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

Abstract

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.

Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design

“…The growing appreciation of the potential utility of the BCP moiety as a bioisostere of para -substituted phenyl rings has stimulated considerable effort to develop synthetic methodologies designed to access new substitution patterns of this compact bicyclic ring system. The recent development of synthetic approaches to 2-substituted bicyclo[1.1.1]­pentane derivatives has provided a platform with which to explore potential mimics of an ortho -substituted phenyl ring . These motifs have been examined in the context of the BCP analogues 82b , 82d , and 82f of the microsomal triglyceride transfer protein (MTP) inhibitor lomitapide ( 82a ), the fungicide boscalid ( 82c ), and the VEGFR2 kinase inhibitor axitinib ( 82e ), respectively, as summarized in Table .…”

“…The recent development of synthetic approaches to 2-substituted bicyclo[1.1.1]­pentane derivatives has provided a platform with which to explore potential mimics of an ortho -substituted phenyl ring . These motifs have been examined in the context of the BCP analogues 82b , 82d , and 82f of the microsomal triglyceride transfer protein (MTP) inhibitor lomitapide ( 82a ), the fungicide boscalid ( 82c ), and the VEGFR2 kinase inhibitor axitinib ( 82e ), respectively, as summarized in Table . Interestingly, the isostere concept was extended to the smoothened inhibitor sonidegib ( 82g ), in which the meta -substituted phenyl ring was replaced with the 2-substituted bicyclo[1.1.1]­pentane-1-carboxylic acid found in 82h , a design that recognized the potential versatility of the bond vectors associated with the BCP ring system.…”

“…However, for the BCP analogues, the vector geometries associated with this ring system extend the distance between the sulfur atom and the amide oxygen to 4.0 Å, with a torsion angle of 67° (Figure B). This is believed to distort the optimal stereochemical arrangement of the methyl amide moiety, disrupting its interactions with the kinase and resulting in reduced potency …”

“…159 These motifs have been examined in the context of the BCP analogues 82b, 82d, and 82f of the microsomal triglyceride transfer protein (MTP) inhibitor lomitapide (82a), the fungicide boscalid (82c), and the VEGFR2 kinase inhibitor axitinib (82e), respectively, as summarized in Table 68. 159 Interestingly, the isostere concept was extended to the smoothened inhibitor sonidegib (82g), in which the metasubstituted phenyl ring was replaced with the 2-substituted bicyclo[1.1.1]pentane-1-carboxylic acid found in 82h, a design that recognized the potential versatility of the bond vectors associated with the BCP ring system. In the case of 82c, 82e, and 82g, significant improvements in aqueous solubility were noted with the bioisosteric BCP analogues despite expressing similar LogD values compared to the progenitor compounds.…”

“…This is believed to distort the optimal stereochemical arrangement of the methyl amide moiety, disrupting its interactions with the kinase and resulting in reduced potency. 159 The homologous bicyclo[2.1.1]hexane ring system 83b has also been explored for its potential to function as an Fsp 3 -rich mimic of an ortho-disubstituted phenyl ring 83a, with the key dimensions subtending its isosteric potential depicted in Figure 29. 160 The bicyclo[2.1.1]hexane derivative 84b was synthesized as a model of the -substituted prototype 84a, and while both displayed similar LogD values, 84b exhibited improved aqueous solubility compared to 84a (Figure 30).…”