Straightforward and facile synthesis of a bioactive component from zingiber cassumunar ROXB.

Article abstract of DOI:10.1080/00397911.2013.846380

Straightforward and facile synthesis of a bioactive component A from Zingiber cassumunarRoxb. is described. The phenylbutenoid dimer A was reported to possess anti-inflammatory and cytotoxic activities. The optically active cyclohexene ring fragment was o

Full text of DOI:10.1080/00397911.2013.846380

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Straightforward and Facile Synthesis of
a Bioactive Component from Zingiber
cassumunar Roxb.
Yuanying Fang a , Zunhua Yang a b & Haeil Park a
a College of Pharmacy, Kangwon National University , Chuncheon ,
Republic of Korea
b College of Pharmacy, Jiangxi University of Traditional Chinese
Medicine , Nanchang , China
Accepted author version posted online: 04 Dec 2013.Published
online: 28 Mar 2014.
To cite this article: Yuanying Fang , Zunhua Yang & Haeil Park (2014) Straightforward and Facile
Synthesis of a Bioactive Component from Zingiber cassumunar Roxb., Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 44:9, 1212-1217, DOI:
10.1080/00397911.2013.846380
To link to this article: http://dx.doi.org/10.1080/00397911.2013.846380
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Synthetic Communications®, 44: 1212–1217, 2014
Copyright © Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397911.2013.846380
STRAIGHTFORWARD AND FACILE SYNTHESIS
OF A BIOACTIVE COMPONENT FROM ZINGIBER
CASSUMUNAR ROXB.
Yuanying Fang,1 Zunhua Yang,1,2 and Haeil Park1
1College of Pharmacy, Kangwon National University, Chuncheon, Republic
of Korea
2College of Pharmacy, Jiangxi University of Traditional Chinese Medicine,
Nanchang, China
GRAPHICAL ABSTRACT
Abstract Straightforward and facile synthesis of a bioactive component A from Zingiber
cassumunar Roxb. is described. The phenylbutenoid dimer A was reported to possess
anti-inflammatory and cytotoxic activities. The optically active cyclohexene ring frag-
ment was obtained via the highly diastereo- and enantioselective Diels–Alder reaction of
chiral acryloyloxazolidinones (1a and 1b) and 1-(4-hydroxy-3-methoxyphenyl)butadiene
(2). The enantiomeric excess of Diels–Alder adducts 3a and 3b were determined via high-
performance liquid chromatotography of the corresponding bis-acetate (6). The greatest
enantiomeric excess (99.9% ee) was obtained when the 4-phenyloxazolidin-2-one (1a) chi-
ral auxiliary was used in combination with TiCl4. The optically pure bioactive compound
A was prepared from the optically active Diels–Alder adduct (3a) in two additional steps.
Keywords Chiral auxiliaries; Diels–Alder reaction; enantioselective synthesis; phenyl-
butenoid dimer
INTRODUCTION
Several bioactive components were isolated from Zingiber cassumunar
Roxb., the tropical ginger widely distributed in Southeast Asia.[1,2] The extracted
oil of this herb was known as Plai oil in Thailand and is used as massage oil by
Received May 28, 2013.
Address correspondence to Haeil Park, College of Pharmacy, Kangwon National University,
Chuncheon, Republic of Korea. E-mail: haeilp@kangwon.ac.kr
1212

SYNTHESIS OF BIOACTIVE PHENYLBUTENOID DIMER
1213
Figure 1. Retrosynthetic analysis of the phenylbutnoid dimer A.
massage therapists. Among isolated bioactive components, ( )-trans-3- (4-hydroxy-
3-methoxyphenyl)-4-((E)-3,4-dimethoxystyryl)cyclohex-1-ene (racemic mixture of A,
Fig. 1), was reported to possess both anti-inflammatory and cytotoxic activities in
recent studies.[2,3] Therefore, it was interesting for medicinal chemists to rebuild the
structure and improve bioactivity of the phenylbutenoid dimer A.
The Diels–Alder (DA) reaction is one of the most powerful methods for
constructing cyclohexene ring systems and has been used as a key step in many
notable syntheses of complex natural products. Evans’s oxazolidinone chiral auxil-
iaries, which were initially developed for aldol and alkylation reactions, have found
extensive applications in organic synthesis and have continually been employed over
the past 20 years.[4,5] The phenylbutenoid dimer A can be synthesized via DA reaction
following the strategy. The cyclohexene ring fragment of the target compound A with
two vicinal stereogenic centers can be efficiently constructed by DA reaction between
an appropriately substituted diene and an unsaturated carbonyl analog. Dienophiles
with chiral auxiliaries can be utilized to obtain optically active DA adducts.
In our ongoing research toward discovery of potential drug candidates with
anti-inflammatory activity from oriental medicinal herbs, we were interested in this
compound. However, because of difficulties in isolation and purification, devel-
opment of an efficient total synthesis of the compound A was needed not only to
obtain sufficient amount of sample for in vivo tests but also to synthesize a number
of analogs for conducting structure–activity relationship study (SARs). In addition,
development of an asymmetric synthetic method for the bioactive substance was also
necessary because optical isomers of chiral compounds usually showed different bio-
logical activity. Herein we report a straightforward and facile synthesis of an optically
active phenylbutenoid dimer A.
RESULTS AND DISCUSSION
Chiral acryloyloxazolidinones (1a and 1b) were prepared from the correspond-
ing commercially available oxazolidinones and acrylic acid and used as the dieno-
philes for the DA reactions. As the diene for DA reaction, 1-(4-hydroxy-3-methoxy)
phenylbutadiene (2) was prepared from commercial vanillin in two steps. As outlined
in Scheme 1, reactions of chiral oxazolidinones with acrylic acid, pivaloyl chloride,
and Et3N in tetrahydrofuran (THF) produced 4-phenyl (1a, 86%) and 4-isopropyl (1b,
56%) acryloyl analogs.[6] Zinc-mediated allylation of vanillin, followed by dehydration
reaction in the presence of p-toluenesulfonic acid, gave the diene (2) in 52% yield. The
asymmetric DA reaction between the dienophile (1a) and diene (2) with Et2AlCl as

1214
Y. FANG, Z. YANG AND H. PARK
Scheme 1. Reagents and conditions: (i) acrylic acid, pivaloyl chloride, LiCl, Et3N, THF, −20°C to rt, 4h, 86%
(for 1a), 56% (for 1b); (ii) allyl bromide, Zn(dust), aqueous NH4Cl solution, THF, 0°C, 0.5h; (iii) PTSA,
toluene, reflux, 1 h, 52% in two steps; (iv) Et2AlCl, CH2Cl2, −78°C, 5 h, 60% (for 3a); TiCl4, CH2Cl2,
−20°C, 2h, 95% (for 3b), 92% (for 3a); (v) DIBAL-H, CH2Cl2, −78°C, 2h, 74%; (vi) (3,4-dimethoxybenzyl)
triphenylphosphonium bromide, n-BuLi, toluene, −20°C to reflux, 41%.
the Lewis acid yielded a single DA adduct (3a) in 60% yields and 93.8% enantiomeric
excess (Table 1, entry 1).[5] However, the desired product was not detected when 1b
was used under the same condition. Excellent yields and greater enantiomeric excesses
were obtained when TiCl4 was used as Lewis acid (entry 3 and 4).[7] The products 3a
and 3b were identified as 3,4-cis stereoisomers based on the coupling constant val-
1
ues in H NMR data.[8,9] Reduction of the DA adducts afforded aldehyde 4 in 74%
yield. The reaction in Schlosser conditions between aldehyde 4 and (3,4-dimethoxy-
benzyl)triphenylphosphonium bromide at −20°C to reflux yielded the optically active
compound A as a single diastereomer. Thus, optically active trans-3-(4-hydroxy-3-
methoxyphenyl)-4-((E)-3,4-dimethoxystyryl)cyclohex-1-ene (A) was successfully
synthesized via chiral DA reaction as the key step as described in Scheme 1. Our
procedure provided the target molecule (A) with excellent enantiomeric excess (ee)
in two steps from the DA adducts (3a and 3b). The synthesis of optically active phe-
nylbutenoid dimers via a similar method has been reported.[10] However, their method
required a much longer sequence (five steps from the DA adducts) to obtain the opti-
cally active phenylbutenoid dimmers with the natural trans stereochemistry, produced
a by-product with Z-stereochemistry during Horner–Wadsworth–Emmons condensa-
tion, and did not provide detailed conditions and data for determining ee. Our results
provided detailed experimental conditions for complete separation of the peaks in
high-performance liquid chromatographic (HPLC) analysis with a chiral column.
Table 1. Results of the asymmetric Diels–Alder reactionsa
Entry
Dienophile
Lewis acid
Product
Yield (%)b
ee (%)c
1
2
3
4
1a
1b
1b
1a
Et2AlCl
Et2AlCl
TiCl4
3a
NDd
3b
60
ND
95
93.8
ND
97.1
99.9
TiCl4
3a
92
aReaction conditions: dienophile 1 (1.0 equiv), diene 2 (1.5 equiv), Et2AlCl
(1.0 equiv), CH2Cl2, −78°C, 5 h; or dienophile 1 (1.0 equiv), diene 2 (1.5 equiv),
TiCl4 (1.0 equiv), CH2Cl2, −20°C, 2 h.
bIsolated yield after chromatography.
cBased on the chiral HPLC analysis of diacetate 6.
dNot detected.

SYNTHESIS OF BIOACTIVE PHENYLBUTENOID DIMER
1215
Scheme 2. Reagents and conditions: (i) LAH, THF, 0°C to rt, 4h, 63%; (ii) Ac2O, pyridine, CH2Cl2, 0°C
to rt, 2h, 78%.
Enantiomeric excesses of the DA adducts 3a and 3b were determined by HPLC
analysis on a chiral column (Shimazu Chiracel OD, 250mm×4.6mm i.d.) in com-
parison with racemic products using hexane/EtOH/i-PrOH/t-BuOH(480/2/1/1) as the
mobile phase. Determination of ee by HPLC failed because the DA adducts (3a, 3b)
and the compound 4 did not afford clean baseline separation of the peaks. Reduction
of the DA adducts afforded the corresponding alcohol (5). However, complete chiral
separation in HPLC analysis with the alcohol (5) was also not successful. Therefore,
we converted the alcohol to its acetate (6) as described in Scheme 2. The compound 6
gave spectra with cleanly separated baseline of two peaks on HPLC analysis (Table 1).
It was determined that the enantiomeric excesses of the DA reactions were
dependent on both the chiral auxiliary and Lewis acid. The DA reaction between
the dienophile with the 4-phenyloxazolidin-2-one chiral auxiliary (1a) and TiCl4
gave best result as shown in Table 1 (>99.9% ee). Inhibitory activities of nitric
oxide (NO) production from lipopolysaccharide (LPS)-treated BV2 cells of opti-
cally active compound A and racemic compound A were evaluated. These data will
be published in other scientific journals soon.
EXPERIMENTAL
All chemicals were obtained from commercial suppliers and used without
further purification. All solvents used for reactions were freshly distilled from proper
dehydrating agent under nitrogen gas. All solvents used for chromatography were
1
purchased and directly applied without further purification. HNMR spectra were
recorded on a Bruker Avance 300 (300-MHz) and Bruker DPX 400 (400-MHz) spec-
trometers. Chemical shifts are reported in parts per million (ppm) downfield relative
to tetramethylsilane (TMS) as an internal standard. Peak splitting patterns are abbre-
viated as m (multiplet), s (singlet), bs (broad singlet), d (doublet), bd (broad doublet),
t (triplet), dd (doublet of doublets), and ddd (doublet of double doublet). 13CNMR
spectra were recorded on a Bruker DPX 400 (100-MHz) spectrometer, fully decou-
pled, and chemical shifts are reported in parts per million (ppm) downfield relative to
TMS as an internal standard. HPLC was carried out on a Wellchrom HPLC system
(Knauer, Germany) equipped with a Shimazu Chiracel OD (250mm×4.6mm i.d.).
Optical rotation data were collected by a Jasco DIP-1000 digital polarimeter. Mass
spectrawererecordedonaVoyagerDESTRMALDI-TOFmassspectrometer.Melting
points were recorded on a Fisher-Johns microscopic-scale melting-point apparatus.

1216
Y. FANG, Z. YANG AND H. PARK
Analytical thin-layer chromatography (TLC) was performed using commercial glass
plates with silica gel 60F254 purchased from Merck. Chromatographic purification
was carried out by flash chromatography using Kieselgel 60 (230–400 mesh, Merck).
(3,4-Dimethoxybenzyl)triphenylphosphonium bromide was prepared according to
the literature method.[11]
Synthesis of (S)-3-((1R,2S)-2-(4-Hydroxy-3-methoxyphenyl)cyclohex-3-
enecarbonyl)-4-phenyloxazolidin-2-one (3a)
To a solution of 1a (0.15g, 0.69mmol) in CH2Cl2 (7mL) were added Et2AlCl
(0.69mL, 1m in CH2Cl2) dropwise and 2 (0.16g, 0.91mmol) in CH2Cl2 (3mL) at
−78°C.The reaction was stirred for 5h, then warmed to 0°C, quenched with 1 N
HCl (2mL), and extracted with CH2Cl2 (30mL). The organic layer was washed with
saturated NaHCO3 (10mL) and brine (10mL), dried overmgSO4, filtered, and evap-
orated. The residue was purified by column chromatography (hexane–cetone, 4:1) to
give 3a (0.16g, 60%) as a white solid. Mp 148–150°C; [α]14 D +278.1 (c 0.1, CHCl3).
1HNMR (400mHz, CDCl3): δ=7.35–7.10 (m, 5H, phenyl), 6.52 (d, J=1.9Hz, 1H,
ArH), 6.2™, J=8.1Hz, 1H, ArH), 6.15 (dd, J=8.1, 1.9Hz, 1H, ArH), 5.88 (m, 1H,
vinyl), 5.70 (m, 1H, vinyl), 5.37 (s, 1H, OH), 5.32 (dd, J=8.8, 3.8Hz, 1H, H-4),
4.63 (t, J=8.8Hz, 1H, H-5), 4.32 (dd, J=8.8, 3.8Hz, 1H, H-5), 4.12-3.97 (m, 2H,
CHCHC=O), 3.62 (s, 3H, OCH3), 2.30–1.70 (m, 4H, CH2CH2). 13CNMR (100mHz,
CDCl3): δ=173.8, 153.9, 146.2, 144.5, 139.0, 132.4, 129.3, 129.2, 128.9, 127.4, 127.1,
122.4, 114.0, 112.0, 70.3, 58.2, 56.1, 44.0, 42.0, 24.3, 21.2. MS (MALDI-TOF):m/z
[M + Na]+ 416.1546.
Compound 3a
Following a similar procedure using TiCl4 as Lewis acid at −20°C, 3a was
obtained as a white solid (92%). [α]14 D +403.2 (c 0.1, CHCl3).
Supporting Information
Full experimental detail, 1H and 13C NMR spectra, MS data, and HPLC traces
are available for this article.
CONCLUSION
In conclusion, a straightforward and facile synthetic procedure for the synthe-
sis of optically active, naturally occurring, phenylbutenoid dimer A was developed
via highly diastereo- and enantioselective Diels–Alder reaction as the key step. The
greater enantiomeric excesses of reactions with TiCl4 catalyst may due to formation
of the tight titanium complex instead of the aluminum complex. Our present method
enables us to efficiently generate sufficient amounts of (+)-trans-3-(4-hydroxy-3-
methoxyphenyl)-4-((E)-3,4-dimethoxystyryl)cyclohex-1-ene (A) in very few syn-
thetic operations (two steps from the DA adducts) without any unnecessary steps

SYNTHESIS OF BIOACTIVE PHENYLBUTENOID DIMER
1217
(protection–deprotection of phenol group), with extremely high stereoselectivity
(single product as cis form) and enantiomeric excess (>99.9%). Therefore, our syn-
thetic procedure can be efficiently applied to SAR studies of compound A.
ACKNOWLEDGMENT
The authors thank New Drug Development Research Institute and Central
Laboratory of Kangwon National University for the use of analytical instruments
and bioassay facilities.
FUNDING
This research was supported by University–Industry Cooperation Foundation
of Kangwon National University (Foreign Post-doc Invitation Program).
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
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