- Rapid Access to γ-Amino-α-aryl Alcohol Scaffolds via an Enamine-Based Heck Coupling
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The γ-amino-α-aryl alcohol is a key functional group for the design of inhibitors directed toward a critical family of metabolic enzymes. Here we report the transformation of simple aryl halides to a highly functionalized benzyl (3-oxo-3-arylpropyl)carbamate intermediate that can rapidly be converted to a high value γ-amino-α-aryl alcohol. This chemistry is realized through a two-step process involving an enamine-based Heck coupling (EBHC) followed by a one-pot catalytic Cbz-deprotection and ketone reduction of EBHC products.
- Li, Bowen,Tochtrop, Gregory P.
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p. 3851 - 3855
(2022/03/02)
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- Stereoselective Synthesis of C-Vinyl Glycosides via Palladium-Catalyzed C?H Glycosylation of Alkenes
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C-vinyl glycosides are an important class of carbohydrates and pose a unique synthetic challenge. A new strategy has been developed for stereoselective synthesis of C-vinyl glycosides via Pd-catalyzed directed C?H glycosylation of alkenes with glycosyl chloride donors using an easily removable bidentate auxiliary. Both the γ C?H bond of allylamines and the δ C?H bond of homoallyl amine substrates can be glycosylated in high efficiency and with excellent regio- and stereoselectivity. The resulting C-vinyl glycosides can be further converted to a variety of C-alkyl glycosides with high stereospecificity. These reactions offer a broadly applicable method to streamline the synthesis of complex C-vinyl glycosides from easily accessible starting materials.
- Chen, Gong,He, Gang,Qiao, Tianjiao,Sun, Qikai,Wang, Quanquan,Zhang, Huixing
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supporting information
p. 19620 - 19625
(2021/08/09)
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- Tuning Isonitrile/Tetrazine Chemistry for Accelerated Deprotection and Formation of Stable Conjugates
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The isocyano group is a valuable functionality for bioorthogonal reactions because it rapidly reacts with tetrazines to either form stable conjugates or release payloads from 3-isocyanopropyl groups. Here we provide mechanistic insights into the dissociative steps that follow the initial cycloaddition and analyze how structural modifications affect these processes. Three main outcomes of this study have important implications for designing such groups for bioorthogonal applications. First, anion-stabilizing substituents at C-2 of the 3-isocyanopropyl group promote β-elimination and accelerate deprotection. Second, tetrazines with bulky substituents form stable imine conjugates even with primary isonitriles that are otherwise rapidly hydrolyzed. Third, the elimination step is independent from hydrolysis to the aldehyde and instead can occur directly from the imine intermediate. These findings will allow tuning the structures of tetrazine and isonitrile reactants for application in bioorthogonal ligation and release chemistry.
- Xu, Minghao,Deb, Titas,Tu, Julian,Franzini, Raphael M.
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p. 15520 - 15529
(2019/11/29)
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- RAPIDLY RELEASED BIOORTHOGONAL CAGING GROUPS
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Bioorthogonal molecules are disclosed and described. A bioorthogonal a molecule having a structure according to: Formula (I); where R2, R3, and R4 are independently selected from H, a substituted or unsubstituted C1/
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Page/Page column 36
(2019/12/25)
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- HYDROXY ALIPHATIC SUBSTITUTED PHENYL AMINOALKYL ETHER DERIVATIVES
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New hydroxy aliphatic substituted phenyl aminoalkyl ether compounds of formula (I), compositions thereof and their use as a medicament in the treatment of nervous system diseases and/or the treatment of developmental, behavioral and/or mental disorders associated with cognitive deficits.
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Paragraph 0363-0364
(2015/12/24)
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- Hydroxy aliphatic substituted phenyl aminoalkyl ether derivatives
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New hydroxy aliphatic substituted phenyl aminoalkyl ether compounds of formula (1), compositions thereof and their use as a medicament in the treatment of nervous system diseases and/or the treatment of developmental, behavioral and/or mental disorders associated with cognitive deficits.
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Page/Page column
(2014/07/08)
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- Total synthesis of fluoxetine and duloxetine through an in situ imine formation/borylation/transimination and reduction approach
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We report efficient, catalytic, asymmetric total syntheses of both (R)-fluoxetine and (S)-duloxetine from α,β-unsaturated aldehydes conducting five sequential one-pot steps (imine formation/copper mediated β-borylation/transimination/reduction/oxidation) followed by the specific ether group formation which deliver the desired products (R)-fluoxetine in 45% yield (96% ee) and (S)-duloxetine in 47% yield (94% ee). This journal is the Partner Organisations 2014.
- Calow, Adam D. J.,Fernandez, Elena,Whiting, Andrew
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p. 6121 - 6127
(2014/08/05)
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- Catalytic asymmetric alkylation reactions for the construction of protected ethylene-amino and propylene-amino motifs attached to quaternary stereocentres
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An efficient catalytic and stereoselective method for the direct construction of protected ethylene-amino and propylene-amino scaffolds attached to quaternary stereocentres is reported. Preliminary investigations revealed a mild base catalysed nucleophilic ring opening of N-sulfonyl aziridines using the commercially available phosphazene base 2-tert-butylimino-2-diethylamino-1,3- dimethyl-perhydro-1,3,2-diazaphosphorine (BEMP) was possible and resulted in highly efficient alkylation reactions with a range of methine carbon acids. This reaction could be rendered highly asymmetric (up to 97 % ee) by employing phase-transfer catalysis to control stereoinduction. Incorporation of alkyl substituents onto the aziridine electrophile, resulted in a highly diastereoselective (up to 30:1 d.r.) variant of this methodology. A further extension using N-protected cyclic sulfamidates as the electrophilic component was successful with a range of pro-nucleophiles (up to 96 % ee and 45:1 d.r.) and allowed a range of nitrogen protecting groups (carbamate, sulfonyl, phosphonyl, benzyl) to be incorporated into the alkylation adducts. Finally, the utility of the products have been demonstrated in the synthesis of useful heterocycles and compounds bearing structural components of natural products. Open sesame: The enantio- and diastereoselective nucleophilic ring opening of protected aziridines and cyclic sulfamidates using asymmetric phase-transfer catalysis (PTC) is reported. The ring-opening alkylation reactions create quaternary chiral centres containing ethylene- and propylene-amino motifs in good yields with good to excellent enantioselectivities (see scheme). These reactions are broad in scope and a wide range of pro-nucleophiles are tolerated. Copyright
- Moss, Thomas A.,Barber, David M.,Kyle, Andrew F.,Dixon, Darren J.
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supporting information
p. 3071 - 3081
(2013/03/28)
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- Catalytic decarboxylative fluorination for the synthesis of Tri- and difluoromethyl arenes
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Treatment of readily available α,α-difluoro- and α-fluoroarylacetic acids with Selectfluor under Ag(I) catalysis led to decarboxylative fluorination. This operationally simple reaction gave access to tri- and difluoromethylarenes applying a late-stage fluorination strategy. Translation to [18F]labeling is demonstrated using [ 18F]Selectfluor bis(triflate), a reagent affording [ 18F]tri- and [18F]difluoromethylarenes not within reach with [18F]F2.
- Mizuta, Satoshi,Stenhagen, Ida S.R.,O'Duill, Miriam,Wolstenhulme, Jamie,Kirjavainen, Anna K.,Forsback, Sarita J.,Tredwell, Matthew,Sandford, Graham,Moore, Peter R.,Huiban, Mickael,Luthra, Sajinder K.,Passchier, Jan,Solin, Olof,Gouverneur, Véronique
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supporting information
p. 2648 - 2651
(2013/07/11)
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- PYRAZOLO PYRIMIDINES
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Compounds of formula and pharmaceutically acceptable salts thereof are described, as well as the pharmaceutical compositions containing said compounds and their pharmaceutically acceptable salts, and the use of said compounds and pharmaceutical compositions for the treatment, control or amelioration of proliferative diseases, including cancer, Down syndrome or early onset Alzheimer's disease.
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- 1,6- AND 1,8-NAPHTHYRIDINES
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Compounds of formula and pharmaceutically acceptable salts thereof are described, as well as the pharmaceutical compositions containing said compounds and their pharmaceutically acceptable salts, and the use of said compounds and pharmaceutical compositions for the treatment, control or amelioration of proliferative diseases, including cancer, Down syndrome or early onset Alzheimer's disease.
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-
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- CARBOXYLIC ACID ARYL AMIDES
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Compounds of formula and pharmaceutically acceptable salts thereof are described, as well as the pharmaceutical compositions containing said compounds and their pharmaceutically acceptable salts, and the use of said compounds and pharmaceutical compositions for the treatment, control or amelioration of proliferative diseases, including cancer.
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Page/Page column 11; 12
(2012/07/28)
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- PYRAZOLO PYRIMIDINES AS DYRK1A AND DYRK1B INHIBITORS
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Compounds of formula and pharmaceutically acceptable salts thereof are described, as well as the pharmaceutical compositions containing said compounds and their pharmaceutically acceptable salts, and the use of said compounds and pharmaceutical compositions for the treatment, control or amelioration of proliferative diseases, including cancer, Down syndrome or early onset Alzheimer's disease.
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Page/Page column 22
(2012/08/07)
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- PYRIDO PYRIMIDINES
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Compounds of formula and pharmaceutically acceptable salts thereof are described, as well as the pharmaceutical compositions containing said compounds and their pharmaceutically acceptable salts, and the use of said compounds and pharmaceutical compositions for the treatment, control or amelioration of proliferative diseases, including cancer, Down syndrome or early onset Alzheimer's disease.
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Page/Page column 16
(2012/07/28)
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- IMIDAZO PYRAZINES
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Compounds of formula and pharmaceutically acceptable salts thereof are described, as well as the pharmaceutical compositions containing said compounds and their pharmaceutically acceptable salts, and the use of said compounds and pharmaceutical compositio
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Page/Page column 21
(2012/09/25)
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- Design, synthesis and evaluation of substituted N-(3-arylpropyl)-9,10- dihydro-9-oxoacridine-4-carboxamides as potent MDR reversal agents in cancer
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A novel class of molecules with structure N-(3-arylpropyl)-9,10-dihydro-9- oxoacridine-4-carboxamides (20-29) were designed by generating a pharmacophore for potent MDR reversal activity using phase drug design software. The designed molecules were synthesized by a novel synthesis route and evaluated for their inhibitory effects on the transport activity of P-glycoprotein (P-gp) by standard Hoechst 33342 assay method. Based on the pIC50 values of ten title compounds screened, three compounds exhibited better activity as compared to Verapamil used as standard.
- Velingkar,Dandekar
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experimental part
p. 504 - 510
(2012/01/06)
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- Microwave-assisted synthesis and evaluation of substituted aryl propyl acridone-4-carboxamides as potential chemosensitizing agents for cancer
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A novel class of compounds with structure Aryl propyl acridone-4- carboxamides were synthesized by conventional and microwave (MW) irradiation methods and evaluated for their inhibitory effects on the transport activity of P- glycoprotein (P-gp) by standard Hoechst 33342 assay method. The title compounds with phenoxy substitution exhibited better activity.
- Velingkar, Vinaykumar S.,Dandekar, Vikrant D.
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p. 268 - 275
(2013/01/10)
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- Catalytic enantio- and diastereoselective alkylations with cyclic sulfamidates
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(Figure Presented) Open for business: The enantio- and diastereoselective nucleophilic ring opening of five-membered and six-membered cyclic sulfamidates under asymmetric phase-transfer catalysis is presented. A range of pro-nucleophiles have been successfully alkylated in good yields and in good to excellent enantioselectivites.
- Moss, Thomas A.,Alonso, Beatriz,Fenwick, David R.,Dixon, Darren J.
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supporting information; experimental part
p. 568 - 571
(2010/04/05)
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- INHIBITORS OF Akt ACTIVITY
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Invented are novel thiophene compounds, the use of such compounds as inhibitors of protein kinase B activity and in the treatment of cancer and arthritis.
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Page/Page column 57
(2010/11/27)
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- INHIBITORS OF AKT ACTIVITY
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Invented are novel 1 H-imidazo[4,5-c]pyridin-2-yl compounds, the use of such compounds as inhibitors of protein kinase B activity and in the treatment of cancer and arthritis.
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Page/Page column 122
(2008/06/13)
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- The resolution of important pharmaceutical building blocks by palladium-catalyzed aerobic oxidation of secondary alcohols
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The palladium-catalyzed aerobic oxidative kinetic resolution of key pharmaceutical building blocks is described. Substrates investigated are relevant to the enantioselective preparation of Prozac, Singulair, and the promising hNK-1 receptor antagonist from Merck. The latter provides the most selective aerobic oxidative kinetic resolution yet described.
- Caspi, Daniel D.,Ebner, David C.,Bagdanoff, Jeffrey T.,Stoltz, Brian M.
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p. 185 - 189
(2007/10/03)
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- One-pot sequence for the decarboxylation of α-amino acids
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Treatment of an α-amino acid with N-bromosuccinimide in water at pH 5 or in an alcoholic-aqueous ammonium chloride mixture, followed by addition of nickel(II) chloride and sodium borohydride, effected an overall decarboxylation via an intermediate nitrile to afford the corresponding amine in good yield.
- Laval, Gilles,Golding, Bernard T.
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p. 542 - 546
(2007/10/03)
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- Arylpropanolamines incorporating an antioxidant function as neuroprotective agents
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A series of arylpropanolamines containing dipyrrolidinylpyrimidines as an antioxidant function have been synthesized and evaluated as dual function neuroprotective agents. Their in vitro efficacy as sodium channel blocking agents and antioxidants has been evaluated and compared with those of the ethanolamine derivative (1), which has been shown to be neuroprotective in a rat model of stroke. The ability of the present compounds to displace 3H-BTX toxin from sodium-ion channels in a rat brain membrane fraction was shown to be largely independent of the substituents on the aryl ring, which suggests that this activity may be mainly associated with the aminopyrimidine moiety. Structure-activity relationships for antioxidant efficacy were less clear, but the unsymmetrical pyrimidines were consistently more active than their symmetrical isomers. A brief theoretical investigation of this observation is reported.
- Joubran, Lida,Jackson, W. Roy,Campi, Eva M.,Robinson, Andrea J.,Wells, Bradley A.,Godfrey, Peter D.,Callaway, Jennifer K.,Jarrott, Bevyn
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p. 597 - 605
(2007/10/03)
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- Metal-organic compounds: A new approach for drug discovery: N1-(4-methyl-2-pyridyl)-2,3,6-trimethoxybenzamide copper(II) complex as an inhibitor of human immunodeficiency virus 1 protease
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The use of metal-organic complexes is a potentially fruitful approach for the development of novel enzyme inhibitors. They hold the attractive promise of forming stronger attachments with the target by combining the co-ordination ability of metals with th
- Lebon, Florence,Boggetto, Nicole,Ledecq, Marie,Durant, Francois,Benatallah, Zohra,Sicsic, Sames,Lapouyade, Rene,Kahn, Olivier,Mouithys-Mickalad, Ange,Deby-Dupont, Ginette,Reboud-Ravaux, Michele
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p. 1863 - 1873
(2007/10/03)
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- Synthesis and preliminary biological characterization of a new potential 125I-radioligand for dopamine and serotonin receptors
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The synthesis and a preliminary biological characterization of a new class of N-benzyl-aminoalcohols which have serotonin (5-HT2) and dopamine (D2) receptor affinity is described. In vitro competition binding studies were conducted with the new molecules and 3H-spiperone on crude membrane preparation from rat striatum and frontal cortex. One of these compounds, 3-benzylamino-1-(4-fluoro-2-iodophenyl)-propan-1-ol (6f), whose IC50 values are in the micromolar range for both the D2 and 5-HT2 receptors, was prepared in iodine-125 labelled form (6i) by nucleophilic substitution of the bromine atom of 3-benzylamino-1-(2-bromo-4-fluorophenyl)-propan-1-ol (6d). In the in vivo studies, conducted on rats, the radiolabelled molecule 6i shows a good capacity to cross the blood-brain barrier (BBB) with a mean value of first pass cerebral extraction (E) of ca. 50% when the regional cerebral blood flow, measured with microsphere technique, is in the experimental animal's physiologic range (0.8-1 mL/min/g). A preliminary in vitro autoradiographic distribution on coronal rat brain slices of the radioiodinated molecule showed that it was preferentially localized in the striatum and in the cerebral regions rich in dopamine- and serotonin receptors, even if a high non-specific binding was observed.
- Guarna,Menchi,Berti,Cini,Bottoncetti,Raspanti,Politi,Pupi
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p. 3197 - 3206
(2007/10/03)
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- New routes to diethyl 1-alkenylphosphoramidates
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New routes to N-(diethoxyphosphoryl)imines derived from enolizable carbonyl compounds have been investigated. Three different procedures were studied: (i) the aza-Claisen condensation of ethyl-[N-(diethoxyphosphoryl)]-formimidate with enolizable ketones, (ii) the reaction between diethyl N-sulfinylphosphoramidate and aliphatic aldehydes, and (iii) the thermally induced reaction of diethyl phosphoramidate with ketone diethyl acetals. With two exceptions in all cases the products were identified as diethyl 1-alkenylphosphoramidates with no spectroscopically detectable amounts of imine tautomers. The aza-Claisen condensation can be recommended as a simple and effective route to diethyl 1-alkenyl-3-oxophosphoramidates. (C) 2000 Elsevier Science Ltd.
- Napieraj, Anna,Zawadzki, Stefan,Zwierzak, Andrzej
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p. 6299 - 6305
(2007/10/03)
-
- 1,4-benzodioxin derivatives
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PCT No. PCT/JP96/01252 Sec. 371 Date Nov. 12, 1997 Sec. 102(e) Date Nov. 12, 1997 PCT Filed May 13, 1996 PCT Pub. No. WO96/35685 PCT Pub. Date Nov. 14, 1996A 1,4-benzodioxin derivative represented by formula (I) wherein A is an aryl group or a (C3-C8)cycloalkyl group, R1 and R2 individually are a hydrogen atom, a halogen atom, an alkyl group, a trifluoromethyl group, an alkoxy group, an aryl group, an aryloxy group, or R1 and R2 together form a methylenedioxy group, R3 is a hydrogen atom or an alkyl group, R4 is a hydrogen atom or CO2R5, R5 is a hydrogen atom or an alkyl group, X is a radical of formula (II) or (III) wherein n is 1 or 2. The compounds are useful for a prophylactic or therapeutic agent for diabetes, hyperglycemia and obesity.
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- SYNTHESIS AND STRUCTURE OF 6-PHENYLCYCLOPHOSPHAMIDES
-
6-Phenylcyclophosphamides have been synthesized from methyl benzoate and acetonitrile to benzoyl acetonitrile followed by reduction to amino alcohol and condensation with bis(2-chloroethyl)phosphoramidic dichloride.The two diastereomers have been separated and their structures have been assigned on the basis of ir, P-31 nmr and X-ray crystallography.
- Shih, Yun-Er,Wang, Jy-Shih,Liu, Ling-Kang
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p. 1599 - 1603
(2007/10/02)
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- 1,3-Dipolar Addition of Oximes to Olefins. Conversion of Aldoximes to Nitriles under Mild Conditions
-
Under certain conditions Oximes react directly with olefins in a 1,3-dipolar fashion to produce isoxazolidines.N-Unsubstituted isoxazolidines can also be produced by reacting some nitrones with olefins and subsequent removal of the N-substituent.Aldoximes are converted to nitriles under mild conditions by dimethyl succinimidylsulfonium chloride and triethylamine.
- Dalgard, N. K. A.,Larsen, K. E.,Torssell, K. B. G.
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p. 423 - 432
(2007/10/02)
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