Solid-phase asymmetric synthesis using a polymer-supported chiral Evans'-type oxazolidin-2-one

This protocol describes the synthesis of (S)-4-(4-hydroxybenzyl)-oxazolidin-2-one, its attachment to a Merrifield-Cl resin and its use for asymmetric synthesis. The chiral auxiliary is prepared in four steps from N-Boc-L-tyrosine on a multigram scale in high yield and attached to Merrifield-Cl resin via its phenolic group to afford a solid-supported chiral auxiliary for asymmetric synthesis that takes ∼7 d to prepare. A procedure for its N-acylation is reported and a method for carrying out diastereoselective solid-supported Evans' syn-aldol reactions is described, with aldol products being cleaved from the polymer by either hydrolysis or reduction. The use of the supported auxiliary for two sequential 'on-bead' reactions has been demonstrated for the synthesis of a chiral cyclopropane aldol and a γ-lactone in a >95:5 diastereomeric ratio. These polymer-supported reactions are carried out in IRORI Kan resin capsules to protect the polymer support from mechanical degradation, thus allowing multiple on-bead reactions to be performed.