- Accessing tetrahydrofuran-based natural products by microbial Baeyer-Villiger biooxidation
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A heterobicyclic lactone obtained by stereoselective Baeyer-Villiger biooxidation with recombinant whole-cells expressing cyclopentanone monooxygenase from Comamonas sp. NCIMB 9872 was used for formal total syntheses of various natural products containing
- Mihovilovic, Marko D.,Bianchi, Dario A.,Rudroff, Florian
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Read Online
- Discovery of MK-6169, a Potent Pan-Genotype Hepatitis C Virus NS5A Inhibitor with Optimized Activity against Common Resistance-Associated Substitutions
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We describe the discovery of MK-6169, a potent and pan-genotype hepatitis C virus NS5A inhibitor with optimized activity against common resistance-associated substitutions. SAR studies around the combination of changes to both the valine and aminal carbon region of elbasvir led to the discovery of a series of compounds with substantially improved potency against common resistance-associated substitutions in the major genotypes, as well as good pharmacokinetics in both rat and dog. Through further optimization of key leads from this effort, MK-6169 (21) was discovered as a preclinical candidate for further development.
- Yu, Wensheng,Tong, Ling,Selyutin, Oleg,Chen, Lei,Hu, Bin,Zhong, Bin,Hao, Jinglai,Ji, Tao,Zan, Shuai,Yin, Jingjun,Ruck, Rebecca T.,Curry, Stephanie,McMonagle, Patricia,Agrawal, Sony,Rokosz, Laura,Carr, Donna,Ingravallo, Paul,Bystol, Karin,Lahser, Frederick,Liu, Rong,Chen, Shiying,Feng, Kung-I,Cartwright, Mark,Asante-Appiah, Ernest,Kozlowski, Joseph A.
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p. 3984 - 4003
(2018/05/14)
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- Synthesis of tetrahydrofuran-based natural products and their carba analogs via stereoselective enzyme mediated Baeyer–Villiger oxidation
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In this work we present efficient formal syntheses of several biologically interesting natural products (showdomycin, goniofufurone, trans-kumausyne) and their novel carba analogs by applying different Baeyer–Villiger monooxygenases. This strategy provides access to tetrahydrofuran-based natural products, C-nucleosides and both antipodes of the corresponding carba analogs in high optical purities (up to >95% ee) starting from simple achiral and commercially available building blocks (tetrabromoacetone, furan and cyclopentadiene). The striking key features of this chemo-enzymatic approach are the introduction of four stereogenic centers in as few as three reaction steps within a desymmetrization approach and the short-cut of several reaction sequences by the implementation of a biocatalytic step.
- Rudroff, Florian,Bianchi, Dario A.,Moran-Ramallal, Roberto,Iqbal, Naseem,Dreier, Dominik,Mihovilovic, Marko D.
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p. 7212 - 7221
(2016/10/29)
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- Functional characterization of recombinant hyoscyamine 6β-hydroxylase from Atropa belladonna
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(-)-Hyoscyamine, the enantiomerically pure form of atropine, and its derivative scopolamine are tropane alkaloids that are extensively used in medicine. Hyoscyamine 6β-hydroxylase (H6H, EC 1.14.11.11), a monomeric α-ketoglutarate dependent dioxygenase, converts (-)-hyoscyamine to its 6,7-epoxy derivative, scopolamine, in two sequential steps. In this study, H6H of Atropa belladonna (AbH6H) was cloned, heterologously expressed in Escherichia coli, purified and characterized. The catalytic efficiency of AbH6H, especially for the second oxidation, was found to be low, and this may be one of the reasons why Atropa belladonna produces less scopolamine than other species in the same family. 6,7-Dehydrohyoscyamine, a potential precursor for the last step of epoxidation, was shown not to be an obligatory intermediate in the biosynthesis of scopolamine using purified AbH6H with an in vitro 18O labeling experiment. Moreover, the nitrogen atom in the tropane ring of (-)-hyoscyamine was found to play an important role in substrate recognition.
- Li, Jing,Van Belkum, Marco J.,Vederas, John C.
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experimental part
p. 4356 - 4363
(2012/08/28)
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- HEPATITIS C VIRUS INHIBITORS
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The present disclosure relates to compounds, compositions and methods for the treatment of hepatitis C virus (HCV) infection. Also disclosed are pharmaceutical compositions containing such compounds and methods for using these compounds in the treatment o
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Page/Page column 66-67
(2012/03/09)
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- Facile synthesis and ring-opening cross metathesis of carbo- and heterocyclic bicyclo[3.2.1]oct-6-en-3-ones using gaseous olefinic reaction partners
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The title compounds were prepared by a facile [4+3]-cycloaddition strategy involving sonochemistry. The oxyallyl species required for the reaction with the corresponding diene was generated from a suitable perbromo ketone with activated zinc under sonific
- Mihovilovic, Marko D.,Groetzl, Birgit,Kandioller, Wolfgang,Snajdrova, Radka,Muskotal, Adel,Bianchi, Dario A.,Stanetty, Peter
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p. 463 - 470
(2007/10/03)
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- Synthesis of the C38-C44 segment of altohyrtin A - with an addendum on the preparation of 8-oxabicyclo[3,2.1]oct-6-en-3-one
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The densely funtionalized C38-C44 segment F of altohyrtin A with its five contiguous stereogenic centers was prepared in 10 steps and in 28% overall yield (two steps per stereogenic center), from 8- oxabicyclo[3.2.1]oct-6-en-3-one as a template. The preparation of the title compound 1, m.p. 38 °C, is described on a 0.5 m scale in a three-step-two- stage reaction from acetone anti furan. The oxacycle was stored without change at room temperature.
- Kim,Hoffmann
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p. 2195 - 2201
(2007/10/03)
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- Synthesis of 8-oxa analogues of norcocaine endowed with interesting cocaine-like activity
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In order to further explore the importance of cocaine's bridge nitrogen atom in binding to the dopamine transporter (DAT), we have synthesized the previously known racemic 8-oxa-norcocaines 3-6 in which the nitrogen atom has been replaced by oxygen. Additionally, to avoid incorrect interpretations of biological data that may stem from the use of racemic materials, several of these analogues were synthesized and tested in non-racemic form. (-)-8-Oxa- norcocaine (3) was found to bind to the cocaine recognition site and to inhibit the dopamine transporter with potencies only about 8-fold and 4- fold, respectively, less than those of norcocaine (2). (-)-8-Oxa- pseudonorcocaine (4) as well as (+)-8-oxa-norcocaine (3) were found to be comparable in activity to (-)-oxa-norcocaine. These pharmacological findings support our earlier suggestion that cocaine is likely to bind in its neutral form to the DAT.
- Kozikowski, Alan P.,Simoni, Daniele,Roberti, Marinella,Rondanin, Riccardo,Wang, Shaomeng,Du, Pingfeng,Johnson, Kenneth M.
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p. 1831 - 1836
(2007/10/03)
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- Asymmetric synthesis of polyacetate derived building clocks with α- oxyanion functionality. Lewis acid catalyzed opening of 2,9- dioxabicyclo[3.3.1]nonan-3-ones
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All four stereoisomeric cyclic 3,5,7-trihydroxyheptanoic acid equivalents of the polyacetate aldol type (Scheme 1) are obtainable from 8- oxabicyclo[3.2.1]oct-6-en-3-one which functions as a meso-configurated 4-way optical switch. Lewis acid assisted nucl
- Dunkel, Ralf,Hoffmann
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p. 8385 - 8396
(2007/10/03)
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- HIGHLY STEREOSELECTIVE, TOTAL SYNTHESIS OF β-C-HEXOPYRANOSYL DERIVATIVES
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One Diels-Alder adduct of furan to 1-cyanovinyl acetate is converted to 8-oxabicyclooct-6-en-2-one which is transformed into β-C-hexopyranosides including 2-deoxy and 2,3-unsaturated derivatives.
- Fattori, Daniela,Vogel, Pierre
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p. 1017 - 1018
(2007/10/02)
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- Enantioselective deprotonation of 8-oxabicyclo[3.2.1]octan-3-one systems using homochiral lithium amide bases
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The asymmetric transformation of oxabicyclic ketones 6 and 7 into non-racemic enol silanes 12 (88% ee) and 10 (85% ee), respectively, was achieved using the homochiral lithium amide base 4. Conversion of 10 into a known key intermediate 15 for C-nucleosid
- Bunn,Cox,Simpkins
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p. 207 - 218
(2007/10/02)
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- The Demjanov and Tiffeneau-Demjanov one-carbon ring enlargements of 2-aminomethyl-7-oxabicyclo[2.2.1]heptane derivatives. The stereo- and regioselective additions of 8-oxabicyclo [3.2.1]oct-6-en-2-one to soft electrophiles
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Nitrosation of 7-oxabicyclo[2.2.1]hept-5-en-2-exo-ylmethyl amine (20) gave 7-oxabicydo[2.2.1]hept-5-en-2-exo-methanol (22) whereas 7-oxabicyclo[2.2.1]hept-5-en-2-endo-ylmethylamine (21) afforded a 1:1 mixture of 7-oxabicydo[3.2.1]oct-6-en-2-ols (23) and 8-oxabicydo[3.2.1]oct-3-en-2-ols (24). Nitrosations of 2-exo- (28) and 2-endo-aminomethyl-7-oxabicyclo[2.2.1]hept-5-en-2-ol (29) gave mixtures of 8-oxabicydo[3.2.1]oct-6-en-2-one (25) and 8-oxabicydo[3.2.1]oct-6-en-3-one (37). The preference for the C(3) methylene group migration giving 25 was the best (12:1) in the case of the 2-endo-aminomethyl alcohol 29. Compared with the nitrosations of bicydo[2.2.1]heptane analogues, the 7-oxa bridge in 28 and 29 enhances the preference for the C(3) methylene group migration vs. the C(1) methine group migration. The Tiffeneau-Demjanov one-carbon ring enlargement reactions of 2-exo-aminomethyl-7-oxabicyclo[2.2.1]hepta-2-endo-ol (30). 2-exo-aminomethyl-5-chloro (32) and 2-exo-aminomethyl-6-chloro-7-oxabicyclo[2.2.1]hept-5-en-endo-ol (33) are also reported. Under kinetically controlled conditions, 8-oxabicydo[3.2.1]oct-6-en-2-one (25) adds to electrophiles EX=PhSeCl, PhSeBr. 2,4-(NO)2C6H3SCl with high stereo- and regioselectivity giving the corresponding 8-oxabicyclo [3.2.1]-octan-2-ones where E substitutes the exo position of C(6) and X the exo position of C(7).
- Fattori, Daniela,Henry, Sylvie,Vogel, Pierre
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p. 1649 - 1664
(2007/10/02)
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- CNS-agents: Synthesis and properties of 3-anilino-8-oxatropanes
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Reaction of the 8-oxabicyclooctenone and -octanone derivatives 3 and 4 with aniline and metal hydrides yields the 3α-isomers of the aniline derivatives 7 and 8, preferably. The configuration can be determined by NMR-spectroscopy and by cyclization to the
- Eiden,Kainz
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- An Efficient Route to the Tropane Alkaloids
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We describe the use of diethylzinc in conjunction with polybromo ketones for the production of oxyallyls, and the interception of these intermediates by furans and methyl pyrrole-N-carboxylate.This methodology allows the production of gramme quantities of tropane alkaloids, and 2-substituted 8-oxabicyclooct-6-en-3-ones that have been either difficult or impossible to prepare.
- Mann, John,Barbosa, Luiz-Claudio de Almeida
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p. 787 - 790
(2007/10/02)
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- Methoxy- and Dichloro-Substituted Oxyallyl Intermediates
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Solvolysis of 1-chloro-1-methoxy-2-propanone (1a) and 3-methoxy-2-oxopropyl mesylate (2c) in basic 2,2,2-trifluoroethanol affords the same product, 1-methoxy-1-(2,2,2-trifluoroethoxy)-2-propanone (6), by way of an enolization-ionization mechanism.The oxyallyl intermediate 3 can be trapped by furan and 2-methylfuran in a cycloaddition. 1,1,3-Trichloro-2-propanone (13) reacts with basic trifluoroethanol in a Favorskii rearrangement to give the trifluoroethyl ester of cis-3-chloroacrylic acid (19).The intermediate, 1,3-dichloroallylium-2-olate (20), combines with furan, 2,5-dimethylfuran, cyclopentadiene, and spirohexadiene to form the cycloadducts 22a-d in good yields.In contrast, 1,3-dichloro-2-propanone (10) does not follow the enolization-ionization pathway; in LiClO4/Et2O/NEt3 the selfcondensation product 12 arises.
- Foehlisch, Baldur,Krimmer, Dieter,Gehrlach, Eberhard,Kaeshammer, Dietmar
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p. 1585 - 1594
(2007/10/02)
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- Thromboxane A2 Analogues from 8-Oxabicyclooct-6-en-3-ones
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We describe approaches to thromboxane A2 analogues (3), (4), and (32) which contain 2,6-dioxabicyclooctane and 2,6-dioxatricyclo3,7>nonane ring system.Both were derived from 2-substituted 8-oxabicyclooct-6-en-3-
- Bowers, Kevin G.,Mann, John,Walsh, E. Brian,Howarth, Oliver W.
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p. 1657 - 1666
(2007/10/02)
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- Generation and Cycloaddition of Oxallyl Intermediates from 2-Bromo-3-pentanone and Pentachloroacetone in 2,2,3,3-Tetrafluoro-1-propanol
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2-Bromo-3-pentanone (1) reacts with cyclopentadiene, spirohepta-4,6-diene, furan, 2,5-dimethylfuran, and ω-functionalized 2-alkylfurans in 2,2,3,3-tetrafluoro-1-propanol/sodium 2,2,3,3-tetrafluoropropoxide to form the cycloadducts of the oxallyl intermediate 3 in high yields.The other 1,3-dienes investigated gave low yields of the corresponding cycloadducts.With 4-methyl-1,3-pentadiene and 2-methoxy-1,3-butadiene, cycloadducts are observed.Tetrachloroallylium-2-olate, generated from 1,1,1,3,3-pentachloro-2-propanone (25) undergoes cycloadditions to 26-28 with furan and the substituted furans 22-24 in moderate yields.These cycloadducts were dechlorinated by the Zn/Cu couple.The intramolecular Claisen condensation of the bicyclic oxoester 30 affords the enolized tricyclic 1,3-diketone 34 which can be methylated stereoselectively at the angular position to give 35.
- Foehlisch, Baldur,Gehrlach, Eberhard,Geywitz, Barbara
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p. 1815 - 1824
(2007/10/02)
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- Rearrangement of Aryl-8-oxabicyclooctenones: Synthesis of Novel Biaryls and 1-Aryl-3-furylpropanones
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The formation of 3-arylbenzaldehydes through rearrangement of 3-aryl-8-oxabicyclooct-2-en-7-ones is reported, together with various rearrangement reactions of 2-aryl-8-oxabicyclooct-6-en-3-ones, and a novel approach to the natural product acamelin.
- Mann, John,Wilde, Philip D.,Finch, Mark W.
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p. 1543 - 1544
(2007/10/02)
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- NATURAL PRODUCT SYNTHESIS VIA THE POLYBROMO KETONE-IRON CARBONYL REACTION
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Application of the polybromo ketone-iron carbonyl reaction to natural product synthesis is summarized.The general synthesis of tropane alkaloids has been achieved via the reductive cyclocoupling of sym-tetrabromoacetone with N-methoxycarbonylpyrrole as the key step.Ready availability of 8-oxabicyclooct-6-en-3-one from the tetrabromoacetone and furan has opened a new, efficient entry to natural C-nucleosides including pseudouridine, pseudocytidine, and showdomycin.The artificial analogues such as 2-thiopseudouridine, 6-azapseudouridine, pseudoisocytidine, etc., are also obtainable.The oxabicyclic ketones bearing an isopropyl substituent at the appropriate position serve as intermediates for the synthesis of naturally occurring troponoids, nezukone, α-thujaplicin, and hinokitiol (β-thujaplicin).Carbocamphenilone and camphenic acid have been prepared through the reaction of 1,1,3-tribromo-3-methylbutan-2-one and cyclopentadiene.The cyclocondensation of α,α'-dibromo ketone and a styrene derivative leads to the single-step synthesis of α-cuparenone. 1,3-Dibromo-3,7-dimethyloct-6-en-2-one derived from nerol (or geraniol) undergoes the biogenetic-type double cyclization.The iron carbonyl-assisted intramolecular cyclocoupling gives camphor accompanied by other monoterpenic ketones.A mixture of campherenone and epicampherenone has been obtained from related dibromo ketone prepared from farnesols.The hetero reaction by use of dibromo ketones and N,N-dimethylcarboxamides, forming 3 (2H)-furanones, is employable for the preparation of muscarine alkaloid derivatives.
- Noyori, R.,Hayakawa, Y.
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p. 5879 - 5886
(2007/10/02)
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- The Synthesis of (+/-)-10a-Homo-11a-carbathromboxane A1, a Stable Thromboxane A Analogue
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The thromboxane A1 (TXA1) analogue (1), which retains the characteristic bridge oxygen atom of the TXA molecule, has been synthesized from the bicyclic ketone (2).Stereochemical control of alkylation of the bicyclic ketone (2) was ac
- Ansell, Martin F.,Mason, Jonathan S.,Caton, Michael P. L.
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p. 1061 - 1068
(2007/10/02)
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- Oxyallyls in Synthesis. Preparation of Analogues of Muscarine and &α-Multistriatin
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Oxyallyls react readily with furans, and we have used the cycloadducts formed in the syntheses of structural analogues of the natural products muscarine and α-multistriatin.In addition we give details of a new method of forming oxyallyls from monobromo-ke
- Cowling, Antony P.,Mann, John,Usmani, Attique A.
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p. 2116 - 2119
(2007/10/02)
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- Synthetic and Structural Studies of the Lolium Alkaloids
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Application of transannular cyclizations to the synthesis of bridged pyrrolizidine alkaloids such as loline (1) is described.The general method involves bromination of 3-aza-9-oxabicyclonon-7-ene (5), leading directly to the skeleton (12a) of the lolium alkaloids.Unsuccessful attempts to replace the bromine are described.The X-ray structure of the synthetic compound 12a as well as loline itself (1) and the biogenesis of lolium alkaloids are also discussed.
- Wilson, Stephen R.,Sawicki, Robert A.,Huffman, J. C.
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p. 3887 - 3891
(2007/10/02)
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