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...

We have shown that azadirachtin, a compound from the neem tree, Azadirachta indica, and selected semi-synthetic derivatives, block the development of the motile male malarial gamete in vitro. Changes in the hemiacetal group at position C11 in the molecule result in a loss of activity in this assay. The motility of fully formed male gametes, and other selected flagellated cells, is unaffected by azadirachtin in vitro. These findings raise the possibility of developing azadirachtin-based compounds as antimalarials with transmission-blocking potential, as well as permitting the further study of structure-activity relationships in these compounds.

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We describe in full the first synthesis of the potent insect antifeedant azadirachtin through a highly convergent approach. An O-alkylation reaction is used to unite decalin ketone and propargylic mesylate fragments, after which a Claisen rearrangement constructs the central C8-C14 bond in a stereoselective fashion. The allene which results from this sequence then enables a second critical carbon-carbon bond forming event whereby the [3.2.1] bicyclic system, present in the natural product, is generated via a 5-exo-radical cyclisation process. Finally, using knowledge gained through our early studies into the reactivity of the natural product, a series of carefully designed steps completes the synthesis of this challenging molecule.