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. 2022 Oct 13;13(1):6056.
doi: 10.1038/s41467-022-33827-3.

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

Rachel C Epplin  1 , Shashwati Paul  1 , Loïc Herter  2 , Christophe Salome  2 , Erin N Hancock  1   3 , Jay F Larrow  4   5 , Erich W Baum  4   5 , David R Dunstan  4   5 , Carol Ginsburg-Moraff  4 , Thomas C Fessard  6 , M Kevin Brown  7
Affiliations

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

Rachel C Epplin et al. Nat Commun. .

Abstract

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.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Background.
A Exit vector analysis to establish the 3D positions of substituents relative to each other. B Known aromatic ring isosteres for para-substituted aromatic rings with a representative example. C Known aromatic ring isosteres for meta-substituted aromatic rings. D [2]-Ladderane as isosteres for aromatic rings E [2]-Ladderane as rigidified cyclohexanes.
Fig. 2
Fig. 2. Synthetic strategy.
A Synthesis of [2]-ladderane building blocks. B Other examples that can be prepared by the outlined route. ITX 2-i-Prthioxanthone, DMP Dess Martin periodinane, LED light emitting diode, p-ABSA asdfasdfasd p-acetamidosulfonylazide, TIPS Triisopropylsilyl.
Fig. 3
Fig. 3. Derivatization of [2]-ladderane building blocks.
A Transformation of the ladderane building block to other structures of relevance in medicinal chemistry. B Ni-catalyzed cross-coupling of redox-active esters. C Synthesis of ladder-mazapertine. DPPA diphenylphosphoryl azide, CDI carbonyl diimidazole, TBAF tetrabutylammonium fluoride, DMP Dess Martin periodinane, EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, DMAP 4-dimethylaminopyridine.
Fig. 4
Fig. 4. [2]-Ladderane as rigidified 1,3-cyclohexane.
The ladderane compounds can be converted via standard chemical reactions to functional groups common to drug like molecules. DPPA dipenylphosphoryl azide, LDA lithium diisopropylamide.
Fig. 5
Fig. 5. Preliminary comparisons to arenes/cyclohexanes.
Evaluation of the ladderane, aryl, and cyclohexyl compounds shows little difference in the physicochemical properties.
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