Periodic Reporting for period 1 - SmART (Samarium-catalyzed Asymmetric Radical Transformations)
Reporting period: 2020-06-01 to 2022-05-31
Complex biologically-active molecules, containing linked rings of atoms and possessing elaborate 3D forms, represent the ultimate challenge for synthetic chemists. As many of society’s established and future drugs, agrochemicals, and biological probes, boast intricate architectures, the ability to efficiently generate molecular complexity from simple starting materials is vital. Radical cyclization cascade reactions could well provide the solution; they have the potential to deliver complex, densely-packed, polycyclic architectures, with control of three dimensional shape, in one-step. Unfortunately, carrying out reactions with radicals in an enantiocontrolled fashion remains challenging due to their high reactivity. This is particularly the case for radicals generated using the classical reagent, SmI2.
Bringing together the Procter group’s recent breakthroughs in chiral ligand control and catalysis using SmI2, Dr Agasti’s ‘SmART’ project will develop the first catalytic enantioselective reactions using SmI2. Furthermore, the new catalytic processes will be used to convert relatively simple feedstocks into high-value, complex, cyclic molecules bearing multiple stereocentres with high enantio- and diastereocontrol. Previously, such molecules could only be prepared by laborious multi-step synthesis. Dr Agasti’s approach will therefore streamline complex molecule synthesis, saving time and money, and minimizing chemical waste.
Bringing together the Procter group’s recent breakthroughs in chiral ligand control and catalysis using SmI2, Dr Agasti’s ‘SmART’ project will develop the first catalytic enantioselective reactions using SmI2. Furthermore, the new catalytic processes will be used to convert relatively simple feedstocks into high-value, complex, cyclic molecules bearing multiple stereocentres with high enantio- and diastereocontrol. Previously, such molecules could only be prepared by laborious multi-step synthesis. Dr Agasti’s approach will therefore streamline complex molecule synthesis, saving time and money, and minimizing chemical waste.
During SmART, Dr Agasti has had considerable success in two main project areas:
1.SmI2-Catalyzed Intermolecular Coupling of Cyclopropyl Ketones and Alkynes
The archetypal single electron transfer reductant, samarium(II) diiodide (SmI2, Kagan’s reagent), remains one of the most important reducing agents and mediators of radical chemistry after four decades of widespread use in synthesis. While the chemistry of SmI2 is very often unique, and thus the reagent is indispensable, it is almost invariably used in superstoichiometric amounts, thus raising issues of cost and waste. Of the few reports of the use of catalytic SmI2, all require the use of superstoichiometric amounts of a metal coreductant to regenerate Sm(II). Here, we describe a SmI2-catalyzed intermolecular radical coupling of aryl cyclopropyl ketones and alkynes. The process shows broad substrate scope and delivers a library of decorated cyclopentenes with loadings of SmI2 as low as 15 mol %. The radical relay strategy negates the need for a superstoichiometric coreductant and additives to regenerate SmI2. Crucially, our study uncovers an intriguing link between ketone conformation and efficient cross-coupling and thus provides an insight into the mechanism of radical relays involving SmI2. The study lays further groundwork for the future use of the classical reagent SmI2 in contemporary radical catalysis.
2. A catalytic alkene insertion approach to bicyclo[2.1.1]hexane bioisosteres
C(sp3)-rich bicyclic hydrocarbon scaffolds, as exemplified by bicyclo[1.1.1]pentanes play an increasingly high-profile role as saturated bioisosteres of benzenoids in medicinal chemistry and crop science. Substituted bicyclo[2.1.1]hexanes (BCHs) are emerging bicyclic hydrocarbon bioisosteres for ortho- and meta-substituted benzenes, but are difficult to access. Therefore, a general synthetic route to BCHs is needed if their potential as bioisosteres is to be realized. Here we describe a broadly applicable catalytic approach that delivers substituted BCHs by intermolecular coupling between olefins and bicyclo[1.1.0]butyl (BCB) ketones. The SmI2–catalysed process works for a wide range of electron-deficient alkenes and substituted BCB ketones, operates with SmI2 loadings as low as 5 mol% and is underpinned by a radical relay mechanism that is supported by density functional theory calculations. The product BCH ketones have been shown to be versatile synthetic intermediates through selective downstream manipulation and the expedient synthesis of a saturated hydrocarbon analogue of the broad-spectrum antimicrobial, phthalylsulfathiazole.
1.SmI2-Catalyzed Intermolecular Coupling of Cyclopropyl Ketones and Alkynes
The archetypal single electron transfer reductant, samarium(II) diiodide (SmI2, Kagan’s reagent), remains one of the most important reducing agents and mediators of radical chemistry after four decades of widespread use in synthesis. While the chemistry of SmI2 is very often unique, and thus the reagent is indispensable, it is almost invariably used in superstoichiometric amounts, thus raising issues of cost and waste. Of the few reports of the use of catalytic SmI2, all require the use of superstoichiometric amounts of a metal coreductant to regenerate Sm(II). Here, we describe a SmI2-catalyzed intermolecular radical coupling of aryl cyclopropyl ketones and alkynes. The process shows broad substrate scope and delivers a library of decorated cyclopentenes with loadings of SmI2 as low as 15 mol %. The radical relay strategy negates the need for a superstoichiometric coreductant and additives to regenerate SmI2. Crucially, our study uncovers an intriguing link between ketone conformation and efficient cross-coupling and thus provides an insight into the mechanism of radical relays involving SmI2. The study lays further groundwork for the future use of the classical reagent SmI2 in contemporary radical catalysis.
2. A catalytic alkene insertion approach to bicyclo[2.1.1]hexane bioisosteres
C(sp3)-rich bicyclic hydrocarbon scaffolds, as exemplified by bicyclo[1.1.1]pentanes play an increasingly high-profile role as saturated bioisosteres of benzenoids in medicinal chemistry and crop science. Substituted bicyclo[2.1.1]hexanes (BCHs) are emerging bicyclic hydrocarbon bioisosteres for ortho- and meta-substituted benzenes, but are difficult to access. Therefore, a general synthetic route to BCHs is needed if their potential as bioisosteres is to be realized. Here we describe a broadly applicable catalytic approach that delivers substituted BCHs by intermolecular coupling between olefins and bicyclo[1.1.0]butyl (BCB) ketones. The SmI2–catalysed process works for a wide range of electron-deficient alkenes and substituted BCB ketones, operates with SmI2 loadings as low as 5 mol% and is underpinned by a radical relay mechanism that is supported by density functional theory calculations. The product BCH ketones have been shown to be versatile synthetic intermediates through selective downstream manipulation and the expedient synthesis of a saturated hydrocarbon analogue of the broad-spectrum antimicrobial, phthalylsulfathiazole.
During SmART, Dr Agasti has significantly advanced the state of the art in sustainable catalysis.
1. He has developed the first cross-coupling reactions catalyzed by SmI2 alone.
2. He has applied such couplings in a catalytic approach to important C(sp3)-rich bicyclic hydrocarbon scaffolds for use as benzene bioisosteres.
Societal Implications
Dr Agasti has developed synthetic methods that use a traditional stoichiometric reagent in catalytic fashion.
His development of the first use of SmI2 – traditionally a ‘stoichiometric’ reagent – as a catalyst is a major step forward in the field of sustainable catalysis by reducing cost and waste, improving atom economy, and opening-up the use of SmI2 to the European catalysis community (and beyond), working in industry and academia. In particular, industrial beneficiaries from his studies will include the pharmaceutical, agrochemical, fine chemical, and materials industries. The high-impact publications arising from his work and the presentations given by Prof Procter have raised the profile of European science and has attracted investment in research – from funding councils and industry. Dr Agasti's new catalysis may eventually prove useful for the synthesis of molecules and products of great benefit to society.
1. He has developed the first cross-coupling reactions catalyzed by SmI2 alone.
2. He has applied such couplings in a catalytic approach to important C(sp3)-rich bicyclic hydrocarbon scaffolds for use as benzene bioisosteres.
Societal Implications
Dr Agasti has developed synthetic methods that use a traditional stoichiometric reagent in catalytic fashion.
His development of the first use of SmI2 – traditionally a ‘stoichiometric’ reagent – as a catalyst is a major step forward in the field of sustainable catalysis by reducing cost and waste, improving atom economy, and opening-up the use of SmI2 to the European catalysis community (and beyond), working in industry and academia. In particular, industrial beneficiaries from his studies will include the pharmaceutical, agrochemical, fine chemical, and materials industries. The high-impact publications arising from his work and the presentations given by Prof Procter have raised the profile of European science and has attracted investment in research – from funding councils and industry. Dr Agasti's new catalysis may eventually prove useful for the synthesis of molecules and products of great benefit to society.