378 Proc. Jpn. Acad., Ser. B 95 (2019) [Vol. 95, Review Discovery and development of pyrethroid insecticides † By Noritada MATSUO*1,*2, (Communicated by Keisuke SUZUKI, M.J.A.) Abstract: Pyrethroid insecticides contain natural pyrethrins extracted from pyrethrum flowers, and their synthetic derivatives, pyrethroids. The present article provides an overview of the structure of natural pyrethrins, and the discovery and development of pyrethroids with an emphasis on the background of selected compounds. The stereochemical relationships among pyrethroid secondary alcohols, and toxicologic and environmental effects of pyrethroids are also discussed. Finally, the pyrethroid resistance of mosquitoes and future aspects of pyrethroids are addressed. Keywords: pyrethrins, pyrethroids, insecticide, stereochemistry, pyrethroid resistance The first scientific report was published by a 1. Introduction and early studies Japanese biologist, Fujitani, in 1909.1) His findings Natural pyrethrum extracts from flowers of had a remarkable impact on many chemists through- Tanacetum cinerariaefolium (Fig. 1(a)) are the main out the world regarding the insecticidal activity of insecticides used for household and post-harvest pyrethrum extracts. Another Japanese chemist, insect control due to their low mammalian toxicity, Umetaro Suzuki, famous for the discovery of vitamin rapid knockdown activity, and high efficacy against B1 (Oryzanin) in rice bran, became interested in the a wide range of insect pests, especially mosquitoes. insecticidal ingredients in pyrethrum and suggested These flowers are cultivated in Tasmania (Australia), to his students, Yamamoto and Takei, that they East Africa (Tanzania, Rwanda, and Kenya), and clarify the chemical structure of pyrethrum. In 1923, southern China. In 2016, the amount of dried flowers Yamamoto was the first to report that the chemical reached approximately 10,000 metric tons. structures of the active ingredients in pyrethrum In Japan, pyrethrum seeds were independently contained a cyclopropane ring.2) introduced by Tamari and Ueyama in the 1880s. In 1924, Staudinger and Ruzicka, both Nobel Ueyama cultivated pyrethrum flowers in the prize winners, disclosed their extensive investigation Wakayama prefecture and confirmed the insecticidal during 1910–1916 on the active ingredients in the activity of pyrethrum extracts. He traveled around pyrethrum extracts, which included the esters of Japan, even to Hokkaido, and encouraged people to cyclopropanecarboxylic acid derivatives with hydrox- cultivate pyrethrum flowers, which gradually increas- ycyclopentanones.3) Although the structure of the ed the production of pyrethrum in Japan. Pyrethrum alcohol moiety was incorrect, the structures of the extracts were mainly used to control lice (lice acid moieties were correct. Given that NMR and IR powder) in those days, but Ueyama’s wife, Yuki, instruments had yet to be invented, their results envisaged a mosquito coil (Fig. 1(b)). The develop- should be highly regarded. The correct structures, ment of the mosquito coil enabled the control of pyrethrins I and II, were finally established in 1944 mosquitoes for several hours, and is widely used by LaForge and Barthel,4) as shown in Fig. 2. These around the world to control mosquitoes. authors concurrently separated two more relevant compounds, cinerins I and II from the pyrethrum *1 School of Science and Technology, Kwansei Gakuin extracts. University, Sanda, Hyogo, Japan. The absolute configuration of the acid moiety *2 SC Environmental Science Co., Ltd., Osaka, Japan. † of pyrethrin I was unambiguously determined by Correspondence should be addressed: N. Matsuo, School Crombie and Harper in 1954,5) and shortly thereafter of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda, Hyogo 669-1337, Japan (e-mail: nor87168@ in 1955, that of pyrethrin II was determined by cf6.so-net.ne.jp). Inouye and Ohno.6) Moreover in 1958, Katsuda and doi: 10.2183/pjab.95.027 ©2019 The Japan Academy No. 7] Discovery and development of pyrethroid insecticides 379 (a) (b) Fig. 1. (a) Pyrethrum flowers; (b) Mosquito coil. 1 2 O R R Pyrethrin I : CH O 3 Pyrethrin II : CO2CH3 O R1 R2 O Cinerin I : CH3 CH3 Cinerin II : CO2CH3 CH3 O Jasmolin I : CH3 CH2CH3 Jasmolin II : CO CH CH CH O R1 2 3 2 3 Fig. 2. Structures of natural pyrethrins. 380 N. MATSUO [Vol. 95, < DDT > OH O Cl CH Cl 2 Cl + Cl3CH OH CCl3 O < Allethrin > CO2Et O CO2Et O O O O OH Allethrin O OH O A Fig. 3. Structure of allethrin. 2 O + HC CH Inouye confirmed the absolute configuration of the OH OH alcohol moiety, pyrethrolone.7) In 1966, Godin and co-workers isolated two more related minor constit- O 8) A N2CHCO2Et uents, jasmolins I and II (Fig. 2). O Studies of structural modifications of natural pyrethrins were recorded early in the 20th century. CO2Et O Staudinger and Ruzicka reported many derivatives Fig. 4. Comparison of commercial processes of DDT and in 1924.3) Although some of these derivatives allethrin. exhibited only slight insecticidal activity, it is important to acknowledge the foresight of these researchers regarding natural pyrethrins as a lead The discovery of allethrin prompted chemists compound, before the structures of the alcohol worldwide to investigate structural modifications of moieties were elucidated. the pyrethroid alcohol and acid moieties, and later Over the last 90 years, several investigations even the essential ester function. These efforts have focused on the structural modifications of resulted in the development of a number of pyreth- natural pyrethrins. The first pyrethroid, allethrin roids with diverse characteristics, not only for the (Fig. 3), was discovered by Schechter and LaForge control of household insect pests, but also for in 1949.9) agricultural use. These derivatives are remarkably In 1949, Matsui at Sumitomo Chemical Co., Ltd. more potent, economical, and stable than the original was interested in a commercial process for producing natural pyrethrins. allethrin as a household insecticide.10) He modified The development of commercial pyrethroids is the FMC Corporation’s process (FMC Corporation is shown in the figure of a tree classified by their a chemical company in the U.S.A.) and successfully structures (Fig. 5). At the main trunk A, the produced allethrin on a commercial scale in 1953. discovery of 3-phenoxybenzyl alcohol and ,-cyano- This process at that time is shown in Fig. 4 in 3-phenoxybenzyl alcohol moieties gained great comparison with the process for DDT, which was commercial importance as agricultural insecticides. commonly used as a household insecticide in those There are a few boughs from the main trunk and days. Notably, DDT could be synthesized in a single several diphenyl ether-type pyrethroids were com- step, whereas the synthesis of allethrin required more mercialized for agricultural use. N-Hydroxymethyl- than 10 steps, which was much more expensive than type pyrethroids, which have strong knockdown natural pyrethrins. At the beginning, therefore, it activity against various insect pests, are placed at was difficult to commercialize allethrin due to the trunk B. Allethrin-type pyrethroids are placed at lengthy synthesis. Due to poor harvests of pyrethrum trunk C. Prallethrin, the structure of which is most flowers in the 1950s, however, commercial allethrin similar to Pyrethrin I, is placed at the end of trunk was gradually accepted in the market. The initial C. The fourth trunk D contains tetrafluorobenzyl- research on pyrethroids by Matsui firmly established type pyrethroids. The pyrethroids indicated in yellow the basis for several novel inventions of pyrethroids, in Fig. 5 were invented by chemists at Sumitomo which were conducted thereafter by many chemists Chemical. The author made great contributions to at Sumitomo Chemical. the inventions of the pyrethroids indicated in pink. No. 7] Discovery and development of pyrethroid insecticides 381 FF O O O FF Ujihara 1998 FF O O Cl OEt Si FF Cl O Naumann F 1985 Katsuda 1984 O OEt CN O O O CF3 O O Cl O O O CF3 Nakatani Matsuo 1981 1981 Bentley O Cl 1980 FF O O CF3 O Plummer CN O N 1978 OEt O Cl N O O CN O O Cl FF O H Cl Huff N CF3 O 1979 Itaya O Holan Cl 1977 1977 Katsuda 1975 CN O O CN O Br Cl H O O O Br O O Ohno Kitamura CN O 1973 1973 O Cl CN O O Cl O O O O Cl CN O O Cl O O Elliott 1972 Matsuo 1971 O O O O Itaya O 1968 O O O O O Matsui 1966 N O O O Elliott O Ueda 1965 O 1964 A O B Schechter 1947 C O O D O Pyrethrin I Fig. 5. Development of pyrethroids shown in the tree. 382 N. MATSUO [Vol. 95, Section 2 describes the background stories of the O inventions of selected important pyrethroids. N OR The impressive aspects of pyrethroid research O have been extensively reviewed.11)–18) Tetramethrin Merge O O OR 2. Background stories of inventions of selected N important pyrethroids N O O Merge O Over the last 6 decades, more than 30 pyreth- Prallethrin O R Imiprothrin roids have been commercialized. Each pyrethroid N has its own background story. Selected examples for N the development of commercialized pyrethroids are O Xn described in this section according to each trunk in 5 Fungicide Fig. 5. Most of them were invented by chemists at Fig. 7. Background of imiprothrin (Itaya 1979). Sumitomo Chemical, and others (Deltamethrin, Silafluofen and Terallethrin) are disclosed on the basis of my interviews with the inventors. 2.1. Trunk B, N-hydroxymethyl-type pyre- throids, tetramethrin and imiprothrin. 2.1.1. Tetramethrin the first synthetic pyrethroid with strong knockdown activity. Ueda at Sumitomo Chemical Co. Ltd., attempted to synthesize amide (1, Fig. 6) instead of the ester in 2,4-dimethylbenzyl chrysanthemate, which was reported by Barthel in 1958.19) He used the Gabriel synthesis to obtain 2,4-dimethylbenzylamine, followed by acylation with chrysanthemoyl chloride to produce amide 1.