Cycloadditions for the Formation of Functionalized Biorelevant N-Heterocycles

Davis, Anna, Chemistry - Graduate School of Arts and Sciences, University of Virginia
Hilinski, Michael, CHEM, University of Virginia

Nitrogen heterocycles constitute a class of highly privileged motifs in complex molecule synthesis. Specifically, cyclic compounds with a nitrogen atom in their ring structure constitute most FDA-approved drugs, pharmaceutical leads, and natural products. For this reason, synthetic chemists have sought out strategies to efficiently assemble complex molecular frameworks containing N-heterocycles for nearly as long as synthetic chemistry has been studied. Among these strategies, cycloaddition reactions have continuously been established as a highly effectual method for the rapid and atom-economical formation of molecular complexity with a high degree of chemo-, regio-, and stereoselectivity. Herein we report three novel cycloadditions for the incorporation and formation of N-heterocycles in biorelevant structures: the vinylazaarene Diels-Alder [4+2], the organocatalytic aza-Pauson-Khand formal [2+2+1], and the pyridyl vinylcyclopropane [5+1] using a nitrene source as a one-atom component.

Cyclohexyl azaarenes constitute a biorelevant motif present in a variety of FDA-approved drugs and several more pharmaceutical candidates. Six-membered carbon rings are common retrons for the Diels-Alder reaction, however, very few examples exist of vinylazaarenes being employed as dienophiles, whether thermally or promoted by Lewis acids. Our work addresses this deficiency in the literature, utilizing the same chemical principles that govern increased yields, regioselectivity, and diastereoselectivity under Lewis acid-catalysis of a,b-unsaturated carbonyl dienophiles compared to their thermal counterparts. The scope of this reaction includes unactivated dienes, scalability up to 10 grams, and access to biorelevant scaffolds. The presence of a highly Lewis basic lone pair in conjugation with a dienophilic olefin opens the established vinylazaarene scope to additional means of Lewis acid catalysis, including enantioselective methods.

Five-membered N-heterocycles such as pyrroles and pyrrolidines are also highly prominent in drug discovery. Organocatalysis is an attractive option for the syntheses of druglike molecules owing to cost-efficacy over many metal catalysts and non-toxicity in the body. We have expanded upon previously established reactivity and mechanistic understanding of the Hilinski iminium organocatalyst to establish a formal [2+2+1] reaction for the diastereo- and regioselective formation of pyrrolines: synthetic precursors to both aromatic and aliphatic five-membered N-heterocycles and biorelevant motifs of rising prominence themselves. In this work, the iminium catalyst cyclizes a nitrene precursor, a styrene, and an alkyne in a stepwise fashion similar to the metal-catalyzed Pauson-Khand reaction to furnish a partially saturated ring. This reaction represents an unprecedented chemical transformation in its own right, as no metal-catalyzed approaches to the same three-component formal cycloaddition have been identified.

PHD (Doctor of Philosophy)
cycloadditions, nitrenes, heterocycles
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