- High spatiotemporal control of spontaneous reactions using ultrasound-triggered composite droplets
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Achieving high spatial and temporal control over a spontaneous reaction is a particularly challenging task with potential breakthroughs in various fields of research including surface patterning and drug delivery. We report here an exceptionally effective method that allows attaining such control. This method relies on a remotely triggered ultrasound-induced release of a reactant encapsulated in a composite microdroplet of liquid perfluorohexane. More specifically, the demonstration was achieved by locally applying a focused 2.25 MHz transducer onto a microfluidic channel in which were injected composite microdroplets containing a solution of an azidocoumarin and an external flow containing a reactive alkyne.
- Bezagu, Marine,Errico, Claudia,Chaulot-Talmon, Victor,Monti, Fabrice,Tanter, Mickael,Tabeling, Patrick,Cossy, Janine,Arseniyadis, Stellios,Couture, Olivier
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Read Online
- Calcium-Catalyzed Synthesis of 1,2-Disubstituted 3-Benzazepines
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A short and highly stereoselective chiral pool synthesis of tetrahydro-3-benzazepines as potential drug molecules is described, using simple enantiopure amino acids as the chiral building blocks. Intramolecular Friedel-Crafts alkylation towards seven-membered rings was achieved with high diastereoselectivity for the first time and accomplished by a biocompatible calcium catalyst. The simple and cost efficient approach allows for the variation of all substituents in the 3-benzazepine by a change of the substitution pattern in one or more of the reagents, while leaving the general synthetic route unchanged. Furthermore, assignment of the absolute configuration of the 3-benzazepine derivative is straightforward, based on the amino acid building block employed. A new stereoselective chiral pool synthesis of 1,2-disubstituted 3-benzazepines was developed, using enantiopure amino acids as chiral building blocks. The key step is based on the first diastereoselective Friedel-Crafts cyclization towards this pharmacologically highly interesting compound class and accomplished by a biocompatible calcium catalyst. The modular concept allows for variation of all substituents, leaving the general synthetic route unchanged.
- Damsen, Helena,Niggemann, Meike
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Read Online
- Strain-accelerated formation of chiral, optically active buta-1,3-dienes
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The formal [2+2] cycloaddition-retroelectrocyclization (CA-RE) reactions between tetracyanoethylene (TCNE) and strained, electron-rich dibenzo-fused cyclooctynes were studied. The effect of ring strain on the reaction kinetics was quantified, revealing that the rates of cycloaddition using strained, cyclic alkynes are up to 5500 times greater at 298 K than those of reactions using unstrained alkynes. Cyclobutene reaction intermediates, as well as buta-1,3-diene products, were isolated and their structures were studied crystallographically. Isolation of a rare example of a chiral buta-1,3-diene that is optically active and configurationally stable at room temperature is reported. Computational studies on the enantiomerization pathway of the buta-1,3-diene products showed that the eight-membered ring inverts via a boat conformer in a ring-flip mechanism. In agreement with computed values, experimentally measured activation barriers of racemization in these compounds were found to be up to 26 kcalmol-1.
- Chiu, Melanie,Tchitchanov, Boris H.,Sanhueza, Italo A.,Trapp, Nils,Schweizer, W. Bernd,Diederich, Franois,Zimmerli, Daniel,Schoenebeck, Franziska
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Read Online
- Kinetic Resolution of Neopentylic Secondary Alcohols by Cu-H-Catalyzed Enantioselective Silylation with Hydrosilanes
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A nonenzymatic kinetic resolution of sterically congested alcohols having a quaternary carbon atom in the β-position is reported. The catalyst system CuCl/NaOtBu/(R,R)-Ph-BPE together with a 3,5-xylyl-substituted tertiary hydrosilane enable enantioselective silylation of the hydroxy group. Several alcohols are obtained with good to excellent selectivity factors, and there are no other known straightforward methods to access these motifs.
- Oestreich, Martin,Papadopulu, Zaneta
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supporting information
p. 438 - 441
(2021/01/13)
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- METHOD OF FORMING MONOMERS AND FURFURAL FROM LIGNOCELLULOSE
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The present disclosure relates to a method of producing monophenolicmonomers and furfural from lignocellulosic biomass beating the biomass in a solvent together with a zeolite based catalyst.
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Page/Page column 20; 22; 23
(2020/06/05)
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- Synthesis of Benzo[ b]furans by Intramolecular C-O Bond Formation Using Iron and Copper Catalysis
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One-pot processes for the synthesis of benzo[b]furans from 1-aryl- or 1-alkylketones using nonprecious transition metal catalysts have been developed. Regioselective iron(III)-catalyzed halogenation of the aryl ring, followed by iron- or copper-catalyzed O-arylation allowed the synthesis of various structural analogues, including the benzo[b]furan-derived natural products corsifuran C, moracin F, and caleprunin B.
- Henry, Martyn C.,Sutherland, Andrew
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supporting information
p. 2766 - 2770
(2020/03/30)
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- Rapid Access to Azabicyclo[3.3.1]nonanes by a Tandem Diverted Tsuji–Trost Process
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A three-step synthesis of the 2-azabicyclo[3.3.1]nonane ring system from simple pyrroles, employing a combined photochemical/palladium-catalysed approach is reported. Substrate scope is broad, allowing the incorporation of a wide range of functionality relevant to medicinal chemistry. Mechanistic studies demonstrate that the process occurs by acid-assisted C?N bond cleavage followed by β-hydride elimination to form a reactive diene, demonstrating that efficient control of what might be considered off-cycle reactions can result in productive tandem catalytic processes. This represents a short and versatile route to the biologically important morphan scaffold.
- Steeds, Hannah G.,Knowles, Jonathan P.,Yu, Wai L.,Richardson, Jeffery,Cooper, Katie G.,Booker-Milburn, Kevin I.
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supporting information
p. 14330 - 14334
(2020/10/12)
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- Electrochemical Aminoxyl-Mediated Oxidation of Primary Alcohols in Lignin to Carboxylic Acids: Polymer Modification and Depolymerization
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An electrochemical process has been developed for chemoselective oxidation of primary alcohols in lignin to the corresponding carboxylic acids. The electrochemical oxidation reactions proceed under mildly basic conditions and employ 2,2,6,6-tetramethyl-1-piperidine N-oxyl (TEMPO) and 4-acetamidoO (ACT) as catalytic mediators. Lignin model compounds and related alcohols are used to conduct structure-reactivity studies that provide insights into the origin of the reaction selectivity. The method is applied to the oxidation of lignin extracted from poplar wood chips via a mild acidolysis method, and the reaction affords a novel polyelectrolyte material. Gel permeation chromatography data for the oxidized lignin shows that this material has a molecular weight and molecular weight distribution very similar to that of the extracted lignin, but notable differences are also evident. Base titration reveals a significant increase in the acid content, and the oxidized lignin has much higher water solubility relative to the extracted lignin. Treatment of the oxidized lignin under acidic conditions results in depolymerization of the material into characterized aromatic monomers in nearly 30 wt% yield.
- Rafiee, Mohammad,Alherech, Manar,Karlen, Steven D.,Stahl, Shannon S.
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p. 15266 - 15276
(2019/10/19)
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- Transaminase-Catalyzed Continuous Synthesis of Biogenic Aldehydes
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The physiological role of biogenic aldehydes, such as 3,4-dihydroxyphenylacetaldehyde (DOPAL), has been associated with cardiovascular and neurodegenerative disorders. The availability of these substrates is limited and robust synthetic methodologies would greatly facilitate further biological studies. Herein, a transaminase-mediated single-step process in continuous mode, which leads to excellent product yields (90–95 %), is reported. Coimmobilization of the pyridoxal phosphate (PLP) cofactor eliminated the need for exogenous addition of this reagent without affecting the longevity of the system, delivering a truly self-sufficient process.
- Contente, Martina L.,Paradisi, Francesca
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p. 2830 - 2833
(2019/08/12)
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- Lignin Valorization by Cobalt-Catalyzed Fractionation of Lignocellulose to Yield Monophenolic Compounds
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Herein, a catalytic reductive fractionation of lignocellulose is presented using a heterogeneous cobalt catalyst and formic acid or formate as a hydrogen donor. The catalytic reductive fractionation of untreated birch wood yields monophenolic compounds in up to 34 wt % yield of total lignin, which corresponds to 76 % of the theoretical maximum yield. Model compound studies revealed that the main role of the cobalt catalyst is to stabilize the reactive intermediates formed during the organosolv pulping by transfer hydrogenation and hydrogenolysis reactions. Additionally, the cobalt catalyst is responsible for depolymerization reactions of lignin fragments through transfer hydrogenolysis reactions, which target the β-O-4′ bond. The catalyst could be recycled three times with only negligible decrease in efficiency, showing the robustness of the system.
- Rautiainen, Sari,Di Francesco, Davide,Katea, Sarmad Naim,Westin, Gunnar,Tungasmita, Duangamol N.,Samec, Joseph S. M.
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p. 404 - 408
(2019/01/04)
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- Modular synthesis and biological investigation of 5-hydroxymethyl dibenzyl butyrolactones and related lignans
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Dibenzyl butyrolactone lignans are well known for their excellent biological properties, particularly for their notable anti-proliferative activities. Herein we report a novel, efficient, convergent synthesis of dibenzyl butyrolactone lignans utilizing the acyl-Claisen rearrangement to stereoselectively prepare a key intermediate. The reported synthetic route enables the modification of these lignans to give rise to 5-hydroxymethyl derivatives of these lignans. The biological activities of these analogues were assessed, with derivatives showing an excellent cytotoxic profile which resulted in programmed cell death of Jurkat T-leukemia cells with less than 2% of the incubated cells entering a necrotic cell death pathway.
- Davidson, Samuel J.,Pilkington, Lisa I.,Dempsey-Hibbert, Nina C.,El-Mohtadi, Mohamed,Tang, Shiying,Wainwright, Thomas,Whitehead, Kathryn A.,Barker, David
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- Synthesis of Substrates for Aldolase-Catalysed Reactions: A Comparison of Methods for the Synthesis of Substituted Phenylacetaldehydes
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Methods for the synthesis of phenylacetaldehydes (oxidation, one-carbon chain extension) were compared by using the synthesis of 4-methoxyphenylacetaldehyde as a model example. Oxidations of 4-methoxyphenylethanol with activated DMSO (Swern oxidation) or manganese dioxide gave unsatisfactory results; whereas oxidation with 2-iodoxybenzoic acid (IBX) produced 4-methoxyphenylacetaldehyde in reasonable (75%) yield. However, Wittig-type one-carbon chain extension with methoxymethylene-triphenylphosphine followed by hydrolysis gave an excellent (81% overall) yield of 4-methoxyphenylacetaldehyde from 4-methoxybenzaldehyde (a cheap starting material). This approach was subsequently used to synthesise a set of 10 substituted phenylacetaldehydes in good to excellent yields.
- Al-Smadi, Derar,Enugala, Thilak Reddy,Norberg, Thomas,Kihlberg, Jan,Widersten, Mikael
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supporting information
p. 1187 - 1190
(2018/03/26)
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- Method of coupling, and the coupling method using the aromatic group-substituted heterocyclic compound
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Provided is an easy method (coupling method) capable of easily synthesizing a compound group in which aromatic molecules and aromatic molecules are coupled, a compound group in which aromatic molecules and alkene molecules are coupled, and the like without producing halogen waste and without the need to use scarce and expensive palladium. A compound (A) shown by general formula (A): Ar-H and a compound (B1) shown by general formula (B1): RaOCO-Ar', a compound (B2) shown by general formula (B2): RbCH=C(Ar")2, or a compound (B3) shown by general formula (B3): RcOCOCH=C(Ar")2 are reacted in the presence of a nickel compound.
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Paragraph 0303; 0308-0309; 0311
(2020/09/17)
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- Hypervalent Iodine(III)-Mediated Cascade Cyclization of Propargylguanidines and Total Syntheses of Kealiinine B and C
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An oxidative cascade cyclization of propargylguanidines promoted by phenyliodonium diacetate (PIDA) was developed. The protocol provides an efficient route for the synthesis of the alkaloids kealiinines B and C as well as homologues. The difference in the electronic nature of the acetylene substituent resulted in two ways of the cyclization. A plausible mechanism is proposed based on the experimental results.
- Tian, Guilong,Fedoseev, Pavel,Van der Eycken, Erik V.
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supporting information
p. 5224 - 5227
(2017/04/24)
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- Design and synthesis of neolamellarin a derivatives targeting heat shock protein 90
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In this study, we designed and synthesized a novel family of neolamellarin A derivatives that showed high inhibitory activity toward heat shock protein 90 (Hsp90), a kinase associated with cell proliferation. The 3,4-bis(catechol)pyrrole scaffold and the benzyl group with methoxy modification at N position of pyrrole are essential to the Hsp90 inhibitory activity and cytotoxicity of these compounds. Western blot analysis demonstrated that these compounds induced dramatic depletion of the examined client proteins of Hsp90, and accelerated cancer cell apoptosis. Docking simulations suggested that the binding mode of 9p was similar to that of the VER49009, a potent inhibitor of Hsp90. Further molecular dynamics simulation indicated that the hydrophobic interactions as well as the hydrogen bonds contributed to the high affinity of 9p to Hsp90.
- Jiang, Long,Yin, Ruijuan,Wang, Xueting,Dai, Jiajia,Li, Jing,Jiang, Tao,Yu, Rilei
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supporting information
p. 24 - 33
(2017/04/21)
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- Strategies for the construction of morphinan alkaloid AB-rings: Regioselective Friedel-Crafts-type cyclisations of γ-aryl-β-benzoylamido acids with asymmetrically substituted γ-aryl rings
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The regioselectivity of the Friedel-Crafts-type cyclisation of a range of γ-aryl-β-benzoylamido acids, bearing oxy substituents at the C(3)- and C(4)-positions of the γ-aryl ring, has been investigated. In all of the cases examined (with 3,4-dimethoxy, 3,4-methylenedioxy and 3-hydroxy-4-methoxy substituents) the Lewis acid promoted cyclisation proceeds with exclusive regioselectivity for attack at the C(6)-position rather than at the C(2)-position, and furnishes the corresponding N- and O-protected 3-amino-6,7-dihydroxy-1-tetralone derivatives. This inherent regioselectivity can be overturned by the regioselective introduction of chlorine as a blocking group for the C(6)-position; subsequent Lewis acid promoted cyclisation then proceeds with exclusive regioselectivity for attack at the C(2)-position to deliver the corresponding N- and O-protected 3-amino-5-chloro-7,8-dihydroxy-1-tetralone derivative. These complementary cyclisation protocols represent useful methods for the preparation of these benzo-fused carbocyclic ring systems, which are the functionalised AB-rings of a range of morphinan alkaloids.
- Davies, Stephen G.,Goddard, Euan C.,Roberts, Paul M.,Russell, Angela J.,Smith, Andrew D.,Thomson, James E.,Withey, Jonathan M.
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p. 274 - 284
(2017/03/01)
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- Synthesis of 3-Arylpyridines via Palladium/Copper-Catalyzed Annulation of Allylamine/1,3-Propanediamine and Aldehydes
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A novel and efficient method for the synthesis of 3-arylpyridines from allylamine/propanediamine and aldehydes by palladium/copper-catalyzed oxidative tandem cyclization has been developed. With this reaction, a series of desired 3-arylpyridines was synthesized in moderate yields via C-C/C-N bond formation and 6-endo/exo-trig cyclization.
- Yang, Xiaodong,Yang, Shenghua,Xiang, Likui,Pang, Xiaobo,Chen, Baohua,Huang, Guosheng,Yan, Rulong
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supporting information
p. 3732 - 3736
(2016/01/25)
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- NOVEL COMPOUND OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, AND PHARMACEUTICAL COMPOSITION CONTAINING SAME AS ACTIVE INGREDIENT
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The present invention relates to a novel compound inhibiting Hsp 90 and to a pharmaceutical composition including same as an active ingredient. Compounds of formula 1 and formula 2 according to the present invention inhibit the accumulation of HIF-1α protein, which is an Hsp90 client protein, by suppressing Hsp90 expression, and effectively inhibit the activity of vascular endothelial growth factor (VEGF). Furthermore, said compounds have low cytotoxicity and can thus be used as an active ingredient for the treatment of diabetic retinopathy and arthritis.
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- NOVEL COMPOUND OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, AND PHARMACEUTICAL COMPOSITION CONTAINING SAME AS ACTIVE INGREDIENT
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The present invention relates to a compound inhibiting Hsp90 and a pharmaceutical composition comprising the same as an active ingredient. The compounds represented by formula 1 and formula 2 of the present invention suppress the expression of Hsp90 so that they can inhibit the accumulation of HIF-1α, the Hsp90 client protein, and also efficiently inhibit the activation of VEGF. In addition, these compounds display low cytotoxicity, so that they can be effectively used as an active ingredient of an anti-cancer agent, a diabetic retinopathy treating agent, and an anti-arthritic agent.
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- Organocatalytic Enantioselective Pictet-Spengler Approach to Biologically Relevant 1-Benzyl-1,2,3,4-Tetrahydroisoquinoline Alkaloids
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(Figure Presented) A general procedure for the synthesis of 1-benzyl-1,2,3,4-tetrahydroisoquinolines was developed, based on organocatalytic, regio- and enantioselective Pictet-Spengler reactions (86-92% ee) of N-(o-nitrophenylsulfenyl)-2-arylethylamines with arylacetaldehydes. The presence of the o-nitrophenylsulfenyl group, together with the MOM-protection in the catechol part of the tetrahydroisoquinoline ring system, appeared to be a productive combination. To demonstrate the versatility of this approach, 10 biologically and pharmaceutically relevant alkaloids were prepared using (R)-TRIP as the chiral catalyst: (R)-norcoclaurine, (R)-coclaurine, (R)-norreticuline, (R)-reticuline, (R)-trimemetoquinol, (R)-armepavine, (R)-norprotosinomenine, (R)-protosinomenine, (R)-laudanosine, and (R)-5-methoxylaudanosine.
- Ruiz-Olalla, Andrea,Würdemann, Martien A.,Wanner, Martin J.,Ingemann, Steen,Van Maarseveen, Jan H.,Hiemstra, Henk
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p. 5125 - 5132
(2015/05/27)
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- 2,3-BENZODIAZEPINES
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What is described are BET protein-inhibitory, in particular BRD4-inhibitory 2,3-benzodiazepines of the general formula (I) in which R1a, R1b, R1c, R2, R3, R4, R5, A and X have the meanings given in the description, intermediates for preparing the compounds according to the invention, pharmaceutical compositions comprising the compounds according to the invention and their prophylactic and therapeutic use for hyperproliferative disorders, in particular for tumour disorders. Also described is the use of BET protein inhibitors for benign hyperplasias, atherosclerotic disorders, sepsis, autoimmune disorders, vascular disorders, viral infections, for neurodegenerative disorders, for inflammatory disorders, for atherosclerotic disorders and for the control of male fertility.
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Paragraph 1883; 1884; 1885; 1886
(2015/07/27)
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- The importance of the 6- and 7-positions of tetrahydroisoquinolines as selective antagonists for the orexin 1 receptor
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Selective antagonism of the orexin 1 (OX1) receptor has been proposed as a potential mechanism for treatment of drug addiction. We have previously reported studies on the structure-activity relationships of tetrahydroisoquinoline-based antagonists. In this report, we elucidated the respective role of the 6- and 7-substitutions by preparation of a series of either 6-substituted tetrahydroisoquinolines (with no 7-substituents) or vice versa. We found that 7-substituted tetrahydroisoquinolines showed potent antagonism of OX1, indicating that the 7-position is important for OX1 antagonism (10c, Ke = 23.7 nM). While the 6-substituted analogs were generally inactive, several 6-amino compounds bearing ester groups showed reasonable potency (26a, Ke = 427 nM). Further, we show evidence that suggests several compounds initially displaying insurmountable antagonism at the OX1 receptor are competitive antagonists with slow dissociation rates.
- Perrey, David A.,Decker, Ann M.,Li, Jun-Xu,Gilmour, Brian P.,Thomas, Brian F.,Harris, Danni L.,Runyon, Scott P.,Zhang, Yanan
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p. 5709 - 5724
(2015/11/11)
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- 2, 3-benzodiazepins
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What is described are BET protein-inhibitory, in particular BRD4-inhibitory 2,3-benzodiazepines of the general formula (I) in which R1a, R1b, R1c, R2, R3, R4, R5, A and X have the meanings given in the description, intermediates for preparing the compounds according to the invention, pharmaceutical compositions comprising the compounds according to the invention and their prophylactic and therapeutic use for hyperproliferative disorders, in particular for tumour disorders. Also described is the use of BET protein inhibitors for benign hyperplasias, atherosclerotic disorders, sepsis, autoimmune disorders, vascular disorders, viral infections, for neurodegenerative disorders, for inflammatory disorders, for atherosclerotic disorders and for the control of male fertility.
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Paragraph 0691-0692
(2016/10/08)
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- Borontribromide-mediated C-C bond formation in cyclic ketones: A transition metal free approach
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Borontribromide (BBr3) is a well-known demethylating agent. The current investigation was focused on a new application of borontribromide as a C-C bond forming agent in cyclic ketones. In this study, borontribromide mediated C-C bond formation reactions of tetralones, chromenone, thiochromenone and indanones were explored. A methoxy group containing ketones showed selective C-C bond formation reaction instead of demethylation of the methoxy group. MM2 steric energy calculations for the final products showed that the reaction favored the formation of exo- or endo-cyclic double bond containing products, depending upon their low MM2 steric energy in a specific frame structure, as observed in X-ray crystallography. A comprehensive crystallographic and pi-stacking analysis of product 10a demonstrated the formation of 10a as an enantiomeric mixture, and its centre of inversion was stabilized by a set of three unique pi-pi interactions.
- Ahmad, Imran,Pathak, Vinay,Vasudev, Prema G.,Maurya, Hardesh K.,Gupta, Atul
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p. 24619 - 24634
(2014/07/07)
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- Total synthesis of (-)-Haouamine B pentaacetate and structural revision of haouamine B
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The enantiocontrolled total synthesis of (-)-haouamine B pentaacetate was accomplished via an optically active indane-fused β-lactam, which was prepared by a newly developed Friedel-Crafts reaction. Subsequent cleavage of the β-lactam and an intramolecular McMurry coupling reaction provided the core indane-fused tetrahydropyridine, which led to the elucidation of the structure, as proposed by Trauner and Zuba.
- Momoi, Yuichi,Okuyama, Kei-Ichiro,Toya, Hiroki,Sugimoto, Kenji,Okano, Kentaro,Tokuyama, Hidetoshi
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p. 13215 - 13219
(2015/01/09)
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- A straightforward organocatalytic alkylation of 2-arylacetaldehydes: An approach towards bisabolanes
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A highly stereoselective organocatalytic aalkylation of 2-arylacetaldehydes with a commercially available carbenium tetrafluoroborate is described. The stereoselective alkylation was carried out in acetonitrile/ water, under air in the presence of a commercially available imidazolidinone (MacMillan's catalyst). Key intermediates for the synthesis of bisabolanes were obtained through a simple chemistry. In particular a direct, enantioselective and facile synthesis of (R)-(-)-curcumene is described.
- Gualandi, Andrea,Canestrari, Pietro,Emer, Enrico,Cozzi, Pier Giorgio
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supporting information
p. 528 - 536
(2014/05/20)
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- A continuous flow solution to achieving efficient aerobic anti-Markovnikov Wacker oxidation
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An aerobic anti-Markovnikov Wacker oxidation for the flow-synthesis of arylacetaldehydes is reported. In the process, flow chemistry techniques have provided a means to control and minimise the over-oxidation of sensitive products. The reaction showed general applicability to various functionalised styrenes and provided a process capable of a multi-gram scale. Copyright
- Bourne,Ley
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supporting information
p. 1905 - 1910
(2013/08/23)
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- Biarylphosphonite gold(I) complexes as superior catalysts for oxidative cyclization of propynyl arenes into indan-2-ones
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Striking gold: A series of variously functionalized propynyl arenes was smoothly converted into indan-2-ones by a new gold(I)-catalyzed oxidative cyclization process. [LAu]NTf2 (Tf=trifluoromethanesulfonyl) is a superior catalyst both in terms of yield and kinetics for the present transformation. Copyright
- Henrion, Guilhem,Chavas, Thomas E. J.,Le Goff, Xavier,Gagosz, Fabien
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supporting information
p. 6277 - 6282
(2013/07/11)
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- C-H alkenylation of azoles with enols and esters by nickel catalysis
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Rather u(Ni)que: Two new C-H alkenylation reactions, that is C-H/Ci￡O alkenylation and decarbonylative C-H alkenylation, of azoles are uniquely catalyzed by Ni/dcype. These azole alkenylation reactions are successfully applied to the convergent formal synthesis of siphonazoleB.
- Meng, Lingkui,Kamada, Yuko,Muto, Kei,Yamaguchi, Junichiro,Itami, Kenichiro
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supporting information
p. 10048 - 10051
(2013/10/01)
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- Design, synthesis, and biological evaluation of novel deguelin-based heat shock protein 90 (HSP90) inhibitors targeting proliferation and angiogenesis
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Deguelin exhibits potent apoptotic and antiangiogenic activities in a variety of transformed cells and cancer cells. Deguelin also exhibits potent tumor suppressive effects in xenograft tumor models for many human cancers. Our initial studies confirmed that deguelin disrupts ATP binding to HSP90 and consequently induces destabilization of its client proteins such as HIF-1α. Interestingly, a fluorescence probe assay revealed that deguelin and its analogues do not compete with ATP binding to the N-terminus of HSP90, unlike most HSP90 inhibitors. To determine the key parts of deguelin that contribute to its potent HSP90 inhibition, as well as its antiproliferative and antiangiogenic activities, we have established a structure-activity relationship (SAR) of deguelin. In the course of these studies, we identified a series of novel and potent HSP90 inhibitors. In particular, analogues 54 and 69, the B- and C-ring-truncated compounds, exhibited excellent antiproliferative activities with IC50 of 140 and 490 nM in the H1299 cell line, respectively, and antiangiogenic activities in zebrafish embryos in a dose dependent manner (0.25-1.25 μM).
- Chang, Dong-Jo,An, Hongchan,Kim, Kyoung-Suk,Kim, Hyun Ho,Jung, Jinkyung,Lee, Jung Min,Kim, Nam-Jung,Han, Young Taek,Yun, Hwayoung,Lee, Sujin,Lee, Geumwoo,Lee, Seungbeom,Lee, Ju Sung,Cha, Jong-Ho,Park, Ji-Hyeon,Park, Ji Won,Lee, Su-Chan,Kim, Sang Geon,Kim, Jeong Hun,Lee, Ho-Young,Kim, Kyu-Won,Suh, Young-Ger
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p. 10863 - 10884
(2013/03/13)
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- The catalytic potential of Coptis japonica NCS2 revealed - Development and utilisation of a fluorescamine-based assay ETI
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The versatility and potential of a norcoclaurine synthase (NCS) from Coptis japonica NCS2 has been investigated, together with the development and application of a novel fluorescence-based high-throughput assay using nearly forty amines/aldehydes. The stereocontrol exerted by CjNCS2 on selected non-natural substrates has been determined, where the tetrahydroisoquinolines (THIAs) were formed as the (1S)-isomer in >95% ee, as observed with the natural product norcoclaurine. Docking calculations involving THIA mechanism intermediates, utilising the reported Thalictrum flavum NCS X-ray crystallographic structure, were carried out and combined with the CjNCS2 screening results to further understand the mode of action of NCS. These findings suggested that in addition to the key active-site residues K122 and E110, D141 is also mechanistically essential for the enzymatic transformation. The exceptional tolerance of NCS towards aldehyde substrates is furthermore supported by our proposed mechanism in which the aldehydes protrude out of the enzymatic pocket. Copyright
- Pesnot, Thomas,Gershater, Markus C.,Ward, John M.,Hailes, Helen C.
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supporting information
p. 2997 - 3008
(2013/01/15)
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- Biocatalytic production of tetrahydroisoquinolines
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The promiscuity of the enzyme norcoclaurine synthase is described. This biocatalyst yielded a diverse array of substituted tetrahydroisoquinolines by cyclizing dopamine with various acetaldehydes in a Pictet-Spengler reaction. This enzymatic reaction may provide a biocatalytic route to a range of tetrahydroisoquinoline alkaloids.
- Ruff, Bettina M.,Br?se,O'Connor, Sarah E.
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supporting information; experimental part
p. 1071 - 1074
(2012/03/27)
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- Microwave-assisted synthesis of 5-substituted 2-aminothiophenes starting from arylacetaldehydes
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An easy three-step pathway for the synthesis of arylacet-aldehydes from the corresponding carboxylic acids in very high yields is described. Their use as precursors of 5-substituted-2-aminothiophenes is illustrated via a microwave-assisted Gewald reaction. This method allows obtaining the expected compounds in a shorter time and with better yields and purities than the classical procedures. Georg Thieme Verlag Stuttgart - New York.
- Revelant, Germain,Dunand, Sandrine,Hesse, Stephanie,Kirsch, Gilbert
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p. 2935 - 2940
(2011/11/01)
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- Total synthesis of (±)-armepavines and (±)-nuciferines from (2-nitroethenyl)benzene derivatives
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A concise route to armepavine 1 and nuciferine 2 and 3, which can be isolated from the leaves of Nelumbo nucifera (Nymphaceae), has been achieved in which the longest linear sequence is only six steps from commercially available benzaldehyde in 28%, 21%, and 20% overall yield, respectively. The key transformations in the synthesis are the radical cyclization of aryl bromide with Bu3SnH and the Pictet-Spengler reaction of N-substituted amine with aldehyde. Copyright Taylor & Francis Group, LLC.
- Chang, Chia-Fu,Huang, Chu-Yun,Huang, Yu-Chao,Lin, Kuan-Yu,Lee, Yean-Jang,Wang, Chau-Jong
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experimental part
p. 3452 - 3466
(2011/02/22)
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- On the regioselectivity of the PIFA-mediated bis(trifluoroacetoxylation) of styrene-type compounds
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The addition of the hypervalent iodine reagent PIFA [phenyliodine(III) bis(trifluoroacetate)] to a series of styrene-type compounds results in the bis(trifluoroacetoxylation) of the double bond as two possible 1,2- and 1,1-regioisomers. We found that 1,1-regioisomers resulted to be unstable during chromatographic purification yielding the related arylacetaldehydes. In this paper, we show our efforts to explore the regioselectivity of this reaction, and to rationalize the results with respect to the electronic nature of the corresponding aryl ring through alternative mechanistic pathways.
- Tellitu, Imanol,Domínguez, Esther
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p. 2465 - 2470
(2008/09/19)
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- Mild and selective hydrozirconation of amides to aldehydes using Cp 2Zr(H)Cl: Scope and mechanistic insight
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An investigation of the use of Cp2Zr(H)Cl (Schwartz's reagent) to reduce a variety of amides to the corresponding aldehydes under very mild reaction conditions and in high yields is reported. A range of tertiary amides, including Weinreb's amides, can be converted directly to the corresponding aldehydes with remarkable chemoselectivity. Primary and secondary amides proved to be viable substrates for reduction as well, although the yields were somewhat diminished as compared to the corresponding tertiary amides. Results from NMR experiments suggested the presence of a stable, 18-electron zirconacycle intermediate that presumably affords the aldehyde upon water or silica gel workup. A series of competition experiments revealed a preference of the reagent for substrates in which the lone pair of the nitrogen is electron releasing and thus more delocalized across the amide bond by resonance. This trend accounts for the observed excellent selectivity for tertiary amides versus esters. Experiments regarding the solvent dependence of the reaction suggested a kinetic profile similar to that postulated for the hydrozirconation of alkenes and alkynes. Addition of p-anisidine to the reaction intermediate resulted in the formation of the corresponding imine mimicking the addition of water that forms the aldehyde.
- Spletstoser, Jared T.,White, Jonathan M.,Tunoori, Ashok Rao,Georg, Gunda I.
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p. 3408 - 3419
(2007/10/03)
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- PHENYLALKANOL COMPOUNDS
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The present invention relates to phenylalkanol compounds of formula (I) and derivatives, prodrugs, isomers and/or tautomers thereof. The present invention also relates to processes for the preparation of a compound of formula (I) and their use as pharmaceutical or veterinary agents, in particular as modulators of the vanilloid receptor for the treatment and/or prophylaxis of pain.
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Page/Page column 30; 31
(2010/11/25)
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- A convenient synthesis of 1-benzyl-1,2,3,4-tetrahydroisoquinolines by combined Strecker/Bruylants reaction
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Strecker reaction of iodophenethylamines with phenylacetaldehydes afforded the corresponding α-aminonitriles, which on treatment with i-propyl magnesium chloride underwent a Bruylants reaction to give the title compounds. Their structures were deduced by NMR and by an independent preparation starting from papaverine. The educts were easily available by standard procedures. Springer-Verlag 2004.
- Reimann, Eberhard,Ettmayr, Christian
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p. 1289 - 1295
(2007/10/03)
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- The Oxidation of 3-Aryl-1-propenes by Oxidative System of RuCl 3-NaIO4-Phase Transfer Catalyst
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Methyleugenol 1a was oxidized to give 3,4-dimethoxyphenylacetaldehyde by the oxidative system containing the RuCl3-NaIO4-phase transfer catalyst. The yield and spectroscopic properties were obtained from the stable acetaldoxim 3a. Furthermore, this oxidation system could be applied to other arylpropenes, thus, safrole, 4-methoxyallylbenzene, allylbenzene, and the corresponding arylacetaldehyde formed.
- Yuasa, Yoshifumi,Shibuya, Shiroshi,Yuasa, Yoko
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p. 3947 - 3952
(2007/10/03)
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- A novel straightforward synthesis of enantiopure tetrahydroisoquinoline alkaloids
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A novel, direct, and high-yielding stereoselective method for enantiopure 1-substituted tetrahydroisoquinolines (THIQ) is described. The successful approach, which creates the stereocenter during the formation of the THIQ nucleus is based on (i) formation of chiral 2,3-substituted perhydro-1,3-benzoxazines derived from (-)-8-aminomenthol, (ii) diastereoselective intramolecular ring opening of the N,O-acetal moiety by an arylmetal generated from the substituent at the nitrogen atom in the perhydrobenzoxazine ring, and (iii) removal of the chiral auxiliary appendage. The starting perhydrobenzoxazines are easily prepared from (-)-8-aminomenthol and two different aldehydes, and the intramolecular opening is stereospecific, leading to a single stereoisomer. The method allows the preparation of a wide variety of enantiopure 1-substituted THIQ, with different substituents at C-1, by changing the nature of the starting aldehydes.
- Pedrosa,Andres,Iglesias
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p. 243 - 250
(2007/10/03)
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- Two general routes to 1,4-disubstituted-2,3,4,5-tetrahydro- 1H-3-benzazepines.
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[structure] Two general routes to 1,4-disubstituted-2,3,4, 5-tetrahydro-1H-3-benzazepines are described. Both routes utilize an appropriately functionalized phenethylamino alcohol as the penultimate intermediate: the first route makes use of the reductive amination of a benzyl alkyl ketone with alpha-(aminomethyl)benzyl alcohol, while the second route utilizes the addition of a Grignard reagent to the oxazolidine derived from a substitued phenylacetaldehyde and alpha-(methylaminomethyl)benzyl alcohol. In all cases studied, the cis-1,4-disubstituted-2,3,4, 5-tetrahydro-1H-3-benzazepine was obtained as the major product.
- Gerritz,Smith,Nanthakumar,Uehling,Cobb
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p. 4099 - 4102
(2007/10/03)
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- Indium(III) chloride-promoted rearrangement of epoxides: A selective synthesis of substituted benzylic aldehydes and ketones
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A simple and efficient procedure for the rearrangement of substituted epoxides catalyzed by InCl3 has been developed. Aryl-substituted epoxides isomerize with complete regioselectivity to form a single carbonyl compound via cleavage of the benzylic C-O bond. The reactions are simple, fast, and high yielding. This procedure is very mild compared to those catalyzed with BF3 and other Lewis acids and compatible with several acid-sensitive functionalities. This protocol provides a highly selective synthesis of substituted benzylic aldehydes and ketones. However, rearrangement of alkyl- substituted epoxides is not very selective.
- Ranu, Brindaban C.,Jana, Umasish
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p. 8212 - 8216
(2007/10/03)
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- Oxidations of benzyl and phenethyl phenyl sulfides. Implications for the mechanism of the microsomal and biomimetic oxidation of sulfides
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The study of the oxidation of 4-methoxyphenethyl phenyl sulfide and 3,4-dimethoxyphenethyl phenyl sulfide with potassium 12-tungstocobalt(III)ate [Co(III)W] suggests that in the radical cations of 3,4,5-(MeO)3PhCH2SPh (4) and 2,4,6(MeO)3PhCH2SPh (5) the positive charge is not localized on the sulfur atom, but in the benzylic aromatic ring. Nevertheless, in the biomimetic and microsomal oxidation of 4 and 5 the products observed are exclusively sulfoxides and sulfones, which appears in contrast with a mechanism involving the formation of an intermediate sulfide radical cation followed by a fast oxygen rebound. A direct oxygen transfer mechanism seems most likely.
- Baciocchi, Enrico,Lanzalunga, Osvaldo,Pirozzi, Bruno
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p. 12287 - 12298
(2007/10/03)
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- Synthesis of 1,2-Bis(3,4-dimethoxyphenyl)-1,3-propanediol Starting from trans-1,3-Bis(3,4-dimethoxyphenyl)-2,3-epoxy-1-propanone
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erythro-1,2-Bis(3,4-dimethoxyphenyl)-1,3-propanediol has been synthesized (yield, 72percent) by acid-catalysed rearrangement of trans-2,3-bis(3,4-dimethoxyphenyl)-2,3-epoxy-1-propanone yielding 1,3-bis(3,4-dimethoxyphenyl)-3-oxopropanal (and its enol form) an subsequent reduction of this compound with sodium tetrahydridoborate. threo-1,2-Bis(3,4-dimethoxyphenyl)-1,3-propanediol (yield, 1-2percent), meso-hydroveratroin, 1,2-bis(3,4-dimethoxyphenyl)ethanol, 1,2-bis(3,4-dimethoxyphenyl)-1-propanol and 3,4-dimethoxybenzyl alcohol were also present in the reaction product.Reduction in alkaline solution lowered the yield notably owing to deformylation/reduction leading to the formation of substantial amounts of 1,2-bis(3,4-dimethoxyphenyl)ethanol.The general applicability of the synthetic method involving rearrangement of 1,3-diaryl-2,3-epoxy-1-propanones for the synthesis of lignin model compounds of the 1,2-diaryl-1,3-propanediol type is evaluated.
- Li, Shiming,Lundquist, Knut,Stomberg, Rolf
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p. 867 - 871
(2007/10/02)
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- Novel Photooxidation of Alkenes Sensitized by p-Dimethoxybenzene
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Photoexcited p-dimethoxybenzene catalyses oxidative cleavage of various alkenes to corresponding carbonyls in the presence of oxygen.
- Bhalerao, Uday T.,Sridhar, Madabhushi
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p. 4341 - 4342
(2007/10/02)
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- Tricarbonylchromium(0) Promoted Stereoselective Cyclisations of the N-3,4-Dimethoxyphenethyl Derivatives of the 1-Phenyl Ethanolamines Halostachine, Ephedrine and Pseudoephedrine to 1-Phenyl-N-Methyl-7,8-Dimethoxy-1,2,4,5-Tetrahydrobenzazepines
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Acid promoted cyclisation of homochiral (R)-N-(3,4-dimethoxyphenethyl)-halostachine proceeds with almost total racemisation to yield 1-phenyl-N-methyl-1,2,4,5-tetrahydrobenzazepine (e.e, 6percent).Coordination of the cyclisation precursor to the tricarbonylchromium(0) moiety renders the cyclisation completely stereospecific to afford, after decomplexation, homochiral (+)-(R)-1-phenyl-N-methyl-1,2,4,5-tetrahydrobenzazepine. (-)-(1R,2S)-N-(3,4-Dimethoxyphenethyl)ephedrine undergoes acid mediated cyclisation to furnish trans-(-)-(1R,2S)-1-phenyl-2-methyl-N-methyl-7,8-dimethoxy tetrahydrobenzazepine as a single diastereoisomer.In contrast, the epimeric cyclisation precursor (-)-(1R,2R)-N-(3,4-dimethoxyphenethyl)pseudoephedrine cyclises to give a mixture (ratio 91:9) of trans- and cis-1-phenyl-2-methyl-N-methyl-7,8-dimethoxy tetrahydrobenzazepine.However, cyclisation of the tricarbonylchromium(0) complex of (-)-(1R,2R)-N-(3,4-dimethoxyphenethyl)pseudo-ephedrine is completely stereoselective to yield trans-(+)-(1S,2R)-1-phenyl-2-methyl-N-methyl-7,8-dimethoxy tetrahydrobenzazepine after decomplexation.
- Coote, Steven J.,Davies, Stephen G.,Middlemiss, David,Naylor, Alan
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- A Convenient Strategy for Homologation of p-Oxygenated Benzaldehydes
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It is shown that p-oxygenated benzaldehydes can be conveniently obtained by pyrolysis of the corresponding oxiranes.
- Haridas, K.,Dev, Sukh
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p. 1018 - 1020
(2007/10/02)
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