Cis-Selective Double Spirocyclization via Dearomatization and Isomerization under Thermodynamic Control.

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Synthetic Chemistry

Background:

• Spiro compounds are crucial scaffolds in pharmaceutical research.
• Existing synthetic methods for dispirocycles are limited compared to monospirocycles.

Purpose of the Study:

• To develop a novel, highly cis-selective synthetic method for 5/6/5-dispirocyclic structures.
• To explore the synthesis of substituted pyrrolidine and gamma-lactam containing dispirocycles.

Main Methods:

• Utilized a series of N-arylpropiolamides as starting materials.
• Employed a reaction pathway leading to cis-selective dispirocycle formation.
• Investigated thermodynamic control and diastereomeric equilibrium.

Main Results:

• Achieved a highly cis-selective synthesis of 5/6/5-dispirocyclic compounds.
• Successfully incorporated various substituents into the pyrrolidine and gamma-lactam rings.
• Demonstrated that cis- and trans-diastereomers are in equilibrium, favoring cis-adducts.

Conclusions:

• The developed method provides efficient access to complex cis-dispirocyclic scaffolds.
• The high cis-selectivity is attributed to thermodynamic control via isomerization.
• These findings offer valuable synthetic strategies for pharmaceutical applications.