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

Abstract

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.

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