Nα-Fmoc-Protected ω-Azido- and ω-Alkynyl-L-amino Acids as Building Blocks for the Synthesis of "Clickable" Peptides

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 Cu-I-catalyzed Huisgen 1,3-dipolar [3+2] cycloaddition of an alkynyl to an azido function, presented an unmet need for specifically designed alpha-amino-acid-derived building blocks. Herein we report the synthesis of unnatural homologous series of N-alpha-Fmoc-protected omega-yne- and omega-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 N-alpha-Fmoc-omega-azido-L-amino acids were prepared from either the omega-amino or the omega-hydroxy precursors by the respective diazo-transfer reactions and sequential nucleophilic substitutions initially by halide followed by azide. The homologous N-alpha-Fmoc-omega-yne-L-amino acids were prepared by alkylation of a chiral auxiliary, which is a Ni-II complex of Schiff base derived from glycine and (S)-2-(N-benzyiprolyl)aminobenzophenone, with omega-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-disubsbtuted 1, 2,3 -triazolyl-containing side-chain-to-side-chain bridges. ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)