Stereoselective Nondirected α-C(sp³)-H Functionalization of Oxygen Heterocycles

Area of Science:

• Organic Chemistry
• Catalysis
• Medicinal Chemistry

Background:

• Oxygen-containing heterocycles are crucial in drug discovery.
• Enantioselective synthesis of these compounds is challenging due to limitations in existing methods.
• Functionalizing C(sp³)-H bonds in saturated heterocycles offers potential but faces steric and directing group challenges.

Purpose of the Study:

• To develop novel methods for stereoselective functionalization of nondirected oxygen-containing heterocycles.
• To enable the synthesis of chiral heterocyclic drug candidates and complex carbohydrates.
• To overcome limitations in current enantioselective synthesis strategies.

Main Methods:

• Utilized hydrogen atom transfer (HAT)/nickel dual catalysis for C(sp³)-H arylation and alkenylation.
• Developed a new catalytic system for enantioselective C(sp³)-H alkylation.
• Employed experimental and density functional theory (DFT) studies to elucidate reaction mechanisms and enantioselectivity.

Main Results:

• Successfully constructed chiral oxygen heterocycles via enantioselective C(sp³)-H arylation and alkenylation.
• Achieved stereoselective construction of C(sp³)-C(sp³) bonds through enantioselective C(sp³)-H alkylation.
• Developed a versatile method for synthesizing C-glycosides and arylated quaternary stereocenters in carbohydrates.

Conclusions:

• The developed HAT/nickel dual catalysis provides a powerful platform for stereoselective C(sp³)-H functionalization of saturated oxygen heterocycles.
• This methodology significantly expands the scope of chiral heterocyclic synthesis, offering new avenues for drug discovery.
• The approach is applicable to the synthesis of natural products, pharmaceuticals, and valuable synthetic building blocks.