Methylene activation reached new heights
Technique that enantioselectively derivatizes targeted C–H bonds could have widespread applications
An organic synthesis method that took flight this year could prove to have an unusually wide wingspan. Developed by Jin-Quan Yu and coworkers at Scripps Research Institute California after a 14-year effort, the reaction advances a long-standing goal: activating specific C–H bonds in organic compounds and converting them catalytically and enantioselectively into C–C bonds or other derivatives.
Since there’s no shortage of C–H bonds in organic compounds, the technique has lots of potential for widespread applicability. Specifically, the new reaction uses a palladium catalyst and quinoline-based ligand to convert β-methylenes—CH2 groups two carbon atoms away from amides or carboxylic acids—into chiral centers (Science2016, DOI: 10.1126/science.aaf4434).
Synthetic organic chemists had previously developed ways to activate several types of C–H bonds, such as by preinstalling activating groups in substrates. But the ability to target C–H bonds of unactivated methylene groups and then derivatize them catalytically and enantioselectively had been largely unsolved.
“Yu’s trailblazing group has managed to bring to reality what might have been considered seemingly impossible,” commented Erick M. Carreira, an expert on asymmetric synthesis at the Swiss Federal Institute of Technology (ETH), Zurich.
Since the paper came out, Yu and his coworkers have been developing their approach further by extending it to create chiral centers near other functional groups, such as alkyl amines. A number of applications for the β-methylene reaction have already been identified at Bristol-Myers Squibb and another pharmaceutical company, “but optimization is needed to improve the yield for the complex substrates at hand,” Yu says. “We are negotiating to license this technology to a chemical development company.”