Asymmetric Synthesis of Salicylaldehyde Equivalents to Generate Molecular Complexity

I. Enantioselective Hydrophosphonylation of Salicylaldehydes Catalyzed by Copper(II) Bis(oxazoline) Complexes Enantioselective Pudovik reactions of salicylaldehydes catalyzed by copper(II) bis(oxazoline) are disclosed. The bifunctional catalyst serves a dual role of activation of the salicylaldehyde for nucleophilic addition and generation of a reactive P(III) phosphite species. Mechanistic experiments indicate that pathways involving substrate inhibition of the catalyst are operative in this transformation, providing an explanation for substrate-dependent sluggish reaction turnover. II. A Site-Specific Synthetic Route to Substituted Inda(box) Ligands and Application to the Asymmetric Pudovik Reaction of Salicylaldehydes Aminoindanol-derived bis(oxazoline) ligands are widely used in metal-catalyzed transformations, but the synthesis of structural derivatives is challenging. The gram-scale, seven-step synthesis of five bromine-functionalized inda(box) ligands that have varied bridge substituents is presented. The bromoinda(box) ligands undergo late-stage modification via Pd-catalyzed cross-couplings, which allows for the synthesis of 12 unique inda(box) ligands. This improved regioselective synthetic route could enable the discovery of new asymmetric metal-catalyzed transformations through modification of the inda(box) ligand architecture. III. Asymmetric Dearomatization of Salicylaldehydes Enabled by Chirality Transfer via an Oxidation State Protecting Group We report progress toward a new process for the enantioselective dearomatization of salicylaldehydes via a novel reaction platform. Salicylaldehydes were first converted to alpha-hydroxyphosphonates using a Pudovik reaction. The salicyl hydroxyphosphonates readily undergo a dearomative epoxidation reaction with excellent diastereoselectivity to generate phosphono-spiroepoxydienones. The highly reactive dienones are competent dienes and engage a survey of dienophiles in Diels-Alder cycloadditions. Work continues to demonstrate reductive openings of the cycloadducts to reveal the parent aldehyde. The short sequence of steps constitutes a new manifold for salicylaldehyde dearomatization and may be useful for the total synthesis of tetrodotoxin.