Low-cost chiral acid catalyst

A common method for making one enantiomer of a small molecule is to use a chiral Brønsted acid to guide its synthesis. But enantioselective proton-donating acids can be expensive and laborious to make. Now, Columbia University chemists Tristan H. Lambert, Chirag D. Gheewala, and Bridget E. Collins have come up with a chiral Brønsted acid that can be assembled from inexpensive starting materials (Science 2016, DOI: 10.1126/science.aad0591). The catalyst (shown) is made by first reacting dimethyl malonate and dimethylacetylene dicarboxylate to create 1,2,3,4,5-pentacarbomethoxycyclopentadiene. This aromatic pentaester is then condensed with naturally occurring (–)-menthol. The chemists calculate that it costs about $4.00 per g to make the natural enantiomer of the catalyst and $5.50 per g to make the unnatural isomer. The catalyst’s aromatic stabilization is key to its proton-donating prowess. It works well in Mukaiyama-Mannich and oxocarbenium aldol reactions with catalyst loadings as low as 0.01 mol %. The Columbia team also used 1,2,3,4,5-pentacarbomethoxycyclopentadiene to prepare alternative chiral amide catalysts.