Escaping from Flatland: Substituted Bridged Pyrrolidine Fragments with Inherent Three-Dimensional Character

The pressure to deliver new medicines to the patient continues to grow along with increases in compound failure rate, thus putting the current R&D model at risk. Analysis has shown that increasing the three-dimensionality of potential drug candidates decreases the risk of failure and improves binding selectivity and frequency. For this reason many workers have taken a new look at the power of photochemistry as a means to generate novel sp 3 rich scaffolds for use in drug discovery programs. Here we report the design, synthesis, and computational structural analysis of a series of 2,4-methanoprolines having inherent 3D character (PMI and PBF scores) significantly higher than that of the broader AbbVie Rule of 3 (Ro3) collection.