Substrate-controlled switchable asymmetric annulations to access polyheterocyclic skeletons

Area of Science:

• Organic Chemistry
• Catalysis
• Asymmetric Synthesis

Background:

• Morita-Baylis-Hillman (MBH) carbonates are versatile synthons.
• Isatins are privileged heterocyclic scaffolds in medicinal chemistry.
• Developing efficient catalytic methods for complex molecule synthesis is crucial.

Purpose of the Study:

• To disclose a novel domino process for synthesizing tetrahydrofuro[2',3':4,5]pyrano[2,3-b]indoles.
• To investigate the switchable annulation reactions leading to spirooxindoles.
• To elucidate the reaction mechanisms using computational methods.

Main Methods:

• Asymmetric catalysis using cinchona-derived tertiary amines.
• Reactions involving MBH carbonates of isatins with acrylates and α-cyano-α,β-unsaturated ketones.
• Density functional theory (DFT) calculations for mechanistic studies.

Main Results:

• A domino process was discovered, yielding highly enantioenriched tetrahydrofuro[2',3':4,5]pyrano[2,3-b]indoles.
• Switchable [3+2] annulations were achieved, producing spirooxindoles with a cyclopentene motif.
• DFT calculations provided insights into the reaction pathways and selectivity.

Conclusions:

• A novel, enantioselective domino cascade reaction for complex indole derivatives was developed.
• The catalytic system demonstrates tunable reactivity, enabling access to different molecular architectures.
• Mechanistic understanding facilitates the design of new synthetic strategies.