Metal-Free trans-Aziridination of Zerumbone: Synthesis and Biological Evaluation of Aziridine Derivatives of Zerumbone

Article abstract of DOI:10.1002/ejoc.201700410

Herein, we describe a metal-free, iodosobenzene diacetate mediated trans-aziridination of zerumbone by the direct use of sulfonamides. Preliminary in vitro screening showed that the synthesized compounds had better antiproliferative and antidiabetic activ

Full text of DOI:10.1002/ejoc.201700410

A Journal of
Accepted Article
Title: Metal-Free trans-Aziridination of Zerumbone: Synthesis and
Biological Evaluation of Aziridine Derivatives of Zerumbone
Authors: Greeshma Gopalan, Dhanya B P, Saranya J, Reshmitha T
R, Baiju T V, Meenu M T, Mangalam S Nair, Nisha P, and
Kokkuvayil Vasu Radhakrishnan
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700410
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10.1002/ejoc.201700410
European Journal of Organic Chemistry
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Metal-Free trans-Aziridination of Zerumbone: Synthesis and
Biological Evaluation of Aziridine Derivatives of Zerumbone
Greeshma Gopalan,[a,b] Bhandara Purayil Dhanya,[a,b] Jayaram Saranya,[b] Thankappan Remadevi
Reshmitha,[a,c] Thekke Veettil Baiju,[a,b] Murugan Thulasi Meenu,[a,b] Mangalam S. Nair,[a,b] Prakasan
Nisha*[a,c] and Kokkuvayil Vasu Radhakrishnan*[a,b]
Herein, we describe
a
metal-free, iodosobenzenediacetate
describe our efforts in the trans-aziridination of zerumbone by
employing iodosobenzenediacetate (PIDA) under metal-free
conditions. Also, the preliminary anti-proliferative as well as anti-
diabetic screenings of the synthesized derivatives were carried
out.
mediated trans-aziridination of zerumbone by the direct use of
sulphonamides. The preliminary in vitro-screening showed
better anti-proliferative and anti-diabetic activity compared to
parent compound zerumbone.
Natural products, especially plant-derived compounds occupy a
proficient position in the development of numerous useful drugs.
Diversity oriented synthesis has been used in success for the
generation of biologically relevant/drug-like molecules via simple
chemical transformation of readily available natural products. [1]
For the past few decades, there has been surge in the
development of new plant-derived medicines[2] and in this line,
Zingiber zerumbet Smith (L.), has attained much attention from
the scientific community because of its interesting biological
properties.[3] As a continuation of our ongoing work on the
synthesis of bio-actives from affordable and easily available
natural sources, we were interested in the structural modification
of zerumbone, the marker compound present in Zingiber
zerumbet.[4]
Figure 1. Biologically relevant aziridine bearing molecules
We set off our investigation with zerumbone (1) and
benzenesulphonamide
(2a)
in
the
presence
of
iodosobenzenediacetate as the oxidising agent and KI as the
promoter in dichloromethane at room temperature for 12 hours.
To our delight, we obtained the desired product in 42 % yield.
The structure of the product was well characterized using
various spectroscopic analyses and unambiguously confirmed
by single crystal X-ray analysis of compound 3l.
Aziridines are one of the important synthetic targets due to its
biological profile (Figure 1) as well as its ring strain, which
makes it an active and versatile intermediate for further
functionalization.[5]
Though zerumbone-epoxide is naturally
occurring, there are no report on its nitrogen counterpart. Hence,
taking new challenges in the functionalization of zerumbone may
result in the formation of valuable bio-active agents. In 2006,
Minakata et al. reported the first metal-free aziridination reaction
of olefins with sulphonamides as the nitrogen source using tert-
butyl hypoiodite.[6] While numerous methods are known, the
metal-free hypervalent iodine mediated aziridination reactions
have achieved much attention during last decade due to its
practically favourable reaction conditions. The hypervalent
iodine-iminoiodinane mediated amination, aziridination and
halocyclisation reactions of olefins attained considerable
attention during the last few years.[7] In the present work, we
[a]
[b]
Academy of Scientific and Innovative Research (AcSIR), CSIR-
NIIST, Thiruvananthapuram-695019
Greeshma Gopalan, Bhandara Purayil Dhanya, Jayaram
Saranya, Thekke Veettil Baiju, Murugan Tulasi Meenu, Dr.
Mangalam S. Nair and Dr. Kokkuvayil Vasu Radhakrishnan
Organic chemistry section, National Institute for
Interdisciplinary Science and Technology (CSIR),
Thiruvananthapuram, India-695019
E-mail: radhu2005@gmail.com
Home page URL: http://www.niist.res.in/english/scientists/k-v-
radhakrishnan/personal.html
Scheme 1. Metal-free aziridation of alkenes using sulphonamide.
[c]
Thankappan Remadevi. Reshmitha and Dr. Prakasan Nisha
Agroprocessing and Technology Division, National Institute for
Interdisciplinary Science and Technology (CSIR),
Thiruvananthapuram, India-695 019.
The reaction conditions were optimised with various additives,
solvents and temperature. From the optimization studies, a
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10.1002/ejoc.201700410
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combination of zerumbone 1 equiv., sulphonamide 2 equiv.,
PIDA 1.5 equiv., potassium iodide 2 equiv., in 2 mL of
dichloromethane at room temperature for 12 h was found to be
the best condition, with 62 % yield (Table 1). Also, to improve
the yield of the reactions, we synthesized an ylide between
iodosobenzenediacetate and benenesulphonamide which on
reaction with zerumbone yielded the corresponding product in
60 % yield. Aziridination through ylide formation from PIDA,
followed by reaction with zerumbone was unsuccessful with
sulphonamides except 2a and 2j. The reaction worked well with
zerumbone and sulphonamides in presence of PIDA as the
oxidizing agent.
A plausible mechanism for the trans-aziridination of zerumbone
is shown in Scheme 2. Initially iodosobenzenediacetate reacts
with iodide ion to give a ligand exchanged halonium species A
which simultaneously converts into an active hypohalite
intermediate B. The intermediate B on reaction with zerumbone
at its unactivated double bond forms an intermediate C and the
subsequent intermolecular addition of sulphonamide followed by
the SN2 replacement reaction gives D. The elimination of
hydroiodide from D led to trans-product with complete selectivity.
Table 2. Scope with various sulphonamides
Table 1. Optimisation studies for aziridine synthesis
Reaction conditions: zerumbone (1 equiv.), sulphonamide (2 equiv.), PIDA
(1.5 equiv.), KI (2 equiv.), [a]isolated yield.
[a]
Reaction conditions: zerumbone (1 equiv.), sulphonamide (1 equiv.),
PIDA (1.5 equiv.), KI (1 equiv.), [b]zerumbone (1 equiv.), sulphonamide
(2 equiv.), PIDA (1.5 equiv.), KI (2 equiv.), [c]isolated yield.
With the optimal conditions in hand, we further investigated the
scope of the reaction with functionally different sulphonamides
(Table 2). Sulphonamides bearing various functional groups at
para position were found to be the suitable substrate for this
transformation. Moreover, steric hindrance plays an important
role in the yield of the reaction. In comparison with ortho
substituted sulphonamides, para functionalized substrates
afforded good yield except in the case of 2,3-
dichlorobenzenesulphonamide (entry 7). Also, in the case of
sulphanilamide 2y (entry 25), due to its poor solubility in
dichloromethane, we obtained only a trace amount of product.
Scheme 2. Proposed reaction mechanism for aziridination of zerumbone
The modern drug discovery is mainly focusing on the target
oriented synthesis of novel pharmacophores which amplifies the
synthesis of active drugs. Natural products are evolutionarily
optimised as drug-like molecules and profoundly impacted
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10.1002/ejoc.201700410
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advances in biology and therapy. Many of the natural products
and their derivatives have recognised for many years as a
potent α-glucosidase inhibitor with an IC50 value of 45.845 
1.075 µM than the standard drug, acarbose (82.635  0.075 µM).
In the α- amylase inhibition studies, 3g showed better activity
with an IC50 value, 30.490.36 µM and derivative 3k exhibited
most potent anti-glycation property with an IC50 value 47.865 
0.405 µM (standard ascorbic acid 149.6050.375 µM). From the
results we demonstrate that 3g bearing two halogen atoms
showed promising anti-diabetic activity compared to other
derivatives. The results of our studies areshown in Table 4.[9]
source of therapeutic agents. Having in hand
a set of
zerumbone-aziridine derivatives (3a-3z), we undertook a study
of their anti-proliferative and anti-diabetic properties.
In the present work we carried out in vitro cytotoxic studies of
zerumbone-aziridine derivatives against five human cancer cell
lines viz., A549 (Human lung adenocarcinoma), HCT116
(Human colon carcinoma), HeLa (Human cervix carcinoma),
HT1080 (Human Fibrosarcoma) and MDAMB231 (Human breast
adenocarcinoma) using MTT assay and the results were
tabulated in terms of IC50 values (Table 3). The treatment of
zerumbone and its synthetic derivatives on normal cell line
(H9c2 - rat heart myoblast cells) showed nontoxicity when
compared to other cell lines.[8]
Table 4. Anti-diabetic screening studies
Table 3. Anti-proliferative studies of zerumbone and its aziridine derivatives
IC50 values of the zerumbone derivatives which showed maximum activity are
highlighted using bold letters; values represented are an average of three
independent experiments ± SD
IC50 values of the zerumbone derivatives which showed maximum activity
are highlighted using bold letters; values represented are an average of
three independent experiments ± SD
In summary, we have employed a metal-free one pot strategy for
the trans- aziridination of zerumbone using sulphonamides as
the reaction partners for the first time and the derivatives were
screened for anti-proliferative as well as anti-diabetic activities.
Among the zerumbone-aziridine derivatives screened, 3e and 3r
displayed superior anti-proliferative activity than the parent
compound towards Human colon carcinoma and Human breast
adenocarcinoma cell lines. Also, in the anti-diabetic screening
studies, most of the derivatives exhibited promising α-
glucosidase inhibition properties than the parent zerumbone
molecule. Further investigations on the synthetic utility of
zerumbone-aziridine derivatives are in progress.
Among the sixteen derivatives screened, compounds 3e and 3r
showed significant growth inhibition against HT1080, A549 and
MDAMB231cell lines after 24 hours of incubation compared to
zerumbone and other compounds.
Inhibition of digestive enzymes (α-glucosidase, α-amylase etc.)
is one of the targets for the control and management of
postprandial glycaemia in diabetic treatment. During prolonged
hyperglycaemia, advanced glycation end products (AGEs) are
formed in the body due to the modifications of proteins or lipids
that become non-enzymatically glycated and oxidized after
contact with sugars. AGEs formed under hyperglycemic
conditions are reported to lead to various diabetic complications.
Compounds which reduce glycation products As a search for
new hyperglycaemic lead compounds from biologically relevant
zerumbone molecule, we also evaluated the in vitro α-
glucosidase, α-amylase and anti-glycation activity of some of the
derivatives. From the screening studies, 3j turned out to be more
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10.1002/ejoc.201700410
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Experimental Section
General Procedure for aziridination of zerumbone with
sulphonamide : A mixture of Zerumbone(1.0 equiv.), Sulphonamide (2.0
equiv.), iodosobenzenediacetate (1.5 equiv.), and KI (2 equiv.) were
weighed in a reaction tube, Dichloromethane (2 mL) was added and
allowed to stir at room temperature for 12 hours. The reaction mixture
was then quenched with aqueous sodium thiosulphate solution and
extracted with dichloromethane, dried over anhydrous sodium sulfate.
The solvent was evaporated in vacuo and the residue on silica gel (100-
200 mesh) column chromatography with mixtures of hexane-ethyl
acetate yielded the products.
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2q (1equiv.l) in water (10 mL), sulfonylchloride(1.2 equiv.) was added
and stirred at room temperature until the reaction was complete. The
reaction mixture was then extracted with ethylacetate, dried over
anhydrous sodium sulfate, then concentrated under reduced pressure
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research fellowship. Authors also thank, Natural products for
affordable for healthcare (NaPAHA CSC-0130), SERB project
GAP-135639 and Council of Scientific and Industrial Research
(12th FYP project, ORIGIN-CSC-0108) for financial assistance
from, New Delhi. Dr. Sunil Varughese is greatly acknowledged
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Ms S. Aathira of CSIR-NIIST for recording NMR and mass
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[11] CCDC number for compound 3l is 1530684.
Keywords: Zerumbone • aziridination • hypervalent compounds
• Sulphonamides • anti-proliferative • anti-diabetic
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Entry for the Table of Contents (Please choose one layout)
COMMUNICATION
Metal-free Aziridination *
Greeshma Gopalan, Bhandara Purayil
Dhanya, Jayaram Saranya, Thankappan
Remadevi Reshmitha, Thekke Veettil
Baiju Murugan Thulasi Meenu,
Mangalam S. Nair, Prakasan Nisha* and
Kokkuvayil Vasu Radhakrishnan*
Text for Table of Contents
Page No. – Page No.
Metal-Free trans-Aziridination of
Zerumbone: Synthesis and Biological
Evaluation of Aziridine Derivatives of
Zerumbone
* The reaction of zerumbone with sulphonamides, via a one-pot metal free synthetic strategy using iodosobenzenediacetate
as the oxidising agent furnished the zerumbone-aziridine derivatives. We also carried out the anti-proliferative as well as anti-
diabetics screening of the synthesised compounds.
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