1,2-Difunctionalized Bicyclo[1.1.1]pentanes: Long Sought After Bioisosteres for ortho/meta-Substituted Arenes

Abstract

<p>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 synthesis of useful building blocks bearing alcohol, amine, and carboxylic acid functional handles has been achieved from a simple common intermediate. Several ortho and/or meta-substituted benzene analogues as well as simple molecular matched pairs have also been prepared using this platform. In-depth biological and computational studies are currently in progress to validate the ortho and/or meta-character of these new bioisosteres. Results of these investigations will be reported in due course.</p>

Synthesis of Multi-Substituted Bicycloalkyl Boronates: An Intramolecular Coupling Approach to Alkyl Bioisosteres

“…A primary alkyl Bpin (R 2 = H, R 3 = H) underwent smooth cyclization to the C1, C3 disubstituted BCP Bpin 16. Starting from secondary alkyl Bpins, a variety of C1, C2 and C3 trisubstituted BCPs, including C2-alkyl (17)(18)(19)(20)(21)(22)14) and C2-aryl substituted (23) BCP Bpins were prepared. Lastly, subjecting tertiary alkyl Bpin starting materials to cyclization condensations afforded BCPs with di-substituted C2 side chains (24,25).…”

“…Currently BCPs are synthesized from the highly strained [1.1.1]propellane (6) (the strain energy of the C-C bond = ~59~65 kcal/mol) 7-9 , using methodologies pioneered by Wiberg 7 , Michl 10 , Baran 11 , and others 12-20 , wherein 6 is transformed to symmetric and asymmetric BCPs using either single-or two-electron transfer pathways (Figure 1B). These efforts have primarily focused on accessing C1 and/or C3substituted BCPs until two recent reports 21,22 disclosed strategies for the systematic functionalization of the backbone (C2) of BCPs. In addition to strain-release, Wurtz…”

Synthesis and Use of Versatile [1.1.1]Bicyclopentylaldehyde Building Blocks

“…35 Synthesis of C-substituted BCP-s was investigated by the group of Walsh, leading to mono substituted [1.1.1]bicyclopentanes. [36][37] Not surprisingly, many of the pathways to bicyclopentane containing molecules proceeds via a BCP-aldehyde intermediate, [10][11][12][13][14][15][38][39][40][41][42] as aldehydes are amongst the most versatile functions in organic synthesis. In contrast the synthesis of these molecules usually involves lengthy synthesis, and no precedence of their general synthesis is showcased in the literature.…”

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

“…1A). Only recently have reports emerged delineating creative approaches to fill this gap [an initial disclosure of this study was deposited on ChemRxiv (21); subsequently, two additional reports (22,23) have appeared describing different and orthogonal strategies]. This is certainly due to the absence of synthetic methods to achieve 1,2-difunctionalization of BCPs rather than the lack of desire to replace orthoand metadisubstituted benzenes in bioactive molecules, which has been regularly mentioned over the years (3)(4)(5)(6)(7)(8).…”