Synthesis and Stereostructure-Activity Relationship of Novel Pyrethroids Possessing Two Asymmetric Centers on a Cyclopropane Ring

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.


Introduction
Chiral discrimination between the diastereomers and enantiomers is a pivotal subject [1,2] concerning the development of synthetic pyrethroid insecticides [1][2][3][4][5][6]. The original natural 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 pyrethroids containing a 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 three synthetic designs and the structure activity relationships (SARs) of cyclopropane pyrethroids I, II, and III with three chiral centers ( Figure 2) [12][13][14][15]. Apparent chiral discrimination among three sets of 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 estertype 1 and ether-type 2 (Scheme 1). The design of 1 and 2 involved a "reverse connection approach" between the a and b positions in fenvalerate and between the c and d positions in an etofenprox analogue (methyl and 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.   pyrethroids containing a 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 three synthetic designs and the structure activity relationships (SARs) of cyclopropane pyrethroids I, II, and III with three chiral centers ( Figure 2) [12][13][14][15]. Apparent chiral discrimination among three sets of 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 estertype 1 and ether-type 2 (Scheme 1). The design of 1 and 2 involved a "reverse connection approach" between the a and b positions in fenvalerate and between the c and d positions in an etofenprox analogue (methyl and 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.   pyrethroids containing a 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 three synthetic designs and the structure activity relationships (SARs) of cyclopropane pyrethroids I, II, and III with three chiral centers ( Figure 2) [12][13][14][15]. Apparent chiral discrimination among three sets of 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 estertype 1 and ether-type 2 (Scheme 1). The design of 1 and 2 involved a "reverse connection approach" between the a and b positions in fenvalerate and between the c and d positions in an etofenprox analogue (methyl and 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.  Scheme 1. Our synthetic design for novel pyrethroids with two chiral centers 1 and 2, both with two 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.
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).

Alternative Synthesis of Achiral Etofenprox Analogues for Reference Compounds
Two reported cyclopropane-type etofenprox analogues, I (13) [25] and II (14) [25], the parent compounds of 9, were synthesized as reasonable reference compounds for comparing the insecticidal activity (Scheme 8). The KOH/cat. tetrabutylammonium bromide (TBAB)-mediated reaction of 4chlorobenzyl 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-I (13) through alcohol 12 with an overall yield of 68%. Hydroxylation crosscoupling using analogue I (13) also proceeded smoothly in this case to produce analogue II (14) with an 80% yield (2 steps). 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). 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).

Alternative Synthesis of Achiral Etofenprox Analogues for Reference Compounds
Two reported cyclopropane-type etofenprox analogues, I (13) [25] and II (14) [25], the parent compounds of 9, were synthesized as reasonable reference compounds for comparing the insecticidal activity (Scheme 8). The KOH/cat. tetrabutylammonium bromide (TBAB)-mediated reaction of 4chlorobenzyl 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-I (13) through alcohol 12 with an overall yield of 68%. Hydroxylation crosscoupling using analogue I (13) also proceeded smoothly in this case to produce analogue II (14) with an 80% yield (2 steps). 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). 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.
a The bioassay method is described in the Materials and Methods section. b 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 [13,14], the ether-type, not the cyanohydrin ester type, was the active form.
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 [13,14], the ether-type, not the cyanohydrin ester type, was the active form.
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 [13,14], the ether-type, not the cyanohydrin ester type, was the active form.
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 [13,14], the ether-type, not the cyanohydrin ester type, was the active form.
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 [13,14], the ether-type, not the cyanohydrin ester type, was the active form.
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 [13,14], the ether-type, not the cyanohydrin ester type, was the active form.
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 [13,14], the ether-type, not the cyanohydrin ester type, was the active form.
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 [13,14], the ether-type, not the cyanohydrin ester type, was the active form.

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 1 H NMR, and 100 MHz and 125 MHz for 13 C-NMR. Chemical shifts (δ ppm) in CDCl3 were reported downfield from TMS (= 0) for 1 H NMR. For 13 C-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 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 11,12,13,14,16,17,18, and etofenprox are available in the supplementary information. 1 H-, 13 C-NMR spectra for compounds (±)-5, (±)-3, (1R*,2S*)-4, 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 [13,14], the ether-type, not the cyanohydrin ester type, was the active form.

Conclusions
We envisaged syntheses of simple and accessible novel cyclopropane-type pyrethroids with two chiral centers on the cyclopropane ring: cyanohydrin ester-type 1 and ether-type 2. The design of 1 and 2 involved a "reverse connection approach" derived from fenvalerate and etofenprox, respectively. The synthesis of chiral 2-methylcyclopropanes 1 and 2 were performed by accessible ring-opening reactions of 4-chlorobenzyl cyanide with commercially available (±)-, (R)-, and (S)-propylene oxides 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 1 compounds exhibited insecticidal activity, whereas among the four ether-type compounds 2, only the (1R,2R)-2 enantiomer had significantly more activity than (1S,2S)-2. The present clear chiral 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.