- Synthesis of Thrombin Inhibitor DuP 714
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The asymmetric synthesis of thrombin inhibitor DuP 714 (1) is described.The route uses the Matteson boronic ester homologation to prepare the key intermediate, α-aminoboronic acid 4.New methodology was developed for the formamidination of boroornithine peptides and for pinanediol boronate ester cleavage.
- Wityak, John,Earl, Richard A.,Abelman, Matthew M.,Bethel, Yvonne B.,Fisher, Barbara N.,et al.
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- Fe-Catalyzed Anaerobic Mukaiyama-Type Hydration of Alkenes using Nitroarenes
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Hydration of alkenes using first row transition metals (Fe, Co, Mn) under oxygen atmosphere (Mukaiyama-type hydration) is highly practical for alkene functionalization in complex synthesis. Different hydration protocols have been developed, however, control of the stereoselectivity remains a challenge. Herein, highly diastereoselective Fe-catalyzed anaerobic Markovnikov-selective hydration of alkenes using nitroarenes as oxygenation reagents is reported. The nitro moiety is not well explored in radical chemistry and nitroarenes are known to suppress free radical processes. Our findings show the potential of cheap nitroarenes as oxygen donors in radical transformations. Secondary and tertiary alcohols were prepared with excellent Markovnikov-selectivity. The method features large functional group tolerance and is also applicable for late-stage chemical functionalization. The anaerobic protocol outperforms existing hydration methodology in terms of reaction efficiency and selectivity.
- Bhunia, Anup,Bergander, Klaus,Daniliuc, Constantin Gabriel,Studer, Armido
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supporting information
p. 8313 - 8320
(2021/03/08)
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- Discovery of novel 20S proteasome inhibitors by rational topology-based scaffold hopping of bortezomib
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A series of structurally novel proteasome inhibitors 1–12 have been developed based rational topology-based scaffold hopping of bortezomib. Among these novel proteasome inhibitors, compound 10 represents an important advance due to the comparable proteasome-inhibitory activity (IC50 = 9.7 nM) to bortezomib (IC50 = 8.3 nM), the remarkably higher BEI and SEI values and the effectiveness in metabolic stability. Therefore, compound 10 provides an excellent lead suitable for further optimization.
- Xu, Yulong,Yang, Xicheng,Chen, Yiyi,Chen, Hao,Sun, Huijiao,Li, Wei,Xie, Qiong,Yu, Linqian,Shao, Liming
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supporting information
p. 2148 - 2152
(2018/05/25)
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- Boric acid compounds, and preparation method and use thereof
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The invention relates to the fields of pharmaceutical chemistry and medicine therapeutics, concretely relates to a new boric acid compounds, and a preparation method and a use thereof, and especially relates to new substituted five-membered heterocyclic boric acid and substituted benzo five-membered boric acid compounds, and a preparation method thereof. A result of bioactive screening test of the substituted five-membered heterocyclic boric acid and substituted benzo five-membered boric acid compounds having a structure represented by a formula shown in the description shows that the compounds have a proteasome inhibition effect, and can be further used for preparing medicines for treating proteasome correlated diseases.
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Paragraph 0164; 0165; 0166
(2017/09/21)
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- A Modular Approach to the Asymmetric Synthesis of Cytisine
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The asymmetric synthesis of (+)-and (-)-cytisine starts with Matteson homologations for the construction of a chiral C3-building block. Conversion of the C3-building block into a dihydropyridone is achieved by straightforward functional group interconversions and ring closing metathesis. After bromination, this central building block was diastereospecifically converted into cytisine in five steps.
- Struth, Felix R.,Hirschhaüser, Christoph
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supporting information
p. 958 - 964
(2016/03/01)
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- Synthetic method of chiral vicinal diol and product thereof
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The invention provides a synthetic method of chiral vicinal diol, which comprises the following steps: (1) adding alkene used as a precursor of the chiral vicinal diol and dichloromethane into a reaction device, adding alkali, and then at a temperature of minus 50 DEG C to minus 15 DEG C, adding a phase-transfer catalyst and then adding potassium permanganate or sodium permanganate in batches to perform a reaction so as to obtain an intermediate a; (2) adding the intermediate a into the reaction device, adding ethyl ether and petroleum ether with stirring, then adding boric acid in batches, and dropwise adding aqueous solution of potassium hydroxide to perform a reaction so as to obtain an intermediate b; (3) adding the intermediate b into the reaction device, adding ethyl ether and water, and then under the ice bath cooling condition, dropwise adding hydrofluoric acid, and stirring overnight at a low temperature to obtain the chiral vicinal diol. According to the synthetic method provided by the invention, the potassium permanganate or the sodium permanganate which is cheap, has low toxicity and pollutes the environment a little is used as a reaction reagent, and industrial synthetic production of a chiral vicinal diol compound is achieved.
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Paragraph 0039-0040
(2017/05/26)
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- TRIPEPTIDE BORONIC ACID OR BORONIC ESTER, PREPARATIVE METHOD AND USE THEREOF
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The present invention discloses proteasome inhibitors of tripeptide boronic acids or boronic esters represented by Formula (I), preparative method and use thereof. The proteasome inhibitors are therapeutical agents for treating malignant tumor, various nervous system degenerative diseases, muscle cachexia or diabetes, wherein the malignant tumor is leukemia, gastric cancer, hepatocarcinoma or nasopharyngeal carcinoma.
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Paragraph 0072
(2016/11/07)
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- Engineering Rieske Non-Heme Iron Oxygenases for the Asymmetric Dihydroxylation of Alkenes
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The asymmetric dihydroxylation of olefins is of special interest due to the facile transformation of the chiral diol products into valuable derivatives. Rieske non-heme iron oxygenases (ROs) represent promising biocatalysts for this reaction as they can be engineered to efficiently catalyze the selective mono- and dihydroxylation of various olefins. The introduction of a single point mutation improved selectivities (≥95 %) and conversions (>99 %) towards selected alkenes. By modifying the size of one active site amino acid side chain, we were able to modulate the regio- and stereoselectivity of these enzymes. For distinct substrates, mutants displayed altered regioselectivities or even favored opposite enantiomers compared to the wild-type ROs, offering a sustainable approach for the oxyfunctionalization of a wide variety of structurally different olefins. Modulation by mutation: Rieske non-heme iron oxygenases can be used as efficient biocatalysts for the selective oxyfunctionalization of various olefins yielding vicinal cis-diols and allylic alcohols. Introduction of a single amino acid substitution in the active sites of two selected oxygenases resulted in variants with improved stereoselectivities and product formations.
- Gally, Christine,Nestl, Bettina M.,Hauer, Bernhard
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supporting information
p. 12952 - 12956
(2015/11/02)
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- METHODS FOR THE SYNTHESIS OF SPHINGOMYELINS AND DIHYDROSPHINGOMYELINS
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The present invention includes methods for the synthesis of sphingomyelins and dihydrosphingomyelins. The present invention also includes methods for the synthesis of sphingosines and dihydrosphingosines. The present invention further includes methods for the synthesis of ceramides and dihydroceramides.
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Paragraph 0253-0255
(2014/09/30)
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- TRIPETIDE BORONIC ACID OR BORONIC ESTER, PREPARATIVE METHOD AND USE THEREOF
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The present invention discloses proteasome inhibitors of tripeptide boronic acids or boronic esters represented by Formula (I), preparative method and use thereof. The proteasome inhibitors are therapeutical agents for treating malignant tumor, various nervous system degenerative diseases, muscle cachexia or diabetes, wherein the malignant tumor is leukemia, gastric cancer, hepatocarcinoma or nasopharyngeal carcinoma.
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- Design, synthesis, biological evaluation, and Structure-Activity Relationship (SAR) discussion of dipeptidyl boronate proteasome inhibitors, Part I: Comprehensive understanding of the SAR of α-amino acid boronates
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New series of dipeptidyl boronate inhibitors of 20S proteasome were designed and synthesized. The comprehensive understanding of the SAR was obtained by utilizing the variation of four substituents. From the screened compounds in enzyme, novel inhibitors 49 and 50 were identified to be highly potent druglike candidates with IC50 values of 1.2 and 1.6 nM, respectively, which showed better activities than the drug bortezomib on the market. Two hematologic human tumor cell lines, HL-60 and U266, were significantly sensitive to both candidates and showed nearly the same potency as the standard bortezomib with IC50 values less than 10 nM. But as for most of the eight human solid tumor cell lines, both candidates were more potent than the standard with the IC50 value range of 9.8-70 nM. The activity evaluation of the stereoisomers showed that changing R-isomers to S-isomers greatly reduced the potency and even induced inactivity.
- Zhu, Yongqiang,Zhao, Xin,Zhu, Xinrong,Wu, Gang,Li, Yuejie,Ma, Yuheng,Yuan, Yunxia,Yang, Jie,Hu, Yang,Ai, Li,Gao, Qingzhi
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experimental part
p. 4192 - 4199
(2010/01/16)
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- A study of transesterification of chiral (-)-pinanediol methylboronic ester with various structurally modified diols
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The transesterification of chiral (-)-pinanediol methylboronic ester was studied with various structurally modified diols by 1H NMR to understand the factors influencing the unusual stability of this boronic ester as well as to find ways of recovering pinanediol from its methylboronic ester. In all the cases, reactions were allowed to proceed to equilibrium. The preliminary experiments indeed have shown some encouraging results (displacement of pinanediol up to 40-53%). Amongst cyclopentane-based cis-1,2-diols, endo-2-phenyl-exo,exo-2,3-norbornane-diol appeared to be the most effective diol in displacing pinanediol (38%). In the cases of pinane-based diols, the best result was obtained with 2-ethyl-6,6-dimethylbicyclo[3.1.1]heptane-cis-2,3-diol (53%). It was interesting to observe that the transesterification with 2-phenyl-6,6-dimethylbicyclo[3.1.1]heptane-cis-2,3-diol resulted in a 50% conversion after 4 days only, whereas the former diol took 24 days to reach equilibrium.
- Roy, Chandra D.,Brown, Herbert C.
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p. 747 - 753
(2008/02/09)
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- Expanding the scope of PNA-encoded libraries: divergent synthesis of libraries targeting cysteine, serine and metallo-proteases as well as tyrosine phosphatases
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Seven PNA-encoded combinatorial libraries targeting proteases and phosphatases with covalent reversible and irreversible mechanism-based inhibitors were prepared. The libraries were synthesized using modified PNA monomers, which dramatically increase the water solubility of the libraries in biologically relevant buffers. The libraries were shown to selectively inhibit targeted enzymes.
- Debaene, Fran?ois,Da Silva, Julien A.,Pianowski, Zbigniew,Duran, Fernando J.,Winssinger, Nicolas
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p. 6577 - 6586
(2008/02/05)
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- Accelerating ligands for osmium tetraoxide catalyzed racemic dihydroxylation of α-pinene
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Osmium tetraoxide catalyzed racemic cis-dihydroxylation of α-pinene usinf N-oxide as cooxidant and hexamethylenetetraamine as accelerating ligand in tert-butyl alcohol gives excellent yield of α-pinanediol.
- Erdik,Kahya,Daskapan
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- Biotransformation of (-)- and (+)-isopinocampheol by three fungi
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The biotransformation of (-)-isopinocampheol and (+)-isopinocampheol by Glomerella cingulata has been studied. Both substrates were converted to three pinanediols, respectively. The major metabolic products obtained were diols. The main product of (-)-isopinocampheol was (1R, 2R, 3S, 4S, 5R)-3,4- pinanediol, and that of the (+)-enantiomer was (1S, 2S, 3S, 5R, 7R)-3,7- pinanediol. These results confirmed that the oxidation by G. cingulata took place with enantioselectivity. In addition. the same substrates were also converted by other fungi such as Rhizoctonia solani and Aspergillus niger. Some similarities exist between the main products of the metabolism of R. solani, while those of A. niger were somewhat different.
- Miyazawa, Mitsuo,Suzuki, Yasuhiro,Kameoka, Hiromu
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p. 945 - 950
(2007/10/03)
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- Kinetics of Osmium Tetraoxide Catalyzed Trimethylamine N-Oxide Oxidations of Cyclohexene and α-Pinene to Diols
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The kinetics of the osmium tetraoxide catalyzed oxidation of cyclohexene and of α-pinene with trimethylamine N-oxide in aqueous tert-butyl alcohol are first order in total osmium species, first order in trimethylamine N-oxide, and zero order in alkene but are strongly dependent on which alkene is used.Thus, the rate-determining step is attack of the trimethylamine N-oxide on the osmium(VI) ester, which is the major reservoir of osmium in the system.The reaction of cyclohexene is inhibited by pyridine with an inverse first-order dependence.Addition of α-pinene in slight excess of the osmium tetraoxide inhibits the oxidation of cyclohexene by more than 2 orders of magnitude, but additional α-pinene has no further effect.The oxidation of α-pinene is not inhibited by pyridine or cyclohexene.Oxidation of trans-stilbene in the presence of α-pinene results in slight (3percent) but mechanistically significant asymmetric induction.A side reaction in the dihydroxylation of α-pinene, overoxidation to α-hydroxy ketone, is suppressed by increasing the concentration of trimethylamine N-oxide.
- Erdik, Ender,Matteson, Donald S.
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p. 2742 - 2748
(2007/10/02)
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- Organoboranes. LI. Convenient procedures for the recovery of pinanediol in asymmetric synthesis via one-carbon homologation of boronic esters
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Matteson's asymmetric synthesis via a one-carbon homologation of the pinanediol boronic esters with (dichloromethyl)litihium at -100 deg C results in the insertion of a chloromethyl group into the carbon-carbon bond with > 99percent diastereoselectivity.This procedure makes possible the asymmetric synthesis of the chiral moiety, RR'CH*B(OR'')2, providing an alternative route to chiral hydroboration for these valuable chiral intermediates.Unfortunately, this method suffers from the remarkable difficulty encountered in the recovery of the pinanediol chiral auxiliary, making this asymmetric synthesis impractical.Fortunately, a systematic study of the problem has uncovered convenient procedures for the recovery of pinanediol from pianendiol boronate esters
- Brown, Herbert C.,Rangaishenvi, Milind V.
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- REACTIONS OF p-TOLUENESULFONIC ACID TERPENE DERIVATIVES WITH LITHIUM IN ETHYLAMINE
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Reactions of terpene p-toluenesulfonamides and p-toluenesulfonates with lithium in ethylamine were stated to afford, exclusively or mainly, respective amines and alcohols as the result of N-S or O-S bond cleavage.Presence of hydroxyl groups is not a hindrance. 2α-Hydroxy-3α-tosyloxypinane undergoes, partially, a rearrangement.The mechanism of that reaction is discussed.
- Rykowski, Zbigniew,Gubrynowicz, Olaf,Wrzesien, Justyna
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p. 1237 - 1244
(2007/10/02)
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- A Highly Efficient Osmium Tetraoxide Catalyzed Oxidation of Sterically Hindered Olefins to Diols
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The use of trimethylamine oxide as oxidizing agent in the presence of catalytic amounts of osmium tetraoxide and pyridine in refluxing aqueous t-butyl alcohol efficiently converts sterically hindered olefins to diols without forming the α-hydroxy ketones or other by-products encountered with previously known procedures.Trisubstituted olefins with which this procedure has proved successful include α-pinene, the methyl and methoxyethoxymethyl ethers of nopol, ethyl chrysanthemumate, and, marginally, 3-methyl-3-penten-2-one.The disubstituted olefins cyclooctene and E-4-methyl-2-pentene were hydroxylated efficiently.The new procedure also proved more efficient than t-butyl hydroperoxide for hydroxylation of tetramethylethylene.Pyridine not only failed to enhance but substantially reduced the relatively mediocre yield of diol from α-pinene when N-methylmorpholine N-oxide was used as oxidizing agent.
- Ray, Rahul,Matteson, Donald S.
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p. 119 - 123
(2007/10/02)
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