Cobalt-catalyzed selective α-alkylation and α-heteroarylation processes of α-amino esters and peptide derivatives are described. These cross-dehydrogenative reactions occur under mild conditions and allow for the rapid assembly of structurally diverse α-amino carbonyl compounds. Unlike enolate chemistry, these methods are distinguished by their site-specificity, occur without racemization of the existing chiral centers, and exhibit total selectivity for aryl glycine motifs over other amino acid units, hence providing ample opportunities for peptide modifications.
Site-selective chemical modifications that target proteinogenic amino acid residues complement the methods entailing genetic manipulation, thereby allowing straightforward and rapid access to engineered proteins. The incorporation of the trifluoromethyl group into amino acids within a peptide sequence results in relevant peptidomimetics with unique biomedicinal properties. As a result, the last decade has witnessed the development of a powerful set of protocols toward the selective trifluoromethylation of smallto-medium size peptides and proteins in a late-stage fashion. This minireview seeks to highlight those particularly compelling cases published in the last years.[a] I.
Site-selective functionalization
of C–H bonds within a peptide framework poses a challenging
task of paramount synthetic relevance. Herein, we report an operationally
simple C(sp2)–H trifluoromethylation of tryptophan
(Trp)-containing peptides. This fluorination technique is characterized
by its chirality preservation, tolerance of functional groups, and
scalability and exhibits chemoselectivity for Trp residues over other
amino acid and heterocyclic units. As a result, it represents a sustainable
tool toward the late-stage peptide modification and protein engineering.
An efficient ligand-free Fe-catalyzed oxidative Ugi-type reaction toward the assembly of α-amino amides and short peptides is described. The reaction proceeds through the α-C(sp)-H oxidation of N,N-dimethylanilines and further nucleophilic attack of the resulting iminium species by isocyanides. Additive screening showed that judicious choice of the carboxylic acid could lead to the formation of α-amino imides via a 3-component reaction. The process occurs with operational simplicity and is compatible with a variety of sensitive functional groups.
The functionalization of otherwise unreactive C–H bonds holds great promise for reducing reliance on existing functional groups while improving energy efficiency and atom economy. One of the most powerful strategies exploits chelation assistance through reversible coordination with metal catalysts. This microreview summarizes the most recent advances in the use of 1,2,3‐triazoles as versatile directing groups in the field of C–H functionalization. The main feature is the modular and straightforward assembly of the required triazoles through “click” chemistry, and such procedures therefore constitute practical synthetic tools of utmost importance for the late‐stage diversification of “click compounds”, which are ubiquitous moieties in drug discovery and material science.
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