CORDIS - EU research results

Development of a Synergistic Catalysis Protocol for the Enantioselective Functionalisation of Aldehydes

Final Report Summary - SYNCAT (Development of a Synergistic Catalysis Protocol for the Enantioselective Functionalisation of Aldehydes)

Whilst the field of organic synthesis has progressed to the stage that almost any synthetic target can be prepared from readily available precursors given sufficient time and resources, there still remain structural motifs that are difficult to access directly using classical synthetic methods.

The concept of synergistic catalysis, in which two catalysts work to activate two different reaction components enabling the formation of a new bond, has emerged as a powerful strategy in chemical synthesis. In many cases, this dual activation by two separate catalysts enables transformations that would be otherwise impossible in the presence of a single catalyst. Based on this concept, the SYNCAT project set out to investigate the development of broadly applicable synthetic methodology enabling access to privileged structural motifs.

The direct functionalisation of C–H bonds represents the ideal reaction for synthetic organic chemists. The appeal of such transformations results from their capacity to enable the rapid build-up of molecular complexity from simple and otherwise inert building blocks. Despite recent efforts, the development of mild and general strategies for the engagement of sp3 C–H bonds in bond forming reactions remains an ongoing challenge for synthetic chemists.

During the first year of the Fellowship, the focus of research was the development of a method for the direct arylation of allylic C–H bonds. Through the synergistic merger of photoredox catalysis and organocatalysis, a mild strategy for the coupling of alkene substrates with a range of arene coupling partners was developed. The strategy relied on the coupling of two transiently generated radicals; one generated through a hydrogen atom abstraction event, and the other generated via the single electron reduction of an electron deficient arene. The transformation shows broad functional group tolerance and can be applied to complex substrates, enabling the functionalisation of late-stage synthetic intermediates. Furthermore, it was demonstrated that the reaction could also be applied to benzylic substrates, providing an expedient method for the synthesis of diarylmethanes.

During the second year of the Fellowship, research set out to combine the hydrogen atom abstraction reaction developed during the first year of the Fellowship with the field of transition metal catalysis. This strategy would combine the benefits of the photoredox-mediated organocatalytic C–H functionalisation reaction along with the broad coupling partner scope enabled through the employment of a transition metal catalyst.

During the course of these studies, it was found that when alcohols were employed as the reaction solvent, the intended C–H functionalisation product was not formed, instead coupling of the alcohol with the aryl bromide coupling partner was the major reaction pathway. After optimisation, the etherification reaction was found to be compatible with a range of primary and secondary alcohols. Furthermore, a range of aryl bromide coupling partners could also be employed. Whilst similar transformations have been reported using palladium and copper catalysis, the transformation using nickel catalysis has only limited precedent. The use of photoredox catalysis to enable previously challenging transformations has exciting implications for the field of organometallic chemistry and it is expected that this concept will find extensive applications throughout the field of synthetic chemistry.

Finally, during the concluding months of the Outgoing Phase, significant steps were made towards the development of a broadly applicable C–H functionalisation reaction. The reaction, enabled through the synergistic merger of photoredox catalysis, organocatalysis and transition metal catalysis, provides a method through which a variety of substrates that would normally be considered benign under classical reaction conditions can be expediently functionalised in a predictable manner. The optimisation of this reaction has since been completed and the substrate scope has been evaluated. The optimised reaction conditions are tolerant of a broad range of functional groups enabling the coupling of a diverse array of substrates. This broadly applicable transformations is expected to find a variety of applications across the field of chemical synthesis.

During the Return Phase of the Fellowship, research has predominantly focused on the development of a palladium-mediated enantioselective C–H activation reaction. Through the use of a chiral phosphoric acid ligand, in combination with a palladium catalyst, simple amine substrates can be converted into the corresponding aziridines with high levels of enantioselectivity. An array of functional groups are tolerated in the reaction enabling the synthesis of a range of pharmaceutically relevant molecules. Importantly, the use of chiral phosphoric acids ligands in palladium-mediated enantioselective C–H activation reactions has little precedent, and it is therefore expected that this work will provide a base on which a series of novel enantioselective C–H activation processes can be developed.

It is hoped that the transformations developed over the course of this Fellowship will find widespread applications across the field of chemical synthesis from drug discovery programmes to the large-scale manufacture of pharmaceuticals and agrochemicals. Furthermore, if successful, the concepts developed during the course of these studies should provide a broad base on which a range of novel transformations can be developed.