Triplet Carbene Insertion Enables Modular Access to C2-Substituted Bicyclo[1.1.1]pentanes

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Synthetic Chemistry

Background:

• Bicyclo[1.1.1]pentanes (BCPs) are valuable saturated bioisosteres for planar aromatic rings.
• C2-substituted BCPs offer unique three-dimensional structural motifs, expanding chemical space beyond traditional arenes.
• Efficient synthesis of BCP scaffolds is challenging due to their complex topology.

Purpose of the Study:

• To develop a robust and modular synthetic strategy for C2-substituted bicyclo[1.1.1]pentanes.
• To explore the utility of bicyclo[1.1.0]butanes as precursors for BCP synthesis.
• To demonstrate the broad applicability of the new method in medicinal chemistry.

Main Methods:

• Direct synthesis of C2-substituted BCPs from bicyclo[1.1.0]butanes and diazo compounds.
• Utilizing homolytic cleavage and carbene insertion via triplet energy transfer.
• Formation of 1,4-biradical intermediates followed by radical recombination.

Main Results:

• A modular and efficient method for synthesizing C2-substituted BCPs was established.
• The methodology allows for systematic access and diversification of 3D BCP architectures.
• The BCP scaffold successfully replaced phenyl groups in 15 diverse bioactive molecules.

Conclusions:

• The developed strategy provides a practical platform for accessing C2-functionalized BCPs.
• This work facilitates the exploration of BCPs as bioisosteres in drug discovery.
• The method enables rapid diversification of three-dimensional molecular skeletons.