Transannular C-H functionalization of cycloalkane carboxylic acids

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Catalysis

Background:

• Cyclic organic molecules are prevalent in pharmaceuticals, offering control over molecular shape, bioavailability, and specificity.
• Developing efficient methods for synthesizing functionalized carbocycles is crucial for drug discovery and development.
• Site-selective C-H functionalization of cycloalkanes presents challenges due to ring strain during transannular C-H palladation.

Purpose of the Study:

• To develop novel ligands for enabling direct site-selective C-H functionalization of saturated carbocycles.
• To achieve transannular C-H arylation of small- to medium-sized cycloalkane carboxylic acids.
• To demonstrate the utility of the developed method in the synthesis of biologically active molecules.

Main Methods:

• Synthesis and application of two classes of novel ligands: quinuclidine-pyridones (L1, L2) and sulfonamide-pyridones (L3).
• Employing C-H activation strategies for the direct arylation of cycloalkane carboxylic acids.
• Investigating the regioselectivity of the C-H functionalization across various ring sizes (cyclobutane to cyclooctane).

Main Results:

• The developed ligands successfully enabled transannular γ-methylene C-H arylation of cycloalkanes.
• Excellent γ-regioselectivity was achieved, even in the presence of multiple β-C-H bonds.
• The protocol facilitated two-step formal syntheses of complex, patented biologically active small molecules, significantly reducing synthetic steps.

Conclusions:

• This work introduces a powerful new method for the molecular editing of saturated carbocycles via C-H activation.
• The developed ligand systems overcome previous challenges in site-selective C-H functionalization of strained cyclic systems.
• This advance provides a more efficient and direct synthetic route to valuable carbocyclic scaffolds for medicinal chemistry.