Enantioselective Radical Cascade Cyclization to Axially Chiral Medium-Sized Lactones

Area of Science:

• Organic Chemistry
• Catalysis
• Stereoselective Synthesis

Background:

• Conventional methods for synthesizing axially chiral medium-sized lactones often require strict reaction conditions and prefunctionalized substrates.
• Radical chemistry offers an alternative but achieving high enantioselectivity remains challenging.

Purpose of the Study:

• To develop a synergistic photoredox/copper-catalyzed radical cascade cyclization for the enantioselective synthesis of axially chiral medium-sized lactones.
• To utilize alkyl halides as radical precursors for a more versatile synthetic strategy.

Main Methods:

• Employing a photoredox catalyst and a chiral copper complex for a synergistic catalytic system.
• Generating radicals from alkyl halides via single electron transfer (SET) initiated by photoredox catalysis.
• Facilitating radical addition to non-polarized alkenes followed by intramolecular C-O bond formation.

Main Results:

• Achieved high yields (up to 83%) and excellent enantioselectivity (up to 96% e.e.) with high diastereomeric ratios (>20:1 d.r.).
• Demonstrated synthetic utility through late-stage diversification of bioactive molecules.
• Theoretical calculations identified C-O bond formation as the stereodetermining step.

Conclusions:

• The developed method provides an efficient and stereoselective route to axially chiral medium-sized lactones.
• The strategy overcomes limitations of traditional ionic pathways by using readily available alkyl halides.
• A central-to-axial chirality relay mechanism governs the stability of the chiral scaffold.