General approach to neolignan-core of the boehmenan natural product family

Article abstract of DOI:10.1007/s00706-017-2132-4

Abstract: A novel approach to the neolignan-core skeletons of boehmenan natural products and to dehydrodiconiferyl alcohol glucosides based on the Fe(III)-promoted oxidative coupling has been achieved. Obtained common intermediates were further selectively modified to yield the basic molecular core possessing three orthogonally protected alkoxy functionalities available for further selective modifications. Graphical abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s00706-017-2132-4

Monatsh Chem
https://doi.org/10.1007/s00706-017-2132-4
ORIGINAL PAPER
General approach to neolignan-core of the boehmenan natural
product family
1
Zuzana Barbuscakova Hana Kozubıkova Frantisek Zalesak Karel Dolezal
1
2
1,3
•
•
•
•
ˇˇ´
1,2,3
´
´
´
ˇ
´ ˇ´
ˇ
ˇ´
Jirı Pospısil
´ˇ
Received: 3 December 2017 / Accepted: 10 December 2017
Ó Springer-Verlag GmbH Austria, part of Springer Nature 2017
Abstract A novel approach to the neolignan-core skele-
tons of boehmenan natural products and to
dehydrodiconiferyl alcohol glucosides based on the Fe(III)-
promoted oxidative coupling has been achieved. Obtained
common intermediates were further selectively modified to
yield the basic molecular core possessing three orthogo-
nally protected alkoxy functionalities available for further
selective modifications.
Introduction
Neolignans belong to the phenylpropanoid-derived family
of plant secondary metabolites that are obtained via the
Shikimate biosynthetic pathway [1]. Phenylpropanoids, the
direct secondary metabolites obtained from the Shikimate
pathway, are further modified within plant cells to furnish
structurally diverse biologically active natural products. In
nature, basic phenylpropanoids are further dimerized or
polymerized with the help of peroxidases, laccases, and
enzyme-promoted phenol oxidative coupling [2, 3], fur-
nishing various classes of natural products [4] (lignins,
lignans, neolignans, etc.).
Graphical abstract
Our interest is to understand the oxidation processes
[2, 3] related to the phenolic plant secondary metabolites
on a molecular level and relate their effects on human
health. Thus, we are focused on the investigation of plant
produced phenolic compounds and their oxidative coupling
products [5]. Unfortunately, the plant metabolome contains
virtually thousands of various phenylpropanoid-related
compounds. As a consequence, identification of com-
pounds of interest is challenging. To face such problems,
we have focused our synthetic efforts on the development
of synthetic strategies that allows us to yield the majority of
phenylpropanoid-based phytochemicals in a short end
efficient manner.
Keywords Biomimetic synthesis Á Natural products Á
Enzymes Á Oxidative coupling
ˇ´
´ˇ
j.pospisil@upol.cz
& Jirı Pospısil
1
Department of Chemical Biology and Genetics, Centre of the
The first step in this quest was establishing a short and
efficient way to phenylpropanoid monomers and struc-
turally related coumarins [6]. Next, we focused our
attention to phenylpropanoid C-8, C-5 homocoupling
products—8-50-neolignans 2—and their functional group
derivatives containing the 2,3-dihydrobenzofuran motive 3
(Scheme 1).
´
Region Hana for Biotechnological and Agricultural Research,
Faculty of Science, Palacky University, Slechtitelu 27,
ˇ
´
˚
783 71 Olomouc, Czech Republic
2
3
Department of Organic Chemistry, Faculty of Science,
ˇ
Palacky University, tr. 17. listopadu 1192/12, 771 46
Olomouc, Czech Republic
´
Laboratory of Growth Regulators, Palacky University and
Institute of Experimental Botany AS CR, Slechtitelu 27,
In the literature, the synthesis of benzofurans is widely
covered [7, 8] and many different approaches to
ˇ
˚
783 71 Olomouc, Czech Republic
123

ˇˇ´ ´
Z. Barbuscakova et al.
Scheme 1
benzofuran-core structures have been developed. Most of
these approaches are based either on the use of enzymes
(peroxidases, laccases) [9], biomimicking radical homo-
couplings [10], or on the use of transition metal-mediated
coupling reactions [11]. In our case, we wished to adopt a
short, efficient and easy to scale-up approach to benzofuran
skeletons included in boehmenan family natural products 4
and dehydrodiconiferyl glucose (DCG) derivatives 5
(Scheme 2). Our interest in these two targets arose from
their biological activity. Some time ago, it was suggested
that DCG 5 derivatives may act as cytokinins (phytohor-
mones) within the plant signaling pathways [12]. On the
other hand, boehmenans 5 were identified from extraction-
driven biological tests of various plant extracts used in
traditional Chinese medicine [13]. Based on the
preliminary studies, boehmenan-type structures 5 regulate
the Wnt/b-catenin signaling pathway important to treat,
e.g. ,non-small cell lung cancer [14]. From a synthesis view
point, DCG structure 4 [15] and boehmenan 5a [16] have
been already published. However, in our case, we wished
to develop a short and efficient approach that would allow
us to prepare not only targeted compounds but also their
structural analogues.
Results and discussion
We planned to approach the synthesis of dihydrobenzofu-
ran-core skeleton of 4 and 5 in a modular fashion where
both aromatic rings of the core scaffold could be possibly
Scheme 2
123

General approach to neolignan core of the boehmenan natural product family
modified prior to the dihydrofuran-ring assembly. Such
Having an access to the desired starting materials, the
approach, thus, excluded all homodimerization methods
commonly based on the transition metal-promoted oxida-
tive coupling reactions (e.g., starting from methyl ferulate
and catalyzed by FeIII [17] or AgI [18] salts). On the other
hand, oxidative coupling reactions allow rapid, short and
very convenient assembly of the targeted benzofuran
molecular core of the neolignan natural products. Thus, we
decided to base our approach on iron(III)-catalyzed
oxidative coupling of b-ketoester 7 and phenol 6 [19, 20]
followed by Mg-promoted trans reduction of the formed
benzofurane adduct 8 [21] (Scheme 3).
FeIII-promoted oxidative coupling could then be attempted
(Table 2). Upon screening of various reported oxidative
coupling conditions [19, 20], we were delighted to observe
the formation of the desired benzofuran 8a albeit in mod-
erate yield (Table 2, entry 3). Subsequent trans selective
reduction [21] of the furan core 8a to the dihydrofuran
skeleton yielded the desired neolignan 9a in 59% yield
(Scheme 5).
Alternatively, we decided to prepare the same product
9a via a homodimerization process. Thus, methyl fumarate
6a was reacted under various literature protocols to yield
the desired product 13 (Table 3). Both enzymatic as well as
transition metal-catalyzed homocoupling conditions were
attempted, and the desired product 13 was obtained in the
best case in 28% yield and 91:9 trans/cis selectivity
(Table 3, entry 2). The corresponding MOM-protected
neolignan derivative 9a was then prepared in 89% yield
using the standard protecting group protocol (Scheme 6).
Finally having acquired the substantial amount of
neolignan core 9a, we could start the second aim of our
project—selective modification of the ester groups. First,
global DIBAL-H reduction of both methyl esters in 9a to
the corresponding alcohols was attempted. The reduction
proceeded well and no product of undesired unsaturated
olefin reduction was observed. Desired diol 14 was then per
acetylated and the MOM-protected phenolic group was
removed to yield DCG 4 core neolignan structure 16 in 3
steps (from intermediate 9a) in 59% yield.
The synthesis of targeted neolignans 4 and 5 core
structure started with the preparation of the coupling
partners methyl ferulate 6a and b-ketoester 7a (Scheme 4).
In the case of ester 6a, our recently developed microwave-
assisted synthetic protocol was applied and the desired
compound was prepared in 98% yield and [ 95:1 E/Z
selectivity starting from vanillin 10 [6]. b-Ketoester 7a was
prepared from vanillin (10) in three steps consisting of
phenolic group MOM protection, followed by Fe-promoted
Reformatsky-type condensation [22], and finished with
PCC oxidation of b-hydroxy group. The desired product 7a
was prepared in 18% overall yield.
The Reformatsky reaction—transformation of aldehyde
11 to hydroxyester 12 in this sequence— is worth of
mentioning. Surprisingly, we found that the FeIII modifi-
cation of the Reformatsky protocol gave in our hands
superior yields over the ‘‘classical’’ Zn-promoted protocols
(Table 1). Although, even in this case, the desired product
12 was formed in rather low yield of 25%. We speculate
that the presence of electron-rich aromatic aldehyde might
be a reason for the observed low yields.
Next, selective monoreduction of the dihydrofuran ring-
attached methyl ester group was attempted (Table 4). In
our synthetic plans, it was important to distinguish both
ester groups (respectively, generated primary alcohols) to
Scheme 3
123

ˇˇ´ ´
Z. Barbuscakova et al.
Scheme 4
Table 1 Reformatsky reaction between aldehyde 11 and methyl a-bromo acetate—reaction conditions optimization
Entry
Conditions
11a/%
12a/%
1
Zn (10 equiv), BrCH2CO2Me (5 equiv), toluene, 90 °C
Zn (10 equiv), BrCH2CO2Me (5 equiv), THF, 60 °C
Zn (10 equiv), BrCH2CO2Me (5 equiv), THF, 60 °C
FeCl3 (3 equiv), Mg (10 equiv), BrCH2CO2Me (2 equiv), THF, 60 °C
FeCl3 (3 equiv), Mg (10 equiv), BrCH2CO2Me (2 equiv), THF, RT
65
81
43
73
29
4
6
2
3b
2
4
5
5
25
aRefers to pure isolated compounds
bBrCH2CO2Me was slowly added as a THF solution
be able to later on selectively introduce various ester
functionalities or other substituents to prepare all possible
members of the boehmenan family (Scheme 1). First, the
reduction of MOM-protected diester 9b was attempted.
Unfortunately, the desired alcohol product 18 was not
obtained under any evaluated reaction conditions (Table 4,
entries 1–8). In all cases, nonselective reduction of both
ester functionalities and/or complex mixture of partially
reduced products were/was obtained. It was speculated that
the reason for this reaction mixture behaving this way is
due to the stabilization of the mono-reduced DHF-ring
placed ester functionality.
It was speculated that the presence of the MOM-pro-
tecting group might stabilize the monoreduced
intermediate 20 (Scheme 7). To disrupt generated inter-
mediate 20, the reaction mixture must be warmed up and
the competitive reduction of a,b-unsaturated ester group in
the side chain occurs. To test our hypothesis, the phenol
functionality in neolignan 13 was protected in the form of
TBS ether and the reduction of the resulting TBS –
123

General approach to neolignan core of the boehmenan natural product family
Table 2 Screening of oxidative radical coupling reaction conditions
Entry
Conditions
Yielda/%
1
2
3
4
5
6
FeCl3 (10 mol%), 2,20-dipyridine (5 mol%), DTBP (2.5 equiv), DCE, 70 °C
FeCl3 (10 mol%), 2,20-dipyridine (10 mol%), DTBP (2.5 equiv), DCE, 70 °C
FeCl3 (10 mol%), NHPI (5 mol%), DTBP (2.5 equiv), DCE, 70 °C
FeCl3 (10 mol%), NHPI (10 mol%), DTBP (2.5 equiv), DCE, 70 °C
FeCl3 (10 mol%), DTBP (2.5 equiv), DCE, 70 °C
23
11
36
12
5
FeCl3 (10 mol%), atmospheric air, DCE, 70 °C
14
DTBP diterbutylperoxide, NHPI N-hydroxyphthalimide
aRefer to pure isolated compound
Scheme 5
Table 3 Benzofuran 9a synthesis: oxidative homocoupling reaction
Entry
Conditions
Yielda/%
trans/cisb
1
2
3
4
5
6
7
K3[Fe(CN)6] (2.1 equiv), CH2Cl2/CHCl3 = 1:9 (V/V), RT
Ag2O (2.1 equiv), acetone/benzene = 3:1, RT
22
28
7
82:18
91:9
Ag2O (2.1 equiv), CH2Cl2, RT
89:11
92:8
Ag2O (2.1 equiv), CH2Cl2/H2O = 1:1 (v/v), RT
13
7
HRPc, 1 M aq. H2O2 (10 equiv), phosphate buffer pH = 7.3
HRPc, 1 M aq. H2O2 (10 equiv), phosphate buffer pH = 4.5
HRPc, 1 M aq. H2O2 (10 equiv), phosphate buffer pH = 7.3 (dark)
81:19
71:29
89:11
11
10
aRefer to pure isolated compound
1
bBased on the H NMR analysis
c25KU HRP used (1 mg per 1 mmol of 6a)
123

ˇˇ´ ´
Z. Barbuscakova et al.
Scheme 6
neolignan 17 was attempted. Gratifyingly, the desired
alcohol 18b was prepared selectively with use of LiBH4 in
82% (Table 4, entry 12). No product of the second ester
reduction was observed during the reaction.
and methyl ester group (transformed to the corresponding
alcohol with TMSOK hydrolysis followed by a BH3-re-
duction system).
Finally, selective hydrogenation of a,b-unsaturated
olefin function in 18b yielded the key intermediate 19. The
switch in the protecting group, thus, allowed us to achieve
the synthesis of the boehmenan-core skeleton 19 that
possesses three key oxygenated functional groups with
orthogonal protecting groups—free hydroxy, TBS-pro-
tected phenol (to be removed with TBAF/AcOH system),
Conclusion
We have developed a novel approach to the core skeleton
of boehmenan (5) and DCG (4) natural products. Our
approach allows the preparation of such neolignan-type
skeletons via an oxidative coupling reaction. However, in
123

General approach to neolignan core of the boehmenan natural product family
Table 4 Selective reduction of diester 9a or 17 to alcohol 18
Entry
PG
Conditions
Yielda/%
1
MOM
MOM
MOM
MOM
MOM
MOM
MOM
MOM
TBS
DIBAL-H (2.1 equiv), CH2Cl2, - 78 °C
DIBAL-H (2.1 equiv), CH2Cl2, - 50 °C
DIBAL-H (2.1 equiv), toluene, - 35 °C
DIBAL-H (2.1 equiv), toluene, 0 °C
DIBAL-H (2.1 equiv), THF, - 78 °C
DIBAL-H (2.1 equiv), THF, - 20 °C
LiBH4 (2.1 equiv), THF, - 78 °C
LiBH4 (2.1 equiv), THF, - 40 °C
DIBAL-H (2.1 equiv), THF, - 78 °C
DIBAL-H (2.1 equiv), THF, - 40 °C
LiBH4 (2.1 equiv), THF, - 78 °C
LiBH4 (3.0 equiv), THF, - 78 °C
No reaction
n.d.b
2
3
No reaction
n.d.
4
5
No reaction
n.d.b
6
7
No reaction
n.d.b
8
9c
10
11d
12
23%
n.d.b
TBS
TBS
57%
TBS
82%
aRefer to pure isolated compound
bComplex mixture
cReaction mixture also contained unreacted diester 17 (54%)
dIncomplete conversion of 17
Scheme 7
123

ˇˇ´ ´
Z. Barbuscakova et al.
comparison with the literature, our approach is versatile
allowing the synthesis of products possessing a variety of
substitution patterns on the presented aromatic rings. For
the time being our approach suffers from the low yielding
coupling step. We believe that systematic evaluation of the
aromatic substitution influence of the phenolic coupling
partner on the reactivity of the system will allow us to carry
out the coupling reaction with better yields. On the other
hand, our approach allows the preparation of the desired
dihydrobenzofuran skeleton with superior trans/cis selec-
tivity than that of any of the tested literature homocoupling
reaction conditions could provide.
coupling constants (J) are reported in Hz. HRMS data were
obtained using quadrupole/ion trap mass analyzer. Analysis
and assignments were made by comparison with literature
spectroscopic data or using 2D-COSY, HSQC, HMBC,
2D-NOESY, and NOEdiff experiments.
All microwave irradiation experiments were carried out in
a dedicated CEM-Discover mono-mode microwave appa-
ratus. The reactor was used in the standard configuration as
delivered, including proprietary software. The reactions
were carried out in 30 cm3 glass vials sealed with a Silicone/
PTFE Vial caps top, which can be exposed to a maximum of
250 °C and 20 bar internal pressure. The temperature was
measured with an IR sensor on the outer surface of the pro-
cess vial. After the irradiation period, the reaction vessel was
cooled to ambient temperature by gas jet cooling.
At this time, we are developing a new set of conditions
that will hopefully allow the desired oxidative coupling
reaction to occur in greater yields. The Mg-promoted
selective trans reduction followed by the resulting
stereoisomer separation should allow us to prepare targeted
natural products as single enantiomers and to establish the
absolute stereochemistry of the isolated boehmenan natural
products.
Methyl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate (6a)
A suspension of 0.76 g of vanillin 10 (5.00 mmol) and
1.84 g of stabilized Wittig ylide (5.5 mmol) in 5.0 cm3 of
toluene was placed in a microwave vial (35 cm3) equipped
with a magnetic stirring bar. The vial was sealed with a
Silicone/PTFE Vial cap and placed in a CEM Discover
reactor. The resulting mixture was then irradiated (300 W)
for 10 min (fixed time) at 150 °C. The reaction mixture
was allowed to cool down, transferred to a round-bottom
flask and the toluene was removed under vacuum. The
residue was purified by column chromatography (SiO2;
petroleum ether:EtOAc = 4:1–[ 2:1) yielded 1.02 g of
resulting ester 6a (98%) in [ 95:1 E/Z ratio. M.p.:
64–65 °C (Ref. [6], 63–65 °C); 1H NMR (500 MHz,
CDCl3): d = 7.60 (d, J = 16.0 Hz, 1H), 7.03 (ddd,
J = 16.2, 7.9, 1.9 Hz, 2H), 6.90 (d, J = 8.2 Hz, 1H),
6.27 (d, J = 15.9 Hz, 1H), 6.15–5.98 (m, 1H), 3.89 (s, 3H),
3.78 (s, 3H) ppm; 13C NMR (126 MHz, CDCl3):
d = 167.92, 148.10, 146.89, 145.11, 126.98, 123.13,
115.15, 114.87, 109.48, 56.00, 51.74 ppm; MS (ESI):
m/z = 209 ([M?H]?); HRMS (ESI): m/z calculated (for
C11H13O4?) 209.0814, found 209.0815.
Experimental
All reactions were performed in round-bottom flasks fitted
with rubber septa using the standard laboratory techniques.
Reactions sensitive to air and/or moisture were performed
under a positive pressure of argon. Analytical thin-layer
chromatography (TLC) was performed using aluminum
plates pre-coated with silica gel (silica gel 60 F254, Mer-
ck). TLC plates were visualized by exposure to ultraviolet
light and then were stained by submersion in basic potas-
sium
permanganate
solution
or
in
ethanolic
phosphomolybdic acid solution followed by brief heating.
Flash-column chromatography was carried out on silica gel
˚
(60 A, 230–400 mesh, Sigma-Aldrich) using Petroleum
ether/EtOAc solvent mixtures.
All reagents and enzymes were obtained from com-
mercial suppliers (Sigma-Aldrich or Acros Organics) and
were used without further purification. Dry solvents were
obtained using standard drying protocols: THF was dis-
tilled under argon from sodium benzophenone ketyl;
CH2Cl2 was distilled from CaH2.
3-Methoxy-4-(methoxymethoxy)benzaldehyde (11)
A solution of 10.0 g of vanillin (10, 65.7 mmol) in 66 cm3
CH2Cl2 was cooled to 0 °C and 18.3 cm3 of iPr2EtN
(105 mmol) was added. After 5 min, 40.7 cm3 of MOM-Cl
in toluene (85.4 mmol, 2.1 M solution in toluene) was
added dropwise and the resulting mixture was stirred at RT
for 24 h. Saturated aq. NH4Cl (50 cm3) was added and the
resulting layers were separated. Aqueous layer was
extracted with CH2Cl2 (3 9 50 cm3) and combined
organic layers were washed with 50 cm3 brine, dried over
Na2SO4, and evaporated under reduced pressure. The
residue was purified by column chromatography (SiO2;
petroleum ether:EtOAc = 4:1–[ 2:1) yielded 12.5 g of 11
Nuclear magnetic resonance spectra were recorded
using Bruker Avance II 300, JEOL 400ECS or JEOL
500ECA instruments at 25 °C. 1H NMR and 13C NMR
spectra were recorded in CDCl3. Chemical shifts (d/ppm)
1H NMR are reported in a standard fashion relative to the
remaining CHCl3 present in CDCl3 (dH = 7.27 ppm). 13C
NMR chemical shifts (d/ppm) are reported relative to
CHCl3 (dC = 77.23 ppm, central line of triplet). Proton
coupling patterns are represented as singlet (s), doublet (d),
doublet of doublet (dd), triplet (t), and multiplet (m), and
1
(85%). M.p.: 40–41 °C (Ref. [23], 39–40 °C); H NMR
(500 MHz, CDCl3): d = 3.53 (s, 3H), 3.95 (s, 3H), 5.33 (s,
123

General approach to neolignan core of the boehmenan natural product family
2H), 7.15–7.19 (m, 1H), 7.28 (dd, J = 7.7, 1.0 Hz, 1H),
7.44 (d, J = 1.1 Hz, 1H), 9.87 (s, 1H) ppm; 13C NMR
(126 MHz, CDCl3): d = 56.2, 56.7, 95.2, 109.7, 114.8,
126.6, 131.2, 150.2, 152.2, 191.2 ppm; MS (ESI):
m/z = 197 ([M?H]?); HRMS (ESI): m/z calculated (for
C10H13O4?) 197.0808, found 197.0808.
150.4, 151.7, 170.8, 193.8 ppm; MS (ESI): m/z = 269
([M?H]?); HRMS (ESI): m/z calculated (for C13H17O6
?
)
269.1020, found 269.1021.
Methyl (E)-7-methoxy-5-(3-methoxy-3-oxoprop-1-en-1-yl)-
2-[3-methoxy-4-(methoxymethoxy)phenyl]benzofuran-3-
carboxylate (8a, C24H24O9)
Methyl
3-hydroxy-3-[3-methoxy-4-(methoxymethoxy)-
A solution of 0.366 g di-tert-butyl peroxide (2.5 mmol) in
1.0 cm3 of 1,2-dichloroethane was added drop-wise into a
stirred solution of 0.268 g of 7a (1.0 mmol), 0.229 g of
phenol 6a (1.1 mmol), 0.09 g N-hydroxyphthalimide
(0.05 mmol), and 0.16 g FeCl3 (0.1 mmol) in 2 cm3 of
1,2-dichloroethane under an argon atmosphere at room
temperature. The reaction mixture was heated at 70 °C
(external) for 24 h. The solvent was removed under
reduced pressure and the residue was purified by column
chromatography (SiO2; petroleum ether:EtOAc = 4:1–
[ 2:1–[ 1:1) and yielded 0.164 g of benzofuran 8a
phenyl]propanoate (12, C13H18O6)
A mixture of 1.0 g 11 (5.1 mmol), 0.96 cm3 of methyl
bromoacetate (10.2 mmol), and 2.48 g of FeCl3
(15.3 mmol) in 51 cm3 of dry THF was stirred at RT and
372 mg of Mg (124 mmol, fine powder) was added at once.
The resulting mixture was stirred at RT for 24 h before it
was diluted with 35 cm3 H2O and 65 cm3 EtOAc. The
resulting suspension was stirred for additional 15 min
before it was filtered through CeliteÒ. The whole mixture
was diluted with 20 cm3 2% HCl and the layers were
separated. The aqueous layer was extracted with EtOAc
(3 9 25 cm3). Combined organic layers were washed with
25 cm3 water and 25 cm3 brine, dried over Na2SO4,
evaporated under reduced pressure. The residue was
purified by column chromatography (SiO2; petroleum
ether:EtOAc = 4:1– [ 2:1– [ 1:1) yielding 0.345 g of
resulting hydroxy ester 12 (25%). 1H NMR (500 MHz,
CDCl3): d = 2.71 (dd, J = 16.4, 3.6 Hz, 1H), 2.78 (dd,
J = 16.3, 9.3 Hz, 1H), 3.52 (s, 3H), 3.74 (s, 3H), 3.90 (s,
3H), 5.10 (dd, J = 9.2, 3.6 Hz, 1H), 5.22 (s, 2H), 5.64
(broad s, 1H), 6.88 (d, J = 8.3 Hz, 1H), 6.98 (d,
J = 2.0 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H) ppm; 13C
NMR (126 MHz, CDCl3): d = 43.4, 52.2, 56.1, 56.4, 70.3,
95.7, 109.4, 116.5, 137.1, 146.2, 150.1, 173.1 ppm; MS
(ESI): m/z = 271 ([M?H]?); HRMS (ESI): m/z calculated
(for C13H19O6?) 271.1176, found 271.1179.
1
(36%). M.p.: 168–169 °C; H NMR (400 MHz, CDCl3):
d = 3.50 (s, 3H), 3.94 (s, 3 H), 3.96 (s, 3 H), 4.02 (s, 3 H),
4.04 (s, 3H), 5.06 (s, 2 H), 6.41 (d, J = 15.9 Hz, 1H), 6.95
(d, J = 8.4 Hz, 1H), 7.23 (d, J = 2.1 Hz, 1H), 7.44 (dd,
J = 8.4, 1.6 Hz, 1H), 7.56 (d, J = 1.7 Hz, 1H), 7.76 (d,
J = 15.8 Hz, 1H), 7.80 (s, 1 H) ppm; 13C NMR
(100.1 MHz, CDCl3): d = 51.2, 52.4, 54.2, 56.4, 58.9,
92.7, 110.0, 111.5, 111.6, 114.5, 115.6, 116.2, 121.2,
122.9, 128.1, 131.2, 143.3, 146.4, 146.6, 148.9, 149.9,
160.4, 167.5, 167.9 ppm; MS (ESI): m/z = 457 ([M?H]?);
HRMS (ESI): m/z calculated (for C24H25O9?) 457.1493,
found 457.1490.
Methyl (2R,3R)-7-methoxy-5-((E)-3-methoxy-3-oxoprop-1-
en-1-yl)-2-[3-methoxy-4-(methoxymethoxy)phenyl]-2,3-di-
hydrobenzofuran-3-carboxylate (9a, C24H26O9)
Magnesium powder (0.08 g, 3.3 mmol) followed by
0.012 g of NH4Cl (0.22 mmol) were added to a solution
of 0.05 g of 8a (0.11 mmol) in 4 cm3 of THF/MeOH [1:1
(v/v)] mixture cooled to - 10 °C. The resulting mixture
was vigorously stirred and then slowly allowed warm to
RT over 4 h. The reaction was cooled to - 40 °C before
being quenched by the addition of 20 cm3 of saturated
aqueous NH4Cl. The mixture was allowed to warm to RT
before being partitioned between 20 cm3 of H2O and
20 cm3 of CH2Cl2. Resulting layers were separated and the
aqueous layer was extracted with CH2Cl2 (2 9 20 cm3).
The combined organic phases were dried over Na2SO4, and
evaporated under reduced pressure. The residue was
purified by column chromatography (SiO2; petroleum
ether:EtOAc = 4:1–[ 2:1–[ 1:1) and yielded 0.060 g of
dihydrobenzofuran 9a (59%, trans/cis = [ 95:1). 1H NMR
(500 MHz, CDCl3): d = 3.50 (s, 3H), 3.81 (s, 3H), 3.84 (s,
3H), 3.87 (s, 3H), 3.93 (s, 3H), 4.35 (d, J = 8.1 Hz, 1H),
5.22 (s, 2H), 6.14 (d, J = 8.1 Hz, 1H), 6.33 (d,
J = 15.9 Hz, 1H), 6.92 (dd, J = 12.0, 2.5 Hz, 1H), 6.95
Methyl 3-[3-methoxy-4-(methoxymethoxy)phenyl]-3-oxo-
propanoate (7a, C13H16O6)
A solution of 0.11 g of 12 (0.4 mmol) in 4 cm3 of dry
CH2Cl2 was stirred at RT and 0.176 g of PCC (pyridinium
chlorochromate, 0.8 mmol) was added. The resulting
mixture was stirred at RT for 12 h before 0.3 g of
CeliteÒ was added in one portion. The whole mixture
was stirred at RT for additional 10 min. The whole mixture
was filtered through a plug of 2 g of CeliteÒ. Filter cake
was washed with CH2Cl2 (3 9 25 cm3) and combined
filtrates were dried over Na2SO4, and evaporated under
reduced pressure. The residue was purified by column
chromatography (SiO2; petroleum ether:EtOAc = 4:1–
[ 2:1–[ 1:1) and yielded 0.092 g of ketoester 7a (86%).
1H NMR (500 MHz, CDCl3): d = 3.53 (s, 3H), 3.76 (s,
3H), 3.95 (s, 3H), 3.98 (s, 2H), 5.33 (s, 2H), 7.20 (d,
J = 8.4 Hz, 1H), 7.51 (dd, J = 8.3, 2.1 Hz, 1H), 7.57 (d,
J = 2.1 Hz, 1H) ppm; 13C NMR (126 MHz, CDCl3):
d = 45.4, 52.2, 56.0, 56.4, 95.9, 112.2, 116.6, 135.4, 142.8,
123

ˇˇ´ ´
Z. Barbuscakova et al.
(s, 2H), 7.03 (d, J = 1.6 Hz, 1H), 7.13 (d, J = 8.0 Hz,
1H), 7.19 (d, J = 1.3 Hz, 1H), 7.65 (d, J = 16.0 Hz, 1H)
ppm; 13C NMR (126 MHz, CDCl3): d = 51.9, 53.1, 55.6,
56.2, 56.3, 56.4, 87.4, 95.6, 109.8, 112.3, 115.8, 116.5,
118.1, 118.9, 125.8, 128.8, 133.8, 144.9, 146.9, 150.1,
The residue was purified by column chromatography
(SiO2; petroleum ether:EtOAc = 4:1– [ 2:1) and yielded
0.239 g of diacetal 15 (82%, trans/cis = [ 95:1). 1H NMR
(500 MHz, CDCl3): d = 2.05 (s, 3H), 2.11 (s, 3H), 3.51 (s,
3H), 3.78 (td, J = 7.2, 5.3 Hz, 1H), 3.86 (s, 3H), 3.92 (s,
3H), 4.31 (dd, J = 11.1, 7.5 Hz, 1H), 4.44 (dd, J = 11.2,
5.4 Hz, 1H), 4.72 (dd, J = 6.7, 1.2 Hz, 2H), 5.22 (s, 2H),
5.51 (d, J = 7.1 Hz, 1H), 6.16 (dt, J = 15.9, 6.6 Hz, 1H),
6.61 (d, J = 16.0 Hz, 1H), 6.89 (s, 2H), 6.92 (dd,
J = 11.1, 2.1 Hz, 2H), 7.12 (d, J = 8.2 Hz, 1H) ppm;
13C NMR (126 MHz, CDCl3): d = 20.9, 21.1, 50.4, 56.0,
56.1, 56.3, 65.3, 65.4, 88.5, 95.5, 109.6, 110.6, 115.4,
116.3, 118.8, 121.2, 127.7, 130.6, 134.5, 134.7, 144.5,
146.7, 148.3, 150.0, 170.9, 171.0 ppm; MS (ESI):
m/z = 488 ([M?H]?); HRMS (ESI): m/z calculated (for
C26H31O9?) 487.1962, found 487.1966.
150.1, 167.8, 170.9 ppm; MS (ESI): m/z = 459 ([M?H]?);
?
HRMS (FAB): m/z calculated (for C24H26NaO9
)
481.1469, found 481.1470.
(E)-3-[(2R,3S)-3-(Hydroxymethyl)-7-methoxy-2-[3-meth-
oxy-4-(methoxymethoxy)phenyl]-2,3-dihydrobenzofuran-5-
yl]prop-2-en-1-ol (14, C22H26O7)
A solution of 0.436 g 9a (0.95 mmol) in 10 cm3 of CH2Cl2
was cooled to - 78 °C and 4.8 cm3 of DIBAL-H
(4.73 mmol, as 1 M solution in CH2Cl2) was added
dropwise. The resulting solution was stirred at - 78 °C
for 30 min and additional 2 h at RT. The resulting mixture
was re-cooled to - 78 °C and 10 cm3 of sat. aq. sol. of
Rochel’s salt was added. The whole mixture was allowed
to stir at RT for 12 h. The resulting layers were separated
and the aqueous layer was extracted with DCM
(3 9 20 cm3). Combined organic layers were washed with
20 cm3 of brine, dried over Na2SO4, and evaporated under
reduced pressure. The residue was purified by column
chromatography (SiO2; petroleum ether:EtOAc = 2:1–
[ 1:1) and yielded 0.400 g of diol 14 (92%, trans/-
(E)-3-[(2R,3S)-3-(Acetoxymethyl)-2-(4-hydroxy-3-methoxy-
phenyl)-7-methoxy-2,3-dihydrobenzofuran-5-yl]allyl
acetate (16, C24H26O8)
A solution of 0.331 g of 15 (0.68 mmol) in 10 cm3 of Et2O
was cooled to 0 °C and 0.525 g of MgBr2ÁEt2O (2.0 mmol)
was added. The resulting mixture was allowed to warm to
RT and stirred for 3 h. Water (15 cm3) was added and the
whole mixture was extracted with CH2Cl2 (3 9 20 cm3).
Combined organic layers were washed with 10 cm3 brine,
dried over Na2SO4, and evaporated under reduced pressure.
The residue was purified by column chromatography
(SiO2; petroleum ether:EtOAc = 2:1–[ 1:1) and yielded
1
cis = [ 95:1). H NMR (500 MHz, CDCl3): d = 7.07 (d,
J = 8.3 Hz, 1H), 6.94 (d, J = 1.8 Hz, 1H), 6.89 (dd,
J = 8.3, 2.1 Hz, 1H), 6.84 (d, J = 3.1 Hz, 2H), 6.50 (d,
J = 15.9 Hz, 1H), 6.19 (dt, J = 15.6, 5.8 Hz, 1H), 5.57 (d,
J = 6.7 Hz, 1H), 5.18 (s, 2H), 4.24 (d, J = 6.1 Hz, 2H),
3.90 (dd, J = 11.0, 6.4 Hz, 1H), 3.87 (s, 3H), 3.84 (dd,
J = 10.7, 5.8 Hz, 1H), 3.82 (s, 3H), 3.57 (dd, J = 11.9,
6.1 Hz, 1H), 3.47 (s, 3H), 2.79 (s, J = 31.1 Hz, 2H) ppm;
13C NMR (126 MHz, CDCl3): d = 150.00, 148.31, 146.43,
144.46, 135.50, 131.29, 131.02, 128.35, 126.53, 118.71,
116.39, 115.05, 110.56, 109.83, 95.54, 88.05, 77.23, 63.76,
60.60, 56.30, 56.11, 56.05, 53.66 ppm; MS (ESI):
m/z = 403 ([M?H]?); HRMS (ESI): m/z calculated (for
C22H27O7?) 403.1751, found 403.1748.
1
0.235 g of phenol 16 (78%, trans/cis = [ 95:1). H NMR
(500 MHz, CDCl3): d = 2.06 (s, 3H), 2.11 (s, 3H),
3.19–3.33 (m, 1H), 3.74 (s, 3H), 3.93 (s, 3H), 4.70 (s,
2H), 4.72 (dd, J = 6.6, 1.3 Hz, 2H), 5.64 (broad s, 1H),
6.16 (s, 1H), 6.19 (td, J = 15.8, 6.5 Hz, 1H), 6.58 (d,
J = 15.7 Hz, 1H), 6.81 (d, J = 8.2 Hz, 1H), 6.85 (dd,
J = 7.9, 2.0 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.99 (dd,
J = 7.2, 1.7 Hz, 2H) ppm; 13C NMR (126 MHz, CDCl3):
d = 20.8, 21.1, 55.8, 56.2, 64.1, 65.3, 77.4, 93.2, 110.3,
111.2, 114.3, 116.6, 119.0, 120.0, 122.4, 123.3, 126.3,
129.2, 132.0, 134.1, 144.6, 150.1, 170.8, 171.2 ppm; MS
(ESI): m/z = 443 ([M?H]?); HRMS (ESI): m/z calculated
(for C24H27O8?) 443.1700, found 443.1702.
(E)-3-[(2R,3S)-3-(Acetoxymethyl)-7-methoxy-2-[3-meth-
oxy-4-(methoxymethoxy)phenyl]-2,3-dihydrobenzofuran-5-
yl]allyl acetate (15, C26H30O9)
Methyl (2R,3R)-2-[4-[(tert-butyldimethylsilyl)oxy]-3-meth-
oxyphenyl]-7-methoxy-5-((E)-3-methoxy-3-oxoprop-1-en-
1-yl)-2,3-dihydrobenzofuran-3-carboxylate
A solution of 0.241 g of 14 (0.6 mmol) in 6 cm3 of CH2Cl2
was cooled to 0 °C and 0.886 cm3 of Et3N (6.35 mmol)
was added. The resulting mixture was stirred for 5 min and
0.213 cm3 of acetyl chloride (3 mmol) was added. The
resulting mixture was allowed to warm to RT and stirred
for additional 36 h. Saturated aq. NaHCO3 (20 cm3) was
added and resulting layers were separated. Aqueous layer
was extracted with CH2Cl2 (3 9 20 cm3) and the com-
bined organic layers were washed with 10 cm3 of brine,
dried over Na2SO4, and evaporated under reduced pressure.
(17, C28H36O8Si)
A solution of 0.414 g of 13 (1.0 mmol) and 0.340 g of
imidazole (5.0 mmol) in 10 cm3 of dry DMF was cooled to
0 °C and 0.181 g of TBSCl was added in one portion. The
resulting mixture was stirred at RT for 12 h before it was
diluted with 25 cm3 of sat. aq. NaHCO3. The whole
mixture was extracted with EtOAc (3 9 25 cm3) and the
organic layers were combined, washed with 10 cm3 brine,
123

General approach to neolignan core of the boehmenan natural product family
dried over Na2SO4, and evaporated under reduced pressure.
The residue was purified by column chromatography
(SiO2; petroleum ether:EtOAc = 20:1–[ 10:1) and
yielded 0.501 g of TBS-protected phenol 17 (95%,
trans/cis = [ 95:1). 1H NMR (500 MHz, CDCl3):
d = 0.13 (s, 6H), 0.96 (s, 9H), 3.81 (s, 3H), 3.84 (s, 3H),
3.87 (s, 3H), 3.93 (s, 3H), 4.35 (d, J = 8.1 Hz, 1H), 6.14
(d, J = 8.1 Hz, 1H), 6.33 (d, J = 15.9 Hz, 1H), 6.92 (dd,
J = 12.0, 2.5 Hz, 1H), 6.95 (s, 2H), 7.03 (d, J = 1.6 Hz,
1H), 7.13 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 1.3 Hz, 1H),
7.65 (d, J = 16.0 Hz, 1H) ppm; 13C NMR (126 MHz,
CDCl3): d = - 4.5, 19.1, 25.8, 53.1, 55.6, 56.2, 56.3, 56.4,
87.4, 109.8, 112.3, 115.8, 116.5, 118.1, 118.9, 125.8,
128.8, 133.8, 144.9, 146.9, 150.1, 150.1, 167.8, 170.9 ppm;
MS (ESI): m/z = 530 ([M?H]?); HRMS (ESI): m/z
calculated (for C28H37O8Si?) 529.2252, found 529.2250.
was then filtered through a pad of CeliteÒ and the filter
cake was washed with EtOAc (3 9 20 cm3). Combined
organic layers were evaporated under reduced pressure and
the residue was purified by column chromatography (SiO2;
CH2Cl2:MeOH = 100:1–[ 70:1) yielding 0.047 g of
1
desired reduced product 19 (95%). H NMR (500 MHz,
CDCl3): d = 0.13 (s, 6H), 0.98 (s, 9H), 2.58 (dd, J = 8.4,
7.1 Hz, 1H), 2.64 (dd, J = 8.4, 7.1 Hz, 1H), 2.85 (t,
J = 7.8 Hz, 1H), 2.88–2.99 (m, 1H), 3.46 (p, J = 7.2 Hz,
1H), 3.69 (s, 3H), 3.78 (s, 3H), 3.88 (s, 3H), 3.98 (dd,
J = 11.1, 5.8 Hz, 1H), 4.04 (dd, J = 12.6, 5.9 Hz, 1H),
5.54 (d, J = 7.4 Hz, 1H), 6.66–6.70 (m, 1H), 6.71 (d,
J = 7.9 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H), 6.85 (dd,
J = 8.2, 2.1 Hz, 1H), 6.91 (d, J = 2.1 Hz, 1H) ppm; 13C
NMR (126 MHz, CDCl3): d = - 4.5, - 4.4, 18.7, 25.6,
25.9, 31.1, 36.4, 51.9, 53.9, 55.6, 55.7, 64.1, 88.1, 110.4,
112.5, 116.1, 119.0, 121.0, 132.0, 134.2, 134.7, 142.4,
144.4, 147.1, 151.3, 173.7 ppm; MS (ESI): m/z = 504
([M?H]?); HRMS (ESI): m/z calculated (for C27H39O7-
Si?) 503.2460, found 503.2459.
Methyl (E)-3-[(2R,3S)-2-[4-[(tert-butyldimethylsilyl)oxy]-
3-methoxyphenyl]-3-(hydroxymethyl)-7-methoxy-2,3-dihy-
drobenzofuran-5-yl]acrylate (18, C27H36O7Si)
A solution of 0.264 g of 17 (0.5 mmol) in 10 cm3 of THF
was cooled to - 78 °C and 1.5 cm3 of LiBH4 (3.0 mmol,
1.0 M solution in THF) was added dropwise. Resulting
mixture was stirred at - 78 °C for additional 30 min. The
cooling bath was removed and the whole mixture was
stirred at RT for additional 2 h. Saturated aqueous NH4Cl
(20 cm3) was added and resulting layers were separated.
Aqueous layer was extracted with EtOAc (3 9 25 cm3)
and combined organic layers were washed with 15 cm3
brine, dried over Na2SO4, and evaporated under reduced
pressure. The residue was purified by column chromatog-
raphy (SiO2; petroleum ether:EtOAc = 2:1–[ 1:1) and
yielded 0.202 g of monoester 18 (82%, trans/-
cis = [ 95:1). 1H NMR (500 MHz, benzene-d6):
d = 0.11 (s, 6H), 1.01 (s, 9H), 3.18 (s, 3H), 3.26 (p,
J = 6.1 Hz, 1H), 3.29 (s, 3H), 3.34 (dd, J = 10.2, 6.5 Hz,
1H), 3.38 (dd, J = 10.7, 5.5 Hz, 1H), 3.49 (s, 3H), 5.55 (d,
J = 6.5 Hz, 1H), 6.43 (d, J = 15.9 Hz, 1H), 6.69 (d,
J = 1.4 Hz, 1H), 6.71 (d, J = 1.5 Hz, 1H), 6.82 (6.69 (d,
J = 1.4 Hz, 1H), 6.86 (d, J = 1.1 Hz, 1H), 7.86 (d,
J = 15.9 Hz, 1H) ppm; 13C NMR (126 MHz, benzene-
d6): d = - 4.7, 18.4, 25.7, 50.9, 53.5, 54.8, 55.4, 64.0,
88.2, 110.0, 112.6, 115.2, 117.5, 118.5, 120.9, 128.0,
128.4, 129.2, 135.1, 145.0, 145.1, 145.2, 151.3, 167.2 ppm;
MS (ESI): m/z = 502 ([M?H]?); HRMS (ESI): m/z
calculated (for C27H37O7Si?) 501.2303, found 501.2304.
Acknowledgements The financial support by the Ministry of Edu-
cation, Youth and Sports of the Czech Republic (Grant LO1204 from
the National Program of Sustainability I) as well as by the Internal
Grant Agency of Palacky University for H.K. (IGA_PrF_2017_010)
and F.Z. (IGA_PrF_2017_009) is gratefully acknowledged. J.P. is
ˇ
grateful to Prof. M. Strnad (Palacky University) and to Dr. K. Dolezal
(Palacky University) for their continuous support.
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drobenzofuran-5-yl]propanoate (19, C27H38O7Si)
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(1.3 atm) and stirred at RT for 2 h. The resulting mixture
123

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123