Lewis acid enhancement by hydrogen-bond donors for asymmetric catalysis

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Science  10 Nov 2017:
Vol. 358, Issue 6364, pp. 761-764
DOI: 10.1126/science.aao5894

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Lewis acid catalysis tackled by tag team

Molecular catalysts with two closely spaced nitrogen-hydrogen groups can act like a tweezer, activating a carbon center by latching onto a leaving group through double hydrogen bonding and then pulling it away. In the resultant ion pair, the shape of the catalyst can bias an ensuing reaction to favor just one of two possible mirror-image products. Banik et al. used this motif to activate a Lewis acid cocatalyst, pulling a leaving group off silicon instead of carbon (see the Perspective by Mattson). The combined pair of catalysts is more effective for reactions such as asymmetric cycloadditions that involve weaker leaving groups on carbon.

Science, this issue p. 761; see also p. 720


Small-molecule dual hydrogen-bond (H-bond) donors such as ureas, thioureas, squaramides, and guanidinium ions enjoy widespread use as effective catalysts for promoting a variety of enantioselective reactions. However, these catalysts are only weakly acidic and therefore require highly reactive electrophilic substrates to be effective. We introduce here a mode of catalytic activity with chiral H-bond donors that enables enantioselective reactions of relatively unreactive electrophiles. Squaramides are shown to interact with silyl triflates by binding the triflate counterion to form a stable, yet highly Lewis acidic, complex. The silyl triflate-chiral squaramide combination promotes the generation of oxocarbenium intermediates from acetal substrates at low temperatures. Enantioselectivity in nucleophile additions to the cationic intermediates is then controlled through a network of noncovalent interactions between the squaramide catalyst and the oxocarbenium triflate.

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