Photocatalytic Deracemisation of Amines

ended

A method is proposed for the deracemisation of tertiary amines via the joint action of three distinct molecular catalysts - an Ir(III) photocatalyst, a chiral Brønsted base and a chiral thiol hydrogen-atom transfer additive. Through sequential visible-light driven electron transfer (ET), proton transfer (PT) and hydrogen-atom transfer (HAT), proximal stereocentres to amine functional groups can be selectively targeted for destruction of the undesired substrate enantiomer, and restored as the desired. An optical enrichment in the amine sample then builds over time, without other chemical change taking place. The two separate chiral catalysts work in tandem on two mechanistically distinct elementary steps, resulting in an amplification of asymmetric induction. Initial substrate activation is non-stereoselective, meaning that the total amount of substrate is capable of being processed, in stark contrast to typical chemical resolution methods. The method requires no stoichiometric reagents, produces no stoichiometric waste, is redox-neutral, and consumes only visible light photos. We believe this method will be of direct utility to the synthetic organic and medicinal chemistry communities, offering more efficient and more sustainable synthetic routes to target molecules, and going beyond the existing state-of-the-art. In the return phase of the project, the method is extended to the control of amine substrate diastereoisomers, in a tandem process involving C–N bond formation. Through appropriate catalyst selection we aim to develop complimentary methods to access either the thermodynamic or kinetic isomer – something difficult to achieve with existing epimerisation protocols. The concepts introduced here address fundamental questions of absolute and relative stereocontrol, retrosynthetic design, asymmetric autocatalysis and the utility of light as a driver of chemical change against a thermodynamic gradient, to achieve an out-of-equilibrium product distribution.