Periodic Reporting for period 1 - BCPPlus (New directions in bicyclopentane research)
Reporting period: 2018-07-16 to 2020-07-15
The pharmaceutical industry is increasingly seeking new tactics for the structural modification of drug candidates that avoid problems with metabolic susceptibility, or to improve pharmacokinetic properties. Analogues called 'bioisosteres', which mimic the dimensions and substituent vectors of problematic structural motifs, but which are not themselves subject to the same pharmacological limitations, offer one solution. These are often based on scaffolds that are not found in ‘typical’ drug candidates. Within this growing field, rigid polycycles such as bicyclo[1.1.1]pentane (BCP) are receiving significant attention as arene bioisosteres, as they exhibit similar size and shape. Current methods for BCP synthesis require harsh conditions; this limits product scope and therefore the development of medicinally-relevant compounds. The invention of new methodology to access this motif will revolutionize use of BCPs in the pharmaceutical sector.
The knowledge generated from this project will advance our understanding of caged hydrocarbons, transition metal catalysis and photoredox catalysis and will facilitate and accelerate the production of high-value pharmaceutical chemicals bearing BCP motifs. Translation of this research to drug discovery programs will create opportunities for commercialisation, adding substantial value to the biotechnology and pharmaceutical sectors. In addition, this proposal will lead to strong and rewarding national and international collaborations with global pharmaceutical and academic leaders.
Objectives:
The central objective of the project is to create methodology which will allow for the widespread use of the BCP motif in medicinal and agrochemical industries. Specifically we sought to:
Explore general and mild ATRA-based syntheses of BCP derivatives with a particular focus on exploiting photoredox catalysis;
Functionalize the bicyclo[1.1.1]pentane ring system, focussing on transition metal and photoredox catalysed transformations;
Synthesise novel bicyclo[1.1.1]pentanes analogues of peptidic and non-peptidic drugs and natural product analogues.
Conclusions:
The methods which we have developed in this project enable easy synthesis to BCP compounds, significantly increasing the accessibility of these compounds in medicinal chemistry. These methodologies are already being utilised in the drug discovery programmes of our industrial collaborators and we anticipate that this research will soon result in new drugs which feature the BCP motif.
The knowledge generated from this project will advance our understanding of caged hydrocarbons, transition metal catalysis and photoredox catalysis and will facilitate and accelerate the production of high-value pharmaceutical chemicals bearing BCP motifs. Translation of this research to drug discovery programs will create opportunities for commercialisation, adding substantial value to the biotechnology and pharmaceutical sectors. In addition, this proposal will lead to strong and rewarding national and international collaborations with global pharmaceutical and academic leaders.
Objectives:
The central objective of the project is to create methodology which will allow for the widespread use of the BCP motif in medicinal and agrochemical industries. Specifically we sought to:
Explore general and mild ATRA-based syntheses of BCP derivatives with a particular focus on exploiting photoredox catalysis;
Functionalize the bicyclo[1.1.1]pentane ring system, focussing on transition metal and photoredox catalysed transformations;
Synthesise novel bicyclo[1.1.1]pentanes analogues of peptidic and non-peptidic drugs and natural product analogues.
Conclusions:
The methods which we have developed in this project enable easy synthesis to BCP compounds, significantly increasing the accessibility of these compounds in medicinal chemistry. These methodologies are already being utilised in the drug discovery programmes of our industrial collaborators and we anticipate that this research will soon result in new drugs which feature the BCP motif.
We initially explored complementary synthetic methodology to install the BCP motif into complex molecules, with a specific focus on the development of photocatalytic methods to effect these transformations. The photoredox activation of carbon–halogen bonds to access carbon-centered radicals is well-established, but despite many examples of addition of these intermediates to carbon–carbon π-bonds, the equivalent additions to [1.1.1]propellane remained unknown. This chemistry presents an attractive, mild and atom-economical strategy to access medicinally-important BCP molecules and was investigated for the first 9 months of this project. This strategy was ultimately successful. Highlights of this work include the first reported additions of (hetero)aryl radicals to [1.1.1]propellane and numerous examples of the addition of non-stabilized alkyl radicals, providing access to a wide variety of BCP products. This methodology addressed previous limitations within the field. This work resulted in approximately 90 examples and currently represents the state-of-the-art in the synthesis of BCPs. This work has been published in a high-impact journal: ACS Catal. 2019, 9, 9568, and was presented at an international conference (9th Pacific Symposium on Radical Chemistry, USA), and at various national meetings, winning 2nd place in the organic division of the #RSCPoster Twitter Conference.
We next foccussed on addressing the challenging prospect of direct functionalization of the BCP system. Previous work within the group focussed on strategies which were unsustainable and, while such methods can generate useful products, the harsh conditions required to achieve this limited the suitability of this chemistry for industrial applications. We foccussed on the development of an industry-friendly protocol to efficiently couple BCP iodides which were synthesised in objective 1 to form medicinally-relevant products. Using an iron-catalyzed Kumada cross-coupling protocol, we were able to the easily couple BCP iodides with Grignard reagents. The final 10 months of this fellowship was dedicated to this project and resulted in approximately 40 examples. This currently represents the state-of-the-art in the synthesis of di-carbon-substituted BCPs. This work has recently been published in a high-impact journal: Angew. Chem. Int. Ed., 2020. doi:10.1002/anie.202004090.
We next foccussed on addressing the challenging prospect of direct functionalization of the BCP system. Previous work within the group focussed on strategies which were unsustainable and, while such methods can generate useful products, the harsh conditions required to achieve this limited the suitability of this chemistry for industrial applications. We foccussed on the development of an industry-friendly protocol to efficiently couple BCP iodides which were synthesised in objective 1 to form medicinally-relevant products. Using an iron-catalyzed Kumada cross-coupling protocol, we were able to the easily couple BCP iodides with Grignard reagents. The final 10 months of this fellowship was dedicated to this project and resulted in approximately 40 examples. This currently represents the state-of-the-art in the synthesis of di-carbon-substituted BCPs. This work has recently been published in a high-impact journal: Angew. Chem. Int. Ed., 2020. doi:10.1002/anie.202004090.
These methodologies are already being utilised in the drug discovery programmes of our industrial collaborators and we anticipate that this research will soon result in new drugs which feature the BCP motif.