Highly Efficient and Enantioselective Iridium-Catalyzed Asymmetric Reductive Cycloetherification.

Area of Science:

• Organic Chemistry
• Catalysis
• Asymmetric Synthesis

Background:

• Tetrahydrofurans (THFs) and tetrahydropyrans (THPs) are prevalent structural motifs in natural products and pharmaceuticals.
• Efficient and enantioselective methods for synthesizing substituted THFs and THPs are highly sought after in synthetic chemistry.

Purpose of the Study:

• To develop a novel iridium-catalyzed asymmetric hydrogenation (AH) protocol for the synthesis of enantioenriched aliphatic THFs and THPs.
• To explore the application of dynamic kinetic resolution asymmetric hydrogenation (DKR-AH) for constructing THP scaffolds with multiple stereocenters.

Main Methods:

• Iridium-catalyzed asymmetric hydrogenation (AH) of γ- and δ-hydroxy ketones.
• Dynamic kinetic resolution asymmetric hydrogenation (DKR-AH) for constructing THP scaffolds.
• Mechanistic studies to elucidate the reaction pathway involving cyclic, aliphatic oxocarbenium ions.

Main Results:

• High yields and excellent enantioselectivities (up to 99% ee) were achieved for various enantioenriched THFs and THPs.
• Successful implementation of DKR-AH yielded enantioenriched THP scaffolds with two contiguous stereocenters (up to 92% yield, 98.5:1.5 er, >20:1 dr).
• Gram-scale synthesis demonstrated the practicality of the catalytic enantioselective approach.

Conclusions:

• The developed catalytic protocol provides rapid access to diverse enantioenriched THFs and THPs.
• The methodology is effective for synthesizing complex cyclic ethers, serving as valuable building blocks for natural products and bioactive molecules.
• The study highlights the key role of AH in the challenging transformation of cyclic, aliphatic oxocarbenium ions.