- Preparation method of alpha-deuterated olefine aldehyde
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The invention relates to a preparation method of alpha-deuterated olefine aldehyde, which comprises the following steps: by taking alpha, beta-olefine aldehyde as a raw material, carrying out a reversible Michael addition mechanism under the action of deuterium water, a nucleophilic reagent and an organic catalyst to obtain an alpha-deuterated olefine aldehyde compound. The method has high selectivity, and does not generate deuterated by-products at other positions. The alpha-deuterated olefine aldehyde compound prepared by the invention has great application value, can be further widely converted to prepare mono (poly) deuterated olefin and derivatives, olefine acid, conjugated olefine aldehyde, eneyne and other compounds, and has important significance in drug synthesis.
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Paragraph 0026; 0097-0102
(2022/03/27)
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- Tandem oxidation-dehydrogenation of (hetero)arylated primary alcohols via perruthenate catalysis
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Tandem oxidative-dehydrogenation of primary alcohols to give a,b-unsaturated aldehydes in one pot are rare transformations in organic synthesis, with only two methods currently available. Reported herein is a novel method using the bench-stable salt methyltriphenylphosphonium perruthenate (MTP3), and a new co-oxidant NEMO&middoPF6 (NEMO = N-ethyl-N-hydroxymorpholinium) which provides unsaturated aldehydes in low to moderate yields. The Ley-Griffith oxidation of (hetero)arylated primary alcohols with N-oxide co-oxidants NMO (NMO = N-methylmorpholine N-oxide)/NEMO, is expanded by addition of the N-oxide salt NEMO&middoPF6 to convert the intermediate saturated aldehyde into its unsaturated counterpart. The discovery, method development, reaction scope, and associated challenges of this method are highlighted. The conceptual value of late-stage dehydrogenation in natural product synthesis is demonstrated via the synthesis of a polyene scaffold related to auxarconjugatin B.
- Bettencourt, Christian J.,Chow, Sharon,Moore, Peter W.,Read, Christopher D.G.,Jiao, Yanxiao,Bakker, Jan Peter,Zhao, Sheng,Bernhardt, Paul V.,Williams, Craig M.
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p. 652 - 659
(2021/09/08)
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- Method for preparing olefine aldehyde by catalyzing terminal alkyne or terminal conjugated eneyne and diphosphine ligand used in method
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The invention discloses a method for preparing olefine aldehyde by catalyzing terminal alkyne or terminal conjugated eneyne and a diphosphine ligand used in the method. According to the invention, indole-substituted phosphoramidite diphosphine ligand which is stable in air and insensitive to light is synthesized by utilizing a continuous one-pot method, and the indole-substituted phosphoramidite diphosphine ligand and a rhodium catalyst are used for jointly catalyzing to successfully achieve a hydroformylation reaction of aromatic terminal alkyne and terminal conjugated eneyne under the condition of synthesis gas for the first time, so that an olefine aldehyde structure compound can be rapidly and massively prepared, and particularly, a polyolefine aldehyde structure compound which is more difficult to synthesize in the prior art can be easily prepared and synthesized, and a novel method is provided for synthesis and modification of drug molecules, intermediates and chemical products.
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Paragraph 0155-0157
(2021/05/29)
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- Regioselective Silylations of Propargyl and Allyl Pivalates through Ca-Promoted Reductive C(sp3)-O Bond Cleavage
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A practical protocol for the regioselective preparation of 3-phenylpropargylsilanes and 3-phenylallylsilanes in yields of 36-77 and 48-86%, respectively, from readily accessible 3-phenylpropargyl and 1-phenylallyl pivalates was developed through reductive C(sp3)-O bond cleavage. This method represents the first example of the direct application of vastly abundant calcium granules to a reductive coupling reaction. A broad range of propargylsilanes and allylsilanes are simply prepared using easy-to-handle pivalates and chlorotrimethylsilane under mild catalyst-free and additive-free conditions.
- Zhang, Tianyuan,Zheng, Suhua,Kobayashi, Taro,Maekawa, Hirofumi
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supporting information
p. 7129 - 7133
(2021/09/18)
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- Selective Rhodium-Catalyzed Hydroformylation of Terminal Arylalkynes and Conjugated Enynes to (Poly)enals Enabled by a π-Acceptor Biphosphoramidite Ligand
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The hydroformylation of terminal arylalkynes and enynes offers a straightforward synthetic route to the valuable (poly)enals. However, the hydroformylation of terminal alkynes has remained a long-standing challenge. Herein, an efficient and selective Rh-catalyzed hydroformylation of terminal arylalkynes and conjugated enynes has been achieved by using a new stable biphosphoramidite ligand with strong π-acceptor capacity, which affords various important E-(poly)enals in good yields with excellent chemo- and regioselectivity at low temperatures and low syngas pressures.
- Zhao, Jiangui,Zheng, Xueli,Tao, Shaokun,Zhu, Yuxin,Yi, Jiwei,Tang, Songbai,Li, Ruixiang,Chen, Hua,Fu, Haiyan,Yuan, Maolin
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supporting information
p. 6067 - 6072
(2021/08/16)
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- Substrate-Controlled Chemo-/Enantioselective Synthesis of α-Benzylated Enals and Chiral Cyclopropane-Fused 2-Chromanone Derivatives
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Substrate-controlled cascade reactions between α,β-unsaturated aldehydes or their analogues and 2,4-dinitrobenzyl chloride in the presence of a chiral secondary amine as the catalyst and base were developed, to obtain a broad spectrum of α-benzylated enals and enantioenriched cyclopropane-fused chroman-2-one derivatives. The cyclopropane-tethered iminium ion clearly served as a key intermediate in these reactions to trigger stereochemical outcomes, one of which was supported by a control experiment. (Figure presented.).
- Byeon, Huimyoung,Ryu, Sunghyeon,Yoo, Eun Jeong,Yang, Jung Woon
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supporting information
p. 5085 - 5091
(2021/09/20)
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- Biocatalytic Asymmetric Cyclopropanations via Enzyme-Bound Iminium Ion Intermediates
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Cyclopropane rings are an important structural motif frequently found in many natural products and pharmaceuticals. Commonly, biocatalytic methodologies for the asymmetric synthesis of cyclopropanes rely on repurposed or artificial heme enzymes. Here, we engineered an unusual cofactor-independent cyclopropanation enzyme based on a promiscuous tautomerase for the enantioselective synthesis of various cyclopropanes via the nucleophilic addition of diethyl 2-chloromalonate to α,β-unsaturated aldehydes. The engineered enzyme promotes formation of the two new carbon-carbon bonds with excellent stereocontrol over both stereocenters, affording the desired cyclopropanes with high diastereo- and enantiopurity (d.r. up to 25:1; e.r. up to 99:1). Our results highlight the usefulness of promiscuous enzymes for expanding the biocatalytic repertoire for non-natural reactions.
- Kunzendorf, Andreas,Poelarends, Gerrit J.,Saifuddin, Mohammad,Saravanan, Thangavelu,Xu, Guangcai
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supporting information
p. 24059 - 24063
(2021/10/07)
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- Potent Inhibition of Nicotinamide N-Methyltransferase by Alkene-Linked Bisubstrate Mimics Bearing Electron Deficient Aromatics
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Nicotinamide N-methyltransferase (NNMT) methylates nicotinamide (vitamin B3) to generate 1-methylnicotinamide (MNA). NNMT overexpression has been linked to a variety of diseases, most prominently human cancers, indicating its potential as a therapeutic target. The development of small-molecule NNMT inhibitors has gained interest in recent years, with the most potent inhibitors sharing structural features based on elements of the nicotinamide substrate and the S-adenosyl-l-methionine (SAM) cofactor. We here report the development of new bisubstrate inhibitors that include electron-deficient aromatic groups to mimic the nicotinamide moiety. In addition, a trans-alkene linker was found to be optimal for connecting the substrate and cofactor mimics in these inhibitors. The most potent NNMT inhibitor identified exhibits an IC50 value of 3.7 nM, placing it among the most active NNMT inhibitors reported to date. Complementary analytical techniques, modeling studies, and cell-based assays provide insights into the binding mode, affinity, and selectivity of these inhibitors.
- Buijs, Ned,Campagna, Roberto,Emanuelli, Monica,Gao, Yongzhi,Innocenti, Paolo,Jespers, Willem,Martin, Nathaniel I.,Parsons, Richard B.,Sartini, Davide,Van Haren, Matthijs J.,Van Westen, Gerard J. P.,Zhang, Yurui,Gutiérrez-De-Terán, Hugo
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p. 12938 - 12963
(2021/09/11)
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- Highly Regio- A nd Enantioselective Hydrogenation of Conjugated α-Substituted Dienoic Acids
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Highly regio- A nd enantioselective hydrogenation of conjugated α-substituted dienoic acids was realized for the first time using Trifer-Rh complex, providing a straightforward method for the synthesis of chiral α-substituted ?,?′-unsaturated acids. DFT calculations revealed N+H-O hydrogen bonding interaction is formed to stabilize the transition state and the coordination of 4,5-double bond to Rh(III) center would facilitate the reductive elimination process. This hydrogenation provided a gram-scale synthesis of the precursor of sacubitril.
- Liu, Xian,Liu, Song,Wang, Quanjun,Zhou, Gang,Yao, Lin,Ouyang, Qin,Jiang, Ru,Lan, Yu,Chen, Weiping
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p. 3149 - 3154
(2020/04/09)
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- Enantioselective Aldol Addition of Acetaldehyde to Aromatic Aldehydes Catalyzed by Proline-Based Carboligases
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Aromatic β-hydroxyaldehydes, 1,3-diols, and α,β-unsaturated aldehydes are valuable precursors to biologically active natural products and drug molecules. Herein we report the biocatalytic aldol condensation of acetaldehyde with various aromatic aldehydes to give a number of aromatic α,β-unsaturated aldehydes using a previously engineered variant of 4-oxalocrotonate tautomerase [4-OT(M45T/F50A)] as carboligase. Moreover, an efficient one-pot two-step chemoenzymatic route toward chiral aromatic 1,3-diols has been developed. This one-pot chemoenzymatic strategy successfully combined a highly enantioselective aldol addition step catalyzed by a proline-based carboligase [4-OT(M45T/F50A) or TAUT015] with a chemical reduction step to convert enzymatically prepared aromatic β-hydroxyaldehydes into the corresponding 1,3-diols with high optical purity (e.r. up to >99:1) and in good isolated yield (51-92%). These developed (chemo)enzymatic methodologies offer alternative synthetic choices to prepare a variety of important drug precursors.
- Biewenga, Lieuwe,Charnock, Simon J.,Guo, Chao,Poelarends, Gerrit J.,Saifuddin, Mohammad,Saravanan, Thangavelu
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p. 2522 - 2527
(2020/03/11)
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- Boosting multiple photo-assisted and temperature controlled reactions with a single redox-switchable catalyst: Solvents as internal substrates and reducing agent
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An alternative and economically viable process for the synthesis of β-aryl enals, enones and the aryl amines has been developed by partial oxidation of ethanol, isopropanol and N, N-dimethyl formamide (DMF). The formation of β-aryl enals, enones and the aryl amines was catalyzed by a mixed metal oxides layer of cobalt and chromium supported on halloysite nanotubes, designated as CoCr2O4-HNT. The C[sbnd]C and C[sbnd]N bond formation reactions were found to be influenced by temperature and the nature of base. The condensation of aldehyde with in situ generated acetaldehyde by ethanol oxidation forming β-aryl enals occurred selectively at 120 °C. The partial oxidation of isopropanol to acetone and its condensation with aldehydes forming β-aryl enones occurred at room temperature. Increase in temperature caused the liberation of hydrogen gas from isopropanol and allowed the reversible reduction of aldehydes to alcohols. Increase in temperature in isopropanol and increase in base concentration in ethanol causes the selective reduction of aldehydes to alcohols. Besides being active for the Claisen-Schmidt type of reactions and the aryl halides amination process, the synthesized catalyst was also found to be highly active for the photocatalytic oxidation of benzyl alcohols in absence of any external oxidizing agent. The positive holes (h+) generated at the Co(II) site as evident from EPR analysis was considered to be responsible for high photocatalytic activity of the material reducing the recombination rate of holes and electrons (e?). Density Functional Theory calculations were performed to understand the mechanism of ethanol oxidation to acetaldehyde.
- Bania, Kusum K.,Baruah, Manash J.,Bhattacharyya, Pradip K.,Das, Biraj,Karunakar, Galla V.,Roy, Subhasish,Saikia, Lakshi,Saikia, Pinku,Sharma, Mukesh
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p. 104 - 121
(2020/06/01)
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- Palladium-Catalyzed [5 + 2] Annulation of Vinylethylene Carbonates with Barbiturate-Derived Alkenes
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A palladium/XantPhos-catalyzed [5 + 2] annulation of VECs with electron-deficient alkenes having an isolated carbon-carbon double bond has been developed to afford spirobarbiturate-tetrahydrooxepines. This study provides an expedient assembly of biologically interesting spirobarbiturate-tetrahydrooxepines. The easy scalability and versatile transformability of the reaction products were also exhibited.
- Chen, Yuehua,Deng, Hao,Gao, Xing,Guo, Hongchao,Jiang, Feng,Wang, Wei,Wu, Yongjun,Zhu, Dongyu
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supporting information
p. 7158 - 7163
(2020/10/02)
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- Pd-Au-Y as Efficient Catalyst for C-C Coupling Reactions, Benzylic C-H Bond Activation, and Oxidation of Ethanol for Synthesis of Cinnamaldehydes
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Pd-Au nanoalloy supported on zeolite-Y (Pd-Au-Y) matrix was found to be an effective catalyst for C-Cl bond activation and oxidative coupling of 2-naphthol, leading to the formation of various biaryl products and 1,1′-bi-2-naphthol, BINOL. The same catalyst was also highly efficient for selective oxidation of benzylic alcohols to benzaldehydes. Cinnamaldehydes were obtained directly from benzaldehydes by aldol condensation with acetaldehyde generated in situ by partial oxidation of ethanol in the presence of Pd-Au-Y catalyst at 120 °C under basic condition. The biaryl products were also obtained directly from benzylic alcohols in a one-pot system by reacting with phenylboronic acid. The formation of biaryls from benzylic alcohols was believed to occur via one-pot benzylic C-H and C-Cl bond activation. A high % yield of biaryls, BINOL, aldehydes, and cinnamaldehydes was obtained by performing different reactions using the single Pd-Au-Y catalyst. The strong interaction of chloro-benzylic alcohol was predominantly located at active gold species. X-ray photoelectron and diffuse reflectance spectroscopic studies revealed the strong interaction between Pd and Au particles. Electrochemical studies provided proper evidence for the individual role of the nanoparticles (NPs) in one-pot synthesis of biaryls from benzylic alcohols.
- Sharma, Mukesh,Das, Biraj,Baruah, Manash J.,Biswas, Subir,Roy, Subhasish,Hazarika, Anil,Bhargava, Suresh K.,Bania, Kusum K.
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p. 5860 - 5875
(2019/06/17)
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- Highly γ-Regioselective 1,2-Addition of α,β-Unsaturated Oxime Ethers with Allylzinc Bromides: A Straightforward Approach for the Synthesis of Homoallylic Amines
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A highly regioselective reaction between allylzinc bromide reagents and α,β-unsaturated oxime ethers for the one-step synthesis of the homoallylic amines is reported. This process is a regioselective 1,2-addition reaction providing a new γ-position with carbon-carbon bond formation. Furthermore, the reaction substrates are widely applicable and can be produced in a high yield.
- Yang, Bo,Zhang, Songlin
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supporting information
p. 3736 - 3746
(2019/09/30)
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- Iron(III)/O2-Mediated Regioselective Oxidative Cleavage of 1-Arylbutadienes to Cinnamaldehydes
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A simple, efficient, and environmentally benevolent regioselective oxidative cleavage of 1-arylbutadienes to cinnamaldehydes mediated by iron(III) sulfate/O2 has been developed. The reaction offered good yields and excellent regioselectivity and showed good functional group tolerance (31 examples). The method is important, as few reports with limited substrate scope are available for such excellent oxidative cleavage of conjugated dienes.
- Bhowmik, Amit,Fernandes, Rodney A.
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supporting information
p. 9203 - 9207
(2019/11/14)
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- Vinylogous Reactivity of Cyclic 2-Enones: Organocatalysed Asymmetric Addition to 2-Enals to Synthesize Fused Carbocycles
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A method for asymmetric and site selective annulations at the γ and γ′ positions of cyclic 2-enones with α,β-unsaturated aldehydes has been developed. The organocatalysed [3+3]-annulations proceed with high levels of regio-, diastereo-, and enantioselectivity, affording a series of high value fused carbocycles. Further elaboration gave key lactones (both bridged and fused).
- Sofiadis, Manolis,Kalaitzakis, Dimitris,Sarris, John,Montagnon, Tamsyn,Vassilikogiannakis, Georgios
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supporting information
p. 6742 - 6746
(2019/04/13)
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- Discovery of novel piperonyl derivatives as diapophytoene desaturase inhibitors for the treatment of methicillin-, vancomycin- and linezolid-resistant Staphylococcus aureus infections
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Inhibition of S. aureus diapophytoene desaturase (CrtN) could serve as an alternative approach for addressing the tricky antibiotic resistance by blocking the biosynthesis of carotenoid pigment which shields the bacterium from host oxidant killing. In this study, we designed and synthesized 44 derivatives with piperonyl scaffold targeting CrtN and the structure-activity relationships (SARs) were examined extensively to bring out the discovery of 21b with potent efficacy and better hERG safety profile compared to the first class CrtN inhibitor benzocycloalkane derivative 2. Except the excellent pigment inhibitory activity against wild-type S. aureus, 21b also showed excellent pigment inhibition against four pigmented MRSA strains. In addition, H2O2 killing and human whole blood killing assays proved 21b could sensitize S. aureus to be killed under oxidative stress conditions. Notably, the murine study in vivo validated the efficacy of 21b against pigmented S. aureus Newman, vancomycin-intermediate S. aureus Mu50 and linezolid-resistant S. aureus NRS271.
- Wei, Hanwen,Mao, Fei,Ni, Shuaishuai,Chen, Feifei,Li, Baoli,Qiu, Xiaoxia,Hu, Linghao,Wang, Manjiong,Zheng, Xinyu,Zhu, Jin,Lan, Lefu,Li, Jian
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p. 235 - 251
(2018/01/17)
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- Dehydrogenative Synthesis of Linear α,β-Unsaturated Aldehydes with Oxygen at Room Temperature Enabled by tBuONO
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Synthesis of linear α,β-unsaturated aldehydes via a room-temperature oxidative dehydrogenation has been realized by the cocatalysis of an organic nitrite and palladium with molecular oxygen as the sole clean oxidant. Linear α,β-unsaturated aldehydes could be efficiently prepared under aerobic catalytic conditions directly from the corresponding saturated linear aldehydes. Besides linear products, the aromatic analogy could also be smoothly achieved by the same standard method. The organic nitrite redox cocatalyst and alcohol solvent play a key role for realizing this method.
- Wang, Mei-Mei,Ning, Xiao-Shan,Qu, Jian-Ping,Kang, Yan-Biao
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p. 4000 - 4003
(2017/06/19)
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- Metal- and Acid-Free Methyl Triflate Catalyzed Meyer-Schuster Rearrangement
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A novel metal- and acid-free preparation of synthetically useful α,β-unsaturated carbonyl compounds from propargyl alcohols has been realized. This Meyer-Schuster rearrangement process is effectively catalyzed by methyl triflate (20 mol%) to prepare a broad scope of conjugated E -enals and E -enones generally in good to excellent yields (up to 90%). This reaction procedure operates under mild conditions (70 °C), in air, with short reaction times (1 h). Moreover, a carbocation intermediate trapped by the solvent 2,2,2-trifluoroethanol was isolated during this transformation.
- Yang, Lu,Zeng, Qingle
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p. 3149 - 3156
(2017/07/12)
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- Oxygenative and Dehydrogenative [3 + 3] Benzannulation Reactions of α,β-Unsaturated Aldehydes and γ-Phosphonyl Crotonates Mediated by Air: Regioselective Synthesis of 4-Hydroxybiaryl-2-carboxylates
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Regioselective synthesis of 4-hydroxybiphenyl-2-carboxylates via the base-mediated oxygenative [3 + 3] benzannulation reaction of α,β-unsaturated aldehydes and γ-phosphonyl crotonates is reported. A hydroxyl group is installed in the final product on the originally phosphorus-bound carbon via a novel oxygenative and dehydrogenative transformation. The reaction proceeds rapidly in an open flask, uses atmospheric oxygen as an oxidant, and affords good yields of substituted biaryl phenols. (Chemical Equation Presented).
- Joshi, Prabhakar Ramchandra,Nanubolu, Jagadeesh Babu,Menon, Rajeev S.
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supporting information
p. 752 - 755
(2016/03/01)
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- An efficient palladium-catalyzed synthesis of cinnamaldehydes from acrolein diethyl acetal and aryl iodides and bromides
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(Matrix presented) The reaction of aryl iodides and bromides with acrolein diethyl acetal in the presence of Pd(OAc)2, nBu 4NOAc, K2CO3, KCl, and DMF, at 90°C until the disappearance of the acetal followed by the addition of 2 N HCl to the crude reaction mixture, affords cinnamaldehydes in good to high yields. A variety of functional groups are tolerated in the aryl halides, including ether, aldehyde, ketone, ester, dialkylamino, nitrile, and nitro groups. The presence of substituents close to the oxidative addition site does not hamper the reaction.
- Battistuzzi, Gianfranco,Cacchi, Sandro,Fabrizi, Giancarlo
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p. 777 - 780
(2007/10/03)
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- Phase transfer Wittig reaction with 1,3-dioxolan-2-yl-methyltriphenyl phosphonium salts: An efficient method for vinylogation of aromatic aldehydes
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Aldehydes were efficiently transformed into allylic dioxolanes by a Wittig-type reaction, using 1,3-dioxolan-2-yl-methyltriphenylphosphonium bromide under phase transfer conditions. The substituent kinetic effects were studied, and related to Hammett values and electrochemical potentials.
- Daubresse, Nicolas,Francesch, Charlette,Rolando, Christian
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p. 10761 - 10770
(2007/10/03)
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