Natural Product Inspired Synthesis of Heterocyclic Systems: Functionalized Dibenzoxepinones and Pyrrolic Compounds
MetadataShow full item record
Plant and microbial alkaloids have a rich history stemming from their structural diversity and medicinal applications. Accordingly, these natural products and their derivatives continue to pique interest within the synthetic and biosynthetic communities. Heterocyclic motifs are common among the alkaloids; the unique chemical transformations and biosynthetic origins of these systems thus present a versatile platform for the generation of structurally diverse molecules. Chapter one of this thesis describes the development of an efficient route to key cularine alkaloid intermediate, Manske’s ketone. Optimization and scope studies were conducted leading to a robust and general two-step synthesis of functionalized dibenzo[b,f]oxepin-10(11H)-ones via nucleophilic aromatic substitution (SNAr) and palladium-catalyzed intramolecular α-arylation. We have demonstrated the utility of these ubiquitous heterocyclic systems by further cross-coupling chemistry. The scope of the α-arylation methodology was additionally expanded to provide 11-substituted dibenzoxepinones; application to benzofused nitrogen- and sulfur-containing 7-membered heterocycles is also described. Studies into the curious formation of a trimethoxy-substituted xanthone, the major product under previously described intramolecular α-arylation conditions, are currently ongoing. Chapter two describes the evaluation and synthesis of two related classes of bioactive pyrrole-containing alkaloids, the prodiginines and tambjamines. The proton affinity of cyclic tambjamine MYP1 was compared to linear analogue BE-18591 through determination of the apparent pKa values. The increased basicity of the macrocyclic derivative was rationalized by its structural rigidity. This chapter also details adjacent investigations into the chemoenzymatic synthesis of prodiginines. The substrate tolerance of the terminal condensation enzyme involved in prodigiosin biosynthesis, PigC, was demonstrated for a brominated monopyrrolic substrate. In contrast, the production of this novel analogue was unsuccessful by a purely synthetic approach. Preliminary studies into the functionalization of related pyrrolic compounds are also described.
URI for this recordhttp://hdl.handle.net/1974/26432
Request an alternative formatIf you require this document in an alternate, accessible format, please contact the Queen's Adaptive Technology Centre
The following license files are associated with this item: