An efficient synthesis of dichotomine a via cyclization of l-tryptophan derivative

Article abstract of DOI:10.14233/ajchem.2013.14662

A new synthetic method for dichotomine A is reported. The key step of the synthetic process is the efficient cyclization of L-tryptophan derivative via a modified Bischler-Napieralski reaction which aluminium chloride is used as a mild catalyst. Dichotomine A is obtained in 5 steps and 63.9 % yield.

Full text of DOI:10.14233/ajchem.2013.14662

Asian Journal of Chemistry; Vol. 25, No. 11 (2013), 6387-6390
http://dx.doi.org/10.14233/ajchem.2013.14662
An Efficient Synthesis of Dichotomine A via Cyclization of L-Tryptophan Derivative
1
1,*
2
2
1
XIU XIAO SHI , DIAN HE , SHAO BAI LI , XIN LEI and HUAN YANG
1School of Pharmacy, Lanzhou University, Lanzhou 730000, P.R. China
2State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P.R. China
*Corresponding author: Fax: +86 931 8915686; Tel: +86 13008738922; E-mail: hed@lzu.edu.cn
(Received: 11 October 2012;
Accepted: 10 May 2013)
AJC-13477
A new synthetic method for dichotomine A is reported. The key step of the synthetic process is the efficient cyclization of L-tryptophan
derivative via a modified Bischler-Napieralski reaction which aluminium chloride is used as a mild catalyst. DichotomineA is obtained in
5 steps and 63.9 % yield.
Key Words: Dichotomine A, β-Carboline alkaloids, Aluminium chloride, Cyclization.
the potentially same chiral group of dichotomine A. The
synthesis route was designed in Scheme-I.
INTRODUCTION
β-Carbolines represent a large group of alkaloids widely
distributed in nature, occurring in plants, marine organisms
and insects, most importantly, in foods and in human tissues
and body fluids. They have diverse medicinal properties1-6 such
as inhibition of topoisomerase and monoamine oxidase, binding
to benzodiazepine and serotonin receptors and intercalating
into DNA. Dichotomines A, B, C and D, new β-carboline-type
alkaloids, were first isolated from the roots of Stellaria
dichotoma in 20047. They showed an antiallergic effect on ear
passive cutaneous anaphylaxis reaction in mice and inhibitory
activity on the release of β-hexosaminidase in RBL-2H3 cells.
As shown in Fig. 1, the structure of dichotomines A, B, C and
D include a chiral group respectively.Although many methodo-
logies concerned the synthesis of β-carbolines8-13, the synthesis
of dichotomines is quite limited. Dichotomine C was obtained
by Omura and co-workers14 based on the microwave assisted
thermal electrocyclic reaction of a 1-azahexatriene system.
Nemet and Defterdarovic15 had synthesized dichotomine A as
racemic mixture via reactions of L-tryptophan or L-tryptophan
methyl ester with methyl glyoxal under acidic conditions.
Zhang and co-works16 had synthesized dichotomines A, B, C
and D starting from L-tryptophan methyl ester and 2,3-O-
isopropylidene-D-glyceraldehyde. From this total synthesis,
dichotomineA was obtained in 13 steps and only in 24 % yield.
So, we developed a new synthetic method for dichotomine A,
which could reduce steps and obtain a higher yield.
OH
OH
(R)
H
N
15
(S)
H
N
OH
2
H
14
9
N
N
1
8
10
13
N
N
3
7
COOR
12
11
COOH
6
Dichotomine B: R=H
Dichotomine C: R=CH3
Dichotomine D: R=CH2CH2CH3
4
5
COOH
Compound A
Dichotomine A
Fig. 1. Structure of dichotomines
EXPERIMENTAL
Melting point was determined in capillary tubes on an
electrothermal PIF YRT-3 apparatus and without correction.
The optical rotation of dichotomine A was measured with a
WZZ-1S polarimeter at room temperature. All reactions were
monitored by analytical thin-layer chromatography and silica
gel F254 was used in TLC. Merck kieselgel 60 (230-400 mesh)
was used for column chromatography and ethyl acetate/
petroleum ether mixtures served as the mobile phase.The structure
of all compounds was confirmed by 1H NMR, 13C NMR spectra
and mass spectroscopy. The H NMR and 13C NMR spectra
1
were obtained on Bruker Avance-300 NMR spectrometers in
CDCl3 with tetramethylsilane (TMS) as an internal standard,
unless otherwise stated. Chemical shifts were reported as δ (ppm).
Mass Spectra was measured on a HP-5988 mass spectrometer
and optical rotation was detected by WXG-4 polarimeters.
Synthesis of (S)-2-acetoxypropionyl chloride (10): The
mixture of L-lactic acid (7) (20 mmol) and acetic anhydride
We chose L-tryptophan and L-lactic acid as raw material
because they were inexpensive, commercially available and

6388 Shi et al.
Asian J. Chem.
O
O
O
O
(S)
(S)
(S)
g
h
i
(S)
OH
OH
HO
OAc
AcO
AcO
Cl
AcO
9
7
L-lactic acid
8
10
H
N
H
N
O
AcO
H
N
(S)
(S)
OAc
O
10
a
NH2
NH2
Cl
NH
(S)
(S)
(S)
b
COOH
COOMe
1
COOMe
OH
L-trytophan
3
2
OAc
(S)
H
N
OAc
(S)
H
N
(S)
H
N
e
f
d
N
c
N
N
(S)
COOMe
COOH
COOMe
4
5
Dichotomine A 6
Scheme-I: Reagents and conditions: (a) MeOH, SOCl2, reflux, 5 h; (b) Et3N, reflux, 5 min; (c) AlCl3, MeCN, reflux, 10 h; (d) Pd/C, p-xylene, reflux, 12 h; (e)
NaOH/H2O, EtOH, reflux, 1h; (f) HCl; (g) acetic anhydride, 4 h; (h) HCl/H2O, 15 min; (i) SOCl2, CH2ClCH2Cl, reflux, 6 h
(6 mL, 6.37 g, 62 mmol) stirred for 4 h at 80 ºC led to comp-
ound (8) and was cooled to 40 ºC, then the solution of water
(1.2 mL) and HCl (0.1 mL) was added quickly and after being
stirred for 15 min at ambient temperature, 1,2-dichloroethane
(40 mL) and thionyl chloride (10 mL) were also added. The
mixture was stirred for 3 h at 40 ºC and refluxed for 4 h. Then
the byproduct acetyl chloride translated from the relic acetic
acid and thionyl chloride was distilled off at low pressure.
The obtained crude product was not purified, used directly.
Preparation of L-tryptophan methyl ester (2): Thionyl
chloride was added to the solution of L-tryptophan (1) (0.36
g, 1.8 mmol) in excess anhydrous methanol (10 mL) at 0 ºC.
The mixture was allowed to warm to ambient temperature and
then stirred for 5 h at reflux temperature. The methanol was
evaporated under reduced pressure and the residue was alka-
lized by 10 % sodium bicarbonate solution until the pH value
was adjusted to 8-9. The solution was extracted with 1,2-
dichloroethane (3 × 10 mL) and the organic phase was dried
over anhydrous sodium sulfate and concentrated under reduced
pressure affording compound 2 (0.39 g, 98 %) as colourless oil:
MS m/z 218 (M+, 46), 130 (100), 159 (58); 1H NMR (300
MHz CDCl3) δ 8.76 (1H, s, NH), 7.61 (1H, d, J = 8.0 Hz),
7.32 (1H, d, J = 7.9Hz), 7.18 (1H, t, J = 8.2 Hz), 7.01 (1H, t,
J = 8.1 Hz), 6.97 (1H, s, H-2), 3.86 (1H, m, 11-H), 3.71 (3H,
s, -OCH3), 3.29 (1H, dd, J = 4.8, 4.3 Hz, CH2), 3.06 (1H, dd,
J = 6.6, 6.1 Hz, CH2), 1.69 (2H, s, -NH2); 13C NMR (75 MHz
CDCl3): δ 30.6 (CH2, C-10), 51.9 (-CH3, C-13), 54.8 (-CH, C-
11), 110.5 (CH, C-3), 111.2 (CH, C-8), 118.5 (CH, C-5), 119.2
(CH, C-7), 121.9 (CH, C-6), 123.1 (CH, C-2), 127.3 (C, C-4),
136.2 (C, C-9), 175.6 (CO, C-12).
added to the stirring solution of L-tryptophan methyl ester (2)
0.39 g (1.8 mmol) in 10 mL dry 1, 2-dichloroethane. At a low
temperature, (S)-2-acetoxypropionyl chloride (10) was added
dropwise and the mixture was monitored by TLC (ethyl acetate/
petroleum ether =1:1) until the complete disappearance of
L-tryptophan methyl ester on TLC. The solution was washed
with saturated salt water (3 × 10 mL). 1,2-dichloroethane was
steamed out under the reduced pressure. The residue was
purified by column chromatography using petroleum ether/
ethyl acetate (2:1, v/v) as the eluent to give N-(O-acetoxy-
propionyl)-L-tryptophan methyl ester (3) (0.39 g, 88.6 %) as
colourless oil:
MS m/z 332 (M+, 10), 272 (12), 130 (100), 201 (38); 1H
NMR (300 MHz CDCl3) δ 8.25 (1H, s, NH), 7.53 (1H, d, J =
8.0 Hz, NHCO), 7.36 (1H, d, J = 7.9 Hz, H-5), 7.14 (2H, m,
H-6, 7), 7.01 (1H, s, H-8), 6.53 (1H, s, CH), 4.93 (1H, m, H-
11), 4.51 (1H, m, H-14), 3.35 (3H, s, -OCH3), 3.29 (1H, dd, J
= 4.9, 12.4 Hz, H-10'), 2.84 (1H, dd, J = 6.8, 12.8 Hz, H-10''),
1.94 (3H, s, -OAc), 1.38 (3H, m, -CH3); 13C NMR (75 MHz
CDCl3): δ 16.2 (CH3, C-15), 20.3 (CH3, C-17), 30.9 (CH2, C-
10), 51.6 (CH3, C-19), 54.8 (CH, C-11), 79.5 (CH, C-14), 110.9
(C, C-3), 111.2 (CH, C-8), 119.1 (CH, C-5), 120.3 (CH, C-7),
122.6 (CH, C-6), 122.4 (CH, C-2), 127.2 (C, C-4), 136.5 (C,
C-9), 170.3 (C, C-18), 171.6 ( C, C-16), 172.4 (C, C-13).
Synthesis of 1-(1'-O-acetoxypropionyl)-ethyl-3-(methoxy-
carbonyl)-(3, 4-2H)-β-carboline (4): To a solution of comp-
ound 3 (1.0 g, 3 mmol) in anhydrous acetonitrile (30 mL),
aluminium chloride (0.1 g, 1equiv) was added. After the
mixture was stirred for 10 h at 80 ºC, the catalyst was removed
by filtration and the solution was distilled off under reduced
pressure. The caput mortuum was dissolved in dichloromethane
(30 mL) and washed with water (3 × 20 mL). The dichloro-
Synthesis of N-(O-acetoxypropionyl)-L-tryptophan
methyl ester (3): Triethylamine 0.25 mL (5.4 mmol) was

Vol. 25, No. 11 (2013)
An Efficient Synthesis of Dichotomine A via Cyclization of L-Tryptophan Derivative 6389
methane was dried over anhydrous sodium sulfate and
distilled off under reduced pressure. The residue was purified
by column chromatography using petroleum ether/ethyl
acetate (5:3, v/v) as the eluent to give the compound 4 (0.82 g,
87.3 %) as colourless oil:
121.7 (C, C-12), 122.0 (CH, C-5), 128.3 (CH, C-7), 128.5 (C,
C-11), 135.8 (C, C-10), 136.6 (C, C-13), 140.7 (C, C-3), 147.4
(C, C-1), 167.1 (C, C-16).
RESULTS AND DISCUSSION
MS m/z 314 (M+, 12), 255 (63), 196 (100), 168 (45), 147
L-tryptophan and L-lactic acid are commercially available
as natural products. Firstly, in order to improve the reactivity
of amino group, L-tryptophan methyl ester is obtained via
esterification of L-tryptophan17. Compound 3 can be obtained
through N-acylation reaction with L-tryptophan methyl ester,
L-lactic acid or L-lactic acid methyl ester. But, the yield of
product is low and purification difficult. So, (S)-2-acetoxy-
propionyl chloride was used instead of L-lactic acid methyl
ester or L-lactic acid. What was more, -NH- on compound 2
did not need to be protected because (S)-2-acetoxypropionyl
chloride tended to react with -NH2 much more easily. Due to
the much quicker rate of anhydride hydrolyzation than the
one of ester hydrolyzatoin in compound 8, compound 9 could
be obentained by controlling the quantization of water. The
obtained crude product compound 10 was not purified and
used directly.
1
(85), 122 (56), 59 (65); H NMR (300 MHz CDCl3) δ 8.25
(1H, s, NH-9), 7.53 (1H, d, J = 8.0Hz, H-5), 7.36 (1H, d, J =
7.8Hz, H-8), 7.14 (2H, m, H-6, 7), 4.93 (1H, m, H-14), 4.51
(1H, m, H-3), 3.65 (3H, s, -OCH3), 3.29 (1H, dd, J = 4.6, 12.8
Hz, H-4'), 2.88 (1H, dd, J = 6.9, 12.4 Hz, H-4''), 1.94 (3H, s,
H-18), 1.38 (3H, d, J = 5.8 Hz, H-15); 13C NMR (75 MHz
CDCl3): δ 14.1 (CH3, C-15), 20.7 (CH3, C-19), 30.3 (CH2,
C-4), 51.9 (CH3, C-17), 64.9 (CH, C-3), 75.5 (CH, C-14), 111.1
(CH, C-8), 112.9 (CH, C-5), 118.8 (CH, C-7), 119.1 (CH,
C-6), 121.7 (C, C-12), 125.9 (C, C-11), 126.6 (C, C-10), 138.7
(C, C-13), 170.3 (C, C-18), 173.4 (C, C-16).
Synthesis of 1-(1'-O-acetoxypropionyl)-ethyl-3-
(meth-oxycarbonyl)-β-carboline (5): Compound 4 (1 mmol)
was dissolved in p-xylene (10 mL) and 5 % Pd/C (0.01 g) was
added. The mixture was refluxed for 12 h, then the catalyst
was removed by filtration and p-xylene was distilled off under
reduced pressure. The residue was dissolved in chloroform
and the solution was washed with ammonium hydroxide. Then
the organic layer was separated and the aqueous layer was
washed several times with chloroform. All organic layers were
combined and dried by K2CO3. After distilling off the chloro-
form under reduced pressure, the remained oil was chromato-
graphed on petroleum ether/ethyl acetate (5:3, v/v) to provide
yellow oil compound 5 (86.0 % yield).
MS m/z 312 (M+, 8), 254 (82), 194 (100), 167 (54), 149
(86), 120 (60), 59 (56); 1H NMR (300 MHz CDCl3) δ 10.61
(1H, s, NH-9), 8.39 (1H, s, H-4), 8.12 (1H, d, J = 7.5 Hz, H-
5), 7.63 (1H, d, J = 7.6 Hz, H-8), 7.50 (1H, t, J = 7.8 Hz, H-7),
7.29 (1H, t, J = 7.9 Hz, H-6), 5.42 (1H, m, H-14), 3.89 (3H, s,
-OCH3), 2.21 (3H, s, H-18), 1.28 (3H, d, J = 5.4Hz, H-15);
13C NMR (75 MHz CDCl3): δ 19.6 (CH3, C-15), 21.1 (CH3, C-
19), 51.6 (CH3, C-17), 71.1 (CH, C-14), 111.2 (CH, C-8), 113.4
(CH, C-4), 119.1 (CH, C-5), 119.6 (CH, C-7), 121.3 (CH, C-
6), 121.6 (C, C-11), 127.4 (C, C-12), 131.0 (C, C-10), 133.6
(C, C-1), 143.2 (C, C-13), 148.5 (C, C-3), 165.3 (C, C-16),
170.3 (C, C-18).
Compound 4 could be synthesized through Bischler-
Napieralski reaction18-22. But the cyclization reaction under
catalysis of PCl5, POCl3 and P2O5, gave only compound A
(Fig. 1) which lost the chiral group. Manske23 had reported
aluminum chloride as cyclizing agent for synthesis of
tetrahydroisoquinolines at 1927. So aluminum chloride was
used in our synthesis route as a mild catalyst and target
compound 4 was obtained in a very satisfied yield (87.3 %
yield). Dichotomine A is obtained via oxidation reaction and
hydrolysis reaction.
Conclusion
We have achieved a new total synthesis of dichomonine
A via a modified Bischler-Napieralski reaction which aluminium
chloride is used as a mild cyclization reagent instead of PCl5,
POCl3 or P2O5. Dichomonine A was obtained in 5 steps and in
63.9 % yield. It also provides a novel method to synthesize
dichomonines B, C and D.
ACKNOWLEDGEMENTS
The authors are thankful to the Fundamental Research
Funds for the Central Universities for financial support. The
item number is lzujbky-2010-137.
Synthesis of dichotomineA (6): To the solution of comp-
ound 5 (1.25 g, 4 mmol) in ethanol solvent (10 mL), NaOH/
H2O (12 mmol/2 mL) was added. The mixture was refluxed
for 2 h and then the solution was extracted with a mixture of
ethyl acetate and water (1:1, v/v). The aqueous phase was
separated and then acidified with aqueous HCl (20 mmol).
Dichotomine A was crystallized as yellowish powder (1.0 g,
98.0 % yield). Dichotomine A: m.p. 267.1-267.5 ºC, [a]20D -
9.1º (C = 0.8, MeOH).
MS m/z 256 (M+, 10), 238 (20), 223 (68), 149 (100); 1H
NMR (400 MHz DMSO-d6), δ (ppm) 10.82 (1H, s, NH-9),
7.65 (1H, d, J = 7.8 Hz, H-4), 7.35 (2H, d, J = 7.5 Hz, H-5, 8),
7.27 (1H, m, H-7), 7.02 (1H, m, H-6), 5.78 (1H, m, H-14),
1.66 (1H, s, -OH), 1.18 (3H, d, J = 7.4 Hz, H-15); 13C NMR
(100 MHz DMSO-d6) δ = 21.6 (CH3, C-15), 67.4 (CHOH,
C-14), 112.1 (CH, C-8), 116.6 (CH, C-4), 120.6 (CH, C-6),
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