The chemistry of azadirachtin

Abstract

Introduction 1.1 Insect Pest Management 1.2 The Neem Tree, Azadirachta indica A. Juss (Meliaceae) 1.3 Azadirachtin Biosynthesis 1.4 Azadirachtins and Related Compounds 1.5 The Biological Effects of Azadirachtin I .6 Discovery and Structure Determination 2.1 Hydroxyl Group Reactivity 2.2 Hydrogenation 2.3 Reactions of the C-22-C-23 Enol Ether 2.4 Saponification Reactions 2.5 Functional Group Chemistry of Azadirachtol 2.6 Oxidation Reactions 2.7 Functional Group Chemistry of 7-Ketoazadirachtins 2.8 Retro-aldol Reaction Studies 2.9 Skeletal Rearrangements 2 Natural Product Modification 3 The Synthesis of Azadirachtin-derived Di hydrofuranacetal Components 3.1 The Shibasaki Route to Azadirachtin 3.2 The Synthesis of Racemic Hydrofuranacetals Related to Azadirachtin 3.3 The Preparation of an Enantiomerically Pure Hydrofuranylacetal Intermediate 3.4 The Preparation of Prototype Coupling Fragments 3.5 The Preparation of Enantiomerically Pure Insect Antifeedants Based on Azadirachtin 4 Decalin Synthesis 4.1 Other Approaches to Azadirachtin 4.2 Early Approaches to a Decalin Fragment 4.3 A Remote Oxidation Approach 4.4 An Angular Hydroxymethylation Approach 4.5 An Intact Hydroxymethylene Residue Approach 4.6 Factors Influencing Intramolecular Diels-Alder 4.7 A Silicon Directed IMDA Approach 4.8 The Dimethyl(pheny1)silyl Group as a Stereocontrol 4.9 Elaboration of an A-Ring Syn-1,3-diol for Total Cyclization Element for Intramolecular Diels-Alder Reactions Synthesis Studies 4.10 Tetrahydrofuran Annulation 5 Structure-Activity Relationships 6 Conclusions 7 References NATURAL PRODUCT REPORTS, 1993-S. V. LEY, A. A. DENHOLM AND A. WOOD 113 0 (23) Nakanishi's azadirachtin (24) Kubo's deacetylazadirachtinol(25) prieurianin bond joining two halves. This conclusion drawn on the basis of an upfield shift in the 13C NMR resonance of C-13 with respect to that of azadirachtin was truly serendipitous given the now known homology between the two compounds. The single C-8 4 -1 4 bond joining two 'halves' accounts well for the temperature dependent NMR behaviour of azadirachtin, an observation which was not pursued until after an unequivocal structure was available for azadirachtin. The implication of this type of behaviour on the structure of a similarly arranged compound prieurianin (25)52 was known in 1975 and if the analogy with azadirachtin had been noticed at this time it may have profoundly influenced Nakanishi's original deductions. Frenzied activity, initiated in 1985 by the publication of the first reappraised azadirachtin structure (26),53 was culminated later in that year with the unequivocal assignment of azadirachtin through single crystal X-ray analysis.54 The structure suggested by Ley and c o -w ~r k e r s ~~ in early 1985 represented a significant advance in showing the presence of a C-8 angular methyl group and a C-9-C-10 annulated tetrahydrofuranacetal moiety. This revised structure was based on 2D-NOESY and ID NOE difference spectroscopy which revealed the presence of H-1 -H-19 and H-2-H-I9 interactions thus placing th...

Toxic effects of neem seed cake on the larval-pupal (prepupal) stage of Mediterranean fruit fly (Diptera: Tephritidae)

“…Azadirachtin and 3-tigloylazadirachtol are the main insecticide metabolites present in the seeds and are probably responsible for immature medfly mortality. In the neem seed, there are also other molecules with chemical structure very similar to azadirachtin, but with variable biological activity [12,[33][34][35].…”

A standard procedure for the micropropagation of the neem tree ( Azadirachta indica A. Juss)

“…The first commercial neem insecticide, Margosan-O, was registered by the Environmental Protection Agency (EPA) in 1985 for use on non-food crops (Jacobson 1988;Larson 1993) and since then the number of commercial and experimental neem insecticides has increased markedly with Azatin (Agridyne Technologies, USA) recently receiving EPA approval for use on food crops (Johnson et al 1994). Azadirachtin, which shows antifeedant and growth-regulatory activities against a wide range of insects, is the major bioactive chemical present in neem kernels (Ley et al 1993) with the average yield from seeds being around 2-4 mg g -1 dry weight seed kernels (National Research Council 1992). Azadirachtin yields are, however, variable, being dependent on plant ecotype and environment (Ermel et al 1986;Singh 1986).…”

Unusually versatile plant genus Azadirachta with many useful and so far incompletely exploited properties for agriculture, medicine and industry

“…Synthetic efforts towards obtaining the aza structure have been successful (Ley et al 1993, Veitch et al 2007, 2008 but are more of academic than practical interest because of the lengthy and expensive reaction sequence required. More promising for continuously harvesting azadirachtin in vitro from suspension cultures of plant cells seemed to be the callus culture approach of Morgan and Allan (2002).…”

“…Numerous agricultural, sociocultural, veterinary medical, medical, and industrial uses have been described (Eppler et al 1986;Schmutterer et al 1981Schmutterer und Ascher 1984, 1987Schmutterer 1995Schmutterer , 2002A/B, 2005Ahmed 2002;Ketkar & Ketkar 2002;Rembold & Mwangi 2002;Schmutterer & Singh 2002;Talwar et al 2002;Schmutterer and Huber 2005;Van der Esch et al 2009). Major parts of the history and use of neem have been dealt with by several authors (Butterworth & Morgan 1968;Bilton et al 1987;Isman et al 1996;Isman 1997Isman , 2002Ketkar 2009;Kraus 2002A/B;Koul 2004;Ley et al 1993;Morgan & Allan 2002;Morgan 2006Morgan , 2009National Research Council 1992;Rembold 2002;Saxena 2002A-D;Siddiqui et al 2009;Veitch et al 2007Veitch et al , 2008, and their respective co-workers, cited in Schmutterer (2002A). For a short review see also , for a major review see Morgan (2009).…”