Pd-catalyzed site-selective C(sp²)–H radical acylation of phenylalanine containing peptides with aldehydes

Abstract

A novel Pd-catalyzed δ-C(sp2)–H functionalization reaction with readily available aldehydes towards the assembly of non-proteogenic acylated Phe-containing oligopeptides is presented.

Pd‐Catalyzed C(sp2)−H Alkoxycarbonylation of Phenethyl‐ and Benzylamines with Chloroformates as CO Surrogates

“…To understand the reaction pathway as well as some of the observed experimental evidences, we further performed DFT studies for the C(sp 2 )−H alkoxycarbonylation of PA‐Phe‐OMe ( 1 a ) with ClCO 2 Et ( 2 a ). Assuming a similar reaction pathway to that of related PA‐directed Pd‐catalyzed C−H functionalization processes, [15d, 17] we proposed the mechanism depicted in Scheme 5 entailing monomeric palladium intermediates. Complexation of 1 a with Pd(OAc) 2 would initially afford Pd II complex In‐tA , [15d, 17c] which would next undergo a directed ortho ‐selective cyclometallation to provide the six‐membered palladacycle IntB [21] .…”

“…Assuming a similar reaction pathway to that of related PA‐directed Pd‐catalyzed C−H functionalization processes, [15d, 17] we proposed the mechanism depicted in Scheme 5 entailing monomeric palladium intermediates. Complexation of 1 a with Pd(OAc) 2 would initially afford Pd II complex In‐tA , [15d, 17c] which would next undergo a directed ortho ‐selective cyclometallation to provide the six‐membered palladacycle IntB [21] . The latter would next undergo oxidative addition with ethyl chloroformate to provide the corresponding Pd IV IntC , which would ultimately deliver the mono‐carbonylated product complex PC‐1 through a C−C bond‐forming reductive elimination.…”

Recent Progress in Palladium‐Catalyzed Radical Reactions

“…reported a palladium‐catalyzed ortho ‐C( sp 2 )−H acylation to construct acylation compound 286 using phenylalanine 284 containing peptides and aldehydes 285 (Scheme 79). [59] A range of aldehydes bearing electron‐rich, electron‐poor or sterically bulky substituents were subjected to this reaction, providing the desired products in complete regioselectivity. Additionally, polypeptides were investigated that proceed smoothly to deliver the corresponding products.…”

Aldehydes: magnificent acyl equivalents for direct acylation

“…At the beginning, the aldehyde reacted with hydroxylamine to form a nitrone intermediate Segundo and Correa in 2019 reported Pd-catalyzed oxidative coupling between phenylalanine based peptides with aldehydes for site-selective C(sp 2 )-H acylation using DCP (dicumyl peroxide) as oxidizing agent and Ag 2 CO 3 as additive. 104 With the optimized reaction conditions the scope of C(sp 2 )-H acylation of phenylalanine derivatives was investigated by coupling with a wide variety of aldehydes and the desired products could be obtained in moderate to excellent yields (Scheme 71A). Aryl aldehydes having electron-releasing (Me, OMe, Et 2 N, 2,3-dihydrofuryl) groups resulted the mixture of mono-and di-acylated compounds, which could be easily separated.…”