Rapid Access to 3-Substituted Bicyclo[1.1.1]pentanes

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Drug Discovery

Background:

• Benzene rings are common in pharmaceuticals, but researchers seek bioisosteres for improved properties.
• Bicyclo[1.1.1]pentanes (BCPs) are C(sp3)-enriched phenyl bioisosteres used to enhance pharmacokinetic profiles.
• 3-Arylated BCPs are known, but 3-alkylated BCPs are underexplored due to synthetic challenges.

Purpose of the Study:

• To develop a mild and unified method for synthesizing both alkyl and aryl-substituted BCPs.
• To overcome limitations of current de novo synthesis and reactive feedstock requirements for BCP preparation.
• To enable broader adoption of BCPs in drug discovery programs.

Main Methods:

• Utilized dual copper-photoredox catalysis for BCP synthesis.
• Employed bench-stable precursors for a streamlined process.
• Demonstrated applicability to diverse substrates including saturated motifs, aryl residues, and heterocycles.

Main Results:

• Successfully prepared both alkyl and aryl-substituted BCPs using a single, mild method.
• The dual copper-photoredox catalysis approach proved effective and versatile.
• BCP functionalities were installed on various medicinally relevant chemical structures.

Conclusions:

• A novel, efficient method for BCP synthesis has been established.
• This approach facilitates the incorporation of valuable 3-alkylated BCP motifs.
• The developed methodology broadens the utility of BCPs in medicinal chemistry and drug development.