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.
| Date of Award | 24 Jun 2022 |
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| Original language | English |
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| Awarding Institution | - University Of Strathclyde
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| Sponsors | University of Strathclyde |
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| Supervisor | David Lindsay (Supervisor) & John Murphy (Supervisor) |
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