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 in order to be effective.  In this talk, I will describe a mode of catalytic activity with chiral H-bond donors that enables enantioselective reactions of relatively unreactive electrophiles.  Chiral H-bond donors interact with simple Lewis and Bronsted acids by binding the counterion to form a complex with enhanced acidity and reactivity. For example, we have found that silyl triflate-chiral squaramide combinations promote 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 non-covalent interactions between the squaramide catalyst and the cationic intermediate.  This reactivity principle can be applied to a wide variety of S<sub>N</sub>1-like processes, including to the enantioselective construction of fully-substituted carbon stereocenters.

Chrial H-bond donor/Lewis acid cooperativity

2019 Spring National Meeting

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