Desing And Synthesis Of Neonicotinoid Compounds With BIS-THF Structure

The discovery of neonicotinoid insecticides is considered to be a big breakthrough in the field of pesticides. Neonicotinoids quickly become the largest selling insecticide varieties since the invention of imidacloprid. Neonicotinoid insecticides which have a unique structure and outstanding insecticidal activity is new class of insecticide. Neonicotinoid insecticides acting on the insect nicotinic acetylcholine receptors (nAChRs) have the characteristics of high potency, broad insecticidal spectra and low mammalian toxicity. With frequent use of neonicotinoid insecticides, researchers are constantly looking to develop new high activity structure neonicotinoid compounds because of the resistance.This paper reviews the research progress in the rational design of neonicotinoid insecticides based on target structure and role model、structure transformation、and mechanisms associated with insect nAChRs. After analyzing the mechanism and structure activity relationships of neonicotinoid compounds, we reform the heterocyclic moiety by using Bis-THF which is a key structure in the HIV-1 protease inhibitors. Neonicotinoid compounds with novel structure are designed and synthesized. This thesis is composed of following sections:1. The synthetic routes of (3R,3aS,6aR) hexahydrofuro[2,3-b] furan-3-ol is explored and improved. By protecting 5,6-hydroxyl group、H2O2、sodium hypochlorite oxidation, L-ascorbic acid can be generated (S)-glyceraldehyde acetonide. By Horner-Wadsworth-Emmons reaction, Michael addition, Nef reaction, then lithium borohydride reduction, cyclization, (S)-glyceraldehyde acetonide can be generated (3R,3aS,6aR)hexahydrofuro [2,3-b] furan-3-ol. The synthetic steps have been optimized and the overall yield was 9.3%.2. With (3R,3aS,6aR)hexahydro-furo[2,3-b] furan-3-ol as a starting material, a new unreported hexahydrofuro[2,3-b]furan-3-yl derivative intermediates:((3R,3aS,6aR)-hexa hydrofuro[2,3-b] furan-3-yl) methylamine has been designed and synthesized.3. With ((3R,3aS,6aR)hexahydro-furo[2,3-b] furan-3-yl) methylamine as a key intermediate, two unreported neonicotinoid insecticide analogues have been synthesized. The structures of the compounds have been confirmed by 1H-NMR and MS.4. The crystalline diffraction conforms the configuration of Lake ketone P-toluenesulfonate and (3R,3aS,6aR)hexahydrofuro [2,3-b] furan-3-carbonitrile.The amelioration of this paper is described as follows:1. The designed synthetic route colligated the advantages and avoided the disadvantages of the reported routes, materials and catalysts can be obtained easily. Conditions and procedures are optimized.2. A new intermediate ((3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl) methylamine has been designed and synthesized.3. Two unreported neonicotinoid compounds containing novel Bis-THF structure have been synthesized.4. In this study, a novel heterocyclicpharmacophore Bis-THF structure is introduced to neonicotinoid pesticide molecules, which is expected to become a new generation of high efficiency and low toxicity of neonicotinoid insecticides. It has significant scientific significance and application prospects...