An efficient synthesis and bioactivity evaluation of oxazole-containing natural hinduchelins A-D and their derivatives

Article abstract of DOI:10.1039/C9OB00352E

Oxazoles are an important class of biologically active metabolites from nature, and exhibit broad biological activities as the lead for drug discovery. Hinduchelins are a class of unusual natural products with an oxazole unit, isolated from Streptoalloteichus hindustanus, and with a potential iron-chelating ability. These compounds are the first identified naturally occurring unusual oxazole derivatives to possess a catechol unit. However, some of these compounds are not abundant in nature, and thus, the efficient syntheses of these compounds are advantageous in exploring their potential applications. This paper reports the efficient synthesis and bio-evaluation of hinduchelins A-D and their derivatives with convenient procedures and high yields.

Full text of DOI:10.1039/C9OB00352E

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An efficient synthesis and bioactivity evaluation of
oxazole-containing natural hinduchelins A–D and
their derivatives†
Cite this: DOI: 10.1039/c9ob00352e
Shaoyong Ke, * Zhigang Zhang, Liqiao Shi, Manli Liu, Wei Fang, Yani Zhang,
Zhaoyuan Wu, Zhongyi Wan, Tong Long and Kaimei Wang*
Oxazoles are an important class of biologically active metabolites from nature, and exhibit broad biologi-
cal activities as the lead for drug discovery. Hinduchelins are a class of unusual natural products with an
oxazole unit, isolated from Streptoalloteichus hindustanus, and with a potential iron-chelating ability.
These compounds are the first identified naturally occurring unusual oxazole derivatives to possess a
catechol unit. However, some of these compounds are not abundant in nature, and thus, the efficient
syntheses of these compounds are advantageous in exploring their potential applications. This paper
reports the efficient synthesis and bio-evaluation of hinduchelins A–D and their derivatives with con-
venient procedures and high yields.
Received 13th February 2019,
Accepted 20th March 2019
DOI: 10.1039/c9ob00352e
rsc.li/obc
Amyris texana etc. These diaryloxazole alkaloids show broad
bioactivity such as antimycobacterial activity, anticancer
Introduction
Natural products have been widely used as lead molecules for activity etc. Meanwhile, several of the novel oxazole-amide
the discovery of novel drugs1–3 and agrochemicals4–7 over the derivatives (Fig. 1) have also been isolated and characterized as
past century, and they possess enormous structural and chemi- potential antitumor, anti-tuberculosis, and anti-proliferative
cal diversity that can afford an opportunity to explore novel agents.24–27 Very recently, several unusual aryl-oxazole alka-
candidates with different mechanisms of action and unique loids have also been isolated from Streptoalloteichus hindusta-
biological properties from the existing agents.
nus by Abe et al.,28 and these compounds (hinduchelins A–D
In particular, these small molecules of natural products in Fig. 1) have a special structural moiety similar to the unit in
containing heterocyclic rings have attracted a great deal of amamistatin. The test of iron-binding properties of these
attention due to their extensive biological properties.8 Among natural products was performed, and some molecules showed
them, oxazole skeletons with five-membered heterocycles moderate ability to induce pyoverdine production at 50 μM.
arouse many researchers’ interest,9,10 and many oxazole-type
Besides the aforementioned natural oxazole alkaloids,
natural products11–28 have been elucidated as potential anti- many synthetic methods for various oxazole derivatives have
bacterial, antifungal, anticancer, antiviral, and antioxidation been explored,14,18,29,30 and many synthetic derivatives have
agents, monoamine oxidase inhibitors etc. Indolyl-oxazole also been investigated and developed as potential drugs or
derivatives11–18 are an important class of oxazole-type natural agrochemicals,31–35 and therefore the unique structure and
products, and these natural compounds and their derivatives important bioactivity of oxazole heterocyclic derivatives have
have been demonstrated to exhibit broad biological and generated significant interest in the total synthesis of such
pharmaceutical
activities.
2,5-Disubstituted
oxazole compounds. Thus, we intend to develop an effective synthetic
alkaloids19–23 are another kind of oxazole natural product with strategy for the study of hinduchelins A–D and their deriva-
special structures, and isolated from different plants such as tives. Afterwards, process development for the novel hinduche-
lin analogues with potential pharmacological or agroactivities
involving structural optimization and bioassay screening helps
us to explore the mechanism of action for the biological
activity of hinduchelin derivatives. Herein, we report the first
total synthesis of hinduchelins A–D and their derivatives,
and the in vitro cytotoxicity, and antibacterial, fungicidal and
insecticidal activities of these compounds have also been
evaluated.
National Biopesticide Engineering Research Centre, Hubei Biopesticide Engineering
Research Centre, Hubei Academy of Agricultural Sciences, Wuhan 430064, People’s
Republic of China. E-mail: shaoyong.ke@nberc.com, keshaoyong@163.com,
kaimei.wang@nberc.com; Tel: +86-27-59101919
†Electronic supplementary information (ESI) available: The synthetic methods
for target compounds, and 1H NMR, 13C NMR and ESI-MS spectra for all the
intermediates and target compounds. See DOI: 10.1039/c9ob00352e
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Fig. 1 Biologically active naturally occurring oxazole-amide alkaloids.
mediate 2 was treated with the corresponding o-veratraldehyde or
o-vanillin via a heterocyclization reaction29 to afford the hetero-
cyclic intermediates 4a–b, which were reduced with zinc powder
Results and discussion
Retrosynthetic analysis
The retrosynthetic analysis for hinduchelins A–D is described in the presence of acetic acid to obtain the key intermediates aryl-
in Scheme 1. From Scheme 1, we can find that these hinduche- oxazole carboxylates 5a–b. After this, the intermediates aryl-
lins A–D can be divided into two parts including carboxylic oxazole carboxylic acids 6a–b were conveniently obtained by the
acid and substituted phenethylamine. This relies on an initial hydrolysis of the corresponding aryl-oxazole carboxylates 5a–b in
disconnection of the amide bond to give the corresponding the presence of sodium hydroxide, and the corresponding spectra
oxazole-containing carboxylic acid and substituted phenethyl- for these intermediates 5a–b and 6a–b are described in the ESI.†
amine. The synthesis of the oxazole-containing carboxylic acid
Synthesis of hinduchelins A and B
could be processed from aldehydes (o-veratraldehyde and
o-vanillin) and ethyl 2-(hydroxyimino)-3-oxobutanoate via the
heterocyclization reaction.
For the synthesis of hinduchelin A, the corresponding (S)-2-
amino-1-phenylethanol (7) and intermediate 5a were first used
to explore the transformation. The corresponding aryl-oxazole
5a was treated with an amine (7) in refluxing ethanol to give
the target hinduchelin A in 18% isolated yield. The direct
coupling reaction between aryl-oxazole 6a and amine 7 was
also investigated using a coupling reagent. Fortunately, hindu-
chelin A was produced in 64% yield (isolated yield). In
addition, further UPLC-MS analyses also confirmed that the
General synthesis of hinduchelins A–D
According to the retrosynthetic analysis, the following total
synthesis procedures for hinduchelins A–D were provided and
investigated (Scheme 2).
Synthesis of oxazole-containing carboxylic acid fragments
According to the retrosynthetic analysis, the substituted oxazole- compounds obtained via these two methods are consistent.
containing carboxylic acids are the key molecular fragments, and With 2-(2-methoxyphenyl)ethanamine 8 being available, the
can be prepared from the commonly available reagent ethyl aceto- required 2-(2-aminoethyl)phenol 9 was synthesized by de-
acetate. The ethyl acetoacetate 1 was transformed into ethyl methylation using HBr in the presence of acetic acid
2-(hydroxyimino)-3-oxobutanoate 2 when treated with sodium (Scheme 2). Hinduchelin B was prepared using a similar coup-
nitrite in the presence of acetic acid. Then the obtained inter- ling reaction to that of hinduchelin A with a yield of 65%.
Scheme 1 Retrosynthetic analysis for hinduchelins A–D.
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Scheme 2 Synthesis of hinduchelins A–D. Reagents and conditions: (a) NaNO2, AcOH, H2O, 0–5 °C, 1.5 h, 95%; (b) HCl(g), AcOH, 5–10 °C, 2–3 h;
(c) Zn, AcOH, 45–50 °C, 3–4 h, 88% for 5a, and 82% for 5b; (d) NaOH, MeOH, H2O, rt, overnight, 83% for 6a, and 76% for 6b; (e) HOBt, EDCI, Et3N,
DMF, rt, 20–45 h, 64–82%; (f) HBr, AcOH, reflux, 4 h; and (g) EtOH, reflux, 42 h, 18%.
1
Synthesis of hinduchelins C and D
tures. For H NMR studies of hinduchelin A, the typical signal
for the proton of CH attached OH was resonated as a triplet at
Based on the aforementioned investigation of the synthesis of
hinduchelins A and B, and with the intermediate 6b in hand,
the different substituted 2-phenylethanamines 9 or 10 can be
efficiently transformed into the corresponding target hindu-
chelins C and D with the yields of 74% and 82%, respectively.
1
4.89 ppm, and the two sets of signals that emerged in their H
NMR spectrum in the ranges 3.76–3.72 and 3.50–3.46 ppm
were assigned to the protons of the methylene group linked to
the amino group. In addition, the signal peaks for three
methyl groups are very obvious, and the signals at lower fields
1
in the corresponding H NMR spectrum were attributed to the
Synthesis of hinduchelin A–D derivatives
NH and aromatic protons. In the original spectra, hinduche-
lins B–D has similar spectral characteristics to those of hindu-
chelin A. The 13C NMR spectra of compounds hinduchelins A–
D display obvious peaks in the alkyl region indicating the pres-
ence of the methyl, methylene and methine groups, and other
peaks appearing at lower fields were assigned to the hetero-
cyclic and aromatic moiety. The electrospray ionization mass
spectra (ESI-MS) for hinduchelins A–D were measured on a
WATERS ACQUITY UPLC® H-CLASS PDA (Waters®) instrument
(Xevo TQD), and the ion peak or adduct ions of the synthesized
In order to investigate the possible structure–activity relation-
ships, some derivatives of natural hinduchelins A–D have been
prepared according to the aforementioned method, and the
general synthetic route is described in Scheme 3.
Spectroscopy studies
All the structures of target compounds were demonstrated by
1
their H NMR, 13C NMR and mass spectroscopy, and all these
spectral data were in good agreement with the proposed struc-
Scheme 3 Synthesis of hinduchelin A–D derivatives.
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compounds were investigated. Experimentally, in the positive Agricultural Sciences, and the authors also gratefully acknowl-
ion mode, the ESI-MS of these compounds exhibit the obvious edge the partial support from the National Natural Science
molecular peaks of [M + H]+ and [M + Na]+ with relative abun- Foundation of China (31501695) and Hubei Agricultural
dance. All the characteristic peaks observed in the 1H NMR Science Innovation Centre (2016-620-000-001-039).
and 13C NMR spectra for hinduchelins A–D and their deriva-
tives are described in the ESI,† and they are almost consistent
with the reported data from ref. 28. In particular, the optical
rotation for hinduchelin A was also determined on an Autopol
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