Chromium-Catalyzed Stereodivergent Carbonyl Addition Dictated by Non-Covalent Interactions

Area of Science:

• Organic Chemistry
• Catalysis
• Drug Discovery

Background:

• Stereodivergent synthesis is crucial for drug discovery, aiming to produce all stereoisomers from a single precursor.
• Controlling stereochemistry in radical reactions is challenging due to unstable intermediates.
• Chiral beta-fluoro alcohols are important building blocks in medicinal chemistry.

Purpose of the Study:

• To develop a unified chromium-catalyzed platform for stereodivergent synthesis of chiral beta-fluoro alcohols.
• To demonstrate ligand-controlled stereoselectivity via a radical-polar crossover mechanism.
• To enable the synthesis of all four stereoisomers of fluorosugar derivatives.

Main Methods:

• Utilizing a chromium-catalyzed radical-polar crossover mechanism.
• Employing distinct ancillary ligands (chiral bisoxazoline and pyridine-imidazoline) to control stereochemical outcomes.
• Investigating non-covalent interactions (hydrogen bonding, pi-pi stacking) that dictate selectivity.

Main Results:

• Achieved fully ligand-controlled stereodivergent synthesis of chiral beta-fluoro alcohols.
• Demonstrated that ancillary ligands, not substrates, dictate stereochemistry.
• Chiral bisoxazoline ligand favored syn-diastereomers via hydrogen bonding; pyridine-imidazoline ligand favored anti-isomers via pi-pi stacking.
• Successfully synthesized all four stereoisomers of fluorosugar derivatives.

Conclusions:

• The developed chromium-catalyzed platform offers a versatile approach to stereodivergent synthesis.
• Ligand design is key to controlling stereochemistry in radical-based reactions.
• This method provides programmable access to diverse stereoisomers for pharmaceutical applications.