- Electrochemical Ring-Opening Dicarboxylation of Strained Carbon-Carbon Single Bonds with CO2: Facile Synthesis of Diacids and Derivatization into Polyesters
-
Diacids are important monomers in the polymer industry to construct valuable materials. Dicarboxylation of unsaturated bonds, such as alkenes and alkynes, with CO2 has been demonstrated as a promising synthetic method. However, dicarboxylation of C-C single bonds with CO2 has rarely been investigated. Herein we report a novel electrochemical ring-opening dicarboxylation of C-C single bonds in strained rings with CO2. Structurally diverse glutaric acid and adipic acid derivatives were synthesized from substituted cyclopropanes and cyclobutanes in moderate to high yields. In contrast to oxidative ring openings, this is also the first realization of an electroreductive ring-opening reaction of strained rings, including commercialized ones. Control experiments suggested that radical anions and carbanions might be the key intermediates in this reaction. Moreover, this process features high step and atom economy, mild reaction conditions (1 atm, room temperature), good chemoselectivity and functional group tolerance, low electrolyte concentration, and easy derivatization of the products. Furthermore, we conducted polymerization of the corresponding diesters with diols to obtain a potential UV-shielding material with a self-healing function and a fluorine-containing polyester, whose performance tests showed promising applications.
- Liao, Li-Li,Wang, Zhe-Hao,Cao, Ke-Gong,Sun, Guo-Quan,Zhang, Wei,Ran, Chuan-Kun,Li, Yiwen,Chen, Li,Cao, Guang-Mei,Yu, Da-Gang
-
supporting information
p. 2062 - 2068
(2022/02/10)
-
- Controllable stereoinversion in DNA-catalyzed olefin cyclopropanationviacofactor modification
-
The assembly of DNA with metal-complex cofactors can form promising biocatalysts for asymmetric reactions, although catalytic performance is typically limited by low enantioselectivities and stereo-control remains a challenge. Here, we engineer G-quadruplex-based DNA biocatalysts for an asymmetric cyclopropanation reaction, achieving enantiomeric excess (eetrans) values of up to +91% with controllable stereoinversion, where the enantioselectivity switches to ?72% eetransthrough modification of the Fe-porphyrin cofactor. Complementary circular dichroism, nuclear magnetic resonance, and fluorescence titration experiments show that the porphyrin ligand of the cofactor participates in the regulation of the catalytic enantioselectivityviaa synergetic effect with DNA residues at the active site. These findings underline the important role of cofactor modification in DNA catalysis and thus pave the way for the rational engineering of DNA-based biocatalysts.
- Cheng, Yu,Hao, Jingya,Jia, Guoqing,Li, Can,Lu, Shengmei,Miao, Wenhui
-
p. 7918 - 7923
(2021/06/16)
-
- Synthesis, structure and reactivity of iridium complexes containing a bis-cyclometalated tridentate C^N^C ligand
-
In an effort to synthesize cyclometalated iridium complexes containing a tridentate C^N^C ligand, transmetallation of [Hg(HC^N^C)Cl] (1) (H2C^N^C = 2,6-bis(4-tert-butylphenyl)pyridine) with various organoiridium starting materials has been studied. The treatment of1with [Ir(cod)Cl]2(cod = 1,5-cyclooctadiene) in acetonitrile at room temperature afforded a hexanuclear Ir4Hg2complex, [Cl(κ2C,N-HC^N^C)(cod)IrHgIr(cod)Cl2]2(2), which features Ir-Hg-Ir and Ir-Cl-Ir bridges. Refluxing2with sodium acetate in tetrahydrofuran (thf) resulted in cyclometalation of the bidentate HC^N^C ligand and formation of trinuclear [(C^N^C)(cod)IrHgIr(cod)Cl2] (3). On the other hand, refluxing [Ir(cod)Cl]2with1and sodium acetate in thf yielded [Ir(C^N^C)(cod)(HgCl)] (4). Chlorination of4with PhICl2gave [Ir(C^N^C)(cod)Cl]·HgCl2(5·HgCl2) that reacted with tricyclohexylphosphine to yield Hg-free [Ir(C^N^C)(cod)Cl] (5). Chloride abstraction of5with silver(i) triflate (AgOTf) gave [Ir(C^N^C)(cod)(H2O)](OTf) (6) that can catalyze the cyclopropanation of styrene with ethyl diazoacetate. Reaction of1and [Ir(CO)2Cl(py)] (py = pyridine) with sodium acetate in refluxing thf afforded [Ir(C^N^C)(HgCl)(py)(CO)] (7), in which the carbonyl ligand is coplanar with the C^N^C ligand. On the other hand, refluxing1with (PPh4)[Ir(CO)2Cl2] and sodium acetate in acetonitrile gave [Ir(C^N^C)(κ2C,N-HC^N^C)(CO)] (8), the carbonyl ligand of which istransto the pyridyl ring of the bidentate HC^N^C ligand. Upon irradiation with UV light8in thf was isomerized to8′, in which the carbonyl istransto a phenyl group of the bidentate HC^N^C ligand. The isomer pair8and8′exhibited emission at 548 and 514 nm in EtOH/MeOH at 77 K with lifetime of 84.0 and 64.6 μs, respectively. Protonation of8withp-toluenesulfonic acid (TsOH) afforded the bis(bidentate) tosylate complex [Ir(κ2C,N-HC^N^C)2(CO)(OTs)] (9) that could be reconverted to8upon treatment with sodium acetate. The electrochemistry of the Ir(C^N^C) complexes has been studied using cyclic voltammetry. Reaction of [Ir(PPh3)3Cl] with1and sodium acetate in refluxing thf led to isolation of the previously reported compound [Ir(κ2P,C-C6H4PPh2)2(PPh3)Cl] (10). The crystal structures of2-5,8,8′,9and10have been determined.
- Cheng, Shun-Cheung,Cheung, Wai-Man,Chong, Man-Chun,Ko, Chi-Chiu,Leung, Wa-Hung,Sung, Herman H.-Y.,Williams, Ian D.
-
p. 8512 - 8523
(2021/06/28)
-
- Controlling the Activity of a Caged Cobalt-Porphyrin-Catalyst in Cyclopropanation Reactions with Peripheral Cage Substituents
-
In this study, three novel cubic cages were synthesized and utilized to encapsulate a catalytically active cobalt(II) meso-tetra(4-pyridyl)porphyrin guest. The newly developed caged catalysts (Co-G@Fe8(Zn-L ? 1)6, Co-G@Fe8(Zn-L ? 2)6 and Co-G@Fe8(Zn-L ? 3)6) can be easily synthesized and differ in exo-functionalization, which are either none, polar or apolar groups. This leads to a different polarity of the peripheral environment surrounding the cage, which affects the (relative) local concentration of the substrates surrounding the cage and hence indirectly influences the substrate availability of the catalysis embedded in the active site of the caged catalyst systems. The resulting increased local substrate concentrations give rise to higher catalytic activities of the respective caged catalyst in metalloradical catalyzed cyclopropanation reactions. Interestingly, the catalytic activity is the highest when the apolar cage catalyst (Co-G@Fe8(Zn-L ? 1)6) is used, and lowest with the polar analog (Co-G@Fe8(Zn-L ? 3)6). In addition, the catalytic activity of the cage without exo-functionalities (Co-G@Fe8(Zn-L ? 2)6) is nearly two times lower than that of Co-G@Fe8(Zn-L ? 1)6 and three times higher than that of Co-G@Fe8(Zn-L ? 3)6, which further demonstrates the effect of the peripheral functionalities on the cyclopropanation reaction.
- Mouarrawis, Valentinos,Bobylev, Eduard O.,de Bruin, Bas,Reek, Joost N. H.
-
supporting information
p. 2890 - 2898
(2021/07/09)
-
- Synthesis of ruthenium–dithiocarbamate chelates bearing diphosphine ligands and their use as latent initiators for atom transfer radical additions
-
Nine representative [Ru(S2CNEt2)2(diphos)] complexes were prepared in almost quantitative yields (91–97%) from [RuCl2(p-cymene)]2, sodium diethyldithiocarbamate trihydrate, and a diphosphine (dppm, dppe, dppp, dppb, dpppe, dppen, dppbz, dppf, or DPEphos), using a novel, straightforward, one-pot procedure. The recourse to a monomodal microwave reactor was instrumental in reaching the thermodynamic equilibria favoring the targeted monometallic trichelates. All the products were fully characterized by using various analytical techniques and the molecular structures of seven of them were determined by X-ray crystallography. NMR, XRD, and IR spectroscopies evidenced a significant contribution of the thioureide resonance form Et2N+=CS22– to the electronic structure of the 1,1-dithiolate ligand. MS/MS spectrometry showed the formation of phosphine-free [Ru(S2CNEt2)2]+ cations in the gas phase, except when starting from [Ru(S2CNEt2)2(dppbz)]. The activity of the nine complexes was probed in three different catalytic processes, viz., the cyclopropanation of styrene with ethyl diazoacetate, the synthesis of vinyl esters from benzoic acid and 1-hexyne, and the atom transfer radical addition (ATRA) of carbon tetrachloride and methyl methacrylate. In the first two reactions, the saturated trichelates were poorly efficient. This was most likely due to their high stability, which prevented the formation of coordinatively unsaturated species. Contrastingly, with a turnover number of 2000 and an initial turnover frequency of 2080 h–1 for a 0.05 mol% catalyst loading, the [Ru(S2CNEt2)2(dppm)] complex emerged as a very robust, latent ATRA initiator, whose activity matched or outperformed those displayed by the most efficient ruthenium catalysts described so far.
- Aldin, Mohammed Zain,Delaude, Lionel,Zaragoza, Guillermo
-
supporting information
(2021/08/03)
-
- Catalytic cyclopropanation, antimicrobial, and DFT properties of some chelated transition metal(II) complexes
-
Transition Metal (II) complexes of general formula [MII(NH2C2H4NH2)3][B(C6F5)4]2 (1-6), where (M= Mn, Fe, Co, Ni, Cu, Zn) have been synthesized and characterized in the solid state and in solution using elemental, thermogravimetric analysis, EPR, 11B-NMR and IR spectroscopy. All complexes were used as catalysts for the cyclopropanation reaction with a variety of olefins. Excellent yields up to 93% were obtained using complex 5. All prepared complexes were used as anti-bacterial agents against different types of bacteria (Gram-negative and Gram-positive), and as anti-fungal agents. Complex 6 showed the highest activity with MIC value of 8 μg/mL against Staphylococcus aureus (Gram-positive bacteria), and of 16 μg/mL against candida albicans. To get more insights into their structural features, molecular geometries of all prepared complexes were fully optimized using density functional theory calculations at the M06-2X/6-311+G** level of theory.
- Ababneh, Taher S.,Al-Dawood, Lina A.,Al-Momani, Waleed M.,Hijazi, Ahmed K.,Taha, Ziyad A.
-
-
- Noncanonical Heme Ligands Steer Carbene Transfer Reactivity in an Artificial Metalloenzyme**
-
Changing the primary metal coordination sphere is a powerful strategy for tuning metalloprotein properties. Here we used amber stop codon suppression with engineered pyrrolysyl-tRNA synthetases, including two newly evolved enzymes, to replace the proximal histidine in myoglobin with Nδ-methylhistidine, 5-thiazoylalanine, 4-thiazoylalanine and 3-(3-thienyl)alanine. In addition to tuning the heme redox potential over a >200 mV range, these noncanonical ligands modulate the protein's carbene transfer activity with ethyl diazoacetate. Variants with increased reduction potential proved superior for cyclopropanation and N–H insertion, whereas variants with reduced Eo values gave higher S–H insertion activity. Given the functional importance of histidine in many enzymes, these genetically encoded analogues could be valuable tools for probing mechanism and enabling new chemistries.
- Dunkelmann, Daniel,Hayashi, Takahiro,Hilvert, Donald,Mittl, Peer R. E.,Ota, Yusuke,Pott, Moritz,Tinzl, Matthias
-
supporting information
p. 15063 - 15068
(2021/06/09)
-
- Encapsulating ruthenium in silica using a single source precursor: Differing outcomes for a cycloaddition reaction
-
The complex [Ru2(CO)4(μ-O2CCH2OSi(OEt)3)2(PPh3)2] was used as a single-source precursor to prepare silica-encapsulated ruthenium via hydrolysis followed by calcination. While the silica-encapsulated ruthenium catalyst and the molecular precursor both catalysed the [2 + 1] cycloaddition reaction between alkenes and ethyl diazoacetate to form cyclopropanes, the intermediate hydrolysis product partially directed the reaction towards [2 + 3] cycloaddition to form cyclic five-membered pyrazolines.
- Barik, Chandan Kr,Ganguly, Rakesh,Garcia, Felipe,Leong, Weng Kee
-
-
- A de novo peroxidase is also a promiscuous yet stereoselective carbene transferase
-
By constructing an in vivo-assembled, catalytically proficient peroxidase, C45, we have recently demonstrated the catalytic potential of simple, de novo-designed heme proteins. Here, we show that C45's enzymatic activity extends to the efficient and stereoselective intermolecular transfer of carbenes to olefins, heterocycles, aldehydes, and amines. Not only is this a report of carbene transferase activity in a completely de novo protein, but also of enzyme-catalyzed ring expansion of aromatic heterocycles via carbene transfer by any enzyme.
- Stenner, Richard,Steventon, Jack W.,Seddon, Annela,Anderson, J.L. Ross
-
p. 1419 - 1428
(2020/01/28)
-
- COMPOSITIONS AND METHODS FOR CATALYSTS BASED ON BRIDGED CHIRAL AMIDOPORPHYRINS AND THEIR METAL COMPLEXES
-
In one aspect, the disclosure relates to a mode of asymmetric induction in radical processes based on enhanced hydrogen-bonding capability and the situation of metal centers in cavity-like chiral environments. Also disclosed is an asymmetric system for stereoselective synthesis of cyclopropane and aziridine derivatives. The disclosed Co(II)-based metalloradical system has been shown to have an unusual capability of controlling both the degree and sense of asymmetric induction in cyclopropanation and aziridination reactions in a systematic manner. The disclosed system is applicable to a broad scope of substrates having diazo or azido moieties and exhibits a remarkable profile of reactivity and selectivity, providing access to cyclopropane diastereomers and aziridine enantiomers in highly enantioenriched forms. Also disclosed are catalysts useful in the disclosed processes. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present disclosure.
- -
-
Paragraph 0014; 0251; 0252; 0264
(2020/11/30)
-
- Enhancedcis- And enantioselective cyclopropanation of styrene catalysed by cytochrome P450BM3 using decoy molecules
-
We report the enhancedcis- and enantioselective cyclopropanation of styrene catalysed by cytochrome P450BM3 in the presence of dummy substrates,i.e.decoy molecules. With the aid of the decoy molecule R-Ibu-Phe, diastereoselectivity for thecisdiastereomers
- Suzuki, Kazuto,Shisaka, Yuma,Stanfield, Joshua Kyle,Watanabe, Yoshihito,Shoji, Osami
-
p. 11026 - 11029
(2020/10/05)
-
- Gold Complexes with ADAP Ligands: Effect of Bulkiness in Catalytic Carbene Transfer Reactions (ADAP = Alkoxydiaminophosphine)
-
A family of gold(I) complexes of composition AuCl(ADAP) (ADAP = alkoxydiaminophosphine) has been synthetized through a one-pot simple protocol in which the ADAP ligand is prepared in situ before reaction with the Au(I) source. Structural data demonstrate that these ADAP ligands exert a trans effect superior to those of phosphine or phosphite ligands. Evaluation of the buried volume (percentVBur) indicates a steric hindrance higher than those of several NHC, PR3, and P(OR3) ligands, in the context of AuCl(L) complexes. These complexes promote the catalytic transfer of a carbene group from ethyl diazoacetate to alkenes and alkanes. In the case of styrene, both the Csp2-H bonds and the Ca? C bond are functionalized, the relative ratio depending on the catalyst employed and correlating well with the percentVBur value. Data available allow proposing that these compounds display quite similar electronic properties but differ in steric properties, a variable that can be readily controlled upon modifying the alkoxy group at the ADAP ligand by simply replacing the starting alcohol employed in the synthesis.
- Fructos, Manuel R.,Molina, Francisco,Pérez, Pedro J.,Pizarro, Juan Diego
-
supporting information
(2020/07/14)
-
- Three-Component Reaction for the Synthesis of Highly Functionalized Propargyl Ethers
-
Multicomponent reactions provide efficient means to access molecular complexity. Herein, we report a copper-catalyzed three-component reaction of diazo compounds, alcohols and ethynyl benziodoxole (EBX) reagents for the synthesis of propargyl ethers. Extensive variations of the three partners of the reaction is possible, leading to highly functionalized and structurally diverse products under mild conditions. Alkynylation of a copper ylide intermediate is postulated as key step for this transformation.
- Pisella, Guillaume,Gagnebin, Alec,Waser, Jér?me
-
supporting information
p. 10199 - 10204
(2020/07/17)
-
- Synthesis method of cyclopropane compounds
-
The invention provides a synthesis method of cyclopropane compounds. The cyclopropane compounds have a structure as shown in a general formula I which is described in the specification. The synthesismethod comprises the following step: reacting olefin compounds A with ethyl diazoacetate under the catalytic action of a supported rhodium catalyst to obtain the cyclopropane compounds, wherein the structural formula of the olefin compounds A is shown in the specification. The synthesis method provided by the invention has the advantages of high reaction efficiency, short time, yield even reaching90% or above, and good repeatability. In addition, copper halide or an acetyl halide similar additive is not needed in the synthesis method, and the supported rhodium catalyst is adopted, so that theenvironmental protection property is relatively high.
- -
-
Paragraph 0031-0039
(2020/10/14)
-
- Cationic iron porphyrins with sodium dodecyl sulphate for micellar catalysis of cyclopropanation reactions
-
Here, we report that the combination of cationic iron porphyrins with sodium dodecyl sulphate (SDS) gives rise to efficient micellar catalysis of cyclopropanation reactions of styrene derivatives, using diazoacetates as carbene precursors. This simple, yet effective approach for cyclopropanations illustrates the power of micellar catalysis.
- Maaskant, Ruben V.,Polanco, Ehider A.,Van Lier, Roos C. W.,Roelfes, Gerard
-
supporting information
p. 638 - 641
(2020/02/11)
-
- Tuning Rh(ii)-catalysed cyclopropanation with tethered thioether ligands
-
Dirhodium(ii) paddlewheel complexes have high utility in diazo-mediated cyclopropanation reactions and ethyl diazoacetate is one of the most commonly used diazo compounds in this reaction. In this study, we report our efforts to use tethered thioether ligands to tune the reactivity of RhII-carbene mediated cyclopropanation of olefins with ethyl diazoacetate. Microwave methods enabled the synthesis of a family of RhII complexes in which tethered thioether moieties were coordinated to axial sites of the complex. Different tether lengths and thioether substituents were screened to optimise cyclopropane yields and minimise side product formation. Furthermore, good yields were obtained when equimolar diazo and olefin were used. Structural and spectroscopic investigation revealed that tethered thioethers changed the electronic structure of the rhodium core, which was instrumental in the performance of the catalysts. Computational modelling of the catalysts provided further support that the tethered thioethers were responsible for increased yields. This journal is
- Abshire, Anthony,Cressy, Derek,Darko, Ampofo,Sheffield, William,Zavala, Cristian
-
supporting information
p. 15779 - 15787
(2020/11/24)
-
- Origin of High Stereocontrol in Olefin Cyclopropanation Catalyzed by an Engineered Carbene Transferase
-
Recent advances in metalloprotein engineering have led to the development of a myoglobin-based catalyst, Mb(H64V,V68A), capable of promoting the cyclopropanation of vinylarenes with high efficiency and high diastereo- and enantioselectivity. Whereas many enzymes evolved in nature often exhibit catalytic proficiency and exquisite stereoselectivity, how these features are achieved for a non-natural reaction has remained unclear. In this work, the structural determinants responsible for chiral induction and high stereocontrol in Mb(H64V,V68A)-catalyzed cyclopropanation were investigated via a combination of crystallographic, computational (DFT), and structure-activity analyses. Our results show the importance of steric complementarity and noncovalent interactions involving first-sphere active site residues, heme-carbene, and the olefin substrate in dictating the stereochemical outcome of the cyclopropanation reaction. High stereocontrol is achieved through two major mechanisms: first, by enforcing a specific conformation of the heme-bound carbene within the active site, and second, by controlling the geometry of attack of the olefin on the carbene via steric occlusion, attractive van der Waals forces, and protein-mediated π-π interactions with the olefin substrate. These insights could be leveraged to expand the substrate scope of the myoglobin-based cyclopropanation catalyst toward nonactivated olefins and to increase its cyclopropanation activity in the presence of a bulky α-diazo-ester. This work sheds light on the origin of enzyme-catalyzed enantioselective cyclopropanation, furnishing a mechanistic framework for both understanding the reactivity of current systems and guiding the future development of biological catalysts for this class of synthetically important, abiotic transformations.
- Tinoco, Antonio,Wei, Yang,Bacik, John-Paul,Carminati, Daniela M.,Moore, Eric J.,Ando, Nozomi,Zhang, Yong,Fasan, Rudi
-
p. 1514 - 1524
(2019/02/03)
-
- Effect of proximal ligand substitutions on the carbene and nitrene transferase activity of myoglobin
-
Engineered myoglobins were recently shown to be effective catalysts for abiological carbene and nitrene transfer reactions. Here, we investigated the impact of substituting the conserved heme-coordinating histidine residue with both proteinogenic (Cys, Ser, Tyr, Asp) and non-proteinogenic Lewis basic amino acids (3-(3′-pyridyl)-alanine, p-aminophenylalanine, and β-(3-thienyl)-alanine), on the reactivity of this metalloprotein toward these abiotic transformations. These studies showed that mutation of the proximal histidine residue with both natural and non-natural amino acids result in stable myoglobin variants that can function as both carbene and nitrene transferases. In addition, substitution of the proximal histidine with an aspartate residue led to a myoglobin-based catalyst capable of promoting stereoselective olefin cyclopropanation under nonreducing conditions. Overall, these studies demonstrate that proximal ligand substitution provides a promising strategy to tune the reactivity of myoglobin-based carbene and nitrene transfer catalysts and provide a first, proof-of-principle demonstration of the viability of pyridine-, thiophene-, and aniline-based unnatural amino acids for metalloprotein engineering.
- Moore, Eric J.,Fasan, Rudi
-
p. 2357 - 2363
(2019/03/21)
-
- Next-Generation D2-Symmetric Chiral Porphyrins for Cobalt(II)-Based Metalloradical Catalysis: Catalyst Engineering by Distal Bridging
-
Novel D2-symmetric chiral amidoporphyrins with alkyl bridges across two chiral amide units on both sides of the porphyrin plane (designated “HuPhyrin”) have been effectively constructed in a modular fashion to permit variation of the bridge length. The CoII complexes of HuPhyrin, [Co(HuPhyrin)], represent new-generation metalloradical catalysts where the metal-centered d-radical is situated inside a cavity-like ligand with a more rigid chiral environment and enhanced hydrogen-bonding capability. As demonstrated with cyclopropanation and aziridination as model reactions, the bridged [Co(HuPhyrin)] functions notably different from the open catalysts, exhibiting significant enhancement in both reactivity and stereoselectivity. Furthermore, the length of the distal alkyl bridge can have a remarkable influence on the catalytic properties.
- Hu, Yang,Lang, Kai,Tao, Jingran,Marshall, McKenzie K.,Cheng, Qigan,Cui, Xin,Wojtas, Lukasz,Zhang, X. Peter
-
supporting information
p. 2670 - 2674
(2019/02/13)
-
- A transition-metal-free & diazo-free styrene cyclopropanation
-
An operationally simple and broadly applicable novel cyclopropanation of styrenes using gem-diiodomethyl carbonyl reagents has been developed. Visible-light triggered the photoinduced generation of iodomethyl carbonyl radicals, able to cyclopropanate a wide array of styrenes with excellent chemoselectivity and functional group tolerance. To highlight the utility of our photocyclopropanation, we demonstrated the late-stage functionalization of biomolecule derivatives.
- Herraiz, Ana G.,Suero, Marcos G.
-
p. 9374 - 9379
(2019/10/22)
-
- Chiral 1,8-naphthyridine based ligands: Syntheses and characterization of Di- and tetranuclear copper (I) and silver (I) complexes
-
Oxazoline and camphor-pyrazole units are introduced on the 1,8-naphthyridine scaffold to access chiral ligands L1, L2 and L3. Metalation of these chiral ligands with Cu(I) and Ag(I) precursors afforded di- and tetranuclear complexes [Cu4I4(L1)2] (1), [Cu4I4(L2)2] (2), [Cu2I2(L3)] (3), [Cu2I(L2)2](OTf) (4), [Ag2(L1)2](OTf)2 (5) and [Ag4(L2)4Br](OTf)3 (6), containing [M4Xn] (n = 1,4 and X = Br, I) or [M2Xn] (n = 0, 1, 2 and X = I) core. All complexes are structurally characterized. Naphthyridine-derived ligands reveal bridge-chelate coordination motif and hold two metal centers in close proximity. The tetranuclear complexes are dimer of dinuclear complexes bridged by the halides. Electronic absorption and emission spectra of copper complexes are reported. Catalytic utility of all complexes are examined for asymmetric transformations but they showed poor activity probably due to limited solubility and coordinative saturation at the metal centers. The best results are obtained with [L3/Cu salt] combination for cyclopropanation of styrene, N–H bond insertion and nitroaldol (Henry) reactions with very low enantioselectivity.
- Sarkar, Mithun,Pandey, Pragati,Bera, Jitendra K.
-
supporting information
p. 518 - 528
(2018/11/24)
-
- Chiral 2,2'-dipyridine ligand, preparation method thereof, and application of ligand in preparation of chiral cyclopropane derivatives
-
The invention provides a chiral 2,2'-dipyridine ligand, a preparation method thereof, and an application of the ligand in the preparation of chiral cyclopropane derivatives. The chiral 2,2'-dipyridineligand is represented by formula (1) or formula (1'), can be used for efficiently preparing the chiral cyclopropane derivatives, and has the advantages of high yield, good stereoselectivity, easinessin separation and purification, and high practical values.
- -
-
Paragraph 0117-0118; 0129
(2019/10/01)
-
- Z-bpy, a New C2-Symmetric Bipyridine Ligand and Its Application in Enantioselective Copper(I)-Catalyzed Cyclopropanation of Olefins
-
A rigid C2-symmetric chiral bipyridine ligand Z-bpy with a triptycene-like backbone was designed and synthesized from simple chemicals in a scalable route. Using this new ligand, copper(I) catalyzed cyclopropanation of styrenes with commercial ethyl diazoacetate produced various corresponding cyclopropanes in high yields, diastereoselectivity and enantioselectivity up to 97% ee.
- Ouyang, Yizhao,Zhan, Miao,Zhou, Jing,Jiao, Jiao,Hu, Hao,Yamada, Yoichi M. A.,Li, Pengfei
-
supporting information
p. 807 - 810
(2019/07/04)
-
- Rhodium Porphyrin Catalyzed Regioselective Transfer Hydrogenolysis of C-C σ-Bonds in Cyclopropanes with iPrOH
-
A new rhodium porphyrin catalyzed regioselective transfer hydrogenolysis of both activated and unactivated cyclopropanes employing iPrOH as the hydrogen source was discovered. The reaction mechanism for the C-C σ-bond activation of cyclopropanes was identified through an initial radical substitution with rhodium(II) metalloporphyrin radical to give a rhodium porphyrin alkyl, followed by hydrogenolysis with iPrOH to give the corresponding acyclic alkanes and regenerate rhodium(II) metalloporphyrin radical.
- Chen, Chen,Feng, Shiyu,Chan, Kin Shing
-
p. 2582 - 2589
(2019/07/02)
-
- Network topology and cavity confinement-controlled diastereoselectivity in cyclopropanation reactions catalyzed by porphyrin-based MOFs
-
In this work, we show that the stereoselectivity of a reaction can be controlled by directing groups of substrates, by network topology and by local cavity confinement of metal-organic framework (MOF) catalysts. We applied the porphyrin-based PCN-224(Rh), which contains no stereocenters in the cyclopropanation reaction using ethyl diazoacetate (EDA) as carbene source. When styrene and other non-coordinating olefins are used as substrates, high activity, but no diastereoselectivity is observed. Interestingly, conversion of 4-amino- and 4-hydroxystyrene substrates occurs with high diastereomeric ratios (dr) of up to 23 : 1 (trans : cis). We attribute this to local pore confinement effects as a result of substrate coordination to neighboring Rh-centers, which position the olefin with respect to the active site, causing a break of local symmetry of the coordinated substrate. The effect of local pore confinement was improved by using PCN-222(Rh) as catalyst, which is a structural analog of PCN-224(Rh) with characteristic Kagomé topology featuring shorter Rh-Rh distances. A remarkable dr of 42 : 1 (trans : cis) was observed for 4-aminostyrene. In this case, the length of the substrate corresponds to the average distance between two neighboring Rh centers within the pores of PCN-222(Rh), which drastically boosts the diastereoselectivity. This work showcases how diastereomeric control can be achieved by favorable substrate-catalyst interactions and thoughtful adjustment of confined reaction space using porphyrin-based MOFs, in which stereocenters are inherently absent.
- Epp, Konstantin,Bueken, Bart,Hofmann, Benjamin J.,Cokoja, Mirza,Hemmer, Karina,De Vos, Dirk,Fischer, Roland A.
-
p. 6452 - 6459
(2019/11/20)
-
- Stereoselective Cyclopropanation of Electron-Deficient Olefins with a Cofactor Redesigned Carbene Transferase Featuring Radical Reactivity
-
Engineered myoglobins and other hemoproteins have recently emerged as promising catalysts for asymmetric olefin cyclopropanation reactions via carbene-transfer chemistry. Despite this progress, the transformation of electron-poor alkenes has proven to be very challenging using these systems. Here, we describe the design of a myoglobin-based carbene transferase incorporating a non-native iron-porphyrin cofactor and axial ligand, as an efficient catalyst for the asymmetric cyclopropanation of electron-deficient alkenes. Using this metalloenzyme, a broad range of both electron-rich and electron-deficient alkenes are cyclopropanated with high efficiency and high diastereo- A nd enantioselectivity (up to >99% de and ee). Mechanistic studies revealed that the expanded reaction scope of this carbene transferase is dependent upon the acquisition of metallocarbene radical reactivity as a result of the reconfigured coordination environment around the metal center. The radical-based reactivity of this system diverges from the electrophilic reactivity of myoglobin and most of the known organometallic carbene-transfer catalysts. This work showcases the value of cofactor redesign toward tuning and expanding the reactivity of metalloproteins in abiological reactions, and it provides a biocatalytic solution to the asymmetric cyclopropanation of electron-deficient alkenes. The metallocarbene radical reactivity exhibited by this biocatalyst is anticipated to prove useful in the context of a variety of other synthetic transformations.
- Carminati, Daniela M.,Fasan, Rudi
-
p. 9683 - 9697
(2019/10/19)
-
- Novel dirhodium coordination polymers: The impact of side chains on cyclopropanation
-
Seven novel dirhodium coordination polymers (Rh2-Ln) (n = 1-7) are prepared by employing bitopic ligands to connect dirhodium nodes. The formation of the framework is confirmed by attenuated total reflectance Fourier transform infrared (ATR-FTIR) and 1H → 13C cross polarization magic angle spinning nuclear magnetic resonance (CP MAS NMR) spectroscopy. Defect sites resulting from incomplete ligand substitution are revealed by 19F MAS NMR. The random stacking behavior of the frameworks in the obtained solid is analyzed by scanning electron microscopy (SEM) and X-ray diffraction (XRD). The Rh2/O interaction in neighboring layers is investigated by diffuse reflectance ultra-violet visible light (DR-UV-vis) spectroscopy and X-ray photoelectron spectroscopy (XPS). This interaction is relevant to understand the catalytic behavior of various Rh2-Ln catalysts in the cyclopropanation of styrene with ethyl diazoacetate (EDA). In this context, the structure-reactivity relationship is discussed by taking into consideration both interlayer Rh2/O interactions and steric effects of side chains.
- Liu, Jiquan,Xu, Yeping,Groszewicz, Pedro B.,Brodrecht, Martin,Fasel, Claudia,Hofmann, Kathrin,Tan, Xijuan,Gutmann, Torsten,Buntkowsky, Gerd
-
p. 5190 - 5200
(2018/10/23)
-
- Confinement of Fe-Al-PMOF catalytic sites favours the formation of pyrazoline from ethyl diazoacetate with an unusual sharp increase of selectivity upon recycling
-
The catalytic properties of a chemically stable iron porphyrin MOF were evaluated in a reaction with ethyl diazoacetate. In contrast to its homogeneous counterpart, an Fe-porphyrin-MOF features a different reaction pathway leading to the formation of pyrazoline due to the confinement of catalytic sites within the MOF network. Unexpectedly, a sharp increase of the selectivity from 35% (run 1) to 86% (run 5) occurs upon catalyst recycling.
- Abeykoon, Brian,Devic, Thomas,Grenèche, Jean-Marc,Fateeva, Alexandra,Sorokin, Alexander B.
-
supporting information
p. 10308 - 10311
(2018/09/21)
-
- ARTIFICIAL METALLOENZYMES CONTAINING NOBLE METAL-PORPHYRINS
-
The present invention is drawn to artificial metalloenzymes for use in cyclopropanation reactions, amination and C—H insertion.
- -
-
Paragraph 0351
(2018/11/21)
-
- Rhodium Complexes of a New-Generation Sapphyrin: Unique Structures, Axial Chirality, and Catalysis
-
Rhodium insertion into the new 5,10,15,20-tetrakis(trifluoromethyl)sapphyrin was found to be much more facile than for other analogues, owing to NH???F hydrogen-bonding interactions that stabilise the pyrrole-inverted structure characteristic of the metallated product. The thus-obtained rhodium(I) complexes have axial chirality, and the enantiomers were resolved. The latter were found to interconvert quite rapidly in a process that involves a tautomerisation-like movement of the metal fragment between the five N atoms. The rhodium sapphyrins were investigated as catalysts for organic synthesis, by studying their carbene-transfer activity in the cyclopropanation of styrene with ethyl diazoacetate and comparing it to that of rhodium corroles.
- Chen, Qiu-Cheng,Saltsman, Irena,Kaushansky, Alexander,Xiao, Zi-Ye,Fridman, Natalia,Zhan, Xuan,Gross, Zeev
-
p. 17255 - 17261
(2018/11/10)
-
- An Artificial Heme Enzyme for Cyclopropanation Reactions
-
An artificial heme enzyme was created through self-assembly from hemin and the lactococcal multidrug resistance regulator (LmrR). The crystal structure shows the heme bound inside the hydrophobic pore of the protein, where it appears inaccessible for substrates. However, good catalytic activity and moderate enantioselectivity was observed in an abiological cyclopropanation reaction. We propose that the dynamic nature of the structure of the LmrR protein is key to the observed activity. This was supported by molecular dynamics simulations, which showed transient formation of opened conformations that allow the binding of substrates and the formation of pre-catalytic structures.
- Villarino, Lara,Splan, Kathryn E.,Reddem, Eswar,Alonso-Cotchico, Lur,Gutiérrez de Souza, Cora,Lledós, Agustí,Maréchal, Jean-Didier,Thunnissen, Andy-Mark W. H.,Roelfes, Gerard
-
supporting information
p. 7785 - 7789
(2018/06/04)
-
- Enhanced Electrophilicity of Heterobimetallic Bi-Rh Paddlewheel Carbene Complexes: A Combined Experimental, Spectroscopic, and Computational Study
-
Dirhodium paddlewheel complexes are indispensable tools in modern organometallic catalysis for the controlled decomposition of diazo-compounds. Tuning the reactivity of the thus-formed transient carbenes remains an active and dynamic field of research. Herein, we present our findings that the distal metal center plays an as yet underappreciated role in modulating this reactivity. Replacement of one rhodium atom in the bimetallic core for bismuth results in the formation of a significantly more electrophilic carbene complex. Bismuth-rhodium catalysts thereby facilitate previously unknown modes of reactivity for α-diazoester compounds, including the cyclopropanation of alkenes as electron deficient as trichloroethylene. While dirhodium paddlewheel complexes remain the catalysts of choice for many carbene-mediated transformations, their bismuth-rhodium analogues exhibit complementary reactivity and show great potential for small molecule and solvent activation chemistry. DFT calculations highlight the importance of metal-metal bonding interactions in controlling carbene electrophilicity. The paucity of these interactions between the 4d orbitals of rhodium and the 6p orbitals of bismuth results in weaker π-back-bonding interactions for bismuth-rhodium carbene complexes compared to dirhodium carbene complexes. This leads to weakening of the rhodium-carbene bond and to a more carbene-centered LUMO, accounting for the observed enhancement in bismuth-rhodium carbene electrophilicity. These findings are supported by a detailed spectroscopic study of the "donor-donor" carbene complexes Rh2(esp)2C(p-MeOPh)2 (19) and BiRh(esp)2C(p-MeOPh)2 (20), employing a combination of UV-vis and resonance Raman spectroscopy. The results reveal that carbene chemoselectivity in MRh(L)4 catalysis can be modulated to a previously unrecognized extent by the distal metalloligand.
- Collins, Lee R.,Van Gastel, Maurice,Neese, Frank,Fürstner, Alois
-
supporting information
p. 13042 - 13055
(2018/10/15)
-
- Synthesis method of 2-phenylcyclopropane-1-carboxylic acid
-
The invention provides a synthesis method of 2-phenylcyclopropane-1-carboxylic acid and particularly relates to the technical field of compound preparation. The synthesis method includes steps of: (S1) dissolving triethyl phosphonoacetate and a catalyst in an ether inert solvent, dropwise adding phenylethylene oxide at certain reaction temperature, performing a reaction for certain time at the temperature to obtain an intermediate product, ethyl 2-phenylcyclopropaneformate; (S2) concentrating the reaction liquid in the (S1) to remove organic solvent, adding an alkaline solution for hydrolysis,acidifying the reaction liquid with acid solution, and filtering and drying the product to obtain the final product, 2-phenylcyclopropane-1-carboxylic acid. The synthesis method has simple steps andis improved in yield.
- -
-
Paragraph 0020-0025; 0027-0029; 0032; 0033; 0034; 0037-0039
(2018/11/04)
-
- Generation and Reactivity of Electron-Rich Carbenes on the Surface of Catalytic Gold Nanoparticles
-
The reactive nature of carbenes can be modulated, and ultimately reversed, by receiving additional electron density from a metal. Here, it is shown that Au nanoparticles (NPs) generate an electron-rich carbene on surface after transferring electron density to the carbonyl group of an in situ activated diazoacetate, as assessed by Fourier transformed infrared (FT-IR) spectroscopy, magic angle spinning nuclear magnetic resonance (MAS NMR), and Raman spectroscopy. Density functional theory (DFT) calculations support the observed experimental values and unveil the participation of at least three different Au atoms during carbene stabilization. The surface stabilized carbene shows an extraordinary stability against nucleophiles and reacts with electrophiles to give new products. These findings showcase the ability of catalytic Au NPs to inject electron density in energetically high but symmetrically allowed valence orbitals of sluggish molecules.
- Oliver-Meseguer, Judit,Boronat, Mercedes,Vidal-Moya, Alejandro,Concepción, Patricia,Rivero-Crespo, Miguel ángel,Leyva-Pérez, Antonio,Corma, Avelino
-
supporting information
p. 3215 - 3218
(2018/03/13)
-
- Reversible Metalation and Catalysis with a Scorpionate-like Metallo-ligand in a Metal-Organic Framework
-
The installation of metallo-ligands in metal-organic frameworks (MOFs) is an effective means to create site-isolated metal centers toward single-site heterogeneous catalysis. Although trispyrazolyborate (Tp) and tripyrazolylmethane (Tpm) form one of the most iconic classes of homogeneous catalysts, neither has been used as a metallo-ligand for the generation of MOFs thus far. Here, we show that upon in situ metalation with CuI, a tricarboxylated Tpm ligand reacts with ZrOCl2 to generate a new MOF exhibiting neutral scorpionate-like chelating sites. These sites undergo for facile demetalation and remetalation with retention of crystallinity and porosity. When remetalated with CuI, the MOF exhibits spectroscopic features and catalytic activity for olefin cyclopropanation reactions that are similar to the molecular [Cu(CH3CN)Tpm]PF6 complex (Tpm? = tris(3,5-dimethylpyrazolyl)methane). These results demonstrate the inclusion of Tp or Tpm metallo-ligands in a MOF for the first time and provide a blueprint for immobilizing Tpm? catalysts in a spatially isolated and well-defined environment.
- Sun, Chenyue,Skorupskii, Grigorii,Dou, Jin-Hu,Wright, Ashley M.,Dinca, Mircea
-
p. 17394 - 17398
(2019/01/04)
-
- Synthesis, characterization, and catalytic evaluation of ruthenium-diphosphine complexes bearing xanthate ligands
-
The reaction of [RuCl2(p-cymene)]2 with potassium O-ethylxanthate and a set of nine representative Ph2P-X-PPh2 bidentate phosphines (dppm, dppe, dppp, dppb, dpppe, dppen, dppbz, dppf, and DPEphos) afforded monometallic [Ru(S2COEt)2(diphos)] chelates 1-9 in 62-96% yield. All the products were fully characterized by using various analytical techniques and their molecular structures were determined by X-ray crystallography. They featured a highly distorted octahedral geometry with a S-Ru-S bite angle close to 72° and P-Ru-P angles ranging between 73° and 103°. Bond lengths and IR stretching frequencies recorded for the anionic xanthate ligands strongly suggested a significant contribution of the EtO+CS22- resonance form. 1H NMR and XRD analyses showed that the methylene protons of the ethyl groups were diastereotopic due to a strong locking of their conformation by a neighboring phenyl ring. On cyclic voltammetry, quasi-reversible waves were observed for the Ru2+/Ru3+ redox couples with E1/2 values ranging between 0.65 and 0.80 V vs. Ag/AgCl. The activity of chelates 1-9 was probed in three catalytic processes, viz., the synthesis of vinyl esters from benzoic acid and 1-hexyne, the cyclopropanation of styrene with ethyl diazoacetate, and the atom transfer radical addition of carbon tetrachloride and methyl methacrylate. In the first case, 31P NMR analysis of the reaction mixtures showed that the starting complexes remained mostly unaltered despite the harsh thermal treatment that was applied to them. In the second case, monitoring the rate of nitrogen evolution revealed that all the catalysts under investigation behaved similarly and were rather slow initiators. In the third case, [Ru(S2COEt)2(dppm)] was singled out as a very active and selective catalyst already at 140 °C, whereas most of the other complexes resisted degradation up to 160 °C and were only moderately active. Altogether, these results were in line with the high stability displayed by [Ru(S2COEt)2(diphos)] chelates 1-9.
- Zain Aldin, Mohammed,Maho, Anthony,Zaragoza, Guillermo,Demonceau, Albert,Delaude, Lionel
-
p. 13926 - 13938
(2018/10/20)
-
- Cyclopropanations via Heme Carbenes: Basic Mechanism and Effects of Carbene Substituent, Protein Axial Ligand, and Porphyrin Substitution
-
Catalytic carbene transfer to olefins is a useful approach to synthesize cyclopropanes, which are key structural motifs in many drugs and biologically active natural products. While catalytic methods for olefin cyclopropanation have largely relied on rare transition-metal-based catalysts, recent studies have demonstrated the promise and synthetic value of iron-based heme-containing proteins for promoting these reactions with excellent catalytic activity and selectivity. Despite this progress, the mechanism of iron-porphyrin and hemoprotein-catalyzed olefin cyclopropanation has remained largely unknown. Using a combination of quantum chemical calculations and experimental mechanistic analyses, the present study shows for the first time that the increasingly useful C-C functionalizations mediated by heme carbenes feature an FeII-based, nonradical, concerted nonsynchronous mechanism, with early transition state character. This mechanism differs from the FeIV-based, radical, stepwise mechanism of heme-dependent monooxygenases. Furthermore, the effects of the carbene substituent, metal coordinating axial ligand, and porphyrin substituent on the reactivity of the heme carbenes was systematically investigated, providing a basis for explaining experimental reactivity results and defining strategies for future catalyst development. Our results especially suggest the potential value of electron-deficient porphyrin ligands for increasing the electrophilicity and thus the reactivity of the heme carbene. Metal-free reactions were also studied to reveal temperature and carbene substituent effects on catalytic vs noncatalytic reactions. This study sheds new light into the mechanism of iron-porphyrin and hemoprotein-catalyzed cyclopropanation reactions and it is expected to facilitate future efforts toward sustainable carbene transfer catalysis using these systems.
- Wei, Yang,Tinoco, Antonio,Steck, Viktoria,Fasan, Rudi,Zhang, Yong
-
p. 1649 - 1662
(2018/02/17)
-
- Mild Ring-Opening 1,3-Hydroborations of Non-Activated Cyclopropanes
-
The Brown hydroboration reaction, first reported in 1957, is the addition of B?H across an olefin in an anti-Markovnikov fashion. Here, we solved a long-standing problem on mild 1,3-hydroborations of non-activated cyclopropanes. A three-component system including cyclopropanes, boron halides, and hydrosilanes has been developed for borylative ring-opening of cyclopropanes following the anti-Markovnikov rule, under mild reaction conditions. Density functional theory (M06-2X) calculations show that the preferred pathway involves a cationic boron intermediate which is quenched by hydride transfer from the silane.
- Wang, Di,Xue, Xiao-Song,Houk, Kendall N.,Shi, Zhuangzhi
-
supporting information
p. 16861 - 16865
(2018/11/27)
-
- Orthogonal Expression of an Artificial Metalloenzyme for Abiotic Catalysis
-
A cytochrome P450 was engineered to selectively incorporate Ir(Me)-deuteroporphyrin IX (Ir(Me)-DPIX), in lieu of heme, in bacterial cells. Cofactor selectivity was altered by introducing mutations within the heme-binding pocket to discriminate the deuteroporphyrin macrocycle, in combination with mutations to the P450 axial cysteine to accommodate a pendant methyl group on the Ir(Me) center. This artificial metalloenzyme was investigated for activity in non-native metallocarbenoid-mediated olefin cyclopropanation reactions and showed enhanced activity for aliphatic and electron-deficient olefins when compared to the native heme enzyme. This work provides a general strategy to augment the chemical functionality of heme enzymes in cells with application towards abiotic catalysis.
- Reynolds, Evan W.,Schwochert, Timothy D.,McHenry, Matthew W.,Watters, John W.,Brustad, Eric M.
-
p. 2380 - 2384
(2017/11/16)
-
- Mechanistic studies on gold-catalyzed direct arene c-h bond functionalization by carbene insertion: The coinage-metal effect
-
The catalytic functionalization of the Csp2-H bond of benzene by means of the insertion of the CHCO2Et group from ethyl diazoacetate (N2= CHCO2Et) has been studied with the series of coinage-metal complexes IPrMCl (IPr = 1,3-bis- (diisopropylphenyl)imidazol-2-ylidene) and NaBArF 4 (BArF 4 = tetrakis(3,5-bis(trifluoromethyl)phenyl)borate). For Cu and Ag, these examples constitute the first use of such metals toward this transformation, which also provides ethyl cyclohepta-2,4,6-trienecarboxylate as a byproduct from the so-called Buchner reaction. In the case of methyl-substituted benzenes, the reaction exclusively proceeds onto the aromatic ring, the Csp3-H bond remaining unreacted. A significant coinage-metal effect has been observed, since the gold catalyst favors the formation of the insertion product into the Csp2-H bond whereas copper and silver preferentially induce the formation of the cycloheptatriene derivative. Experimental studies and theoretical calculations have explained the observed selectivity in terms of the formation of a common Wheland intermediate, resembling an electrophilic aromatic substitution, from which the reaction pathway evolves into two separate routes to each product.
- Fructos, Manuel R.,Besora, Maria,Braga, Ataualpa A. C,Díaz-Requejo, M. Mar,Maseras, Feliu,Perez, Pedro J.
-
supporting information
p. 172 - 179
(2017/04/04)
-
- Stereoselective Olefin Cyclopropanation under Aerobic Conditions with an Artificial Enzyme Incorporating an Iron-Chlorin e6 Cofactor
-
Myoglobin has recently emerged as a promising biocatalyst for catalyzing carbene-mediated cyclopropanation, a synthetically valuable transformation not found in nature. Having naturally evolved for binding dioxygen, the carbene transferase activity of this metalloprotein is severely inhibited by it, imposing the need for strictly anaerobic conditions to conduct these reactions. In this report, we describe how substitution of the native heme cofactor with an iron-chlorin e6 complex enabled the development of a biocatalyst capable of promoting the cyclopropanation of vinylarenes with high catalytic efficiency (up to 6970 TON), turnover rate (>2000 turnovers/min), and stereoselectivity (up to 99% de and ee) in the presence of oxygen. The artificial metalloenzyme can be recombinantly expressed in bacterial cells, enabling its application also in the context of whole-cell biotransformations. This work makes available a robust and easy-to-use oxygen-tolerant biocatalyst for asymmetric cyclopropanations and demonstrates the value of porphyrin ligand substitution as a strategy for tuning and enhancing the catalytic properties of hemoproteins in the context of abiological reactions.
- Sreenilayam, Gopeekrishnan,Moore, Eric J.,Steck, Viktoria,Fasan, Rudi
-
p. 7629 - 7633
(2017/11/10)
-
- Enzyme stabilization via computationally guided protein stapling
-
Thermostabilization represents a critical and often obligatory step toward enhancing the robustness of enzymes for organic synthesis and other applications. While directed evolution methods have provided valuable tools for this purpose, these protocols are laborious and time-consuming and typically require the accumulation of several mutations, potentially at the expense of catalytic function. Here, we report a minimally invasive strategy for enzyme stabilization that relies on the installation of genetically encoded, nonreducible covalent staples in a target protein scaffold using computational design. This methodology enables the rapid development of myoglobin-based cyclopropanation biocatalysts featuring dramatically enhanced thermostability (ΔTm = +18.0°C and ΔT50 = +16.0°C) as well as increased stability against chemical denaturation [ΔCm (GndHCl) = 0.53 M], without altering their catalytic efficiency and stereoselectivity properties. In addition, the stabilized variants offer superior performance and selectivity compared with the parent enzyme in the presence of a high concentration of organic cosolvents, enabling the more efficient cyclopropanation of a water-insoluble substrate. This work introduces and validates an approach for protein stabilization which should be applicable to a variety of other proteins and enzymes.
- Moore, Eric J.,Zorine, Dmitri,Hansen, William A.,Khare, Sagar D.,Fasan, Rudi
-
p. 12472 - 12477
(2017/11/24)
-
- Metal Substitution Modulates the Reactivity and Extends the Reaction Scope of Myoglobin Carbene Transfer Catalysts
-
Engineered myoglobins have recently emerged as promising scaffolds for catalyzing carbene-mediated transformations. In this work, we investigated the effect of altering the metal center and first-sphere coordination residue on the carbene transfer reactivity of myoglobin. To this end, we first established an efficient protocol for the recombinant expression of myoglobin variants incorporating metalloporphyrins with non-native metals, including second- and third-row transition metals (ruthenium, rhodium, iridium). Characterization of the cofactor-substituted myoglobin variants across three different carbene transfer reactions (cyclopropanation, N–H insertion, S–H insertion) revealed a major influence of the nature of the metal center, its oxidation state and first-sphere coordination environment on the catalytic activity, stereoselectivity, and/or oxygen tolerance of these artificial metalloenzymes. In addition, myoglobin variants incorporating manganese- or cobalt-porphyrins were found capable of catalyzing an intermolecular carbene C–H insertion reaction involving phthalan and ethyl α-diazoacetate, a reaction not supported by iron-based myoglobins and previously accessed only using iridium-based (bio)catalysts. These studies demonstrate how modification of the metalloporphyrin cofactor environment provides a viable and promising strategy to enhance the catalytic properties and extend the reaction scope of myoglobin-based carbene transfer catalysts. (Figure presented.).
- Sreenilayam, Gopeekrishnan,Moore, Eric J.,Steck, Viktoria,Fasan, Rudi
-
supporting information
p. 2076 - 2089
(2017/06/23)
-
- MYOGLOBIN-BASED CATALYSTS FOR CARBENE TRANSFER REACTIONS
-
Methods are provided for carrying out carbene transfer transformations such as olefin cyclopropanation reactions, carbene heteroatom-H insertion reactions (heteroatom = N, S, Si), sigmatropic rearrangement reactions, and aldehyde olefination reactions with high efficiency and selectivity by using a novel class of myoglobin-based biocatalysts. These methods are useful for the synthesis of a variety of organic compounds which contain one or more new carbon-carbon or carbon-heteroatom (N, S, or Si) bond. The methods can be applied for conducting these transformations in vitro (i.e., using the biocatalyst in isolated form) and in vivo (i.e., using the biocatalyst in a whole cell system).
- -
-
Paragraph 0087; 00360; 00361
(2016/06/14)
-
- Gram-Scale Synthesis of Chiral Cyclopropane-Containing Drugs and Drug Precursors with Engineered Myoglobin Catalysts Featuring Complementary Stereoselectivity
-
Engineered hemoproteins have recently emerged as promising systems for promoting asymmetric cyclopropanations, but variants featuring predictable, complementary stereoselectivity in these reactions have remained elusive. In this study, a rationally driven strategy was implemented and applied to engineer myoglobin variants capable of providing access to 1-carboxy-2-aryl-cyclopropanes with high trans-(1R,2R) selectivity and catalytic activity. The stereoselectivity of these cyclopropanation biocatalysts complements that of trans-(1S,2S)-selective variants developed here and previously. In combination with whole-cell biotransformations, these stereocomplementary biocatalysts enabled the multigram synthesis of the chiral cyclopropane core of four drugs (Tranylcypromine, Tasimelteon, Ticagrelor, and a TRPV1 inhibitor) in high yield and with excellent diastereo- and enantioselectivity (98–99.9% de; 96–99.9% ee). These biocatalytic strategies outperform currently available methods to produce these drugs.
- Bajaj, Priyanka,Sreenilayam, Gopeekrishnan,Tyagi, Vikas,Fasan, Rudi
-
supporting information
p. 16110 - 16114
(2016/12/26)
-
- Non-covalent immobilization of chiral copper complexes on Al-MCM41: Effect of the nature of the ligand
-
Cu-Al-MCM41, prepared by deposition of copper(II) triflate with incipient wetness impregnation and thermal treatment under air flow, can be modified with different chiral ligands of the bis(oxazoline) family. The efficiency of the supported chiral catalysts in the enantioselective cyclopropanation of styrenes with ethyl diazoacetate depends on the nature of the ligand. The azabis(oxazolines) perform much better than the bis(oxazolines) and give stable catalysts that can be used for at least five consecutive runs, with productivities that can reach values close to 1000 molecules of cyclopropane per copper site. The best enantioselectivities obtained with these catalysts are in the range of 60-70% ee in the reaction at 90 °C.
- Feldman, Robert A.,Fraile, José M.
-
-
- Synthesis and catalytic applications of 1,2,3-triazolylidene gold(i) complexes in silver-free oxazoline syntheses and C-H bond activation
-
A series of novel 1,2,3-triazolylidene gold(i) chloride complexes have been synthesised and fully characterised. Silver-free methodologies for chloride ion abstraction of these complexes were evaluated for their potential as Au-based catalyst precursors. Using simple potassium salts or MeOTf as chloride scavengers produced metal complexes that catalyse both the regioselective synthesis of oxazolines and the C-H activation of benzene or styrene for carbene transfer from ethyl diazoacetate. These results indicate that Ag-free activation of 1,2,3-triazolylidene gold(i) chloride complexes is feasible for the generation of catalytically active Au triazolylidene species. However, silver-mediated activation imparts substantially higher catalytic activity in oxazoline synthesis.
- Pretorius, René,Fructos, Manuel R.,Müller-Bunz, Helge,Gossage, Robert A.,Pérez, Pedro J.,Albrecht, Martin
-
p. 14591 - 14602
(2016/09/28)
-
- Iron(II) N-heterocyclic carbene complexes in catalytic one-pot Wittig reactions: Mechanistic insights
-
An iron(II) N-heterocyclic carbene (NHC) complex is applied as catalyst for aldehyde olefination with ethyl diazoacetate (EDA) in the presence of triphenylphosphine. The reaction leads to high olefin yields with very good E-selectivities. The key step of the reaction is the catalytic in situ generation of a phosphorus ylide. Mechanistic studies reveal two possible pathways for the formation of the Wittig reagent with respect to the carbene source being the metal carbene (NHC)FeIV[dbnd]CH(CO2Et), and phosphazine, Ph3P[dbnd]N[sbnd]N[dbnd]CH(CO2Et). Based on the experimental observations a new mechanism for the transformation of phosphazine is proposed.
- Karaca, ?zden,Anneser, Markus R.,Kück, Jens W.,Lindhorst, Anja C.,Cokoja, Mirza,Kühn, Fritz E.
-
p. 213 - 220
(2016/10/25)
-
- Benzofuran-7-alkylamine compounds and applications thereof
-
The inventor designs and synthesizes benzofuran-7-alkylamine compounds with a novel structure. The test results show that most of the disclosed benzofuran-7-alkylamine compounds have a strong activity on inhibiting the synthesis of golden yellow pigment, and some compounds have an extremely strong inhibiting activity on pigments of drug resistant bacteria (S.aureus USA400 MW2, USA300 LAC, Mu50), and prominently enhance the hydrogen peroxide killing and human blood killing in vitro. In vivo, for the animal model infected by sensitive strain (S.aureus Newman) and two drug resistant strains (S.aureus USA400 MW2, Mu50), the planting of bacteria in internal organs (kidney, heart, and liver) of mice is prominently reduced. The benzofuran-7-alkylamine compounds are advantageously used for producing novel anti-bacterium drugs.
- -
-
Paragraph 0238-0241
(2016/10/10)
-
- Discovery of a Novel Inhibitor of Histone Lysine-Specific Demethylase 1A (KDM1A/LSD1) as Orally Active Antitumor Agent
-
We report the stereoselective synthesis and biological activity of a novel series of tranylcypromine (TCPA) derivatives (14a-k, 15, 16), potent inhibitors of KDM1A. The new compounds strongly inhibit the clonogenic potential of acute leukemia cell lines. In particular three molecules (14d, 14e, and 14g) showing selectivity versus MAO A and remarkably inhibiting colony formation in THP-1 human leukemia cells, were assessed in mouse for their preliminary pharmacokinetic. 14d and 14e were further tested in vivo in a murine acute promyelocytic leukemia model, resulting 14d the most effective. Its two enantiomers were synthesized: the (1S,2R) enantiomer 15 showed higher activity than its (1R,2S) analogue 16, in both biochemical and cellular assays. Compound 15 exhibited in vivo efficacy after oral administration, determining a 62% increased survival in mouse leukemia model with evidence of KDM1A inhibition. The biological profile of compound 15 supports its further investigation as a cancer therapeutic.
- Vianello, Paola,Botrugno, Oronza A.,Cappa, Anna,Dal Zuffo, Roberto,Dessanti, Paola,Mai, Antonello,Marrocco, Biagina,Mattevi, Andrea,Meroni, Giuseppe,Minucci, Saverio,Stazi, Giulia,Thaler, Florian,Trifiró, Paolo,Valente, Sergio,Villa, Manuela,Varasi, Mario,Mercurio, Ciro
-
p. 1501 - 1517
(2016/03/08)
-