Highly Selective and Modular Assembly of Densely Substituted Tetrahydrofurans

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Catalysis

Background:

• Densely substituted heterocycles, particularly sp3-heterocycles with multiple vicinal stereocenters, are crucial in natural products and pharmaceuticals.
• Multisubstituted tetrahydrofurans (THFs) are privileged structural motifs, but their synthesis is often step-intensive and lacks generalized, robust methods for precise stereocontrol.
• Existing methods for THF synthesis are frequently target-specific and underdeveloped for rapid, stereoselective introduction of multiple substituents from simple precursors.

Purpose of the Study:

• To develop a novel, generalized, and robust synthetic methodology for constructing multisubstituted tetrahydrofurans (THFs) with high stereochemical control.
• To enable modular assembly of THFs from abundant building blocks, facilitating rapid access to diverse and complex structures.
• To achieve precise chemo-, regio-, diastereo-, and enantioselectivity in THF synthesis.

Main Methods:

• Synergistic metallaphotoredox-Lewis acid catalysis was employed to construct four bonds in THF derivatives.
• The methodology facilitates modular assembly from readily available precursors.
• Experimental and computational studies were conducted to elucidate the reaction mechanism.

Main Results:

• A distinct approach was developed for the synthesis of tetrahydrofurans (THFs) bearing up to four stereocenters.
• The method demonstrates precise chemo-, regio-, diastereo-, and enantioselectivity.
• High-throughput experimentation (HTE) was utilized to showcase the potential for generating diverse THF-based libraries.

Conclusions:

• The presented synergistic metallaphotoredox-Lewis acid catalysis provides an efficient and versatile strategy for constructing complex, stereochemically rich tetrahydrofurans (THFs).
• This methodology overcomes limitations of existing synthetic routes, offering modularity and high selectivity.
• The developed approach holds significant promise for accelerating drug discovery and development through rapid library generation.