Developing a ‘Reverse-Biomimetic’ Synthesis of Arogenate and its Analogues using a Dearomatising Intramolecular Acylation Strategy.

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)

Abstract

Arogenate is a key intermediate in the shikimate biosynthetic pathway to aromatic amino acids tyrosine and phenylalanine. Though two previous syntheses have been reported in the literature, no functionalised derivatives have yet been reported. This work focuses on a ‘reverse-biomimetic’ synthesis of arogenate starting from the inexpensive, enantiopure amino acid L-tyrosine. Interestingly, the synthetic route proceeds via a novel and mechanistically unusual dearomatising spirocyclisation reaction. This intramolecular acylation, which utilises a carbamoyl chloride tether to produce a spirocyclic lactam, can be performed using low-cost reagents and without the need for heavy metals or toxic species. A synthesis of arogenate has been realised with a 19.6% overall yield in seven steps.

The biosynthetic pathways to aromatic amino acids are present in plants, bacteria and fungi but completely absent in animals. It has long been thought that arogenate analogues may be potent competitive inhibitors of arogenate dehydrogenase and dehydratase and enable the development of new, safe and selective herbicides and/or antibiotics. Using the many points for derivatisation of the spirocyclic intermediate on the route to arogenate provides an opportuntity for various functionalisations. The application of this new route to arogenate shows its efficacy to produce a collection of arogenate derivatives which may possess biological activity.

Date of Award29 Sep 2020
Original languageEnglish
Awarding Institution
  • The University of Bristol
SupervisorJonathan P Clayden (Supervisor) & Chris L Willis (Supervisor)

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