Asymmetric Synthesis of α-Aryl Quaternary Amino Acids Exploiting Unusual Urea Reactivity

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)

Abstract

Amino acids containing quaternary centres can be accessed by the alkylation or arylation of tertiary amino acid enolates. The arylation of tertiary amino acid enolates, however, has proved problematic due to the challenging Csp3–Csp2 coupling. Many of the methods available for the arylation of tertiary amino acid enolates are not general and many of them give racemic products or rely on heavy metal catalysis. α-Aryl quaternary amino acids form components of several bioactive compounds; hence the need for a general, metal free route towards their enantioselective synthesis.
In this work, the intramolecular arylation of amino acid enolates employing either phase transfer catalysis (PTC), self-regeneration of stereocentres (SRS) or a chiral auxiliary approach in inducing enantioselectivity has been developed. All the methods take advantage of the unusual ability of metallated Nꞌ-aryl,N-benzyl ureas to undergo aryl migration from the urea distal nitrogen to the benzylic methylene. For the first time, N to C aryl migration in tertiary amino acid-derived Nꞌ-aryl ureas was facilitated by the use of mild inorganic bases, and this led to the formation of new quaternary amino acid derivatives arylated at the α-carbon. In addition, the mild conditions of photoredox catalysis was used to initiate radical conjugate addition to Nꞌ-aryl urea derivatives of dehydroalanine (Dha) and subsequent intramolecular arylation of the enolate formed. To the best of the author’s knowledge, illustrated in this thesis, is the first example of the synthesis of α-aryl quaternary amino acids through conjugate addition to Nꞌ-aryl urea derivatives of Dha.
Date of Award29 Sep 2020
Original languageEnglish
Awarding Institution
  • The University of Bristol
SponsorsSchlumberger Foundation
SupervisorAnthony P Davis (Supervisor) & Jonathan P Clayden (Supervisor)

Cite this

Asymmetric Synthesis of α-Aryl Quaternary Amino Acids Exploiting Unusual Urea Reactivity
Okoh, M. A. (Author). 29 Sep 2020

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)