Palladium-Catalyzed Enantioselective Cycloadditions of Aliphatic 1,4-Dipoles: Access to Chiral Cyclohexanes and Spiro [2.4] heptanes

Design and exploration of new intermediates
for chemo-, regio-,
and stereoselective cycloadditions remain a formidable challenge in
modern organic synthesis. Compared to the well-developed 1,3-dipolar
cycloadditions, Pd-catalyzed1,4-dipolar cycloadditions are generally
limited to specialized substrates due to the inherent nature of the
thermodynamically driven intramolecular transformations and undesired
isomerizations. Herein, we demonstrate the use of ligated palladium
catalysts to control and modulate the intermolecular reactivity of
aliphatic 1,4-dipoles, enabling two distinctive cycloaddition pathways
with a broad scope of acceptors. This atom-economic process also features
an eco-friendly in situ deprotonation strategy to
generate the corresponding active palladium-mediated dipoles. Overall,
a diverse array of chiral 6-membered rings and spiro [2.4] heptanes
were prepared in high yield and selectivity. In addition, an unexpected
property of cyano-stabilized carbanions was discovered and investigated,
which can be useful in designing and predicting future transformations.