Organocatalytic Highly Enantioselective Formal [1,3] Sigmatropic Rearrangement of Indole Alkyl Ethers and Mechanistic Insight

Highly enantioselective [1,3] sigmatropic rearrangement represents a grand challenge in asymmetric organocatalysis. Herein, we disclose a chiral phosphoramide (R)-NPA-Cy mediated [1,3] sigmatropic rearrangement of 2-alkoxy indoles to access a diverse array of highly enantio-enriched oxindoles. The catalyst displayed good to high chiral control (89–99% ee) while maintaining a high efficiency (up to 99% yield). More than 60 examples were demonstrated. Mechanistic and computational studies revealed that the C–O bond cleavage of indole ether substrates can generate contact ion pairs stabilized by (R)-NPA-Cy via noncovalent interactions. Different catalyst–substrate noncovalent interactions were observed in the competing transition states leading to enantiomeric oxindoles, serving as the major factor determining enantioselectivity. In addition, this reaction was applied to the total syntheses of both enantiomers of (−)- and (+)-fusaspoid A in only five steps and reassigned their rotation values, correcting the original misassignments.