Propellane-free access to bicyclo[1.1.1]pentanes.

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Drug Discovery

Background:

• Bicyclo[1.1.1]pentane (BCP) is a 3D bioisostere for benzene, enhancing drug properties.
• Traditional synthesis relies on [1.1.1]propellane, limiting access to complex BCP derivatives.

Purpose of the Study:

• To review recent propellane-free synthetic strategies for multisubstituted and bridge-functionalized BCPs.
• To assess the scope and limitations of emerging BCP synthesis methodologies.

Main Methods:

• Intramolecular diradical couplings
• Carbene-mediated ring expansions
• Two-electron disconnections

Main Results:

• Emerging methods offer alternatives to propellane-based BCP synthesis.
• These strategies facilitate access to highly strained and sterically hindered BCPs.
• The reviewed methods expand the toolkit for medicinal chemists.

Conclusions:

• Propellane-free routes are crucial for accessing diverse BCP scaffolds.
• Further synthetic development is needed to address remaining challenges.
• Advanced BCP derivatives hold significant potential for pharmaceutical research.