Nα-Fmoc-protected ω-azido- and ω-alkynyl-L- amino acids as building blocks for the synthesis of "clickable" peptides

Abstract

The 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 N α-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, 2008.