- N-Heterocyclic Carbene-Catalyzed Enantioselective Intramolecular Annulations to Construct Benzo-Fused Pyranones with Quaternary Stereocenter
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A highly enantioselective intramolecular NHC-catalyzed approach for the synthesis of benzo-fused pyranones bearing quaternary stereocenter is described. The developed methodology is based on annulation reaction between acyl anion intermediates and β,β-disubstituted Michael acceptors. The reaction offers streamlined and effective access to target products in a highly stereoselective manner. (Figure presented.).
- Dzieszkowski, Krzysztof,Rafiński, Zbigniew
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Read Online
- Modular Total Synthesis of iso-Archazolids and Archazologs
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Full details on the design, development, and successful implementation of suitable synthetic strategies directed toward the total synthesis of iso-archazolids and archazologs are reported. Both a biomimetic and a multistep total synthesis of iso-archazolid B, the most potent and least abundant archazolid, are described. The bioinspired conversion from archazolid B was realized by a high-yielding 1,8-Diazabicyclo[5.4.0]undec-7-ene catalyzed one-step double-bond shift. A highly stereoselective total synthesis was accomplished in 25 steps, involving a sequence of highly stereoselective aldol reactions, an efficient aldol condensation to forge two elaborate fragments, and a challenging ring-closing metathesis macrocyclization with an unusual Stewart-Grubbs catalyst. These strategies proved to be generally useful and could be successfully implemented for the preparation of three novel iso-archazolids as well as five novel archazologs, lacking the thiazole side chain. A wide variety of further archazolids and archazologs may now be targeted for exploration of the promising anticancer potential of these polyketide macrolides.
- Dedenbach, Simon,Menche, Dirk,Rivière, Solenne,Ruiz, Johal,Scheeff, Stephan
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p. 10190 - 10223
(2021/08/16)
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- COMPOUNDS AND SYNTHETIC METHODS FOR THE PREPARATION OF RETINOID X RECEPTOR-SPECIFIC RETINOIDS
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Provided herein are compounds useful for the preparation of compounds that have retinoid-like biological activity. Also provided herein are processes for the preparation of compounds that have retinoid-like biological activity.
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Paragraph 191-194
(2019/06/05)
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- NEW SUBSTITUTED AZAINDOLINE DERIVATIVES AS NIK INHIBITORS
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The present invention relates to pharmaceutical agents useful for therapy and/or prophylaxis in a mammal, and in particular to inhibitors of NF-κB-inducing kinase (NIK - also known as MAP3K14) useful for treating diseases such as cancer, inflammatory disorders, metabolic disorders and autoimmune disorders. The invention is also directed to pharmaceutical compositions comprising such compounds, and to the use of such compounds or pharmaceutical compositions for the prevention or treatment of diseases such as cancer, inflammatory disorders, metabolic disorders including obesity and diabetes, and autoimmune disorders.
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Page/Page column 160; 161
(2019/01/21)
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- THERAPEUTIC COMPOUNDS
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The invention provides compounds formula (I) and salts thereof: wherein the bond represented by ---- is a single bond or a double bond, and R1 has any of the values defined in the specification. The compounds are useful for treating conditions including Alzheimer's disease, Parkinson's disease, diabetes, cancer, and psychotic disorders such as schizophrenia.
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Paragraph 0065; 0066
(2018/05/15)
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- Multifunctional Cyclopentadienes as a Scaffold for Combinatorial Bioorganometallics in [(η5-C5H2R1R2R3)M(CO)3] (M=Re, 99mTc) Piano-Stool Complexes
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Multifunctional cyclopentadiene (Cp) ligands and their rhenium and 99mTc complexes were prepared by a versatile synthetic route. The properties of these Cp ligands can be tuned on demand, either during their synthesis (variation of R1) or through post-synthetic functionalization with two equal or different vectors (V1 and V2). Variation of these groups enables a combinatorial approach in the synthesis of bioorganometallic complexes. This is demonstrated by the preparation of Cp ligands containing both electron-donating and electron-withdrawing groups at the R1 position and their subsequent homo- or heterofunctionalization with biovector models (benzylamine and phenylalanine) under standard amide bond-formation conditions. All ligands can be coordinated to the fac-[Re(CO)3]+ and fac-[99mTc(CO)3]+ cores to give tetrafunctional complexes in straightforward and functional-group-tolerant procedures. The 99mTc complexes were prepared in one step, in 30 min, and under aqueous conditions from generator-eluted [99mTcO4]?.
- Frei, Angelo,Spingler, Bernhard,Alberto, Roger
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supporting information
p. 10156 - 10164
(2018/07/29)
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- Asymmetric Reductive Carbocyclization Using Engineered Ene Reductases
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Ene reductases from the Old Yellow Enzyme (OYE) family reduce the C=C double bond in α,β-unsaturated compounds bearing an electron-withdrawing group, for example, a carbonyl group. This asymmetric reduction has been exploited for biocatalysis. Going beyond its canonical function, we show that members of this enzyme family can also catalyze the formation of C?C bonds. α,β-Unsaturated aldehydes and ketones containing an additional electrophilic group undergo reductive cyclization. Mechanistically, the two-electron-reduced enzyme cofactor FMN delivers a hydride to generate an enolate intermediate, which reacts with the internal electrophile. Single-site replacement of a crucial Tyr residue with a non-protic Phe or Trp favored the cyclization over the natural reduction reaction. The new transformation enabled the enantioselective synthesis of chiral cyclopropanes in up to >99 % ee.
- Heckenbichler, Kathrin,Schweiger, Anna,Brandner, Lea Alexandra,Binter, Alexandra,Toplak, Marina,Macheroux, Peter,Gruber, Karl,Breinbauer, Rolf
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supporting information
p. 7240 - 7244
(2018/06/15)
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- METHOD FOR SYNTHESIS OF 9-CIS-BETA-CAROTENE AND FORMULATIONS THEREOF
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The present invention relates to a method for total chemical synthesis of 9-cis-β-carotene (9CBC), and further provides stable formulations thereof.
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Paragraph 0052
(2017/12/29)
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- PROCESS FOR THE SYNTHESIS OF (2E, 4E, 6Z, 8E)-8-(3,4-DIHYDRONAPHTHALEN-1(2H)-YLIDENE)-3,7-DIMETHYLOCTA-2, 4, 6-TRIENOIC ACID
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This invention relates to a novel method for the synthesis of (2E,4E,6Z,8E)-8-(3,4- dihydronaphthalen-1 (2H)-ylidene)-3,7-dimethylocta-2,4,6-trienoic acid. In particular, the invention relates to several improvements in several individual steps of the multi- step synthesis scheme
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Paragraph 0096
(2017/10/13)
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- Synthesis of apo-13- and apo-15-lycopenoids, cleavage products of lycopene that are retinoic acid antagonists
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Consumption of the tomato carotenoid, lycopene, has been associated with favorable health benefits. Some of lycopene's biological activity may be due to metabolites resulting from cleavage of the lycopene molecule. Because of their structural similarity to the retinoic acid receptor (RAR) antagonist, β-apo-13-carotenone, the "first half" putative oxidative cleavage products of the symmetrical lycopene have been synthesized. All transformations proceed in moderate to good yield and some with high stereochemical integrity allowing ready access to these otherwise difficult to obtain terpenoids. In particular, the methods described allow ready access to the trans isomers of citral (geranial) and pseudoionone, important flavor and fragrance compounds that are not readily available isomerically pure and are building blocks for many of the longer apolycopenoids. In addition, all of the apo-11, apo-13, and apo-15 lycopenals/lycopenones/lycopenoic acids have been prepared. These compounds have been evaluated for their effect on RAR-induced genes in cultured hepatoma cells and, much like β-apo-13-carotenone, the comparable apo-13-lycopenone and the apo-15-lycopenal behave as RAR antagonists. Furthermore, molecular modeling studies demonstrate that the apo-13-lycopenone efficiently docked into the ligand binding site of RARα. Finally, isothermal titration calorimetry studies reveal that apo-13-lycopenone acts as an antagonist of RAR by inhibiting coactivator recruitment to the receptor.
- Narayanasamy, Sureshbabu,Sun, Jian,Pavlovicz, Ryan E.,Eroglu, Abdulkerim,Rush, Cassandra E.,Sunkel, Benjamin D.,Li, Chenglong,Harrison, Earl H.,Curley, Robert W.
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p. 1021 - 1029
(2017/05/17)
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- TETRASUBSTITUTED ALKENE COMPOUNDS AND THEIR USE
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Disclosed herein are compounds, or pharmaceutically acceptable salts thereof, and methods of using the compounds for treating breast cancer by administration to a subject in need thereof a therapeutically effective amount of the compounds or pharmaceutically acceptable salts thereof. The breast cancer may be an ER-positive breast cancer and/or the subject in need of treatment may express a mutant ER-α protein.
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Paragraph 0398; 0399
(2016/12/22)
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- Iron-catalyzed aerobic C-H functionalization of pyrrolones
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The aerobic oxidation of pyrrolones catalyzed by Fe(OTf)3 to form reactive N-acyliminium ion intermediates that undergo nucleophilic additions with alcohols to give the corresponding products in moderate to good yields is described.
- Liu, Li-Wei,Wang, Zhen-Zhen,Zhang, Hui-Hui,Wang, Wan-Shu,Zhang, Ji-Zong,Tang, Yu
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supporting information
p. 9531 - 9534
(2015/06/08)
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- Conformationally Defined Rexinoids and Their Efficacy in the Prevention of Mammary Cancers
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(2E,4E,6Z,8Z)-8-(3′,4′-Dihydro-1′(2H)-naphthalen-1′-ylidene)-3,7-dimethyl-2,3,6-octatrienoinic acid (UAB30) is currently undergoing clinical evaluation as a novel cancer prevention agent. In efforts to develop even more highly potent rexinoids that prevent breast cancer without toxicity, we further explore here the structure-activity relationship of two separate classes of rexinoids. UAB30 belongs to the class II rexinoids and possesses a 9Z-tetraenoic acid chain bonded to a tetralone ring, whereas the class I rexinoids contain the same 9Z-tetraenoic acid chain bonded to a disubstituted cyclohexenyl ring. Among the 12 class I and class II rexinoids evaluated, the class I rexinoid 11 is most effective in preventing breast cancers in an in vivo rat model alone or in combination with tamoxifen. Rexinoid 11 also reduces the size of established tumors and exhibits a therapeutic effect. However, 11 induces hypertriglyceridemia at its effective dose. On the other hand rexinoid 10 does not increase triglyceride levels while being effective in the in vivo chemoprevention assay. X-ray studies of four rexinoids bound to the ligand binding domain of the retinoid X receptor reveal key structural aspects that enhance potency as well as those that enhance the synthesis of lipids.
- Atigadda, Venkatram R.,Xia, Gang,Deshpande, Anil,Wu, Lizhi,Kedishvili, Natalia,Smith, Craig D.,Krontiras, Helen,Bland, Kirby I.,Grubbs, Clinton J.,Brouillette, Wayne J.,Muccio, Donald D.
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supporting information
p. 7763 - 7774
(2015/10/20)
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- METHOD FOR PRODUCING 4-HALOSENECIOIC ACID DERIVATIVE
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In addition the present invention refers to high yield and a low cost method for preparing derivatives hour Osan which it counts 4-halo in provides. General formula (1) : (in formula, the protector for a difference from an R) the reel alcohol which will know derivatives represented by, characterized by reacting a halogenating agent, general formula (2) : (in formula, R the equal to the meanings exhibits, for a difference from an represent halogen X) represented by derivatives of 4-halo hour Osan which it counts is manufacturing method.
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Page/Page column 0070-0072
(2016/11/24)
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- Tailoring 3,3'-dihydroxyisorenieratene to hydroxystilbene: Finding a resveratrol analogue with increased antiproliferation activity and cell selectivity
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Four novel compounds were designed by "tailoring" 3,3'-dihydroxyisorenieratene (a natural carotenoid) based on an isoprene unit retention truncation strategy. Among them, the smallest molecule 1 (2,3,6,2',3',6'-hexamethyl-4,4'-dihydroxy-trans-stilbene) was concisely synthesized in a one-pot Stille-Heck tandem sequence, and surfaced as a promising lead molecule in terms of its selective antiproliferative activity mediated by blocking the NCI-H460 cell cycle in G1 phase. Additionally, theoretical calculations and cell uptake experiments indicate that the unique polymethylation pattern of compound 1 significantly induces a conformational change shift out of planarity and increases its cell uptake and metabolic stability. The observation should be helpful to rationally design resveratrol-inspired antiproliferative agents. Four novel compounds were designed by "tailoring" 3,3'-dihydroxyisorenieratene (a natural carotenoid) based on an isoprene unit retention truncation strategy. Among them, the smallest molecule 1 was concisely synthesized by a one-pot Stille-Heck tandem sequence, and surfaced as a promising lead molecule in terms of its selective antiproliferative activity (see figure).
- Kang, Yan-Fei,Yan, Wen-Jing,Zhou, Ting-Wen,Dai, Fang,Li, Xiu-Zhuang,Bao, Xia-Zhen,Du, Yu-Ting,Yuan, Cui-Hong,Wang, Hai-Bo,Ren, Xiao-Rong,Liu, Qiang,Jin, Xiao-Ling,Zhou, Bo,Zhang, Jie
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supporting information
p. 8904 - 8908
(2014/07/22)
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- Synthesis and herbicidal activity of diphenyl ether derivatives containing unsaturated carboxylates
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A series of novel diphenyl ether derivatives containing unsaturated carboxylates were designed and synthesized. Their structures were identified by 1H nuclear magnetic resonance and elemental analyses. The bioassays indicated that the compounds 5b and 5c exhibited good herbicidal activities against velvetleaf at a concentration of 30-40 g/hm2. The relationship between structure and herbicidal activity was also discussed. Among unsaturated carboxylates group, butenoate is the most promising one. Amonst them, 4-ethoxy-4-oxobutenyl 5-(2-chloro-4-(trifluoromethyl)phenoxy)-2- nitrobenzoate 5b was identified as the most promising candidate due to its high protoporphyrinogen IX oxidase inhibition effect (pI50 = 6.64) and good herbicidal activity against broadleaf weeds with selectivity to soybean and low toxicity to mammals.
- Yu, Haibo,Yang, Huibin,Cui, Dongliang,Lv, Liang,Li, Bin
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scheme or table
p. 11718 - 11726
(2012/04/04)
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- The absolute configuration of the pyrrolosesquiterpenoid glaciapyrrol A
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The total syntheses of the structurally unique and moderately cytotoxic pyrrolosesquiterpenoid glaciapyrrol A that has been isolated from a marine streptomycete by Macherla et al.1 and of seven of its stereoisomers have been performed from geraniol or nerol, respectively, using a known diastereoselective Ru-catalysed approach for the synthesis of tetrahydrofurans previously reported by Stark and co-workers.5 Comparison of 1H and 13C NMR data unambiguously clarified the relative configuration of natural glaciapyrrol A that was previously only partly solved from the available NMR data. An enantioselective synthesis was carried out resulting in the unnatural enantiomer (11S,12R,15R)-(-)-glaciapyrrol A. These data establish the absolute configuration of the natural product as (11R,12S,15S)-(+)-glaciapyrrol A.
- Riclea, Ramona,Dickschat, Jeroen S.
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supporting information; experimental part
p. 11930 - 11934
(2011/11/29)
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- Syntheses, antiproliferative activity and theoretical characterization of acitretin-type retinoids with changes in the lipophilic part
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Acitretin analogs, incorporating changes in the lipophilic part, were efficiently synthesized from commercially available aromatic aldehydes or methyl ketones using the Wittig or Horner-Wadsworth-Emmons reaction. Their antiproliferative activity was evaluated against human breast MCF-7 epithelial cells. Analogs 3, 4, 8 and 11 exhibited strong, dose-dependent, antiproliferative activity on the tested cell line. Analog 3, incorporating three methoxy groups in the aromatic ring, exhibited the strongest inhibitory effect at 10 μM. High-level all electron conventional ab initio and density functional theory quantum chemical calculations were performed to obtain the molecular structure, electron charge distribution and polarization properties of all compounds of interest in this work. The most active analogs were planar and were characterized by larger dipole moments than the other synthesized molecules. Another factor of importance to the analysis of the activity of these molecules is the dipole polarizability.
- Magoulas, George E.,Bariamis, Stavros E.,Athanassopoulos, Constantinos M.,Haskopoulos, Anastasios,Dedes, Petros G.,Krokidis, Marios G.,Karamanos, Nikos K.,Kletsas, Dimitris,Papaioannou, Dionissios,Maroulis, George
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experimental part
p. 721 - 737
(2011/03/20)
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- Conjugate boration of β,β-disubstituted unsaturated esters: Asymmetric synthesis of functionalized chiral tertiary organoboronic esters
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Challenging tertiary organoboronic esters containing a β-ester group were prepared enantioselectively via the asymmetric conjugate boration of β,β-disubstituted α,β-unsaturated esters with a copper-phosphine catalyst (see scheme). The functionalized organoboron derivatives can be utilized as a carbon nucleophile to form all-carbon quaternary centers. Copyright
- Feng, Xinhui,Yun, Jaesook
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supporting information; scheme or table
p. 13609 - 13612
(2011/02/28)
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- Highly enantioselective synthesis of tetrahydro-β-carbolines and tetrahydro-γ-carbolines via Pd-catalyzed intramolecular allylic alkylation
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A novel Pd-catalyzed intramolecular allylic alkylation of indoles allows THBCs and THGCs to be effectively synthesized in high yields and excellent enantiomeric excesses (ee up to 97%). Copyright
- Bandini, Marco,Melloni, Alfonso,Piccinelli, Fabio,Sinisi, Riccardo,Tommasi, Simona,Umani-Ronchi, Achille
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p. 1424 - 1425
(2007/10/03)
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- Aglairubine - Discrepancies during the course of structure elucidation
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A short synthesis of the originally proposed structure 1 for the putrescine alkaloid aglairubine is presented as well as for a conceivable structure alternative 11. Due to the ascertained mismatch of spectroscopical data for synthetic and natural compounds, the published aglairubine structure has to be revised.
- Detterbeck, Richard,Hesse, Manfred
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p. 4609 - 4612
(2007/10/03)
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- Development of a synthesis of lankacidins: an investigation into 17-membered ring formation
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Studies are reported concerning the synthesis of macrocyclic analogues of the lankacidins.The long-chain trienylphosphonate 33 has been synthesized as a mixture of epimers at C(7), by a convergent route which involved alkylation of ethyl 2-methyl-3-oxobutanoate 10 by the 10-(tert-butyldimethylsilyloxy)-3,9-dimethyldeca-2,4,8-trienyl chloride 11 to give 27 followed by an aldol addition to the aldehyde 12.Stereoselective reduction then gave the 1,3-syn-diol 35 which was protected as its acetonide 36.However, it did not prove possible to hydrolyse the 1,3-dioxolane ring in 36 to reveal the keto phosphate grouping and leave the acetonide component intact.To avoid this problem, acrolein was added to the alkylated keto ester 27 to give the aldol product 40 as a mixture of diastereoisomers.Stereoselective reduction gave the 1,3-syn-diols 41 and 42, in a ratio of 75:25, which were separated and taken through to the δ-lactones 47 and 48.The lactone 47 corresponds to the C(14)-C(12) fragment of the lankacidins, and the diol 41 is an advanced intermediate for a synthesis of a 17-membered macrocyclic analogue of the lankacidins.The diols 41 and 42 were protected as their acetonides 43 and 44 and these were taken through to the 16-formyl-2-oxophosphonates 7 and 57.Cyclisations into the cycloheptadeca-2,4,8,10-tetraenones 8 and 58 were carried out using potassium carbonate in the presence of 18-crown-6 in toluene at 100 deg C.Alternative conditions for the cyclisations were less successful as were attempts to cyclise the halogeno sulfones 62 and 63 although the 17-acetoxy sulfone 64 was cyclised using tetrakis(triphenylphosphine)palladium(0) and 1,3-bis(triphenylphosphino)propane, but only in a modest yield (18percent).Deprotection and reduction of the cyclised products have been briefly investigated.
- Mata, Ernesto G.,Thomas, Eric J.
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p. 785 - 800
(2007/10/02)
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- SYNTHESIS OF RADIOACTIVE ZEATIN RIBOSIDE AND RELATED COMPOUNDS BY ALKYLATION OF PURINE MOIETIES
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A method for the synthesis of (E)-4-(tetrahydropyran-2-yloxy)-3-methylbut-2-enyl bromide is described and its use in the synthesis of 3H>zeatin riboside, zeatin and a xanthine derivative by alkylation is reported.
- Young, H.,Letham, D. S.,Hocart, C. H.,Eichholzer, J. V.
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p. 385 - 386
(2007/10/02)
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- Novel compositions
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Substituted alkenoates and alkanoates, intermediates therefor, synthesis thereof, and their use for the control of pests.
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- A CONVENIENT SYNTHESIS OF (+/-) ASCOCHLORIN
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A convergent total synthesis of (+/-) ascochlorin is described.
- Safaryn, J. E.,Chiarello, J.,Chen, K.-M.,Joullie, M. M.
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p. 2635 - 2642
(2007/10/02)
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- SYNTHESIS OF (E)-β-FLUOROMETHYLENEGLUTAMIC ACID
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A potential dual-enzyme activated inhibitor of γ-aminobutyric acid transaminase, (E)-β-fluoromethyleneglutamic acid, was prepared from ethyl 3,3-dimethylacrylate in 11 steps.
- McDonald, Ian A.,Palfreyman, Michael G.,Jung, Michel,Bey, Philippe
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p. 4091 - 4092
(2007/10/02)
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- SYNTHETIC INVESTIGATIONS INTO THE CHEMISTRY OF POLYENE COMPOUNDS XLVII. TOTAL SYNTHESIS OF (+/-)-(2E,4E,6E,6Z,8E)-3,7-DIMETHYL-9-(2,6-DIMETHYL-3-OXO-6-ETHOXYCARBONYL-1-CYCLOHEXENYL)-2,4,6,8-NONATETRAENOIC ACID. THE WITTIG REACTION AT HIGH PRESURES
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The synthesis of the C20 retinoids (+/-)-2E,4E,6E,6Z,8E-3,7-dimethyl-9-(2,6-dimethyl-3-oxo-6-ethoxycarbonyl-1-cyclohexenyl)-2,4,6,8-nonatetraenoic acid the previously undescribed ethyl (+/-)-2E,4Z,6E-2-isopropenyl-5-methyl-7-(2,6-dimethyl-3-oxo-6-ethoxycarbonyl-1-cyclohexenyl)-2,4,6-heptatrienoate was realized by the C10 + C10 to C20 scheme with the use of the Wittig reaction at high presure.
- Zhidkova, T. A.,Stashina, G. A.,Bekker, A. R.,Vakulova, L. A.,Zhulin, V. M.,Samokhvalov, G. I.
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p. 2328 - 2333
(2007/10/02)
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- Polyenic acids. II. Antifungal and bacteriostatic 4-bromo hexa-2,4 dienoic acids derivatives
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Some structural modifications of the dienic chain of 2,4 (2 E, 4 E)-hexadienoic acid - functionalisation, cyclic integration, epoxydation - were investigated. Only ω-oxydation allowed gain in bacteriostatic activity without reducing fungistatic activity of the reference compound: esters 10, 11 and 19. The corresponding acids 10a and 11a show a slight drop in fungistatic activity.
- Le Baut,Sparfel,Clairc,et al.
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p. 447 - 455
(2007/10/02)
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- The Synthesis of 5-Hydroxy-2,4-dimethyl-1-hexene-1,5-dicarboxylic Acid (Nemorensic Acid)
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The synthesis of nemorensic acid in the open-chain form, i.e. of 5-hydroxy-2,4-dimethyl-1-hexene-1,5-dicarboxylic acid is described.
- Roeder, Erhard,Wiedenfeld, Helmut,Frisse, Manfred
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p. 803 - 806
(2007/10/02)
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