Rapid Access to 2-Substituted Bicyclo[1.1.1]pentanes.

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Drug Discovery

Background:

• Aryl rings in pharmaceuticals can be replaced by saturated carbocyclic structures like bicyclo[1.1.1]pentanes (BCPs) to enhance pharmacokinetic properties.
• 1,3-difunctionalized BCPs are effective bioisosteres for para-substituted arenes, but rapid synthesis of 2-substituted BCPs (ortho-/meta-arene replacements) remains a challenge.
• Existing methods for 2-substituted BCPs involve lengthy, nonmodular sequences, often requiring pre-installation of substituents before BCP core formation.

Purpose of the Study:

• To develop a general and rapid synthetic strategy for 2-substituted BCPs.
• To enable direct functionalization of the BCP core's C-H bonds for streamlined synthesis.
• To create novel 2-substituted BCP synthetic linchpins as versatile precursors for complex molecules.

Main Methods:

• A generalizable synthetic linchpin strategy utilizing radical C-H abstraction of the BCP core.
• Mild generation of a strong hydrogen atom abstractor for one-pot synthesis of BCP linchpins.
• Two novel metallaphotoredox protocols for one-step access to electrophilic and nucleophilic 2-substituted BCP fragments.

Main Results:

• Rapid, one-pot synthesis of novel 2-substituted BCP synthetic linchpins.
• Expedient access to previously inaccessible electrophile and nucleophile fragments at the 2-position of BCPs.
• Successful synthesis of four pharmaceutical analogues using the new platform, demonstrating comparable or improved properties.

Conclusions:

• The reported platform enables a streamlined pathway to diverse 2-substituted BCPs.
• This approach overcomes limitations of current methods, offering modularity and efficiency.
• The synthesized 2-substituted BCPs hold significant potential for drug development, offering improved properties over aryl-containing counterparts.