- Titanocene(III) chloride mediated radical-induced synthesis of 3,4-dihydroisocoumarins: synthesis of (±)-hydrangenol, (±)-phyllodulcin, (±)-macrophyllol and (±)-thunberginol G
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A radical-promoted synthesis of 3,4-dihydroisocoumarins has been achieved in moderate to good yields using titanocene(III) chloride (Cp2TiCl) as the radical initiator. The total synthesis of four naturally occurring dihydrocoumarins hydrangenol, phyllodulcin, macrophyllol and thunberginol G has been accomplished using the radical technology. Cp2TiCl was prepared in situ from commercially available titanocene dichloride (Cp2TiCl2) and Zn-dust in THF under argon.
- Mandal, Samir Kumar,Roy, Subhas Chandra
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experimental part
p. 11050 - 11057
(2009/04/11)
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- Radical-mediated synthesis of 3,4-dihydroisocoumarins: total synthesis of hydrangenol
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A radically promoted synthesis of 3,4-dihydroisocoumarins has been achieved in moderate to good yields using titanocene(III) chloride (Cp2TiCl) as the radical initiator. The total synthesis of (±)-hydrangenol has been completed using this radical technology. Cp2TiCl was prepared in situ from commercially available titanocene dichloride (Cp2TiCl2) and Zn-dust in THF under argon.
- Mandal, Samir Kumar,Roy, Subhas Chandra
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p. 4131 - 4134
(2008/02/03)
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- Synthesis of 3-substituted 8-hydroxy-3,4-dihydroisocoumarins via successive lateral and ortho-lithiations of 4,4-dimethyl-2-(o-tolyl)oxazoline
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Sequential treatment of 4,4-dimethyl-2-(o-tolyl)oxazoline in THF with sec-BuLi, aromatic or aliphatic aldehydes, sec-BuLi, B(OMe)3, and H2O2 produced the laterally alkylated and ortho-hydroxylated oxazolines in one-pot. Treatment of these products with TFA in aqueous THF provided 3-substituted 8-hydroxy-3,4-dihydroisocoumarins in 44-75% overall yields. This procedure allowed the short synthesis of (±)-hydrangenol and (±)-phyllodulcin, naturally occurring 3,4-dihydroisocoumarins of pharmacological interest. A more economical synthesis of (±)-phyllodulcin via the trianion intermediate is also described.
- Tahara, Naruki,Fukuda, Tsutomu,Iwao, Masatomo
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p. 5117 - 5120
(2007/10/03)
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- Efficient syntheses of (+/-)-hydrangenol, (+/-)-phyllodulcin and (+/-)-macrophyllol
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In this paper we report on a efficient and flexible synthetic route towards the total syntheses of the dihydrocoumarine derivatives hydrangenol (1), phyllodulcin (1a) and macrophyllol (6b). The syntheses started with a readily available phosphonium salt 2 and suitable modified benzaldehydes 3/3a/3b resulting in 46 to 61 percent overall yields in three to four-steps sequences. The racemic products could be separated by chiral HPLC. The evidence of the (R)-enantiomer for sweetness could be demonstrated for 1a.
- Guenes, Mehmet,Speicher, Andreas
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p. 8799 - 8802
(2007/10/03)
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- Development of bioactive functions in Hydrangeae Dulcis Folium. VI. Syntheses of thunberginols A and F and their 3'-deoxy-derivatives using regiospecific lactonization of stilbene carboxylic acid: Structures and inhibitory activity on histamine release of hydramacrophyllols A and B
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Lactonization reaction of 2-carboxystilbene mediated by copper(II) chloride proceeded regiospecifically to give the five-membered lactone, while the bromolactonizations using N-bromosuccinimide and anodic oxidation were found to furnish the six-membered lactone. Using these regiospecific lactonization reactions as a key step, antiallergic and antimicrobial isocoumarins and the benzylidenephthalides thunberginols A and F and their 3'-deoxyanalogs were synthesized from phyllodulcin and hydrangenol. Two phthalides called hydramacrophyllols A and B were isolated from Hydrangeae Dulcis Folium and their stereostructures were determined on the basis of physicochemical and chemical evidence, which included the syntheses of hydramacrophyllols A and B from hydrangenol by the application of the lactonization method using copper(II) chloride. In addition, hydramacrophyllols A and B were found to exhibit an inhibitory effect on the histamine release from rat peritoneal exudate cells induced by antigen- antibody reaction.
- Yoshikawa, Masayuki,Shimada, Hiromi,Yagi, Nobuhiro,Murakami, Nobutoshi,Shimoda, Hiroshi,Yamahara, Johji,Matsuda, Hisashi
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p. 1890 - 1898
(2007/10/03)
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- Reaction of Benzocyclobutenoxides with Aldehydes: Synthesis of Peshawarine and Other 3,4-Dihydroisocoumarins
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Deprotonation of benzocyclobutenols 6 in presence of aromatic aldehydes affords benzopyranols 7 in high yield.In the key step of this process, an o-tolualdehyde anion generated by the known ring-opening of benzocyclobutenoxides adds to the aldehyde to give 7 which is easily oxidized to 3-substituted 3,4-dihydroisocoumarins 8 including intermediates in some natural product syntheses.For example, reaction of 6-methoxybenzocyclobutenol (1) with LTMP and p-anisaldehyde gave in 96percent yield to benzopyranol 16, which subsequently was converted to (+/-)-hydrangenol (17).Similar treatment of 1 with LDA and isovanillin benzyl ether afforded the benzopyranol 19 (87percent yield) which already has been converted to (+/-)-phyllodulcin (21).Finally, reaction of 5,6-(methylenedioxy)benzocyclobutenol (10) with LTMP and the aldehyde 26 (from treatment of hydrastinine with ClCO2Me) followed by methanolysis produced the acetal 28 in 96percent yield.The overall yield was 65percent for the five-step synthesis of the alkaloid (+/-)-peshawawine (24) from 10 and 26.Extension of the process to aliphatic aldehydes was illustrated by the preparation of 32 from benzocyclobutenol and isobutyraldehyde in 69percent overall yield after oxidation with PCC.
- Fitzgerald, John J.,Pagano, Alex R.,Sakoda, Vianne M.,Olofson, R. A.
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p. 4117 - 4121
(2007/10/02)
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- SYNTHESES OF DIHYDROISOCOUMARINS, (+/-)-HYDRANGENOL AND (+/-)-PHYLLODULCIN, UTILIZING AN ANNELATION REACTION OF ENAMINONES WITH ETHYL ACETOACETATE. STUDIES ON THE β-CARBONYL COMPOUNDS CONNECTED WITH THE β-POLYKETIDES XIII
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Naturally occurring dihydroisocoumarins, (+/-)-hydrangenol (1) and (+/-)-phyllodulcin (2) were synthesized from the enaminones (3) and (4) by the annelation reactions with ethyl acetoacetate (5).
- Takeuchi, Naoki,Nakano, Takako,Goto, Kaori,Tobinaga, Seisho
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p. 289 - 297
(2007/10/02)
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- A HIGHLY EFFICIENT PREPARATION OF LUNULARIC ACID AND SOME BIOLOGICAL ACTIVITIES OF STILBENE AND DIHYDROSTILBENE DERIVATIVES
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Lunularic acid, an acid possessing dormancy inducing, antifungal, thromboxane synthetase and hyaluronidase inhibitory and plant growth inhibitory activities, was obtained quantitatively from hydrangenol by reduction using sodium borohydride-palladium chloride.Some stilbene and dihydrostilbene derivatives prepared from hydrangenol and its glucoside also showed plant growth inhibitory, hyaluronidase inhibitory and piscicidal activities.Key Word Index - Lunularic acid; dihydrostilbenes; stilbenes; hydrangenol; dihydroisocoumarin; sodium borohydide-palladium chloride reduction; dormancy; plant growth inhibitory activity; piscicidal activity; hyaluronidase inhibitory activity.
- Hashimoto, Toshihiro,Tori, Motoo,Asakawa, Yoshinori
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p. 109 - 114
(2007/10/02)
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- TOTAL SYNTHESIS OF (+/-)-HYDRANGENOL
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The title compound 8 has been synthesized in five steps and in about 33percent overall yield from 3-methoxyphenylacetic acid, 1.Acid 1 was condensed with anisole in polyphosphoric acid to give 3',4-dimethoxydeoxybenzoin, 2, which was converted to the ethylene acetal 3.The latter was metallated with buthyllithium and carbonated giving crude 3',4-dimethoxydeoxybenzoin-2'-carboxylic acid, 4, from which 3,4-dihydro-8-methoxy-3-(4'-methoxyphenyl)isocoumarin, 7, was obtained either by reduction with sodium borohydride and dehydration, or dehydration to 8-methoxy-3-(4'-methoxyphenyl)isocoumarin, 6, and catalytic hydrogenation.Finally, demethylation of 6 to 8 was performed with boron tribromide.
- Napolitano, Elio,Ramacciotti, Antonella,Fiaschi, Rita
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p. 101 - 104
(2007/10/02)
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- Ortho-Lithiated Tertiary Benzamides. Chain Extension via o-Toluamide Anion and General Synthesis of Isocoumarins Including Hydrangenol and Phyllodulcin
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Lithiation of N,N-diethyl-2-methylbenzamide (2a) followed by condensation with aromatic aldehydes and basic hydrolysis leads to 3-aryl-3,4-dihydroisocoumarins 4 in modest overall yields.Adoption of this methodology to N,N-dimethyl-2-methyl-6-methoxybenzamide (7b) provides isocoumarins 9a and 9b which by selective demethylation procedures yields hydrangenol (10a) and phyllodulcin (10c), naturally occurring isocoumarins of pharmacological interest.A one-pot, abbreviated procedure for the preparation of both 9a and 9b starting with N,N-Dimethyl-2-methoxybenzamide (6c) is also described.
- Watanabe, Mitsuaki,Sahara, Masanori,Kubo, Masaki,Furukawa, Sunao,Billedeau, R. J.,Snieckus, V.
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p. 742 - 747
(2007/10/02)
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- DIRECTED METALATION OF TERTIARY BENZAMIDES. SHORT SYNTHESES OF HYDRANGENOL AND PHYLLODULCIN
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Brief syntheses of isocumarin natural products hydragenol(2) and phyllodulcin(3) via ortho-lithiated benzamide intermediates are described.
- Watanabe, M.,Sahara, M.,Furukawa, S.,Billedeau, R.,Snieckus, V.
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p. 1647 - 1650
(2007/10/02)
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