Synthesis of a Polymer‐Bound Galactosylamine and Its Application as an Immobilized Chiral Auxiliary in Stereoselective Syntheses of Piperidine and Amino Acid Derivatives

A 2,3,4‐tri‐ O ‐pivaloylated β‐ D ‐galactopyranosyl azide bearing a hydroxy‐functionalized spacer unit at the C‐6 position of the galactose was synthesized and immobilized on the solid phase by using a polymer‐bound chlorosilane. The azide was reduced to the corresponding galactopyranosylamine, which served as a versatile chiral auxiliary in highly diastereoselective Ugi four‐component condensation reactions at ambient temperature. Fluoride‐induced cleavage from the polymeric support furnished N ‐glycosylated N ‐acylated α ‐amino acid amides. The reaction of the immobilized galactosylamine with aldehydes gave rise to the corresponding aldimines, which underwent a domino Mannich–Michael condensation reaction with Danishefsky's diene at ambient temperature to yield 2‐substituted 5,6‐didehydropiperidin‐4‐ones on the solid phase. Subsequent cleavage with tetra‐ n ‐butylammonium fluoride delivered the N ‐glycosylated products in high yields, purities, and diastereoselectivities. A chemoselective 1,4‐hydride addition to the polymer‐bound dehydropiperidinones was achieved in the presence of the bulky oxygenophilic Lewis acid methylaluminum [bis(2,6‐di‐ tert ‐butyl‐4‐methylphenoxide)]. The conjugate addition of cyano‐modified Gilman reagents to the immobilized dehydropiperidinones furnished 2,6‐ cis ‐substituted piperidine derivatives as the major diastereomers that were isolated after cleavage from the support.