Toward intrinsically colored peptides: Synthesis and investigation of the spectral properties of methylated azatryptophans in tryptophan‐cage mutants

Abstract

Tryptophan has been taken as the basic scaffold for a chromophore whose indole residue can be further functionalized by the introduction of endocyclic nitrogen atoms or by N-methylation. When compared with exocyclic modifications, modifying tryptophan in an endocyclic fashion (through atomic substitution) should not perturb the steric profile of the amino acid side chain to such a large extent as that of an exocyclic modification, while simultaneously modulating the polarity, hydrogen-bonding ability, and spectral properties of the amino acid. Of particular interest is that the spectral properties can be tailored such that the chromophore can be monitored at wavelengths that exceed natural protein fluorescence. Ideally, the optimum excitation wavelength should be between 300 and 350 nm, and the emission wavelength should be ≥500 nm such that no cross-excitation/fluorescence occurs. Here, we report the synthesis of amino acid labels that exhibit large red shifts in their fluorescence profiles and their use in peptides.

Photochemical formation of quinone methides from peptides containing modified tyrosine

“…40 It is a synthetic mini-protein, derived from exendin-4, 41 with a known and defined secondary structure, widely used to study folding dynamics and their pathways. 41,42 Recently, the TC5b analogue was used for the incorporation of non-canonical fluorescent amino acids into the core of the tryptophan cage forming motif (Trp 6 and Pro [17][18][19] ) 43 and from the development of this system, TC10b was found to be a more suitable analogue of Trp-Cage for the current experiments reported here, showing that the QM precursor can be imbedded into proteins whilst retaining its photochemical reactivity. QMs formed in the photochemical reactions initiate alkylation of proteins.…”

Atroposelective Total Synthesis of Darobactin A

“…To begin, two of the key unnatural amino acids (AAs) required for the synthesis were fashioned using decarboxylative cross-coupling methodology (Scheme A). Previously, such derivatives were prepared from serine in two steps (requiring the use of CuCN) − or from 2-prop-2-ynoxyoxane in four steps , requiring Schöllkopf’s auxiliary . By employing decarboxylative alkynylation, a scalable synthesis of 9 was achieved in one step from commercially available 6 .…”