Highly Diastereoselective Hydroxy-Aza-Prins Cyclization: Rapid Access to 4′-Hydroxy Six-Membered Spiro Azacyclic Oxindoles

A highly diastereoselective nucleophilic addition of hydroxy-aza-Prins cyclization through umpolung allylation of <i>N</i>-2,2,2-trifluoroethylisatin ketimines is described. This novel synthetic approach controls the stereocenter at the C4' position of 4'-hydroxy six-membered spiro azacyclic oxindoles based on the presence or absence of hydrogen bonding interactions with nucleophiles. The reactions, involving palladium-catalyzed Tsuji-Trost umpolung allylation and aza-Prins cyclization, proceed smoothly with allyl acetate in the presence of Pd(PPh₃)₄, DBU, H₂O, and TMSOTf. This one-pot protocol produces selective axial-4'-hydroxy six-membered spiro azacyclic oxindoles in excellent yields. In contrast, using the acetoxy group as a nucleophile in acetoxy-aza-Prins cyclization enables the synthesis of selective equatorial-4'-acetoxy six-membered spiro azacyclic oxindoles.