Palladium-Catalyzed Enantioselective Relay Heck Arylation of Enelactams: Accessing α,β-Unsaturated δ-Lactams

Abstract

In this report, we describe the construction of chiral α,β-unsaturated δ-lactams, a widely used pharmacophore, in high yields and excellent enantioselectivities using an oxidative relay Heck arylation reaction. This strategy also allows facile access to 7-substituted α,β-unsaturated ε-lactam products and δ-lactams containing a tetrasubstituted nitrogen-bearing stereocenter.

Enantioselective C2‐Alkylation of Indoles through a Redox‐Relay Heck Reaction of 2‐Indole Triflates

“…Use of benzylether-substituteda llylic alcohol 13 afforded the desired product 14 in modesty ield but excellent enantioselectivity.R acemic secondary allylic alcohol 15 afforded the correspondingk etone 16 in good yield and enantioselectivity. The yield of ketone 16 in this reaction is > 50 %, which suggests the stereocenter formed in the product is under catalystc ontrol and this reaction is not ak inetic resolution.F inally,w ee xplored the use of an allylic alcohol bearing ap rimary tosyl-protected alcohol ( 17). Under our reaction conditions, the (formal) alkylation occurs selectively between the indole C2 and the alkene carbon distalt ot he primary unprotected alcohol to give 18 in good yield and enantioselectivity.…”

“…16 It is also possible to use ene-lactam 27 as a coupling partner in this chemistry, leading to products 28a - c in excellent yield and slightly diminished enantioselectivity. 17 This reaction provides rapid and modular access to the core of natural products and drug candidates ( vide supra ).…”

Enantioselective Heck Arylation of Acyclic Alkenol Aryl Ethers: Synthetic Applications and DFT Investigation of the Stereoselectivity

“…Among the cyclic activated alkenes that can be employed in enantioselective Heck reactions, it includes tetrahydropyrans, dihydrofurans, endocyclic enecarbamates, and enelactams . Enantioselective arylations on these systems rely basically on the use of BPMO ligands both with aryl triflates and halides, aryl boronic acids and N , N ligands, or, to a lesser extent, diazonium salts and N , N ‐ligands . Recently, an efficient palladium‐catalyzed enantioselective Heck alkenylation of acyclic aryl enol ethers using alkenyl triflates was reported by Sigman and coworkers (Scheme a) .…”

Intermolecular Heck Coupling with Hindered Alkenes Directed by Potassium Carboxylates

“…[9] Notably,the groundbreaking work of Hallberg [10] and Carretero [11] used tethered functional groups bearing basic nitrogens to alter arylation regiochemistry and relay stereochemical information, with the former able to form quaternary centers from af ully-substituted, albeit polarized substrate.Aseminal report from White and co-workers in 2008 established that oxidative Heck conditions could engage unbiased terminal olefins using weakly directing functional groups to yield terminally arylated products, [12] and Sigman in 2014 extended the asymmetric redox-relay Heck reaction to trisubstituted olefins with oxidative conditions. [15] Heck reactions with sterically hindered and unbiased olefins remain non-trivial in many cases,evidenced by recent syntheses of k-opioid receptor agonists 20-nor-SalA [16] and O6C-20-nor-SalA. [15] Heck reactions with sterically hindered and unbiased olefins remain non-trivial in many cases,evidenced by recent syntheses of k-opioid receptor agonists 20-nor-SalA [16] and O6C-20-nor-SalA.…”

“…[13,14] With the exception of enelactams,r edox-relay Heck reactions do not tolerate cyclic substrates,w hich tend to yield mixtures of regioisomers. [15] Heck reactions with sterically hindered and unbiased olefins remain non-trivial in many cases,evidenced by recent syntheses of k-opioid receptor agonists 20-nor-SalA [16] and O6C-20-nor-SalA. [17] Al ate-stage Heck arylation on ah indered, unbiased olefin could not be achieved using traditional or oxidative Heck conditions.H owever,i ncorporation of acarboxylic acid close to the alkene significantly accelerated arylation relative to deactivation of the palladium catalyst or decomposition of the aryl halide,3 -bromofuran ( Figure 1c).…”