- Total syntheses of the sesquiterpenes β-corymbolol and corymbolone
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The first total synthesis of racemic corymbolone, an eudesmane sesquiterpene isolated from Cyperus species used in traditional medicine to treat many diseases, is reported. In the developed sequence, the immediate precursor of corymbolone is the diol β-corymbolol, an epimer at C1 of the natural α-corymbolol. Thus, starting from the readily available Wieland-Miescher Ketone, the title compounds were achieved in 11 and 12 steps, respectively, in ca. 3% overall yield.
- Ferraz, Helena M.C.,Souza, Antonio J.C.,Tenius, Beatriz S.M.,Bianco, Graziela G.
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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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- Discovery of New Carbonyl Reductases Using Functional Metagenomics and Applications in Biocatalysis
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Enzyme discovery for use in the manufacture of chemicals, requiring high stereoselectivities, continues to be an important avenue of research. Here, a sequence directed metagenomics approach is described to identify short chain carbonyl reductases. PCR from a metagenomic template generated 37 enzymes, with an average 25% sequence identity, twelve of which showed interesting activities in initial screens. Six of the most productive enzymes were then tested against a panel of 21 substrates, including bulkier substrates that have been noted as challenging in biocatalytic reductions. Two enzymes were selected for further studies with the Wieland Miescher ketone. Notably, enzyme SDR-17, when co-expressed with a co-factor recycling system produced the anti-(4aR,5S) isomer in excellent isolated yields of 89% and 99% e.e. These results demonstrate the viability of a sequence directed metagenomics approach for the identification of multiple homologous sequences with low similarity, that can yield highly stereoselective enzymes with applicability in industrial biocatalysis. (Figure presented.).
- Newgas, Sophie A.,Jeffries, Jack W. E.,Moody, Thomas S.,Ward, John M.,Hailes, Helen C.
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p. 3044 - 3052
(2021/04/26)
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- Total synthesis of JBIR-03 and asporyzin C
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The first enantioselective total synthesis of JBIR-03 and asporyzin C, indole diterpenoids of fungal origin exhibiting a range of pharmacologically important biological activities, has been accomplished from a known bicyclic keto alcohol in 13 and 14 steps, respectively. A hydroxy-directed cyclopropanation and Pd(II)-mediated indole ring formation were exploited as the key steps to obtain a pivotal pentacylic intermediate, which was converted into asporyzin C via chain elongation using cross-metathesis and then into JBIR-03 by Pd(II)-catalyzed tetrahydrofuran ring formation in an exclusively diastereoselective manner.
- Murokawa, Tetsuro,Enomoto, Masaru,Teranishi, Takaaki,Ogura, Yusuke,Kuwahara, Shigefumi
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p. 4107 - 4109
(2018/10/15)
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- Study of Cascade Ring-Closing Metathesis Reactions en Route to an Advanced Intermediate of Taxol
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A highly functionalized intermediate in the synthesis of Taxol has been synthesized, which features the tricyclic core and the required oxygen substituents at C1, C2, C7, C10, and C13. The key step, a ring-closing dienyne metathesis (RCDEYM) reaction, has
- Letort, Aurélien,Long, De-Liang,Prunet, Jo?lle
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p. 12318 - 12331
(2016/12/23)
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- CONTRACEPTIVE AGENTS
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The invention provides compounds of formula I, II, III, or IV: wherein R1 to R11, X, and Y have any of the values defined in the specification. The compounds inhibit Na, K-ATPase α4 and are useful as contraceptive agents.
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Paragraph 0201-0202
(2014/02/15)
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- Viridin analogs derived from steroidal building blocks
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Naturally occurring furanosteroids such as viridin and wortmannin have long been known as potent inhibitors of the lipid kinase PI-3K. We have been interested in directly accessing analogs of these complex natural products from abundant steroid feedstock materials. In this communication, we describe the synthesis of viridin/wortmannin hybrid molecules from readily available building blocks that function as PI-3K inhibitors and maintain their electrophilic properties. The compounds also show anti-proliferative effects against a breast cancer line.
- Viswanathan, Kishore,Ononye, Sophia N.,Cooper, Harold D.,Kyle Hadden, M.,Anderson, Amy C.,Wright, Dennis L.
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p. 6919 - 6922,4
(2020/09/02)
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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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- Dowex 50WX4-100: An efficient catalyst for the tetrahydropyranylation of alcohols
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The ion-exchange resin Dowex 50WX4-100 has been found to catalyze efficiently the protection reaction of a variety of alcohols with 2,3-dihydro-4H pyran (DHP) and dichloromethane at ambient conditions. Copyright Taylor & Francis Group, LLC.
- Poon,Banerjee, Ajoy K.,Bedoya, Liadis,Laya, Manuel S.,Cabrera, Elvia V.,Albornoz, Karla M.
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experimental part
p. 3369 - 3377
(2011/03/19)
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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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- An expedient enantioselective strategy for the oxatetracyclic core of platensimycin
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An enantioselective route for the synthesis of oxatetracyclic core of platensimycin is reported for the first time using a 5-exo-trig cyclization followed by intramolecular etherification as key reactions. The requisite dienynone for the radical cyclizati
- Kaliappan, Krishna P.,Ravikumar, Velayutham
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p. 2417 - 2419
(2008/02/07)
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- Studies directed toward the synthesis of terreulactone A: Rapid construction of the A, B, C rings
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An efficient, rapid synthesis of the A, B, C rings of terreulactone A is described. Key steps in the synthesis include a diastereoselective benzylic acid rearrangement to create the desired quaternary center at C2 and a mild bromolactonization
- Liu, Haibo,Siegel, Dionicio R.,Danishefsky, Samuel J.
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p. 423 - 425
(2007/10/03)
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- The hydroxylation of the enantiomeric hexahydro-10-methylnaphthal-4-en-3- ones by Cephalosporium aphidicola
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The enantiomeric hexahydro-10-methylnaphthal-4-en-3-ones are hydroxylated by the fungus, Cephalosporium aphidicola at C-6 and at C-9 (steroid-like enantiomer) or at C-1 (steriod enantiomer).
- Parvez, Aslam,Hanson, James R.
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p. 647 - 648
(2007/10/03)
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- A convenient chemoenzymatic synthesis of (4aS,5S)-(+)-4,4a,5,6,7,8-hexahydro-5-hydroxy-4a-methylnaphthalen-2(3H)-one
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We have developed a convenient chemoenzymatic method for the preparation of (4aS,5S)-4,4a,5,6,7,8-hexahydro-5-hydroxy-4a-methylnaphthalen-2(3H)-one by taking advantage of the excellent enantioselectivity of alcalase. Four different esters were compared, and the butanoate ester was found to be the best substrate. The stereochemistry of the product is the same as the one predicted from the binding model of alcalase. A simple extraction/partition procedure was used to separate the hydroxyenone product from the remaining ester. This practical procedure would be very useful in a gram-scale operation for securing the title compound in high optical purity.
- Lo, Lee-Chiang,Shie, Jung-Jing,Chou, Tzyy-Chao
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p. 282 - 285
(2007/10/03)
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- Enzymatic resolution of cis- and trans-1,2,3,4,6,7,8,8a-octahydro-8a-methyl-6-oxo-naphthyl acetate derivatives
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Extensive screenings using commercially available enzymes were performed in relation to the asymmetric hydrolysis reactions of the (±)-cis- (1, 3 and 5) and (±)-trans-1,2,3,4,6,7,8,8a-octahydro-8a-methyl-6-oxo-naphthyl acetates (7, 9 and 11). The combinations of enzymes from plants and cis-equatorial compounds as well as the combinations of lipases from microorganisms and trans-axial-5-methoxycarbonyl acetate showed high enantiomeric ratio in asymmetric hydrolysis. However, the enantiomeric ratio of the combinations of lipases from microorganisms and trans-axial isomers except trans-axial-5-methoxycarbonyl derivative was less satisfactory. High E values (>200) were observed when β-amylase from wheat and lipase from Candida cylindracea were used for the (±)-cis-acetate 1 and the (±)-trans-isomer 7, respectively, to obtain the corresponding chiral products with high enantiomeric ratios (>99:1).
- Shimizu, Nobuko,Akita, Hiroyuki,Kawamata, Takeshi
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p. 2123 - 2131
(2007/10/03)
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- Synthesis of the AB-ring of 9,11-secosterols
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The first total synthesis of AB-ring system of an antiproliferative and cytotoxic 9,11-secosterol 1 is described. Enantiomerically pure (3S,5S,6S,10S)-3,6-diacetoxy-10-methylbicyclo[4.4.0]decan-9-one8 (steroidal numeration) was prepared from (S)-Wieland-Miescher ketone.
- Aav, Riina,Kanger, T?nis,Pehk, T?nis,Lopp, Margus
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p. 529 - 531
(2007/10/03)
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- Efficient kinetic resolution of (±)-4-methyl-Hajos-Parrish ketone by baker's yeast reduction
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Kinetic resolution of (±)-4-methyl-Hajos-Parrish ketone (±)-2a using baker's yeast reduction was investigated. The reaction rate and enantiomeric purity depended on the concentration of substrate and yeast. Under concentrated conditions, (-)-2a and the alcohol (+)-3 were obtained in high enantiomeric excess. Copyright (C) 2000 Elsevier Science Ltd.
- Hioki, Hideaki,Hashimoto, Takefumi,Kodama, Mitsuaki
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p. 829 - 834
(2007/10/03)
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- Access to Wieland-Miescher ketone in an enantiomerically pure form by a kinetic resolution with yeast-mediated reduction
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Both enantiomers of Wieland-Miescher ketone [3,4,8,8a-tetrahydro-8a- methyl-1,6(2H, 7H)-naphthalenedione], in a highly enantiomerically enriched form, became readily available by a newly developed kinetic resolution with yeast-mediated reduction. From a screening of yeast strains, Torulaspora delbrueckii IFO 10921 was selected. The collected cells of this strain, obtained by an incubation in a glucose medium, smoothly reduced only the isolated carbonyl group of the (S)enantiomer, while the (R)-enantiomer remained intact. Starting from both enantiomers (~70% ee) prepared by an established proline-mediated asymmetric Robinson annulation, the reduction with T. delbrueckii gave the (R)-enantiomer (98% ee) and the corresponding alcohol (4aS,5S)-4,4a,5,6,7,8-hexahydro-5-hydroxy-4a-methyl-2(3H)- naphthalenone (94% ee, 94% de) in preparative scale in nearly quantitative yields. An approach for the asymmetric synthesis of the Wieland-Miescher ketone was also successful. 2-Methyl-2-(3-oxobutyl)-1,3-cyclohexanedione, the prochiral precursor, was reduced with this strain to give a cyclic acetal form of (2S,3S)-3-hydroxy-2-methyl-2-(3-oxobutyl)cyclohexanone, in a stereomerically pure form.
- Fuhshuku, Ken-Ichi,Funa, Nobutaka,Akeboshi, Tomohiro,Ohta, Hiromichi,Hosomi, Hiroyuki,Ohba, Shigeru,Sugai, Takeshi
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p. 129 - 135
(2007/10/03)
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- Total synthesis of (-)-hispanolone and an improved approach towards prehispanolone
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On the basis of the recently reported construction of (±)-hispanolone (2), the enantiomerically pure form of (-),2, employed in our partial synthesis of the specific platelet activating factor receptor antagonist prehispanolone (3), was prepared from (S)-
- Cheung, Wing Shun,Wong, Henry N. C.
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p. 11001 - 11016
(2007/10/03)
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- Steric and complexation effects on the 1,4-addition reaction of lithium dimethylcuprate with rigid α,β-unsaturated ketones
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Reaction of lithium dimethylcuprate with a series of substituted 10- methyl-l(9)-octal-2-ones in diethyl ether give 1,4-addition products with the same ring junction stereochemistry as the parent, unsubstituted α,β- unsaturated ketone. The reactivity of the system is modified by groups positioned axially and 1,3 with respect to the β-carbon of the enone. Alkoxy substituents are generally activating, particularly if they are syn with respect to the incoming methyl group.
- Vellekoop, A. Samuel,Smith, Robin A.J.
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p. 11971 - 11994
(2007/10/03)
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- Efficient method for inversion of secondary alcohols by reaction of chloromethanesulfonates with cesium acetate
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Inversion of a variety of secondary alcohols using the (chloromethylsulfonyl)oxy group as a favorable leaving group with cesium acetate in the presence of 18-crown-6 has been performed to give the inverted acetates in high yields.
- Shimizu, Takeshi,Hiranuma, Sayoko,Nakata, Tadashi
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p. 6145 - 6148
(2007/10/03)
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- Total synthesis of baccatin III and taxol
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An intramolecular Heck reaction (90 → 91) serves as the key step in the total synthesis of the titled compounds. The synthetic route is based on utilizing the Wieland-Miescher ketone (5) as a matrix to provide the C and D rings of the targets and to provide functionality implements for joining this sector to an A ring precursor (6). Catalytically induced enantiotopic control and early emplacement of the oxetane are other features of the route.
- Danishefsky, Samuel J.,Masters, John J.,Young, Wendy B.,Link,Snyder, Lawrence B.,Magee, Thomas V.,Jung, David K.,Isaacs, Richard C. A.,Bornmann, William G.,Alaimo, Cheryl A.,Coburn, Craig A.,Di Grandi, Martin J.
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p. 2843 - 2859
(2007/10/03)
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- Ring expansion by tandem double Tebbe-Claisen technology
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2-Cyclohexenone rings that form part of a larger structural assembly are amenable to peracid oxidation with formation of an epoxy lactone.These intermediates are readily transformed under acidic, basic, or neutral conditions to ring-contracted aldehydo lactones, which are then subjected to condensation with a slight excess of Tebbe reagent.These conditions result in methylenation of carbonyl groups and set the stage for operation of a Claisen rearrangement.When the latter is catalyzed by Tribal, the sigmatropic process occurs at room temperature.With systems typified by 17 and 24, the isomerization is complete within 15 min.The pre sence of a proximate angular methyl group as in 9b, 29, and 37 exerts a retarding kinetic effect.In such examples, a period of 6 h is required to achieve completion.Swern oxidation completes the conversion to the 4-cyclooctenones, where the two carbons stemming from the Tebbe reagent are inserted bewtween the original carbonyl and α-olefinic carbons.The overall process is tolerant of ether functionality and additional sites of unsaturation.
- Paquette, Leo A.,Philippo, Christophe M. G.,Vo, Nha Huu
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p. 1356 - 1365
(2007/10/02)
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- Chemoselective reductions with sodium borohydride
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Under the appropriate reaction conditions, sodium borohydride is a highly chemoselective reducing agent.The order of reactivity among carbonyl groups is conjugated enonesketonesconjugated aldehydesaldehydes.In general, a carbonyl group of one type can be selectively reduced in the presence of a carbonyl group of a less reactive type.Reactions are conducted with excess sodium borohydride at -78 deg C in solvent mixtures of methanol or ethanol in dichloromethane.Key words: sodium borohydride, chemoselective reductions.
- Ward, Dale E.,Rhee, Chung K.
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p. 1206 - 1211
(2007/10/02)
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- An Enantioselective Total Synthesis of (+)-Atisirene by Intramolecular Double Michael Reaction
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1,6-Conjugate addition of 2-methoxybenzylmagnesium bromide to 4-methylene-3,5,5-trimethylcyclohex-2-enone (7), followed by hydrocyanation, gave (+/-)-(1RS,2SR)-2--1,3,3-trimethyl-5-oxocyclohexanecarbonitrile (9), which was conver
- Ihara, Masataka,Toyota, Masahiro,Fukumoto, Keiichiro,Kametani, Tetsuji
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p. 2151 - 2162
(2007/10/02)
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- OXIDATION OF ALKENES TO ENONES USING tert-BUTYL HYDROPEROXIDE IN THE PRESENCE OF CHROMIUM CARBONYL CATALYSTS
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Treatment of alkenes with t-butyl hydroperoxide in the presence of Cr(CO)6 or Cr(CO)x(CH3CN)y species results in oxidation of allylic methylene groups to give α,β-unsaturated ketones, selectively in the presence of certain alcohols, and in moderate to excellent yields.
- Pearson, Anthony J.,Chen, Yong-Shin,Hsu, Shih-Ying,Ray, Tapan
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p. 1235 - 1238
(2007/10/02)
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- METAL-ASSISTED REACTIONS-12. UNUSUAL SELECTIVITY IN THE REDUCTION OF KETONES WITH ZINC OR CADMIUM BIS-TETRAHYDROBORATE/DIMETHYLFORMAMIDE COMPLEX
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Zinc bis-tetrahydroborate forms a solid complex with dimethylformamide (DMF) of composition, Zn(BH4)2*1.5DMF.Unlike zinc bis-tetrahydroborate itself, the complex with DMF can be stored as a solid at room temperature.Ketones and aldehydes are reduced to the corresponding alcohols by the complex but the mechanism of reduction appears to be different from that using zinc bis-tetrahydroborate itself and from other tetrahydroborates in that only one hydride equivalent from each BH4- unit is utilized and not four.Further, although saturated aliphatic ketones are reduced rapidly to alcohols, aromatic ketones react much more slowly and α,β-unsaturated ketones react very slowly so that the complex appears to have selective reducing potential with regard to different classes of ketones.It is also apparent that the zinc bis-tetrahydroborate/DMF complex reduces sterically hindered saturated ketones much more slowly than it does unhindered ketones.An analogous cadmium bis-tetrahydroborate/DMF complex can be prepared in solution and reacts with ketones similarly to the zinc complex.
- Hussey, Brendan J.,Johnstone, Robert A. W.,Boehm, Peter,Entwistle, Ian D.
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p. 3769 - 3774
(2007/10/02)
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