- LP99: Discovery and synthesis of the first selective BRD7/9 bromodomain inhibitor
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The bromodomain-containing proteins BRD9 and BRD7 are part of the human SWI/SNF chromatin-remodeling complexes BAF and PBAF. To date, no selective inhibitor for BRD7/9 has been reported despite its potential value as a biological tool or as a lead for future therapeutics. The quinolone-fused lactam LP99 is now reported as the first potent and selective inhibitor of the BRD7 and BRD9 bromodomains. Development of LP99 from a fragment hit was expedited through balancing structure-based inhibitor design and biophysical characterization against tractable chemical synthesis: Complexity-building nitro-Mannich/lactamization cascade processes allowed for early structure-activity relationship studies whereas an enantioselective organocatalytic nitro-Mannich reaction enabled the synthesis of the lead scaffold in enantioenriched form and on scale. This epigenetic probe was shown to inhibit the association of BRD7 and BRD9 to acetylated histones invitro and in cells. Moreover, LP99 was used to demonstrate that BRD7/9 plays a role in regulating pro-inflammatory cytokine secretion.
- Clark, Peter G. K.,Vieira, Lucas C. C.,Tallant, Cynthia,Fedorov, Oleg,Singleton, Dean C.,Rogers, Catherine M.,Monteiro, Octovia P.,Bennett, James M.,Baronio, Roberta,Müller, Susanne,Daniels, Danette L.,Méndez, Jacqui,Knapp, Stefan,Brennan, Paul E.,Dixon, Darren J.
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- N-heterocyclic carbene catalyzed C-C bond cleavage in redox esterifications of chiral formylcyclopropanes
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(Chemical Equation Presented) A clean break: An N-heterocyclic carbene catalyzes the ring-opening of chiral non-racemic formylcyclopropanes, with simultaneous oxidation of the aldehyde function and without the need for stoichiometric reagents. The activated carboxylate intermediate is trapped by a variety of nucleophiles, thus leading to chiral esters, thioesters, or carboxylic acids (see scheme; DBU = 1,8-diazabicyclo-[5.4.0]undec-7-ene, EWG = electron-withdrawing group, Nu = nucleophile.)
- Sohn, Stephanie S.,Bode, Jeffrey W.
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Read Online
- One-step hydrothermal amino-grafting of graphene oxide as an efficient solid base catalyst
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A one-step hydrothermal route is developed to prepare amino-grafted graphene oxide as an environmentally benign heterogeneous solid base catalyst.
- Zhang, Yicheng,Chen, Chunlin,Wu, Guangjun,Guan, Naijia,Li, Landong,Zhang, Jian
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Read Online
- Synthesis and antiarrhythmic activity of (1,3-dimethyl-5-nitro-5- hexahydropyrimidinyl)-propionic acid methyl ester
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(1,3-Dimethyl-5-nitro-5-hexahydropyrimidinyl)propionic acid methyl ester (I) was obtained with a 83% yield using a Mannich type reaction of 4-nitrobutanoic acid methyl ester with excess formalin and methylamine. It was found that compound I possesses low toxicity and shows antiarrhythmic activity on models of arrhythmia induced by intravenous injections of calcium chloride and aconitine in rats.
- Shakirov,Yarmukhamedov,Vlasova,Baibulatova,Khisamutdinova,Gabdrakhmanova,Karachurina,Baschenko
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Read Online
- Solvent-Free Henry and Michael Reactions with Nitroalkanes Promoted by Potassium Carbonate as a Versatile Heterogeneous Catalyst
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The use of a simple weak inorganic base such as potassium carbonate facilitated the formation of carbon-carbon bonds through both the Henry and the Michael reactions with nitrocompounds. The application of this catalyst under environmentally friendly solventless heterogeneous conditions gave satisfactory to good yields of β-nitroalcohols, involving aliphatic and aromatic starting materials, as well as high to excellent yields in the formation of Michael adducts using several different Michael acceptors and nitroalkanes.
- Bosica, Giovanna,Polidano, Kurt
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- Oxidative Amidation of Nitroalkanes with Amine Nucleophiles using Molecular Oxygen and Iodine
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The formation of amides and peptides often necessitates powerful yet mild reagent systems. The reagents used, however, are often expensive and highly elaborate. New atom-economical and practical methods that achieve such goals are highly desirable. Ideally, the methods should start with substrates that are readily available in both chiral and non-chiral forms and utilize cheap reagents that are compatible with a wide variety of functional groups, steric encumberance, and epimerizable stereocenters. A direct oxidative method was developed to form amide and peptide bonds between amines and primary nitroalkanes simply by using I2 and K2CO3 under O2. Contrary to expectations, a 1:1 halogen-bonded complex forms between the iodonium source and the amine, which reacts with nitronates to form α-iodo nitroalkanes as precursors to the amides.
- Li, Jing,Lear, Martin J.,Kawamoto, Yuya,Umemiya, Shigenobu,Wong, Alice R.,Kwon, Eunsang,Sato, Itaru,Hayashi, Yujiro
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supporting information
p. 12986 - 12990
(2015/11/02)
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- Synthesis of functionalized γ-lactone via Sakurai exo -cyclization/rearrangement of 3,3-bis(silyl) enol ester with a tethered acetal
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An efficient synthesis of functionalized γ-lactones has been developed involving Sakurai exo-cyclization/rearrangement of 3,3-bis(silyl) enol esters with a tethered acetal. While the steric and electronic effects of geminal bis(silane) favor the desired Sakurai pathway, the methoxy species formed in the deprotection step also facilitates both cyclization and rearrangement. The synthetic value of this approach has been demonstrated by efficiently transforming the E-vinylsilane into enyne and the γ-lactone moiety into multisubstituted THF.
- Yin, Zhiping,Liu, Zengjin,Huang, Zhenggang,Chu, Yang,Chu, Zhiwen,Hu, Jia,Gao, Lu,Song, Zhenlei
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supporting information
p. 1553 - 1556
(2015/03/30)
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- Catalytic Asymmetric Synthesis of Isoxazolines from Silyl Nitronates
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1,3-Dipolar cycloadditions of triisopropylsilyl nitronates and 2-alkylacroleins produced isoxazolines bearing a chiral quaternary center in high yields and enantioselectivities with the aid of a chiral oxazaborolidine catalyst. One chiral isoxazoline product was converted to (R)-(+)-Tanikolide in 9 steps in a total yield of 43%. (Chemical Equation Presented).
- Han, Xiaoyu,Dong, Li,Geng, Caiwei,Jiao, Peng
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supporting information
p. 3194 - 3197
(2015/07/15)
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- Stereoselective aza-Henry reaction of chiral tert-butanesulfinyl imines with methyl or ethyl 4-nitrobutanoate: Easy access to enantioenriched 6-substituted piperidine-2,5-diones
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The base-catalyzed addition of 4-nitrobutanoates 6 to N-tert-butanesulfinyl imines 8 under solvent-free reaction conditions proceeded with high face diastereoselectivity. The resulting β-nitroamine derivatives 9 were easily transformed into 6-substituted piperidine-2,5-diones 11 upon removal of the sulfinyl group with concomitant δ-lactam formation and functional group transformation under Nef reaction conditions.
- Garca-Muoz, M. Jess,Foubelo, Francisco,Yus, Miguel
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p. 1419 - 1432
(2015/06/02)
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- Cascade formation of isoxazoles: Facile base-mediated rearrangement of substituted oxetanes
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Give me five! Nitro compounds and oxetan-3-one react through an intriguing cascade sequence to give isoxazole-4-carbaldehydes using inexpensive reagents in a one-pot procedure (see scheme; Ms=methanesulfonyl). A variety of 3-substituted isoxazole-4-carbaldehydes were obtained in high overall yields.
- Burkhard, Johannes A.,Tchitchanov, Boris H.,Carreira, Erick M.
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supporting information; scheme or table
p. 5379 - 5382
(2011/07/08)
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- Synthesis of γ-nitro aliphatic methyl esters via michael additions promoted by microwave irradiation
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A simple and efficient protocol has been developed for the direct synthesis of γ-nitrobutyric acid methyl esters under microwave irradiation. This methodology reduces reaction times from days to minutes, compared to conventional conditions. Additionally, these conditions increased yields and provided cleaner reactions.
- Escalante, Jaime,Francisco, D. Diaz-Coutino
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experimental part
p. 1595 - 1604
(2010/03/24)
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- Synthesis of [3-13C]-, [4-13C]- and [11- 13C]-porphobilinogen
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[4-13C]-porphobilinogen 1a, [3-13C]-porphobilinogen 1b and [11-13C]-porphobilinogen 1c are prepared from [1- 13C]-3-(tetrahydropyran-20-yloxy)-propionaldehyde 2a, methyl [4- 13C]-4-nitrobutyrate 3b and [1-13C]-isocyanoacetonitrile 5c, respectively. The building blocks 2, 3 and 5 can be prepared efficiently in any isotopomeric form. Via base-catalyzed condensation of these building blocks porphobilinogen can be enriched with 13C and 15N stable isotopes at any position and combination of positions. Copyright
- Dawadi, Prativa B. S.,Schulten, Els A. M.,Lugtenburg, Johan
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experimental part
p. 341 - 349
(2011/07/08)
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- A practical and scaleable total synthesis of the jaborandi alkaloid (+)-pilocarpine
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The total synthesis of (+)-pilocarpine (as its nitrate salt) has been achieved in nine steps and 30% overall yield starting from racemic 2-(2′,2′-dimethoxyethyl)propane-1,3-diol, which was desymmetrised via an enzymatic protocol. A high yielding synthesis of a key α-ethylidene lactone precursor has been developed, which involves the palladium-catalysed decarboxylation/carbonylation of a 1,3-dioxan-2-one for formation of the γ-butyrolactone ring. Subsequent hydrogenation of the α-ethylidene lactone introduces the C(3)-stereochemistry to give a 72:28 mixture of (+)-pilocarpine and (+)-isopilocarpine, which are readily separable via recrystallisation of the (+)-pilocarpine nitrate salt.
- Davies, Stephen G.,Roberts, Paul M.,Stephenson, Peter T.,Storr, Helen R.,Thomson, James E.
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scheme or table
p. 8283 - 8296
(2009/12/28)
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- Evaluation of pyrrolidin-2-imines and 1,3-thiazolidin-2-imines as inhibitors of nitric oxide synthase
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Syntheses and evaluation of pyrrolidin-2-imines and 1,3-thiazolidin-2- imines as inhibitors of nitric oxide synthase (NOS) are discussed. An extensive SAR was established for pyrrolidin-2-imines class of compounds. The amidines came out as the most potent inhibitors in addition to displaying selectivity.
- Shankaran,Donnelly, Karla L.,Shah, Shrenik K.,Guthikonda, Ravindra N.,MacCoss, Malcolm,Humes, John L.,Pacholok, Stephen G.,Grant, Stephan K.,Kelly,Wong
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p. 4539 - 4544
(2007/10/03)
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- An improved coupling procedure for the Barton-Zard pyrrole synthesis
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An improved final step in the Barton-Zard pyrrole synthesis uses inexpensive potassium carbonate as base in the coupling-cyclization reaction of vic-nitro-acetates with isocyanides. In this modification the isolated yields of synthetically useful 2-carboalkoxypyrroles (1a,b and 3) and 2-(p-toluenesulfonyl)pyrroles (2a,b) consistently rise to the 78-89% range. Conversion of 2a to 5-(p-toluenesulfonyl)-2-pyrrolinone 4 is conveniently and directly achieved by reaction with 30% hydrogen peroxide in acetic acid, thus circumventing the commonly used two step procedure involving bromination followed by solvolysis.
- Bobal,Lightner
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p. 527 - 530
(2007/10/03)
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- 1,5,7-Triazabicyclo[4.4.0]dec-1-ene (TBD), 7-methyl-TBD (MTBD) and the polymer-supported TBD (P-TBD): Three efficient catalysts for the nitroaldol (Henry) reaction and for the addition of dialkyl phosphites to unsaturated systems
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The 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) and its 7-methyl derivative (MTBD) have been proven to be of great synthetic utility as catalysts in the nitroaldol (Henry) reaction and for the addition of dialkyl phosphites to a variety of carbonyl compounds. The catalysts were in many cases superior to the parent tetramethylguanidine (TMG). In general the reaction proceeds in a few minutes at 0°C. The polymer-supported-TBD (P- TBD) was also proven to be an efficient promoter of the above cited nucleophilic additions. (C) 2000 Elsevier Science Ltd.
- Simoni, Daniele,Rondanin, Riccardo,Morini, Massimo,Baruchello, Riccardo,Invidiata, Francesco Paolo
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p. 1607 - 1610
(2007/10/03)
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- Enantiospecific Total Synthesis of the Sarpagine Related Indole Alkaloids Talpinine and Talcarpine as Well as the Improved Total Synthesis of Alstonerine and Anhydromacrosalhine-methine via the Asymmetric Pictet-Spengler Reaction
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The enantiospecific total synthesis of talpinine 1 and talcarpine 2 has been accomplished from D-(+)-tryptophan in 13 steps (11 reaction vessels) in 10% and 9.5% overall yields, respectively. Moreover, this synthetic approach has been employed for the improved synthesis of alstonerine 3 and anhydromacrosalhine-methine 4 in 12% and 14% overall yield, respectively. A convenient synthetic route for the enantiospecific, stereospecific preparation of the key intermediate (-)-Na-H, Nb-benzyl tetracyclic ketone 15a via the asymmetric Pictet-Spengler reaction on a multihundredgram scale has been developed. A diastereocontrolled (>30:1) anionic oxy-Cope rearrangement and the intramolecular rearrangement to form ring-E and an Nb-benzyl/Nb-methyl transfer reaction also served as key steps. This general approach can now be utilized for the synthesis of macroline/ sarpagine related indole alkaloids and their antipodes for biological screening.
- Yu, Peng,Wang, Tao,Li, Jin,Cook, James M.
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p. 3173 - 3191
(2007/10/03)
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- Supported phenolates as efficient catalysts of the Michael reaction
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Simple, heterogeneous base catalysts based on supported phenolates can be easily prepared and are very active and selective in the Michael reaction.
- Macquarrie, Duncan J.
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p. 4125 - 4128
(2007/10/03)
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- Synthesis of Benzyl and tert-Butyl 3-(2-Methoxycarbonylethyl)-4-methylpyrrole-2-carboxylates from Methyl 4-Oxobutanoate
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Condensation of methyl 4-oxobutanoate with nitroethane in the presence of 4-dimethylaminopyridine, followed by treatment with acetic anhydride, afforded a nitroacetoxyester 10b.Subsequent reaction with isocyanoacetate esters and DBU in refluxing tetrahydrofuran gave the synthetically valuable pyrroles 1a and 1b.
- Drinan, Martin A.,Lash, Timothy D.
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p. 255 - 258
(2007/10/02)
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- Regioselective synthesis of 5-unsubstituted benzyl pyrrole-2-carboxylates from benzyl isocyanoacetate
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A general synthesis of 5-unsubstituted benzyl pyrrole-2-carboxylates was developed based on the reaction of β-nitroacetates with benzyl isocyanoacetate. The advantage of this route over other pyrrole syntheses was the regiochemical control of the substitution pattern on the pyrrole ring.
- Ono,Katayama,Nisyiyama,Ogawa
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p. 707 - 710
(2007/10/02)
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- Michael Additions Catalyzed by Metal(II) Complexes
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Michael-addition reactions have been found to proceed in the presence of the Ni(OAc)2 or Co(OAc)2-2,2'-bypiridine complex in DMF under neutral conditions at room temperature without any by-product.The reactions of chalcone and its derivatives with nitromethane generally gave good results.The effects of metal(II) ions, ligands, counter ions, and solvents on the catalysis were examined, and the features of the metal-complex-catalyzed Michael reactions were studied, with some considerations also being given to the catalysis mechanism.
- Watanabe, Ken-ichi,Miyazu, Ken-ichi,Irie, Kazuro
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p. 3212 - 3215
(2007/10/02)
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- Silyl Nitronates in Organic Synthesis. Routes to Heterocycles and Cyclopentanoids. Synthesis of Allethrolone and Calythrone. Acylation and Cyanohydroxylation of Double Bonds. An Exploratory Study
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Silyl nitronates are versatile reagents for the preparation of heterocycles by dipolar addition to double bonds.The intermediate isoxazolidines can be transformed to 2-isoxazolines, isoxazoles, furans, dihydrofuranones, pyrazoles, pyridazines and pyridazones.Reduction of 2-isoxazolines with Ti3+ leads to hydroxylated 1,4-diketones, which subsequently can be cyclized to cyclopentenones.Routes to calythrone, rethrolones, prostanoids and a number of naturally occurring dihydrofuranones are devised, as well as synthetic procedures for acylation, preparation of endiones, hydroxyacylation, cyanation and hydroxycyanation of double bonds.
- Andersen, Soeren H.,Das, Nalin B.,Joergensen, Ruth D.,Kjeldsen, Gunhild,Knudsen, Jes S.,et al.
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- MICHAEL ADDITIONS CATALYZED BY NICKEL(II) OR COBALT(II)ACETATE-2,2'-BIPYRIDINE COMPLEXES
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In the presence of nickel(II) or cobalt(II)acetate-2,2'-bipyridine complexes, α,β-unsaturated ketones, methyl acrylate, and acrylonitrile were found to react with nitromethane, malononitrile, and aniline at room temperature under neutral condition to afford addition products in good yields.
- Irie, Kazuo,Miyazu, Ken-ichi,Watanabe, Ken-ichi
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p. 353 - 354
(2007/10/02)
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