1,2-Difunctionalized bicyclo[1.1.1]pentanes: Long-sought-after mimetics for ortho/meta-substituted arenes.

Proceedings of the National Academy of Sciences of the United States of America 2021 Jul 13

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The development of a versatile platform for the synthesis of 1,2-difunctionalized bicyclo[1.1.1]pentanes to potentially mimic ortho/meta-substituted arenes is described. The syntheses of useful building blocks bearing alcohol, amine, and carboxylic acid functional handles have been achieved from a simple common intermediate. Several ortho- and meta-substituted benzene analogs, as well as simple molecular matched pairs, have also been prepared using this platform. The results of in-depth ADME (absorption, distribution, metabolism, and excretion) investigations of these systems are presented, as well as computational studies which validate the ortho- or meta-character of these bioisosteres.

Citation

Jin-Xin Zhao, Yu-Xuan Chang, Chi He, Benjamin J Burke, Michael R Collins, Matthew Del Bel, Jeff Elleraas, Gary M Gallego, T Patrick Montgomery, James J Mousseau, Sajiv K Nair, Matthew A Perry, Jillian E Spangler, Julien C Vantourout, Phil S Baran. 1,2-Difunctionalized bicyclo[1.1.1]pentanes: Long-sought-after mimetics for ortho/meta-substituted arenes. Proceedings of the National Academy of Sciences of the United States of America. 2021 Jul 13;118(28)