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Synthesis

Chemists Devise Kilogram-Scale Route To Chiral Lactone Building Block

Four-step synthesis and chiral resolution of Taniguchi lactone requires no chromatography

by Carmen Drahl
May 12, 2014 | APPEARED IN VOLUME 92, ISSUE 19

Don’t be fooled by the Taniguchi lactone’s small structure—it’s been a starting point in some big syntheses, including the first stereoselective assembly of quinine. Chemists have a handful of ways of making the lactone. But those routes didn’t work at the kilogram scale required by Fredrik von Kieseritzky of Swedish organic electronics firm Arubedo; Yeliu Wang of contract research organization Beijing Honghui Meditech, in China; and Magnus Axelson of Sweden’s Karolinska University. So the trio took matters into their own hands. Their four-step synthesis and chiral resolution method is capable of producing kilogram quantities of a single enantiomer of the Taniguchi lactone without any chromatography, which saves time, solvent, and money (Org. Process Res. Dev. 2014, DOI: 10.1021/op500096j). After assembling the racemic lactone, the team developed a process to obtain the single enantiomer. They first opened the ring with (S)-1-benzylmethylamine and a titanium dehydrating agent. Those conditions hadn’t been used before, but they successfully obtained a mixture of ring-opened products. Then they isolated the needed intermediate by crystallization. Finally, they chose acidic hydrolysis to re-form the (S)-Taniguchi lactone. Chemists typically conduct that step under basic conditions, which aren’t amenable to kilogram scales, the researchers note. They add that the titanium-mediated step is likely to work for other lactones.

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