Enediyne containing natural products have promising potential as cancer therapeutics due to their unique molecular architecture. The (Z)-1,5-diyn-3-ene subunit in the enediyne core can undergo cycloaromatization to yield a diradical capable of scission of the DNA double helix. While the biological mechanism of action is well established, almost nothing is known about the biosynthesis of the enediyne core. Specifically, researchers have been unable to identify a cyclase enzyme capable of ring-closing acyclic precursors. In the case of 9-membered enediynes, we propose that the bicyclic enediyne core is formed biosynthetically via spontaneous (i.e. non-enzymatic) cyclization from an acyclic precursor. In the course of examining this hypothesis, we serendipitously encountered a [4+2] cyclization between a diyne and an alkyne. The product of such a cycloaddition is one of the oldest and most interesting reactive intermediates in organic chemistry, o-benzyne. This process, which we have termed a hexadehydro-Diels-Alder (HDDA) reaction, has remained almost entirely unexploited until now. The strategy unites an entirely atom-economical, thermal generation of arynes with their in situ elaboration into a diverse set of polysubstituted benzenoids. HDDA precursor triynes cycloisomerize in a very exergonic fashion to produce complex benzyne intermediates, which are trapped with a variety of inter- and intra-molecular functionalities in an efficient and selective manner. The byproduct-free environment in which the benzynes are generated allows for new trapping reactions to be discovered and for mechanistic pathways to be interrogated and elucidated.
University of Minnesota Ph.D. dissertation. August 2014. Major: Chemistry. Advisor: Thomas R. Hoye. 1 computer file (PDF); xiii, 283 pages.
Woods, Brian Patrick.
Spontaneity to serendipity: from an enediyne core biosynthetic hypothesis to the hexadehydro-Diels-Alder reaction.
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