Dearomative Indole (3 + 2) Cycloaddition Reactions

A diastereoselective
(3 + 2) dearomative annulation of 3-substituted
indoles with α-haloketones has been developed. Significant regiochemical
control was observed. This methodology provides easy access to highly
functionalized cyclopenta- or cyclohexa-fused indoline compounds,
which are common structures of many natural products. The synthetic
potential of this reaction was demonstrated in the concise syntheses
of the core structures of vincorine, isocorymine, and aspidophylline
A. DFT studies (B3LYP-D3/6-311++G**/MeOH) on cyclization mechanisms
involving the 2-hydroxyallyl cation and its deprotonated oxyallyl
cation have been performed. Under the reaction conditions, with a
sparingly soluble Na2CO3 base, both species
may be present and both pathways are viable. Both pathways support
the formation of the experimentally observed O-bound
intermediate, its transformation to the final product, the regiochemical
and eventual stereochemical outcome of the kinetic cyclization product,
and the thermodynamic preference for formation of the final stereoisomer.