Periodic Reporting for period 1 - CuTAN (Copper-Catalyzed Multicomponent Reactions in Tandem Processes for Target Molecule Synthesis)
Okres sprawozdawczy: 2021-01-04 do 2023-01-03
The invention of processes that can form several bonds, stereocentres and rings in a single process is key to a sustainable future in synthetic chemistry. Multicomponent reactions and tandem procedures are two strategies that enable the rapid build-up of molecular complexity from simple reagents. By combining these two strategies into a single procedure, the diversity, complexity and value of products can be further enhanced along with the efficiency and economy of their construction.
In this project, the Fellow has developed novel copper-catalyzed multicomponent couplings of unsaturated hydrocarbon feedstocks with imines and boron reagents. These procedures provide high-value amine products with high regio-, diastero- and, in some cases, enantiocontrol. The products bear a variety of synthetic handles, for example, amino, alkynyl/alkenyl, and boryl groups, thus the products are primed for subsequent transformation. The Fellow has exploited this functionality in tandem intramolecular couplings (e.g. using palladium and gold catalysts) to provide core cyclic structures of drug molecules and natural products. Thus, through a tandem procedure of; 1) copper-catalyzed borofunctionalization, and; 2) subsequent transition-metal catalyzed cyclization, he has gained efficient access to highly sought-after complex molecules. Overall, the sustainable processes provide high-value, chiral, cyclic motifs from abundant, achiral, linear feedstocks.
In this project, the Fellow has developed novel copper-catalyzed multicomponent couplings of unsaturated hydrocarbon feedstocks with imines and boron reagents. These procedures provide high-value amine products with high regio-, diastero- and, in some cases, enantiocontrol. The products bear a variety of synthetic handles, for example, amino, alkynyl/alkenyl, and boryl groups, thus the products are primed for subsequent transformation. The Fellow has exploited this functionality in tandem intramolecular couplings (e.g. using palladium and gold catalysts) to provide core cyclic structures of drug molecules and natural products. Thus, through a tandem procedure of; 1) copper-catalyzed borofunctionalization, and; 2) subsequent transition-metal catalyzed cyclization, he has gained efficient access to highly sought-after complex molecules. Overall, the sustainable processes provide high-value, chiral, cyclic motifs from abundant, achiral, linear feedstocks.
In this Action, Dr Satpathi aimed to develop tandem, one-pot processes involving imines that deliver important, functionalized amine products that are hard to make using the current state-of-the-art in synthesis. In particular, he wished to develop the copper-catalyzed enantioselective union of imines, allenes/enynes, and diborons to selectively give intermediates that can then converted using a different transition metal catalyst – in the same reaction vessel – to high-value cyclic nitrogen-containing compounds of biological significance.
Prior to the action, the Procter group had reported enantioselective copper-catalyzed three component coupling of imines, allenes/enynes and B2pin2 that delivered functionalized homoallylic amines with universally high regio-, diastereo-, and enantiocontrol.
Dr Satpathi first utilized an efficient, enantio- and diastereoselective, copper-catalyzed coupling of imines, allenes, and diborons to give homoallylic amines. The process shows broad substrate scope and delivers complex, chiral homoallylic amines. Next, Dr Satpathi added a palladium catalyst to the reaction vessel to convert these homoallylic amine intermediates to important cyclic products from a copper/palladium-catalyzed tandem process. The main focus of the study was to prepare densely functionalized benzocyclobutenes (BCBs) for the first time – BCBs are of growing interest in materials and medicinal chemistry, although general routes for their provision remain underexplored. Crucially, by simple variation of experimental conditions or substrate modification, our strategy was expanded to deliver indoline and quinoline derivatives – via a Buchwald-Hartwig cyclization, suitable for further manipulations. Importantly, Dr Satpathi’s studies identified enantioselective conditions for the tandem catalytic protocol.
Dr Satpathi next moved on to utilize an efficient, enantio- and diastereoselective, copper-catalyzed coupling of imines, enynes, and diborons to give homopropargylic amines. The process shows broad substrate scope and delivers complex, chiral homopropargylic amines with high selectivity. Dr Satpathi then added a gold catalyst to the reaction vessel to convert these homopropargylic amine intermediates to important pyrroline products from a copper/gold-catalyzed tandem process. Furthermore, Dr Satpathi recognized that by adding a hydride reducing agent to the reaction vessel he could convert the pyrrolines to important, biologically relevant, pyrrolidines resulting from a borylative coupling/heterocyclization/reduction tandem process. Importantly, Dr Satpathi’s studies identified enantioselective conditions for the tandem catalytic protocol.
In the future, we will utilize Dr Satpathi’s new tandem catalysis tools to prepare bioactive natural product and drug targets in a sustainable fashion. We believe that the new methods will also be of high value to academic and industrial synthetic chemists involved in drug discovery and materials science.
The results obtained from Dr Satpathi’s Fellowship have resulted in one publication in the high-quality international journal, ACS Catalysis, with a further manuscript being prepared for publication. The results from Dr Satpathi’s Fellowship have been presented at several international conferences around the world by the Host and in a national meeting by the Fellow.
Prior to the action, the Procter group had reported enantioselective copper-catalyzed three component coupling of imines, allenes/enynes and B2pin2 that delivered functionalized homoallylic amines with universally high regio-, diastereo-, and enantiocontrol.
Dr Satpathi first utilized an efficient, enantio- and diastereoselective, copper-catalyzed coupling of imines, allenes, and diborons to give homoallylic amines. The process shows broad substrate scope and delivers complex, chiral homoallylic amines. Next, Dr Satpathi added a palladium catalyst to the reaction vessel to convert these homoallylic amine intermediates to important cyclic products from a copper/palladium-catalyzed tandem process. The main focus of the study was to prepare densely functionalized benzocyclobutenes (BCBs) for the first time – BCBs are of growing interest in materials and medicinal chemistry, although general routes for their provision remain underexplored. Crucially, by simple variation of experimental conditions or substrate modification, our strategy was expanded to deliver indoline and quinoline derivatives – via a Buchwald-Hartwig cyclization, suitable for further manipulations. Importantly, Dr Satpathi’s studies identified enantioselective conditions for the tandem catalytic protocol.
Dr Satpathi next moved on to utilize an efficient, enantio- and diastereoselective, copper-catalyzed coupling of imines, enynes, and diborons to give homopropargylic amines. The process shows broad substrate scope and delivers complex, chiral homopropargylic amines with high selectivity. Dr Satpathi then added a gold catalyst to the reaction vessel to convert these homopropargylic amine intermediates to important pyrroline products from a copper/gold-catalyzed tandem process. Furthermore, Dr Satpathi recognized that by adding a hydride reducing agent to the reaction vessel he could convert the pyrrolines to important, biologically relevant, pyrrolidines resulting from a borylative coupling/heterocyclization/reduction tandem process. Importantly, Dr Satpathi’s studies identified enantioselective conditions for the tandem catalytic protocol.
In the future, we will utilize Dr Satpathi’s new tandem catalysis tools to prepare bioactive natural product and drug targets in a sustainable fashion. We believe that the new methods will also be of high value to academic and industrial synthetic chemists involved in drug discovery and materials science.
The results obtained from Dr Satpathi’s Fellowship have resulted in one publication in the high-quality international journal, ACS Catalysis, with a further manuscript being prepared for publication. The results from Dr Satpathi’s Fellowship have been presented at several international conferences around the world by the Host and in a national meeting by the Fellow.
The development of novel chemical processes that streamline access to high-value material, and do it in a sustainable manner, is fundamental to Society and has great potential from an industrial perspective. Dr Satpathi’s Fellowship has focused on the development of tandem catalytic processes for the assembly of cyclic nitrogen-containing derivatives. As nitrogen is present in the majority of pharmaceuticals and agrochemicals, methodologies facilitating access to nitrogen-containing cyclic motifs has the potential to impact the full range of chemical industries.
Dr Satpathi’s work has facilitated an industrial collaboration with AstraZeneca who supported a PhD student working on enantioselective copper-catalyzed multicomponent couplings as part of tandem one-pot processes.
Dr Satpathi’s work has facilitated an industrial collaboration with AstraZeneca who supported a PhD student working on enantioselective copper-catalyzed multicomponent couplings as part of tandem one-pot processes.