Dearomative Spirocyclization of Tryptamine-Derived Isocyanides via Iron-Catalyzed Carbene Transfer

Area of Science:

• Organic Chemistry
• Catalysis
• Synthetic Methodology

Background:

• Tryptamine-derived isocyanides are key precursors for synthesizing spirocyclic indolenines and indolines.
• Dearomatization of the indole moiety is a crucial step in constructing these complex molecular architectures.
• Efficient catalytic methods are needed for the construction of these valuable heterocyclic compounds.

Purpose of the Study:

• To develop a novel iron-catalyzed method for carbene transfer and spirocyclization.
• To utilize tryptamine-derived isocyanides and α-diazo esters for constructing spirocyclic indolenines and indolines.
• To demonstrate the utility of this cascade reaction in the synthesis of complex natural products.

Main Methods:

• Employing tetrabutylammonium iron carbonyl nitrosyl (Bu₄N[Fe(CO)₃NO]) as a catalyst.
• Utilizing α-diazo esters as carbene precursors for transfer reactions.
• Reacting with 3-(2-isocyanoethyl)indoles to form ketenimine intermediates.
• Inducing spontaneous dearomative spirocyclization of the intermediates.

Main Results:

• Successful iron-catalyzed carbene transfer from α-diazo esters to 3-(2-isocyanoethyl)indoles.
• Formation of ketenimine intermediates that readily undergo spirocyclization.
• Efficient synthesis of spirocyclic indolenine and indoline scaffolds.
• Demonstrated application in the formal total synthesis of four monoterpenoid indole alkaloids.

Conclusions:

• The reported iron-catalyzed cascade reaction provides a powerful and efficient strategy for synthesizing spirocyclic indolenines and indolines.
• This methodology offers a valuable tool for accessing complex indole alkaloid natural products.
• The study highlights the potential of iron catalysis in dearomatization reactions and complex molecule synthesis.