No abstract

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.

A short synthesis of (±)-g-lycorane 6 is described using two different radical cyclisations. The key step is the formation of tetrahydroindolone 9 by a nickel-promoted 5-endo radical cyclisation. This is followed by a tributylstannane-mediated 6-endo ring closure to the tetracyclic lactam 10 which is readily reduced to (±)-g-lycorane 6.N-Alkenyl-trichloroacetamides 1 undergo unusual 5-endo-trig radical cyclisation when treated with Bu 3 SnH and AIBN, affording saturated g-lactams 2 (Scheme 1). 1 In contrast, we recently reported that unsaturated lactams 3 are formed when the same trichloroacetamides are treated with nickel powder and acetic acid in refluxing 2-propanol. 2 A 5-endo cyclisation of the radical derived from 1 is also involved, but the ensuing radical A is not reduced as in the Bu 3 SnH-mediated cyclisation: a surprisingly easy oxidation occurs in this case giving the corresponding cation B which undergoes elimination, further reduction and a final elimination of HCl to give lactam 3. This results in the one-step creation of a new carbon-carbon bond and the introduction of two double bonds. 3 The oxidation step is still not clear and occurs presumably via electron transfer to the starting trichloroacetamide 1 with the possible intervention of traces of cupric ions in the medium. Scheme 1A wide range of such tetrahydroindolones can therefore be obtained since the method is tolerant of many functional groups and requires simple starting materials. Moreover, the presence of the diene system in a structure such as 3 allows a great variety of further transformations. We have recently implemented this unusual radical chemistry in a short approach to Erythrina alkaloids 4 using an intramolecular Friedel-Crafts cyclisation between an electron-rich aromatic ring on the side chain R and the acyliminium arising from protonation of the diene moiety (connection at C-7a, indole numbering in compound 3). 5 Amaryllidaceae alkaloids 6 are also ideal synthetic targets for our methodology. Ring closure at C-7 of the diene system using 6-endo radical cyclisation 7 or intramolecular Heck reaction 8 should allow the rapid construction of Lycorine-type alkaloids. On the other hand, connection at C-3 or C-3a could serve to construct Montanine-type or Crinane-type alkaloids.Recently an asymmetric synthesis of (-)-g-lycorane has been reported using a 5-endo radical cyclisation, 9 which prompts us to disclose our own results concerning the synthesis of this class of alkaloids. Figure 1Lycorine 4 is representative of the large class of Amaryllidaceae alkaloids (Figure 1). Most synthetic efforts have been devoted to the total synthesis of this alkaloid and its reduced congeners, a-and g-lycorane, 5 and 6. 6 We present in this paper a very short synthesis of g-lycorane 6, as an illustration of our new methodology. 10,11 Condensation of cyclohexanone with the piperonal derived amine 7 12 followed by acylation with trichloroacetyl chloride afforded trichloroacetamide 8 13 in 73% yield. Subsequent treatment with nickel powder, acetic...