Thesis

Expanding the scope of asymmetric redox-relay oxidative Heck transformations

Creator
Rights statement
Awarding institution
  • University of Strathclyde
Date of award
  • 2022
Thesis identifier
  • T17028
Person Identifier (Local)
  • 201851064
Qualification Level
Qualification Name
Department, School or Faculty
Abstract
  • The asymmetric redox-relay oxidative Heck reaction for the generation of remote tertiary stereocentres has been extensively developed for acyclic systems (Chapter 1). However, little progress has been made on equivalent cyclic systems, which are of high synthetic value. A redox-relay oxidative Heck strategy has been successfully applied for the stereoselective synthesis of 2,6-trans-tetrahydropyrans (Chapter 2). A resolution of commercially available racemic dihydropyranyl-alcohol starting material was successfully optimised, delivering the desired products in moderate to good yield and enantioselectivity. To further improve the yield it was found that readily accessible enantiopure dihydropyranyl-alcohol could be used. This led to the desired products in excellent enantioselectivities of typically ≥99:1 e.r. The 2,6-trans-tetrahydropyrans generated are interesting chiral building blocks, which may be of use to the pharmaceutical industry due to their lead-likeness properties identified during LLAMA analysis. This developed methodology has subsequently been applied in the 6-step total synthesis of (‒)-epi-centrolobine from commercially available racemic dihydropyranyl starting material. Through gaining a thorough understanding of the reaction, the reaction conditions could be further simplified, removing the requirement for both a co-oxidant and molecular sieves (Chapter 3). The developed conditions endeavour to act as a step towards a safer, more efficient and economic scale-up of redox-relay oxidative Heck transformations, and have successfully been applied to a number of literature systems, performing in comparable yield and enantioselectivity in all cases. New chemical systems were subsequently explored under a redox-relay oxidative Heck regime (Chapter 4). The tetrahydropyran series displayed promise for further expansion of the scope to secondary alcohols and aldehydes as the terminal acceptor. N-Heterocycles only delivered partial migration products, with no evidence of exo-cyclic migration, however these are still interesting scaffolds that warrant further exploration. Quaternary stereocentres were also accessed in excellent enantioselectivities starting from a commercially available methyl lactone. A preliminary exploration of translating the redox-relay oxidative Heck reaction to five- and seven-membered heterocyclic ring systems is also described.
Advisor / supervisor
  • Pascoe, David D.
  • Lindsay, David M.
Resource Type
Note
  • Previously held under moratorium in Chemistry Department (GSK) from 26th July 2022 to 1st August 2024. The confidentiality statement on each page of this thesis DOES NOT apply
DOI
Funder
Embargo Note
  • The digital version of this thesis is restricted to Strathclyde users only until 26th July 2027.

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