Overview of Kenji Mori’s pheromone synthesis series

Abstract

It was the late Professor Kenji Mori, the giant of pheromone synthesis and pioneer of pheromone stereochemistry, who laid the foundation for the practical application of insect pheromones, which play an important role in Integrated Pest Management, one of the key concepts of agriculture in the 21st century. Therefore, it would be meaningful to retrace his achievements at this time, three and a half years after his death. In this review, we would like to introduce some of his notable synthetic studies from his Pheromone Synthesis Series and reconfirm his contributions to the development of pheromone chemistry and their impacts on natural science.

Introduction

Pheromones, defined as semiochemicals (signal substances) that act between other individuals within the same species, play an essential role in chemical communication among organisms, particularly in Insecta. However, rather than discussing the various aspects of pheromones in detail, this review will focus on an overview of the late Professor Kenji Mori’s Pheromone Synthesis Series (PSS). It has already been three and a half years since Kenji Mori (KM) passed away.^† Although many obituaries have been published^1–5) and a memorial issue has recently been edited and published in J. Chem. Ecol.,⁶⁾ there is still no review article focusing on his PSS. Since pest management with pheromones is an essential component of Integrated Pest Management (IPM), one of the key concepts of agriculture in the 21st century, this review may provide a valuable opportunity for J. Pest. Sci. readers to follow in the footsteps of KM, who spearheaded the development of pheromone science. However, although the scientific careers of both authors began with pheromone synthesis under KM’s supervision, neither is currently involved in pheromone science. Not just us, but at least in academia, none of his disciples have inherited his pheromone synthesis. This is because he told his disciples in academia, “As long as you are doing pheromone-related research, you will continue to be recognized as a Mori’s disciple. To be an independent researcher in academia, you should not do pheromone-centered research.” Nevertheless, since we are not pheromone experts and are not sufficiently competent to provide an overview of pheromone science/chemistry, this review will deal only with KM’s pheromone synthesis. Candidly, we may not be able to eliminate our bias as his disciples, but we would like to share with you what he strived for by pheromone synthesis, what he showed the world as a result, and how his achievements have influenced science today.

1. Before KM’s pheromone synthesis series

1.1. The starting point of pheromone science

Although an overview of the history of pheromone science/chemistry would require an enormous amount of journal space, it is necessary to mention only the starting point. It is well known that the existence of pheromone was suggested in the famous Fabre’s Book of Insects, but pheromone chemistry started in 1959 when Butenandt clarified the structure of the sex pheromone of the silkworm moth Bombyx mori, bombykol [(10E,12Z)-10,12-hexadecadienol] (Fig. 1).^7–10) Butenandt et al. isolated 12 mg of bombykol [as its 4-(4-nitrophenylazo)benzoate derivative] from half a million females. This research was a historical monument, but it is very interesting and suggestive that bombykol exhibited general properties of pheromones that would later be revealed one after another. For example, as mentioned above, bombykol is present in nature only in very small quantities. It is also an extremely bioactive substance, showing activity at 10⁻¹⁵ g/mL. In addition, its stereochemistry (E/Z isomerism) is important for its activity^10,11); the natural (10E,12Z)-isomer was at least 10¹⁰ times more active than other E/Z isomers, as revealed by the stereoselective synthesis of all isomers and their bioassay. Note that although bombykol is not associated with the concept of chirality, many of the pheromones discovered since then are chiral, and the relationship between stereochemistry and pheromonal activity has become a central issue of pheromone science.

Fig. 1. Structures of bombykol and its derivative.

1.2. Before the dawn of pheromone synthesis

For more than 45 years since the 1970s, Prof. Mori has provided strong leadership in pheromone science from the standpoint of synthetic organic chemistry. During his lifetime, he authored more than 1,000 scientific publications, including more than 850 original papers, more than half of which were related to pheromones. Before moving on to the main part of this article, we would like to briefly introduce how he got started in pheromone synthesis.

KM started his scientific career in the Laboratory of Biological Chemistry, Department of Agricultural Chemistry, the University of Tokyo, working on the isolation and purification of enzymes.¹²⁾ Incidentally, this laboratory is well known for once being headed by Professor Umetaro Suzuki, the famous discoverer of vitamin B₁. Three years later, he moved to the Laboratory of Organic Chemistry led by Professor Masanao Matsui and began his career as a synthetic organic chemist. His first synthetic target was the famous plant hormone gibberellin. Considering the level of synthetic organic chemistry at the time, the synthesis of gibberellins was an extremely challenging task, but he succeeded in completing the first synthesis of gibberellin A₄ in 1967 (Fig. 2).¹³⁾ This achievement not only made him a global rising star in the organic synthesis community, but also inspired him to initiate pheromone synthesis. The following is a famous anecdote. When young KM completed the first synthesis of gibberellin, Professor Kei Arima, a world-famous applied microbiologist in the same department, said to him, “Dr. Mori, congratulations on completing the synthesis of gibberellin. But you spent nine years on it. Don’t forget that the fungus Gibberella fujikuroi makes gibberellins in a couple of days.” Inspired by these words, KM embarked on pheromone synthesis after thoroughly considering what should be synthesized using the power of synthetic organic chemistry. Gibberellins are diterpenes with complex structures, whereas pheromones are generally volatile and thus structurally small and simple. Although he may not have explicitly envisioned the breakthrough discoveries described below, his interest as a chemist shifted to chirality, the synthesis of optically active compounds, and the correlation between structure and biological activity. At that time, organic synthesis of natural products, including his own gibberellin synthesis, meant the synthesis of their racemates, and almost no synthetic organic chemists were aiming to synthesize optically active compounds. In other words, the significance of synthesizing optically active compounds was not at all understood in the scientific community, and thus, the dawn of enantioselective synthesis of natural products, including pheromones, had not yet begun.

Fig. 2. KM’s formal synthesis of (±)-gibberellin A₄.

2. KM’s pheromone synthesis series

2.1. KM’s first pheromone synthesis

KM published his first paper on pheromone synthesis in 1973.¹⁴⁾ This paper reported the determination of the absolute configuration of (Z)-(−)-14-methyl-8-hexadecen-1-ol (1) and methyl (Z)-(−)-14-methyl-8-hexadecenoate, sex pheromone components of the dermestid beetle Trogoderma inclusum. The full paper of this study was later reported as PSS #1.¹⁵⁾ This enantioselective synthesis started with commercially available alcohol (S)-2 with established absolute configuration, as shown in Fig. 3. Aside from the details of the synthesis, the absolute configuration of the natural pheromone was determined to be R, since the synthesized (S)-1 was dextrorotatory and the naturally occurring 1 was levorotatory. This was the first instance in which the absolute configuration of a pheromone was determined through chemical synthesis. Since then, enantioselective synthesis has become one of the standard methods for determining the absolute configuration of naturally occurring pheromones. This synthesis employed the so-called “chiral pool method,” which is not surprising considering that this synthetic study was conducted before the era of asymmetric reactions. However, this methodology was frequently employed in subsequent PSS, which would be interpreted as his preference for speed, solidity, and straightforwardness in his synthesis. Notably, in later years, the genuine pheromone of T. inclusum was found to be the corresponding aldehyde. This aldehyde was also synthesized by KM et al., and they demonstrated that only (R)-enantiomer has strong attraction activity.^16–18)

Fig. 3. Synthesis of (S)-(+)-1, the sex pheromone of T. inclusum (PSS #1).

2.2. The first unpredictable result in PSS

Since the time of Louis Pasteur, it has been a kind of dogma that there is only one enantiomer that is meaningful to life and organisms. Even in the world of pheromones, this is by far the predominant, but as summarized later, there are quite a few exceptions, and KM’s PSS has revealed them to the world one by one. Although many natural scientists now know that the relationship between stereochemistry and activity of bioactive substances is not always simple, it is no exaggeration to say that KM’s PSS convinced the world of this new concept. At any rate, described below is the first unpredictable result in PSS.

Sulcatol (6-methyl-5-hepten-2-ol, 3) is the aggregation pheromone of the ambrosia beetle Gnathotrichus sulcatus, and the naturally occurring pheromone was shown to be a mixture of (S)-3 and (R)-3 (65 : 35) based on the modified Mosher method.¹⁹⁾ At that time, however, it was unclear why the natural pheromone is a mixture of enantiomers. In PSS #8, KM completed the synthesis of both enantiomers of 3 starting from both enantiomers of glutamic acid (Fig. 4),²⁰⁾ and succeeded in solving the above mystery. Laboratory and field bioassays using his synthetic samples revealed that G. sulcatus responded to 3 only when both enantiomers were present, and also that racemic 3 exhibited stronger activity than the naturally occurring 65 : 35 enantiomeric mixture.²¹⁾ This is the first surprise in PSS and the world’s first example of the synergistic response of enantiomers. Collaboration with chemical ecologists was essential to obtain this novel and epoch-making finding, and this was where KM excelled.

Fig. 4. Synthesis of sulcatol (PSS #8).

Around the same time, another uncommon structure–bioactivity relationship was reported in the sex pheromone of the gypsy moth Lymantria dispar (cis-7,8-epoxy-2-methyloctadecane, known as disparlure), in which the non-natural (7S,8R)-(−)-disparlure inhibits the pheromonal activity of the genuine (7R,8S)-(+)-disparlure.^22,23) In short, we began to recognize that the world of pheromones is not simple.

2.3. The most impressive finding in PSS

The world of pheromones is littered with surprising structure–activity relationships. Perhaps the most surprising and impressive of these may be that of olean (7-dioxaspiro[5.5]undecane, 4), the sex pheromone of the olive fruit fly Bactrocera (Dacus) oreae. KM et al. synthesized 4 enantioselectively by two methods and published them as PSS #74²⁴⁾ and #79,²⁵⁾ the latter of which is summarized in Fig. 5. In both cases, not only (S)-4 but also (R)-4 was synthesized from (S)-malic acid through the transacetalization “trick.” In #79, 5 was converted to ent-5 via ent-5′. In these studies, “Mori’s dithiepine method” was also developed. Incidentally, PSS contained many syntheses that were not only steady and consistent but also novel and original from the viewpoint of synthetic methodology, which undoubtedly enhanced his reputation as a synthetic organic chemist.

In laboratory and field bioassays using the synthesized enantiomers of 4, males responded only to (R)-4 under both conditions, while females responded only to (S)-4 in the laboratory. This means that (R)-4 functions as a sex attractant to males, and (S)-4 may act as a short-range restraint and an aphrodisiac during mating.²⁶⁾ The world of pheromones is full of wonders.

Fig. 5. Synthesis of olean (PSS #79).

2.4. The most surprising ending in PSS

In most cases, the recognition of stereochemistry in insect pheromones is strict. However, there are still exceptions, and 3,11-dimethyl-2-nonacosanone (6), the sex pheromone of the German cockroach Blattella germanica, is a prime example. KM reported the synthesis of all four stereoisomers of 6 twice and published them as PSS #39²⁷⁾ and #119.²⁸⁾ The former synthesis not only revealed that the naturally occurring pheromone is (3S,11S)-isomer, but also that all stereoisomers exhibit approximately equal pheromonal activity. Although this was an unusual and interesting new finding, KM was slightly skeptical of the result. This was because the enantiomeric purity of the starting material used for that synthesis was 92% e.e., meaning that the synthesized 6 were slightly impure enantiomerically and diastereomerically. Therefore, in the second synthesis, two enantiomerically pure starting materials, ethyl (R)-3-hydroxybutanoate and (R)-citronellol, were used. As shown in Fig. 6, the highlight of this synthesis was the separation of the diastereomers based on intramolecular hemiacetalization, which resulted in the synthesis of all four pure diastereomers of 6. This synthesis and subsequent bioassay reconfirmed the previous findings. One would think that this would be the end of the story, but a more surprising conclusion awaited us. In fact, subsequent detailed EAG studies revealed that at very low concentrations, as found in nature, the natural (3S,11S)-isomer is less active than the other three stereoisomers.²⁹⁾ Who could have expected that the natural isomer would be the least active? The world of pheromones is indeed very deep.

Fig. 6. Synthesis of the German cockroach pheromone (PSS #119).

2.5. The most heated discussion in PSS

Without a doubt, the pheromone that received the most attention in the 1980s was, periplanone-A (PA), a sex pheromone component of the American cockroach Periplaneta americana. At the time, the genuine structure of PA was in chaos, and the so-called “periplanone controversy” was raging. The following is the story of how the controversy was settled. Note that another pheromone component of P. americana recognized at the time was periplanone-B (PB), but the structure of PB was confirmed without confusion.

2.5.1. Background of the controversy

The first report on the structural determination of PA was disclosed by Persoons et al. in 1978, and its plausible stereochemistry was implicitly suggested as 9 in 1982 by his group.³⁰⁾ They observed that PA (Persoons’s PA) was unstable and changed into a stable biologically inactive product (PA 22-VII) bearing a cis-fused octalin nucleus. Independently, Hauptmann et al. conducted the reisolation of the pheromone and identified germacrane-type sesquiterpene 10 as its sex pheromone component³¹⁾; 10 was also isolated by Nishino et al., while Persoons’s PA was isolated neither by the Hauptmann nor by the Nishino groups. Although Hauptmann et al. confirmed the structure of 10 by its total synthesis, their highly diastereoselective epoxide-forming reaction at C10 could not be reproduced by other synthetic chemists, leaving a question about the stereochemistry at C10. Quite confusingly, compound 10, which displayed distinctly different spectral data as compared to Persoons’s PA, was also named periplanone-A (Hauptmann’s PA) without any discussion about its relationship with Persoons’s PA. Almost at the same time, Macdonald et al. proposed 11 as the correct stereochemistry of Persoons’s PA through the total synthesis of an analog of 9 and presumed that 11 might be an artifact derived from genuine PA based on discussion concerning the stability of PA. Actually, compound 12 synthesized by them as a possible precursor of 11 exhibited potent pheromonal activity, which led them to propose that 12 (10-epi-10) must be genuine PA.³²⁾ Another proposal on the structure of Persoons’s PA was put forward by Shizuri et al.³³⁾ Based on synthetic studies on 9 and its diastereomer coupled with reexamination of the spectral data reported for Persoons’s PA, they concluded that Persoons’s PA should have structure 13 instead of 9 (Fig. 7).

Fig. 7. Structures of periplanone-A proposed by Persoons (a), Hauptmann (b), Macdonald (c), and Shizuri (d).

2.5.2. Settlement of the controversy

The above-described discussions on the structure of Persoons’s PA posed three questions to be answered: (1) What is the true structure of Persoons’s PA?; (2) Are Persoons’s PA and Hauptmann’s PA both pheromone components, or is the former an artifact derived from the latter?; and (3) Given the situation that all previous syntheses of 10 were conducted as racemic syntheses and the epimer of 10 (i.e., 12) was reported to exhibit potent pheromonal activity, can the stereochemistry of 10 including its absolute configuration be said unambiguous? The outline of the synthesis of Hauptmann’s PA and related compounds to answer these questions are presented in Fig. 8 (PSS #124).³⁴⁾ Optically active cyclohexanone 14 was converted into (Z)-15 and (E)-15, the former of which was transformed to 4,7-cis-16 and the latter to 4,7-trans-16 via the anionic oxy-Cope rearrangement as the key step. The ten-membered ring enone 4,7-cis-16 was elaborated into a separable mixture of (−)-10 and (+)-12, and 4,7-trans-16 was converted into their enantiomers, (+)-10 and (−)-12 by the same sequence of reactions. Fortunately, optically active Hauptmann’s PA [(−)-10], which exhibited potent pheromonal activity, was obtained as a crystalline solid and its structure was determined unequivocally by X-ray crystallography, while the activities of Macdonald’s PA [(+)-12] and the enantiomer of Hauptmann’s PA [(+)-10] were trifling [1/10,000 and 1/1,000 of the activity of (−)-10, respectively]. Based on these results, the structure of Hauptmann’s PA [(−)-10] was decisively confirmed. Furthermore, exposure of (−)-10 to GLC conditions (oven temperature, 220°C) employed by Persoons et al. for their final purification of PA afforded in 71% yield a product whose IR, NMR, and MS were identical with those of PA isolated by Persoons et al. The structure of the thermolysis product was unambiguously determined to be 13 (Shizuri’s PA) through X-ray crystallography of its derivative. Therefore, the genuine structure of Persoons’s PA was concluded to be 13, and Persoons’s PA was demonstrated to be an artifact generated from Hauptmann’s PA. Unexpectedly, it was also revealed that pure 13 was stable and exhibited no pheromonal activity contrary to Persoons’s observations. Probably, the instability and pheromonal activity of 13 reported by Persoons et al. would be ascribable to the presence of a minute amount of impurity that promotes its rearrangement into PA 22-VII³⁵⁾ and to contamination of Hauptmann’s PA, respectively. Based on the synthetic studies described above, the names of periplanones were revised as shown at the bottom of Fig. 8.³⁶⁾ KM was always committed to pursuing an accurate synthesis and eliminating ambiguity from his work. That is why he was able to put an end to this high-profile controversy.

Fig. 8. Synthesis of Hauptmann’s PA and related compounds (PSS #124).

2.6. Practical application of pheromone-based pest management

The properties of insect pheromones have potential applications in pest control, and this very pest control technology plays an important role in IPM. However, the authors are not experts in the pheromone application and therefore are not in a position to discuss the impact of KM’s PSS on today’s pheromone application. Therefore, we would like to replace the discussion on this topic by presenting the following representative examples of the relationship between PSS and pheromone-based pest management.

2.6.1. Serricornin

Serricornin (7-hydroxy-4,6-dimethyl-3-nonanone, 17) is the sex pheromone of the cigarette beetle Lasioderma serricorne, a major pest of tobacco leaves and stored grains. In 1982, its absolute configuration was established as 4S, 6S, and 7S (PSS #53),³⁷⁾ and subsequently (4S,6S,7R)-17 was shown to inhibit the pheromonal activity of the natural stereoisomer.³⁸⁾ It should be noted that (4S,6S,7S)-17 exists as an equilibrium mixture with cyclic hemiacetal in certain solutions (Fig. 9; PSS #66).³⁹⁾ In any case, the fact that one non-natural isomer has inhibitory activity means that 17 must be synthesized with high stereoselectivity if it is to be used as an attractant for pest control. Although KM’s synthetic method has not been used in actual industrial production, his synthesis and related research have indeed improved pheromone traps for L. serricorne and their prolific use today.

Fig. 9. Synthesis of serricornin (PSS #66).

2.6.2. Disparlure

Disperlure is the sex pheromone of the gypsy moth Lymantria dispar. In the case of disparlure, (7R,8S)-(+)-enantiomer is active as a pheromone, whereas its antipode inhibits the pheromone response as already mentioned in Section 2.2.²¹⁾ The enantioselective synthesis of disparlure appears twice in PSS #25⁴⁰⁾ and #86.⁴¹⁾ As shown in Fig. 10, the Sharpless’ asymmetric epoxidation was the key step in the latter synthesis. However, the enantiomeric purity of the resulting epoxy alcohol (18) was unexpectedly unsatisfactory at 84% e.e. Therefore, KM converted 18 into the corresponding 3,5-dinitrobenzoate and recrystallized it, improving its enantiomeric purity to 100% e.e. and completing the synthesis of enantiomerically pure disparlure. This synthesis demonstrates his strong commitment to extremely high purity and his willingness to incorporate novel and useful reactions.

Fig. 10. Synthesis of disparlure (PSS #86).

2.6.3. Japonilure

Japonilure [(Z)-tetradec-5-en-4-olide] is the aggregation pheromone of the Japanese beetle Popillia japonica, a notorious pest all over the world. In the case of japonilure, Tumlinson found that (R)-enantiomer is active as a pheromone, whereas (S)-enantiomer exhibits inhibitory activity.⁴²⁾ The enantioselective synthesis of japonilure appears twice in PSS #32⁴³⁾ and #61.⁴⁴⁾ In the latter synthesis, KM used a certain asymmetric reduction⁴⁵⁾ and achieved high optical purity by recrystallization methodology (Fig. 11). This synthesis is also a good example of his commitment to high purity.

Fig. 11. Synthesis of japonilure (PSS #61).

The above two pheromones are representative pheromones in which the non-natural enantiomer inhibits the pheromonal activity of the genuine enantiomer. Therefore, in order to use these pheromones in practical applications, it is necessary “in principle” to synthesize them with high enantioselectivity. Such requirements are currently found in most cases in the production and supply of pharmaceuticals and other life science-related compounds. Since life is composed of chiral elements such as amino acids, nucleic acids, sugars, etc., such requirements may be taken for granted. Conversely, however, it should be noted that stereoselective synthesis is not always essential, since “selective” synthesis is generally more costly than “non-selective” synthesis, and there is always a trade-off between effectiveness and cost. In other words, it is also true that latent properties of pheromones, such as high species specificity and strict structure–activity relationships, are not welcome in the field of pheromone applications.

2.6.4. Actual application of pheromone-based pest management

Pheromone-applied products commercialized and available today can be classified into two categories according to their use: for attraction and mating disruption. Applications of the former are subdivided into pheromone-baited traps and lures for mass-trapping, both of which are based on the inherent nature of aggregation or sex pheromones to attract pests. One of the typical uses of pheromone-baited traps is to monitor the presence of insects, indicate the level of infestation, and evaluate the most suitable treatment and time of application, while the objective of lures for mass-trapping is to capture the highest number of insects in a trap and directly control the pest population. In contrast, the basic strategy of mating disruption is to reduce the number of pests in the next generation by permeating the air in the target fields with pheromones released from pheromone dispensers, thereby disrupting chemical communication between the sexes and preventing normal mating and reproduction. All these have their own suitable uses, and each has its own important raison d’etre.

A specific example of pheromone-baited traps is that for L. serricorne containing serricornin (17), which is marketed in Japan by Fuji Flavor Co., Ltd. This pheromone trap for L. serricorne forms the core of Fuji Flavor’s pheromone-related business, and KM once served as an advisor to this company for four and a half years. Incidentally, the current core of pheromone-applied products, at least in terms of sales, are those for mating disruption (especially for various moth species), which are recognized as one of the promising pest control methods. Shin-Etsu Chemical Co., Ltd. is one of the world leaders in this field. The pheromones of various moths targeted by this pest control method generally have no chirality and have some degree of structural commonality across species, which has encouraged the expansion of this-type of method. Whatever the structure of the pheromone and whatever the specific control method, pheromones employed for practical applications must be supplied by chemical synthesis, with very few exceptions. In this sense, KM’s PSS and related studies provide insight into practical applications of pheromone-based pest management. There are several estimates on the global market for pheromone-applied products, two of which estimate that it will reach around US$3 billion in 2021 and over US$6 billion by 2026.^46,47) This rapid growth projection is probably due to social conditions that encourage the promotion of environmentally friendly pest management.

2.7. The sunset of PSS: KM’s final papers

Incredibly, PSS was driven by KM himself in its later years: since #222,⁴⁸⁾ published in 2003, PSS has a total of 21 “single-authored” original papers. The last “single-authored” one was #264, which reported synthetic studies on gomadalactones, the sex pheromone components of the white-spotted longicorn beetle Anoplophora malasiaca, and was published shortly after his death (Fig. 12).⁴⁹⁾

Fig. 12. Synthetic studies on gomadalactones (PSS #264).

His last paper was #265, which described the synthesis and stereochemical composition of two pheromone components (19 and 20) of the female Korean apricot wasp Eurytoma maslovskii (Fig. 13).⁵⁰⁾ Note that this final project was directed by KM on his sickbed before his death. Unfortunately, he passed away without seeing the end of this project, but his colleagues who followed his wishes have completed and published their research. The most important aspect of this study was the application of the Ohrui–Akasaka method,⁵¹⁾ a powerful method for obtaining stereochemical information about asymmetric centers far from a particular functional group. As a result, the stereochemical compositions of 19 and 20 were fully elucidated: i) the ratio of 19 to 20 is 70.5 : 29.5; ii) the stereochemical composition of 19 is (2S,10S) : (2S,10R) : (2R,10S) : (2R,10R)=0.7 : 91.4 : 1.6 : 6.2; iii) that of 20 is (2S,8S) : (2S,8R) : (2R,8S) : (2R,8R)=69.9 : 1.0 : 11.8 : 17.3. In his later years, KM preferred to employ this powerful chirality-discriminating method, which has appeared frequently in PSS since #245.⁵²⁾ This is because it can discriminate the stereochemistry between extremely distant asymmetric centers and can be applied to minute sample volumes. In other words, KM was eager to incorporate new and useful methods throughout his life. Of course, this paper contains all the essential elements of his pheromone research: precise synthesis, bioassay using synthetic samples, collaboration with chemical ecologists and analytical chemists, and an indomitable spirit to pursuit the truth. In short, he remained the giant of pheromone synthesis until the very end.

Fig. 13. Structures of two pheromonal compounds (19 and 20) of the Korean apricot wasp. and their Ohrui–Akasaka derivatives (PSS #265).

KM was a brilliant sun shining on pheromone chemistry/science and a genuine experimental scientist who continued his benchwork until his death. The authors witnessed KM writing papers (PSS #264 and others), directing the last research project (PSS #265), and inspiring his colleagues and disciples on his sickbed. His last efforts are unforgettable and will remain in the mind of authors like the “green flash,” a rare and divine natural phenomenon observed at sunset.

2.8. Summary of the relationships between stereochemistry and pheromonal activity

Through a total of 265 PSS, the world has encountered various unexpected matters. KM preferred to classify the relationship between stereochemistry and pheromonal activity into 10 categories (A to J). Accordingly, at the end of this chapter, we present his preferred classification (Fig. 14). In the future, as pheromone science develops further, this classification will continue to get closer to perfection. Heavenly KM must be wishing for this.

Fig. 14. Relationships between stereochemistry and pheromonal activity.

• Category A: Only one enantiomer is bioactive. [common in other bioactive molecules]
• Category B: Only one enantiomer is active as a pheromone, but its antipode inhibits the action of the pheromone. [japonilure, disparlure, etc.]
• Category C: Only one enantiomer is bioactive, but its diastereomer inhibits the action of the pheromone. [serricornin]
• Category D: The natural pheromone is a single enantiomer, but its diastereomer is also active. [the maritime pine scale pheromone]
• Category E: The natural pheromone is a single enantiomer, but all stereoisomers are bioactive. [the German cockroach pheromone]
• Category F: Different enantiomers are used by different species even in the same genus. [ipsdienol]
• Category G: Both enantiomers are required for bioactivity. [sulcatol]
• Category H: The natural pheromone is a mixture of the four stereoisomers. The most active isomer of these is less active than the natural mixture. [tribolure]
• Category I: One enantiomer is active on males, while the antipode is active on females. [olean]
• Category J: Only the meso-isomer is active. [the tsetse fly pheromone]

Conclusion

It has been fifty years since Professor Kenji Mori began his pheromone synthesis. The most important and decisive thing he showed the world through PSS was that “nature is not simple, but full of surprises and diversity.” His epic 265-chapter voyage was propelled by his insatiable curiosity as a natural scientist, the outstanding foresight that made him a pioneer, and the novel, precise, and practical organic syntheses he developed. Underlying them must have been his love, respect, and awe for nature. In any case, it is difficult to imagine what pheromone science/chemistry would be like today without the contribution of KM.

^† KM died from a myocardial infarction on April 16, 2019.

Acknowledgments

The authors thank Drs. Takeshi Kinsho, Takeru Watanabe (both Shin-Etsu Chemical Co., Ltd.), and Shinetsu Muto (Fuji Flavor Co., Ltd.) for reviewing this manuscript and for their helpful comments. We would like to express our gratitude to all those who participated in and/or supported PSS. Finally, this review is dedicated to Ms. Keiko Mori, who has supported KM with love and dedication over many years.

References

• 1) W. Francke: Professor Kenji Mori, 21 March 1935–16 April 2019. J. Chem. Ecol. 45, 808–809 (2019).
• 2) M. Sasaki and N. Matsuo: In memory of Professor Kenji Mori. Japanese J. Pesticide Sci. 44, 259–260 (2019), in Japanese.
• 3) H. Takikawa: In memory of Professor Kenji Mori. J. Synth. Org. Chem. Jpn. 77, 773–774 (2019), in Japanese.
• 4) H. Takikawa: In memory of Professor Kenji Mori. Biosci. Biotechnol. Biochem. 85, 192–193 (2021).
• 5) H. Takikawa: Memories of Professor Kenji Mori, the giant of pheromone synthesis. J. Chem. Ecol. 48, 477–478 (2022).
• 6) D. R. Hall, P. H. G. Zarbin, T. Ando and S. Schulz: Tribute to Professor Kenji Mori and his contribution to Chemical Ecology. J. Chem. Ecol. 48, issue 5–6 (2022).
• 7) A. Butenandt, R. Beckman, D. Stamm and E. Hecker: Über den Sexuallockstoff des Seidenspinners Bombyx mori. Reindarstellung und Konstitution. Z. Naturforsch. B 14b, 283–284 (1959).
• 8) A. Butenandt, R. Beckman and E. Hecker: Über den Sexuallockstoff des Seidenspinners, I. Der biologische Test und die Isolierung des reinen Sexuallockstoffes Bombykol. Hoppe Seylers Z. Physiol. Chem. 324(Jahresband), 71–83 (1961).
• 9) A. Butenandt, R. Beckman and D. Stamm: Über den Sexuallockstoff des Seidenspinners, II. Konstitution und Konfiguration des Bombykols. Hoppe Seylers Z. Physiol. Chem. 324(Jahresband), 84–97 (1961).
• 10) A. Butenandt and E. Hecker: Synthese des Bombykols, des Sexual-Lockstoffes des Seidenspinners, und seiner geometrischen Isomeren. Angew. Chem. 73, 349–353 (1961).
• 11) A. Butenandt, E. Hecker, M. Hopp and W. Koch: Über den Sexuallockstoff des Seidenspinners, IV. Die Synthese des Bombykols und der cis-trans-isomeren Hexadecadien-(10.12)-ole-(1). Justus Liebigs Ann. Chem. 658, 39–64 (1962).
• 12) M. Nakamura and K. Mori: Colorimetric determination of inorganic phosphorus in the presence of glucose-1-phosphate and adenosine triphosphate. Nature 182, 1441–1443 (1958).
• 13) K. Mori, M. Shiozaki, N. Itaya, M. Matsui and Y. Sumiki: Synthesis of substances related to gibberellins Part 21. Total synthesis of (±)-gibberellins A₂, A₄, A₉ and A₁₀. Tetrahedron 25, 1293–1321 (1969).
• 14) K. Mori: Absolute configuration of (−)-14-methyl-cis-8-hexadecen-1-ol and methyl (−)-14-methyl-cis-8-hexadecenoate, the sex attractant of female dermestid beetle, Trogoderma inclusum Le Conte. Tetrahedron Lett. 14, 3869–3872 (1973).
• 15) K. Mori: Pheromone synthesis Part 1. Absolute configuratin of (−)-14-methylhexadec-8-cis-en-1-ol and methyl (−)-14-methylhexadec-8-cis-enoate, the sex pheromone of female dermestid beetle. Tetrahedron 30, 3817–3820 (1974).
• 16) K. Mori, T. Suguro and M. Uchida: Pheromone synthesis Part 23. Synthesis of optically active forms of (Z)-14-methylhexadec-8-enal, the pheromone of female dermestid beetle. Tetrahedron 34, 3119–3123 (1978).
• 17) K. Mori, S. Kuwahara, H. Z. Levinson and A. R. Levinson: Pheromone synthesis Part 52. Synthesis and biological activity of both (E)- and (Z)-isomers of optically pure (S)-14-methyl-8-hexadecenal (trogodermal), the antipodes of the pheromone of the khapra beetle. Tetrahedron 38, 2291–2297 (1982).
• 18) H. Z. Levinson and K. Mori: The pheromone activity of chiral isomers of trogodermal for male khapra beetles. Naturwissenschaften 67, 148–149 (1980).
• 19) K. J. Byrne, A. A. Swigar, R. M. Silverstein, J. H. Borden and E. Stokkink: Sulcatol: Population aggregation pheromone in the scolytid beetle, Gnathotrichus sulcatus. J. Insect Physiol. 20, 1895–1900 (1974).
• 20) K. Mori: Pheromone synthesis Part 8. Synthesis of optically active forms of sulcatol, the aggregation pheromone in the scolytid beetle, Gnathotrichus sulcatus. Tetrahedron 31, 3011–3012 (1975).
• 21) J. H. Borden, L. Chong, J. A. McLean, K. N. Slessor and K. Mori: Gnathotrichus sulcatus: Synergistic response to enantiomers of the aggregation pheromone sulcatol. Science 192, 894–896 (1976).
• 22) M. Yamada, T. Saito, K. Katagiri, S. Iwaki and S. Marumo: Electroantennogram and behavioral responses of the gypsy moth to enantiomers of disparlure and its trans analogs. J. Insect Physiol. 22, 755–761 (1976).
• 23) J. P. Vite, D. Klimetzek, G. Loskant, R. Hedden and K. Mori: Chirality of insect pheromones: Response interruption by inactive antipodes. Naturwissenschaften 63, 582–583 (1976).
• 24) K. Mori, T. Uematsu, K. Yanagi and M. Minobe: Pheromone synthesis Part 74. Synthesis of the optically active forms of 4,10-dihydroxy-1,7-dioxaspiro[5.5]undecane and their conversion to the enantiomers of 1,7-dioxaspiro[5.5]undecane, the olive fly pheromone. Tetrahedron 41, 2751–2758 (1985).
• 25) K. Mori, H. Watanabe, K. Yanagi and M. Minobe: Pheromone synthesis Part 79. Synthesis of the enantiomers of 1,7-dioxaspiro[5.5]undecane, 4-hydroxy-1,7-dioxaspiro[5.5]undecane, and 3-hydroxy-1,7-dioxaspiro[5.5]undecane, the components of the olive fruit fly pheromone. Tetrahedron 41, 3663–3672 (1985).
• 26) G. Haniotakis, W. Francke, K. Mori, H. Redlich and V. Shurig: Sex-specific activity of (R)-(−)- and (S)-(+)-1,7-dioxaspiro[5.5]undecane, the major pheromone of Dacus oleae. J. Chem. Ecol. 12, 1559–1568 (1986).
• 27) K. Mori, S. Masuda and T. Suguro: Pheromone synthesis Part 39. Stereocontrolled synthesis of all of the possible stereoisomers of 3,11-dimethylnonacosan-2-one and 29-hydroxy-3,11-dimethylnonacosan-2-one, the female sex pheromone of the German cockroach. Tetrahedron 37, 1329–1340 (1981).
• 28) K. Mori and H. Takikawa: Pheromone synthesis Part 119. A new synthesis of the four stereoisomers of 3,11-dimethyl-2-nonacosanone, the female-produced sex pheromone of the German cockroach. Tetrahedron 46, 4473–4486 (1990).
• 29) D. Eliyahu, K. Mori, H. Takikawa, W. S. Leal and C. Schal: Behavioral activity of stereoisomers and a new component of the contact sex pheromone of female German cockroach, Blattella Germanica. J. Chem. Ecol. 30, 1839–1848 (2004).
• 30) C. J. Persoons, P. E. J. Verwiel, F. J. Ritter and W. J. Nooyen: Studies on sex pheromone of American cockroach, with emphasis on structure elucidation of periplanone-A. J. Chem. Ecol. 8, 439–451 (1982).
• 31) H. Hauptmann, G. Mühlbauer and H. Sass: Identifizierung und synthese von periplanon A. Tetrahedron Lett. 27, 6189–6192 (1986).
• 32) T. L. Macdonald, C. M. Delahunty and J. S. Sawyer: Synthetic studies of periplanone A, a sex pheromone of Periplaneta americana. Heterocycles 25, 305–313 (1987).
• 33) Y. Shizuri, S. Yamaguchi, Y. Terada and S. Yamamura: What is the correct structure for periplanone A? Tetrahedron Lett. 28, 1795–1798 (1987).
• 34) S. Kuwahara and K. Mori: Pheromone synthesis, Part 124. Synthesis of both the enantiomers of Hauptmann’s periplanone-A and clarification of the structure of Persoons’s periplanone-A. Tetrahedron 46, 8083–8092 (1990).
• 35) K. Mori and Y. Igarashi: Pheromone synthesis, Part 120. Synthesis of (±)-PA 22-VII, the racemate of the rearrangement product of Persoons’s periplanone-A. Tetrahedron 46, 5101–5112 (1990).
• 36) C. J. Persoons, F. J. Ritter, P. E. J. Verwiel, H. Hauptmann and K. Mori: Nomenclature of American cockroach sex pheromones. Tetrahedron Lett. 31, 1747–1750 (1990).
• 37) K. Mori, H. Nomi, T. Chuman, M. Kohno, K. Kato and M. Noguchi: Pheromone synthesis Part 53. Synthesis and absolute stereochemistry of serricornin [(4S,6S,7S)-4,6-dimethyl-7-hydroxy-3-nonanone], the sex pheromone of the cigarette beetle. Tetrahedron 38, 3705–3711 (1982).
• 38) M. Mori, K. Mochizuki, M. Kohno, T. Chuman, A. Ohnishi, H. Watanabe and K. Mori: Inhibitory action of (4S,6S,7R)-isomer to pheromonal activity of serricornin, (4S,6S,7S)-7-hydroxy-4,6-dimethyl-3-nonanone. J. Chem. Ecol. 12, 83–89 (1986).
• 39) K. Mori and H. Watanabe: Pheromone synthesis Part 66. A new synthesis of serricornin [(4S,6S,7S)-7-hydroxy-4,6-dimethyl-3-nonanone], the sex pheromone of the cigarette beetle. Tetrahedron 41, 3423–3428 (1985).
• 40) K. Mori, T. Takigawa and M. Matsui: Pheromone synthesis Part 25. Stereoselective synthesis of the both enantiomers of disparlure, the pheromone of the gypsy moth. Tetrahedron 35, 833–837 (1979).
• 41) K. Mori and T. Ebata: Pheromone synthesis Part 86. Synthesis of optically active pheromones with an epoxy Ring. (+)-Disparlure and both the enantiomers of (3Z,6Z)-cis-9,10-epoxy-3,6-heneicosadiene. Tetrahedron 42, 3471–3478 (1986).
• 42) J. H. Tumlinson, M. G. Klein, R. E. Doolittle, T. L. Ladd and A. T. Proveaux: Identification of the female Japanese beetle sex pheromone: inhibition of male response by an enantiomer. Science 197, 789–792 (1977).
• 43) K. Sato, T. Nakayama and K. Mori: Pheromone synthesis Part 32. New synthesis of the both enantiomers of (Z)-5-(1-decenyl)oxacyclopentan-2-one, the pheromone of the Japanese beetle. Agric. Biol. Chem. 43, 1571–1575 (1979).
• 44) S. Senda and K. Mori: Pheromone synthesis Part 61. Asymmetric synthesis of (R,Z)-(−)-5-(1-decenyl)oxacyclopentan-2-one, the pheromone of the Japanese beetle. Agric. Biol. Chem. 47, 2595–2598 (1983).
• 45) R. S. Brinkmeyer and V. M. Kapoor: Asymmetric reduction. Reduction of acetylenic ketones with chiral hydride agent. J. Am. Chem. Soc. 99, 8339–8341 (1977).
• 46) https://researchstation.jp/report/MAM/26/Agricultural_Pheromones_2026_MAM2619.html
• 47) https://www.gii.co.jp/report/tbrc1120219-agricultural-pheromones-global-market-report.html
• 48) K. Mori: Pheromone synthesis Part 222. Synthesis of the enantiomers of 21-methyl-7-hentriacontanone and a stereoisomeric mixture of 5-acetoxy-19-methylnonacosane, candidates for the female sex pheromone of the screwworm fly, Cochliomyia hominivorax. Biosci. Biotechnol. Biochem. 67, 2224–2231 (2003).
• 49) K. Mori: Pheromone synthesis Part 264. Synthesis of the core 3-oxabicyclo[3.3.0]octane structures of gomadalactones A, B and C, the components of the contact sex pheromone of the white-spotted longicorn beetle, Anoplophora malasiaca. Tetrahedron 75, 3387–3398 (2019).
• 50) Y. Ohkubo, K. Akasaka, Y. Masuda, S. Konishi, C. Y. Yang, H. Takikawa and K. Mori: Pheromone synthesis Part 265. Synthesis and stereochemical composition of two pheromonal compounds of the female Korean apricot wasp, Eurytoma maslovskii. Tetrahedron 76, 131410 (2020).
• 51) K. Imaizumi, H. Terashima, K. Akasaka and H. Ohrui: Highly potent chiral labeling reagents for the discrimination of chiral alcohols. Anal. Sci. 19, 1243–1249 (2003).
• 52) K. Akasaka, S. Tamogami, R. W. Beeman and K. Mori: Pheromone synthesis. Part 245. Synthesis and chromatographic analysis of the four stereoisomers of 4,8-dimethyldecanal, the male aggregation pheromone of the red flour beetle, Tribolium castaneum. Tetrahedron 67, 201–209 (2011).