With the advent of high throughput screening procedures to identify potential new pharmaceuticals, there is a great demand for new synthetic methods that allow the rapid, atom efficient, stereospecific synthesis of new molecules and frameworks. Aromatic heterocycles are ideal synthons for functionalized polycyclic compounds. Aromatic heterocycles are widely available, are chemically stable, and yet are readily derivatized. Most significantly, however, they constitute cyclic skeletons composed entirely of unsaturated carbons.This proposal is a natural extension of an earlier NIH-supported program that explored the ability of osmium(ll) to promote novel organic transformations on aromatic heterocycles. Although a broad array of new reaction pathways was discovered this fundamentally new methodology has the practical limitations of high cost and difficulties in handling the toxic, air-sensitive reagent. In addition, the osmium technology did not easily lend itself to asymmetric variants. The present proposal will develop dearomatization reactions for aromatic heterocycles, utilizing an entirely new class of rhenium and molybdenum chiral-at-metal dearomatization agents that allow greater versatility in the scope of reactions, better handling and purification, and absolute stereocontrol, all at significantly lower cost.A broad range of new chemical transformations is anticipated. Once developed, this technology could have a significant impact on the ability of synthetic chemists to rapidly and efficiently produce milligram to gram quantities of potentially pharmacologically valuable compounds starting from widely available aromatic precursors. This in turn would facilitate the execution of structure/activity relationship studies required for optimization of new pharmaceuticals.
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