The development of novel ring expansion methodologies for direct and stereoselective access to complex sp3-rich amine scaffolds.

  • Charlie Mikan

Abstract

Two novel ring expansion methodologies have been developed, which enable enantio- and diastereo-selective access to sp3-rich mono- and polycyclic medium and macrocyclic amine ring systems. The first approach enables facile two-carbon homologation of 2-alkenyl-pyrrolidines and piperidines into their azepane and azocane homologues (Scheme A). The use of activating groups such as esters, amides, phenyl groups and alkenes allows this expansion to proceed in a direction which is not controlled purely by ring size via conjugation of the alkene within the final product. The viability of this ring expansion is also easily predictable using DFT calculations. The reaction occurs under palladium-catalysis conditions with mild conditions allowing broad functional group tolerance, in a highly enantioretentive fashion when starting from enantiopure starting materials. Opposite enantioenriched (S)- and (R)-azepanes can be obtained simply by switching the alkene geometry from a single enantiomer of the starting material. The azepanes produced are highly diversifiable and undergo facile amidation reactions, intramolecular Heck cyclisations and diastereoselective [3 + 2] cycloadditions.
Date of Award3 Sept 2024
Original languageEnglish
Awarding Institution
  • Northumbria University
SupervisorJonathan Knowles (Supervisor) & David Tetard (Supervisor)

Keywords

  • palladium catalysed ring expansion of allylic amines
  • enantio- and diastereoselective
  • azepane and azocane synthesis
  • oxiadative cleavage/ Double Mannich Synthesis
  • tropinone synthesis

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