cas 154714-19-9, 5-HYDROXY-2,2-DIMETHYL-4H-BENZO[D][1,3]DIOXIN-4-ONE

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Divinylcarbinol Desymmetrization Strategy: A Concise and Reliable Approach to Chiral Hydroxylated Fatty Acid Derivatives
By the aid of the catalytic desymmetrization of divinylcarbinol as one-pot asymmetric induction and protection of olefin, asymmetric total syntheses of two chiral hydroxylated fatty acid derivatives were successfully achieved. The desired stereoisomers could be concisely prepared in mild conditions in a highly convergent manner. Thus, this novel strategy can help stereochemical elucidations of natural products, which have difficulties in spectroscopic stereochemical analyses due to their local symmetries in the vicinities of the stereogenic secondary hydroxyl units.
Sugimoto, Kenji,Kobayashi, Ami,Kohyama, Aki,Sakai, Haruka,Matsuya, Yuji
p. 3970 - 3980
(2021)
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Integrating Epigenetic Modulators into NanoScript for Enhanced Chondrogenesis of Stem Cells
N-(4-Chloro-3-(trifluoromethyl)phenyl)-2-ethoxybenzamide (CTB) is a small molecule that functions by altering the chromatin architecture to modulate gene expression. We report a new CTB derivative with increased solubility and demonstrate CTB's functionality by conjugating it on the recently established NanoScript platform to enhance gene expression and induce stem cell differentiation. NanoScript is a nanoparticle-based artificial transcription factor that emulates the structure and function of transcription factor proteins (TFs) to effectively regulate endogenous gene expression. Modifying NanoScript with CTB will more closely replicate the TF structure and enhance CTB functionality and gene expression. To this end, we first conjugated CTB onto NanoScript and initiated a time-dependent increase in histone acetyltransferase activity. Next, because CTB is known to trigger the pathway involved in regulating Sox9, a master regulator of chondrogenic differentiation, we modifed a Sox9-specific NanoScript with CTB to enhance chondrogenic gene activity and differentiation. Because NanoScript is a tunable and robust platform, it has potential for various gene-regulating applications, such as stem cell differentiation.
Patel, Sahishnu,Pongkulapa, Thanapat,Yin, Perry T.,Pandian, Ganesh N.,Rathnam, Christopher,Bando, Toshikazu,Vaijayanthi, Thangavel,Sugiyama, Hiroshi,Lee, Ki-Bum
p. 4598 - 4601
(2015)
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Practical, large-scale synthesis of 2,2-dimethyl-5-hydroxy-4-oxo-benzo- 1,4-dioxin
Modification of a known procedure employing the interaction of thionyl chloride, acetone, and 2,6-dihydroxybenzoic acid was found, to provide the title compound in multikilogram quantities of acceptable yield and purity.
Hadfield,Schweitzer,Trova,Green
p. 1025 - 1028
(1994)
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Enantioselective Chemical Syntheses of the Furanosteroids (-)-Viridin and (-)-Viridiol
Herein we describe concise enantioselective chemical syntheses of (-)-viridin and (-)-viridiol. Our convergent approach couples two achiral fragments of similar complexity and employs an enantioselective intramolecular Heck reaction to set the absolute stereochemical configuration of an all-carbon quaternary stereocenter. To complete the syntheses of these base- and nucleophile-sensitive natural products, we conduct carefully orchestrated site- and diastereoselective oxidations and other transformations. Our work is the first to generate these targets as single enantiomers.
Del Bel, Matthew,Abela, Alexander R.,Ng, Jeffrey D.,Guerrero, Carlos A.
p. 6819 - 6822
(2017)
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Synthesis and Structure-Activity Relationship of Xenocoumacin 1 and Analogues as Inhibitors of Ribosomal Protein Synthesis
Ribosomal protein synthesis is an important target in antibacterial drug discovery. Numerous natural products have served as starting points for the development of antibiotics. We report here the total synthesis of xenocoumacin 1, a natural product that binds to 16S ribosomal RNA at a highly conserved region, as well as analogues thereof. Preliminary structure–activity relationship studies were aimed at understanding and modulating the selectivity between eukaryotic and prokaryotic ribosomes. Modifications were mainly tolerated in the aromatic region. Whole-cell activity against Gram-negative bacteria is limited by efflux and penetration, as demonstrated in genetically modified strains of E. coli. Analogues with high selectivity for eukaryotic ribosomes were identified, but it was not possible to obtain inhibitors selective for bacterial protein synthesis. Achieving high selectivity (albeit not the desired one) was thus possible despite the high homology between eukaryotic and prokaryotic ribosomes in the binding region.
Zumbrunn, Cornelia,Krüsi, Daniela,Stamm, Christina,Caspers, Patrick,Ritz, Daniel,Rueedi, Georg
supporting information
p. 891 - 897
(2020/12/15)

Synthesis and Evaluation of Ginkgolic Acid Derivatives as SUMOylation Inhibitors
SUMOylation has emerged as an important post-translational modification that has been shown to modulate protein activity associated with various signaling pathways, and consequently, it has emerged as an important therapeutic target. While several natural products have been shown to inhibit enzymes involved in the SUMOylation process, there has been little progress toward the development of more selective and potent SUMOylation inhibitors. Ginkgolic acid was one of the first natural products discovered to inhibit the SUMO E1 enzyme. Despite its use to mechanistically investigate the SUMOylation process, ginkgolic acid also modulates other pathways as well. In this Letter, preliminary structure-activity relationships for ginkgolic acid as a SUMOylation inhibitor are presented.
Brackett, Christopher M.,García-Casas, Ana,Castillo-Lluva, Sonia,Blagg, Brian S. J.
supporting information
p. 2221 - 2226
(2020/12/17)

PROCESS AND INTERMEDIATES FOR THE PREPARATION OF VOXELOTOR
The invention relates to a process for the preparation of Voxelotor, or a salt or solvate thereof, which comprises the use of a compound of formula (I) or (I'), or a salt or solvate thereof.
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(2020/07/14)

Antibacterial Anacardic Acid Derivatives
We report on the antibacterial activity of five phenolic lipids derived from anacardic acid characterized by increasing alkyl chain lengths with 6, 8, 10, 12, or 14 carbon atoms. The compounds were profiled for their physicochemical properties, transport across epithelial monolayers, cytotoxicity, and antibacterial activity as compared to common antibiotics. No cytotoxicity was reported in cell lines of fibroblast, hepatic, colorectal, or renal origin. C10 and C12 significantly increased the survival in a Galleria mellonella model infected with multi-drug-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant Enterococci (VRE) as compared to the untreated control group. Future studies are required to corroborate these findings in relevant animal model systems of infection.
F?rtig, Niclas,Faber, Franziska,Holzgrabe, Ulrike,Kowalick, Kristin,Masota, Nelson,Meinel, Lorenz,Ohlsen, Knut,Saedtler, Marco
p. 1674 - 1685
(2020/09/11)

A Heck-Based Strategy to Generate Anacardic Acids and Related Phenolic Lipids for Isoform-Specific Bioactivity Profiling
A synthetic strategy for phenolic lipids such as anacardic acid and ginkgolic acid derivatives using an efficient and selective redox-relay Heck reaction followed by a stereoselective olefination is reported. This approach controls both the alkene position and stereochemistry, allowing the synthesis of natural and unnatural unsaturated lipids as single isomers. By this strategy, the activities of different anacardic acid and ginkgolic acid derivatives have been examined in a matrix metalloproteinase inhibition assay.
Weigel, William K.,Dennis, Taylor N.,Kang, Amrik S.,Perry, J. Jefferson P.,Martin, David B. C.
supporting information
p. 6234 - 6238
(2018/10/05)

BORONIC ACID DERIVATIVES AND THERAPEUTIC USES THEREOF
Disclosed herein are antimicrobial compounds compositions, pharmaceutical compositions, the method of use and preparation thereof. Some embodiments relate to boronic acid derivatives and their use as therapeutic agents, for example, β-lactamase inhibitors (BLIs).
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Paragraph 0269

(2018/02/28)

Structure-inspired design of a sphingolipid mimic sphingosine-1-phosphate receptor agonist from a naturally occurring sphingomyelin synthase inhibitor
Ginkgolic acid obtained as a sphingomyelin synthase inhibitor from a plant extract library inspired the concept of sphingolipid mimics. Ginkgolic acid-derived N-acyl anilines and ginkgolic acid 2-phosphate (GA2P) respectively mimic ceramide and sphingosine 1-phosphate (S1P) in structure and function. The GA2P-induced phosphorylation of ERK and internalization of S1P receptor 1 (S1P1) indicated potent agonist activity. Docking studies revealed that GA2P adopts a similar binding conformation to the bound ligand ML5, which is a strong antagonist of S1P1.
Swamy, Mahadeva M. M.,Murai, Yuta,Ohno, Yusuke,Jojima, Keisuke,Kihara, Akio,Mitsutake, Susumu,Igarashi, Yasuyuki,Yu, Jian,Yao, Min,Suga, Yoshiko,Anetai, Masaki,Monde, Kenji
supporting information
p. 12758 - 12761
(2018/12/01)

6-sulfonate pyrimidyl salicylate compound and preparation method and application thereof
The invention relates to the field of herbicides and discloses a 6-sulfonate pyrimidyl salicylate compound and a preparation method and application thereof. The compound has a structure as shown in a formula (1). The method for preparing the 6-sulfonate pyrimidyl salicylate compound comprises the steps of (1) carrying out first contact reaction on the compound as shown in a formula (2) and R2SO2Cl to obtain a compound as shown in a formula (3); and (2) carrying out second contact reaction on the compound as shown in the formula (3) and trifluoroacetic acid. The 6-sulfonate pyrimidyl salicylate compound has a good inhibition effect on acetohydroxyacid synthase, and has significant resistance inhibition effect on weeds which are resistant to an acetohydroxyacid synthase inhibitor herbicide, thereby controlling weed resistance plants caused by acetohydroxyacid synthase. The formulas are as shown in the specification.
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Paragraph 0135; 0139; 0140; 0141

(2017/07/19)

Gold(I)-Catalyzed Cyclization for the Synthesis of 8-Hydroxy-3- substituted Isocoumarins: Total Synthesis of Exserolide F
A highly regioselective gold(I)-catalyzed 6-endo-dig cyclization of 2,2-dimethyl-5-(alkynyl)-4H-benzo[d][1,3]dioxin-4-ones for the synthesis of 8-hydroxy-3-substituted isocoumarins is described. Key features of the reaction include the broad substrate scope, scalability, and tolerance for protecting groups. The synthetic utility of this novel method is demonstrated by the first total synthesis of exserolide F, an isocoumarin-containing polyol natural product.
Mallampudi, N. Arjunreddy,Reddy, G. Sudhakar,Maity, Saurabh,Mohapatra, Debendra K.
supporting information
p. 2074 - 2077
(2017/04/28)

Two Routes to 4-Fluorobenzisoxazol-3-one in the Synthesis of a 5-HT4 Partial Agonist
A potent 5-HT4 partial agonist, 1 (PF-04995274), targeted for the treatment of Alzheimer's disease and cognitive impairment, has been prepared on a multi-kilogram scale. The initial synthetic route, that proceeded through a 4-substituted 3-hydroxybenzisoxazole core, gave an undesired benzoxazolinone through a Lossen-type rearrangement. Route scouting led to two new robust routes to the desired 4-substituted core. Process development led to the efficient assembly of the API on a pilot plant scale under process-friendly conditions with enhanced throughput. In addition, crystallization of a hemicitrate salt of the API with pharmaceutically beneficial properties was developed to enable progression of clinical studies.
Widlicka, Daniel W.,Murray, John C.,Coffman, Karen J.,Xiao, Chunguang,Brodney, Michael A.,Rainville, Joseph P.,Samas, Brian
p. 233 - 241
(2016/03/04)

Total Syntheses of (-)-Spirooliganones A and B and Their Diastereoisomers: Absolute Stereochemistry and Inhibitory Activity against Coxsackie Virus B3
To investigate the effects of configuration on bioactivity, spirooliganones A and B and their six diastereoisomers (1-8) were synthesized in 11 steps. The key benzopyran core was assembled by intermolecular [4 + 2] hetero-Diels-Alder cycloaddition between (-)-sabinene and o-quinone methide, which was generated from the corresponding o-hydroxybenzyl alcohol. After establishing the absolute configuration, the inhibitory activities of spirooliganones 1-8 against Coxsackie virus B3 were evaluated, and the primary structure-activity relationships were analyzed. Compound 3 was the most potent compound, with an IC50 of 0.41 μM.
Zhao, Nan,Ren, Xiaodong,Ren, Jinhong,Lü, Haining,Ma, Shuanggang,Gao, Rongmei,Li, Yuhuan,Xu, Song,Li, Li,Yu, Shishan
supporting information
p. 3118 - 3121
(2015/06/30)

Synthesis and structure-activity studies of the V-ATPase inhibitor saliphenylhalamide (SaliPhe) and simplified analogs
An efficient total synthesis of the potent V-ATPase inhibitor saliphenylhalamide (SaliPhe), a synthetic variant of the natural product salicylihalamide A (SaliA), has been accomplished aimed at facilitating the development of SaliPhe as an anticancer and antiviral agent. This new approach enabled facile access to derivatives for structure-activity relationship studies, leading to simplified analogs that maintain SaliPhe's biological properties. These studies will provide a solid foundation for the continued evaluation of SaliPhe and analogs as potential anticancer and antiviral agents.
Garcia-Rodriguez, Jose,Mendiratta, Saurabh,White, Michael A.,Xie, Xiao-Song,De Brabander, Jef K.
supporting information
p. 4393 - 4398
(2015/10/12)

Oxidative cyclization of alkenoic acids promoted by AgOAc
Alkenoic acids derived from salicylic acid and analogues undergo an unexpected oxidative cyclization process triggered by AgOAc leading to 4H-benzo[d][1,3]dioxin-4-ones. The process is affected by the substitution on the aryl and the allyl units.
Carrillo-Arcos, Ulises A.,Rojas-Ocampo, Jonathan,Porcel, Susana
supporting information
p. 479 - 483
(2016/01/09)

Identification of 6-benzyloxysalicylates as a novel class of inhibitors of 15-lipoxygenase-1
Lipoxygenases metabolize polyunsaturated fatty acids into signalling molecules such as leukotrienes and lipoxins. 15-lipoxygenase-1 (15-LOX-1) is an important mammalian lipoxygenase and plays a crucial regulatory role in several respiratory diseases such as asthma, COPD and chronic bronchitis. Novel potent and selective inhibitors of 15-LOX-1 are required to explore the role of this enzyme in drug discovery. In this study we describe structure activity relationships for 6-benzyloxysalicylates as inhibitors of human 15-LOX-1. Kinetic analysis suggests competitive inhibition and the binding model of these compounds can be rationalized using molecular modelling studies. The most potent derivative 37a shows a Ki value of 1.7 μM. These structure activity relationships provide a basis to design improved inhibitors and to explore 15-LOX-1 as a drug target.
Eleftheriadis, Nikolaos,Thee, Stephanie,Te Biesebeek, Johan,Van Der Wouden, Petra,Baas, Bert-Jan,Dekker, Frank J.
p. 265 - 275
(2015/03/30)

First enantioselective total synthesis of penicimarin B, aspergillumarins A and B
A convergent enantioselective synthesis of penicimarin B, aspergillumarin A and B has been reported using Brown's allylation, DeBrabander-Bhattacharjee lactonization and Grubbs cross coupling metathesis. During this synthesis we have standardized the conditions for DeBrabande-Bhattacharjee lactonization to obtain excellent yield (>90%).
Yadav, Jhillu Singh,Mishra, Anand Kumar,Dachavaram, Soma Shekar,Ganesh Kumar,Das, Saibal
supporting information
p. 2921 - 2923
(2014/05/06)

Evolution of an oxidative dearomatization enabled total synthesis of vinigrol
The evolution of the synthetic strategy resulting in a total synthesis of vinigrol is presented. Oxidative dearomatization/intramolecular Diels-Alder cycloaddition has served as the successful cornerstone for all of the approaches. Extensive radical cyclization efforts to form the tetracyclic core resulted in interesting and surprising reaction outcomes, none of which could be advanced to vinigrol. These cyclization obstacles were successfully overcome by using Heck instead of radical cyclizations. The total synthesis features a trifluoroethyl ether protecting group being used for the first time in organic synthesis. The logic of its selection and the group's importance beyond protecting the C8a hydroxyl group is presented along with a discussion of strategies for its removal. Because of the compact tetracyclic cage the route is built around many unusual reaction observations and solutions have emerged. For example, a first of its kind Grob fragmentation reaction featuring a trifluoroethyl leaving group has been uncovered, interesting interrupted selenium dioxide allylic oxidations have been observed as well as intriguing catalyst and counterion dependent directed hydrogenations.
Yang, Qingliang,Draghici, Cristian,Njardarson, Jon T.,Li, Fang,Smith, Brandon R.,Das, Pradipta
supporting information
p. 330 - 344
(2014/01/06)

Biomimetic asymmetric total syntheses of spirooliganones A and B
Biomimetic total syntheses of potent antiviral spirooliganones A and B were achieved with 3% and 2% yield, respectively, in 12 steps from commercially available materials. The synthetic strategy was inspired primarily by the biogenetic hypothesis and was enabled by two independent cascade events: (i) an unprecedented reaction involving aromatic Claisen rearrangement/o-quinone methide formation/hetero-Diels-Alder cycloaddition to construct the tetracyclic framework and (ii) phenol oxidative dearomatization/spirocyclization to build the spiro-fused cyclohexadienone/tetrahydrofuran moiety.
Song, Liyan,Yao, Hongliang,Tong, Rongbiao
supporting information
p. 3740 - 3743
(2014/08/05)

Biomimetic synthesis of functionalized γ-resorcylates from dioxinone derivatives
Biomimetic syntheses of functionalized γ-resorcylates from 2,2,6-trimethyl-4H-1,3-dioxin-4-one derivatives are reported. Cross metathesis of 2,2-dimethyl-6-vinyl-4H-1,3-dioxin-4-one with homoallylic esters or aldol reactions of tert-butyl or benzyl esters with 1-(2,2-dimethyl-4-oxo-4H-1,3- dioxin-6-yl)-acetone and related ketones followed by aromatization under mild Appel-type reaction conditions gave a range of γ-resorcylates.
Blencowe, Peter S.,Barrett, Anthony G. M.
supporting information
p. 4844 - 4853
(2014/08/05)

Novel chemical synthesis of ginkgolic acid (13:0) and evaluation of its tyrosinase inhibitory activity
A novel efficient synthesis of ginkgolic acid (13:0) from abundant 2,6-dihydroxybenzoic acid was successfully developed through a state-of-the-art palladium-catalyzed cross-coupling reaction and catalytic hydrogenation with an overall yield of 34% in five steps. The identity of the synthesized ginkgolic acid (13:0) was confirmed by nuclear magnetic resonance, mass spectrometry, infrared, and high-performance liquid chromatography. The reaction sequence of this method can be readily extended to the synthesis of other ginkgolic acids. The synthesized ginkgolic acid (13:0) exhibited promising anti-tyrosinase activity (IC50 = 2.8 mg/mL) that was not correlated to antioxidant activity as probed by 1,1-diphenyl-2-picrylhydrazyl, 2,2′-azino-bis(3- ethylbenzothiazoline-6-sulfonic acid), ferric reducing ability of plasma, and oxygen radical absorbance capacity assays. The synthetic strategy developed in this work will significantly facilitate biological studies of ginkgolic acids that have great potential applications in food and pharmaceuticals.
Fu, Yuanqing,Hong, Shan,Li, Duo,Liu, Songbai
p. 5347 - 5352
(2013/07/27)

Discovery of a novel activator of 5-lipoxygenase from an anacardic acid derived compound collection
Lipoxygenases (LOXs) and cyclooxygenases (COXs) metabolize poly-unsaturated fatty acids into inflammatory signaling molecules. Modulation of the activity of these enzymes may provide new approaches for therapy of inflammatory diseases. In this study, we screened novel anacardic acid derivatives as modulators of human 5-LOX and COX-2 activity. Interestingly, a novel salicylate derivative 23a was identified as a surprisingly potent activator of human 5-LOX. This compound showed both non-competitive activation towards the human 5-LOX activator adenosine triphosphate (ATP) and non-essential mixed type activation against the substrate linoleic acid, while having no effect on the conversion of the substrate arachidonic acid. The kinetic analysis demonstrated a non-essential activation of the linoleic acid conversion with a KA of 8.65 μM, αKA of 0.38 μM and a β value of 1.76. It is also of interest that a comparable derivative 23d showed a mixed type inhibition for linoleic acid conversion. These observations indicate the presence of an allosteric binding site in human 5-LOX distinct from the ATP binding site. The activatory and inhibitory behavior of 23a and 23d on the conversion of linoleic compared to arachidonic acid are rationalized by docking studies, which suggest that the activator 23a stabilizes linoleic acid binding, whereas the larger inhibitor 23d blocks the enzyme active site.
Wisastra, Rosalina,Kok, Petra A.M.,Eleftheriadis, Nikolaos,Baumgartner, Matthew P.,Camacho, Carlos J.,Haisma, Hidde J.,Dekker, Frank J.
p. 7763 - 7778
(2014/01/06)

SOMATOSTATIN MIMETICS
Somatostatin is a tetradecapeptide that regulates, through binding to its receptors (SSTRs), a number of processes including the release of growth hormone and other pituitary hormones. Disclosed herein are a number of somatostatin mimetics that exhibit potential utility as therapeutic agents. Formula (I)
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(2012/10/18)

The scent of bacteria: Headspace analysis for the discovery of natural products
Volatile compounds released by 50 bacterial strains, 45 of them actinobacteria in addition to three chloroflexi and two myxobacteria, have been collected by use of a closed-loop stripping apparatus, and the obtained headspace extracts have been analyzed by GC-MS. Excluding terpenes that have recently been published elsewhere, 254 compounds from all kinds of compound classes have been identified. For unambiguous compound identification several reference compounds have been synthesized. Among the detected volatiles 12 new natural products have been found, in addition to mellein, which was released by Saccharopolyspora erythraea. The iterative PKS for this compound has recently been identified by in vitro experiments, but mellein production in S. erythraea has never been reported before. These examples demonstrate that headspace analysis is an important tool for the discovery of natural products that may be overlooked using conventional techniques. The method is also useful for feeding experiments with isotopically labeled precursors and was applied to investigate the biosynthesis of the unusual nitrogen compound 1-nitro-2-methylpropane, which arises from valine. Furthermore, several streptomycetes emitted compounds that were previously recognized as insect pheromones, thus questioning if bacterial symbionts are involved in insect communication.
Citron, Christian A.,Rabe, Patrick,Dickschat, Jeroen S.
supporting information
p. 1765 - 1776
(2013/01/15)

Towards a library of chromene cannabinoids: A combinatorial approach on solid supports
A novel solid-phase synthesis towards classical cannabinoids is presented. Starting from immobilized salicylaldehydes the desired THC-analogous tricycles are obtained in four atom-economic steps including cleavage. The reagents of the employed reactions (domino oxa-Michael-aldol, Wittig, and Diels-Alder) can be varied easily, providing the basis for a combinatorial approach. Overall yields range from 20-60%. Georg Thieme Verlag Stuttgart New York.
Kapeller, Dagmar C.,Br?se, Stefan
supporting information; experimental part
p. 161 - 164
(2011/03/19)

(R)-4-((4-((4-(TETRAHYDROFURAN-3-YLOXY)BENZO[D]ISOXAZOL-3-YLOXY)METHYL)PIPERIDIN-1-YL)METHYL)TETRAHYDRO-2H-PYRAN-4-OL, A PARTIAL AGONIST OF 5-HT4 RECEPTORS
(R)-4-((4-((4-(tetrahydrofuran-3-yloxy)benzo[d]isoxazol-3- yloxy)methyl)piperidin-1-yl)methyl)tetrahydro-2H-pyran-4-ol and its use in treating neurodegenerative disorders, is described herein.
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(2011/09/19)

Direct C-glycosylation of organotrifluoroborates with glycosyl fluorides and its application to the total synthesis of (+)-varitriol
A mild, stereoselective, and quick approach to accessing alkynyl and alkenyl C-glycosides via BF3?Et2O promoted coupling of organotrifluoroborates and glycosyl fluorides is reported. The application of this method was further demonstrated by the concise and efficient total synthesis of (+)-varitriol in only seven steps.
Zeng, Jing,Vedachalam, Seenuvasan,Xiang, Shaohua,Liu, Xue-Wei
supporting information; experimental part
p. 42 - 45
(2011/03/22)

Synthesis of a benzomacrolactone-based somatostatin mimetic
The benzomacrolactone is a framework found in numerous natural products. The synthesis of an orthogonally functionalized benzomacrolactone from d-glucosamine and a salicylic acid derivative is described. This macrolactone was used for the synthesis of a somatostatin mimetic that has submicromolar affinity for the human somatostatin receptor 4 (hSSTR4).
Zhou, Jian,Matos, Marie-Christine,Murphy, Paul V.
scheme or table
p. 5716 - 5719
(2011/12/05)

Development of a general, sequential, ring-closing metathesis/ intramolecular cross-coupling reaction for the synthesis of polyunsaturated macrolactones
A general strategy for the construction of macrocyclic lactones containing conjugated Z,Z-1,3-diene subunits is described. The centerpiece of the strategy is a sequential ring-closing metathesis (RCM) that forms an unsaturated siloxane ring, followed by an intramolecular cross-coupling reaction with a pendant alkenyl iodide. A highly modular assembly of the various precursors allowed the preparation of unsaturated macrolactones containing 11-, 12-, 13-, and 14-membered rings. Although the RCM process proceeded uneventfully, the intramolecular cross-coupling required extensive optimization of palladium source, solvent, fluoride source, and particularly fluoride hydration level. Under the optimal conditions (including syringe pump high dilution), the macrolactones were produced in 53-78% yield as single stereoisomers. A benzo-fused 12-membered-ring macrolactone containing an E,Z-1,3-diene unit was also prepared by the same general strategy. The E-2-styryl iodide was prepared by a novel Heck reaction of an aryl nonaflate with vinyltrimethylsilane followed by iododesilylation with ICl.
Denmark, Scott E.,Muhuhi, Joseck M.
scheme or table
p. 11768 - 11778
(2010/10/03)

Synthesis of a novel polyhydroxylated salicylic acid lactone framework
The facile preparation of a novel 8-membered polyhydroxylated salicylic acid lactone from 2,6-dihydroxybenzoic acid and sodium thio-D-glucose is described. The key step involved a sodium hydride promoted intramolecular lactonization in the presence of excess TMSCl, which led to isolation of the "natural product like" lactone.
Rountree, J. S. Shane,Murphy, Paul V.
supporting information; experimental part
p. 871 - 874
(2009/07/18)

A new synthesis of (-)-epipyriculol: a phytotoxic metabolite
A convenient synthesis of the phytotoxic natural product epipyriculol has been accomplished in 17 steps from methyl l-tartrate. The synthetic strategy is based upon the use of a butanediacetal-protected scaffold as central core from which the alkenyl side chains were assembled.
Leyva, Antonio,Blum, Francesca E.,Ley, Steven V.
p. 4711 - 4717
(2008/09/21)

Structure-activity relationships of semisynthetic mumbaistatin analogs
Mumbaistatin (1), a new anthraquinone natural product, is one of the most potent known inhibitors of hepatic glucose-6-phosphate translocase, an important target for the treatment of type II diabetes. Its availability, however, has been limited due to its extremely low yield from the natural source. Starting from DMAC (5, 3,8-dihydroxyanthraquinone-2-carboxylic acid), a structurally related polyketide product of engineered biosynthesis, we developed a facile semisynthetic method that afforded a variety of mumbaistatin analogs within five steps. This work was facilitated by the initial development of a DMAC overproduction system. In addition to reinforcing the biological significance of the anthraquinone moiety of mumbaistatin, several semisynthetic analogs were found to have low micromolar potency against the translocase in vitro. Two of them were also active in glucose release assays from primary hepatocytes. The synergistic combination of biosynthesis and synthesis is a promising avenue for the discovery of new bioactive substances.
Lee, Taek Soon,Das, Abhirup,Khosla, Chaitan
p. 5207 - 5218
(2008/03/13)

Regiocontrolled intramolecular cyclizations of carboxylic acids to carbon-carbon triple bonds promoted by acid or base catalyst
We systematically investigated, for the first time, the relationship between regioselectivity and acid/base effects in the cyclization reactions between carboxylic acids and carbon-carbon triple bonds. We found novel acid- and base-promoted cyclizations to selectively give isocoumarin or pyran-2(2H)-one and phthalide or furan-2(5H)-one skeletons, respectively, and established a catalytic version of regioselective heterocyclic ring synthesis. Density functional theory calculations and application to a short route to thunberginol A were also described.
Uchiyama, Masanobu,Ozawa, Hiroki,Takuma, Kazuya,Matsumoto, Yotaro,Yonehara, Mitsuhiro,Hiroya, Kou,Sakamoto, Takao
p. 5517 - 5520
(2007/10/03)

Efficient and selective reduction protocols of the 2,2-dimethyl-1,3- benzodioxan-4-one functional group to readily provide both substituted salicylaldehydes and 2-hydroxybenzyl alcohols
Two complementary procedures have been developed that selectively allow for the synthesis of either substituted salicylaldehydes or the corresponding 2-hydroxylbenzyl alcohols upon treatment of the 2,2-dimethyl-1,3-benzodioxan-4- one functional group with DIBAL-H or LAH, respectively.
Bajwa, Naval,Jennings, Michael P.
p. 3646 - 3649
(2007/10/03)

Stereoselective synthesis of (+)-SCH 351448: A unique ligand system for sodium, calcium, and other cations
(+)-SCH 351448 (Na+ salt A) was synthesized employing ring-closing olefin metathesis reaction of an open diene diester intermediate for construction of the 28-membered macrodiolide structure. The open diene diester was prepared from the monomeric hydroxy carboxylic acid and two different olefin fragments. The monomeric hydroxy acid was synthesized via Julia-Julia coupling reaction of intermediates derived from the same olefinic fragments. Oxane units in these fragments were prepared by radical cyclization reactions of β-alkoxyacrylates. Analogous SCH 351448 salts incorporating other mono- and divalent cations may be prepared. Under acidic conditions, SCH 351448 (Na+ salt A) was the most stable complex, but SCH 351448 (Ca2+ salt) and (Na+ salt B) appear to be physiologically important species.
Kang, Eun Joo,Cho, Eun Jin,Ji, Mi Kyung,Lee, Young Eun,Shin, Dong Mok,Choi, Soo Young,Chung, Young Keun,Kim, Jong-Seo,Kim, Hie-Joon,Lee, Sueg-Geun,Lah, Myoung Soo,Lee, Eun
p. 6321 - 6329
(2007/10/03)

Total synthesis of (-)-salicylihalamide.
A concise total synthesis of the potent cytotoxic marine natural products salicylihalamide A and B (la, b) is reported. Key steps of our approach were the asymmetric hydrogenation reactions of beta-keto esters 18 and 32 catalyzed by [((S)-BINAP)Ru-Cl2]2. NEt3 and the cyclization of the macrolide core by ring closing olefin metathesis (RCM) using the "second-generation" ruthenium carbene complex 24 as the catalyst which bears an imidazol-2-ylidene ligand. The EIZ ratio obtained in this macrocyclization reaction was determined by the protecting groups at the remote phenolic OH group of the cyclization precursor. The elaboration of the resulting cycloalkene 37 into the final target involved a CrCl2-mediated synthesis of vinyliodide 49 which, after deprotection, did undergo a copper-catalyzed cross-coupling process with the (Z,Z)-configurated carboxamide 42 to form the labile enamide moiety of 1. Compound 42 was derived from a palladium-catalyzed Negishi coupling between butynylzinc chloride and 3-iodoacrylate 39 followed by a Lindlar reduction of enyne 40 thus obtained and a final aminolysis of the ester group.
Fuerstner,Dierkes,Thiel,Blanda
p. 5286 - 5298
(2007/10/03)

Asymmetric synthesis of the fully functional macrolide core of salicylihalamide: remote control of olefin geometry during RCM.
A catalysis-based approach to the core region 24 of the antitumor agents salicylihalamides A and B is reported. Key steps are two asymmetric hydrogenations of beta-keto esters 13 and 16 catalyzed by [(R)-BINAP.RuCl(2)](2).NEt(3) and an RCM-based macrocyclization effected by the NHC-containing ruthenium carbene 21. The stereochemical outcome of the latter reaction is controlled by remote substituents on the phenolic OH group of the cyclization precursor 23.
Fuerstner,Thiel,Blanda
p. 3731 - 3734
(2007/10/03)

Substituted pyridylsalicylaldehyde or -salicylic acid derivatives, their preparation and their use as herbicides
Substituted pyridylsalicylaldehyde and --salicylic acid derivatives of the formula I STR1 where R is a formyl group, a CO2 H group or a radical which can be hydrolyzed to CO2 H and the other substituents have the following meanings: R2 is halogen, alkyl, haloalkyl, alkoxy, haloalkoxy or alkylthio; X is nitrogen or CR13, R13 being hydrogen or halogen or together with R3 forming a 3- to 4-membered alkylene or alkenylene chain in which at least one methylene group is replaced by oxygen; R3 is halogen, alkyl, haloalkyl, alkoxy, haloalkoxy or alkylthio, or R3 is linked with R13 as indicated above to give a 5- or 6-membered ring; Y is oxygen or sulfur; Py is a substituted pyridine ring, are described.
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(2008/06/13)

Pyridine-N-oxide-substituted salicylaldehyde or salicyclic acid derivatives, their preparation and their use as herbicides
Pyridine-N-oxide-substituted salicylaldehyde and salicylic acid derivatives of the general formula I STR1 where R is a formyl group, a CO2 H group or a radical which can be hydrolyzed to CO2 H and the other substituents have the following meanings: R2 is halogen, alkyl, haloalkyl, alkoxy, haloalkoxy or alkylthio; X is nitrogen or CR13, R13 being hydrogen or halogen or together with R3 forming a 3- to 4-membered alkylene or alkenylene chain in which at least one methylene group is replaced by oxygen; R3 is halogen, alkyl, haloalkyl, alkoxy, haloalkoxy or alkylthio, or R3 is linked with R13 as indicated above to give a 5- or 6-membered ring; Y is oxygen or sulfur; R14 -R17 are an unsubstituted or alkyl-substituted cycloalkyl group; an unsubstituted or substituted alkyl group; an unsubstituted or substituted alkoxy or alkylthio group; a dialkylamino group or a dialkylaminoxy group; an unsubstituted or substituted alkenyl or alkynyl group, hydrogen, halogen, nitro or cyano, are described.
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(2008/06/13)

Substituted 1,3-benzadioxane-4-ones and 1,3-benzathioxane-4-ones, their preparation and their conversion to crop protection agents
Cyclic acetals of the formula I STR1 where the substituents have the following meanings: R1 and R2 are hydrogen, unsubstituted or substituted alkyl or phenyl; additionally R1 and R2 together are an unsubstituted or substituted C2 -C6 -alkylene chain; Y is oxygen or sulfur; A has the meaning as given in claim 1; a process for preparing the acetals I and their use for the production of crop protection compositions are described.
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(2008/06/13)