Next generation bioisosteres - photocatalytic construction of azabicycles Nicoleta Lazar 1 , Paul Burton 2 , Rosemary Croft 2 , Joseph Mason 3 , Adam Smalley 4 , Jonathan W. Burton 1 and Michael C. Willis 1 1 University of Oxford, UK, 2 Syngenta, UK, 3 GSK, UK, 4 UCB, UK
Drug candidates with a higher fraction of sp 3 (Fsp 3 ) centres have a greater likelihood of passing clinical trials and becoming a commercial drug. 1, 2 Possibly the most explored strategy to enhance Fsp 3 is the replacement of aromatic rings with caged hydrocarbons including bicyclo[1.1.1]pentane and bicyclo[2.2.2]octane fragments. While the chemical, physical and pharmacological properties of benzene bioisosteres have been more widely explored, 3 the bioisosteres of heteroaromatic molecules constitute an emerging field, with quinuclidine-containing drugs largely derived from naturally occurring cinchona alkaloids. In this project, we have designed a synthetic route to quinuclidine 3 , centred around the development of a photocatalytic 6- exo -trig cyclisation for the construction of the [2.2.2]-bicyclic motif. We have established a pathway to the key allylpiperidine intermediate 2 , with current work focusing on the optimisation of the radical cyclisation. This will be followed by the use of the chloride as a handle for further functionalisation. In parallel, we have developed an orthogonal photocatalytic method to access fused bicyclic heteroaromatic structures, a highly prevalent motif amongst medicinally and biologically active molecules. We are currently expanding this methodology towards building a library of functionalised fused bicyclic lactams of varying ring sizes. In this presentation, we will explore the different synthetic approaches undertaken towards both quinuclidine 3 and bicyclic lactam 6 , detail the different strategies’ limitations and expand on their use in constructing the successful robust routes. References 1. Lovering, F.; Bikker, J.; Humblet, C., Journal of Medicinal Chemistry 2009 , 52 (21), 6752-6756 2. Lovering, F., MedChemComm 2013 , 4 (3), 515 3. Mykhailiuk, P. K., Organic & Biomolecular Chemistry 2019 , 17 (11), 2839-2849
P28
© The Author(s), 2022
Made with FlippingBook Learn more on our blog