PyBox ligands, as a significant class of chiral ligands, are characterized by a pyridine ring flanked by two oxazoline groups. First successfully synthesized by Nishiyama in 1989, this class of ligands has demonstrated broad application potential in the field of asymmetric catalysis. To date, PyBox ligands have been extensively employed in diverse catalytic reaction systems, encompassing cyclopropanation, Aldol reactions, Diels-Alder reactions, Friedel-Crafts reactions, Mannich reactions, Michael reactions, Strecker reactions, redox reactions, cycloadditions, cross-coupling reactions, and propargylic substitutions. Recently, the team of Christopher Uyeda at Purdue University achieved precise control over the E/Z geometric configuration of achiral alkene products via a cobalt-catalyzed reductive coupling reaction between 1,1-dichloroethylene and chiral secondary allylic alcohols. The reaction mechanism proceeds as follows: a PyBox-ligand-modified cobalt catalyst initially governs the face-selective addition to the allylic alcohol, followed by a trans-selective β-hydroxy elimination that ultimately determines the E/Z configuration of the alkene product. Notably, utilizing a pair of PyBox ligand enantiomers enables highly selective synthesis of E- and Z-configured alkenes, respectively.

The application of PyBox ligands in this reaction exhibits the following highlights:

: The chirality of PyBox ligands is switchable. (S,S)-L1 affords a product E/Z ratio of 13:1, while (R,R)-L1 inverts the ratio to 1:13. This enables stereodivergent synthesis without altering reaction conditions, establishing the ligand as the core determinant of E/Z selectivity.

: Through tridentate coordination to the cobalt center via pyridine and bis-oxazoline groups, ligand dissociation is prevented, ensuring the integrity of the multi-step catalytic cycle.

: Moderate electronic effects fine-tune the Lewis acidity of the cobalt center, promoting trans-selective β-hydroxy elimination. DFT calculations indicate a low energy barrier of 0.7 kcal/mol for this step, preventing erosion of selectivity.

: The system accommodates aryl/heteroaryl substrates and natural product-derived allylic alcohols, tolerates functional groups such as boronic esters, and does not interfere with functionalization of alkenyl zinc intermediates (e.g., deuteration, iodination).

To support related research, our company has made six PyBox ligands available and offers custom synthesis services. We cordially welcome inquiries and collaborations!

Authors: Mingxin Liu, Vibha V. Kanale, and Christopher Uyeda*

Title: Application of Asymmetric Catalysis in the E/Z‑Stereodivergent Synthesis of Alkenes

DOI: 10.1021/jacs.5c15281