A novel approach towards dibenzylbutyrolactone lignans involving heck and radical reactions: Application to (±)-matairesinol synthesis

Article abstract of DOI:10.1002/ejoc.200700440

A highly regio- and stereoselective Heck reaction of iodoarenes with vinylated malonates, generated in situ by fluoride-induced protiodesilylation of alkenylsilanols/disiloxanes to give functionalized styrenes and 1,4-diaryl-1-butenes has been developed. The dibenzylbutyrolactone lignan skeletons have been achieved from 1,4-diaryl-1-butenes by two routes involving diastereoselective radical cyclization as the key step. This strategy has successfully been applied in the synthesis of (±)-matairesinol. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200700440

FULL PAPER
DOI: 10.1002/ejoc.200700440
A Novel Approach Towards Dibenzylbutyrolactone Lignans Involving Heck and
Radical Reactions: Application to (؎)-Matairesinol Synthesis
Rekha Singh,[a] Gobind C. Singh,[a] and Sunil K. Ghosh*[a]
Keywords: Olefination / Stereoselective synthesis / Radical cyclization / Dibenzylbutyrolactone / Matairesinol
A highly regio- and stereoselective Heck reaction of iodo-
involving diastereoselective radical cyclization as the key
arenes with vinylated malonates, generated in situ by fluoride- step. This strategy has successfully been applied in the syn-
induced protiodesilylation of alkenylsilanols/disiloxanes to
give functionalized styrenes and 1,4-diaryl-1-butenes has
been developed. The dibenzylbutyrolactone lignan skeletons
have been achieved from 1,4-diaryl-1-butenes by two routes
thesis of (Ϯ)-matairesinol.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
its application to the synthesis of (Ϯ)-matairesinol[13] (Fig-
ure 2). A communication on a part of this work has already
been published.[14]
Introduction
Lignans constitute a class of natural products which have
widespread occurrence in various plants.[1] The classifica-
tion of lignans is based on their carbon skeleton as shown
in Figure 1. Although having modest size and complexity,
these molecules possess a great diversity of structures asso-
ciated with significant pharmacological activities. The most
common feature in these molecules is that the two aryl
groups are separated by a C-4 unit (Figure 1). The synthesis
of dibenzylbutyrolactone lignans has attracted added atten-
tion because of their immunoregulatory,[2] neuroprotec-
tive,[3] anticancer,[4] tumor[5] and HIV[6] properties. Besides
these, dibenzylbutyrolactone lignans have also served as in-
termediates in the synthesis of other classes of lignans.[7]
A number of strategies[8] have been developed to achieve
stereocontrolled synthesis of dibenzylbutyrolactone lignans
including diastereoselective conjugate addition to butenol-
ide,[9] alkylation of succinic acid derivatives/butanolide,[10]
oxidative homocoupling[11] and radical reactions.[12] We en-
visaged the functionalized 1,4-diaryl-1-butene 1 (Scheme 1)
as a potent precursor for the synthesis of dibenzylbutyrolac-
tone lignans because they possess two aryl groups with a
1,4-relationship. The present strategy comprised the genera-
tion of 1 by Heck coupling of vinylated malonates with aryl
iodides followed by regio- and stereoselective radical cycli-
zation of intermediates 2 or 3 (X = S or Se) leading to the
desired dibenzylbutyrolactones 4. Herein, we present full
details of our new approach to dibenzylbutyrolactones and
Figure 1. Classification of lignans.
[a] Bio-Organic Division, Bhabha Atomic Research Centre,
Mumbai, 400 085, India
Fax: +91-22-25505151
E-mail: ghsunil@barc.gov.in
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Scheme 1. Retrosynthetic analysis of dibenzylbutyrolactones.
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Dibenzylbutyrolactone Lignans Involving Heck and Radical Reactions
Scheme 3. Cross-coupling silanol/disiloxane 5a/6a with iodo-
benzene.
Figure 2. Structure of matairesinol.
ane 6a. Under the coupling conditions, the silanes first un-
dergo a rapid fluoride-induced protiodesilylation to yield
the vinylated malonate 9a, which then participates in a
Heck reaction[22] with iodobenzene in the presence of
[Pd(allyl)Cl]2 to give 10a.
Results and Discussion
Heck Reaction of Vinylated Malonates with Iodoarenes
In a recent publication, we reported[15] a general method
for the preparation of 1-substituted alkenylsilanols 5/dis-
iloxanes 6 from the corresponding alkenyl(phenyl)silanes
Optimization of Heck Reaction Conditions
Our present studies therefore aimed first to establish con-
ditions for the cine-coupled product, namely 10a, from the
in situ generated terminal olefin 9a. In general, conven-
tional Heck reaction of aryl iodides proceeds smoothly with
electron-deficient terminal alkenes.[22] However, electroni-
cally neutral or electron-rich alkenes in general do not serve
as good partners for the coupling,[23] although some en-
couraging results have been reported recently by Lyapkalo
et al.[24] using alkenyl nonalflates as coupling partners un-
der ligand free palladium catalysis. In our initial cross-
coupling studies, the reaction of 9a (either pure or gener-
ated in situ) with iodobenzene was carried out under the
conventional Heck conditions using Pd(OAc)2/(o-Tol)3P in
the presence or absence of TBAF at 80 °C. The reaction
was extremely slow with a conversion of Ͻ5% in both the
cases even after 40 h. We next choose [Pd(allyl)Cl]2 as the
catalyst because of our previous[15] success with it in ipso
cross-coupling reactions. Reaction of the silanes 5a/6a with
iodobenzene (1.5 equiv.), in the presence of TBAF
(1.5 equiv.), TBAOH (1 equiv.) and [Pd(allyl)Cl]2 at room
temperature for 40 h provided the desired terminally substi-
tuted styryl product 10a in 42% isolated yield. The coupling
yield could not be improved by increasing the reaction tem-
perature to 40–80 °C because of the formation of many by-
products. It has been shown by Jeffery[25] that the addition
7
[16] (Scheme 2) and their application in Hiyama–Denmark-
type[17–20] cross-coupling reactions with iodoarenes. Our ex-
ploratory studies[15] on this cross-coupling reaction of a
mixture of silanol 5a and disiloxane 6a with iodobenzene
using [Pd(allyl)Cl]2 as the catalyst and tetrabutylammonium
fluoride (TBAF) or a combination of TBAF and tetrabu-
tylammonium hydroxide (TBAOH)[20] as the promoter in
various solvents gave a mixture of ipso-coupled 1-substi-
tuted styrene 8a, vinylated malonate 9a, formed due to pro-
tiodesilylation of silanes and the cine-coupled styrene deriv-
ative 10a (Scheme 3).
Scheme 2. Preparation of silanol/disiloxane 5a/6a.
We looked into the details about the formation of the of tetrabutylammonium salts enhances the yield of Heck
cine-coupled product and confirmed that it did not form by products and allows the reaction to be performed in organic
the direct cross-coupling[21] of the silanol 5a or the disilox- or aqueous media or in a combination of both. At this
Table 1. Optimization of cine-coupling conditions with silanol/disiloxane 5a/6a and iodobenzene.[a]
Entry
Catalyst [equiv.]
Et3N [equiv.]
TBACl [equiv.]
Ratio[b] of 10a/9a
Yield of 10a [%][c]
[d]
1
2
3
4
5
6
7
8
0.05
0.05
0.05
0.05
0.05
0.03
0.05
0.05
–
1.5
1.0
0.75
0.5
0.75
0.75
0.75
1.0
1.0
1.0
1.0
1.0
1.0
0.5
1.5
55:45
75:25
82:18
90:10
85:15
50:50
70:30
92:8
–
61
68
75
70
[d]
–
58
75
[a] The reactions were performed using 1 equiv. of the mixture of silanol 5a and disiloxane 6a, 1.5 equiv. of TBAF and 1.5 equiv. of
iodobenzene, in DMF (1.33  with respect to silanol) along with catalyst [Pd(allyl)Cl]2, Et3N and TBACl in appropriate quantities as
mentioned at 80 °C for 40 h. [b] The ratio was determined by 1H NMR spectroscopic analysis of the crude product. [c] Refers to the
yield of spectroscopically pure product isolated after silica gel chromatography. [d] Products were not isolated.
Eur. J. Org. Chem. 2007, 5376–5385
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FULL PAPER
Table 2. Synthesis of styryl derivatives 10 from silanol/disiloxane 5a/6a and aryl iodides.
stage, we, therefore, introduced tetrabutylammonium chlo-
ride (TBACl) as an additive in our coupling reaction and
used Et3N as a base in place of TBAOH. This modification
dramatically improved the yield of desired product 10a, and
therefore, a study on optimization of the coupling condi-
tions was performed by varying the proportions of reagents
as shown in Table 1. Accordingly, the coupling was effected
efficiently in the presence of TBACl (1 equiv.), Et3N
(0.75 equiv.), TBAF (1.5 equiv.) and [Pd(allyl)Cl]2
(0.05 equiv.) with heating of the mixture at 80 °C for 40 h
(Table 1, Entry 4). cine-Coupled product 10a was obtained
in 75% yield exclusively as the (E) isomer as judged from
1
its H NMR (J = 16 Hz) spectrum. There was no trace of
Scheme 4. Preparation of silanol/disiloxane embodied with substi-
tuted benzyl group.
its regioisomer 8a. The scope of this coupling reaction was
subsequently generalized with silanol 5a/disiloxane 6a and
a few functionalized iodoarenes. The styryl derivatives 10a–
e were formed in very good yields and with excellent regio-
and stereoselectivities. Regioisomeric olefinic products 8
and the (Z) isomers of styrenes 10 could not be detected in
the crude reaction product as judged by 1H NMR spec-
troscopy. The results are summarized in Table 2.
Further, the synthesis of matairesinol required alkenylsil-
anol/disiloxane embodied with a substituted benzyl group.
Alkenyl(phenyl)silane 7d, required for this purpose was pre-
pared with a slight modification of our previously re-
ported[16] dimethylsulfonium methylide mediated one-pot
olefination–alkylation procedure. Under the standard con-
Heck Reaction Leading to 1,4-Diaryl-1-butenes
After successful development of Heck reaction condi- ditions, silylalkylidene malonate 11[26] was treated with di-
tions for the substituted styrene derivatives 10, we focused methylsulfonium methylide generated from the reaction
our attention on the preparation of 1,4-diaryl-1-butenes 1, using 1.2 equiv. of trimethylsulfonium iodide and 2.5 equiv.
as they are expected to serve as intermediates in the general of sodium dimsylate in THF/DMSO (7:3), and the reaction
synthesis of lignans and dibenzylbutyrolactone class in par- was quenched with benzyl bromide 12, which provided de-
ticular. In this context, we prepared the required benzylated sired vinylsilane 7d in 62% yield (Scheme 5). In the modi-
silanol/disiloxanes 5b,c/6b,c following our earlier described fied procedure, the ylide was generated using 3 equiv. of
procedure[15] from alkenyl(phenyl)silanes 7b,c[16] by using Me3SI and nBuLi[27] in THF, and the yield of the reaction
trifluoromethanesulfonic acid as shown in Scheme 4.
improved to 80%.
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Dibenzylbutyrolactone Lignans Involving Heck and Radical Reactions
Scheme 7. Preparation of benzyl-substituted silanols/disiloxanes
5d/6d.
Scheme 5. Preparation of functionalized benzyl vinylsilane.
possibility for the synthesis of this type of functionalized
disiloxanes. For this, silylidene malonate 11 was subjected
to our alkenyl silanol preparation conditions[15] using
CF3SO3H, which exclusively gave disiloxane 16 in nearly
quantitative yield. Disiloxane 16 underwent a smooth di-
methylsulfonium methylide mediated double olefination
(Me3SI + nBuLi) followed by double alkylation with benzyl
bromide 12 in the same pot (Scheme 8) to give desired alk-
enyl disiloxane 6d in very good yield.
The synthesis of bromide 12 has been reported in the
literature[28] but we followed a different route starting from
vanillin. For this, the hydroxy group of vanillin was pro-
tected as its benzyl ether 13 and was subjected to Canniz-
zaro reaction conditions to give acid 14 and alcohol 15 in
very good yields. The alcohol was converted to benzyl bro-
mide 12 using phosphorus tribromide (Scheme 6). This
Cannizzaro method not only provided us with the precursor
of 12 but also acid 14, an intermediate for another compo-
nent (vide infra) for the synthesis of (Ϯ)-matairesinol.
Scheme 8. Preparation of disiloxane 6d.
Having developed the protocols for silanol/disiloxane
containing functionalized benzyl groups and optimization
of the cine-coupling (Table 1 and 2) with silanol/disiloxane,
we studied the scope of this reaction with silanols 5b–d/
disiloxanes 6b–d with a few functionalized iodoarenes as
presented in Table 3. The cine-coupled products, i.e. (E)-1,4-
diaryl-1-butenes 1a–i, were obtained in very good yields
again, with very high regio- and stereocontrol. The iodo-
arenes were either commercially available or prepared by
following the literature procedures.[29] Iodoarene 17 re-
quired for the synthesis of diaryl butene 1i was prepared in
a few steps as depicted in Scheme 9. Carboxylic acid 14,
obtained from the Cannizzaro reaction (Scheme 6), was
converted into Boc-protected aniline derivative 18. Boc de-
protection followed by a Sandmeyer reaction gave iodo-
arene 17 in moderate yield.
Scheme 6. Preparation of 4-benzyloxy-3-methoxybenzyl bromide.
In our previous experiments, we could selectively convert
simple alkenyl(phenyl)silanes 7a–c to the corresponding sil-
anols/disiloxanes easily. Our next challenge was to selec-
tively convert the phenylsilyl functionality to a silanol in a
complex system like that of alkenyl(phenyl)silane 7d. When
vinylsilane 7d was treated with trifluoromethanesulfonic
acid in dichloromethane at –2 °C or even at lower tempera-
tures, we did not obtain the desired silanol/disiloxane 5d/
6d, but the starting silane degraded to unknown byprod-
ucts. This degradation was presumably due to the noncom-
patibility of the benzyloxy group present therein to the reac-
tion conditions. Fortunately, trifluoroacetic acid in dichloro-
methane at room temperature could selectively arylprotio-
desilylate to give desired silanol 5d associated with a trace
amount of disiloxane 6d (Scheme 7).
Although the yield of this arylprotiodesilylation reaction
was excellent, it required longer reaction time for comple-
tion. In the course of this investigation we explored another Scheme 9. Preparation of 4-benzyloxy-3-methoxy iodobenzene.
5379
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R. Singh, G. C. Singh, S. K. Ghosh
FULL PAPER
Table 3. Coupling of benzylated silanols/siloxanes with various iodoarenes.
Synthesis of Dibenzylbutyrolactones and (؎)-Matairesinol
ucts 1. We explored the synthesis of model dibenzylbutyrol-
actone lignan skeletons from 1,4-diaryl-1-butene 1a follow-
ing two routes as depicted in Scheme 10.
Model Synthesis of Dibenzylbutyrolactones
After studying the cine-coupling of silanols/disiloxanes 5/
Diester 1a was first hydrolyzed to racemic acid 19a. Ini-
6 with various iodoarenes, we turned our attention towards tially in the first route, acid 19a was converted to its methyl-
the synthesis of lignan skeletons from these coupling prod- thiomethyl and phenylthiomethyl esters; but neither of them
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Dibenzylbutyrolactone Lignans Involving Heck and Radical Reactions
78:22). The proposed transition states (TS) for ring closures
are shown in Figure 3, which resemble the chair form of
cyclohexane, and the substituent at the 4-position is dis-
posed pseudo equatorially. As the olefins in A and B have
(E) stereochemistry, the facile ring closure results in pre-
dominant formation of trans 2,3-disubstituted lactones. Al-
though, the olefin geometry will not have any direct effect
on the stereochemical outcome as shown in proposed tran-
sition states C and D for (Z) olefins, but would impede the
cyclization process due to steric hindrance.
Figure 3. Proposed transition states for radical cyclizations.
Synthesis of (؎)-Matairesinol
For the synthesis of matairesinol, diester 1i was hy-
drolyzed with KOH to give monoacid 19b, which was then
converted into phenylselenomethyl ester 2b as shown in
Scheme 10. Synthesis of model dibenzylbutyrolactone lignan skel-
etons.
underwent a smooth radical cyclization.[30] Later, the acid
was transformed to phenylselenomethyl ester[30] 2a, which
to our delight underwent a facile tin hydride mediated radi-
cal cyclization ultimately to provide trans dibenzylbutyro-
lactone 4a as the major product (trans/cis, 78:22), as ex-
pected to be the dominant isomer on the basis of Beckwith’s
model[31] for stereoselectivity in 5-exo radical cyclizations.
The stereoisomeric lactones, trans-4a and cis-4a, were
separated by fractional crystallization. The cis stereochem-
istry of the minor isomer was confirmed by recording nOe
spectra and about 5% nOe enhancement was observed be-
tween H1 and H2 (Scheme 10) in the lactone ring. In the
second route, acid 19a was reduced to alcohol 20 and sub-
sequently converted to phenylselenocarbonate[32] 3a. Tin
hydride induced radical cyclization then provided trans di-
benzylbutyrolactone 4b with good selectivity (trans/cis, Scheme 11. Synthesis of matairesinol.
Eur. J. Org. Chem. 2007, 5376–5385
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R. Singh, G. C. Singh, S. K. Ghosh
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131.76, 133.95 (2 C), 137.19, 140.38, 146.91, 148.58, 148.89, 170.47
(2 C) ppm. MS (ESI): m/z (%) = 570 (10.90) [M + 24]+, 569 (100)
[M + 23]+, 469 (5.13). C32H38O6Si (546.7): calcd. C 70.30, H 7.01;
found C 70.65, H 7.32.
Scheme 11. Like the model synthesis, the tributyltin hydride
mediated radical cyclization provided bis(benzyl)-protected
matairesinol 4c and its cis diastereoisomer (trans/cis, 85:15)
in 78% yield. The individual isomers were separated from
the mixture by fractional crystallization. The major isomer
trans-4c on catalytic hydrogenation provided (Ϯ)-matairesi-
nol 4d in nearly quantitative yield. The minor isomer cis-4c
could also be epimerized to the desired major isomer trans-
4c by the reported procedure.[33]
General Procedure for the Preparation of Silanols/Disiloxanes Using
Trifluoromethanesulfonic Acid – 2-[3,3-Diethoxycarbonyl-4-(3-meth-
oxyphenyl)-1-butenyl]dimethylsilanol (5c) and 1,1,3,3-1,3-Bis[(3,3-di-
ethoxycarbonyl)-4-(3-methoxyphenyl)-1-butenyl]tetramethyldisilox-
ane (6c): Trifluoromethanesulfonic acid (0.25 mL, 2.75 mmol,
5.5 equiv.) was rapidly added to a stirred solution of alkenylsilane
7c (220 mg, 0.5 mmol, 1 equiv.) in dichloromethane (3.6 mL) at
–10 °C (bath). The reaction mixture was stirred under those condi-
tions for 10 min and poured into ice-cold ammonia solution (30%
aqueous solution, 3 mL). The organic layer was separated, and the
aqueous phase was extracted with chloroform. The combined or-
ganic extracts were dried (MgSO4) and evaporated to give a mix-
ture of disiloxane 6c and silanol 5c (6c/5c, 55:45) (187 mg, 100%).
Disiloxane 6c (116 mg, 63%) and silanol 5c (28 mg, 15%) were eas-
ily separable by column chromatography. Data for Silanol 5c: Rf =
Conclusions
We have developed a highly regio- and stereoselective
Heck reaction of iodoarenes with vinylated malonates, gen-
erated in situ by fluoride induced protiodesilylation of alk-
enylsilanol/disiloxanes to give functionalized styryl deriva-
tives and (E)-1,4-diaryl-1-butenes in very good yields. A dis-
iloxane embodied with acid-sensitive benzyl-protected aryl
group was prepared by a novel dimethylsulfonium meth-
0.2 (hexane/EtOAc, 85:15). IR (neat): ν = 3592, 1729 (C=O), 1257,
˜
1
1177 cm–1. H NMR (200 MHz, CDCl3): δ = 0.1 (s, 6 H, SiMe2),
ylide mediated double olefination reaction followed by 1.21 (t, J = 7.2 Hz, 6 H, 2ϫCO2CH2CH3), 2.20 (br. s, 1 H, OH),
3.40 (s, 2 H, ArCH2-), 3.75 (s, 3 H, ArOMe), 4.07–4.23 (m, 4 H,
2 ϫ CO2CH2CH3), 5.91 (s, 1 H, C=CHAHB), 5.95 (s, 1 H,
C=CHAHB), 6.68–6.75 (m, 3 H, Ar), 7.12 (t, J = 8 Hz, 1 H, Ar)
ppm. 13C NMR (50 MHz, CDCl3): δ = 0.88 (2 C), 13.51 (2 C),
42.63, 54.66, 61.22 (2 C), 64.43, 111.96, 115.88, 122.49, 128.57,
129.49, 137.34, 149.85, 158.88, 170.68 (2 C) ppm. MS (EI): m/z (%)
= 363 (0.2) [M – OH]+, 317 (4), 289 (89), 261 (16), 185 (20), 159
(30), 121 (100), 75 (91). C19H28O6Si (380.5): calcd. C 59.97, H 7.42;
found C 59.60, H 7.35. Data for Disiloxane 6c: Rf = 0.37 (hexane/
double benzylation. The dibenzylbutyrolactone lignan skel-
etons have been prepared from 1,4-diaryl-1-butenes by two
routes involving stereoselective radical cyclization as the key
step. The (E) stereochemistry of 1,4-diaryl-1-butenes was
very crucial for the facile radical cyclization to give the de-
sired lactones. This strategy has successfully been applied
for the synthesis of (Ϯ)-matairesinol.
EtOAc, 85:15). IR (neat): ν = 2984, 2909, 2838, 1729 (C=O), 1598,
˜
1488, 1257, 1177, 790 cm–1. 1H NMR (200 MHz, CDCl3): δ = –0.02
(s, 12 H, 2ϫSiMe2), 1.19 (t, J = 6 Hz, 12 H, 4ϫCO2CH2CH3),
3.39 (s, 4 H, 2ϫArCH2-), 3.74 (s, 6 H, 2ϫArOMe), 4.06–4.18 (m,
8 H, 4ϫCO2CH2CH3), 5.96 (s, 2 H, 2ϫC=CHAHB), 6.04 (s, 2 H,
2ϫC=CHAHB), 6.66–6.73 (m, 6 H, Ar), 7.10 (t, J = 8 Hz, 2 H,
Ar) ppm. 13C NMR (50 MHz, CDCl3): δ = 2.04 (4 C), 13.61 (4 C),
42.75 (2 C), 54.67 (2 C), 60.95 (4 C), 64.28 (2 C), 111.86 (2 C),
116.09 (2 C), 122.71 (2 C), 128.50 (2 C), 130.11 (2 C), 137.59 (2
C), 149.75 (2 C), 158.93 (2 C), 170.35 (4 C) ppm. MS: m/z (%) =
766 (6) [M + 24]+, 765 (15) [M + 23]+, 645 (25), 556 (27), 363 (18),
189 (32), 159 (100). HRMS: calcd. for C38H54O11Si2Na [M + Na]
765.3102; found 765.3077.
Experimental Section
General Procedure for the Olefination–Alkylation of Ethyl 2-
Ethoxycarbonyl-3-dimethyl(phenyl)silyl-2-propenoate (11) Using
Trimethylsulfonium Iodide/nBuLi – Ethyl 2-(4-Benzloxy-3-meth-
oxybenzyl)-3-dimethyl(phenyl)silyl-2-ethoxycarbonyl-3-butenoate
(7d): A solution of nbutyllithium (1.6  in hexane, 0.94 mL,
1.5 mmol, 3 equiv.) was added to a stirred suspension of trimeth-
ylsulfonium iodide (306 mg, 1.5 mmol, 3 equiv.) in THF (2 mL) at
–10 °C under an atmosphere of argon, and the reaction mixture
was stirred at the same temperature for 15 min. A solution of 2-
silyl alkylidene malonate 11 (153 mg, 0.5 mmol, 1 equiv.) in dry
THF (1 mL) was rapidly cannulated to the above reaction mixture.
The reaction mixture was slowly brought to room temperature in
a span of 45 min. After 15 min at room temperature, the reaction
mixture was cooled in an ice-water bath and bromide 12 (231 mg,
0.75 mmol, 1.5 equiv.) was added into the reaction mixture. After
18 h at room temperature, the reaction mixture was quenched with
water and extracted with diethyl ether. The combined extract was
washed with brine, dried with MgSO4 and concentrated. The resi-
due was purified by chromatography to give pure vinylated product
General Procedure for the Preparation of Silanols/Disiloxanes Using
Trifluoroacetic Acid – 2-[4-(4-benzyloxy-3-methoxyphenyl)-3,3-di-
ethoxycarbonyl-1-butenyl]dimethylsilanol (5d) and 1,1,3,3-1,3-Bis[4-
(4-benzyloxy-3-methoxyphenyl)-3,3-diethoxycarbonyl-1-butenyl]tet-
ramethyldisiloxane (6d): Trifluoroacetic acid (1.7 mL, 22.61 mmol,
19 equiv.) was added to the stirred solution of vinylsilane 7d
(650 mg, 1.19 mmol, 1 equiv.) in dichloromethane (4.5 mL) at 0 °C.
After 1.5 h at room temperature, the reaction mixture was poured
into ice-cooled 30% aqueous ammonia solution and the organic
7d (218 mg, 80%). R = 0.4 (hexane/EtOAc, 85:15). IR (neat): ν =
˜
f
3066, 2980, 2957, 2903, 1731 (C=O), 1259 (SiMe), 1110 (SiPh) phase was separated. The organic phase was washed with brine,
1
cm–1. H NMR (200 MHz, CDCl3): δ = 0.27 (s, 6 H, SiMe2), 1.12
(t, J = 7.2 Hz, 6 H, 2ϫCO2CH2CH3), 3.38 (s, 2 H, ArCH2-), 3.83
(s, 3 H, MeOAr), 4.03 (q, J = 7.2 Hz, 4 H, 2ϫCO2CH2CH3), 5.14
dried with MgSO4 and evaporated to give a mixture of silanol 5d
and disiloxane 6d (5d/6d, 87:13) (571 mg, 100%). The material was
purified by chromatography to give pure silanol 5d (425 mg, 73%)
(s, 2 H, PhCH2O-), 5.74 (s, 1 H, C=CHAHB), 6.06 (s, 1 H, and disiloxane 6d (105 mg, 18%). Data for 5d: Rf = 0.25 (hexane/
C=CHAHB), 6.62 (dd, J = 8, 2 Hz, 1 H, Ar), 6.74 (d, J = 8 Hz, 1
H, Ar), 6.76 (d, J = 2 Hz, 1 H, Ar), 7.20–7.50 (m, 10 H, 2ϫPh)
EtOAc, 85:15). IR (neat): ν = 3650–3200 (br., OH), 1727 (C=O),
˜
1590, 1514, 1260, 1142 cm–1. 1H NMR (200 MHz, CDCl3): δ =
ppm. 13C NMR (50 MHz, CDCl3): δ = –0.56 (2 C), 13.73 (2 C), 0.11 (s, 6 H, SiMe2), 1.18 (t, J = 7 Hz, 6 H, 2ϫCO2CH2CH3), 1.96
42.12, 55.80, 61.16 (2 C), 64.78, 70.88, 113.55, 114.51, 122.81, (br. s, 1 H, OH), 3.36 (s, 2 H, ArCH2-), 3.83 (s, 3 H, MeOAr),
127.11 (2 C), 127.29 (2 C), 127.65, 128.34, 128.41 (2 C), 129.62, 4.02–4.20 (m, 4 H, 2ϫCO2CH2CH3), 5.10 (s, 2 H, PhCH2O-), 5.89
5382
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5376–5385

Dibenzylbutyrolactone Lignans Involving Heck and Radical Reactions
(s, 1 H, C=CHAHB), 5.93 (s, 1 H, C=CHAHB), 6.58 (dd, J = 8,
1H NMR (200 MHz, CDCl3): δ = 2.98 (dd, J = 7.2, 13.6 Hz, 1 H,
2 Hz, 1 H, Ar), 6.71 (d, J = 8 Hz, 1 H, Ar), 6.73 (d, J = 2 Hz, 1 PhCHAHB), 3.23 (dd, J = 7.4, 13.6 Hz, 1 H, PhCHAHB), 3.51 (q,
H, Ar), 7.26 –7.42 (m, 5 H, Ph) ppm. 13C NMR (50 MHz, CDCl3): J = 7.6 Hz, 1 H, CHCO2H), 3.82 (s, 3 H, MeOAr), 6.11 (dd, J
δ = 1.16 (2 C), 13.84 (2 C), 42.57, 55.86, 61.55 (2 C), 64.94, 70.92,
113.66, 114.27, 122.50, 127.18 (2 C), 127.70, 128.45 (2 C), 129.32,
129.62, 137.16, 147.07, 149.02, 150.32, 171.18 (2 C) ppm. MS
(ESI): m/z (%) = 510 (4.49) [M + 24]+, 509 (53.20) [M + 23]+, 469
= 8.7, 15.8 Hz, 1 H, ArCHB=CHA-), 6.43 (d, J = 15.8 Hz, 1 H,
ArCHB=CHA-), 6.88 (d, J = 8.6 Hz, 2 H, Ar), 7.19–7.33 (m, 7 H,
Ar), 10.68 (br. s, 1 H, COOH) ppm. 13C NMR (50 MHz, CDCl3):
δ = 38.61, 51.18, 55.20, 113.89 (2 C), 123.76, 126.48, 127.54 (2 C),
(7.69), 413 (8.97), 411 (14.10), 337 (5.13). C26H34O7Si (486.6): 128.37 (2 C), 129.04 (2 C), 129.28, 132.64, 138.26, 159.23,
calcd. C 64.17, H 7.04; found C 63.92, H 6.89. Data for 6d: Rf = 179.97 ppm. MS (EI): m/z (%) = 282 (10) [M]+, 207 (22), 191 (100),
0.5 (hexane/EtOAc, 85:15). IR (neat): ν = 3064, 3015, 2981, 1730
163 (36). C18H18O3 (282.3): calcd. C 76.57, H 6.43; found C 76.34,
˜
(C=O), 1606, 1590, 1513, 1260, 1037 cm–1. 1H NMR (200 MHz, H 6.50.
CDCl3): δ = 0.01 (s, 12 H, 2ϫSiMe2), 1.17 (t, J = 7.2 Hz, 12 H,
General Procedure for the Preparation of Phenylselenomethyl Ester –
4 ϫ CO2CH2CH3), 3.35 (s, 4 H, 2 ϫ ArCH2-), 3.82 (s, 6 H,
2ϫMeOAr), 3.97–4.21 (m, 8 H, 4ϫCO2CH2CH3), 5.09 (s, 4 H,
2ϫPhCH2O-), 5.99 (d, J = 1.1 Hz, 2 H, 2ϫC=CHAHB), 6.02 (d,
J = 1.1 Hz, 2 H, 2 ϫ C=CHAHB), 6.56 (dd, J = 8, 2 Hz, 2 H,
2ϫAr), 6.71 (d, J = 8 Hz, 2 H, 2ϫAr), 6.72 (d, J = 2 Hz, 2 H,
2ϫAr), 7.24–7.44 (m, 10 H, 2ϫPh) ppm. 13C NMR (50 MHz,
CDCl3): δ = 2.37 (4 C), 13.85 (4 C), 42.57 (2 C), 55.82 (2 C), 61.17
(4 C), 64.66 (2 C), 70.96 (2 C), 113.66 (2 C), 114.44 (2 C), 122.70
(2 C), 127.14 (4 C), 127.66 (2 C), 128.41 (4 C), 129.59 (2 C), 130.12
(2 C), 137.21 (2 C), 146.99 (2 C), 148.95 (2 C), 150.18 (2 C), 170.72
(4 C) ppm. ESI MS: m/z (%) = 979 (4.5) [M + 25]+, 978 (32) [M
+ 24]+, 977 (100) [M + 23]+, 497 (3.85), 469 (3.21), 365 (21.79).
C52H66O13Si2 (955.2): calcd. C 65.38, H 6.96; found C 65.70, H
7.06.
Phenylselenomethyl (E)-(2RS)-2-Benzyl-4-(4-methoxyphenyl)-3-but-
enoate (2a): A mixture of acid 19a (200 mg, 0.71 mmol, 1 equiv.),
N,N-diisopropylethylamine (0.125 mL, 0.71 mmol, 1 equiv.), chlo-
romethylphenyl selenide[30] (150 mg, 0.73 mmol, 1 equiv.), NaI
(107 mg, 0.71 mmol) and DME (2 mL) were heated at 80 °C under
argon over 18 h. The reaction mixture was diluted with diethyl
ether and washed with water. The organic extract was dried with
MgSO4 and the solvents evaporated. The residue was purified by
chromatography on silica gel to give ester 2a (278 mg, 87%). Rf =
0.3 (hexane/EtOAc, 95:5). IR (CHCl ): ν = 3060, 3029, 2954, 2836,
˜
3
1737 (C=O), 1606, 1511, 1251, 1134, 1033, 967 (trans C=C),
741 cm–1 1H NMR (200 MHz, CDCl3): δ = 2.92 (dd, J = 7,
.
13.6 Hz, 1 H, PhCHAHB), 3.18 (dd, J = 7.8, 13.6 Hz, 1 H,
PhCHAHB), 3.48 (q, J = 7.8 Hz, 1 H, CHCO2), 3.81 (s, 3 H,
General Procedure for the Palladium-Catalyzed Cross-Coupling of MeOAr), 5.50 (d, J = 10 Hz, 1 H, OCHAHBSePh), 5.57 (d, J =
Silanols/Disiloxanes with Iodoarenes in the Presence of TBAF,
TBACl and Et3N in DMF – Ethyl (E)-2-Ethoxycarbonyl-2-methyl-
4-phenyl-3-butenoate (10a): In a typical experiment, a solution of
TBAF (1  in DMF, 4 mL, 4 mmol, 1.5 equiv.) was added to a
mixture of silanol 5a and disiloxane 6a (715 mg, 2.66 mmol based
on silanol) at 80 °C. After 5 min, a solution of TBACl (1  in
DMF, 2.6 mL, 2.6 mmol, 1 equiv.), iodobenzene (880 mg, 4 mmol,
1.5 equiv.), Et3N (0.28 mL, 2 mmol, 0.75 equiv.) and [Pd(allyl)Cl]2
(48 mg, 0.13 mmol, 0.05 equiv.) were added, and the mixture was
heated at 80 °C under a blanket of nitrogen in a Schlenk flask for
40 h. The reaction mixture was cooled, diluted with hexane/EtOAc
(8:2) and washed with water. The organic extract was concentrated
and purified by column chromatography to give 10a (550 mg,
10 Hz, 1 H, OCHAHBSePh), 6.04 (dd, J = 8.6, 15.8 Hz, 1 H,
ArCHB=CHA-), 6.38 (d, J = 15.8 Hz, 1 H, ArCHB=CHA-), 6.84
(d, J = 8.8 Hz, 2 H, Ar), 7.16–7.28 (m, 10 H, Ar), 7.49 (dd, J =
1.8, 8.8 Hz, 2 H, Ar) ppm. 13C NMR (50 MHz, CDCl3): δ = 38.44,
51.02, 54.97, 62.13, 113.73 (2 C), 123.73, 126.29, 127.36 (2 C),
127.52, 128.18 (2 C), 128.92 (4 C), 129.12, 129.29, 132.30, 133.19
(2 C), 138.19, 159.08, 172.47 ppm. MS (ESI): m/z (%; 80Se only) =
475 (6) [M + 23]+, 295 (34), 189 (13.3), 159 (100).
General Procedure for the Radical Cyclization Reaction Using Tribu-
tyltin Hydride – (2RS,3RS)-2-Benzyl-3-(4-methoxybenzyl)butyrolac-
tone (4a): A solution of Bu3SnH (0.12 mL, 0.45 mmol, 1.15 equiv.)
and AIBN (7 mg, 0.038 mmol, 0.1 equiv.) in dry benzene (5 mL)
was added slowly to a stirred solution of ester 2a (171 mg,
0.38 mmol, 1 equiv.) in benzene (24 mL) under argon at 80 °C
within 4 h. The reaction mixture was heated at for another 30 min,
cooled and the solvents evaporated. The residue was purified by
chromatography on silica gel to give a mixture of trans-4a and cis-
4a (102 mg, 92%) as a colourless solid. On fractional crystallization
from hexane/EtOAc, trans-4a (75 mg, 67%) and cis-4a (20 mg,
18%) were obtained. Data for trans-4a: M.p. 77 °C. Rf = 0.2 (hex-
75%). R = 0.37 (hexane/EtOAc, 95:5). IR (neat): ν = 1731 (C=O),
˜
f
967 (trans C=C) cm–1. 1H NMR (200 MHz, CDCl3): δ = 1.26 (t, J
= 7.2 Hz, 6 H, 2ϫMeCH2OCO), 1.66 [s, 3 H, MeC(CO2Et)2], 4.22
(q, J = 7.2 Hz, 4 H, 2ϫMeCH2OCO), 6.48 (d, J = 16.4 Hz, 1 H,
ArCHB=CHA-), 6.69 (d, J = 16.4 Hz, 1 H, ArCHB=CHA-), 7.23–
7.42 (m, 5 H, Ar) ppm. 13C NMR (50 MHz, CDCl3): δ = 13.98 (2
C), 20.31, 55.63, 61.64 (2 C), 126.57 (2 C), 127.64, 127.84, 128.52
(2 C), 130.72, 136.50, 171.10 (2 C) ppm. MS (EI): m/z (%) = 277
(3) [M + 1]+, 276 (21) [M]+, 204 (10), 203 (21), 175 (5), 158 (14),
147 (28), 131 (32), 129 (100), 128 (23), 115 (19), 91 (7), 77 (5).
C16H20O4 (276.3): calcd. C 69.54, H 7.30; found C 69.30, H 7.52.
ane/EtOAc, 90:10). IR (CHCl ): ν = 3020, 2933, 2838, 1766 (C=O),
˜
3
1
1611, 1513, 1249, 1216, 756 cm–1. H NMR (500 MHz, CDCl3): δ
= 2.46–2.52 (m, 2 H, CHCH2O-, ArCHAHB), 2.57–2.63 (m, 2 H,
COCH, ArCHAHB), 2.95 (dd, J = 7.5, 14 Hz, 1 H, PhCHAHB),
3.08 (dd, J = 5, 14 Hz, 1 H, PhCHAHB), 3.78 (s, 3 H, MeOAr),
3.84 (t, J = 8.5 Hz, 1 H, OCHAHB), 4.07 (t, J = 8 Hz, 1 H, OCHA-
HB), 6.80 (d, J = 8.5 Hz, 2 H, Ar), 6.91 (d, J = 8.8 Hz, 2 H, Ar),
7.18 (d, J = 7.5 Hz, 2 H, Ar), 7.24 (t, J = 7.5 Hz, 1 H, Ar), 7.30
(t, J = 7.5 Hz, 2 H, Ar) ppm. 13C NMR (50 MHz, CDCl3): δ =
34.95, 37.46, 41.36, 46.24, 55.18, 71.07, 114.00 (2 C), 126.79, 128.61
(2 C), 129.23 (2 C), 129.49 (2 C), 129.84, 137.69, 158.28,
178.50 ppm. C19H20O3 (296.4): calcd. C 77.00, H 6.80; found C
General Procedure for the Hydrolysis of Diethyl Esters – (E)-(2RS)-
2-Benzyl-4-(4-methoxyphenyl)-3-butenoic Acid (19a): An aqueous
solution of KOH (5 , 8 mL) was added dropwise to a stirred solu-
tion of diester 1a (1.52 g, 3.98 mmol, 1 equiv.) in EtOH (30 mL)
at room temperature. After 4 h, the solvent was evaporated under
reduced pressure and the residue was diluted with water. The mix-
ture was once extracted with Et2O and the aqueous phase was co-
oled, acidified with HCl (4 ) and extracted with ethyl acetate. The
organic extract was evaporated and the residue was crystallized
(EtOAc/hexanes) to give acid 19a (985 mg, 88%). M.p. 116–117 °C.
77.13, H 7.04. Data for cis-4a: M.p. 57 °C. IR (CHCl ): ν = 3061,
˜
3
3027, 2935, 2836, 1769 (C=O), 1611, 1513, 1249, 1179, 1035,
1
IR (CHCl ): ν = 3600–3260 (br., OH), 2978, 2938, 2840, 1731
752 cm–1. H NMR (500 MHz, CDCl3): δ = 2.33 (t, J = 14 Hz, 1
˜
3
(C=O), 1606, 1509, 1441, 1247, 1030, 977 (trans C=C), 760 cm–1.
H, ArCHAHB), 2.60–2.65 (m, 1 H, CHCH2O-), 2.85 (dd, J = 11,
Eur. J. Org. Chem. 2007, 5376–5385
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5383

R. Singh, G. C. Singh, S. K. Ghosh
FULL PAPER
15 Hz, 1 H, PhCHAHB), 2.93 (dd, J = 3.5, 15 Hz, 1 H, ArCHAHB),
by column chromatography to give (Ϯ)-matairesinol 4d[13a] (19 mg,
3.09–3.14 (m, 1 H, COCH), 3.33 (dd, J = 4.5, 15 Hz, 1 H, 95%). R = 0.1 (hexane/EtOAc, 70:30). IR (CHCl ): ν = 3540 (OH),
˜
f
3
PhCHAHB), 3.78 (s, 3 H, MeOAr), 4.00 (dd, J = 5, 9.5 Hz, 1 H, 3019, 2938, 2849, 1765 (C=O), 1612, 1515, 1270, 1238, 1216, 1153,
1
OCHAHB), 4.04 (d, J = 9.5 Hz, 1 H, OCHAHB), 6.81 (d, J =
8.5 Hz, 2 H, Ar), 6.95 (d, J = 8.8 Hz, 2 H, Ar), 7.25–7.31 (m, 3 H,
Ar), 7.36 (t, J = 7 Hz, 2 H, Ar) ppm. 13C NMR (50 MHz, CDCl3):
δ = 30.76, 31.94, 39.95, 45.17, 55.20, 69.36, 114.06 (2 C), 126.63,
1122, 1034, 756 cm–1. H NMR (500 MHz, CDCl3): δ = 2.42–2.58
(m, 3 H, CHAHBAr, -CHCH2O-, -CHCOO-), 2.61 (dd, J = 6.5,
13.5 Hz, 1 H, CHAHBAr), 2.87 (dd, J = 14, 7 Hz, 1 H, CHAHBAr),
2.94 (dd, J = 14.5, 5.5 Hz, 1 H, CHAHBAr), 3.80 (s, 3 H, ArOMe),
128.33 (2 C), 128.73 (2 C), 129.84 (2 C), 130.30, 138.58, 158.27, 3.81 (s, 3 H, ArOMe), 3.88 (dd, J = 7.5, 9 Hz, 1 H, -OCHAHB-),
177.93 ppm. C19H20O3 (296.4): calcd. C 77.00, H 6.80; found 77.35,
H 6.95.
4.14 (dd, J = 9, 7.5 Hz, 1 H, -OCHAHB-), 5.51 (s, 1 H, OH), 5.53
(s, 1 H, OH), 6.4 (d, J = 2 Hz, 1 H, Ar), 6.50 (dd, J = 8, 1.5 Hz, 1
H, Ar), 6.59 (dd, J = 8, 1.5 Hz, 1 H, Ar), 6.60 (s, 1 H, Ar), 6.79
(d, J = 8 Hz, 1 H, Ar), 6.81 (d, J = 8 Hz, 1 H, Ar) ppm. 13C NMR
(125 MHz): δ = 34.54, 38.29, 40.95, 46.53, 55.75, 55.80, 71.30,
110.89, 111.43, 114.02, 114.36, 121.29, 122.04, 129.50, 129.73,
144.36, 144.50, 146.55, 146.67, 178.76 ppm.
(E)-(2RS)-2-Benzyl-4-(4-methoxyphenyl)-3-butenol (20): A solution
of acid 19a (634 mg, 2.25 mmol, 1 equiv.) in THF (25 mL) was
added to a stirred suspension of LAH (350 mg, 10 mmol,
4.4 equiv.) in THF (25 mL). The reaction mixture was heated at
reflux for 4 h, cooled in an ice-bath and excess LAH was destroyed
by adding moist ether into it. The complex was decomposed by the
dropwise addition of a saturated aqueous Na2SO4 solution (3 mL).
The reaction mixture was filtered through Celite and the filtrate
was evaporated. The residue was crystallized from EtOAc/hexane
to give alcohol 20 (576 mg, 96%). M.p. 65 °C. Rf = 0.3 (hexane/
Supporting Information (see footnote on the first page of this arti-
cle): Complete experimental details for all preparative procedures,
full characterization of all starting materials and products along
1
with copies of H and 13C NMR spectra.
EtOAc, 80:20). IR (CHCl ): ν = 3600–3100 (br., OH), 3027, 2932,
˜
3
Acknowledgments
2836, 1607, 1510, 1247, 1175, 1034, 968 (trans C=C), 755, 701 cm–1.
1H NMR (200 MHz, CDCl3): δ = 2.03 (br. s, 1 H, OH), 2.61–2.95
(m, 3 H, PhCH2CH-), 3.53–3.73 (m, 2 H, -CH2OH), 3.82 (s, 3 H,
MeOAr), 5.98 (dd, J = 7.8, 16 Hz, 1 H, ArCHB=CHA-), 6.40 (d, J
= 16 Hz, 1 H, ArCHB=CHA-), 6.88 (d, J = 8.6 Hz, 2 H, Ar), 7.21–
7.33 (m, 7 H, Ar, Ph) ppm. 13C NMR (50 MHz, CDCl3): δ = 37.78,
47.29, 55.12, 65.04, 113.79 (2 C), 125.88, 127.17 (2 C), 128.15 (2
C), 128.35, 129.09 (2 C), 129.80, 131.46, 139.61, 158.84 ppm. MS
(ESI): m/z (%) = 291 (6) [M + 23]+, 251 (7), 159 (34), 143 (100)
ppm. HRMS (ESI): calcd. for C18H20O2Na [M + Na] 291.1361;
found 291.1370.
The authors are thankful to Dr. L. P. Badheka, BOD, BARC for
his assistance in carrying out a few experiments.
[1] a) D. C. Ayres, J. D. Loike in Lignans: Chemical, Biological and
Clinical Properties, Cambridge University Press, Cambridge,
1990; b) N. G. Lewis, L. B. Davis, “Lignans: Biosynthesis and
Function” in Comprehensive Natural Product Chemistry (Ed.:
U. Sankura) Elsevier, Amsterdam, 1999, vol. 1, pp. 639–712; c)
R. S. Ward, Tetrahedron 1990, 46, 5029–5041.
[2] J. Y. Cho, A. R. Kim, E. S. Yoo, K. U. Baik, M. H. Park, J.
Pharm. Pharmacol. 1999, 51, 1267–1273.
[3] a) Y. P. Jang, S. R. Kim, Y. C. Kim, Planta Med. 2001, 67, 470–
472; b) Y. P. Jang, S. R. Kim, Y. H. Choi, J. Kim, S. G. Kim,
G. J. Markelonis, T. H. Oh, Y. C. Kim, J. Neurosci. Res. 2002,
68, 233–240.
[4] a) T. Hirano, M. Gotoh, K. Oka, Life Sci. 1994, 55, 1061–
1069; b) M. Takasaki, T. Konoshima, K. Komatsu, H. Tokuda,
H. Nishino, Cancer Lett. 2000, 158, 53–59.
[5] K. D. R. Setchell, A. M. Lawson, F. L. Mitchell, H. Ad-
lercreutz, D. N. Kirk, M. Axelson, Nature 1980, 287, 740–742.
[6] a) E. Eich, H. Pertz, M. Kaloga, J. Schulz, M. R. Fesen, A.
Mazumder, Y. Pommier, J. Med. Chem. 1996, 39, 86–95; b) L.-
M. Yang, S.-J. Lin, T.-H. Yang, K.-H. Lee, Bioorg. Med. Chem.
Lett. 1996, 6, 941–944.
[7] a) A. Pelter, R. S. Ward, A. Abd-el-Ghani, J. Chem. Soc. Perkin
Trans. 1 1996, 1353–1357; b) N. Kise, T. Ueda, K. Kumada, Y.
Terao, N. Ueda, J. Org. Chem. 2000, 65, 464–468; c) R. S.
Ward, D. D. Hughs, Tetrahedron 2001, 57, 4015–4022; d) R. S.
Ward, D. D. Hughs, Tetrahedron 2001, 57, 5633–5639.
[8] R. S. Ward, “Recent Advances in the Chemistry of Lignans”
in Studies in Natural Products Chemistry, Bioactive Natural
Products, Part E (Ed.: A. U. Rahman) Elsevier, Amsterdam,
2000, vol. 1, pp. 739–798 and references cited therein.
[9] a) J. Brinksma, H. Van Der Deen, A. Van Oeveren, B. L. Fer-
inga, J. Chem. Soc. Perkin Trans. 1 1998, 4159–4163; b) A.
Van Oeveren, J. F. G. A. Jansen, B. L. Feringa, J. Org. Chem.
1994, 59, 5999–6007; c) A. Pelter, R. S. Ward, D. M. Jones, P.
Maddocks, Tetrahedron: Asymmetry 1990, 1, 857–860; d) H.
Zimmer, J. Rothe, J. M. Holbert, J. Org. Chem. 1960, 25, 1234–
1235.
(E)-(2RS)-2-Benzyl-4-(4-methoxyphenyl)-1-(phenylselenocarbonyl-
oxy)-3-butene (3a): A solution of triphosgene (110 mg, 0.37 mmol,
0.66 equiv.) in dichloromethane (1 mL) was added to a stirred solu-
tion of alcohol 20 (147 mg, 0.55 mmol, 1 equiv.) and pyridine
(0.09 mL, 1.1 mmol, 2 equiv.) in dichloromethane (2.5 mL) at
–15 °C under an argon atmosphere. The reaction mixture was al-
lowed to attain 10 °C, left for about 2 min and again cool to 0 °C.
Triethylamine (0.155 mL, 1.1 mmol, 2 equiv.) was added into the
reaction mixture followed by the addition of PhSeH (0.12 mL,
1.1 mmol, 2 equiv.). After 30 min, the reaction mixture was stirred
at room temperature for 15 min. The reaction mixture was diluted
with diethyl ether and washed with water, dried and the solvents
evaporated. The residue was purified by chromatography to give 3a
(223 mg, 91%). Rf = 0.5 (hexane/EtOAc, 10:90). 1H NMR
(200 MHz, CDCl3): δ = 2.70–2.90 (m, 3 H, PhCH2CH-), 3.81 (s, 3
H, MeOAr), 4.21–4.32 (m, 2 H, CH2OCOSe), 5.85 (dd, J = 7.6,
15.8 Hz, 1 H, ArCHB=CHA-), 5.38 (d, J = 15.8 Hz, 1 H, ArCHB=
CHA-), 6.85 (d, J = 8.6 Hz, 2 H, Ar), 7.11–7.39 (m, 10 H, Ar,
2ϫPh), 7.61 (dd, J = 2.2, 7.8 Hz, 2 H, COSePh) ppm. 13C NMR
(50 MHz, CDCl3): δ = 37.76, 43.73, 55.08, 69.94, 113.78 (2 C),
125.92, 126.11, 126.80, 127.25 (2 C), 128.22 (2 C), 128.98, 129.10
(4 C), 129.77, 131.28, 135.78 (2 C), 138.71, 158.94, 166.60 ppm.
MS (ESI): m/z (% 80Se only) = 475 (1) [M + 23]+, 263 (13), 253
(48), 251 (100), 159 (25), 147 (65).
(2RS,3RS)-2,3-Bis(4-hydroxy-3-methoxybenzyl)butyrolactone (4d):
Palladium on charcoal (10% on Pd, 5 mg) was added to a solution
of bis(benzyl) ether 4c (30 mg, 0.056 mmol, 1 equiv.) in EtOH
(4 mL), and the mixture stirred under H2 for 24 h. The reaction
mixture was filtered through a pad of Celite, washed with EtOAc
and evaporated under reduced pressure. The residue was purified
[10] a) J. W. Bode, M. P. Doyle, M. M. Protopopova, Q.-L. Zhou,
J. Org. Chem. 1996, 61, 9146–9155; b) D. J. Bennett, P. L. Pick-
ering, N. S. Simpkins, Chem. Commun. 2004, 1392–1393; c) D.
Enders, V. Lausberg, D. L. Signore, O. M. Berner, Synthesis
2002, 515–522.
5384
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5376–5385

Dibenzylbutyrolactone Lignans Involving Heck and Radical Reactions
[11] a) F. Zhu, W. Li, Q. Wang, Z. Hou, Synlett 2006, 1780–1782;
b) N. Kise, T. Ueda, K. Kumada, Y. Terao, N. Ueda, J. Org.
Chem. 2000, 65, 464–468; c) R. S. Ward, Chem. Soc. Rev. 1982,
11, 75–125; d) R. C. D. Brown, N. A. Swain, Synthesis 2004,
811–827; e) J. L. Belletire, D. F. Fry, J. Org. Chem. 1987, 52,
2549–2555; f) Y. Takei, K. Mori, M. Matsui, Agric. Biol. Chem.
1973, 37, 637–641.
[12] a) J. Fischer, A. J. Reynolds, L. A. Shark, M. S. Sherburn, Org.
Lett. 2004, 6, 1345–1348; b) J. L. Belletire, N. O. Mahmoodi,
J. Nat. Prod. 1992, 55, 194–206.
has been reported, see: a) J. C. Anderson, S. Anguille, R. Bai-
ley, Chem. Commun. 2002, 2018–2019; b) J. C. Anderson, R. H.
Munday, J. Org. Chem. 2004, 69, 8971–8974.
[22] a) R. F. Heck, Org. React. 1982, 27, 345–390; b) E. Negishi in
Handbook of Organopalladium Chemistry for Organic Synthesis,
John Wiley & Sons, New York, 2002, vol. 1, part IV.
[23] a) G. D. Daves, A. Hallberg, Chem. Rev. 1989, 89, 1433–1445;
b) W. Cabri, I. Candiani, Acc. Chem. Res. 1995, 28, 2–7.
[24] M. A. K. Vogel, C. D. W. Stark, I. M. Lyapkalo, Adv. Synth.
Catal. 2007, 349, 1019–1024.
[13] a) M. M. A. Rahman, P. M. Dewick, D. E. Jackson, J. A.
Lucas, Phytochemistry 1990, 29, 1971–1980; b) P. K. Agrawal,
R. P. Rastogi, Phytochemistry 1982, 21, 1459–1461.
[14] R. Singh, G. C. Singh, S. K. Ghosh, Tetrahedron Lett. 2005,
46, 4719–4722.
[25] T. Jeffery, Tetrahedron 1996, 52, 10113–10130.
[26] a) P. Iyer, S. K. Ghosh, Tetrahedron Lett. 2002, 43, 9437–9440;
b) S. M. Date, P. Iyer, S. K. Ghosh, Synth. Commun. 2004, 34,
405–411.
[27] D. M. Hodgson, M. J. Fleming, S. J. Stanway, Org. Lett. 2005,
[15] S. K. Ghosh, R. Singh, G. C. Singh, Eur. J. Org. Chem. 2004,
7, 3295–3298.
4141–4147.
[28] J. Mitra, A. K. Mitra, Indian J. Chem., Sect. B 1994, 33, 953–
956.
[29] S. Adimurthy, G. Ramachandraiah, P. K. Ghosh, A. V. Bede-
kar, Tetrahedron Lett. 2003, 44, 5099–5101.
[16] a) S. M. Date, R. Singh, S. K. Ghosh, Org. Biomol. Chem.
2005, 3, 3369–3378; b) S. K. Ghosh, R. Singh, S. M. Date,
Chem. Commun. 2003, 636–637.
[17] a) F. Diederich, P. J. Stang in Metal-Catalyzed Cross-Coupling
Reactions, Wiley-VCH, Weinheim, Germany, 1998; b) E. Negi-
shi in Handbook of Organopalladium Chemistry for Organic
Synthesis, John Wiley & Sons, NY, 2002, vol. 1, part III.
[18] T. Hiyama, E. Shirakawa in Topics in Current Chemistry Vol.
219: Cross-Coupling Reactions, Springer, Berlin, 2002, pp. 61–
88.
[30] A. L. J. Beckwith, P. E. Pigou, Aust. J. Chem. 1986, 39, 77–87.
[31] A. L. J. Beckwith, C. H. Schiesser, Tetrahedron 1985, 41, 3925–
3941.
[32] a) M. D. Bachi, E. Bosch, Heterocycles 1989, 28, 579–582; b)
J. Pfenninger, C. Heuberger, W. Graf, Helv. Chim. Acta 1980,
63, 2328–2337; c) P. E. Maligres, K. C. Nicolaou, W. Wrasidlo,
Bioorg. Med. Chem. Lett. 1993, 3, 1051–1054; d) S. Takahashi,
T. Nakata, Tetrahedron Lett. 1999, 40, 727–730.
[33] R. S. Ward, A. Pelter, M. I. Edwards, J. Gilmore, Tetrahedron
1996, 52, 12799–12814.
[19] S. E. Denmark, R. F. Sweis, Acc. Chem. Res. 2002, 35, 835–
846.
[20] S. E. Denmark, D. Wehrli, Org. Lett. 2000, 2, 565–568.
[21] The direct cross-coupling of alkenyl(phenyl)silane by an alken-
ylsilanol with iodobenzene to produce a cine-coupled product
Received: May 16, 2007
Published Online: August 30, 2007
Eur. J. Org. Chem. 2007, 5376–5385
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