- Synthesis and biological activity of novel acyclic versions of neplanocin A
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Novel acyclic Neplanocin A analogues were designed and synthesized. The coupling of the alkyl bromide 6 with nucleosidic bases (T, U, 5-FU, 5-IU, C, A) and desilylation afforded a series of novel acyclic nucleosides. The synthesized compounds 13-18 were evaluated for their antiviral and antitumor activity.
- Wu, Ying,Hong, Joon Hee
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- Nitroxides: Synthesis and paramagnetic properties of an α-hydroxymethyl derivative of DOXYL
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The synthesis of new but unstable α-(hydroxymethyl)oxazolidin-3-oxyls was achieved after protection by silylation of the hydroxyl groups in order to avoid decomposition in diamagnetic nitrones. Relaxivity studies of (R,S)-4-(hydroxymethyl)-2,2,4-trimethyloxazolidin-3-oxyl 1 show no beneficial effect due to the presence of an hydroxymethyl group in the vicinity of the N-O group on the paramagnetic properties of nitroxides.
- Chaouni-Benabdallah, Aziz,Subra, Guy,Bonnet, Pierre A.,Fernandez, Jean P.,Chapat, Jean P.,Vallet, Patrick,Muller, Robert N.
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- BICYCLIC SULFONAMIDES
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Provided herein are compounds of Formulae (I) and (II), or pharmaceutically acceptable salts of the foregoing, pharmaceutical compositions that include a compound described herein (including pharmaceutically acceptable salts of a compound described herein
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Paragraph 0186
(2020/08/28)
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- Hydrogenative metathesis of enynes via piano-stool ruthenium carbene complexes formed by alkyne gem-hydrogenation
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The only recently discovered gem-hydrogenation of internal alkynes is a fundamentally new transformation, in which both H atoms of dihydrogen are transferred to the same C atom of a triple bond while the other position transforms into a discrete metal carbene complex. [Cp?RuCl]4 is presently the catalyst of choice: the resulting piano-stool ruthenium carbenes can engage a tethered alkene into either cyclopropanation or metathesis, and a prototypical example of such a reactive intermediate with an olefin ligated to the ruthenium center has been isolated and characterized by X-ray diffraction. It is the substitution pattern of the olefin that determines whether metathesis or cyclopropanation takes place: a systematic survey using alkenes of largely different character in combination with a computational study of the mechanism at the local coupled cluster level of theory allowed the preparative results to be sorted and an intuitive model with predictive power to be proposed. This model links the course of the reaction to the polarization of the double bond as well as to the stability of the secondary carbene complex formed, if metathesis were to take place. The first application of "hydrogenative metathesis"to the total synthesis of sinularones E and F concurred with this interpretation and allowed the proposed structure of these marine natural products to be confirmed. During this synthesis, it was found that gem-hydrogenation also provides opportunities for C-H functionalization. Moreover, silylated alkynes are shown to participate well in hydrogenative metathesis, which opens a new entry into valuable allylsilane building blocks. Crystallographic evidence suggests that the polarized [Ru-Cl] bond of the catalyst interacts with the neighboring R3Si group. Since attractive interligand Cl/R3Si contacts had already previously been invoked to explain the outcome of various ruthenium-catalyzed reactions, including trans-hydrosilylation, the experimental confirmation provided herein has implications beyond the present case.
- Peil, Sebastian,Bistoni, Giovanni,Goddard, Richard,Fürstner, Alois
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supporting information
p. 18541 - 18553
(2020/11/17)
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- Hydrogenative Cyclopropanation and Hydrogenative Metathesis
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The unusual geminal hydrogenation of a propargyl alcohol derivative with [CpXRuCl] as the catalyst entails formation of pianostool ruthenium carbenes in the first place; these reactive intermediates can be intercepted with tethered alkenes to give either cyclopropanes or cyclic olefins as the result of a formal metathesis event. The course of the reaction is critically dependent on the substitution pattern of the alkene trap.
- Peil, Sebastian,Guthertz, Alexandre,Biberger, Tobias,Fürstner, Alois
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supporting information
p. 8851 - 8856
(2019/05/28)
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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
(2019/01/21)
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- One-Step Synthesis of 3,4-Disubstituted 2-Oxazolidinones by Base-Catalyzed CO2 Fixation and Aza-Michael Addition
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2-Oxazolidinones are saturated heterocyclic compounds, which are highly attractive targets in modern drug design. Herein, we describe a new, single-step approach to 3,4-disubstituted 2-oxazolidinones by aza-Michael addition using CO2 as a carbonyl source and 1,1,3,3-tetramethylguanidine (TMG) as a catalyst. The modular reaction, which occurs between a γ-brominated Michael acceptor, CO2 and an arylamine, aliphatic amine or phenylhydrazine, is performed under mild conditions. The regiospecific reaction displays good yields (av. 75 %) and excellent functional-group compatibility. In addition, late-stage functionalization of drug and drug-like molecules is demonstrated. The experimental results suggest a mechanism consisting of several elementary steps: TMG-assisted carboxylation of aniline; generation of an O-alkyl carbamate; and the final ring-forming step through an intramolecular aza-Michael addition.
- Mannisto, Jere K.,Sahari, Aleksi,Lagerblom, Kalle,Niemi, Teemu,Nieger, Martin,Sztanó, Gábor,Repo, Timo
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supporting information
p. 10284 - 10289
(2019/08/01)
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- Synthesis and Biological Evaluation of (E)-4-Hydroxy-3-methylbut-2-enyl Phosphate (HMBP) Aryloxy Triester Phosphoramidate Prodrugs as Activators of Vγ9/Vδ2 T-Cell Immune Responses
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The aryloxy triester phosphoramidate prodrug approach has been used with success in drug discovery. Herein, we describe the first application of this prodrug technology to the monophosphate derivative of the phosphoantigen HMBPP and one of its analogues. Some of these prodrugs exhibited specific and potent activation of Vγ9/Vδ2 T-cells, which were then able to lyse bladder cancer cells in vitro. This work highlights the promise of this prodrug technology in the discovery of novel immunotherapeutics.
- Davey, Martin S.,Malde, Roshni,Mykura, Rory C.,Baker, Alfie T.,Taher, Taher E.,Le Duff, Cécile S.,Willcox, Benjamin E.,Mehellou, Youcef
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p. 2111 - 2117
(2018/03/21)
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- Modular synthesis of the pyrimidine core of the manzacidins by divergent Tsuji-Trost coupling
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The design, development and application of an efficient procedure for the concise synthesis of the 1,3-syn- and anti-tetrahydropyrimidine cores of manzacidins are reported. The intramolecular allylic substitution reaction of a readily available joint urea-type substrate enables the facile preparation of both diastereomers in high yields. The practical application of this approach is demonstrated in the efficient and modular preparation of the authentic heterocyclic cores of manzacidins, structurally unique bromopyrrole alkaloids of marine origin. Additional features of this route include the stereoselective generation of the central amine core with an appending quaternary center by an asymmetric addition of a Grignard reagent to a chiral tert-butanesulfinyl ketimine following an optimized Ellman protocol and a cross-metathesis of a challenging homoallylic urea substrate, which proceeds in good yields in the presence of an organic phosphoric acid.
- Bretzke, Sebastian,Scheeff, Stephan,Vollmeyer, Felicitas,Eberhagen, Friederike,Rominger, Frank,Menche, Dirk
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supporting information
p. 1111 - 1121
(2016/07/06)
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- Ruthenium-catalyzed oxidative kinetic resolution of unactivated and activated secondary alcohols with air as the hydrogen acceptor at room temperature
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Enantiopure alcohols are versatile building blocks for asymmetric synthesis and the kinetic resolution (KR) of racemic alcohols is a reliable method for preparing them. Although many KR methods have been developed, oxidative kinetic resolution (OKR), in which dioxygen is used as the hydrogen acceptor, is the most atom-efficient. Dioxygen is ubiquitous in air, which is abundant and safe to handle. Therefore, OKR with air has been intensively investigated and the OKR of benzylic alcohols was recently achieved by using an Ir catalyst without any adjuvant. However, the OKR of unactivated alcohols remains a challenge. An [(aqua)Ru(salen)] catalyzed OKR with air as the hydrogen acceptor was developed, in which the aqua ligand is exchanged with alcohol and the Ru complex undergoes single electron transfer to dioxygen and subsequent alcohol oxidation. This OKR can be applied without any adjuvant to activated and unactivated alcohols with good to high enantioselectivity. The unique influence of substrate inhibition on the enantioselectivity of the OKR is also described. Alcohol resolution: An (aqua)ruthenium salen complex catalyzes the efficient oxidative kinetic resolution of both activated and unactivated secondary alcohols with air as the hydrogen acceptor at room temperature. The reaction is compatible with various functional groups, including halogen, ether, silyl ether, and ester groups. The reaction rate is lower at higher substrate concentrations as a result of substrate inhibition.
- Mizoguchi, Hirotaka,Uchida, Tatsuya,Katsuki, Tsutomu
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supporting information
p. 3178 - 3182
(2014/04/03)
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- Heterobicyclic sphingosine 1-phosphate analogs
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Compounds that have agonist activity at one or more of the S1P receptors are provided. The compounds are sphingosine analogs that, after phosphorylation, can behave as agonists at S1P receptors.
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(2014/04/18)
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- BENZOTHIOPHENE SULFONAMIDES AND OTHER COMPOUNDS THAT INTERACT WITH GLUCOKINASE REGULATORY PROTEIN
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The present invention relates to benzothiophene sulfonamides and other compounds that interact with glucokinase regulatory protein. In addition, the present invention relates to methods of treating type 2 diabetes, and other diseases and/or conditions where glucokinase regulatory protein is involved using the compounds, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions that contain the compounds, or pharmaceutically acceptable salts thereof.
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Page/Page column 233
(2013/12/03)
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- HETEROBICYCLIC SPHINGOSINE 1-PHOSPHATE ANALOGS
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Compounds that have agonist activity at one or more of the SlP receptors are provided. The compounds are sphingosine analogs that, after phosphorylation, can behave as agonists at SlP receptors.
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Page/Page column 62
(2010/05/14)
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- Flow ozonolysis using a semipermeable Teflon AF-2400 membrane to effect gas - Liquid contact
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(Figure Presented) A flow-through chemistry apparatus has been developed which allows gases and liquids to contact via a semipermeable Teflon AF-2400 membrane. In this preliminary investigation, the concept was proven by application to the ozonolysls of a series of alkenes.
- O'Brien, Matthew,Baxendale, Ian R.,Ley, Steven V.
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supporting information; experimental part
p. 1596 - 1598
(2010/06/16)
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- Acyloins from Morita-Baylis-Hillman adducts: an alternative approach to the racemic total synthesis of bupropion
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In this Letter, we describe an easy and straightforward strategy for the preparation of acyloins (α-hydroxyketones) from Morita-Baylis-Hillman adducts, based on a Curtius rearrangement. Different acyloins were obtained with good overall yield (>40% for three steps). To exemplify the synthetic usefulness of this strategy, total synthesis of (±)-bupropion, a dopamine, and nor-epinefrine reuptake inhibitor has been accomplished in eight steps with an overall yield of 25%.
- Amarante, Giovanni W.,Rezende, Patrícia,Cavallaro, Mayra,Coelho, Fernando
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p. 3744 - 3748
(2008/09/21)
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- Low pressure carbonylation of heterocycles
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Heterocycles, e.g., epoxides, are carbonylated at low pressure with high percentage conversion to cyclic, ring expanded products using the catalyst where L is tetrahydrofuran (THF).
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Page/Page column 4
(2008/06/13)
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- Carbonylative ring opening of terminal epoxides at atmospheric pressure
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(Chemical Equation Presented) The carbonylative opening of terminal epoxides under mild conditions has been developed using Co2-(CO) 8 as the catalyst. Under 1 atm of carbon monoxide and at room temperature in methanol, propylene oxide is converted to methyl 3-hydroxybutanoate in up to 89% yield. This transformation is general for many terminal epoxides bearing alkyl, alkenyl, aryl, alkoxy, chloromethyl, phthalimido, and acetal functional groups. The opening takes place without epimerization at the secondary stereocenter.
- Denmark, Scott E.,Ahmad, Moballigh
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p. 9630 - 9634
(2008/03/17)
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- Practical β-lactone synthesis: Epoxide carbonylation at 1 atm
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A readily prepared bimetallic catalyst is capable of effecting epoxide carbonylation to produce β-lactones at substantially lower CO pressures than previously reported catalyst systems. A functionally diverse array of β-lactones is produced in excellent yields at CO pressures as low as 1 atm. This procedure allows for epoxide carbonylation on a multigram scale without the requirement of specialized, high-pressure equipment.
- Kramer, John W.,Lobkovsky, Emil B.,Coates, Geoffrey W.
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p. 3709 - 3712
(2007/10/03)
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- Novel approach to the (-)-sparteine-mediated synthesis of kainoids: Total synthesis of (-)-α-kainic acid by (-)-sparteine-mediated deprotonation
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We report a new synthesis of kainoids via allyllithium compounds using an intramolecular cycloalkylation as the key step. Preparation of different substituted pyrrolidines was carried out by using carbamates, that react with the chiral base n-BuLi/(-)-sparteine with strong selection between the diastereotopic protons adjacent to the carbamate group in favour for the pro-S proton. (-)-α-Kainic acid was synthetized from D-serine methyl ester hydrochloride, based on a (-)-sparteine-mediated asymmetric deprotonation of an intermediate carbamate that, by stereospecific anti-SN′S E′ intramolecular cycloalkylation, leads to the pyrrolidine ring precursor of (-)-α-kainic acid, in high yield and diastereoselectivity. Related approaches, starting from L-glutamic acid failed. The intermediate pyrrolidine was further transformed to (-)-α-kainic in three steps. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005.
- Martinez, M. Montserrat,Hoppe, Dieter
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p. 1427 - 1443
(2007/10/03)
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- Diastereoselectivity in the Carroll rearrangement of β-keto esters of tertiary allylic alcohols
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Carroll rearrangement of β-keto esters derived from tertiary allylic alcohols, for example, 7, under basic conditions followed by decarboxylation of the resulting β-keto acids yielded the expected γ, δ-unsaturated methyl ketones 8 with a range of olefin geometries from 100:0 to 1:1.8 E/Z, depending on the relative steric requirements of the two groups at the allylic center.
- Jung, Michael E.,Duclos, Brian A.
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p. 107 - 109
(2007/10/03)
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- Total synthesis of (±)-acetoxyodontoschismenol using zirconium chemistry
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The dolabellane diterpene (±)-acetoxyodontoschismenol has been synthesised for the first time by a short route in which a three component coupling on zirconium is used to assemble all the carbons needed for the skeleton in one-pot.
- Baldwin, Ian R.,Whitby, Richard J.
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p. 2786 - 2787
(2007/10/03)
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- A ribozyme with michaelase activity: synthesis of the substrate precursors.
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The ability to generate RNA molecules that can catalyze complex organic transformations not only facilitates the reconstruction and plausibility of possible prebiotic reaction pathways but is also crucial for elucidating the potential of the application of RNA catalysts in organic syntheses. Iterative RNA selection previously identified a ribozyme that catalyzes the Michael addition of a cysteine thiol to an alpha,beta-unsaturated amide. This reaction is chemically similar to the rate limiting step of the thymidylate synthase reaction, which is the corresponding reaction of a cysteine thiol to the double-bond of the uracil nucleobase. Here we provide a detailed description of the synthesis of the ribozyme substrates and the substrate oligonucleotides used for its characterization and the investigation of the background reaction. We also describe the further characterization of the ribozyme with respect to substrate specificity. We show that the thiol group of the cysteine nucleophile is essential for the reaction to proceed. When substituted for a thiomethyl group, no reaction takes place.
- Eisenfuehr, Alexander,Arora, Paramjit S,Sengle, Gerhard,Takaoka, Leo R,Nowick, James S,Famulok, Michael
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p. 235 - 249
(2007/10/03)
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- Design and synthesis of α,β-unsaturated carbonyl compounds as potential ACE inhibitors
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The α,β-unsaturated amide that is incorporated into the basic structural frame of a simple substrate molecule of angiotensin converting enzyme was found to serve as a Michael acceptor for the catalytic carboxylate of Glu-127, inhibiting the enzyme irreversibly. (C) 2000 Editions scientifiques et medicales Elsevier SAS.
- Choo, Hea-Young Park,Peak, Kyung-Hee,Park, Jongsei,Kim, Dong Hyun,Chung, Hak Soon
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p. 643 - 648
(2007/10/03)
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- Synthesis of 2-C-Methyl-D-erythritol 4-phosphate: The first pathway-specific intermediate in the methylerythritol phosphate route to isoprenoids
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(matrix presented) 2-C-Methyl-D-erythritol 4-phosphate (4), formed from 1-deoxy-D-xylulose 5-phosphate (3), is the first pathway-specific intermediate in the methylerythritol phosphate route for the biosynthesis of isoprenoid compounds in bacteria, algae, and plant chloroplasts. In this report, 4 was synthesized from 1,2-propanediol (7) in seven steps with an overall yield of 32% and in an enantiomeric excess of 78%.
- Koppisch, Andrew T.,Blagg, Brian S. J.,Poulter, C. Dale
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p. 215 - 217
(2007/10/03)
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- Chemocontrolled reduction of α-keto esters by hydrides: A possible solution for selective reduction of the ester function
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α-keto primary alcohols or α-silyloxy ketones have been obtained with a high level of selectivity from enolic α-keto esters in two steps, with the reduction of the α-silyloxy α,β-unsaturated ester by LiAlH4 as the key step. The methodology developed in this work represents a 'reversed' chemoselective reduction of the ester group instead of the keto of an enolic α-keto ester due to a one-pot sequential ester reduction-desilylation or silyl migration process.
- Dalla,Catteau
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p. 6497 - 6510
(2007/10/03)
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- Asymmetric synthesis of (R)(-)-dimethyl citramalate
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An asymmetric synthesis of (R)(-)-dimethyl citramalate (1), involving halolactonization by using (S)(-)-proline as a chiral auxiliary, is reported.
- Jew, Sang-Sup,Kim, Hyun-Ah,Song, Sam-Mi,Jang, Jung-Sook,Park, Hyeung-Geun
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p. 153 - 156
(2007/10/03)
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- Probing Ergot Alkaloid Biosynthesis: Synthesis and Feeding of a Proposed Intermediate along the Biosynthetic Pathway. A New Amidomalonate for Tryptophan Elaboration
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The total synthesis of the diastereoisomeric amino acids 2 and their N-trideuteriomethyl analogues has been carried out.These compounds represent possible intermediates along the biosynthetic pathway from 4-(γ,γ-dimethylallyl)tryptophan (1) to the ergot alkaloids (e.g., 3a).The synthetic scheme features the preparation of an (indolylvinyl)metalic reagent from 4-ethynylindole via a hydrostannylation/metal-metal exchange sequence, as well as the preparation of dimethyl amino>malonate, a new amidomalonate reagent for tryptophan elaboration.Incorporation experiments with Claviceps sp.SD58 followed by GC-MS analysis of the major alkaloid, elymoclavine, showed that neither diastereomer of 2-d3 is an ergot alkaloid precursor.
- Kozikowski, Alan P.,Okita, Makoto,Kobayashi, Motomasa,Floss, Heinz G.
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p. 863 - 869
(2007/10/02)
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- Antimicrobial N-acyl-2-azetidinones
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The present invention provides novel compositions of matter and processes for their preparation. Particularly, the present invention relates to novel monocyclic β-lactams of formula I, having a carbonyl group, other than a negatively charged group, attached to the N-1 position. The compounds are useful as antimicrobial agents or as intermediates thereto. The present invention also provides a novel process for making these compounds which utilizes palladium (O)--catalyzed carbonylation of an appropriate 2-bromo-1-propen-3-yl amine and novel intermediates prepared by this process.
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