Synthesis and fungicidal activity of tryptophan analogues–the unexpected calycanthaceous alkaloid derivatives

Article abstract of DOI:10.1080/14786419.2016.1230117

A series of 21?N-protected tryptophan derivatives were synthesised from tryptophan in good yields. Their structures were characterised by IR,¹H NMR,¹³C NMR, DEPT (90° and 135°) and MS analysis. The synthesised compounds were evaluated against a wide variety of plant pathogen fungi. Compounds a19 and a21 displayed activity against Fusarium oxysporum (F. oxysporum), and compound a21 showed high activity against F. oxysporum and Eggplant Verticillium, with EC₅₀values of 58.27 and 77.39?μg?mL^?1, respectively. Considering that the bioassay of the title compounds was evaluated, effects of the chain alkyl substituents may contribute to the significant variations in fungicidal potency. Their structure–antifungal activity relationships were also discussed. These results will pave the way for further design, structural modification and development of calycanthaceous alkaloids as antimicrobial agents.

Full text of DOI:10.1080/14786419.2016.1230117

Natural Product Research
Formerly Natural Product Letters
ISSN: 1478-6419 (Print) 1478-6427 (Online) Journal homepage: http://www.tandfonline.com/loi/gnpl20
Synthesis and fungicidal activity of tryptophan
analogues – the unexpected calycanthaceous
alkaloid derivatives
Shaojun Zheng, Yongdong Gu, Longbo Li, Rui Zhu, Xingwei Cai, Hongjin Bai &
Jiwen Zhang
To cite this article: Shaojun Zheng, Yongdong Gu, Longbo Li, Rui Zhu, Xingwei Cai, Hongjin
Bai & Jiwen Zhang (2016): Synthesis and fungicidal activity of tryptophan analogues –
the unexpected calycanthaceous alkaloid derivatives, Natural Product Research, DOI:
10.1080/14786419.2016.1230117
To link to this article: http://dx.doi.org/10.1080/14786419.2016.1230117
View supplementary material
Published online: 21 Sep 2016.
Submit your article to this journal
Article views: 5
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=gnpl20
Download by: [George Mason University]
Date: 30 September 2016, At: 03:57

Natural Product research, 2016
ꢁꢁp://ꢂx.ꢂꢃi.ꢃꢄg/10.1080/14786419.2016.1230117
ꢀ
Synthesis and fungicidal activity of tryptophan analogues –
the unexpected calycanthaceous alkaloid derivatives
a,d
a
c
a
a
b
Shaojun Zheng , Yongdong Gu , Longbo Li , Rui Zhu , Xingwei Cai , Hongjin Bai and
Jiwen Zhang
c
ꢅ
sꢆꢀꢃꢃꢇ ꢃf enviꢄꢃnmꢈnꢁꢅꢇ ꢅnꢂ cꢀꢈmiꢆꢅꢇ enginꢈꢈꢄing, Jiꢅngꢉꢊ univꢈꢄꢉiꢁy ꢃf sꢆiꢈnꢆꢈ ꢅnꢂ tꢈꢆꢀnꢃꢇꢃgy,
b
Zꢀꢈnjiꢅng, P.r. cꢀinꢅ; Kꢈy lꢅbꢃꢄꢅꢁꢃꢄy ꢃf Pꢄꢃꢁꢈꢆꢁiꢃn & uꢁiꢇizꢅꢁiꢃn ꢃf Biꢃꢇꢃgiꢆꢅꢇ rꢈꢉꢃꢊꢄꢆꢈꢉ in tꢅꢄim Bꢅꢉin ꢃf
Xinjiꢅng Pꢄꢃꢂꢊꢆꢁiꢃn ꢅnꢂ cꢃnꢉꢁꢄꢊꢆꢁiꢃn cꢃꢄpꢉ/cꢃꢇꢇꢈgꢈ ꢃf lifꢈ sꢆiꢈnꢆꢈꢉ, tꢅꢄim univꢈꢄꢉiꢁy, aꢇꢅꢄ, P.r. cꢀinꢅ; Kꢈy
lꢅbꢃꢄꢅꢁꢃꢄy ꢃf Bꢃꢁꢅniꢆꢅꢇ Pꢈꢉꢁiꢆiꢂꢈ r & d in sꢀꢅꢅnxi Pꢄꢃvinꢆꢈ, Yꢅngꢇing, P.r. cꢀinꢅ; cꢃꢇꢇꢅbꢃꢄꢅꢁivꢈ Innꢃvꢅꢁiꢃn
ꢆ
ꢂ
cꢈnꢁꢈꢄ ꢃf sꢀip tꢈꢆꢀnꢃꢇꢃgy in Jiꢅngꢉꢊ cꢃꢇꢇꢈgꢈꢉ ꢅnꢂ univꢈꢄꢉiꢁiꢈꢉ/Mꢅꢄinꢈ eqꢊipmꢈnꢁ ꢅnꢂ tꢈꢆꢀnꢃꢇꢃgy Inꢉꢁiꢁꢊꢁꢈ
fꢃꢄ Jiꢅngꢉꢊ univꢈꢄꢉiꢁy ꢃf sꢆiꢈnꢆꢈ ꢅnꢂ tꢈꢆꢀnꢃꢇꢃgy, Zꢀꢈnjiꢅng, P.r. cꢀinꢅ
ABSTRACT
ARTICLE HISTORY
rꢈꢆꢈivꢈꢂ 12 Mꢅy 2016
aꢆꢆꢈpꢁꢈꢂ 3 aꢊgꢊꢉꢁ 2016
A series of 21 N-protected tryptophan derivatives were synthesised
from tryptophan in good yields. Their structures were characterised
1
13
by IR, H NMR, C NMR, DEPT (90° and 135°) and MS analysis. The
synthesised compounds were evaluated against a wide variety of
plant pathogen fungi. Compounds a19 and a21 displayed activity
against Fusarium oxysporum (F. oxysporum), and compound a21
showed high activity against F. oxysporum and Eggplant Verticillium,
KEYWORDS
cꢅꢇyꢆꢅnꢁꢀꢅꢆꢈꢃꢊꢉ ꢅꢇkꢅꢇꢃiꢂꢉ;
ꢉynꢁꢀꢈꢉiꢉ; fꢊngiꢆiꢂꢅꢇ ꢅꢆꢁiviꢁy;
ꢅgꢄꢃꢆꢀꢈmiꢆꢅꢇꢉ; ꢁꢄypꢁꢃpꢀꢅn
−1
with EC50 values of 58.27 and 77.39 μg mL , respectively. Considering
that the bioassay of the title compounds was evaluated, effects of the
chain alkyl substituents may contribute to the significant variations in
fungicidal potency. Their structure–antifungal activity relationships
were also discussed. These results will pave the way for further design,
structural modification and development of calycanthaceous alkaloids
as antimicrobial agents.
CONTACT sꢀꢅꢃjꢊn Zꢀꢈng
ꢉz281ꢆꢅm@jꢊꢉꢁ.ꢈꢂꢊ.ꢆn; hꢃngjin Bꢅi
bꢀj67@163.ꢆꢃm, ꢉkybꢀj@ꢁꢅꢄꢊ.ꢈꢂꢊ.ꢆn;
Jiwꢈn Zꢀꢅng nwzjw@nwꢉꢊꢅf.ꢈꢂꢊ.ꢆn
sꢊppꢇꢈmꢈnꢁꢅꢇ ꢂꢅꢁꢅ fꢃꢄ ꢁꢀiꢉ ꢅꢄꢁiꢆꢇꢈ ꢆꢅn bꢈ ꢅꢆꢆꢈꢉꢉꢈꢂ ꢀꢁꢁp://ꢂx.ꢂꢃi.ꢃꢄg/10.1080/14786419.2016.1230117
2016 Infꢃꢄmꢅ uK limiꢁꢈꢂ, ꢁꢄꢅꢂing ꢅꢉ tꢅyꢇꢃꢄ & Fꢄꢅnꢆiꢉ Gꢄꢃꢊp
©

2
S. ZHENG ET AL.
1
. Introduction
Natural products with novel scaffolds always afford an opportunity to discover novel anti-
microbial agents that operate by modes of action different from those that are already
known. Consequently, the resulting new agrochemicals have the opportunity to overcome
resistance to chemicals currently in use (Walter 2002; Newman & Cragg 2007; Lin et al. 2012).
Calycanthaceous alkaloids (Zhang, Li, Ji et al. 2009; Xiang et al. 2010) (Figure 1), mainly dis-
tributed in China, North America and Australia (Kozomara et al. 2008; Zhang et al. 2014), are
an important class of alkaloid that can be isolated from roots, leaves, flowers and fruits of
chimonanthus praecox (Liu et al. 2008). These compounds have demonstrated important
biological activities such as anticonvulsant, antifungal, antiviral, analgesic, anti-tumour and
melanogenesis inhibitory properties (Zhang, Gao et al. 2009; Lv et al. 2012; Araki et al. 2013;
Gui et al. 2014). Because of their broad spectrum of biological properties, a number of studies
aimed at the synthesis and antimicrobial activity of calycanthaceous alkaloids have been
reported (Hino &Yamada 1963; Hall et al. 1967; Fang et al. 1994; Movassaghi & Schmidt 2007;
Ruiz-Sanchis et al. 2011; Li et al. 2012; Araki et al. 2013; Peng et al. 2013; Kim & Movassaghi
2015; Xu & Cheng 2015). However, little attention has been paid to the structural optimisation
of the core structure tetrahydropyrroloindole of calycanthaceous alkaloids for their antimi-
crobial activities. Therefore, we envisioned that the structural optimisation might be a lead
for the discovery of novel agricultural fungicides.
Herein, a series of N-protected tryptophan derivatives were synthesised using tryptophan
as starting material via an efficient method. Their antimicrobial effects and structure anti-
fungal activity relationships were investigated. To the best of our knowledge, the antimicro-
bial activities of the synthetic derivatives were reported for the first time.
2
. Results and discussion
2
.1. Synthesis
The synthetic route of the title compounds is outlined in Scheme 1. The N-protected tryp-
tophan derivatives were synthesised using tryptophan as the starting material via alkylation
at the 1-N position. Alkylation resulted in unexpected ring opening of the calycanthaceous
alkaloids core structure at the C–N bond, and the possible mechanism of the unexpected
ring opening of the calycanthaceous alkaloids core structure at the C–N bond is shown in
Figure 2; 21 tryptophan methyl ester derivatives were synthesised, 19 of which have not
1
been previously characterised. The synthesised compounds were characterised by H NMR,
13
C NMR, DEPT (90° and 135°) and MS analysis.
Figure 1. sꢁꢄꢊꢆꢁꢊꢄꢈꢉ ꢃf ꢆꢅꢇyꢆꢅnꢁꢀꢅꢆꢈꢃꢊꢉ ꢅꢇkꢅꢇꢃiꢂꢉ.

NATꢀRAL PRꢁDꢀCT RESEARCH
3
Figure 2. tꢀꢈ pꢃꢉꢉibꢇꢈ mꢈꢆꢀꢅniꢉm ꢃf ꢁꢀꢈ ꢊnꢈxpꢈꢆꢁꢈꢂ ꢄing ꢃpꢈning ꢃf ꢁꢀꢈ ꢆꢅꢇyꢆꢅnꢁꢀꢅꢆꢈꢃꢊꢉ ꢅꢇkꢅꢇꢃiꢂꢉ ꢆꢃꢄꢈ
ꢉꢁꢄꢊꢆꢁꢊꢄꢈ ꢅꢁ ꢁꢀꢈ c–N bꢃnꢂ.
2
.2. Fungicidal activity
The biological activities of these compounds towards a wide variety of plant pathogen fungi
were evaluated, with the following results:
Inhibitory effects of N-protected tryptophan derivatives against phytopathogenic fungus are
listed in Table 1. Mycelium growth inhibition assay was utilised, with carbendazim as a positive
control, to evaluate the biological activities of the 21 synthesised N-protected tryptophan
derivatives against Eggplant Verticillium (E. Verticillium), Fusarium oxysporum (F. oxysporum),
Colletrotrichum gloesporioides, Botrytis cinerea (B. cinerea), Alternaria alternate (A. alternate),
Gibberella zeae (G. zeae), Sclerotinia sclerotiorum (S. sclerotiorum) and Curvularia lunata
−1
(
C. lunata) at the concentration of 100 μg mL . Among the synthesised compounds, com-
pounds a19 and a21 displayed activity against F. oxysporum, and compound a21 showed
high activity against F. oxysporum and E. Verticillium, with EC values of 58.27 and
5
0
−
1
7
7.39 μg mL , respectively(Tables 2 and 3).
3
. Experimental
3
.1. Instruments and chemicals
All reagents and solvents were of reagent grade or purified according to standard methods
before use. Analytical thin-layer chromatography (TLC) was performed with silica gel plates
using silica gel 60 GF254 (Qingdao Haiyang Chemical Co., Ltd.). Melting points were measured
1
on an electrothermal digital apparatus made in Beijing and were uncorrected. The H NMR
13
(
500 MHz) and C NMR (125 MHz) were obtained on a Bruker AM-500 FT NMR spectrometer
with CDCl as the solvent and TMS as the internal standard. MS were recorded under ESI
3
conditions using aThermo LCQ Fleet instrument. Infrared spectra were measured on a Nicolet
−1
FT-IR-20SX instrument using a potassium bromide (KBr) disc, scanning from 625 to 4000 cm .
ptical rotation was measured by Rudolph Autopol II. Yields were not optimised. The title
compounds were synthesised under a nitrogen atmosphere.
ꢁ

4
S. ZHENG ET AL.

NATꢀRAL PRꢁDꢀCT RESEARCH
5
Table 2. Inꢀibiꢁꢃꢄy ꢈffꢈꢆꢁ ꢃf a21 ꢅgꢅinꢉꢁ F. oxysporum.
Fusarium oxysporum
Correlation coefficient (r2)
EC50 ± SD (μg mL−1)
Compound
Regression equation
a21
Y = 0.3413X + 3.6126
0.8395
58.27 ± 3.31
Table 3. Inꢀibiꢁꢃꢄy ꢈffꢈꢆꢁ ꢃf a21 ꢅgꢅinꢉꢁ F. oxysporum ꢅnꢂ Eggplant Verticillium.
Fusarium oxysporum
Eggplant Verticillium
Regression
equation
Corre-
lation
coeffi-
EC50 ± SD
Regression
equation
Correlation
coefficient
EC50 ± SD
−
1
−1
(μg mL )
(μg mL )
2
(r )
2
Compound
cient (r )
a21
Y = 0.3413X + 3.6126
0.8395
58.27 ± 3.31 Y = 0.5703X + 2.5501
0.8470
77.39 ± 1.68
Scheme 1. synꢁꢀꢈꢁiꢆ ꢄꢃꢊꢁꢈ fꢃꢄ ꢁꢀꢈ ꢁiꢁꢇꢈ ꢆꢃmpꢃꢊnꢂꢉ a1-a21.
3
.2. Synthesis
The general synthetic methods for compounds a1–a21 are depicted in Scheme 1.
3
.2.1. Synthesis of compound 6
To a stirred solution of tryptophan (4.08 g, 20 mmol) in 30 mL of methanol was added thionyl
chloride (1.74 mL, 24 mmol, 1.2 eq.) dropwise at 0 °C. The resulting mixture was allowed to
warm to RT for a further 1 h. The solvents were removed to provide the desired product 6.
3
.2.2. Synthesis of compound 7
To a solution of the compound 6 (3.27 g, 15 mmol) in 20 mL of pyridine was added methyl
chloroformate (1.44 mL, 18 mmol, 1.2 eq.) dropwise at 0 °C. The resulting mixture was allowed
to warm to RT until TLC monitoring indicated the disappearance of the material 6 (0.5 h),
and then, the reaction mixture was quenched with methanol (1 mL) and extracted three
times with ethyl acetate. The organic extracts were combined, washed with brine, dried over
Na Sꢁ and concentrated. Purification by flash chromatography on silica gel (petroleum
2
4
ether: acetone = 4:1) afforded the compound 7.
3
.2.3. Synthesis of compound 8
To the compound 7 (2.77 g, 10 mmol) was added 27 mL of H Pꢁ (85%), and the mixture
3
4
was stirred until TLC monitoring indicated the disappearance of the material 7 (12 h). The
reaction mixture was poured into ice water and neutralised to pH 7 with a saturated NaHCꢁ3

6
S. ZHENG ET AL.
and extracted three times with ethyl acetate. The separated organic phase was washed with
water and brine and dried over Na Sꢁ . The solvent was removed under reduced pressure.
2
4
The crude product 8 was used for the next step without further purification.
3
.2.4. General procedure for the preparation of compounds a1–a21
To a solution of the compound 8 (276 mg, 1 mmol) in acetonitrile (20 mL) was added NaHCꢁ3
252 mg, 3 mmol, 3 eq.) and the corresponding desired reagents (b-series) (1.5 mmol, 1.5 eq.).
(
The resulting mixture was refluxed for 12 h. and then extracted three times with dichlo-
romethane. The organic extracts were combined, washed with brine, dried over Na Sꢁ and
2
4
concentrated. Purification by flash chromatography on silica gel afforded the compounds
a1-a21.
Methyl N-(methoxycarbonyl)-1-methyl-L-tryptophanate(a1) (Taniguchi et al. 1983):
1
Reagents: methyl iodide. colourless crystals, H NMR (CDCl , 500 MHz) δ 3.29 (d, 2H, J = 5.1),
3
3
.66 (s, 3H), 3.68 (s, 3H), 3.74 (s, 3H), 4.67 (d, 1H, J = 7.6), 5.23 (d, 1H, J = 6.8), 6.84 (s, 1H), 7.11
1
3
(
t, 1H, J = 7.7), 7.22 (t, 1H, J = 7.7), 7.27 (t, 1H, J = 8.2), 7.52 (d, 1H, J = 7.9) C NMR (CDCl3,
25 MHz) δ 27.80 (CH ), 32.72 (CH ), 52.29 (CH ), 52.33 (CH ), 54.48 (CH), 108.24 (C), 109.32
1
2
3
3
3
(CH), 118.67 (CH), 119.19 (CH), 121.82 (CH), 127.46 (CH), 128.03 (C), 136.93 (C), 156.48 (C),
172.51 (C).
The data of the other compounds and the NMR spectral details can be found in the
Supplementary data.
3
.3. Biological assay
The antimicrobial activity of N-protected tryptophan derivatives was measured according
to the previously reported method (Zhang, Li & Wu 2009; Zhang et al. 2013).
3
.3.1. Inhibition of spore germination method
The spore suspension was adjusted with sterile distilled water. The compounds dissolved in
% dimethyl sulfoxide (DMSꢁ), and then, dilutions with the spore suspensions were made
1
−
1
in a concentration of 100.0 μg mL . A known volume of 70 μL of the spore suspensions was
taken onto the glass slide. About 100 spores were counted, and percentage of spore germi-
nation was calculated. Carbendazim was used as the positive control and the blank test. All
experiments were conducted in triplicate. EC was determined by performing the bioassay
5
0
−1
as described above with concentrations of 100, 75, 50, 37.5 and 25 μg mL , respectively.
3
.3.2. Inhibition of the growth of fungal mycelium
The tested pathogenic fungi: E. Verticillium, F. oxysporum, Colletotrichum gloesporioides, B.
cinerea, A. alternate, G. zeae, S. sclerotiorum and C. lunata were provided by the Institute of
Pesticides, Northwest A&F ꢀniversity. The tested compounds dissolved in 1% of DMSꢁ were
screened for antifungal activity in vitro by measurement of inhibitory zone diameter. The
general procedure is as follows:
Cultures of the test fungus were maintained on potato-dextrose-agar medium and were
subcultured in Petri dishes prior to testing. The ready-made medium was suspended in
distilled water. Stock solutions were prepared by dissolving the test materials in sterile dis-
−1
tilled water and diluted to a concentration of 100.0 μg mL . The medium was poured into

NATꢀRAL PRꢁDꢀCT RESEARCH
7
a set of two Petri dishes (two replicates) under aseptic conditions in a laminar flow chamber.
When the medium in the plates was partially solidified, a 5-mm-thick disc of fungus (spores
and mycelium) cut from earlier subcultured Petri dishes was placed at the centre of the
semi-solid medium and the lids of the dishes were replaced. The treated and control dishes
were kept in an incubator at 26 (±2) °C till the fungal growth in the control dishes was almost
complete (2 ± 3 days). The mycelial growth of fungus (mm) in both treated (T) and control
(C). About 1% of DMSꢁ and carbendazim were used as the negative control and the positive
control, respectively. Petri dishes were measured diametrically in three different directions,
and the growth inhibition (I) was calculated using the formula:
I(%) = {(C-d) − (T-d)}∕(C-d) × 100
where d: diameter of the cut fungus, C: diameter of the control fungus, T: diameter of the
treated fungus (measurement unit: mm, two colonies were counted in two dishes. It was
repeated for three times.). EC50 was determined by performing the bioassay as described
above with five different concentrations.
4
. Conclusions
In conclusion, 21 N-protected tryptophan derivatives were synthesised by modification
at the 1-N position, and evaluated for their antimicrobial activity against a wide variety
of plant pathogen fungi. The bioassays indicated that among the synthesised com-
pounds, the short-chain alkyl substituents at the 1-N position exhibited high degrees
of activity against Bacillus subtilis, while the long-chain alkyl substituents at the 1-N
position showed no activity. The analogues a19 and a21 demonstrated high degrees
of activity against F. oxysporum, sharing fluorine substituents at 2, 6-position on the
phenyl groups in common. ꢁn the basis of the SAR analysis, it can be concluded that
the variances among substituents on the 1-N position showed a significant relationship
with fungicidal activity against a wide variety of plant pathogen fungi. Furthermore,
considering that the bioassay of the title compounds was evaluated, effects of the chain
alkyl substituents may contribute to the significant variations in fungicidal potency.
These results will pave the way for further design, structural modification and develop-
ment of calycanthaceous alkaloids as antimicrobial agents.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This work was supported by the National Natural Science Foundation of China [grant number
31360079], [grant number 21372185], [grant number 21502073]; the Natural Science Foundation of
Jiangsu Province [grant number BK 20150465]; Collaborative innovation Center of Ship Technology in
Jiangsu Colleges and ꢀniversities/Marine Equipment and Technology Institute for Jiangsu ꢀniversity
of Science and Technology [grant number HZ2016012].

8
S. ZHENG ET AL.
References
Araki T, Manabe Y, Fujioka K, Yokoe H, Kanematsu M, Yoshida M, Shishido K. 2013. Total syntheses of
(±)-folicanthine and (±)-chimonanthine via a double intramolecular carbamoylketene–alkene [2+2]
cycloaddition. Tetrahedron Lett. 54:1012–1014.
Fang CL, Horne S, Taylor N, Rodrigo R. 1994. Dimerization of a 3-substituted oxindole at C-3 and its
application to the synthesis of (.+–.)-folicanthine. J Am Chem Soc. 116:9480–9486.
Gui RY, Liang WW, Yang SX, Llu L, Qin JC. 2014. Chemical composition, antifungal activity and toxicity
of essential oils from the leaves of Chimonanthus praecox located at two different geographical
origin. Asian J Chem. 26:4445–4448.
Hall ES, McCapra F, Scott AI. 1967. Biogenetic-type synthesis of the calycanthaceous alkaloids.
Tetrahedron. 23:4131–4141.
Hino T, Yamada S-I. 1963. Total synthesis of (±)-folicanthine. Tetrahedron Lett. 4:1757–1760.
Kim J, Movassaghi M. 2015. Biogenetically-inspired total synthesis of epidithiodiketopiperazines and
related alkaloids. Acc Chem Res. 48:1159–1171.
Kozomara B, Vinterhalter B, Radojević L, Vinterhalter D. 2008. In vitro propagation of Chimonanthus
praecox (L.), a winter flowering ornamental shrub. In Vitro Cell Dev Biol: Plant. 44:142–147.
LiY-X, Wang H-X, Ali S, Xia X-F, LiangY-M. 2012. Iodine-mediated regioselective C2-amination of indoles
and a concise total synthesis of (±)-folicanthine. Chem Commun. 48:2343–2345.
Lin L, Mulholland N, Wu Q-Y, Beattie D, Huang S-W, Irwin D, Clough J, Gu Y-C, Yang G-F. 2012. Synthesis
and antifungal activity of novel sclerotiorin analogues. J Agric Food Chem. 60:4480–4491.
Liu Y, Liu Y, Xiao H, Gao R, Tian X. 2008. Synthesis and insecticidal activities of novel derivatives of
podophyllotoxin: Part XII. Pestic Biochem Physiol. 91:116–121.
Lv JS, Zhang LL, Chu XZ, Zhou JF. 2012. Chemical composition, antioxidant and antimicrobial activity of
the extracts of the flowers of the Chinese plant Chimonanthus praecox. Nat Prod Res. 26:1363–1367.
Movassaghi M, Schmidt MA. 2007. Concise total synthesis of (−)-calycanthine, (+)-chimonanthine, and
(+)-folicanthine. Angew Chem Int Edit. 46:3725–3728.
Newman DJ, Cragg GM. 2007. Natural products as sources of new drugs over the last 25 years. J Nat
Prod. 70:461–477.
Peng Y, Luo L, Yan CS, Zhang JJ, Wang YW. 2013. Ni-catalyzed reductive homocoupling of unactivated
alkyl bromides at room temperature and its synthetic application. J ꢁrg Chem. 78:10960–10967.
Ruiz-Sanchis P, Savina SA, Albericio F, Álvarez M. 2011. Structure, bioactivity and synthesis of natural
products with hexahydropyrrolo[2,3-b]indole. Chem Eur J. 17:1388–1408.
Taniguchi M, Gonsho A, Nakagawa M, Hino T. 1983. Cyclic tautomers of tryptophans and tryptamines.
VI. Preparation of Na-alkyl-,5-chloro-, and 5-nitrotryptophan derivatives. Chem Pharm Bull. 31:1856–
1865.
Walter MW. 2002. Structure-based design of agrochemicals. J Nat Prod. 19:278–291.
Xiang L, Zhao K, Chen L. 2010. Molecular cloning and expression of Chimonanthus praecox farnesyl
pyrophosphate synthase gene and its possible involvement in the biosynthesis of floral volatile
sesquiterpenoids. Plant Physiol Biochem. 48:845–850.
Xu JB, Cheng kJ. 2015. Studies on the alkaloids of the calycanthaceae and their syntheses. Molecules.
20:6715–6738.
Zhang JW, Gao JM, XuT, Zhang XC, MaYT, Jarussophon S, KonishiY. 2009. Antifungal activity of alkaloids
from the seeds of chimonanthus praecox. Chem Biodivers. 6:838–845.
Zhang JW, Li SK, Ji ZQ, Hu ZN, Wu WJ. 2009. Synthesis and insecticidalactivity of novel dimers of
celangulin-V and podophyllotoxin. Chem Nat Compd. 45:507–510.
Zhang JW, Li SK, Wu WJ. 2009. The main chemical composition and in vitro antifungal activity of the
essential oils of ꢁcimum basilicum Linn. var. pilosum (Willd.) Benth. Molecules. 14:273–278.
Zhang WJ, Wei SP, Zhang JW, Wu WJ. 2013. Antibacterial activity composition of the fermentation broth
of streptomyces djakartensis NW35. Molecules. 18:2763–2768.
Zhang J, Cui L, Li L, Hu Z, Zhang Q, Hu Z, Wu W. 2014. Synthesis and insecticidal activities of novel
nitrogenous derivatives of celangulin-V. Nat Prod Commun. 9:745–748.