Direct chemical derivatization of natural plant extract: Straightforward synthesis of natural plant-like hydantoin

Article abstract of DOI:10.1016/j.tetlet.2016.01.054

The direct chemical derivatization of natural plant extracts that would enable the straightforward synthesis of natural plant-like molecules seemed to be far from reality due primarily to the inherently complex chemical property of the extract. After mode

Full text of DOI:10.1016/j.tetlet.2016.01.054

Tetrahedron Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Direct chemical derivatization of natural plant extract:
straightforward synthesis of natural plant-like hydantoin
⇑
⇑
Keisuke Tomohara , Tomohiro Ito, Naoto Hasegawa, Atsushi Kato, Isao Adachi
Department of Hospital Pharmacy, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The direct chemical derivatization of natural plant extracts that would enable the straightforward syn-
thesis of natural plant-like molecules seemed to be far from reality due primarily to the inherently com-
plex chemical property of the extract. After model studies, the envisioned derivatization was realized
under the rationally designed Bucherer–Bergs reaction conditions to afford unnatural hydantoin with
tetrasubstituted carbon from the ethyl acetate extract of Curcuma zedoaria. The reaction proceeded with
enough chemoselectivity to identify the desired product from the mixture by the reliable guidance of
spectroscopic analyses.
Received 9 November 2015
Revised 12 January 2016
Accepted 15 January 2016
Available online xxxx
Keywords:
Direct chemical derivatization
Natural plant extract
Bucherer–Bergs reaction
Hydantoin
Ó 2016 Published by Elsevier Ltd.
Tetrasubstituted carbon
Curcuma zedoaria
Natural plant products and their derivatives have played pivotal
roles in both pharmaceutical and agrochemical discoveries. In fact,
many approved pharmaceuticals and agrochemicals as well as
their candidates have their origin in natural plant products.1 In
addition to their successes and potentials as origins, the natural
plant extract itself has been used as a ‘chemical library’, that is,
an assembly of molecules rich in structural diversity for biological
assay in early drug discovery. Thus, natural plant products have
long been and will continue to be important sources of valuable
chemicals. Despite such continuous demand for new natural plant
products or related molecules, the chances of finding novel biolog-
ically active compounds have become more difficult.2 It is partially
because most of them have already been described in the literature
especially for plants with pronounced pharmacological activities,
but more importantly because their discoveries still continue to
depend on a more or less accidental process regardless of whether
guided by biological activities or not. Chemists are now enlisting
combinatorial chemistry,3 diversity-oriented synthesis,4 and
enzyme engineering5 as alternative approaches toward creating
natural plant product-like molecules in combination with acquir-
ing structural diversity. It should be strongly emphasized that
the advances in these methodologies have opened up robust solu-
tions for the designated production of natural plant product-like
molecules. Here, as an attractive alternative in terms of practical
operation and scope, it would be quite reasonable that direct
chemical derivatization of natural plant product extracts could
provide another approach to construct natural plant product-like
molecules. Furlan and co-workers have recently reported the first
example of the direct chemical derivatization of natural plant
extracts, where
a novel unnatural alkaloid was successfully
obtained.6 Since then, direct chemical derivatization of natural
plant extracts has become a tool for creating natural plant pro-
duct-like molecules, and been excellently applied to ammonoly-
sis,7 sulfonylation,8 bromination,9 and epoxidation and
subsequent ring-opening reaction10 of natural plant extracts.11
Despite the advent of methodology for direct chemical derivati-
zation of natural plant extracts, its application has been only rarely
examined for several reasons. Firstly, it is because the inherently
complex nature of extracts leads to the unpredictable results on
the occasion of their derivatization so that the reaction system
strongly demands the compatibility with the composition of
extracts. In addition, a previous report has also described the diffi-
culties in identifying the desired products from derivatized
extracts.10 This was attributed to increasingly complicated profiles
of derivatized extracts resulting from unwanted or uncontrollable
side reactions and remaining reagents after general work-up. As
a result, direct chemical derivatization of natural plant extracts,
with its successes, still looks quite difficult. Therefore, further
research is needed to provide the proof of concept and improve
its scope and practicality.
⇑
Corresponding authors. Tel.: +81 76 434 7868; fax: +81 76 434 5155 (K.T.); tel.:
+81 76 434 7860; fax: +81 76 434 5155 (I.A.).
E-mail addresses: tomohara@med.u-toyama.ac.jp (K. Tomohara), adachi@med.
u-toyama.ac.jp (I. Adachi).
http://dx.doi.org/10.1016/j.tetlet.2016.01.054
0040-4039/Ó 2016 Published by Elsevier Ltd.
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K. Tomohara et al. / Tetrahedron Letters xxx (2016) xxx–xxx
Considered these challenges in direct chemical derivatization of
natural plant extracts, the following requirements must be met: (1)
the derivatization should take place in a chemoselective manner to
minimize the unpredictable complication of the reaction system
under reaction conditions. (2) The desired product should be easily
detected by and purified with the reliable guidance of spectro-
scopic and analytical methods. (3) Then this becomes much easier
especially when the constructed motif is scarce in the natural
sources. With these in mind, it was thought that our envisioned
story toward direct chemical derivatization of natural plant
extracts could be realized by the Bucherer–Bergs four component
reaction (Fig. 1).12 Under the Bucherer–Bergs reaction conditions,
the electrophilic carbonyl group is transformed into a hydantoin
motif (imidazolidine-2,4-dione), beginning from the nucleophilic
attack of ammonia to the electrophilic carbonyl group. Although
a carbonyl group is known to be one of the most abundant func-
tionalities in natural plant extracts,6 targeted electrophilic ketones
can be certainly differentiated from other carbonyl groups during
the course of the reaction with the nucleophile, then this would
overcome the complication and realize the chemoselective deriva-
tization even in the complex reaction system. The existence of
electrophilic ketones could be estimated by the measurement of
C@O stretching vibration in the IR spectra as shown below. More-
over, the product hydantoin is much more polar than the starting
ketone and this will be beneficial to identify the desired hydantoin
when the reaction is applied to the extracts comprising the mole-
cules with low polarity. Although some naturally occurring hydan-
toins were identified from microbial13 and marine14 organisms, to
our knowledge there has been no report in isolating them from
Figure 1. Direct chemical derivatization of natural plant extract.
Table 1
Optimization of reaction conditions
Entry
Temp
Time (h)
Yield (%)
1
60 °C
rt
rt
4
24
24
97
Quant.
98
2
3a
a
Performed with 5.0 equiv of KCN and 25 equiv of (NH4)2CO3 in EtOH/H2O
(0.1 M, 1:1).
Table 2
Scope and limitations
a
a
Entry
1
[v (C@O)] (cmÀ1
)
2
Yield (%)
Entry
1
[v (C@O)] (cmÀ1
)
2
Yield (%)
1
2
3
4
5
6
1b
1c
1d
1a
1e
1f
1746 (neat)
1727 (KBr)
1719 (KBr)
1716 (neat)
1714 (neat)
1710 (neat)
2b
2c
2d
2a
2e
2f
95
85
92
98
85
90
7
8
9
10
11
1g
1h
1i
1j
1k
1743 (KBr)
1705 (KBr)
1681 (neat)
1660 (KBr)
1630 (KBr)
2g
2h
2i
2j
2k
N. R.b
N. R.b
42c
N. R.b
N. R.b
a
b
c
Wave number of C@O (shown in red) stretching vibration in IR spectra.
No reaction occurred and the substrate was recovered.
The substrate was recovered.
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K. Tomohara et al. / Tetrahedron Letters xxx (2016) xxx–xxx
3
Table 3
plants, and this will also facilitate the identification of the desired
13C NMR chemical shifts (ppm) of compounds 3, 4
hydantoin. These features fulfill the aforementioned requirements,
therefore it can be said that the Bucherer–Bergs reaction is suitable
to direct derivatization of natural plant extracts.
First of all, the reaction conditions were optimized in the
model reactions using 4-phenyl-2-butanone (1a) as a representa-
tive substrate having an electrophilic ketone (Table 1). According
to the reported conditions,15 1a was smoothly converted into the
corresponding hydantoin 2a in 97% yield (entry 1). The reported
Bucherer–Bergs reaction conditions are generally accompanied
with heating to complete the reaction, but this will potentially
cause undesired side reaction or unnecessary decomposition of
innocuous substrates in the case of direct derivatization of the
natural plant extract. That is why the reaction temperature was
then optimized. As a result, even at room temperature the
desired 2a was obtained in quantitative yield although a longer
reaction time was needed (entry 2). As another consideration, it
was investigated whether the reaction could be compatible with
the conditions loading the excess amount of reagents at high
dilution, assuming the situation where the exact concentration
of electrophilic ketones in the extract cannot be answered. Fortu-
nately, the hydantoin 2a was again obtained without the loss of
yield even under the conditions using the excess amount of
reagents (entries 2 vs 3).
Then, the reactions using various carbonyl compounds were
conducted to find out the scope and limitations of substrates for
the Bucherer–Bergs reaction (Table 2). Here, it was found that IR
analysis helped us not only to estimate the reactivity of carbonyl
compounds under the optimized Bucherer–Bergs reaction condi-
tions but also to pick up the suitable substrates (natural plant
extracts that have electrophilic ketones for derivatization). For
compounds 1a–1f having an electrophilic carbonyl group which
showed C@O stretching vibrations over 1710 cmÀ1 in the IR spec-
tra the reactions proceeded in good to excellent yields (85–98%),
and then their olefin, amide, and carbamate were all inert under
C
1
3a
4b
24.1
CH
CH2
CH2
C
24.2
24.3
22.7
22.8
37.4
37.4
61.9
62.0
23.3
23.4
27.4
128.0
200.5
48.5
19.3
19.4
146.1
146.1
23.1
23.1
23.6
23.7
18.7
18.8
178.5
178.5
156.4
156.4
CH
CH2
CH2
C
2
3
4
5
23.4
43.9
200.8
24.1
CH
CH
6
7
8
9
28.0
CH2
C
C
CH2
C
CH2
C
C
CH2
C
128.1
201.7
48.9
10
20.1
11
147.4
C
C
12
13
14
23.5
23.4
30.1
CH3
CH3
CH3
CH3
CH3
CH3
15
16
17
19.0
CH3
CH3
C
C
a
Measured in CDCl3.
Measured in DMSO-d6. A 1:1 mixture of diastereomers.
the reaction conditions as expected. As for D-camphor (1g) with a
sterically hindered ketone, however, no reaction occurred and
the substrate was completely recovered. The reaction of the com-
b
pound carrying conjugated ketone, such as
a-tetralone (1i),
resulted in low conversion at room temperature because of its rel-
atively low electrophilicity. The reactions of coumarin (1h) and 6-
hydroxyflavone (1k), whose skeletons are familiar in natural plant
extracts, resulted in no reaction. An amide was also inert under the
reaction conditions as exemplified in the reaction using N-(4-
ethoxyphenyl)acetamide (1j). These results indicate that when
the proper substrate (extract) is selected by the guidance of IR
analysis and applied to the optimized Bucherer–Bergs reaction
conditions, then our visionary derivatization would be accom-
plished without the unpredictable complication even in the com-
plex reaction system.
Figure 2. Significant HMBC correlations as represented by the arrows.
With the optimized reaction conditions in hand, our visionary
journey hopefully went toward direct derivatization of natural
plant extract. Here, the derivatization was thoughtfully affected
with the ethyl acetate extract of commercially available dried
rhizome of Curcuma zedoaria Roscoe (Zingiberaceae) due to the
desirable chemical property16 as well as the remarkable features
in pharmacological interests.17 Thus, the ethyl acetate extract
was directly derivatized under the optimized Bucherer–Bergs
reaction conditions. Then the rough fractionation and subsequent
repeated normal phase silica-gel column chromatography gave
the only derivatized product 4 as a 1:1 mixture of diastere-
omers,18 which should be derived from curcumenone (3).19 Here,
the process of its isolation was reliably guided by the character-
istic signals of hydantoin motif in both 1H NMR and IR measure-
ments. In 1H NMR spectra, a more acidic NH signal of hydantoin
motif appeared around 10 ppm when measured in DMSO-d6. As
Figure 3. Structures of isolated sesquiterpenes.
a complementary, the construction of hydantoin could also be
detected by IR measurement where the absorbance of two dis-
tinct symmetric [vsym(C@O)] and asymmetric [vasym(C@O)]
stretching vibrations of its 1,3-dicarbonyl moiety are known to
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4
K. Tomohara et al. / Tetrahedron Letters xxx (2016) xxx–xxx
appear in the range of 1800–1766 cmÀ1 and 1757–1722 cmÀ1
,
Acknowledgments
respectively.20 The former absorbance notably encouraged us to
follow up the desired hydantoin throughout the whole course
of purification. The structure of 4 was characterized by using
1H NMR, 13C NMR (Table 3), DEPT, 1H–13C heteronuclear single
quantum coherence (HSQC) and 1H–13C heteronuclear multiple
bond connectivity (HMBC) (Fig. 2), IR, MS measurements (see,
Supplementary data). The signals in 13C NMR spectrum of 4 were
resembled to those of 3 except for the signals assignable to C-3,
C-4, and C-14. In comparing to 3, those signals were shifted to
higher magnetic field corresponding to the formation of the
hydantoin motif. These evidences certainly indicated that the
product 4 should be derived from curcumenone (3). It is note-
worthy that the obtained product has a new chiral stereocenter
within hydantoin skeleton and such a 5,5-disubstituted hydan-
toin is not only an interesting motif particularly from the view-
We wish to thank an anonymous reviewer for valuable com-
ments on a manuscript of this study. This work was financially
supported by the JSPS KAKENHI Grant Number 26870217 and
the Tamura Science and Technology Foundation.
Supplementary data
Supplementary data associated with this article can be found, in
theonlineversion, at http://dx.doi.org/10.1016/j.tetlet.2016.01.054.
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In conclusion, the straightforward synthesis of novel natural
plant product-like hydantoin with tetrasubstituted carbon has
been described through the direct derivatization of ethyl acetate
extract of C. zedoaria using the Bucherer–Bergs four components
reaction. The present study attained the chemoselective derivati-
zation by proper choices of substrate and reaction system, there-
fore minimized the problems of complication, and enabled easy
access to novel natural plant-like molecule just in a single step
operation from the natural plant extract. Our quests are now going
ahead with plans to attain the large-scale examination and the
multiple productions of natural product-like molecules in combi-
nation with biological characterization. Thus, this methodology
will serve to provide a robust platform for creating natural plant
product-like molecules and enhance the continuous usefulness of
natural plants as renewable resources of chemicals.
Please cite this article in press as: Tomohara, K.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.01.054