Nα‐Fmoc‐Protected ω‐Azido‐ and ω‐Alkynyl‐L‐amino Acids as Building Blocks for the Synthesis of “Clickable” Peptides

Abstract

AbstractThe growing interest in the 1,4‐disubstituted‐1,2,3‐triazolyl moiety as an amide bond surrogate and its formation through very mild, chemoselective, and bioorthogonal CuI‐catalyzed Huisgen 1,3‐dipolar [3+2] cycloaddition of an alkynyl to an azido function, presented an unmet need for specifically designed α‐amino‐acid‐derived building blocks. Herein we report the synthesis of unnatural homologous series of Nα‐Fmoc‐protected ω‐yne‐ and ω‐azido‐L‐amino acids compatible with the Fmoc/tBu‐based solid‐phase peptide synthesis. These building blocks can be incorporated into pseudopeptides that can serve as precursors of inter‐ and intramolecular click reactions. The homologous Nα‐Fmoc‐ω‐azido‐L‐amino acids were prepared from either the ω‐amino or the ω‐hydroxy precursors by the respective diazo‐transfer reactions and sequential nucleophilic substitutions initially by halide followed by azide. The homologous Nα‐Fmoc‐ω‐yne‐L‐amino acids were prepared by alkylation of a chiral auxiliary, which is a NiII complex of Schiff base derived from glycine and (S)‐2‐(N‐benzylprolyl)aminobenzophenone, with ω‐bromoalkynes. These building blocks will be instrumental for constructing side‐chain modified peptides, interside‐chain peptide chimera, peptide small molecule conjugates, and cyclopeptides, which were cyclized through 1,4‐disubstituted 1,2,3‐triazolyl‐containing side‐chain‐to‐side‐chain bridges. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)