Programmable late-stage functionalization of bridge-substituted bicyclo[1.1.1]pentane bis-boronates

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Drug Discovery

Background:

• Modular functionalization is key for exploring chemical space in drug discovery.
• The bicyclo[1.1.1]pentane (BCP) motif is a promising benzene bioisostere for improving drug properties.
• Current methods for synthesizing C2-substituted BCP analogues are limited by multi-step de novo synthesis.

Purpose of the Study:

• To develop a programmable bis-functionalization strategy for late-stage sequential derivatization of BCP bis-boronates.
• To enable efficient exploration of structure-activity relationships (SARs) for multisubstituted BCP motifs in drug candidates.

Main Methods:

• Utilized the chemoselectivity of BCP bis-boronates for selective functionalization.
• Developed a sequential derivatization strategy involving C3-boronic pinacol esters (Bpin) and C2-Bpin.
• Enabled late-stage modification of BCP scaffolds.

Main Results:

• Achieved highly selective activation and functionalization of the C3 bridgehead position while preserving the C2 position.
• Successfully synthesized C1,C2-disubstituted and C1,C2,C3-trisubstituted BCPs.
• Opened access to previously unexplored chemical space within BCP motifs.

Conclusions:

• The developed strategy allows for versatile exploration of SARs for BCP-containing drug candidates.
• This method overcomes limitations of previous synthetic approaches for BCP analogues.
• Facilitates the discovery of novel drug candidates with improved physicochemical properties.