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引言
1
Chromophores that absorb in the tissue-penetrant far-red/near-infrared window have long served as photocatalysts to generate singlet oxygen for photodynamic therapy. However, the cytotoxicity and side reactions associated with singlet oxygen sensitization have posed a problem for using long-wavelength photocatalysis to initiate other types of chemical reactions in biological environments. Herein, silicon-Rhodamine compounds (SiRs) are described as photocatalysts for inducing rapid bioorthogonal chemistry using 660 nm light through the oxidation of a dihydrotetrazine to a tetrazine in the presence of trans-cyclooctene dienophiles. SiRs have been commonly used as fluorophores for bioimaging but have not been applied to catalyze chemical reactions. A series of SiR derivatives were evaluated, and the Janelia Fluor-SiR dyes were found to be especially effective in catalyzing photooxidation (typically 3%). A dihydrotetrazine/tetrazine pair is described that displays high stability in both oxidation states. A protein that was site-selectively modified by trans-cyclooctene was quantitatively conjugated upon exposure to 660 nm light and a dihydrotetrazine. By contrast, a previously described methylene blue catalyst was found to rapidly degrade the protein. SiR-red light photocatalysis was used to cross-link hyaluronic acid derivatives functionalized by dihydrotetrazine and trans-cyclooctenes, enabling 3D culture of human prostate cancer cells. Photoinducible hydrogel formation could also be carried out in live mice through subcutaneous injection of a Cy7-labeled hydrogel precursor solution, followed by brief irradiation to produce a stable hydrogel. This cytocompatible method for using red light photocatalysis to activate bioorthogonal chemistry is anticipated to find broad applications where spatiotemporal control is needed in biological environments.
2
Metal-catalyzed enantioselective conjugate additions are highly reliable methods for stereoselective synthesis; however, multicomponent reactions that are initiated by conjugate arylation of acyclic π-systems are rare. These reactions generally proceed with poor diastereoselectivity while requiring basic, moisture sensitive organometallic nucleophiles. Here, we show that Rh-catalysts supported by a tetrafluorobenzobarrelene ligand (Ph-tfb) enable the enantio-, diastereo-, and Z-selective α,δ-difunctionalization of electron-deficient 1,3-dienes with organoboronic acid nucleophiles and aldehyde electrophiles to generate Z-homoallylic alcohols with three stereocenters. The reaction accommodates diene substrates activated by ester, amide, ketone, or aromatic groups and can be used to couple aryl, alkenyl, or alkyl aldehydes. Diastereoselective functionalization of the Z-olefin unit in the addition products allows for the generation of compounds with five stereocenters in high dr and ee. Mechanistic studies suggest aldehyde allylrhodation is the rate-determining step, and unlike reactions of analogous Rh-enolates, the Rh-allyl species generated by δ-arylation undergoes aldehyde trapping rather than protonolysis, even when water is present as a cosolvent. These findings should have broader implications in the use of privileged metal-catalyzed conjugate addition reactions as entry points toward the preparation of acyclic molecules containing nonadjacent stereocenters.
3
Alkynylcyclopropanes have found promising applications in both organic synthesis and medicinal chemistry but remain rather underexplored due to the challenges associated with their preparation. We describe a convenient two-step methodology for the alkynylcyclopropanation of alkenes, based on the rhodium(II)-catalyzed decarbenation of 7-alkynyl cycloheptatrienes. The catalytic system employed circumvents a fundamental problem associated with these substrates, which usually evolve via 6-endo-dig cyclization or ring-contraction pathways under metal catalysis. This unique performance unlocks a rapid access to a diverse library of alkynylcyclopropanes (including derivatives of complex drug-like molecules), versatile intermediates that previously required much lengthier synthetic approaches. Combining experiments and DFT calculations, the complete mechanistic picture for the divergent reactivity of alkynylcycloheptatrienes under metal catalysis has been unveiled, rationalizing the unique selectivity displayed by rhodium(II) complexes.
4
Mononuclear Pd(I) species are putative intermediates in Pd-catalyzed reactions, but our knowledge about them is limited due to difficulties in accessing them. Herein, we report the isolation of a Pd(I) amido complex, [(BINAP)Pd(NHArTrip)] (BINAP = 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene, ArTrip = 2,6-bis(2′,4′,6′-triisopropylphenyl)phenyl), from the reaction of (BINAP)PdCl2 with LiNHArTrip. This Pd(I) amido species has been characterized by X-ray crystallography, electron paramagnetic resonance, and multiedge Pd X-ray absorption spectroscopy. Theoretical study revealed that, while the three-electron–two-center π-interaction between Pd and N in the Pd(I) complex imposes severe Pauli repulsion in its Pd–N bond, pronounced attractive interligand dispersion force aids its stabilization. In accord with its electronic features, reactions of homolytic Pd–N bond cleavage and deprotonation of primary amines are observed on the Pd(I) amido complex.
5
Copolymerization of olefin with carbon monoxide has received considerable interest from both academia and industry, and the introduction of polar carbonyl group renders the resultant polyketones with excellent mechanical strength, crystallinity, photodegradability, hydrophilicity, surface, and barrier properties. However, most of the reported polyketones are difficult to be processed because of limited solubility in common solvents and high melting temperature (Tm ∼ 260 °C) resulting from the strictly alternative structure. Nonalternating copolymerization of ethylene with CO is a very promising method to circumvent the problem of processability of traditional perfectly alternating polyketone. In the contribution, the palladium coordinated diphosphazane monoxide substituted by strong electron-donating groups is discovered to be highly reactive for producing nonalternating polyketones, and up to 24.2% extra ethylene incorporation has lowered Tm values to 147 and 165 °C and further improved thermal stability (Td ∼ 339 °C) of the resultant materials. Our data demonstrates that cationic palladium complexes can also exhibit excellent reactivity and an unprecedented nonalternating degree in this copolymerization.
6
As halogen bonding is a weak, transient interaction, its description in solution is challenging. We demonstrate that scalar coupling constants (J) are modulated by halogen bonding. The binding-induced magnitude change of one-bond couplings, even up to five bonds from the interaction site, correlates to the interaction strength. We demonstrate this using the NMR data of 42 halogen-bonded complexes in dichloromethane solution and by quantum chemical calculations. Our observation puts scalar couplings into the toolbox of methods for characterization of halogen bond complexes in solution and paves the way for their applicability for other types of weak σ-hole interactions.
7
Axially chiral styrenes are of great interest since they may serve as a class of novel chiral ligands in asymmetric synthesis. However, only recently have strategies been developed for their enantioselective preparation. Thus, the development of novel and efficient methodologies is highly desirable. Herein, we reported the first tandem iridium catalysis as a general strategy for the synthesis of axially chiral styrenes enabled by Asymmetric Allylic Substitution-Isomerization (AASI) using cinnamyl carbonate analogues as electrophiles and naphthols as nucleophiles. In this approach, axially chiral styrenes were generated through two independent iridium-catalytic cycles: iridium-catalyzed asymmetric allylic substitution and in situ isomerization via stereospecific 1,3-hydride transfer catalyzed by the same iridium catalyst. Both experimental and computational studies demonstrated that the isomerization proceeded by iridium-catalyzed benzylic C–H bond oxidative addition, followed by terminal C–H reductive elimination. Amid the central-to-axial chirality transfer, the hydroxyl of naphthol plays a crucial role in ensuring the stereospecificity by coordinating with the Ir(I) center. The process accommodated broad functional group compatibility. The products were generated in excellent yields with excellent to high enantioselectivities, which could be transformed to various axially chiral molecules.
8
Three-dimensional aromaticity arising from the close stacking of two antiaromatic π-conjugated macrocycles has recently received considerable attention. Here, a cyclophane consisting of two antiaromatic Ni(II) norcorrole units tethered with two flexible alkyl chains was synthesized. The norcorrole cyclophane showed crystal polymorphism providing three different solid-state structures. Surprisingly, one of them adopted an aligned face-to-face stacking arrangement with negligible displacement along the slipping axis. Although the exchange repulsion between two π-clouds should be maximized in this orientation, the π–π distance is remarkably close (3.258 Å). Three-dimensional aromaticity in this conformation has been supported experimentally and theoretically as evidenced by small bond length alternations as well as the presence of a diatropic ring current. An analogous cyclophane with two aromatic Ni(II) porphyrin units was prepared for comparison. The porphyrin cyclophane exhibited a slipped-stacking conformation with a larger displacement (2.9 Å) and a larger interplanar distance (3.402 Å) without noticeable change of the aromaticity of each porphyrin unit. In solution, the norcorrole cyclophane forms a twist stacking arrangement with effective interplanar orbital overlap and exists in an equilibrium between stacked and nonstacked structures. Thermodynamic parameters of the stacking process were estimated, revealing an inherently large attractive interaction operating between two norcorrole units, which has been further supported by energy decomposition analysis.
9
The past 20 years have seen an extensive implementation of nickel in homogeneous catalysis through the development of unique reactivity not easily achievable by using noble transition metals. Many catalytic cycles propose Ni(I) complexes as potential reactive intermediates, yet the scarcity of nickel(I) precursors and the lack of a general, non-ligand-specific protocol for their synthesis have hampered progress in this field of research. This has in turn also limited the access to novel, well-defined Ni(I) species for the development of new catalytic reactions. Herein, we report a simple, general route to access a wide variety of Ni(I)–phenolate complexes via an unusual example of an olefinic Ni(I) complex, [Ni(COD)(OPh*)] (COD = 1,5-cyclooctadiene, OPh* = O(tBu)3C6H2). This route has proven to be highly efficient for several coordination numbers and ligand classes enabling access to the following complexes: [Ni(IPr)(OPh*)] (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene), [Ni(dcype)(OPh*)] (dcype = 1,2-bis(dicyclohexylphosphino)ethane), [Ni(dppe)(OPh*)] (dppe = 1,2-bis(diphenylphosphino)ethane), and [Ni(terpy)(OPh*)] (terpy = 2,2′:6′,2″-terpyridine). Moreover, reacting [Ni(dcype)(OPh*)] with trimethylsilyl triflate has led to the isolation of a unique example of a cationic binuclear Ni(I)–arene complex. All these complexes have been characterized by single-crystal X-ray, DFT, and EPR analyses, thus providing crucial experimental and theoretical information about their coordination environment and confirming a d9 electronic structure for all complexes involved. Overall, this new synthetic approach offers exciting opportunities for the discovery of new stoichiometric and catalytic reactivity as well as the mechanistic elucidation of Ni-based catalytic cycles.
10
Water electrolysis is a promising approach toward low-cost renewable fuels; however, the high overpotential and slow kinetics limit its applicability. Studies suggest that either dinuclear copper (Cu) centers or the use of borate buffer can lead to efficient catalysis. We previously demonstrated the ability of peptoids—N-substituted glycine oligomers—to stabilize high-oxidation-state metal ions and to form self-assembled di-copper-peptoid complexes. Capitalizing on these features herein we report on a unique Cu-peptoid duplex, Cu2(BEE)2, that is a fast and stable homogeneous electrocatalyst for water oxidation in borate buffer at pH 9.35, with low overpotential and a high turnover frequency of 129 s–1 (peak current measurements) or 5503 s–1 (FOWA); both are the highest reported for Cu-based water electrocatalysts to date. BEE is a peptoid trimer having one 2,2′-bipyridine ligand and two ethanolic groups, easily synthesized on solid support. Cu2(BEE)2 was characterized by single-crystal X-ray diffraction and various spectroscopic and electrochemical techniques, demonstrating its ability to maintain stable in four cycles of controlled potential electrolysis, leading to a high overall turnover number of 51.4 in a total of 2 h. Interestingly, the catalytic activity of control complexes having only one ethanolic side chain is 2 orders of magnitude lower than that of Cu2(BEE)2. On the basis of this comparison and on mechanistic studies, we propose that the ethanolic side chains and the borate buffer have significant roles in the high stability and catalytic activity of Cu2(BEE)2; the −OH groups facilitate protons transfer, while the borate species enables oxygen transfer toward O–O bond formation.
11
Photocleavable protecting groups (PPGs) play a pivotal role in numerous studies. They enable controlled release of small effector molecules to induce biochemical function. The number of PPGs attached to a variety of effector molecules has grown rapidly in recent years satisfying the high demand for new applications. However, until now molecules carrying PPGs have been designed to activate function only in a single direction, namely the release of the effector molecule. Herein, we present the new approach Two-PPGs-One-Molecule (TPOM) that exploits the orthogonal photolysis of two photoprotecting groups to first release the effector molecule and then to modify it to suppress its induced effect. The moiety resembling the tyrosyl side chain of the translation inhibitor puromycin was synthetically modified to the photosensitive ortho-nitrophenylalanine that cyclizes upon near UV-irradiation to an inactive puromycin cinnoline derivative. Additionally, the modified puromycin analog was protected by the thio-coumarylmethyl group as the second PPG. This TPOM strategy allows an initial wavelength-selective activation followed by a second light-induced deactivation. Both photolysis processes were spectroscopically studied in the UV/vis- and IR-region. In combination with quantum-chemical calculations and time-resolved NMR spectroscopy, the photoproducts of both activation and deactivation steps upon illumination were characterized. We further probed the translation inhibition effect of the new synthesized puromycin analog upon light activation/deactivation in a cell-free GFP translation assay. TPOM as a new method for precise triggering activation/deactivation of effector molecules represents a valuable addition for the control of biological processes with light.
12
The total synthesis of leiodermatolide A was accomplished in 13 steps (LLS). Transfer hydrogenative variants of three carbonyl additions that traditionally rely on premetalated reagents (allylation, crotylation, and propargylation) are deployed together in one total synthesis.
13
The first and asymmetric total syntheses of two C11-oxygenated hetisine-type diterpenoid alkaloids, namely, (+)-davisinol and (+)-18-benzoyldavisinol, is described. The concise synthetic approach features a HAT-initiated transannular redox radical cyclization, an ODI-Diels–Alder cycloaddition, and an acylative kinetic resolution. By incorporating an efficient late-stage assembly of the azabicycle, our strategy would streamline the synthetic design of C20-diterpenoid alkaloids and pave the way for their modular syntheses.
14
We hypothesized that the proximity-driven ubiquitylation of E3-interacting small molecules could affect the degradation of E3 ubiquitin ligases. A series of XIAP BIR2 domain-binding small molecules was modified to append a nucleophilic primary amine. This modification transforms XIAP binders into inducers of XIAP degradation. The degradation of XIAP is E1- and proteasome-dependent, dependent on the ligase function of XIAP, and is rescued by subtle modifications of the small molecule that would obviate ubiquitylation. We demonstrate in vitro ubiquitylation of the small molecule that is dependent on its interaction with XIAP. Taken together, these results demonstrate the designed ubiquitylation of an engineered small molecule and a novel approach for the degradation of E3 ubiquitin ligases.
15
Aerobic alcohol oxidations catalyzed by transition metal salts and aminoxyls are prominent examples of cooperative catalysis. Cu/aminoxyl catalysts have been studied previously and feature “integrated cooperativity”, in which CuII and the aminoxyl participate together to mediate alcohol oxidation. Here we investigate a complementary Fe/aminoxyl catalyst system and provide evidence for “serial cooperativity”, involving a redox cascade wherein the alcohol is oxidized by an in situ-generated oxoammonium species, which is directly detected in the catalytic reaction mixture by cyclic step chronoamperometry. The mechanistic difference between the Cu- and Fe-based catalysts arises from the use iron(III) nitrate, which initiates a NOx-based redox cycle for oxidation of aminoxyl/hydroxylamine to oxoammonium. The different mechanisms for the Cu- and Fe-based catalyst systems are manifested in different alcohol oxidation chemoselectivity and functional group compatibility.
16
17
Luminescent metal–organic frameworks (LMOFs) demonstrate strong potential for a broad range of applications due to their tunable compositions and structures. However, the methodical control of the LMOF emission properties remains a great challenge. Herein, we show that linker engineering is a powerful method for systematically tuning the emission behavior of UiO-68 type metal–organic frameworks (MOFs) to achieve full-color emission, using 2,1,3-benzothiadiazole and its derivative-based dicarboxylic acids as luminescent linkers. To address the fluorescence self-quenching issue caused by densely packed linkers in some of the resultant UiO-68 type MOF structures, we apply a mixed-linker strategy by introducing nonfluorescent linkers to diminish the self-quenching effect. Steady-state and time-resolved photoluminescence (PL) experiments reveal that aggregation-caused quenching can indeed be effectively reduced as a result of decreasing the concentration of emissive linkers, thereby leading to significantly enhanced quantum yield and increased lifetime.
18
Both 1,2,4-trisubstitution and dearomative 1,2,4-trifunctionalization of benzyne have been accomplished from sulfoxides bearing a penta-2,4-dien-1-yl moiety. These cascade transformations proceed through a benzyne insertion into the S═O bond and an uncommon regiospecific anionic [4,5]-sigmatropic rearrangement, furnishing a C–O, C–S, and C–C bond on the C1-, C2-, and C4-position of a benzene ring, respectively. This study showcases new cascade benzyne reaction modes involving both distal C–H bond functionalization and dearomatization.
19
A novel, one-step N-dehydrogenation of amides to enamides is reported. This reaction employs the unlikely combination of LiHMDS and triflic anhydride, which serves as both the electrophilic activator and the oxidant, and is characterized by its simple setup and broad substrate scope. The synthetic utility of the formed enamides was readily demonstrated in a range of downstream transformations.