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Reduction carves path to chiral compounds

Asymmetrical Zn is key to compounds with 4 different carbon groups

by Leigh Krietsch Boerner
June 13, 2021 | A version of this story appeared in Volume 99, Issue 22


A zinc catalyst can convert malonic esters to chiral compounds with four different carbon substituents.

Many pharmaceuticals need to be a certain shape to fit into the binding pocket of the enzyme they target. Synthesizing molecules with the desired chirality requires controlled addition of functional groups, which is challenging. Now Pengwei Xu and Zhongxing Huang from the University of Hong Kong have made this process a little easier. They found a way to transform malonic esters into chiral compounds with four different carbon substituents (Nat. Chem. 2021, DOI: 10.1038/s41557-021-00715-0). The chemists created six classes of molecules containing a variety of functional groups, which wasn’t possible with prior methods.

Previously, researchers used pig liver esterases to transform malonic esters into chiral compounds. But these enzymes don’t work well when the esters have bulky side groups or multiple side groups similar in size, which limits the enzymes’ utility. The team used cheap starting materials to make a library of malonic esters of different sizes. The researchers used tetradentate prolinol ligands and a dinuclear diethylzinc catalyst to reduce one ester group to make over 70 compounds. These include amino and hydroxyl esters, alcohols, and diols, all in moderate to good yields and as high as 98% enantioselectivity. This catalyst works in the presence of multiple functional groups, including amines, olefins, and thioethers, Huang says.

The diethylzinc catalyst spontaneously ignites in air, but Huang says the team is researching alternatives. This tool will allow researchers to make a wider variety of complex natural products more easily and is a good companion to the existing enzyme method, Huang says.



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