Copper-Catalysed Borylative Synthesis of High Value Amines

  • Fabien Talbot

Student thesis: Phd

Abstract

Amines constitute a fundamental functionality in organic chemistry and are present in the majority of important small molecules such as active pharmaceutical ingredients. Accessing novel amine-containing building blocks represents a key challenge to unlock new chemical spaces and develop drug-like molecules. In the current context of global warming, the environmental impact of chemical processes is becoming an essential factor. The urgent need for sustainable synthesis has propelled the emergence of new strategies such as multicomponent reactions (MCRs); processes that allow access to complex molecules in a single step from three or more simple starting materials. MCRs not only adhere to several principles of green chemistry, but also are ideal methods to build small libraries of compounds for drug discovery. Herein, novel copper-catalysed borylative MCRs are described for the synthesis of complex, high value, amine-containing building blocks that would otherwise be difficult to access via other means. The copper-catalysed borylative MCR approach is used to assemble readily available allenes and α-ketiminoesters into valuable quaternary α-amino acid derivatives in high yields and with good diastereoselectivity. The applicability of the process is demonstrated on a range of substrates bearing compatible functionalities. The versatile vinyl boronic ester handle the products contain allow further transformations. Furthermore, quaternary α-amino ester products can be incorporated into peptides, enabling potential applications in peptide folding studies. The copper-catalysed borylative MCR approach is used to synthesise complex precursors in a single step, which can be further transformed into two distinct, yet equally important cyclic scaffolds. On the one hand, elusive benzocyclobutenes (BCBs) can be obtained under mild conditions; this constitutes a rare example of stereoselective and modular BCB synthesis. On the other hand, highly functionalised, medicinally-relevant indolines can be obtained from the same precursor, using the same catalyst. Both cyclised products are obtained in good yields and with excellent stereoselectivity, and conditions for an enantioselective variant are disclosed. Synthesis of a BCB-containing quaternary α-amino acid derivative is also reported, and the concept is extended to quinoline derivatives.
Date of Award31 Dec 2021
Original languageEnglish
Awarding Institution
  • The University of Manchester
SupervisorDavid Procter (Supervisor)

Keywords

  • benzocyclobutenes
  • asymmetric
  • indolines
  • palladium
  • copper
  • borylation
  • allenes
  • multicomponent
  • allylation

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