Synthesis of a new π‐deficient phenylalanine derivative from a common 1,4‐diketone intermediate and study of the influence of aromatic density on prolyl amide isomer population

Abstract

Enantiopure (2S)-N-(Boc)-3-(6-methylpyridazinyl)alanine (14) has been synthesized to serve as a phenylalanine analog lacking significant pi-donor capability. Two approaches were developed to furnish the target compound from L-aspartic acid as chiral educt in respectively six and nine steps and 13% and 12% yields. In both routes, a key homoallylic ketone intermediate was synthesized by a copper-catalyzed cascade addition of vinylmagnesium bromide to a carboxylic ester. Dipeptide models Ac-Xaa-Pro-NHMe (21a-c) were prepared and the relative populations of prolyl cis- and trans-amide isomers were measured in chloroform, dimethylsulfoxide, and water by proton NMR spectroscopy in order to assess the significance of the electron density of the neighboring aromatic residue on the prolyl amide geometry.

Synthesis of Protected 2-Pyrrolylalanine for Peptide Chemistry and Examination of Its Influence on Prolyl Amide Isomer Equilibrium

“…Pyrrole 7 was prepared in three steps from β-amino ester 4, which was obtained in four steps with a 47% yield from L-aspartic acid as the chiral educt. 16 The Cu-catalyzed cascade addition of excess vinylmagnesium bromide to methyl ester 4 in THF at −45 °C gave homoallylic ketone 5 in 63% yield (Scheme 1). 16,26 Pyrrole 7 was prepared by olefin oxidation and Paal−Knorr condensation.…”

“…16 The Cu-catalyzed cascade addition of excess vinylmagnesium bromide to methyl ester 4 in THF at −45 °C gave homoallylic ketone 5 in 63% yield (Scheme 1). 16,26 Pyrrole 7 was prepared by olefin oxidation and Paal−Knorr condensation. γ-Ketoaldehyde 6 was made from olefin 5 using a mixture of OsO 4 −NaIO 4 and 2,6-lutidine in dioxane/water in 95% yield.…”

“…15−17 For example, in Ac-Xaa-Pro-NHMe, the cis-amide isomer population was reduced on changing the Xaa residue from Phe to electron deficient arylalanine residues, 17 such as pyradizinylalanine. 16 Histidine analogs (i.e., thienylalanine, furylalanine, triazolylalanine, tetrazolylalanine, thiazolylalanine, imidazolylalanine, and pyrazolylalanine) have been used to study the importance of the hydrogen bond acceptor and donator properties of the imidazole side chain. 2f−h Components of naturally occurring peptides from marine organisms, 18 amino acids bearing fivemembered heterocycle side chains have been employed in peptidomimetics, 19 macromolecular scafolds, 20 and highthroughput synthesis.…”

Applications of γ,δ-Unsaturated Ketones Synthesized by Copper-Catalyzed Cascade Addition of Vinyl Grignard Reagents to Esters

“…Aromatic side chains can have significant influence on peptide folding and recognition. 49 Aromatic effects on amide isomer equilibrium N-terminal to prolyl residues were studied by the synthesis and spectroscopic analysis of Ac-Xaa-Pro-NHMe dipeptide models 103−105 bearing π−enriched pyrrolylalanine, 15,50 π−deficient pyridazinylalanine, 14 and phenylalanine as control (Scheme 19).…”

“…53 Higher cis-isomer populations were observed in Ac-Xaa-Pro-NHMe with Phe (e.g., 105) than π−deficient pyridazinylalanine (e.g., 104) in various solvents (Table 1). 14 On the other hand, the π-electron− enriched pyrrolyalanine (e.g., 103) exhibited a limited influence on the cis-isomer population indicating that other factors may be necessary for such an interaction. 15 3.5.…”