Rhodium catalysed asymmetric synthesis of tertiary amines

Abstract

The asymmetric synthesis of tertiary amines is a highly desirable goal, but far fewer efficient synthetic methods exist for their synthesis, relative to primary and secondary amines. A possible atom-efficient method of tertiary amine formation is catalytic hydrogenation. Despite the demand, there are only a few reported examples of asymmetric enamine hydrogenation, and none of these conditions are efficient enough to be viable for industrial processes. Until 2019, there were no reported examples of tertiary amine formation by using direct asymmetric reductive amination using H₂ as the reductant. This thesis describes the development of both enantioselective and diastereoselective reductive aminations, using hydrogen gas and homogeneous rhodium catalysts. The enantioselective reductive amination uses an electron deficient phanephos ligand and reduces bicyclic aryl ketones at low catalyst loadings but moderate selectivity. The diastereoselective reductive amination uses electron deficient monophosphines as ligands and includes many chiral 3-substituted cyclic ketones in the substrate scope, mainly 3- arylcyclohexanones. These 3-arylcyclohexanones substrates were synthesised by rhodium catalysed conjugate addition. This enantioselective conjugate addition was combined with our diastereoselective reductive amination, to form a highly stereoselective one-pot process. The rhodium used in the conjugate addition was recycled for the reductive amination step using an ‘assisted tandem catalysis’ strategy. The rhodium catalyst was modified in situ by the sequential addition of a monophosphine ligand, allowing it to catalyse the second step. This process formed a chiral tertiary amine with high selectivity and conversion. While developing this one-pot process, BOBPHOS, a phospholane-phosphite ligand, was identified as a highly active ligand in rhodium catalysed conjugate additions. The potential of BOBPHOS-Rh catalysed conjugate additions of challenging substrates like piperidones, coumarins and heteroarylboronic acids was examined, leading to improved protocols.

Date of Award	24 Jun 2020
Original language	English
Awarding Institution	University of St Andrews
Supervisor	Matt Clarke (Supervisor)