- Evaluation of 2-(piperidine-1-yl)-ethyl (PIP) as a protecting group for phenols: Stability to ortho-lithiation conditions and boiling concentrated hydrobromic acid, orthogonality with most common protecting group classes, and deprotection via Cope elimination or by mild Lewis acids
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A new protecting group, 2-(piperidine-1-yl)-ethyl (PIP), was evaluated as a protecting group for phenols. The PIP group was stable to ortho-lithiation conditions and refluxing with concentrated hydrobromic acid. Deprotection was accomplished by two routes, oxidation to N-oxides followed by Cope elimination (CE) and subsequent hydrolysis or ozonolysis of the vinyl ether or one-step deprotection by BBr3?Me2S. The PIP group is orthogonal to the O-benzyl, O-acetyl, O-t-butyldiphenylsilyl, O-methyl, O-p-methoxybenzyl, O-allyl, O-tetrahydropyranyl and N-t-butoxy carbonyl groups. The CE step was systematically studied and was found to give higher yields when the reaction was performed in the presence of silylating agents.
- Norén, Rolf
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- Evolution of a 4-Benzyloxy-benzylamino Chemotype to Provide Efficacious, Potent, and Isoform Selective PPARα Agonists as Leads for Retinal Disorders
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Peroxisome proliferator-activated receptor alpha (PPARα) is expressed in retinal Müller cells, endothelial cells, and in retinal pigment epithelium; agonism of PPARα with genetic or pharmacological tools ameliorates inflammation, vascular leakage, neurodegeneration, and neovascularization associated with retinal diseases in animal models. As such, PPARα is a promising drug target for diabetic retinopathy and age-related macular degeneration. Herein, we report proof-of-concept in vivo efficacy in an streptozotocin-induced vascular leakage model (rat) and preliminary pharmacokinetic assessment of a first-generation lead 4a (A91). Additionally, we present the design, synthesis, and evaluation of second-generation analogues, which led to the discovery of 4u and related compounds that reach cellular potencies 2,700-fold selectivity for PPARα over other PPAR isoforms. These studies identify a pipeline of candidates positioned for detailed PK/PD and pre-clinical evaluation.
- Dou, Xiaozheng,Nath, Dinesh,Shin, Henry,Nurmemmedov, Elmar,Bourne, Philip C.,Ma, Jian-Xing,Duerfeldt, Adam S.
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p. 2854 - 2876
(2020/04/10)
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- Rhodium-Catalyzed Parallel Kinetic Resolution of Racemic Internal Allenes Towards Enantiopure Allylic 1,3-Diketones
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A rare case of a parallel kinetic resolution of racemic 1,3-disubstituted allenes by means of a rhodium-catalyzed addition to 1,3-diketones furnishing enantiopure allylic 1,3-diketones is described. Mechanistic experiments demonstrate that the different allene enantiomers react in parallel to either the diastereomeric E- or Z-allylic 1,3-diketones with the same absolute configuration of the newly formed stereogenic center. A broad substrate scope demonstrates the synthetic utility of this new method.
- Hilpert, Lukas J.,Breit, Bernhard
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p. 9939 - 9943
(2019/06/24)
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- Inhibition of tyrosine phenol-lyase by tyrosine homologues
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We have designed, synthesized, and evaluated tyrosine homologues and their O-methyl derivatives as potential inhibitors for tyrosine phenol lyase (TPL, E.C. 4.1.99.2). Recently, we reported that homologues of tryptophan are potent inhibitors of tryptophan indole-lyase (tryptophanase, TIL, E.C. 4.1.99.1), with Ki values in the low μM range (Do et al. Arch Biochem Biophys 560:20–26, 2014). As the structure and mechanism for TPL is very similar to that of TIL, we postulated that tyrosine homologues could also be potent inhibitors of TPL. However, we have found that homotyrosine, bishomotyrosine, and their corresponding O-methyl derivatives are competitive inhibitors of TPL, which exhibit Ki values in the range of 0.8–1.5?mM. Thus, these compounds are not potent inhibitors, but instead bind with affinities similar to common amino acids, such as phenylalanine or methionine. Pre-steady-state kinetic data were very similar for all compounds tested and demonstrated the formation of an equilibrating mixture of aldimine and quinonoid intermediates upon binding. Interestingly, we also observed a blue-shift for the absorbance peak of external aldimine complexes of all tyrosine homologues, suggesting possible strain at the active site due to accommodating the elongated side chains.
- Do, Quang,Nguyen, Giang T.,Phillips, Robert S.
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p. 2243 - 2251
(2016/08/26)
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- A concise and scalable strategy for the total synthesis of dictyodendrin B based on sequential C-H functionalization
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A sequential C-H functionalization strategy for the synthesis of the marine alkaloid dictyodendrin B is reported. Our synthesis begins from commercially available 4-bromoindole and involves six direct functionalizations around the heteroarene core as part of a gram-scale strategy towards the natural product.
- Pitts, Andrew K.,O'Hara, Fionn,Snell, Robert H.,Gaunt, Matthew J.
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supporting information
p. 5451 - 5455
(2015/04/27)
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- Light-mediated deoxygenation of alcohols with a dimeric gold catalyst
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A new protocol for the reductive deoxygenation of primary alcohols was explored. This photo-mediated method combines a novel approach to bromination of alcohols merged with the powerful reducing capability of [Au2(dppm)2]Cl2 [dppm = 1,1-bis(diphenylphosphino)methane] as a photoredox catalyst. The highly efficient methods discussed are marked by the use of UVA light-emitting diodes, which have significantly reduced reaction times and lowered setup cost.
- McCallum, Terry,Slavko, Ekaterina,Morin, Mathieu,Barriault, Louis
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supporting information
p. 81 - 85
(2015/02/18)
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- Construction of chiral 2-substituted octahydroindoles from cyclic ketones and nitroolefins bearing only one α-substituent
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A dual catalytic system has been developed following the screening of a series of chiral primary amine catalysts and chiral phosphoric acid catalysts for the Michael addition of cyclic ketones to nitroolefins bearing only one α-substituent. The resulting γ-nitro ketones, which contain a substituent on the carbon connected to the nitro group, were formed in excellent yields (>80%) with high levels of stereoselectivity (up to 94:6 dr and 98% ee) when the reaction was performed in benzene at 0 °C with 10 mol% of the optimal amine/phosphoric acid combination (1:1) as a catalyst. Subsequent reduction of the nitro group followed by intramolecular reductive amination could afford optically active cis-octahydroindole analogues bearing a non-functional substituent at their 2-position.
- Han, Yong,Zheng, Bo,Peng, Yungui
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supporting information
p. 1136 - 1142
(2015/04/22)
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- Discovery of a new class of potent MMP inhibitors by structure-based optimization of the arylsulfonamide scaffold
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A new class of potent matrix metalloproteinase (MMP) inhibitors designed by structure-based optimization of the well-known arylsulfonamide scaffold is presented. Molecules show an ethylene linker connecting the sulfonamide group with the P1' aromatic portion and a D-proline residue bearing the zinc-binding group. The affinity improvement provided by these modifications led us to discover a nanomolar MMP inhibitor bearing a carboxylate moiety as zinc-binding group, which might be a promising lead molecule. Notably, a significant selectivity for MMP-8, MMP-12, and MMP-13 was observed with respect to MMP-1 and MMP-7.
- Mori, Mattia,Massaro, Assunta,Calderone, Vito,Fragai, Marco,Luchinat, Claudio,Mordini, Alessandro
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supporting information
p. 565 - 569
(2013/07/26)
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- A novel method to access chiral nonnatural 2,4-disubstituted pyrrolidines from aldehydes and nitroolefins only with an α-substituent
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A series of α-substituted nitroolefins were employed in organocatalytic asymmetric Michael reactions with aldehydes. γ-Nitro carbonyl products were achieved in good yields (up to 86%) with good stereoselectivities (up to 96% ee and 24 : 1 dr). Reduction of the nitro group followed by intramolecular reductive amination successfully afforded various novel optically active 2,4-disubstituted pyrrolidine compounds.
- Zheng, Bo,Wang, Hui,Han, Yong,Liu, Changlu,Peng, Yungui
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supporting information
p. 4561 - 4563
(2013/06/04)
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- Total synthesis of dictyodendrins A-E
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A highly efficient total synthesis of dictyodendrins A-E was accomplished. The synthesis features a novel benzyne-mediated one-pot indoline formation/cross-coupling sequence for the construction of a highly substituted key indoline intermediate. Peripheral substituents were introduced onto this intermediate in a modular fashion to complete the total synthesis of dictyodendrins A-E. A benzyne-mediated one-pot indoline formation/cross-coupling sequence is used for the construction of a highly substituted common indole intermediate. The peripheral substituents were introduced using a Friedel-Crafts reaction on the indole intermediate in a modular fashion to complete the total synthesis. Copyright
- Tokuyama, Hidetoshi,Okano, Kentaro,Fujiwara, Hideto,Noji, Toshiharu,Fukuyama, Tohru
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supporting information; experimental part
p. 560 - 572
(2011/10/03)
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- Synthesis of raphanuside, an unusual oxathiane-fused thioglucoside isolated from the seeds of Raphanus sativus L.
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Raphanuside (1), an unusual oxathiane-fused thioglycoside isolated from the seeds of Raphanus sativus L., was synthesized via 10 steps and in 11% overall yield.{A figure is presented}.
- Yang, Fei,Lian, Gaoyan,Yu, Biao
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experimental part
p. 309 - 314
(2010/03/26)
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- Total synthesis of dictyodendrin A and B
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(Figure Presented) In-do-line of fire: A highly efficient total synthesis of the title compounds features a novel benzyne-mediated one-pot indoline formation/cross-coupling sequence for the construction of a highly substituted key indoline intermediate. The peripheral substituents were then introduced onto the intermediate in a modular fashion to complete the total syntheses of dictyodendrin A and B.
- Okano, Kentaro,Fujiwara, Hideto,Noji, Toshiharu,Fukuyama, Tohru,Tokuyama, Hidetoshi
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supporting information; experimental part
p. 5925 - 5929
(2010/10/03)
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- Trithiocarbonates-Exploration of a new head group for HDAC inhibitors
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Inhibition of histone deacetylases class I/II enzymes is a new, promising approach for cancer therapy. In the present study, we disclose a new structural class of HDAC inhibitors with the trithiocarbonate motif. A clear structure-activity-relationship was obtained for the cap-linker motif and the putative Zn2+ complexing head group. Selected analogs display potent inhibition of HDAC enzymatic activity and a cellular potency comparable to that of suberoylanilide hydroxamic acid (SAHA), recently approved for treatment of patients with advanced cutaneous T-cell lymphoma.
- Dehmel, Florian,Ciossek, Thomas,Maier, Thomas,Weinbrenner, Steffen,Schmidt, Beate,Zoche, Martin,Beckers, Thomas
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p. 4746 - 4752
(2008/12/21)
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- Total syntheses of the telomerase inhibitors dictyodendrin B, C, and E
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Concise and flexible total syntheses of the pyrrolo[2,3-c]carbazole alkaloids dictyodendrin B (2), C (3), and E (5) are described. These polycyclic telomerase inhibitors of marine origin derive from the common intermediate 18 which was prepared on a multigram scale by a sequence comprising a TosMIC cycloaddition with formation of the pyrrole A-ring, a titanium-induced reductive oxoamide coupling reaction to generate an adjacent indole nucleus, and a photochemical 6π-electrocyclization/aromatization tandem to forge the pyrrolocarbazole core. Conversion of 18 into dictyodendrin C required selective manipulations of the lateral protecting groups and oxidation with peroxoimidic acid to form the vinylogous benzoquinone core of the target. Zinc-induced reductive cleavage of the trichloroethyl sulfate ester then completed the first total synthesis of 3. Its relatives 2 and 5 also originate from compound 18 by a selective bromination of the pyrrole entity followed by elaboration of the resulting bromide 27 via metal-halogen exchange or cross-coupling chemistry, respectively. Particularly noteworthy in this context is the generation of the very labile p-quinomethide motif of dictyodendrin E by a palladium-catalyzed benzyl cross-coupling reaction followed by vinylogous oxidation of the resulting product 41 with DDQ. The Suzuki step could only be achieved with the aid of the borate complex 40 formed in situ from p-methoxybenzylmagnesium chloride and 9-MeO-9-BBN, whereas alternative methods employing benzylic boronates, -trifluoroborates, or -stannanes met with failure.
- Fuerstner, Alois,Domostoj, Mathias M.,Scheiper, Bodo
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p. 8087 - 8094
(2007/10/03)
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- Total synthesis of dictyodendrin B
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A concise total synthesis of dictyodendrin B (1) is reported, a scarce marine alkaloid endowed with promising telomerase inhibitory activity. Key steps of the chosen route are a reductive cyclization of ketoamide 11 to indole 12 mediated by low-valent titanium (from TiCl3 and KC8) followed by a photochemical 6π-electrocyclization, which was performed in the presence of Pd/C and nitrobenzene to effect concomitant dehydrogenation/aromatization of the product initially formed. Regioselective bromination of the resulting pyrrolocarbazole 13 followed by lithium/bromine exchange and quenching of the resulting organolithium species with p-methoxybenzaldehyde installed the side chain at C2. Oxidation of the benzylic alcohol 15 thus obtained to ketone 17 was best achieved with catalytic amounts of tetra-n-propylammonium perruthenate (TPAP) and N-methylmorpholine-N-oxide (NMO) in dilute CH2Cl2 solution to avoid the formation of undue amounts of the unsymmetrical dimer 16. Ketone 17 was elaborated into the natural product by selective cleavage of the isopropyl ether with BCl3, introduction of the sulfate moiety with the aid of trichloroethyl chlorosulfuric acid ester, deprotection of all lateral methyl ether groups, and final reductive cleavage of the trichloroethyl ester moiety. The spectroscopic data of synthetic dictyodendrin B thus formed matched those of an authentic sample in all regards. Moreover, it was shown that global deprotection of the peripheral -OH groups in pyrrolo[2,3-c]carbazole 13 is accompanied by spontaneous air-oxidation to form the quinone core of dictyodendrin C. Copyright
- Fuerstner, Alois,Domostoj, Mathias M.,Scheiper, Bodo
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p. 11620 - 11621
(2007/10/03)
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- Indoles
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A 1,4-substituted cyclic amine derivative represented by the following formula or a pharmacologically acceptable salt thereof: wherein A, B, C, D, T, Y, and Z each represent a methine or a nitrogen linkage; R1, R2, R3, R4, and R5 each represent a substituent; n represents 0 or an integer of 1 to 3; m represents 0 or an integer of 1 to 6; and p represents an integer of 1 to 3. The compounds have serotonin antagonism. They are therefore clinically useful as medicaments, in particular, for treating, ameliorating, and preventing spastic paralysis. They are also useful as central muscle relaxants for ameliorating myotonia.
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- Fused pyridine derivatives
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The present provides a condensed pyridine compound (I) represented by the following formula: (wherein, R2represents ring A represents benzene ring, pyridine ring, thiophene ring or furan ring; and B represents its pharmaceutically acceptable salt or hydrates thereof, which is a clinically useful medicament having a serotonin antagonism, in particular, that for treating, ameliorating or preventing spastic paralysis or central muscle relaxants for ameliorating myotonia.
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- Structure-activity relationship for a series of 2-substituted 1,2,3,4- tetrahydro-9H-pyrido[3,4-b]indoles: Potent subtype-selective inhibitors of N- methyl-D-aspartate (NMDA) receptors
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A series of 2-substituted 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indoles was synthesized as potential antagonists for the NR1(A)/2B subtype of N-methyl- D-aspartate (NMDA) receptors. Assayed by electrical recording under steady- state conditions, 7-hydroxy-2-(4-phenylbutyl)-1,2,3,4-tetrahydropyrido-[3,4- b]indole (30) was the most potent compound in the series having an IC50 value of 50 nM at the NR1(A)/2B receptors.
- Tamiz, Amir P.,Whittemore, Edward R.,Woodward, Richard M.,Upasani, Ravindra B.,Keana, John F.W.
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p. 1619 - 1624
(2007/10/03)
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- Stereochemical control in microbial reduction. Part 31: Reduction of alkyl 2-oxo-4-arylbutyrates by baker's yeast under selected reaction conditions
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Treatment of baker's yeast with phenacyl chloride in an aqueous-organic solvent has been proven to be an effective method of inhibiting the enzymes that afford (S)-enantiomers of α-hydroxy esters in the reduction of α-keto esters. The procedure is effective for the whole-cell system to produce the (R)-product with high chemical yield and high enantiomeric excess.
- Dao, Duc Hai,Okamura, Mutsuo,Akasaka, Takeshi,Kawai, Yasushi,Hida, Kouichi,Ohno, Atsuyoshi
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p. 2725 - 2737
(2007/10/03)
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- A Convenient Conversion of Primary Amines into the Corresponding Halides Radical Promoted Halodeamination via N-Substituted-N-Tosylhydrazines
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Treatment of 1-substituted-1-tosylhydrazines with 2 equivalents of NCS or NBS in dry THF in presence of light affords the corresponding alkyl halides in good yields.This reaction presumably involves the initial formation of a stabilized hydrazyl radical which is halogenated in a radical chain process.Elimination of p-toluenesulfinic acid and extrusion of nitrogen leads to the corresponding alkyl halide.This route provides an improved method for halodeamination under neutral reaction conditions.
- Collazo, Luis R.,Guziec, Frank S.,Hu, Wei-Xiao Jr.,Pankayatselvan, Ratnadevi
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p. 7911 - 7914
(2007/10/02)
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- Unusually Long Lifetimes of the Singlet Derived from 4-Azido-2,3,5,6-tetrafluorobenzamides
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Laser flash photolysis (308 nm, 20 ns, 150 mJ) of 4-azido-2,3,5,6-tetrafluorobenzamides, esters, and thioesters generate singlet nitrenes which can be intercepted with pyridine to produce strongly absorbing ylides.It was possible to resolve the rate of formation of the ylides as a function of pyridine concentration.This has lad to direct measurements of the absolute rate constants of (a) the reaction of the nitrene with pyridine, (b) ring expansion of the nitrene to a ketenimine, and (c) singlet to triplet nitrene intersystem crossing.
- Marcinek, Andrzej,Platz, Matthew S.,Chan, Stephen Y.,Floresca, Rey,Rajagopalan, Krishnan,et al.
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p. 412 - 419
(2007/10/02)
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- Covenient Halodeamination and Hydrodeamination of Primary Amines
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Treatment of p-toluenesulfonamides of primary amines with 2 equiv of chloroamine at room temperature in the presence of base leads to reductive deamination.If excess chloroamine is present, the corresponding alkyl or aryl halides are obtained instead in good yields.Both reactions presumably proceed via tosylhydrazine and diazene intermediates; the course of the reaction is often governed by steric hindrance.Treatment of the isolated tosylhydrazine intermediate with base and chloroamine, bromine, or iodine also leads to the corresponding halides in very good yields.
- Guziec, Frank S.,Wei, Dongchu
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p. 3772 - 3776
(2007/10/02)
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- SYNTHESIS OF 1,2,3,4,5,6-HEXAHYDRO-8-HYDROXY-2,6-EPITHIO-3-BENZAZOCINE
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In anticipation of diminishing narcotism of 1,2,3,4,5,6-hexahydro-8-hydroxy-2,6-methano-3-benzazocine opioids, the corresponding 2,6-epithio-3-benzazocines (2) have been synthesized by intramolecular cyclization of 1-(2-aminoethyl)-3,4-dihydro-1H-2-benzothiopyrans (9) with tert-butyl hypochlorite, and subsequent treatment of the 5-membered cyclic aminosulfonium salts (17) with NaOH.
- Hori, Mikio,Ozeki, Hiroyuki,Iwamura, Tatsunori,Shimizu, Hiroshi,Kataoka, Tadashi,Iwata, Noriyuki
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- 3-Methylcyclohex-2-enone Derivatives as Initiators of Cyclisation. Part 1. Introduction and Synthesis of 2-Substituted 3-methylcyclohex-2-enones
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A series of C-2 substituted 3-methylcyclohex-2-enones has been prepared using the Hagemann ester route.A new synthesis of these compounds has been developed which involves the alkylation of the N,N-diethylaminoethyl ether of 1-hydroxy-5-methylcyclohexa-1,5-diene.The cyclohexenones have been converted into the corresponding α,β-epoxyketones using alkaline hydrogen peroxide.
- Amupitan, Joseph A.,Huq, Enamul,Mellor, Michael,Scovell, Edward G.,Sutherland, James K.
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p. 747 - 749
(2007/10/02)
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- PREPARATION OF HOMOLOGS OF L-2-AMINO-5-(p-METOXYPHENYL)PENTANOIC ACID
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Lower and higher homologs, L-2-amino-4-(p-methoxyphenyl)butanoic acid (L-amb) and L-2-amino-6-(p-methoxyphenyl)hexanoic acid (L-Amh), of L-2-amino-5-(p-methoxyphenyl)pentanoic acid were prepared by optical resolution of N-acetyl-DL-Amb and of N-acetyl-DL-Amh with Aspergillus acylase.N-acetyl DL-Amb or N-acetyl-DL-Amh was synthesized from (acetamido malonic acid by heating with p-xylene.
- Kosui, Nobuo,Waki, Michinori,Kato, Tetsuo,Izumiya, Nobuo
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p. 918 - 920
(2007/10/02)
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- Hypolipidemic alkenesulfonamides
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Method for lowering blood liped levels in mammals, using certain derivatives of N-carbamoyl-2-phenylethenesulfonamide, many of which are novel.
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