- Aza and oxo Diels-Alder reactions using cis-cyclohexadienediols of microbial origin: Chemoenzymatic preparation of synthetically valuable heterocyclic scaffolds
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Aza and oxo Diels-Alder reactions using enantiopure cis-cyclohexadienediols were studied. These dienediols were obtained from the biotransformation of monosubstituted arenes using bacterial dioxygenases (toluene and benzoate dioxygenases). Ethyl glyoxylate and its N-tosyl imine were used as dienophiles to afford the corresponding hetero Diels-Alder bicyclic adducts with excellent regio- and stereoselectivities. Quantum chemical calculations at the B3LYP/6-31+G(d,p) level of theory were performed to rationalize the observed selectivities especially the stereochemical aspects of the cycloadditions. The synthetic importance of these adducts is highlighted for the preparation of enantiopure 2,2,3,4,5,6-hexasubstituted piperidine and tetrahydropyran from toluene.
- Pazos, Mariana,Martínez, Sebastián,Vila, María Agustina,Rodríguez, Paola,Veiga, Nicolás,Seoane, Gustavo,Carrera, Ignacio
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- Concise chemoenzymatic synthesis of methyl d-2,3-dideoxyriboside
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The synthesis of methyl α- and β-d-2,3-dideoxyriboside from a non-carbohydrate source is presented. The source of chirality is the microbial oxidation of halobenzenes to produce cyclohexadienediols, which are transformed into the final product in five steps with high chemical and enantiomeric purity.
- Ramos, Juan C.,Bracco, Paula,Mazzini, Mauro,Fernandez, Jose R.,Gamenara, Daniela,Seoane, Gustavo A.
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Read Online
- Synthesis and biological evaluation of 10-benzyloxy-Narciclasine
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A chemoenzymatic convergent synthesis of 10-benzyloxy narciclasine from bromobenzene was accomplished in 16 steps. The key transformations included toluene dioxygenase-mediated hydroxylation, nitroso Diels-Alder reaction and intramolecular Heck cyclization. The unnatural derivative of narciclasine was subjected to biological evaluation and its activity was compared to other C-10 and C-7 compounds prepared previously.
- Du, Liqin,Hudlicky, Tomas,Kornienko, Alexander,Ticli, Vincenzo,Zhao, Zhenze
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- Chemoenzymatic synthesis of hygromycin aminocyclitol moiety and its C2 epimer
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This manuscript describes the enantioselective synthesis of the aminocyclitol moiety of the antibiotic hygromycin A in eight steps and 39 % overall yield from a non-chiral starting material. The sequence made use of an initial enzymatic step to transfer chirality to an aromatic ring and was followed by selective organic chemistry transformations (oxidation, pro-tection, azidation, hydrolysis) of the six-membered ring in order to achieve the target. The approach is also amenable to the synthesis of other related unnatural analogues as exemplified by the synthesis of the C2 epimer of the natural aminocyclitol. All the intermediates were fully characterized, and the absolute stereochemistry assigned by spectrometric methods.
- Carrau, Gonzalo,Bellomo, Ana Inés,Suescun, Leopoldo,Gonzalez, David
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p. 788 - 802
(2019/01/08)
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- Site-Directed Mutagenesis Studies on the Toluene Dioxygenase Enzymatic System: Role of Phenylalanine 366, Threonine 365 and Isoleucine 324 in the Chemo-, Regio-, and Stereoselectivity
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Toluene Dioxygenase (TDO) enzymatic complex has been widely used as a biocatalyst for the regio- and enantioselective preparation of cis-cyclohexadienediols, which are very important starting materials for organic synthesis. However, the lack of regio- and stereodiversity of the dioxygenation process by TDO and related dioxygenases constitutes a clear drawback when planning the use of these diols in synthetic schemes. In this work, we developed three TDO mutants in residues phenylalanine 366, threonine 365 and isoleucine 324, with the aim to alter the chemo-, regio- and stereoselectivity of the biotransformation of arenes. While no changes in the regioselectivity of the process were observed, dramatic variations in the chemo- and enantioselectivity were found for mutants I324F, T365N and F366 V in a substrate-dependent manner. (Figure presented.).
- Vila, María Agustina,Umpiérrez, Diego,Veiga, Nicolás,Seoane, Gustavo,Carrera, Ignacio,Rodríguez Giordano, Sonia
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p. 2149 - 2157
(2017/06/23)
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- A chemoenzymatic route to chiral siloxanes
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An approach employing two enzymes—toluene dioxygenase and immobilized lipase B from Candida antarctica (N435)—was explored as a potential biocatalytic method for the coupling of chiral diols with siloxane species. Analysis of reaction mixtures using1H NMR spectroscopy suggested that up to 66% consumption of the siloxane starting materials had occurred. Oligomeric species were observed and chiral products from the coupling of a cyclic diol with a siloxane molecule were isolated and characterized by MALDI-ToF MS and GPC. Immobilized lipases from Rhizomucor miehei and Thermomyces lanuginosus were also explored as potential catalysts for the coupling reactions, however, their use only returned starting material.
- Naoum, Ravi,Séguin, Jacqueline P.,Trant, John F.,Frampton, Mark B.,Hudlicky, Tomá?,Zelisko, Paul M.
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supporting information
p. 4027 - 4031
(2016/07/06)
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- Antifungal activity of a library of cyclitols and related compounds
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The antifungal activity of a library of 32 cyclitols and derivatives, including 6 previously unreported cyclitol amino acid conjugates, was studied against the clinically important yeasts Candida albicans, Candida tropicalis and Cryptococcus neoformans along with Saccharomyces cerevisiae. Bioautography followed by standardized microbroth dilution methods were used and allowed to identify an azidoinositol glycoside (11) and an azidoconduritol linked to an aromatic aldehyde (18) as promising compounds. The results suggest the relevance of exploring synthetic cyclitolic structures as potential antifungal leaders.
- Bellomo, Ana,Bertucci, Ana,De La Sovera, Victoria,Carrau, Gonzalo,Raimondi, Marcela,Zacchino, Susana,Stefani, Helio A.,Gonzalez, David
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- Chemoenzymatic synthesis of trans -tetrahydrofuran cores of annonaceous acetogenins from bromobenzene
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Two types of trans-THF cores, present in acetogenins, have been synthesized by an intramolecular iodoetherification reaction. The starting alkenol was obtained in a few steps from a chiral cis-diol resulting from microbial oxidation of bromobenzene. The cyclization gave complete stereoselectivity for trans-THF cores with either (S,S) or (R,R) configurations at the THF chiral carbons.
- Ramos, Juan Carlos,Brovetto, Margarita,Seoane, Gustavo A.
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p. 1982 - 1985
(2013/06/05)
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- Chemoenzymatic preparation of (6R)-5,6-dihydro-2H-pyran-2-one: A ubiquitous structural motif of biologically active lactones
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A chemoenzymatic synthesis of an enantiopure 6-substituted 5,6-dihydro-2H-pyran-2-one using bromobenzene as a starting material is presented. This important structural motif is found in a large number of chiral lactones that present a wide range of biological activities. The key features of the preparation include enzymatic dioxygenation of bromobenzene using Escherichia coli JM109 (pDTG601), microwave-assisted acyloin cleavage, and tin mediated lactonization. The stereochemical assignment for the alcohol was confirmed by NMR analysis of Moshers derivatives.
- Carrera, Ignacio,Brovetto, Margarita,Seoane, Gustavo A.
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p. 1467 - 1472
(2013/12/04)
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- Chemoenzymatic synthesis of a mixed phosphine-phosphine oxide catalyst and its application to asymmetric allylation of aldehydes and hydrogenation of alkenes
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The chemoenzymatic synthesis of a Lewis basic phosphine-phosphine oxide organocatalyst from a cis-dihydrodiol metabolite of bromobenzene proceeds via a palladium-catalysed carbon-phosphorus bond coupling and a novel room temperature Arbuzov [2,3]-sigmatropic rearrangement of an allylic diphenylphosphinite. Allylation of aromatic aldehydes were catalysed by the Lewis basic organocatalyst giving homoallylic alcohols in up to 57% ee. This compound also functioned as a ligand for rhodium-catalysed asymmetric hydrogenation of acetamidoacrylate giving reduction products with ee values of up to 84%.
- Boyd, Derek R.,Bell, Mark,Dunne, Katherine S.,Kelly, Brian,Stevenson, Paul J.,Malone, John F.,Allen, Christopher C. R.
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scheme or table
p. 1388 - 1395
(2012/03/27)
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- Development of oseltamivir phosphonate congeners as anti-influenza agents
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Oseltamivir phosphonic acid (tamiphosphor, 3a), its monoethyl ester (3c), guanidino-tamiphosphor (4a), and its monoethyl ester (4c) are potent inhibitors of influenza neuraminidases. They inhibit the replication of influenza viruses, including the oseltamivir-resistant H275Y strain, at low nanomolar to picomolar levels, and significantly protect mice from infection with lethal doses of influenza viruses when orally administered with 1 mg/kg or higher doses. These compounds are stable in simulated gastric fluid, liver microsomes, and human blood and are largely free from binding to plasma proteins. Pharmacokinetic properties of these inhibitors are thoroughly studied in dogs, rats, and mice. The absolute oral bioavailability of these compounds was lower than 12%. No conversion of monoester 4c to phosphonic acid 4a was observed in rats after intravenous administration, but partial conversion of 4c was observed with oral administration. Advanced formulation may be investigated to develop these new anti-influenza agents for better therapeutic use.
- Cheng, Ting-Jen R.,Weinheimer, Steven,Tarbet, E. Bart,Jan, Jia-Tsrong,Cheng, Yih-Shyun E.,Shie, Jiun-Jie,Chen, Chun-Lin,Chen, Chih-An,Hsieh, Wei-Che,Huang, Pei-Wei,Lin, Wen-Hao,Wang, Shi-Yun,Fang, Jim-Min,Hu, Oliver Yoa-Pu,Wong, Chi-Huey
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p. 8657 - 8670
(2013/01/15)
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- An efficient route for the synthesis of chiral conduritol-derivative carboxamides via palladium-catalyzed aminocarbonylation of bromocyclohexenetetraols
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A family of chiral conduritol-derivative carboxamides was synthesized through palladium-catalyzed aminocarbonylation of diastereoisomeric bromocyclohexenetetraols, previously prepared through biotransformation of bromobenzene by mutant strains of Pseudomonas putida F39/D. The coupling reactions of bromocyclohexenetetraols with CO and different amines, such as tert-butylamine, aniline, and piperidine, were performed in the presence of in situ generated Pd(0)/PPh3 catalyst. The methodology was applied to the corresponding iodo-cyclohexenetetraol derivative, using (L)-alanine and (L)-valine methyl ethers as N-nucleophiles. The resulting carboxamides were obtained in highly chemoselective reactions, isolated, and fully characterized.
- Carrilho, Rui M.B.,Heguaburu, Viviana,Schapiro, Valeria,Pandolfi, Enrique,Kollár, László,Pereira, Mariette M.
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scheme or table
p. 6935 - 6940
(2012/08/29)
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- Chemoenzymatic formal synthesis of (-)- and (+)-epibatidine
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The cis-dihydrocatechol, derived from enzymatic cis-dihydroxylation of bromobenzene using the microorganism Pseudomonas putida UV4, was converted into (-)-epibatidine in eleven steps with complete stereocontrol. In addition, an unprecedented palladium-catalysed disproportionation reaction gave the (+)-enantiomer of an advanced key intermediate employed in a previous synthesis of epibatidine.
- Boyd, Derek R.,Sharma, Narain D.,Kaik, Magdalena,McIntyre, Peter B. A.,Stevenson, Paul J.,Allen, Christopher C. R.
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p. 2774 - 2779,6
(2020/08/31)
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- Efficient enantiodivergent total synthesis of (+) and (-)-bromoxone
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The total synthesis of (+)-bromoxone and a formal synthesis of (-)-bromoxone were performed in a simple chemoenzymatic manner, starting from bromobenzene, and using an enantiodivergent strategy. The usefulness of chiral cyclohexadienediols derived from the biotransformations of monosubstituted-aromatic compounds as building blocks for the preparation of natural epoxyenones was confirmed.
- Labora, Maitia,Pandolfi, Enrique M.,Schapiro, Valeria
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scheme or table
p. 153 - 155
(2010/04/29)
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- Formal total synthesis of (-)- and (+)-balanol: two complementary enantiodivergent routes from vinyloxiranes and vinylaziridines
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Formal total syntheses of both enantiomers of balanol have been achieved by the preparation of the protected hexahydroazepine core 2. Two complementary routes have been investigated. The first relied on the regioselective opening of 1,2-epoxycyclohex-3-ene with a chiral-auxiliary version of the Burgess reagent to provide a diastereomeric pair of cis-fused cyclic sulfamidates. The sulfamidates were transformed to trans-amino benzoates with ammonium benzoate and, after separation, converted to (-)-2 and (+)-2 by oxidative cleavage and reductive amination. The second approach utilized vinylaziridines derived from 1-bromo-2,3-dihydroxycyclohexa-4,6-diene obtained by the whole-cell fermentation of bromobenzene with Escherichia coli JM109(pDTG601). Stereoselective opening of the aziridines generated the requisite trans-amino alcohol derivatives, which after saturation of the vinyl bromide moieties were converted to (-)-2 and (+)-2 by oxidative cleavage of the cis-diol and reductive amination. Experimental and spectral data are provided for all new compounds.
- Gilmet, Jacqueline,Sullivan, Bradford,Hudlicky, Tomas
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body text
p. 212 - 220
(2009/04/06)
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- Chemoenzymatic synthesis of glycosyl-deoxyinositol derivatives. First example of a fagopyritol β-analogue containing an aminoinositol unit
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The first synthesis of two fagopyritol β-analogues (β-d-galactopyranosyl-(1′→1)-conduramine F-4 and β-d-galactopyranosyl-(1′→3)-4-aminodeoxy-l-chiro-inosito l) has been accomplished by a chemoenzymatic route in satisfactory yields. The key step of the synthesis is the TMSOTf-promoted glycosylation reaction of a deoxyconduritol derivative. The methodology is amenable to scale-up and expandable to the preparation of other pseudofagopyritols.
- Bellomo, Ana,Bonilla, Julia B.,Lopez-Prados, Javier,Martin-Lomas, Manuel,Gonzalez, David
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scheme or table
p. 2061 - 2064
(2010/03/01)
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- Novel deoxy-selenylconduritols: chemoenzymatic synthesis and biological evaluation
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The first synthesis of two selenyldeoxycyclitols (4-bromo-2-phenylselenyl conduritol F and 6-phenylselenylconduritol F) is reported via a chemoenzymatic enantioselective route. The key step of the synthesis is the selenolysis of a vinyl epoxide. The new compounds were evaluated for their capacity to inhibit the growth of different microorganisms using a modification of the agar diffusion technique with thin layer chromatography plates as support.
- Bellomo, Ana,Bertucci, Ana,Stefani, Helio,Vazquez, Alvaro,Gonzalez, David
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scheme or table
p. 2673 - 2676
(2010/04/29)
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- Synthesis of unnatural cyclitols via a combined enzymatic-palladium catalysis approach
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The Suzuki-Miyaura cross-coupling reaction of a hydroxylated vinyl bromide obtained by a chemoenzymatic approach with a diverse range of potassium organotrifluoroborates has been accomplished catalyzed by Pd(PPh3)4 in satisfactory yields. A variety of functional groups are tolerated in the nucleophilic partner.
- Bellomo, Ana,Gonzalez, David,Stefani, Hèlio A.
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p. 1136 - 1142
(2008/04/13)
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- Chemoenzymatic synthesis and biological evaluation of (-)-conduramine C-4
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Previously unreported (-)-conduramine C-4 was synthesized in six steps from a bacterial bromobenzene metabolite in 23% overall yield. The chemoenzymatic route involved toluene dioxygenase dihydroxylation, β-epoxidation, epoxide ring-opening, Staudinger reduction, radical debromination, and Amberlite- catalyzed hydrolysis. (-)-Conduramine C-4 and other related compounds synthesised were assayed for galactosidase-activity inhibition against β-D-galactoside galactohidrolase isolated from Aspergillus oryzae. Copyright Taylor & Francis Group, LLC.
- Bellomo, Ana,Giacomini, Cecilia,Brena, Beatriz,Seoane, Gustavo,Gonzalez, David
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p. 3509 - 3518
(2008/03/13)
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- Catalytic thiolysis of chemoenzymatically derived vinylepoxides. Efficient synthesis of homochiral phenylthioconduritol F
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The chemoenzymatic synthesis of enantiomerically pure phenylthioconduritol F obtained in 44% overall yield is described. The key step of the synthesis is the Yb(III) thiolysis of a vinyl epoxide, which was studied in depth. The methodology is amenable to scale up and expandable to the preparation of other thiocyclitols.
- Bellomo, Ana,Gonzalez, David
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p. 474 - 478
(2007/10/03)
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- Medium-scale preparation of useful metabolites of aromatic compounds via whole-cell fermentation with recombinant organisms
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The whole-cell fermentation of aromatic coumpounds with Escherichia coli JM109 (pDTG601) on a medium scale (10-15L) produces enantiopure cyclohexadienediols. A detailed procedure for the fermentation is described, and yields for several metabolites are provided. A similar procedure using E. coli JM109 (pDTG602) affords catechols. The dienediols are useful for asymmetric synthesis, and several important targets originating from these metabolites are tabulated.
- Endoma, Mary Ann,Bui, Vu P.,Hansen, Jeff,Hudlicky, Tomas
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p. 525 - 532
(2013/09/06)
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- Chemoenzymatic enantiodivergent synthesis of 1,2-dideoxy-2-amino-1- fluoro-allo-inositol
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Both enantiomers of dideoxyfluoroamino inositols (+)-9 and (-)-9 were synthesized from bromocyclohexadiene cis-diol 1 obtained by microbial oxidation of bromobenzene with toluene dioxygenase. Selective introduction of the amino group was achieved through S(N)2 displacement of triflates 7, 11. Fluorine was selectively introduced via trans-diaxial epoxide opening with tetrabutylphosphonium fluoride dihydrofluoride (TBPF-DF).
- Oppong, Kofi A.,Hudlicky, Tomas,Yan, Fengyang,York, Chentao,Nguyen, Ba V.
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p. 2875 - 2880
(2007/10/03)
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- Scaffolded bis-azasugars: A dual warhead approach to glycosidase inhibition
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Double Suzuki coupling was achieved with vinyl bromide 7, synthesized from the bromobenzene microbial oxidation metabolite bromocyclohexadienediol 6 and α,ω-diborane coupling partners derived from the hydroboration of the corresponding diene. Ozonolysis and selective reduction protocols served to provide selectively the α/α or β/β tethered polyhydroxylated piperidine ring systems (bis-azabugars). The C8 linked DMJ analogue 1 showed inhibitory activity against glycosidase enzymes.
- Johns, Brian A.,Johnson, Carl R.
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p. 749 - 752
(2007/10/03)
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- Enzymatic and chemoenzymatic synthesis and stereochemical assignment of cis-dihydrodiol derivatives of monosubstituted benzenes
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Toluene dioxygenase-catalysed oxidation of mono-substituted benzene substrates (R = F, Cl, Br, I, Me, Et, CH2OAc, CH=CH2, C=CH, CF3, CN, OMe, OEt, SMe) in growing cultures of Pseudomonas putida UV4 yielded the corresponding cis-dihydrodiol metabolites. Palladium-catalysed cross-coupling of cis-(1S,2S)-1,2-dihydroxy-3-iodocyclohexa-3,5-diene with a range of tributyltin compounds provided a chemoenzymatic route to a further series of cis-dihydrodiol derivatives of monosubstituted benzenes (R = D, CH2CH=CH2, Bun, SEt, SPr1, SBu1, SPh, SC6H4Me-4). The enantiopurities and absolute configurations of the cis-dihydrodiols, obtained by both enzymatic and chemoenzymatic routes, were determined by several new methods including 1H NMR spectroscopic analysis of the bis-MTPA esters of the 4-phenyl-1,2,4-triazoline-3,5-dione cycloadducts, X-ray crystallography, circular dichroism spectroscopy and stereochemical correlation.
- Boyd, Derek R.,Sharma, Narain D.,Byrne, Breige,Hand, Mark V.,Malone, John F.,Sheldrake, Gary N.,Blacker, John,Dalton, Howard
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p. 1935 - 1943
(2007/10/03)
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- Inositol synthesis: Concise preparation of L-chiro-inositol and muco- inositol from a common intermediate
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Fully stereoselective large-scale syntheses have been attained for L- chiro-inositol (2) and muco-inositol (3) by means of controlled peripheral oxygenation of cyclohexadiene diol 1.
- Brammer Jr., Larry E.,Hudlicky, Tomas
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p. 2011 - 2014
(2007/10/03)
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- A practical multigram-scale synthesis of allo-inositol
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Allo-Inositol was prepared on a multigram scale starting with bromobenzene in seven steps by three different cis-dihydroxylations (enzymatic, OsO4 and RuO4 catalyzed) employed in tandem.
- Desjardins, Michel,Brammer Jr., Larry E.,Hudlicky, Tomas
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- Chemoenzymatic synthesis of the morphine skeleton via radical cyclization and a C10-C11 closure
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A short synthesis of a morphinan skeleton has been accomplished. The key steps involve enzymatic dihydroxylation of β-bromoethyl benzene, vinyl and aryl radical cyclizations, and Friedel-Crafts closure of an aziridinium ion or an acid-catalyzed closure of an aldehyde to form the C10-C11 bond.
- Butora, Gabor,Hudlicky, Tomas,Fearnley, Stephen P.,Gum, Andrew G.,Stabile, Michele R.,Abboud, Khalil
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p. 8155 - 8158
(2007/10/03)
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- Enantioselective Bacterial Biotransformation Routes to cis-Diol Metabolites of Monosubstituted Benzenes, Naphthalene and Benzocycloalkenes of Either Absolute Configuration
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Enzyme-catalysed kinetic resolution and asymmetric dihydroxylation routes to enantiopure cis-diol metabolites of arenes and benzocycloalkenes of either absolute configuration have been developed using appropriate strains of the bacterium Pseudomonas putida.
- Allen, Christopher C. R.,Boyd, Derek R.,Dalton, Howard,Sharma, Narain D.,Brannigan, Ian,et al.
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p. 117 - 118
(2007/10/02)
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- Enzymatic and Chemical Syntheses of cis-Dihydrodiol Derivatives of Monocyclic Arenes
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Metabolism of bromobenzene and iodobenzene by growing cultures of Pseudomonas putida UV4 gave the corresponding cis-dihydrodiol products 1 and 2 in high yields; subsequent direct chemical substitution of the halogen atoms in these metabolites provided a new range of enantiomerically pure cis-dihydrodiols of known absolute configuration.
- Boyd, Derek R.,Hand, Mark V.,Sharma, Narain D.,Chima, Jagdeep,Dalton, Howard,Sheldrake, Gary N.
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p. 1630 - 1632
(2007/10/02)
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