- Synthesis and inhibition studies of sulfur-substituted squalene oxide analogues as mechanism-based inhibitors of 2,3-oxidosqualene-lanosterol cyclase
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The synthesis and biological evaluation of three new sulfur-substituted oxidosqualene (OS) analogues (1-3) are presented. In these analogues, C-11, C-15, or C-18 in the OS skeleton was replaced by sulfur. The sulfur position in the OS skeleton was chosen to disrupt one or more key processes involved in cyclization: (a) the folding of the B-ring into a boat conformation, (b) the anti-Markovnikov cyclization leading to the C-ring, or (c) the formation of the D-ring during the lanosterol biosynthesis. Enzyme inhibition kinetics using homogeneous mammalian oxidosqualene cyclases (OSC) were also examined for the previously reported S-19 analogue 4. The four analogues were potent inhibitors of mammalian OSCs (IC50 = 0.05-2.3 μM for pig and rat liver OSC) and fungal cell-free Candida albicans OSC (submicromolar IC50 values). In particular, the S-18 analogue 3 showed the most potent inhibition toward the rat liver enzyme (IC50 = 50 nM) and showed potent, selective inhibition against the fungal enzyme (IC50 = 0.22 nM, 10-fold more potent than the S- 19 analogue 4). Thus, 3 is the most potent OSC inhibitor known to date. The K(i) values ranged from 0.5 to 4.5 μM for pig OSC, with 3 and 4 showing about 10-fold higher potency for rat liver OSC. Interestingly, the S-18 analogue 3 showed time-dependent irreversible inhibition with homogeneous pig liver OSC (k(inact) = 0.06 min-1) but not with rat OSC.
- Stach, Dirk,Zheng, Yi Feng,Perez, Alice L.,Oehlschlager, Allan C.,Abe, Ikuro,Prestwich, Glenn D.,Hartman, Peter G.
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- Stereoselective Directed Cationic Cascades Enabled by Molecular Anchoring in Terpene Cyclases
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Cascade reactions appeared as a cutting-edge strategy to streamline the assembly of complex structural scaffolds from naturally available precursors in an atom-, as well as time, labor- and cost-efficient way. We herein report a strategy to control cation
- Schneider, Andreas,Jegl, Philipp,Hauer, Bernhard
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supporting information
p. 13251 - 13256
(2021/04/30)
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- Asymmetric Cation-Olefin Monocyclization by Engineered Squalene–Hopene Cyclases
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Squalene–hopene cyclases (SHCs) have great potential for the industrial synthesis of enantiopure cyclic terpenoids. A limitation of SHC catalysis has been the enzymes’ strict (S)-enantioselectivity at the stereocenter formed after the first cyclization step. To gain enantio-complementary access to valuable monocyclic terpenoids, an SHC-wild-type library including 18 novel homologs was set up. A previously not described SHC (AciSHC) was found to synthesize small amounts of monocyclic (R)-γ-dihydroionone from (E/Z)-geranylacetone. Using enzyme and process optimization, the conversion to the desired product was increased to 79 %. Notably, analyzed AciSHC variants could finely differentiate between the geometric geranylacetone isomers: While the (Z)-isomer yielded the desired monocyclic (R)-γ-dihydroionone (>99 % ee), the (E)-isomer was converted to the (S,S)-bicyclic ether (>95 % ee). Applying the knowledge gained from the observed stereodivergent and enantioselective transformations to an additional SHC-substrate pair, access to the complementary (S)-γ-dihydroionone (>99.9 % ee) could be obtained.
- Aeberli, Natalie,Berweger, Raphael,Bornscheuer, Uwe T.,Buller, Rebecca,Dossenbach, Sandro,Eichenberger, Michael,Eichhorn, Eric,Flachsmann, Felix,Hüppi, Sean,Hortencio, Lucas,Patsch, David,Voirol, Francis,Vollenweider, Sabine
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supporting information
p. 26080 - 26086
(2021/09/20)
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- BIOSYNTHESIS OF CHEMICALLY DIVERSIFIED NON-NATURAL TERPENE PRODUCTS
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The disclosure relates to compounds of the formulae (l)-(IV) and their use as substrates for making terpenoids. New substrates for terpene biosynthesis and methods for making new types of terpenes are described herein. Diterpenes occupy a unique molecular
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Page/Page column 123-124
(2021/05/15)
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- Capturing the Monomeric (L)CuH in NHC-Capped Cyclodextrin: Cavity-Controlled Chemoselective Hydrosilylation of α,β-Unsaturated Ketones
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The encapsulation of copper inside a cyclodextrin capped with an N-heterocyclic carbene (ICyD) allowed both to catch the elusive monomeric (L)CuH and a cavity-controlled chemoselective copper-catalyzed hydrosilylation of α,β-unsaturated ketones. Remarkably, (α-ICyD)CuCl promoted the 1,2-addition exclusively, while (β-ICyD)CuCl produced the fully reduced product. The chemoselectivity is controlled by the size of the cavity and weak interactions between the substrate and internal C?H bonds of the cyclodextrin.
- Bistri-Aslanoff, Olivia,Derat, Etienne,Leloux, Sébastien,Leyssens, Tom,Ménand, Micka?l,Meijide Suárez, Jorge,Riant, Olivier,Roland, Sylvain,Sollogoub, Matthieu,Xu, Guangcan,Zhang, Pinglu,Zhang, Yongmin
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p. 7591 - 7597
(2020/03/23)
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- Diastereo- and Enantioselective Cross-Couplings of Secondary Alkylcopper Reagents with 3-Halogeno-Unsaturated Carbonyl Derivatives
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Chiral secondary alkylcopper reagents were prepared from the corresponding alkyl iodides with retention of configuration by an I/Li-exchange using tBuLi (?100 °C, 1 min) followed by a transmetalation with CuBr?P(OEt)3 (?100 °C, 20 s). These ste
- Kremsmair, Alexander,Skotnitzki, Juri,Knochel, Paul
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supporting information
p. 11971 - 11973
(2020/09/07)
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- Adult Monochamus alternatus attractant and preparation method thereof
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The invention discloses an adult Monochamus alternatus attractant and a preparation method thereof, and belongs to the technical field of insect attractant production. The main effective component ofthe adult Monochamus alternatus attractant is an artificially synthesized compound having a high attracting effect on Monochamus alternatus, and comprises a botanical compound and a diluent. The attractant has the advantages of reasonability in proportioning and high trapping efficiency, and can efficiently monitor, trap and kill adult Monochamus alternatus. The invention also provides a synthesisroute and the synthesis method of the artificially synthesized compound with the high attracting effect on Monochamus alternatus. The adult Monochamus alternatus attractant is prepared from geranylacetone, a reducing agent and acetyl chloride. The method has the advantages of simple raw materials, environmentally friendly steps, high production efficiency and good industrial application prospect,can be used for preparing the adult Monochamus alternatus attractant on a large scale, and has high practical application values.
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Paragraph 0025-0034
(2020/02/29)
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- Enantioselective synthesis and absolute configuration of the sex pheromone of Hedypathes betulinus (Coleoptera: Cerambycidae)
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The male-produced sex pheromone of Hedypathes betulinus was identified as a mixture of (E)-6,10-dimethyl-5,9-undecadien-2-one (geranylacetone) (1) and its respective alcohol (2) and acetate (3). Kinetic resolution of alcohol (2) promoted by CAL-B in organic media provided both, (R)-(-)-(E)-6,10-dimethyl-5,9- undecadien-2-yl acetate (3) and (S)-(+)-(E)-6,10-dimethyl-5,9-undecadien-2-ol (2) in high enantiomeric purity. Comparative GC analysis using a chiral column revealed the natural constituents as being (R)-(3) and a mixture of (R)- and (S)-(2) in a ratio of 82.3% and 17.6%, respectively.
- Vidal, Diogo M.,Fonseca, Marcy G.,Zarbin, Paulo H.G.
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supporting information; experimental part
p. 6704 - 6706
(2011/02/23)
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- Biomimetic syntheses from squalene-like precursors: Synthesis of ent- abudinol B and reassessment of the structure of muzitone
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We achieved the stereoselective syntheses of two different structural patterns corresponding to the enantiomers of the marine natural products abudinol B and muzitone, by developing two-directional tandem biomimetic cyclizations of polyepoxides of squalene analogues in which one alkene was functionalized as an enolsilane. In the course of this work, we demonstrated that the structure of muzitone was misassigned.
- Boone, Matthew A.,Tong, Rongbiao,McDonald, Frank E.,Lense, Sheri,Cao, Rui,Hardcastle, Kenneth I.
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supporting information; experimental part
p. 5300 - 5308
(2010/06/17)
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- Male produced pheromone in Tetropium fuscum (F.) and Tetropium cinnamopterum (Kirby) (Coleoptera: Cerambycidae)
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Described herein is (E)-6,10-dimethyl-5,9-undecadien-2-ol (geranyl acetol), termed here fuscumol, which has been identified as a male-produced pheromone emitted by Tetropium fuscum (F.) and Tetropium cinnamopterum. Also described are novel derivatives thereof e.g. esters, methods for the synthesis thereof and to a composition comprising fuscumol plus host volatiles e.g. a synthetic blend of monoterpenes plus ethanol, for attracting male and female T. fuscum and female T. cinnamopterum.
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Page/Page column 5
(2009/04/24)
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- Total syntheses of durgamone, nakorone, and abudinol B via biomimetic oxa- and carbacyclizations
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The first biomimetic total syntheses of ent-nakorone, ent-durgamone, and ent-abudinol B were accomplished by combining features of tandem polyepoxide cyclization with biomimetic polyene cyclization. The present biomimetic synthesis route offers efficient
- Tong, Rongbiao,Valentine, Jason C.,McDonald, Frank E.,Cao, Rui,Fang, Xikui,Hardcastle, Kenneth I.
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p. 1050 - 1051
(2007/10/03)
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- Enantioselective reduction of aromatic and aliphatic ketones catalyzed by ruthenium complexes attached to β-cyclodextrin
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Water-soluble chiral Ru complexes with a β-cyclodextrin unit have been shown to catalyze the reduction of aliphatic ketones (see scheme) with up to 97% ee and in good to excellent yields in the presence of sodium formate. The β-cyclodextrin unit is an essential component of the catalyst. It contributes to the unprecedented levels of enantioselectivity observed through the preorganization of the substrates in the hydrophobic cavity.
- Schlatter, Alain,Kundu, Mrinal K.,Woggon, Wolf-D.
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p. 6731 - 6734
(2007/10/03)
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- Chlorosulfonic acid as a convenient electrophilic olefin cyclization agent
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Among several sulfonic acids studied (MeSO3H, p-TsOH, H2SO4, ClSO3H, FSO3H), the scarcely used chlorosulfonic acid showed to be an efficient agent for electrophilic olefin cyclizations with internal nucleophilic termination, in a similar manner that is well-established with fluorosulfonic acid. Its availability, lower price and relatively lesser handling problems makes ClSO3H an advantageous cyclizing agent particularly for high-scale applications. The stereochemical outcome of these cyclizations has been rationalized.
- Linares-Palomino, Pablo J.,Salido, Sofía,Altarejos, Joaquín,Sánchez, Adolfo
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p. 6651 - 6655
(2007/10/03)
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- First total synthesis of (±) Hedaol B
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Hedaol B, a new bisnorditerpene isolated from the Japanese brown alga Sargassum. sp., was first synthesized starting from geranyl acetone, alkylation of silyl cyanide as the key step.
- Li, Ying,Lu, Biao,Li, Chunhong,Li, Yulin
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p. 1417 - 1423
(2007/10/03)
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- Palladium-catalyzed reduction of ketones with nBu2SnH2
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Whereas the Pd(PPh3)4-catalyzed reduction of ketones with nBu3SnH does not proceed at all, the use of nBu2SnH2, instead of nBu3SnH, leads to the efficient reduction of a variety of ketones in the presence of a catalytic amount of Pd(PPh3)4 under mild conditions, providing the corresponding alcohols in good yields. The stereoselectivity in the reduction of cyclic ketones is also investigated by using this Pd(PPh3)4/nBu2SnH2 reduction system.
- Kamiya, Ikuyo,Ogawa, Akiya
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p. 1701 - 1703
(2007/10/03)
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- Biotransformations of acyclic terpenoids, (±)-trans-Nerolidol and geranylacetone, by Glomerella cingulata
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Microbial transformations of (±)-trans-nerolidol and geranylacetone were carried out with a plant pathogenic fungus, Glomerella cingulata. (±)-trans-Nerolidol and geranylacetone were hydrated at a remote double bond as the main metabolic pathway. A large amount of (E)-3,7,11-trimethyl-1,6-dodecadiene-3,11-diol and small amount of (E)-3,7,11-trimethyl-1,6-dodecadiene-3,10,11-triol were obtained from (±)-trans-nerolidol. Geranylacetone was transformed to (E)-10-hydroxy-6,10-dimethyl-5-undecen-2-one as the major metabolite. (E)-9,10-Dihydroxy-6,10-dimethyl-5-undecen-2-one, (E)-6,10-dimethyl-5,9-undecadien-2-ol, (E)-6,10-dimethyl-5-undecene-2,9,10-triol, and (E)-6,10-dimethyl-5-undecene-2,10-diol were also obtained from geranylacetone. The structures of metabolic products were determined by spectroscopic data.
- Miyazawa, Mitsuo,Nankai, Hirokazu,Kameoka, Hiromu
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p. 1543 - 1547
(2007/10/03)
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- BIOTRANSFORMATIONS OF ACYCLIC TERPENOIDS; (+/-)-CIS-NEROLIDOL AND NERYLACETONE, BY PLANT PATHOGENIC FUNGUS, GLOMERELLA CINGULATA
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Microbial transformations of (+/-)-cis-nerolidol and nerylacetone were investigated using the plant pathogenic fungus, Glomerella cingulata.Both (+/-)-cis-nerolidol and nerylacetone were mainly oxidized at the remote double bond. (+/-)-cis-nerolidol was transformed into (Z)-3,7,11-trimethyl-1,6-dodecadien-3,10,11-triol while nerylacetone was transformed into (Z)-9,10-dihydroxy-6,10-dimethyl-5-undecen-2-one as the major metabolite.In addition, the biotransformation of nerylacetone resulted in hydration at the remote double bond and reduction of the carbonyl group and produced (Z)-6,10-dimethyl-5,9-undecadien-2-ol, (Z)-10-hydroxy-6,10-dimethyl-5-undecen-2-one and (Z)-6,10-dimethyl-5-undecen-2,9,10-triol.The structures of the metabolic products were determined by spectroscopic data. - Keywords: Glomerella cingulata; biotransformation; microbial transformation; plant pathogenic fungus; (+/-)-cis-nerolidol; nerylacetone.
- Miyazawa, Mitsuo,Nankai, Hirokazu,Kameoka, Hiromu
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p. 1133 - 1138
(2007/10/02)
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- Synthesis of a potential enzyme-specific inhibitor of squalene synthase
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A multi-step synthesis of phosphinylphosphonate analogue 12 of the proposed farnesyl-farnesyl-enzyme (FFE) intermediate in the enzymatic conversion of farnesyl pyrophosphate to squalene is described.In addition, evidence is presented of the inhibitory effect of 12 on squalene synthase.
- Valentijn, A. R. P. M.,Haan, R. de,Hagens, S.,Kant, E. de,Marel, G. A. van der,et al.
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p. 332 - 336
(2007/10/02)
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- Synthesis of sulfur- and sulfoxide-substituted 2,3-oxidosqualenes and their evaluation as inhibitors of 2,3-oxidosqualene-lanosterol cyclase
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2,3-Oxidosqualene (23-OS) analogs that contain thioether (52-55) and sulfoxide (56-60) at positions normally occupied by carbons considered to be cationic during 2,3-oxidosqualene-lanosterol cyclase (OSC) cyclization (C-6, C-10, C-14, and C-19) were synthesized and tested as substrate mimic inhibitors of fungal and mammalian OSC. The analogs were found to be potent inhibitors of cyclase in cell-free extracts of Candida albicans and rat liver. Thioether analogs were more potent than the corresponding sulfoxides. In both series, those 2,3-OS analogs containing a sulfur at the position normally occupied by C-19 were the most potent. With C. albicans cyclase, the IC50 for thioether 55 was 0.0023 μM while 60 exhibited an IC50 of 0.065 μM, which are the lowest values reported for a inhibitor of this enzyme. Similarly, thioether 55 displayed an IC50 of 0.00082 μM for rat liver cyclase which is the best inhibitor up to date for this enzyme. These results suggest that mimics with modification in the region of C-19 of 2,3-OS have a high affinity for the active site of these enzymes. The same series of analogs (52-60) were also tested for inhibition of cholesterol biosynthesis in intact MDBK (Madin Darbin bovine kidney) cells and for in vitro antifungal activity against C. albicans.
- Zheng, Yi Feng,Oehlschlager, Allan C.,Georgopapadakou, Nafsika H.,Hartman, Peter G.,Scheliga, Petra
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p. 670 - 680
(2007/10/02)
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- MICROBIAL OXIDATION OF GERANYLACETONE AND GERANYLOXYCOUMARIN, AURAPTEN
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Geranylacetone and geranyloxycoumarin (aurapten) were investigated with 14 selected microorganisms for ω-hydroxylation and epoxydation of the subterminal double bond.Trichoderma koningii and Verticillium theobromae are in principal useable for both reactions of geranylacetone.Although the yields of these preferably intended reactions were low, while ω-1-, ω-3-, ω-4-hydroxylations partially combined with reductive side reactions take place, the results gave an insight in the different pathways of oxidations dependent on the microorganism used.In contrast aurapten is transformed in relatively high yield the E- or/and Z-configurated ω-alcohols (auraptenols) and to the aurapten-6,7-epoxide.The exclusively useable microorganisms for the oxidation of aurapten selected from the 237 strains tested were Nocardia alba and Bacillus cereus, which both formed enantioselectively the naturally configurated epoxyaurapten R-(+)--7-oxycoumarin in yields of 10,5percent respectively 21percent of excellent optical purity of 99percentee.
- Mueller, A.,Abraham, W.-R.,Kieslich, K.
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p. 405 - 424
(2007/10/02)
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- Utility of microbes in organic synthesis: Selective transformations of acyclic isoprenoids by Aspergillus niger
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Bioconversion of acyclic isoprenoids using a strain of Aspergillus niger results in hydroxylated metabolites with regio- and stereoselectivity.The organism carries out oxidation of the terminal allylic methyl group and the remote double bond in all the compounds tested (I-VII).However, these two activities seem to have preferential structural requirements.When an acyclic isoprenoid with a ketone functionality such as geranylacetone is used as the substrate, the organism also carries out the asymmetric reduction of the keto group.All the metabolites formed have beenpurified and characterized by conventional spectroscopic methods and quantification has been made by gas chromatographic analyses.
- Madyastha, K M,Gururaja, T L
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p. 609 - 614
(2007/10/02)
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- Synthesis and Activity of Juvenile Hormone Analogues (JHA)
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From geranylacetone and by the use of a variety of reagents, twelve analogues of the juvenile hormone III were synthesized.The compounds (5-16) have an isoprenic structure bearing at the extreme of the chain functional groups as carbonate, carbamate, thiolcarbonate, thiolcarbamate, carbonyloxyimino and thiol carbonyloxyimino.Compounds 5-9 present the normal unsaturated isoprenic chain while compounds 10-16 have a monoepoxide function.All the compounds were tested for their respective juvenile hormone activity for Triatoma infestans and Rhodnius prolixus.The most active compounds were those having a thiol carbonate group independently of the oxidation state of the molecule.The synthetic procedures and the biological results are discussed. - Keywords: Juvenile Hormone Analogues, Activity, Synthesis
- Rodriguez, Juan B.,Gros, Eduardo G.,Stoka, Angel M.
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p. 1038 - 1042
(2007/10/02)
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- A Stereospecific Synthesis of (Z)-δ-Halo-γ,δ-unsaturated Ketones via Haloboration Reaction of Terminal Alkynes
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Michael-type reactions of (Z)-β-bromo- and iodoalkenyl-9-borabicyclononanes (5), readily available by haloboration of 1-alkynes, with acyclic α,β-unsaturated ketones (2) in a nonpolar solvent under Lewis acidic conditions are presented.The products, (Z)-δ-halo-γ,δ-unsaturated ketones (6), are obtained in stereochemically pure form (>98 percent).Since the haloalkenylboranes (5) are prepared in situ from haloboranes (4) and 1-alkynes, the present reaction provides a stereospecific, one-pot, and general synthesis of the title compounds (6).When methyl vinyl ketone (MVK) is used as the Michael acceptor, aldol condensation of the intermediate boron enolate with an excess of MVK occurs.However, the aldol (7) is transformed into the parent haloenone (6') without difficulty upon subsequent, in situ treatment with a base.The same product (6') is prepared directly by the reaction with 3-(trimethylsilyl)-3-buten-2-one.Synthetic utility of the present method is demonstrated by selective syntheses of several natural products.Sulcatol (11) is obtained in an overall yield of 63 percent starting from propyne.In a similar manner, trans-geranyl acetone (14) and trans-nerolidol (15) are prepared stereospecifically (>98 percent) in 62 and 72 percent yields, respectively, from 6-methyl-5-hepten-1-yne (12).
- Satoh, Yoshitaka,Serizawa, Hirokazu,Hara, Shoji,Suzuki, Akira
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p. 5225 - 5228
(2007/10/02)
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- STEREOSPECIFIC ANNELATIONS OF ETHYLENIC β-PHENYLSELENOETHERS BY ACID CATALYSIS
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It will be shown with several examples that it is possible to effect with exceptional ease on monounsaturated ethers, 1.5-phenylseleno group migration, quantitatively, by the action of anhydrous Lewis or Broensted acids at 0 deg C.However, the presence of
- Rouessac, Annick,Rouessac, Francis
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p. 4165 - 4170
(2007/10/02)
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