General approach to 2, 3-dibenzyl-γ-butyrolactone lignans: application to the total synthesis of (±)-5'-methoxyyatein, (±)-5'-methoxyclusin, and ( ± )-4' -hydroxycubebinone

Article abstract of DOI:10.1002/ejoc.201000318

The total synthesis of natural lignans 5'-methoxyyatein (1), 5'-methoxyclusin (2), and 4'-hydroxycubebmone (3), inracemic form, has been achieved by a newly developed strategy, wherein lithium, naphthalenide induced decyanation was employed as a key opera

Full text of DOI:10.1002/ejoc.201000318

FULL PAPER
DOI: 10.1002/ejoc.201000318
General Approach to 2,3-Dibenzyl-γ-butyrolactone Lignans: Application to the
Total Synthesis of (؎)-5Ј-Methoxyyatein, (؎)-5Ј-Methoxyclusin, and
(؎)-4Ј-Hydroxycubebinone
Prashanth K. Amancha,[a,b] Hsing-Jang Liu,*[a] Tai Wei Ly,[c] and Kak-Shan Shia*[b]
Keywords: Lignans / Natural products / Lactones / Total synthesis / Synthetic methods
The total synthesis of natural lignans 5Ј-methoxyyatein (1),
5Ј-methoxyclusin (2), and 4Ј-hydroxycubebinone (3), in race-
mic form, has been achieved by a newly developed strategy,
wherein lithium naphthalenide induced decyanation was
employed as a key operation to establish the essential trans
configuration of the butyrolactone ring.
wish to report that natural lignans 1, 2, and 3 (Figure 1), in
racemic form, have been synthesized in an effective syn-
thetic sequence, making use of lithium naphthalenide[13]
(LN)-induced decyanation as a key step to establish the
essential trans relation of the substituents on the butyro-
lactone ring.
Introduction
To date, several hundred lignans have been discovered in
many plant species from various parts, including the bark,
root, leaf, flower, fruit, and seed. Lignans are also assumed
to function as phytoalexins, providing protection for the
plants against diseases and pests such as wood rot fungi.[1]
Structurally, lignans are dimeric propyl phenols; the natural
products are broadly divided into eight classes.[2] Among
them, dibenzylbutyrolactone lignans are an important fam-
ily, and they are noted for a wide variety of biological activi-
ties, including cytotoxic and antiviral, as well as cancer pro-
tective properties.[3–5]
Koga and co-workers reported the first total synthesis of
dibenzylbutyrolactone lignans deoxypodorhizon and hino-
kinin in optically pure form by the use of a chiral intermedi-
ate derived from -glutamic acid.[6] Subsequently, many
compounds of the series such as cordigerine, isoyatein, and
cubebinone have also been synthesized.[7–9] Dibenzylbutyro-
lactone lignan (+)-5Ј-methoxyyatein (1) was first identified
in 2003 from the whole plant of Peperomia duclouxii, tradi-
tionally used to treat various types of cancer in the south-
west provinces of China.[10] Two years later, its congeners
(–)-5Ј-methoxyclusin (2) and (–)-4Ј-hydroxycubebinone (3)
were isolated[11] from the fruits of Piper cubeba, a popular
medicinal plant extensively used in Indonesia for the treat-
ment of asthma, diarrhea, and abdominal pain.[12] To ac-
quire an adequate amount of these lignans to validate their
claimed anticancer and/or antiviral activities, herein, we
Figure 1. Natural dibenzylbutyrolactone lignans.
Results and Discussion
Using dibenzylbutyrolactone (8) as an initial model, our
retrosynthetic strategy is outlined in Scheme 1. It is antici-
pated that target 8 should be obtained through LN-induced
reductive decyanation of compound 7, as indicated by many
successful historical cases.[14] The formation of desired in-
termediate 7 could probably be effected through a two-step
synthetic sequence involving intramolecular Knoevenagel
condensation–hydrogenation[15] followed by benzylation
from cyano ester 5, which could be readily provided by
treating keto alcohol 4 with cyanoacetic acid.
Along the axis of the retrosynthetic analysis, 8 was pre-
[a] Department of Chemistry, National Tsing Hua University,
Hsinchu 30013, Taiwan, R.O.C
pared according to
a synthetic sequence shown in
[b] Division of Biotechnology and Pharmaceutical Research,
National Health Research Institutes,
Miaoli County 35053, Taiwan, R.O.C
Fax: +886-37-586456
Scheme 2. Cyano ester 5 was obtained in 90% yield by cou-
pling keto alcohol 4, readily prepared through a documen-
ted two-step procedure,[16] with cyanoacetic acid in the pres-
ence of Me2NPOCl2 and pyridine.[17] Other coupling rea-
E-mail: ksshia@nhri.org.tw
[c] Axikin Pharmaceuticals, Inc.,
10835 Road to the Cure, Suite 250, San Diego, CA 92121, USA gents such as N,NЈ-dicyclohexylcarbodiimide (DCC) and 1-
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Cyano ester 5 thus obtained was subjected to tandem
Knoevenagel condensation and hydrogenation in one pot
with -proline and Hantzsch ester (diethyl 1,4-dihydro-2,6-
dimethyl-3,5-pyridinedicarboxylate)[15a,15b] to afford butyro-
lactone 6 as a pair of inseparable diastereomers (1:2.5) in
92% yield. As reported,[15c] Knoevenagel condensation cat-
alyzed with -proline can also be effected with pyrrolidine
and other pyrrolidine-based catalysts, and mechanistically,
subsequent Hantzsch ester reduction on the Knoevenagel
product might result in racemic diastereomers. Compound
6 was subsequently treated with benzyl bromide under basic
conditions. The benzylation was assumed to take place pref-
erentially from the sterically less hindered side to give di-
Scheme 1. Retrosynthetic analysis of dibenzylbutyrolactone (8).
ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) gave
rise to desired product 5 under similar conditions albeit in
moderate yields (60–70%).
benzylcyanobutyrolactone
7 (82%) as the only dia-
stereomer. Finally, removal of the cyano group in 7 was
achieved by LN-induced reductive decyanation to give de-
sired trans-dibenzylbutyrolactone 8, the spectroscopic data
(1H and 13C NMR) of which are in high agreement with
those reported in the literature.[8,9]
Encouraged by the synthesis of 8, we embarked on the
total synthesis of lignans 1 and 2 by using 5-methoxypiper-
onal, commercially available, as the starting material
(Scheme 3). Aldehyde 9 was subjected to Corey–Fuchs ole-
fination[18] to furnish vinyl dibromide 10 (80%). Elimi-
nation and lithium–halogen exchange of 10 followed by
trapping the ensuing lithium alkynylide with paraformalde-
hyde gave alkynol 11 in 92% yield. Compound 11 thus ob-
tained was smoothly converted into keto alcohol 13 in 59%
yield via intermediate 12 over two steps, involving but-
Scheme 2. Reagents and conditions: (i) (CH3)2NPOCl2, pyridine,
CNCH2COOH, CH2Cl2, 0 °C to room temp., 24 h, 90%; (ii) -pro-
line, Hantzsch ester, ethanol, room temp., 24 h, 92%; (iii) benzyl anethiol addition and acidic hydrolysis.[16]
bromide, K2CO3, THF, room temp., 24 h, 82%; (iv) LN
With keto alcohol 13 in hand, its esterification with cya-
noacetic acid was carried out efficiently by using (CH3)2-
(3.5 equiv.), THF, –45 °C, 30 min then NH4Cl (aq.), –45 °C to
room temp., 78%.
Scheme 3. Reagents and conditions: (i) CBr4, PPh3, CH2Cl2, 0 °C, 2 h, 80%; (ii) nBuLi, THF, –78 °C, (CH2O)n, room temp., 3 h, 92%;
(iii) BuSH, NaOH, CH3CN, 75 °C, 2 h, 82%; (iv) C2H5OH/1  H2SO4 (4:1), 50 °C, 24 h, 72%; (v) (CH3)2NPOCl2, pyridine,
CNCH2COOH, CH2Cl2, 0 °C to room temp., 24 h, 92%; (vi) -proline, Hantzsch ester, ethanol, room temp., 24 h, 82%; (vii) 3,4,5-
trimethoxybenzyl bromide, K2CO3, THF, room temp., 24 h, 80%; (viii) LN (3.5 equiv.), THF, –45 °C, 30 min then NH4Cl (aq.), –45 °C
to room temp., 95%; (ix) DIBAL, toluene, –78 °C, 2 h, 72 %.
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General Approach to 2,3-Dibenzyl-γ-butyrolactone Lignans
NPOCl2/pyridine[17] to yield key intermediate 14 (92%),
Similarly, aldehyde 18, readily obtained from 17 by benz-
which in turn underwent intramolecular Knoevenagel con- ylation, was subjected to Corey–Fuchs olefination, lithium–
densation–hydrogenation[15] in one pot to afford butyro- halogen exchange and elimination, butanethiol addition–
lactone 15 as a pair of inseparable diastereomers (1:2.1) in hydrolysis, esterification, and intramolecular Knoevenagel
82% yield. This diastereomeric mixture was further alkyl- condensation–hydrogenation to furnish butyrolactone 24 as
ated with 3,4,5-trimethoxybenzyl bromide to give trans-di- a pair of inseparable diastereomers (1:1.5) in 28% yield over
benzylbutyrolactone 16 (80%), the structure of which was six steps. This diastereomeric mixture was further alkylated
unambiguously confirmed by an X-ray crystallographic with 5-methoxypiperonyl bromide to give butyrolactone 25
analysis (Figure 2).[19] The identification of 16 also lends as a single product (82%), which was again assumed to be
support to the structural assignment of previous cyano- the trans isomer as suggested by analogue 16. Deprotection
butyrolactone 7. Finally, the cyano group was reductively of the benzyl group in 25 was efficiently completed under
removed with LN to afford 95% of the racemic form of standard conditions (H2, 10% Pd/C) in 10 min, giving rise
desired lignan 1, the spectroscopic data (1H and 13C NMR) to the corresponding cyano lactone 26 (98%; Scheme 4),
of which were highly consistent with those reported in the which in turn underwent typical LN-induced decyanation
literature.[10] Further reduction of product 1 with DIBAL to afford target 3 in 95% yield. The spectroscopic data (1H
produced lignan 2 as a pair of inseparable epimers (1:1.4) and 13C NMR) of synthetic lignan 3 are in full agreement
in 72% yield. The spectroscopic data (1H and 13C NMR) with those reported in the literature.[11] As such, the total
for the major epimer were found to be in good agreement synthesis of natural lignans 5Ј-methoxyyatein (1), 5Ј-meth-
with those reported in the literature.[11]
oxyclusin (2), and 4Ј-hydroxycubebinone (3), in racemic
form, was accomplished in an overall yield of 25, 18, and
19% in 8, 9, and 10 steps, respectively, starting from the
appropriate phenolic aldehydes.
Conclusions
In conclusion, we have developed a new and general
strategy to access 2,3-dibenzyl-γ-butyrolactone lignans with
ease. It is highly conceivable that this synthetic approach
might find potential utility to generate a library of structur-
ally diverse 2,3-disubstituted butyrolactones, including nat-
ural as well as non-natural lignans, for the purpose of new
drug discovery. Currently, its enantioselective version is un-
Figure 2. The X-ray picture of butyrolactone 16 (thermal ellipsoids
are shown at 50% probability).
Scheme 4. Reagents and conditions: (i) benzyl bromide, K2CO3, THF, reflux, 12 h, 92%; (ii) CBr4, PPh3, CH2Cl2, 0 °C, 2 h, 82 %;
(iii) nBuLi, THF, –78 °C, (CH2O)n, room temp., 3 h, 85%; (iv) BuSH, NaOH, CH3CN, 75 °C, 2 h, 80%; (v) ethanol/1  H2SO4 (4:1),
50 °C, 24 h, 70%; (vi) (CH3)2NPOCl2, pyridine, CNCH2COOH, CH2Cl2, 0 °C to room temp., 24 h, 88%; (vii) -proline, Hantzsch ester,
ethanol, room temp., 24 h, 80%; (viii) 5-methoxypiperonyl bromide, K2CO3, THF, room temp., 24 h, 82%; (ix) H2, Pd/C (10% w/w),
methanol, room temp., 10 min, 98%; (x) LN (3.5 equiv.), THF, –45 °C, 30 min then NH4Cl (aq.), –45 °C to room temp., 95%.
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H), 4.19 (dd, J = 9.6, 5.1 Hz, 1 H), 3.80 (dd, J = 7.8, 1.0 Hz, 1 H),
3.18–3.13 (m, 1 H), 3.07–3.06 (m, 1 H), 2.76 (dd, J = 10.2, 10.1, Hz,
1 H) ppm. 13C NMR (150 MHz, CDCl3, selected peaks of minor
isomer): δ = 167.8 (CO), 136.3 (C), 128.7 (2 CH), 127.6 (2 CH),
127.3 (CH), 112.8 (CN), 70.8 (CH2), 40.0 (CH), 37.2 (CH), 34.8
der active investigation with particular emphasis on synthe-
sizing advanced intermediates (i.e., 7, 16, and 25) in enan-
tiomerically pure form through the process of asymmetric
catalytic hydrogenation.[20]
(CH ) ppm. IR (CH Cl , cast): ν = 3063, 3029, 2912, 2254, 1783,
˜
2
2
2
1165, 1014 cm–1. HRMS (EI): calcd. for C12H11NO2 201.0790;
Experimental Section
found 201.0789.
General: All reactions were performed under an argon or nitrogen
atmosphere unless otherwise stated. All solvents were dried prior
to use, and reagents were employed as received. Analytical thin-
layer chromatography was performed on SiO2 60 F-254 plates, and
flash column chromatography was carried out by using SiO2 60
(particle size 0.040–0.055 mm, 230–400 mesh), both of which are
available from Merck. Visualization was performed under UV irra-
diation at 254 nm followed by staining with vanillin (60 g of vanillin
in 1 L of 95% ethanol containing 10 mL of conc. H2SO4) and char-
ring with a heat gun. Fourier transform infrared spectra (IR) were
recorded with a Bomen MR-100 instrument. 1H and 13C NMR
spectra were recorded with a Bruker Avance EX 400 FT NMR or
Bruker DMX-600. [D]Chloroform was used as the solvent and
TMS (δ = 0.00 ppm) as an internal standard. Chemical shifts are
reported as δ values in ppm as referenced to TMS. Multiplicities
are recorded as s (singlet), d (doublet), t (triplet), q (quartet), quint.
(quintet), sext. (sextet), sept. (septet), dd (doublet of doublets), dt
(doublet of triplets), br. (broadened), m (multiplet). HRMS were
taken with a JEOL JMS-HX110 spectrometer.
(3R*,4R*)-3,4-Dibenzyl-2-oxotetrahydrofuran-3-carbonitrile (7): To
a solution of compound 6 (0.50 g, 2.48 mmol) in THF (10 mL) at
room temperature under an argon atmosphere was added K2CO3
(0.41 g, 2.98 mmol). After stirring the mixture for 30 min, benzyl
bromide (0.35 mL, 2.98 mmol) was added dropwise. The reaction
mixture was stirred for 24 h at room temperature and then diluted
with water and extracted with EtOAc (3ϫ20 mL). The combined
organic layer was dried with MgSO4, filtered, and concentrated un-
der reduced pressure. The residue was purified by flash chromatog-
raphy on silica gel (EtOAc/n-hexane, 1:9) to afford compound 7
(0.59 g, 82% yield) as a white solid. M.p. 100–102 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.39–7.06 (m, 10 H), 4.09–4.0 (m, 2 H),
3.36 (dd, J = 25.8, 14.0 Hz, 2 H), 2.78–2.64 (m, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 170.3 (CO), 136.4 (C), 132.8 (C),
130.1 (2 CH), 129.0 (2 CH), 128.9 (2 CH), 128.5 (2 CH), 128.3
(CH), 127.3 (CH), 115.2 (CN), 70.3 (CH2), 48.2 (C), 43.4 (CH),
39.3 (CH ), 35.1 (CH ) ppm. IR (CH Cl , cast): ν = 2954, 2923,
˜
2
2
2
2
2259, 1757, 1419, 1184 cm–1. HRMS (EI): calcd. for C19H17NO2
291.1259; found 291.1257.
2-Oxo-3-phenylpropyl Cyanoacetate (5): To a solution of cyano-
acetic acid (0.50 g, 5.88 mmol, 1.0 equiv.) in anhydrous CH2Cl2
(80 mL) at 0 °C was added sequentially pyridine (1.43 mL,
17.63 mmol, 3.0 equiv.), N,N-dimethyl phosphoramidodichloridate
(3R*,4R*)-3,4-Dibenzyldihydrofuran-2(3H)-one (8): To a solution of
compound 7 (0.20 g, 0.69 mmol) in THF (10 mL) at –45 °C under
an argon atmosphere was added a solution of lithium naphthalen-
ide (LN, 3.5 equiv.) in THF by syringe. After stirring the mixture
for 30 min at –45 °C, saturated aqueous ammonium chloride solu-
tion (2–3 mL) was added at the same temperature by syringe. The
reaction mixture was stirred for another 30 min at room tempera-
ture and then diluted with water and extracted with EtOAc
(3ϫ10 mL). The combined organic layer was dried with MgSO4,
filtered, and concentrated under reduced pressure. The residue was
purified by flash chromatography on silica gel (EtOAc/n-hexane,
1:9) to afford target 8 (0.14 g, 78% yield) as a colorless oil. 1H
NMR (600 MHz, CDCl3): δ = 7.30–7.15 (m, 8 H), 6.99–6.97 (m, 2
H), 4.07 (dd, J = 9.0, 7.7 Hz, 1 H), 3.84 (dd, J = 9.0, 8.0 Hz, 1 H),
3.09 (dd, J = 14.0, 5.1 Hz, 1 H), 2.96 (dd, J = 14.0, 7.1 Hz, 1 H),
2.65–2.59 (m, 2 H), 2.52–2.49 (m, 2 H) ppm. 13C NMR (150 MHz,
CDCl3): δ = 178.5 (CO), 137.9 (C), 137.6 (C), 129.2 (2 CH), 128.7
(2 CH), 128.7 (2 CH), 128.5 (2 CH), 126.9 (CH), 126.7 (CH), 71.1
(CH2), 46.4 (CH), 41.2 (CH), 38.4 (CH2), 35.0 (CH2) ppm. IR
(1.40 mL, 11.76 mmol, 2.0 equiv.), and compound
4 (0.88 g,
5.88 mmol, 1.0 equiv.). The resulting solution was stirred at room
temperature under an argon atmosphere for 24 h. The solution was
poured into ice-cold 1  hydrochloric acid (100 mL) and extracted
with CH2Cl2 (4ϫ25 mL), and the combined organic layer was
dried with MgSO4, filtered, and concentrated under reduced pres-
sure. The residue was purified by flash chromatography on silica
gel (EtOAc/n-hexane, 2:8) to afford compound 5 (1.15 g, 90% yield)
as a white solid. M.p. 95–97 °C. 1H NMR (400 MHz, CDCl3): δ =
7.35–7.18 (m, 5 H), 4.79 (s, 2 H), 3.72 (s, 2 H), 3.52 (s, 2 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 199.4 (CO), 162.4 (CO), 132.2
(C), 129.3 (2 CH), 128.9 (2 CH), 127.5 (CH), 112.7 (CN), 68.8
(CH ), 46.1 (CH ), 24.2 (CH ) ppm. IR (CH Cl , cast): ν = 2954,
˜
2
2
2
2
2
2259, 1757, 1725, 1419, 1184 cm–1. HRMS (EI): calcd. for
C12H11NO3 217.0739; found 217.0742.
4-Benzyl-2-oxotetrahydrofuran-3-carbonitrile (6): To a solution of
compound 5 (1.00 g, 4.60 mmol, 1.0 equiv.) in ethanol (200 mL)
was added -proline (0.12 g, 0.92 mmol, 0.2 equiv.) and the
Hantzsch ester (1.17 g, 4.60 mmol, 1.0 equiv.), and the resulting re-
action mixture was stirred at 25 °C for 24 h. The crude reaction
mixture was concentrated under reduced pressure and directly
loaded onto a silica gel column with or without aqueous workup
and purified by flash chromatography on silica gel (EtOAc/n-hex-
(CH Cl , cast): ν = 3027, 2921, 1772, 1496, 1455, 1148, 1016 cm–1.
˜
2
2
HRMS (EI): calcd. for C18H18O2 266. 1307; found 266.1304.
6-(2,2-Dibromoethenyl)-4-methoxy-1,3-benzodioxole (10): To a solu-
tion of carbon tetrabromide (9.20 g, 27.75 mmol, 1.0 equiv.) in
CH2Cl2 (75 mL) was added triphenylphosphane (14.56 g,
55.51 mmol, 2.0 equiv.) portion wise over 5 min at 0 °C, and the
resulting dark-red solution was stirred for 30 min at the same tem-
ane, 0.5:9.5) to afford compound 6 (0.86 g, 92% yield) as a colorless perature. A solution of 5-methoxypiperonal (9; 5.00 g, 27.75 mmol,
oil. 1H NMR (600 MHz, CDCl3, major isomer): δ = 7.36–7.14 (m, 1.0 equiv.) in CH2Cl2 (75 mL) was added, and the reaction mixture
5 H), 4.41 (dd, J = 9.2, 7.6 Hz, 1 H), 4.03 (t, J = 9.4 Hz, 1 H), 3.42
(dd, J = 11.0, 0.8 Hz, 1 H), 3.22–3.18 (m, 1 H), 3.05 (dd, J = 14.0,
6.0, Hz, 1 H), 2.87 (dd, J = 14.0, 8.3 Hz, 1 H) ppm. 13C NMR
was stirred for 1 h at 0 °C and then warmed up to room tempera-
ture. Stirring was continued for another 2 h. A 1:1 mixture of H2O/
brine solution was added, and the layers were separated. The aque-
(150 MHz, CDCl3, major isomer): δ = 167.8 (CO), 125.4 (C), 129.2 ous layer was extracted with CH2Cl2 (6ϫ25 mL), and the com-
(2 CH), 129.0 (2 CH), 128.8 (CH), 114.2 (CN), 71.3 (CH2), 43.0 bined organic layer was dried with MgSO4, filtered, and concen-
(CH), 37.0 (CH), 36.5 (CH2) ppm. 1H NMR (600 MHz, CDCl3, trated under reduced pressure. The crude material was purified by
selected peaks of minor isomer): δ = 4.28 (dd, J = 9.7, 6.1 Hz, 1
flash chromatography on silica gel (EtOAc/n-hexane, 2:8) to afford
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General Approach to 2,3-Dibenzyl-γ-butyrolactone Lignans
compound 10 (7.46 g, 80% yield) as a white solid. M.p. 48–50 °C.
1H NMR (400 MHz, CDCl3): δ = 7.32 (s, 1 H), 6.79 (s, 1 H), 6.68
(s, 1 H), 5.95 (s, 2 H), 3.87 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 148.6 (C), 143.2 (C), 136.2 (2 CH), 135.5 (C), 129.4
3-(7-Methoxy-1,3-benzodioxol-5-yl)-2-oxopropyl Cyanoacetate (14):
To a solution of cyanoacetic acid (0.60 g, 7.05 mmol, 1.0 equiv.) in
anhydrous CH2Cl2 (80 mL) at 0 °C was added sequentially pyridine
(1.71 mL, 21.16 mmol, 3.0 equiv.), N,N-dimethyl phosphoramidod-
(C), 102.4 (CH), 101.7 (CH2), 88.1 (C), 56.5 (CH3) ppm. IR ichloridate (1.68 mL, 14.11 mmol, 2.0 equiv.), and compound 13
(CH Cl , cast): ν = 2894, 1628, 1506, 1429, 1135, 1045, 930 cm–1.
HRMS (EI): calcd. for C10H8Br2O3 335.8820; found 335.8825.
(1.58 g, 7.05 mmol, 1.0 equiv.). The resulting solution was stirred
at room temperature under an argon atmosphere for 24 h. The
solution was poured into ice-cold 1  hydrochloric acid (100 mL)
and extracted with CH2Cl2 (4ϫ25 mL), and the combined organic
layer was dried with MgSO4, filtered, and concentrated under re-
duced pressure. The residue was purified by flash chromatography
on silica gel (EtOAc/n-hexane, 5:5) to afford compound 14 (1.9 g,
92% yield) as brown crystals. M.p. 118–121 °C. 1H NMR
(400 MHz, CDCl3): δ = 6.35 (s, 1 H), 6.34 (s, 1 H), 5.94 (s, 2 H),
4.80 (s, 2 H), 3.87 (s, 3 H), 3.62 (s, 2 H), 3.56 (s, 2 H) ppm. 13C
NMR (150 MHz, CDCl3): δ = 199.3 (CO), 162.4 (CO), 149.3 (C),
143.8 (C), 134.8 (C), 126.2 (C), 112.5 (CN), 108.7 (CH), 103.4
(CH), 101.6 (CH2), 68.7 (CH2), 56.6 (CH3), 46.2 (CH2), 24.3 (CH2)
˜
2
2
3-(7-Methoxy-1,3-benzodioxol-5-yl)prop-2-yn-1-ol (11): To a solu-
tion of compound 10 (14.00 g, 41.66 mmol, 1.0 equiv.) in THF
(150 mL) was added nBuLi (2.5  in hexanes, 41.67 mL, 2.5 equiv.)
slowly by syringe at –78 °C, and the solution was stirred at –78 °C
for 45 min and paraformaldehyde (1.89 g, 62.50 mmol, 1.5 equiv.)
was added slowly with a powder funnel. The resulting reaction mix-
ture was stirred at room temperature for 3 h. Saturated aqueous
ammonium chloride solution was added, and the layers were sepa-
rated. The aqueous layer was extracted with EtOAc (6ϫ25 mL),
and the combined organic layer was dried with MgSO4, filtered,
and concentrated under reduced pressure. The crude material was
purified by flash chromatography on silica gel (EtOAc/n-hexane,
2:8) to afford compound 11 (7.91 g, 92% yield) as a white solid.
M.p. 60–62 °C. 1H NMR (400 MHz, CDCl3): δ = 6.58 (s, 1 H),
6.54 (s, 1 H), 5.91 (s, 2 H), 4.40 (s, 2 H), 3.80 (s, 3 H), 2.73 (s, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 148.3 (C), 143.1 (C),
136.0 (C), 115.8 (C), 111.5 (CH), 105.7 (CH), 101.6 (CH2), 85.6
ppm. IR (CH Cl , cast): ν = 2968, 2941, 2253, 1751, 1732, 1094,
˜
2
2
928 cm–1. HRMS (EI): calcd. for C14H13NO6 291.0743; found
291.0748.
4-[(7-Methoxy-1,3-benzodioxol-5-yl)methyl]-2-oxotetrahydrofuran-
3-carbonitrile (15): To a solution of compound 14 (1.00 g,
3.43 mmol, 1.0 equiv.) in ethanol (200 mL) was added -proline
(0.08 g, 0.69 mmol, 0.2 equiv.) and the Hantzsch ester (0.87 g,
3.43 mmol, 1.0 equiv.), and the resulting reaction mixture was
stirred at 25 °C for 24 h. The crude reaction mixture was concen-
trated under reduced pressure and directly loaded onto a silica gel
column without aqueous workup and purified by flash column
chromatography (EtOAc/n-hexane, 2:8) to give compound 15
(C), 85.2 (C), 56.3 (CH ), 51.2 (CH ) ppm. IR (CH Cl , cast): ν =
˜
3
2
2
2
3352, 2920, 2226, 1623, 1510, 1434, 1010, 1156, 972 cm–1. HRMS
(EI): calcd. for C11H10O4 206.0579; found 206.0581.
(2Z)-2-(Butylsulfanyl)-3-(7-methoxy-1,3-benzodioxol-5-yl)prop-2-
en-1-ol (12): To a suspension of compound 11 (2.00 g, 9.70 mmol,
1.0 equiv.) and powdered NaOH (0.46 g, 11.64 mmol, 1.2 equiv.)
in CH3CN (20 mL) was added butanethiol (1.56 mL, 14.55 mmol,
1.5 equiv.) by syringe, and the slurry was heated to 75 °C for 2 h.
The crude reaction mixture was concentrated to a dark orange oil,
and the residue was purified by flash chromatography on silica gel
(EtOAc/n-hexane, 1:9) to afford compound 12 (2.35 g, 82% yield)
as a red colored oil: 1H NMR (400 MHz, CDCl3): δ = 6.93 (s, 1
H), 6.85 (s, 1 H), 6.68 (s, 1 H), 5.96 (s, 2 H), 4.78 (s, 2 H), 3.88 (s,
3 H), 2.75 (q, J = 7.4 Hz, 2 H), 1.55–1.50 (m, 2 H), 1.41–1.34 (m,
2 H), 0.88 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 170.5 (C), 148.4 (C), 143.0 (C), 134.7 (C), 132.5 (CH), 130.3
(C), 109.6 (CH), 103.6 (CH), 101.5 (CH2), 68.0 (CH2), 56.4 (CH3),
31.8 (CH2), 31.4 (CH2), 21.8 (CH2), 13.5 (CH3) ppm. IR (CH2Cl2,
1
(1.03 g, 82% yield) as a colorless oil. H NMR (600 MHz, CDCl3,
major isomer): δ = 6.36 (s, 1 H), 6.29 (s, 1 H), 5.96 (s, 2 H), 4.44
(dd, J = 9.4, 7.4 Hz, 1 H), 4.02 (t, J = 9.4 Hz, 1 H), 3.89 (s, 3 H),
3.43 (d, J = 10.5 Hz, 1 H), 3.16–3.12 (m, 1 H), 2.95 (dd, J = 14.1,
5.9 Hz, 1 H), 2.76 (dd, J = 14.1, 8.4 Hz, 1 H) ppm. 13C NMR
(150 MHz, CDCl3, major isomer): δ = 166.9 (CO), 150.9 (C), 139.4
(C), 134.5 (C), 133.3 (C), 115.5 (CN), 108.5 (CH), 102.7 (CH),
101.7 (CH2), 71.2 (CH2), 56.9 (CH3), 43.2 (CH), 37.1 (CH), 37.0
(CH2), 29.7 (CH2) ppm. 1H NMR (600 MHz, CDCl3, selected
peaks of minor isomer): δ = 6.31 (s, 1 H), 6.30 (s, 1 H), 4.30 (dd,
J = 9.7, 6.2 Hz, 1 H), 4.21 (dd, J = 9.7, 5.4 Hz, 1 H), 3.88 (s, 3 H),
3.74 (d, J = 7.8 Hz, 1 H), 3.08 (dd, J = 13.9, 6.2 Hz, 1 H), 3.02–
2.98 (m, 1 H), 2.68 (dd, J = 13.9, 9.6 Hz, 1 H) ppm. 13C NMR
(150 MHz, CDCl3, selected peaks of minor isomer): δ = 101.6
(CH2), 71.1 (CH2), 56.9 (CH3), 40.4 (CH), 36.7 (CH2), 35.0 (CH2)
cast): ν = 3426, 2958, 1627, 1506, 1428, 1221, 1021 cm–1. HRMS
˜
(EI): calcd. for C15H20O4S 296.1082; found 296.1081.
1-Hydroxy-3-(7-methoxy-1,3-benzodioxol-5-yl)propan-2-one
(13):
ppm. IR (CH Cl , cast): ν = 2921, 2846, 2253, 1784, 1634, 1091,
˜
2
2
Compound 12 (2.00 g, 6.75 mmol, 1.0 equiv.) was diluted with a
stock solution of ethanol/1  H2SO4 (4:1, 50 mL). The biphasic
mixture was heated to 50 °C to form a homogeneous solution,
which was stirred for 24 h at 50 °C. The solution was warmed to
room temperature and brine (100 mL) was added. The organic
layer was separated, and the aqueous layer was extracted with
EtOAc (4ϫ25 mL). The combined organic layer was dried with
MgSO4, filtered, and concentrated under reduced pressure. The res-
idue was purified by flash chromatography on silica gel (EtOAc/
n-hexane, 2:8) to afford compound 13 (1.08 g, 72% yield) as a white
931 cm–1. HRMS (EI): calcd. for C14H13NO5 275.0794; found
275.0793.
(3R*,4R*)-4-{(7-Methoxybenzo[d][1,3]dioxol-5-yl)methyl}-2-oxo-3-
(3,4,5-trimethoxybenzyl)tetrahydrofuran-3-carbonitrile (16): To
a
solution of compound 15 (0.50 g, 1.82 mmol) in THF (10 mL) at
room temperature under an argon atmosphere was added K2CO3
(0.30 g, 2.18 mmol) in one portion. After stirring for 30 min, a solu-
tion of 3,4,5-trimethoxybenzyl bromide (0.57 g, 2.18 mmol) in
THF (5 mL) was added by syringe. The resulting reaction mixture
was stirred for 24 h at the same temperature. The mixture was di-
luted with water and extracted with EtOAc (3ϫ20 mL). The com-
1
solid. M.p. 60–63 °C. H NMR (400 MHz, CDCl3): δ = 6.37 (s, 1
H), 6.33 (s, 1 H), 5.94 (s, 2 H), 4.26 (s, 2 H), 3.86 (s, 3 H), 3.59 (s,
2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 207.3 (CO), 149.0 bined organic layer was dried with MgSO4, filtered, and concen-
(C), 143.5 (C), 134.4 (C), 126.8 (C), 108.7 (CH), 103.3 (CH), 101.3 trated under reduced pressure. The residue was purified by flash
(CH2), 67.3 (CH2), 56.4 (CH3), 45.4 (CH2) ppm. IR (CH2Cl2, cast): chromatography on silica gel (EtOAc/n-hexane, 2:8) to afford com-
ν = 3449, 2901, 1721, 1635, 1509, 1434, 1198, 1133, 1143, 1093,
pound 16 (0.66 g, 80% yield) as a white crystalline solid. M.p. 150–
153 °C. H NMR (600 MHz, CDCl3): δ = 6.37 (s, 2 H), 6.23 (s, 2
H), 5.88 (s, 2 H), 4.15 (dd, J = 9.4, 7.1 Hz, 1 H), 3.99 (t, J = 9.4 Hz,
˜
1
927 cm–1. HRMS (EI): calcd. for C11H12O5 224.0685; found
224.0691.
Eur. J. Org. Chem. 2010, 3473–3480
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3477

P. K. Amancha, H.-J. Liu, T. W. Ly, K.-S. Shia
FULL PAPER
1 H), 3.82 (s, 3 H), 3.78 (s, 6 H), 3.77 (s, 3 H), 3.23 (d, J = 14.0 Hz,
poured into water and extracted with EtOAc (4ϫ25 mL). The
1 H), 3.09 (d, J = 14.0 Hz, 1 H), 2.69–2.58 (m, 3 H) ppm. 13C combined organic layer was dried with MgSO4, filtered, and con-
NMR (150 MHz, CDCl3): δ = 170.3 (CO), 153.3 (C), 149.1 (C),
centrated under reduced pressure. The residue was purified by flash
143.6 (C), 137.8 (C), 134.2 (C), 130.6 (C), 128.3 (C), 115.3 (CN),
chromatography on silica gel (EtOAc/n-hexane, 3:7) to afford com-
108.3 (CH), 107.1 (CH), 102.2 (CH), 101.4 (CH2), 70.3 (CH2), 60.7 pound 18 (6.87 g, 92% yield) as a colorless oil. 1H NMR
(CH3), 56.5 (CH3), 56.0 (CH3), 48.0 (C), 43.0 (CH), 39.4 (CH2), (400 MHz, CDCl3): δ = 9.84 (s, 1 H), 7.46–7.28 (m, 5 H), 7.09 (s,
35.1 (CH ) ppm. IR (CH Cl , cast): ν = 2941, 2238, 1786, 1636,
2 H), 5.11 (s, 2 H), 3.88 (s, 6 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 191.0 (CHO), 153.8 (C), 142.2 (C), 137.0 (C), 131.7
(C), 128.4 (CH), 128.4 (CH), 128.1 (CH), 128.0 (CH), 106.5 (CH),
˜
2
2
2
1592, 1509, 1459, 1130, 928 cm–1. HRMS (EI): calcd. for
C24H25NO8 455.1580; found 455.1581.
74.9 (CH ), 56.1 (CH ) ppm. IR (CH Cl , cast): ν = 2940, 2842,
˜
2
3
2
2
(؎)-5Ј-Methoxyyatein (1): To a solution of compound 16 (0.20 g,
0.44 mmol) in THF (10 mL) at –45 °C under an argon atmosphere
was added a solution of lithium naphthalenide (3.5 equiv.) in THF.
After stirring the mixture for 30 min at –45 °C, saturated aqueous
ammonium chloride solution (2–3 mL) was added at the same tem-
perature by syringe. The reaction mixture was stirred for another
30 min at room temperature and was diluted with water and ex-
tracted with EtOAc (3ϫ10 mL). The combined organic layer was
dried with MgSO4, filtered, and concentrated under reduced pres-
sure. The residue was purified by flash chromatography on silica
gel (EtOAc/n-hexane, 2:8) to afford lignan 1 (0.18 g, 95% yield) as
a colorless oil. 1H NMR (600 MHz, CDCl3): δ = 6.34 (s, 1 H), 6.34
(s, 1 H), 6.15 (br. s, 1 H), 6.13 (br. s, 1 H), 5.91 (m, 2 H), 4.17 (dd,
J = 9.1, 7.3 Hz, 1 H), 3.88 (dd, J = 9.1, 7.3 Hz, 1 H), 3.83 (s, 3 H),
3.80 (s, 3 H), 3.80 (s, 3 H), 3.79 (s, 3 H), 2.93 (dd, J = 14.0, 5.3 Hz,
1 H), 2.88 (dd, J = 14.0, 6.7 Hz, 1 H), 2.59 (dd, J = 13.3, 6.3 Hz,
1 H), 2.54–2.50 (m, 1 H), 2.51 (dd, J = 13.3, 8.1 Hz, 1 H), 2.46–
2.45 (m, 1 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 178.5 (CO),
153.2 (C), 153.2 (C), 149.1 (C), 143.5 (C), 136.8 (C), 133.9 (C),
133.3 (C), 132.3 (C), 108.2 (CH), 106.1 (CH), 106.1 (CH), 102.4
(CH), 101.4 (CH2), 71.1 (CH2), 60.8 (CH3), 56.7 (CH3), 56.1 (CH3),
56.1 (CH3), 46.4 (CH), 41.0 (CH), 38.6 (CH2), 35.2 (CH2) ppm. IR
1692, 1587, 1327, 1126 cm–1. HRMS (EI): calcd. for C16H16O4
272.1049; found 272.1049.
2-(Benzyloxy)-5-(2,2-dibromoethenyl)-1,3-dimethoxybenzene (19):
This compound was prepared from 18 by following a synthetic pro-
cedure similar to that described for 10. Treatment of 18 (5.00 g,
18.36 mmol, 1.0 equiv.) with carbon tetrabromide (6.09 g,
18.36 mmol, 1.0 equiv.) and triphenylphosphane (9.63 g,
36.72 mmol, 2.0 equiv.) gave compound 19 (6.45 g, 82% yield) as a
white solid. M.p. 76–78 °C. 1H NMR (400 MHz, CDCl3): δ = 7.47
(d, J = 8.0 Hz, 2 H), 7.39 (s, 1 H), 7.34–7.27 (m, 3 H), 6.77 (s, 2
H), 5.01 (s, 2 H), 3.81 (s, 6 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 153.1 (C), 137.5 (C), 137.1 (C), 136.5 (CH), 130.5 (C), 128.3
(CH), 128.0 (CH), 127.8 (CH), 105.7 (CH), 88.5 (C), 74.8 (CH2),
56.0 (CH ) ppm. IR (CH Cl , cast): ν = 2998, 2958, 1579, 1453,
˜
3
2
2
1418, 1245, 1130 cm–1. HRMS (EI): calcd. for C17H16Br2O3
427.9446; found 427.9435.
3-[4-(Benzyloxy)-3,5-dimethoxyphenyl]prop-2-yn-1-ol (20): This
compound was prepared from 19 by following a synthetic pro-
cedure similar to that described for 11. Treatment of 19 (5.00 g,
11.68 mmol, 1.0 equiv.) with nBuLi (2.5  in hexanes, 11.68 mL,
2.5 equiv.) and paraformaldehyde (0.53 g, 17.52 mmol, 1.5 equiv.)
gave compound 20 (2.96 g, 85% yield) as a white solid. M.p. 60–
62 °C. 1H NMR (400 MHz, CDCl3): δ = 7.45 (d, J = 1.6 Hz, 2 H),
7.43–7.28 (m, 3 H), 6.64 (s, 2 H), 5.0 (s, 2 H), 4.46 (s, 2 H), 3.78
(s, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 153.2 (C), 137.5
(C), 137.3 (C), 128.4 (CH), 128.0 (CH), 127.8 (CH), 117.6 (C),
108.8 (CH), 86.4 (C), 85.4 (C), 74.9 (CH2), 56.0 (CH3), 51.3 (CH2)
(CH Cl , cast): ν = 2938, 1766, 1508, 1452, 1126, 927 cm–1. HRMS
˜
2
2
(EI): calcd. for C23H26O8 430.1628; found 430.1630.
(؎)-5Ј-Methoxyclusin (2): To a solution of lignan 1 (0.10 g,
0.23 mmol) in anhydrous toluene (5 mL) was added a solution of
diisobutylaluminum hydride (1.0  in hexane, 0.70 mL, 0.70 mmol)
over a period of 5 min (the solution turned yellow) at –78 °C. After
2 h at –78 °C, the reaction mixture was warmed to room tempera-
ture and treated with a saturated aqueous ammonium chloride
solution (5 mL). The reaction mixture was extracted with EtOAc
(3ϫ10 mL), and the combined organic layer was dried with
MgSO4, filtered, and concentrated under reduced pressure. The res-
idue was purified by flash chromatography on silica gel (EtOAc/n-
hexane, 1:9) to afford a pair of inseparable epimers (1:1.4) of lignan
2 (0.072 g, 72% yield) as a pale-yellow oil. 1H NMR (600 MHz,
CDCl3, selected peaks of the major isomer): δ = 6.30 (s, 1 H), 6.30
(s, 1 H), 6.19 (s, 1 H), 6.18 (s, 1 H), 5.89 (s, 2 H), 5.22 (br. s, 1 H),
4.0 (m, 1 H), 3.82 (s, 3 H), 3.81 (s, 3 H), 3.78 (s, 3 H), 3.78 (s, 3
H), 3.76 (m, 1 H), 2.76 (m, 1 H), 2.58 (m, 1 H), 2.43 (m, 1 H), 2.18
(m, 1 H), 2.15 (m, 1 H) ppm. 13C NMR (150 MHz, CDCl3, selected
peaks of the major isomer): δ = 153.0 (C), 153.0 (C), 148.8 (C),
143.4 (C), 136.3 (C), 134.9 (C), 134.5 (C), 133.4 (C), 107.9 (CH),
105.7 (CH), 105.6 (CH), 103.3 (CH), 102.4 (CH), 101.2 (CH2), 72.1
(CH2), 60.8 (CH3), 56.5 (CH3), 56.0 (CH3), 56.0 (CH3), 52.8 (CH),
ppm. IR (CH Cl , cast): ν = 3419, 2938, 2221, 1578, 1502, 1236,
˜
2
2
1127 cm–1. HRMS (EI): calcd. for C18H18O4 298.1205; found
298.1199.
(Z)-3-[4-(Benzyloxy)-3,5-dimethoxyphenyl]-2-(butylthio)prop-2-en-
1-ol (21): This compound was prepared from 20 by following a
synthetic procedure similar to that described for 12. Treatment of
20 (2.00 g, 6.70 mmol, 1.0 equiv.) with powdered NaOH (0.32 g,
8.04 mmol, 1.2 equiv.) in CH3CN (20 mL) and butanethiol
(1.08 mL, 10.06 mmol, 1.5 equiv.) gave compound 21 (2.08 g, 80%
1
yield) as a red oil. H NMR (400 MHz, CDCl3): δ = 7.47 (d, J =
7.2 Hz, 2 H), 7.33–7.26 (m, 3 H), 6.93 (s, 2 H), 6.72 (s, 1 H), 5.0
(s, 2 H), 4.80 (s, 2 H), 3.81 (s, 6 H), 2.76 (q, J = 7.4 Hz, 2 H), 1.56–
1.51 (m, 2 H), 1.40–1.34 (m, 2 H), 0.88 (t, J = 7.4 Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 170.2 (C), 152.7 (C), 137.5 (C),
136.2 (C), 132.4 (CH), 131.1 (C), 128.1 (CH), 127.8 (CH), 127.5
(CH), 106.7 (CH), 74.7 (CH2), 67.7 (CH2), 55.8 (CH3), 31.6 (CH2),
31.2 (CH ), 21.6 (CH ), 13.3 (CH ) ppm. IR (CH Cl , cast): ν =
˜
2
2
3
2
2
46.0 (CH), 39.1 (CH ), 34.1 (CH ) ppm. IR (CH Cl , cast): ν =
˜
2
2
2
2
3412, 2957, 1221, 1578, 1332, 1128 cm–1. HRMS (EI): calcd. for
3416, 2935, 1509, 1452, 1240, 1128, 928 cm–1. HRMS (EI): calcd.
C22H28O4S 388.1708; found 388.1708.
for C23H28O8 432.1784; found 432.1786.
1-[4-(Benzyloxy)-3,5-dimethoxyphenyl]-3-hydroxypropan-2-one (22):
This compound was prepared from 21 by following a synthetic pro-
cedure similar to that described for 13. Treatment of 21 (2.00 g,
5.15 mmol, 1.0 equiv.) with ethanol/1  H2SO4 (4:1) gave com-
4-(Benzyloxy)-3,5-dimethoxybenzaldehyde (18): To a suspension of
aldehyde 17 (5.00 g, 27.45 mmol, 1.0 equiv.) and potassium carbon-
ate (7.97 g, 57.64 mmol, 2.1 equiv.) in THF (100 mL) was added
benzyl bromide (3.92 mL, 32.93 mmol, 1.2 equiv.). The resulting re-
action mixture was heated at reflux for 12 h, then cooled and
1
pound 22 (1.14 g, 70% yield) as a white solid. M.p. 58–61 °C. H
NMR (400 MHz, CDCl3): δ = 7.47 (d, J = 7.2 Hz, 2 H), 7.34–7.26
3478
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3473–3480

General Approach to 2,3-Dibenzyl-γ-butyrolactone Lignans
(m, 3 H), 6.38 (s, 2 H), 4.96 (s, 2 H), 4.26 (s, 2 H), 3.78 (s, 6 H),
127.7 (CH), 126.8 (C), 115.3 (CN), 109.9 (CH), 105.4 (CH), 104.1
(CH), 101.5 (CH2), 74.8 (CH2), 70.3 (CH2), 56.6 (CH3), 55.9 (CH3),
3.62 (s, 2 H), 2.80 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 207.3 (CO), 153.6 (C), 137.6 (C), 136.1 (C), 128.3 (CH), 128.0 48.0 (C), 43.0 (CH), 39.0 (CH2), 35.4 (CH2) ppm. IR (CH2Cl2,
(CH), 127.7 (CH), 106.2 (CH), 74.9 (CH2), 67.4 (CH2), 56.0 (CH3), cast): ν = 2940, 2842, 2238, 1784, 1592, 1508, 1455, 1129, 926 cm–1.
˜
45.9 (CH ) ppm. IR (CH Cl , cast): ν = 3479, 2939, 2841, 1722,
HRMS (EI): calcd. for C30H29NO8 531.1893; found 531.1888.
˜
2
2
2
1591, 1505, 1242, 1126 cm–1. HRMS (EI): calcd. for C18H20O5
(3R*,4R*)-4-(4-Hydroxy-3,5-dimethoxybenzyl)-3-{(7-methoxybenzo-
[d][1,3]dioxol-5-yl)methyl}-2-oxotetrahydrofuran-3-carbonitrile (26):
A mixture of compound 25 (0.50 g, 0.94 mmol) and Pd/C (10%,
0.05 g) in MeOH (25 mL) was stirred under a H2 atmosphere for
10 min at room temperature. The crude reaction mixture was fil-
tered through Celite, and the filtrate was concentrated under re-
duced pressure. The residue was purified by flash chromatography
on silica gel (EtOAc/n-hexane, 1:1) to afford compound 26 (0.41 g,
98% yield) as a white solid. M.p. 107–110 °C. 1H NMR (600 MHz,
CDCl3): δ = 6.34 (s, 1 H), 6.33 (s, 1 H), 6.32 (s, 1 H), 6.26 (s, 1 H),
5.96 (dd, J = 4.0, 1.0 Hz, 2 H), 5.48 (br. s, 1 H), 4.15 (dd, J = 9.4,
7.0 Hz, 1 H), 4.02 (t, J = 9.4 Hz, 1 H), 3.85 (s, 6 H), 3.84 (s, 3 H),
3.28 (d, J = 14.1 Hz, 1 H), 3.05 (d, J = 14.1 Hz, 1 H), 2.79–2.77
(m, 1 H), 2.68–2.62 (m, 2 H) ppm. 13C NMR (150 MHz, CDCl3):
δ = 170.3 (CO), 149.1 (C), 147.3 (C), 143.8 (C), 135.2 (C), 133.9
(C), 127.4 (C), 126.9 (C), 115.3 (CN), 110.0 (CH), 105.2 (CH),
104.2 (CH), 101.6 (CH2), 70.4 (CH2), 56.7 (CH3), 56.2 (CH3), 48.1
316.1311; found 316.1312.
3-[4-(Benzyloxy)-3,5-dimethoxyphenyl]-2-oxopropyl Cyanoacetate
(23): This compound was synthesized from 22 by following a syn-
thetic procedure similar to that described for 14. Treatment of 22
(2.23 g, 7.05 mmol, 1.0 equiv.) with cyanoacetic acid (0.60 g,
7.05 mmol, 1.0 equiv.), pyridine (1.71 mL, 21.16 mmol, 3.0 equiv.),
and
N,N-dimethyl
phosphoramidodichloridate
(1.68 mL,
14.11 mmol, 2.0 equiv.) gave compound 23 (2.38 g, 88% yield) as a
brown crystalline solid. M.p. 83–85 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.46 (d, J = 7.6 Hz, 2 H), 7.34–7.24 (m, 3 H), 6.38 (s,
2 H), 4.97 (s, 2 H), 4.80 (s, 2 H), 3.79 (s, 6 H), 3.65 (s, 2 H), 3.55
(s, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 199.4 (CO), 162.4
(CO), 153.6 (C), 137.5 (C), 136.0 (C), 128.3 (CH), 128.0 (CH),
127.7 (CH), 112.7 (CN), 106.2 (CH), 74.8 (CH2), 68.6 (CH2), 56.0
(CH ), 46.3 (CH ), 24.1 (CH ) ppm. IR (CH Cl , cast): ν = 2939,
˜
3
2
2
2
2
2842, 2261, 1762, 1736, 1592, 1423, 1244, 1126 cm–1. HRMS (EI):
(C), 43.3 (CH), 39.2 (CH ), 35.3 (CH ) ppm. IR (CH Cl , cast): ν
˜
2
2
2
2
calcd. for C21H21NO6 383.1369; found 383.1362.
= 3480, 2939, 2847, 2239, 1783, 1635, 1516, 1456, 1216, 1115,
925 cm–1. HRMS (EI): calcd. for C23H23NO8 441.1424; found
441.1422.
4-[4-(Benzyloxy)-3,5-dimethoxybenzyl]-2-oxotetrahydrofuran-3-carb-
onitrile (24): This compound was synthesized from 23 by following
a synthetic procedure similar to that described for 15. Treatment of
23 (1.00 g, 2.61 mmol, 1.0 equiv.) with -proline (0.06 g, 0.52 mmol,
0.2 equiv.) and the Hantzsch ester (0.67 g, 2.61 mmol, 1.0 equiv.)
(؎)-4Ј-Hydroxycubebinone (3): This compound was synthesized
from 26 by following a synthetic procedure similar to that described
for lignan 1. Treatment of cyanobutyrolactone 26 (0.20 g,
0.45 mmol) with lithium naphthalenide (3.5 equiv.) followed by
quenching with saturated aqueous ammonium chloride solution
gave lignan 3 (0.18 g, 95% yield) as a pale-yellow oil. 1H NMR
(600 MHz, CDCl3): δ = 6.28 (s, 1 H), 6.27 (s, 1 H), 6.26 (s, 1 H),
6.26 (s, 1 H), 5.91 (s, 2 H), 5.44 (s, 1 H), 4.17 (dd, J = 9.0, 7.2 Hz,
1 H), 3.88 (dd, J = 9.1, 7.2 Hz, 1 H), 3.83 (s, 3 H), 3.82 (s, 3 H),
3.82 (s, 3 H), 2.92 (dd, J = 14.0, 5.2 Hz, 1 H), 2.83 (dd, J = 14.0,
7.1 Hz, 1 H), 2.58–2.57 (m, 2 H), 2.57–2.49 (m, 1 H), 2.48–2.45 (m,
1 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 178.5 (CO), 148.9
(C), 147.1 (C), 147.1 (C), 143.5 (C), 134.0 (C), 133.5 (C), 132.1 (C),
128.9 (C), 108.6 (CH), 105.4 (CH), 105.1 (CH), 103.2 (CH), 101.4
(CH2), 71.2 (CH2), 56.6 (CH3), 56.3 (CH3), 56.2 (CH3), 46.4 (CH),
1
gave compound 24 (0.77 g, 80% yield) as a colorless oil. H NMR
(600 MHz, CDCl3, major isomer): δ = 7.46–7.44 (m, 2 H), 7.33–
7.31 (m, 2 H), 7.29–7.26 (m, 1 H), 6.31 (s, 2 H), 4.96 (s, 2 H), 4.39–
4.36 (m, 1 H), 3.99–3.96 (m, 1 H), 3.79 (s, 6 H), 3.78 (d, J = 8.9 Hz,
1 H), 3.16–3.12 (m, 1 H), 2.95 (ab, d, J = 14.0, 5.8 Hz, 1 H), 2.74
(ab, d, J = 14.0, 8.5 Hz, 1 H) ppm. 13C NMR (150 MHz, CDCl3,
major isomer): δ = 167.8 (CO), 153.9 (C), 137.5 (C), 136.2 (C),
131.3 (C), 128.5 (CH), 128.1 (CH), 127.9 (CH), 114.3 (CN), 105.8
(CH), 75.0 (CH2), 71.3 (CH2), 56.2 (CH3), 42.9 (CH), 37.0 (CH),
36.9 (CH2) ppm. 1H NMR (600 MHz, CDCl3, selected peaks of
minor isomer): δ = 6.38 (s, 2 H), 4.25–4.23 (m, 1 H), 4.18–4.16 (m,
1 H), 3.79 (s, 6 H), 3.41 (d, J = 8.9 Hz, 1 H), 3.07–3.04 (m, 1 H),
3.03–2.98 (m, 1 H), 2.66–2.63 (m, 1 H) ppm. 13C NMR (150 MHz,
CDCl3, selected peaks of minor isomer): δ = 167.9 (CO), 153.8 (C),
137.6 (C), 136.0 (C), 132.2 (C), 128.4 (CH), 112.9 (CN), 105.7
(CH), 70.7 (CH2), 56.1 (CH3), 40.1 (CH), 37.1 (CH), 35.2 (CH2)
41.2 (CH), 38.8 (CH ), 35.0 (CH ) ppm. IR (CH Cl , cast): ν =
˜
2
2
2
2
3504, 2938, 1763, 1626, 1613, 1513, 1454, 1325, 1124, 1106,
922 cm–1. HRMS (EI): calcd. for C22H24O8 416.1471; found
416.1459.
ppm. IR (CH Cl , cast): ν = 2940, 2248, 1787, 1591, 1459,
˜
2
2
1127 cm–1. HRMS (EI): calcd. for C21H21NO5 367.1420; found
367.1416.
Acknowledgments
(3R*,4R*)-4-[4-(Benzyloxy)-3,5-dimethoxybenzyl]-3-{[7-methoxy-
benzo[d][1,3]dioxol-5-yl]methyl}-2-oxotetrahydrofuran-3-carbonitrile
(25): This compound was synthesized from 24 by following a syn-
thetic procedure similar to that described for 16. Treatment of 24
(0.50 g, 1.36 mmol) with K2CO3 (0.23 g, 1.63 mmol) and 5-meth-
oxypiperonyl bromide (0.4 g, 1.63 mmol) gave compound 25
(0.59 g, 82% yield) as a white solid. M.p. 122–125 °C. 1H NMR
(600 MHz, CDCl3): δ = 7.45 (d, J = 8.8 Hz, 2 H), 7.30–7.25 (m, 3
H), 6.35 (s, 1 H), 6.31 (s, 2 H), 6.25 (s, 1 H), 5.91 (dd, J = 3.3,
1.4 Hz, 2 H), 4.97 (s, 2 H), 4.16 (dd, J = 9.4, 7.1 Hz, 1 H), 4.02 (t,
J = 9.4 Hz, 1 H), 3.83 (s, 3 H), 3.79 (s, 6 H), 3.25 (d, J = 14.1 Hz,
1 H), 3.01 (d, J = 14.1 Hz, 1 H), 2.76 (dd, J = 12.5, 4.8 Hz, 1 H),
2.68–2.66 (m, 1 H), 2.65 (dd, J = 12.5, 9.1 Hz, 1 H) ppm. 13C NMR
(150 MHz, CDCl3): δ = 170.2 (CO), 153.7 (C), 149.0 (C), 143.6 (C),
137.4 (C), 135.7 (C), 135.0 (C), 132.1 (C), 128.1 (CH), 127.9 (CH),
We are grateful to the National Science Council and the National
Health Research Institutes of the Republic of China for financial
support.
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Received: March 8, 2010
Published Online: May 11, 2010
3480
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Eur. J. Org. Chem. 2010, 3473–3480