Hydroformylation and Late-Stage Diversification on Densely Functionalized Cores of Influenza Endonuclease Inhibitors

This work describes synthetic strategies to access diverse chemical matter in a series of inhibitors of the cap-dependent Flu endonuclease. Our approaches toward this goal encompass (i) the development of a modular, diastereoselective route to the tricyclic cores and (ii) the use of advanced intermediates for late-stage diversification. Key to realizing both strategies is the development of an efficient, functional group-tolerant, chemoselective hydroformylation step that can be executed in the presence of the metal binding motif common to this inhibitor family. The established synthetic route provides access to advanced intermediates on gram scale. Furthermore, late-stage diversification conditions that tolerate the presence of the pyridone-based binding motif are reported, allowing for rapid access to a broad range of chemical matter.