Optimisation and Scope of a Palladium-Catalysed Allylic Alkylation Cascade

<p>The design and development of new chemical reactions is crucial for progress in organic synthesis research. Cascade reactions, involving two or more steps carried out in situ in a single pot, provide a step-efficient and atom-economic route to synthesise polycyclic ring systems. The synthesis of new heterocyclic ring systems provides valuable routes towards complex natural products. Previous work in the Harvey group led to the development of a regioselective palladium-catalysed allylic alkylation (Pd-AA) cascade. This research aims to expand the scope and utility of this existing Pd-AA cascade, by optimising the current reaction conditions and exploring a range of non-symmetric pyran-based bis-electrophiles and nitrogen and sulfur-based β-carbonyl bis-nucleophiles.  Isomeric 2,3-unsaturated silyl glycosides based on D-glucose and D-galactose were successfully synthesised. These substrates were assessed as bis-electrophiles in the Pd-AA cascade. The yield of the cascade was successfully optimised with the glucose-derived substrate 4-hydroxy-6-methylpyran-2-one, using Pd₂(dba)₃ and Xantphos, to 87% from the previously reported 77% yield. However, the galactose-derived silyl glycoside formed an undesired pyranone as the major product. Additionally, a series of β-dicarbonyl compounds (4-hydroxy-6-methylpyran-2-one analogues) were assessed as bis-nucleophiles in the Pd-AA cascade, with all of the analogues forming complex mixtures of side products and a fully unsaturated pyranone as the major isolated product.</p>