Building Three-Dimensional Complexity by Intramolecular 2-Aminoallyl Cation-Diene (4+3) Cycloaddition

Area of Science:

• Organic Chemistry
• Catalysis
• Medicinal Chemistry

Background:

• High demand for C(sp3)-rich three-dimensional polycycles in organic synthesis and medicinal chemistry.
• Existing synthetic methods are limited for constructing diverse cycloheptanoid-containing polycyclic scaffolds.
• Need for a catalytic platform to access these valuable molecular architectures.

Purpose of the Study:

• To develop a novel catalytic method for constructing cycloheptanoid-containing polycyclic scaffolds.
• To establish a versatile platform for synthesizing functionalized polycycles relevant to bioactive molecules.
• To demonstrate the synthetic utility through total synthesis of natural products.

Main Methods:

• Copper-catalyzed intramolecular 2-aminoallyl cation-diene (4+3) cycloaddition reactions.
• Utilized 1,3-diene-tethered ethynyl methylene cyclic carbamates as substrates.
• Mechanistic studies to elucidate the reaction pathway and selectivity.

Main Results:

• Successfully constructed diverse cycloheptanoid-containing polycyclic scaffolds.
• The resulting products were highly functionalized and amenable to further chemical transformations.
• Demonstrated synthetic utility via total synthesis of natural products (±)-mint ketone and (±)-aphanamol I.

Conclusions:

• The developed copper-catalyzed (4+3) cycloaddition provides an efficient and versatile route to complex polycyclic structures.
• The method offers access to scaffolds found in numerous bioactive natural products.
• Mechanistic studies confirmed a concerted [4π+2π] cycloaddition mechanism, favoring an endo-selective pathway.