- Enantioselective α-Etherification of Branched Aldehydes via an Oxidative Umpolung Strategy
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Saturated carbonyl compounds are, via their enolate analogues, inherently nucleophilic at the α-position. In the presence of a benzoquinone oxidant, the polarity of the α-position of racemic α-branched aldehydes is inverted, allowing for an enantioselective etherification using readily available oxygen-based nucleophiles and an amino acid-derived primary amine catalyst. A survey of benzoquinone oxidants identified p-fluoranil and DDQ as suitable reaction partners. p-Fluoranil enables the preparation of α-aryloxylated aldehydes using phenol nucleophiles in up to 91 % ee, following either a one-step or a two-step, one-pot protocol. DDQ allows for a more general etherification protocol in combination with a broader range of alcohol nucleophiles with enantioselectivities up to 95 % ee. Control experiments and isolation of a key quinol intermediate supports a mechanism proceeding via an SN2 dynamic-kinetic resolution. These studies provide the basis for an aminocatalytic umpolung concept that allows for the asymmetric construction of tertiary ethers in the α-position of aldehydes.
- Corti, Vasco,J?rgensen, Karl Anker,Lamhauge, Johannes N.,Liu, Yidong
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supporting information
p. 18728 - 18733
(2021/07/12)
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- Design of multifaceted antioxidants: Shifting towards anti-inflammatory and antihyperlipidemic activity
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Oxidative stress and inflammation are two conditions that coexist in many multifactorial diseases such as atherosclerosis and neurodegeneration. Thus, the design of multifunctional compounds that can concurrently tackle two or more therapeutic targets is an appealing approach. In this study, the basic NSAID structure was fused with the antioxidant moieties 3,5-di-tert-butyl-4-hydroxybenzoic acid (BHB), its reduced alcohol 3,5-di-tert-butyl- 4-hydroxybenzyl alcohol (BHBA), or 6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid (Trolox), a hydrophilic analogue of α-tocopherol. Machine learning algorithms were utilized to validate the potential dual effect (anti-inflammatory and antioxidant) of the designed analogues. Derivatives 1-17 were synthesized by known esterification methods, with good to excellent yields, and were pharmacologically evaluated both in vitro and in vivo for their antioxidant and anti-inflammatory activity, whereas selected compounds were also tested in an in vivo hyperlipidemia protocol. Furthermore, the activity/binding affinity of the new compounds for lipoxygenase-3 (LOX-3) was studied not only in vitro but also via molecular docking simulations. Experimental results demonstrated that the antioxidant and anti-inflammatory activities of the new fused molecules were increased compared to the parent molecules, while molecular docking simulations validated the improved activity and revealed the binding mode of the most potent inhibitors. The purpose of their design was justified by providing a potentially safer and more efficient therapeutic approach for multifactorial diseases.
- Kourounakis, Angeliki,Lambrinidis, George,Tzara, Ariadni
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- Copper-catalyzed hydroformylation and hydroxymethylation of styrenes
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Hydroformylation catalyzed by transition metals is one of the most important homogeneously catalyzed reactions in industrial organic chemistry. Millions of tons of aldehydes and related chemicals are produced by this transformation annually. However, most of the applied procedures use rhodium catalysts. In the procedure described here, a copper-catalyzed hydroformylation of alkenes has been realized. Remarkably, by using a different copper precursor, the aldehydes obtained can be further hydrogenated to give the corresponding alcohols under the same conditions, formally named as hydroxymethylation of alkenes. Under pressure of syngas, various aldehydes and alcohols can be produced from alkenes with copper as the only catalyst, in excellent regioselectivity. Additionally, an all-carbon quaternary center containing ethers and formates can be synthesized as well with the addition of unactivated alkyl halides. A possible reaction pathway is proposed based on our results. This journal is
- Franke, Robert,Geng, Hui-Qing,Meyer, Tim,Wu, Xiao-Feng
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p. 14937 - 14943
(2021/12/02)
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- Carbon monoxide and hydrogen (syngas) as a C1-building block for selective catalytic methylation
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A catalytic reaction using syngas (CO/H2) as feedstock for the selective β-methylation of alcohols was developed whereby carbon monoxide acts as a C1 source and hydrogen gas as a reducing agent. The overall transformation occurs through an intricate network of metal-catalyzed and base-mediated reactions. The molecular complex [Mn(CO)2Br[HN(C2H4PiPr2)2]]1comprising earth-abundant manganese acts as the metal component in the catalytic system enabling the generation of formaldehyde from syngas in a synthetically useful reaction. This new syngas conversion opens pathways to install methyl branches at sp3carbon centers utilizing renewable feedstocks and energy for the synthesis of biologically active compounds, fine chemicals, and advanced biofuels.
- Kaithal, Akash,H?lscher, Markus,Leitner, Walter
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p. 976 - 982
(2021/02/06)
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- Manganese-catalysed transfer hydrogenation of esters
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Manganese catalysed ester reduction using ethanol as a hydrogen transfer agent in place of dihydrogen is reported. High yields can be achieved for a range of substrates using 1 mol% of a Mn(i) catalyst, with an alkoxide promoter. The catalyst is derived from a tridentate P,N,N ligand.
- Oates, Conor L.,Widegren, Magnus B.,Clarke, Matthew L.
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supporting information
p. 8635 - 8638
(2020/08/21)
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- Manganese(I)-Catalyzed β-Methylation of Alcohols Using Methanol as C1 Source
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Highly selective β-methylation of alcohols was achieved using an earth-abundant first row transition metal in the air stable molecular manganese complex [Mn(CO)2Br[HN(C2H4PiPr2)2]] 1 ([HN(C2H4PiPr2)2]=MACHO-iPr). The reaction requires only low loadings of 1 (0.5 mol %), methanolate as base and MeOH as methylation reagent as well as solvent. Various alcohols were β-methylated with very good selectivity (>99 %) and excellent yield (up to 94 %). Biomass derived aliphatic alcohols and diols were also selectively methylated on the β-position, opening a pathway to “biohybrid” molecules constructed entirely from non-fossil carbon. Mechanistic studies indicate that the reaction proceeds through a borrowing hydrogen pathway involving metal–ligand cooperation at the Mn-pincer complex. This transformation provides a convenient, economical, and environmentally benign pathway for the selective C?C bond formation with potential applications for the preparation of advanced biofuels, fine chemicals, and biologically active molecules.
- Kaithal, Akash,van Bonn, Pit,H?lscher, Markus,Leitner, Walter
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supporting information
p. 215 - 220
(2019/12/03)
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- Ruthenium(II)-Catalyzed β-Methylation of Alcohols using Methanol as C1 Source
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Selective introduction of methyl branches into the carbon chains of alcohols can be achieved with low loadings of ruthenium precatalyst [RuH(CO)(BH4)(HN(C2H4PPh2)2)] (Ru-MACHO-BH) using methanol both as methylating reagent and as reaction medium. A wide range of structurally divers alcohols was β-methylated with excellent selectivity (>99 %) in fair to high yields (up to 94 %) under standard conditions, and turnover numbers up to 18,000 could be established. The overall reaction rate of the complex catalytic network appears to be governed by interconnection of the individual subcycles through availability of the reactive intermediates. The synthetic procedure opens pathways to important structural motifs following the Green Chemistry principles.
- Kaithal, Akash,Schmitz, Marc,H?lscher, Markus,Leitner, Walter
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p. 5287 - 5291
(2019/05/28)
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- Determination of the Absolute Configuration of β-Chiral Primary Alcohols Using the Competing Enantioselective Conversion Method
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A method for determining the absolute configuration of β-chiral primary alcohols has been developed. Enantioenriched alcohols were acylated in the presence of either enantiomer of the enantioselective acylation catalyst HBTM, and the faster reaction was determined by measuring product conversion using 1H NMR spectroscopic analysis. An empirical mnemonic was developed that correlates the absolute configuration of the alcohol to the faster reacting catalyst. Successful substrates for this method include primary alcohols that bear a "directing group" on the stereogenic center; directing groups include arenes, heteroarenes, enones, and halides.
- Burns, Alexander S.,Wagner, Alexander J.,Fulton, Jennifer L.,Young, Kyle,Zakarian, Armen,Rychnovsky, Scott. D.
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p. 2953 - 2956
(2017/06/07)
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- Accessible protocol for asymmetric hydroformylation of vinylarenes using formaldehyde
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We report herein on an accessible protocol for the asymmetric hydroformylation of vinylarenes using formaldehyde as a substitute for syngas. The regioselectivity (branched/linear = up to 96/4) and enantioselectivity (up to 95% ee) can be attributed to the use of chiral Ph-bpe as a ligand. This journal is
- Morimoto, Tsumoru,Fujii, Tetsuji,Miyoshi, Kota,Makado, Gouki,Tanimoto, Hiroki,Nishiyama, Yasuhiro,Kakiuchi, Kiyomi
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supporting information
p. 4632 - 4636
(2015/04/27)
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- Laccase-Mediator System for Alcohol Oxidation to Carbonyls or Carboxylic Acids: Toward a Sustainable Synthesis of Profens
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By combining two green and efficient catalysts, such as the commercially available enzyme laccase from Trametes versicolor and the stable free radical 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO), the oxidation in water of some primary alcohols to the corresponding carboxylic acids or aldehydes and of selected secondary alcohols to ketones can be accomplished. The range of applicability of bio-oxidation is widened by applying the optimized protocol to the oxidation of enantiomerically pure 2-arylpropanols (profenols) into the corresponding 2-arylpropionic acids (profens), in high yields and with complete retention of configuration.
- Galletti, Paola,Pori, Matteo,Funiciello, Federica,Soldati, Roberto,Ballardini, Alberto,Giacomini, Daria
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p. 2684 - 2689
(2016/12/23)
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- Chemoenzymatic synthesis of (2S)-2-arylpropanols through a dynamic kinetic resolution of 2-arylpropanals with alcohol dehydrogenases
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We applied Horse Liver Alcohol Dehydrogenase (HLADH) to the enantioselective synthesis of six (2S)-2-arylpropanols, useful intermediates in the synthesis of Profens. The influence of substrate structure and reaction conditions on yields and enantioselectivity were investigated. The high yields and high enantioselectivity towards the (S)-enantiomer obtained in the bioreduction of 2-arylpropionic aldehydes, clearly indicate the achievement of a DKR process through a combination of an enzyme-catalyzed kinetic reduction with a chemical base-catalyzed racemization of the unreacted aldehydes. The racemization step is represented by the keto-enol equilibrium of the aldehyde and can be controlled by modulating pH and reaction conditions.
- Galletti, Paola,Emer, Enrico,Gucciardo, Gabriele,Quintavalla, Arianna,Pori, Matteo,Giacomini, Daria
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supporting information; experimental part
p. 4117 - 4123
(2010/10/03)
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- Use of a robust dehydrogenase from an archael hyperthermophile in asymmetric catalysis-dynamic reductive kinetic resolution entry into (s)-profens
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Described is an efficient heterologous expression system for Sulfolobus solfataricus ADH-10 (Alcohol Dehydrogenase isozyme 10) and its use in the dynamic reductive kinetic resolution (DYRKR) of 2-arylpropanal (Profen-type) substrates. Importantly, among the 12 aldehydes tested, a general preference for the (S)-antipode was observed, with high ee's for substrates corresponding to the NSAIDs (nonsteroidal anti-inflammatory drugs) naproxen, ibuprofen, flurbiprofen, ketoprofen, and fenoprofen. To our knowledge, this is the first application of a dehydrogenase from this Sulfolobus hyperthermophile to asymmetric synthesis and the first example of a DYRKR with such an enzyme. The requisite aldehydes are generated by Buchwald-Hartwig-type Pd(0)-mediated α-arylation of tert-butyl propionate. This is followed by reduction to the aldehyde in one [lithium diisobutyl tert-butoxyaluminum hydride (LDBBA)] or two steps [LAH/Dess-Martin periodinane]. Treatment of the profenal substrates with SsADH in 5% EtOH/phosphate buffer, pH 9, with catalytic NADH at 80 °C leads to efficient DYRKR, with ee's exceeding 90% for 9 aryl side chains, including those of the aforementioned NSAIDs. An in silico model, consistent with the observed broad side chain tolerance, is presented. Importantly, the SsADH-10 enzyme could be conveniently recycled by exploiting the differential solubility of the organic substrate/product at 80 °C and at rt. Pleasingly, SsADH-10 could be taken through several thermal cycles, without erosion of ee, suggesting this as a generalizable approach to enzyme recycling for hyperthermophilic enzymes. Moreover, the robustness of this hyperthermophilic DH, in terms of both catalytic activity and stereochemical fidelity, speaks for greater examination of such archaeal enzymes in asymmetric synthesis.
- Friest, Jacob A.,Maezato, Yukari,Broussy, Sylvain,Blum, Paul,Berkowitz, David B.
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supporting information; experimental part
p. 5930 - 5931
(2010/07/05)
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- Trichosporon beigelli esterase (TBE): A versatile esterase for the resolution of economically important racemates
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A hydrolase producing strain Trichosporon beigelli esterase (TBE) isolated from local cottage cheese in its native form has displayed versatility and high efficacy in the kinetic resolution of a wide range of economically important substrates, which include racemic secondary alcohols, such as 1-(6-methoxy-2-naphthyl)ethanol (E ~ 316), 1-(3,4-methylenedioxyphenyl) ethanol and pentanol (E ~ 180 and 156 resp.), and alkyl esters of carboxylic acids such as ibuprofen (E ~ 340), 2-(benzylthio)propanoic acid (E ~ 1000). In other substrates such as in the primary alcohol 2-(6-methoxy-2- naphthyl)propan-1-ol and carboxylic acids such as 2-(5-bromo-6-methoxy-2- naphthyl)propanoic acid, 2-(2-naphthyloxy)propanoic acid, and substituted 2-thiopropanoic acids, it displayed moderate to low selectivity. Commercial lipases such as CCL, PPL, and PSL were also used in the resolution of the substrates for comparative studies.
- Koul, Surrinder,Koul, Jawahir Lal,Singh, Budh,Kapoor, Munish,Parshad, Rajinder,Manhas, Kuldeep S.,Taneja, Subhash C.,Qazi, Ghulam N.
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p. 2575 - 2591
(2007/10/03)
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- Chemoenzymatic synthesis of antiinflammatory drugs in enantiomerically pure form
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A novel chemoenzymatic route to chiral antiinflammatory drugs in enantiomerically pure form is described. Copyright (C) 2000 Elsevier Science Ltd.
- Basak, Amit,Nag, Ahindra,Bhattacharya, Gautam,Mandal, Subrata,Nag, Sikha
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p. 2403 - 2407
(2007/10/03)
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- Process for preparation of 2-(6-methoxy-2-naphthyl)propionic acid and intermediates therefor utilizing 2,6-diisopropylnaphthalene
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A process is disclosed for the synthesis of 2-(6-methoxy-2-naphthyl)propionic acid that utilizes 2,6-diisopropylnaphthalene.
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- Compounds having one or more aminosulfaonyloxy radicals useful as pharmaceuticals
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Methods of treating chronic arthritis and osteoporosis which utilize both known and novel compounds which would fall under the general formula:(HO)p--A--[--OS(O) 2 NR 1 R 2 ] zwherein A encompasses a wide range of values including but not limited to aryl, loweralkyl, cycloalkyl, and carbohydrates including sucrose and fructose; p is equal to the number of unreacted hydroxy groups contained on the molecule and may be zero; z is the number of --OS(O) 2 NR 1 R 2 groups and is always at least one; R 1 and R 2 are selected from hydrogen, loweralkyl, carboxy and the like; a novel process for preparing the compounds is provided wherein an appropriate sulfamic acid aryl ester is reacted with a hydroxy substituted A radical which may or may not contain thereon protected carboxyl, amino or hydroxy substituents, in an aprotic solvent containing a tertiary amine base. Pharmaceutical compositions for the treatment of chronic arthritis and osteoporosis are also provided.
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- Sulfamates as antiglaucoma agents
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Sulfamate esters of the formula where A is aryloxyalkyl, p is the number of unreacted hydroxy groups present on the alkyl moiety and may be zero, z is the number of --OS(O)2 NR1 R2 groups attached to carbons of the alkyl moiety and is always at least one; R1 and R2 are selected from hydrogen, loweralkyl, carboxy, and the like are useful in treating glaucoma.
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- IBUPROFEN AND NAPROXEN VIA ORGANOBORANES
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The sequential Pd-catalyzed couplings of aryl bromides and triflates with the appropriate organoboranes provide the key steps in new synthetic routes to both ibuprofen and naproxen in racemic form.
- Rivera, Isaac,Colberg, Juan C.,Soderquist, John A.
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p. 6919 - 6922
(2007/10/02)
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- Synthesis of 2,6-Disubstituted Dihydronaphthalenes and Naphthalenes by Electrocyclic Reaction of o-Quinodimethane. A Synthesis of (+/-)-Naproxen
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A survey of the electrocyclic reactions of o-quinodimethanes generated in situ by the thermolysis of dihydrobenzocyclobutenes with a variety of olefinic substituents at C-1 is reported.These reactions provide convenient access to the 2,6-disubstituted dihydronaphthalenes (11) and the naphthalenes (12).Thermolysis of the benzocyclobutenes (10) at 180 deg C in the presence of manganese dioxide affords in good yields the 2,6-di- and 2,3,6-tri-substituted naphthalenes (12) and (16).The naphthalenes (12b,f,h) thus obtained were easily converted into (+/-)-naproxen (5).
- Shishido, Kozo,Yamashita, Akitake,Hiroya, Kou,Fukumoto, Keiichiro
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p. 469 - 475
(2007/10/02)
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- STEREOSELECTIVE SYNTHESIS OF (E)-2-ALKENE-1,4-DIOLS VIA METALLATED ALLYLIC SULPHOXIDES
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Reaction of allyl sulphinyl anion with chiral α-methylaldehydes affords α- or γ-adducts in highly regiocontrolled fashion, depending on reaction conditions.From the α-adducts syn (E)-2-alkene-1,4-diols are obtained as major (d.r. 2:1 28:1) products by thiophile promoted desulphurization.
- Annunziata, Rita,Cinquino, Mauro,Cozzi, Franco,Raimondi, Laura,Stefanelli, Stefania
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p. 5443 - 5450
(2007/10/02)
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