Pd-mediated reactions have emergeda sapowerful tool for the site-selective and bioorthogonall ate-stage diversification of amino acids, peptides and related compounds. Indole moieties of tryptophan derivatives are susceptible to C 2 H-activation, whereas halogenated aromatic amino acids such as halophenylalanines or halotryptophans provide ab road spectrum of different functionalisations. The compatibility of transition-metal-catalysed cross-couplings with functional groups in peptides, other biologically active compoundsa nd even proteins hasb een demonstrated. ThisReview primarily compiles the applicationo fd ifferent crosscoupling reactions to modify halotryptophans,h alotryptophan containing peptides or halogenated, biologically active compounds derived from tryptophan. Moderna pproaches use regio-and stereoselective biocatalytic strategies to generate halotryptophans and derivatives on ap reparative scale. The combination of bio-and chemocatalysis in cascade reactions is given by the biocompatibility and bioorthogonality of Pd-mediated reactions. Pd-Catalysed C 2 ÀHA ctivationo fT ryptophansThe C 2 position of indoles and tryptophans can be selectively addressed by transition-metal-catalysed C(sp 2 )ÀHa ctiva- [a] H. Gruß,P rof. Dr.N.S ewald

N-methylated amino acids are found in Nature in various biological compounds. N-methylation of amino acids has been shown to improve pharmacokinetic properties of peptide drugs due to conformational changes, improved proteolytic stability and/or higher lipophilicity. Due to these characteristics N-methylated amino acids received increasing interest by the pharmaceutical industry. Syntheses of N-methylated amino acids by chemical and biocatalytic approaches are known, but often show incomplete stereoselectivity, low yields or expensive co-factor regeneration. So far a one-step fermentative process from sugars has not yet been described. Here, a one-step conversion of sugars and methylamine to the N-methylated amino acid N-methyl-l-alanine was developed. A whole-cell biocatalyst was derived from a pyruvate overproducing C. glutamicum strain by heterologous expression of the N-methyl-l-amino acid dehydrogenase gene from Pseudomonas putida. As proof-of-concept, N-methyl-l-alanine titers of 31.7 g L−1 with a yield of 0.71 g per g glucose were achieved in fed-batch cultivation. The C. glutamicum strain producing this imine reductase enzyme was engineered further to extend this green chemistry route to production of N-methyl-l-alanine from alternative feed stocks such as starch or the lignocellulosic sugars xylose and arabinose.

Fluorescent styryl‐tryptophans have been synthesized by a Mizoroki–Heck cross‐coupling from unprotected bromotryptophan in aqueous medium showing promising spectrophotometric properties for possible application in fluorescence labelling of biomolecules. Moreover, this strategy permits a modular combination of biocatalytic halogenation by using immobilized FAD‐dependent tryptophan halogenases and Pd‐mediated chemocatalysis in a multistep one‐pot process.

Mild reactionc onditions are highly desirable for bio-orthogonal side chain derivatizations of amino acids, peptides or proteins due to the sensitivity of these substrates. Transition metal catalysed cross-couplingss uch as Suzuki-Miyaura reactions are highly versatile, but usually require unfavourable reaction conditions, in particular,w hen applied with aryl bromides. Ligand-free solvent-stabilised Pd-nanoparticles represent an efficient and sustainable alternative to conventional phosphine-based catalysts,b ecause the cross-coupling can be performed at considerably lower temperature. We report on the applicationo fs uch ah ighly reactive heterogeneousc atalystf or the Suzuki-Miyaura cross-coupling of brominated tryptophan derivatives. The solvent-stabilised Pd-nanoparticles are even more efficient than the literature-known ADHP-Pd precatalyst. Interestingly, the latter also leads to the formation of quasi-homogeneous Pd-nanoparticles as the catalytic species. One advantage of our approach is the compatibilityw ith aqueousa nd aerobic conditions at near-ambient temperatures and short reaction times of only 2h.T he influence of different N a-protecting groups,b oronic acids as well as the impact of different amino acid side chainsi nb romotryptophan-containing peptides has been studied.N otably,asurprising acceleration of the catalysis was observed when palladium-coordinating side chainsw ere presenti np roximal positions.

Synthetic methods on the macrocyclization of peptides are of high interest since they facilitate the synthesis of various types of potentially bioactive compounds, e.g. addressing targets like protein−protein-interactions. Herein, we report on an efficient method to construct tryptathionine-cross-links in peptides between the amino acids Trp and Cys. This reaction not only is the basis for the total synthesis of the death cap toxin α-amanitin but also provides rapid access to various new amanitin analogues. This study for the first time presents a systematic compilation of structure−activity relations (SAR) of amatoxins with regard to RNA polymerase II inhibition and cytotoxicity with one amanitin derivative of superior RNAP II inhibition. The present approach paves the way for the synthesis of structurally diverse amatoxins as future payloads for antibody−toxin conjugates in cancer therapy.