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Asymmetric α-arylation of α-amino acids via rearrangement of urea derivatives
[Thesis]. Manchester, UK: The University of Manchester; 2015.
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Abstract
Quaternary amino acids are biologically important and useful building blocks for both natural product and pharmaceutical targets. They can be made from their naturally occurring proteinogenic tertiary counterparts through methods such as alkylation. However, α-arylation of amino acids is challenging with only a small number of methods available, which are far from general and access only a limited substrate scope.The N to C rearrangement chemistry established in the Clayden group allowed us to develop a transition metal-free arylation of amino acid enolates. This works by intramolecular delivery of an aromatic ring tethered via a urea linkage and has been used to synthesise a variety of protected and unprotected hydantoins, which are derivatives of quaternary amino acids.Investigation of the reaction mechanism using in situ infra-red spectroscopy (ReactIR) revealed a total of six successive species on the reaction pathway from the starting carboxylic acid to the product hydantoin through analysis of the carbonyl stretching frequencies.This methodology has also been extended to the challenging asymmetric synthesis of quaternary amino acids. Introduction of pseudoephedrine as a chiral auxiliary to control the stereochemistry of the amino acid enolate arylation leads to enantiomerically enriched hydantoins. Further development of this asymmetric methodology to allow for hydantoin hydrolysis involved an in situ protection. The reaction involved protection, enolisation, arylation, cyclisation and deprotection in one-pot. Hydantoins containing electron-rich aromatic rings were formed selectively and were cleaved into synthetically valuable enantiomerically enriched α-arylated quaternary amino acids.