Comprehensive Strategies to Bicyclic Prolines: Applications in the Synthesis of Potent Arginase Inhibitors, by Derun Li, Hongjun Zhang, Thomas W. Lyons, Min Lu, Abdelghani Achab, Qinglin Pu, Matthew Childers, Matthew J. Mitcheltree, Jialiang Wang, Theodore A. Martinot, Spencer E. McMinn, David L. Sloman, Anandan Palani, Adam Beard, Lisa Nogle, Symon Gathiaka, Josep Saurí, Hai-Young Kim, Donovon Adpressa, Peter Spacciapoli, J. Richard Miller, Rachel L. Palte, Charles A. Lesburg, Jared Cumming, and Christian Fischer. ACS Med. Chem. Lett. 2021, 12, 11, 1678–1688. https://doi.org/10.1021/acsmedchemlett.1c00258
Comprehensive synthetic strategies afforded a diverse set of structurally unique bicyclic proline-containing arginase inhibitors with a high degree of three-dimensionality. The analogs that favored the Cγ-exo conformation of the proline improved the arginase potency over the initial lead. The novel synthetic strategies reported here not only enable access to previously unknown stereochemically complex proline derivatives but also provide a foundation for the future synthesis of bicyclic proline analogs, which incorporate inherent three-dimensional character into building blocks, medicine, and catalysts and could have a profound impact on the conformation of proline-containing peptides and macrocycles.
Structure Elucidation by NMR 