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Asymmetric Copper Catalyzed Multicomponent Coupling

Periodic Reporting for period 1 - CuCAN (Asymmetric Copper Catalyzed Multicomponent Coupling)

Reporting period: 2018-06-01 to 2020-05-31

We have developed a copper-catalyzed approach to high value, functionalised nitrogen-containing molecular architectures by combining readily available feedstocks with high control of regiochemistry and absolute and relative stereochemistry. The enantioselective multicomponent coupling allows one-pot access to functionalised homoallylic amines (including those bearing quaternary stereocentres) that are privileged substructures in bioactive compounds and versatile precursors to other biologically-significant motifs. Our low-cost metal catalyzed enantioselective process also delivers N-heterocyclic building blocks whose value will be illustrated through efficient target syntheses of drugs, natural products and tools for biology. Our recent discovery of a copper-catalyzed borylative allylation of imines leaves us uniquely placed to meet this challenge.

The development of operationally simple methods for the rapid and efficient, catalytic construction of high value products from simple starting materials is key to the future of synthetic science and thus society. Moreover, if high value chiral products can be assembled from several readily available achiral components in a one-pot process then diverse collections of important compounds can be quickly constructed by simple variation of the material inputs. Even more challenging, but attractive to the scientific community, would be a multicomponent process catalyzed by a low-cost metal using a commercially-available ligand to control the regiochemistry and relative and absolute stereochemistry of the cross-coupling process.

In this project we have developed novel methodology for the construction of high value stereoselective amine compounds and applied it to the study of nitrogen based bioactive target synthesis. We have accomplished the project objectives by addressing three specific aims:

AIM 1: Methodology development for enantioselective, multicomponent approach to high value amines
AIM 2: Application of enantioselective method in bioactive target and library synthesis
AIM 3: Methodology development for new multicomponent reaction
1. Dr Manna has developed an efficient, enantio- and diastereoselective, copper-catalyzed coupling of imines, 1,3-enynes, and diborons. The process shows broad substrate scope and delivers complex, chiral homopropargyl amines; useful building blocks en route to biologically-relevant compounds. In particular, functionalized homopropargyl amines bearing up to three contiguous stereocenters can be prepared in a single step. The products provide access to important targets, including beta-amino acids and N-heterocycles. This work has been published in Angewandte Chemie.

2. Dr Manna has developed an enantio- and diastereoselective copper-catalyzed difunctionalization of alkenes and exploited the process for the generation of interesting boryl-functionalized nitrogen heterocycles possessing quaternary carbon centers. The method shows a broad substrate scope and delivers biologically importance heterocycles. This work is currently being prepared for publication.

We have exploited Dr Manna's new technology for the synthesis of biologically important compounds such as amino acids and nitrogen-containing heterocyclic; both of which are key components of drug molecules. Dr Manna's findings have and will be published in leading international journals.
In this project we have developed one-pot processes involving imines that deliver important, functionalised amine products that are hard to make using the current state-of-the-art in synthesis. In particular, we have developed the enantioselective union of imines, alkenes, and boron–X components, mediated by an inexpensive, readily available copper catalyst. The couplings deliver versatile functionalised amines that are privileged substructures in bioactive compounds and are flexible building blocks for the construction of other biologically-significant motifs. Prior to our work, a palladium-catalyzed one-pot, two stage approach represented the state-of-the-art in the area. While effectively addressing issues of absolute stereocontrol, the palladium-catalyzed process relies on a relatively expensive, supply-risk metal, delivers unsubstituted rather than the more varied branched motifs, and typically requires in situ oxidation of the products before material can be isolated. In this project, we have significantly advanced the state-of-the-art in the field by developing an enantioselective copper-catalyzed process, extending the method to asymmetric nitrogen heterocycle synthesis, and applying the catalytic asymmetric process to the synthesis of biologically relevant targets, allowing our versatile products to selectively interact with our chiral world.
Graphical abstract for one element of the study