Axially chiral molecules that have high barriers to rotation about a single bond are called atropisomers. Methods to generate single-chirality atropisomers and other axially chiral molecules are becoming more mainstream, but diverse heterobiaryl systems appear less frequently in the literature. This project aims to fill this gap through the asymmetric synthesis of atropisomeric β-carbolines, which have been shown to be useful bioactive small molecules. We will describe a 5-step synthesis of a model substrate that then undergoes a [2+2+2] cyclotrimerization reaction to form a substituted 1-aryl-β-carboline. We will describe our development of this sequence followed by our optimization studies of the key [2+2+2] cyclization step, including solvent, temperature, and ligand screens. We will report the exclusive regioselectivity of this reaction, as well as preliminary results on inducing enantioselectivity through the use of chiral ligands. These data are supported by transition state calculations of the reductive elimination step using density functional theory as well as barrier to rotation calculations with a range of substituents.

Progress towards the synthesis of chiral heterobiaryl atropisomers via [2+2+2] cyclotrimerization

ACS Spring 2022

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