Chiral ligands are important in asymmetric catalysis. ^pivZPhos (pictured above on the right), for example, can be used as a P-chiral ligand in copper-catalyzed asymmetric hydrogenations or aminoborations. It is generally prepared from a dihydrobenzoazaphosphole precursor (pictured above on the left). This precursor is usually obtained using chiral column separation, which is a variant of column chromatography with a chiral stationary phase. This process is often expensive and time-consuming and can be challenging to scale up.

Yongda Zhang, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA, and colleagues have developed a more practical synthesis of this P-chiral dihydrobenzoazaphosphole precursor. The team used a chiral chemical resolution step with (1S,2S)-diaminocyclohexane as the resolution reagent (instead of the usual chiral column separation) to resolve a racemic mixture of the desired precursor. They combined the precursor with (1S,2S)-diaminocyclohexane in acetonitrile to obtain a solid adduct of the desired enantiomer with the diaminocyclohexane. The solid provides an enantiomeric ratio of about 94:6.

After further optimization of the stoichiometry and the reaction time, the researchers achieved enantiomeric ratios of over 99:1 and yields of 68–70 %. When the solid was treated with HCl in water, the desired precursor was released. It can be converted to ^pivZPhos in three steps. According to the researchers, the developed approach could allow for the production of the ligand precursor on a large scale.

• A Practical Method for the Large-Scale Preparation of the P-Chiral Dihydrobenzoazaphosphole Core by Chemical Resolution,
  Jean-Nicolas Desrosiers, Yibo Xu, Stephanie C. Kosnik, Bo Qu, Kendricks S. Lao, Chris H. Senanayake, Yongda Zhang,
  J. Org. Chem. 2022.
  https://doi.org/10.1021/acs.joc.2c00495