1,2-Difunctionalized bicyclo[1.1.1]pentanes: Long-sought-after mimetics for ortho/meta-substituted arenes.
Jin-Xin ZhaoYu-Xuan ChangChi HeBenjamin J BurkeMichael R CollinsMatthew Del BelJeff ElleraasGary M GallegoT Patrick MontgomeryJames J MousseauSajiv K NairMatthew A PerryJillian E SpanglerJulien C VantouroutPhil S BaranPublished in: Proceedings of the National Academy of Sciences of the United States of America (2021)
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.