Saturated heterocycles are widespread pharmacophores in marketed therapeutics and are advantageous scaffolds for the elaboration of new drugs. Their attractive properties include a low molecular weight and a high sp3 character, which result in improved physicochemical profiles. However, there are limited tools to enable the elaboration of building blocks from common feedstock such as intact heterocyclic rings. The ability to selectively probe any of the potential 3D exit vectors running along the C(sp3)–H bonds would be extremely valuable in terms of modulating ligand target complementarity, as well as generating molecules with new topologies in uncharted chemical space. Catalytic C–H functionalisation offers the potential to aid expansion along C(sp3)–H bonds of choice. However, with C–H bonds remote from the heteroatom being less acidic and less distinguishable, achieving regio- and stereoselectivity is a challenge. This thesis presents a strategy for accessing a novel stereodefined 3,4-disubstitution pattern on 6-membered heterocycles by Pd-catalysed directed functionalisation.
Section 2.1 describes the mono-arylation at the C(3) position on unbiased saturated 6-membered heterocycles with a C(4) aminoquinoline amide directing group. Excellent conversions and selectivities for the cis diastereomer were achieved at unprecedently mild temperatures for this type of transformation (<50 °C), with access to single trans diastereomers enabled by a facile one-pot arylation epimerisation.
Section 2.2 describes the removal of the aminoquinoline directing group in a divergent fashion to unveil polar functionalities such as nitriles, amides, carboxylic acids and alcohols. This allowed the assembly of a fragment library with a range of substitution patterns and a diversity of binding elements.
Section 2.3 illustrates the generation of building blocks for DNA-encoded libraries. Tri- and even tetrafunctional scaffolds with novel designs could be accessed using the functionalisation protocol.
Finally, section 2.4 presents the development of the first enantioselective C(sp3)–H functionalisation at an unactivated position in saturated heterocycles.