R&D｜Nature Chemistry
引言
1
Visible light enables catalytic formation of weak chemical bonds with molecular hydrogen
Yoonsu Park, Sangmin Kim, Lei Tian, Hongyu Zhong, Gregory D. Scholes & Paul J. Chirik
Nature Chemistry (2021)Cite this article
Abstract
The synthesis of weak chemical bonds at or near thermodynamic potential is a fundamental challenge in chemistry, with applications ranging from catalysis to biology to energy science. Proton-coupled electron transfer using molecular hydrogen is an attractive strategy for synthesizing weak element–hydrogen bonds, but the intrinsic thermodynamics presents a challenge for reactivity. Here we describe the direct photocatalytic synthesis of extremely weak element–hydrogen bonds of metal amido and metal imido complexes, as well as organic compounds with bond dissociation free energies as low as 31 kcal mol−1. Key to this approach is the bifunctional behaviour of the chromophoric iridium hydride photocatalyst. Activation of molecular hydrogen occurs in the ground state and the resulting iridium hydride harvests visible light to enable spontaneous formation of weak chemical bonds near thermodynamic potential with no by-products. Photophysical and mechanistic studies corroborate radical-based reaction pathways and highlight the uniqueness of this photodriven approach in promoting new catalytic chemistry.
2
Selectivity control in hydrogenation through adaptive catalysis using ruthenium nanoparticles on a CO2-responsive support
Alexis Bordet,
Sami El Sayed,
Matthew Sanger,
Kyle J. Boniface,
Deepti Kalsi,
Kylie L. Luska,
Philip G. Jessop &
Walter Leitner
Nature Chemistry (2021)Cite this article
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Abstract
With the advent of renewable carbon resources, multifunctional catalysts are becoming essential to hydrogenate selectively biomass-derived substrates and intermediates. However, the development of adaptive catalytic systems, that is, with reversibly adjustable reactivity, able to cope with the intermittence of renewable resources remains a challenge. Here, we report the preparation of a catalytic system designed to respond adaptively to feed gas composition in hydrogenation reactions. Ruthenium nanoparticles immobilized on amine-functionalized polymer-grafted silica act as active and stable catalysts for the hydrogenation of biomass-derived furfural acetone and related substrates. Hydrogenation of the carbonyl group is selectively switched on or off if pure H2 or a H2/CO2 mixture is used, respectively. The formation of alkylammonium formate species by the catalytic reaction of CO2 and H2 at the amine-functionalized support has been identified as the most likely molecular trigger for the selectivity switch. As this reaction is fully reversible, the catalyst performance responds almost in real time to the feed gas composition.
3
A catalytic asymmetric cross-coupling approach to the synthesis of cyclobutanes
F. Wieland Goetzke,
Alexander M. L. Hell,
Lucy van Dijk &
Stephen P. Fletcher
Nature Chemistry (2021)Cite this article
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Abstract
Stereodefined four-membered rings are common motifs in bioactive molecules and versatile intermediates in organic synthesis. However, the synthesis of complex, chiral cyclobutanes is a largely unsolved problem and there is a need for general and modular synthetic methods. Here we report a series of asymmetric cross-coupling reactions between cyclobutenes and arylboronic acids which are initiated by Rh-catalysed asymmetric carbometallation. After the initial carborhodation, Rh–cyclobutyl intermediates undergo chain-walking or C–H insertion so that overall a variety of additions such as reductive Heck reactions, 1,5-addition and homoallylic substitution are observed. The synthetic applicability of these highly stereoselective transformations is demonstrated in the concise syntheses of the drug candidates Belaperidone and PF-04862853. We anticipate this approach will be widely adopted by synthetic and medicinal chemists. While the carbometallation approach reported here is exemplified with Rh and arylboronic acids, it is likely to be applicable to other metals and nucleophiles.
4
Chemical profiling of DNA G-quadruplex-interacting proteins in live cells
Xiaoyun Zhang,
Jochen Spiegel,
Sergio Martínez Cuesta,
Santosh Adhikari &
Shankar Balasubramanian
Nature Chemistry volume 13, pages626–633 (2021)Cite this article
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Abstract
DNA–protein interactions regulate critical biological processes. Identifying proteins that bind to specific, functional genomic loci is essential to understand the underlying regulatory mechanisms on a molecular level. Here we describe a co-binding-mediated protein profiling (CMPP) strategy to investigate the interactome of DNA G-quadruplexes (G4s) in native chromatin. CMPP involves cell-permeable, functionalized G4-ligand probes that bind endogenous G4s and subsequently crosslink to co-binding G4-interacting proteins in situ. We first showed the robustness of CMPP by proximity labelling of a G4 binding protein in vitro. Employing this approach in live cells, we then identified hundreds of putative G4-interacting proteins from various functional classes. Next, we confirmed a high G4-binding affinity and selectivity for several newly discovered G4 interactors in vitro, and we validated direct G4 interactions for a functionally important candidate in cellular chromatin using an independent approach. Our studies provide a chemical strategy to map protein interactions of specific nucleic acid features in living cells.
5
Mechanism of molybdate insertion into pterin-based molybdenum cofactors
Corinna Probst,
Jing Yang,
Joern Krausze,
Thomas W. Hercher,
Casseday P. Richers,
Thomas Spatzal,
Khadanand KC,
Logan J. Giles,
Douglas C. Rees,
Ralf R. Mendel,
Martin L. Kirk &
Tobias Kruse
Nature Chemistry (2021)Cite this article
773 Accesses
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Abstract
The molybdenum cofactor (Moco) is found in the active site of numerous important enzymes that are critical to biological processes. The bidentate ligand that chelates molybdenum in Moco is the pyranopterin dithiolene (molybdopterin, MPT). However, neither the mechanism of molybdate insertion into MPT nor the structure of Moco prior to its insertion into pyranopterin molybdenum enzymes is known. Here, we report this final maturation step, where adenylated MPT (MPT–AMP) and molybdate are the substrates. X-ray crystallography of the Arabidopsis thaliana Mo-insertase variant Cnx1E S269D D274S identified adenylated Moco (Moco–AMP) as an unexpected intermediate in this reaction sequence. X-ray absorption spectroscopy revealed the first coordination sphere geometry of Moco trapped in the Cnx1E active site. We have used this structural information to deduce a mechanism for molybdate insertion into MPT–AMP. Given their high degree of structural and sequence similarity, we suggest that this mechanism is employed by all eukaryotic Mo-insertases.
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Site-selective tyrosine bioconjugation via photoredox catalysis for native-to-bioorthogonal protein transformation
Beryl X. Li,
Daniel K. Kim,
Steven Bloom,
Richard Y.-C. Huang,
Jennifer X. Qiao,
William R. Ewing,
Daniel G. Oblinsky,
Gregory D. Scholes &
David W. C. MacMillan
Nature Chemistry (2021)Cite this article
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Abstact
The growing prevalence of synthetically modified proteins in pharmaceuticals and materials has exposed the need for efficient strategies to enable chemical modifications with high site-selectivity. While genetic engineering can incorporate non-natural amino acids into recombinant proteins, regioselective chemical modification of wild-type proteins remains a challenge. Herein, we use photoredox catalysis to develop a site-selective tyrosine bioconjugation pathway that incorporates bioorthogonal formyl groups, which subsequently allows for the synthesis of structurally defined fluorescent conjugates from native proteins. A water-soluble photocatalyst, lumiflavin, has been shown to induce oxidative coupling between a previously unreported phenoxazine dialdehyde tag and a single tyrosine site, even in the presence of multiple tyrosyl side chains, through the formation of a covalent C–N bond. A variety of native proteins, including those with multiple tyrosines, can successfully undergo both tyrosine-specific and single-site-selective labelling. This technology directly introduces aldehyde moieties onto native proteins, enabling rapid product diversification using an array of well-established bioorthogonal functionalization protocols including the alkyne–azide click reaction.
7
Catalytic reductive desymmetrization of malonic esters
Pengwei Xu &
Zhongxing Huang
Nature Chemistry volume 13, pages634–642 (2021)Cite this article
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Abstract
Desymmetrization of fully substituted carbons with a pair of enantiotopic functional groups is a practical strategy for the synthesis of quaternary stereocentres, as it divides the tasks of enantioselection and C−C bond formation. The use of disubstituted malonic esters as the substrate of desymmetrization is particularly attractive, given their easy and modular preparation, as well as the high synthetic values of the chiral monoester products. Here, we report that a dinuclear zinc complex with a tetradentate ligand can selectively hydrosilylate one of the carbonyls of malonic esters to give α-quaternary β-hydroxyesters, providing a promising alternative to the desymmetric hydrolysis using carboxylesterases. The asymmetric reduction features excellent enantiocontrol that can differentiate sterically similar substituents and high chemoselectivity towards the diester motif of substrates. Together with the versatile preparation of malonic ester substrates and post-reduction derivatization, the desymmetric reduction has enabled the synthesis of a diverse array of quaternary stereocentres with distinct structural features.
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Switching on prodrugs using radiotherapy
Jin Geng,
Yichuan Zhang,
Quan Gao,
Kevin Neumann,
Hua Dong,
Hamish Porter,
Mark Potter,
Hua Ren,
David Argyle &
Mark Bradley
Nature Chemistry (2021)Cite this article
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Abstract
Chemotherapy is a powerful tool in the armoury against cancer, but it is fraught with problems due to its global systemic toxicity. Here we report the proof of concept of a chemistry-based strategy, whereby gamma/X-ray irradiation mediates the activation of a cancer prodrug, thereby enabling simultaneous chemo-radiotherapy with radiotherapy locally activating a prodrug. In an initial demonstration, we show the activation of a fluorescent probe using this approach. Expanding on this, we show how sulfonyl azide- and phenyl azide-caged prodrugs of pazopanib and doxorubicin can be liberated using clinically relevant doses of ionizing radiation. This strategy is different to conventional chemo-radiotherapy radiation, where chemo-sensitization of the cancer takes place so that subsequent radiotherapy is more effective. This approach could enable site-directed chemotherapy, rather than systemic chemotherapy, with 'real time’ drug decaging at the tumour site. As such, it opens up a new era in targeted and directed chemotherapy.
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A versatile living polymerization method for aromatic amides
Subhajit Pal,
Dinh Phuong Trinh Nguyen,
Angélique Molliet,
Mahshid Alizadeh,
Aurélien Crochet,
Roberto D. Ortuso,
Alke Petri-Fink &
Andreas F. M. Kilbinger
Nature Chemistry volume 13, pages705–713 (2021)Cite this article
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Abstract
Polycondensation polymers typically follow step-growth kinetics assuming all functional groups are equally likely to react with one another. If the reaction rates with the chain end can be selectively accelerated, living polymers can be obtained. Here we report on two chlorophosphonium iodide reagents that have been synthesized from triphenylphosphine and tri(o-methoxyphenyl)phosphine. The former activates aromatic carboxylic acids as acid chlorides in the presence of secondary aromatic amines and the latter even in the presence of primary aromatic amines. These reagents allow p-aminobenzoic acid derivatives to form solution-stable activated monomers that polymerize in a living fashion in the presence of amine initiators. Other aryl amino acids and even dimers of aryl amino acids can be polymerized in a living fashion when slowly added to the phosphonium salt in the presence of an amine initiator. Diblock copolymers and triblock terpolymers of aryl amino acids can be prepared even in the presence of electrophilic functional groups.
10
Cyclic polyacetylene
Zhihui Miao,
Stella A. Gonsales,
Christian Ehm,
Frederic Mentink-Vigier,
Clifford R. Bowers,
Brent S. Sumerlin &
Adam S. Veige
Nature Chemistry (2021)Cite this article
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Abstract
Here we demonstrate the synthesis of cyclic polyacetylene (c-PA), or [∞]annulene, via homogeneous tungsten-catalysed polymerization of acetylene. Unique to the cyclic structure and evidence for its topology, the c-PA contains >99% trans double bonds, even when synthesized at −94 °C. High activity with low catalyst loadings allows for the synthesis of temporarily soluble c-PA, thus opening the opportunity to derivatize the polymer in solution. Absolute evidence for the cyclic topology comes from atomic force microscopy images of bottlebrush derivatives generated from soluble c-PA. Now available in its cyclic form, initial characterization studies are presented to elucidate the topological differences compared with traditionally synthesized linear polyacetylene. One advantage to the synthesis of c-PA is the direct synthesis of the trans–transoid isomer. Low defect concentrations, low soliton concentration, and relatively high conjugation lengths are characteristics of c-PA. Efficient catalysis permits the rapid synthesis of lustrous flexible thin films of c-PA, and when doped with I2, they are highly conductive (398 (±76) Ω−1 cm−1).