Concise enantioselective synthesis of furan lignans (-)-dihydrosesamin and (-)-acuminatin and furofuran lignans (-)-sesamin and (-)-methyl piperitol by radical cyclization of epoxides

Article abstract of DOI:10.1055/s-2005-872173

Enantioselective syntheses of furan lignans (-)-dihydrosesamin and (-)-acuminatin and furofuran lignans (-)-sesamin and (-)-methyl piperitol were achieved in up to only three steps in 43%, 42%, 63%, and 60% overall yield, respectively, with high optical purity through stereoselective intramolecular radical cyclization of suitably substituted epoxy olefinic ethers using bis(cyclopentadienyl)titanium(III) chloride as the radical initiator. The key intermediate, chiral epoxy alcohol 4, was prepared by the Sharpless kinetic resolution method. The titanium(III) initiator was prepared in situ from commercially available titanocene dichloride and activated zinc dust in tetrahydrofuran. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-872173

PAPER
2913
Concise Enantioselective Synthesis of Furan Lignans (–)-Dihydrosesamin and
(–)-Acuminatin and Furofuran Lignans (–)-Sesamin and (–)-Methyl Piperitol
by Radical Cyclization of Epoxides
Enantioselective
S
ynthe
s
is of Furan a
l
nd Fur
a
ofura
n
L
ign
b
ans by
R
adical Cy
B
clization of
E
pox
a
ides nerjee, Subhas Chandra Roy*
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India
Fax +91(33)24732805; E-mail: ocscr@mahendra.iacs.res.in
Received 1 March 2005; revised 18 May 2005
ber of interesting syntheses of these furan and furofuran
Abstract: Enantioselective syntheses of furan lignans (–)-dihy-
drosesamin and (–)-acuminatin and furofuran lignans (–)-sesamin
and (–)-methyl piperitol were achieved in up to only three steps in
43%, 42%, 63%, and 60% overall yield, respectively, with high op-
lignans in racemic form7 have been reported, there are
only a few reports for the enantioselective synthesis of
these lignans. To our knowledge, there is only one report8
tical purity through stereoselective intramolecular radical cycliza- for the lengthy synthesis of optically active dihydrosesa-
tion of suitably substituted epoxy olefinic ethers using
bis(cyclopentadienyl)titanium(III) chloride as the radical initiator.
min using a highly erythro-selective aldol reaction. The
methods reported for enantioselective synthesis of furofu-
The key intermediate, chiral epoxy alcohol 4, was prepared by the
ran lignans are based on the diastereoselective hetero-Di-
Sharpless kinetic resolution method. The titanium(III) initiator was
els–Alder reaction,9 a tandem conjugate addition–aldol
prepared in situ from commercially available titanocene dichloride
reaction of the thioacetal to the chiral butenolide,10 an ox-
and activated zinc dust in tetrahydrofuran.
idative coupling of enantiomerically enriched b-oxo es-
Key words: enantioselectivity, lignans, radical cyclizations, transi-
ters followed by reduction and acid-promoted
tion metals, titanium
cyclization,11 and an asymmetric Strecker reaction fol-
lowed by a Michael addition.12 Recently, a furofuran lig-
nan (+)-membrine has been synthesized13 using chiral
Due to their widespread occurrence in nature1,4 and broad
organoselenium intermediates. A formal synthesis of (+)-
range of biological activities,2 lignans have attracted con-
sesamin in 62% ee has also been reported recently using a
siderable interest over the years. Two major subgroups of
chirotopical Heck reaction.14 Further advances should
lignans are composed of tri- and tetrasubstituted tetrahy-
seek to develop efficient asymmetric approaches that have
drofurans and substituted 3,7-dioxabicyclooctanes, the
the flexibility to allow access to different substitution pat-
synthesis of which poses interesting and often unsolved
terns for the synthesis of analogues for biological testing.
problems of stereocontrol. Because of the structural com-
Therefore, our goal was to develop a short and enantiose-
plexity and associated biological activities, lignans are
lective route, by using readily available building blocks,
challenging targets for organic chemists. Dihydrosesamin
to synthesize different types of lignans in enantiomerical-
and acuminatin are representatives of biologically active
ly pure form. In continuation of our efforts15 towards the
furan lignans with two identical or different aromatic moi-
synthesis of naturally occurring lignans in racemic form
eties, respectively. Dihydrosesamin3 was isolated from
by radical cyclization of epoxides using a transition-metal
Daphne tangutica maxim and it has been used as an abor-
radical initiator, we report here a full account on the enan-
tifacient and in the treatment of rheumatism and tooth-
tioselective total synthesis of furan lignans (–)-dihy-
ache. Acuminatin4 was isolated from Machilus thunbergii
drosesamin (1a) and (–)-acuminatin (1d) and furofuran
and Epimedium acuminatum and was found to exhibit di-
lignans (–)-sesamin (2a) and (–)-methyl piperitol (2b)
verse hepatoprotective activities, perhaps by serving as a
(Figure 1) in good overall yield by employing radical
potent antioxidant. Sesamin and methyl piperitol are rep-
technology. Lignans 1d, 2a, and 2b are the enantiomers of
resentatives of biologically active symmetrical and un-
the naturally occurring compounds (+)-acuminatin, (+)-
symmetrical
2,6-diaryl-3,7-dioxabicyclo[3.3.0]octane
sesamin, and (+)-methyl piperitol, respectively. To the
best of our knowledge, this radical cyclization strategy
has not been used before for the asymmetric synthesis of
these lignans.
lignans, respectively. Sesamin5 was isolated from hydro-
cotyle plants and was found to inhibit the growth of silk-
worm (Bombyx mori) larvae. It also shows weak juvenile
hormone activity in the milkweed bug (Oncopeltus fascia-
tus) and functions as a regulator of cholesterol and li-
noleate metabolism in rats. Methyl piperitol6 was isolated
from Helichrysum bracteatum and it possesses platelet ac-
tivating factor (PAF) antagonist activity. Although a num-
Because of its mildness and its regio- and stereoselectivi-
ty, the hex-5-enyl radical cyclization has been extensively
applied in the construction of oxacyclic compounds lead-
ing to tetrahydrofuran derivatives. A bromoalkene or a
bromoalkyne derivative has been used widely as a radical
precursor16 and tin hydrides as the radical initiator. As the
tin compounds are toxic and difficult to separate from the
products, an alternative nontoxic and easily separable rad-
SYNTHESIS 2005, No. 17, pp 2913–2919
Advanced online publication: 12.08.2005
DOI: 10.1055/s-2005-872173; Art ID: T02705SS
x
x.
x
x
.
2
0
0
5
© Georg Thieme Verlag Stuttgart · New York

2914
B. Banerjee, S. C. Roy
PAPER
OMe
Therefore, our synthetic plan mainly relied on the prepa-
ration of chiral epoxy alcohols 4 from the corresponding
allylic alcohols 3 using the Sharpless kinetic resolution
method. The starting allylic alcohols 3a and 3b were pre-
pared by the standard procedure from the corresponding
aryl aldehyde and vinyl magnesium bromide.18 Com-
pound 3a was subjected to Sharpless kinetic resolution19
using (+)-diethyl tartrate in the presence of titanium(IV)
isopropoxide [Ti(i-PrO)4], tert-butyl hydroperoxide, and
4-Å molecular sieves in dry dichloromethane at –20 °C to
give the corresponding chiral epoxy alcohol 4a (Ar1 = 3,4-
methylenedioxyphenyl) in 43% yield (84% based on the
recovered S-allylic alcohol 5a) and with 98% ee. Similar-
ly, alcohol 4b (Ar1 = 3,4-dimethoxyphenyl) was prepared
in 45% yield (81% based on the recovered S-allylic alco-
hol 5b) and with 96% ee (Scheme 2).
O
O
OH
OH
OH
O
O
O
O
O
O
1a
1d
O
O
O
O
O
O
H
H
H
H
O
O
O
O
MeO
O
Ti(iPrO)4, (+)-DET
+
OMe
2a
2b
Ar1
OH
Ar1
OH
Ar1
OH
t-BuOOH, MS,
CH2Cl2, –20 °C
3
4
5
Figure 1
4a, 43%, 98% ee
4b, 45%, 96% ee
NaH
THF-DMSO (10:1)
0–10 °C, 15 min,
then
ical initiator for the intramolecular radical cyclizations is
still desirable.
7a, 82%
7b, 83%
7c, 88%
Ar2CH=CHCH2Br
The selective one-electron reduction of an epoxide,17 by
the stoichiometric as well as catalytic one-electron trans-
fer reagent bis(cyclopentadienyl)titanium(III) chloride
(Cp2TiCl), represents an invaluable synthetic tool as the
intermediate radical can be trapped in subsequent reac-
tions. Usually, high regioselectivity is observed as the ep-
oxide cleavage via C–O homolysis is guided by the
relative stabilities of the intermediate radicals.
6
Ar2
O
O
O
OMe
R
Ar1
O
F3C
Ar1
Ph
O
8
7
a, Ar1 = Ar2 = 3,4-Methylenedioxyphenyl
b, Ar1 = 3,4-Dimethoxyphenyl
Ar2 = 3,4-Methylenedioxyphenyl
c, Ar1 = 3,4-Methylenedioxyphenyl
Ar2 = 4-Benzyloxy-3-methoxyphenyl
From the retrosynthetic analysis shown in Scheme 1, it
can be assumed that both types of lignans 1a and 1d and
2a and 2b can be synthesized by stereoselective radical
cyclization of chiral epoxy olefinic ethers, which in turn
can be prepared by condensation of chiral epoxy alcohols
with the appropriate cinnamyl bromide.
Scheme 2 Synthesis of epoxy ethers
1
The enantiomeric excess was determined by H NMR
spectroscopic analysis of the corresponding Mosher
esters20 8a and 8b derived from 4a and 4b, respectively,
with (R)-(+)-a-methoxy-a-(trifluoromethyl)phenylacetic
acid. The chiral epoxy alcohol 4a was treated with bro-
mide 6a (Ar2 = 3,4-methylenedioxyphenyl) in the pres-
ence of sodium hydride in tetrahydrofuran–dimethyl
sulfoxide (10:1) to afford the epoxy olefinic ether 7a in
82% yield. Similarly, ethers 7b and 7c were prepared
from bromides 6b (Ar2 = 3,4-methylenedioxyphenyl) and
6c (Ar2 = 4-benzyloxy-3-methyloxyphenyl) in 83 and
88% yield, respectively.
The radical initiator Cp2TiCl was easily generated17 in situ
from commercially available titanocene dichloride
(Cp2TiCl2) and activated zinc dust in tetrahydrofuran; a
satisfactory reagent was prepared by vigorously stirring
the red solution for one hour under an argon atmosphere
at room temperature.
OH
Ar2
Ar2
O
Ar1
O
1a, 1d
Ar2
Ar1
O
O
H
H
Ar1
O
2a, 2b
Ar2
O
+
Ar1
OH
Ar1
OH
Br
Scheme 1 Retrosynthetic analysis
Synthesis 2005, No. 17, 2913–2919 © Thieme Stuttgart · New York

PAPER
Enantioselective Synthesis of Furan and Furofuran Lignans by Radical Cyclization of Epoxides
2915
The epoxy olefinic ether 7a on treatment with Cp2TiCl in lution was stirred with an excess of iodine at the same
tetrahydrofuran at room temperature for 1.5 h, followed temperature for 1 h to give (–)-sesamin (2a) as the only
by acidic workup, gave the cyclized product 1a together isolated product in 91% yield, the specific rotation of
with a minor isomer in a ratio of 5:1 in 87% yield which was opposite to naturally occurring (+)-sesamin22
(Scheme 3). Similarly, the epoxy olefinic ether 7c under {Lit.23 [a]D22 +68.7 (c 0.40, CHCl3)}. Under identical re-
identical reaction conditions afforded the cyclized prod- action conditions, compound 7b afforded (–)-methyl pip-
uct 1c together with a minor isomer in a 5:1 ratio in 85% eritol (2b) in 90% yield with opposite specific rotation
yield.
compared to naturally occurring (+)-methyl piperitol24
{Lit.6a [a]D22 +73.6 (c 0.35, CHCl3)}, also known as Ko-
busin. Here, double cyclizations furnished the furofurans
in better yields and with higher stereoselectivity com-
pared to the monocyclizations. This could be accounted
for by rapid cyclization at a higher temperature (60 °C)
leading to the highly stereoselective product, which might
be facilitated by the reaction of iodine with the organoti-
tanium intermediate I present in the reaction mixture to
give intermediate II (Scheme 4). The second furan moiety
formation was found to be a highly controlled reaction
arising from an intramolecular SN2 attack on the iodine-
substituted carbon of II giving the stable products 2 with
all the substituents equatorial. This can be explained using
1H NMR spectra; for example, for symmetrical 2a, only
one doublet at d 4.71 (J = 4.3 Hz) for both C-2 and C-6
benzylic protons was observed, but for unsymmetrically
substituted furofuran lignans (Ar1 π Ar2) such as (–)-
methyl piperitol (2b), two doublets at d 4.72 (J = 3.9 Hz)
and 4.74 (J = 4.1 Hz) for the C-2 and C-6 benzylic pro-
tons, partially overlapped with each other, were observed.
Other one-electron reduction reagents, such as samari-
um(II) iodide, might influence the opening of epoxides to
undergo radical cyclization reactions, but we were inter-
ested only in Cp2TiCl.
Ar2
OH
O
Cp2TiCl, THF
r.t., 1.5 h
then H3O+
Ar2
O
Ar1
Ar1
for 7a and 7c
O
1a, 63%
1c, 61%
1
7
Cp2TiCl, THF
60 °C, 10 min
then I2, 1 h
H2/Pd-C (10%)
ethyl acetate,
1.5 h, 93%
7a, 91%
7b, 90%
for 1c
1d
Ar2
O
H
H
Ar1
O
2
a, Ar1 = Ar2 = 3,4-Methylenedioxyphenyl
b, Ar1 = 3,4-Dimethoxyphenyl
Ar2 = 3,4-Methylenedioxyphenyl
c, Ar1 = 3,4-Methylenedioxyphenyl
Ar2 = 4-Benzyloxy-3-methoxyphenyl
Scheme 3 Radical cyclization of epoxy ethers
The ratio of the two isomers was determined from the C-
2 benzylic proton that appeared in the 1H NMR spectra as
a doublet at d 4.80 (J = 6.2 Hz) for the major isomer and
at d 4.60 (J = 8.0 Hz) for the minor isomer in the crude
product mixture obtained from 7a, and as a doublet at d
4.79 (J = 6.6 Hz) for the major isomer and at d 4.61 (J =
7.9 Hz) for the minor isomer in the crude product mixture
obtained from 7c. The major isomers 1a and 1c were sep-
arated by preparative TLC (20% EtOAc–light petroleum)
in 63% and 61% yield, respectively. The specific rotation
of the major isomer 1a was nearly identical with that of
naturally occurring (–)-dihydrosesamin.3,8 The benzyl
ether 1c on catalytic hydrogenolysis over 10% palladium
on charcoal in ethyl acetate afforded (–)-acuminatin (1d)
in 93% yield, the specific rotation of which was opposite
Ar2
Ar2
OTi(IV)
OTi(IV)
I2
Ti(IV)
I
Ar1
Ar1
O
O
I
II
Scheme 4
In conclusion, we have successfully achieved the enan-
tioselective total synthesis of furan lignans (–)-dihydro-
sesamin and (–)-acuminatin and furofuran lignans (–)-
sesamin and (–)-methyl piperitol by radical cyclization of
epoxides using a transition-metal radical source in up to
only three steps in respectable overall yields and with high
optical purity. To the best of our knowledge, radical cy-
clizations of epoxides used for the concise enantioselec-
tive synthesis of lignans have not yet been reported in the
literature.
to natural (+)-acuminatin21 {Lit.21[a]D +11.1 (c 0.09,
25
CHCl3)}. To our knowledge, this is the first report for the
synthesis of optically active (–)-acuminatin. Because nei-
ther the minor isomer nor a derivative formed by reaction
of its hydroxy group could be separated chromatographi-
cally in pure form, its stereochemistry remains uncertain.
The reasons for the high diastereoselectivity observed in
the radical cyclizations have already been explained thor-
oughly by our group15 during the synthesis of lignans in
racemic forms.
The compounds described are all optically active. Melting points
were determined in open capillary tubes and are uncorrected. The
1H and 13C NMR spectra were recorded in CDCl3 on 300 MHz and
75 MHz spectrometers (Bruker), respectively, using TMS as the in-
ternal standard. IR spectra of solids (KBr) and liquids (neat) were
recorded on a Shimadzu FTIR-8300 instrument. The Et2O and THF
In addition, the epoxy olefinic ether 7a was treated with
Cp2TiCl in tetrahydrofuran at 60 °C, and the resulting so-
Synthesis 2005, No. 17, 2913–2919 © Thieme Stuttgart · New York

2916
B. Banerjee, S. C. Roy
PAPER
were dried (Na), and CH2Cl2 and DMSO were freshly distilled from
P2O5 and CaH2, respectively. Light petroleum (bp 60–80 °C) and
silica gel (60–120 mesh) were used for column chromatography.
Preparative TLC was performed using Merck precoated silica 60
F254 plates (0.2 mm). Optical rotations were determined on a pola-
rimeter (JASCO, P-1020) at the sodium D line using spectroscopic
grade CHCl3 at the concentration indicated. Elemental analyses
were performed on an analytical instrument (Dr. Hans Hosli, 0A1,
468) in our analytical laboratory. High-resolution mass spectra were
obtained using a Qtof Micro YA263 instrument.
1H NMR (300 MHz, CDCl3): d = 2.17 (br s, OH), 2.81 (t, J = 4.7
Hz, 1 H), 2.98 (dd, J = 4.9, 2.7 Hz, 1 H), 3.23–3.26 (m, 1 H), 3.90
(s, 3 H), 3.92 (s, 3 H), 4.90 (d, J = 2.1 Hz, 1 H), 6.87–6.98 (m, 3 H).
13C NMR (75 MHz, CDCl3): d = 44.3, 55.5, 56.1, 56.2, 71.4, 109.9,
111.4, 119.1, 132.7, 149.1, 149.3.
Anal. Calcd for C11H14O4: C, 62.85; H, 6.71. Found: C, 62.75; H,
6.60.
(R)-(+)-[(S)-1,3-Benzodioxol-5-yl][(2S)-oxiran-2-yl]methyl
3,3,3-Trifluoro-2-methoxy-2-phenylpropanoate (8a):
To a solution of 4a (30 mg, 0.15 mmol) in CH2Cl2 (3 mL) was added
(R)-(+)-a-methoxy-a-(trifluoromethyl)phenylacetic acid (43.6 mg,
0.18 mmol), DCC (37 mg, 0.18 mmol), and a catalytic amount of
DMAP (3.7 mg, 0.03 mmol). The mixture was stirred overnight at
r.t. The solid was filtered off, the filtrate was concentrated, and the
residue was purified by column chromatography (silica gel, 10%
EtOAc–light petroleum) to afford 8a as a viscous liquid; yield: 54.8
mg (89%).
(S)-1,3-Benzodioxol-5-yl[(2S)-oxiran-2-yl]methanol (4a):
Activated powdered 4-Å molecular sieves (150 mg, 25 wt%) in dry
CH2Cl2 (5 mL) were placed in a flame-dried, 50-mL, two-necked
round-bottom flask under an argon atmosphere. The apparatus was
cooled to –20 °C and a solution of (+)-DET (104 mg, 0.505 mmol)
in dry CH2Cl2 (2 mL) [previously stirred with 4-Å molecular sieves
(50 mg) for 20 min] and a solution of Ti(i-PrO)4 (0.1 mL, 0.337
mmol) in dry CH2Cl2 (2 mL) [previously stirred with 4-Å molecular
sieves (50 mg) for 20 min] were cannulated sequentially into the re-
action flask with stirring. After 20 min, 5.5 M t-BuOOH in decane
(0.61 mL) was added to the mixture and it was stirred at –20 °C for
another 0.5 h. Then, a solution of allylic alcohol 3a (600 mg, 3.37
mmol) in dry CH2Cl2 (4 mL) [previously stirred with 4-Å molecular
sieves (75 mg) for 20 min] was cannulated into the mixture and the
stirring was continued for further 4 h. Finally, an aqueous solution
of 30% tartaric acid (3.4 mL) was added, the mixture was stirred for
0.5 h, and the temperature was allowed to warm to 0 °C. Most of the
CH2Cl2 was removed under reduced pressure and the residue was
stirred at 0 °C for 0.5 h with 30% aq NaOH (3.5 mL) saturated with
NaCl. The resulting mixture was filtered through celite using Et2O
and the filtrate was placed in a separatory funnel and the organic
layer was separated. The aqueous layer was extracted with Et2O
(1 × 30 mL) and the combined ethereal extracts were washed with
brine (30 mL) and dried (Na2SO4). The solvent was removed under
reduced pressure and the residue obtained was purified by column
chromatography (silica gel, 30% EtOAc–light petroleum) to give
pure epoxide 4a as a colorless viscous liquid [yield: 280 mg (43%)]
with 98% ee [by 1H NMR spectroscopic analysis of the correspond-
ing (R)-(+)-a-methoxy-a-(trifluoromethyl)phenylacetic acid ester 8
prepared following a standard procedure20] together with the unre-
acted S-allylic alcohol 5a [yield: 290 mg (48%)].
IR (neat): 3018, 2918, 2848, 1753, 1504, 1490, 1446 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.63 (dd, J = 5.1, 2.5 Hz, 1 H),
2.73 (t app, J = 4.2 Hz, 1 H), 3.18–3.22 (m, 1 H), 3.47 (s, 3 H), 5.98
(s, 2 H), 6.04 (d, J = 3.6 Hz, 1 H), 6.79–6.90 (m, 3 H), 7.33–7.46
(m, 5 H).
13C NMR (75 MHz, CDCl3): d = 44.1, 52.3, 55.2, 75.0, 101.2, 107.7,
108.2, 108.3, 121.5, 121.9, 125.0, 127.2, 128.1, 128.2, 128.3, 129.4,
129.6, 147.8, 148.1, 165.3.
HRMS: m/z [M + H]+ calcd for C20H17F3O6: 411.1055; found:
411.1017.
(R)-(+)-[(S)-(3,4-Dimethoxyphenyl)][(2S)-oxiran-2-yl]methyl
3,3,3-Trifluoro-2-methoxy-2-phenylpropanoate (8b):
Ester 8b was prepared from 4b following the same procedure as de-
scribed for 8a and was formed as a viscous liquid in 90% yield
(55 mg).
IR (neat): 3020, 2933, 2848, 1753, 1517, 1465, 1168, 1026 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.65 (dd, J = 5.0, 2.4 Hz, 1 H),
2.75 (dd, J = 4.8, 3.8 Hz, 1 H), 3.23–3.27 (m, 1 H), 3.48 (s, 3 H),
3.85 (s, 3 H), 3.91 (s, 3 H), 6.08 (d, J = 3.6 Hz, 1 H), 6.85–6.99 (m,
3 H), 7.31–7.45 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 44.4, 52.5, 55.4, 55.8, 55.9, 75.5,
110.6, 111.1, 111.2, 120.3, 121.4, 125.2, 127.3, 127.4, 128.3, 129.6,
129.7, 132.2, 149.2, 149.7, 165.5.
HRMS: m/z [M + H]+ calcd for C21H21F3O6: 427.1368; found:
427.1324.
4a
[a]D31 +70.5 (c 1.1, CHCl3).
IR (neat): 3417, 2993, 2900, 1610, 1504, 1488, 1444, 1247, 1037
cm–1.
1H NMR (300 MHz, CDCl3): d = 2.32 (br s, OH), 2.77 (t, J = 4.9
Hz, 1 H), 2.95 (dd, J = 4.8, 2.6 Hz, 1 H), 3.16–3.19 (m, 1 H), 4.83
(d, J = 2.3 Hz, 1 H), 5.96 (s, 2 H), 6.78–6.89 (m, 3 H).
5-[(1E)-3-{(S)-1,3-benzodioxol-5-yl[(2S)-oxiran-2-yl]meth-
oxy}prop-1-enyl]-1,3-benzodioxole (7a):
13C NMR (75 MHz, CDCl3): d = 44.1, 55.5, 71.2, 101.5, 107.4,
108.6, 120.4, 133.9, 147.8, 148.2.
To a stirred suspension of NaH (50 mg, 60% dispersion, 2.06 mmol)
in dry THF–DMSO (10:1, 4 mL) was added dropwise a solution of
epoxy alcohol 4a (200 mg, 1.03 mmol) in dry THF (7mL) at 0–10
°C under N2. After the evolution of hydrogen ceased (15 min), a so-
lution of cinnamyl bromide 6a (300 mg, 1.24 mmol) in THF (6 mL)
was added dropwise at 0 °C over 25 min. The mixture was then
stirred at r.t. for 8 h and carefully decomposed with ice water. After
removal of most of the THF under reduced pressure, the resulting
residue was extracted with Et2O (4 × 50 mL). The combined ethe-
real extracts were washed with H2O (2 × 15 mL) and dried
(Na2SO4). The solvent was removed under reduced pressure and the
dark brown residue obtained was purified by column chromatogra-
phy (silica gel, 30% EtOAc–light petroleum) to give 7a as a color-
less viscous liquid; yield: 300 mg (82%).
Anal. Calcd for C10H10O4: C, 61.86; H, 5.19. Found: C, 61.73; H,
5.12.
(S)-(3,4-Dimethoxyphenyl)[(2S)-oxiran-2-yl]methanol (4b):
Compound 4b was prepared from 3b following the same procedure
as described for 4a and was formed as a viscous liquid in 45% yield
(290 mg) with 96% ee together with the unreacted S-allylic alcohol
5b (270 mg, 45%).
4b
[a]D31 +75.8 (c 1.0, CHCl3).
IR (neat): 3492, 2941, 2841, 1633, 1593, 1519, 1464, 1454, 1421,
1142, 1022 cm–1
[a]D27.7 +60.5 (c 1.8, CHCl3).
Synthesis 2005, No. 17, 2913–2919 © Thieme Stuttgart · New York

PAPER
Enantioselective Synthesis of Furan and Furofuran Lignans by Radical Cyclization of Epoxides
2917
IR (neat): 2994, 2895, 1672, 1606, 1503, 1488, 1444, 1249, 1039
cm–1.
1H NMR (300 MHz, CDCl3): d = 2.74–2.81 (m, 2 H), 3.12–3.16 (m,
1 H), 3.99 (ddd, J = 12.4, 6.6, 1.3 Hz, 1 H), 4.12 (ddd, J = 12.5, 5.6,
1.4 Hz, 1 H), 4.31 (d, J = 4.0 Hz, 1 H), 5.86 (s, 2 H), 5.89 (s, 2 H),
6.02–6.12 (m, 1 H), 6.44 (d, J = 15.8 Hz, 1 H), 6.70–6.91 (m, 6 H).
13C NMR (75 MHz, CDCl3): d = 45.5, 54.8, 69.8, 79.9, 101.5, 101.6,
106.2, 108.0, 108.6, 108.7, 121.5, 121.6, 124.3, 131.5, 132.5, 132.8,
147.7, 148.0, 148.3, 148.4.
resulting residue was extracted with Et2O (4 × 30 mL) and the com-
bined ethereal extracts were washed successively with sat. aq
NaHCO3 (1 × 15 mL) and brine (1 × 15 mL), and finally dried
(Na2SO4). The solvent was removed under reduced pressure and the
brown residue obtained was purified by column chromatography
(silica gel, 40% EtOAc–light petroleum) to give a colorless viscous
liquid (88 mg, 87%) as a mixture of two isomers in a ratio of 5:1.
The minor isomer could not be separated in pure form. It was al-
ways contaminated with the major isomer. The major isomer was
separated by preparative TLC (20% EtOAc–light petroleum) to af-
ford 1a as a crystalline solid; yield: 64 mg (63%).
Anal. Calcd for C20H18O6: C, 67.80; H, 5.1. Found: C, 67.72; H
5.11.
mp 97–99 °C (Lit.3 98–99 °C)
26.5
25
[a]D
dine)}.
–15.2 (c 0.8, pyridine) {Lit.3 [a]D –15.9 (c 0.67, pyri-
5-[(1E)-3-{(S)-(3,4-dimethoxyphenyl)[(2S)-oxiran-2-yl]meth-
oxy}prop-1-enyl]-1,3-benzodioxole (7b):
Compound 7b was prepared from 4b by condensation with 6b fol-
lowing the same procedure as described for 7a and was formed as a
viscous liquid in 83% yield (293 mg).
[a]D27.7 +52.8 (c 0.6, CHCl3).
IR (KBr): 3409, 2916, 2848, 1610, 1504, 1488, 1442, 1247, 1039
cm–1.
1H NMR (300 MHz, CDCl3): d = 1.55 (br s, OH), 2.33–2.38 (m, 1
H), 2.54 (dd, J = 13.4, 10.5 Hz, 1 H), 2.61–2.75 (m, 1 H), 2.88 (dd,
J = 13.4, 5.2 Hz, 1 H), 3.69–3.79 (m, 2 H), 3.90 (dd, J = 10.5, 6.7
Hz 1 H), 4.06 (dd, J = 8.5, 6.6 Hz 1 H), 4.80 (d, J = 6.2 Hz, 1 H),
5.93 (s, 2 H), 5.94 (s, 2 H), 6.63–6.85 (m, 6 H).
13C NMR (75 MHz, CDCl3): d = 33.2, 42.3, 52.7, 61.0, 73.0, 82.9,
100.9, 101.0, 106.3, 108.0, 108.2, 108.9, 119.0, 121.4, 134.1, 137.1,
146.0, 146.9, 147.8, 147.9.
IR (neat): 2997, 2902, 1677, 1604, 1504, 1444, 1250 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.74–2.82 (m, 2 H), 3.16–3.20 (m,
1 H), 3.88 (s, 3 H), 3.89 (s, 3 H), 4.01 (ddd, J = 12.5, 6.5, 1.2 Hz, 1
H), 4.13 (ddd, J = 12.4, 5.8, 1.3 Hz, 1 H), 4.33 (d, J = 4.2 Hz, 1 H),
5.94 (s, 2 H), 6.04–6.13 (m, 1 H), 6.45 (d, J = 15.8 Hz, 1 H), 6.72–
6.92 (m, 6 H).
Anal. Calcd for C20H20O6: C, 67.41; H, 5.65. Found: C, 67.32; H,
5.61.
13C NMR (75 MHz, CDCl3): d = 45.5, 54.8, 56.3, 69.8, 80.0, 101.3,
106.1, 108.6, 110.2, 110.5, 111.3, 120.3, 121.5, 124.3, 131.0, 131.4,
132.8, 147.7, 148.3, 149.4, 149.5.
[(2R,3S,4S)-4-(4-benzyloxy-3-methoxybenzyl)-2-(1,3-benzo-
dioxol-5-yl)tetrahydrofuran-3-yl]methanol (1c):
Anal. Calcd for C21H22O6: C, 68.10; H, 6.51. Found: C, 67.98; H,
6.50.
Compound 7c was subjected to the radical cyclization reaction fol-
lowing the same procedure as described for 1a to give a mixture of
two isomers as a colorless viscous liquid in a ratio of 5:1. The minor
isomer could not be separated in pure form. It was always contami-
nated with the major isomer. The major isomer was separated by
preparative TLC (20% EtOAc–light petroleum) to afford 1c as a
viscous liquid in 61% yield (62 mg).
5-{(S)-{[(2E)-3-(4-benzyloxy-3-methoxyphenyl)prop-2-
enyl]oxy}[(2S)-oxiran-2-yl]methyl}-1,3-benzodioxole (7c):
Compound 7c was prepared from 4a by condensation with 6c fol-
lowing the same procedure as described for 7a and was formed as a
viscous liquid in 88% yield (420 mg).
[a]D27.7 +42.3 (c 2.0, CHCl3).
[a]D27 –20.5 (c 0.8, CHCl3).
IR (neat): 3018, 2887, 1605, 1510, 1488, 1215 cm–1.
IR (neat): 2918, 2871, 1602, 1585, 1514, 1504, 1487, 1444, 1247,
1137, 1037 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.59 (br s, OH), 2.32–2.41 (m, 1
H), 2.55 (dd, J = 13.4, 10.6 Hz, 1H), 2.67–2.79 (m, 1 H), 2.91 (dd,
J = 13.3, 5.1 Hz, 1 H), 3.71–3.80 (m, 2 H), 3.86–3.95 (m, 1 H), 3.87
(s, 3 H), 4.05 (dd, J = 8.7, 6.4 Hz, 1 H), 4.79 (d, J = 6.6 Hz, 1 H),
5.12 (s, 2 H), 5.94 (s, 2 H), 6.64–6.84 (m, 6 H), 7.26–7.45 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 33.1, 42.3, 52.7, 55.7, 60.9, 71.1,
73.0, 82.8, 101.0, 106.3, 108.0, 112.5, 114.2, 119.1, 120.4, 120.6,
127.2, 127.8, 128.5, 133.6, 136.1, 137.0, 137.2, 146.6, 146.9, 147.8,
149.6.
1H NMR (300 MHz, CDCl3): d = 2.76–2.81 (m, 2 H), 3.12–3.16 (m,
1 H), 3.90 (s, 3 H), 4.00 (dd, J = 12.1, 6.3 Hz, 1 H), 4.13 (dd, J =
12.3, 5.7 Hz, 1 H), 4.33 (d, J = 4.0 Hz, 1 H), 5.15 (s, 2 H), 5.97 (s,
2 H), 6.06–6.16 (m, 1 H), 6.45 (d, J = 15.8 Hz, 1 H), 6.81–6.94 (m,
6 H), 7.26–7.44 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 45.4, 54.8, 56.3, 69.9, 71.4, 79.8,
101.4, 108.0, 108.5, 109.9, 114.4, 120.0, 121.4, 124.3, 127.6, 127.7,
128.2, 128.3, 128.9, 132.1, 132.3, 132.9, 137.1, 148.0, 148.3, 149.2,
149.6.
Anal. Calcd for C27H28O6: C, 72.30; H, 6.29. Found: C, 72.21; H,
6.26.
Anal. Calcd for C27H26O6: C, 72.63; H, 5.87. Found: C, 72.43; H,
5.86.
(–)-Acuminatin (1d):
(–)-Dihydrosesamin (1a):
Compound 1c (40 mg, 0.089 mmol) in dry EtOAc (7 mL) was sub-
jected to hydrogenolysis with H2 and 10% Pd/C (25 mg) at r.t. and
with constant stirring for 1.5 h. The catalyst was then filtered off,
the filtrate was concentrated under reduced pressure, and the resi-
due obtained was purified by column chromatography (silica gel,
40% EtOAc–light petroleum) to give 1d as a colorless viscous liq-
uid; yield: (30 mg, 93%).
A solution of Cp2TiCl2 (155 mg, 0.62 mmol) in dry THF (8 mL) was
stirred with activated Zn dust (115 mg, 1.77 mmol) for 1 h under ar-
gon [activated Zn dust was prepared by washing commercially
available Zn dust (20 g) with 4 M HCl (60 mL), followed by thor-
ough washing with H2O, and finally with dry acetone, and then dry-
ing in vacuo]. The resulting green solution was then added dropwise
to a stirred solution of epoxide 7a (100 mg, 0.282 mmol) in dry THF
(7 mL) at r.t. under argon over a period of 30 min. The mixture was
stirred for an additional 1 h and decomposed with 10% H2SO4 (10
mL). After removal of most of the THF under reduced pressure, the
[a]D26.5 –10.6 (c 0.5, CHCl3).
IR (neat): 3018, 2939, 1604, 1514, 1488, 1442, 1215 cm–1.
Synthesis 2005, No. 17, 2913–2919 © Thieme Stuttgart · New York

2918
B. Banerjee, S. C. Roy
PAPER
1H NMR (300 MHz, CDCl3): d = 2.32–2.40 (m, 1 H), 2.53 (dd, J =
13.5, 10.8, Hz, 1 H), 2.68–2.76 (m, 1 H), 2.91 (dd, J = 13.2, 5.3 Hz,
1 H), 3.71–3.81 (m, 2 H), 3.83–3.94 (m, 1 H), 3.86 (s, 3 H), 4.05
(dd, J = 8.7, 6.6 Hz, 1 H), 4.77 (d, J = 6.5 Hz, 1 H), 5.50 (s, PhOH),
5.93 (s, 2 H), 6.67–6.92 (m, 6 H).
13C NMR (75 MHz, CDCl3): d = 33.3, 42.4, 52.8, 56.0, 60.8, 73.0,
82.8, 101.0, 106.6, 108.0, 111.2, 114.4, 119.1, 121.3, 132.2, 137.1,
144.0, 146.5, 146.9, 147.8.
References
(1) (a) Rao, C. B. S. Chemistry of lignans; Andhra University
Press: Andhra, India, 1978. (b) Whiting, D. A. Nat. Prod.
Rep. 1985, 2, 191. (c) Whiting, D. A. Nat. Prod. Rep. 1987,
4, 499. (d) Whiting, D. A. Nat. Prod. Rep. 1990, 7, 349.
(e) Ward, R. S. Nat. Prod. Rep. 1993, 10, 1. (f) Ward, R. S.
Nat. Prod. Rep. 1995, 12, 183.
(2) (a) Gottlieb, O. R. In New Natural Products and Plant Drugs
with Pharmacological, Biological or Therapeutic Activity;
Springer: Berlin, 1987, 227. (b) MacRae, W. D.; Towers, G.
H. N. Phytochemistry 1984, 23, 1207; and references cited
therein.
Anal. Calcd for C20H22O6: C, 67.03; H, 6.19. Found: C, 66.92; H,
6.15.
(–)-Sesamin (2a):
(3) Lin-Gen, Z.; Seligmann, O.; Lotter, H.; Wagner, H.
Phytochemistry 1983, 22, 265.
(4) Ward, R. S. Nat. Prod. Rep. 1997, 14, 43; and references
cited therein.
(5) Bertram, S. H.; Vander der steur, J. P. K.; Waterman, H. I.
Biochem. Z. 1928, 1, 197.
A solution of Cp2TiCl2 (155 mg, 0.619 mmol) in dry THF (8 mL)
was stirred with activated Zinc dust (115 mg, 1.77 mmol) for 1 h un-
der argon. The resulting green solution was then added dropwise to
a stirred solution of epoxide 7a (100 mg, 0.28 mmol) in dry THF (7
mL) at 60 °C under argon over a period of 10 min. After 10 min, a
solution of I2 (97 mg, 0.38 mmol) in THF (2 mL) was added via sy-
ringe. The mixture was kept at 60 °C with constant stirring for a fur-
ther 1 h and then decomposed with sat. aq NH4Cl (10 mL). Most of
the THF was removed under reduced pressure and the resulting res-
idue obtained was extracted with Et2O (4 × 50 mL). The combined
ethereal extracts were thoroughly washed with 10% aq Na2S2O3
(3 × 25 mL) and brine (1 × 20 mL), and then dried (Na2SO4). The
solvent was removed under reduced pressure and the dark mass ob-
tained was purified by column chromatography (silica gel, 20%
EtOAc–light petroleum) to give 2a as a crystalline solid; yield: 91
mg (91%).
mp 122–124°C (Lit.22a 123–124.5 °C).
[a]D26 –66.8 (c 0.30, CHCl3).
IR (KBr): 2918, 2850, 1608, 1502, 1488, 1442, 1245, 1037 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.03–3.07 (m, 2 H), 3.88 (dd, J =
9.2, 3.5 Hz, 2 H), 4.25 (dd, J = 9.1, 6.8 Hz, 2 H), 4.71 (d, J = 4.3 Hz,
2 H), 5.95 (s, 4 H), 6.77–6.84 (m, 6 H).
(6) (a) Hoke, M.; Hansel, R. Arch. Pharm. (Weinheim, Ger.)
1972, 33, 305. (b) Pan, J.-X.; Hensens, O. D.; Zink, D. L.;
Chang, M. N.; Hwang, S.-B. Phytochemistry 1987, 26, 1377.
(7) (a) Stevens, D. R.; Whiting, D. A. J. Chem. Soc., Perkin
Trans. 1 1990, 425. (b) Stevens, D. R.; Whiting, D. A. J.
Chem. Soc., Perkin Trans. 1 1992, 633. (c) Pelter, A.;
Ward, R. S.; Venkateswarlu, R.; Kamakshi, C. Tetrahedron
1991, 47, 1275. (d) Beroza, M.; Schechter, M. S. J. Am.
Chem. Soc. 1956, 78, 1242. (e) Orito, K.; Yorita, K.;
Suginome, H. Tetrahedron Lett. 1991, 32, 5999.
(f) Bradley, H. M.; Knight, D. W. J. Chem. Soc., Chem.
Commun. 1991, 1641. (g) Takano, S.; Samizu, K.;
Ogasawara, K. J. Chem. Soc., Chem. Commun. 1993, 1032.
(h) Orito, K.; Sasaki, T.; Suginome, H. J. Org. Chem. 1995,
60, 6208; and references cited therein.
(8) Yamauchi, S.; Tanaka, T.; Kinoshita, Y. J. Chem. Soc.,
Perkin Trans. 1 2001, 2158.
(9) Takano, S.; Ohkawa, T.; Tamori, S.; Satoh, S.; Ogasawara,
K. J. Chem. Soc., Chem. Commun. 1988, 189.
13C NMR (75 MHz, CDCl3): d = 53.3, 70.6, 84.7, 100.0, 105.4,
107.1, 118.3, 134.0, 146.0, 146.9.
(10) Oeveren, A.; Jansen, J. F. G. A.; Feringa, B. L. J. Org. Chem.
1994, 59, 5999.
(11) Kise, N.; Fujimoto, A.; Ueda, N. Tetrahedron: Asymmetry
2002, 13, 1845.
Anal. Calcd for C20H18O6: C, 67.80; H, 5.12. Found: C, 67.74; H,
5.10.
(12) Enders, D.; Lausberg, V.; Signore, G. D.; Berner, O. M.
Synthesis 2002, 515.
(–)-Methyl Piperitol (2b):
(–)-Methyl piperitol (2b) was prepared from 7b by following the
same procedure as described for 2a and was formed as a viscous liq-
uid in 90% yield (90 mg).
[a]D25 –71.5 (c 0.40, CHCl3).
(13) (a) Wirth, T.; Kulicke, K. J.; Fragale, G. J. Org. Chem. 1996,
61, 2686. (b) Wirth, T. Liebigs Ann./Recl. 1997, 1155.
(c) Brown, R. C. D.; Swain, N. A. Synthesis 2004, 811.
(14) Samizu, K.; Ogasawara, K. Chem. Lett. 1995, 543.
(15) (a) Rana, K. K.; Guin, C.; Roy, S. C. Tetrahedron Lett. 2000,
41, 9337. (b) Roy, S. C.; Rana, K. K.; Guin, C. J. Org.
Chem. 2002, 67, 3242.
(16) (a) Ueno, Y.; Chino, K.; Watanabe, M.; Moriya, O.;
Okawara, M. J. Am. Chem. Soc. 1982, 104, 5564. (b) Stork,
G.; Mook, R. Jr.; Biller, S. A.; Rychnovskyu, S. D. J. Am.
Chem. Soc. 1983, 105, 3741.
(17) (a) Rajanbabu, T. V.; Nugent, W. A. J. Am. Chem. Soc.
1994, 116, 986; and references cited therein. (b) Gansäuer,
A.; Bluhm, H. Chem. Rev. 2000, 100, 2771. (c) Gansäuer,
A.; Pierobon, M.; Bluhm, H. Synthesis 2001, 2500.
(18) Srikrishna, A.; Yelamaggad, C. V.; Kumar, P. P. J. Chem.
Soc., Perkin Trans. 1 1999, 2877.
IR (neat): 2916, 2848, 1606, 1504, 1490, 1442, 1249, 1039 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.06–3.12 (m, 2 H), 3.80–3.97 (m,
2 H), 3.88 (s, 3 H), 3.90 (s, 3 H), 4.22–4.28 (m, 2 H), 4.72 (d, J =
3.9 Hz, 1 H), 4.74 (d, J = 4.1 Hz, 1 H), 5.95 (s, 2 H), 6.77–6.91 (m,
6 H).
13C NMR (75 MHz, CDCl3): d = 54.6, 54.8, 56.3, 56.5, 72.1, 72.2,
86.2, 86.3, 101.5, 106.9, 108.6, 109.8, 111.6, 118.7, 119.8, 134.0,
135.6, 147.5, 148.4, 149.1, 149.7.
Anal. Calcd for C21H22O6: C, 68.10; H, 6.51. Found: C, 68.01; H,
6.50.
Acknowledgment
B.B. thanks CSIR, New Delhi for awarding the Fellowship.
Synthesis 2005, No. 17, 2913–2919 © Thieme Stuttgart · New York

PAPER
Enantioselective Synthesis of Furan and Furofuran Lignans by Radical Cyclization of Epoxides
2919
(19) (a) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.;
Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987,
109, 5765; and references cited therein. (b) Procter, G.
Asymmetric Synthesis; Oxford University Press Inc.: New
York, 1996, 178.
(20) (a) Searle, P. A.; Molinski, T. F. J. Am. Chem. Soc. 1996,
118, 9422. (b) Mohapatra, D. K.; Yellol, G. S. ARKIVOC
2005, iii, 144.
(21) Tanaka, H.; Nakamura, T.; Ichino, K.; Ito, K.
Phytochemistry 1989, 28, 952.
(22) (a) Ina, H.; Asai, A.; Ushida, T. Planta Med. 1987, 228.
(b) Greger, H.; Hofer, O. Tetrahedron 1980, 36, 3551.
(23) Hansel, R.; Zander, D. Arch. Pharm. 1961, 294, 699.
(24) Iida, T.; Nakano, M.; Ito, K. Phytochemistry 1982, 21, 673.
Synthesis 2005, No. 17, 2913–2919 © Thieme Stuttgart · New York