Synthesis of protected 2-pyrrolylalanine for peptide chemistry and examination of its influence on prolyl amide isomer equilibrium

Article abstract of DOI:10.1021/jo3005809

Protected enantiopure 2-pyrrolylalanine was synthesized for application in peptide science as an electron-rich arylalanine (histidine) analog with π-donor capability. (2S)-N-(Boc)-N′-(Phenylsulfonyl)-, (2S)-N,N′-bis-(phenylsulfonyl)-, and (2S)-N,N′-bis-(Boc)-3-(2- pyrrolyl)alanines (10, 3, and 14, respectively) were made in 13-17% overall yields and six to seven steps from oxazolidine β-methyl ester 4. Homoallylic ketone 5 was prepared by a copper-catalyzed cascade addition of vinylmagnesium bromide to ester 4 and converted to pyrrolyl amino alcohol 7 by olefin oxidation and Paal-Knorr condensation. Protecting group shuffle and oxidation of the primary alcohol enabled the synthesis of pyrrolylalanines. The bis-Boc analog 14 proved useful in peptide chemistry and was employed to make N-acetyl-pyrrolylalaninyl-proline N′′-methylamide 25. A study of the influence of the pyrrole moiety on the prolyl amide isomer equilibrium of 25 using ¹H NMR spectroscopy in chloroform, DMSO, and water demonstrated that the pyrrolylalanine peptide exhibited behavior and conformations different from those of other arylalanine analogs.