Access to Chiral Chromenones through Organocatalyzed Mannich/Annulation Sequence

Area of Science:

• Organic Chemistry
• Asymmetric Synthesis
• Medicinal Chemistry

Background:

• Chiral chromenones are valuable heterocyclic compounds with diverse biological activities.
• Accessing enantiomerically pure chromenones, particularly those with α-amino stereocenters, remains a synthetic challenge.

Purpose of the Study:

• To develop an efficient and practical method for synthesizing chiral chromenones containing an α-amino stereogenic center.
• To explore the utility of quinine-derived squaramide catalysts in promoting tandem reactions for chromenone synthesis.

Main Methods:

• A novel tandem reaction sequence involving Mannich reaction, cycloketalization, and dehydration was employed.
• Functionalized imines were generated *in situ* from 1-(2-hydroxyaryl)-1,3-diketones and amines.
• Quinine-derived squaramide was utilized as an organocatalyst to promote asymmetric induction.

Main Results:

• The method successfully synthesized a wide range of chiral chromenones bearing propargylamine or α-amino ester moieties.
• The reactions proceeded with good yields and high enantioselectivities, up to 98% ee.
• Fifty-four diverse examples of chiral chromenones were accessed, demonstrating the broad applicability of the method.

Conclusions:

• The reported method provides an efficient and practical route to enantiomerically enriched α-amino chromenones.
• The use of quinine-derived squaramide organocatalyst is effective for promoting the cascade reaction and achieving high stereocontrol.
• This approach offers a valuable tool for the synthesis of complex chiral molecules with potential pharmaceutical applications.