Naturally occurring bioactive 5-ethylidenehydantoins as inspiration for the development of analogues

Article abstract of DOI:10.1080/00397911.2018.1467457

Many naturally occurring 5-ethylidenehydantoins and their derivatives exhibit extensive biological activities; this characteristic has inspired us to prepare analogues. Fourteen such analogues with the core structure of 5-ethylidenehydantoin were synthesi

Full text of DOI:10.1080/00397911.2018.1467457

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
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Naturally occurring bioactive 5-
ethylidenehydantoins as inspiration for the
development of analogues
Qunying Yu, Jingmou Yu, Haiou Bao, Xiao Hu, Danxia Ying, Lixia Wu, Fang
Liu, Honghong Jiang, Zhong Jinxia & Shuihua Zhang
To cite this article: Qunying Yu, Jingmou Yu, Haiou Bao, Xiao Hu, Danxia Ying, Lixia Wu, Fang
Liu, Honghong Jiang, Zhong Jinxia & Shuihua Zhang (2018): Naturally occurring bioactive 5-
ethylidenehydantoins as inspiration for the development of analogues, Synthetic Communications,
DOI: 10.1080/00397911.2018.1467457
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https://doi.org/10.1080/00397911.2018.1467457
Naturally occurring bioactive 5-ethylidenehydantoins
as inspiration for the development of analogues
Qunying Yu, Jingmou Yu, Haiou Bao, Xiao Hu, Danxia Ying, Lixia Wu, Fang Liu,
Honghong Jiang, Zhong Jinxia, and Shuihua Zhang
School of Pharmacy and Life Sciences, Jiujiang University, Jiujiang 332000, People’s Republic of China
ABSTRACT
ARTICLE HISTORY
Received 9 September 2017
Many naturally occurring 5-ethylidenehydantoins and their derivatives
exhibit extensive biological activities; this characteristic has inspired
us to prepare analogues. Fourteen such analogues with the core
structure of 5-ethylidenehydantoin were synthesized from readily
available components with yields of up to 82%.
KEYWORDS
5-ethylidenehydantoins;
skeleton; tetrasubstituted
GRAPHICAL ABSTRACT
Introduction
5-Ethylidenehydantoins have
a unique skeleton, and many naturally occurring
5-ethylidenehydantoins exhibit a variety of biological activities.[1–4] For instance, anticancer,
GlyR-modulating, antikinase and naturally toxic effects are produced by the natural
compounds phenylmethylenehydantoin (PMH);[5,6] 8E-30-deimino-30-oxoaplysinopsin and
8Z-30-deimino-30-oxoaplysinopsin;[7] three pyrrole-imidazole alkaloids [(E)-axinohydantoin,
(Z)-axinohydantoin and (Z)-debromoaxinohydantoin];[8,9] and parazoanthines B-E,[10]
respectively (Scheme 1). In addition, certain 5-spiro hydantoins, such as 6-((5S,9R)-9-(4-
cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro-[4.4]nonan-7-yl)
nicotinic acid[11] and 5-[(5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-
CONTACT Qunying Yu
qunyingyu@qq.com
School of Pharmacy and Life Sciences, Jiujiang University, Xunyang
East Road, No.320, Jiujiang 332000, People’s Republic of China.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2018 Taylor & Francis

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Q. YU ET AL.
Scheme 1. Naturally occurring 5-ethylidenehydantoins.
dioxo-1,3,7-triazaspiro[4.4]non-7-yl-methyl]-3-thiophenecarboxylic acid, have been selected
for testing in clinical trials.[12]
Interestingly, 5-ethylidenehydantoins are also extremely important synthetic inter-
mediates.[13] 5-Ethylidenehydantoins can undergo epoxidation, methanol addition and
conjugate addition reactions with different types of nucleophiles to produce numerous
hydantoin derivatives that exhibit a variety of biological activities.[14–21] Unsurprisingly,
these features have inspired chemists to design synthetic protocols. To date, methods to
obtain 1,5-di-, 3,5-di- and 5-substituted ethylidenehydantoins are readily accessible;[22–24]
however, there are few strategies for preparing tetrasubstituted 5-ethylidenehydantoins.
Given the unique core structure and potent biological activities of 5-ethylidenehydantoins,
we report here a representative scenario for synthesizing these compounds from readily
available components with the objective of constructing this core structure and providing
available analogues for screening biological activities.

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Results and discussion
To achieve our objective, we first synthesized an array of suitably activated α,β-unsaturated
carboxylic acids bearing two carbonyl groups at the β position. Alkylation, bromination
and dehydrobromination were performed in sequence. The t-butyl group was selectively
removed using trifluoroacetic acid (Scheme 2). Second, with activated α,β-unsaturated
carboxylic acids in hand, we induced these molecules to react effectively with symmetric
carbodiimides to afford an array of 1,3,5-trisubstituted hydantoins (with d and r
Scheme 2. Preparation of suitably activated α,β-unsaturated carboxylic acids and 1,3,5-trisubstituted
hydantoins. (A) t-butyl bromoacetate, K2CO3, CH3CN;[26] (B) t-butyl bromoacetate, NaH, THF;[27]
(C) NBS, DBU (15%), CH2Cl2;[28] (D) Et3N, Et2O;[29] (E) CF3COOH, CH2Cl2;[30] (F) DCC or DIC.[31]
Temperature Time
Yield
Entry Substrate R1
R2
Ph
R3
Base Solvent
(ꢀC)
(min) Product (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
5a
5a
5a
5a
5a
5a
5a
5a
5b
5b
5c
5c
5d
5d
5e
5e
5f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
i-Pr
-
-
-
-
-
-
-
-
none CH3CN
KHCO3 CH3CN
K3PO4 CH3CN
K3PO4 CH3CN
K3PO4 CH3CN
40
40
72
72
72
90
90
90
40
90
90
90
90
90
85
90
70
70
85
85
70
70
85
85
85
30 6a
30 6a
trace
15
64
68
66
65
82
68
41
61
72
67
42
54
56
37
36
35
64
72
50
66
55
62
49
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
5
6a
49 6a
30 6a
16 6a
30 6a
30 6a
30 6b
30 6b
30 6c
30 6c
20 6d
KOH
Toluene
K3PO4 Toluene
DMAP Toluene
K3PO4 CH3CN
K3PO4 Toluene
DMAP Toluene
K3PO4 Toluene
K3PO4 Toluene
DMAP Toluene
DMAP Toluene
K3PO4 Toluene
DMAP Toluene
DMAP Toluene
DMAP Toluene
DMAP Toluene
DMAP Toluene
DMAP Toluene
DMAP Toluene
DMAP Toluene
DMAP Toluene
i-Pr
CH3 c-C6H11
CH3 c-C6H11
CH3 i-Pr
CH3 i-Pr
EtO i-Pr
-
-
7
7
6d
6e
EtO i-Pr
15 6e
30 6f
30 6g
22 6h
22 6i
20 6j
20 6k
30 6l
25 6m
25 6n
MeO MeO c-C6H11
-
-
5g
5h
5i
MeO MeO i-Pr
EtO EtO i-Pr
EtO EtO c-C6H11
i-PrO i-PrO i-Pr
5j
5k
5l
5m
5n
i-PrO i-PrO c-C6H11
CH3 EtO c-C6H11
CH3 CH3 c-C6H11
CH3 CH3 i-Pr
-
-
-

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Scheme 3. Preparation of 5-ethylidenehydantoin analogues.
diastereomers) via domino condensation/aza-Michael/N!O acyl migration (Scheme 2).[25]
Finally, the obtained 1,3,5-trisubstituted hydantoins underwent dehydrogenation mediated
by a PhI(OAc)/base system, and the 5-σ bonds of hydantoins were transformed into 5-π
bonds, yielding tetrasubstituted 5-ethylidenehydantoin analogues (Scheme 3).
The reaction sequences are portrayed in Scheme 2.
Dehydrogenation of compound 5a using PhI(OAc)2 as the oxidant was selected as the
benchmark reaction to explore the optimization of reaction conditions. Although our
findings are tentative, negligible quantities of 6a were observed in the absence of a
base (Scheme 3, entry 1). Markedly superior results were observed when KHCO3 was
replaced with K3PO4 (entries 2–3). Switching the solvent to toluene resulted in an opti-
mized 82% isolated yield for 6a at 90 ꢀC (entry 7). Changing the base from K3PO4 to
DMAP also slightly increased product yields (entries 11–12, 13–14 and 15–16). After the
judicious optimization of reaction parameters, we identified a protocol involving sub-
strate and DMAP in toluene that was suitable for our purposes. Notably, identical
reactivity was observed when both R1 and R2 were alkyl or alkoxy groups; however, a
significant reduction in yields was observed when both R1 and R2 were alkyl or alkoxy
groups rather than aryl groups. Unsurprisingly, Z and E isomers were obtained when R1
and R2 were not the same. Overall, 14 tetrasubstituted 5-ethylidenehydantoins were
prepared, with yields ranging from 35% to 82% (Scheme 3). Our method expands
the scope of available substrates and provides easy access to structurally diverse
5-ethylidenehydantoins that could be further functionalized. Approximately 20 min was
required to complete the dehydrogenation. Further investigations aimed at testing the
biological activities of related compounds are currently on-going in our laboratories.
Conclusion
In summary, we have developed a new route to synthesize tetrasubstituted 5-ethylidene-
hydantoins, which have an important, naturally occurring skeleton. Dehydrogenation
was mediated by PhI(OAc)2, which is a mild, highly stable oxidant with low toxicity.
Our conditions enable a fast and convenient approach to hydantoins.
Experimental section
General methods
NMR spectra were recorded on Bruker DPX-400, DRX-500 and DRX-600 instruments.
1
Chemical shifts were reported as d values relative to internal chloroform (d 7.26 for H

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5
NMR and 77.00 for 13C NMR). High-resolution mass spectra (EI) were obtained on an
API QStar Pulsar instrument. Infrared spectra were recorded on an FT-IR spectrometer.
Silica gel (Wakogel, 300–400 mesh) was used for column chromatography. Yields refer
to chromatographically and spectroscopically (1H NMR) homogeneous materials. Unless
otherwise noted, materials obtained from commercial suppliers were used without
additional purification. Toluene was distilled over CaH2. THF (tetrahydrofuran) was dis-
tilled over sodium before use.
Key procedure for the preparation of 5-ethylidenehydantoin analogues (6a–6n)
Two equivalents of PhI(OAc)2 and 3 equivalents of base were added to an 0.1 M
solution of 1,3,5-trisubstituted hydantoin (5a–n) (1 equiv) in toluene. The reaction mix-
ture was stirred at an appropriate temperature (ꢁ85 ꢀC). After the starting material had
been completely consumed (ꢁ20 min), water and EtOAc were added. The organic layer
was separated, and the aqueous layer was extracted with EtOAc (three times). The com-
bined organic layers were washed with brine, dried with Na2SO4 and concentrated
in vacuo. Flash column chromatography afforded the desired compound (6a–n).
Acknowledgements
The authors thank Jiujiang University and Jiangxi Province for financial support of this work.
This work was supported by Jiujiang University, the grant number is 8879562.
Disclosure statement
The authors declare no competing financial interests.
Supporting Information
1
Complete experimental details, H and 13C NMR spectra, HRMS and IR data, and information
regarding materials can be found in the “Supplementary Content” section of this article’s webpage.
References
[1] Hirai, K.; Fuchikami, T.; Fujita, A.; Hirose, H.; Yokota, M.; Nagato, S. Eur. Pat. Appl. E P
262,428,1988; Chem. Abstr. 1988, 109, 93010k.
[2] Cremlyn, R. J. W.; Jethwa, S.; Joiner, G.; White, D. Relat. Elem. 1988, 36, 99.
[3] Thenmozhiyal, J. C.; Wong, P. T.-H.; Chui, W.-K. J. Med. Chem. 2004, 47, 1527.
[4] Carmi, C.; Cavazzoni, A.; Zuliani, V.; Lodola, A.; Bordi, F.; Plazzi, P. V.; Alfieri, R. R.;
Petronini, P. G.; Mor, M. Bioorg. Med. Chem. Lett. 2006, 16, 4021.
[5] Mudit, M.; Khanfar, M.; Muralidharan, A.; Thomas, S.; Shah, G. V.; Soest, R. W. M. V.;
Sayed, K. A. E. Bioorg. Med. Chem. 2009, 17, 1731.
[6] Khanfar, M. A.; Asal, B. A.; Mudit, M.; Kaddoumi, A.; Sayed, K. A. E. Bioorg. Med. Chem.
Lett. 2009, 17, 6032.
[7] Balansa, W.; Islam, R.; Gilbert, D. F.; Fontaine, F.; Xiao, X.; Zhang, H.; Piggott, A. M.;
Lynch, J. W.; Capon, R. J. Bioorg. Med. Chem. Lett. 2013, 21, 4420.
[8] (a) Jin, Z. Nat. Prod. Rep. 2011, 28, 1143. (b) Tutino, F.; Posteri, H.; Borghi, D.; Quartieri,
F.; Mongelli, N.; Papeo, G. Tetrahedron, 2009, 65, 2372.
[9] Sosa, A. C. B.; Yakushijin, K.; Horne, D. A. J. Org. Chem. 2002, 67, 4498.

6
Q. YU ET AL.
[10] Cachet, N.; Genta-Jouve, G.; Regalado, E. L.; Mokrini, R.; Amade, P.; Culioli, G.; Thomas,
O. P.; J. Nat. Prod. 2009, 72, 1612.
[11] Watterson, S. H.; Xiao, Z.; Dodd, D. S.; Tortolani, D. R.; et al. J. Med. Chem. 2010, 53,
3814.
[12] Potin, D.; Launay, M.; Monatlik, F.; Malabre, P.; Fabreguettes, M.; et al. J. Med. Chem.
2006, 49, 6946.
[13] He, X.-Y.; Zou, P.; Qiu, J.; Hou, L.; Jiang, S.; Liu, S.; Xie, L. Bioorg. Med. Chem. Lett.
2011, 19, 6726.
[14] Warner-Lambert Co. 1-Substituted-phenyl-4-alkyl hydantoinpiperizine compounds as anti-
hypertensive agenta. U.S. Pat. 4,462,198A, 1984; Chem. Abstr. 1986, 101, 38476b.
[15] Cortes, S.; Liao, Z.-K.; Watson, D.; Kohn, H. J. Med. Chem. 1985, 28, 601.
[16] Rizzi, J. P.; Schnur, R. C.; Hutson, N. J.; Kraus, K. G.; Kelbaugh, P. R. J. Med. Chem. 1989,
32, 1208.
[17] Barraclough, P.; Caldwell, A. G.; Harris, C. J.; Jackson, W. P.; Whittle, B. J. R. J. Chem.
SOC., Perkin Trans. 1. 1989, 10, 1815.
[18] Sarges, R.; Schnur, R. C.; Belletire, J. L.; Peterson, M. J. J. Med. Chem. 1988, 31, 230.
[19] Bahy, A.; Kacem, Y.; Hassine, B. B. Synth. Commun. 2010, 40, 1377.
[20] Pham, T. Q.; Pyne, S. G.; Skelton, B. W.; White, A. H. J. Org. Chem. 2005, 70, 6369.
[21] Sankhavasi, W.; Kohmoto, S.; Yamamoto, M.; Nishio, T.; Iida, I.; Yamada, K. Bull. Chem.
Soc. Jpn. 1992, 65, 935.
[22] Meanwell, N. A.; Roth, H. R.; Smith, E. C. R.; Wedding, D. L.; Wright, J. J. K. J. Org.
Chem. 1991, 56, 6897.
[23] Mathur, N. C.; Wong, S. K.; Shechter, H. Tetrahedron Lett. 2003, 44, 5141.
[24] Palacios, F.; Legido, M.; Heredia, I. P.; Ezpeleta, J. M.; Rubiales, G. Heterocycles. 2001, 55,
1641.
[25] Volonterio, A.; Arellano, C. R. D.; Zanda, M. J. Org. Chem. 2005, 70, 2161.
€
€
[26] Tormakangas, O. P.; Toivola, R. J.; Karvinen, E. K.; Koskinen, A. M. P. Tetrahedron. 2002,
58, 2175.
[27] Goh, K. K. K.; Kim, S.; Zard, S. Z. Org. Lett. 2013, 15, 4818.
[28] Y. Zhao, X. Jiang, Y.-Y. Yeung. Angew. Chem. Int. Ed. Engl 2013, 52, 8597.
[29] Scott, D. M.; McPhail, A. T.; Porter, N. A. Tetrahedron Lett. 1990, 31, 1679.
[30] Lenz, G. R.; Lessor, R. A. Org. Synth. 1998, 9, 268.
[31] Maggi, R.; Bosica, G.; Gherardi, S.; Oro, C.; Sartori, G.; Green Chem. 2005, 7, 182.