Heterocycles are a privileged motif in pharmaceutically relevant compounds and are found in more than 85% of biologically-active molecules.1 As such, understanding the roles of these moieties and improving access to them is of upmost importance in drug discovery. Chapter I provides a conformational analysis of the novel, heterocyclic cyclopropylpyran (3‑oxabicyclo[4.1.0]heptane, CPP) moiety with five-membered heterocyclic compounds. Previous conformational and synthetic studies of the CPP moiety with six-membered systems showed that this was bioisosteric with morpholine in kinase inhibitors, due to coplanar conformations.2,3 A hypothesis was developed and suggested that overlap of π-like orbitals in the cyclopropyl ring with those in the heteroaromatic π-system was in part responsible for the coplanarity, supported by quantum mechanical (QM) modelling. Application of QM modelling and subsequent synthesis of furans, pyrroles and isoxazoles with three pyran analogues (CPP, dihydropyran (DHP) and tetrahydropyran (THP)) provided very little evidence for electronic effects, with the smaller five-membered systems allowing coplanar conformations for all furan and isoxazole pyran analogues, as shown in Figure 1. [See text for figure] This included the THP analogues, which crystallised twisted with six-membered systems. Following this, an enantioselective synthesis of the bicyclo[4.1.0]heptane moiety was investigated, aimed at accessing an intermediate to enable installation of the CPP moiety onto a range of heterocyclic systems (Figure 2) [See text for figure]. Gold-catalysed cycloisomerisation of 1,6-enynes gave the desired 3-azabicyclo[4.1.0]hept-4-enes with good enantioselectivities. Optimisation of this method led to the discovery of a scalable one-pot cycloisomerisation-reduction process, followed by oxidation of a vinyl group to a carboxylic acid in one step. Preliminary studies into the use of this acid as a means of installing the azabicyclo[4.1.0]heptane moiety gave mixed results; however, a potassium trifluoroborate salt could be accessed and successfully implemented in subsequent Suzuki-Miyaura cross-coupling reactions with 2-bromopyridine. Chapter II reports a modern adaptation of the Huisgen approach to 1,3,4-oxadiazoles, a heterocyclic motif which finds application in biologically active molecules and electron transporting materials in organic light emitting diodes. Current synthetic methods towards this scaffold are known within the literature; however, these may require toxic and difficultto handle reagents, alongside the use of bespoke intermediates. An under-utilised approach towards this moiety is the Huisgen reaction wherein a 5-substituted tetrazole and acid chloride or acid anhydride are combined under high temperatures to afford the 1,3,4-oxadiazole via a nitrile imine intermediate. Implementation of flow photochemistry with a UV-B lamp under significantly more mild reaction conditions was found to facilitate the formation of the nitrile imine intermediate. Furthermore, integration of benign carboxylic acid starting materials represented a significant advancement in the applicability of this approach, which has been exemplified by a broad substrate scope and comparable efficiency to existing approaches.
| Date of Award | 29 Jun 2021 |
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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 | Craig Jamieson (Supervisor) & Glenn Burley (Supervisor) |
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