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.