Tetrodotoxin (TTX) and azadirachtin share many common characteristics. Both are legendary in folklore, the former as the potent toxin of the Japanese puffer fish, the latter as the mysterious ingredient of the neem tree, used for thousands of years throughout the Indian subcontinent as a insecticide and germicide. Both compounds defied several decades of effort by eminent chemists on several continents towards structure elucidation, both structures being finally solved by physical rather than chemical methods. TTX exerts its action by blocking ion channels of excitable membranes, and this property is highly valued since it allows biochemists to identify and isolate these poorly understood biological structures. At the present time the puffer fish is the major source of the TTX used in laboratories, and there is a great need for a flexible synthetic approach that will permit the preparation of analogs for use in structure/activity studies. From such studies a better understanding of the transmission of impulses through excitable membranes will emerge. Azadirachtin is available from its natural source in greater quantities than TTX, and so chemical transformations have already shed light on some aspects of its structure/activity profile. But because of the complexity of the molecule, far more needs to be done. In addition to using it for its insecticidal properties, rural Indians use the neem tree for dental care. Thus they chew the soft branches of the tree, the juice acting as a dentifrice and the fibers as dental floss. A German toothpaste has recently appeared on the market which incorporates azadirachtin. The chemical basis for this dental care has yet to be clarified. Both molecules may be regarded as """"""""densely-functionalized carbocycles"""""""", a category of natural products for which our laboratory has been developing methodology in the context of our carbohydrate-to-carbocycle transformations. For several years we have shown free radical methods to be ideal for carbohydrate manipulations in view of the fact that the multiple functional groups present in these substances are usually unaffected during these reactions. In view of the rich functionalization of TTX and azadirachtin, the application of free-radical procedures for their construction therefore resonates with our interests, and indeed in our approach to both molecules, free radical methodology features very prominently for several key transformations. Also of long standing interest is the Diels Alder reaction, ever since our laboratory showed that there are dramatic differences in rates and yield between carbohydrate alpha-enones and their carbocyclic counterparts. It is therefore very appropriate that our approach to azadirachtin combines both of these methodologies, free radical and Diels Alder.
| Fraser-Reid, B; Chen, X T; Haag, D et al. (2000) IMDA/aldol strategy for transforming carbohydrates into functionalized trans-decalins. Chirality 12:488-95 |
