New Methods Towards Efficient, Catalytic C-O and C-N Bond Forming Reactions

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Combee, Logan, Chemistry - Graduate School of Arts and Sciences, University of Virginia
Hilinski, Michael, AS-Chemistry, University of Virginia

In nature, the efficiency and specificity of enzymes allows for rapid transformations of simple molecules into complex, stereodefined bioactive compounds. Years of chemical research have been aimed at understanding and mimicking these transformations through catalysis. Despite this, the need remains for synthetic chemists to develop methods which can replicate this kind of selectivity in order to have access to many therapeutic natural products which to date are synthetically inaccessible. With this challenge in mind, the methods we have developed introduce new means of efficient C–O and C–N bond formation under catalytic conditions.

Direct functionalization of otherwise unreactive C–H bonds represents one such biosynthetic paradigm not fully realized by modern synthetic methods. Among these, developments in catalytic C–H amination have seen marked success with transition metal complexes. Our aim has been to add a new avenue in C–H functionalization through organocatalysis which might offer unique advantages and selectivity. We have demonstrated the first organocatalytic method capable of direct C–H amination using the substrate as the limiting reagent.

In addition to nitrene transfer to C–H bonds, transfer of a nitrene equivalent has long been applied through aziridination of olefins in a formal [2+1] cycloaddition. There exist, however, very few methods that utilize nitrogen as a 1- atom components in other [n+1] cyclizations, with the only examples leading to 5-membered heterocycles. Investigations with vinylcyclopropanes led us to identify a promising aza-[5+1] cycloaddition initiated by nitrene transfer in which vinylcyclopropanes are converted to substituted tetrahydropyridines via chemoselective ring expansion of the cyclopropane. As an initial study, two complementary approaches have been developed giving rise to valuable, stereodefined N-heterocycles in a single step.

For many years, epoxy-ene cyclizations – like those found in steroid biosynthetic pathways – have been a powerful tool for rapid intramolecular ring formation. Limited reports exist, however, of intermolecular applications due to the instability of the necessary intermediates. We discovered that these intermediates could be applied intermolecularly via a [3+2] cycloaddition. With appropriate selection of conditions and Lewis acid, styrenes were readily cyclized with aryl epoxides to yield stereodefined tetrahydrofurans with modest diastereoselectivity in good yields. This method allows use of inexpensive commercial feedstock chemicals to be readily converted on a decagram scale with very low catalyst loading in under 10 minutes.

PHD (Doctor of Philosophy)
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