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

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journal contribution
posted on 2012-08-03, 00:00 authored by Aurélie A. Dörr, William D. Lubell
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.