The ability of supramolecular hosts to exert simultaneous control over multiple stereocenters renders them not only synthetically valuable, but worthy targets for mechanistic analysis to rationalize microenvironment selectivity.1 Supramolecular host 1 is characterized by a hydrophobic interior and a highly charged, dodecanionic framework. This structure stabilizes cationic intermediates, enabling efficient acid catalysis within its core. The ability of host 1 to stabilize iminium ions motivated us to develop a 1-catalyzed aza-Darzens condensation to generate substituted aziridines.2 Host 1 provides high trans selectivity while the background process provides the cis diastereomer in poor yields, indicating the host overrides the intrinsic diastereoselectivity of the reaction. Subjecting enantiopure host 2, which self-assembles as a single diastereomer, to the aza-Darzens conditions gave excellent enantioselectivity and reactivity. Inspired by this result we developed a library of nine new enantiopure supramolecular hosts via substitution of the external chiral amide, in order to gain a better understanding on the role of this auxiliary on active site speciation. Subjecting these new hosts to the reaction conditions provided disparate reactivity and enantioselectivity across the catalyst series. Further investigation of this effect revealed that differing host encapsulation dynamics plays a role in reaction selectivity, with the most flexible hosts being the most enantioselective catalysts for the transformation.

Development of a library of enantiopure nano-vessels for asymmetric catalysis

ACS Spring 2022

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