Development of Immobilized SPINOL-Derived Chiral Phosphoric Acids for Catalytic Continuous Flow Processes. Use in the Catalytic Desymmetrization of 3,3-Disubstituted Oxetanes

A family of C₂-symmetrical 1,1′-spirobiindane-7,7′-diol (SPINOL) derivatives containing polymerizable styryl units has been prepared through a highly convergent approach. Radical copolymerization of these monomers with styrene has allowed the synthesis of a family of immobilized SPINOL-derived chiral phosphoric acids (SPAs) where the combination of the restricted axial flexibility of the SPINOL units and the existence of extended and adaptable chiral walls adjacent to them leads to enhanced stereocontrol in catalytic processes. The optimal immobilized species (Cat f) brings about the catalytic desymmetrization of 3,3-disubstituted oxetanes in up to 90% yield with up to >99% enantioselectivity, exhibiting a very high recyclability (no decrease in conversion or enantioselectivity after 16, 16-h runs). To exploit these characteristics, a continuous flow process has been implemented and operated for the sequential preparation of 17 diverse enantioenriched products. The suitability of the flow setup for gram scale preparations (20 mmol scale), the stability of Cat f for long periods of time with intermittent use in flow, and its deactivation/reactivation by treatment with pyridine/hydrochloric acid in dioxane have been demonstrated. Density functional theory has been employed to provide a rational justification of the deep effect on enantioselectivity arising from the presence of sterically bulky substituents at the 6,6′-positions of the SPINOL unit. The main structural features of Cat f have subsequently been incorporated to the design of a simplified homogeneous analog available in a straightforward manner (Cat g) that performs the benchmark desymmetrization reaction with similar yields and enantioselectivities as Cat f, providing a convenient alternative for cases when single use in solution is sought.