Periodic Reporting for period 1 - NewBorN (Unveiling new B-, N- containing structures through photoredox catalysis)
Reporting period: 2018-07-31 to 2020-07-30
The main original objective of the project was the construction of new B-, N-containing structures via photo-induced 1,2-migration of boronate ate complex, which would open significant opportunities in synthesis of biological compounds. Building upon the boronate complex radical reactivity reported recently, we propose to generate N-centred radicals through photoredox catalysis, and trap them with vinyl boronate complexes. The methodology will lead to a novel three component coupling where new C-C and C-N bonds are formed in one-pot, providing a new synthetic avenue for the preparation of β-amino boronic esters. These novel methodologies benefit from the formation of highly functionalized products bearing synthetically versatile boronic ester moieties. Furthermore, amino boronic esters or boronic acids have been demonstrated to act as peptidomimetics. Specifically, β-amino boronic acids have shown significant antibacterial activity against Mycobacterium tuberculosis. In the modified plan, we also developed new methodology for the transformation of [1.1.1]propellane. [1.1.1]propellane is the most important starting material for quick access to functionalized bicyclo[1.1.1]pentanes (BCPs) which are highly valuable surrogates of aromatic rings in drug discovery for their more favorable pharmacokinetic properties, including improved aqueous solubility, increased membrane permeability, and higher metabolic stability. Therefore, exploring novel strategies to synthesize diverse 1,3-bifunctionalized BCPs is of great significance in drug evolution. Finally, using [1.1.1]propellane as readily available stuff, we realised the efficient synthesis of divergent functionalized BCPs including alkenyl-, alkyl-, and aryl-BCP derivatives, tertiary boronic ester substituted BCPs, and highly functionalized α-chiral BCPs, which are not accessible by classical strategies. Moreover, we have also developed a new approach to methylenespiro[2.3]-hexane derivatives via a nickel-catalyzed cyclopropanation of alkenes with [1.1.1]propellane. This nickel-catalyzed process unveils a new reaction mode that will enhance the application of [1.1.1]propellane in the synthesis of complex molecules.
1. In original plan, to examine the hypothesis for the N-centered radical addition to alkenyl boronates, various nitrogen radical precursors including aryl azides, acyl azides, different amines with polarized N-X bonds (X: I, O, Cl) were synthesized in good to high yields. In our preliminary studies, the reaction conditions were optimized on model vinyl boronic ester with various N-centered radical precursors to identify the best conditions for the construction of desired products. Unfortunately, all the N-centered radical precursors used in the reactions failed to provide the desired products in acceptable yields.
2. In modified plan, we focused on the develop new methodology for the transformation of [1.1.1]propellane: a) a new synthesis of 1,3-disubstituted BCP derivatives through three-component or four-component coupling reactions of [1.1.1]propellane with organometallic reagents and organoboronic esters was achieved. These approaches could be applied to the synthesis of alkenyl-, alkyl-, and aryl-BCP derivatives, and tertiary boronic ester substituted BCPs containing contiguous quaternary centres. This efficient multi-component reaction strategy provides a highly modular approach for the preparation of libraries of structurally diverse BCPs. b) a new strategy for the highly enantioselective construction of α-chiral BCPs in a concise fashion from readily available [1.1.1]propellane was realised. This was accomplished by a highly efficient iridium-catalysed asymmetric allylic substitution of BCP-zinc intermediates readily generated through the reaction of Grignard reagents, [1.1.1]propellane and ZnCl2 in situ, which provided a versatile synthetic handle for the preparation of a diverse range of highly functionalized α-chiral BCPs. c) a new approach to methylenespiro[2.3]-hexane derivatives via a nickel-catalysed cyclopropanation of alkenes with [1.1.1]propellane was developed. This nickel-catalyzed process unveils a new reaction mode that will enhance the application of [1.1.1]propellane in the synthesis of complex molecules.
3.As the first authorship, the results from this fellowship have produced three high-quality articles in international journals including JACS, Angew, and Org. Lett., which will give high visibility to our novel concept to inspire the global chemical community. The fellow attended the following two conferences: Youth Forum in East China Normal University (invited speaker, Shanghai, April, 2019) and the 7th International Forum of Huazhong University of Science and Technology for Outstanding Young Talents (invited speaker, Wuhan, December, 2019). In the dissemination activities, the projects were presented to outstanding young chemists from different countries, and European Union has been acknowledged following the rules detailed in the EU Horizon-2020 portal. The fellow has attended the Bristol Synthesis Meeting in the year 2019. During this meeting held in the UoB, the fellow introduced his projects to the most influential international academics.
2. In modified plan, we focused on the develop new methodology for the transformation of [1.1.1]propellane: a) a new synthesis of 1,3-disubstituted BCP derivatives through three-component or four-component coupling reactions of [1.1.1]propellane with organometallic reagents and organoboronic esters was achieved. These approaches could be applied to the synthesis of alkenyl-, alkyl-, and aryl-BCP derivatives, and tertiary boronic ester substituted BCPs containing contiguous quaternary centres. This efficient multi-component reaction strategy provides a highly modular approach for the preparation of libraries of structurally diverse BCPs. b) a new strategy for the highly enantioselective construction of α-chiral BCPs in a concise fashion from readily available [1.1.1]propellane was realised. This was accomplished by a highly efficient iridium-catalysed asymmetric allylic substitution of BCP-zinc intermediates readily generated through the reaction of Grignard reagents, [1.1.1]propellane and ZnCl2 in situ, which provided a versatile synthetic handle for the preparation of a diverse range of highly functionalized α-chiral BCPs. c) a new approach to methylenespiro[2.3]-hexane derivatives via a nickel-catalysed cyclopropanation of alkenes with [1.1.1]propellane was developed. This nickel-catalyzed process unveils a new reaction mode that will enhance the application of [1.1.1]propellane in the synthesis of complex molecules.
3.As the first authorship, the results from this fellowship have produced three high-quality articles in international journals including JACS, Angew, and Org. Lett., which will give high visibility to our novel concept to inspire the global chemical community. The fellow attended the following two conferences: Youth Forum in East China Normal University (invited speaker, Shanghai, April, 2019) and the 7th International Forum of Huazhong University of Science and Technology for Outstanding Young Talents (invited speaker, Wuhan, December, 2019). In the dissemination activities, the projects were presented to outstanding young chemists from different countries, and European Union has been acknowledged following the rules detailed in the EU Horizon-2020 portal. The fellow has attended the Bristol Synthesis Meeting in the year 2019. During this meeting held in the UoB, the fellow introduced his projects to the most influential international academics.
The tasks detailed in both the original DoA and the modified DoA have been carefully examined. The plan for dissemination has also been followed with minor modifications. The impact detailed in the original DoA and modified DoA is described as following:
1) Impact on the researcher's career: the fellow has gained a lot of research experiences during the implementation of the projects. He has also established his research network with many outstanding young chemists in the host group, and has established his reputation in the fields of boron chemistry and [1.1.1]propellane chemistry through publishing the results in high-impact journals and presenting his work in international conferences. Completing independent projects while supervising younger colleagues or collaborating with other chemists during this fellowship greatly enhanced his management and communication skills. As a result, the fellow obtained an independent research academic position in Dalian University of Technology, a prestigious university in China.
2) Contributing to European Research Area and EU priorities: harnessing chemical technologies effectively and sustainably is a key element for achieving EU sustainable development. The projects introduce new efficient methodologies toward transformation of [1.1.1]propellane which will contribute to ensure a EU sustainable future.
3) Impact on the academic community: the chemistry detailed in the modified action has resulted in three publications in high-impact international journals, which tremendously impacted academia, triggering growing interest about the topics discovered, including nickel carbene, synthesis of BCPs, and boron chemistry.
4) Impact on the industry: both functionalized BCPs and boronic esters are highly useful motifs in drug discovery. The new developed methodologies on synthesis of 1,3-fucntionalized BCPs opened new significant chemical space. The discoveries are expected to significantly impact the pharmaceutical industry via introducing new avenues to synthesize previously inaccessible BCP-functionalized compounds.
1) Impact on the researcher's career: the fellow has gained a lot of research experiences during the implementation of the projects. He has also established his research network with many outstanding young chemists in the host group, and has established his reputation in the fields of boron chemistry and [1.1.1]propellane chemistry through publishing the results in high-impact journals and presenting his work in international conferences. Completing independent projects while supervising younger colleagues or collaborating with other chemists during this fellowship greatly enhanced his management and communication skills. As a result, the fellow obtained an independent research academic position in Dalian University of Technology, a prestigious university in China.
2) Contributing to European Research Area and EU priorities: harnessing chemical technologies effectively and sustainably is a key element for achieving EU sustainable development. The projects introduce new efficient methodologies toward transformation of [1.1.1]propellane which will contribute to ensure a EU sustainable future.
3) Impact on the academic community: the chemistry detailed in the modified action has resulted in three publications in high-impact international journals, which tremendously impacted academia, triggering growing interest about the topics discovered, including nickel carbene, synthesis of BCPs, and boron chemistry.
4) Impact on the industry: both functionalized BCPs and boronic esters are highly useful motifs in drug discovery. The new developed methodologies on synthesis of 1,3-fucntionalized BCPs opened new significant chemical space. The discoveries are expected to significantly impact the pharmaceutical industry via introducing new avenues to synthesize previously inaccessible BCP-functionalized compounds.