HALOBORYLATION · Electrophilic-induced asymmetric boronate rearrangements via CAPT catalysis. A novel approach towards the formal trifunctionalization of alkenes.

Electrophilic-induced asymmetric boronate rearrangements via CAPT catalysis. A novel approach towards the formal trifunctionalization of alkenes.

The significance of enantiomerically pure compounds in the pharmaceutical industry–around 50% of the marketed drugs possess at least one stereocenter-has motivated vast scientific efforts towards the development of stereoselective methodologies for their preparation, especially after FDA’s policy for the development of stereoisomeric drugs in 1992. This paradigmatic shift from racemates to single-enantiomer drugs has brought asymmetric synthesis into the mainstream of the drug discovery process. The handedness associated with organizing the transition state in a catalytic process, such that only a single enantiomer of a chiral product is produced, is the key to asymmetric catalysis. Since the first reports from Knowles in the 60s, chemists have made significant inroads in the synthesis of optically active molecules using synthetic chiral catalysts. The success of asymmetric catalysis can largely be attributed to the development of structurally diverse catalysts with tunable stereoelectronic properties, as well as the discovery of distinct activation modes for harnessing multiple functionalities. Nevertheless, genuine de novo design of catalysts for novel asymmetric transformations is not commonplace. The overarching goal of our research stands on the establishment of new foundations for novel constructions and mode of operation of chiral catalysts, which have the potential to make the chemical community think in a different light, opening up a previously inaccessible reaction space to build enantioenriched molecules. In this regard, enzymatic catalysis in Nature represents a paragon of what we strive to achieve as synthetic chemists, comprising the factors of substrate organization and activation, transition state stabilization and product release all in one highly efficient package. Despite this, the vast majority of synthetic catalysts behave as stereochemically rigid scaffolds, ignoring the evidence of other models presented to us by the natural world; the reorganization event, whereby the enzyme and the ligand mold together via mutual induced-fit shifting of their conformational ensemble has been largely overlooked. We have found evidence of an analogous induced-fit mechanism in a double axially chiral phosphoric acid that adapts its conformation, akin to the active pocket of an enzyme, to catalyze the first highly enantioselective allenoate-Claisen rearrangement.

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