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Powerful pairing spurs Lewis acids into action

Chiral squaramide and triflate combine to make an enhanced noncovalent catalyst

by Bethany Halford
November 13, 2017 | A version of this story appeared in Volume 95, Issue 45

An example of an enatioselective [4 + 3] cycloaddition in which a chiral squaramide-triflate pair creates a strong Lewis acid catalyst.

Noncovalent catalysts that feature dual hydrogen bonds have been used in a variety of enantioselective reactions by directly activating substrate molecules. But they typically require highly reactive electrophilic substrates to work well. Harvard University chemists Eric N. Jacobsen, Steven M. Banik, Anna Levina, and Alan M. Hyde wondered if they could overcome this obstacle by using a dual-hydrogen-bonding catalyst indirectly. They pair squaramides capable of forming two hydrogen bonds with triflate anions to create an enhanced Lewis acid (Science 2017, DOI: 10.1126/science.aao5894). This combination leads to the formation of oxocarbenium ion intermediates from acetals at low temperatures. The chemists use the noncovalent catalyst in enantioselective Mukaiyama aldol reactions as well as [4 + 3] cycloadditions (example shown). “The use of hydrogen-bond donors should no longer be restricted to conventional catalytic methods reliant on the direct activation of substrates,” writes Anita E. Mattson, an expert on noncovalent catalysis at Worcester Polytechnic Institute, in a commentary that accompanies the paper. “Instead, the future of hydrogen-bond-donor catalysis should include exploitation of hydrogen bonding and anion recognition in the production of new catalytic species to enable reactivity patterns that are otherwise inaccessible.”


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