The first total synthesis of anemarchalconyn and anemarcoumarin A

Article abstract of DOI:10.1080/10286020.2016.1275583

Anemarchalconyn (1) and anemarcoumarin A (2), the natural bioactive compounds isolated from the rhizomes of Anemarrhena asphodeloides Bunge (Liliaceae), were first totally synthesized using easily available materials in short, convenient routes with overall yields of 32 and 48%.

Full text of DOI:10.1080/10286020.2016.1275583

Journal of Asian Natural Products Research
ISSN: 1028-6020 (Print) 1477-2213 (Online) Journal homepage: http://www.tandfonline.com/loi/ganp20
The first total synthesis of anemarchalconyn and
anemarcoumarin A
Jing-Xia Zhang, Zhe-Yu Li, Yu-Chi Wang, Wen-Bo Ma, Ming Hou, Sheng-Hua
Cao, Ke-Hui Tang & Hong-Bo Dong
To cite this article: Jing-Xia Zhang, Zhe-Yu Li, Yu-Chi Wang, Wen-Bo Ma, Ming Hou,
Sheng-Hua Cao, Ke-Hui Tang & Hong-Bo Dong (2017): The first total synthesis of
anemarchalconyn and anemarcoumarin A, Journal of Asian Natural Products Research, DOI:
10.1080/10286020.2016.1275583
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Date: 23 February 2017, At: 04:55

Journal of asian natural Products research, 2017
http://dx.doi.org/10.1080/10286020.2016.1275583
The first total synthesis of anemarchalconyn and
anemarcoumarin A
Jing-Xia Zhanga,b, Zhe-Yu Lia,b, Yu-Chi Wanga, Wen-Bo Maa, Ming Houa,
Sheng-Hua Caoa, Ke-Hui Tanga and Hong-Bo Donga
aantibiotics research and re-evaluation Key laboratory of sichuan Province, sichuan industrial institute
of antibiotics, chengdu university, chengdu 610052, china; bcollege of Pharmacy, chengdu university of
traditional chinese Medicine, chengdu 611137, china
ABSTRACT
ARTICLE HISTORY
received 13 september 2016
accepted 19 december 2016
Anemarchalconyn (1) and anemarcoumarin A (2), the natural bioactive
compounds isolated from the rhizomes of Anemarrhena asphodeloides
Bunge (Liliaceae), were first totally synthesized using easily available
materials in short, convenient routes with overall yields of 32 and 48%.
KEYWORDS
Anemarrhena asphodeloides;
anemarcoumarin a;
anemarchalconyn; total
synthesis
1. Introduction
Anemarrhena asphodeloides Bunge (Liliaceae) is a perennial plant widely cultivated in sev-
eral Asian countries such as China, Korea, and Japan to fulfill pharmaceutical demands.
e rhizomes of this plant, known as “Zhi Mu,” are one of the most common traditional
Chinese medicines, which has been used for their antidiabetic and antiphlogistic properties
for decades [1]. In recent years, researchers found that the main bioactive natural compo-
nents of A. asphodeloides were xanthones, norlignans, and steroidal saponins which have
various biological activities such as antidiabetic, antioxidant, antifungal, and antidepressant
effects [2–6].
Anemarchalconyn (1) (Figure 1) which exhibited a strong inhibitory effect to preadipocyte
3T3-L1 cells [7] was first isolated from the rhizomes of A. Asphodeloides. Anemarcoumarin
A (2) was also first isolated from rhizomes of A. Asphodeloides [7] as well as the branches
CONTACT hong-Bo dong
donghongbo@cdu.edu.cn
© 2017 informa uK limited, trading as taylor & francis Group

2
J.-X. ZHANG ET AL.
and leaves of Caesalpinia spinosa Kuntze (Tara) from Yunnan province [8]. In view of their
pharmacological importance and as part of our research program of investigating biologi-
cally active compounds of traditional Chinese medicine “Zhi Mu,” we first report efficient
methods to get both anemarchalconyn (1) and anemarcoumarin A (2) with easily available
materials and high overall yields.
2. Results and discussion
First, our synthetic approach to get anemarchalconyn (1) was started from commercially
available compounds 3 and 4 (Scheme 1). e phenylacetylene compound 3 was treated
with n-butyllithium in dry THF at −78 °C and then benzaldehyde 4 was added dropwise to
afford alcohol 5 in excellent yields. en, Dess–Martin oxidant reagent was used to oxidize
compound 5 hydroxyl into ketone 6, both methyls of which were removed in the presence
of BBr3 to get anemarchalconyn (1) in 43% yield.
en, we investigated the synthesis of anemarcoumarin A (2) using resorcinol 7 as
the key starting material (Scheme 2) at first. Resorcinol 7, upon Vilsmeier–Haack reac-
tion with DMF and POCl3, afforded benzaldehyde 8. e obtained benzaldehyde 8 was
methylated in the presence of dimethylsulfate to get corresponding anisole 9. en, we
developed a Perkin cyclization for the synthesis of substituted coumarin 10, which could
be applied to produce the key intermediate 12 with Zhou’s method [9]. e crude mixture,
which was attained under Zhou’s conditions including an excess of methylanisole, tert-butyl
Figure 1. structures of anemarchalconyn (1) and anemarcoumarin a (2).
Scheme 1. synthetic route of anemarchalconyn (1). reagents and conditions: (a) (i) n-Buli, thf, and
hexane, −78 °c, 1 h; (ii) compound 4 inthf, −78 °c to room temperature, 4 h. (b) dess–Martin periodinane,
ch2cl2, room temperature, 8 h. (c) BBr3, dry ch2cl2, 0 °c to room temperature, 3 h.

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
3
perbenzoate (TBPB), catalyst Cu(OAc)2, and in N2 atmosphere for 24 h at 100 °C, was
purified by chromatography and afforded only one new product 11 (based on 1H, 13C NMR
and mass spectrometry).
So we resorted to the traditional Wittig route for key intermediate 12. e required alky-
lated phosphorane 15 could be obtained from unsubstituted phosphorane 13 and equimolar
ratio of methoxybenzyl bromide 14 using CHCl3 as a solvent. As shown in Scheme 3, the
phosphorane 15 was reacted with anisole 9 in refluxing toluene to get E-hydroxy ester 16
which could cyclize neat under nitrogen atmosphere to give coumarin 12 [10]. en, both
methyls of compound 12 were removed by BBr3 in CH2Cl2 to get anemarcoumarin A 2.
Scheme 2. design of initial attempt to prepare anemarcoumarin a (2) by reported reaction. reagents and
conditions: (a) (i) Pocl3, dMf, and ch3cn, room temperature, 2 h; (ii) resorcinol 7, ch3cn, −15 °c to room
temperature, 3 h. (b) (ch3)2so4, K2co3, acetone, reflux, 5 h. (c) ch3coona, acetic anhydride, dMf, under
n2 atmosphere, 180 °c, 5 h. (d) compound 10, cu(oac)2, tert-butyl perbenzoate (tBPB), 4-methylanisole
(5 ml), 100 °c, 24 h.
Scheme 3. synthetic route of anemarcoumarin a (2). reagents and conditions: (a) (i) chcl3, reflux, 8 h;
(ii) 20% naoh, 20 min. (b) compound 9, toluene, reflux, 15 h. (c) 230 °c, 3 h. (d) BBr3, dry ch2cl2, room
temperature, 3 h.

4
J.-X. ZHANG ET AL.
In conclusion, anemarchalconyn (1) and anemarcoumarin A (2) were synthesized
through short, convenient routes with overall yields of 32 and 48%, respectively. e syn-
thesis for these natural compounds from “Zhi Mu” utilizes fairly inexpensive reagents and
is an environmentally friendly process. is work builds a solid foundation for further study
on the bioactivity of this Chinese medicine.
3. Experimental
3.1. General experimental procedures
Melting points were measured on X-4 digital display microscopic melting point appa-
ratus (Tianjin Xintian Optical Analytical Instruments Co. Ltd., Tianjin, China) and are
uncorrected. 1H and 13C NMR spectra were recorded on Bruker Avance 400 (Bruker Co.,
Fallanden, Switzerland) instrument (using tetramethylsilane as the internal standard). HR–
MS were obtained on Bruker Apex II mass spectrometer (Bruker Co., Bremen, Germany).
e solvents were analytical grade and newly distilled before usage.
3.2. General procedures for the synthetic compounds
3.2.1. Synthesis of 13-bis(4-methoxyphenyl)prop-2-yn-1-ol (5)
Under N2 at −78 °C, to a solution of alkynes 3 (1.58 g, 12 mmol) and dry THF (15 ml) in a
Schlenk tube, 5 ml of n-BuLi (2.5 M in hexane, 12.5 mmol) was added in a dropwise man-
ner for 20 min, and the reaction mixture was kept at −78 °C for 1 h. en, benzaldehyde 4
(1.36 g, 10 mmol) in 10-ml THF was added to the mixture in a dropwise manner, and the
mixture was stirred for 4 h until the temperature raised up to r.t. slowly. en, the resulting
residue was quenched by 20-ml 1 N HCl and extacted with ethyl acetate (15 ml × 3), and
the organic layer was further washed with brine and dried with anhydrous sodium sul-
fate. e residue was filtered, concentrated, and purified by chromatography with hexane/
ethyl acetate (v/v, 10/1) to afford a colorless liquid product 5 3.2 g (82% yield). 1H NMR
(400 MHz, CDCl3) δ: 7.54 (d, J = 8.7 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.7 Hz,
2H), 6.84 (d, J = 8.8 Hz, 2H), 5.63 (s, 1H), 3.82 (s, 3H), 3.81 (s, 3H), which was identical to
that in the literature [11].
3.2.2. Synthesis of 13-bis(4-methoxyphenyl)prop-2-yn-1-one (6)
To a solution of compound 5 (2.56 g, 9.6 mmol) in CH2Cl2 (100 ml), Dess–Martin periodi-
nane (DMP, 4.85 g, 11.5 mmol) was added at 0 °C. Afer 5 min, the reaction mixture was
allowed to warm to r.t. and stirred for 8 h. e mixture was washed with saturated Na2S2O3
solution (40 ml) and then saturated NaHCO3 solution (40 ml). e combined aqueous
layers were extracted with CH2Cl2 (30 ml). Afer drying over MgSO4, the organic phase
was concentrated and purified by chromatography with hexane/ethyl acetate (v/v, 50/1) to
afford a white solid compound 6 (2.31 g, 90% yield), m.p. 79–81 °C, 1H NMR (400 MHz,
CDCl3) δ: 8.19 (d, J = 8.9 Hz, 2H), 7.63 (d, J = 8.9 Hz, 2H), 6.98 (d, J = 8.9 Hz, 2H), 6.93 (d,
J = 8.9 Hz, 2H), 3.90 (s, 3H), 3.86 (s, 3H), which was identical to that in the literature [11].

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
5
3.2.3. Synthesis of anemarcoumarin A (1)
Under N2, compound 6 (0.53 g, 2 mmol) and 10-ml dry CH2Cl2 were introduced into the
reaction flask and cooled in an ice bath. e boron tribromide (0.74 ml, 8 mmol) in 10-ml
dry CH2Cl2 was slowly introduced through a dropping funnel. Afer addition of boron tri-
bromide, the reaction mixture is warmed to r.t. for 3 h. e reaction mixture was acidified
with 10% sodium hydroxide solution and extracted with CH2Cl2 (3 × 10 ml). e com-
bined organic solution was washed with brine, dried over anhydrous Na2SO4, filtered, and
evaporated to give a solid residue. e residue was further purified using chromatography
developed by CHCl3/CH3OH (v/v, 10/1) to afford 0.20-g anemarcoumarin A 1 as orange
powder (43% yield), m.p. 77–81 °C, 1H NMR (400 MHz, CD3OD) δ: 7.92 (d, J = 8.8 Hz,
2H), 7.63 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H); 13C NMR
(100 MHz, CD3OD) δ: 178.3, 166.3, 163.5, 136.1, 132.9, 131.3, 115.7, 115.1, 112.9, 95.1,
87.4, which was identical to that in the literature [7].
3.2.4. Synthesis of 24-dihydroxybenzaldehyde (8)
To a cold (0 °C) mixture of DMF (15 ml) and acetonitrile (100 ml), POCl3 (18 g, 117.4 mmol)
was added dropwise in 20-ml acetonitrile and then allowed to warm to r.t. Afer 30 min
of stirring, the mixture was cooled to 0 °C and m-dihydroxybenzene (11 g, 99.9 mmol)
in acetonitrile (30 ml) was added dropwise. e mixture was then stirred at 0 °C for 1 h.
e crystals separated were collected by filtration, washed with a small amount of cold
acetonitrile, and then recrystallized from water to give the product 9.82 g (71% yield), m.p.
134–136 °C, 1H NMR (400 MHz, DMSO-d6) δ: 10.89 (s, 1H), 10.62 (s, 1H), 9.93 (s, 1H),
7.53 (d, J = 8.6 Hz, 1H), 6.39 (dd, J = 8.6, 2.2 Hz, 1H), 6.32 (d, J = 2.2 Hz, 1H), which was
identical to that in the literature [12].
3.2.5. Synthesis of 2-hydroxy-4-methoxybenzaldehyde (9)
To a solution of 24-dihydroxybenzaldehyde 8 (4 g, 28.9 mmol) in 50 ml acetone, K2CO3
(4 g, 28.9 mmol) and dimethyl sulfate (3.65 g, 28.9 mmol) were added; then the mixture
was refluxed for 6 h. Afer the reaction mixture was cooled and insoluble material was
removed by filtration, the filtrate was concentrated under reduced pressure. e residue
was recrystallized from water–alcohol to give the compound 2 (3.8 g, 86.3% yield), m.p.
1
41–43 °C, H NMR (400 MHz, CDCl3) δ: 11.49 (s, 1H), 9.72 (s, 1H), 7.43 (d, J = 8.7 Hz,
1H), 6.54 (dd, J = 8.7, 2.2 Hz, 1H), 6.43 (d, J = 2.2 Hz, 1H), 3.86 (s, 3H), which was identical
to that in the literature [12].
3.2.6. Synthesis of 7-methoxy-2H-chromen-2-one (10)
Under nitrogen atmosphere, a mixture of 2-hydroxy-4-methoxybenzaldehyde 9 (2.6 g,
17.1 mmol), NaOAc (4.2 g, 51.3 mmol), and ethanoyl ethanoate (7.15 g, 70 mmol) in DMF
30 ml was stirred at 180 °C for 6 h. Afer the reaction mixture was cooled, it was added
to 100 ml 10% HCl, then extracted with EtOAc (30 ml × 3). e combined organic phase
was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. e
residue was recrystallized from water–alcohol to give the product 10 (2.35 g, 78% yield) as
a white solid, m.p. 141–143 °C, 1H NMR (400 MHz, CDCl3) δ: 7.65 (d, J = 9.5 Hz, 1H), 7.38
(d, J = 8.6 Hz, 1H), 6.84 (dd, J = 8.6, 2.4 Hz, 1H), 6.80 (d, J = 2.4 Hz, 1H), 6.24 (d, J = 9.5 Hz,
1H), 3.87 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 162.8, 161.2, 155.8, 143.4, 128.8, 113.0,
112.5, 112.5, 100.8, 55.7.

6
J.-X. ZHANG ET AL.
3.2.7. 4-Methoxybenzyl benzoate (11)
A 10-ml Schlenk tube was charged with Cu(OAc)2 (18 mg, 5 mol%) and coumarin 10
(0.41 g, 2 mmol). e tube was evacuated and backfilled with nitrogen thrice. TBPB (0.78 g,
4 mmol) in methylanisole (10 ml) was added by syringe. e tube was then sealed, and
the mixture was stirred at 100 °C for 24 h. Upon completion of the reaction, the mixture
was diluted with EtOAc. e solvent was then removed under vacuum. e residue was
purified by chromatography on silica gel (gradient eluent of EtOAc/petroleum ether, 1:30)
to give compound 11 (0.81 g), as a colourless liquid (yield 84% based on TBPB). 1H NMR
(400 MHz, CDCl3) δ: 8.07–8.04 (m, 2H), 7.53–7.50 (m, 1H), 7.43–7.38 (m, 4H), 6.94–6.89
(m, 2H), 5.29 (s, 2H), 3.80 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 166.5, 159.7, 133.0,
130.3, 130.1, 129.7, 128.4, 128.2, 114.0, 66.6, 55.3; ESI-MS: m/z 243.3 [M + H]+, which was
identical to that in the literature [13].
3.2.8. Synthesis of ethyl (E)-3-(2-hydroxy-4-methoxyphenyl)-2-(4-methoxybenzyl)
acrylate (16)
To a solution of methoxybenzyl bromide (4.0 g, 20 mmol) in dry chloroform (10 ml), Wittig
reagent 13 (6.8 g, 19 mmol) in dry chloroform (10 ml) was added at r.t. en, the mix-
ture was refluxed for 8 h. Afer the reaction mixture was cooled, the solvent was removed
under reduced pressure to get the phosphonium salt as an oil. is salt was dissolved in
water (150 ml) and benzene (100 ml) was added to it. e mixture was then alkalized with
2 mol/L NaOH. e benzene layer was separated and the aqueous layer was extracted with
benzene (50 ml × 2). e combined oganic phase was dried over Na2SO4 and solvent was
removed to get a phosphorane 15 (8.7 g, 93% yield). A mixture of phosphorane 15 (8.7 g,
18.5 mmol) and compound 9 (2.8 g, 18.5 mmol) was refluxed in dry toluene for 15 h. When
the reaction was over (monitored by TLC, hexane/ethyl acetate, v/v 9/1), the solvent was
removed under reduced pressure. e residue obtained was chromatographed over silica
gel using hexane/ethyl acetate (v/v 30/1) as an eluent to furnish compound 16 (4.4 g, 70%
yield) as a white solid, m.p. 59–63 °C, 1H NMR (400 MHz, CDCl3) δ: 7.93 (s, 1H), 7.14 (d,
J = 8.4 Hz, 1H), 7.07 (d, J = 8.7 Hz, 2H), 6.80 (d, J = 8.7 Hz, 2H), 6.45–6.41 (m, 2H), 5.93
(s, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.81 (s, 2H), 3.77 (s, 3H), 3.76 (s, 3H), 1.23 (t, J = 7.1 Hz,
3H), which was identical to that in the literature [10].
3.2.9. Synthesis of 7-methoxy-3-(4-methoxybenzyl)-2H-chromen-2-one (12)
e hydroxy ester 16 (2.0 g, 5.8 mmol) was heated neat in nitrogen atmosphere for 3 h. e
residue obtained was flash chromatographed over silica gel using hexane/ethyl acetate (v/v,
8/2) as an eluent, to get a white solid compound 12 (1.4 g, 83% yield), m.p. 135–138 °C,
1H NMR (400 MHz, CDCl3) δ: 7.26–7.23 (m, 1H), 7.21 (s, 1H), 7.20 (d, J = 8.6 Hz, 2H),
6.88 (d, J = 8.6 Hz, 2H), 6.80–6.78 (m, 2H), 3.85 (s, 3H), 3.81 (s, 3H), 3.79 (s, 2H); 13C
NMR (100 MHz, CDCl3) δ: 162.0, 161.9, 158.4, 154.7, 139.1, 130.3, 129.9, 128.2, 126.2,
114.1, 113.1, 112.3, 100.4, 55.7, 55.3, 35.5. HR-ESI-MS m/z: 297.1121 [M + H]+ (cacld for
C18H17O4, 297.1121).
3.2.10. Synthesis of anemarchalconyn (2)
Compound 6 (0.59 g 2 mmol) and 10-ml dry CH2Cl2 were introduced into the reaction
flask and cooled in an ice bath under N2. e boron tribromide (0.55 ml, 6 mmol) in
10-ml dry CH2Cl2 is slowly introduced through a dropping funnel. Afer addition of boron

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
7
tribromide, the reaction mixture is warmed to r.t. for 2 h. en, the reaction mixture was
quenched with 20-ml 10% sodium hydroxide solution at 0 °C; the white solids precipitated
were collected by filtration, washed with a small amount of cold CH2Cl2 and water to get
1
pure anemarchalconyn 2 (88% yield) as a light yellow powder. m.p. 78–81 °C, H NMR
(400 MHz, CD3OD) δ: 7.41 (s, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 8.3 Hz, 2H), 6.74
(d, J = 8.3 Hz, 2H), 6.73 (dd, J = 8.4, 2.0 Hz, 1H), 6.66 (d, J = 2.0 Hz, 1H), 3.67 (s, 2H). 13
C
NMR (100 MHz, CD3OD) δ: 164.2, 162.4, 157.1, 156.1, 141.6, 131.2, 130.5, 130.0, 125.9,
116.3, 114.5, 113.5, 103.0, 36.4, which was identical to that in the literature [7].
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
Financial support from the Open Foundation of Antibiotics Research and Re-evaluation Key
Laboratory of Sichuan Province [grant number ARRLKF15-08] is greatly acknowledged.
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