Total synthesis of (±)-sacidumlignans D and A through Ueno-Stork radical cyclization reaction

Article abstract of DOI:10.1039/c3ob00053b

Efficient synthesis of (±)-sacidumlignan D (4) has been successfully achieved employing Ueno-Stork radical cyclization of α-bromo acetal 21 as a key step. Two synthetic approaches for the symmetrical diaryl ketone 19 have been discussed in detail. Notably, sacidumlignan A (1) can be also efficiently synthesized in only 7 steps with 25% overall yield, where acid triggered tandem reaction starting from analogous Ueno-Stork cyclization product 27 played an important role. Moreover, potentially biomimetic conversion from (±)-sacidumlignan D (4) to sacidumlignan A (1) could be realized. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ob00053b

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Total synthesis of ( )-sacidumlignans D and A through
Ueno–Stork radical cyclization reaction†
Cite this: Org. Biomol. Chem., 2013, 11,
2498
Jian-Jian Zhang,‡a Chang-Song Yan,‡a Yu Peng,*a Zhen-Biao Luo,a Xiao-Bo Xua and
Ya-Wen Wangb
Efficient synthesis of ( )-sacidumlignan D (4) has been successfully achieved employing Ueno–Stork
radical cyclization of α-bromo acetal 21 as a key step. Two synthetic approaches for the symmetrical diaryl
ketone 19 have been discussed in detail. Notably, sacidumlignan A (1) can be also efficiently synthesized
in only 7 steps with 25% overall yield, where acid triggered tandem reaction starting from analogous
Ueno–Stork cyclization product 27 played an important role. Moreover, potentially biomimetic conversion
from ( )-sacidumlignan D (4) to sacidumlignan A (1) could be realized.
Received 10th January 2013,
Accepted 11th February 2013
DOI: 10.1039/c3ob00053b
www.rsc.org/obc
Introduction
The plant Sarcostemma acidum (Roxb.) grows in and over trees
and shrubs near the seashore of Hainan Island of China and
is applied in folklore medicine to remedy chronic cough and
postnatal hypogalactia.1 In 2005, investigation into chemical
components of the only species of this genus distributed in
China by Yue and co-workers resulted in the isolation of four
new lignans, namely, sacidumlignans A–D (1–4) from the etha-
nolic extract of the whole plant.2 Sacidumlignan D (4) was
assigned as a rearranged tetrahydrofuran lignan with an
unprecedented skeleton by extensive 2D NMR techniques
(Fig. 1). Notably, sacidumlignan A (1) possesses the aryl-
naphthalene backbone, and demonstrates moderate anti-
microbial activities against two Gram-positive bacteria in vitro.
We are interested in the total synthesis of these two natural
products, especially their conversion relationship albeit Yue
and co-workers did not propose a plausible biogenetic syn-
thetic route.
The first total synthesis of racemic sacidumlignan D (4) was
completed with a longest linear sequence (LLS) of 14 steps in
an overall yield of 2.7% from known bromo-o-vanillin by
Ramana and co-worker featuring the utilization of reverse
Fig. 1 Structures of sacidumlignans A, B, C and D.
Wacker oxidation (Scheme 1a),3a and the whole route involved
triple adjustment of protecting groups (–OAllyl→–OAc→
–OTBS). Subsequently, naturally occurring sacidumlignan D (4)
was also synthesized by the same group employing an
improved 11-step route (17% overall yield) from known com-
pound and the analogous C–O bond construction as the key
step for the formation of γ-lactol.3b Starting from a common
γ-lactone intermediate, sacidumlignan A (1) was obtained as
well in 14 steps with 9.4% overall yield. In our current study, a
distinctively different strategy was adopted (Scheme 1b): the
Ueno–Stork radical cyclization4 is responsible for the
aState Key Laboratory of Applied Organic Chemistry and College of Chemistry and
Chemical Engineering, Lanzhou University, Lanzhou 730000, People’s Republic of
China. E-mail: pengyu@lzu.edu.cn; Fax: +86-931-8912582; Tel: +86-931-3902316
bKey Laboratory of Nonferrous Metals Chemistry and Resources Utilization of Gansu
Province and College of Chemistry and Chemical Engineering, Lanzhou University,
Lanzhou 730000, People’s Republic of China
†Electronic supplementary information (ESI) available: Copies of 1H, 13C NMR,
1H–1H COSY and NOE spectra. CCDC 912716, 912717 and 912718. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c3ob00053b
‡These authors contributed equally to this work.
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Py = pyridine] catalysis system as a tin-free approach for this
key transformation, and disappointedly found that the cyclic
acetal 7 was obtained in only 16% yield accompanied by the
significant formation of 5 (60–70% yield) resulted from facile
β-elimination. Eventually, we turned our attention to classical
conditions (Bu3SnH, AIBN, Δ) for the Ueno–Stork radical cycli-
zation. Thus, subjection of precursor 6 to the above described
radical conditions afforded the desired 7 as a mixture of incon-
sequential diastereomers (d.r. = 1.5 : 1) smoothly in 94% yield
in gram scale. Next, γ-lactone 8 could be easily obtained in
94% isolated yield through oxidation of ethyl-protected lactol 7
mediated by an excess of m-CPBA and BF3·Et2O.9 The stereo-
selective incorporation of the C(8) methyl group could be
realized through highly diastereoselective methylation of
γ-lactone 8. Under optimized conditions [LiHMDS (4.0 equiv.),
THF, −78 °C, 1.0 h, then MeOTf (2.0 equiv.), −78 °C, 4.0 h],
the trans-dimethyl γ-lactone 9 (d.r. = 30 : 1, determined by
1H NMR) was produced in 85% yield, whose stereochemistry
assignment was unambiguously confirmed by its single-crystal
structure analysis.10 With 9 in hand, the reduction of lactone
with LiAlH4 followed by TFA treatment of the resulting crude
diol afforded tetrahydrofuran 10 in 92% overall yield, and
therefore the whole route (6 steps, 64% overall yield)
established the feasibility for the total synthesis of sacidum-
lignan D.
Based on the success of synthesizing sacidumlignan D’s
skeleton, early-stage incorporation of the C(8) methyl group
was further investigated in order to extend the application
scope of Ueno–Stork cyclization (Scheme 2B). To this end,
commercially available ethyl propenyl ether (E : Z = 1.7 : 1) was
utilized to give β-bromo acetal 11 as a mixture of inseparable
diastereomers (d.r. = 1.7 : 1) in 94% yield following the similar
procedure for 6. The analogous Ueno–Stork cyclization of 11
proceeded smoothly, a mixture of four diastereomers (d.r. =
2.4 : 1.2 : 2.2 : 1) 12 can be obtained in 90% yield, among which
the least polar isomer was carefully separated by column
chromatography and its relative stereochemistry had been
assigned according to the corresponding NOE spectra.11 After
efficient oxidation of 12 with m-CPBA, four diastereomers
reduced to a mixture of two inseparable ones 9′ (d.r. = 1 : 1).
Since a trans relationship of the C(8) and C(8′) methyl groups
is desired, the epimerization reaction12 of 9′ to 9 promoted by
Scheme 1 Retrosynthetic analysis of sacidumlignans D and A.
establishment of the key C–C bond for the formation of the
corresponding acetal. To the best of our knowledge, the appli-
cation of the Ueno–Stork radical cyclization in the total syn-
thesis of lignans class remains largely unexplored5 although
the great value of this methodology had been proved in the
field of natural products synthesis.6 Herein, we disclose the
successful exploit of this strategy, as demonstrated in the
efficient synthesis of ( )-sacidumlignan D (4) in 9 steps (LLS)
from commercially available materials with 24% overall yield
and 8 column chromatography manipulation. Moreover, a
concise synthesis of sacidumlignan A (1) can be achieved
(7 steps with 25% overall yield) from analogous Ueno–Stork
cyclization product 27, and a plausible biomimetic conversion
relationship between ( )-sacidumlignan D (4) and sacidum-
lignan A (1) was also revealed.
Results and discussion
We began by examining the synthesis of model substrate 10 a base was next investigated. We screened some bases includ-
that possesses the skeleton of sacidumlignan D. As shown in ing DBU, NaOMe, t-BuOM (M = Li, K), MHMDS (M = Li, Na, K)
Scheme 2A, gem-diphenyl allyl alcohol 5 can be readily pre- in different solvents at variable temperature, and eventually
pared from benzophenone and vinylmagnesium bromide in found that excess KHMDS followed by quenching with aq.
almost quantitative yield. The initial access to β-bromo acetal 6 NH4Cl is superior for the desired inversion of the C(8) stereo-
with ethyl vinyl ether and conventional bromination reagents genic center. In addition, the expected trans-dimethyl diastereo-
such as NBS proved to be difficult owing to steric hindrance mer could be further enriched through the repeated reaction
imparted from tertiary allyl alcohol 5. This problem can be sequence (reduction to diastereomeric diol and easy separa-
solved through attack of the more reactive 1,2-dibromo-1- tion; oxidation of cis-dimethyl diol to the corresponding
ethoxyethane generated in situ from Br2 and ethyl vinyl ether,7 lactone followed by the second run epimerization to 9), which
to 5 promoted by N,N-dimethylaniline. Thus, the desired 6 was provided an alternative to satisfy the need of subsequent
isolated in 95% yield in 10 gram scale, and set the stage for synthesis.
the following Ueno–Stork radical cyclization. We firstly choose
Interestingly, another important value of 12 as a mixture of
our recent developed Ni(0)·2EC·Py8 [EC = ethyl crotonate, inconsequential diastereomers had been proved in the direct
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Scheme 2 Model studies for sacidumlignan D. Reagents and conditions: (a) vinylmagnesium bromide (1.1 equiv.), THF, 0 °C to rt, 2 h, 98%; (b) Br2 (15.0 equiv.),
ethyl vinyl ether or (E : Z = 1.7 : 1) ethyl propenyl ether (16.0 equiv.), CH2Cl2, −78 °C, 15 min, to rt, 15 min; then alcohol 5 (1.0 equiv.), N,N-dimethylaniline (30.0
equiv.), −78 to 0 °C, 10 h, then rt, 12 h, 95% for 6 or 94% (d.r. = 1.7 : 1, determined by 1H NMR) for 11; (c) Bu3SnH (10.0 equiv.), AIBN (3.0 equiv.), PhMe, 85 °C,
1.5 h, 94% (d.r. = 1.5 : 1, determined by 1H NMR) for 7 or 90% (d.r. = 2.4 : 1.2 : 2.2 : 1, determined by GC-MS) for 12; (d) m-CPBA (3.0 equiv.), BF3·Et2O (2.0 equiv.),
CH2Cl2, rt, 15 min, 94% for 8 or 92% (trans–cis = 1 : 1, determined by 1H NMR) for 9’; (e) LiHMDS (4.0 equiv.), THF, −78 °C, 1 h, then MeOTf (2.0 equiv.), −78 °C, 4 h,
85%; (f) LiAlH4 (2.5 equiv.), THF, 0 °C, 1.0 h; TFA (2.0 equiv.), CH2Cl2, 0 °C, 5 min, 92% over 2 steps; (g) KHMDS (4.0 equiv.), PhMe, −15 °C, 12 h then aq. NH4Cl, 95%
(d.r. = 9 : 1, determined by 1H NMR).
access to 13 with sacidumlignan A’s skeleton. As shown in
Encouraged by successful model studies, the total synthesis
Scheme 3, simple exposure of 12 in the solution of CH2Cl2 of sacidumlignan D was next pursued. Firstly, we carried out
containing TsOH and CF3CO2H at room temperature for 10 h, the efficient synthesis of functionalized diaryl ketone 19
arylnaphthalene 13 could be isolated in 62% yield. This (Scheme 4). Starting from o-vanillin, the aldehyde 14 could be
remarkable cascade would be made up of the following obtained by regioselective bromination and benzyl protection
sequential transformations: (i) ring-opening of cyclic acetal 12 of free –OH with deca-gram scale. The choice for a benzyl pro-
takes places upon the addition of acid; (ii) The facile dehy- tecting group is important owing to its compatibility with the
dration of the resulting tertiary benzyl alcohol 12i would afford successive steps that would greatly improve overall synthesis
oxonium 12ii; (iii) the intramolecular Friedel–Crafts reaction efficiency compared to frequent adjustment of protecting
of reactive species 12ii would generate aryldihydronaphthalene groups in the previous route.3a The Dakin oxidation14 of 14 fol-
12iii that converts to more stable arylnaphthalene 13 through lowed by alkaline hydrolysis afforded phenol 15. The new gen-
the elimination of EtOH molecule. It is noteworthy that a erated free –OH was converted its methyl ether 16 in almost
similar transformation is known although the naphthalene quantitative yield after treatment with K2CO3 and MeI. The
derivative was observed as undesired byproduct there.12a More whole route for bromide 16 is efficient with 65% overall yield
importantly, gem-diphenyl tetrahydrofuran 10 can also trans- albeit in 5 steps. The alternative step economic pathway could
formed to 13 in 54% (68% brsm) yield under similar acidic be realized through the utilization of commercially available
conditions,13 and this interesting cascade shed a light on the syringol, and simple treatment with Br2 and BnBr under
plausible chemical correlation between sacidumlignan D and strong base conditions could give bromide 16 in comparable
A. The possible reaction mechanism is described in Scheme 3 yield as well. Another building block 17 was prepared in only
(bottom), involving a series of transformations via intermedi- one step from commercially available syringaldehyde in almost
acy 10i–10iv: (i) acid promoted ring-opening of 10 takes places quantitative yield. With sufficient amounts of 16 and 17 in
regioselectively followed by β-elimination, affording tetra- hand, the coupling of these two fragments was then investi-
substituted alkene 10ii; (ii) Friedel–Crafts reaction of 10ii gated. Upon the subjection to aryl lithium, generated in situ
would generate aryldihydronaphthalene 10iv that converts to from bromide 16 with n-BuLi at −78 °C, aldehyde 17 could be
the more stable arylnaphthalene 13 upon aerobic oxidation.
smoothly transformed into diaryl carbinol 18 in 83% isolated
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Scheme 3 Model studies for sacidumlignan A.
Scheme 4 Efficient synthesis of diaryl ketone 19. Reagents and conditions: (a) Br2 (1.1 equiv.), Na2CO3 (1.1 equiv.), CHCl3, 20 °C, 2 d, 87%; (a’) NaH (0.01 equiv.),
NBS (1.06 equiv.), CH2Cl2–MeOH (125 : 1), −45 °C, 2.5 h, rt, 8 h; NaH (1.1 equiv.), DMF, 0 °C, 8 min, rt, 0.5 h; then n-Bu4NI (0.13 equiv.), BnBr (2.4 equiv.), rt, over-
night, 71%; (b) NaH (1.1 equiv.), DMF, 0 °C, 0.5 h; then n-Bu4NI (0.13 equiv.), BnBr (4.8 equiv.), rt, overnight, 97%; (b’) The condition is similar to that given in (b);
NaH (1.1 equiv.), DMF, 0 °C, 0.5 h; then n-Bu4NI (0.2 equiv.), BnBr (4.8 equiv.), rt, overnight, 96%; (c) m-CPBA (2.0 equiv.), CH2Cl2, 0 °C to rt, 2 d; (d) KOH (10% in
water), EtOH, rt, 2 h, 79% over 2 steps; (e) K2CO3 (1.4 equiv.), DMF, 0 °C, 30 min; then MeI (1.6 equiv.), n-Bu4NI (0.2 equiv.), 0 °C to rt, 10 h, 97%; (f) 16, n-BuLi (1.1
equiv.), THF, −78 °C, 30 min; then aldehyde 17 (1.2 equiv.), −78 °C, 20 min, then to rt, 2 h, quench by aq. NH4Cl, 83% or I2 (1.6 equiv.), K2CO3 (3.0 equiv.), t-BuOH,
reflux, 10 h, 85%; (g) PDC (1.5 equiv.), CH2Cl2, 10 °C, 24 h, 100%.
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Scheme 5 Total synthesis of ( )-sacidumlignan D (4). Reagents and conditions: (a) vinylmagnesium bromide (1.1 equiv.), THF, 0 °C to rt, 2 h, 86%; (b) Br2 (8.0
equiv.), ethyl vinyl ether (10.0 equiv.), CH2Cl2, −78 °C, 40 min; then alcohol 20 (1.0 equiv.), N,N-dimethylaniline (15.0 equiv.), −78 to 0 °C, 3 h, then 18 °C, 15 h,
73%; (c) n-Bu3SnH (10.0 equiv.), AIBN (3.0 equiv.), PhMe, 85 °C, 1.0 h, 90% (d.r. = 2.3 : 1); (d) m-CPBA (2.9 equiv.), BF3·Et2O (2.0 equiv.), CH2Cl2, rt, 10 s, 80%; (e)
LiHMDS (4.0 equiv.), THF, −78 °C, 1.0 h, then MeOTf (3.0 equiv.), −78 °C, 4 h, 91%; (f) LiAlH4 (3.0 equiv.), THF, 0 °C, 0.5 h; TFA (2.0 equiv.), CH2Cl2, 0 °C, 5 min, 95%;
(g) H2 (1 atm), Pd/C (10%, 5.0 equiv.), EtOAc–MeOH (1 : 1), 25 °C, 0.5 h, 100%.
yield after quenching with saturated aqueous NH4Cl. The next
oxidation of 18 with PDC led to the formation of functiona-
lized diaryl ketone 19 in quantitative yield. Furthermore,
inspired by Togo’s recent cascade protocol,15 we also investi-
gated the feasibility of access to 19 in one-pot. Indeed, the alk-
oxide lithium intermediate 17i could give 17ii without
purification that would deliver to 19 in 85% isolated yield
through elimination of HI assisted by K2CO3.
With sufficient amounts of diaryl ketone 19 in hand, the
total synthesis of sacidumlignan D was then completed
(Scheme 5) based on successful experience of model studies.
gem-Diaryl allyl alcohol 20 can be synthesized from 19 and
Fig. 2 X-ray crystal structure of ( )-sacidumlignan D (4).
vinylmagnesium bromide in 86% yield. The access to β-bromo
acetal 21 with ethyl vinyl ether under previous optimized con-
ditions proved to be smooth, and the desired Ueno–Stork
natural product2,18 and in the previous racemic synthesis.3a
radical cyclization precursor could be obtained in 75% yield.
The structure assignment of synthetic ( )-sacidumlignan D (4)
Again, the classical conditions (Bu3SnH, AIBN, Δ) allowed the
cyclization to proceed smoothly which afforded the cyclic was unambiguously confirmed by its single-crystal structure
analysis (Fig. 2).10 It is noteworthy that the present route (9
acetal 22 as a mixture of inconsequential separable diastereo-
steps, 8 column chromatography separation, 24% overall yield)
mers (d.r. = 2.3 : 1) in 90% yield. This cyclization also easily
took place under less toxic (TMS)3SiH/AIBN conditions,16 and for ( )-sacidumlignan D is superior to the previous racemic
one by Ramana and co-workers (14 steps, 2.7% overall yield).3a
the desired 22 could be isolated in 85% yield. Oxidation of
Our next focus was the total synthesis of sacidumlignan A
cyclic acetal 22 mediated by m-CPBA and BF3·Et2O can provide
γ-lactone 23 in 80% isolated yield under carefully controlled (1). As shown in Scheme 6, previously synthesized diaryl allyl
alcohol 20 and dibromide derived from ethyl propenyl ether
were employed to prepare β-bromo acetal 26 as a mixture of
conditions due to the highly electron-donating aromatic rings
compared to model substrate 7. Methylation of γ-lactone 23 is
highly diastereoselective, and only one diastereomer 24 can be inseparable diastereomers (d.r. = 1.7 : 1) in 82% yield following
a similar procedure for model substrate 11. The analogous
Ueno–Stork cyclization of 26 proceeded smoothly, providing a
observed under shown condition. With 24 in hand, the
reduction of lactone with LiAlH4 followed by TFA treatment
afforded benzyl protected sacidumlignan D 25 in 95% overall mixture of inconsequential diastereomers 27 in 90% yield. The
key skeletal rearrangement from cyclic acetal 27 to aryl-
naphthalene 28 took place at room temperature as expected
yield. Eventually, 25 could be transformed to ( )-sacidum-
lignan D without purification under hydrogenolysis con-
ditions.17 The NMR spectroscopic data of the synthetic under acidic conditions, and the desired benzyl protected saci-
dumlignan A could be obtained in 65% isolated yield.
( )-sacidumlignan D (4) agree with those reported for the
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Scheme 6 A concise total synthesis of sacidumlignan A (1). Reagents and conditions: (a) Br2 (10.0 equiv.), ethyl propenyl ether (E : Z = 1.7 : 1, 10.5 equiv.), CH2Cl2,
−78 °C, 20 min; then alcohol 20 (1.0 equiv.), N,N-dimethylaniline (20.0 equiv.), −78 °C, 0.5 h, then rt, 5 h, 82% (d.r. = 1.7 : 1); (b) Bu3SnH (8.0 equiv.), AIBN (3.0
equiv.), PhMe, 85 °C, 1.0 h, 90%; (c) TsOH (1.0 equiv.), CH2Cl2, 25 °C, 10 h, 65%; (d) H2 (1 atm), Pd/C (10%, 5.0 equiv.), EtOAc–MeOH (1 : 1), 25 °C, 5 min, 100%.
Scheme 7 Conversion of ( )-sacidumlignan D to sacidumlignan A.
Fig. 3 X-ray crystal structure of sacidumlignan A (1).
Conclusions
In summary, we have provided an additional example for the
Compared to use of a mixture of two Brønsted acids in the
model study (12→13), only TsOH as milder medium can
trigger this cascade reaction, which is attributed to electron-
rich aromatic rings in 27 that would make the above men-
tioned intramolecular Friedel–Crafts reaction proceed much
easier. Eventually, 28 could be transformed to sacidumlignan
A (1) in quantitative yield under similar hydrogenolysis con-
ditions, whose NMR spectroscopic data well agree with those
reported for the natural product2 except for the appearance of
phenolic –OH peaks, and in the previous synthesis.3b,19 The
structure assignment of synthetic sacidumlignan A (1) was also
unambiguously confirmed by its single-crystal structure analy-
sis (Fig. 3).10 The last two steps of the synthetic sequence
could be exchanged, that is, first hydrogenation then tandem
cyclization of free phenol intermediate initiated by acid can
also afford sacidumlignan A with identical efficiency. Notably,
sacidumlignan A can be efficiently accessed (7 steps with 25%
synthetic application of Ueno–Stork radical cyclization strategy
in lignans class natural products, and achieved total synthesis
of ( )-sacidumlignan D (4) successfully in 9 steps (LLS) from
commercially available materials with 24% overall yield and 8
column chromatography protocols. Employing analogous
Ueno–Stork radical cyclization product 27, sacidumlignan A (1)
can be also efficiently synthesized in only 7 steps with 25%
overall yield, where acid triggered cascade reaction played an
important role. More interestingly, facile conversion from
( )-sacidumlignan D (4) to sacidumlignan A (1) has been
observed for the first time, providing an alternative pathway
for the access to other arylnaphthalene lignans.
Experimental section
General
overall yield versus 14-steps route with 9.4% overall yield from For product purification by flash column chromatography,
Ramana’s synthesis3b) employing the present new route.
silica gel (200–300 mesh) and petroleum ether (bp. 60–90 °C)
Interestingly, plausible conversion relationship of ( )-saci- are used. All solvents were purified and dried by standard tech-
dumlignan D (4) to A (1) has been also disclosed based on niques, and distilled prior to use. All organic extracts were
the model studies (10→13, Scheme 3). As shown in Scheme 7, dried over Na2SO4 or MgSO4, unless otherwise noted. All exper-
exposure of sacidumlignan
D (4) in the solution of iments were conducted under an argon or nitrogen atmos-
ClCH2CH2Cl containing 5 equivalent of TsOH at 50 °C for 32 h phere in oven-dried or flame-dried glassware with magnetic
and simple work-up could afforded arylnaphthalene sacidum- stirring, unless otherwise specified. NMR spectra were
lignan A (1) in 44% yield (66% brsm) along with the recovery measured on 300, 400 and 600 MHz instruments. All 1H
of small amounts (ca. 33%) of 4, and therefore chemical corre- chemical shifts (δ) are relative to residual protic solvent
lation of these two natural products was established.
(CHCl3: δ 7.26 ppm; CD3COCD3: δ 2.05 ppm), and all 13C
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chemical shifts (δ) are relative to the solvent (CHCl3: δ 128.4 (2C), 128.1 (2C), 128.0 (2C), 127.7, 127.6 (2C), 127.2,
77.00 ppm; CD3COCD3: δ 29.92 ppm). Mass spectra data were 118.6, 96.6, 85.3, 59.9, 32.5, 14.9 ppm; HRMS (ESI): m/z calcd
measured with ESI or APCI positive ion mode. Infrared spectra for C19H2179BrO2Na+ [M + Na]+: 383.0617, found: 383.0620.
were recorded on FT-IR spectrophotometer.
5-Ethoxy-3-methyl-2,2-diphenyltetrahydrofuran (7). In
a
1,1-Diphenylprop-2-en-1-ol (5). To a stirred solution of benzo- 500 mL, two-necked, round-bottom flask, α-bromo acetal 6
phenone (7.28 g, 20.0 mmol) in anhydrous THF (100 mL) was (3.0 g, 8.3 mmol) was dissolved in anhydrous toluene (300 mL)
added vinylmagnesium bromide (0.7 M in THF, 62.8 mL, followed by the addition of n-Bu3SnH (22.3 mL, 83 mmol, 10
44.0 mmol, 1.1 equiv.) dropwise via syringe at 0 °C. The result- equiv.) and AIBN (4.1 g, 24.9 mmol, 3 equiv.) under argon. The
ing mixture was stirred for 0.5 h at this temperature, then resulting mixture was heated to 85 °C and stirred for 1.5 h.
warmed to room temperature and further stirred for 2 h. The Then reaction mixture was cooled to room temperature and
reaction was carefully quenched by saturated aqueous NH4Cl directly concentrated under reduced pressure. The resulting
(30 mL), and the mixture is concentrated under reduced crude residue was dissolved in Et2O (30 mL) and added satu-
pressure to remove THF. The resulting mixture was extracted rated aqueous KF·2H2O (30 mL). The mixture was stirred for
with EtOAc (3 × 60 mL), and the combined organic layers were 2 h and the n-Bu3SnF precipitate was filtered. The filtrate was
separated and washed with water (3 × 20 mL) and brine extracted with Et2O (2 × 50 mL), and the combined organic
(40 mL) respectively, dried over Na2SO4, filtered and concen- layers were washed with brine (10 mL), dried over Na2SO4, fil-
trated under reduced pressure. The resulting crude allyl tered and concentrated under reduced pressure. The resulting
alcohol 5 (8.24 g, 98% yield) as a colorless oil could be used crude residue was purified by flash column chromatography
directly for the next step without further purification. Rf = 0.42 (petroleum ether→petroleum ether–EtOAc = 20 : 1) on silica
(petroleum ether–EtOAc = 10 : 1); IR (film): νmax = 3557, 3458, gel to afford the mixture 7 as two inconsequential diastereo-
3059, 3028, 1641, 1599, 1491, 1447, 1325, 1167, 1028, 999, 972, isomers (d.r. = 1 : 1.5, 2.2 g, 94% yield). Colorless oil; Rf = 0.64
1
924, 763, 701, 634, 573 cm−1; H NMR (400 MHz, CDCl3): δ = (petroleum ether–EtOAc = 4 : 1); IR (film): νmax = 3059, 2973,
7.37 (d, J = 8.0 Hz, 4H), 7.30 (t, J = 8.0 Hz, 4H), 7.26–7.21 (m, 2931, 2931, 2901, 1599, 1491, 1448, 1377, 1346, 1185, 1115,
2H), 6.49 (dd, J = 17.2 Hz, 10.4 Hz, 1H), 5.30 (d, J = 17.2 Hz, 1052, 996, 923, 896, 755, 701 cm−1 1H NMR (400 MHz,
;
1H), 5.29 (d, J = 10.4 Hz, 1H), 2.31 (s, 1H, –OH) ppm; 13C NMR CDCl3): δ = 7.48 (t, J = 7.2 Hz, 5H), 7.39 (t, J = 7.6 Hz, 2H), 7.31
(100 MHz, CDCl3): δ = 145.7 (2C), 143.5, 128.1 (4C), 127.2 (2C), (t, J = 7.2 Hz, 5H), 7.25–7.22 (m, 8H), 7.17–7.13 (m, 5H),
126.9 (4C), 114.0, 79.4 ppm; HRMS (ESI): m/z calcd for 5.43–5.42 (d, J = 4.8 Hz, 1.5H), 5.22 (dd, J = 5.6 Hz, 3.6 Hz, 1H),
C15H14ONa+ [M + Na]+: 233.0937, found: 233.0936.
4.09–4.02 (m, 1H), 3.71–3.59 (m, 2.5H), 3.48–3.40 (m, 1.5H),
(1-(2-Bromo-1-ethoxyethoxy)prop-2-ene-1,1-diyl)dibenzene 3.36–3.27 (m, 1.5H), 3.10–3.01 (m, 1H), 2.22 (quin, J = 6.8 Hz,
(6). In a 1 L, round-bottom flask, Br2 (23.2 mL, 450 mmol, 15 1H), 2.09 (ddd, J = 12.4, 6.4, 1.2 Hz, 1.5H), 1.86 (ddd, J = 12.6,
equiv.) was dissolved in dry CH2Cl2 (200 mL) and cooled to 10.0, 5.2 Hz, 1.5H), 1.75 (ddd, J = 13.0, 6.0, 4.0 Hz, 1H), 1.32 (t,
−78 °C. To the resulting solution was added ethyl vinyl ether J = 7.2 Hz, 3H), 0.98 (t, J = 7.2 Hz, 4.5H), 0.90 (d, J = 7.2 Hz,
(45.5 mL, 480 mmol, 16 equiv.) dropwise over a 30 min period, 3H), 0.82 (d, J = 7.2 Hz, 4.5H) ppm; 13C NMR (100 MHz,
and the mixture was stirred for 15 min at −78 °C then 10 min CDCl3): δ = 147.4, 147.0, 144.1, 144.0, 128.1 (2C), 127.7 (2C),
at room temperature. This system was cooled to −78 °C again 127.48 (2C), 127.46 (2C), 126.92 (2C), 126.88 (2C), 126.8, 126.7,
and transferred via cannula to another round bottom flask 126.5 (2C), 126.4, 126.2, 126.1 (2C), 103.3, 102.5, 91.2, 90.6,
where the solution of allyl alcohol 5 (6.3 g, 30.0 mmol) and 64.2, 62.4, 40.8, 40.0, 39.5, 39.4, 17.7, 17.4, 15.5, 14.9 ppm;
N,N-dimethylaniline (114 mL, 900 mmol, 30 equiv.) in CH2Cl2 HRMS (ESI): m/z calcd for C19H22O2Na+ [M + Na]+: 305.1512,
(400 mL) had been prepared. The resulting mixture was found: 305.1516.
warmed to 0 °C and further stirred for 10 h then 12 h at 25 °C.
4-Methyl-5,5-diphenyldihydrofuran-2(3H)-one
(8). To
a
Eventually, the reaction mixture was carefully quenched by stirred solution of acetal 7 (1.15 g, 4.0 mmol) in CH2Cl2
aqueous HCl (1.0 M, 100 mL) and poured into a separatory (30 mL) was added m-CPBA (75%, 2.8 g, 12.0 mmol, 3.0 equiv.)
funnel. The combined organic layers were washed with at room temperature followed by the addition of BF3·Et2O
aqueous HCl (1.0 M, 6 × 40 mL), water (30 mL) and brine (0.9 mL, 7.2 mmol, 2.0 equiv.). After 15 min, the reaction
(40 mL), dried over MgSO4, filtered and concentrated under mixture was quenched by saturated aqueous Na2SO3 (3 mL)
reduced pressure. The resulting crude residue was purified by and extracted with CH2Cl2 (3 × 30 mL). The organic layers were
flash column chromatography (petroleum ether–EtOAc
=
washed with saturated aqueous NaHCO3 (4 × 10 mL), water
30 : 1) on silica gel to afford the desired 6 (10.3 g, 95% yield) as (15 mL) and brine (15 mL), then dried over Na2SO4, filtered
a pale yellow oil. Rf = 0.48 (petroleum ether–EtOAc = 60 : 1); IR and concentrated under reduced pressure. The resulting crude
(film): νmax = 3060, 2977, 2927, 1598, 1491, 1447, 1103, 1016, residue was purified by flash column chromatography (pet-
1
764, 701 cm−1; H NMR (400 MHz, CDCl3): δ = 7.39–7.36 (m, roleum ether–EtOAc = 3 : 1) on silica gel to afford the desired 8
2H), 7.35–7.32 (m, 2H), 7.31–7.28 (m, 4H), 7.27–7.23 (m, 2H), (947 mg, 94% yield) as a white solid. Rf = 0.44 (petroleum
6.67 (dd, J = 17.2 Hz, 10.8 Hz, 1H), 5.40 (dd, J = 10.8, 1.2 Hz, ether–EtOAc = 4 : 1); Mp. 104–106 °C (Hexane); IR (film): νmax
=
1H), 4.92 (dd, J = 17.2, 1.2 Hz, 1H), 4.80 (dd, J = 6.4, 4.4 Hz, 3061, 2974, 2927, 1783, 1493, 1450, 1219, 1164, 979, 931, 758,
1
1H), 3.49–3.42 (m, 2H), 3.37–3.30 (m, 2H), 1.06 (t, J = 7.2 Hz, 701 cm−1; H NMR (400 MHz, CDCl3): δ = 7.51 (d, J = 7.2 Hz,
3H) ppm; 13C NMR (100 MHz, CDCl3): δ = 143.9, 143.2, 140.8, 2H), 7.36 (d, J = 7.2 Hz, 2H), 7.29–7.25 (m, 3H), 7.23–7.22
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(m, 3H), 3.42 (ddd, J = 19.2, 12.0, 7.2 Hz, 1H), 2.71 (dd, J = 17.2, CH2Cl2 (3 × 10 mL). The combined organic layers were washed
7.2, 1H), 2.32 (dd, J = 17.2, 4.8 Hz, 1H), 0.91 (d, J = 7.2 Hz, 3H) with water (5 mL) and brine (5 mL) respectively, dried over
ppm; 13C NMR (100 MHz, CDCl3): δ = 175.7, 140.8, 140.5, Na2SO4, filtered and concentrated under reduced pressure.
128.6 (2C), 128.2 (2C), 128.1, 127.4, 126.1 (2C), 125.6 (2C), The resulting crude residue was purified by flash column
92.2, 38.1, 37.5, 17.2 ppm; HRMS (ESI): m/z calcd for chromatography (petroleum ether–EtOAc = 10 : 1) on silica gel
C17H17O2+ [M + H]+: 253.1223, found: 253.1224.
to afford 44 mg (92% yield over 2 steps) of the desired 10 as a
(trans)-3,4-Dimethyl-5,5-diphenyldihydrofuran-2(3H)-one colorless oil. Rf = 0.84 (petroleum ether–EtOAc = 4 : 1); IR
(9). A 25 mL round-bottom flask was charged with HMDS (film): νmax = 3059, 3026, 2962, 2927, 2872, 1598, 1491, 1449,
1
(580 mg, 3.6 mmol, 6.0 equiv.) in anhydrous THF (5.0 mL) and 1044, 754, 701 cm−1; H NMR (400 MHz, CDCl3): δ = 7.44 (d,
the resulting solution was cooled to −78 °C followed by the J = 7.6 Hz, 2H), 7.33 (d, J = 7.6 Hz, 2H), 7.27–7.21 (m, 3H),
addition of n-BuLi (1.6 M in THF, 1.5 mL, 2.4 mmol, 1.1 7.18–7.13 (m, 3H), 4.33 (t, J = 7.6 Hz, 1H), 3.47 (dd, J = 10.4,
equiv.) dropwise via syringe. After 1 h, a solution of γ-lactone 8 8.0 Hz, 1H), 2.45 (dq, J = 10.6, 6.8 Hz, 1H), 2.07–1.95 (m, 1H),
(152 mg, 0.6 mmol) in anhydrous THF (5.0 mL) was added 1.00 (d, J = 6.8 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H) ppm; 13C NMR
dropwise via syringe at this temperature and stirring was con- (100 MHz, CDCl3): δ = 147.1, 144.9, 128.0 (2C), 127.4 (2C),
tinued for 1.0 h. Then the resulting enolate was treated with 127.3 (2C), 127.0, 126.9 (2C), 126.4, 90.5, 73.9, 49.1, 40.5, 15.6,
MeOTf (140 μL, 1.2 mmol, 2.0 equiv.) at −78 °C, and the 14.4 ppm; HRMS (ESI): m/z calcd for C18H21O+ [M + H]+:
methylation reaction was continued for 4.0 h at the same 253.1587, found: 253.1585.
temperature then quenched by saturated aqueous NH4Cl
(1-(2-Bromo-1-ethoxypropoxy)-prop-2-ene-1,1-diyl)dibenzene
(5 mL). The reaction mixture was allowed to warm to room (11). In a 500 mL, round-bottom flask, Br2 (7.7 mL, 150 mmol,
temperature, extracted with EtOAc (3 × 30 mL). The combined 15 equiv.) was dissolved in dry CH2Cl2 (70 mL) and cooled to
organic layers were separated and washed with water (15 mL) −78 °C. To the resulting solution was added ethyl propenyl
and brine (20 mL) respectively, dried over Na2SO4, filtered and ether (E : Z = 1.7 : 1, 17.6 mL, 160 mmol, 16 equiv.) dropwise
concentrated under reduced pressure. The resulting crude over a 30 min period, and the mixture was stirred for 20 min at
residue was purified by flash column chromatography (pet- −78 °C then 10 min at room temperature. This system was
roleum ether–EtOAc = 15 : 1) on silica gel to afford the desired cooled to −78 °C again and transferred via cannula to another
9 (136 mg, 85% yield, d.r. = 30 : 1) which was dissolved in round bottom flask where the solution of allyl alcohol 5 (2.1 g,
EtOAc and hexane again. After a few days, white crystals were 10.0 mmol) and N,N-dimethylaniline (38.2 mL, 300 mmol, 30
obtained by slow evaporation of solvent at room temperature equiv.) in CH2Cl2 (200 mL) had been prepared. The resulting
and suitable for X-ray analysis of single crystal structure. Rf = mixture was warmed to 0 °C and further stirred for 10 h then
0.54 (petroleum ether–EtOAc = 4 : 1); Mp. 99–101 °C (Hexane); 10 h at 25 °C. Eventually, the reaction mixture was carefully
IR (film): νmax = 3060, 2971, 2933, 1775, 1449, 1307, 1231, quenched by aqueous HCl (1.0 M, 60 mL) and poured into a
1
1185, 980, 767, 742, 701 cm−1; H NMR (400 MHz, CDCl3): δ = separatory funnel. The combined organic layers were washed
7.46 (d, J = 7.2 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.40–7.33 (m, with aqueous HCl (1.0 M, 6 × 30 mL), water (30 mL) and brine
3H), 7.32–7.27 (m, 3H), 7.09 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 7.6 (40 mL), dried over MgSO4, filtered and concentrated under
Hz, 1H), 2.93 (dq, J = 12.0, 6.8 Hz, 1H), 2.37 (dq, J = 12.0, 6.8 reduced pressure. The resulting crude residue was purified by
Hz, 1H), 1.27 (d, J = 6.8 Hz, 3H), 1.06 (d, J = 6.8 Hz, 3H) ppm; flash column chromatography (petroleum ether–EtOAc
=
13C NMR (100 MHz, CDCl3): δ = 178.6, 143.1, 140.1, 128.5 (2C), 30 : 1) on silica gel to afford the desired 11 (3.52 g, 94% yield,
128.4, 128.1 (2C), 127.7, 126.9 (2C), 126.7 (2C), 90.6, 46.2, 41.0, d.r. = 1.7 : 1) as a pale yellow oil. Rf = 0.55 (petroleum ether–
16.1, 13.1 ppm; HRMS (ESI): m/z calcd for C18H19O2+ [M + H]+: EtOAc = 30 : 1); IR (film): νmax = 3060, 2977, 2929, 1634, 1600,
267.1380, found: 267.1381.
1491, 1447, 1407, 1376, 1201 1098, 1074, 1032, 763, 702 cm−1
;
(trans)-3,4-Dimethyl-2,2-diphenyltetrahydrofuran (10). To a 1H NMR (400 MHz, CDCl3): δ = 7.40–7.35 (m, 11H), 7.33–7.21
stirred solution of γ-lactone 9 (48 mg, 0.18 mmol) in anhy- (m, 16H), 6.70 (dd, J = 17.2, 10.8 Hz, 1H), 6.63 (dd, J = 17.2,
drous THF (6 mL) at 0 °C was added LiAlH4 (17 mg, 10.8 Hz, 1.7H), 5.41 (d, J = 10.8 Hz, 1.7H), 5.37 (d, J = 10.8 Hz,
0.45 mmol, 2.5 equiv.) carefully. The reaction mixture was 1H), 4.98 (d, J = 17.2 Hz, 1.7H), 4.97 (d, J = 17.2 Hz, 1H), 4.65
stirred for 1.0 h at this temperature and quenched carefully by (d, J = 3.2 Hz, 1.7H), 4.55 (d, J = 4.8 Hz, 1H), 4.14–4.08 (m, 1H),
saturated aqueous NH4Cl (0.5 mL). The resulting precipitate 4.06–4.00 (m, 1.7H), 3.38–3.29 (m, 2.7H), 3.25–3.14 (m, 2.7H),
was then filtered with a short plug of Celite and washed with 1.73 (d, J = 6.8 Hz, 5.1H), 1.72 (d, J = 6.8 Hz, 3H), 1.03 (t, J = 6.8
CHCl3 (3 × 5 mL). The filtrate was extracted with CHCl3 (3 × Hz, 5.1H), 1.01 (t, J = 6.8 Hz, 3H) ppm; 13C NMR (150 MHz,
10 mL). The combined organic layers were washed with water CDCl3): δ = 144.3, 144.1, 143.4, 143.0, 141.2, 140.8, 128.9 (2C),
(3 × 3 mL) and brine (4 mL) respectively, dried over Na2SO4, fil- 128.5 (3C), 128.3 (3C), 128.2 (2C), 127.8 (2C), 127.8, 127.7 (2C),
tered and concentrated under reduced pressure. The resulting 127.6, 127.5 (2C), 127.3, 127.1, 118.7, 118.3, 99.8, 99.7, 85.2,
crude diol could be used directly without further purification. 84.8, 64.1, 61.4, 50.4, 49.4, 20.6, 19.1, 14.95, 14.90 ppm; HRMS
To a solution of the above diol in CH2Cl2 (0.8 mL) at 0 °C was (ESI): m/z calcd for C20H2379BrO2Na+ [M + Na]+: 397.0774,
added TFA (27 μL, 0.36 mmol, 2.0 equiv.) in one portion. After found: 397.0775.
5 minutes, the reaction was quenched by saturated aqueous
5-Ethoxy-3,4-dimethyl-2,2-diphenyltetrahydrofuran (12). In a
NaHCO3 (2 mL) and the aqueous layer was extracted with 500 mL, two-necked, round-bottom flask, α-bromo acetal 11
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+
(823 mg, 2.2 mmol) was dissolved in anhydrous toluene 12.9, 11.5, 10.1 ppm; HRMS (APCI): m/z calcd for C18H19O2
(80 mL) followed by the addition of n-Bu3SnH (5.9 mL, [M + H]+: 267.1380, found: 267.1391.
22 mmol, 10 equiv.) and AIBN (1.08 g, 6.6 mmol, 3 equiv.)
2,3-Dimethyl-1-phenylnaphthalene (13). To a stirred solu-
under argon. The resulting mixture was heated to 85 °C and tion of the diastereoisomeric mixture 12 (30 mg, 0.1 mmol) in
stirred for 1.5 h. Then reaction mixture was cooled to room CH2Cl2 (1 mL) was added p-TsOH·H2O (19 mg, 0.1 mmol, 1.0
temperature and directly concentrated under reduced pressure. equiv.) and CF3CO2H (75 μL, 1.0 mmol, 10.0 equiv.) at 25 °C.
The resulting crude residue was dissolved in Et2O (10 mL) and After 10 h, the reaction mixture was carefully quenched by
added saturated aqueous KF·2H2O (10 mL). The mixture was saturated aqueous NaHCO3 (2 mL) and extracted with CH2Cl2
stirred for 2 h and the n-Bu3SnF precipitate was filtered. The (3 × 10 mL). The organic layers were washed with water (5 mL)
filtrate was extracted with Et2O (2 × 30 mL), and the combined and brine (5 mL), then dried over Na2SO4, filtered and concen-
organic layers were washed with brine (10 mL), dried over trated under reduced pressure. The resulting crude residue
Na2SO4, filtered and concentrated under reduced pressure. was purified by flash column chromatography (petroleum
The resulting crude residue was purified by flash column ether→petroleum ether–EtOAc = 100 : 1) on silica gel to afford
chromatography (petroleum ether→petroleum ether–EtOAc = the desired 13 (15 mg, 65% yield) as a colorless oil. Rf = 0.55
20 : 1) on silica gel to afford the mixture 12 of 4 diastereo- (petroleum ether–EtOAc = 100 : 1); IR (film): νmax = 3056, 2966,
isomers (d.r. = 2.4 : 1.2 : 2.2 : 1 determined by GC-MS, 586 mg, 2925, 2872, 1605, 1509, 1456, 1296, 1246, 1184, 1034, 831, 752,
1
90% yield) as a colorless oil among which the least polar 703 cm−1; H NMR (400 MHz, CDCl3): δ = 7.76 (d, J = 8.0 Hz,
isomer was isolated and characterized. Rf = 0.50 (petroleum 1H), 7.66 (s, 1H), 7.49 (t, J = 8.0 Hz, 2H), 7.43 (d, J = 7.2 Hz,
ether–EtOAc = 20 : 1); IR (film): νmax = 3059, 2959, 2929, 2874, 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.30–7.22 (m, 4H), 2.49 (s, 3H),
2857, 1597, 1491, 1450, 1379, 1178, 1109, 1052, 1021, 989, 747, 2.13 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ = 140.5, 138.3,
1
701 cm−1; H NMR (400 MHz, CDCl3): δ = 7.44 (d, J = 7.6 Hz, 135.4, 133.1, 131.9, 131.7, 130.3 (2C), 128.3 (2C), 127.2, 126.93,
2H), 7.32 (t, J = 7.6 Hz, 2H), 7.25–7.21 (m, 3H), 7.17 (d, J = 126.86, 126.3, 124.84, 124.79, 21.2, 17.6 ppm; HRMS (APCI):
7.2 Hz, 1H), 7.10 (d, J = 7.2 Hz, 2H), 5.23 (d, J = 4.8 Hz, 1H), m/z calcd for C18H17+ [M + H]+: 233.1325, found: 233.1323.
3.61–3.54 (m, 1H), 3.42–3.37 (m, 1H), 2.83–2.78 (m, 1H),
(Alternative procedure for 13 from 10) To a stirred solution
2.02–1.93 (m, 1H), 1.02 (d, J = 6.8 Hz, 3H), 0.90 (t, J = 7.2 Hz, of 10 (12 mg, 0.047 mmol) in CH2Cl2 (2 mL) was added
3H), 0.78 (d, J = 6.8 Hz, 3H) ppm; 13C NMR (150 MHz, CDCl3): p-TsOH·H2O (91 mg, 0.48 mmol, 10.0 equiv.) and CF3CO2H
δ = 148.1, 144.4, 127.7 (2C), 127.33 (2C), 127.30 (2C), 126.6, (36 μL, 0.48 mmol, 10.0 equiv.) at room temperature. After stir-
126.53 (2C), 126.47, 104.2, 90.6, 62.1, 45.8, 44.4, 15.8, 14.8, ring for 15 h at 40 °C, the reaction mixture was quenched by
11.2 ppm; HRMS (ESI): m/z calcd for C20H24O2Na+ [M + Na]+: saturated aqueous NaHCO3 (2 mL) and extracted with CH2Cl2
319.1669, found: 319.1679.
(3 × 10 mL). The organic layers were washed with water (5 mL)
(cis trans)-3,4-Dimethyl-5,5-diphenyldihydrofuran-2(3H)- and brine (5 mL), then dried over Na2SO4, filtered and concen-
+
one (9′). To a stirred solution of the diastereoisomeric mixture trated under reduced pressure. The resulting crude residue
12 (533 mg, 1.8 mmol) in CH2Cl2 (15 mL) was added m-CPBA was purified by flash column chromatography (petroleum
(75%, 1.27 g, 5.4 mmol, 3.0 equiv.) at room temperature fol- ether→petroleum ether–EtOAc = 100 : 1) on silica gel to afford
lowed by the addition of BF3·Et2O (0.45 mL, 3.6 mmol, 2.0 the desired 13 (6 mg, 54% yield) as a colorless oil along with
equiv.). After 15 min, the reaction mixture was quenched by the recovery of 2.4 mg (20%) of 10.
saturated aqueous Na2SO3 (1 mL) and extracted with CH2Cl2
2-(Benzyloxy)-5-bromo-3-methoxybenzaldehyde
(14). This
(3 × 20 mL). The organic layers were washed with saturated bromination reaction was carried out through modified known
aqueous NaHCO3 (4 × 5 mL), water (10 mL) and brine (15 mL), procedure.20 In a 500 mL, two-necked, round-bottom flask,
then dried over Na2SO4, filtered and concentrated under o-vanillin (16.0 g, 105 mmol) was dissolved in CH2Cl2 (220 mL)
reduced pressure. The resulting crude residue was purified by and cooled to 0 °C. To this stirred solution was added anhy-
flash column chromatography (petroleum ether–EtOAc = 6 : 1) drous Na2CO3 (12.4 g, 116 mmol, 1.1 equiv.) portionwise. Then
on silica gel to afford the desired 9′ (d.r. = 1 : 1, 440 mg, 92% Br2 (5.9 mL, 114.3 mmol, 1.09 equiv.) was added dropwise to
yield) as a white solid. Rf = 0.54 (petroleum ether–EtOAc = the above mixture with well stirring. After the addition, the
4 : 1); IR (film): νmax = 3061, 2974, 2933, 1776, 1494, 1450, reaction mixture was warmed to room temperature and stirred
1334, 1231, 1196, 968, 764, 702 cm−1 1H NMR (400 MHz, for 2 days. Then the reaction was carefully quenched by satu-
;
CDCl3): δ = 7.56 (d, J = 7.2 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), rated aqueous NaHSO3 (30 mL) and the resulting precipitate
7.37–7.33 (m, 6H), 7.32–7.28 (m, 2H), 7.27–7.21 (m, 5H), was removed by filtration. The filtrate was extracted with
7.21–7.17 (m, 1H), 7.07 (d, J = 8.4 Hz, 2H), 3.38 (quin, J = CH2Cl2 (400 mL), and the combined organic layers were
6.8 Hz, 1H), 2.91 (dq, J = 12.0, 6.8 Hz, 1H), 2.79 (quin, J = 6.8 Hz, washed with water (3 × 40 mL) and brine (30 mL) respectively,
1H), 2.35 (dq, J = 12.0, 6.8 Hz, 1H), 1.24 (d, J = 6.8 Hz, 3H), dried over Na2SO4, filtered and concentrated under reduced
1.15 (d, J = 7.6 Hz, 3H), 1.04 (d, J = 6.8 Hz, 3H), 0.71 (d, J = pressure to afford the desired bromo-o-vanillin (21.0 g, 87%
6.8 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ = 178.3, 178.0, yield) as a yellow solid. Rf = 0.37 (petroleum ether–EtOAc =
142.9, 142.7, 141.0, 139.9, 128.6 (2C), 128.24 (2C), 128.20 (2C), 8 : 1); Mp. 112–115 °C (Hexane); IR (film): νmax = 2982, 2925,
128.1, 127.84 (2C), 127.78, 127.5, 127.0, 126.7 (2C), 126.5 (2C), 2877, 2854, 2022, 1653, 1464, 1388, 1274, 1256, 1201, 957, 850,
125.6 (2C), 125.1 (2C), 90.3, 90.2, 46.0, 42.2, 40.8, 40.0, 15.9, 761, 708 cm−1
;
1H NMR (400 MHz, CDCl3): δ = 11.00 (s, 1H,
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–OH), 9.86 (s, 1H), 7.31 (d, J = 1.8 Hz, 1H), 7.18 (d, J = 1.8 Hz, hydrolysis reaction was continued for 2 h then quenched by
1H), 3.92 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ = 195.4, aqueous HCl (10%, 30 mL). The resulting mixture was stirred
150.9, 149.3, 126.1, 121.3, 120.8, 111.0, 56.6 ppm; HRMS (ESI): for 0.5 h and poured into a separatory funnel. The aqueous
m/z calcd for C8H879BrO3+ [M + H]+: 230.9651, found: 230.9653. layer was extracted with EtOAc (3 × 150 mL), and the combined
This resulting material could be used directly without further organic layers were washed with water (3 × 30 mL) and brine
purification. To the stirred solution of the above bromo-o- (10 mL), dried over Na2SO4, filtered and concentrated under
vanillin (20.0 g, 87 mmol) in DMF (95 mL) was added NaH reduced pressure. The resulting crude residue was carefully
(60% dispersion in mineral oil, 3.83 g, 95.7 mmol, 1.1 equiv.) purified by flash column chromatography (petroleum ether–
portionwise at 0 °C. The resulting mixture was stirred for 0.5 h EtOAc = 6 : 1) on silica gel to furnish the desired 15 (6.81 g,
further followed by the addition of BnBr (50 mL, 410 mmol, 79% yield over 2 steps) as a colorless oil. Rf = 0.56 (petroleum
4.8 equiv.) dropwise and n-Bu4NI (4.2 g, 11.4 mmol, 0.13 ether–EtOAc = 4 : 1); IR (film): νmax = 3031, 2939, 2840, 1592,
equiv.). This alkylation reaction was carried out overnight, 1494, 1452, 1325, 1213, 1167, 1107, 973, 838, 754, 730,
1
then quenched by carefully by H2O (10 mL), diluted with 698 cm−1; H NMR (400 MHz, CDCl3): δ = 7.38–7.33 (m, 5H),
CH2Cl2 (800 mL) and poured into a separatory funnel. The 6.71 (d, J = 2.4 Hz, 1H), 6.62 (d, J = 2.4 Hz, 1H), 5.63 (s, 1H,
combined organic layers were separated and washed with –OH), 5.02 (s, 2H), 3.85 (s, 3H) ppm; 13C NMR (100 MHz,
water (6 × 50 mL) and brine (50 mL) respectively, dried over CDCl3): δ = 152.9, 150.3, 136.8, 133.5, 128.71 (2C), 128.65,
Na2SO4, filtered and concentrated under reduced pressure. 128.5 (2C), 116.5, 111.7, 107.8, 75.4, 56.1 ppm; HRMS (APCI):
The resulting crude residue was purified by flash column m/z calcd for C14H1479BrO3 [M + H]+: 309.0126, found:
+
chromatography (petroleum ether–EtOAc = 100 : 1→petroleum 309.0114.
ether–EtOAc = 6 : 1) on silica gel to furnish the desired 14
2-(Benzyloxy)-5-bromo-1,3-dimethoxybenzene (16). In
a
(27.1 g, 97% yield) as a white solid. Rf = 0.73 (petroleum ether– 200 mL, two-necked, round-bottom flask, the above phenol 15
EtOAc = 8 : 1); Mp. 85–87 °C (Hexane); IR (film): νmax = 3073, (5.34 g, 17.3 mmol) was dissolved in DMF (65 mL) and cooled
3031, 2882, 1683, 1576, 1479, 1375, 1311, 1266, 1234, 1211, to 0 °C. The resulting solution was added K2CO3 (3.34 g,
1
1185, 1076, 957, 844, 737, 700, 581 cm−1; H NMR (400 MHz, 24.3 mmol, 1.4 equiv.) slowly and the mixture was stirred for
CDCl3): δ = 10.09 (s, 1H), 7.48 (d, J = 2.4 Hz, 1H), 7.39–7.26 (m, 0.5 h followed by the addition of MeI (1.7 mL, 27.3 mmol, 1.6
5H), 7.25 (d, J = 2.4 Hz, 1H), 5.16 (s, 2H), 3.94 (s, 3H) ppm; 13
C
equiv.) dropwise and n-Bu4NI (1.30 g, 3.5 mmol, 0.2 equiv.).
NMR (100 MHz, CDCl3): δ = 188.7, 153.9, 150.1, 135.8, 131.1, This methylation reaction was carried out overnight, and the
128.8 (2C), 128.7 (2C), 121.6, 120.8, 117.1, 76.4, 56.4, resulting precipitate was removed by filtration. The cake was
56.4 ppm; HRMS (ESI): m/z calcd for C15H1379BrO3Na+ washed with Et2O (3 × 50 mL), and the combined organic
[M + Na]+: 342.9940, found: 342.9944.
layers were washed with water (5 × 30 mL) and brine (40 mL)
2-(Benzyloxy)-5-bromo-3-methoxyphenol (15). In a 100 mL, respectively, dried over Na2SO4, filtered and concentrated
two-necked, round-bottom flask, the above benzyl-protected under reduced pressure. The resulting crude residue was puri-
bromo-o-vanillin 14 (9.1 g, 28 mmol) was dissolved in CH2Cl2 fied by flash column chromatography (petroleum ether–EtOAc
(58 mL) and cooled to 0 °C. To this stirred solution was added = 100 : 1→10 : 1) on silica gel to afford the desired 16 (5.43 g,
m-CPBA (75%, 13.0 g, 56.5 mmol, 2.0 equiv.) portionwise. The 97% yield) as a white solid. Rf = 0.71 (petroleum ether–EtOAc =
reaction mixture was then warmed to room temperature and 3 : 1); Mp. 55–57 °C (Hexane); IR (film): νmax = 3090, 3030,
stirred for 2 days. Then the reaction was quenched by saturated 2863, 1587, 1495, 1457, 1408, 1378, 1305, 1225, 1184, 1011,
1
aqueous Na2SO3 (30 mL) and the stirring was continued for 982, 834, 813, 733, 698, 578 cm−1; H NMR (400 MHz, CDCl3):
0.5 h. The mixture was diluted with CH2Cl2 (3 × 200 mL), and δ = 7.47 (d, J = 6.8 Hz, 2H), 7.38–7.29 (m, 3H), 6.72 (s, 2H), 4.99
the combined organic layers were separated and washed with (s, 2H), 3.81 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3): δ =
saturated aqueous NaHCO3 (3 × 30 mL), water (30 mL) and 154.2, 137.5, 136.1, 128.5 (2C), 128.1 (2C), 127.9, 116.2, 109.0
brine (50 mL) respectively, dried over Na2SO4, filtered and con- (2C), 75.0 (2C), 56.3 (2C) ppm; HRMS (ESI): calcd for
centrated under reduced pressure to furnish the desired C15H1679BrO3+ [M + H]+: 323.0277, found: 323.0280.
formate as a colorless oil, which was used directly for the next
(Alternative procedure for 16)21 In a 100 mL, two-necked,
hydrolysis step without further purification. Rf = 0.56 (pet- round-bottom flask, the syringol (3.0 g, 20 mmol) was dis-
roleum ether–EtOAc = 4 : 1); IR (film): νmax = 3089, 3032, 1744, solved in CH2Cl2 (50 mL) and MeOH (0.4 mL). The resulting
1586, 1490, 1449, 1410, 1373, 1202, 1276, 1218, 1113, 1068, solution was then cooled to −45 °C followed by the addition of
1
970, 835, 750, 698, 581 cm−1; H NMR (400 MHz, CDCl3): δ = NaH (60% dispersion in mineral oil, 10 mg, 0.01 equiv.) por-
8.15 (s, 1H, –OC(O)H), 7.42–7.31 (m, 5H), 6.99 (d, J = 2.4 Hz, tionwise. After 15 min, NBS (3.7 g, 21 mmol, 1.06 equiv.) was
1H), 6.91 (d, J = 2.0 Hz, 1H), 5.02 (s, 2H), 3.90 (s, 3H) ppm; 13
C
added portionwise during a period of 8 min and the bromina-
NMR (100 MHz, CDCl3): δ = 158.5, 154.4, 143.9, 139.0, 136.7, tion reaction mixture was stirred for 2.5 h at −45 °C then 8 h
128.4 (2C), 128.3 (2C), 128.2, 117.9, 115.8, 114.1, 75.0, at to room temperature. The reaction was carefully quenched
56.4 ppm; HRMS (ESI): m/z calcd for C15H1379BrO4Na+ by water (10 mL) and the mixture was extracted with EtOAc
[M + Na]+: 358.9889, found: 358.9894. Thus, the above crude (3 × 35 mL), and the combined organic layers were washed
formate was dissolved in aqueous EtOH (64 mL) and added with water (3 × 20 mL) and brine (30 mL), dried over Na2SO4,
aqueous KOH (10%, 26 mL) at room temperature. The filtered and concentrated under reduced pressure. The
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resulting crude residue could be filtered through a short plug
Bis(4-(benzyloxy)-3,5-dimethoxyphenyl)methanol (18). In a
of silica gel (elution with petroleum ether–EtOAc), providing 100 mL, two-necked, round-bottom flask, the bromide 16
the desired 4-bromo-syringol (3.50 g) as a yellow solid which (972 mg, 3 mmol) was dissolved in anhydrous THF (6 mL) and
could be used directly for the next step without further purifi- cooled to −78 °C. The resulting solution was treated with
cation. The small amount of sample was purified by flash n-BuLi (1.6 M in THF, 2.06 mL, 3.3 mmol, 1.1 equiv.) dropwise
column chromatography (petroleum ether–EtOAc
= 10 : via syringe and the mixture was stirred for 0.5 h at this temp-
1→petroleum ether–EtOAc = 5 : 1) on silica gel for characteriz- erature followed by the addition of the solution of aldehyde 17
ation: Rf = 0.65 (petroleum ether–EtOAc = 4 : 1); Mp. 92–94 °C (980 mg, 3.6 mmol, 1.2 equiv.) in THF (2 mL). The reaction
(Hexane), (lit.20 mp. 93–100 °C); IR (film): νmax = 3423, 2956, mixture was stirred for 20 min at −78 °C then allowed to warm
2925, 2851, 1610, 1504, 1459, 1417, 1359, 1235, 1210, 1114, to room temperature, and stirred further for 2 h. The reaction
1
769 cm−1; H NMR (400 MHz, CDCl3): δ = 6.72 (s, 2H), 5.45 (s, was carefully quenched by saturated aqueous NH4Cl (6 mL),
1H), 3.87 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3): δ = 147.6 and extracted with EtOAc (3 × 30 mL). The combined organic
(2C), 134.1, 111.1, 108.6 (2C), 56.5 (2C) ppm; HRMS (APCI): layers were separated and washed with water (3 × 15 mL) and
m/z calcd for C8H8O379Br+ [M
−
H]+: 230.9651, found: brine (20 mL) respectively, dried over Na2SO4, filtered and con-
230.9652. The above crude 4-bromo-syringol (3.50 g, centrated under reduced pressure. The resulting crude residue
14.9 mmol) was dissolved in DMF (50 mL) then cooled to 0 °C was purified by flash column chromatography (petroleum
followed by the addition of NaH (60% dispersion in mineral ether–EtOAc = 5 : 1) on silica gel to afford the desired 18
oil, 657 mg, 1.1 equiv.) portionwise during a period of 5 min. (1.29 g, 83% yield) as a colorless oil. Rf = 0.50 (petroleum
After stirring for 8 min at 0 °C, the reaction mixture was ether–EtOAc = 2 : 1); IR (film): νmax = 3488, 3002, 2837, 2023,
warmed to room temperature and stirred for 30 min followed 1592, 1501, 1460, 1419, 1328, 1233, 1127, 985, 913, 839, 734,
1
by the addition of BnBr (35.9 mL, 24 mmol, 2.4 equiv.) drop- 697 cm−1; H NMR (400 MHz, CDCl3): δ = 7.52 (d, J = 8.0 Hz,
wise and n-Bu4NI (717 mg, 1.9 mmol, 0.13 equiv.). This alkyl- 4H), 7.38–7.27 (m, 6H), 6.58 (s, 4H), 5.66 (s, 1H), 5.03 (s, 4H),
ation reaction was carried out overnight, then carefully 3.79 (s, 12H), 2.76 (brs, 1H, –OH) ppm; 13C NMR (100 MHz,
quenched by H2O (5 mL) and extracted with Et2O (3 × 50 mL). CDCl3): δ = 153.3 (4C), 139.3 (2C), 137.6 (2C), 135.9 (2C), 128.3
The combined organic layers were separated and washed with (4C), 128.0 (4C), 127.7 (2C), 103.6 (4C), 76.0, 74.8 (2C), 56.0
water (9 × 15 mL) and brine (20 mL) respectively, dried over (4C) ppm; HRMS (ESI): calcd for C31H32O7Na+ [M + Na]+:
Na2SO4, filtered and concentrated under reduced pressure. 539.2040, found: 539.2047.
The resulting crude residue was purified by flash column
Bis(4-(benzyloxy)-3,5-dimethoxyphenyl)methanone (19). To
chromatography (petroleum ether–EtOAc = 100 : 1→petroleum a stirred solution of diarylcarbinol 18 (1.25 g, 2.4 mmol) in
ether–EtOAc = 20 : 1) to afford the desired 16 (4.48 g, 71% CH2Cl2 (8 mL) was added PDC (1.35 g, 3.6 mmol, 1.5 equiv.)
yield).
portionwise at 0 °C. The resulting mixture was stirred for 24 h
4-(Benzyloxy)-3,5-dimethoxybenzaldehyde (17). To a stirred further at 10 °C, then filtered and concentrated under reduced
solution of syringaldehyde (3.64 g, 20 mmol) in DMF (40 mL) pressure to afford the desired 19 (1.24 g, 100% yield) as a
was added NaH (60% dispersion in mineral oil, 890 mg, white solid. This resulting material could be used directly for
22.2 mmol, 1.1 equiv.) portionwise at 0 °C. The resulting the next Grignard addition reaction without further purifi-
mixture was stirred for 0.5 h further at room temperature fol- cation. Rf = 0.58 (petroleum ether–EtOAc = 2 : 1); Mp. 84–86 °C
lowed by the addition of BnBr (11.5 mL, 96.8 mmol, 4.84 (Hexane); IR (film): νmax = 2940, 2838, 2024, 1635, 1576, 1501,
equiv.) dropwise and n-Bu4NI (1.6 g, 4.3 mmol, 0.2 equiv.). 1465, 1412, 1337, 1234, 1176, 1126, 977, 860, 741, 697 cm−1
;
This alkylation reaction was carried out overnight, then care- 1H NMR (400 MHz, CDCl3): δ = 7.51 (d, J = 7.2 Hz, 4H),
fully quenched by H2O (8 mL), diluted with CH2Cl2 (100 mL) 7.38–7.27 (m, 6H), 7.06 (s, 4H), 5.15 (s, 4H), 3.86 (s, 12H) ppm;
and poured into a separatory funnel. The combined organic 13C NMR (100 MHz, CDCl3): δ = 194.8, 153.0 (4C), 140.5 (2C),
layers were separated and washed with water (5 × 15 mL) and 137.3 (2C), 132.8 (2C), 128.4 (4C), 128.1 (4C), 127.9 (2C), 107.4
brine (20 mL) respectively, dried over Na2SO4, filtered and con- (4C), 74.9 (2C), 56.2 (4C) ppm; HRMS (ESI): calcd for
centrated under reduced pressure. The resulting crude residue C31H31O7+ [M + H]+: 515.2064, found: 515.2079.
was purified by flash column chromatography (petroleum
(One-pot procedure for 19) The bromide 16 (486 mg,
ether–EtOAc = 100 : 1→petroleum ether–EtOAc = 20 : 1) on 1.5 mmol) was dissolved in anhydrous THF (3 mL) and cooled
silica gel to furnish the desired 17 (5.2 g, 96% yield) as a white to −78 °C. The resulting solution was treated with n-BuLi
solid. Rf = 0.43 (petroleum ether–EtOAc = 3 : 1); Mp. 62–63 °C (1.6 M in THF, 1.03 mL, 1.65 mmol, 1.1 equiv.) dropwise via
(Hexane); IR (film): νmax = 2919, 2848, 1689, 1585, 1493, 1458, syringe and the mixture was stirred for 0.5 h at this tempera-
1419, 1383, 1324, 1226, 1123, 734, 696, 580 cm−1 1H NMR ture followed by the addition of the solution of aldehyde 17
;
(400 MHz, CDCl3): δ = 9.84 (s, 1H), 7.47–7.45 (m, 2H), (490 mg, 1.8 mmol, 1.2 equiv.) in THF (2 mL). The reaction
7.35–7.28 (m, 3H), 7.10 (s, 2H), 5.12 (s, 2H), 3.87 (s, 6H) ppm; mixture was stirred for 20 min at −78 °C then allowed to warm
13C NMR (100 MHz, CDCl3): δ = 191.0, 153.8 (2C), 142.2, 137.1, to room temperature, and stirred further for 1 h. Then, after
131.8, 128.3 (2C), 128.1 (2C), 127.9, 106.5 (2C), 74.9, 56.1 (2C) the removal of THF, t-BuOH (3 mL) was added followed by the
ppm; HRMS (ESI): calcd for C16H17O4 [M + H]+: 273.1121, addition of I2 (610 mg, 2.4 mmol, 1.6 equiv.) and K2CO3
+
found: 273.1125.
(620 mg, 4.5 mmol, 3.0 equiv.). The resulting mixture was
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stirred for 10 h at refluxing condition. The reaction was then 1H), 4.69 (t, J = 5.6 Hz, 1H), 3.74 (s, 6H), 3.72 (s, 6H), 3.45–3.39
quenched by saturated aqueous Na2SO3 (6 mL), and extracted (m, 2H), 3.37–3.31(m, 2H), 1.08 (t, J = 6.8 Hz, 3H) ppm; 13C
with EtOAc (3 × 15 mL). The combined organic layers were sepa- NMR (100 MHz, CDCl3): δ = 152.9 (2C), 152.7 (2C), 140.6,
rated and washed with water (3 × 10 mL) and brine (10 mL) 139.1, 138.2, 137.8, 137.7, 136.1, 136.0, 128.51 (2C), 128.45
respectively, dried over Na2SO4, filtered and concentrated (2C), 128.0 (4C), 127.81, 127.76, 118.1, 106.2 (2C), 106.0 (2C),
under reduced pressure. The resulting crude residue was care- 97.0, 85.6, 74.83, 74.78, 60.8, 56.19 (2C), 56.16 (2C), 32.8,
fully purified by flash column chromatography (petroleum 15.1 ppm; HRMS (APCI): calcd for C37H42O879Br+ [M + H]+:
ether–EtOAc = 7 : 1→petroleum ether–EtOAc = 5 : 1) on silica 693.2058, found: 693.2088.
gel to afford the desired 19 (656 mg, 85% yield).
2,2-Bis(4-(benzyloxy)-3,5-dimethoxyphenyl)-5-ethoxy-3-methyl-
1,1-Bis(4-(benzyloxy)-3,5-dimethoxyphenyl)prop-2-en-1-ol tetrahydrofuran (22). In a 250 mL, two-necked, round-bottom
(20). To a stirred solution of diarylketone 19 (451 mg, flask, α-bromo acetal 21 (623 mg, 0.9 mmol) was dissolved in
0.88 mmol) in anhydrous THF (3.5 mL) was added vinylmag- anhydrous toluene (100 mL) followed by the addition of
nesium bromide (0.7 M in THF, 1.4 mL, 0.98 mmol, 1.1 equiv.) n-Bu3SnH (2.4 mL, 9 mmol, 10 equiv.) and AIBN (440 mg,
dropwise via syringe at 0 °C. The resulting mixture was 2.7 mmol, 3 equiv.) under argon. The resulting mixture was
warmed to room temperature and further stirred for 2 h. The heated to 85 °C and stirred for 1 h. Then reaction mixture was
reaction was carefully quenched by saturated aqueous NH4Cl cooled to room temperature and directly concentrated under
(5 mL), and extracted with CH2Cl2 (3 × 20 mL). The combined reduced pressure. The resulting crude residue was dissolved in
organic layers were separated and washed with water (3 × Et2O (10 mL) and added saturated aqueous KF·2H2O (10 mL).
5 mL) and brine (10 mL) respectively, dried over Na2SO4, fil- The mixture was stirred for 2 h and the n-Bu3SnF precipitate
tered and concentrated under reduced pressure. The resulting was filtered. The filtrate was extracted with Et2O (2 × 30 mL),
crude residue was purified by flash column chromatography and the combined organic layers were washed with brine
(petroleum ether–EtOAc = 4 : 1) on silica gel to afford the (10 mL), dried over Na2SO4, filtered and concentrated under
desired 20 (410 mg, 86% yield) as a colorless oil. Rf = 0.48 (pet- reduced pressure. The resulting crude residue was purified by
roleum ether–EtOAc = 2 : 1); IR (film): νmax = 3479, 3029, 3001, flash column chromatography (petroleum ether→petroleum
2935, 2867, 2837, 1589, 1500, 1456, 1413, 1323, 1236, 1126, ether–EtOAc = 15 : 1) on silica gel to afford 22 (560 mg, 90%
1
993, 841, 756, 734, 698 cm−1; H NMR (400 MHz, CDCl3): δ = yield, more polar isomer/less polar isomer = 2.3 : 1). (more polar
7.48 (d, J = 6.8 Hz, 4H), 7.35–7.27 (m, 6H), 6.58 (s, 4H), 6.42 diastereomer) colorless oil; Rf = 0.40 (petroleum ether–EtOAc =
(dd, J = 17.2 Hz, 10.8 Hz, 1H), 5.34 (d, J = 17.2 Hz, 1H), 5.32 (d, 2 : 1); IR (film): νmax = 3030, 2968, 2935, 2872, 2837, 1588,
J = 10.8 Hz, 1H), 5.02 (s, 4H), 3.75 (s, 12H), 2.28 (s, 1H, –OH) 1504, 1457, 1412, 1375, 1330, 1238, 1128, 1063, 986, 918, 831,
1
ppm; 13C NMR (100 MHz, CDCl3): δ = 153.0 (4C), 143.1, 141.1 734, 698 cm−1; H NMR (400 MHz, CDCl3): δ = 7.50–7.43 (m,
(2C), 137.8 (2C), 136.0 (2C), 128.4 (4C), 128.1 (4C), 127.8 (2C), 4H), 7.35–7.25 (m, 6H), 6.71 (s, 2H), 6.34 (s, 2H), 5.41 (d, J =
114.0, 104.4 (4C), 79.6, 74.9 (2C), 56.1 (4C) ppm; HRMS (ESI): 4.4 Hz, 1H), 5.04 (s, 2H), 4.99 (s, 2H), 3.79 (s, 6H), 3.77–3.69
calcd for C33H33O6+ [M − OH − e]+: 525.2272, found: 525.2280. (m, 1H), 3.71 (s, 6H), 3.52–3.44 (m, 1H), 3.28–3.19 (m, 1H),
5,5′-(1-(2-Bromo-1-ethoxyethoxy)prop-2-ene-1,1-diyl)bis- 2.11 (dd, J = 12.8, 6.8 Hz, 1H), 1.86 (ddd, J = 12.5, 10.4, 4.8 Hz,
(2-(benzyloxy)-1,3-dimethoxybenzene) (21). In a 50 mL 1H), 1.03 (t, J = 6.8 Hz, 3H), 0.81 (d, J = 6.8 Hz, 3H) ppm; 13C
round-bottom flask, Br2 (0.95 mL, 19.0 mmol, 8 equiv.) was NMR (100 MHz, CDCl3): δ = 152.8 (2C), 152.6 (2C), 142.9,
dissolved in anhydrous CH2Cl2 (25 mL) and cooled to −78 °C. 139.4, 137.85, 137.83, 135.7, 135.6, 128.5 (2C), 128.4 (2C),
To the resulting solution was added ethyl vinyl ether (2.3 mL, 128.02 (2C), 127.99 (2C), 127.73, 127.69, 104.6 (2C), 104.3 (2C),
23.8 mmol, 10 equiv.) dropwise over a 5 min period, and the 102.6, 90.8, 74.83, 74.79, 62.5, 56.23, 56.20, 56.08, 56.06, 40.9,
+
mixture was stirred for 40 min at −78 °C. This system was 40.2, 17.3, 15.0 ppm; HRMS (APCI): calcd for C37H43O8
cooled to −78 °C again, and transferred via cannula to another [M + H]+: 615.2952, found: 615.2946.
round bottom flask where the solution of allyl alcohol 20
5,5-Bis(4-(benzyloxy)-3,5-dimethoxyphenyl)-4-methyldihydro-
(1.29 g, 2.38 mmol) and N,N-dimethylaniline (4.5 mL, furan-2(3H)-one (23). To a stirred solution of acetal 22 (85 mg,
35.7 mmol, 15 equiv.) in CH2Cl2 (20 mL) had been prepared. 0.16 mmol) in CH2Cl2 (4.0 mL) was added m-CPBA (95%,
The resulting mixture was gradually warmed to 0 °C over a 3 h 85 mg, 0.47 mmol, 2.9 equiv.) at room temperature followed by
period and further stirred for 15 h at 18 °C. Eventually, the the addition of BF3·Et2O (40.6 μL, 0.32 mmol, 2.0 equiv.). After
reaction mixture was directly concentrated under reduced 10 s, the reaction mixture was quenched by saturated aqueous
pressure. The resulting crude residue was purified by flash Na2SO3 (10 mL) and extracted with CH2Cl2 (30 mL). The
column
chromatography
(petroleum
ether–EtOAc
=
organic layers were washed with saturated aqueous NaHCO3
30 : 1→10 : 1) on neutral Al2O3 to afford the desired 21 (1.20 g, (10 mL), water (10 mL) and brine (10 mL), then dried over
73% yield) as a colorless oil. Rf = 0.38 (petroleum ether–EtOAc Na2SO4, filtered and concentrated under reduced pressure.
= 6 : 1); IR (film): νmax = 2972, 2919, 2869, 1585, 1500, 1455, The resulting crude residue was purified by flash column
1413, 1374, 1235, 1124, 734, 695 cm−1 1H NMR (400 MHz, chromatography (P petroleum ether–EtOAc = 2 : 1) on silica gel
;
CDCl3): δ = 7.48–7.45 (m, 4H), 7.34–7.26 (m, 6H), 6.58 (s, 2H), to afford the desired 23 (75 mg, 80% yield) as a colorless oil.
6.56 (dd, J = 17.4, 10.4 Hz, 1H), 6.55 (s, 2H), 5.37 (dd, J = 10.4, Rf = 0.31 (petroleum ether–EtOAc = 2 : 1); IR (film): νmax
1.6 Hz, 1H), 5.06 (s, 2H), 5.03 (s, 2H), 5.02 (dd, J = 17.2, 1.6 Hz, 2936, 2840, 1785, 1590, 1505, 1458, 1416, 1333, 1243, 1182,
=
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1
1129, 979, 930, 735, 699 cm−1; H NMR (400 MHz, CDCl3): δ = 5 minutes, the reaction was quenched by saturated aqueous
7.46 (t, J = 8.0 Hz, 4H), 7.35–7.27 (m, 6H), 6.70 (s, 2H), 6.45 (s, NaHCO3 (5 mL) and the aqueous layer was extracted with
2H), 5.02 (s, 2H), 5.00 (s, 2H), 3.82 (s, 6H), 3.75 (s, 6H), CH2Cl2 (3 × 10 mL). The combined organic layers were washed
3.35–3.26 (m, 1H), 2.74 (dd, J = 17.2, 7.6 Hz, 1H), 2.33 (dd, J = with water (5 mL) and brine (5 mL) respectively, dried over
17.2, 4.0 Hz, 1H), 0.89 (d, J = 6.8 Hz, 3H) ppm; 13C NMR Na2SO4, filtered and concentrated under reduced pressure.
(100 MHz, CDCl3): δ = 175.6, 153.4 (2C), 153.3 (2C), 138.2, The resulting crude residue was purified by flash column
137.63, 137.60, 137.0, 136.1, 136.0, 128.40 (2C), 128.37 (2C), chromatography (petroleum ether–EtOAc = 2 : 1) on silica gel
128.1 (2C), 128.1 (2C), 127.9, 127.8, 103.9 (2C), 103.0 (2C), to afford 19 mg (95% yield over 2 steps) of the desired 25 as a
92.3, 74.9, 74.8, 56.4 (2C), 56.2 (2C), 38.4, 37.7, 17.2 ppm; colorless oil. Rf = 0.75 (petroleum ether–EtOAc = 3 : 2); IR
+
HRMS (ESI): calcd for C35H37O8 [M + H]+: 585.2483, found: (film): νmax = 2956, 2924, 2853, 1586, 1500, 1455, 1410, 1328,
1
585.2496.
1235, 1126, 1014, 732, 696 cm−1; H NMR (400 MHz, CDCl3):
(trans)-5,5-Bis(4-(benzyloxy)-3,5-dimethoxyphenyl)-3,4-dimethyl- δ = 7.49 (d, J = 7.2 Hz, 2H), 7.45 (d, J = 6.8 Hz, 2H), 7.35–7.24
dihydrofuran-2(3H)-one (24). A 10 mL, round-bottom flask was (m, 6H), 6.66 (s, 2H), 6.37 (s, 2H), 5.03 (s, 2H), 4.99 (s, 2H),
charged with LiHMDS (1.0 M in THF, 1.2 mL, 1.2 mmol, 10.0 4.31 (t, J = 7.6 Hz, 1H), 3.80 (s, 6H), 3.71 (s, 6H), 3.48 (dd, J =
equiv.) under argon and the resulting solution was cooled to 10.0, 8.4 Hz, 1H), 2.42–2.34 (m, 1H), 2.08–1.96 (m, 1H), 1.02
−78 °C. To this precooled base, a solution of γ-lactone 23 (d, J = 6.4 Hz, 3H), 0.86 (d, J = 6.8 Hz, 3H) ppm; 13C NMR
(70 mg, 0.12 mmol) in THF (1.0 mL) was added dropwise via (100 MHz, CDCl3): δ = 153.0 (2C), 152.4 (2C), 142.5, 140.4, 137. 8
syringe and stirring was continued for 1.0 h at this tempera- (2C), 136.0, 135.4, 128.4 (4C), 128.1 (2C), 128.0 (2C), 127.73,
ture. Then resulting enolate was treated with MeOTf (40 μL, 127.67, 104.8 (2C), 104.5 (2C), 90.7, 74.9, 74.8, 73.8, 56.3 (2C),
0.36 mmol, 3.0 equiv.) at −78 °C, and the methylation reaction 56.0 (2C), 49.8, 40.7, 15.7, 14.5 ppm; HRMS (ESI): calcd for
was continued for 1.0 h at the same temperature then C36H41O7+ [M + H]+: 585.2847, found: 585.2857.
quenched by saturated aqueous NH4Cl (10 mL). The reaction
( )-Sacidumlignan D (4). Benzylated sacidumlignan D 25
mixture was allowed to warm to room temperature, diluted (60 mg, 0.107 mmol) was dissolved in a mixture of EtOAc–
with CH2Cl2 (30 mL) and poured into a separatory funnel. The MeOH (1 : 1, 8 mL) followed by the addition of 10 wt% Pd/C
combined organic layers were separated and washed with (568 mg, 0.54 mmol, 5.0 equiv.) at 25 °C. The whole system
water (2 × 5 mL) and brine (10 mL) respectively, dried over with three-way Teflon stopcock connected to a standard
Na2SO4, filtered and concentrated under reduced pressure. balloon was evacuated and backfilled with H2, and this proto-
The resulting crude residue was purified by flash column col was repeated three times. Then the heterogeneous mixture
chromatography (petroleum ether–EtOAc = 3 : 1) on silica gel was allowed to stir at 25 °C under a positive pressure of hydro-
to afford 65 mg (91% yield) of the desired 24 as a colorless oil. gen. After 0.5 h, the hydrogenation reaction finished, and the
Rf = 0.47 (petroleum ether–EtOAc = 2 : 1); IR (film): νmax
=
reaction mixture was filtered directly though Celite, washed
2926, 2855, 1773, 1589, 1503, 1456, 1414, 1332, 1243, 1128, with EtOAc (4 × 5 mL), and concentrated to afford the desired
1
995, 736, 698 cm−1; H NMR (400 MHz, CDCl3): δ = 7.48–7.43 ( )-sacidumlignan D (4) (43 mg, 100% yield) as a colorless
(m, 4H), 7.36–7.27 (m, 6H), 6.65 (s, 2H), 6.24 (s, 2H), 5.04 (s, crystal. Rf
=
0.40 (petroleum ether–EtOAc
=
1 : 1);
2H), 5.01 (s, 2H), 3.81 (s, 6H), 3.70 (s, 6H), 2.89–2.81 (m, 1H), Mp. 112–114 °C (EtOAc–n-Pentane = 1 : 20); IR (film): νmax
=
2.44–2.36 (m, 1H), 1.28 (d, J = 7.2 Hz, 3H), 1.05 (d, J = 6.4 Hz, 2956, 2930, 2872, 1611, 1514, 1455, 1418, 1326, 1214, 1114,
1
3H) ppm; 13C NMR (100 MHz, CDCl3): δ = 178.4, 153.3 (2C), 731 cm−1; H NMR (400 MHz, CDCl3): δ = 6.68 (s, 2H), 6.40 (s,
153.0 (2C), 138.4, 137.6 (2C), 137. 0, 136.3, 135.6, 128.41 (2C), 2H), 5.52 (s, 1H, –OH), 5.44 (s, 1H, –OH), 4.30 (t, J = 7.6 Hz,
128.38 (2C), 128.1 (2C), 128.0 (2C), 127.9, 127.8, 104.7 (2C), 1H), 3.87 (s, 6H), 3.80 (s, 6H), 3.46 (dd, J = 10.0, 8.0 Hz, 1H),
104.1 (2C), 90.6, 74.9, 74.8, 56.4 (2C), 56.2 (2C), 46.3, 41.1, 2.38 (dq, J = 10.4, 6.8 Hz, 1H), 2.05–1.95 (m, 1H), 1.02 (d, J =
16.2, 13.2 ppm; HRMS (ESI): calcd for C36H39O8 [M + H]+: 6.4 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H) ppm; H NMR (400 MHz,
+
1
599.2639, found: 599.2651.
CD3COCD3): δ = 7.16 (s, 1H, –OH), 7.05 (s, 1H, –OH), 6.78 (s,
2,2-Bis(4-(benzyloxy)-3,5-dimethoxyphenyl)-3,4-dimethyltetra- 2H), 6.53 (s, 2H), 4.26 (t, J = 7.6 Hz, 1H), 3.80 (s, 6H), 3.73 (s,
hydrofuran (25). To a stirred solution of γ-lactone 24 (20 mg, 6H), 3.34 (dd, J = 10.0, 8.0 Hz, 1H), 2.42 (dq, J = 10.0, 6.8 Hz,
0.033 mmol) in anhydrous THF (1 mL) at 0 °C was added 1H), 2.04–1.96 (m, 1H), 0.98 (d, J = 6.8 Hz, 3H), 0.86 (d, J = 6.8 Hz,
LiAlH4 (3 mg, 0.1 mmol, 3.0 equiv.). The reaction mixture was 3H) ppm; 13C NMR (100 MHz, CDCl3): δ = 146.5 (2C), 146.0
stirred for 0.5 h at this temperature and quenched carefully by (2C), 138.1, 136.2, 133.9, 133.3, 104.5 (2C), 104.2 (2C), 90.7,
saturated aqueous NH4Cl (5 mL). The resulting precipitate was 73.7, 56.5, 56.4, 56.2 (2C), 49.6, 40.6, 15.7, 14.5 ppm; 13C/DEPT
then filtered with a short plug of Celite (elution with 10 mL of NMR (100 MHz, CD3COCD3): δ = 148.2 (s, 2C), 147.8 (s, 2C),
CH2Cl2) and the filtrate was extracted with CH2Cl2 (3 × 15 mL). 139.2 (s), 136.9 (s), 136.0 (s), 135.6 (s), 106.2 (d, 2C), 105.8 (d,
The combined organic layers were washed with water (3 × 2C), 91.3 (s), 74.0 (t), 56.9 (q, 2C), 56.7 (q, 2C), 51.0 (d), 42.1
+
5 mL) and brine (5 mL) respectively, dried over Na2SO4, filtered (d), 16.8 (q), 15.2 (q) ppm; HRMS (ESI): calcd for C22H29O7
and concentrated under reduced pressure. The resulting crude [M + H]+: 405.1908, found: 405.1914.
diol could be used directly without further purification. To a
5,5′-(1-(2-Bromo-1-ethoxypropoxy)prop-2-ene-1,1-diyl) bis(2-
stirred solution of the above diol in CH2Cl2 (1 mL) at 0 °C was (benzyloxy)-1,3-dimethoxybenzene) (26). In a 50 mL, round-
added TFA (5 μL, 0.066 mmol, 2.0 equiv.) in one portion. After bottom flask, Br2 (0.24 mL, 4.8 mmol, 10 equiv.) was dissolved
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in dry CH2Cl2 (15 mL) and cooled to −78 °C. To the resulting 4.8 Hz, 1H), 5.03 (s, 2H), 4.98 (s, 2H), 3.79 (s, 6H), 3.72–3.65
solution was added ethyl propenyl ether (E : Z = 1.7 : 1, (m, 1H), 3.69 (s, 6H), 3.48–3.41 (m, 1H), 2.11 (sext, J = 6.8 Hz,
0.49 mL, 5 mmol, 10.5 equiv.) dropwise over a 10 min period, 1H), 2.02–1.92 (m, 1H), 1.03 (d, J = 6.8 Hz, 3H), 0.97 (t, J = 7.2
and the mixture was stirred for 20 min at −78 °C. This system Hz, 3H), 0.77 (d, J = 6.8 Hz, 3H) ppm; 13C NMR (100 MHz,
was transferred via cannula to another round bottom flask CDCl3): δ = 152.7 (2C), 152.5 (2C), 143.7, 139.8, 137.87, 137.84,
where the solution of allyl alcohol 20 (262 mg, 0.48 mmol) and 135.54, 135.51, 128.51 (2C), 128.45 (2C), 128.03 (2C), 127.99
N,N-dimethylaniline (1.2 mL, 9.6 mmol, 20 equiv.) in CH2Cl2 (2C), 127.70, 127.66, 105.8, 104.9 (2C), 104.2 (2C), 90.9, 74.9,
(5 mL) had been prepared. The resulting mixture was further 74.8, 62.3, 56.4, 56.23, 56.21, 56.0, 46.5, 44.6, 15.8, 14.9,
stirred for 0.5 h at −78 °C then 5 h at 25 °C. Eventually, the 11.3 ppm; HRMS (ESI): calcd for C38H48NO8 [M + NH4]+:
+
reaction mixture was carefully quenched by water and poured 646.3374, found: 646.3383.
into a separatory funnel. The organic layers were washed with
2-(Benzyloxy)-5-(4-(benzyloxy)-3,5-dimethoxyphenyl)-1,3-
aqueous HCl (1.0 M, 3 × 10 mL), water (10 mL) and brine dimethoxy-6,7-dimethylnaphthalene (28). To a stirred solu-
(10 mL), dried over Na2SO4, filtered and concentrated under tion of the diastereoisomeric mixture 27 (12 mg, 20 μmol) in
reduced pressure. The resulting crude residue was purified by CH2Cl2 (1 mL) was added p-TsOH·H2O (4 mg, 20 μmol, 1.0
flash column chromatography (petroleum ether–EtOAc
=
equiv.) at 25 °C. After 10 h, the reaction mixture was directly
10 : 1) on silica gel (basified with 1% Et3N) to afford the concentrated under reduced pressure, and the resulting crude
desired 26 (278 mg, 82% yield, d.r. = 1.7 : 1) as a colorless oil. residue was purified by flash column chromatography (pet-
Rf = 0.44 (petroleum ether–EtOAc = 4 : 1); IR (film): νmax
3087, 2935, 2867, 1653, 1582, 1501, 1457, 1413, 1371, 1333, 28 (7 mg, 65% yield) as a colorless solid. Rf = 0.67 (petroleum
1238, 1127, 1008, 916, 846, 736, 699 cm−1; (major isomer) 1H ether–EtOAc = 4 : 1); Mp. 122–123 °C (CH2Cl2); IR (film): νmax
NMR (400 MHz, CDCl3): δ = 7.49–7.44 (m, 4H), 7.34–7.24 (m, 3030, 2924, 2852, 1580, 1492, 1460, 1406, 1372, 1337, 1259,
6H), 6.60 (s, 2H), 6.59 (s, 2H), 6.53 (dd, J = 17.2, 10.8 Hz, 1H), 1237, 1126, 1091, 919, 732, 699 cm−1 1H NMR (400 MHz,
=
roleum ether–EtOAc = 6 : 1) on silica gel to afford the desired
=
;
5.37 (dd, J = 10.8, 1.2 Hz, 1H), 5.07 (dd, J = 17.2, 1.2 Hz, 1H), CDCl3): δ = 7.88 (s, 1H), 7.54 (d, J = 7.2 Hz, 4H), 7.39–7.29 (m,
5.06 (s, 2H), 5.04 (s, 2H), 4.49 (d, J = 4.0 Hz, 1H), 4.11–4.04 (m, 6H), 6.47 (s, 1H), 6.45 (s, 2H), 5.16 (s, 2H), 5.10 (s, 2H), 4.05 (s,
1H), 3.73 (s, 12H), 3.36–3.27 (m, 1H), 3.26–3.18 (m, 1H), 1.70 3H), 3.78 (s, 6H), 3.65 (s, 3H), 2.48 (s, 3H), 2.14 (s, 3H) ppm;
(d, J = 6.8 Hz, 3H), 1.03 (t, J = 7.2 Hz, 3H) ppm; 13C NMR 13C NMR (100 MHz, CDCl3): δ = 153.6 (2C), 152.1, 147.6, 139.2,
(100 MHz, CDCl3): δ = 152.8 (2C), 152.7 (2C), 140.7, 139.3, 137.9, 137.8, 137.3, 136.3, 135.3, 133.2, 133.0, 129.0, 128.6
138.3, 137.8, 137.7, 136.1 (2C), 128.5 (2C), 128.4 (2C), 128.0 (2C), 128.29 (2C), 128.25 (2C), 128.0 (2C), 127.9, 127.8, 122.7,
(4C), 127.77, 127.75, 118.2, 106.5 (2C), 106.1 (2C), 100.1, 85.2, 120.8, 107.1 (2C), 101.6, 75.4, 74.9, 61.6, 56.1 (2C), 55.6, 21.2,
74.83, 74.76, 63.8, 56.2 (4C), 50.3, 19.8, 15.0 ppm; HRMS (ESI): 17.6 ppm; HRMS (ESI): calcd for C36H36O6Na+ [M + Na]+:
m/z calcd for C38H43O879BrNa+ [M + Na]+: 729.2034, found: 587.2404, found: 587.2421.
729.2037.
Sacidumlignan A (1). Benzylated sacidumlignan A 28 (6 mg,
2,2-Bis(4-(benzyloxy)-3,5-dimethoxyphenyl)-5-ethoxy-3,4- 10 μmol) was dissolved in a mixture of EtOAc–MeOH (1 : 1,
dimethyltetrahydrofuran (27). In a 100 mL, two-necked, 3 mL) followed by the addition of 10 wt% Pd/C (53 mg,
round-bottom flask, α-bromo acetal 26 (378 mg, 0.55 mmol) 50 μmol, 5.0 equiv.) at 25 °C. The whole system with three-way
was dissolved in anhydrous toluene (50 mL) followed by the Teflon stopcock connected to a standard balloon was evacu-
addition of n-Bu3SnH (1.5 mL, 4.4 mmol, 8 equiv.) and AIBN ated and backfilled with H2, and this protocol was repeated
(269 mg, 1.65 mmol, 3 equiv.) under argon. The resulting three times. Then the heterogeneous mixture was allowed to
mixture was heated to 85 °C and stirred for 1 h. Then reaction stir at 25 °C under a positive pressure of hydrogen. After
mixture was cooled to room temperature and directly concen- 5 min, the hydrogenation reaction finished, and the reaction
trated under reduced pressure. The resulting crude residue mixture was filtered directly though Celite, washed with EtOAc
was dissolved in Et2O (5 mL) and added saturated aqueous (4 × 5 mL), and concentrated to afford the desired sacidum-
KF·2H2O (5 mL). The mixture was stirred for 1 h and the lignan A (1) (4 mg, 100% yield) as a colorless crystal. Rf = 0.50
n-Bu3SnF precipitate was filtered. The filtrate was extracted (petroleum ether–EtOAc = 1 : 1); Mp. 149.2–149.5 °C (acetone);
with Et2O (2 × 20 mL), and the combined organic layers were IR (film): νmax = 3402, 2935, 2850, 1718, 1673, 1608, 1516,
washed with brine (5 mL), dried over Na2SO4, filtered and con- 1457, 1415, 1341, 1212, 1114, 914, 735, 702 cm−1 1H NMR
;
centrated under reduced pressure. The resulting crude residue (400 MHz, CD3COCD3): δ = 7.76 (s, 1H), 7.67 (s, 1H, –OH), 7.26
was purified by flash column chromatography (petroleum (s, 1H, –OH), 6.58 (s, 1H), 6.49 (s, 2H), 3.97 (s, 3H), 3.84 (s,
ether→petroleum ether–EtOAc = 6 : 1) on silica gel to afford 6H), 3.67 (s, 3H), 2.45 (s, 3H), 2.11 (s, 3H) ppm; 13C NMR
the mixture 27 of four inconsequential diastereoisomers (100 MHz, CD3COCD3): δ = 149.2, 149.0 (2C), 140.8, 138.8,
(309 mg, 90% yield) as a colorless oil among which the less 138.2, 135.9, 133.8, 132.0, 131.9, 127.6, 124.1, 120.6, 108.5
polar component containing two diastereoisomers was isolated (2C), 102.0, 60.8, 56.9 (2C), 56.1, 21.5, 17.7 ppm; HRMS (ESI):
and characterized. IR (film): νmax = 2958, 2925, 2855, 1658, calcd for C22H25O6+ [M + H]+: 385.1646, found: 385.1649.
1589, 1501, 1459, 1412, 1376, 1261, 1100, 1024, 800, 697 cm−1
;
Conversion of ( )-sacidumlignan D (4) to sacidumlignan A
(major isomer) 1H NMR (400 MHz, CDCl3): δ = 7.51–7.43 (m, (1). To a stirred solution of ( )-sacidumlignan D (4) (12 mg,
4H), 7.36–7.24 (m, 6H), 6.68 (s, 2H), 6.34 (s, 2H), 5.22 (d, J = 30 μmol) in ClCH2CH2Cl (1 mL) was added p-TsOH·H2O
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(28 mg, 0.15 mol, 5.0 equiv.) at room temperature. After stir-
ring for 32 h at 50 °C, the reaction mixture was cooled to room
temperature and quenched by saturated aqueous NaHCO3
(2 mL) and extracted with CH2Cl2 (3 × 10 mL). The organic
layers were washed with water (5 mL) and brine (5 mL), then
dried over Na2SO4, filtered and concentrated under reduced
pressure. The resulting crude residue was purified by flash
column chromatography (petroleum ether–EtOAc = 6 : 1) on
silica gel to afford the desired sacidumlignan A (1) (5 mg, 44%
yield) as a colorless solid and recover 4 mg (33%) of ( )-saci-
dumlignan D (4).
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Acknowledgements
This work was supported by NSFC (Nos. 20802029 and
21172096) and the Scientific Research Foundation for the
Returned Overseas Chinese Scholars, the Fundamental
Research Funds for the Central Universities (lzujbky-2012-57),
Program for Changjiang Scholars and Innovative Research
Team in University (PCSIRT: IRT1138) and the “111” Project of
MoE. We are also grateful to Prof. Jian-Min Yue and Prof.
Sheng-Ping Yang (Institute of Materia Medica, Chinese
7 (a) M. Inoue, T. Sato and M. Hirama, Angew. Chem., Int.
Ed., 2006, 45, 4843–4848; (b) J. T. Njardarson,
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Academy of Science) for helpful discussions about the spectra 10 CCDC-912716 (9), CCDC-912718 (4), and CCDC-912717 (1)
of sacidumlignan D.
contain the supplementary crystallographic data for this
paper.
11 See the ESI† for more details.
12 (a) Y. Fukuyama, K. Harada, T. Esumi, D. Hojyo, Y. Kujime,
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J. Am. Chem. Soc., 1983, 105, 3741–3742; for reviews, see: 13 The low yield (8%) of the product with naphthalene skele-
(c) G. Stork, Bull. Chem. Soc. Jpn., 1988, 61, 149–154;
(d) G. Stork, Bull. Soc. Chim. Fr., 1990, 127, 675–680; this
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ton was reported, see: J. M. Barbosa-Filho, M. S. Da Silva,
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18 Personal communication with Prof. Jian-Min Yue and Prof.
reported data in the text is 106.2 ppm that may be a
mistake resulting from typewriting.
Sheng-Ping Yang (one of the co-workers). They told us that
1
3.33 ppm should be correct according to their original H 20 Adapted from similar procedure: A. V. Joshua, S. K. Sharma
NMR spectrum, and their reported data (3.20 ppm) may be
a mistake resulting from typewriting.
and D. N. Abrams, Synth. Commun., 2008, 38, 434–440.
21 Adapted from known procedure: M. E. Jung, P. Y.-S. Lam,
M. M. Mansuri and L. M. Speltz, J. Org. Chem., 1985, 50,
1087–1105.
19 In Ramana’s 13C NMR spectrum for sacidumlignan A in
the ESI,† a peak at 108.2 ppm appeared, while their
This journal is © The Royal Society of Chemistry 2013
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