Synthesis and stereostructure-activity relationship of novel pyrethroids possessing two asymmetric centers on a cyclopropane ring

Article abstract of DOI:10.3390/molecules24061023

2-Methylcyclopropane pyrethroid insecticides bearing chiral cyanohydrin esters or chiral ethers and two asymmetric centers on the cyclopropane ring, were synthesized. These compounds were designed using a “reverse connection approach” between the isopropyl group in Fenvalerate, and between two dimethyl groups in an Etofenprox analogue (the methyl, ethyl form), respectively. These syntheses were achieved by accessible ring opening reactions of commercially available (±)-, (R)-, and (S)-propylene oxides using 4-chlorobenzyl cyanide anion as the crucial step, giving good overall yield of the product with >98% ee. The insecticidal activity against the common mosquito (Culex pipiens pallens) was assessed for pairs of achiral diastereomeric (1R*,2S*)-, (1R*,2R*)-cyanohydrin esters, and (1R*,2S*)-, (1R*,2R*)-ethers; only the (1R*,2R*)-ether was significantly effective. For the enantiomeric (1S,2S)-ether and (1R,2R)-ether, the activity was clearly centered on the (1R,2R)-ether. The present stereostructure?activity relationship revealed that (i) cyanohydrin esters derived from fenvalerate were unexpectedly inactive, whereas ethers derived from etofenprox were active, and (ii) apparent chiral discrimination between the (1S,2S)-ether and the (1R,2R)-ether was observed. During the present synthetic study, we performed alternative convergent syntheses of Etofenprox and novel 4-EtO-type (1S,2S)- and (1R,2R)-pyrethroids from the corresponding parent 4-Cl-type pyrethroids, by utilizing a recently-developed hydroxylation cross-coupling reaction.

Full text of DOI:10.3390/molecules24061023

molecules
Article
Synthesis and Stereostructure-Activity Relationship
of Novel Pyrethroids Possessing Two Asymmetric
Centers on a Cyclopropane Ring
Takashi Taniguchi, Yasuaki Taketomo, Mizuki Moriyama, Noritada Matsuo and Yoo Tanabe *
Department of Chemistry, School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda,
Hyogo 669-1337, Japan; taniguchi.t.am@m.titech.ac.jp (T.T.); dzs31988@kwansei.ac.jp (Y.T.);
ext32196@kwansei.ac.jp (M.M.); nor87168@cf6.so-net.ne.jp (N.M.)
* Correspondence: tanabe@kwansei.ac.jp; Tel.: +81-79-565-8394
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 14 February 2019; Accepted: 9 March 2019; Published: 14 March 2019
Abstract: 2-Methylcyclopropane pyrethroid insecticides bearing chiral cyanohydrin esters or
chiral ethers and two asymmetric centers on the cyclopropane ring, were synthesized. These
compounds were designed using a “reverse connection approach” between the isopropyl group in
Fenvalerate, and between two dimethyl groups in an Etofenprox analogue (the methyl, ethyl form),
respectively. These syntheses were achieved by accessible ring opening reactions of commercially
available ( )-, (R)-, and (S)-propylene oxides using 4-chlorobenzyl cyanide anion as the crucial
±
step, giving good overall yield of the product with >98% ee. The insecticidal activity against
the common mosquito (Culex pipiens pallens) was assessed for pairs of achiral diastereomeric
(1R*,2S*)-, (1R*,2R*)-cyanohydrin esters, and (1R*,2S*)-, (1R*,2R*)-ethers; only the (1R*,2R*)-ether
was significantly effective. For the enantiomeric (1S,2S)-ether and (1R,2R)-ether, the activity was
clearly centered on the (1R,2R)-ether. The present stereostructure-activity relationship revealed
that (i) cyanohydrin esters derived from fenvalerate were unexpectedly inactive, whereas ethers
derived from etofenprox were active, and (ii) apparent chiral discrimination between the (1S,2S)-ether
and the (1R,2R)-ether was observed. During the present synthetic study, we performed alternative
convergent syntheses of Etofenprox and novel 4-EtO-type (1S,2S)- and (1R,2R)-pyrethroids from
the corresponding parent 4-Cl-type pyrethroids, by utilizing a recently-developed hydroxylation
cross-coupling reaction.
Keywords: pyrethroid; structure-activity relationship; asymmetric synthesis; cyclopropane formation;
two asymmetric centers; common mosquito; chiral discrimination; hydroxylation cross-coupling
reaction; fenvalerate; etofenprox
1. Introduction
Chiral discrimination between the diastereomers and enantiomers is a pivotal subject [
1,2]
concerning the development of synthetic pyrethroid insecticides [ ]. The original natural
1–6
chrysanthemic acid components possess cyclopropane structures with 1R,3R (or 3S) chiral centers as the
insecticidally-active ingredient. Fenvalerate was the first distinctive non-cyclopropane-type synthetic
pyrethroid to be reported, and the active S-enantiomer is commercially available as esfenvalerate
(Figure 1) [7]. This concept on this discovery was interpreted by using the disconnection approach on
the cyclopropane bond in natural chrysanthemic acids. The development of the ether-type pyrethroid
etofenprox, on the other hand, overturned the prevailing belief that pyrethroids are composed
of common ester-type moieties. In an independent investigation, the CSIRO (Commonwealth
Scientific and Industrial Research Organisation, Australia) group disclosed pyrethroids containing a
Molecules 2019, 24, 1023; doi:10.3390/molecules24061023
www.mdpi.com/journal/molecules

Molecules 2019, 24, 1023
2 of 19
gem-dihalocyclopropane, cycloprothrin [
8
,9] the S-enantiomer of which is the active ingredient and is
likely superimposable on esfenvalarate (Figure 2).
In our continuing synthetic studies of cyclopropane chemistry [10
,
11], we previously reported
II
15]. Apparent chiral discrimination among three sets of
three synthetic designs and the structure activity relationships (SARs) of cyclopropane pyrethroids
and III with three chiral centers (Figure 2) [12
I,
,
–
eight stereoisomers revealed that each enantiomer (1R,2S,3S) was an insecticidally-active form. Taking
this background into account, we envisaged a further investigation of the synthesis of simpler and more
accessible novel cyclopropane-type pyrethroids with two chiral centers: cyanohydrin ester-type
ether-type (Scheme 1). The design of and involved a “reverse connection approach” between the
and positions in fenvalerate and between the and positions in an etofenprox analogue (methyl and
1 and
2
1
2
a
b
c
d
ethyl form). Furthermore, the present work was performed using an accessible chiral synthetic method,
eliminating the tedious optical resolution and elaborated asymmetric cyclopropanation procedures
used for I-III. Convergent synthesis of etofenprox and the present 4-EtO-type pyrethroids from the
parent 4-Cl-type pyrethroids utilizing a recently developed hydroxylation cross-coupling reaction is
also described.
Figure 1. Two representative non-cyclopropane-type pyrethroids.
Figure 2. Chiral synthetic cyclopropane-type pyrethroids with one and three chiral centers on the
cyclopropane ring.
Scheme 1. Our synthetic design for novel pyrethroids with two chiral centers 1 and 2, both with two
chiral centers on the cyclopropane ring.

Molecules 2019, 24, 1023
3 of 19
2. Results and Discussion
2.1. Syntheses of Novel Pyrethroids Possessing two Asymmetric Centers on the Cyclopropane Ring
Synthetic routes for key cyclopropane precursors
reactions of commercially available ( )-, (R)-, and (S)-propylene oxides by 4-chlorobenzyl cyanide
anion give the corresponding secondary alcohol intermediates. Tosylation of the intermediates
produces 2-(4-chlorophenyl)-4-tosyloxynitriles ( )- , (4R)- , and (4S)- . An SN2-type ring-closing
reaction using mixtures of (4R)- and (4S)- produces the key cyclopropane nitriles (1R*,2S*)-
and (1R*,2R*)- as diastereomers. In a similar manner, two sets of nitriles (1R,2S)- /(1S,2S)- and
4 are outlined in Scheme 2. Ring-opening
±
±
3
3
3
3
3
4
4
4
4
(1S,2R)-4/(1R,2R)-4 can be prepared from (4R)- and (4S)-3, respectively.
(
(
Scheme 2. Synthetic plan for key stereodefined intermediate 4.
The successful accessible cyclopropane formation steps are shown in Scheme 3. The
LHMDS-mediated ring-opening reaction of 4-chlorobenzyl cyanide with ( )-propylene oxide gave
intermediary alcohol ( )- with a yield of 70% with ca. 6:4 diastereoselectivity according to
the reported method [16]. Alcohol ( )- was converted to tosylate ( )- with excellent yield
using TsCl/Et3N/ cat.Me3N HCl reagent [17] (96%, dr = 65:35). We then investigated the crucial
±
±
5
±
5
±
2
•
cyclopropane ring-closing reaction. Hiyama and Takehara’s group reported a relevant study on
stereoselective reactions of 4-methoxybenzyl cyanide with chiral epoxyoctane using three different
bases (NaH, tBuOK, and LDA) [16]. To intentionally obtain diastereomers (1R*,2S*)-
in equal amounts, we applied non-stereoselective conditions using tBuOLi, as shown in Table 1.
The relative stereochemical assignment of cyclopropanes was determined according to the reported
method [16]. Based on the criterion for the deshielding effect of a cis-located benzene ring, methyl
4 and (1R*,2R*)-4
4
protons (0.83 ppm) in (1R*,2R*)-
(1R*,2S*)-4.
4
appeared at a higher chemical shift than those (1.47 ppm) in
Cl
Cl
TsCl (1.5 eq.) /
Cl
2
CN
LHMDS (1.2 eq.)
4
CN
2
O
Et3N (2.0 eq.) / Me3N·HCl (0.1 eq.)
/ MeCN, 0 – 5 °C, 1 h
*
*
+
CN
4
OH
OTs
/ THF, 0 – 5 °C, 2 h
(4R)-5 and (4S)-5
dr = 65:35
(4R)-3 and (4S)-3
dr = 65:35
Cl
Cl
+
tBuOLi (1.2 eq.)
/ Et2O, 78 °C to 0 5 °C, 2.5 h
1
1
CN
CN
LHMDS: Lithium hexamethyldisilazide
TsCl: Tosyl chloride
1.47 ppm
0.83 ppm
2
2
(1R*, 2S*)-4
(1R*, 2R*)-4
Scheme 3. Ring-closing reaction leading to racemic cyclopropane nitriles 4.

Molecules 2019, 24, 1023
4 of 19
Table 1. Stereoselectivity of the ring-closing reaction leading to racemic cyclopropane nitriles 4.
Entry
Solvent
Total Yield of 4/% a
(1R*,2S*)-4/(1R*,2R*)-4 a
91 (83 b)
1
2 c
3
Et2O
Et2O
45/55
49/51
19/81
39/61
c
84
72
83
MTBE (Methyl t-butyl ether)
CPME (Cyclopentyl methyl ether)
4
Determined by 1H-NMR of the crude products. Internal standard: ethylene carbonate. Isolated. The reaction
a
b
was conducted at 0–5 ◦C.
Hydrolysis and successive reduction of (1R*,2S*)-4 and (1R*,2R*)-4 were next examined (Scheme 4).
Conventional hydrolysis of (1R*,2R*)-
with a yield of 84%, whereas (1R*,2S*)-
yield of 30-35%, probably due to the higher cis-methyl group stereocongestion. To address this
issue, DIBAL reduction and a Pinnick oxidation reaction sequence were applied to (1R*,2S*)- to
successfully produce acid (1R*,2S*)- with an overall yield of 76%. LAH reduction of carboxylic acids
4
using NaOH/MeOH-H2O gave carboxylic acid (1R*,2R*)-
6
4
resisted these conditions and was only produced with a
4
6
(1R*,2S*)-
6
and (1R*,2R*)-
6
gave alcohol intermediates (1R*,2S*)-
7
and (1R*,2R*)-
7
with yields of 92%
and 94%, respectively.
Cl
Cl
Cl
NaOH / MeOH-H2O
LiAlH4 (1.6 eq.)
CN
CO2H
/ THF, 0 – 5 °C to 20 – 25 °C, 2 h
OH
4
6
(1R*, 2R*)-
(1R*, 2R*)-
7
(1R*,2R*)-
94%
84%
Cl
Cl
DIBAL (2.0 eq.)
/ toluene,
NaH2PO4 (5.0 eq.)
Cl
CHO
CN
CO2H
/ tBuOH-H2O (4:3),
20 – 25 °C, 1 h
–78 °C to 20 – 25 °C, 1 h
2-methyl-2-butene (10 eq.)
4
(1R*, 2S*)-
NaClO2 (3.0 eq.)
(1R*, 2S*)-6
76%, 2 step
Cl
LiAlH4 (1.6 eq.)
/ THF, 0 – 5 °C to 20 – 25 °C, 2 h
OH
DIBAL: Diisobutylaluminium hydride
(1R*,2S*)-7
92%
Scheme 4. Conversion of racemic nitriles 4 to carboxylic acids 6 and alcohols 7.
Based on these results, cyanohydrin ester formation using acids (1R*,2S*)-
was carried out. Conventional condensation reactions of (1R*,2S*)- and (1R*,2R*)-
bromo(3-phenoxyphenyl)acetonitrile [ ] produced target cyanohydrin esters (1R*,2S*)-
(1R*,2R*)- in yields of 73% and 79%, respectively (Scheme 5). As addressed in the bioassay section
(vide infra), neither cyanohydrin ester (1R*,2S*)- nor (1R*,2R*)- exhibited significant insecticidal
6
and (1R*,2R*)-
with
and
6
6
6
8
9
8
8
8
activity. Accordingly, we abandoned further synthesis of the corresponding chiral compounds.
Scheme 5. Synthesis of cyanohydrin esters (1R*,2S*)-8 and (1R*,2R*)-8.

Molecules 2019, 24, 1023
5 of 19
We next turned our attention to the synthesis of all stereoisomers of achiral and chiral ether-type
pyrethroids (Scheme 6). Conventional ether formation of alcohols (1R*,2S*)- and (1R*,2R*)- with
3-phenoxybenzyl bromide produced a pair of achiral ethers, (1R*,2S*)- and (1R*,2R*)- , with good
yield. Based on the pilot approach, all four sets of chiral ethers, (1R,2S)- , (1S,2S)- , (1S,2R)- , and
(1R,2R)- , were successfully synthesized. It is noteworthy that clean SN2 reactions using tosylates
(4R)- and (4S)- proceeded smoothly to produce four key cyclopropane carbonitrile nitrile precursors,
(1R,2S)- , (1S,2S)- , (1S,2R)- , and (1R,2R)- , with excellent optical purities (all 98% ee, as determined
9
7
7
9
9
9
9
9
9
3
3
4
4
4
4
by HPLC analysis). Related chirality-induced cyclopropane-forming reactions have been addressed in
previous reports, namely a representative review [18], syntheses of liquid crystals [16], and syntheses
of dihydroxy vitamin D3 analogues [19], petrosterol [20], chiral cyclobutanes [21], bicifadin [22],
norchrysanthemic acid [23], and grandisol [23].
Because the bioassay section indicated that only the achiral ether (1R*,2R*)-
9
exhibited significant
insecticidal activity (vide infra), chiral ethers (1S,2S)-9 and (1R,2R)-9 were synthesized to evaluate
chiral discrimination.
Scheme 6. Syntheses of achiral and chiral ethers 9.
To obtain EtO-type parent etofenprox analogues, we designed convergent syntheses of chiral
ethers (1S,2S)-10 and (1R,2R)-10 from (1S,2S)-9 and (1R,2R)-9, respectively (Scheme 7). Fortuitously,
a hydroxylation cross-coupling procedure [24] developed by Buchwald’s group fulfilled this purpose;
the reaction using KOH/Pd(dba)2/tBu-XPhos catalysis and successive ethylation furnished the desired
ethers (1S,2S)-10 and (1R,2R)-10 with a good overall yield. Despite the relatively large molecules
(Molecular wight = 346.9), hydroxylation using 13 proceeded smoothly with a 94% yield without loss
of the cyclopropane and ether functional groups.

Molecules 2019, 24, 1023
6 of 19
.
Scheme 7. Convergent syntheses of EtO-type etofenprox analogues (1S,2S)-10 and (1R,2R)-10.
2.2. Alternative Synthesis of Achiral Etofenprox Analogues for Reference Compounds
Two reported cyclopropane-type etofenprox analogues, 13) [25] and II
compounds of
I
(
(
14) [25], the parent
9
, were synthesized as reasonable reference compounds for comparing the insecticidal
activity (Scheme 8). The KOH/cat. tetrabutylammonium bromide (TBAB)-mediated reaction of
4-chlorobenzyl cyanide with 1,2-dibromoethane gave cyclopropane carbonitrile 11 with an 80%
yield. The aforementioned conventional stepwise reactions starting from 11 led to the production
of etofenprox analogue-
cross-coupling using analogue
II (14) with an 80% yield (2 steps).
I (13) through alcohol 12 with an overall yield of 68%. Hydroxylation
I
(13) also proceeded smoothly in this case to produce analogue
(
(
Scheme 8. Concise synthesis of cyclopropane-type etofenprox analogues-I (13) and -II (14).
This successful outcome prompted us to apply the conversion process in Scheme 8 to the
concise synthesis of etofenprox itself, starting from readily available methyl 4-chlorophenylacetate (15
)
(Scheme 9).
Scheme 9. Alternative concise synthesis of etofenprox.

Molecules 2019, 24, 1023
7 of 19
Dimethylation of 15 using 2MeI/2NaH reagent, followed by LAH-reduction, gave chloro-type
precursor 17 with an 85% yield (2 steps). Conventional etherification of 17 with 3-phenoxybenzyl
bromide afforded precursor 18 (99%). Following the aforementioned hydroxylation and ethylation
sequence, etofenprox was produced with a 72% yield (two steps). The reported method utilized
meta-Cl-surrogate for Friedel-Crafts alkylation and dechlorination [26]. The present method represents
an alternative synthetic method for etofenprox.
2.3. Insecticidal Activity and Stereostructure-Activity Relationship
Insecticidal activity against the common mosquito (Culex pipiens pallens) was assessed for pairs of
achiral diastereomeric cyanohydrin esters (1R*,2S*)-
using fenvalerate as a reference compound (Table 2). The salient results are as follows: (i) neither
cyanohydrin esters (1R*,2S*)- nor (1R*,2R*)- exhibited significant insecticidal activity, even at
8, (1R*,2R*)-8, and ethers (1R*,2S*)-9, (1R*,2R*)-9
8
8
500 ppm. This result did not support our initial hypothesis, described in the introduction section,
i.e., imaginary cyclopropane formation of fenvalerate (“reverse connection approach”) decreased
the activity. Compared with fenvalerate, the solid cyclopropane conformation in
flexible-induced fitting for a conceivable “pyrethroid receptor”. (ii) In contrast, ethers (1R*,2S*)-
(1R*,2R*)- exhibited significant activities at 500 ppm, and (1R*,2R*)- was apparently more active
than (1R*,2S*)- at 250 ppm. With these promising results in our hand, we focused our attention on
chiral discrimination between enantiomeric ether compounds (1R,2R)-9 and (1S,2S)-9.
8
may inhibit
9
and
9
9
9
Table 2. Insecticidal activity of achiral cyanohydrin esters (1R*,2S*)-
(1R*,2S*)-9, (1R*,2R*)-9.
8
, (1R*,2R*)-
8
and achiral ethers
a
Mortality (%) Common Mosquito b
Compound
(1R*,2S*)-8
(1R*,2R*)-8
Structure
500 ppm
250 ppm
C
C
C
C
(1R*,2S*)-9
(1R*,2R*)-9
Fenvalerate
B
A
A
C
A
A
Cl
O
(+)-
O
a
b
The bioassay method is described in the Materials and Methods section. Criteria of the mortality: A, > 90%;
B, 10–90%; C, <10%.
Table 3 lists the results of insecticidal activities of pairs of chiral ethers (1S,2S)-9, (1R,2R)-9, and
EtO-analogues (1S,2S)-10, (1R,2R)-10, in which achiral ethers 13
as reference compounds. The salient features are as follows; (i) Regarding Cl-analogues, (1R,2R)-
exhibited higher activity than (1S,2S)- at 250 ppm; (ii) both (1S,2S)- and (1R,2R)- were inactive at
50 ppm; (iii) EtO-analogues (1R,2R)-10 exhibited a significant activity compared with (1S,2S)-10 at
50 ppm – this clear chiral discrimination between the enantiomers (1S,2S)- or -10 and (1R,2R)- or -10
is noteworthy; (iv) both the reported isosteric cyclopropane compounds 13 and 14 25] ande exhibited
nearly equal activities; (v) All the EtO-analogues were stronger than the Cl-analogues.
, 14, and 18, and etofenprox are selected
9
9
9
9
9
9
[

Molecules 2019, 24, 1023
8 of 19
,
Table 3. Insecticidal activity of chiral ethers (1S,2S)-9, (1R,2R)-9 and achiral reference compounds 13
14, and 18, and etofenprox.
a
Mortality (%) Common Mosquito b
Compound
Structure
250 ppm
50 ppm
10 ppm
(1S,2S)-9
(1R,2R)-9
(1S,2S)-10
(1R,2R)-10
13
C
C
C
A
A
A
A
A
A
C
C
A
B
C
C
C
C
B
14
A
B
18
C
B
Etofenprox
A
A
a
b
The bioassay method is described in the Materials and Methods section. Criteria of the mortality: A, > 90%;
B, 10–90%; C, <10%.
To summarize the results, all of the presented 2-methylcyclopropane pyrethroids with two
asymmetric centers exhibited clear chiral discrimination between the enantiomers, although the
insecticidal activity was slightly weaker than that of the reported parent reported achiral cyclopropane
and dimethyl pyrethroids. Notably, in contrast to our expectations based on a couple of three
asymmetric-center cyclopropane pyrethroids previously reported by our group [13
not the cyanohydrin ester type, was the active form.
,14], the ether-type,
3. Materials and Methods
All reactions were carried out in oven-dried glassware under an argon atmosphere. Flash column
chromatography was performed with silica gel 60 (230–400 mesh ASTM, Merck, Darmstat, Germany).
TLC analysis was performed on Merck 0.25 mm Silicagel 60 F254 plates. Melting points were determined
on a hot stage microscope apparatus (ATM-01, AS ONE, Osaka, Japan) and were uncorrected. NMR
spectra were recorded on a JEOLRESONANCE EXC-400 or ECX-500 spectrometer (JEOL, Akishima,
Japan) operating at 400 MHz or 500 MHz for 1H-NMR, and 100 MHz and 125 MHz for 13C-NMR.
Chemical shifts (δ
ppm) in CDCl3 were reported downfield from TMS (= 0) for 1H-NMR. For 13C-NMR,
chemical shifts were reported in the scale relative to CDCl3 (77.00 ppm) as an internal reference. IR
Spectra were recorded on FT/IR-5300 spectrophotometer (JASCO, Akishima, Japan). Mass spectra
were measured on a JMS-T100LC spectrometer (JEOL). HPLC data were obtained on a SHIMADZU
(Kyoto, Japan) HPLC system (consisting of the following: LC-20AT, CMB20A, CTO-20AC, and detector

Molecules 2019, 24, 1023
9 of 19
SPD-20A measured at 254 nm) using Chiracel AD-H or Ad-3 column (Daicel, Himeji, Japan, 25 cm)
◦
at 25 C. Optical rotations were measured on a JASCO DIP-370 (Na lamp, 589 nm). The synthetic
procedure of 11
1H-, 13C-NMR spectra for compounds (
(1R*,2S*)- , (1R*,2R*)- , (1R*,2S*)- , (1R*,2R*)-
supplementary information.
,
12
,
13
,
14
,
16
,
17
,
18, and etofenprox are available in the supplementary information.
)- , ( )- , (1R*,2S*)- , (1R*,2R*)- , (1R*,2S*)- , (1R*,2R*)-
, (1R*,2S*)- , (1R*,2R*)- , (1R,2R)-10 can see in the
±
5
±
3
4
4
6
6,
8
8
7
7
9
9
(±)-2-(4-Chlorophenyl)-4-hydroxypentanenitrile: (±)-5 (diastereo mixtures)
LHMDS (1.1 M in THF, 10 mL, 11 mmol) was added to a stirred suspension of 4-chlorobenzyl
cyanide (1.52 g, 10 mmol) in THF (13 mL) at 0–5 ◦C under an Ar atmosphere, and the mixture was
stirred at that temperature for 1 h. ( )-Propylene oxide (2.1 mL, 30 mmol) was added to the mixture,
±
which was stirred for 1 h. The mixture was quenched with 1M-HCl aq., which was extracted three times
with AcOEt. The combined organic phase was washed with brine, dried (Na2SO4) and concentrated.
The obtained crude oil was purified by SiO2-gel column chromatography (hexane/AcOEt = 10:1 to 1:2)
to give the desired product (
= 1.23 (d, J = 6.4 Hz, 3H
m, 1H × 13/20), 1.89–2.01 (m, 1H), 2.10–2.17 (m, 1H
J = 5.5 Hz, J = 9.6 Hz, 1H
7/20), 4.14–4.21 (m, 1H), 7.28–7.38 (m, 4H); 13C-NMR (125 MHz; CDCl3)
±
)-
7/20), 1.29 (d, J = 6.0 Hz, 3H
7/20), 3.56–3.67 (m, 1H
3
(1.48 g, 70%, dr = 65:35). Pale yellow oil; 1H-NMR (400 MHz, CDCl3)
13/20), 1.50–1.70 (brs, 1H), 1.79–1.86
13/20), 4.04 (dd,
δ
×
×
(
×
×
×
δ = 23.6, 23.8, 32.7, 33−.71, 43.8, 44.7, 63.9, 65.0, 120.4, 121.1, 128.4, 129.0, 129.2 (2C), 133.7, 133.8, 134.0,
134.4;
ν
(neat)/cm 3424, 2968, 2241, 1493, 1410, 1375, 1130, 1093, 1014, 953, 932, 845, 822, 791, 779,
max
718; HRMS (DART) calcd for C11H12ClNO [M + H]+ 210.0686, found 210.0688.
(4R)-2-(4-Chlorophenyl)-4-hydroxypentanenitrile: (R)-5 (diastereo mixtures)
Following the similar procedure for the preparation of ( )-3, the reaction of chlorobenzyl cyanide
±
(758 mg, 5.0 mmol), (R)-propylene oxide (1.05 mL, 15 mmol), and LHMDS (1.1 M in THF, 5.0 mL,
5.5 mL), and the successive SiO2-gel column chromatographic purification gave the desired product
(R)-5 (813 mg, 78%, dr = 65:35). Pale yellow oil.
(4S)-2-(4-Chlorophenyl)-4-hydroxypentanenitrile: (S)-5 (diastereo mixtures)
Following the similar procedure for the preparation of (
(1.52 g, 10 mmol), (S)-propylene oxide (2.1 mL, 30 mmol) and LHMDS (1.1 M in THF, 8.46 mL, 1.1 mL),
±
)-3, the reaction of chlorobenzyl cyanide
and the successive SiO2-gel column chromatographic purification gave the desired product (S)-
5
(1.57 g, 75%, dr = 65:35). Pale yellow oil.
(±)-4-(4-Chlorophenyl)-4-cyanobutan-2-yl 4-methylbenzenesulfonate: (±)-3 (diastereo mixtures)

Molecules 2019, 24, 1023
10 of 19
TsC1 (286 mg, 1.5 mmol) in MeCN (1.0 mL) was added to a stirred solution of (
±
)-
3
(210 mg,
1.0 mmol, dr =◦65:35), Et3N (202 mg, 2.0 mmol), and Me3N
·
HC1 (10 mg, 0.1 mmol) in MeCN
(1.0 mL) at 0–5 C, and the mixture was stirred for 1 h. Water was added to the mixture, which
was extracted twice with EtOAc. The combined organic phase was washed with water and brine, dried
(Na2SO4) and concentrated. The obtained crude oil was purified by SiO2-gel column chromatography
(hexane/AcOEt = 30:1 to 10:1) to give the desired product (
oil; 1H-NMR (400 MHz, CDCl3)
= 1.27 (d, J = 6.4 Hz, 3H
1.99–2.11 (m, 2H,), 2.47 (s, 3H), 3.81 (dd, J = 5.5 Hz, J = 10.1 Hz, 1H
±
)-
×
3
(350 mg, 96%, dr = 65:35). Pale yellow
7/20), 1.32 (d, J = 6.4 Hz, 3H × 13/20),
13/20), 3.90 (dd, J = 5.5 Hz,
13/20), 7.20–7.40 (m, 6H),
13/20); 13C-NMR (125 MHz; CDCl3)
= 20.3, 20.6, 21.3
δ
×
J = 8.7 Hz, 1H
7.77–7.79 (m, 2H
×
7/20), 4.51–4.59 (m, 1H
7/20), 7.85–7.87 (m, 2H
×
7/20), 4.77–4.85 (m, 1H
×
×
×
δ
(2C), 31.9, 33.0, 41.4, 42.3, 75.7, 76.6, 119.1, 119.8, 127.3, 127.5, 12−81.2, 128.8, 129.0, 129.1, 129.7, 129.8,
132.8, 133.1, 133.2, 133.4, 133.8, 134.0, 144.8, 145.0.;
ν
(neat)/cm 3022, 2984, 2243, 1597, 1493, 1362,
max
1188, 1175, 1096, 1059, 1016, 924, 891, 816, 750, 687, 662.
(2R)-4-(4-Chlorophenyl)-4-cyanobutan-2-yl 4-methylbenzenesulfonate: (R)-3 (diastereo mixtures)
Following the similar procedure for the preparation of (
3.0 mmol, dr = 50:50), TsCl (858 mg, 4.5 mmol), Et3N (607 mg, 6.0 mmol), and Me3N
0.3 mmol), and the successive SiO2-gel column chromatographic purification gave the desired product
±
)-
3
, the reaction of (R)-
5 (629 mg,
·
HCl (29 mg,
(R)-3 (980 mg, 90%, dr = 65:35). Pale yellow oil.
(2S)-4-(4-Chlorophenyl)-4-cyanobutan-2-yl 4-methylbenzenesulfonate: (S)-3 (diastereo mixtures)
Following the similar procedure for the preparation of (
7.34 mmol, dr = 50:50), TsCl (2.10 g, 11.0 mmol), Et3N (1.49 g, 14.7 mmol), and Me3N
0.7 mmol), and the successive SiO2-gel column chromatographic purification gave the desired product
±
)-
3
, the reaction of (S)-
5 (1.54 g,
·
HCl (70 mg,
(S)-3 (2.45 g, 92%, dr = 65:35). Pale yellow oil.
(1R*,2S*)- and (1R*,2R*)-1-(4-Chlorophenyl)-2-methylcyclopropane-1-carbonitrile: (1R*,2S*)-4 and (1R*,2R*)-4
Tosylate (
±
)-
3
(65:35: diastereo mixtures) (942 mg, 2.59 mmol) in Et2O (13 mL) was added to a
78 ◦C under Ar atmosphere,
stirred suspension of tBuOLi (249 mg, 3.11 mmol) in Et2O (13 mL) at
followed by being stirred at the same temperature for 0.5 h. The mixture was allowed to warm to
0–5 C, and was stirred for 2 h. The mixture was quenched with water, which was extracted three times
−
◦

Molecules 2019, 24, 1023
11 of 19
with AcOEt. The combined organic phase was washed with brine, dried (Na2SO4) and concentrated.
The obtained crude oil was purified by SiO2-gel column chromatography (hexane/AcOEt = 50:1) to
give (1R*,2S*)-4 (175mg, 35%) and (1R*,2R*)-4 (161 mg, 32%).
1
(1R*,2S*)-4: Colorless oil; H-NMR (400 MHz, CDCl3)
δ = 1.41 (dd, J = 10.1 Hz, J = 11.9 Hz, 1H),
1.47–1.49 (m, 3H), 1.56–1.60 (m, 2H), 7.18–7.21 (m, 2H), 7.29–7.33 (m, 2H); 13C-NMR (125 MHz, CDCl3):
δ
15.9, 20.0, 25.3(2C), 120.4, 126.8, 128.8, 133.1, 135.2.; ν
max (neat)/cm−1 2968, 2934, 2234, 1495, 1445,
1402, 1369, 1121, 1096, 1015, 889, 849, 827, 764, 727.; HRMS (DART) calcd for C11H10OClN [M + H]+
192.0580, found 192.0573.
(1R*,2R*)-4: Colorless oil; 1H-NMR (400 MHz, CDCl3)
δ = 0.83 (d, J = 6.5 Hz, 3H), 1.26 (dd, J = 5.5 Hz,
J = 6.9 Hz, 1H), 1.74 (dd, J = 5.5 Hz, J = 9.3 Hz, 1H), 1.83–1.94 (m, 1H), 7.25–7.38 (m, 4H); 13C-NMR
−1
(125 MHz; CDCl3):
δ
13.6, 17.4, 19.9, 23.2, 123.2, 128.9, 130.7, 131.0, 134.1.;
ν
(neat)/cm 2966, 2230,
max
1493, 1445, 1396, 1366, 1315, 1124, 1094, 1043, 1014, 997, 908, 862, 827, 789, 729.
(1R,2S)- and (1S,2S)-1-(4-Chlorophenyl)-2-methylcyclopropane-1-carbonitrile: (1R,2S)-4 and (1S,2S)-4
Following the similar cyclization procedure described abave, (1R,2S)-4 (45%) and (1S,2S)-4 (39%)
were prepared from (2R)-3.
21
(1R,2S)-4: Colorless oil; [
α
]
+64.9 (c 1.00, CHCl3); 98% ee, HPLC analysis (Daicel Chiralcel OD-H
D
column, solvent: hexane/ethanol = 150:1, flow rate 0.80 mL/min, 254 nm UV detector), tR(racemate) =
10.38 min and 11.18 min. tR[(1R,2S)-form] = 9.74 min
◦
17
D
(1S,2S)-
4
: White colored solid; m.p. 73–75 C, [
α
]
+36.6 (c 0.7, CHCl3); >98% ee, HPLC analysis
(Daicel Chiralcel OD-H column, solvent: hexane/ethanol = 300:1, flow rate 0.80 mL/min, 254 nm UV
detector), tR(racemate) = 17.41 min and 18.55 min. tR[(1S,2S)-form] = 19.01 min.
(1S,2R) and (1R,2R)-1-(4-Chlorophenyl)-2-methylcyclopropane-1-carbonitrile: (1S,2R)-4, (1R,2R)-4
Following the similar cyclization procedure described above, (1S,2R)-4 (40%) and (1R,2R)-4 (38%)
were prepared from (2S)-3.
23
(1S,2R)-
3
: Colorless oil; [
α
]
−
62.6 (c 0.25, CHCl3); 98% ee, HPLC analysis (Daicel Chiralcel OD-H
D
column, solvent: hexane/ethanol = 150:1, flow rate 0.80 mL/min, 254 nm UV detector), tR(racemate) =
10.38 min and 11.18 min. tR[(1S,2R)-form] = 11.36 min.
20
(1R,2R)-
4
: White colored solid; m.p. 73-74 ◦C; [
α
]
−
33.4 (c 0.33, CHCl3); >98% ee, HPLC analysis
D
(Daicel Chiralcel OD-H column, solvent: hexane/ethanol = 300:1, flow rate 0.80 mL/min, 254 nm UV
detector), tR(racemate) = 17.41 min and 18.55 min. tR[(1R,2R)-form] = 15.01 min.
(1R*,2S*)-1-(4-chlorophenyl)-2-methylcyclopropane-1-carboxylic acid: (1R*,2S*)-6

Molecules 2019, 24, 1023
12 of 19
DIBAL (1.01 M in toluene, 1.98 mL, 2.0 mmol) was added slowly to a stirred solution of (1R*,2S*)-
4
(192 mg, 1.0 mmol) in toluene (10 mL) at
−
78 ◦C under an Ar atmosphere. The mixture was allowed
◦
to warm to 20–25 C over 1 h, and then the mixture was quenched with MeOH. Then, potassium
sodium tartrate tetrahydrate solution was added to the mixture. After stirring for 0.5 h, the mixture
was extracted three times with EtOAc. The combined organic phase was washed with brine, dried
(Na2SO4) and concentrated. The obtained crude aldehyde product (140 mg) was used for the next
step without purification. To a stirred solution of the obtained aldehyde (140 mg), 2-methyl-2-butene
(561 mg, 8.0 mmol) in tBuOH (9 mL), water (4 mL) were added NaH2PO4 (480 mg, 4.0 mmol) in
◦
water (4 mL) and NaClO2 (217 mg, 2.4 mmol) in water (4 mL) at 20–25 C, and the mixture was
stirred at that temperature for 1 h. The reaction mixture was quenched with water and extracted
with AcOEt three times. The combined organic phase was washed with brine, dried (Na2SO4) and
concentrated. Sat. NaHCO3 aq. was added to the residue, which was wasehd with Et2O two times.
The separated aqueous phase was acidified with 1M HCl aq. solution, which was extracted with AcOEt
three times. The combined organic phase was washed with brine, dried (Na2SO4) and concentrated to
give the desired product (1R*,2S*)-6 (160 mg, 76% for two steps). White colored solid; m.p. 136–137 ◦C
1H-NMR (400 MHz, CDCl3)
= 1.33 (dd, J = 4.5 Hz, 8.9 Hz, 1H), 1.37 (d, J = 6.2 Hz, 3H), 1.56 (dd,
J = 4.5 Hz, 7.6 Hz, 1H), 1.59–1.69 (m, 1H), 7.26–7.27 (m, 4H); 13C-NMR (125 MHz; CDCl3):
12.7, 22.6,
max (neat)/cm−1 3011, 2880, 2598, 2363, 1686, 1495, 1420,
;
δ
δ
25.3, 33.7, 128.3, 131.6, 133.0, 139.0, 178.6.;
1312, 1213, 1092, 1013, 889, 829, 754, 719.
ν
(1R,2S)-1-(4-Chlorophenyl)-2-methylcyclopropane-1-carboxylic acid: (1R,2S)-6
Cl
CO2H
Following the similar DIDAL-reduction and Pinnick oxidation procedure described abo◦ve,
(1R,2S)-6 was prepared from (1R,2S)-4 (80%, two steps). White colored crystal; m.p. 104–106 C;
[α]1D6 +120.6 (c 0.16, CHCl3).
(1S,2R)-1-(4-Chlorophenyl)-2-methylcyclopropane-1-carboxylic acid: (1S,2R)-6
Following the similar DIDAL-reduction and Pinnick oxidation procedure described above,
(1S,2R)-6 (79%, 2 steps) was prepared from (1S,2R)-4 (79%, two steps). White colored crystals; m.p.
102–105 ◦C; [α]1D7 −116.4 (c 0.97, CHCl3).
(1R*,2R*)-1-(4-Chlorophenyl)-2-methylcyclopropane-1-carboxylic acid: (1R*,2R*)-6
A mixture of (1R*,2R*)-
4
(381 mg, 2.0 mmol) and NaOH (1.6 g, 40 mmol) in MeOH (10.0 mL) and
◦
H2O (6.6 mL) was heated at 100 C for 16 h. After cooling down, the mixture was quenched with water,
which was washed with Et2O two times. The separated aqueous phase was acidified with 1M HCl aq.
solution, which was extracted with EtOAc three times. The combined organic phase was washed with
brine, dried (Na2SO4) and concentrated to give the desired product (1R*,2R*)-
colored crystals: m.p. 130–133 ◦C; 1H-NMR (400 MHz, CDCl3)
= 0.83 (d, J = 6.4 Hz, 3H), 1.09 (dd,
J = 4.6 Hz, J = 6.9 Hz, 1H), 1.80 (dd, J = 4.6 Hz, J = 9.2 Hz, 1H), 1.90–1.98 (m, 1H), 7.18–7.22 (m, 2H),
6 (358 mg, 84%). White
δ

Molecules 2019, 24, 1023
13 of 19
7.28–7.32 (m, 2H); 13C-NMR (125 MHz; CDCl3):
ν
HRMS (DART) calcd for C11H11ClO2 [M + H]+ 211.0526, found 211.0523.
δ
12.7, 22.6, 25.3, 33.7, 128.3, 131.6, 133.0, 139.0, 178.6.;
max (neat)/cm−1 3011, 2880, 2598, 2363, 1686, 1495, 1420, 1312, 1213, 1092, 1013, 943, 889, 829, 754, 719;
(1R,2R)-1-(4-Chlorophenyl)-2-methylcyclopropane-1-carboxylic acid: (1R,2R)-6
Following the similar hydroxylation procedure described above, (1S,2S)-6 was prepared from
(1S,2S)-4 (92%). White colored crystals; m.p. 103–104 ◦C; [α]D18 −19.0 (c 1.06, CHCl3)
(1S,2S)-1-(4-Chlorophenyl)-2-methylcyclopropane-1-carboxylic acid: (1S,2S)-6
Following the similar hydroxylation procedure described above, (1S,2S)-6 was prepared from
(1S,2S)-4 (92%). White colored crystals; m.p. 101–104 ◦C; [α]D20 +17.8 (c 1.00, CHCl3).
Cyano(3-phenoxyphenyl)methyl(1R*,2S*)-1-(4-chlorophenyl)-2-methylcyclopropane-1-carboxylate: (1R*,2S*)-
8
Et3N (0.06 mL, 0.40 mmol) was added to a stirred mixture of (1R*,2S*)-6 (77 mg, 0.36 mmol)
and bromo(3-phenoxyphenyl)acetonitrile (104 mg, 0.36 mmol) in acetone (0.72 mL) at 0–5 ◦C, and
the mixture was stirred at 20–25 ◦C for 2 h. 1M HCl aq. solution was added to the mixture, which
was extracted twice with ether. The combined organic phase was washed with water, brine, dried
(Na2SO4) and concentrated. The obtained crude oil was purified by SiO2-gel columm chromatography
(hexane/EtOAc = 30:1) to give the desired product (1R*,2S*)-
1H-NMR (400 MHz, CDCl3)
= 1.26 (d, J = 6.0 Hz, 3H 1/2), 1.32 (d, J = 6.0 Hz, 1H
(dd, J = 4.1 Hz, 4.6 Hz, 1H 1/2), 1.36 (dd, J = 4.6 Hz, 8.7 Hz, 1H 1/2), 1.58 (dd, J = 4.6 Hz,
1/2), 1.63–1.73 (m, 1H), 6.31 (s, 1H × 1/2), 6.34
= 12.8, 12.9, 22.5, 22.7, 25.0, 25.2, 33.8, 33.9,
8
(110 mg, 73%). Yellow colored oil;
δ
×
×
1/2), 1.32
×
×
5.0 Hz, 1H × 1/2), 1.60 (dd, J = 4.6 Hz, 5.0 Hz, 1H
×
(s, 1H × 1/2), 6.87–7.49 (m, 13H); 13C-NMR (125 MHz)
δ
62.6, 62.7, 115.7, 116.0, 116.9, 117.0, 119.2, 119.4, 120.1, 120.2, 121.4, 121.6, 124.0, 124.1, 128.5 (2C), 123.0
(2C), 130.5, 130.6, 131.4 (2C), 133.3 (2C), 133.4, 133.6, 138.0 (2C), 156.2, 156.3, 158.0, 158.2, 170.2 (2C);
ν
(neat)/cm−1 2931, 2360, 1734, 1585, 1487, 1155, 1244, 1090, 1015, 692. HRMS (DART) calcd for
max
C25H20ClNO3 [M + H]+ 418.1210, found 418.1192.
Cyano(3-phenoxyphenyl)methyl (1R*,2R*)-1-(4-chlorophenyl)-2-methylcyclopropane-1-carboxylate: (1R*,2R*)-8
Following the similar esterification procedure described above, (1R*,2R*)-
(1R*,2R*)- = 0.83 (d, J = 5.8 Hz, 3H
(79%). Yellow colored oil; 1H-NMR (400 MHz, CDCl3)
0.84 (d, J = 4.8 Hz, 3H 1/2), 1.13 (dd, J = 4.5 Hz, 4.8 Hz, 1H 1/2), 1.16 (dd, J = 4.1 Hz, 4.8 Hz,
1H 1/2), 1.81 (dd, J = 4.5 Hz, 9.3 Hz, 1H 1/2), 1.84 (dd, J = 4.5 Hz, 9.3 Hz, 1H 1/2), 1.89–2.00
(m, 1H), 6.29 (s, 1H 1/2), 6.32 (s, 1H = 15.2, 15.2,
1/2), 6.92–7.49 (m, 13H); 13C-NMR (125 MHz)
8
was prepared from
6
δ
×
1/2),
×
×
×
×
×
×
×
δ

Molecules 2019, 24, 1023
14 of 19
23.6(2C), 24.1, 24.3, 32.7(2C), 62.6(2C), 115.8, 115.9, 116.8, 116.9, 119.3(2C), 119.3(2C), 120.0, 120.1, 121.4,
121.5, 124.0(2C), 128.4(2C), 129.9(2C), 130.5(2C), 132.7(2C), 133.1(2C), 133.4, 133.4, 133.5(2C), 156.2,
156.2, 158.1(2C), 172.2, 172.2;
1045, 745, 690.
ν
(neat)/cm−1 2960, 2359, 1738, 1585, 1487, 1207, 1163, 1112, 1074,
max
(1R*,2S*)-1-(4-Chlorophenyl)-2-methylcyclopropane-1-methanol: (1R*,2S*)-7
Acid (1R*,2R*)-7 (126 mg, 0.6 mmol) in THF (3.0 mL) was added to a stirred suspension of LiAlH4
◦
◦
(36 mg) in THF (1.0 mL) at 0–5 C under an Ar atmosphere, and the mixture was stirred at 20–25 C for
2 h. Sat. NH4Cl aqueous solution was added to the mixture, which was filtered through Celite® using
EtOAc. The separated organic phase was washed with water, brine, dried (Na2SO4), and concentrated.
The obtained crude oil was purified by SiO2-gel column chromatography (hexane/EtOAc = 10:1) to
give the desired product (1R*,2R*)-
J = 5.0 Hz, 5.0 Hz, 1H), 1.01 (dd, J = 5.0 Hz, 8.2 Hz, 1H), 1.19–1.27 (m, 2H), 1.31 (d, J = 6.0 Hz, 3H), 3.74
(d, J = 11.9 Hz, 1H), 3.91 (d, J = 11.9 Hz, 1H), 7.21–7.36 (m, 4H); 13C-NMR (125 MHz)
= 13.9, 19.0,
(neat)/cm−1 3402, 2930, 1493, 1036, 1016, 831. HRMS
7 δ = 0.57 (dd,
(102 mg, 92%). Colorless oil; 1H-NMR (400 MHz)
δ
19.2, 31.2, 66.7, 128.4, 130.3, 132.1, 143.1;
ν
max
(DART) calcd for C11H13ClO [M + H]+ 196.0655, found 196.0651.
(1R*,2R*)-1-(4-Chlorophenyl)-2-methylcyclopropane-1-methanol: (1R*,2R*)-7
Following the similar reduction procedure described above, (1R*,2R*)-7 was prepared from
(1R*,2R*)-
0.80 (d, J = 6.2 Hz, 3H), 0.97 (dd, J = 4.8 Hz, J = 8.7 Hz, 1H), 1.06–1.14 (m, 1H), 1.25-1.45 (s, 1H), 3.38 (d,
6 δ = 0.61 (dd, J = 4.8 Hz, J = 4.8 Hz, 1H),
(94%). Colorless oil; 1H-NMR (400 MHz, CDCl3)
J = 11.2 Hz, 1H), 3.77 (d, J = 11.2 Hz, 1H), 7.24–7.32 (m, 4H); 13C-NMR (125 MHz)
δ = 15.4, 16.1, 16.7,
32.8, 71.7, 128.3, 132.0, 132.2, 138.3; νmax (neat)/cm−1 3347, 2868, 1492, 1091, 1015, 827, 737.
(1R,2S)-1-(4-Chlorophenyl)-2-methylcyclopropane-1-methanol: (1R,2S)-7
Cl
OH
Following the similar reduction procedure described above, (1R,2S)-
(93%). Colorless oil; [α]1D9 +56.6 (c 1.12, CHCl3).
7
7
was prepared from (1R,2S)-
6
6
(1S,2R)-1-(4-Chlorophenyl)-2-methylcyclopropane-1-methanol: (1S,2R)-7
Cl
OH
Following the similar reduction procedure described above, (1S,2R)-
(92%). Colorless oil; [α]1D9 −54.9 (c 0.46, CHCl3).
was prepared from (1S,2R)-
(1R,2R)-1-(4-Chlorophenyl)-2-methylcyclopropane-1-methanol: (1R,2R)-7
Cl
OH

Molecules 2019, 24, 1023
15 of 19
Following the similar reduction procedure described above, (1R,2R)-
7
was prepared from
(1R,2R)-6 (92%). White colored crystals; m.p. 56-57 ◦C; [α]D19 −31.9 (c 0.95, CHCl3).
(1S,2S)-1-(4-Chlorophenyl)-2-methylcyclopropane-1-methanol: (1S,2S)-7
Following the similar reduction procedure described above, (1S,2S)-
7 was prepared from (1S,2S)-6
(93%). White colored crystals; m.p. 51-53 ◦C; [α]D19 +32.4 (c 0.52, CHCl3).
(1R*,2S*)-1-(4-Chlorophenyl)-2-methylcyclopropane-1-methyl 3-phenoxybenzyl ether: (1R*,2S*)-9
A mixture of (1R*,2S*)-7 (183 mg, 0.93 mmol) and 3-phenoxybenzyl bromide (295 mg, 1.12 mmol)
in DMF (0.9 mL) was added to a stirred suspension of NaH (60% dispersion; 45 mg, 1.12 mmol) at
◦
◦
at 0–5 C under an Ar atmosphere, and the mixture was stirred at 20–25 C for 2 h. The mixture
was quenched by water, which was extracted by EtOAc twice. The combined organic phase was
washed with water, brine, dried (Na2SO4), and concentrated. The obtained crude oil was purified
by SiO2-gel column chromatography (hexane/EtOAc = 30:1) to give the desired product (1R*,2S*)-
9
(322 mg, 91%). Colorless oil; 1H-NMR (400 MHz, CDCl3)
δ
= 0.53 (dd, J = 4.6 Hz, J = 4.6 Hz, 1H), 1.01
(dd, J = 4.6 Hz, J = 8.2 Hz, 1H), 1.14–1.28 (m, 4H), 3.51 (d, J = 10.1 Hz, 1H), 3.73 (d, J = 10.1 Hz, 1H), 4.39
(d, J = 12.4 Hz, 1H), 4.44 (d, J = 12.4 Hz, 1H), 6.90–7.01 (m, 5H), 7.10–7.27 (m, 6H), 7.32–7.36 (m, 2H);
13C-NMR (125 MHz)
δ = 14.1, 19.5, 19.7, 28.8, 72.4, 73.9, 117.6, 117.8, 119.0, 122.1, 123.3, 128.1, 129.5,
129.7, 129.8, 131.5, 140.6, 143.9, 157.1, 157.4.; ν
max (neat)/cm−1 2859, 1584, 1445, 1213, 1092, 1076, 957,
831, 748; HRMS (DART) calcd for C24H23ClO2 [M + H]+ 379.1465, found 379.1447.
(1R*,2R*)-1-(4-Chlorophenyl)-2-methylcyclopropane-1-methyl 3-phenoxybenzyl ether: (1R*,2R*)-9
Following the similar etherification procedure described above, (1R*,2R*)-
9 was synthesized from
(1R*,2R*)- = 0.62 (dd, J = 4.8 Hz, J = 4.8 Hz, 1H),
7
(79%). Colorless oil; 1H-NMR (400 MHz, CDCl3)
δ
0.76 (d, J = 6.2 Hz, 3H), 0.94 (dd, J = 4.8 Hz, J = 8.7 Hz, 1H,), 1.03–1.11 (m, 1H), 3.33 (d, J = 9.9 Hz, 1H),
3.53 (d, J = 9.9 Hz, 1H), 4.38 (dd, J = 12.4 Hz, J = 14.7 Hz, 2H), 6.86–6.91 (m, 3H), 6.98–7.01 (m, 2H),
7.09–7.14 (m, 1H), 7.22–7.24 (m, 5H), 7.31–7.37 (m, 2H); 13C-NMR (125 MHz)
δ = 15.4, 16.3, 17.0, 30.5,
72.1, 78.9, 117.4, 117.7, 118.9, 121.9, 123.2, 128.0, 129.5, 129.7, 131.9, 132.0, 138.9, 140.6, 157.0, 157.3;
(neat)/cm−1 2855, 1584, 1445, 1250, 1213, 1092, 1015, 743.
ν
max
(1R,2S)-1-(4-Chlorophenyl)-2-methylcyclopropane-1-methyl 3-phenoxybenzyl ether: (1R,2S)-9
Following the similar etherification procedure described above, (1R,2S)-
(1R,2S)-7 (85%). Colorless oil; [α]2D2 +25.8 (c 1.19, CHCl3).
9 was synthesized from
(1S,2R)-1-(4-Chlorophenyl)-2-methylcyclopropane-1-methyl 3-phenoxybenzyl ether: (1S,2R)-9

Molecules 2019, 24, 1023
16 of 19
Following the similar etherification procedure described above, (1S,2R)-
(1S,2R)-7 (72%). Colorless oil; [α]2D3 -24.5 (c 0.50, CHCl3).
9
was synthesized from
(1R,2R)-1-(4-Chlorophenyl)-2-methylcyclopropane-1-methyl 3-phenoxybenzyl ether: (1R,2R)-9
Cl
O
O
Following the similar etherification procedure described above, (1R,2R)-
(1R,2R)-7 (91%). Colorless oil; [α]2D3 −31.8 (c 0.84, CHCl3).
9 was synthesized from
(1S,2S)-1-(4-Chlorophenyl)-2-methylcyclopropane-1-methyl 3-phenoxybenzyl ether: (1S,2S)-9
Following the similar etherification procedure described above, (1S,2S)-
(1S,2S)-7 (97%). Colorless oil; [α]2D3 +32.4 (c 0.65, CHCl3).
9 was synthesized from
1-((((1R,2R)-1-(4-Ethoxyphenyl)-2-methylcyclopropyl)methoxy)methyl)-3-phenoxybenzene: (1R,2R)-10
A mixture of (1R,2R)-
9
(108 mg, 0.29 mmol), Pd2(dba)3 (5.3 mg, 2 mol%), tBu-XPhos (10 mg,
◦
8 mol%) and KOH (81 mg, 5.0 eq.) in 1,4-dioxane (0.3 mL) and H2O (0.3 mL) was stirred at 100–105 C
for 16 h under an Ar atmosphere. The mixture was cooled down to room temperature, and quenched
with water, which was extracted twice with EtOAc. The combined organic phase was washed with
water, brine, dried (Na2SO4) and concentrated. The obtained crude oil was purified by SiO2-gel column
chromatography (hexane/EtOAc = 20:1) to give the desired phenol product (95 mg, 90%).
K2CO3 (43 mg, 0.31 mmol) and EtI (122 mg, 0.78 mmol) was successively added to a stirred
solution of phenol (92 mg, 0.26 mmol) in DMF (0.5 mL) at 0–5 ◦C under an Ar atmosphere.
◦
The mixture was stirred at 20–25 C for 16 h. The mixture was quenched with water, which was
extracted three times with EtOAc. The combined organic phase was washed with water, brine, dried
(Na2SO4) and concentrated. The obtained crude oil was purified by SiO2-gel column chromatography
(hexane/EtOAc = 20:1) to give the desired product (1R,2R)-10 (84 mg, 83%).
(1R,2R)-10: Colorless oil; [α]2D1 −23.4 (c 0.95, CHCl3); 1H-NMR (400 MHz, CDCl3) δ = 0.60 (dd, J = 4.8
Hz, J = 4.8 Hz, 1H), 0.77 (d, J = 6.2 Hz, 3H), 0.90 (dd, J = 4.8 Hz, J = 8.2 Hz, 1H), 0.99–1.07 (m, 1H), 1.40
(t, J = 7.1 Hz, 3H), 3.34 (d, J = 9.9 Hz, 1H), 3.54 (d, J = 9.9 Hz, 1H), 4.00 (q, J = 7.1 Hz, 2H), 4.39 (t, J =
13.3 Hz, 2H), 6.78–6.82 (m, 2H), 6.86–6.88 (m, 2H), 6.93 (d, J = 8.0 Hz, 1H), 6.98–7.00 (m, 2H), 7.08–7.12
(m, 1H), 7.19–7.22 (m, 2H), 7.23–7.25 (m, 1H), 7.31–7.35 (m, 2H); 13C-NMR (125 MHz) δ = 14.9, 15.4,
16.2, 17.0, 30.2, 63.2, 72.1, 79.3, 113.9, 117.6, 117.7, 118.9, 122.0, 123.2, 129.5, 129.7, 131.5, 132.2, 140.9,
157.2, 157.2, 157.4;
ν
(neat)/cm−1 2980, 2868, 1611, 1584, 1514, 1487, 1445, 1393, 1354, 1288, 1242,
max
1215, 1175, 1140, 1107, 1074, 1049, 959, 924, 835, 789, 735, 692; HRMS (ESI): m/z calcd for C26H28O3 [M
+ Na]+ 411.1936; found: 411.1936.
(1R,2R)-10: Pale yellow oil; [α]2D3 +24.7 (c 0.21, CHCl3).

Molecules 2019, 24, 1023
17 of 19
4. Conclusions
We envisaged syntheses of simple and accessible novel cyclopropane-type pyrethroids with two
chiral centers on the cyclopropane ring: cyanohydrin ester-type and ether-type . The design of
and involved a “reverse connection approach” derived from fenvalerate and etofenprox, respectively.
The synthesis of chiral 2-methylcyclopropanes and were performed by accessible ring-opening
reactions of 4-chlorobenzyl cyanide with commercially available ( )-, (R)-, and (S)-propylene oxides
1
2
1
2
1
2
±
as the crucial step, and provided the products in good overall yield with every >98% ee. During the
synthetic study, we also performed alternative convergent syntheses of etofenprox and 4-EtO-type
cyclopropane analogues from the parent 4-Cl-type pyrethroids utilizing a hydroxylation cross-coupling
reaction that was recently developed by Stradiotto’s group.
The bioassay using common mosquito revealed that none of the four cyanohydrin ester-type
compounds exhibited insecticidal activity, whereas among the four ether-type compounds , only
the (1R,2R)- enantiomer had significantly more activity than (1S,2S)- . The present clear chiral
1
2
2
2
discrimination was also observed for the previously reported “cyanohydrin ester-type cyclopropane”
pyrethroids with three chiral centers. The subtle nature of the stereostructure-activity relationships
is likely a privileged trend in pyrethroid chemistry, and the present finding will contribute to future
discovery in this field.
Supplementary Materials: The following are available online. All starting materials and reagents in this
work are commercially available. All starting materials and reagents in this work are commercially available.
The synthetic procedure of 11
information. Copies of the 1H-, 13C-NMR spectra for compounds (
(1R*,2R*)- , (1R*,2S*)- , (1R*,2R*)- , (1R*,2S*)- , (1R*,2R*)- , (1R*,2S*)-
the supplementary information.
,
12
,
13
,
14
,
16
,
17
,
18, and etofenprox are available in the supplementary
)- , ( )- , (1R*,2S*)- , (1R*,2R*)- , (1R*,2S*)-
, (1R*,2R*)- , (1R,2R)-10 are available in
±
5
±
3
4
4
6,
6
8
8
7
7
9
9
Author Contributions: T.T., Y.T. (Yasuaki Taketomo), and M.M. contributed the majority of experiments. N.M.
gave helpful suggestion for the pyrethroid chemistry. Y.T. (Yoo Tanabe) conceived and designed the project, and
prepared the whole manuscript.
Funding: This research was partially supported by Grant-in-Aids for Scientific Research on Basic Area (B)
“18350056”, Basic Areas (C) 15K05508, and Priority Areas (A) “17035087” and “18037068”, and Exploratory
Research “17655045” from the Ministry of Education, Culture, Sports, Science and Technology (MEXT).
Acknowledgments: We thank Sumika Technoservice Corporation for the supply of all the insecticidal assay data.
Conflicts of Interest: The authors declare no conflict of interest.
Dedication: This article is dedicated to the late professor Teruaki Mukaiyama who died in 2018. Two authors
(Yoo Tanabe and Noritada Matsuo) offer his warmest congratulations to Professor Ben L. Feringa (University of
Groningen, The Netherlands) on being awarded the 2016 Nobel Prize in Chemistry.
References
1.
2.
Elliot, M.; Janes, N.F. Pyrethrum: The Natural Insecticides; Academic Press: New York, NY, USA, 1973.
Soderlund, D.M.; Casida, J.E. Synthetic Pyrethroids; Elliot, M., Ed.; ACS Symposium Series 42; American
Chemical Society: Washington, DC, USA, 1977; p. 173.
3.
4.
5.
Naumann, K. Chemistry of Plant Protection 5, Synthetic Pyrethroid Insecticides; Springer: Berlin, Germany, 1990.
Matsui, M.; Yamamoto, I. Naturally Occurring Insecticides; Marcel Dekker: New York, NY, USA, 1971.
Chamberlain, K.; Matsuo, N.; Kaneko, H.; Khambay, B.P.S. Chirality in Agrochemicals; Kurihara, N.,
Miyamoto, J., Eds.; Wiley: New York, NY, UDA, 1998; p. 9.
6.
7.
Jeanmart, S. Trends in chrysanthemic acid chemistry: A survey of recent Pyrethrum syntheses. Aust. J. Chem.
2003, 56, 559–566. [CrossRef]
Ohno, N.; Fujimoto, K.; Okuno, Y.; Mizutani, M.; Hirano, Y.; Itaya, N.; Honda, T.; Yoshioka, H.
2-Arylalkanoates, a New Group of Synthetic Pyrethroid Esters not Containing Cyclopropanecarboxylates.
Pestic. Sci. 1976, 7, 241–246. [CrossRef]

Molecules 2019, 24, 1023
18 of 19
8.
9.
Holan, G.; O’Keefe, D.F.; Virgona, C.; Walser, R. Structural and biological link between pyrethroids and DDT
in new insecticides. Nature 1978, 272, 734–736. [CrossRef]
Holan, G.; Johnson, W.M.P.; Rihs, K.; Virgona, C.T. Structural and biological link between pyrethroids and
DDT in new insecticides. Pestic. Sci. 1984, 15, 361–368. [CrossRef]
10. Nishii, Y.; Wakasugi, K.; Koga, K.; Tanabe, Y. Chirality Exchange from sp3 Central Chirality to Axial
Chirality: Benzannulation of Optically Active Diaryl-2,2-dichrolocyclopropylmethanols to Axially Chiral
α-Arylnaphthalenes. J. Am. Chem. Soc. 2004, 126, 5358–5359. [CrossRef] [PubMed]
11. Nishii, Y.; Yoshida, T.; Asano, H.; Wakasugi, K.; Morita, J.; Aso, Y.; Yoshida, E.; Motoyoshiya, J.; Aoyama, H.;
Tanabe, Y. Regiocontrolled Benzannulation of Diaryl(gem-dichlorocyclopropyl)methanols for the Synthesis
of Unsymmetrically Substituted α-Arylnaphthalenes: Application to Total Synthesis of Natural Lignan
Lactones. J. Org. Chem. 2005, 70, 2667–2678. [CrossRef] [PubMed]
12. Nishii, Y.; Matsumura, H.; Muroya, Y.; Tsuchiya, T.; Tanabe, Y. Novel Synthetic Pyrethroid Containing a
Halocyclopropane Structure. Biosci. Biotech. Biochem. 1995, 59, 1355–1357. [CrossRef]
13. Nishii, Y.; Wakimura, K.; Tsuchiya, T.; Nakamura, S.; Tanabe, Y. Synthesis and Stereostructure-Activity
Relationship of a Synthetic Pyrethroid, 2-Chloro-1-methyl-3-phenylcyclopropylmethyl 3-Phenoxybenzyl
Ether. J. Chem. Soc. Perkin Trans. 1 1996, 1243–1249. [CrossRef]
14. Nishii, Y.; Maruyama, N.; Wakasugi, K.; Tanabe, Y. Synthesis and Stereostructure-activity Relationship of
Three Asymmetric Center Pyrethroids [2]: 2-Methyl-3-phenylcyclopropylmethyl 3-Phenoxybenzyl Ether
and Cyanohydrin Ester. Bioorg. Med. Chem. 2001, 9, 33–39. [CrossRef]
15. Yasukochi, H.; Atago, T.; Tanaka, A.; Yoshida, E.; Kakehi, A.; Nishii, Y.; Tanabe, Y. Practical, general,
and systematic method for optical resolution of gem-dihalo- and monohalo-cyclopropanecarboxylic acids
utilizing chiral 1,10-binaphthol monomethyl ethers: Application to the synthesis of three chiral pesticides.
Org. Biomol. Chem. 2008, 6, 540–547. [CrossRef] [PubMed]
16. Kusumoto, T.; Nakayama, A.; Sato, K.; Hiyama, T.; Takehara, S.; Shoji, T.; Osawa, M.; Kuriyama, T.;
Nakamura, K.; Fujisawa, T. Synthesis of new optically active cyanocyclopropanes as chiral dopants for
ferroelectric liquid crystals. Tetrahedron Lett. 1991, 32, 939–942. [CrossRef]
17. Yoshida, Y.; Sakakura, Y.; Aso, N.; Okada, S.; Tanabe, Y. Practical and Efficient Methods for Sulfonylation
of Alcohols Using Ts(Ms)Cl/Et3N and Catalytic Me3N.HCl as Combined Base: Promising Alternative to
Traditional Pyridine. Tetrahedron 1999, 55, 2183–2192. [CrossRef]
18. Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A.B. Stereoselective Cyclopropanation Reactions. Chem. Rev.
2003, 103, 977–1050. [CrossRef] [PubMed]
19. Huang, P.; Sabbe, K.; Pottie, M.; Vandewalle, M. A Novel Synthesis of 19-Nor 1α,25-dihydroxyvitamin D3
and Related Analogues. Tetrahedron Lett. 1995, 36, 8299–8302. [CrossRef]
20. Honda, T.; Katoh, M.; Yamane, S. Stereoselective synthesis of petrosterol and a formal synthesis of
aragusterols. J. Chem. Soc. Perkin Trans. 1 1996, 2291–2296. [CrossRef]
21. Man, H.-W.; Hiscox, W.C.; Matteson, D.S. A Highly Enatioselective and Diastereoselective Synthesis of
Cyclobutanes via Boronic Esters. Org. Lett. 1999, 1, 379–381. [CrossRef] [PubMed]
22. Xu, F.; Murry, J.A.; Simmons, B.; Corley, E.; Fitch, K.; Karady, S.; Tschaen, D. Stereocontrolled Synthesis of
Trisubstituted Cyclopropanes: Expedient, Atom-Economical, Asymmetric Syntheses of (+)-Bicifadine and
DOV21947. Org. Lett. 2006, 8, 3885–3888. [CrossRef] [PubMed]
23. Fujiwara, T.; Okabayashi, T.; Takahama, Y.; Matsuo, N.; Tanabe, Y. Ring-Closing Strategy Utilizing Nitrile
α
-Anions: Chiral Synthesis of (+)-Norchrysanthemic Acid and Expeditious Asymmetric Total Synthesis of
(+)-Grandisol. Eur. J. Org. Chem. 2018, 6018–6027. [CrossRef]
24. Anderson, K.W.; Ikawa, T.; Tundel, R.E.; Buchwald, S.L. The Selective Reaction of Aryl Halides with KOH:
Synthesis of Phenols,” Aromatic Ethers, and Benzofurans. J. Am. Chem. Soc. 2006, 128, 10694–10695. [CrossRef]
25. Nishida, S.; Matsuo, N.; Tsushima, K.; Hatakoshi, M.; Hirano, M. Certain phenoxy-benzyloxy ether
derivatives and an insecticidal and/or acaricidal composition containing the same and methods of use.
U.S. Patent 4,562,213, 31 December 1985.

Molecules 2019, 24, 1023
19 of 19
26. Umemoto, M.; Asano, T.; Nagata, T.; Numata, S. Process for producing 3-phenoxybenzyl 2-(4-alkoxyphenyl)-
2-methylpropyl ethers. U.S. Patent 4,542,243, 17 September 1985.
Sample Availability: Samples of the compounds all four acahiral and chiral cyclopropanes 4 are available from
the authors.
©
2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).