R&D｜ACS Catalysis近期报道
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引言
1
The use of iron catalysts in carbon–carbon bond forming reactions is of interest as an alternative to precious metal catalysts, offering reduced cost, lower toxicity, and different reactivity. While well-defined ligands such as N-heterocyclic carbenes (NHCs) and phosphines can be highly effective in these reactions, additional additives such as N-methylpyrrolidone (NMP), N,N,N′,N′-tetramethylethylenediamine (TMEDA), and iron salts that alter speciation can also be employed to achieve high product yields. However, in contrast to well-defined iron ligands, the roles of these additives are often ambiguous, and molecular-level insights into how they achieve effective catalysis are not well-defined. Using a unique physical–inorganic in situ spectroscopic approach, detailed insights into the effect of additives on iron speciation, mechanism, and catalysis can inform further reaction development. In this Perspective, recent advances will be discussed as well as ongoing challenges and potential opportunities in iron-catalyzed reactions.
2
A practical method for kinetic resolution of α-tertiary propargylic amines has been achieved via asymmetric remote aminations of anilines with azodicarboxylates enabled by chiral phosphoric acid catalysis. A broad range of aryl and alkyl groups at the α-position, as well as the substituted alkynyl and N-aryl groups were well tolerated in these reactions, providing high kinetic resolution performances (with an s-factor up to 111). In addition, the α-tertiary amines bearing an α-CN group (the Strecker reaction product) could be kinetically resolved with excellent stereoselectivity as well under the same reaction conditions. Fruitful transformations of the chiral amination products and the recovered propargylic amines demonstrated the power of this method in asymmetric synthesis of α-tertiary amines and their derivatives.
3
Exploring the catalytic promiscuity of enzymes is a longstanding challenge and a current topic of interest. Our group previously modified a cytochrome P450BM3 monooxygenase to perform peroxygenase activity with assistance from a rationally designed dual-functional small molecule (DFSM). However, the DFSM-facilitated P450-H2O2 system showed limited peroxidase activity. On the basis of a mechanistic analysis of the possible competitive oxidation pathways, the present work applies a protein engineering strategy of mutating redox-sensitive residues that enables the peroxygenase system to achieve efficient peroxidase activity. The engineered system exhibits efficient one-electron oxidation activity toward various substrates, including guaiacol, 2,6-dimethoxyphenol, o-phenylenediamine, and p-phenylenediamine. This system attains the best peroxidase activity of any P450 reported to date and rivals most natural peroxidases, suggesting significant potential for practical applications. This work provides insights and strategies relevant for expanding the catalytic promiscuity of P450s through combining the effects of protein engineering and exogenous molecules.
4
Herein, we report a Rh(III)-catalyzed three-component carboamination of alkenes from readily available aryl boronic acids as a carbon source and dioxazolones as nitrogen electrophiles. This protocol provides facile access to valuable amine products including α-amino acid derivatives in good yield and regioselectivity without the need for a directing functionality. A series of experiments suggest a mechanism in which the Rh(III) catalyst undergoes transmetalation with the aryl boronic acid, followed by turnover limiting alkene migratory insertion into the Rh(III)-aryl bond. Subsequently, fast Rh-nitrene formation provides the syn-carboamination product selectively after reductive elimination and proto-demetalation. Importantly, the protocol provides three-component coupling products in preference to a variety of two-component undesired byproducts.
5
A chelation-assisted palladium-catalyzed C═C bond cleavage of α, β-unsaturated ketone to form alkenyl nitrile in the presence of nitrile is disclosed on the basis of a formal group-exchange reaction formulated as C1═C2 + C3 → C1═C3 + C2, differing from normal alkene oxidative cleavage and metathesis type. The isolated key active Pd(II) complex as well as deuterium-labeled experiment revealed the necessity of the chelation group, and a plausible catalytic pathway was proposed.
6
Here, we report an enantioselective nickel-hydride catalyzed hydroalkylation of readily accessible β-alkyl-α,β-unsaturated amides to form structurally diverse β-chiral amides. This process was proposed to proceed through an enantiodifferentiating syn-hydrometalation of nickel hydride, forming chiral alkylnickel at the β-position in which the regioselectivity is different from that with copper hydride. This regio-reversed hydronickellation process provides a complementary approach to access enantioenriched β-functionalization amides with a stereocenter at the β-position.
7
Pd-catalyzed chemo-, regio-, and enantioselective ring-closing/ring-opening cross coupling reaction has been developed with diverse aryl halide-tethered alkenes and benzocyclobutenols as substrates, which renders the highly enantioselective diarylation of unactivated alkenes and provides a convenient method toward chiral 2,3-dihydrobenzofurans bearing a quaternary stereocenter with excellent enantioselectivities (up to 98% ee). The application in concise synthesis of the analogue of cannabinoid receptor 2 agonists is described.
8
Tetracyclines are an eminent family of type II polyketides that possess a variety of decoration on the skeletons. However, apart from the oxidative modification in aureolic acid compounds, there are few cases of the further conversion of α,β-unsaturated ketones in the tetracycline D-ring. Here, we identified two reductases (TjhO5 and TjhD4), which can highly reduce the α,β-unsaturated ketone of the D-ring in unconventional tetracyclines. By identifying related intermediates and conducting isotope incorporation experiments, we demonstrated that the entire transformation could be accomplished by TjhO5 and TjhD4 collectively via two distinct pathways involving different enzymatic mechanisms. A distinctive deoxygenation mechanism was possibly involved in the TjhO5-mediated continuous reduction of C═O to CH2. These findings highlight the unusual post-modification of tetracyclines and facilitate further engineering and biocatalysis to enrich the structural diversities.
9
We describe a general catalytic methodology for the enantioselective dearomative alkylation of pyridine derivatives with Grignard reagents, allowing direct access to nearly enantiopure chiral dihydro-4-pyridones with yields up to 98%. The methodology involves dearomatization of in situ-formed N-acylpyridinium salts, employing alkyl organomagnesium reagents as nucleophiles and a chiral copper (I) complex as the catalyst. Computational and mechanistic studies provide insights into the origin of the reactivity and enantioselectivity of the catalytic process.
10
The Guerbet reaction can be used for the condensation of simple bioalcohols, which simultaneously doubles the carbon count and increases the C:O ratio, to yield valuable commodity chemicals. Here, we report a metal–organic framework (MOF)-derived RuCo catalyst that furnishes 2-ethylhexanol, a plasticizer alcohol currently produced on a 2 Mt/a scale. While the industrial route requires propene, the MOF-derived catalyst uses 1-butanol and delivers turnover numbers up to 1.7 × 106 Ru–1. In combination with K3PO4, it serves as a fully heterogeneous catalyst system that yields the Guerbet alcohol without producing sodium butanoate, a common secondary product from the undesired Cannizzaro reaction.
11
The development of asymmetric carbene transfer reactions using N-sulfonylhydrazones as the diazo surrogate is a long-term issue in organic synthesis since N-sulfonylhydrazones commonly require high temperatures for their decomposition to release reactive diazo compounds. We report on the use of fluoroalkyl-aryl ketone N-triftosylhydrazones as a class of N-sulfonylhydrazone capable of decomposing below 0 °C (to −40 °C). Their application in asymmetric [2 + 1] cycloadditions with alkynes and alkenes catalyzed by a chiral rhodium catalyst is described. This protocol affords a wide variety of fluoroalkylated cyclopropenes and cyclopropanes in high yields and high enantioselectivity and demonstrates broad functional group tolerance. It is noteworthy that these small-ring products feature a fluoroalkyl chiral quaternary carbon center. The origin of enantioselectivity for the cyclopropenation reaction of N-triftosylhydrazones with alkynes was rationalized by density functional theory calculations.
12
Hydrogenation of aromatic molecules in fossil- and bio-derived fuels is essential for decreasing emissions of harmful combustion products and addressing growing concerns around urban air pollution. In this work, we used atomic layer deposition to significantly enhance the hydrogenation performance of a conventional supported Pd catalyst by applying an ultrathin coating of TiO2 in a scalable powder coating process. The TiO2-coated catalyst showed substantial gains in the conversion of multiple aromatic molecules, including a 5-fold improvement in turnover frequency versus the uncoated catalyst in the hydrogenation of naphthalene. This activity enhancement was maintained upon scaling the coating synthesis process from 3 to 100 g. Based on the results from X-ray photoelectron spectroscopy, X-ray absorption spectroscopy, and computational modeling, the activity enhancement was attributed to ensemble effects resulting from partial TiO2 coverage of the Pd surface rather than fundamental changes to the Pd electronic structure. Additional durability testing confirmed that the TiO2 coating improved the thermal and hydrothermal stability of the catalyst as well as tolerance toward sulfur impurities in the reactant stream. Using an economic model of an industrial deep hydrogenation process, we found that an increase in catalyst activity or lifetime of 2× would justify even a relatively high estimate for the cost of TiO2 atomic layer deposition coatings at scale.
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Engineering of nonribosomal peptide synthetases (NRPSs) has faced numerous obstacles despite being an attractive path toward bioactive molecules. Specificity filters in the nonribosomal peptide assembly line determine engineering success, but the relative contribution of the adenylation (A) and condensation (C) domains is under debate. In the engineered, bimodular NRPS sdV-GrsA/GrsB1, the first module is a subdomain-swapped chimera showing substrate promiscuity. On sdV-GrsA and evolved mutants, we have employed kinetic modeling to investigate product specificity under substrate competition. Our model contains one step in which the A-domain acylates the thiolation (T) domain and one condensation step in which deacylation of the T-domain occurs. The simplified model agrees well with the experimentally determined acylation preferences and shows that the condensation specificity is mismatched with the engineered acylation specificity. Our model predicts that product specificity changes during the course of the reaction due to dynamic T-domain loading and that the A-domain overrules the C-domain specificity when the T-domain loading reaches a steady state. Thus, we have established a tool for investigating the poorly accessible C-domain specificity through nonlinear kinetic modeling and gained critical insights into how the interplay of the A- and C-domains determines the product specificity of NRPSs.
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Cyanohydrins (α-hydroxy nitriles) are a special type of nitriles that readily decompose into hydrogen cyanide (HCN) and the corresponding carbonyl compounds. Hydration of cyanohydrins that are readily available through cyanation of aldehydes and ketones provides the most straightforward route to valuable α-hydroxyamides. However, due to low stability of cyanohydrins and deactivation of the catalysts by the released HCN, catalytic direct hydration of cyanohydrins still remains largely unsolved. As a general trend, cyanohydrins containing bulkier substituents, such as α,α-diaryl cyanohydrins, degrade more quickly and thus are more difficult to be hydrated. Here, we report development of cationic platinum catalysts that exhibit high reactivity for hydration of various cyanohydrins. Detailed mechanistic investigations for hydration of nitriles by (P∼P)Pt(PR2OH)X(OTf) reveal a catalytic cycle involving the formation of a five-membered metallacyclic intermediate and subsequent hydrolysis via attacking on the phosphorus of the secondary phosphine oxide (PR2OH) ligand by H2O. We discovered that Pt catalyst A bearing the electron-rich, appropriately small-bite-angle bisphosphine ligand provides super reactivity for hydration of cyanohydrins. The hydration reactions catalyzed by A proceed at ambient temperatures and occur with a wide variety of cyanohydrins, including the most difficult α,α-diaryl cyanohydrins, with good turnover numbers.
17
Understanding the molecular basis for controlled H2O2 activation is of fundamental importance for peroxide-driven catalysis by metalloenzymes. In addition to O2 activation in the presence of stoichiometric reductants, an increasing number of metalloenzymes are found to activate the H2O2 cosubstrate for oxidative transformations in the absence of stoichiometric reductants. Herein, we characterized the X-ray structure of the P450BM3 F87A mutant in complex with the dual-functional small molecule (DFSM) N-(ω-imidazolyl)-hexanoyl-l-phenylalanine (Im-C6-Phe), which enables an efficient peroxygenase activity for P450BM3. Our computational investigations show that the H2O2 activations by P450BM3 are highly dependent on the substrate and the DFSM. In the absence of both the substrate and the DFSM, H2O2 activation via the O–O homolysis mechanism is significantly inhibited by the H-bonding network from the proximal H of H2O2. However, the presence of the substrate expels the solvation waters and disrupts the H-bonding network from the proximal H of H2O2, thus remarkably favoring homolytic O–O cleavage toward Cpd I formation. However, the presence of the DFSM forms a proton channel between the imidazolyl group of the DFSM and the proximal H of H2O2, thus enabling a heterolytic O–O cleavage and Cpd I formation that is greatly favored over the homolysis mechanism. Meanwhile, our simulations demonstrate that the H-bonding network from the distal H of H2O2 is the key to control of the H2O2 activation in the homolytic route. These findings are in line with all available experimental data and highlight the key roles of H-bonding networks in dictating H2O2 activations.
18
We report a copper-catalyzed aminoheteroarylation of unactivated alkenes to access valuable heteroarylethylamine motif. The developed reaction features a copper-catalyzed intermolecular electrophilic amination of the alkenes followed by a migratory heteroarylation. The method applies to alcohol-, amide-, and ether-containing alkenes, overcoming the common requirement of a hydroxyl motif in previous migratory difunctionalization reactions. This reaction is effective for the introduction of diverse aliphatic amines and has good functional group tolerance, which is particularly useful for rich functionalized heteroarenes. This migration-involved reaction was found well suited as a powerful ring-expansion approach for the construction of medium-sized rings that are in great demand in medicinal chemistry.
19
Securinega alkaloids represent a class of plant secondary metabolites with intriguing bridged tetracyclic structures and promising biological activities. Despite extensive synthetic efforts and a number of innovative total syntheses, no relevant biosynthetic genes have been reported to date. In this study, fluesuffine A (1), a C-2 and C-3 functionalized derivative of Securinega alkaloids with a fused 5/5/5/6/5/6/5 congested heptacyclic ring system, was isolated from Flueggea suffruticosa.
20
Energy-transfer processes involving copper complexes are rare. Using an optimized heteroleptic copper complex, Cu(bphen)(XantPhos)BF4, photosensitized E → Z isomerization of olefins is demonstrated. The XantPhos ligand afforded sensitizers with improved catalyst stability, while the bphen ligand lengthened the excited-state lifetime. A series of 25 di- and trisubstituted alkenes underwent photoisomerization, including macrocycles and 1,3-enynes. Cu(bphen)(XantPhos)BF4 could also be employed in a tandem ATRA/photoisomerization process employing arylsulfonyl chlorides, an example of photoisomerization with halide-substituted olefins.
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Ketoreductases are a prominent member of the oxidoreductase family with important applications in biotechnology and metabolic engineering, providing a general method for reversible and stereoselective conversion of C═O and C–OH functional groups. As such, developing a deeper understanding of their substrate selectivity would expand our ability to engineer the enzymatic or microbial production of small-molecule targets. Here, we report the crystal structure and biochemical characterization of a mitochondrial ketoreductase AsHadh2 from Ascaris suum with preference for an α-methyl branched substrate, (S)-3-oxo-2-methylbutyryl-CoA (OMB-CoA), compared to its linear analog, 3-oxo-butyryl-CoA (OB-CoA).