A Convergent Total Synthesis of the Biologically Active Benzofurans Ailanthoidol, Egonol and Homoegonol from Biomass-Derived Eugenol

Article abstract of DOI:10.1055/s-0037-1610169

An efficient, general synthetic protocol for the synthesis of the biologically active benzofurans ailanthoidol, egonol and homoegonol was developed. The key starting material, eugenol, is a naturally occurring and abundant precursor. The protocol, involving sequential acylation and intramolecular Wittig reaction, provides a convenient method for building the benzofuran moiety in good yield.

Full text of DOI:10.1055/s-0037-1610169

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–F
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J. C. Espinoza-Hicks et al.
Paper
Synthesis
A Convergent Total Synthesis of the Biologically Active Benzo-
furans Ailanthoidol, Egonol and Homoegonol from Biomass-
Derived Eugenol
José C. Espinoza-Hicksa
Gerardo Zaragoza-Galána
David Chávez-Floresa
Víctor H. Ramos-Sáncheza
Joaquín Tamarizb
Alejandro A. Camacho-Dávila*a
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5-
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a Facultad de Ciencias Químicas, Universidad Autónoma de Chihuahua,
Circuito Universitario, Campus Universitario, Apartado Postal 669,
Chihuahua, 31115 Chihuahua, Mexico
acamach@uach.mx
b Departamento de Química Orgánica, Escuela Nacional de Ciencias
Biológicas, Instituto Politécnico Nacional, Prol. de Carpio y Plan de
Ayala S/N, 11340 Ciudad de Mexico, Mexico
Received: 06.04.2018
O
Accepted after revision: 03.05.2018
Published online: 28.06.2018
HO
O
DOI: 10.1055/s-0037-1610169; Art ID: ss-2018-m0239-op
O
OCH3
Abstract An efficient, general synthetic protocol for the synthesis of
the biologically active benzofurans ailanthoidol, egonol and homoego-
nol was developed. The key starting material, eugenol, is a naturally oc-
curring and abundant precursor. The protocol, involving sequential acy-
1
OCH3
OCH3
HO
O
lation and intramolecular Wittig reaction, provides
a convenient
method for building the benzofuran moiety in good yield.
OCH3
2
Key words benzofurans, ailanthoidol, egonol, homoegonol, sustain-
OCH3
OH
able synthesis, total synthesis, natural products
HO
O
Benzofuran compounds are an important class of natu-
ral and synthetic products.1 Their wide-ranging biological
activities include antiviral,2 anticancer,3 antimicrobial4 and
antifungal activity,5 among others.6 For instance, egonol (1)
and homoegonol (2) (Figure 1) are benzofuran lignans iso-
lated from plants of the Styrax genus, such as S. officinalis,7
S. americana8 and S. obassia.9 These substances exhibit cy-
tostatic activity against human leukemic HL60 cells.10 An-
other benzofuran lignan, ailanthoidol (3), has been isolated
from the Chinese medicinal plants Zanthoxylum ailan-
thoides and Salvia miltiorrhiza Bunge.11 This compound
suppresses NF-κB activation, which is associated with vari-
ous inflammation-associated mediators.12 The naturally oc-
curring egonol linoleate 4, derived from 1 and linoleic acid,
inhibits acetylcholinesterase. The latter enzyme is involved
in the hydrolysis of acetylcholine, which promotes Aβ pep-
tide aggregation, a process that leads to neural death and is
associated with Alzheimer’s disease.13
OCH3
3
O
O
O
O
O
OCH3
4
Figure 1 Structures of biologically active benzofurans
Due to the importance of the benzofuran scaffold as a
potential source of novel therapeutic agents, insights into
the synthesis of 1–4, their analogues and other benzofuran
lignans is a relevant field of research.14,15 Thus, intense re-
search efforts in organic synthesis have recently aimed to
develop new and efficient synthetic strategies as well as
improve known methods for access to these compounds.
One effective and convergent strategy involves starting ma-
terials containing a common scaffold that can react with di-
verse structural partners to provide a wide range of ana-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

B
J. C. Espinoza-Hicks et al.
Paper
Synthesis
logues.16 Based on several methodologies, many approaches
have been designed for the construction of the benzofuran
core,17 one example being palladium-mediated reactions.18
However, the drawbacks of some of these methods pre-
clude or limit a large-scale application.
One of the methods for obtaining benzofurans III is the
intramolecular Wittig reaction of an (o-hydroxyben-
zyl)triphenylphosphonium halide I with an acid chloride II
or acid anhydride in the presence of triethylamine (Scheme
1).19 Due to the efficiency of this methodology and the
availability of starting materials, it is conceivable to achieve
a total synthesis of natural products 1–3 by using adequate-
ly functionalized (o-hydroxybenzyl)triphenylphosphonium
halides and acid chlorides.
clove oil, eugenol (7), has been employed as the starting
material for the synthesis of diverse organic compounds.22
Therefore, we explored the preparation of compounds 1–3
by starting from this inexpensive and abundant compound.
All these compounds are functionalized benzofurans of po-
tential biological importance.
The aforementioned retrosynthetic analysis indicated
that (hydroxymethyl)eugenol (6) should be the key inter-
mediate leading to the formation of benzofurans 1–3. Thus,
eugenol (7) was reacted with formalin solution in a basic
medium (NaOH) to produce the desired allylic alcohol 6 in
85% yield (Scheme 3).24 Treatment of 6 with triphenylphos-
phonium bromide in acetonitrile, as reported by Hamanaka
and co-workers,25 gave phosphonium salt 5 in 89% yield.
The latter salt was used in the next step without further
purification.
PPh3Cl
Et3N
H3CO
HO
H3CO
HO
R
R-COCl
+
CH2O (aq), NaOH
toluene
reflux
O
OH
MeOH, rt, 4 h
(85%)
I
II
III
OH
Scheme 1 General synthesis of the benzofuran ring system via the in-
7
6
tramolecular Wittig reaction
MeCN, reflux, 1 h
(89%)
The structural analogy between compounds 1–3 is like-
ly derived from a common starting material. The retrosyn-
thetic analysis of compounds 1–3 is illustrated in Scheme 2,
showing that they can be prepared from (o-hydroxyben-
zyl)triphenylphosphonium bromide 5 as the common pre-
cursor. It is possible to obtain the latter compound by start-
ing from alcohol 6, which in turn is easily furnished from a
biomass-derived chemical such as eugenol (7).20 The afore-
mentioned alcohol was previously produced from o-vanil-
Ph3PH Br
H3CO
HO
PPh3Br
5
Scheme 3 Preparation of the key phosphonium salt intermediate 5
from eugenol (7)
lin through
a sequence beginning with O-allylation,
followed by a Claisen rearrangement and finally a hydride
reduction of the resulting aldehyde to afford (hydroxymeth-
yl)eugenol (6).21
The use of biomass-derived organic compounds as
starting materials constitutes one of the main objectives of
green chemistry.22 In recent years, important organic tar-
gets have been synthesized from a starting material ob-
tained from biomass.23 Accordingly, the main constituent of
The design of the synthetic approach to generate the
precursor of the benzofuran ring depended on which of the
natural products 1–3 was targeted (Scheme 4). The synthe-
sis of egonol (1) and homoegonol (2) was achieved by react-
ing the corresponding acid chlorides 11 and 12, respective-
ly, in the presence of phosphonium salt 5 in toluene at re-
flux, with triethylamine as the base. The allylbenzofuran
R1
R1
R1
OH
O
PPh3Br
HO
R2
+
R2
R2
OH
O
OH
O
Cl
OCH3
OCH3
OCH3
OCH3
5
6
1, R1–R2 = –OCH2O–
2, R1 = R2 = OCH3
14, R1–R2 = –OCH2O–
15, R1 = R2 = OCH3
11, R1–R2 = –OCH2O–
12, R1 = R2 = OCH3
3, R1 = OCH3, R2 = OH
16, R1 = OCH3, R2 = OAc
13, R1 = OCH3, R2 = OAc
OH
OCH3
7
Scheme 2 Retrosynthetic analysis of the propyl/propenyl-substituted benzofuran system
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

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J. C. Espinoza-Hicks et al.
Paper
Synthesis
R1
R1
R1
R2
COCl
R1
R2
COOH
HO
5, Et3N
1. NaBH4, I2
(COCl)2
R2
R2
O
toluene, reflux
4 h
2. H2O2, NaOH
O
OCH3
OCH3
8, R1–R2 = –OCH2O–
9, R1 = R2 = OCH3
10, R1 = OCH3, R2 = OAc
11, R1–R2 = –OCH2O–
12, R1 = R2 = OCH3
13, R1 = OCH3, R2 = OAc
14, R1–R2 = –OCH2O–
15, R1 = R2 = OCH3
16, R1 = OCH3, R2 = OAc
1, R1–R2 = –OCH2O–
2, R1 = R2 = OCH3
Scheme 4 General scheme for synthesis of the benzofuran system by the intramolecular Wittig reaction
products 14 and 15 were furnished in 69% and 58% yield,
respectively. Utilizing the procedure of Periasamy and co-
workers,26 hydroboration–oxidation of the allyl chain of 14
and 15 resulted in egonol (1) and homoegonol (2) in 53%
and 83% yield, respectively.
The availability of acid chloride 13 was required for the
synthesis of ailanthoidol (3). The former compound was ob-
tained from O-acetylvanillic acid (10), which in turn was
prepared from commercially available vanillic acid, by a
two-step sequence. Firstly, acetylation of vanillic acid with
acetic anhydride and sulfuric acid as the catalyst afforded
10.27 Then, reaction of 10 with oxalyl chloride provided acid
chloride 13, which was used without further purification.
Finally, a mixture of phosphonium salt 5 and 13 in toluene
was heated to reflux with triethylamine (3 equiv), deliver-
ing 5-allylbenzofuran 16 in 59% yield as a crystalline solid
after purification by chromatography (Scheme 4).
Once the key precursor 16 was in hand, the oxidation
conditions for the allylic chain were explored. Initially, the
procedure reported by Le Bras and co-workers for the allylic
acetoxylation of alkenes28 was tested. Thus, 16 was reacted
with palladium(II) acetate (5 or 10 mol%), benzoquinone (2
equiv) and sodium acetate (2 equiv) in acetic acid at 40 °C
for 24 hours. Analysis of the reaction mixture showed no
conversion into the desired allylic acetate, only a recovery
of the starting substrate 16. In contrast, the method report-
ed by Chen and White was more efficient.29 This method
consists of similar palladium-catalyzed conditions, but in
the presence of dimethyl sulfoxide as the solvent. Conse-
quently, allylbenzofuran 16 was treated with palladium(II)
acetate (10 mol%), benzoquinone (2 equiv) and acetic acid
in DMSO at 40 °C for 24 hours, in the presence of molecular
sieves. The desired ailanthoidol diacetate (17) was generat-
ed in 42% yield. Hydrolysis of both acetyl groups of 17 with
potassium carbonate in methanol furnished ailanthoidol
(3) in 98% yield (Scheme 5). With the aim of improving the
yield of the oxidation step, some variations on the proce-
dure were carried out,30 either by increasing the palladi-
um(II) acetate concentration to 20 mol% or modifying the
equivalents of benzoquinone or acetic acid; however, the
yield of the process was not increased. Indeed, there was no
reaction at all in some experiments.
In summary, we have accomplished the total synthesis
of the biologically active benzofurans egonol (1), homoego-
nol (2) and ailanthoidol (3) by using eugenol (7), which is a
readily available, inexpensive and biomass-derived starting
material. The acylation/intramolecular Wittig reaction cas-
cade process proved to be an efficient method for the for-
mation of the benzofuran scaffold. Furthermore, the palla-
dium(II)-catalyzed allylic acetoxylation of the propenyl side
chain of precursor 16 is a convenient method for the final
key step in the synthesis of 3, albeit in modest yield. There-
fore, this approach may be an expedient strategy for the
synthesis of a variety of substituted 2-arylbenzofurans with
potential biological activity.
All reagents were obtained from commercial suppliers (Sigma-
Aldrich and Oakwood Chemical) unless otherwise stated, and sol-
vents were used as received. All moisture-sensitive reactions were
performed under an argon atmosphere. Reactions were monitored by
analytical TLC (E. Merck 0.25 mm silica gel 60 F254). TLC plates were
visualized by exposure to UV light (254 nm). Benzofuran products
were spotted by their fluorescence under these conditions. Flash col-
umn chromatography was performed with silica gel (Natland 230–
400 mesh). All spectra were recorded at 25 °C. 1H and 13C NMR spec-
tra were recorded on a Bruker Avance III 400 MHz spectrometer using
CDCl3 as solvent. Tetramethylsilane was the reference (0.00 ppm) for
1H NMR and CDCl3 (77.0 ppm) for 13C NMR acquisitions. HRMS data
were recorded on a Jeol JSM-GC Mate-II spectrometer in EI+ mode.
OAc
OH
OCH3
OCH3
OAc
OCH3
OH
Pd(OAc)2, benzoquinone
K2CO3
4Å MS, HOAc
OAc
DMSO, 40 °C, 24 h
O
MeOH, rt, 24 h
98%
O
O
42%
OCH3
OCH3
OCH3
16
17
3
Scheme 5 Palladium-catalyzed allylic oxidation of the propenyl side chain of 16 and hydrolysis to give ailanthoidol (3)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

D
J. C. Espinoza-Hicks et al.
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Synthesis
4-Allyl-2-(hydroxymethyl)-6-methoxyphenol (6)
Acid Chlorides 11, 12 and 13; General Procedure
To a solution of NaOH (1 g, 25 mmol) in H2O (25 mL) was added euge-
nol (7; 5.00 g, 30.5 mmol), and then the mixture was stirred until
complete dissolution was achieved. Subsequently, 35% aqueous form-
aldehyde solution (15 mL, 6.00 g, 200 mmol) was added in one por-
tion. The reaction mixture was stirred at room temperature for 4 h.
Thereafter, the resulting mixture was acidified (pH 5) with HOAc and
extracted with CHCl3 (2 × 35 mL). The combined organic extracts
were washed with H2O (4 × 40 mL) and dried (Na2SO4), and the sol-
vent was removed in vacuo. The crude mixture was purified by col-
umn chromatography over silica gel (hexane/EtOAc, 3:2) to afford 6
(5.03 g, 85%) as a light-yellow oil.
In a one-necked 50-mL round-bottom flask equipped with a magnetic
stirring bar, the corresponding carboxylic acid 8, 9 or 10 (11.55
mmol) was placed in CH2Cl2 (10 mL). Subsequently, addition was
made of a drop of DMF and oxalyl chloride (4 mL, 47 mmol) in one
portion. A vigorous gas emission was immediately released. Stirring
was continued until the gas emission stopped (about 25–30 min), and
then the mixture was heated to reflux for 1 h. The solvent and excess
oxalyl chloride were removed under reduced pressure to furnish the
corresponding acid chloride as a dark-brown syrup. The syrup was
used in the next step without further purification.
1H NMR (400 MHz, CDCl3): δ = 2.63 (br s, 1 H, OH), 3.30 (dm, J = 6.7
Hz, 2 H, ArCH2CH=), 3.86 (s, 3 H, OCH3), 4.70 (s, 2 H, CH2OH), 5.04–
5.09 (m, 2 H, CH2=), 5.93 (ddt, J = 16.8, 10.0, 6.7 Hz, 1 H, CH2CH=), 6.15
(s, 1 H, OH), 6.65 (br s, 1 H, H-3), 6.67 (br s, 1 H, H-5).
13C NMR (101 MHz, CDCl3): δ = 39.8 (ArCH2CH=), 56.0 (OCH3), 61.8
(CH2OH), 110.7 (C-3), 115.6 (CH2=), 120.6 (C-5), 126.1 (C-1), 131.4 (C-
4), 137.6 (CH2CH=), 141.9 (C-2), 146.5 (C-6).
Benzofurans 14, 15 and 16; General Procedure
Phosphonium salt 5 (5.50 g, 10.5 mmol) was suspended in toluene
(60 mL); then, the corresponding acid chloride 11, 12 or 13 (11.55
mmol) and freshly distilled Et3N (4.4 mL, 31.5 mmol) were added se-
quentially. The mixture was heated to reflux under an argon atmo-
sphere for 4 h, and then the solid was removed by filtration and the
solvent evaporated. The residue was purified by column chromatog-
raphy over silica gel (hexane/EtOAc, 9:1) to deliver the corresponding
benzofuran as a solid.
HRMS (EI+): m/z [M+] calcd for C11H14O3: 194.0943; found: 194.0934.
(5-Allyl-2-hydroxy-3-methoxybenzyl)triphenylphosphonium Bro-
mide (5)
5-(5-Allyl-7-methoxybenzofuran-2-yl)benzo[d][1,3]dioxole (14)
Yield: 2.25 g (69%); white solid; mp 67–71 °C (Lit.14f 69–71 °C).
1H NMR (400 MHz, CDCl3): δ = 3.45 (d, J = 6.7 Hz, 2 H, ArCH2CH=), 4.03
(s, 3 H, OCH3), 5.08–5.15 (m, 2 H, CH2=), 6.00 (s, 2 H, OCH2O), 5.97–
6.07 (m, 1 H, CH2CH=), 6.62 (br s, 1 H, H-4), 6.79 (s, 1 H, H-3), 6.87 (d,
J = 8.1 Hz, 1 H, H-5′), 6.97 (br s, 1 H, H-6), 7.32 (d, J = 1.6 Hz, 1 H, H-2′),
7.40 (dd, J = 8.1, 1.6 Hz, 1 H, H-6′).
A solution of 6 (2.64 g, 13.6 mmol) and triphenylphosphine hydro-
bromide (4.70 g, 13.6 mmol) in MeCN (70 mL) was stirred under re-
flux for 1 h. The reaction mixture was concentrated to half-volume
and diluted with Et2O (100 mL). The solid was collected by filtration
and washed with Et2O to give 5 (6.3 g, 89%) as a brownish powder; mp
269–273 °C (Lit.14f 277–278 °C).
13C NMR (101 MHz, CDCl3): δ = 40.5 (ArCH2CH=), 56.0 (OCH3), 100.4
(C-3), 101.3 (OCH2O), 105.5 (C-2′), 107.3 (C-4), 108.6 (C-5′), 112.5 (C-
6), 115.6 (CH2=), 119.1 (C-6′), 124.6 (C-1′), 131.0 (C-3a), 135.6 (C-5),
137.9 (CH2CH=), 142.5 (C-7a), 144.7 (C-7), 147.9 (C-3′ or C-4′), 148.0
(C-3′ or C-4′), 156.0 (C-2).
1H NMR (400 MHz, CDCl3): δ = 3.08 (d, J = 6.6 Hz, 2 H, CH2PPh3Br),
3.78 (s, 3 H, OCH3), 4.85–4.92 (m, 2 H, CH2=), 4.99 (d, J = 13.7 Hz, 2 H,
ArCH2CH=), 5.66 (ddt, J = 16.8, 10.1, 6.7 Hz, 1 H, CH2CH=), 6.31 (br s, 1
H, H-5), 6.57 (br s, 1 H, H-3), 7.64–7.66 (m, 12 H, Ph-H), 7.78–7.79 (m,
3 H, Ph-H).
13C NMR (101 MHz, CDCl3): δ = 39.4 (ArCH2CH=), 51.6 (OCH3), 65.8
(CH2PPh3Br), 111.6 (ArC), 111.6 (ArC), 112.5 (ArC), 112.6 (ArC), 115.7
(CH2=), 117.3 (ArC), 118.2 (ArC), 123.1 (C-1), 123.2 (ArC), 129.9 (ArC),
130.0 (C-3), 131.7 (ArC), 131.8 (C-4), 134.0 (ArC), 134.1 (C-5), 134.9
(CH2CH=), 135.0 (ArC), 136.9 (ArC), 142.9 (ArC), 143.0 (C-2), 147.0 (C-
6), 147.0 (ArC).
HRMS (EI+): m/z [M+] calcd for C19H16O4: 308.1049; found: 308.1041.
5-Allyl-2-(3,4-dimethoxyphenyl)-7-methoxybenzofuran (15)14f
Yield: 1.88 g (58%); white solid; mp 90–92 °C.
1H NMR (400 MHz, CDCl3): δ = 3.46 (d, J = 6.7 Hz, 2 H, ArCH2CH=), 3.93
(s, 3 H, OCH3), 3.99 (s, 3 H, OCH3), 4.03 (s, 3 H, OCH3), 5.08–5.15 (m, 2
H, CH2=), 6.03 (ddt, J = 16.8, 10.0, 6.7 Hz, 1 H, CH2CH=), 6.62 (br s, 1 H,
H-4), 6.84 (s, 1 H, H-3), 6.92 (d, J = 8.4 Hz, 1 H, H-5′), 6.98 (br s, 1 H, H-
6), 7.36 (d, J = 1.9 Hz, 1 H, H-2′), 7.45 (dd, J = 8.4, 1.9 Hz, 1 H, H-6′).
13C NMR (101 MHz, CDCl3): δ = 40.5 (ArCH2CH=), 56.0 (OCH3), 56.0
(OCH3), 56.0 (OCH3), 100.3 (C-3), 107.2 (C-4), 108.0 (C-2′), 111.1 (C-
5′), 112.5 (C-6), 115.7 (CH2=), 118.0 (C-6′), 123.4 (C-1′), 131.1 (C-3a),
135.7 (C-5), 137.9 (CH2CH=), 142.5 (C-7a), 144.7 (C-7), 149.0 (C-3′),
149.4 (C-4′), 156.3 (C-2).
4-Acetoxy-3-methoxybenzoic Acid (O-Acetylvanillic Acid, 10)27
Ac2O (10 mL, 106 mmol) and vanillic acid (10 g, 59.5 mmol) were
placed in a 100-mL round-bottom flask equipped with a magnetic
stirring bar. A catalytic amount of H2SO4 (2 drops) was added and the
mixture was heated to 80 °C for 6 h. After the mixture was cooled to
0 °C and H2O (100 mL) was added, the resulting yellow solid was col-
lected by filtration, washed with H2O (4 × 10 mL) and air-dried at
room temperature to obtain 10 (9.63 g, 77%) as a light-brown pow-
der; mp 140–142 °C (Lit.27 143–145 °C).
HRMS (EI+): m/z [M+] calcd for C20H20O4: 324.1362; found: 324.1364.
1H NMR (400 MHz, CDCl3): δ = 2.35 (s, 3 H, OCOCH3), 3.91 (s, 3 H,
OCH3), 7.15 (d, J = 8.2 Hz, 1 H, H-5), 7.71 (d, J = 1.9 Hz, 1 H, H-2), 7.77
(dd, J = 8.2, 1.9 Hz, 1 H, H-6).
13C NMR (101 MHz, CDCl3): δ = 20.8 (ArOCOCH3), 56.2 (ArOCH3), 113.9
(C-2), 123.1 (C-5), 123.6 (C-6), 128.0 (C-1), 144.5 (C-4), 151.3 (C-3),
168.6 (ArCOCH3), 171.3 (COOH).
4-(5-Allyl-7-methoxybenzofuran-2-yl)-2-methoxyphenyl Acetate
(16)
Yield: 1.89 g (51%); light-yellow crystals; mp 123–125 °C.
1H NMR (400 MHz, CDCl3): δ = 2.34 (s, 3 H, OCOCH3), 3.46 (d, J = 6.7
Hz, 2 H, ArCH2CH=), 3.94 (s, 3 H, OCH3), 4.03 (s, 3 H, OCH3), 5.09–5.16
(m, 2 H, CH2=), 6.03 (ddt, J = 16.8, 10.0, 6.7 Hz, 1 H, CH2CH=), 6.65 (br
s, 1 H, H-4′), 6.93 (s, 1 H, H-3′), 7.00 (br s, 1 H, H-6′), 7.10 (d, J = 8.4 Hz,
1 H, H-6), 7.44–7.46 (m, 2 H, H-5, H-3).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

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J. C. Espinoza-Hicks et al.
Paper
Synthesis
13C NMR (101 MHz, CDCl3): δ = 20.7 (OCOCH3), 40.5 (ArCH2CH=), 55.8
(OCH3), 56.1 (OCH3), 101.8 (C-3′), 107.6 (C-4′), 108.9 (C-3), 112.7 (C-
6′), 115.7 (CH2=), 117.6 (C-5), 123.1 (C-6), 129.3 (C-4), 130.8 (C-3a),
135.8 (C-5′), 137.8 (CH2CH=), 139.8 (C-1), 142.8 (C-7a), 144.8 (C-7′),
151.2 (C-2), 155.5 (C-2′), 169.0 (OCOCH3).
112.4 (C-6), 118.2 (C-6′), 123.6 (C-1′), 131.2 (C-3a), 137.6 (C-5), 142.6
(C-7a), 144.9 (C-7), 149.2 (C-3′ or C-4′), 149.6 (C-3′ or C-4′), 156.4 (C-
2).
HRMS (EI+): m/z [M+] calcd for C20H22O5: 342.1467; found: 342.1474.
HRMS (EI+): m/z [M+] calcd for C21H20O5: 352.1311; found: 352.1301.
(E)-3-(2-(4-Acetoxy-3-methoxyphenyl)-7-methoxybenzofuran-5-
yl)allyl Acetate (Ailanthoidol Diacetate, 17)
Hydroboration–Oxidation of 14 and 15; General Procedure26
A 40-mL Schlenk tube equipped with a stirring bar was charged with
Pd(OAc)2 (22.4 mg, 0.1 mmol, 10 mol%), benzoquinone (217 mg, 2
mmol), 16 (352 mg, 1 mmol) and 4 Å molecular sieves (217 mg). After
sequential addition of DMSO (2 mL) and HOAc (3 mL) via syringe, the
mixture was heated to 40 °C for 24 h. A saturated aqueous solution of
NH4Cl (10 mL) was added and the mixture was extracted with CH2Cl2
(3 × 100 mL). The combined organic layers were washed with H2O (2 ×
100 mL), dried over Na2SO4, filtered and then concentrated in vacuo to
give a brown oil, which was purified by flash column chromatography
over silica gel (hexane/EtOAc, 4:1) to furnish 17 (0.172 g, 42%) as a
dark-brown solid; mp 125–127 °C.
1H NMR (400 MHz, CDCl3): δ = 2.03 (s, 3 H, C3′′-OCOCH3), 2.24 (s, 3 H,
C1-OCOCH3), 3.83 (s, 3 H, OCH3), 3.94 (s, 3 H, OCH3), 4.66 (d, J = 6.4 Hz,
2 H, CH2OAc), 6.17 (dt, J = 15.8, 6.6 Hz, 1 H, ArCH=CH), 6.62 (d, J = 15.8
Hz, 1 H, ArCH=CH), 6.78 (br s, 1 H, H-4′), 6.83 (s, 1 H, H-3′), 7.00 (d, J =
8.8 Hz, 1 H, H-6), 7.06 (br s, 1 H, H-6′), 7.34–7.35 (m, 2 H, H-3, H-5).
Pulverized NaBH4 (115 mg, 3 mmol) and anhydrous THF (20 mL) were
placed in a 100-mL round-bottom flask equipped with a septum and
a magnetic stirring bar. The flask was cooled in an ice–salt bath,
which was followed by the dropwise addition (via syringe) of a solu-
tion of iodine (0.306 g, 1.20 mmol) dissolved in THF (5 mL). The addi-
tion rate was controlled according to the disappearance of the color.
After the mixture was stirred in the cooling bath for 30 min, a solu-
tion of the corresponding alkene 14 or 15 (6.48 mmol) in anhydrous
THF (10 mL) was added dropwise via syringe (during 10 min). The
mixture was stirred at 25 °C for 2 h, then the reaction was quenched
with aqueous 3 N NaOH (12 mL). Subsequently, 30% H2O2 (1.4 mL)
was added dropwise and the mixture was stirred at room tempera-
ture for 1 h, followed by dilution with EtOAc (25 mL) and brine solu-
tion (20 mL). The aqueous phase was extracted with EtOAc (1 × 20
mL) and the combined organic extracts were washed with H2O (2 × 20
mL) and brine (1 × 20 mL), then dried (Na2SO4). The solvent was re-
moved in vacuo and the crude purified by flash column chromatogra-
phy over silica gel (hexane/EtOAc, 3:2, 1:1) to provide the correspond-
ing alcohol 1 or 2 as a solid.
13C NMR (101 MHz, CDCl3): δ = 20.6 (C3′′-OCOCH3), 21.0 (C1-OCO-
CH3), 55.9 (OCH3), 56.0 (OCH3), 65.2 (CH2OAc), 101.9 (C-3′), 104.6 (C-
4′), 108.8 (C-3), 112.2 (C-6′), 117.6 (C-5), 121.9 (ArCH=CH), 123.1 (C-
6), 128.9 (C-4), 130.8 (C-7a), 132.3 (C-5′), 134.7 (ArCH=CH), 139.9 (C-
1), 144.0 (C-3a), 145.0 (C-7′), 151.2 (C-2), 155.8 (C-2′), 168.9 (C1-
OCOCH3), 170.9 (C3′′-OCOCH3).
3-(2-(Benzo[d][1,3]dioxol-5-yl)-7-methoxybenzofuran-5-yl)pro-
pan-1-ol (Egonol, 1)
Yield: 1.13 g (53%); white powder; mp 105–107 °C (Lit.14e 100–
HRMS (EI+): m/z [M+] calcd for C23H22O7: 410.1366; found: 410.1370.
103 °C).
4-(5-((E)-3-Hydroxyprop-1-en-1-yl)-7-methoxybenzofuran-2-yl)-
2-methoxyphenol (Ailanthoidol, 3)
1H NMR (400 MHz, CDCl3): δ = 1.63 (br s, 1 H, OH), 1.94 (quin, J = 6.5
Hz, 2 H, ArCH2CH2CH2OH), 2.76 (t, J = 7.6 Hz, 2 H, ArCH2CH2CH2OH),
3.70 (t, J = 6.4 Hz, 2 H, ArCH2CH2CH2OH), 4.02 (s, 3 H, OCH3), 5.99 (s, 2
H, OCH2O), 6.63 (br s, 1 H, H-4), 6.78 (s, 1 H, H-3), 6.86 (d, J = 8.4 Hz, 1
H, H-5′), 6.96 (s, 1 H, H-6), 7.31 (d, J = 1.2 Hz, 1 H, H-2′), 7.39 (dd, J =
8.1, 1.4 Hz, 1 H, H-6′).
13C NMR (101 MHz, CDCl3): δ = 32.4 (ArCH2CH2CH2OH), 34.6
(ArCH2CH2CH2OH), 56.1 (OCH3), 62.2 (ArCH2CH2CH2OH), 100.3 (C-3),
101.3 (OCH2O), 105.5 (C-2′), 107.2 (C-4), 108.6 (C-5′), 112.2 (C-6),
119.1 (C-6′), 124.6 (C-1′), 130.9 (C-3a), 137.5 (C-5), 142.3 (C-7a),
144.7 (C-7), 147.9 (C-3′ or C-4′), 148.0 (C-3′ or C-4′), 156.0 (C-2).
Diacetate 17 (0.100 g, 0.243 mmol) in anhydrous MeOH (20 mL) was
placed in a 100-mL round-bottom flask equipped with a stirring bar.
Subsequently, K2CO3 (1.000 g, 7.24 mmol) was poured into the mix-
ture, which was stirred at room temperature for 24 h. The solvent was
removed in vacuo and the residue diluted with EtOAc (20 mL) and
H2O (15 mL). The phases were separated, the aqueous phase was ex-
tracted with EtOAc (2 × 10 mL) and the combined organic extracts
were washed with H2O (2 × 25 mL) and brine (1 × 25 mL), then dried
(Na2SO4). Solvent removal in vacuo afforded 3 (0.0775 g, 98%) as a yel-
low solid; mp 193–195 °C (Lit.14a 199–201 °C).
1H NMR (400 MHz, DMSO-d6): δ = 3.85 (s, 3 H, C3′-OCH3), 3.96 (s, 3 H,
C7-OCH3), 4.13 (d, J = 4.4 Hz, 2 H, CH2OH), 5.02 (br s, 1 H, OH), 6.36
(dt, J = 15.9, 5.2 Hz, 1 H, ArCH=CH), 6.59 (d, J = 15.9 Hz, 1 H, ArCH=CH),
6.88 (d, J = 8.2 Hz, 1 H, H-5′), 6.98 (d, J = 1.1 Hz, 1 H, H-6), 7.16 (br s, 2
H, H-3, H-4), 7.31 (dd, J = 8.2, 2.0 Hz, 1 H, H-6′), 7.36 (d, J = 2.0 Hz, 1 H,
H-2′), 9.60 (br s, 1 H, OH).
HRMS (EI+): m/z [M+] calcd for C19H18O5: 326.1154; found: 326.1144.
3-(2-(3,4-Dimethoxyphenyl)-7-methoxybenzofuran-5-yl)propan-
1-ol (Homoegonol, 2)
Prepared from 0.332 g (1.02 mmol) of 15.
Yield: 0.285 g (83%); white powder; mp 115–118 °C (Lit.14d 118–
119 °C).
1H NMR (400 MHz, CDCl3): δ = 1.48 (br s, 1 H, OH), 1.88–2.01 (m, 2 H,
ArCH2CH2CH2OH), 2.73–2.83 (m, 2 H, ArCH2CH2CH2OH), 3.71 (t, J = 6.4
Hz, 2 H, ArCH2CH2CH2OH), 3.92 (s, 3 H, OCH3), 3.98 (s, 3 H, OCH3), 4.03
(s, 3 H, OCH3), 6.64 (d, J = 1.2 Hz, 1 H, H-4), 6.83 (s, 1 H, H-3), 6.92 (d,
J = 8.4 Hz, 1 H, H-5′), 6.96–7.00 (m, 1 H, H-6), 7.36 (d, J = 1.9 Hz, 1 H,
H-2′), 7.45 (dd, J = 8.4, 2.0 Hz, 1 H, H-6′).
13C NMR (101 MHz, DMSO-d6): δ = 55.7 (C7-OCH3), 55.8 (C3′-OCH3),
61.5 (CH2OH), 100.0 (C-3), 104.6 (C-6), 108.9 (C-2′), 110.8 (C-4), 115.9
(C-5′), 118.0 (C-6′), 121.0 (C-1′), 129.1 (C-3a), 129.6 (ArCH=CH), 130.9
(ArCH=CH), 133.2 (C-5), 142.5 (C-7a), 144.6 (C-7), 147.9 (C-4′), 148.0
(C-3′), 156.3 (C-2).
HRMS (EI+): m/z [M+] calcd for C19H18O5: 326.1154; found: 326.1142.
13C NMR (101 MHz, CDCl3): δ = 32.6 (ArCH2CH2CH2OH), 34.8
(ArCH2CH2CH2OH), 56.1 (OCH3), 56.2 (OCH3), 56.2 (OCH3), 62.4
(ArCH2CH2CH2OH), 100.4 (C-3), 107.3 (C-4), 108.2 (C-2′), 111.3 (C-5′),
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

F
J. C. Espinoza-Hicks et al.
Paper
Synthesis
Funding Information
(i) Schreiber, F. G.; Stevenson, R. J. Chem. Soc., Perkin Trans. 1
1976, 1514. (j) Ritchie, E.; Taylor, W. C. Aust. J. Chem. 1969, 22,
1329.
We express our gratitude to the Consejo Nacional de Ciencia y Tec-
nología (CONACYT) (Mexico) for a grant to purchase the NMR instru-
ment (INFR-2014-01-226114). J.T. gratefully acknowledges SIP-IPN
(grants 20170791 and 20180198) and CONACYT (grant 178319) for
financial support. J.T. is a fellow of the EDI-IPN and COFAA-IPN pro-
(15) For syntheses of ailanthoidol, see: (a) Rao, M. L. N.; Awasthi, D.
K.; Banerjee, D. Tetrahedron Lett. 2010, 51, 1979. (b) Lin, S.-Y.;
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Chern, J.-W. J. Org. Chem. 2002, 67, 6772. (d) Kao, C.-L.; Chern, J.-
W. Tetrahedron Lett. 2001, 42, 1111. (e) Lütjens, H.; Scammells,
P. J. Tetrahedron Lett. 1998, 39, 6581. (f) Fuganti, C.; Serra, S. Tet-
rahedron Lett. 1998, 39, 5609. (g) Bates, R. W.; Rama-Devi, T.
Synlett 1995, 1151.
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Supporting Information
(16) (a) Garcia-Castro, M.; Zimmermann, S.; Sankar, M. G.; Kumar, K.
Angew. Chem. Int. Ed. 2016, 55, 7586. (b) Maier, M. E. Org.
Biomol. Chem. 2015, 13, 5302. (c) Serba, C.; Winssinger, N. Eur. J.
Org. Chem. 2013, 4195.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610169.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F