- Benzoheterocyclic Oxime Carbamates Active against Mycobacterium tuberculosis: Synthesis, Structure-Activity Relationship, Metabolism, and Biology Triaging
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Screening of a library of small polar molecules against Mycobacterium tuberculosis (Mtb) led to the identification of a potent benzoheterocyclic oxime carbamate hit series. This series was subjected to medicinal chemistry progression underpinned by structure-activity relationship studies toward identifying a compound for proof-of-concept studies and defining a lead optimization strategy. Carbamate and free oxime frontrunner compounds with good stability in liver microsomes and no hERG channel inhibition liability were identified and evaluated in vivo for pharmacokinetic properties. Mtb-mediated permeation and metabolism studies revealed that the carbamates were acting as prodrugs. Toward mechanism of action elucidation, selected compounds were tested in biology triage assays to assess their activity against known promiscuous targets. Taken together, these data suggest a novel yet unknown mode of action for these antitubercular hits.
- Van Der Westhuyzen, Renier,Mabhula, Amanda,Njaria, Paul M.,Müller, Rudolf,Ngumbu Muhunga, Denis,Taylor, Dale,Lawrence, Nina,Njoroge, Mathew,Brunschwig, Christel,Moosa, Atica,Singh, Vinayak,Rao, Srinivasa P.S.,Manjunatha, Ujjini H.,Smith, Paul W.,Warner, Digby F.,Street, Leslie J.,Chibale, Kelly
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supporting information
p. 9444 - 9457
(2021/07/19)
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- An α-Cyclopropanation of Carbonyl Derivatives by Oxidative Umpolung
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The reactivity of iodine(III) reagents towards nucleophiles is often associated with umpolung and cationic mechanisms. Herein, we report a general process converting a range of ketone derivatives into α-cyclopropanated ketones by oxidative umpolung. Mechanistic investigation and careful characterization of side products revealed that the reaction follows an unexpected pathway and suggests the intermediacy of non-classical carbocations.
- Bauer, Adriano,Di Mauro, Giovanni,Li, Jing,Maulide, Nuno
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supporting information
p. 18208 - 18212
(2020/08/21)
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- Magnesium Aldimines Prepared by Addition of Organomagnesium Halides to 2,4,6-Trichlorophenyl Isocyanide: Synthesis of 1,2-Dicarbonyl Derivatives
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The selective addition of organomagnesium reagents to 2,4,6-trichlorophenyl isocyanide leading to magnesiated aldimines is reported. These aldimines react with Weinreb amides, ketones, or carbonates to provide the corresponding carbonyl derivatives after acidic cleavage. This allows for an efficient synthesis of 1,2-dicarbonyl compounds and α-hydroxy ketones.
- Schw?rzer, Kuno,Bellan, Andreas,Z?schg, Maximilian,Karaghiosoff, Konstantin,Knochel, Paul
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supporting information
p. 9415 - 9418
(2019/05/10)
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- Enolizable β-Fluoroenones: Synthesis and Asymmetric 1,2-Reduction
-
The hydrofluorination of enolizable ynones with AgF in t-BuOH/DMF is reported. The formation of furans as side products can be suppressed using 2,2′-biphenol. The corresponding β-fluoroenones were obtained with good Z-selectivity. A variety of functional groups are tolerated. β-Fluoroenones are vinylogous acid fluorides whose hydrolysis to vinylogous acids can be avoided under the reported reaction conditions. The asymmetric 1,2-reduction of β-fluoroenones to 3-fluoroallylic alcohols is possible with pinacolborane and a Ni(0) catalyst prepared from a pyrimidyloxazoline ligand.
- Zygalski, Lukas,Middel, Christoph,Harms, Klaus,Koert, Ulrich
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supporting information
p. 5071 - 5074
(2018/08/24)
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- Synthesis of Difluoromethyl Ketones from Weinreb Amides, and Tandem Addition/Cyclization of o-Alkynylaryl Weinreb Amides
-
[Difluoro(phenylsulfanyl)methyl]trimethylsilane (PhSCF2SiMe3) underwent a fluoride-induced nucleophilic addition to the carbonyl group of Weinreb amides to provide the corresponding difluoro(phenylsulfanyl)methyl ketones. These were
- Phetcharawetch, Jongkonporn,Betterley, Nolan M.,Soorukram, Darunee,Pohmakotr, Manat,Reutrakul, Vichai,Kuhakarn, Chutima
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supporting information
p. 6840 - 6850
(2017/12/26)
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- Copper(I)-Catalyzed Enantioselective Nucleophilic Borylation of Aliphatic Ketones: Synthesis of Enantioenriched Chiral Tertiary α-Hydroxyboronates
-
A new method was developed for the first catalytic enantioselective borylation of aliphatic ketones. A variety of substrates reacted efficiently with bis(pinacolato)diboron in the presence of a copper(I)/chiral N-heterocyclic carbene complex catalyst to furnish optically active tertiary α-hydroxyboronates with moderate to high enantioselectivities (up to 94 % ee). Notably, the product could be converted into the chiral tertiary alcohol derivative using a stereospecific boron functionalization process. The theoretical study of the mechanism for the enantioselectivity is also described.
- Kubota, Koji,Osaki, Shun,Jin, Mingoo,Ito, Hajime
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supporting information
p. 6646 - 6650
(2017/05/29)
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- A C-H Insertion Approach to Functionalized Cyclopentenones
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Cyclopentenones are synthetically versatile structures, and their straightforward construction from alkynone substrates by employing synthetically streamlining C-H insertion is conceptually appealing and of high synthetic potential. But, its implementation is very limited. Herein we report a Au-catalyzed version, which affords 2-bromocyclopent-2-en-1-ones with a broad scope and synthetically desirable diastereoselectivities. The proposed key intermediate capable of the observed insertion into unactivated C-H bonds is a fully functionalized gold vinylidene, which is generated via a novel intermolecular strategy. This flexible access of likely gold vinylidenes opens various opportunities to explore their versatile reactivities.
- Wang, Youliang,Zarca, Maxence,Gong, Liu-Zhu,Zhang, Liming
-
supporting information
p. 7516 - 7519
(2016/07/06)
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- A deuterated of the IDO inhibitor and its preparation and use (by machine translation)
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The invention provides a deuterated of the IDO inhibitor and its preparation and use, as shown in formula I provide compound or its crystalline form, a pharmaceutically acceptable salt, hydrate or solvate. The preparation of the compound or its crystalline form, a pharmaceutically acceptable salt, hydrate or solvate, can be regarded as the IDO inhibitor, can be used for the treatment of IDO related diseases, in particular cancer, viral infection, depression, neurodegenerative disease, trauma, age-related cataract, organ transplant rejection and autoimmune diseases. (by machine translation)
- -
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Paragraph 0044; 0046; 0047; 0048; 0103; 0105; 0106
(2017/04/22)
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- One-pot transition-metal-free synthesis of weinreb amides directly from carboxylic acids
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Weinreb amides were prepared directly from carboxylic acids, N,O-dimethylhydroxylamine, and phosphorus trichloride in one pot at 60 °C in toluene in high yields, thus avoiding the separation of the moisture and air sensitive intermediate P[NMe(OMe)]3 in advance. Sterically hindered carboxylic acids also give the corresponding Weinreb amides in excellent yields. Various functional groups are tolerated on the carboxylic acid. The method, which is a simple process and gives high yields, is suitable for large-scale production. Georg Thieme Verlag KG Stuttgart · New York.
- Niu, Teng,Wang, Ke-Hu,Huang, Danfeng,Xu, Changming,Su, Yingpeng,Hu, Yulai,Fu, Ying
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p. 320 - 330
(2014/02/14)
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- Organocatalytic oxidation of aldehydes to mixed anhydrides
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TEMPO catalyzes the direct oxidation of aldehydes to mixed anhydrides in the presence of a carboxylic acid. The anhydrides can be converted in situ to esters, secondary, tertiary or Weinreb amides in high yield. Oxidation of the aldehyde directly to 2-propyl esters is also possible using only catalytic amounts of acid. The oxidation reactions are rapid and take place under mild conditions.
- Toledo, Hila,Pisarevsky, Evgeni,Abramovich, Adi,Szpilman, Alex M.
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supporting information
p. 4367 - 4369
(2013/06/05)
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- Ru-catalyzed hydrogenation of 3,5-diketo amides: Simultaneous control of chemo- and enantioselectivity
-
By modulating the chelating priorities of the different directing groups in 3,5-diketo amides with the assistance from coordinating solvent, highly chemo- and enantioselective hydrogenation of the C3-carbonyls was achieved in the presence of [RuCl(benzene)(S)-SunPhos]Cl in THF.
- Li, Wanfang,Fan, Weizheng,Ma, Xin,Tao, Xiaoming,Li, Xiaoming,Xie, Xiaomin,Zhang, Zhaoguo
-
supporting information
p. 8976 - 8978
(2012/11/07)
-
- Catalytic enantioselective construction of β-quaternary carbons via a conjugate addition of cyanide to β,β-disubstituted α,β-unsaturated carbonyl compounds
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The first general catalytic enantioselective conjugate addition of cyanide to β, β-disubstituted α,β-unsaturated ketones and N-acylpyrroles was developed using a strontium catalyst derived from Sr(O iPr)2 and new chiral ligand 5. The reaction exhibited excellent enantioselectivity and a wide substrate scope using 0.5-10 mol % catalyst. 1,4-Adducts containing β-quaternary carbons were exclusively produced over 1,2-adducts. ESI-MS analysis of the strontium catalyst indicated that the active catalyst was a trimetallic Sr/5 = 3:5 complex. The exclusive 1,4-selectivity was partly due to the ability of the strontium complex to promote both a retro-cyanation reaction from the 1,2-adducts and highly enantioselective conjugate cyanation.
- Tanaka, Yuta,Kanai, Motomu,Shibasaki, Masakatsu
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supporting information; experimental part
p. 8862 - 8863
(2010/08/21)
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- A halide-initiated aza-Baylis-Hillman reaction: Generation of unnatural amino acids
-
A series of allenic ketones react with a glyoxylate-derived imine in the presence of MgBr2 through an aza-Morita-Baylis-Hillman (MBH) reaction. The isolation of a variety of unnatural amino acids with unique allene-containing functional groups
- Davis, Lindsey O.,Tobey, Suzanne L.
-
supporting information; experimental part
p. 6078 - 6081
(2011/01/04)
-
- A powerful reagent for synthesis of weinreb amides directly from carboxylic acids
-
A powerful reagent, P[NCH3(OCH3)]3 (3), for conversion of carboxylic acids directly to Weinreb amides was developed. In most cases the yields of the corresponding Weinreb amides were above 90% when P[NCH3(OCHsu
- Niu, Teng,Zhang, Weiming,Huang, Danfeng,Xu, Changming,Wang, Haifeng,Hu, Yulai
-
scheme or table
p. 4474 - 4477
(2009/12/24)
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- PHTHALIMIDE DERIVATIVES AS TRPA1 MODULATORS
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The present invention provides TRPA (Transient Receptor Potential subfamily A) modulators. In particular, compounds described herein are useful for treating or preventing diseases, conditions and/or disorders modulated by TRPAl (Transient Receptor Potential subfamily A, member 1) modulators. Also provided herein are processes for preparing compounds described herein, intermediates used in their synthesis, pharmaceutical compositions thereof, and methods for treating or preventing diseases, conditions and/or disorders modulated by TRPAl.
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Page/Page column 27-28
(2009/10/22)
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- Microwave acceleration in DABAL-Me3-mediated amide formation
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Facile direct coupling of esters and secondary amines to afford tertiary amides proceeds under microwave irradiation using the air-stable trimethylaluminium source DABAL-Me3 [(DABCO)(AlMe3)2]. Excellent yields (88-98%) are attained for cyclic secondary amines in reactions that are complete in 5-16 min. The process can be extended to the formation of Weinreb amides (upto 76% from commercial MeNHOMe·HCl) in a one-pot procedure using NaH to liberate the free methoxyamine.
- Glynn, Daniel,Bernier, David,Woodward, Simon
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p. 5687 - 5688
(2008/12/22)
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- Reactions between weinreb amides and 2-magnesiated oxazoles: A simple and efficient preparation of 2-acyl oxazoles
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(Chemical Equation Presented) Treatment of oxazole or 5-aryl oxazoles with i-PrMgCl smoothly generates the corresponding 2-Grignard reagents, which react with Weinreb amides to provide exclusively 2-acyl oxazole products.
- Pippel, Daniel J.,Mapes, Christopher M.,Mani, Neelakandha S.
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p. 5828 - 5831
(2008/02/09)
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- A facile one-pot synthesis of acyclic β-enamino ketones, an important class of versatile synthetic intermediates
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A one-pot sequential process consisting of nucleophilic substitution of the lithiated acetylides with Weinreb amides followed by a Michael reaction of the extruded N-methoxy-N-methylamine after quenching with saturated NH4Cl, provided β-enamino ketones in high yield and in a single geometrical isomeric form. It has been demonstrated that this method is applicable to a wide variety of such amides and to different acetylides.
- Choudhury, Anusuya,Breslav, Michael,Grimm, Jeffrey S.,Xiao, Tong,Xu, Dawei,Sorgi, Kirk L.
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p. 3069 - 3072
(2008/02/02)
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- PYRROLIDIN-2-ONE DERIVATIVES FOR USE AS DP1 RECEPTOR AGONISTS
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The present invention is directed to compounds that may be used as agonists of prostaglandin receptors. More specifically, the specification describes methods and compositions for making and using DP1 receptor agonists that are pyrrolidin-2-one derivatives.
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Page/Page column 58
(2010/11/08)
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- Compounds and compositions for use in the prevention and treatment of obesity and related syndromes
-
The invention relates to 4-hydroxyisoleucine, isomers, analogs, lactones, salts, and prodrugs thereof, to processes for their preparation, and to pharmaceutical compositions comprising the same. More particularly, the invention relates to the use of those compounds in the prevention and treatment of obesity and related syndromes.
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Page/Page column 56
(2010/11/24)
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- Mechanism of acylation of lithium phenylacetylide with a Weinreb amide
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Additions of lithium phenylacetylide to a Weinreb amide are described. Dimeric lithium acetylide reacts via a monosolvated monomer-based transition structure. The robust tetrahedral intermediate forms sequentially a C 1 2:2 mixed tetramer with
- Qu, Bo,Collum, David B.
-
p. 7117 - 7119
(2007/10/03)
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- Analogs of 4-hydroxyisoleucine and uses thereof
-
The invention relates to analogs of 4-hydroxyisoleucine, and to lactones, pharmaceutically acceptable salts, and prodrugs thereof, to processes for their preparation, and to pharmaceutical compositions comprising the same. The analogs of the invention stimulate both glucose uptake and insulin secretion, and may thus be useful for the prevention and treatment of disorders of carbohydrate or lipid metabolism, including diabetes mellitus (type 1 and type 2 diabetes), pre-diabetes, and Metabolic Syndrome.
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Page/Page column 43
(2008/06/13)
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- Ketone substituted benzimidazole compounds
-
Disclosed are ketone substituted benzimidazole compounds of formula(I): wherein R1, R2, R3, R4 and Xa are defined herein. The compounds of the invention inhibit Itk kinase and are therefore useful for
- -
-
Page/Page column 13
(2010/02/13)
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- Structure-activity relationship of trihexyphenidyl analogs with respect to the dopamine transporter in the on going search for a cocaine inhibitor
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A series of trihexyphenidyl (THP) analogs were used to search for a derivative that could serve as a cocaine inhibitor. A compound that blocks binding of the cocaine analog carboxyfluorotropane (CFT), allows dopamine uptake and exhibits low side effects could serve as a good candidate for that purpose. All analogs were tested for the extent to which they inhibit CFT binding, dopamine uptake and n-methyl scopolamine (NMS) binding. Several structure-function relationships emerged. Methylation/halogenation of THP's benzene ring enhanced the compound's ability to block CFT binding in comparison to its ability to block dopamine uptake (5a-e). Replacement of the cyclohexyl ring with a benzene ring tended to create compounds that had lower affinities to the dopamine transporter (7b compared to THP, 7d compared to 5h, 7c compared to 8c) and modification of THP's piperidine ring tended to enhance affinity to the dopamine transporter (5f-h, 8a, 8c). One analog (5f) that showed little muscarinic activity indicating that it would probably have few side effects was investigated for its effects as an in vivo cocaine inhibitor. However, it showed few antagonistic effects in vivo. Nevertheless, this work greatly elucidates the structure-function relationships required for potential cocaine inhibitors and so lays out promising directions for future research.
- Dar,Thiruvazhi,Abraham,Kitayama,Kopajtic,Gamliel,Slusher,Carroll,Uhl
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p. 1013 - 1021
(2007/10/03)
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- The extraordinary reactions of phenyldimethylsilyllithium with N,N-disubstituted amides
-
The reactions of the silyllithium reagent with tertiary amides was discussed. The enediamines were easily isomerized from cis to trans, easily oxidized to dienediamines and were hydrolyzed to α-aminoketones. If the two equivalents of the silyllithium reagent were used, the product was an α-silylamine. The results show that each member of the homologous series of amides gives rise to a substantially different product.
- Buswell, Marina,Fleming, Ian,Ghosh, Usha,Mack, Stephen,Russell, Matthew,Clark, Barry P.
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p. 3006 - 3017
(2007/10/03)
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- An Efficient One-Pot Synthesis of N-Methoxy-N-methylamides from Carboxylic Acids
-
Several N-methoxy-N-methylamides were prepared by the reaction of the corresponding carboxylic acids with N,O-dimethylhydroxylamine hydrochloride at room temperature using trichloromethyl chloroformate in the presence of triethylamine in excellent yields.
- Kim, Misoo,Lee, Hagyoung,Han, Ki-Jong,Kay, Kwang-Yol
-
p. 4013 - 4018
(2007/10/03)
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- A mild, one-pot method for the conversion of carboxylic acids into the corresponding Weinreb amides
-
Reaction of various carboxylic acids with N,O-dimethylhydroxylamine under modified Mukaiyama amide coupling conditions affords the corresponding Weinerb amides in generally high yield.
- Banwell,Smith
-
p. 2011 - 2019
(2007/10/03)
-
- A ROMPGEL-supported N-hydroxysuccinimide: A host of acylations with minimal purification
-
(formula presented) amides, carbamates, ureas, Weinreb amides, hydroxamic acids Yields 89-98% Purity > 95% A novel N-hydroxysuccinimide ring-opening metathesis polymer is described as a recyclable supported acyl transfer reagent. Amides, carbamates, ureas, Weinreb amides, and hydroxamic acids are all obtained in excellent yields and purities from amines with minimal purification.
- Barrett, Anthony G. M.,Cramp, Susan M.,Roberts, Richard S.,Zecri, Frederic J.
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p. 261 - 264
(2007/10/03)
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- One-pot synthesis of ketones using N-methoxy-N-methyl-2-pyridyl urethane
-
The one-pot reaction of N-methoxy-N-methyl-2-pyridyl urethane with Grignard and organolithium reagents provided an efficient method for the preparation of unsymmetrical ketones.
- Lee, Na Ra,Lee, Jae In
-
p. 1249 - 1255
(2007/10/03)
-
- The sydnone ring as an ortho-director of lithiation. 2. Dilithiation of 3-phenylsydnone and regiospecific @?o-aryl acylation using N-methoxy-N-methylamides
-
Readily available 3-phenylsydnone (1) reacts with n-butyllithium/TMEDA to form the dilithio species 2 which can be regiospecifically acylated at the ortho-aryl position using N-methoxy-N-methylamides (Weinreb's amides).
- Turnbull, Kenneth,Sun, Congcong,Krein, Douglas M.
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p. 1509 - 1512
(2007/10/03)
-
- A new general method for preparation of N-methoxy-N-methylamides. Application in direct conversion of an ester to a ketone
-
The reaction of an ester with N,O-dimethylhydroxylamine and a suitable organomagnesium reagent or lithium amide base provides a general method for the preparation of N-methoxy-N-methylamides. Application in the direct conversion of a highly hindered ester to a ketone, the azasteroid 5α-reductase inhibitor MK-0434, is described.
- Williams, J. Michael,Jobson, Ronald B.,Yasuda, Nobuyoshi,Marchesini, George,Dolling, Ulf-H.,Grabowski, Edward J. J.
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p. 5461 - 5464
(2007/10/02)
-
- N-METHOXY-N-METHYLAMIDES AS EFFECTIVE ACYLATING AGENTS
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Readily preparable N-methoxy-N-methylamides couple in good yields with Grignard and organolithium reagents to produce ketones, and are reduced with hydrides to afford aldehydes.
- Nahm, Steven,Weinreb, Steven M.
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p. 3815 - 3818
(2007/10/02)
-