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.
