Asymmetric syntheses and bio-evaluation of novel chiral esters derived from substituted tetrafluorobenzyl alcohol

Article abstract of DOI:10.1016/j.bmcl.2014.04.055

A series of novel chiral esters derived from tetrafluorobenzyl alcohol were designed and prepared via asymmetric synthesis. The target molecules have been identified on the basis of analytical spectra data. All newly synthesized compounds have been screened their potential insecticidal activity against Plutella xylostella compared with those of fenvalerate and d-trans-phenothrin by standard method, and the respective pairs of enantiomers (3-B1-R/S, 3-C1-R/S, 3-D1-R/S) indicated significantly different activities.

Full text of DOI:10.1016/j.bmcl.2014.04.055

Bioorganic & Medicinal Chemistry Letters 24 (2014) 2734–2736
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Asymmetric syntheses and bio-evaluation of novel chiral esters
derived from substituted tetrafluorobenzyl alcohol
⇑
Shengzhen Xu , Huangyong Li , Xiaohui Wang, Changshui Chen, Minhui Cao, Xiufang Cao
College of Science, Huazhong Agricultural University, Wuhan 430070, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel chiral esters derived from tetrafluorobenzyl alcohol were designed and prepared via
asymmetric synthesis. The target molecules have been identified on the basis of analytical spectra data.
All newly synthesized compounds have been screened their potential insecticidal activity against Plutella
Received 18 February 2014
Revised 25 March 2014
Accepted 9 April 2014
Available online 21 April 2014
xylostella compared with those of fenvalerate and
D-trans-phenothrin by standard method, and the
respective pairs of enantiomers (3-B1-R/S, 3-C1-R/S, 3-D1-R/S) indicated significantly different activities.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Chiral esters
Tetrafluorobenzyl alcohol
Asymmetric syntheses
Activities
During the last two decades, the use of pyrethroids has contin-
uous increased.1 The expansion of pyrethroid use has accompanied
with pyrethroid resistance in pest insect populations, which have
made the vector control more and more difficult.2–4 Therefore,
there is an urgent need to develop new insecticidal structures in
order to combat resistance.5 In the typical commercial pyrethroids,
many structures have a substituted benzyl alcohol moiety such as
Transfluthrin, Dimefluthrin, Meperfluthrin etc.6 Many studies have
also shown that the introduction of fluorine atoms in many com-
pounds could remarkably gain their biological activity.7,8 Accord-
ing to literatures, Musca domestica L. and other insects showed
very low resistance factors against fenfluthrin and other polyfluo-
robenzyl pyrethroid in contrast to the meta phenoxybenzyl pyre-
throids.9 Furthermore, the polyfluorobenzyl pyrethroid could be
used repeatedly to give satisfactory control without causing resis-
tance as their lack of extended residual activity.10 Thus, the less
persistent polyfluorobenzyl pyrethroid could become an interest-
ing material in insect resistance management practices.
aimed at searching for active chiral esters derivatives, we would
like to report herein our effort to design, distereoselectively syn-
thesize, and investigate the bioactivities of novel chiral esters
derived from tetrafluorobenzyl alcohol (Fig. 1).
In the present study, a series of novel chiral esters derivatives 3
were constructed by reacting functionalized chial building blocks 2
with substituted tetrafluorobenzyl alcohol. General procedure for
the preparation of target compounds 3 is outlined in Scheme 1.
The key intermediates N-alkanoylcamphorsultams
1 were
obtained by using a chiral auxiliary as a controlling reagent follow-
ing the literature methods,11–13 which can be conveniently trans-
formed into various chiral acids 2 via a nucleophilic cleavage
reaction of corresponding N-alkanoylcamphorsultams in the pres-
ence of lithium peroxide. The auxiliary sultam recovered here can
also be reused. And then, the dehydration condensation of chiral
acids 2 and tetrafluorobenzyl alcohol gave our desired products
3. All target compounds gave satisfactory chemical analyses, and
the chemical structures of the synthesized compounds are summa-
rized in Table 1. The 1H NMR spectra of compounds 3 indicated dis-
tinctive signals of protons for substituted tetrafluorobenzyl moiety,
which presented a singlet peak in the range 5.50–3.00 ppm. The
general signals at lower and higher fields respectively in their 1H
NMR spectra were assigned to the aromatic and alkyl protons in
the chiral acid units. Their 13C NMR spectra presented obvious
signals of different alkyl carbon (70–5 ppm), and the signals that
appeared at about 170 ppm were attributed to the C@O carbon.
The other signals at about 160–100 ppm in the 13C NMR
spectra were assigned to the aromatic carbon as shown in the
On the other hand, many pyrethroids analogues have one or
more chiral centers, and the enantiomers always exhibited differ-
ent bioactivities. So the questions concerning the synthetic method
to obtain pure active enantiomers, and the influence of stereo-
chemistry upon biological activity for novel chiral compounds
are therefore of two particular interests in this study. Based on
the aforementioned results, as part of our agrochemistry program
⇑
Corresponding author. Tel.: +86 27 87288247.
E-mail address: caoxiufang@mail.hzau.edu.cn (X. Cao).
These authors contributed equally to this work.
http://dx.doi.org/10.1016/j.bmcl.2014.04.055
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

S. Xu et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2734–2736
2735
F
F
Cl
Transfluthrin
O
F
F
Cl
F
R1
F
R3
F
O
F
OH
R1
O
*
R2
O
F
F
R2
O
F
O
Chial Building Blocks
Dimefluthrin
O
F
Novel Chiral Esters
O
Figure 1. Design strategy of novel chiral esters derived from tetrafluorobenzyl alcohol.
F
F
F
F
R3
F
R2
R2
O
F
R3
F
O
HO
R1
I
I
O
N
R1
F
HO
HO
R1
S
II
O
R2
R2
O
O
O
F
F
F
R3
O
O
HO
F
S
F
R1
R1
F
N
O
R1
II
O
R2
F
R3
R2
O
F
1
2
3
Scheme 1. Synthetic route for novel chiral esters 3. Reagent and conditions: (I) LiOH, H2O2, THF–H2O (4:1), 0 °C, 12 h; (II) DCC, DMAP, CH3CN, rt, 10 h.
Table 1
Chemical structures, physical properties of compounds synthesized and their insecticidal activity against Plutella xylostella
Entry
Compd no.
R1
R2
R3
Appearance
Insecticidal activitya (mg/L)
167
100
33.3
11.1
1
2
3
4
5
6
7
8
3-A1-R
3-A1-S
3-B1-R
3-B1-S
3-B2-R
3-B2-S
3-C1-R
3-C1-S
3-D1-R
3-D1-S
Fenvalerate
H
H
H
H
H
H
Bn
Bn
iPr
iPr
iPr
iPr
4-Me-Bn
4-Me-Bn
nBu
nBu
—
CH2OMe
CH2OMe
CH2OMe
CH2OMe
Me
Me
Me
Me
White solid
White solid
White solid
White solid
White solid
White solid
White solid
White solid
White solid
White solid
—
0
0
9
5
9
9
9
0
9
0
9
9
0
0
9
0
9
9
9
0
9
0
9
9
0
0
9
0
9
9
7
0
5
0
9
9
0
0
5
0
7
7
5
0
0
0
9
9
4-MeO
4-MeO
4-Cl
4-Cl
—
9
CH2OMe
CH2OMe
—
10
11
12
—
—
—
—
D-trans-Phenothrin
13
Blank control
—
—
—
—
0
0
0
0
a
Hierarchical levels of insecticidal activity:9 (>90% mortality), 7 (70–90% mortality), 5 (50–69% mortality), 3 (30–49% mortality), 1 (10–29% mortality), 0 (0–9% mortality).
representative spectra. Mass spectra, in particular, also showed the
molecular ion peaks at the appropriate m/z values.
The insecticidal activities in vivo were evaluated according to
the reported method.14 The results of compounds 3-A1-R ꢀ 3-
D1-S against Plutella xylostella are also listed in Table 1.
Interestingly, the results described in Table 1 indicated the
enantiomers always presented different biological activities. Spe-
cifically speaking, the (R)-enantiomers of 3-B1 (entry 3) still dis-
played good activity against Plutella xylostella at the concentration
of 11.1 mg/L, whereas the corresponding (S)-enantiomer (entry 4)
was almost lost activity at the same level. Especially in the cases
of compounds 3-C1 and 3-D1, the (S)-enantiomers (entries 8 and
10) exhibit no activity at highest concentrations (167 mg/L). How-
ever, the enantiomers of compounds 3-B2 (entries 5 and 6) display
little difference in terms of their activities against Plutella xylostella,
implying that this enantiomers need further investigation for their
structure–activity relationships.
In conclusion, a series of new chiral esters 3-A1-R ꢀ 3-D1-S
were distereoselectively synthesized and their potential activities
have been evaluated. The preliminary bioassay results indicated
that some of these derivatives have good insecticidal activity
against Plutella xylostella. From the experimental results, it could
also be concluded that the absolute configuration for target
Generally speaking, as shown in Table 1, some of the synthe-
sized compounds exhibited good insecticidal activities against Plu-
tella xylostella at 11.1 mg/L, such as 3-B1-R, 3-B2-R/S, 3-C1-R,
which present >50% mortality at the lower concentration. Mean-
while, most of the compounds with an R configuration indicated
obviously better activity in contrast with the compounds of S con-
figuration. Changing the group size of R2, we were surprised to find
that most of the compounds with an isopropyl in R2 provided
higher activity than the others (entries 3–6). In addition, some
electron-withdrawing groups and electron-donating substituents
were introduced into the molecules in R1 to explore the influence
of structural changes on activities, the result showed that the influ-
ence was little.

2736
S. Xu et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2734–2736
molecules can affect their activities, and the respective pairs of
enantiomers (3-B1-R/S, 3-C1-R/S, 3-D1-R/S) showed significantly
different activities. To our best knowledge, this is the first report
on the distereoselective syntheses and insecticidal activity of novel
chiral esters derived from tetrafluorobenzyl alcohol, which are
promising lead compounds for further developing novel agrochem-
icals containing fluorine. Further structural optimization and activ-
ity profiles about the designed novel chiral ester derivatives are
well ongoing in our laboratory.
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We gratefully acknowledge the support of this work by the
National Natural Science Foundation of China (31101467).
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Supplementary data
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Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2014.04.
055.