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.