Accessing three-dimensional molecular diversity through benzylic C-H cross-coupling.

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Computational Chemistry

Background:

• Pharmaceutical and agrochemical research requires diverse molecular structures for discovery.
• Traditional cross-coupling methods often yield "flat" molecules, limiting drug-like properties.
• Benzylic C(sp3)-H cross-coupling offers a route to more three-dimensional compounds.

Purpose of the Study:

• To investigate if benzylic C(sp3)-H cross-coupling enhances molecular three-dimensionality.
• To determine the influence of scaffold conformational rigidity on product topology.
• To guide the design of diverse molecular libraries for drug discovery.

Main Methods:

• Creation of a virtual library of over 350,000 benzylic ethers and ureas.
• Analysis of molecular dimensionality based on scaffold flexibility.
• Informatics-guided synthesis and high-throughput experimentation to validate findings.

Main Results:

• Molecular three-dimensionality is significantly influenced by the conformational rigidity of the benzylic scaffold.
• Flexible scaffolds may not improve dimensionality without adopting higher energy conformations.
• A library of diverse, three-dimensional molecules was synthesized across drug-like chemical space.

Conclusions:

• Scaffold design is crucial for achieving desired three-dimensionality in molecules synthesized via benzylic C(sp3)-H cross-coupling.
• This study provides critical insights for developing topologically diverse compound libraries.
• Experimental validation confirms the impact of conformational rigidity on molecular shape.