- Isoform-selective inhibition of the human UDP-glucuronosyltransferase 2B7 by isolongifolol derivatives
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A set of 48 derivatives of the tricyclic sesquiterpenol alcohol isolongifolol was synthesized. The set comprised homochiral and diastereomeric alcohols, amines, chlorohydrins, as well as carboxylic acids, phosphonic acids, and their corresponding esters. The absolute configuration of the epimeric compounds was assigned by 2D NMR experiments [gradient heteronuclear single quantum correlation (gHSQC) and gradient nuclear Overhauser enhancement spectroscopy (gNOESY)] in agreement with crystallographic data. The tricyclic derivatives were assessed as inhibitors of the human UDP-glucuronosyltransferase (UGT) 2B7. The phenyl-substituted secondary alcohol 26b was the best inhibitor in this series and its competitive inhibition constant was 18 nM. Compound 26b was not glucuronidated by UGT2B7 and other hepatic UGT enzymes, presumably due to the high steric hindrance exerted by its bulky phenyl substituent. Its inhibitory activity toward 14 other UGT isoforms of subfamily 1A and 2B was determined, and the data indicated that the tricyclic secondary alcohol 26b was highly selective for UGT2B7 (true selectivity > 1000).
- Bichlmaier, Ingo,Kurkela, Mika,Joshi, Tanmaya,Siiskonen, Antti,Rüffer, Tobias,Lang, Heinrich,Suchanová, Bohumila,Vahermo, Mikko,Finel, Moshe,Yli-Kauhaluoma, Jari
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p. 2655 - 2664
(2008/02/02)
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- Cycloaddition Routes to Tricyclo1,7.02,9>undecanes: A Direct Total Synthesis of (+)-Longifolene via an Intramolecular Diels-Alder Strategy
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The total synthesis of the sesquiterpene (+)-longifolene (1) by an intramolecular Diels-Alder cycloaddition strategy is described.Addition of methyllithium to the epoxyfulvene 13, derived from cyclopentadiene and 3,4-epoxy-2-butanone, led to an exo-tet cyclization of the resulting cyclopentadienyl anion to generate the spirohepta-4,6-diene alcohol 14.Resolution of this material was effected via its menthyl carbonate derivative 15.Oxidation of the (+)-R-alcohol with active MnO2 afforded the cyclopropyl aldehyde 16 which was condensed with the anion derived from methyl 3-methylcrotonate in the presence of cadmium chloride to gen erate the unsaturated lactone 20 or the unsaturated ester 18.Microwave heating of the silyl triene 19 effected cycloaddition to the adduct 21.Hydrogenolysis of the alcohol 22 afforded the "sinularene" skeleton 25.Cyclopropane ring cleavage of the derived ketones 23, 30, and the thiocarbonate 27 was examined but only in the Li/NH3 reduction of 30 was the longifolene skeleton 33 produced as a significant product which unfortunately could not be separated from its isomer 32.Consequently the successful route utilized regiospecific cleavage of the cyclopropane ring in the cyclopentadiene 20 in methanol catalyzed by BF3*Et2O to afford the substituted cyclopentadiene lactone(s) 34 (83percent).Cyclization proceeded smoothly, in a sealed tube, in toluene, in a microwave oven to afford the single tetracyclic adduct 39 in 97percent yield.Double bond hydrogenation and reduction of the lactone with LiAlH4 afforded the substituted longifolene skeleton, and the resulting primary alcohol was acetylated selectively to give 40.Free-radical-mediated replacement of the secondary oxygen functions was accomplished via the phenoxythiocarbonate derivative to afford the methoxy acetate 43.Alternatively the reaction sequence could b e modified to convert 39 to 41 to 42 and then to 43.Methoxy cleavage (Me3SiI) and a second free-radical reaction gave the acetate 44.Pyrolysis of this acetate (525 deg C) provided (+)-longifolene (1).
- Lei, Bo,Fallis, Alex G.
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p. 2186 - 2195
(2007/10/02)
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- Studies in sesquiterpenes-lx reversion of longipinane to himachalane system: Revision of structure of isocentdarol
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Longipinene on exposure to acids rapidly rearranges to furnish α- and β-himachalenes, longifolene and isolongifolene. Longipinene epoxide, under acid catalysis, gives several products resulting from fragmentation and Wagner-Meerwein rearrangement. All products have been fully characterised. Formation of isocentdarol in this reaction requires revision of its stereochemistry at the centre carrying tertiary hydroxyl function.
- Shastri, Mayank H.,Dev, Sukh
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p. 4905 - 4918
(2007/10/02)
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- NEW SESQUITERPENOIDS FROM THE OLEORESIN OF Abies alba
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The structures of four new sesquiterpenoids from the oleoresin of Abies alba have been studied, On the basis of various spectral characteristics, the structures of (10S, 11S)-himachala-2,4-diene, (10S, 11S)-himachala-3(12),4-diene, humula-4,9-dien-8-ol, and (4S, 5S, 10S)-selina-6-en-4-ol have been proposed for the compounds isolated.The stereochemistry of the assymetric centers was determined by the conversion of these compounds into known sesquiterpenes and also by analysis of PMR spectra with a shift reagent.
- Khan, V. A.,Tkachev, A. V.,Pentegova, V. A.
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p. 606 - 611
(2007/10/02)
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- Enanthiospecific synthesis of longiborneol and longifolene
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A trimethylsilyl enol ether (34) derived from camphor (1) undergoes intramolecular Mukaiyama reaction to provide a tricyclic ketone (36) that can serve as a key intermediate in a new enantiospecific synthesis of longiborneol (11) and longifolene (12).
- Kuo, David L.,Money, Thomas
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p. 1794 - 1804
(2007/10/02)
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- Rearrangement/Oxygen Functionalization of Longifolene into Culmorin, a Longibornane Diol Mould Metabolite of Fusarium culmorum
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A ten-step synthesis of (+)-culmorin (2a) from longifolene (1a) which involves formation of 10-ketolongifolene (18) as the key intermediate is described.The known 11-hydroxylongicyclene (15), when exposed to hydrogen bromide in acetic acid gives the novel 8,11-dibromolongibornane (16).On reaction with silver perchlorate in aqueous acetone followed by Jones' oxidation, 16 gives the viable 10-ketolongifolene (18) in 25percent yield.When subjected to acid catalyzed Wagner-Meerwein rearrangement/hydration reaction with 50percent aq. sulphuric acid-acetic acid, 18 affords a mixture of keto olefins (21) and three keto acetates (22), (23) and (24).The required 8β-acetoxy-11-ketolongibornane (22), on hydrolysis/oxidation affords (+)-culmorin diketone (10).Since this diketone has been earlier reduced to the diol 2a, the elaboration of 1a to 10 constitutes a synthesis of (+)-2a itself.
- Reddy, R. Thimma,Nayak, U. R.
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p. 457 - 461
(2007/10/02)
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- Syntheses of (+/-)- and Enantiomerically Pure (+)-Longifolene and of (+/-)- and Enantiomerically Pure (+)-Sativene by an Intramolecular de Mayo Reaction
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Starting from 2-cyclopentenoyl chloride ((RS)- or (S)-8), the racemic as well as the enantiomerically pure (+)-sesquiterpenes longifolene ((+/-)- and (+)-1, resp.) and sativene ((+/-)- and (+)-2, resp.) were synthesized efficiently by a sequence of nine and ten steps, respectively.The key sequence 10 -> 16 -> 3 is the first strategic application of an intramolecular photoaddition/retro-aldolization sequence (intramolecular de Mayo reaction) in organic synthesis.
- Oppolzer, Wolfgang,Godel, Thierry
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p. 1154 - 1167
(2007/10/02)
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- Preparation of Chiral 1-Deuteriobenzenemethanethiols by Using α',β Elimination of Carbanions Derived from Benzylic Thioethers
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The α',β elimination of the carbanion derived from benzyl isolongifolyl thioether and benzyl camphyl thioether gives the chiral benzyl mercaptan, the S isomer with 38 +/- 6percent ee and the R isomer with 49 +/- 7percent ee.The chirality of the benzyl mercaptan was determined by optical rotation of benzyl methyl thioether and thiosulfone.The enantiomeric excess was evaluated from 1H NMR measurement of ethyl (benzylthio)phenylacetate prepared from (-)-mandelic acid.The enantiomeric excess at carbon C-2 of ethyl (benzylthio)phenylacetate wasdetermined with the chiral europium chelate and was about 60percent.These results are discussed with reference to the transition state of the α,β elimination and to related processes.
- Biellmann, Jean-Francois,d'Orchymont, Hugues
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p. 2882 - 2886
(2007/10/02)
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- Longifolene-Derived Amines: A Comparative Hofmann Elimination Study with Isolongifolic Acid and Homoisolongifolic Acid as Precursors
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Isolongifolic acid (2) and homoisolongifolic acid (3) have been transformed into the C15- and C16-N,N-dimethylamino derivatives (8) and (9), respectively.A comparative Hofmann elimination study has revealed that, although both 8 and 9 possess a β-hydrogen available for elimination, the product-outcome is significantly different in the two cases; the major compound in the case of 8 arises from a reversal of the quaternary base to the parent dimethylamine (54percent) although a trivial amount (10percent) of the expected longifolene is also formed; on the other hand, 9 generates the theoretically anticipated vinylnorlongifolane (13) in 37 percent yield comparable with that of the dimethylamine (9) (33percent).Pb(IV)-Cu(II) reaction on the primary acid (3) fails to give longifolene by oxidative decarboxylation.
- Shitole, H. R.,Nayak, U. R.
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- STUDIES IN SESQUITERPENES-LV ISOLONGIFOLENE(PART 6): MECHANISM OF REARRANGEMENT OF LONGIFOLENE TO ISOLONGIFOLENE-I
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The gross mechanism of rearrangement of longifolene to isolongifolene has been elucidated by using site-specifically labelled longifolene-4,4,5,5-d4 and shown to follow the pathway proposed by Berson et al., which involves an exo, exo Me shift, in preference to the endo, endo Me migration route proposed earlier.An efficient synthesis of longifolene-4,4,5,5-d4, the key compound in the present investigation, is described.
- Yadav, J. S.,Nayak, U. R.,Dev, Sukh
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p. 309 - 315
(2007/10/02)
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