- Concise, scalable and enantioselective total synthesis of prostaglandins
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Prostaglandins are among the most important natural isolates owing to their broad range of bioactivities and unique structures. However, current methods for the synthesis of prostaglandins suffer from low yields and lengthy steps. Here, we report a practicability-oriented synthetic strategy for the enantioselective and divergent synthesis of prostaglandins. In this approach, the multiply substituted five-membered rings in prostaglandins were constructed via the key enyne cycloisomerization with excellent selectivity (>20:1 d.r., 98% e.e.). The crucial chiral centre on the scaffold of the prostaglandins was installed using the asymmetric hydrogenation method (up to 98% yield and 98% e.e.). From our versatile common intermediates, a series of prostaglandins and related drugs could be produced in two steps, and fluprostenol could be prepared on a 20-gram scale. [Figure not available: see fulltext.]
- Zhang, Fuhao,Zeng, Jingwen,Gao, Mohan,Wang, Linzhou,Chen, Gen-Qiang,Lu, Yixin,Zhang, Xumu
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p. 692 - 697
(2021/06/01)
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- The curved front row neil intermediate preparation method
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The invention relates to a preparation method for a treprostinil intermediate (I). The preparation method comprises the steps that: a compound of a formula (II) and a compound of a formula (III) or acidic salt thereof react in the presence of a condensing agent to obtain a compound of a formula (IV); the compound of the formula (IV) and a compound of a formula (V) react to obtain a compound of a formula (I). According to the preparation method for the treprostinil intermediate, weinreb amide and alkyne negative ions react to directly obtain a ketone compound (I), so that environment pollution caused by heavy metal (a PCC oxidant) is avoided, and the adoption of a butyl lithium low-temperature reaction method is also avoided. The preparation method for the treprostinil intermediate has the advantages that reaction conditions are mild, the yield is high, the purity of products is high, and the industrial application prospect is wide. (Formulae (I), (II), (III), (IV) and (V) are shown in the specification)
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-
Paragraph 0129; 0130; 0133
(2019/04/02)
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- Total synthesis of natural (?)- and unnatural (+)-Melearoride A
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This communication details the first total synthesis of the 13-membered macrolide, (?)-Melearoride A, as well as unnatural (+)-Melearoride A. The synthesis features a concise 13 step synthesis (11 steps longest linear sequence) that offers flexible stereo-control and multiple opportunities for unnatural analog synthesis to delve into antifungal SAR. The route features a cuprate addition, an Evans asymmetric alkylation, and a ring-closing metathesis (RCM) to close the 13-membered macrocyclic core.
- Reed, Carson W.,Fulton, Mark G.,Nance, Kellie D.,Lindsley, Craig W.
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supporting information
p. 743 - 745
(2019/02/09)
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- Synthesis of treprostinil: Key claisen rearrangement and catalytic pauson-khand reactions in continuous flow
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A new synthesis of treprostinil is described using a plug flow reactor in two of the key steps. First, a Claisen rearrangement reaction is described in scaled flow at multigram amounts. Yields and selectivity of this step are sharply improved compared to those from previous syntheses. Second, the key Pauson-Khand reaction in flow is described under catalytic conditions with 5 mol% of cobalt carbonyl and only 3 equiv. of CO. Scaling up of this reaction safely ensures a good yield of an advanced intermediate which is transformed into treprostinil in three steps. Other improvements are the introduction of the carboxymethyl chain into the phenol from the beginning to reduce the protection-deprotection steps. The synthesis is completed in 14% global yield after 12 linear steps from (S)-epichlorhydrin.
- García-Lacuna, Jorge,Domínguez, Gema,Blanco-Urgoiti, Jaime,Pérez-Castells, Javier
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p. 9489 - 9501
(2019/11/14)
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- Total Synthesis of Emmyguyacins A and B, Potential Fusion Inhibitors of Influenza Virus
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Fungal glycolipids emmyguyacins A and B inhibit the pH-dependent conformational change of hemaglutinin A during replication of the Influenza virus. Herein, we report the first total synthesis and structure confirmation of emmyguyacins A and B. Our efficient route, which involves regioselective functionalization of trehalose, allows rapid access to adequate amounts of chemically pure emmyguyacin analogues including the desoxylate derivatives for SAR studies.
- Jana, Santanu,Sarpe, Vikram A.,Kulkarni, Suvarn S.
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supporting information
p. 6938 - 6942
(2018/10/25)
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- Photocatalytic Asymmetric Epoxidation of Terminal Olefins Using Water as an Oxygen Source in the Presence of a Mononuclear Non-Heme Chiral Manganese Complex
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Photocatalytic enantioselective epoxidation of terminal olefins using a mononuclear non-heme chiral manganese catalyst, [(R,R-BQCN)MnII]2+, and water as an oxygen source yields epoxides with relatively high enantioselectivities (e.g., up to 60% enantiomeric excess). A synthetic mononuclear non-heme chiral Mn(IV)-oxo complex, [(R,R-BQCN)MnIV(O)]2+, affords similar enantioselectivities in the epoxidation of terminal olefins under stoichiometric reaction conditions. Mechanistic details of each individual step of the photoinduced catalysis, including formation of the Mn(IV)-oxo intermediate, are discussed on the basis of combined results of laser flash photolysis and other spectroscopic methods.
- Shen, Duyi,Saracini, Claudio,Lee, Yong-Min,Sun, Wei,Fukuzumi, Shunichi,Nam, Wonwoo
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supporting information
p. 15857 - 15860
(2016/12/23)
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- Total synthesis of the macrocyclic n -methyl enamides palmyrolide a and 2 s -sanctolide a
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Full details of the total syntheses of the initially reported and revised structures of the neuroprotective agent palmyrolide A are reported. The key macrocyclization step was achieved using a sequential ring-closing metathesis/olefin isomerization reaction. Furthermore, the total synthesis of the related macrolide (2S)-sanctolide A is reported. The synthesis used key elements from the synthesis of palmyrolide A, including the RCM/olefin isomerization sequence. The synthetic work described herein serves to facilitate the assignment of stereochemistry of the natural product sanctolide A and demonstrates the utility of this approach for the synthesis of macrocyclic tertiary enamide natural products.
- Wadsworth, Andrew D.,Furkert, Daniel P.,Brimble, Margaret A.
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p. 11179 - 11193
(2015/01/08)
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- Bioproduction of chiral epoxyalkanes using styrene monooxygenase from rhodococcus sp. ST-10 (RhSMO)
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We describe the enantioselective epoxidation of straight-chain aliphatic alkenes using a biocatalytic system containing styrene monooxygenase from Rhodococcus sp. ST-10 and alcohol dehydrogenase from Leifsonia sp. S749. The biocatalyzed enantiomeric epoxidation of 1-hexene to (S)-1,2-epoxyhexane (44.6 mM) using 2-propanol as the hydrogen donor was achieved under optimized conditions. The biocatalyst had broad substrate specificity for various aliphatic alkenes, including terminal, internal, unfunctionalized, and di- and tri-substituted alkenes. Here, we demonstrate that this biocatalytic system is suitable for the efficient production of enantioenriched (S)-epoxyalkanes.
- Toda, Hiroshi,Imae, Ryouta,Itoh, Nobuya
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p. 3443 - 3450
(2015/02/05)
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- A mononuclear manganese complex of a tetradentate nitrogen ligand - Synthesis, characterizations, and application in the asymmetric epoxidation of olefins
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A new chiral manganese complex (C1) bearing a tetradentate nitrogen ligand containing chiral bipyrrolidine and benzimidazole moieties was prepared. The structure of C1 was confirmed by ESI-MS and crystallography. This manganese complex is an active catalyst for the asymmetric epoxidation of various olefins with excellent conversion (up to 99%) and high enantiomeric excess (up to 96%ee) with hydrogen peroxide as the oxidant in the presence of 2-ethylhexanoic acid or acetic acid. Compared with previous structurally similar manganese complexes with different diamine backbones (C2, cyclohexanediamine; C3, diamine from L-proline), C1 showed improved asymmetric induction, especially for simple olefins such as styrene derivatives and substituted chromene. The possible reasons for the improvement of the ee values are discussed in the text on the basis of the crystal structures of the manganese complexes.
- Shen, Duyi,Miao, Chengxia,Wang, Shoufeng,Xia, Chungu,Sun, Wei
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supporting information
p. 5777 - 5782
(2015/02/19)
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- Development of a concise and general enantioselective approach to 255-disubstituted-3-hydroxytetrahydrofurans
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Concise syntheses of 2,5-disubstituted-3-hydroxytetrahydrofurans have been developed that provide access to each configurational isomer of this scaffold from a single aldol adduct. Application of these methods to the rapid preparation of (6S,7S,9S,1QS)- a
- Kang, Baldip,Mowat, Jeffrey,Pinter, Thomas,Britton, Robert
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supporting information; experimental part
p. 1717 - 1720
(2009/09/06)
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- Synthesis of prostaglandin and phytoprostane B1 via regioselective intermodular pauson-khand reactions
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A new approach to the synthesis of prostaglandin and phytoprostanes B 1 is described. The key step is an intermolecular Pauson-Khand reaction between a silyl-protected propargyl acetylene and ethylene. This reaction, promoted by NMO in the presence of 4 A molecular sieves, afforded the 3-fert-butyldimethylsilyloxymethyl-2-substituted-cyclopent-2-en-1- ones (III) in good yield and with complete regioselectivity. Deprotection of the silyl ether, followed by Swern oxidation, gave 3-formyl-2-substituted- cyclopent-2-en-1-ones (II). Julia olefination of the aldehydes II with the suitable chiral sulfone enabled preparation of PPB1 type I and PGB1.
- Vazquez-Romero, Ana,Cardenas, Lydia,Blasi, Emma,Verdaguer, Xavier,Riera, Antoni
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supporting information; experimental part
p. 3104 - 3107
(2009/12/05)
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- Total synthesis and biological evaluation of the cytotoxic resin glycosides ipomoeassin A-F and analogues
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A multitasking C-silylation strategy using the readily available compound 26 as a surrogate for cinnamic acid represents the key design element of a total synthesis of all known members of the ipomoeassin family of resin glyosides. This protecting group maneuver allows the unsaturated acids decorating the glucose subunit of the targets to be attached at an early phase of the synthesis, prevents their participation in the ruthenium-catalyzed ring-closing metathesis (RCM) used to form the macrocyclic ring, and protects them against reduc tion during the hydrogenation of the resulting cycloalkene over Wilkinson's catalyst. As the C-silyl group can be concomitantly removed with the O-TBS substituent using tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF) in acetonitrile, no separate protecting group manipulations were necessary in the final stages, thus contributing to a favorable overall "economy of steps". In addition to the naturally occurring ipomoeassins, a small set of synthetic analogues has also been prepared by "diverted total synthesis". The cytotoxicity of these compounds was assayed with two different cancer cell lines. The recorded data confirm previous findings that the acylation- and oxygenation pattern of these amphiphilic glycoconjugates is highly correlated with their biological activity profile. Ipomoeassin F turned out to be the most promising member of the series, showing IC50 values in the low nanomolar range.
- Nagano, Takashi,Pospisil, Jiri,Chollet, Guillaume,Schulthoff, Saskia,Hickmann, Volker,Moulin, Emilie,Herrmann, Jennifer,Mueller, Rolf,Fuerstner, Alois
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supporting information; experimental part
p. 9697 - 9706
(2010/04/29)
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- Method of preparation of an alkyne with an optically active hydroxyl group in the beta or gamma position of a triple bond and intermediates obtained
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The present invention relates to a method of preparation of an alkyne with an optically active hydroxyl group in the β or γ position of a triple bond and intermediates obtained. The method of the invention for preparation of an alkyne with an optically active hydroxyl group in the β position of a triple bond is characterized in that it comprises the reaction, in the presence of a Lewis acid: of a compound of formula (IV): in which: R is a linear or branched alkyl group having from 1 to 6 carbon atoms. and of a compound of formula (V): [in-line-formulae]R′—C≡C-M ??(V) [/in-line-formulae]in which: R′ represents a hydrogen atom, a linear or branched alkyl group having from 1 to 8 carbon atoms, preferably a methyl group or a trialkylsilyl group. M represents a metal, preferably a metal of group (Ia) of the periodic table, preferably lithium. Another object of the invention comprises the production of an alkyne with an optically active hydroxyl group in the γ position of a triple bond by isomerization of an alkyne with an optically active hydroxyl group in the β position previously obtained.
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Page/Page column 7
(2010/11/25)
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- Syntheses of the macrolide subunits of merremoside-type resin glycosides
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The 20- and 21-membered macrolide subunits of merremoside-type resin glycosides with interesting bioactivity were synthesized via a macrolactonization approach using Corey-Nicolaou protocol in 14 steps with overall yields of 0.7% for 17 and 3.5% for 18 fr
- Zhu, Xing-Mei,He, Li-Li,Yang, Guang-Li,Lei, Ming,Chen, Si-Shi,Yang, Jin-Song
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p. 3510 - 3512
(2007/10/03)
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- Enantioselective epoxidation of terminal alkenes to (R)- and (S)-epoxides by engineered cytochromes P450 BM-3
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Cytochrome P450 BM-3 from Bacillus megaterium was engineered for enantioselective epoxidation of simple terminal alkenes. Screening saturation mutagenesis libraries, in which mutations were introduced in the active site of an engineered P450, followed by recombination of beneficial mutations generated two P450 BM-3 variants that convert a range of terminal alkenes to either (R)- or (S)epoxidc (up to 83 % ee) with high catalytic turnovers (up to 1370) and high epoxidation selectivities (up to 95%). A biocatalytic system using E. coli lysates containing P450 variants as the epoxidation catalysts and in vitro NADPH regeneration by the alcohol dehydrogenase from Thermoanaerobium brockii generates each of the epoxide enantiomers, without additional cofactor.
- Kubo, Takafumi,Peters, Matthew W.,Meinhold, Peter,Arnold, Frances H.
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p. 1216 - 1220
(2007/10/03)
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- Enantioselective hydrolysis of unbranched aliphatic 1,2-epoxides by Rhodotorula glutinis
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Epoxide hydrolase catalysed resolution of aliphatic terminal epoxides has been demonstrated for the hydrolysis of a homologous range of unbranched 1,2-epoxyalkanes by the yeast Rhodotorula glutinis. Both enantioselectivity and reaction rate were strongly influenced by the chain length of the epoxide used. Enantioselectivity showed an optimum in the hydrolysis of 1,2- epoxyhexane (E=84). Resolution of (±)-1,2-epoxyhexane resulted in (S)-1,2- epoxyhexane (e.e.>98%, yield=48%) and (R)-1,2-hexanediol (e.e.=83%, yield=47%).
- Weijers,Botes,Van Dyk,De Bont
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p. 467 - 473
(2007/10/03)
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- The First Total Synthesis of Tricolorin A
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Keywords: glycosylations; macrocycles; one-pot reactions; total synthesis; tricolorin A
- Lu, Shou-Fu,O'yang, QinQin,Guo, Zhong-Wu,Yu, Biao,Hui, Yong-Zheng
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p. 2344 - 2346
(2007/10/03)
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- Total synthesis of tricolorin A
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Tricolorin A (1), a structurally amazing resin glycoside with promising bioactivities from Ipomoea tricolor cav. (convolvulaceae), was synthesized in a total of 45 steps, with the longest linear sequence of 20 steps and overall yield of 0.65% from D-mannitol. The AB disscharide 19-membered lactone 2 was constructured by a regioselective macrolactonization using Corey-Nicolaou protocol. The macrolactone tetrasaccharide 33 was realized either by 'one- pot two-step' glycosylation procedure or by a stepwise assembly employing the 'armed-disarmed' glycosylation strategy.
- Lu, Shou-Fu,O'Yang, QinQin,Guo, Zhong-Wu,Yu, Biao,Hui, Yong-Zheng
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p. 8400 - 8405
(2007/10/03)
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- Enantioselective Synthesis of (R)-(+)-Pulvilloric Acid
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The fungal metabolite (R)-(+)-pulvilloric acid was synthesized for the first time.Reaction of the Grignard reagent of 5 with 2-pentyloxirane (S)-(-)-4 in the presence of 1,5-cyclooctadienecopper(I) chloride as the catalyst led to (S)-(+)-6.The ena
- Roedel, Thomas,Gerlach, Hans
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p. 213 - 216
(2007/10/03)
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- Enzyme Assisted Synthesis of Enantiomerically Pure δ-Lactones
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Both enantiomers series of a wide variety of optically pure 6-alkylated δ-lactones - saturated as well as unsaturated - were prepared via an enzyme mediated route.The key reaction step is the nucleophilic ring opening of enantiomerically pure alkyl-oxiranes, accessible via the corresponding β-hydroxythioesters which can be obtained enantiomerically pure via enzyme catalyzed kinetic resolutions.
- Haase, Bernhard,Schneider, Manfred P.
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p. 1017 - 1026
(2007/10/02)
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- Enantioselective synthesis of epoxides via Sharpless epoxidation of alkenylsilanols
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Enantioselective synthesis of simple epoxides can be achieved by Sharpless epoxidation of alkenylsilanols followed by protodesilylation of the chiral epoxysilanols.The approach has been applied to the synthesis of frontalin.
- Chan, T. H.,Chen, L. M.,Wang, D.,Li, L. H.
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- A CONVENIENT SYNTHESIS OF HOMOCHIRAL δ-ALKYLATED α,β-UNSATURATED δ-LACTONES
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The tert-butyl propiolate ion serves as a convenient and efficient nucleophile in boron trifluoride-catalyzed openings of homochiral, mono-substituted epoxides.The resulting tert-butyl 5-hydroxy-2-alkynoates are converted into the title compounds upon semihydrogenation followed by acid hydrolysis.Specific examples include the synthesis of parasorbic acid and massoilactone, two naturally derived lactones of the present type.The scope of the synthetic protocol is discussed.
- Hoeyer, Thomas,Kjaer, Anders,Lykkesfeldt, Jens
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p. 1042 - 1051
(2007/10/02)
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