Saturated Bioisosteres of ortho‐Substituted Benzenes

Abstract

Saturated bioisosteres of ortho-disubstituted benzenes (bicyclo[2.1.1]hexanes) were synthesized, characterized and validated. These cores were incorporated into the bioactive compounds Valsartan, Boskalid and Fluxapyroxad instead of the benzene ring. The saturated analogues showed as imilar level of antifungal activity compared to that of Boskalid and Fluxapyroxad.

Saturated Bioisosteres of ortho‐Substituted Benzenes

“…As ingle crystallization from hexane allowed isolating the major components 1b-17 b as single stereoisomers.A ll products were synthesized on ag ram scale.S tructures of acids 13 b, 15 b and 16 b were confirmed by X-Ray analysis (Scheme 3). [20] From nitrile-substituted substrates 18-20,the corresponding photochemical cyclization also worked well to give products 18 a-20 a (Scheme 3). Compounds 18 a-20 a were isolated as individual major isomers by column chromatography.…”

The Powerful Symbiosis Between Synthetic and Medicinal Chemistry

“…Expanding on saturated bicyclic benzene replacements, Denisenko et al introduced 1,5-disubstituted bicyclo[2.1.1]hexanes as isolipophilic but potentially more water-soluble bioisosteres of ortho-disubstituted benzenes [17]. Levterov decreases lipophilicity and can increase metabolic stability and aqueous solubility [18].…”

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

“…Bicyclo[1.1.1]pentanes (BCPs) containing substitutions at bridgehead positions (C1, C3) are now widely recognized as saturated bioisosteres for para-substituted benzenes 4 . Analogously, related caged scaffolds with differentiated substitutions (Figure 1A) are expected to be ideal bioisosteres of ortho-or meta-substituted benzenes 5,6 . 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][13][14][15][16][17][18][19][20] , wherein 6 is transformed to symmetric and asymmetric BCPs using either single-or two-electron transfer pathways (Figure 1B).…”