Spiroindolines identify the vesicular acetylcholine transporter as a novel target for insecticide action.

The efficacy of all major insecticide classes continues to be eroded by the development of resistance mediated, in part, by selection of alleles encoding insecticide insensitive target proteins. The discovery of new insecticide classes acting at novel protein binding sites is therefore important for the continued protection of the food supply from insect predators, and of human and animal health from insect borne disease. Here we describe a novel class of insecticides (Spiroindolines) encompassing molecules that combine excellent activity against major agricultural pest species with low mammalian toxicity. We confidently assign the vesicular acetylcholine transporter as the molecular target of Spiroindolines through the combination of molecular genetics in model organisms with a pharmacological approach in insect tissues. The vesicular acetylcholine transporter can now be added to the list of validated insecticide targets in the acetylcholine signalling pathway and we anticipate that this will lead to the discovery of novel molecules useful in sustaining agriculture. In addition to their potential as insecticides and nematocides, Spiroindolines represent the only other class of chemical ligands for the vesicular acetylcholine transporter since those based on the discovery of vesamicol over 40 years ago, and as such, have potential to provide more selective tools for PET imaging in the diagnosis of neurodegenerative disease. They also provide novel biochemical tools for studies of the function of this protein family.

New ventures in the chemistry of avermectins.

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.

Acid-catalyzed aza-Diels-Alder reactions for the total synthesis of (+/-)-lapatin B.

A 5-step total synthesis of microfungal alkaloid (+/-)-lapatin B has been accomplished via a key 2-aza-Diels-Alder reaction. Brønsted acids catalyze the cycloaddition step and provide improved exo selectivity. This synthetic route has been applied to the construction of related spiro-quinazoline structures.