- Grignard reagents: Alkoxide-directed iodine-magnesium exchange at sp 3 centers
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(Chemical Equation Presented) Sequential addition of i-PrMgCl and BuLi to sp3 hybridized iodoalcohols triggers a facile iodine-metal exchange. Intercepting the resulting cyclic Grignard reagents with a slight excess of an electrophile leads to a diverse range of substituted alcohols. The iodine-magnesium exchange strategy is effective with 3-carbon iodoalcohols bearing alkyl substitutents on the carbinol or adjacent carbons and with the chain-extended homolog 4-iodobutan-1-ol.
- Fleming, Fraser F.,Gudipati, Subrahmanyam,Vu, Viet Anh,Mycka, Robert J.,Knochel, Paul
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Read Online
- Fluspirilene Analogs Activate the 20S Proteasome and Overcome Proteasome Impairment by Intrinsically Disordered Protein Oligomers
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Oligomerization of aggregation-prone intrinsically disordered proteins (IDPs), such as α-synuclein, amyloid β, and tau, has been shown to be associated with the pathogenesis of several neurodegenerative diseases, including Parkinson's and Alzheimer's disease. The proteasome is charged with regulating cellular levels of IDPs, but this degradation pathway can become dysregulated leading to their accumulation and subsequent aggregation. Although the pathogenesis of these neurodegenerative diseases is still under intense investigation, it has been shown that the oligomeric forms of IDPs, including α-synuclein and amyloid β, can impair proteasome function. This leads to additional accumulation of the IDPs, further promoting disease progression. Herein, we report the use of small molecule activators of the 20S subcomplex of the proteasome to restore impaired 20S proteasome activity and prevent IDP accumulation and oligomerization. We found that fluspirilene and its new synthetic analog (16) show strong 20S proteasome enhancement (doubling 20S proteolytic activity at μ2 μM, with maximum fold enhancement of μ1000%), overcome impaired proteasome function, and prevent the accumulation of pathogenic IDPs. These findings provide support for the use of 20S enhancers as a possible therapeutic strategy to combat neurodegenerative diseases.
- Fiolek, Taylor J.,Keel, Katarina L.,Tepe, Jetze J.
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p. 1438 - 1448
(2021/05/04)
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- DMSO-Enabled Selective Radical O?H Activation of 1,3(4)-Diols
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Control of selectivity is one of the central topics in organic chemistry. Although unprecedented alkoxyl-radical-induced transformations have drawn a lot of attention, compared to selective C?H activation, selective radical O?H activation remains less explored. Herein, we report a novel selective radical O?H activation strategy of diols by combining spatial effects with proton-coupled electron transfer (PCET). It was found that DMSO is an essential reagent that enables the regioselective transformation of diols. Mechanistic studies indicated the existence of the alkoxyl radical and the selective interaction between DMSO and hydroxyl groups. Moreover, the distal C?C cleavage was realized by this selective alkoxyl-radical-initiation protocol.
- Han, Bing,Jiao, Ning,Jin, Rui,Liu, Guoquan,Liu, Jianzhong,Zhang, Ziyao,Zhu, Yuchao
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supporting information
p. 19851 - 19856
(2020/09/04)
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- Heterocyclization involving benzylic C(sp3)-H functionalization enabled by visible light photoredox catalysis
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A general and efficient method for heterocyclization involving benzylic C(sp3)-H functionalization enabled by visible light photoredox catalysis to access a wide range of structurally diverse oxygen as well as nitrogen heterocycles up to a gram scale is reported. The potential application of this new methodology is demonstrated by the total synthesis of (-)-codonopsinine and (+)-centrolobine. Herein it is proposed that selectfluor, unlike a fluorinating reagent, acts as an oxidative quencher and a hydrogen radical acceptor.
- Pandey, Ganesh,Laha, Ramkrishna,Mondal, Pradip Kumar
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p. 9689 - 9692
(2019/08/15)
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- Analogs of penfluridol as chemotherapeutic agents with reduced central nervous system activity
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Several recent reports have highlighted the feasibility of the use of penfluridol, a well-known antipsychotic agent, as a chemotherapeutic agent. In vivo experiments have confirmed the cytotoxic activity of penfluridol in triple-negative breast cancer model, lung cancer model, and further studies have been proposed to assess its anticancer activity and viability for the treatment of glioblastomas. However, penfluridol anticancer activity was observed at a dosage significantly higher than that administered in antipsychotic therapy, thus raising the concern for the potential onset of CNS side effects in patients undergoing intensive pharmacological treatment. In this study, we evaluate the potential CNS toxicity of penfluridol side by side with a set of analogs.
- Ashraf-Uz-Zaman, Md,Sajib, Md Sanaullah,Cucullo, Luca,Mikelis, Constantinos M.,German, Nadezhda A.
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supporting information
p. 3652 - 3657
(2018/11/03)
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- Copper-catalyzed aerobic C-C bond cleavage of lactols with N-hydroxy phthalimide for synthesis of lactones
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The transformation of cyclic hemiacetals (lactols) into lactones has been achieved by Cu-catalyzed aerobic C-C bond cleavage in the presence of N-hydroxy phthalimide (NHPI). The present process is composed of a multistep sequence including a) formation of exo-cyclic enol ethers by dehydration; b) addition of phthalimide N-oxyl radical to the enol ethers followed by trapping of the resulting C-radicals with molecular oxygen to form peroxy radicals; c) reductive generation of oxy radicals and subsequent β-radical fragmentation to generate lactones.
- Tnay, Ya Lin,Chiba, Shunsuke
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supporting information
p. 873 - 877
(2015/04/14)
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- Concise, stereodivergent and highly stereoselective synthesis of cis-and trans-2-substituted 3-hydroxypiperidines-development of a phosphite-driven cyclodehydration
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A concise (5 to 6 steps), stereodivergent, highly diastereoselective (dr up to >19:1 for both stereoisomers) and scalable synthesis (up to 14 g) of cis- and trans-2-substituted 3-piperidinols, a core motif in numerous bioactive compounds, is presented. This sequence allowed an efficient synthesis of the NK-1 inhibitor L-733,060 in 8 steps. Additionally, a cyclodehydration-realizing simple triethylphosphite as a substitute for triphenylphosphine is developed. Here the stoichiometric oxidized P(V)-byproduct (triethylphosphate) is easily removed during the work up through saponification overcoming separation difficulties usually associated to triphenylphosphine oxide.
- Huy, Peter H.,Westphal, Julia C.,Koskinen, Ari M.P.
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supporting information
p. 369 - 383
(2014/03/21)
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- Efficient, stereodivergent access to 3-piperidinols by traceless P(OEt)3 cyclodehydration
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A stereodivergent and highly diastereoselective (dr up to >19:1 for both isomers), step economic (5-6 steps), and scalable synthesis (up to 14 g) of cis- and trans-2-substituted 3-piperidinols, the core motif of numerous bioactive compounds, providing efficient access to the NK-1 inhibitor L-733,060 is presented. Additionally, a "traceless" (referring to the simplified byproduct separation) cyclodehydration realizing simple P(OEt)3 as a substitute for PPh3 is developed.
- Huy, Peter H.,Koskinen, Ari M. P.
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supporting information
p. 5178 - 5181
(2013/11/06)
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- Chiral phosphoric acid-catalyzed enantioselective and diastereoselective spiroketalizations
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Catalytic enantioselective and diastereoselective spiroketalizations with BINOL-derived chiral phosphoric acids are reported. The chiral catalyst can override the inherent preference for the formation of thermodynamic spiroketals, and highly selective formation of nonthermodynamic spiroketals could be achieved under the reaction conditions.
- Sun, Zhankui,Winschel, Grace A.,Borovika, Alina,Nagorny, Pavel
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supporting information; experimental part
p. 8074 - 8077
(2012/07/14)
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- Synthesis and SAR study of diphenylbutylpiperidines as cell autophagy inducers
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A novel series of diphenylbutylpiperidines as autophagy inducers was described and extensive SAR studies resulted in derivatives (15d-e, 15i-j) with 10-fold greater activity than the lead compounds 1 and 2. Meanwhile, a new synthetic route to diphenylbutyl bromide (6) from bromobenzene and γ-butyrolactone was also reported here.
- Chen, Gang,Xia, Hongguang,Cai, Yu,Ma, Dawei,Yuan, Junying,Yuan, Chengye
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scheme or table
p. 234 - 239
(2011/02/26)
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- DIPHENYLBUTYPIPERIDINE AUTOPHAGY INDUCERS
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Autophagy inducing compounds, methods of their preparation and use, and kits containg said compounds are disclosed herein.
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Page/Page column 7; 84-85
(2011/12/02)
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- Hydroxyarylketones via Ring-Opening of lactones with aryllithium reagents: An expedient synthesis of ( )-anabasamine
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The regioselective ring-opening of lactones (δ-valerolactone and γ-butyrolactone) with aryllithium reagents is reported for the construction of a series of δ-hydroxy aryl ketones and γ-hydroxy aryl ketones. Application of this method for the expeditious syntheses of ( )-anabasamine and its nicotine-related analogue are also described.
- Miao, Lei,Dimaggio, Stassi C.,Trudell, Mark L.
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experimental part
p. 91 - 97
(2010/06/14)
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- COLORIMETRIC-OXYCARBONYL PROTECTING GROUPS FOR USE IN ORGANIC SYNTHESES
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The present invention provides for reagents for the introduction of colorimetric-oxycarbonyl protecting groups, compounds bearing colorimetric-oxycarbonyl protecting groups, and the use thereof in solid-supported organic syntheses of oligonucleotides, polypeptides, polysaccharides, and combinatorial libraries.
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Page/Page column 16
(2010/10/19)
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- DIHYDROPYRIDINE DERIVATIVE
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Compounds having a selective N-type calcium channel antagonistic activity are provided. Dihydropyridine derivatives represented by the following formula: analogs thereof and pharmaceutically acceptable salts thereof have an activity of selectively inhibiting the action of N-type calcium channel, and they are used as therapeutic agents for various diseases relating to N-type calcium channel.
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- Dihydropyridine derivatives
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Compounds having a selective N-type calcium channel antagonistic activity are provided. Dihydropyridine derivatives represented by the following formula: analogs thereof and pharmaceutically acceptable salts thereof have an activity of selectively inhibiting the action of N-type calcium channel, and they are used as therapeutic agents for various diseases relating to N-type calcium channel.
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- SUBSTITUTED QUINOLINES AND ISOQUINOLINES AS CALCIUM CHANNEL BLOCKERS, THEIR PREPARATION AND THE USE THEREOF
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The present invention relates to novel substituted quinolines and isoquinolines and derivatives thereof useful in the treatment of neurological disorders. Methods of preparing the compounds, intermediates useful in the preparation and pharmaceutical compositions containing the compounds are also included. The compounds are useful in treating pain, cerebral ischemia, and other cerebrovascular disorders.
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- Method of preparing optically active homo-beta-amino acids
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The present invention is directed to synthesis of homo-β-amino acids of an optical purity sufficient to exhibit optical activity wherein Curtius rearrangement of 3-mono-substituted succinate acid half ester of an optical purity sufficient to exhibit optical activity is affected and the incipient isocyanate is trapped with a primary or secondary alcohol. The resulting carbamate-protected homo-β-amino esters are then saponified to produce the corresponding carbamate-protected homo-β-amino acids which are deprotected to yield homo-β-amino acids of an optical purity sufficient to exhibit optical activity.
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- Lactones; XIII. Grignard Reaction Followed by Phase-Transfer Oxidation: A Convenient Synthesis of γ,γ-Disubstituted γ-Butyrolactones from γ-Butyrolactone
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Grignard reaction of γ-butyrolactones, followed by oxidation of the resulting reaction mixture produces symmetrically γ,γ-dialkylated diarylated γ-butyrolactones.Phase transfer oxidation with potassium permanganate in benzene/water proves to be the best out of twelve examined oxidation methods.The synthesis is unsuccessful with sterically hindered or oxidizable Grignard reagents.
- Lehmann, Jochen,Marquardt, Norbert
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p. 1064 - 1067
(2007/10/02)
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- CHELATION ASSISTED TRANSMETALLATION OF TETRAALKYL TIN DERIVATIVES: C-METALLATED LITHIOCARBAMATES AS d3 REAGENTS FOR THE SYNTHESIS OF δ-HYDROXYCARBAMATES.
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The γ-stannylcarbamates 4 and 5 were subjected to metallation with two equivalents of BuLi to give the dianions 6 and 7 acting as d3 reagents.The C-metallation involves a chelation assisted transmetallation.
- Zidani, Ahmed,Vaultier, Michel
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p. 857 - 860
(2007/10/02)
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- SYNTHESE DE COMPOSES DIHYDRO-2,3 FURANNIQUES PAR HYDROBORATION D'ALCOOLS β-ACETYLENIQUES
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Hydroboration of β acetylenic alcohols followed by NaOH/H2O2 oxidation leads to hemiacetals of γ aldols which are easily dehydrated to 2,3-dihydrofuran compounds.The reaction gives good yields with hindered alcohols and its stereochemistry may be controlled during the organometallic synthesis of the starting alcohol.
- Dana, Gilbert,Figadere, Bruno,Touboul, Estera
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p. 5683 - 5684
(2007/10/02)
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