Sustainable Synthesis of the Naturally Hypolipidemic Agent α-Asarone

Article abstract of DOI:10.1080/00397911.2015.1041047

(Chemical Equation Presented). A short and practical preparation of α-asarone was developed using the inexpensive methylisoeugenol as a starting material. The utilization of a sequence of tribromination, debromination, and copper-mediated aromatic substitution enabled the stereoselective formation of only the E-isomer of α-asarone in good yield.

Full text of DOI:10.1080/00397911.2015.1041047

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Sustainable Synthesis of the Naturally
Hypolipidemic Agent α-Asarone
Alejandro A. Camacho-Dávilaa, David Chávez-Floresa, Gerardo
Zaragoza-Galána & Víctor H. Ramos-Sáncheza
a Facultad de Ciencias Químicas. Universidad Autónoma de
Chihuahua, Chihuahua, México
Accepted author version posted online: 21 Apr 2015.Published
online: 21 Apr 2015.
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To cite this article: Alejandro A. Camacho-Dávila, David Chávez-Flores, Gerardo Zaragoza-Galán
& Víctor H. Ramos-Sánchez (2015): Sustainable Synthesis of the Naturally Hypolipidemic Agent α-
Asarone, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, DOI: 10.1080/00397911.2015.1041047
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Synthetic Communications1, 0: 1–6, 2015
Copyright © Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397911.2015.1041047
SUSTAINABLE SYNTHESIS OF THE NATURALLY
HYPOLIPIDEMIC AGENT a-ASARONE
Alejandro A. Camacho-Dávila, David Chávez-Flores,
Gerardo Zaragoza-Galán, and Víctor H. Ramos-Sánchez
Facultad de Ciencias Químicas. Universidad Autónoma de Chihuahua,
Chihuahua, México
GRAPHICAL ABSTRACT
Abstract A short and practical preparation of a-asarone was developed using the
inexpensive methylisoeugenol as a starting material. The utilization of a sequence of
tribromination, debromination, and copper-mediated aromatic substitution enabled the
stereoselective formation of only the E-isomer of a-asarone in good yield.
Keywords a-Asarone; atherosclerosis; cardiovascular; sustainable
INTRODUCTION
Today, one of the major causes of heart disease or cardiovascular hearth disease
(CHD) in developed countries is atherosclerosis and associated conditions. One of
the main causes is associated with hyperlipidemia or high blood lipid concentration.
Among the lipids causing this condition are fats and fatty acids, along with cholesterol,
phospholipids, and triglycerides. CHD such as atherosclerosis results from the
formation of plaque inside the arteries—leading to the hardening and narrowing of
the arteries, limiting the flow of nutrients and oxygen to organs such as the heart.[1]
The search for lipid-lowering drugs that may prevent the development of
atherosclerosis has been a very active area of research.[2] Although CHD is mainly
associated with lifestyle it is also obtained as a result of biosynthesis of cholesterol
in the liver, which is regulated by the enzyme 3-hydroxy-3-methylglutaryl-coenzyme
A (HMG-CoA) reductase (HMGR).[3,4] Therefore, if the biosynthesis of cholesterol
Received February 4, 2015.
Address correspondence to Alejandro A. Camacho-Dávila, Facultad de Ciencias Químicas,
Universidad Autónoma de Chihuahua, Campus Universitario 2, Chihuahua, Chih. 31125, México.
E-mail: acamach@uach.mx
1

2
A. A. CAMACHO-DÁVILA ET AL.
Figure 1. Chemical structure of a-asarone.
in the human body can be inhibited, the prevalence of CHD associated with
hyperlipidemia could be reduced. Evidence suggests that the reduction of low density
cholesterol (LDLC) lowers the incidence of mortality associated with CHD. Among
the most effective drugs that reduce the LDLC concentration in plasma are those
that inhibit the HMGR.[5] Among the drugs used in the treatment of hyperlipidemia
are statins, which are either natural compounds derived from fungi or analogs of
them.[6] These drugs represent combined sales of several billion dollars worldwide.[7]
Another natural compound that possesses hypolipidemic activity is a-asarone 1
(Fig. 1). This is the main active component found on the extract of Guatteria gaumeri
Greenman (Annonaceae) bark, a medicinal plant that is used in Mexico for the
treatment of cholelithiasis or gallstones and hypercholesterolemia.[8] Because of this
and other properties, such as insecticidal, antimicrobial, and nematicidal, a-asarone
has received widespread interest. Some derivatives and analogs of a-asarone have
been studied to modify their structures in order to explore their structure–activity
relationship (SAR).[9]
Several methods for the synthesis of a-asarone 1 have been reported,[10] but
most of these suffer from problems associated with the use of not readily available
materials, which are prepared via multistep synthesis or expensive starting materials.
Two of the main methods to form the conjugated double bond are based in the
employment of a Wittig reaction[10b] or the use of Grignard reagents followed by
dehydration.[10a,d] The main problem with these routes are poor yields in the
assembly of the skeleton and=or lack of stereoselectivity, generating mixtures of
the desired E isomer along with substantial amounts of the undesired and toxic
Z isomer, which are difficult to separate or require an extra step in the isomerization
reaction.[11]
In recent years, the use of biomass-derived chemicals in the synthesis of
complex and useful compounds has been associated with sustainability and green
chemistry.[12] There are several organic compounds of biological origin that are
obtained in substantial amounts and are used in the perfumery, flavor, or drug indus-
tries.[13] In the search for a shorter and more stereoselective route to a-asarone,
we considered the use of the inexpensive and readily available methylisoeugenol 2,
which is used in perfumery. As can be noticed from the structure of 2, it only requires
the installation of a methoxy group ortho to the propenyl chain to reach a-asarone.
In this article we present the results of the synthesis of a-asarone from methyl
isoeugenol 2.
Initially, we considered functionalization of C-5 in 2 to install a functional
group capable of being converted either to a phenol or a more preferable methoxy
group (Scheme 1). A previously reported synthesis of a-asarone uses the

SYNTHESIS OF a-ASARONE
3
Scheme 1. Proposed synthesis of a-asarone.
bromoderivative 4 which, through a copper-mediated substitution, installs the
methoxy function with excellent yield.[10a] Thus, we were confronted with the issue
of how to selectively install a good leaving group in the required position without
affecting the double bond on the chain. We reasoned that a selective halogenation
of the aromatic ring would be difficult in the presence of the double bond. Therefore,
we considered that by employing an excess of halogen, we could halogenate the
double bond and the aromatic ring in one step, installing the halogen in the required
position, assisted by the aromatic methoxy groups and the chain.[14] The selective
dehalogenation of the chain dibromoderivative 3 could generate the bromocom-
pound 4, which could be converted to 1 by the reported procedure.[10a]
RESULTS AND DISCUSSION
The reaction of methylisoeugenol, consisting of a mixture of cis=trans isomers
(70=30 ratio by gas chromatography, GC), was reacted with 2.2 equivalents of
bromine in chloroform to afford the corresponding tribromoderivative 3 in 95%
yield. The resulting diastereomeric mixture was used without purification in the
debromination step. Debromination was carried out simply by refluxing crude 3 dur-
ing 2 h with 3 equivalents of sodium iodide in acetone to afford 4 in 80% yield. NMR
spectra showed that 4 consisted of essentially pure E isomer, which did not require
any further purification. The observed stereoselectivity of the dehalogenation reaction
to afford only the E isomer is concordant with the selectivity to trans elimination for
vic-dibromides.[15] Reaction of 4 with excess sodium methoxide in dimethylformamide
(DMF) catalyzed by copper(I) bromide according to the published procedure[10a]
yielded a-asarone 1 as the only isomer in 82% yield after purification. The spectral
data of the obtained product was identical with the published data.
CONCLUSION
In summary, a short three-step stereoselective route to the lipid lowering
agent a-asarone from inexpensive and biomass derived starting material is reported.
This route is amenable to adaptation for large-scale preparation of this compound.

4
A. A. CAMACHO-DÁVILA ET AL.
EXPERIMENTAL
1H and 13C NMR spectra were recorded using a Varian 500 instrument, and the
chemical shifts (d) are given in parts per million (ppm) relative to tetramethylsilane
(TMS) as internal standard (0.00). The mass spectra were recorded on a Jeol
JMS-SX102A spectrometer in the electron-impact (EI) mode at 70 eV and 200 °C
via direct inlet probe. Only the molecular and parent ions (m=z) are reported. Infrared
(IR) spectra were recorded on a Perkin-Elmer FT-IR 2000 instrument. All solvents
and reagents were used as received. Flash column chromatography was carried on
silica gel (Natland). All reactions were performed under nitrogen or argon.
1-Bromo-2-(1,2-dibromopropyl)-4,5-dimethoxybenzene 3
Bromine (3.52 g, 22 mmol) dissolved in CHCl3 (5 mL) was slowly added to a
stirred solution of methylisoeugenol 2 (1.78 g, 10 mmol) dissolved in CHCl3
(50 mL) over 10 min. After this, the reaction mixture was stirred at rt for 2 h. Then,
water (50 mL) was added and the phases separated. The organic phase was succes-
sively washed with an aqueous solution of 10% Na2SO3 (20 mL) and 1 N Na2CO3
(2 × 20 mL). The organic phase was dried (Na2SO4) and concentrated under vacuum.
The dibromide 3 was obtained as a brown syrup which, was used immediately in the
next step without further purification. Crude yield: 3.96 g (95%). A sample was
purified by column chromatograpy (hexanes=EtOAc 8=2). This consisted of a mix-
ture of two isomers. Major isomer 3b:1H NMR (500 MHz, CDCl3) d: 7.00 (s, 1H,
H-3b), 6.98 (s, 1H, H-6b), 5.56 (d, J ¼ 10.1 Hz, 1H, H-10b), 4.61 (dq, J ¼ 10.2,
6.5 Hz, 1H, H-20b), 3.90 (s, 3H, OMe), 3.88 (s, 3H, OMe), 2.04 (d, J ¼ 6.2 Hz, 3H,
H-30b). 13C NMR (126 MHz, CDCl3) d: 149.77 (C4, C5), 148.92 (C4, C5), 131.35
(C1), 114.98 (C6), 113.23 (C2), 111.14 (C3), 57.41 (C10), 56.19 (OMe), 56.16
(OMe), 56.13 (OMe) 50.44 (C20), 25.42 (C30). Minor isomer 3a:1H NMR
(500 MHz, CDCl3) 7.18 (s, 1H, H-3a), 6.97 (s, 1H, H-6a), 5.60 (d, J ¼ 6.0 Hz, 1H,
H-10a), 4.51–4.43 (m, 1H, H-20a), 1.77 (d, J ¼ 6.8 Hz, 3H, H-30a). 13C NMR
(126 MHz, CDCl3) d 149.74 (C4, C5), 148.90 (C4, C5), 129.98 (C1), 114.09 (C6),
58.55 (C10), 56.19 (OMe), 56.16 (OMe), 56.13 (OMe), 53.55 (C20), 24.46 (C30).
HRMS (EIþ) calculated for C11 H13 O2 Br3: 413.8466; found: 413.8477.
(E)-1-Bromo-4,5-dimethoxy-2-(prop-1-en-1-yl)benzene 4
Crude 3 (3.96 g, 9.49 mmol) was added to a solution of NaI (4.26 g,
28.47 mmol) in acetone (100 mL). The mixture was heated to reflux during 3 h.
The reaction mixture was concentrated in vacuo and the residue was diluted with
hexanes (50 mL). To this mixture, water (100 mL) was added and the phases were
separated. The aqueous phase was extracted with hexanes (25 mL). The combined
organic phases were washed with 10% Na2SO3 (2 × 50 mL) and dried (Na2SO4).
Solvent removal in vacuo left a viscous residue, which solidified to a cream-colored
mass. Yield 1.94 g (80%). TLC (9:1 hexane=EtOAc) showed a single spot. IR:
(ATR) cmꢀ1 3084, 3002, 2958, 2911, 2839, 1651, 1599, 1567, 1503, 1463, 1437,
1384, 1339, 1256, 1195, 1162, 1029, 986, 959, 927, 854, 834. 1H NMR
(500 MHz, CDCl3): d 6.97 (s, 1H, H-3), 6.96 (s, 1H, H-6), 6.64 (dq, J ¼ 15.6,

SYNTHESIS OF a-ASARONE
5
1.7 Hz, 1H, H-20), 6.07 (dq, J ¼ 15.6, 6.6 Hz, 1H, H-10), 3.87 (s, 1H, OMe), 3.84 (s, 1H,
OMe), 1.88 (dd, J ¼ 6.7, 1.8 Hz, 3H, H-30). 13C NMR (126 MHz, CDCl3) d 148.59
(C4, C5), 148.43 (C4, C5), 129.82 (C2), 129.51 (C1’), 126.76 (C2’), 115.20 (C6),
113.21 (C1), 108.93 (C3), 56.05 (OMe), 55.90 (OMe), 18.45 (C3’). HRMS (EIþ)
calculated for C11H13O2Br: 256.0099; found: 256.0091. The spectral data of 4 agreed
with the reported values.[10a]
(E)-1,2,4-Trimethoxy-5-(prop-1-en-1-yl)benzene (a-Asarone) 1
NaOCH3 was prepared dissolving Na (5 g, mmol) in CH3OH (100 mL). After
the sodium reacted, most of the methanol was removed in the rotavapor, leaving a
syrup containing NaOCH3 and CH3OH. This was diluted with dry DMF (50 mL),
and Cu2Br2 (1.14 g) was added. The mixture was stirred, and 3 (4.12 g, 16.02 mmol)
was added. The reaction mixture was heated under reflux during 24 h. The resulting
mixture was subjected to evaporation in vacuo to remove most of the DMF, and the
residue diluted with CHCl3 (70 mL). The mixture was diluted with water (100 mL)
and the phases separated. The aqueous phase was extracted with 25 mL of CHCl3,
and the combined chloroformic extracts were washed with water (5 × 25 mL). The
extract was dried (Na2SO4) and concentrated in vacuo to afford a dark syrup, which
was purified by flash chromatography on silica, eluting with 9:1 hexane=ethyl acet-
ate. Yield 2.73 g (82%), yellowish oil that solidified on standing. IR (ATR) (cmꢀ1):
2996, 2955, 2930, 2852, 2833, 1608, 1586, 1509, 1504, 1460, 1453, 1438, 1299, 1270,
1
1202, 1178, 1031, 968, 860, 817. H NMR (500 MHz, CDCl3) d: 6.94 (s, 1H, H-3),
6.65 (dq, J ¼ 15.8, 1.6 Hz, 1H, H-10), 6.49 (s, 1H, H-6), 6.14–6.04 (m, 1H, H-20),
3.87 (s, 3H, OMe), 3.84 (s, 3H, OMe), 3.80 (s, 3H, OMe), 1.88 (dd, J ¼ 6.6,
1.8 Hz, 3H). 13C NMR (126 MHz, CDCl3) d 150.53 (C4, C5), 148.63 (C4, C5),
143.25 (C1) 124.95 (C2), 124.13 (C6), 118.90 (C10), 109.74 (C3), 97.86 (C20), 56.55
(OMe), 56.37 (OMe), 55.97 (C10-OMe), 18.64 (C30). HRMS (EIþ) calculated for
C12H16O3: 208.1100; found: 208.1104. The spectral data of 1 agreed with the
reported values.[10a–10c]
ACKNOWLEDGMENT
We acknowledge the generous support of Escuela Nacional de Ciencias Bioló-
gicas of the Instituto Politécnico Nacional (J. Tamaríz) for recording the NMR and
HRMS spectra.
FUNDING
We thank the Facultad de Ciencias Químicas, Dirección de Investigación y
Posgrado, for the support of this project.
SUPPORTING INFORMATION
Spectral data for all compounds including 1H and 13C NMR spectra and
HRMS for this article can be accessed on the publisher’s website.

6
A. A. CAMACHO-DÁVILA ET AL.
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