New ventures in the chemistry of avermectins

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Abstract

An overview is given on recent work towards new avermectin derivatives of extremely high insecticidal and acaricidal activity. These compounds were prepared from commercially available abamectin (avermectin B1) 1. For the synthesis, many novel entries have been opened up, making use of modern synthetic methods and applying them, for the first time, to the chemistry of avermectins. Several types of avermectin derivatives can be regarded as key innovations in the field. These are, in particular, 4-deoxy-4-(S)-amino avermectins 3, 4′-O-alkoxyalkyl avermectin monosaccharides 5, 4-deoxy-4-C-substituted 4-amino avermectins 6 and 2-substituted avermectins 7. 4-Deoxy-4-(S)-amino avermectins 3 were obtained by the consecutive application of the Staudinger and Aza-Wittig reaction. 4′-O-Alkoxyalkyl avermectin monosaccharides 5 were prepared by alkoxyalkylation of 5-O-protected avermectin monosaccharide. For the synthesis of 4-deoxy-4-C-substituted 4-amino avermectins 6, several methods were used to construct the fully substituted 4-carbon centre, such as a modified Strecker synthesis, the addition of organometallics to a 4-sulfinimine and a modified Ugi approach. In order to prepare 2-substituted avermectins 7, 5-O-protected avermectin monosaccharide was coupled with carbohydrate building blocks. An alternative synthesis involved the hitherto unknown enol ether chemistry of 4-oxo-avermectin and the conjugate addition of a cuprate to an avermectin 2,3-en-4-one. In addition, a number of other highly potent derivatives were synthesised. Examples are 4-O-amino avermectins 8, as well as products arising from intramolecular rhodium catalysed amidations and carbene insertions. A radical cyclisation led to an intriguing rearrangement of the avermectin skeleton. Many of the new avermectins surpassed the activity of abamectin 1 against insects and mites.

Introduction

To date, two avermectins (abamectin 1 and emamectin benzoate 2) have been commercialised in crop protection. Their properties, such as mode of action, chemistry, insecticidal activity, safety, agronomic use and importance in crop protection have been the subject of a recent review.1 In this introduction, only a brief background is given of this chemical class, which was discovered and pioneered by Merck scientists. It will be followed by an overview of recent innovations that originated from Syngenta researchers. Their major contributions will be discussed in detail in the following sections, synthetic chemistry work in particular. The last chapter will highlight he biological activity of the new avermectins.

The naturally occurring avermectins, a group of 16-membered macrocyclic lactones, are fermentation products from Streptomyces avermitilis, a naturally occurring soil Actinomycete. They possess anthelmintic, insecticidal and acaricidal activity. From the fermentation, eight different avermectins were isolated (Fig. 1), which comprise four pairs of homologues. Each pair contains a major component (the a-component) and a minor one (b-component). They are usually produced in a ratio between 80:20 and 90:10. One of these pairs, avermectin B1, that is the mixture of avermectins B1a (>80%) and B1b (<20%), is commonly referred to as avermectin B1 or abamectin 1 (Fig. 2).

Abamectin 1 was introduced as an acaricide and insecticide by Merck Sharp & Dohme Agvet (now Syngenta Crop Protection AG) in 1985 under the trade names Vertimec® and Agrimec®. Subsequently, Merck scientists performed a targeted analoging program around abamectin. They mainly focused on the identification of a compound active against a broad spectrum of Lepidoptera. The program culminated in the discovery of emamectin, which was developed as the benzoate salt (MK-244) for the control of Lepidoptera. Emamectin benzoate 2 was introduced to the market by Novartis (now Syngenta Crop Protection AG) in 1997 under the trade names Proclaim® and Affirm®. Recently, Syngenta scientists have published biocatalytic approaches to the synthesis of emamectin, a topic that will not be covered in this review.2, 3, 4

The goal of avermectin research at Syngenta was to identify compounds with properties such as higher activity, a different activity spectrum and improved safety, as compared with the existing products. Table 1 shows an overview of the new types of avermectins that were the result of this venture. The structures of the most important ones (38) are shown in the schemes of the following chapters, as indicated in Table 1. The other structures (917), which will not be further discussed in detail, are shown in Figure 3.

Section snippets

4″-Deoxy-4″-(S)-amino avermectins

Our objective was to find a process for the specific formation of 4′′-(S)-amines 3, and to compare their pesticidal activity with that of 4′′-(R)-amines such as emamectin 2.5, 6, 7 Access to 4′′-amino avermectins has been commonly achieved by the reductive amination of 4′′-oxo-avermectin. This process results in the predominant generation of the axially disposed 4′′-(R)-configured amine.34 Amines with the equatorial 4′′-(S) configuration occur as by-products, which are difficult to separate.

4′-O-Alkoxyalkyl avermectin monosaccharides

The synthesis and biological activity of alkoxyalkyl derivatives of avermectin and of avermectin mono-saccharide have been described in the patent literature.8 Scheme 2 illustrates the synthesis of monosaccharide derivatives. Avermectin B1 monosaccharide 25 is protected as 5-O TBDMS ether 26. This compound can react with α-chloro ethers to give 27. Deprotection yields alkoxyalkyl ethers 5. Among many highly active derivatives of this kind, methoxymethyl ether 28 showed the most favourable

4″-Deoxy-4″-C-substituted 4″-amino avermectins

With the development of emamectin 2, it was demonstrated that a 4″-amino substituent can dramatically influence the activity spectrum of avermectin derivatives.1 Further evidence for this was observed, when we investigated 4″-(S)-amines 3 and their derivatives 4 (Section 2). In addition, we have described the excellent activity of 4″-alkyl avermectins.21 Therefore, we set out to investigate the synthesis of 4″-deoxy-4″-C-substituted 4″-amines. As a result of our studies, we have identified a

2″-Substituted avermectins

Up until our own work, there were no avermectin derivatives reported that would provide an understanding of the influence of substituents on C-2″ on activity.13 The oleandrose unit in natural avermectins is unfunctionalised on this carbon atom. In addition, due to the vicinity of the anomeric centre, C-2″ is not an obvious position for derivatisation either. In this chapter, two very different approaches towards such targets are summarised.

In our first, somewhat systematic approach, we replaced

Other new chemistry

Considering the different activity spectrum of abamectin 1 and emamectin 2, we became interested in 4″-O-amino-avermectins 8, which might combine the insecticidal properties of both.16, 17 Triflate 18 became the key intermediate in our synthetic plan.30 Upon treatment with N-hydroxyphtalimide, 4″-(R)-triflate 18 was cleanly converted into the 4″-(S)-O-phthalimido derivative 45.38 Deprotection of both the 5-O-silyl ether and the phthalimido group yielded 4″-O-amino avermectin B1 46 in good

Biological activity and safety

All avermectin derivatives mentioned herein have been evaluated in biological screens against many agronomically important pests, such as mites and insects. In Table 2, the most interesting compounds are listed, which were obtained in the synthetic programs discussed in the previous chapters. For the illustration of the pesticidal spectrum, we have chosen tests against Spodoptera littoralis, a Lepidoteran species, Frankliniella occidentalis, a Thrips species and Tetranychus urticae as a

Conclusion

In summary, our recent venture into the rich chemistry of avermectin macrocyclic lacton has resulted in a wealth of novel, extraordinary potent insecticides and acaricides, some of which were found to show an even better safety profile to mammals and the environment than the commercial products from this chemical class. In our studies, we have demonstrated the use of many novel synthetic methods for the modification of avermectin derivatives. In several instances we have encountered completely

Acknowledgements

We wish to acknowledge the valuable contributions of Patrick Ruggle, Michael Schade and Alfred Rindlisbacher for biological evaluations, of Felix Wächter for toxicology support, of Tammo Winkler, Marion Petrzika-Kitzka, Andreas Stämpfli and Ernst Gassmann for analytics support, of William Lutz and Anthony C. O’Sullivan for parallel synthesis support, of Thomas Mätzke and Armando Cicchetti for HPLC separations, of Janet Phillips, Penny Cutler, Judith Blythe and Fergus Earley for binding affinity

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