Ligand Effects in Carboxylic Ester- and Aldehyde-Assisted β-C-H Activation in Regiodivergent and Enantioselective Cycloisomerization-Hydroalkenylation and Cycloisomerization-Hydroarylation, and [2 + 2 + 2]-Cycloadditions of 1,6-Enynes.

Herein, we report room temperature, atom-economic protocols for high regio- and enantioselective tandem cycloisomerization-hydroarylation and cycloisomerization-hydroalkenylation of 1,6-enynes leading to vicinal carba -functionalized pyrrolidines, tetrahydrofurans, and cyclopentanes. The latter steps in these processes involve carbonyl-coordination-assisted ortho- C-H activation of aromatic aldehydes and esters, and, a similar, yet rarely seen, β-C-H activation in the case of the acrylates. Synthetically useful enantioselective versions of such reactions are rare and are limited to the C ₂ -H activation of indoles and pyrroles. A similar reaction is also observed with N -vinylphthalimide, which also has a carbonyl group suitable for C-H activation. A dibenzooxaphosphole ligand, (2 S ,2 S' ,3 S, 3 S' )-MeO-BIBOP was uniquely identified as crucial to achieving the challenging regio- and enantioselectivity. This methodology gives access to substituted five-membered carbo- and heterocyclic compounds in good yields and excellent enantioselectivities under a low catalyst loading. A primary KIE of 3.5 is observed in an intermolecular competition experiment with methyl benzoate and d ₅ -methyl benzoate, which indicates that the C-H cleavage is the turnover-limiting step of this process. Unlike the acrylates, which undergoes exclusive hydroalkenylation, a β, γ-unsaturated ester, methyl but-3-enoate, undergoes the highly enantioselective cycloisomerization-coupling sequence with a 1,6-enyne giving either a [2 + 2 + 2]-cycloaddition with ( S, S )-BDPP or hydroalkenylation with (2 S ,2' S ,3 S ,3' S )-MeO-BIBOP depending on the ligand employed. The ( E )-configuration of the newly formed double bond at the terminal alkynyl carbon (of the starting enyne) in the hydroalkenylation product of β,γ-unsaturated ester suggests a more classical migratory insertion-β-hydride elimination route for the formation of this product.