- Design and Synthesis of Novel Macrocyclic Mer Tyrosine Kinase Inhibitors
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Mer tyrosine kinase (MerTK) is aberrantly elevated in various tumor cells and has a normal anti-inflammatory role in the innate immune system. Inhibition of MerTK may provide dual effects against these MerTK-expressing tumors through reducing cancer cell survival and redirecting the innate immune response. Recently, we have designed novel and potent macrocyclic pyrrolopyrimidines as MerTK inhibitors using a structure-based approach. The most active macrocycles had an EC50 below 40 nM in a cell-based MerTK phosphor-protein ELISA assay. The X-ray structure of macrocyclic analogue 3 complexed with MerTK was also resolved and demonstrated macrocycles binding in the ATP binding pocket of the MerTK protein as anticipated. In addition, the lead compound 16 (UNC3133) had a 1.6 h half-life and 16% oral bioavailability in a mouse PK study.
- Wang, Xiaodong,Liu, Jing,Zhang, Weihe,Stashko, Michael A.,Nichols, James,Miley, Michael J.,Norris-Drouin, Jacqueline,Chen, Zhilong,Machius, Mischa,DeRyckere, Deborah,Wood, Edgar,Graham, Douglas K.,Earp, H. Shelton,Kireev, Dmitri,Frye, Stephen V.
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Read Online
- Porphyrin-based design of bioinspired multitarget quadruplex ligands
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Secondary nucleic acid structures, such as DNA and RNA quadruplexes, are potential targets for cancer therapies. Ligands that interact with these targets could thus find application as anticancer agents. Synthetic G-quartets have recently found numerous applications, including use as bioinspired G-quadruplex ligands. Herein, the design, synthesis and preliminary biophysical evaluation of a new prototype multitarget G-quadruplex ligand, PNAPorphySQ, are reported, where peptidic nucleic acid guanine (PNAG) was incorporated in the porphyrin-templated synthetic G-quartet (PorphySQ). Using fluorescence resonance energy transfer (FRET)-melting experiments, PorphySQ was shown to possess enhanced quadruplex-interacting properties thanks to the presence of four positively charged PNAG residues that improve its electrostatic interactions with the binding site of both DNA and RNA quadruplexes (i.e., their negatively charged and accessible G-quartets), thereby making PNAPorphySQ an interesting prototype of a multitarget ligand. Both the chemical stability and water solubility of PNAPorphySQ are improved over the non-PNA derivative (PorphySQ), which are desirable properties for drug development, and while improvements remain to be made, this ligand is a promising lead for the further development of multitarget G-quadruplex ligands.
- Laguerre, Aurélien,Desbois, Nicolas,Stefan, Loic,Richard, Philippe,Gros, Claude P.,Monchaud, David
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Read Online
- A synthesis of (±)-stemoamide using the intramolecular propargylic Barbier reaction
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A diastereoselective synthesis of the alkaloid stemoamide has been achieved using the intramolecular propargylic Barbier reaction to construct the seven-membered ring. Georg Thieme Verlag Stuttgart.
- Bates, Roderick W.,Sridhar
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Read Online
- Intramolecular [4+1] pyrroline annulation approach to pyrrolizidine alkaloids. Formal total synthesis of (±)-supinidine
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Dienic azide was found to yield two dehydropyrrolizidines on thermolysis. The synthesis of these compounds is described and the mechanistic implications as well as synthetic utility of this new annulation sequence is discussed.
- Hudlicky,Frazier,Kwart
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Read Online
- Evidence That Trimethyllysine Hydroxylase Catalyzes the Formation of (2S,3S)-3-Hydroxy-Nε-trimethyllysine
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Trimethyllysine hydroxylase (TMLH) is an Fe(II) and 2-oxoglutarate (2OG) dependent oxygenase involved in the biomedically important carnitine biosynthesis pathway. A combination of synthetic and NMR studies provides direct evidence that human TMLH catalyzes the stereoselective conversion of (2S)-Nε-trimethyllysine to (2S,3S)-3-hydroxy-Nε-trimethyllysine.
- Reddy, Y. Vijayendar,Al Temimi, Abbas H. K.,White, Paul B.,Mecinovi?, Jasmin
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Read Online
- Palladium/Copper-catalyzed Oxidation of Aliphatic Terminal Alkenes to Aldehydes Assisted by p-Benzoquinone
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The development of an anti-Markovnikov Wacker-type oxidation for simple aliphatic alkenes is a significant challenge. Herein, a variety of aldehydes can be selectively obtained from various unbiased aliphatic terminal alkenes using PdCl2(MeCN)2/CuCl in the presence of p-benzoquinone (BQ) under mild reaction conditions. Isomerization of the terminal alkene to the internal alkene was suppressed via slow addition of the starting material to the reaction mixture. In addition to the Pd catalyst, CuCl and BQ were essential in order to obtain the anti-Markovnikov product with high selectivity. Terminal alkenes bearing a halogen substituent afforded their corresponding aldehydes with high anti-Markovnikov selectivity. The halogen acts as a directing group in the reaction. DFT calculations indicate that a μ-chloro Pd(II)?Cu(I) bimetallic species with BQ coordinated to Cu is the catalytically active species in the case of a terminal alkene without a directing group.
- Komori, Saki,Yamaguchi, Yoshiko,Murakami, Yuka,Kataoka, Yasutaka,Ura, Yasuyuki
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p. 3946 - 3955
(2020/07/06)
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- 2-(1-bromocyclobutyl) pyridine and synthesis method thereof
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The invention belongs to the technical field of organic synthesis, and relates to 2- (1-bromocyclobutyl) pyridine and a synthesis method thereof. The 2 -(-1bromocyclobutyl) pyridine can be used as a medical intermediate, and the synthetic method of the compound comprises the following steps: by taking tetrahydropyrane- 2-ketone as a raw material, carrying out nine steps of reactions including substitution, ring closing, hydrolysis, substitution, substitution, reduction, grignard, substitution and substitution to prepare the 2- (-1bromocyclobutyl) pyridine, so that the synthetic route is simple, the cost is low, and the efficiency is high.
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Paragraph 0008; 0029; 0040-0041; 0048; 0059-0060; 0067
(2020/11/23)
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- Palladium-Catalyzed Aerobic Anti-Markovnikov Oxidation of Aliphatic Alkenes to Terminal Acetals
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Terminal acetals were selectively synthesized from various unbiased aliphatic terminal alkenes and 1,2-, 1,3-, or 1,4-diols using a PdCl2(MeCN)2/CuCl catalyst system in the presence of p-toluquinone under 1 atm of O2 and mild reaction conditions. The slow addition of terminal alkenes suppressed the isomerization to internal alkenes successfully. Electron-deficient cyclic alkenes, such as p-toluquinone, were key additives to enhance the catalytic activity and the anti-Markovnikov selectivity. The halogen groups in the alkenes were found to operate as directing groups, suppressing isomerization and increasing the selectivity efficiently.
- Komori, Saki,Yamaguchi, Yoshiko,Kataoka, Yasutaka,Ura, Yasuyuki
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p. 3093 - 3099
(2019/03/29)
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- Fe(III)-Catalyzed Aerobic Intramolecular N-N Coupling of Aliphatic Azides with Amines
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An Fe(III)-catalyzed intramolecular N-N coupling of aliphatic azidoamines that forms diverse five- and six-membered semisaturated diazoheterocycles using air as an oxidant is reported, providing an alternative to hydrazine-based methods. Mechanistic studies suggest that a N-radical induced intramolecular homolytic substitution (SH2) is involved in ring closure. The power of this N-N bond-forming method is also demonstrated by using it as the final step in a total synthesis of (-)-newbouldine.
- Zhang, Yue,Duan, Dongyu,Zhong, Ying,Guo, Xin-Ai,Guo, Jiawei,Gou, Jing,Gao, Ziwei,Yu, Binxun
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supporting information
p. 4960 - 4965
(2019/09/03)
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- Synthesis method of 5-fluoro-2-(1-bromocyclopropyl) pyridine
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The invention relates to a synthesis method of 5-fluoro-2-(1-bromocyclopropyl) pyridine. 1,4-butyrolactone, ethyl 4-bromobutyrate and 5-fluoro-2-mercaptopyridine are used as raw materials to prepare 5-fluoro-2-(1-bromocyclopropyl) pyridine through eleven steps of reaction. A synthetic route of the 5-fluoro-2-(1-bromocyclopropyl) pyridine is as follows: (as described in the specification). The invention has the advantages that the synthesis method of 5-fluoro-2-(1-bromocyclopropyl) pyridine improves the yield and provides an efficient synthesis method for the synthesis of the compound.
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Paragraph 0005; 0016; 0022; 0027; 0033; 0038; 0044
(2019/08/01)
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- An Intramolecular Cycloaddition Approach to the Kauranoid Family of Diterpene Metabolites
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Synthetic studies toward the ent-kauranoid family of diterpene natural products are reported. An intramolecular (4 + 3) cycloaddition allows the direct elaboration of diverse natural product frameworks, encompassing a challenging bicyclo[3.2.1]octane core. The established routes comprise only a few synthetic operations (3-5 steps), transforming a range of simple starting materials into the tetracyclic scaffolds that are commonly found in many ent-kaurene metabolites.
- Callebaut, Brenda,Hullaert, Jan,Van Hecke, Kristof,Winne, Johan M.
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supporting information
p. 310 - 314
(2019/01/10)
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- Transition-Metal-Free Access to Heteroaromatic-Fused 4-Tetralones by the Oxidative Ring Expansion of the Cyclobutanol Moiety
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Advances in the transition-metal-free cyclobutanol ring expansion to 4-tetralones under N-bromosuccinimide mediation are described. We have expanded the scope of this ring expansion methodology and investigated the effect substituents on the aromatic ring, and the cyclobutanol moiety, have on the outcome of the reaction. Limitations with certain substituents on the cyclobutanol moiety are also described. Further experimental evidence to support our mechanistic understanding is disclosed, and we now preclude the suggested involvement of a primary radical for this transformation.
- Natho, Philipp,Allen, Lewis A. T.,White, Andrew J. P.,Parsons, Philip J.
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p. 9611 - 9626
(2019/08/16)
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- Labeling and Natural Post-Translational Modification of Peptides and Proteins via Chemoselective Pd-Catalyzed Prenylation of Cysteine
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The prenylation of peptides and proteins is an important post-translational modification observed in vivo. We report that the Pd-catalyzed Tsuji-Trost allylation with a Pd/BIPHEPHOS catalyst system allows the allylation of Cys-containing peptides and proteins with complete chemoselectivity and high n/i regioselectivity. In contrast to recently established methods, which use non-native connections, the Pd-catalyzed prenylation produces the natural n-prenylthioether bond. In addition, a variety of biophysical probes such as affinity handles and fluorescent tags can be introduced into Cys-containing peptides and proteins. Furthermore, peptides containing two cysteine residues can be stapled or cyclized using homobifunctional allylic carbonate reagents.
- Schlatzer, Thomas,Kriegesmann, Julia,Schr?der, Hilmar,Trobe, Melanie,Lembacher-Fadum, Christian,Santner, Simone,Kravchuk, Alexander V.,Becker, Christian F. W.,Breinbauer, Rolf
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supporting information
p. 14931 - 14937
(2019/10/11)
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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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p. 7240 - 7244
(2018/06/15)
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- Mechanistic Studies on the Organocatalytic α-Chlorination of Aldehydes: The Role and Nature of Off-Cycle Intermediates
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Herein we report the isolation and characterization of aminal intermediates in the organocatalytic α-chlorination of aldehydes. These species are stable covalent ternary adducts of the substrate, the catalyst and the chlorinating reagent. NMR-assisted kinetic studies and isotopic labeling experiments with the isolated intermediate did not support its involvement in downstream stereoselective processes as proposed by Blackmond. By tuning the reactivity of the chlorinating reagent, we were able to suppress the accumulation of rate-limiting off-cycle intermediates. As a result, an efficient and highly enantioselective catalytic system with a broad functional group tolerance was developed.
- Ponath, Sebastian,Menger, Martina,Grothues, Lydia,Weber, Manuela,Lentz, Dieter,Strohmann, Carsten,Christmann, Mathias
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supporting information
p. 11683 - 11687
(2018/09/10)
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- Diastereoselective synthesis of 2-vinylpyrrolidines and 2-vinylpiperidines by the palladium-catalysed cyclization of amino-allylic carbonates containing a chiral protecting group
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An efficient diastereoselective synthesis of pyrrolidine-and piperidine-type N-heterocycles is reported, by the intramolecular Pd(0)-catalysed cyclization of amino carbonates containing chiral protecting group. The use of chiral auxiliary in the cyclization gave the corresponding heterocyclic derivatives in excellent yields and with good dr values.
- Olszewska, Beata,Jablonska, Aleksandra,Zawisza, Anna
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p. 254 - 271
(2018/09/10)
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- Pharmaceutical composition for use in preventing or treating poly(ADP-ribose)polymerase-1 related diseases containing the same as an active ingredient
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The present invention relates to a novel compound, a method for manufacturing the same, and a pharmaceutical composition for preventing or treating poly(ADP-ribose)polymerase-1 (PARP-1) related diseases containing the compound as an active ingredient. The novel PARP-1 inhibitory compound according to the present invention exhibits an excellent PARP-1 inhibitory effect at a concentration of nanomol unit and further exhibits an excellent cytoprotective effect (cell death inhibitory effect) on ophthalmic diseases or disorders, especially on retinal diseases. The composition containing the compound as an active ingredient is useful as a composition for preventing or treating PARP-1 related diseases, for example, ophthalmic diseases or disorders.(AA) Example 37(BB) Example 39COPYRIGHT KIPO 2018
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Paragraph 0675; 0677-0679
(2018/06/29)
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- Unified Total Synthesis of Stemoamide-Type Alkaloids by Chemoselective Assembly of Five-Membered Building Blocks
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A unified total synthesis of stemoamide-type alkaloids is reported. Our synthetic approach features the chemoselective convergent assembly of five-membered building blocks via stemoamide as the common precursor to tetracyclic natural products. The synthesis consists of two successive coupling reactions of the three five-membered building blocks. The first coupling reaction is the vinylogous Michael addition/reduction sequence, which enables the gram-scale synthesis of stemoamide. The second coupling reaction is a chemoselective nucleophilic addition to stemoamide. While the lactone-selective nucleophilic addition to stemoamide affords saxorumamide and isosaxorumamide, the lactam-selective reductive nucleophilic addition leads to the formation of stemonine. Both chemoselective nucleophilic additions enable direct modification of stemoamide, resulting in highly concise and efficient total syntheses of the stemoamide-type alkaloids.
- Yoritate, Makoto,Takahashi, Yoshito,Tajima, Hayato,Ogihara, Chisato,Yokoyama, Takashi,Soda, Yasuki,Oishi, Takeshi,Sato, Takaaki,Chida, Noritaka
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supporting information
p. 18386 - 18391
(2017/12/15)
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- Visible-Light-Promoted Oxidative [4 + 2] Cycloadditions of Aryl Silyl Enol Ethers
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Visible-light-promoted oxidative [4 + 2] cycloadditions of μ,3-unsaturated silyl enol ethers have been developed to efficiently and diastereoselectively construct polycyclic skeletons under mild conditions. The diastereoselectivities were dependent on the stereoconfiguration of silyl enol ether, substitutions on the link, as well as electric properties of substitutions on aryl rings. The intermediates could be trapped by TEMPO, oxygen or methanol. Mechanistic studies indicated the reaction was initiated by one-electron oxidation of the silyl enol ether.
- Yang, Bo,Lu, Zhan
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p. 7288 - 7300
(2016/08/30)
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- Materials and complexes for the delivery of biologically-active materials to cells
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The invention provides a peptide derivative of formula A-B-C wherein A is a polycationic nucleic acid-binding component;B is a spacer element peptide that is susceptible to cleavage within a cell; andC is a cell surface receptor binding component. The invention also provides a lipid derivative of general formula (I): [in-line-formulae](PEG)q-Linker-Spacer-Cationic headgroup-carbon skeleton-(hydrophobic chain)o [/in-line-formulae] wherein: the Linker is a group susceptible to cleavage within a cell;the Spacer is a group linking the Linker to the Cationic headgroup;q denotes the number of PEG chains and q=1, 2 or 3;o denotes the number of hydrophobic chains and o=1, 2 or 3;the carbon skeleton is a group linking the hydrophobic chains to the cationic headgroup. The peptide and lipid derivatives find use in non-viral gene delivery systems.
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Page/Page column 37; 38; 39; 40
(2017/01/12)
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- Total syntheses of (±)-gephyrotoxin and (±)-perhydrogephyrotoxin
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This article describes the full details of our total syntheses of gephyrotoxin and perhydrogephyrotoxin. Our central strategy toward the total synthesis is based on the use of an N-methoxy group as a reactivity control element. The N-methoxyamide group enabled unique transformations, involving i) the direct coupling reaction of the N-methoxyamide with an aldehyde, and ii) the amide-selective reductive allylation. These reactions were never accomplished without the assistance of the N-methoxy group. The amide-selective reductive allylation of the N-methoxyamide was especially practical, and excluded a number of extra steps including protecting group manipulations and redox reactions in the total syntheses.
- Shirokane, Kenji,Tanaka, Yuya,Yoritate, Makoto,Takayama, Nobuaki,Sato, Takaaki,Chida, Noritaka
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p. 522 - 537
(2015/06/17)
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- Total synthesis of (±)-gephyrotoxin by amide-selective reductive nucleophilic addition
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A chemoselective approach for the total synthesis of (±)- gephyrotoxin has been developed. The key to success was the utilization of N-methoxyamides, which enabled the direct coupling of the amide with an aldehyde and selective reductive nucleophilic addition to the amide in the presence of a variety of sensitive and electrophilic functional groups, such as a methyl ester. This chemoselective approach minimized the use of protecting-group manipulations and redox reactions, which resulted in the most concise and efficient total synthesis of (±)-gephyrotoxin described to date. Aim for selectivity: A chemoselective approach that utilizes N-methoxyamides has been developed for the total synthesis of (±)-gephyrotoxin. The N-methoxy group enabled the direct coupling of the amide with an aldehyde and amide-selective reductive allylation in the presence of a more electrophilic methyl ester, which resulted in the most concise and efficient total synthesis of (±)-gephyrotoxin described to date.
- Shirokane, Kenji,Wada, Takamasa,Yoritate, Makoto,Minamikawa, Ryo,Takayama, Nobuaki,Sato, Takaaki,Chida, Noritaka
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supporting information
p. 512 - 516
(2014/01/23)
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- Enantioselective synthesis of N-heterocycles via intramolecular Pd(0)-catalysed allylic amination
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An efficient and stereoselective synthesis of pyrrolidine-, piperidine-, and azepane-type N-heterocycles is described by the intramolecular Pd(0)-catalysed cyclisation of amino allylic carbonates. The use of chiral ligands gave the corresponding heterocyclic derivatives having er values that were from moderate to good.
- Olszewska, Beata,Kryczka, Bogus?aw,Zawisza, Anna
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p. 9551 - 9556
(2013/10/22)
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- Total synthesis and structural revision of the alkaloid IncargranineB
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Seeing double: Consideration of the biosynthetic origins of incargranineB, which was originally assigned an unprecedented indolo[1.7]naphthyridine structure, led to the proposal of a dipyrroloquinoline framework as a more biosynthetically feasible structure (see scheme; Piv=pivaloyl). This hypothesis was validated by a short biomimetic synthesis of incargranineB.
- Brown, Patrick D.,Willis, Anthony C.,Sherburn, Michael S.,Lawrence, Andrew L.
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supporting information
p. 13273 - 13275
(2014/01/06)
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- A photocleavable linker for the chemoselective functionalization of biomaterials
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The functionalization of matrices with "caged" functional groups and their subsequent selective uncaging is a promising approach for generating patterns of bioactive molecules to guide cell growth or recreate in vivo microarchitectures. To date, this has been limited to caged carboxylic acids, amines and thiols, functional groups found within biological systems. We present a bifunctional caged carbonyl linker as an alternative approach for the chemoselective functionalization of biomaterials. This linker was readily coupled to collagen, employed as a model biomaterial, and underwent rapid uncaging in aqueous media upon irradiation with ultraviolet light to yield free carbonyl groups. Modified surfaces proved to be non-adhesive to cells until the chemoselective reintroduction of adhesion following incubation of uncaged carbonyls with gelatin hydrazide, with native gelatin failing to elicit a cellular response.
- O'Donovan, Liz,De Bank, Paul A.
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supporting information
p. 21878 - 21884,7
(2020/09/02)
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- Synthesis of hydroxy-α-sanshool
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The amide hydroxy-α-sanshool is responsible for the mild numbing sensation experienced when Sichuan (or Szechuan) peppercorns (huajiao) are eaten. It has been synthesized in six steps from simple commercially available starting materials using Wittig reactions as the key transformations for construction of the carbon skeleton. The penultimate synthetic intermediate was 2E,6Z,8E,10E-dodecatetraenoic acid, and its crystalline nature allowed it, and thus hydroxy-α-sanshool, to be purified to a very high level of stereochemical homogeneity.
- Wu, Bo,Li, Kun,Toy, Patrick H.
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supporting information
p. 2564 - 2566,3
(2012/12/11)
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- Viability of 4,5-dihydro-1,2,3,4-oxatriazoles reinvestigated
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The first procedures to prepare 4-bromo-4-methylpentanal and 4-azido-4-methylpentanal are reported. The latter compound and also the parent 4-azidobutanal do not lead to 4,5-dihydro-1,2,3,4-oxatriazoles by intramolecular 1,3-dipolar cycloaddition, although it was claimed to be so in the literature. The NMR spectroscopic data of such heterocycles reported previously do not agree with those of similar substances and are incompatible with 13C NMR spectroscopic chemical shifts calculated by quantum chemical methods in the presented work. These calculations show furthermore that the intramolecular cycloaddition of 4-azidobutanals to give the title compounds is strongly endothermic and thus most probably not possible.
- Firdous, Samia,Banert, Klaus,Auer, Alexander A.
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experimental part
p. 5539 - 5543
(2011/06/21)
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- Chemoenzymatic synthesis of phosphonic acid analogues of L-lysine, L-proline, L-ornithine, and L-pipecolic acid of 99 % ee - Assignment of absolute configuration to (-)-proline
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(±)-ω-Halo-α-(chloroacetoxy)phosphonates were kinetically resolved by use of a protease (Chirazyme P-2). The esters recovered at levels of conversion between 56 and 72 % furnished (S)-alcohols of 99 % ee. These were converted via azides into the phosphonic acid analogues of L-lysine, L-proline, L-ornithine and L-pipecolic acid. (-)-Phosphaproline was transformed into crystalline ureas derived from (R)- and (S)-1-phenylethyl isocyanate. X-ray structure analyses revealed that the levorotary phosphaproline has the R configuration, contrary to earlier reports. Copyright
- Wuggenig, Frank,Schweifer, Anna,Mereiter, Kurt,Hammerschmidt, Friedrich
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scheme or table
p. 1870 - 1879
(2011/05/05)
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- An approach to lauroxanes by iterative use of Co2(CO) 6-acetylenic complexes. A formal synthesis of (+)-laurencin
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A new approach to lauroxanes by a powerful and highly convergent methodology based on iterative use of Co2(CO)6-acetylenic complexes is described. The strategy employs an intermolecular Nicholas reaction to form unsaturated branched linear ethers, a ring closing metathesis to obtain the cobalt complex cyclic ethers, and an isomerization promoted by montmorillonite K-10. A short synthesis of cyclic ethers of seven-, eight-, and nine-membered rings is described. Additionally, the methodology is exemplified by the formal synthesis of (+)-laurencin, a red algae metabolite.
- Ortega, Nuria,Martin, Victor S.,Martin, Tomas
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experimental part
p. 6660 - 6672
(2010/12/19)
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- Formation of carbocycles by intramolecular conjugate displacement: Scopeand mechanistic insights
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A detailed study has been made of a method of ring closure categorized as an all-carbon intramolecular conjugate displacement (ICD). This reaction involves intramolecular addition of a carbanion, which is stabilized by at least one electron-withdrawing group, to a Michael acceptor which has a leaving group in an allylic position. The process formally resembles a combination of Michael addition and S N2' displacement. The overall result is formation of a ring with loss of the allylic leaving group and shift of the original double bond to a new location spanning the positions of the electron-withdrawing substituent of the Michael acceptor subunit and the original allylic leaving group. The starting materials are easily prepared by a selenium-based version of the Morita-Baylis-Hillman reaction. The cyclizations are transition metal free and occur under mild conditions, using DBU or Cs 2CO 3 inMeCN or THF. Acetate is a suitable leaving group and the electron-withd rawing substituent of the Michael acceptor unit can be CO 2R,SO 2Ph, or CN. Six- and seven-membered rings are formed effi ciently, and complex structures, such as those resembling the core of CP-225,917, are easily assembled. The products of these ICD reactions are themselves classical Michael acceptors. A range of mechanisms probably operates, depending on the structure of the starting material and the reaction conditions, but conclusive evidence for a stepwise mechanism was obtained in a suitably biased case, while other observations are compatible with a concerted process or a stepwise path involving a short-lived carbanion that evades capture by a proton source.
- Wang, Lihong,Prabhudas, Bodhuri,Clive, Derrick L. J.
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supporting information; experimental part
p. 6003 - 6012
(2009/09/25)
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- Umpolung of Michael acceptors catalyzed by N-heterocyclic carbenes
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N-Heterocyclic carbenes can catalyze β-alkylations of a range of α,β-unsaturated esters, amides, and nitriles that bear pendant leaving groups to form a variety of ring sizes. In this process, the nucleophilic catalyst transiently transforms the normally electrophilic β carbon into a nucleophilic site through an unanticipated addition-tautomerization sequence. Copyright
- Fischer, Christian,Smith, Sean W.,Powell, David A.,Fu, Gregory C.
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p. 1472 - 1473
(2007/10/03)
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- Enantioselective Synthesis of Bicyclo[6.1.0]nonane-9-carboxylic Acids via Me2AlOTf-Promoted Intramolecular Friedel-Crafts Alkylation of Arenes with the γ-Lactone Moiety of 3-Oxabicyclo[3.1.0]hexan-2-ones
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A strategy to rapidly assemble enantiomerically pure bicyclo [6.1.0]nonane-9-carboxylic acids via Me2AlOTf-promoted intramolecular Friedel-Crafts alkylation of tethered π-nucleophiles with the γ-lactone moiety of 3-oxabicyclo-[3.1.0]hexan-2-ones is described. The approach begins with the enantioselective synthesis of 3-oxabicyclo[3.1.0]hexan-2-ones bearing a tethered π-nucleophile at the 6-position by intramolecular Rh(II)-catalyzed cyclopropanation of allylic diazoacetates, prepared from the corresponding (Z)-allylic alcohols. Me 2AlOTf-induced intramolecular Friedel-Crafts cyclization provides medium-sized carbocycles and heterocycles in high yields without requiring high-dilution or slow substrate addition techniques. The scope and limitations of this synthetic methodology are presented.
- Fillion, Eric,Beingessner, Rachel L.
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p. 9485 - 9488
(2007/10/03)
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- Asymmetric synthesis and structural assignment of (-)-α-conhydrine
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The first asymmetric synthesis of the conium alkaloid (-)-α-conhydrine is reported. Starting from a protected glycol aldehyde hydrazone as chiral precusor, a short route based on our α-alkylation/1,2-addition methodology has been developed. After cleavage of the auxiliary and simultaneous deprotection, the concluding ring closure is accomplished under reductive amination conditions. The title compound is obtained in moderate overall yield and in excellent diastereo- and enantiomeric excess (d.e., e.e. >96%). Single-crystal X-ray crystallography as well as 1H NMR NOE experiments confirm the expected relative and absolute (2R,7S)-configuration of the product.
- Enders, Dieter,Nolte, Bert,Raabe, Gerhard,Runsink, Jan
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p. 285 - 291
(2007/10/03)
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- Palladium-catalyzed sequential alkylation - Alkenylation reactions and their application to the synthesis of fused aromatic rings
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The synthesis of fused aromatic carbocycles from aryl iodides and difunctional acceptors is outlined. This methodology is based on a palladium-catalyzed aromatic substitution followed by an intramolecular Heck sequence. Under the optimized conditions (Pd(OAc)2 (10 mol %), tri-2-furylphosphine (20-30 mol %), norbornene (2 equiv), Cs2CO3 (2 equiv), CH3CN, reflux), bromoenoates react with aryl iodides bearing numerous substituents (F, Cl, CF3, Me, etc.). The expanded description of our initial work as well as the use of polysubstituted aryl iodides is described.
- Lautens, Mark,Paquin, Jean-Francois,Piguel, Sandrine,Dahlmann, Marc
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p. 8127 - 8134
(2007/10/03)
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- Asymmetric Induction in the Michael Initiated Ring Closure Reaction
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The Michael Initiated Ring Closure reaction has been explored with an eye toward achieving asymmetric induction.The formation of three, five and six-membered rings was examined using compounds 1-7 as substrates.In the case of cyclopropane formation, diastereoselectivity was studied over a range of temperatures, the best results being obtained between -68 and -72 degC using lithium t-butylthiolate as the nucleophile and a 10-dicyclohexylsulfamoyl-D-isoborneol-derived auxiliary (72-78percent yield, 50-56percent de; note equation 5).An isokinetic point is believed to occur between -41 and -68 degC.No improvement in de was observed when the Oppolzer sultam was used instead (compound 18).The use of (-)-menthol and (-)-8-phenylmenthol derived auxiliaries led to substantially inferior results (2-6percent de).Five and six-membered rings were formed in good to excellent yields (62-97percent) with diastereomeric excesses reaching as high as 95percent in the case of cyclohexyl ester formation, using lithium diisopropylamide as the nucleophile and the 10-dicyclohexylsulfamoyl-D-isoborneol-derived auxiliary.Note equations 7 and 8.As expected, cyclization affording the five-membered ring adducts proceeded substantially faster than those leading to the six.By conducting both reactions at low temperature, one can use this rate difference to assess the diastrereomeric excess obtained in the conjugate addition of LDA to the six-membered ring precursor 7.The de obtained in this manner (ca. 95percent) agreed within experimental error with that obtained when the reaction was conducted at a temperature where cyclization occurred.
- Amputch, Mary A.,Matamoros, Regina,Little, R. Daniel
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p. 5591 - 5614
(2007/10/02)
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- Intramolecular Photocycloadditions of 1-(ω-Alkenyl)-2-pyridones Possessing an Ester Group on the Olefinic Carbon Chain
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Photochemical reactions of three kinds of 1-(ω-alkenyl)-2-pyridones 1-8 were investigated.Photosensitized cyloadditions of 1-(ω-alkenyl)-2-pyridones and 1,3-bis(ω-alkenyl)-2-pyridone 2-6 afforded intramolecular cycloadducts across the 5,6-bonds of the 2-pyridones to give the tricyclic lactams 14-18: the additions were site-, regio-, and stereospecific.The yields of the adducts diminished in proportion to increased side-chain length.The one possessing the shortest alkenyl group, 1, and the 1--2-pyridones 7 and 8, however, gave no products.On the other hand, direct irradiation of 3 afforded a bicyclic lactam 19.The intramolecular cycloaddition mechanism was discussed in terms of the excited state of 2-pyridone, as calculated by MNDO-CI method.
- Somekawa, Kenichi,Okuhira, Hiroyuki,Sendayama, Masayuki,Suishu, Takaaki,Shimo, Tetsuro
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p. 5708 - 5712
(2007/10/02)
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- Regiochemistry of the Intramolecular Photocycloaddition of Enones to Vinyl Ethers as a Function of Chain Length
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The intramolecular cycloaddition of a cyclohexenone moiety bound to a vinyl ether fragment has been explored.The regiochemistry and the quantum yield of the reaction has been investigated as a function of the chain length n and the position of the methoxy group.It has been found that in those cases where the chain consists of three and four members the position of the methoxy group has no influence on the regiochemistry but on the quantum yield.Only head-to-head cycloaddition is observed.In the case of n = 2 both the regiochemistry and the quantum yield depend strongly on the position of the methoxy group.It is concluded that the main reason for the different behavior of n = 2 is due to a through-bond effect between the two olefinic units mediated by a C2H4 bridge. Key Words: Rule of five / Photocycloaddition / Regiochemistry / Enones / Vinyl ethers
- Gleiter, Rolf,Fischer, Evelyn
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p. 1899 - 1912
(2007/10/02)
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- Studies related to fatty acid desaturation. Part I: Preparation of methyl-substituted nonanols, nonyl bromides and total synthesis of new branched oleic acids
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Convenient pathways for the synthesis of seven structurally defined isomers of methyl-nonanols and methyl-nonylbromides are described.These synthons are used to perform Wittig reactions between convenient phosphoranes and aldehydes in order to obtain seven new octadecenoic acids bearing a methyl grouping on carbons 11 to 17. branched nonan-1-ols / branched 1-nonylbromides / Wittig reactions / methyl 9-bromononanoate / methyl 8-formyloctanoate / methyl 11 or 17-methyloctadec-9-enoates
- Genard, S.,Patin, H.
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p. 397 - 406
(2007/10/02)
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- A novel cyclization reaction of a C-6 substituted uridine analog: An entry to 5,6-dialkylated uridine derivatives
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5,6-Dialkylated uridine derivatives were conveniently synthesized in 5 steps starting from 2',3'-O-isopropylideneuridine (1) in a 43% overall yield. The key reaction is a novel acid catalyzed cyclization reaction of 6-(4-butanal)-2',3'-O-isopropylideneuridine.
- Wang,Kagel,Rao,Mertes
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p. 7005 - 7008
(2007/10/02)
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- SYNTHESES OF PROSTAGLANDIN AND LEUKOTRIENE C7 SYNTHONS THROUGH COMMON INTERMEDIATE COMPOUNDS
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A method is proposed for the production of the C7-synthons used in the synthesis of eicosanoids (the methyl esters of 7-hydroxy-5Z-heptenoic and 6-formyl-5,6-trans-epoxyhexanoic acids) by a common scheme from readily obtainable tetrahydrofuran and propargyl alcohol.
- Bobrova, N. I.,Belosludtsev, Yu. Yu.,Pivnitskii, K. K.
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p. 1873 - 1878
(2007/10/02)
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- Chiral Construction of the Estrane Ring System by an Intramolecular Double Michael Reaction
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Construction of the estrane ring system was achieved by the intramolecular double Michael reaction as the key step.Heating of the α,β-unsaturated enone ester (18), prepared from the optically active indanone (4), with chlorotrimethylsilane, triethylamine, and zinc chloride produced three estrane derivatives (19), (22), and (25).
- Ihara, Masataka,Takahashi, Takako,Shimizu, Noriko,Ishida, Yohhei,Sudow, Izumi,et al.
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p. 529 - 535
(2007/10/02)
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- INTRAMOLECULAR DIELS-ALDER REACTION OF THIOALDEHYDES
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Intramolecular Diels-Alder reaction of thioaldehydes which were generated from bis(trimethylsilyl)sulfide and dienals gave the corresponding bicyclic adducts.
- Segi, Masahito,Takahashi, Mamoru,Nakajima, Tadashi,Suga, Sohei,Sonoda, Noboru
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p. 2431 - 2440
(2007/10/02)
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- FACILE REDUCTION OF ACID CHLORIDES INTO ALDEHYDES USING HYPERVALENT SILICON HYDRIDES.
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Acyl chlorides have been reduced to aldehydes by a simple exchange reaction with pentacoordinated silicon hydrides
- Corriu, R. J. P.,Lanneau, G. F.,Perrot, M.
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p. 1271 - 1274
(2007/10/02)
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- STEREOCONTROLLED TOTAL SYNTHESIS OF (+/-)-NORPATCHOULENOL AND TWO METABOLITES OF PATCHOULI ALCOHOL, (+/-)-HYDROXY PATCHOULI ALCOHOL AND THE CORRESPONDING (+/-)-CARBOXYLIC ACID
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The first total synthesis of the two biooxidation products of patchouli alcohol (2), (+/-)-hydroxy patchouli alcohol (3) and the corresponding (+/-)-carboxylic acid 4, has been achieved in highly stereocontrolled manners.Synthesis of (+/-)-norpatchoulenol (1), the real odoriferous substance of patchouli oil, has been accomplished by the biogenetic route via (+/-)-3 and (+/-)-4.
- Niwa, Haruki,Hasegawa, Takashi,Ban, Norikazu,Yamada, Kiyoyuki
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p. 825 - 834
(2007/10/02)
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- Titanium Oxide-Supported Carbonylmolybdenum Catalyst in Liquid Phase: Application to Allylic Alkylation of Methyl p-Tolylsulfonylacetate
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Titanium oxide-supported carbonylmolybdenum catalyst was applied to selective monoallylation of methyl p-tolylsulfonylacetate using allylic acetates or carbonates in refluxing dioxane.This reaction required both 2,2'-bipyridyl as a ligind and sodium hydride as a base for preparation of the salt of methyl p-tolylsulfonylacetate.
- Masuyama, Yoshiro,Mitsunaga, Yutaka,Kurusu, Yasuhiko,Segawa, Koh-ichi
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p. 3431 - 3432
(2007/10/02)
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- Selective reduction of acyl chlorides to aldehydes by anionic 6B transition-metal hydrides
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Acyl chlorides can be selectively and rapidly reduced, under mild conditions, by group 6B anionic hydrides, HM(CO)4L- (M = Cr, W; L = CO, PR3), giving the corresponding aldehydes and the metal chlorides CIM(CO)4L-. The reaction is nearly quantitative for both aliphatic and aromatic acyl chlorides using solvent systems such as dichloromethane, tetrahydrofuran, or acetonitrile. Only in the presence of acid will the aldehydes consume a second equivalent of hydride, subsequently being reduced to alcohols. The anionic hydrides selectively reduce acyl chlorides in the presence of other reducible groups such as alkyl bromides or nitro aromatics. In situ preexchange of hydrogen by deuterium (HM(CO)4L-/ CH3OD → DM(CO)4L-/CH3OH) allows for deuterium delivery, giving RCDO products, as indicated by 2H NMR.
- Kao,Gaus, Paul L.,Youngdahl, Kay,Darensbourg, Marcetta Y.
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p. 1601 - 1603
(2008/10/08)
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- STEREOCONTROLLED TOTAL SYNTHESIS OF (+/-)-HYDROXY PATCHOULI ALCOHOL AND THE CORRESPONDING (+/-)-CARBOXYLIC ACID, METABOLITES OF PATCHOULI ALCOHOL, AND (+/-)-NORPATCHOULENOL
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The first total synthesis of (+/-)-hydroxy patchouli alcohol (3) and the corresponding (+/-)-carboxylic acid 4, the biooxidation products of patchouli alcohol (2) has been achieved. (+/-)-Norpatchoulenol (1) has also been synthesized by the biogenetic route via 3 and 4.
- Niwa, Haruki,Hasegawa, Takashi,Ban, Norikazu,Yamada, Kiyoyuki
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p. 2797 - 2800
(2007/10/02)
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- CLEAVAGE OF CYCLIC ETHERS WITH BORON BROMIDE. A CONVENIENT ROUTE TO THE BROMOSUBSTITUTED ALCOHOLS, ALDEHYDES AND KETONES
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Cyclic ethers are readily cleaved by BBr3 under mild conditions, providing the corresponding ω-bromoalkylborates (1).Redistribution of 1 with methanol affords ω-bromoalcohols (2).Oxidation of 1 with pyridinium chlorochromate forms the corresponding ω-bromoaldehydes (3).Under these conditions, epoxides yield first the borates of the corresponding bromohydrins, with subsequent oxidation of the intermediate (without isolation), giving the α-bromoketones in high purity and satisfactory yield.
- Kulkarni, Surendra U.,Patil, Vemanna D.
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p. 163 - 167
(2007/10/02)
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