How Thiostrepton Was Made in the Laboratory

Nicolaou, K. C.

doi:10.1002/anie.201205576

Cited by 30 publications

(13 citation statements)

References 87 publications

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“…Using Nicolaou’s methodology various total syntheses were achieved, including the challenging thiostrepton [ 127 , 128 , 168 ], but also GE2270A and GE2270T [ 169 ], and various amythiamicins [ 170 ]. On the other hand, the strategy by Moody relied on a previously formed aza-diene 44 , formed from the condensation of thiazoles 45 and 46 that could react with a different dienophile ( 47 ), yielding the aromatized cycloaddition product 48 [ 126 , 171 ] ( Scheme 14 ).…”

Section: Thiopeptidesmentioning

confidence: 99%

Thiopeptide Antibiotics: Retrospective and Recent Advances

2014

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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.

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Section: Thiopeptidesmentioning

confidence: 99%

Thiopeptide Antibiotics: Retrospective and Recent Advances

2014

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“…The latter underwent 20) through cascade sequences. [54][55][56][57][58] spontaneous tautomerization under the conditions of the reaction leading to (+)-bisorbicillinol (98). On the other hand, sequential exposure of the so-formed (+)-bisorbicillinol (98), first to KHMDS and then to aq.…”

Section: Cascade Reactions In Total Synthesismentioning

confidence: 99%

Total Synthesis Endeavors and Their Contributions to Science and Society: A Personal Account

Nicolaou

Rigol

2019

CCS Chem

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The advent of organic synthesis in the 19th century, serendipitous as it was, set in motion a revolution in science that continues to evolve into increasing levels of sophistication and to expand into new domains of science and technology for the benefits of science and society. Its evolution was always driven by the challenges posed by natural products, whose structures were becoming increasingly complex and diverse. In response to these challenges, synthetic organic chemists were prompted to sharpen their art to reach their target molecules, whose structures were often confirmed only after their synthesis in the laboratory through the art and science of total synthesis. The latter became the “locomotive” and the “flagship” of organic synthesis, for through this practice novel synthetic methods were discovered and invented, and also tested for their generality, applicability, and scope with regard to molecular complexity and diversity. The purpose of total synthesis has also evolved over the years to include aspects beyond the synthesis of the molecule and confirmation of its structure. In this article, we briefly review the evolution of total synthesis in terms of its power and reach and demonstrate its current state of the art that combines fundamentals with translational aspects through examples from our laboratories. The highlighted examples reflect the newly emerged paradigm of the discipline that includes—in addition to the total synthesis of the target molecule—structural elucidations, method discovery and development, design, synthesis, and biological evaluation of analogues for biology and medicine, and training of young students, preparing them for academic and industrial careers in the various disciplines that require knowledge and skills to practice the central science of chemical synthesis. Such disciplines include chemical biology, drug discovery and development, materials science and nanotechnology, and other endeavors whose fundamentals depend and rely on the structure of the molecule and its synthesis.

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“…[1a] Although site-specific modification of 1 is ap ossible approach for improving its aqueous solubility,a rchitectural complexity and ah igh density of delicate functionalities provide af ormidable barrier to successful, site-selective chemical modification. [3,4] Thedehydroalanine (Dha) residues characteristic of 1 and other thiopeptides are reactive sites,most notably as Michael acceptors for av ariety of nucleophilic species. [5] Previously, several studies have been carried out on additions to the Dha residues in 1 (Figure 1, middle).…”

Section: Introductionmentioning

confidence: 99%

Cobalt(III)‐Catalyzed C−H Amidation of Dehydroalanine for the Site‐Selective Structural Diversification of Thiostrepton

et al. 2019

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Thiostrepton is a potent antibiotic against a broad range of Gram‐positive bacteria, but its medical applications have been limited by its poor aqueous solubility. In this work, the first C(sp2)−H amidation of dehydroalanine (Dha) residues was applied to the site selective modification of thiostrepton to prepare a variety of derivatives. Unlike all prior methods for the modification of thiostrepton, the alkene framework of the Dha residue is preserved and with complete selectivity for the Z‐stereoisomer. Additionally, an aldehyde group was introduced by C−H amidation, enabling oxime ligation for the installation of an even greater range of functionality. The thiostrepton derivatives generally maintain antimicrobial activity, and importantly, eight of the derivatives displayed improved aqueous solubility (up to 28‐fold), thereby addressing a key shortcoming of this antibiotic. The exceptional functional group compatibility and site selectivity of CoIII‐catalyzed C(sp2)−H Dha amidation suggests that this approach could be generalized to other natural products and biopolymers containing Dha residues.

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How Thiostrepton Was Made in the Laboratory

Cited by 30 publications

References 87 publications

Thiopeptide Antibiotics: Retrospective and Recent Advances

Thiopeptide Antibiotics: Retrospective and Recent Advances

Total Synthesis Endeavors and Their Contributions to Science and Society: A Personal Account

Cobalt(III)‐Catalyzed C−H Amidation of Dehydroalanine for the Site‐Selective Structural Diversification of Thiostrepton

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