Ruthenium‐Induced Allylcarbamate Cleavage in Living Cells

Streu, Craig; Meggers, Eric

doi:10.1002/anie.200601752

Cited by 272 publications

(272 citation statements)

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“…[20] Remarkably,when using Cp*Ru(cod)Cl as acatalyst, [15a] we observed, after 24 hours,asubstantial formation of the desired cycloadducts with excellent regioselectivity (3aa/3aa' ' = 19:1, 58 % combined yield, entry 2). This good result, together with the previously demonstrated biocompatibility of this type of ruthenium complex, [21] prompted us to further explore the process.D oubling the equivalents of 2a led to an excellent yield of 99 %ofthe desired triazoles after 9hours of stirring at room temperature.Monitoring the reaction at different times confirmed the formation of the products in 78 %y ield after just 30 minutes,w ith the rate being then gradually reduced (entry 4). [22] Thep erformance of [Ir(cod)Cl] 2 could not be improved by using 2equivalents of thioalkyne,(entry 5).…”

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Ruthenium‐Catalyzed Azide–Thioalkyne Cycloadditions in Aqueous Media: A Mild, Orthogonal, and Biocompatible Chemical Ligation

et al. 2017

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The development of efficient metal-promoted bioorthogonal ligations remains as am ajor scientific challenge. Demonstrated herein is that azides undergo efficient and regioselective room-temperature annulations with thioalkynes in aqueous milieu when treated with catalytic amounts of asuitable ruthenium complex. The reaction is compatible with different biomolecules,a nd can be carried out in complex aqueous mixtures such as phosphate buffered saline,c ell lysates,f etal bovine serum, and even living bacteria (E. coli). Importantly,t he reaction is mutually compatible with the classical CuAAC.The copper-catalyzed azide-alkyne cycloaddition (CuAAC), paradigm of "click" chemistry, [1] can be considered among the most relevant chemical transformations discovered in the last decades,w ith countless applications in many areas of science.[2] Theb iological relevance of this reaction stems from its robustness and compatibility with aqueous media, as well as from its good bioorthogonality.[3] However,t he transformation still presents important limitations.T hus,i n addition to being fairly incompatible with thiols,the reaction is essentially restricted to terminal alkynes,aconsequence of am echanism which requires the formation of copper acetylide intermediates (Scheme 1a). An important additional drawback has to do with the side reactivity and toxicity of copper ions in biological contexts.[4] Furthermore,toreach efficient conversions in typically diluted biological settings, the reactive copper(I) species need to be generated in situ using excess amounts of ac opper(II) source and sodium ascorbate,areductant which is not innocent in biological contexts.[5] These issues have been partially addressed by using copper-stabilizing ligands which enhance the biocompatibility and kinetic of the reactions. [6,7] Copper-free,s trainpromoted annulations have been shown to be an efficient alternative, [8] however, these reactions also present limitations associated to the side-reactivity of the reactants.T herefore,the development of new bioorthogonal and biocompatible reactions which address some of the above limitations remains as amajor challenge. [9] In particular, the discovery of robust and aqueous-compatible metal-catalyzed annulations, as alternatives to the CuAAC, represents ah ighly appealing goal. [10] Several azide-alkyne cycloadditions using metals other than copper have been described in recent years, [11] but only the ruthenium variant (RuAAC) [12] has shown am eaningful scope (Scheme 1b). [13] In contrast to the CuAAC, which encompasses dinuclear copper intermediates such as I and II, [14] the ruthenium-promoted reaction involves intermediate species like III,w hich evolve into IV by oxidative cyclometalation, and eventually to the triazole products.[15] In keeping with this scenario,the RuAAC, essentially developed in organic solvents,t olerates disubstituted alkynes but can produce mixtures of regioisomers.Probably,the notion that it is not compatible with water and air atmospheres has precluded more ...

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Ruthenium‐Catalyzed Azide–Thioalkyne Cycloadditions in Aqueous Media: A Mild, Orthogonal, and Biocompatible Chemical Ligation

et al. 2017

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“…We decided to initially apply a ruthenium-catalyzed Alloc deprotection reaction developed by Streu and Meggers that had been previously used in human cell culture. [8] We envisioned connecting this reaction to release of p-aminobenzoic acid (PABA), a biosynthetic precursor to folic acid ( Figure 1B). Organisms that cannot biosynthesize PABA are unable to grow because of defects in nucleotide metabolism.…”

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confidence: 99%

Rescuing Auxotrophic Microorganisms with Nonenzymatic Chemistry

2013

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Chemical manipulations of small molecule metabolites take place in all living systems and are essential for sustaining life through cellular metabolism. [1] The vast majority of these transformations are carried out by macromolecular, enzymatic catalysts. In contrast to the natural world, most chemical reactions employed in laboratory syntheses utilize nonbiological reagents and catalysts. [2] Although non-biological catalysts and reagents have been shown to function in the presence of cells, [3] the question of whether their reactivity can interface with cellular metabolism and influence biological function remains underexplored. We are interested in further developing this aspect of reaction methodology, which we term biocompatible chemistry: non-enzymatic chemical transformations that can be used to manipulate the structures of small molecules in the presence of living organisms. Successful integration of biocompatible chemistry with cellular metabolism would have implications for biotechnology as it could expand the capabilities of biotransformation in ways that are not possible using enzymes. Establishing a link between non-enzymatic catalysis and metabolism could also have potential implications for prebiotic chemistry, as it would suggest that primitive cells could have relied upon non-enzymatic transformations occurring in the surrounding environment to generate essential metabolites. [4] Here we describe biocompatible chemical reactions that interact with microbial metabolism and rescue auxotrophy through the production of essential metabolites. This experimental approach enables us to directly connect the growth of a living organism to the success of a non-biological chemical transformation. *Prof. E. P. Balskus, balskus@chemistry.harvard.edu, http://scholar.harvard.edu/balskus. Supporting information for this article is available on the WWW under http://www.angewandte.org. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptAuxotrophs are organisms that lack the ability to synthesize key nutrients required for growth and survival. [5] The necessary compounds must instead be obtained from external sources, typically the diet or metabolic activities of other organisms living in close proximity. The numerous examples of auxtotrophs in Nature include humans, who are unable to synthesize many essential vitamins and metabolites. It is possible to rescue auxotrophy in bacteria by transformation with genes encoding enzymes that can replace or complement the missing metabolic activity. Restoration of growth in this way constitutes an extremely powerful strategy for selection of evolved biomolecules in the context of directed evolution. [6] Recently, Hecht and co-workers demonstrated that it is possible to rescue the growth of E. coli auxotrophs using de novo protein scaffolds not found in natural systems. [7] Significantly, this result implies that catalysts other than native enzymes can replace key metabolic functions in living cells.Our interest in merging non-enzymat...

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“…We are especially interested in g 5 -cyclopentadienyl ruthenium half-sandwich complexes because of their structure and reactivity. For example, we recently reported ruthenium cyclopentadienyl complexes as substitutionally inert protein kinase inhibitors but also as reactive compounds which can induce the cleavage of protection groups in a biological environment [2,3].…”

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confidence: 99%