eth oxyph en yl)-3-m eth yl-7-m eth -
oxy-5-[(E)-1-p r op en yl]-2,3-d ih yd r oben zo[b]fu r a n (9). A
mixture of 4 (1 g, 3.06 mmol), potassium carbonate (5 g), and
benzyl chloride (0.5 mL) in dry DMF (20 mL) was stirred at
100 °C. After 5 h the reaction mixture was diluted with water
(100 mL) and extracted with dichloromethane (2 × 25 mL).
The organic layer was washed with brine (2 × 20 mL) and
dried. Evaporation of the solvent yielded an oil (900 mg), whose
purification by flash chromatography on Si gel (n-hexane-
ethyl acetate, 3:1) resulted in 9 (750 mg, 61%) as a thick oil:
1H NMR δ 1.37 (3H, d, J 3,Me ) 6.76, C-3-Me), 1.86 (3H, dd,
J 2′′,3′′ ) 6.55, J 1′′,3′′ ) 1.37, H-3′′), 3.45 (1H, m, J 2,3 ) 9.45, J 3,Me
) 6.76, H-3), 3.87 (3H, s, OMe), 3.88 (3H, s, OMe), 5.10 (1H,
Exp er im en ta l Section
Gen er a l Exp er im en ta l P r oced u r es. Melting points were
determined on a Kofler hot stage apparatus and are uncor-
rected. The analytical and preparative TLC were performed
on plates Kieselgel 60 F254 (Merck). Isoeugenol and the
reagents were purchased from Sigma-Aldrich. For workup the
solutions were dried (MgSO4) and concentrated in vacuo. The
1H and 13C NMR spectra were recorded on Bruker WP-200
and Bruker WP-360 (marked by an asterisk*) spectrometers
with TMS as internal standard in CDCl3. The chemical shifts
are given in δ (ppm) and the spin-spin coupling constants (J )
in hertz. HRMS were recorded in EI mode at 70 eV on a VG
7035 MS spectrometer.
(()-2-(4-Hyd r oxy-3-m eth oxyp h en yl)-3-m eth yl-7-m eth -
oxy-5-[(E)-1-p r op en yl]-2,3-d ih yd r oben zo[b]fu r a n , r a c-d e-
h yd r od iisoeu gen ol (4). To a stirred solution of 5 (4 g, 24.39
mmol) in dichloromethane (75 mL) was added dropwise a
solution of IDA (2.5 g, 7.55 mmol) in dichloromethane (100
mL) at room temperature within 4 h and stirring was
continued at room temperature for 48 h. Subsequently, the
same amount of IDA in dichloromethane (100 mL) was added
within 4 h. After stirring the reaction mixture at room
temperature for 2 h, 3 g of solid NaHCO3 was added, and
stirring was continued for 5 h. Subsequently, NaHCO3 was
filtered off, and the solvent was evaporated to give a yellow
oil, whose purification by flash chromatography on Si gel (n-
hexane-ethyl acetate, 6:1) resulted in 4 (1.4 g, 35%) as white
needles with mp 129-132 °C; lit.15 mp 132-133 °C (EtOH);
1H NMR* δ 1.37 (3H, d, J 3,Me ) 6.76, C-3-Me), 1.86 (3H, dd,
J 2′,3′ ) 6.55, J 1′,3′ ) 1.37, H-3′), 3.45 (1H, m, J 2,3 ) 9.45, J 3,3Me
) 6.76, H-3), 3.87 (3H, s, OMe), 3.89 (3H, s, OMe), 5.10 (1H,
d, J 2,3 ) 9.45, H-2), 5.64 (1H, s, OH), 6.10 (1H, m, J 2′′,3′′)6.55,
J 1′′,2′′ ) 15.69, H2′′), 6.36 (1H, dd, J 1′′,2′′ ) 15.69, J 1′′,3′′ ) 1.37,
H-1′′), 6.7-7.1 (5H, m, Ar-H); 13C NMR* δ 17.56 (C-3 Me),
18.31 (C-3′′), 45.59 (C-3), 55.95 (2 OMe), 93.74 (C-2), 108.93
(C-6), 109.33 (C-5′), 113.31 (C-2′), 114.07 (C-4), 119.92 (C-2′′),
123.43 (C-6′), 130.93 (C-1′′), 132.10 (C-5), 132.19 (C-3a), 133.27
(C-1′), 144.14 (C-4′), 145.78 (C-7a), 146.59 (C-3′), 146.66 (C-
7); HRMS m/z 326.1514 (calcd for C20H22O4, 326,1518).
d, J 2,3 ) 9.51, H-2), 5.14 (2H, s, OCH2-), 6.10 (1H, m, J 1′′,2′′
15.69, J 2′′,3′′ ) 6.55, H-2′′), 6.36 (1H, dd, J 1′′,3′′ ) 1.37, J 1′′,2′′
)
)
15.69, H-1′′), 6.57-7.10 (5H, s, Ar-H), 7.20-7.50 (5H, s, OCH2-
Ph); 13C NMR δ 17.66 (C-3-Me), 18.32 (C-3′′), 45.49 (C-3),
55.91 (C-7-OMe), 56.03 (C-3′-OMe), 71.02 (OCH2-), 93.54
(C-2), 109.26 (C-6), 110.12 (C-5′), 113.29 (C-2′), 113.76 (C-4),
119.09 (C-2′′), 123.42 (C-6′), 127.21, 127.76, 128.48 (OCH2Ph),
130.90 (C-1′′), 132.18 (C-3a, C-5), 133.25 (C-1′), 144.14 (C-4′),
145.78 (C-7a), 146.59 (C-3′), 146.66 (C-7); HRMS m/z 416.1983
(calcd for C27H28O4, 416.1987).
(()-2-(4-Ben zyloxy-3-m eth oxyph en yl)-5-for m yl-3-m eth -
yl-7-m eth oxy-2,3-d ih yd r oben zo[b]fu r a n (10). A solution of
9 (750 mg, 1.87 mmol) and OsO4 (80 mg, 0.31 mmol) in dry
dioxane (50 mL) was stirred at room temperature for 24 h.
Subsequently, a solution of sodium periodate (900 mg) in water
(100 mL) was added, and after 24 h the reaction mixture was
extracted with ether, and the organic layer was washed with
an aqueous solution of D-sorbitol and NaHSO3. The solution
was dried and evaporation of the solvent gave an oil (500 mg),
which was purified by flash chromatography on Si gel (n-
hexane-ethyl acetate, 4:1) to afford 10 (386 mg, 50%) as a
colorless thick oil: 1H NMR δ 1.44 (3H, d, J 3,Me ) 6.80, C-3-
Me), 3.61 (1H, m, J 2,3 ) 9.14, J 3,Me, H-3), 3.88 (3H, s, OMe),
(()-th r eo-1-[2-(4-Hyd r oxy-3-m eth oxyp h en yl)-3-m eth yl-
7-m et h oxy-2,3-d ih yd r ob en zo[b]fu r a n -5-yl]-1,2-p r op a n -
d iol (8). A solution of 4 (240 mg, 0.9 mmol) and OsO4 (230
mg, 0.9 mmol) in dry dioxane (10 mL) was stirred at room
temperature. After 2 h, a solution of NaHSO3 in water (10 mL)
was added and stirring was continued at room temperature
for 1 h. Subsequently, the product was extracted with ether
(2 × 20 mL), and the organic layer was washed with an
aqueous solution of D-sorbitol (2 × 20 mL), and dried. Evapo-
ration of the solvent yielded 200 mg of an oil, which was
purified by flash chromatography on Si gel (ethyl acetate-
toluene, 3:1) furnished 5 (133 mg, 49%) as a colorless thick
oil: 1H NMR δ 1.10 (3H, d, J 3,Me ) 6.29, C-3 Me), 1.38 (3H, d,
J 2′′,3′′ ) 6.77, H-3′′), 2.51 (1H, br s, C-1′′ OH), 2.65 (1H, br s,
3.94 (3H, s, OMe), 5.17 (2H, s, OCH2-), 5.25 (1H, d, J 2,3
)
9.51, H2), 6.80-7.10 (5H, m, Ar-H), 7.20-7.50 (5H, m, OCH2-
Ph), 9.85 (1H, s, CHO); 13C NMR δ 17.89 (C-3-Me), 44.86 (C-
3), 56.10 (OMe), 71.06 (OCH2), 94.76 (C-2), 110.14 (C-6), 111.85
(C-5′), 113.92 (C-2′), 119.16 (C-4), 119.98 (C-6′), 127.21, 127.85,
128.53 (CH2Ph), 131.49 (C-3a), 132.25 (C-5), 133.63 (C-1′),
136.97 (C-4′), 144.96 (C-7a), 148.63 (C-3′), 149.98 (C-7), 190.53
(C-1′′); HRMS m/z 404.1626 (calcd for C25H24O5, 404.1623).
(()-2-(4-Ben zyloxy-3-m eth oxyph en yl)-3-m eth yl-7-m eth -
oxy-5-[(E/Z)-2-m eth oxy-1-eth en yl]-2,3-d ih yd r oben zo[b]-

Notes
J ournal of Natural Products, 2000, Vol. 63, No. 6 869
fu r a n (11). To a stirred solution of methoxymethyltriphen-
ylphosphonium chloride18 (500 mg, 1.46 mmol) in dry THF (10
mL) was added potassium tert-butoxide (150 mg) at 0 °C. After
30 min a solution of 10 (216 mg, 0.53 mmol) in dry THF (30
mL) was added and stirring was continued at 0 °C for 30 min.
Subsequently, the solvent was evaporated to give an oil (270
mg), whose purification by flash chromatography on Si gel (n-
hexane-ethyl acetate, 6:1) afforded 11 (115 mg, 50%) as a
colorless oil: 1H NMR δ 1.36 (3H, d, J 3,Me ) 6.76, C-3-Me),
3.45 (1H, m, H-3), 3.66 (3H, s, trans-OMe), 3.76 (3H, s, cis-
OMe), 3.80 (6H, s, 2 OMe), 5.15 (2H, s, OCH2-), 5.0-5.40 (2H,
m, H-2, H-2′′), 5.80 (1H, d, J 1′′,2′′ ) 12.90, H-1′′), 6.05 (1H, d,
J 1′′,2′′ ) 6.92, H-1′′), 6.65-7.15 (5H, m, Ar-H), 7.20-7.60 (5H,
m, OCH2Ph); 13C NMR* δ 17.68 (C-3-Me), 45.60 (C-3), 55.07
(Ar-OMe), 56.54 (vinyl-OMe), 71.12 (OCH2), 93.42 (C-2),
105.41 (C-2′′ trans), 105.88 (C-2′′ cis), 110.26 (C-6), 112.01 (C-
5′), 112.58 (C-2′), 113.93 (C-4), 119.11 (C-6′), 127.25, 127.77,
128.49 (OCH2Ph), 129.58 (C-3a) 129.87 (C-7a), 133.42 (C-1′),
137.15 (C-a), 144.25 (C-4′), 146.17 (C-1′′ cis), 147.57 (C-1′′
trans), 148.27 (C-3′), 149.90 (C-7); HRMS m/z 432.1935 (calcd
for C27H28O5, 432.1936).
(()-2-[2-(4-Ben zyloxy-3-m et h oxyp h en yl)-3-m et h yl-7-
m eth oxy-2,3-d ih yd r oben zo[b]fu r a n -5-yl]-eth a n a l (12). (A)
A solution of 11 (100 mg, 0.23 mmol) in dichloromethane (20
mL) was stirred with 10% HCl (40 mL) at room temperature.
After 30 min, the organic layer was washed with saturated
aqueous NaHCO3 and dried. Evaporation of the solvent gave
12 (80 mg, 82%) as a colorless oil.
(B) The solution of 17 (15 mg, 0.03 mmol) and 10% HCl (5
mL) in dichloromethane (20 mL) was stirred at room temper-
ature for 30 min. Subsequently, the organic layer was washed
with saturated aqueous NaHCO3 and dried. Evaporation of
the solvent gave 12 (10 mg, 74%) as a colorless oil: 1H NMR
δ 1.37 (3H, d, J 3,Me ) 6.94, C-3-Me), 3.48 (1H, m, H-3), 3.64
(2H, d, J 1′′2′′ ) 2.56, H-1′′), 3.87 (6H, s, OMe), 5.12 (1H, d, J 2-3
) 9.51 Hz, H-2), 5.15 (2H, s, OCH2), 6.58-7.5 (10H, m, Ar-
H), 9.74 (1H, t, J 1′′,2′′ ) 2.56, CHO); HRMS m/z 418.1776 (calcd
for C26H26O5, 418.1780).
and 4.94 (1H, d, J 3′′,2′′ ) 5.42, H-2′′), 5.1 (1H, d, J 2,3 ) 9.69,
H-2), 5.15 (2H, s, CH2), 6.76-6.9 (5H, m, Ar-H), 7.22-7.48
(5H, m, CH2Ph); 13C NMR* δ 17.36 (C-3-Me), 45.54 (C-3),
52.04 (ester-OMe), 53.19 and 53.52 (acetal-OMe), 55.30 and
55.08 (C-3′′) 56.03 (OMe), 71.01 (CH2), 93.61 (C-2), 105.15 and
105.39 (C-1′′), 110.13 (C-6), 112.05 (C-2′), 113.73 (C-5′), 115.95
(C-6′), 119.14 (C-4), 127.21, 127.76, 128.47, 137.04 (CH2Ph),
127.65 (C-5), 133.06 (C-1′), 133.24 (C-7), 144.04 (C-3a), 147.04
(C-7a), 148.24 (C-4′), 149.80 (C-3′), 171.90 (COOMe); HRMS
m/z 538.2564 (calcd for C31H38O8, 538.2566).
(()-2-[2-(4-Ben zyloxy-3-m et h oxyp h en yl)-3-m et h yl-7-
m e t h oxy-2,3-d ih yd r ob e n zo[b]fu r a n -5-yl]-3,3-d im e t h -
oxyp r op ion ic Acid (15). To a stirred solution of 14 (148 mg,
0.28 mmol) in methanol (10 mL) was added a solution of
potassium hydroxide (50 mg) in water (2 mL) at 60 °C. After
8 h the reaction mixture was acidified with 10% hydrogen
chloride solution (50 mL) and extracted with dichloromethane
(2 × 20 mL). The organic layer was washed with saturated
sodium hydrogen carbonate solution and dried. Evaporation
of the solvent gave an oil (180 mg), which was purified by flash
chromatography (toluene-ethyl acetate, 4:1) to furnish a
diastereomeric mixture of 15 (120 mg, 83%) as a colorless oil:
1H NMR δ 1.37 (3H, d, J 2,3 ) 6.75, C-3-Me), 3.25 (3H, s, OMe),
3.47 (3H, s, OMe), 3.48 (1H, m, H-3), 3.88 (6H (s) + 2H (d +
d), OMe + H-2′′), 4.91 (1H, d, J ) 3.67, H-3′′), 4.95 (1H, d, J
) 3.68, H-3′′), 5.09 (1H, d, J ) 9.76, H-2), 5.15 (2H, s, OCH2),
6.7-7.6 (10H, m, Ar-H); 13C NMR* δ 17.37 (C-3-Me), 45.57
(C-3), 53.61 and 53.28 (acetal-OMe), 55.42 and 55.01 (C-3′′),
56.09 (OMe), 71.05 (CH2), 93.72 (C-2), 104.82 and 105.07 (C-
2′′), 110.15 (C-6), 112.27 (C-2′), 113.76 (C-5′), 116.17 (C-6′),
119.20 (C-4), 127.21, 127.80, 128.47, 137.07 (CH2Ph), 127.06
(C-5), 133.02 (C-1′), 133.40 (C-7), 144.16 (C-3a), 147.29 (C-7a),
148.29 (C-4′), 149.84 (C-3′), 175.69 (COOH); HRMS m/z
524.2412 (calcd for C30H36O8, 524.2410).
(()-2-(4-Ben zyloxy-3-m eth oxyph en yl)-3-m eth yl-7-m eth -
oxy-5-(2,2-dim eth oxyeth yl)-2,3-dih ydr oben zo[b]fu r an (17).
A solution of 15 (110 mg, 0.21 mmol) in methanol (5 mL) was
stirred at 70 °C in the presence of 10% HCl (1 mL) for 1 h.
Subsequently, the reaction mixture was diluted with water
(10 mL) and extracted with dichloromethane (2 × 20 mL). The
organic layer was washed with water (2 × 20 mL) and
saturated aqueous NaHCO3 (2 × 20 mL) and dried. Evapora-
tion of the solvent gave an oil (60 mg), which was purified by
preparative TLC (toluene-ethyl acetate, 4:1) to furnish 17 (30
(()-Meth yl-(E)-3-[2-(4-ben zyloxy-3-m eth oxyp h en yl)-3-
m eth yl-7-m eth oxy-2,3-d ih yd r oben zo[b]fu r a n -5-yl]p r op e-
n oa te (13). The stirred solution of 10 (340 mg, 0.81 mmol)
and methyl carboxymethyltriphenylphosphorane20 (340 mg) in
dry toluene (50 mL) was heated at 100 °C for 12 h. Subse-
quently, the solvent was evaporated, and the residue (650 mg)
was purified by flash chromatography on Si gel (toluene-ethyl
acetate, 4:1) to obtain 13 (275 mg, 63%) as a colorless oil: 1H
mg, 33%) as a colorless oil: 1H NMR δ 1.36 (3H, d, J 3,Me
)
6.72, C-3-Me), 2.87 (2H, d, J 1′′,2′′ ) 5.56, H-1′′), 3.36 (3H, s,
OMe), 3.5 (3H, s, OMe), 3.5 (1H, m, H-3), 3.88 (6H, s, OMe),
4.54 (1H, t, J ) 5.56, H-2′′), 5.08 (1H, d, J 2,3 ) 9.61, H-2), 5.16
(2H, s, OCH2), 6.6-7.9 (10H, m, Ar-H); HRMS m/z 480.2510
(calcd for C29H36O6, 480.2511).
NMR δ 1.39 (3H, d, J 3,Me ) 6.78, C-3-Me), 3.49 (1H, m, J 2,3
9.63, J 3,Me ) 6.78, H-3), 3.79 (3H, s, ester-OMe), 3.87 (3H, s,
OMe), 3.90 (3H, s, OMe), 5.15 (2H, s, CH2), 5.16 (1H, d, J 2,3
9.63, H-2), 6.31 (1H, d, J 1′′,2′′ ) 15.88, H-2′′), 6.81-7.05 (5H,
)
)
m, Ar-H), 7.26-7.48 (5H, m, OCH2Ph), 7.65 (1H, d, J 1′′,2′′
)
15.88, H-1′′); 13C NMR* δ 17.75 (C-3-Me), 45.12 (C-3), 51.52
(ester-OMe), 56.05 (OMe), 71.03 (OCH2), 94.02 (C-2), 110.12
(C-5′), 111.48 (C-2′), 113.86 (C-4), 115.54 (C-6), 116.54 (C-6′),
119.10 (C-2′′), 127.21, 127.80, 128.49, 137.0 (CH2Ph), 132.68
(C-5), 133.75 (C-1′), 144.45 (C-3a), 145.08 (C-1′′), 148.44 (C-
7a), 149.75 (C-4′), 149.90 (C-3′ and C-7), 167.71 (COOMe);
HRMS m/z 460.1883 (calcd for C28H28O6, 460.1885).
(()-2-[2-(4-Ben zyloxy-3-m et h oxyp h en yl)-3-m et h yl-7-
m eth oxy-2,3-d ih yd r oben zo[b]fu r a n -5-yl]-eth a n ol (18). To
a stirred solution of the aldehyde (12) (25 mg, 0.06 mmol) in
dry methanol (2 mL) was added NaBH4 (5 mg) at room
temperature. Subsequently, after 30 min 500 mg of Si gel was
added to the reaction mixture, and stirring was continued for
a further 30 min. Then the Si gel was filtered off, and
evaporation of the solvent yielded 18 (22 mg, 88%) as a
colorless oil: 1H NMR δ 1.37 (3H, d, J 3,Me ) 6.56, C-3-Me),
2.82 (2H, t, J 1′′,2′′ ) 6.11, H-2′′), 3.5 (1 H, m, H), 3.85 (2H, t, J
) 6.11, H-1′′), 3.87 (6H, s, OMe), 5.08 (1H, d, J ) 9.92, H-2),
5.15 (2H, s, OCH2), 6.6-7.7 (10H, m, Ar-H); HRMS m/z
436.2251 (calcd for C27H32O5, 436.2249).
(()-2-[2-(4-Hydr oxy-3-m eth oxyph en yl)-3-m eth yl-7-m eth -
oxy-2,3-d ih yd r oben zo[b]fu r a n -5-yl]eth a n ol, r a c-F r a gn a -
sol B(2). A solution of 18 (22 mg, 0.052 mmol) in dry methanol
(5 mL) was hydrogenated in the presence of Pd/C (15 mg) at
room temperature. The usual workup gave 2 (15 mg, 76%) as
a colorless oil: 1H NMR δ 1.37 (3H, d, J ) 6.94, C-3-Me),
2.83 (2H, t, J ) 6.58, H-2′′), 3.45 (1H, m, H-3), 3.88 (6H, s,
OMe), 3.9 (2H, t, H-1′′), 5.1 (1H, d, J ) 9.84, H-2), 5.63 (1H,
br s, C-4′-OH), 6.6-7.1 (5H, m, Ar-H); 13C NMR δ 17.56 (C-
3-Me), 39.1 (C-2′′), 45.6 (C-3), 56.0 (OMe), 63.8 (C-1′′), 93.6
(C-2), 109.1 (C-2′), 112.8 (C-6), 114.3 (C-5′), 116.3 (C-4), 119.8
(()-Meth yl-2-[2-(4-ben zyloxy-3-m eth oxyph en yl)-3-m eth -
y l-7-m e t h o x y -2,3-d i h y d r o b e n z o [b ]fu r a n -5-y l]-3,3-
d im eth oxyp r op a n oa te (14). To a solution of 13 (240 mg, 0.52
mmol) in dry methanol (30 mL) was added thallium(III) nitrate
(250 mg, 0.52 mmol) with stirring at room temperature, and
stirring was continued for 1.5 h. Subsequently, brine (0.5 mL)
was added to the reaction mixture, and it was filtered onto
water (100 mL). The product was extracted with dichlo-
romethane (2 × 20 mL). The organic layer was washed with
saturated aqueous NaHCO3 and dried. Evaporation of the
solvent yielded 200 mg of an oil, which was purified by flash
chromatography on Si gel (n-hexane-ethyl acetate, 3:1) to give
a diastereomeric mixture of 14 (148 mg, 54%) as a colorless
oil: 1H NMR* δ 1.37 (3H, dd, J 3,Me ) 6.71, J ) 0.92, C-3-Me),
3.23 (3H, s, OMe), 3.46 (3H, s, OMe), 3.48 (1H, m, J 2,3 ) 9.69,
J 3,Me ) 6.71, H-3), 3.69 (3H, s, OMe), 3.83 and 3.85 (1H, d,
J 3′′,2′′ ) 5.42 (H-3′′), 3.87 (3H, s, OMe), 3.88 (3H, s, OMe), 4.92

870 J ournal of Natural Products, 2000, Vol. 63, No. 6
Notes
(C-6′) 132.2 (C-5, C-1′), 135.0 (C-3a), 144.2 (C-7), 145.8 (C-4′),
146.7(C-7a,C-3′); HRMS m/z 346.1778 (calcd for C20H26O5,
346.1780).
(()-3-[2-(3,4-Dim et h oxyp h en yl)-3-m et h yl-7-m et h oxy-
2,3-d ih yd r oben zo[b]fu r a n -5-yl]-2-p r op en -1-ol, r a c-fr a g-
n a sol C (3). To a stirred solution of LiAlH4 (15 mg) in dry
THF (3 mL) was added a solution of 21 (100 mg, 0.26 mmol)
in 2 mL of dry THF at room temperature. After 30 min, a few
milligrams of Na2SO4 × 10H2O was added to the reaction
mixture. After filtration, the solvent was evaporated to give 3
(74 mg, 80%) as a colorless oil: 1H NMR* δ 1.39 (3H, d, J )
6.68; C-3-Me), 3.48 (1H, m, H-3), 3.87 (3H, s, OMe), 3.88 (3H,
s, OMe), 3.89 (3H, s, OMe), 4.31 (2H, d, J ) 5.95, H-1′′), 5.14
(1H, d, J ) 9.5, H-2), 6.25 (1H, dt, J ) 15.9 and 5.95, H-2′′),
6.57 (1H, d, J ) 15.9, H-3′′), 6.83-7.0 (5H, m, Ar-H); 13C
NMR* δ 17.52 (C-3-Me), 45.39 (C-3), 55.83 (3 OMe), 93.69 (C-
2), 109.43 (C-5′), 109.84 (C-2′), 110.79 (C-6), 114.09 (C-6′),
119.13 (C-4), 126.29 (C-2′′), 130.80 (C-5), 131.25 (C-1′), 132.42
(C-7,C-1′′), 133.31 (C-3a), 144.14 (C-7a), 147.26 (C-4′), 149.08
(C-3′); HRMS m/z 356.1619 (calcd for C21H26O5, 356.1623).
(()-2-(3,4-Dim et h oxyp h en yl)-3-m et h yl-7-m et h oxy-5-
[(E)-1-pr open yl]-2,3-dih ydr oben zo[b]fu r an (19). To a stirred
mixture of 4 (150 mg, 0.46 mmol) and potassium carbonate
(200 mg) in dry acetone (5 mL) was added dimethyl sulfate
(0.1 mL) at 60 °C, and after 2 h the reaction mixture was
diluted with water (15 mL). After 12 h, the reaction mixture
was extracted with dichloromethane (2 × 10 mL) and dried.
Evaporation of the solvent gave 19 (133 mg, 85%) as a colorless
oil: 1H NMR δ 1.37 (3H, d, J 3,Me ) 6.76, C-3-Me), 1.86 (3H,
dd, J 2′′,3′′ ) 6.55, J 1′′,3′′ ) 1.37, H-3′′), 3.45 (1H, m, J 2,3 ) 9.45,
J 3,Me ) 6.76, H-3), 3.87 (9H, s, 3 OMe), 5.12 (1H, d, J 2,3 ) 9.44,
H-2), 6.11 (1H, m, J 2′′,3′′ ) 6.55, J 1′′,2′′ ) 15.69, H-2′′), 6.36 (1H,
dd, J 1′′,2′′ ) 15.69, J 1′′,3′′ ) 1.37, H-1′′), 6.70-7.10 (5H, m, Ar-
H); 13C NMR δ 17.66 (C-3-Me), 18.39 (C-3′′), 45.61 (C-3), 55.95
(OMe), 93.69 (C-2), 109.29 (C-6), 109.54 (C-5′), 110.82 (C-2′),
113.30 (C-4), 119.25 (C-2′′), 123.52 (C-6′), 130.94 (C-1′′), 132.24
(C-3a, C-5), 133.29 (C-1′), 149.16 (C-7, C-3′, C-4′, C-7a); HRMS
Ack n ow led gm en t. The authors thank the National Sci-
ence Foundation (OTKA, T-23687) and the Ministry of Educa-
tion (grant no. 460/1997) for financial support.
m/z 374.1731 (calcd for
C21H26O6, 374.1729); HRMS m/z
356.1985 (calcd for C22H28O4, 356.1987).
(()-2-(3,4-Dim eth oxyph en yl)-5-for m yl-3-m eth yl-7-m eth -
oxy-2,3-d ih yd r oben zo[b]fu r a n (20). A solution of 19 (287
mg, 0.84 mmol) and OsO4 (50 mg, 0.197 mmol) in dry dioxane
(15 mL) was stirred at room temperature for 2 h. Subse-
quently, a solution of sodium periodate (361 mg) in water (10
mL) was added, and after 12 h the reaction mixture was
extracted with ether. The organic layer was washed with an
aqueous solution of D-sorbitol and NaHSO3 and dried. Evapo-
ration of the solvent gave 20 (222 mg, 80%) as white needles
with mp 109-111 °C: 1H NMR δ 1.45 (3H, d, J 3,3Me ) 6.76,
C-3-Me), 3.62 (1H, m, J 2,3 ) 9.45, J 3,Me, H-3), 3.88 (3H, s,
Refer en ces a n d Notes
(1) Nagai, M.; Noguchi, M.; Iizuka, T.; Otani, K.; Kamata, K. Biol. Pharm.
Bull. 1996, 19, 228-232.
(2) Fukuyama, Y.; Mizuta, K.; Nakagawa, K.; Qin, W.; Wa, X. Planta
Med. 1986, 502-504.
(3) Sih, C. J .; Ravikumar, P. R.; Huang, F.; Buckner, C. Whitlock, H. J .
Am. Chem. Soc. 1976, 98, 5412-5413.
(4) Nikaido, T.; Ohmoto, T.; Kinoshita, T.; Sankawa, H.; Nishibe, S.;
Hisada, S. Chem. Pharm. Bull. 1981, 29, 3586-3592.
(5) Kamata, K.; Itzuka, T.; Nagai, M.; Kasuya, Y. Gen. Pharmacol. 1993,
24, 977-981.
(6) Hattori, M.; Hada, S.; Watahiki, A.; Ihara, H.; Shu, Y.-Z.; Kakiuchi,
N.; Mizuno, T.; Namba, T. Chem. Pharm. Bull. 1986, 34, 3885-3893.
(7) Hada, S.; Hattori, M.; Tezuka, Y.; Kikuchi, T.; Namba, T. Phytochem-
istry 1988, 27, 563-568.
(8) Hattori, M.; Yang, X.-W.; Shu, Y.-Z.; Kakiuchi, N.; Tezuka, Y.;
Kikuchi, T.; Namba, T. Chem. Pharm. Bull. 1988, 36, 648-653.
(9) Antus, S.; Bauer, R.; Gottsegen, AÄ .; Seligmann, O.; Wagner, H.
Liebigs. Ann. Chem. 1987, 357-360.
OMe), 3.89 (3H, s, OMe), 3.95 (3H, s, OMe), 5.27 (1H, d, J 2,3
)
9.45, H-2), 6.80-7.50 (5H, m, Ar-H), 9.85 (1H, s, CHO), 13C
NMR δ 17.79 (C-3-Me), 44.80 (C-3), 55.94 (OMe), 56.06 (OMe),
94.83 (C-2), 109.51 (C-6), 111.03 (C-7), 111.87 (C-2′), 131.49
(C-4), 131.66 (C-3a), 133.65 (C-1′), 144.96 (C-5), 149.3 (C-4′),
149.52 (C-3′), 153.22 (C-7a), 190.53 (CHO); HRMS m/z 328.1312
(calcd for C19H20O5, 328.1310).
(()-Meth yl-(E)-3-[2-(3,4-d im eth oxyp h en yl)-3-m eth yl-7-
m eth oxy-2,3-d ih yd r oben zo[b]fu r a n -5-yl]p r op en oa te (21).
To a stirred solution of 20 (222 mg, 0.68 mmol) in dry benzene
(25 mL) was added methyl carboxymethylene-triphenylphos-
phorane19 (340 mg, 1.01 mmol) at 60 °C. After 12 h the solvent
was evaporated to give an oil (280 mg), whose purification by
flash chromatography on Si gel (toluene-ethyl acetate, 4:1)
resulted in 21 (241 mg, 93%) as white needles with mp 66-68
°C: 1H NMR δ 1.41 (3H, d, J 3,Me ) 6.76, C-3-Me), 3.50 (1H,
m, J 2,3 ) 9.33, J 3,Me, H-3), 3.80 (3H, s, COOMe), 3.87 (9H, s, 3
OMe), 5.19 (1H, d, J 2,3 ) 9.33, H-2), 6.32 (1H, d, J 1′′,2′′)16, H-2′′),
6.80-7.10 (5H, m, Ar-H), 7.66 (1H, d, J 1′′,2′′ ) 16, H-1′′); 13C
NMR* δ 17.69 (C-3-Me), 45.21 (C-3), 51.55 (ester-OMe), 55.95
(3 OMe), 94.21 (C-2), 109.53 (C-5′), 110.97 (C-2′), 111.49 (C-
4), 115.86 (C-6), 116.56 (C-6′), 119.23 (C-2′′), 128.49 (C-3a, C-7),
132.11 (C-1′), 133.79 (C-4′, C-3′), 145.10 (C-1′′), 149.26 (C-5),
167.71 (COOMe), HRMS m/z 384.1575 (calcd for C22H24O6,
384.1572).
(10) Antus, S.; Gottsegen, AÄ .; Kolonits, P.; Wagner, H. Liebigs. Ann. Chem.
1989, 593-594.
(11) Antus, S.; Baitz-Ga´cs, E.; Gottsegen, AÄ .; Seligman, O.; Wagner, H.
Liebigs Ann. Chem. 1990, 495-497.
(12) Leffler, J . E.; Story, L. J . J . Am. Chem. Soc. 1967, 89, 2333-2338.
(13) Ku¨rti, L.; Herczegh, P.; Simonyi, M.; Antus, S.; Pelter, A. J . Chem.
Soc., Perkin Trans. 1 1999, 379-380.
(14) Li, W. S.; El-Feraly, F. S. Proc. Nat. Sci. Counc. Repub. China 1981,
145-149.
(15) Leopold, B. Acta Chem. Scand. 1950, 4, 1523-1537.
(16) Baran, J . S. J . Org. Chem. 1960, 25, 257-258.
(17) To˜ke´s, A. L.; Litkei, Gy.; Gula´csi, K.; Antus, S.; Baitz-Ga´cs, E.;
Sza´ntay, Cs.; Darko´, L. L. Tetrahedron 1999, 55, 9283-9296.
(18) Schow, S. R.; McMorris, T. C. J . Org. Chem. 1979, 44, 3760-3769.
(19) Hercouet, A.; Le Corre, M. Tetrahedron Lett. 1979, 2995-2998.
(20) Taylor, E. C.; Robey, R. L.; Lin, K.-T.; Favre, B.; Bozimo, H. T.; Conley,
R. E.; Chiang, C.-S.; McKillop, A.; Ford, M. E. J . Am. Chem. Soc.
1976, 98, 3037-3038.
(21) Antus, S.; Boross, F.; No´gra´di, M. Liebigs Ann. Chem. 1978, 107-117.
NP990327H