Periodic Reporting for period 1 - NewPropChem (New Frontiers in Propellane Chemistry)
Période du rapport: 2022-02-21 au 2024-02-20
This MSC Action is titled “New Frontiers in Propellane Chemistry”. This project aims to: (1) develop chemical tools to characterize a ‘landscape’ of propellane reactivity. (2) explore new methods for the catalytic activation of propellane. (3) develop theory-inspired routes to high value [1.1.1]propellanes and derivatives.
This work is important because the structures of propellane have fascinated chemists for decades; they are not only found in natural molecules, but also act as a valuable source of rigid cage carbocycles. Propellanes are highly strained, and prone to undergo ring-opening cleavage of the central bond. The smallest propellane is [1.1.1]propellane and ring-opening produce bicyclo[1.1.1]pentane (BCP) which is very much attractive in academia and in industry.
Different approaches were tried to synthesize deuterated propellanes and aryl propellanes (WP1). For the synthesis of deuterated propellanes, 4-different routes were tested; out of them strategies A-C were failed, however strategy D worked out (WP1.1). For the synthesis of aryl propellanes, various routes were proposed and investigated, unfortunately all were failed (For the details, see WP1.2). In this project, we mostly spend our time to synthesize deuterated propellanes and aryl propellanes; and were unable to perform another two work packages WP2, and WP3.
Overall assessment. The project has achieved some of its objectives and milestones. However, corrective action will be required.
This work is important because the structures of propellane have fascinated chemists for decades; they are not only found in natural molecules, but also act as a valuable source of rigid cage carbocycles. Propellanes are highly strained, and prone to undergo ring-opening cleavage of the central bond. The smallest propellane is [1.1.1]propellane and ring-opening produce bicyclo[1.1.1]pentane (BCP) which is very much attractive in academia and in industry.
Different approaches were tried to synthesize deuterated propellanes and aryl propellanes (WP1). For the synthesis of deuterated propellanes, 4-different routes were tested; out of them strategies A-C were failed, however strategy D worked out (WP1.1). For the synthesis of aryl propellanes, various routes were proposed and investigated, unfortunately all were failed (For the details, see WP1.2). In this project, we mostly spend our time to synthesize deuterated propellanes and aryl propellanes; and were unable to perform another two work packages WP2, and WP3.
Overall assessment. The project has achieved some of its objectives and milestones. However, corrective action will be required.
We developed a cost-effective, scalable and 3-steps synthetic approach for the synthesis of deuterated propellanes. This strategy provides an access to synthesized different types of labelled [1.1.1]propellane such as [1.1.1]propellane-d6 [1.1.1]propellane-d4 and [1.1.1]propellane-d2. To synthesize aryl propellanes, 4-different strategies were conducted, however, all were failed and more investigation is required on this chemistry.
The critical objectives proposed in the Fellow’s MSCA application have been achieved partially and further investigation is necessary. During this fellowship, we spent most of the time towards the synthesis [1.1.1]propellane-dn (n = 2, 4, and 6), which was challenging. We developed the cost-effective, scalable and a 3-steps synthetic approach to synthesize [1.1.1]propellane-dn (n = 2, 4, and 6). Further studies on synthesizing deuterium labelled bicyclo[1.1.1]pentane (BCP) drug analogues from the [1.1.1]propellane-dn (n = 2, 4, and 6) and their application in mechanistic study (kinetic isotope effect experiment) and in biological system (to investigate pharmacokinetic properties) are require.
The critical objectives proposed in the Fellow’s MSCA application have been achieved partially and further investigation is necessary. During this fellowship, we spent most of the time towards the synthesis [1.1.1]propellane-dn (n = 2, 4, and 6), which was challenging. We developed the cost-effective, scalable and a 3-steps synthetic approach to synthesize [1.1.1]propellane-dn (n = 2, 4, and 6). Further studies on synthesizing deuterium labelled bicyclo[1.1.1]pentane (BCP) drug analogues from the [1.1.1]propellane-dn (n = 2, 4, and 6) and their application in mechanistic study (kinetic isotope effect experiment) and in biological system (to investigate pharmacokinetic properties) are require.
Impact
Impact on the researcher's career. The work undertaken by the researcher was done with constant support from the supervisor – through day-to-day contact, and a series of professional development and training exercises. In the Weekly group meeting, usually two members of the group present their work over the previous 3-4 months to the whole group by PowerPoint presentation (develops presentation skills of the researcher). In the weekly group meetings alternating literature discussion / problem solving on the whiteboard (improves chemistry knowledge and informal presentation skills of the researcher) at the host institution. This gave him the opportunity to be fully dedicated to his project, whilst expanding his knowledge in chemistry. Overall, the researcher benefited from a thorough training in modern organic chemistry – from theoretical knowledge to practical aspects – in a university of excellence. This was only possible thanks to the comfort provided by this prestigious fellowship, which facilitated the daily work of the researcher in the laboratory – by giving him enough funds to order consumables and chemicals. Overall, this postdoctoral position greatly enhanced the career prospects of the researcher and helped him to find another postdoctoral position at the Max Planck Institute of Chemical Energy Conversion at the Mulheim an der Ruhr, Germany, under the direction of Prof. Walter Leitner (director in molecular catalysis). He will transfer the knowledge he gained during his Marie-Curie postdoctoral position at the University of Oxford to his current study.
Project’s Impact. The synthesis of deuterium labelled bicyclopentane (BCP) drug analogues and their application in mechanistic study and in biological system (in collaboration with other research group) are the current goal which could open-up new window in the research of propellane chemistry. We developed the synthetic route of the [1.1.1]propellane-dn (n = 2, 4, and 6) thus giving an opportunity to another researcher to work on this project within the group and, some publications are anticipated. One publication was published (Org. Lett. 2024, 26, 284) where the researcher is as a co-author and another publication will come from the journal Nature Protocols (under minor revision) soon on ‘Synthesis of bicyclo[3.1.1]heptanes meta-substituted arene bioisosteres, from [3.1.1]propellane’ where the researcher is as a first author.
Update of the plan for exploitation and dissemination of results. One publication as a co-author (Org. Lett. 2024, 26, 284) was published on the ‘Synthesis of Heterocycle-Substituted Bicyclo[3.1.1]heptanes and Aza-bicyclo[3.1.1]heptanes via Photocatalytic Minisci Reaction’. A second paper as a first author is now under revision (minor) in the journal Nature Protocols on ‘Synthesis of bicyclo[3.1.1]heptanes meta-substituted arene bioisosteres, from [3.1.1]propellane’. Further work need to be done to explore the deuterium labelled and aryl substituted [1.1.1]propellane chemistry, and publications are anticipated. Throughout the Fellowship, the researcher was encouraged to participate in ongoing Outreach activities within the Chemistry Department, such as the Department Open Day, which includes tours of the various laboratories. The Host group also uses a Lay Summary (includes the topics of the Fellow's research) on the group website to provide comprehensible information on group research to the general public. These publications acknowledge EU funding including the specific grant code (101020227) of the Fellowship.
Impact on the researcher's career. The work undertaken by the researcher was done with constant support from the supervisor – through day-to-day contact, and a series of professional development and training exercises. In the Weekly group meeting, usually two members of the group present their work over the previous 3-4 months to the whole group by PowerPoint presentation (develops presentation skills of the researcher). In the weekly group meetings alternating literature discussion / problem solving on the whiteboard (improves chemistry knowledge and informal presentation skills of the researcher) at the host institution. This gave him the opportunity to be fully dedicated to his project, whilst expanding his knowledge in chemistry. Overall, the researcher benefited from a thorough training in modern organic chemistry – from theoretical knowledge to practical aspects – in a university of excellence. This was only possible thanks to the comfort provided by this prestigious fellowship, which facilitated the daily work of the researcher in the laboratory – by giving him enough funds to order consumables and chemicals. Overall, this postdoctoral position greatly enhanced the career prospects of the researcher and helped him to find another postdoctoral position at the Max Planck Institute of Chemical Energy Conversion at the Mulheim an der Ruhr, Germany, under the direction of Prof. Walter Leitner (director in molecular catalysis). He will transfer the knowledge he gained during his Marie-Curie postdoctoral position at the University of Oxford to his current study.
Project’s Impact. The synthesis of deuterium labelled bicyclopentane (BCP) drug analogues and their application in mechanistic study and in biological system (in collaboration with other research group) are the current goal which could open-up new window in the research of propellane chemistry. We developed the synthetic route of the [1.1.1]propellane-dn (n = 2, 4, and 6) thus giving an opportunity to another researcher to work on this project within the group and, some publications are anticipated. One publication was published (Org. Lett. 2024, 26, 284) where the researcher is as a co-author and another publication will come from the journal Nature Protocols (under minor revision) soon on ‘Synthesis of bicyclo[3.1.1]heptanes meta-substituted arene bioisosteres, from [3.1.1]propellane’ where the researcher is as a first author.
Update of the plan for exploitation and dissemination of results. One publication as a co-author (Org. Lett. 2024, 26, 284) was published on the ‘Synthesis of Heterocycle-Substituted Bicyclo[3.1.1]heptanes and Aza-bicyclo[3.1.1]heptanes via Photocatalytic Minisci Reaction’. A second paper as a first author is now under revision (minor) in the journal Nature Protocols on ‘Synthesis of bicyclo[3.1.1]heptanes meta-substituted arene bioisosteres, from [3.1.1]propellane’. Further work need to be done to explore the deuterium labelled and aryl substituted [1.1.1]propellane chemistry, and publications are anticipated. Throughout the Fellowship, the researcher was encouraged to participate in ongoing Outreach activities within the Chemistry Department, such as the Department Open Day, which includes tours of the various laboratories. The Host group also uses a Lay Summary (includes the topics of the Fellow's research) on the group website to provide comprehensible information on group research to the general public. These publications acknowledge EU funding including the specific grant code (101020227) of the Fellowship.