- Synthesis of the Tetracyclic Structure of Batrachotoxin Enabled by Bridgehead Radical Coupling and Pd/Ni-Promoted Ullmann Reaction
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The steroidal ABCD-ring system of the potent neurotoxin batrachotoxin was efficiently assembled in a convergent fashion. Bridgehead radical coupling between the simple AB-ring and D-ring fragments (3 and 4) formed the sterically congested linkage at the C9-oxygen-attached tetrasubstituted carbon. The C-ring was then cyclized by the Pd/Ni-promoted Ullmann reaction of the vinyl triflate and vinyl bromide of 19, giving rise to tetracyclic structure 1.
- Sakata, Komei,Wang, Yinghua,Urabe, Daisuke,Inoue, Masayuki
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Read Online
- Proline mediated asymmetric ketol cyclization: A template reaction
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1H, 13C and ATR-FTIR Spectroscopic studies reveal that the asymmetric cyclization of prochiral triones 1 and 2 in the presence of S-proline is a template reaction.
- Rajagopal,Moni,Subramanian,Swaminathan
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Read Online
- Identification of Inhibitors of Cholesterol Transport Proteins Through the Synthesis of a Diverse, Sterol-Inspired Compound Collection
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Cholesterol transport proteins regulate a vast array of cellular processes including lipid metabolism, vesicular and non-vesicular trafficking, organelle contact sites, and autophagy. Despite their undoubted importance, the identification of selective modulators of this class of proteins has been challenging due to the structural similarities in the cholesterol-binding site. Herein we report a general strategy for the identification of selective inhibitors of cholesterol transport proteins via the synthesis of a diverse sterol-inspired compound collection. Fusion of a primary sterol fragment to an array of secondary privileged scaffolds led to the identification of potent and selective inhibitors of the cholesterol transport protein Aster-C, which displayed a surprising preference for the unnatural-sterol AB-ring stereochemistry and new inhibitors of Aster-A. We propose that this strategy can and should be applied to any therapeutically relevant sterol-binding protein.
- Laraia, Luca,Olsen, Asger Hegelund,Whitmarsh-Everiss, Thomas
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supporting information
p. 26755 - 26761
(2021/11/17)
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- Potent Anti-Inflammatory, Arylpyrazole-Based Glucocorticoid Receptor Agonists That Do Not Impair Insulin Secretion
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Glucocorticoids (GCs) are widely used in medicine for their role in the treatment of autoimmune-mediated conditions, certain cancers, and organ transplantation. The transcriptional activities GCs elicit include transrepression, postulated to be responsible for the anti-inflammatory activity, and transactivation, proposed to underlie the undesirable side effects associated with long-term use. A GC analogue that could elicit only transrepression and beneficial transactivation properties would be of great medicinal value and is highly sought after. In this study, a series of 1-(4-substituted phenyl)pyrazole-based GC analogues were synthesized, biologically screened, and evaluated for SARs leading to the desired activity. Activity observed in compounds bearing an electron deficient arylpyrazole moiety showed promise toward a dissociated steroid, displaying transrepression while having limited transactivation activity. In addition, compounds 11aa and 11ab were found to have anti-inflammatory efficacy comparable to that of dexamethasone at 10 nM, with minimal transactivation activity and no reduction of insulin secretion in cultured rat 832/13 beta cells.
- Burke, Susan J.,Campagna, Shawn R.,Collier, J. Jason,Dunlap, Lee E.,Fisch, Alexander R.,Kennedy, Brandon J.,Kirkland, Justin K.,Lato, Ashley M.,Prevatte, Carson W.,Smith, Russell T.,Vogiatzis, Konstantinos D.
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p. 1568 - 1577
(2021/10/04)
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- Biocatalytic Approaches to the Enantiomers of Wieland–Miescher Ketone and its Derivatives
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Biocatalytic approaches have been investigated in order to isolate the enantiomers of Wieland–Miescher ketone (1) and of its alcoholic derivatives (cis-2 and trans-3). Specifically, two enzymes from our in-house metagenomic collection of oxidoreductases, IS2-SDR and Dm7α-HSDH, catalyzed the kinetic resolution of the starting racemic ketone 1 or its complete conversion into two diastereomeric products, respectively. Moreover, the kinetic resolution of the racemic cis-alcohol (2) was very efficiently obtained (E?2.000) by lipase PS catalyzed acetylation in dry acetone. All the products were isolated with ee≥95 %. Simple chemical elaborations of some of them allowed to isolate the missing enantiomers.
- Bertuletti, Susanna,Bayout, Ikram,Bassanini, Ivan,Ferrandi, Erica E.,Bouzemi, Nassima,Monti, Daniela,Riva, Sergio
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p. 3992 - 3998
(2021/04/09)
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- Assessing the Recyclability of Supramolecularly Assembled Organocatalytic Species: A Theoretical Insight
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Asymmetric organocatalytic synthesis is a powerful tool in organic chemistry to achieve desired stereoisomers in high purity via mild catalytic routes. The immobilization of homogeneous catalytic species onto heterogeneous phases embodies the evolution of asymmetric catalysis, since it allows the recycling of the catalyst for several runs until degradation. Previously reported non-covalent immobilization of proline-based catalysts for aldol reaction onto magnetic nanoparticles functionalized with β-cyclodextrin (MNP-β-CB) demonstrated the viability of the methodology. This paper proposes two new catalyst recycling strategies based on Cucurbit[7]uril (CB[7]) for the aldol reaction and the Robinson annulation. These recycling methodologies are conceptually different. The former relies on the homogeneous encapsulation of the catalyst in cucurbituril, CB[7] ? Cat, and its recycling in the aqueous phase by extraction of the aldol product with organic solvents. The latter relies on the heterogeneous encapsulation of the catalyst as MNP-CB[7] ? Cat2 system and its recycling by magnetic harvesting. Density functional theory (DFT) calculations have been employed to rationalize the thermodynamics of experimental results, and to suggest caveats and plausible improvements in view of a future catalytic design.
- Llorens, Lluis,Llanes, Patricia,Fianchini, Mauro,Pericàs, Miquel A.
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p. 475 - 484
(2020/03/19)
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- Preparation method of (S)-(+)-3,4,8,8a-tetrahydro-8a-methyl-1,6-(2H,7H)-naphthoquinone
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The invention relates to a preparation method of (S)-(+)-3,4,8,8a-tetrahydro-8a-methyl-1,6-(2H,7H)-naphthoquinone. According to the preparation method, an L-proline derivative is used as a chiral catalyst and microwave radiation is introduced into chiral preparation of the (S)-(+)-3,4,8,8a-tetrahydro-8a-methyl-1,6-(2H,7H)-naphthoquinone for the first time through asymmetric Robinson cyclization reaction under conventional conditions or microwave irradiation conditions. Under proper power, an L-prolinamide type catalyst can keep excellent catalysis performance and the catalysis reaction time isshortened; compared with room-temperature stirring conditions, the synthesis efficiency is greatly improved. The molecular collision is aggravated through the microwave radiation and an intermediatecan more easily pass through an energy barrier to form a transition state, so that the reaction time is remarkably shortened, the preparation efficiency of the (S)-(+)-3,4,8,8a-tetrahydro-8a-methyl-1,6-(2H,7H)-naphthoquinone is greatly improved and the synthesis period is shortened. The method is low in cost, simple and rapid, high in yield and good in stereoselectivity.
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Paragraph 0021-0026
(2019/03/08)
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- Chemoselective Oxidation of Equatorial Alcohols with N-Ligated λ3-Iodanes
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The site-selective and chemoselective functionalization of alcohols in complex polyols remains a formidable synthetic challenge. Whereas significant advancements have been made in selective derivatization at the oxygen center, chemoselective oxidation to the corresponding carbonyls is less developed. In cyclic systems, whereas the selective oxidation of axial alcohols is well known, a complementary equatorial selective process has not yet been reported. Herein we report the utility of nitrogen-ligated (bis)cationic λ3-iodanes (N-HVIs) for alcohol oxidation and their unprecedented levels of selectivity for the oxidation of equatorial over axial alcohols. The conditions are mild, and the simple pyridine-ligated reagent (Py-HVI) is readily synthesized from commercial PhI(OAc)2 and can be either isolated or generated in situ. Conformational selectivity is demonstrated in both flexible 1,2-substituted cyclohexanols and rigid polyol scaffolds, providing chemists with a novel tool for chemoselective oxidation.
- Mikhael, Myriam,Adler, Sophia A.,Wengryniuk, Sarah E.
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supporting information
p. 5889 - 5893
(2019/08/26)
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- Hydrodealkenylative C(sp3)–C(sp2) bond fragmentation
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Chemical synthesis typically relies on reactions that generate complexity through elaboration of simple starting materials. Less common are deconstructive strategies toward complexity—particularly those involving carbon-carbon bond scission. Here, we introduce one such transformation: the hydrodealkenylative cleavage of C(sp3)–C(sp2) bonds, conducted below room temperature, using ozone, an iron salt, and a hydrogen atom donor. These reactions are performed in nonanhydrous solvents and open to the air; reach completion within 30 minutes; and deliver their products in high yields, even on decagram scales. We have used this broadly functionality tolerant transformation to produce desirable synthetic intermediates, many of which are optically active, from abundantly available terpenes and terpenoid-derived precursors. We have also applied it in the formal total syntheses of complex molecules.
- Smaligo, Andrew J.,Swain, Manisha,Quintana, Jason C.,Tan, Mikayla F.,Kim, Danielle A.,Kwon, Ohyun
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p. 681 - 685
(2019/06/11)
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- A synthetic approach to (±)-aristomakine
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We describe the synthesis of trans-11b-methyl-2,3,4,6,11,11b-hexahydro-1H-benzo[a]carbazol-3-ol (2) in five steps from the Wieland-Miescher ketone 3 in 17% overall yield. The N-benzyl analogue (trans-11-Benzyl-11b-methyl-2,3,4,6,11,11b-hexahydro-1H-benzo[a]carbazol-3-ol) 15 was likewise prepared. Attempts thus far to fashion (±)-aristomakine (1) from 2, 15, or derivatives have not been successful.
- Perni, Robert B.,Gribble, Gordon W.
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- Desymmetrisation of: Meso -diones promoted by a highly recyclable polymer-supported chiral phosphoric acid catalyst
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A polystyrene-supported BINOL-derived chiral phosphoric acid has been applied to the desymmetrisation of meso-diones to produce enantioenriched cyclohexenones. The catalytic resin has proven highly active and robust, giving rise to Hajos-Parrish or Wieland-Miescher type products in good yields and enantioselectivities, while allowing for extended recycling.
- Clot-Almenara, Lidia,Rodríguez-Escrich, Carles,Pericàs, Miquel A.
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p. 6910 - 6914
(2018/02/23)
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- Total Synthesis of ent-Pregnanolone Sulfate and Its Biological Investigation at the NMDA Receptor
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A unique asymmetric total synthesis of the unnatural enantiomer of pregnanolone, as well as a study of its biological activity at the NMDA receptor, is reported. The asymmetry is introduced by a highly atom-economic organocatalytic Robinson annulation. A new method for the construction of the cyclopentane D-ring consisting of CuI-catalyzed conjugate addition and oxygenation followed by thermal cyclization employing the persistent radical effect was developed. ent-Pregnanolone sulfate is surprisingly only 2.6-fold less active than the natural neurosteroid.
- Kapras, Vojtech,Vyklicky, Vojtech,Budesinsky, Milos,Cisarova, Ivana,Vyklicky, Ladislav,Chodounska, Hana,Jahn, Ullrich
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p. 946 - 949
(2018/02/23)
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- Strategy towards the enantioselective synthesis of schiglautone A
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Herein is described a convergent enantioselective route to an advanced intermediate in the synthesis of schiglautone A, a Schisandra triterpenoid with an unusual architecture. The synthetic route to this intermediate displaying 6 of the 7 stereocenters builds upon two fragments, an aldehyde elaborated from the Wieland-Miescher ketone, and a ketone. The preparation of the latter features a lithiation-borylation enzymatic resolution sequence, which led to the formation of the desired product with high enantio- and diastereoselectivities. After aldol coupling of the two fragments, the final quaternary stereocenter was installed by cyclopropane opening. The functionalized intermediate was isolated as a single diastereoisomer and thus offers a valuable starting point for further synthetic exploration.
- Le Chapelain, Camille
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supporting information
p. 6242 - 6256
(2017/08/02)
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- Lewis Acid Mediated Nazarov Cyclization as a Convergent and Enantioselective Entry to C-nor-D-homo-Steroids
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A straightforward synthesis of C-nor-D-homo steroids starting from (+)-Wieland–Miescher ketone is reported. This convergent synthetic strategy utilizes a?scalable diastereoselective Nazarov cyclization of functionalized chiral aryl vinyl ketones, allowing for further functionalization. The ability to conduct this key transformation on a multi-gram scale paves the way for the synthesis of a variety of completely new C-nor-D-homo steroids, without the need of a classic steran steroid rearrangement or achiral linear reaction sequences.
- Krieger, Johannes,Smeilus, Toni,Schackow, Oliver,Giannis, Athanassios
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supporting information
p. 5000 - 5004
(2017/04/18)
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- A Highly Active Polymer-Supported Catalyst for Asymmetric Robinson Annulations in Continuous Flow
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The preparation through Robinson annulation of enantiopure building blocks with both academic and industrial relevance, such as the Wieland-Miescher and Hajos-Parrish ketones, has suffered from important drawbacks, such as the need for high catalyst loading or extremely long reaction times. Here we report a heterogenized organocatalyst based on Luo's diamine for fast and broad-scope enantioselective Robinson annulation reactions. The polystyrene-supported diamine 19a enables the high-yield, highly enantioselective preparation of a wide range of chiral bicyclic enones under mild conditions, with reaction times as short as 60 min (batch) or residence times of 10 min (flow). In contrast with its homogeneous counterpart 19b, the catalytic resin 19a experiences a notable increase in catalytic activity with temperature in 2-MeTHF (a 10-fold decrease in reaction times without erosion in enantioselectivity is observed from room temperature to 55 °C). The scope of the transformation in batch mode has been illustrated with 14 examples, including examples only reported in poorly enantioenriched (22n) or in racemic form (22k). Enantiopure 22k has been used as the starting material for a straightforward formal synthesis of the antibiotic and antifeedant sesquiterpene (-)-isovelleral (24). The heterogenized catalyst 19a admits extended recycling (10 cycles) and has been used to develop the first asymmetric Robinson annulations in continuous flow. The potential of the flow process is illustrated by the large-scale preparation of the Wieland-Miescher ketone (65 mmol in 24 h of operation, TON of 117) and by a sequential flow experiment leading to a library of eight enantioenriched diketone compounds.
- Canellas, Santiago,Ayats, Carles,Henseler, Andrea H.,Pericàs, Miquel A.
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p. 1383 - 1391
(2017/08/09)
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- Lipase-catalyzed domino Michael-aldol reaction of 2-methyl-1,3-cycloalkanedione and methyl vinyl ketone for the synthesis of bicyclic compounds
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Synthesis of bicyclic compounds was achieved via a lipase-catalyzed, stereoselective, domino Michael-aldol reaction of 2-methyl-1,3-cycloalkanedione and methyl vinyl ketone. Appropriate reaction conditions, including the type of enzyme, solvent, and temperature, were determined. In addition, the effects of solvent polarity and addtives were investigated. The reaction proceeded in the presence of lipase AS in a solution of 20% acetone in dimethylsulfoxide (DMSO) at 10 °C for 8 days, followed by the addition of p-toluenesulfonic acid (TsOH) to afford bicyclic compounds in 51-83% yields with moderate stereoselectivity. Although this domino Michael-aldol reaction showed only moderate stereoselectivity, even with the acid-supported enhancement of the reaction, these results represent potential new applications for lipase.
- Sano, Kaoru,Kohari, Yoshihito,Nakano, Hiroto,Seki, Chigusa,Takeshita, Mitsuhiro,Tokiwa, Micho,Hirose, Yoshihiko,Uwai, Koji
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supporting information
p. 46 - 54
(2016/01/09)
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- Synthesis of the ABC skeleton of the aglycon of Echinoside A
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Echinoside A is a triterpene saponin isolated from the sea cucumber Actinopyga echinites (JAEGER), which displays potent antitumor activities in vitro and in vivo. Here, we report the synthesis of the ABC-fused ring skeleton of the aglycon of Echinoside A, with the enantiomerically pure (+)-Wieland-Miescher ketone being used as starting material and a Robinson annulation as the key reaction.
- Yu, Jun,Yu, Biao
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p. 1331 - 1335
(2015/10/28)
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- One-pot synthesis of Wieland-Miescher ketone by enzymes
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We first report that lipase from porcine pancreas catalyzed Robinson annulation in the organic media to synthesize the Wieland-Miescher ketone. The promiscuous catalytic activity of lipase in the Robinson reaction is due to an important role played by lipase activity in both the Michael addition and Aldol reaction.
- Lai, Yi-Feng,Zhang, Peng-Fei
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p. 4077 - 4082
(2015/06/30)
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- Bifunctional organocatalysts based on a carbazole scaffold for the synthesis of the Hajos-Wiechert and Wieland-Miescher ketones
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Several bifunctional organocatalysts based on a carbazole scaffold containing a chiral amine and a synthetic oxyanion-hole have been synthesized and successfully applied to the synthesis of the Hajos-Wiechert and Wieland-Miescher ketones (up to 99% ee). Both enamine activation and H-bonding donor ability of these catalysts were evaluated by preparing catalysts differing in the nature of the amine [(R,R)-cyclohexanediamine or l-proline], the H-bond donor functional group (sulfonamide or amide) and the number of NH bonds. Modeling studies and an X-ray structure fully support the obtained results.
- Rubio, Omayra H.,Fuentes De Arriba, ángel L.,Monleón, Laura M.,Sanz, Francisca,Simón, Luis,Alcázar, Victoria,Morán, Joaquín R.
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supporting information
p. 1297 - 1303
(2015/03/05)
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- Investigation of cis- and trans-4-Fluoroprolines as Enantioselective Catalysts in a Variety of Organic Transformations
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Stereoselective fluorination is known to rigidify the ring structure of L-proline, as a result of a combination of electrostatic and hyperconjugative effects associated with the C-F bond. This is a potential strategy for enhancing the enantioselectivity of proline-catalysed reactions. In this study, cis- and trans-4-fluoroprolines were investigated as catalysts in five different organic transformations, including examples of both enamine and iminium ion catalysis. Some significant differences in enantioselectivity were observed between the cis- and trans-isomers of the fluorinated catalysts, confirming that the ring pucker is important. However, no substantial improvements were observed relative to the parent catalyst, L-proline.
- Yap, Daryl Q. J.,Cheerlavancha, Raju,Lowe, Renecia,Wang, Siyao,Hunter, Luke
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- Pyrimidine-derived prolinamides as recoverable bifunctional organocatalysts for enantioselective inter- and intramolecular aldol reactions under solvent-free conditions
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Chiral L-prolinamides 2 containing the (R,R)- and (S,S)-trans-cyclohexane-1,2-diamine scaffold and a 2-pyrimidinyl unit are synthesized and used as general organocatalysts for intermolecular and intramolecular aldol reactions with 1,6-hexanedioic acid as a co-catalyst under solvent-free conditions. The intermolecular reaction between ketone-aldehyde and aldehyde-aldehyde must be performed under wet conditions with catalyst (S,S)-2b at 10 °C, which affords anti-aldols with high regio-, diastereo-, and enantioselectivities. For the Hajos-Parrish-Eder-Sauer-Wiechert reaction, both diastereomers of catalyst 2 give similar results at room temperature in the absence of water to give the corresponding Wieland-Miescher ketone and derivatives. Both types of reactions were scaled up to 1 g, and the organocatalysts were recovered by extractive workup and reused without any appreciable loss in activity. DFT calculations support the stereochemical results of the intermolecular process and the bifunctional role played by the organocatalyst by providing a computational comparison of the H-bonding networks occurring with catalysts 2a and 2b. The intermolecular ketone-aldehyde and aldehyde-aldehyde aldol reactions and the Hajos-Parrish-Eder-Sauer-Wiechert versions with the employment of chiral L-prolinamides containing the (R,R)- and (S,S)-trans-cyclohexane-1,2-diamine scaffold and a 2-pyrimidinyl unit are successfully performed under solvent-free conditions; WMK = Wieland-Miescher ketone.
- Vizcaíno-Milla, Pascuala,Sansano, José M.,Nájera, Carmen,Fiser, Béla,G?mez-Bengoa, Enrique
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supporting information
p. 2614 - 2621
(2015/04/27)
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- Separating agent for optical isomers
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A separating agent for optical isomers that uses a polysaccharide derivative provided by replacing all or a portion of the hydrogen atoms on the hydroxyl groups present in a polysaccharide with two specific atomic groups that act on optical isomers targeted for separation in an optical resolution, wherein the sum of the average introduction ratios of specific terminal substituents in these atomic groups is greater than 3.0 per monosaccharide unit.
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Page/Page column 5-6
(2014/10/29)
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- Recyclable L-proline organocatalyst for Wieland-Miescher ketone synthesis
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Wieland-Miescher ketone 4 was synthesised using L-proline catalyst in the ionic liquid medium via non-selective conjugated addition reaction followed by an enantioselective intermolecular Aldol condensation reaction of triketone 3 intermediate. Short reaction time, recycling of the catalyst, good yield and selectivity are major outcomes of this proposed protocol. Indian Academy of Sciences.
- Srivastava, Vivek
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p. 1523 - 1527
(2014/04/03)
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- Novel supported and unsupported prolinamides as organocatalysts for enantioselective cyclization of triketones
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A novel prolylsulfonamide derived from ethylene diamine and its supported counterpart has been prepared and tested as enantioselective intramolecular aldol reaction of cyclic and acyclic triketones. Good to excellent yields and enantioselectivities have been obtained in water and under solvent free conditions.
- Pedrosa, Rafael,Andrés, José María,Manzano, Rubén,Pérez-López, César
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supporting information
p. 3101 - 3104
(2013/06/27)
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- Towards the synthesis of batrachotoxin-formation of alkynyl stannanes
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Batrachotoxin, isolated from frogs belonging to the genus Phyllobates, is a very potent neurotoxin and a steroidal alkaloid that has been found to block the Na+ channels in nerves and muscles resulting in arrhythmias or cardiac arrest leading to death. Research on this toxin is limited due to difficult isolation but many attempts have been made towards its total and partial synthesis. The present work indicates our efforts towards the formation of steroidal skeleton of this neurotoxin in high/improved yield by employing radical mediated cyclization which led to many interesting results. The successful model study towards the formation of the steroidal skeleton is also reported here.
- Sultan, Aeysha,Raza, Abdul Rauf,Khan, Khalid Mohammed
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p. 1369 - 1383
(2014/01/06)
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- Recoverable silica-gel supported binam-prolinamides as organocatalysts for the enantioselective solvent-free intra- and intermolecular aldol reaction
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Silica-gel supported binam-derived prolinamides are efficient organocatalysts for the direct intramolecular and intermolecular aldol reaction under solvent-free conditions using conventional magnetic stirring. These organocatalysts in combination with benzoic acid showed similar results to those obtained under similar homogeneous reaction conditions using an organocatalyst of related structure. For the intermolecular process, the aldol products were obtained at room temperature and using only 2 equiv of the ketone with high yields, regio-, diastereo- and enantioselectivities. Under these reaction conditions, also the cross aldol reaction between aldehydes is possible. The recovered catalyst can be reused up to nine times providing similar results. More interestingly, these heterogeneous organocatalysts can be used in the intramolecular aldol reaction allowing the synthesis of the Wieland-Miescher and ketone analogues with up to 92% ee, with its reused being possible up to five times without detrimental on the obtained results.
- Ba?ón-Caballero, Abraham,Guillena, Gabriela,Nájera, Carmen,Faggi, Enrico,Sebastián, Rosa María,Vallribera, Adelina
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p. 1307 - 1315
(2013/02/23)
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- Novel aminoimidazole derived proline organocatalysts for aldol reactions
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A series of l-proline amides with 2-aminoimidazole have been synthesized and found to be highly efficient organocatalysts for aldol reactions when an appropriate acid was added to control and activate the acceptor carbonyl group. Under optimized reaction conditions, high yields (over 80%) and high selectivities (ee 98%, de 98/2) were obtained in intermolecular aldol reaction even with only 1 equiv of ketone. Likewise, these systems also can catalyze intramolecular aldol reactions with good results.
- Tang, Gongkun,Guen, Uemit,Altenbach, Hans-Josef
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supporting information
p. 10230 - 10235,6
(2020/09/02)
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- Prolinamide bridged silsesquioxane as an efficient, eco-compatible and recyclable chiral organocatalyst
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A new organic-inorganic hybrid silica material derived from a bis-silylated prolinamide by sol-gel methodology has been successfully applied as a supported organocatalyst in asymmetric aldol and Michael reactions. Our immobilized system presents similar performances to homogeneous prolinamides and added advantages of easy recovery and good recyclability. It fits green chemistry requirements as the reactions are performed in water, at room temperature, with low catalyst loadings (2-16 mol%).
- Monge-Marcet, Amàlia,Pleixats, Roser,Catto?n, Xavier,Man, Michel Wong Chi,Alonso, Diego A.,Nájera, Carmen
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experimental part
p. 2766 - 2772
(2012/01/11)
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- Asymmetric intramolecular aldol reaction mediated by (S)-N-substituted-N- (2-pyrrolidinylmethyl)amine to prepare Wieland-Miescher ketone
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New or known N-substituted-N-(2-pyrrolidinylmethyl)amine derivatives bearing a variety of alkyl and aryl substituents were easily prepared from N-Boc-proline or N-Boc-N-(2-pyrrolidinylmethyl)amine. The enantioselectivity of the intramolecular asymmetric aldol reaction mediated by a combination of the amine derivative and TFA to prepare Wieland-Miescher ketone was examined. During the examination, optimal amount of TFA in the reaction was identified. The Japan Institute of Heterocyclic Chemistry.
- Akahane, Yuichi,Inomata, Kohei,Endo, Yasuyuki
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experimental part
p. 1727 - 1737
(2011/06/17)
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- Enantioselective synthesis of a taxol C ring
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An enantioselective synthesis of a C ring of taxol has been accomplished. The key step is an oxidative cleavage of a derivative of the Wieland-Miescher ketone. A first attempt of a Shapiro reaction modelling the coupling of the C ring with the A fragment of taxol was also successful.
- Ma, Cong,Schiltz, Stephanie,Prunet, Joelle
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experimental part
p. 1579 - 1594
(2012/05/19)
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- Synthesis of monoacylated derivatives of 1,2- cyclohexanediamine. Evaluation of their catalytic activity in the preparation of Wieland-Miescher ketone
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Ureas, carbamoyl derivatives, amides, and sulfonamides can be easily prepared from the strained (R,R)-cylohexanediamine urea (1) in high yield, leaving a free amino group that shows good catalytic activity in intramolecular aldol condensations. The preparation of Wieland-Miescher ketone has been studied with these catalysts.
- Fuentes De Arriba, Angel L.,Seisdedos, David G.,Simon, Luis,Alcazar, Victoria,Raposo, Cesar,Moran, Joaquin R.
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scheme or table
p. 8303 - 8306
(2011/02/27)
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- First total synthesis of (+)-Carainterol A
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The first, stereospecific, and elegant synthesis of the natural product (+)-Carainterol A was developed by using the Robinson annulation reaction as a key step to build the eudesmane sketeton.
- Ma, Kaiqing,Zhang, Chunbo,Liu, Mingming,Chu, Yong,Zhou, Lu,Hu, Changqi,Ye, Deyong
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supporting information; experimental part
p. 1870 - 1872
(2010/09/07)
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- A ring contraction strategy toward a diastereoselective total synthesis of (+)-bakkenolide A
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A diastereoselective route to (+)-bakkenolide A is presented from the readily available optically active Wieland-Miescher ketone. This novel synthesis of this sesquiterpene lactone features the following as key stereoselective transformations: (i) the ring contraction reaction of a octalone mediated by thallium(III) nitrate (TTN); (ii) a hydrogenation to create the cis-fused junction; and (iii) the formation of the C7 quaternary center through an enolate intermediate. Furthermore, during this work, the absolute configuration of a trinorsesquiterpene isolated from Senecio Humillimus was assigned.
- Carneiro, Vania M. T.,Ferraz, Helena M. C.,Vieira, Tiago O.,Ishikawa, Eloisa E.,Silva Jr., Luiz F.
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supporting information; experimental part
p. 2877 - 2882
(2010/08/13)
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- Efficient solvent-free robinson annulation protocols for the highly enantioselective synthesis of the wieland-miescher ketone and analogues
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A highly efficient (93% overall yield) and enantioselective (94% ee) synthesis of the WielandMiescher ketone (10-g scale) through a solvent-free Robinson annulation procedure is reported. The process involves only 1 mol% triethylamine as the base in the initial Michael process and the organocatalyst N-tosyl-(Sa)-binam-L-prolinamide (2mol%) and benzoic acid (0.5 mol% ) for the intramolecular aldol process. This green protocol is applied to a wide range of valuable building block analogues of the Wieland-Miescher ketone (10 examples). Among these, a noteworthy compound for terpene synthesis is the 8a-allyl derivative, which is prepared in 93% yield and 97% ee in a process allowing the recovery and reutilization of the organocatalyst. Furthermore, a one-pot, two-step process has also been developed.
- Bradshaw, Ben,Etxebarria-Jardi, Gorka,Bonjoch, Josep,Viozquez, Santiago F.,Guillena, Gabriela,Najera, Carmen
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experimental part
p. 2482 - 2490
(2009/12/29)
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- Proline imidazolidinones and enamines in Hajos-Wiechert and Wieland-Miescher ketone synthesis
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Readily available aromatic prolinamides obtained from the acid chloride of proline hydrochloride and anilines induce large enantiomeric excesses in intramolecular aldol condensations. Imidazolidinones derived from the reaction of the catalyst and enamines
- de Arriba, ángel L. Fuentes,Simón, Luis,Raposo, César,Alcázar, Victoria,Morán, Joaquín R.
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scheme or table
p. 4841 - 4845
(2009/10/02)
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- Water versus solvent-free conditions for the enantioselective inter- and intramolecular aldol reaction employing l-prolinamides and l-prolinethioamides as organocatalysts
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Organocatalysts 1, derived from L-proline and (1S,2R)-cis-l-aminoindan-2-ol or (R)-l-aminoin-dane, are evaluated as promoters in the direct asymmetric aldol reaction between ketones and aromatic aldehydes in the presence of water and under solvent-free reaction conditions. L-Prolinethioamides 1c and 1d exhibited higher enantioselectivity than the corresponding prolinamides 1a and 1b in the model aldol reaction between cyclohexanone and 4-nitro-benzaldehyde in the presence of 4-nitrobenzoic acid as cocatalyst. In particular, L-prolinethioamide 1d (5 mol%), derived from L-proline and (R)-1-amino-indane, is shown as the most efficient organocatalyst studied promoting the direct aldol reaction of cyclo-alkyl, alkyl, and a-functionalized ketones with aromatic aldehydes in the presence of water and under solvent-free reaction conditions employing only 2 equivalents of nucleophile. Generally, anft-aldol products are obtained in high yields and excellent diastereo- and enantioselectivities (up to > 98/2 until syn, up to 98% ee). Solvent-free conditions give slightly higher dr and ee than using water as solvent. In addition, organocatalyst Id can be easily recovered by extractive work-up and reused. Prolinethio-amide Id (5 mol%) in combination with 4-NO2C6H4CO2H (5 mol%) is also a very effective or-ganocatalytic system for the asymmetric solvent-free intramolecular Haj os-Parrish-Eder-Sauer-Wiechert reaction with comparable or higher levels of enantioselectivity (up to 88% ee) to other reported catalysts in organic solvents.
- Almasi, Diana,Alonso, Diego A.,Balaguer, Andrea-Nekane,Najera, Carmen
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supporting information; scheme or table
p. 1123 - 1131
(2009/12/07)
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- A new chiral synthesis of Wieland-Miescher ketone catalyzed by a combination of (S)-N- benzyl-N(2-pyrrolidinylmethyl)amine derivative and bronsted acid
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New or known N-benzyl-N (2-pyrrolidinylmethyl)amine derivatives bearing a variety of substituents on the aromatic ring were easily prepared from N-Boc-proline or NBoc-prolinol. The enantioselectivity of the intramolecular asymmetric aldol reaction mediated by a combination of the amine derivative and Bronsted acid to prepare Wieland-Miescher ketone was examined in detail. During the examination, remarkable substitutional effects on the aromatic ring were observed. Development of a catalytic version of the reaction was successfully achieved by the use of N(9-anthracenyl)methyl-N(2-pyrrolidinyl-methyl)amine in the presence of dichloroacetic acid.
- Akahane, Yuichi,Inomata, Kohei,Endo, Yasuyuki
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experimental part
p. 1065 - 1078
(2010/10/03)
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- Chiral phosphoric acid catalyzed desymmetrization of meso-1,3diones: Asymmetric synthesis of chiral cyclohexenones
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Chiral effectiveness: The title transformation is applicable to a wide variety of substrates to give chiral cyclohexenones in high yields and with excellent enantioselecti vity (see scheme). To clarity the origin of the enantioselectivity ONIOM calculations were carried out
- Mori, Keiji,Katoh, Takuya,Suzuki, Tohru,Noji, Takuya,Yamanaka, Masahiro,Akiyama, Takahiko
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supporting information; experimental part
p. 9652 - 9654
(2010/04/28)
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- N-Tosyl-(Sa)-binam-L-prolinamide as highly efficient bifunctional organocatalyst for the general enantioselective solvent-free aldol reaction
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N-Tosyl-(Sa)-binam-L-prolinamide (5 mol%) and benzoic acid (1 mol%) were used as catalysts in the enantioselective direct aldol reaction between different ketones and aldehydes under solvent-free conditions in the presence or absence of water. Under these reaction conditions it was possible to reduce the amount of required ketone to two equivalents to give the corresponding aldol products with high yields, regio-, diastereo- and enantioselectivities. The aldol reaction between aldehydes or the intramolecular aldol reaction can be also performed with excellent results. Georg Thieme Verlag Stuttgart.
- Guillena, Gabriela,Nájera, Carmen,Viózquez, Santiago F.
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scheme or table
p. 3031 - 3035
(2009/10/16)
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- Synthesis of a dysidiolide-inspired compound library and discovery of acetylcholinesterase inhibitors based on protein structure similarity clustering (PSSC)
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Biologically relevant compound collections are a major prerequisite for efficient protein ligand development and ultimately for drug discovery. We herein describe the development of a compound collection inspired by the decalin core motif of two natural products, dysidiolide 1 and sulfiricin 2, both inhibitors of the Cdc25A phosphatase. Several keto-functionalized decalinols were synthesized in solution, immobilized on Merrifield resin equipped with a dihydropyranyl linker, and then subjected to aldol condensation reactions with different aldehydes leading to exocyclic E-configured olefins. Further diversity-increasing transformations on the solid support included Sonogashira, Suzuki, and Heck reactions, Cu-catalyzed conjugate addition and Grignard reactions, alkylation reactions in the α-position to a ketone, Wittig reactions, and reductive animations. In total, 483 compounds were synthesized. Cdc25A and AChE exhibit structural similarity in their ligand-sensing cores and were thus grouped into a protein structure similarity cluster (PSSC). A screen for AChE inhibition of a subset of 162 compounds yielded three micromolar inhibitors of AChE with IC50 values 20 μM.
- Scheck, Michael,Koch, Marcus A.,Waldmann, Herbert
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p. 4792 - 4802
(2008/09/21)
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- Prolinamide/PPTS-catalyzed Hajos-Parrish annulation: Efficient approach to the tricyclic core of cylindricine-type alkaloids
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A series of Wieland-Miescher ketone analogues bearing highly functionalized substituents are efficiently constructed in high enantioselectivities and good yields using catalytic amounts of prolinamide and PPTS. We have successfully utilized this reaction as a key step to synthesize the tricyclic core of cylindricine type alkaloids. Georg Thieme Verlag Stuttgart.
- Zhang, Xiao-Ming,Wang, Min,Tu, Yong-Qiang,Fan, Chun-An,Jiang, Yi-Jun,Zhang, Shu-Yu,Zhang, Fu-Min
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scheme or table
p. 2831 - 2835
(2009/05/07)
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- Short α/β-peptides as catalysts for intra- and intermolecular aldol reactions
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(Chemical Equation Presented) Short α/β-peptides, containing conformationally restricted cis-β-aminocyclopropylcarboxylic acid units as turn-inducing elements, have been found to be efficient catalysts for inter-and intramolecular aldol reactions. The tripeptide H-(L)-Pro--(L)-Pro-OH was identified to perform especially well in homogeneous and heterogeneous aqueous solutions as well as in organic solvents.
- D'Elia, Valerio,Zwicknagl, Hans,Reiser, Oliver
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p. 3262 - 3265
(2008/09/19)
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- Structural constraints for C2-symmetric heterocyclic organocatalysts in asymmetric aldol reactions
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Asymmetric aldol reactions were studied in the presence of heterocyclic bimorpholine- and bipiperidine-type organocatalysts. Bimorpholine derivatives were found to be more reactive and more selective in intramolecular, as well as intermolecular, reactions.
- Laars, Marju,Kriis, Kadri,Kailas, Tiiu,Mueuerisepp, Aleksander-Mati,Pehk, Tonis,Kanger, Tonis,Lopp, Margus
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p. 641 - 645
(2008/09/20)
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- Prolinamides versus prolinethioamides as recyclable catalysts in the enantioselective solvent-free inter- and intramolecular aldol reactions
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A solvent-free asymmetric and direct anti-aldol reaction of aliphatic ketones with aromatic aldehydes catalyzed by recyclable L-prolineamides and L-prolinethioamides 3 is studied. The L-prolinethioamide 3d (5 mol%), derived from L-Pro and (R)-1-aminoindane, is the most efficient catalyst for this process affording the anti-aldol adducts in high yields with excellent diastereo-and enantioselectivities (up to >98/2 dr, up to 98% ee) at 0°C or room temperature. Prolinethioamide 3d is an effective organocatalyst for the first asymmetric, solvent-free, intramolecular Hajos-Parrish-Eder-Sauer-Wiechert reaction with comparable or higher levels of enantioselectivity (up to 88% ee) to reported catalysts in organic solvents. Moreover, organocatalyst 3d can be easily recovered and reused by a simple acid/base extraction.
- Almasi, Diana,Alonso, Diego A.,Najera, Carmen
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supporting information; experimental part
p. 2467 - 2472
(2009/08/14)
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- Combining multi-catalysis and multi-component systems for the development of one-pot asymmetric reactions: Stereoselective synthesis of highly functionalized bicyclo[4.4.0]decane-1,6-diones
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We have developed a direct amine/acid-catalyzed stereoselective hydrogenation of a variety of Wieland-Miescher (W-M) ketones, Hajos-Parrish (H-P) ketones and their analogs with organic hydrides (Hantzsch esters) as the hydrogen source. This astonishingly simple and biomimetic approach was used to construct highly functionalized chiral bicyclo[4.4.0]decane-1,6-diones 6 in a diastereoselective fashion. This is an example of the development of a new technology by the combination of multiple catalysts and components in one pot to deliver highly functionalized chiral molecules. The Royal Society of Chemistry 2008.
- Ramachary, Dhevalapally B.,Sakthidevi, Rajasekar
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supporting information; experimental part
p. 2488 - 2492
(2009/02/02)
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- Microwave-assisted asymmetric organocatalysis. A probe for nonthermal microwave effects and the concept of simultaneous cooling
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(Chemical Equation Presented) A series of five known asymmetric organocatalytic reactions was re-evaluated at elevated temperatures applying both microwave dielectric heating and conventional thermal heating in order to probe the existence of specific or nonthermal microwave effects. All transformations were conducted in a dedicated reactor setup that allowed accurate internal reaction temperature measurements using fiber-optic probes. In addition, the concept of simultaneous external cooling while irradiating with microwave power was also applied in all of the studied cases. This method allows a higher level of microwave power to be administered to the reaction mixture and, therefore, enhances any potential microwave effects while continuously removing heat. For all of the five studied (S)-proline-catalyzed asymmetric Mannich- and aldol-type reactions, the observed rate enhancements were a consequence of the increased temperatures attained by microwave dielectric heating and were not related to the presence of the microwave field. In all cases, in contrast to previous literature reports, the results obtained either with microwave irradiation or with microwave irradiation with simultaneous cooling could be reproduced by conventional heating at the same reaction temperature and time in an oil bath. No evidence for specific or nonthermal microwave effects was obtained.
- Hosseini, Masood,Stiasni, Nikola,Barbieri, Vera,Kappe, C. Oliver
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p. 1417 - 1424
(2007/10/03)
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- Evaluating β-amino acids as enantioselective organocatalysts of the Hajos-Parrish-Eder-Sauer-Wiechert reaction
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A systematic study of the effect of substitution within the β-amino acid framework indicates that both β2- and β3- amino acids catalyse the Hajos-Parrish-Eder-Sauer-Wiechert reaction with poor to reasonable levels of enantioselectivity. These results led to the evaluation of the conformationally constrained β-amino acid (1R,2S)-cispentacin, which catalyses the Hajos-Parrish-Eder-Sauer-Wiechert reaction with comparable or higher levels of enantioselectivity to l-proline. The Royal Society of Chemistry.
- Davies, Stephen G.,Russell, Angela J.,Sheppard, Ruth L.,Smith, Andrew D.,Thomson, James E.
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p. 3190 - 3200
(2008/03/14)
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- Bimorpholine-mediated enantioselective intramolecular and intermolecular aldol condensation
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(Chemical Equation Presented) Monosalts of N-substituted bimorpholine derivatives are efficient organocatalysts in intramolecular and intermolecular aldol reactions. The properties of the catalysts can be tuned either by the selection of an appropriate acid for the salt formation or by the change of a substituent at the nitrogen atom. In aldol condensation, i-Pr-substituted bimorpholine is the most stereoselective catalyst affording products in high yield with enantioselectivities up to 95% ee.
- Kanger, Tonis,Kriis, Kadri,Laars, Marju,Kailas, Tiiu,Mueuerisepp, Aleksander-Mati,Pehk, Tonis,Lopp, Margus
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p. 5168 - 5173
(2008/02/08)
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- Synthesis and use of 3,3′-bimorpholine derivatives in asymmetric Michael addition and intramolecular aldol reaction
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The synthesis of 3,3′-bimorpholine and its N-alkyl derivatives is described. These new diamine derivatives were revealed to be efficient organocatalysts for the asymmetric Michael addition of aldehydes to nitroalkenes with excellent enantioselectivity (up to 90% ee). The potential of these organocatalysts was also demonstrated for the highly enantioselective intramolecular aldol reaction affording the Wieland-Miescher ketone with tremendous enantioselectivity (up to 95% ee). Georg Thieme Verlag Stuttgart.
- Sulzer-Mosse, Sarah,Laars, Marju,Kriis, Kadri,Kanger, Tonis,Alexakis, Alexandre
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p. 1729 - 1732
(2008/02/08)
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- An alternative chiral synthesis of Wieland-Miescher ketone mediated by (S)-2-(pyrrolidinylmethyl)pyrro-lidine: Remarkable effects of Br?nsted acid
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The enantioselectivity of the intramolecular asymmetric aldol reaction mediated by (S)-2-(pyrrolidinylmethyl)pyrrolidine to prepare Wieland-Miescher ketone was examined in detail. A remarkable inversion of enantioselectivity was observed when a Br?nsted acid was used as a co-catalyst. Development of the reaction to Robinson annulation was successfully achieved by the use of (S)-2-(pyrrolidinylmethyl)pyrrolidine as a Br?nsted base, followed by trifluoroacetic acid as a Br?nsted acid.
- Akahane, Yuichi,Inage, Naoko,Nagamine, Takashi,Inomata, Kohei,Endo, Yasuyuki
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p. 637 - 648
(2008/09/18)
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