[2]-Ladderanes as isosteres for meta-substituted aromatic rings and rigidified cyclohexanes

• Published in: Nature communications Vol. 13; no. 1; p. 6056
• Main Authors: Epplin, Rachel C., Paul, Shashwati, Herter, Loïc, Salome, Christophe, Hancock, Erin N., Larrow, Jay F., Baum, Erich W., Dunstan, David R., Ginsburg-Moraff, Carol, Fessard, Thomas C., Brown, M. Kevin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13-10-2022; Nature Publishing Group; Nature Portfolio
• Subjects: 639/638/309/2419; 639/638/403/933; Acids; Aromatic compounds; Aromatic hydrocarbons; Chemistry; Cyclohexanes; Humanities and Social Sciences; multidisciplinary; Oxidation; Pharmaceutical sciences; Physicochemical properties; Saturated hydrocarbons; Science; Science (multidisciplinary); Substitutes
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-33827-3

Aromatic ring isosteres and rigidified saturated hydrocarbons are important motifs to enable drug discovery. Herein we disclose [2]-ladderanes as a class of
meta
-substituted aromatic ring isosteres and rigidified cyclohexanes. A straightforward synthesis of the building blocks is presented along with representative derivatization. Preliminary studies reveal that the [2]-ladderanes offer similar metabolic and physicochemical properties thus establishing this class of molecules as interesting motifs.
The development of new classes of isosteres and building blocks is crucial to the advancement of medicinal chemistry programs. Here, the authors report the synthesis and development of ladderanes to act as replacements for meta-substituted aromatic rings and cyclohexanes.