General access to cubanes as benzene bioisosteres

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Drug Discovery

Background:

• Replacing benzene rings with sp³-hybridized bioisosteres can enhance drug pharmacokinetics and maintain biological activity.
• Rigid, strained frameworks like cubane offer metabolic stability due to high C-H bond strength and closely mimic benzene's geometry.
• Current limitations restrict cubane's use to mono- or para-substituted benzene replacements due to synthetic challenges and cross-coupling incompatibility.

Purpose of the Study:

• To develop efficient synthetic routes for 1,3- and 1,2-disubstituted cubane precursors.
• To establish robust cross-coupling protocols compatible with the cubane scaffold.
• To enable the comprehensive use of cubane as a bioisostere for all benzene substitution patterns in drug candidates.

Main Methods:

• Synthesis of 1,3-disubstituted cubane using a cyclobutadiene precursor.
• Photolytic C-H carboxylation for accessing 1,2-disubstituted cubane building blocks.
• Development of copper-catalyzed cross-coupling reactions (C-N, C-C(sp³), C-C(sp²), C-CF₃) leveraging specific copper reactivity.

Main Results:

• Expedient routes to key 1,3- and 1,2-disubstituted cubane intermediates were established.
• Novel cross-coupling methods were successfully applied to the cubane scaffold, overcoming previous limitations.
• Facile elaboration of all cubane isomers into potential drug candidates is now achievable.

Conclusions:

• The developed synthetic strategies and cross-coupling protocols significantly expand the utility of cubane in medicinal chemistry.
• Cubane can now be effectively employed as a bioisostere for ortho-, meta-, and para-substituted benzenes.
• This advancement facilitates the design of drug candidates with improved pharmacokinetic properties through ideal benzene ring replacement.