Design and synthesis of sinomenine isoxazole derivatives via 1,3-dipolar cycloaddition reaction

Article abstract of DOI:10.1080/14786419.2019.1677649

A novel structure of sinomenine isoxazole derivatives is synthesised from sinomenine hydrochloride and aromatic aldehydes and requires six steps. 19 target compounds have been obtained in good yields. The sinomenine hydrochloride transforms to 4-alkynyl sinomenine, which is a key intermediate product to synthesise the target sinomenine isoxazole compounds, after a neutralisation reaction with ammonia and substitution reaction with 3-chloropropyne. Another key intermediate product is 1,3-dipole, which can be obtained from aromatic aldehyde. After treatment with hydroxylamine hydrochloride and then sodium carbonate solution, aromatic aldehyde is converted to aldehyde oxime, which reacts with N-chlorosuccinimide (NCS) to afford aryl hydroximino chloride. 1,3-Dipole is eventually formed in situ while triethylamine (TEA) in DMF is added dropwise. Then 4-alkynyl sinomenine is added to provide the sinomenine isoxazole derivative via 1,3-dipolar cycloaddition reaction as the key step. All the target compounds are characterised by melting point, ¹H NMR, ¹³C NMR, HRMS and FT-IR spectroscopy.

Full text of DOI:10.1080/14786419.2019.1677649

Natural Product Research
Formerly Natural Product Letters
ISSN: 1478-6419 (Print) 1478-6427 (Online) Journal homepage: https://www.tandfonline.com/loi/gnpl20
Design and synthesis of sinomenine isoxazole
derivatives via 1,3-dipolar cycloaddition reaction
Hongmei Pan, Tong Lu, Xuedan Wu, Chengwen Gu, Naili Tao, Biao Zhang, Ao
Wang, Guangmei Chen, Kehua Zhang, Jie Cheng & Jie Jin
To cite this article: Hongmei Pan, Tong Lu, Xuedan Wu, Chengwen Gu, Naili Tao, Biao Zhang,
Ao Wang, Guangmei Chen, Kehua Zhang, Jie Cheng & Jie Jin (2019): Design and synthesis of
sinomenine isoxazole derivatives via 1,3-dipolar cycloaddition reaction, Natural Product Research,
DOI: 10.1080/14786419.2019.1677649
To link to this article: https://doi.org/10.1080/14786419.2019.1677649
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Published online: 17 Oct 2019.
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NATURAL PRODUCT RESEARCH
https://doi.org/10.1080/14786419.2019.1677649
Design and synthesis of sinomenine isoxazole derivatives
via 1,3-dipolar cycloaddition reaction
Hongmei Pana, Tong Lua, Xuedan Wua, Chengwen Gua, Naili Taoa, Biao Zhanga,
Ao Wanga, Guangmei Chena, Kehua Zhanga, Jie Chengb and Jie Jina
aSchool of Materials and Chemical Engineering, Anhui Jianzhu University, Hefei, P. R. China;
bDepartment of Chemistry, Anhui Institute for Food and Drug Control, Hefei, P. R. China
ABSTRACT
ARTICLE HISTORY
Received 18 July 2019
Accepted 22 September 2019
A novel structure of sinomenine isoxazole derivatives is synthes-
ised from sinomenine hydrochloride and aromatic aldehydes and
requires six steps. 19 target compounds have been obtained in
good yields. The sinomenine hydrochloride transforms to
4-alkynyl sinomenine, which is a key intermediate product to
synthesise the target sinomenine isoxazole compounds, after a
neutralisation reaction with ammonia and substitution reaction
with 3-chloropropyne. Another key intermediate product is 1,3-
dipole, which can be obtained from aromatic aldehyde. After
treatment with hydroxylamine hydrochloride and then sodium
carbonate solution, aromatic aldehyde is converted to aldehyde
oxime, which reacts with N-chlorosuccinimide (NCS) to afford aryl
hydroximino chloride. 1,3-Dipole is eventually formed in situ while
triethylamine (TEA) in DMF is added dropwise. Then 4-alkynyl
sinomenine is added to provide the sinomenine isoxazole deriva-
tive via 1,3-dipolar cycloaddition reaction as the key step. All the
target compounds are characterised by melting point, 1H NMR,
13C NMR, HRMS and FT-IR spectroscopy.
KEYWORDS
Sinomenine; isoxazole;
synthesis; derivative; 1,3-
dipolar
cycloaddition reaction
1. Introduction
Sinomenine is a natural product mainly used for the treatment of rheumatoid arthritis
(Tang et al. 2006), joint swelling and pain (Teng et al. 2011), and has a curative effect
with an effective rate of over 90% (Huang and Cheng 2002). However, there are some
disadvantages when treating diseases, for example, hypersusceptibility and large dose
CONTACT Jie Jin
jinjie@ahjzu.edu.cn; Kehua Zhang
zkhzhang@163.com; Jie Cheng
chengjie_234@163.com
Supplemental data for this article can be accessed at https://doi.org/10.1080/14786419.2019.1677649.
ß 2019 Informa UK Limited, trading as Taylor & Francis Group

2
H. PAN ET AL.
Scheme 1. Synthesis of sinomenine isoxazole derivatives.
(Tang et al. 2006). In order to obtain derivatives with less side effects and better bio-
logical activities, many structural modification researches of sinomenine have been
reported to reduce these side effects and improve its further applications, some com-
pounds show good biological activities (Zhou et al. 2014; Zhao et al. 2016; Wei
et al. 2017).
Sinomenine is isolated from the stems and roots of the plant Sinomenium acutum
(Cheong et al. 2007), native to China and Japan (Yamasaki 1976; Garcia et al. 2016).
Structurally, sinomenine is similar to morphinane skeleton, and possesses four fused
rings and a number of chemically active groups (Tang et al. 2018), such as 1-aromatic
hydrogen, 3-anisole, 4-phenol, 6-carbonyl group, 7-enol ether, and 17-tertiary amine,
this determines that sinomenine is suitable for structural modification. Heterocycles
are often considered to be key active structures of drug molecules, therefore, modify-
ing the heterocyclic structure on sinomenine is an effective way to increase biological
activities (Zheng et al. 2011; Chai et al. 2012; Wang et al. 2012; Zhou et al. 2015). Our
group has previously reported isoxazoline derivatives of sinomenine with moderate to
good activities (Jin et al. 2013). Consequently, as an in-depth research work, here we
report a novel sinomenine heterocyclic derivative, sinomenine isoxazole derivatives, as
far as we know, this is also the first report of this type of structure.
2. Results and discussion
The free phenolic hydroxyl on ring A is readily oxidised by air and may be the main
cause of hypersusceptibility (Zheng et al. 2012, 2014), therefore, we choose 4-OH as
our modification site to reduce this side effect. Isoxazole is a five-membered nitrogen
heterocycle, which is present in a variety of molecules with excellent biological activ-
ities. Isoxazole can be synthesised by 1,3-dipolar cycloaddition reaction from an alkyne
and a 1,3-dipole. There are two ways to construct sinomenine isoxazole derivatives.
One is to construct an alkyne on sinomenine and then react it with a 1,3-dipole, and
the other is to construct 1,3-dipole on sinomenine and then react it with an alkyne,
however, this method may cause the 6-carbonyl group to participate simultaneously
in the formation of 1,3-dipole reaction, resulting in unwanted by-products. So, we
choose the first method to synthesise our target sinomenine isoxazole moleculars. The
synthetic route toward the target compounds is outlined in Scheme 1 and requires 6
steps (Scheme 1).

NATURAL PRODUCT RESEARCH
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Figure 1. Sinomenine isoxazole derivatives.

4
H. PAN ET AL.
The sinomenine hydrochloride one is neutralised with ammonia to form sinome-
nine 2, which reacts with 3-chloropropyne under the action of KOH in DMF to form
4-alkynyl sinomenine 3, this is a key intermediate product to synthesise the target
sinomenine isoxazole compounds. Another key intermediate product to synthesise the
isoxazole is 1,3-dipole, which can be obtained from aromatic aldehyde 4. After treat-
ment with hydroxylamine hydrochloride and then sodium carbonate solution, aromatic
aldehyde four is converted to aldehyde oxime 5, which reacts with N-chlorosuccini-
mide (NCS) to afford aryl hydroximino chloride 6, 1,3-dipole seven is eventually
formed in situ from six while triethylamine (TEA) in DMF is added dropwise. Then 4-
alkynyl sinomenine three is added to provide the sinomenine isoxazole derivative 8.
On our target isoxazole heterocycle, sinomenine is linked to the 5-site of isoxazole,
and the 3-site substituent is an aromatic ring derived from the aromatic aldehyde
reactant. In this report, a variety of different substituted aromatic aldehydes are used
as reactants to obtain a total of 19 sinomenine isoxazole derivatives (Figure 1). From
the experimental results, we can see that aromatic aldehydes with electron withdraw-
ing groups provide higher yields of sinomenine isoxazole derivatives, while slightly
lower yields with electron-donating aromatic aldehydes, this indicates that electron
withdrawing groups can enhance the cyclisation activity of the 1,3-dipole.
3. Experimental
For all experimental procedures and compound characterisation information, please
see the supplementary material relating to this article.
4. Conclusion
In conclusion, we have described an effective method to synthesise a novel structure
of sinomenine isoxazole derivatives. The key intermediate product of 4-alkynyl sinome-
nine three is obtained with almost quantitative yield, which can be used directly in
the next step by simply washing off the base with water and drying with anhydrous
sodium sulfate, and does not require column chromatography. The key step of 1,3-
dipolar cycloaddition reaction is suitable for all different substituent groups, and 19
target compounds have been synthesised in good to excellent yields. Sinomenine is
clinically available for the treatment of rheumatoid arthritis (RA), so these compounds
might serve as valuable candidates for anti-inflammatory drug discovery. Further
applications of 4-alkynyl sinomenine three for the synthesis of other sinomenine
heterocyclic derivatives are in progress.
Disclosure statement
No potential conflict of interest is reported by the authors.
Funding
This work is supported by the Anhui University Natural Science Research Project (KJ2019A0770,
KJ2019JD19) and the Science and Technology Innovation Foundation for College
Students (C19000).

NATURAL PRODUCT RESEARCH
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ORCID
Jie Jin
http://orcid.org/0000-0001-7842-3116
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