Phosphine-Catalyzed Annulations and Their Applications

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DESCRIPTION (provided by applicant): Naturally occurring small organic molecules, such as alkaloids, are isolated in optically active forms. The overall pharmacological importance of alkaloids has attracted much scientific interest for these classes of natural products over the years. Alkaloids are the main agents of many ancient folk medicines. These naturally occurring agents are still widely used, but modern synthetic organic chemistry has made it possible to produce a supplementary group of semi-synthetic analogs that have served to extend the range of usefulness of the alkaloids. The focus in our research is to develop new reactions that will enhance the dexterity of organic synthesis as a whole. This proposal addresses our preliminary findings in the area of phosphine-catalyzed annulations and their applications in the chemical synthesis of natural products of medicinal significance. The reactions we have developed are new and hold tremendous potential in synthesizing chiral heterocycles, which can be used as starting materials for a variety of syntheses. In particular, we surmised that a [4+2] annulation of 2-alkyl-2,3-butadienoates with aldimines to form tetrahydropyridines could be geared to the chemical synthesis of indole alkaloids, such as hirsuteine, hirsutine, alstonerine, macroline, alstomicine, and reserpine. Despite the advent of numerous catalytic asymmetric reaction processes, syntheses of these alkaloids in enantiomerically pure forms currently rely on either chemical resolution or use of enantiomerically pure starting materials. Of course, catalytic asymmetric processes are ideal from an economic and environmental standpoint. Therefore, we propose design and synthesis of new chiral phosphines from naturally occurring carbohydrates. Our strategy is especially desirable since carbohydrates are one of nature's most abundant and cheap sources of chirality and thereby provide cost effective starting materials for catalyst synthesis. Using these chiral phosphines in our [4+2] annulation in catalytic asymmetric fashion, we can efficiently prepare the target alkaloid molecules in their natural forms, starting from cheaper racemic starting materials. The targets chosen are highly relevant to national public health, specifically the treatment of the common cold, hypertension, amoebic dysentery, malaria, arrhythmia, and cancer. For example, hirsutine, one of the target natural products, shows to be 11 to 20 times more effective against the influenza A virus (subtype H3N2) than the clinically used ribavirin.