Merging Photoredox with 1,2-Boronate Rearrangements: New Opportunities for Rapid Increase in Molecular Complexity
Lead Research Organisation:
University of Bristol
Department Name: Chemistry
Abstract
In the last decade photoredox reactions have emerged as tremendously versatile processes for organic synthesis, enabling reactive radical species to be generated at specific positions in an organic molecule under exceptionally mild conditions (visible-light irradiation). Over the same decade we have developed a suite of transformations exploiting the fundamental chemistry of boron, many of which involve 1,2-metallate rearrangement of boronate complexes. We now seek to merge these two major pillars of synthetic methodology, which are currently unconnected, photoredox reactions and polar 1,2-metallate rearrangements, to create a new field, which we believe has significant potential for organic synthesis.
Photoredox chemistry enables the generation of electrophilic radicals from e.g. electron-poor alkyl halides (bromomalonate). We propose to react the electrophilic radical generated with a vinyl boronate complex. Being electron rich, vinyl boronates should readily react with electron-deficient radicals leading to radical anions. The radical anions, being electron rich, should undergo facile one-electron oxidation by the ground-state oxidized photocatalyst (which regenerates the photocatalyst) and this will result in concerted 1,2-alkyl migration. 1,2-Metallate rearrangements normally employ leaving groups adjacent to boron but here we are proposing to oxidise a radical adjacent to a boronate to achieve the same transformation, a process that has not been previously reported. This should provide a novel process where two new C-C bonds are formed in one-pot, bearing versatile functional groups for further transformations, and preliminary results have demonstrated that this is indeed feasible. Furthermore, there is also the potential to render the process asymmetric for the creation of both tertiary and quaternary stereogenic centres.
The rapid exponential growth of photoredox systems that have been described over the last decade provides us with a cornucopia of methods that can be exploited with our 1,2-metallate rearrangement. We will take the most important transformations reported to date that have the greatest synthetic potential and use them with our vinyl boronates. These include the generation of fluorinated radicals (e.g. CHF2, CF3, CnF2n+1), nitrogen-centred radicals, and aryl radicals. We will also take the opportunity to see if photoredox reactions can be applied to novel species that have not been previously explored as this will expand both fields. The potential to make this chemistry asymmetric is especially challenging but use of Meggers' catalyst gives some hope that this can be achieved.
By studying unusual boronate complexes derived from natural products, new opportunities to create highly interesting structures with biological potential become apparent. For example, boronate complexes of glycals can be easily made and subjecting them to photoredox-mediated transformations will lead to a suite of novel sugars with 2-amino or 2-perfluoro substituents. By retaining the boron atom, these can be transformed into sialic acid analogues and anhydro sugars.
By combining two major fields of endeavour, novel chemistry will emerge with new structures harbouring novel properties for exploitation.
Photoredox chemistry enables the generation of electrophilic radicals from e.g. electron-poor alkyl halides (bromomalonate). We propose to react the electrophilic radical generated with a vinyl boronate complex. Being electron rich, vinyl boronates should readily react with electron-deficient radicals leading to radical anions. The radical anions, being electron rich, should undergo facile one-electron oxidation by the ground-state oxidized photocatalyst (which regenerates the photocatalyst) and this will result in concerted 1,2-alkyl migration. 1,2-Metallate rearrangements normally employ leaving groups adjacent to boron but here we are proposing to oxidise a radical adjacent to a boronate to achieve the same transformation, a process that has not been previously reported. This should provide a novel process where two new C-C bonds are formed in one-pot, bearing versatile functional groups for further transformations, and preliminary results have demonstrated that this is indeed feasible. Furthermore, there is also the potential to render the process asymmetric for the creation of both tertiary and quaternary stereogenic centres.
The rapid exponential growth of photoredox systems that have been described over the last decade provides us with a cornucopia of methods that can be exploited with our 1,2-metallate rearrangement. We will take the most important transformations reported to date that have the greatest synthetic potential and use them with our vinyl boronates. These include the generation of fluorinated radicals (e.g. CHF2, CF3, CnF2n+1), nitrogen-centred radicals, and aryl radicals. We will also take the opportunity to see if photoredox reactions can be applied to novel species that have not been previously explored as this will expand both fields. The potential to make this chemistry asymmetric is especially challenging but use of Meggers' catalyst gives some hope that this can be achieved.
By studying unusual boronate complexes derived from natural products, new opportunities to create highly interesting structures with biological potential become apparent. For example, boronate complexes of glycals can be easily made and subjecting them to photoredox-mediated transformations will lead to a suite of novel sugars with 2-amino or 2-perfluoro substituents. By retaining the boron atom, these can be transformed into sialic acid analogues and anhydro sugars.
By combining two major fields of endeavour, novel chemistry will emerge with new structures harbouring novel properties for exploitation.
Planned Impact
There are four broad areas where this research will have an impact:
1. Advancing scientific knowledge in bringing together two unconnected major areas of chemistry - photoredox and 1,2-metallate rearrangements. Furthermore, we expect that the successful development of the project presented herein will provide a new conceptual framework and inspiration for the development of related photochemical transformations based on the reactivity of metallate complexes.
2. Providing well-trained scientists with excellent skills across chemistry, including in synthesis, organometallic chemistry, organoboron chemistry, photochemistry, physical organic chemistry, and spectroscopy. The breadth of skills together with additional wide-ranging training in managing research provided by the group and the university will lead to professional scientists equipped to solve the diverse molecular problems of the future. These highly skilled and accomplished young researchers, who will have had the opportunity to make contributions and gain expertise in a highly challenging and rewarding area of contemporary science will be ideally placed to support the needs of the academic and industrial sectors. The UK chemical and pharmaceutical industries, who are major contributors to UK wealth, rely on this output. For example in the last 2 years, our recent PhDs and post-docs have joined UCB Celltech, Domainex, Cancer Research UK, Charles River, Proximagen Limited, and Evotec as well as academic appointments at Sheffield and Manchester.
3. Economic benefit to the Pharmaceutical, Agrochemical and Fine Chemicals Industries. These industries are interested in reactions and strategies that provide greater efficiency and selectivity in transformations and in new reactions that expand the available chemical space that can be probed by novel molecules as this could lead to new products. The new methodologies will not only lead to a significantly expanded landscape of readily available organic molecules but also greater efficiency and selectivity in the synthesis of complex molecules. In particular, the synthesis of new carbohydrate derivatives will provide novel structures for the synthesis of antibiotics and other drug candidates.
Scale up of photochemistry has traditionally been a problem but Booker-Milburn's flow photochemistry has solved this to a point where it is being employed by Merck on multi-ton scale (400T pa for a photoredox reaction). Booker-Milburn has established a spin-out company (Photodiversity Ltd) and any new reactions of commercial value could be scaled up here, however we will explore the best possible route to market.
4. Societal benefit through the promotion and use of new science by researchers in the UK and internationally. The potential for application in the pharmaceutical industry sector could make an impact on health and well-being. (i) Synthesis of novel compounds for drug design: The successful realization of the present project will provide novel interesting structures e.g. new aminoglycosides, sialic acid and anhydro-glycoside analogues for drug discovery, thus constituting a route for the treatment of challenging diseases. (ii) Contributing to the environment: Harnessing chemical technologies effectively and sustainably is a key element for a sustainable future. Visible light is a green and boundless energy source and opens the possibility for the utilization of solar light for the development of energetically unfavourable processes in a highly selective manner.
Finally, we expect this work into creating fundamentally new methodology, which could find new applications and open up new fields of research, to lead to a significant impact in the field. This would result in attracting high quality of individuals from abroad to our research group. This is likely to benefit UK in having a greater pool of highly talented and highly trained scientists that UK plc can potentially recruit from.
1. Advancing scientific knowledge in bringing together two unconnected major areas of chemistry - photoredox and 1,2-metallate rearrangements. Furthermore, we expect that the successful development of the project presented herein will provide a new conceptual framework and inspiration for the development of related photochemical transformations based on the reactivity of metallate complexes.
2. Providing well-trained scientists with excellent skills across chemistry, including in synthesis, organometallic chemistry, organoboron chemistry, photochemistry, physical organic chemistry, and spectroscopy. The breadth of skills together with additional wide-ranging training in managing research provided by the group and the university will lead to professional scientists equipped to solve the diverse molecular problems of the future. These highly skilled and accomplished young researchers, who will have had the opportunity to make contributions and gain expertise in a highly challenging and rewarding area of contemporary science will be ideally placed to support the needs of the academic and industrial sectors. The UK chemical and pharmaceutical industries, who are major contributors to UK wealth, rely on this output. For example in the last 2 years, our recent PhDs and post-docs have joined UCB Celltech, Domainex, Cancer Research UK, Charles River, Proximagen Limited, and Evotec as well as academic appointments at Sheffield and Manchester.
3. Economic benefit to the Pharmaceutical, Agrochemical and Fine Chemicals Industries. These industries are interested in reactions and strategies that provide greater efficiency and selectivity in transformations and in new reactions that expand the available chemical space that can be probed by novel molecules as this could lead to new products. The new methodologies will not only lead to a significantly expanded landscape of readily available organic molecules but also greater efficiency and selectivity in the synthesis of complex molecules. In particular, the synthesis of new carbohydrate derivatives will provide novel structures for the synthesis of antibiotics and other drug candidates.
Scale up of photochemistry has traditionally been a problem but Booker-Milburn's flow photochemistry has solved this to a point where it is being employed by Merck on multi-ton scale (400T pa for a photoredox reaction). Booker-Milburn has established a spin-out company (Photodiversity Ltd) and any new reactions of commercial value could be scaled up here, however we will explore the best possible route to market.
4. Societal benefit through the promotion and use of new science by researchers in the UK and internationally. The potential for application in the pharmaceutical industry sector could make an impact on health and well-being. (i) Synthesis of novel compounds for drug design: The successful realization of the present project will provide novel interesting structures e.g. new aminoglycosides, sialic acid and anhydro-glycoside analogues for drug discovery, thus constituting a route for the treatment of challenging diseases. (ii) Contributing to the environment: Harnessing chemical technologies effectively and sustainably is a key element for a sustainable future. Visible light is a green and boundless energy source and opens the possibility for the utilization of solar light for the development of energetically unfavourable processes in a highly selective manner.
Finally, we expect this work into creating fundamentally new methodology, which could find new applications and open up new fields of research, to lead to a significant impact in the field. This would result in attracting high quality of individuals from abroad to our research group. This is likely to benefit UK in having a greater pool of highly talented and highly trained scientists that UK plc can potentially recruit from.
Organisations
People |
ORCID iD |
| Varinder Aggarwal (Principal Investigator) |
Publications
Pagire S
(2023)
Convergent Deboronative and Decarboxylative Phosphonylation Enabled by the Phosphite Radical Trap "BecaP"
in Journal of the American Chemical Society
Shu C
(2020)
Photoinduced Fragmentation Borylation of Cyclic Alcohols and Hemiacetals.
in Organic letters
Shu C
(2020)
Metal-free photoinduced C(sp3)-H borylation of alkanes.
in Nature
Wu J
(2019)
Catalyst-Free Deaminative Functionalizations of Primary Amines by Photoinduced Single-Electron Transfer
in Angewandte Chemie International Edition
Wu J
(2019)
Catalyst-Free Deaminative Functionalizations of Primary Amines by Photoinduced Single-Electron Transfer
in Angewandte Chemie
Wu J
(2023)
Photoredox-Catalyzed Decarboxylative Bromination, Chlorination and Thiocyanation Using Inorganic Salts.
in Angewandte Chemie (International ed. in English)
Wu J
(2023)
Photoredox-Catalyzed Decarboxylative Bromination, Chlorination and Thiocyanation Using Inorganic Salts
in Angewandte Chemie
| Description | In the last decade photoredox reactions have emerged as tremendously versatile processes for organic synthesis, enabling reactive radical species to be generated at specific positions in an organic molecule under exceptionally mild conditions (visible-light irradiation). Over the same decade we have developed a suite of transformations exploiting the fundamental chemistry of boron, many of which involve 1,2-metallate rearrangement of boronate complexes. We have been able to merge these two major pillars of synthetic methodology, which were previously unconnected, photoredox reactions and polar 1,2-metallate rearrangements, to create a field which we believe has significant potential for organic synthesis. The work has been highly successful and led to many academics following our lead as it has further contributed to the field of radical polar-crossover reactions where a radical that has been generated undergoes either oxidation or reduction leading to an even more reactive species that undergoes further controlled transformations. This has led to numerous novel processes which in our case led to the formation of two new C-C bonds, bearing versatile functional groups for further transformations. A major goal in organic synthesis is to develop efficient reactions to convert abundant, unreactive, feedstock chemicals into valuable reagents that can be used in the synthesis of fine chemicals, such as pharmaceuticals and agrochemicals. To address this challenge, the conversion of carbon-hydrogen bonds into carbon-boron bonds, known as C-H borylation, would be ideal since C-H bonds are so abundant and carbon-boron bonds are so versatile. Indeed, the broad utility of boron compounds in organic synthesis was recognised through awarding the 1979 and 2010 Nobel Prizes in Chemistry. However, the abundance of C-H bonds also leads to additional challenges; how to select one C-H bond from a sea of many others. Furthermore, C-H bonds are generally unreactive, which means that forcing reaction conditions are required, most commonly using high temperatures and expensive precious metal catalysts. This work describes a new C-H borylation method that, unlike all previously reported examples, proceeds at ambient temperature and does not require a metal catalyst. This was accomplished by developing a mechanistically unique approach, where a simple chloride catalyst is used in place of precious metals. Key to the success of the reaction was the use of violet-light irradiation to provide the chloride catalyst with enough energy to break "unreactive" C¬-H bonds and form free-radical intermediates. These free-radicals are efficiently trapped by a boron reagent to form carbon-boron bonds, which represents a conceptual advance in C-H borylation chemistry. Crucially, the mild reaction conditions and distinct mechanism of this photoinduced borylation enable laser-like precision as to which of the myriad C-H bonds is transformed. Unusually, the strongest C-H bonds, those attached to methyl groups, are targeted over weaker secondary and tertiary C-H bonds, a unique feature of this novel free-radical process. |
| Exploitation Route | The original work was highly cited (>100 citations since 2017). |
| Sectors | Agriculture, Food and Drink,Chemicals,Healthcare,Pharmaceuticals and Medical Biotechnology |