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Abstract

This work describes the development of deracemization methodologies towards the synthesis of cyclobutenes by combining the efficiency of highly efficient photochemical reactions with the powerful selectivity that can be imparted by transition metal catalysis. An atom-economical stereoselective synthesis of cis-disubstituted cyclobutenes through palladium-catalyzed allylic alkylation is presented, using stabilized nucleophiles such as malonates and azlactones. The synthetic value of the products obtained was illustrated by their conversion into highly substituted cyclobutene and cyclobutane rings, in a short sequence from commercially available 2-pyrone. A new methodology providing easy access to 3-substituted 2-pyrones based on Suzuki cross-couplings is presented. Another part of this work describes a deracemization strategy through the employment of palladium in combination with a TADDOL-derived phosphoramidite, allowing access to highly enantioenriched cis-cyclobutenes. Rational design based on a serendipitous observation led to a highly selective synthesis of trans-cyclobutenes, simply by changing the ligand employed. A diastereodivergent deracemization was developed, through which the reaction can be tuned to generate cis- or trans-cyclobutenes. In the last part, a hitherto unknown highly selective diastereodivergent de-epimerization to afford either cis- or trans-cyclobutenes is described. This method hinges on the symmetry of a common intermediate formed from the four possible stereoisomers of the substrate. The experiments performed showcased the importance of the presence of the carboxylate group and the mechanistic rationale is presented and discussed.