The oxadi-π-methane rearrangement of 2,4-cyclohexadienones
to bicyclic ketones was found to proceed with high enantioselectivity
(92–97% ee) in the presence of catalytic amounts
of a chiral Lewis acid (15 examples, 52–80% yield). A notable
feature of the transformation is the fact that it proceeds on the
singlet hypersurface and that no triplet intermediates are involved.
Rapid racemic background reactions were therefore avoided, and the
catalyst loading could be kept low (10 mol %). Computational studies
suggest that the enantioselectivity is determined within a Lewis acid
bound singlet intermediate via a conical intersection. The utility
of the method was demonstrated by a concise synthesis of the natural
product trans-chrysanthemic acid.
α‐Trifluoromethyl azocanes are accessible from 2‐(trifluoropropan‐2‐ol) piperidines by metal‐free ring‐expansion involving a bicyclic azetidinium intermediate. The opening of the azetidinium intermediate was achieved by various nucleophiles (amines, alcoholates, carboxylates, phosphonates, halides and pseudo‐halides) with an excellent regio‐ diastereo‐ and enantioselectivity and in good yields. The relative configuration of the piperidines and azocanes were assigned and the deprotected azocanes offer opportunities for further derivatization.
A strong enantiodivergence ranging from +92% ee to −45%
ee was observed in the oxadi-π-methane rearrangement of 2,4-cyclohexadienones.
Oxazaborolidine-based Lewis acid catalysts of the same absolute configuration
were applied in all cases, and the stereochemical outcome is solely
a function of the oxazaborolidine substituents. Based on the results
of an extended catalyst library screening (27 examples) and by interrogating
plausible catalyst–substrate complexes in the ground state
with density functional theory (DFT) methods, we could link the switch
in enantioselectivity to a change in substrate binding. If the typical
substrate binding at the convex catalyst side is inhibited by bulky
substituents, our results indicate that substrates instead bind to
the concave side, and enantiomeric products result. Studies by TDDFT
in the S1 excited state further clarified the mechanistic
picture by connecting efficient product formation with trajectories
that reach a conical intersection with more excess energy. Our analysis
was validated by the stereochemical outcome achieved with five structurally
different catalysts.
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