This thesis describes approaches towards the development of a non-enzymatic acylative dynamic kinetic resolution of alcohols, both in a one-pot fashion and also via membrane-enhanced processes. Dynamic kinetic resolution (DKR) is a desirable process that if achieved would greatly increase yields of enantioenriched compounds compared to kinetic resolution (KR). The first chapter discusses the large scale synthesis of two key 4-DMAP based catalysts developed in the Spivey group for use in acylative alcohol and amine KR: one based on a 4-(di-n-butylamino)pyridine core (‘DBAP*’) and one based on a 5-azaindoline core (‘5-Azy*’).
Initial steps towards the syntheses of both catalysts were performed on large scales, and a successful classical resolution procedure was developed by our collaborators at Eli Lilly for the HPLC-free resolution of DBAP*.
The carbamylative KR of phenylalanine methyl ester was investigated, and while conditions whereby the background reaction was minimised were found, the selectivity achieved with the 5-Azy* catalyst was too small (<7) to be developed into a DKR. Further studies into the development of a room-temperature alcohol KR were successful, and moderate selectivity was achieved with DBAP* and an acyl donor compatible with a racemisation catalyst for the KR of 1-(1-naphthyl)ethanol. The focus of the second half of this thesis is the development of the room-temperature KR into a DKR process. Our initial efforts into developing a one-pot process were hampered by deactivation of DBAP* by the ruthenium-based racemisation catalyst, as well as side-reactions occurring during decomposition of the acyl donor. Nevertheless, good ee and yield were achieved for the DKR of 1-(1-naphthyl)ethanol using a batch-wise addition process. The viability of a membrane-enhanced process for the DKR was investigated, whereby the two catalytic systems were separated into chambers by nanofiltration membranes. During these studies a MEDKR rig was constructed and tested, showing good initial results, with the promise of improved performance once membrane properties are optimised.
Finally, we discuss the possibility that adding small quantities of a tertiary alcohol into an acylative alcohol KR can significantly increase the selectivity in these reactions, with a 100% increase in selectivity to s >100 displayed by optimal substrates in our systems.