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Catalysis

Complementary cross-coupling methods offer better synthetic routes to atropisomeric biaryls

The compounds are valuable chiral ligands in asymmetric catalysis

by Tien Nguyen
March 28, 2019 | APPEARED IN VOLUME 97, ISSUE 13

 

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Two new synthetic routes can create NOBIN and BINAM compounds, which are valuable chiral ligands for asymmetric catalysis.

Reactions that let chemists selectively make one enantiomer of a molecule over another fall into a field of modern organic chemistry called asymmetric catalysis. These reactions are crucial for synthesizing pharmaceutical compounds that squeeze into specifically shaped binding pockets on proteins and other target biomolecules. To control which enantiomer is produced by these reactions, chemists rely on chiral catalysts or ligands.

Among the most relied-upon chiral ligands are atropisomeric binaphthyl compounds, molecules with two naphthalene groups stacked atop each other that swivel very slowly about a single bond. These molecules are also useful as fluorescent sensors, microporous polymers, and stationary phases in chiral separations. Two such promising compounds in this class are 2-amino-2'-hydroxy-1,1'-binaphthyl (NOBIN) and 1,1'-binaphthyl-2,2'-diamine (BINAM). But the compounds are underexplored compared with popular 1,1'-bi-2-naphthol (BINOL) compounds because they’re more expensive and have been challenging to make in a chiral way. Previous methods could synthesize them but required prefunctionalizing the starting compounds, which meant more steps to get to the final products.

Now, researchers at the Southern University of Science and Technology in Shenzhen, China, avoid prefunctionalization and report two complementary cross-coupling strategies that directly stitch together binaphthalene starting molecules to produce a range of NOBIN and BINAM compounds (Nat. Catal. 2019, DOI: 10.1038/s41929-019-0247-1). Run under mild conditions, both reactions require a Lewis acid catalyst in combination with various chiral ligands. The team used a zinc-catalyzed method to make differentially substituted NOBIN compounds and a nickel-catalyzed method to produce NOBIN and BINAM products.

This work provides the most diverse access thus far to these types of molecules, says Jeffrey L. Gustafson, an organic chemist at San Diego State University. Greater choice in chiral compounds gives chemists more freedom to tune the selectivity of their particular reaction, he says. “When you’re developing a catalyst, one or two atoms can make the difference between a good catalyst and a great catalyst.”

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