Studies towards a Penitrem D Model
One of My PhD Projects
The penitrems are a family of tremorgenic mycotoxins, isolated in 1981 from the ergot fungus Penicillium crustosum. Pharmacological and biochemical studies indicated that these toxins interfere with amino-acid neurotransmitter-release mechanisms. Essentially, Penitrems cause an excessive release of neurotransmitters into the synaptic cleft, and overstimulate the receptors on the postsynaptic membrane. The displayed neurological dysfunctions (tremors, convulsions, limb weakness and ataxia) are not unlike the symptoms observed in human disorders such as Wilson’s disease and multiple sclerosis.
Along with a few other graduate students, we have been pushing to extend existing methodology to the synthesis of the hexacyclic core of Penitrem D. Key of our approach is a double tandem-radical-ionic cyclization mediated by samarium diiodide. To tease that appart: Two different initial radicals cyclizing to form two rings, the resulting radicals getting reduced to organosamarium species, which undergoes anionic chemistry. And because there is a lot happening with these 8 equivalents of samarium diiodide, it has been difficult to optimize the reaction sequence.