Xavier Just-Baringo

Thiopeptide Antibiotics: Retrospective and Recent Advances

Thiopeptides, or thiazolyl peptides, are a relatively new family of antibiotics that already counts with more than one hundred different entities. Although they are mainly isolated from soil bacteria, during the last decade, new members have been isolated from marine samples. Far from being limited to their innate antibacterial activity, thiopeptides have been found to possess a wide range of biological properties, including anticancer, antiplasmodial, immunosuppressive, etc. In spite of their ribosomal origin, these highly posttranslationally processed peptides have posed a fascinating synthetic challenge, prompting the development of various methodologies and strategies. Regardless of their limited solubility, intensive investigations are bringing thiopeptide derivatives closer to the clinic, where they are likely to show their veritable therapeutic potential.

Thiopeptide Engineering: A Multidisciplinary Effort towards Future Drugs

The recent development of thiopeptide analogues of antibiotics has allowed some of the limitations inherent to these naturally occurring substances to be overcome. Chemical synthesis, semisynthetic derivatization, and engineering of the biosynthetic pathway have independently led to complementary modifications of various thiopeptides. Some of the new substances have displayed improved profiles, not only as antibiotics, but also as antiplasmodial and anticancer drugs. The design of novel molecules based on the thiopeptide scaffold appears to be the only strategy to exploit the high potential they have shown in vitro. Herein we present the most relevant achievements in the production of thiopeptide analogues and also discuss the way the different approaches might be combined in a multidisciplinary strategy to produce more sophisticated structures.

Total Synthesis and Stereochemical Assignment of Baringolin

The thiopeptide antibiotic baringolin has been synthesized, and its structure and stereochemistry have been confirmed. The use of a strategy based on palladium-catalyzed cross-couplings permitted a modular construction of this natural product.

EDOTn and MIM, new peptide backbone protecting groups

In recent years, backbone protection has allowed the synthesis of complex peptidic sequences of high interest by preventing chain aggregation and aspartimides formation. Nevertheless, the backbone protectors currently used have some drawbacks: they are difficult to remove and show high steric hindrance. The new backbone protectors presented in this study (EDOTn and MIM) represent an improvement in both aspects.

Total synthesis of aeruginazole A.

The first total synthesis of Aeruginazole A, prepared via a convergent strategy that involved both solid-phase peptide synthesis and solution phase chemistry and that enabled conservation of the stereochemistry of the intermediates, is reported.

Dissecting the Structure of Thiopeptides: Assessment of Thiazoline and Tail Moieties of Baringolin and Antibacterial Activity Optimization

Several analogues of baringolin (1) were prepared to evaluate the role of its characteristic thiazoline ring and pentapeptidic tail with the aim of defining structure-activity relationships for these moieties. The thiazoline ring appeared as a crucial moiety to maintain a broad scope of activities against different Gram-positive bacteria. Further modifications were performed to simplify the structure of the natural product and assess the role of its tail, resulting in an enhanced in vitro performance. Analogue 25, with the thiazole-containing macrocycle and a 4-aminocyclohexane-1-carboxylic acid moiety in place of the pentapeptidic tail, was identified as a much more potent analogue, capable of overcoming the absence of the thiazoline ring and performing extraordinarily well against all strains tested. This is the first library of thiopeptide analogues produced by chemical synthesis alone, which demonstrates the robustness and convenience of the synthetic strategy used.

Chiral Thiazoline and Thiazole Building Blocks for the Synthesis of Peptide- Derived Natural Products

Thiazoline and thiazole heterocycles are privileged motifs found in numerous peptide-derived natural products of biological interest. During the last decades, the synthesis of optically pure building blocks has been addressed by numerous groups, which have developed a plethora of strategies to that end. Efficient and reliable methodologies that are compatible with the intricate and capricious architectures of natural products are a must to further develop their science. Structure confirmation, structure-activity relationship studies and industrial production are fields of paramount importance that require these robust methodologies in order to successfully bring natural products into the clinic. Todays chemist toolbox is assorted with many powerful methods for chiral thiazoline and thiazole synthesis. Ranging from biomimetic approaches to stereoselective alkylations, one is likely to find a suitable method for their needs.

Reduction of Selenoamides to Amines Using SmI2–H2O

Selenoamides are selectively reduced to amines by SmI2 with H2O. The process is general for primary, secondary, and tertiary aryl and alkyl selenoamide substrates and selectively delivers amine products. The reduction proceeds under mild conditions using SmI2 activated by straightforward addition of H2O, and does not require an additional Lewis base additive.

Overcoming synthetic challenges in target synthesis using SmI2: recent advances

Samarium (ii) iodide (SmI2, Kagans reagent) is one of the most important reducing agents in organic synthesis. Its unique reactivity and selectivity makes it ideal for mediating key steps in target syntheses often providing outcomes that simply cannot be matched by other reagents. In this review we present selected examples of the application of SmI2 in target-oriented synthesis during the last four years and describe the enabling role the reagent has played in the construction of natural products, unnatural bioactive compounds, and organic materials.