Amino acids and peptides play an important role in nature, as well as in organic and pharmaceutical chemistry. Therefore, the easy, straightforward and versatile access of biogenic and unnatural derivatives is still highly demanding. This micro‐review intends to provide to the reader the current state of the art on site‐selective C–H bond functionalization technology applied on α‐amino acids and peptides, focusing on the different C–H positions that can successfully be addressed to date. It is structured in two main parts implying i) the α‐C–H functionalization at the peptide backbone and ii) the modification of the side‐chain. Herein, metal‐catalyzed C–H activation, oxidative C–H functionalization, as well as light mediated approaches, are discussed considering the challenges in reactivity and selectivity. The great potential of these transformations is also depicted with the derivatization and macrocyclization of complex peptides leading to products of pharmaceutical importance.
A versatile photoredox‐catalyzed synthesis of unnatural amino acids and peptides is presented. Commercially available Ru(bpy)3(PF6)2 was efficiently used as visible light photocatalyst in combination with a broad number of different types of radical precursors in the coupling with several dehydrogenated amino acid residues. This method provides new entries to the mild, selective and direct modification of both simple and complex peptide‐like compounds towards novel structures with improved or unusual properties. Hence, (fluorinated)alkyl halides, arylsulfonyl chlorides or various N‐(acyloxy)phthalimides (NHPI esters) were effectively reacted with a series of natural and unnatural α,β‐dehydroamino acids and dipeptides. Moreover, the applicability of the process was also proved by the late stage functionalization of the naturally occurring peptide thiostrepton.
Over the past few years, the development of oxidative methodologies towards efficient and selective direct Csp-H bond functionalization processes has attracted tremendous attention from synthetic chemists. However, only a little attention has been given to the key role of the nature of the oxidant. This review aims at providing a brief summary of the recent advances in mild and more benign oxidative Csp-H bond functionalization reactions, which are classified according to the type of oxidation system employed.
A visible light-mediated photocatalyzed C-C-bond forming method for the benzylic C-H functionalization of phenolether containing synthetic building blocks based on a radical-cation/deprotonation strategy is reported. This method allows the mild,...
The first one‐pot procedure for the double copper(I)‐catalyzed oxidative Csp3−H azidation–CuAAC process, implying unstable azide intermediates and easy‐to‐remove reagents under water‐tolerant conditions, is presented. The combination of tert‐butyl hydroperoxide as oxidant and TMSN3 as azide source for the C−H bond azidation, which produces harmless side‐products such as tBuOH and H2O, probed to be perfectly compatible with the following cycloaddition step. Highly demanding 1,2,3‐triazoles could be then directly obtained in good overall yields by extraction or simple crystallization, thus avoiding chromatography purifications. The potential of this methodology, has also being highlighted by the successful reaction of alkynes presenting interesting complex biological moieties based for example on biotin, DNA base or cinchona alkaloid units.
A simple and mild
Cu-catalyzed oxidative three-component oxidative
Ugi-type method for the synthesis of a variety of substituted imides
has been developed. In this direct imidation approach, benzoyl peroxide
serves as both the oxidant and the carboxylate source, allowing not
only the functionalization of C(sp3)–H bonds in
α-position to an amine but also benzylic substrates. This procedure
presents a wide substrate-type and functional group tolerance. Moreover,
the mildness of the method permitted us to extend its application
to the late stage functionalization of complex natural products such
as the alkaloids brucine and strychnine, leading to interesting highly
functionalized imide derivatives. On the basis of experimental and
computational studies, a plausible mechanism has been proposed.
In this work, we report the first selective, photocatalyzed [2+2]-cycloaddition of dehydroamino acids with styrenetype olefins. This simple, mild, and scalable approach relies on the use of the triplet energy transfer catalyst [Ir(dFCF 3 ppy 2 )dtbpy]PF 6 under visible light irradiation and provides fast access to valueadded substituted strained cyclobutane α-amino acid derivatives.
The Cover Feature shows the versatile modern C‐H functionalization approach of peptides towards unnatural derivatives with improved or unusual applications. Similar to the metamorphosis of caterpillars into butterflies, peptides can be transformed into important new structures by site selective modification of different C‐H bonds. Depending on the method, C‐H cleavage at various positions of the amino acid units, can provide an easy access to novel pharmaceuticals and materials, as well as to molecular recognition applications. More information can be found in the https://doi.org/10.1002/ejoc.201800896
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