- Studies on asymmetric total synthesis of (?)-β-hydrastineviaa chiral epoxide ring-opening cascade cyclization strategy
-
Herein, facile and enantioselective approaches to synthesize the core phthalide tetrahydroisoquinoline scaffold of (?)-β-hydrastineviaboth a CF3COOH-catalyzed (86% ee) and KHMDS-catalyzed (78% ee) epoxide ring-opening/transesterification cascade cyclization from chiral epoxide under very mild conditions are described. The key elements include a highly enantioselective epoxidation using the Shi ketone catalyst and an intramolecular CF3COOH-catalyzed cascade cyclization in one pot, and a late-stage C-3′ epimerization under MeOK/MeOH conditions as the key steps to achieve the first total synthesis of (?)-β-hydrastine (up to 81% ee).
- Cheng, Maosheng,Li, Jihui,Liu, Yongxiang,Meng, Jiaxin,Qin, Qiaohua,Song, Xinjing,Wu, Tianxiao,Zhao, Dongmei,Zheng, Yang
-
p. 18953 - 18958
(2020/06/08)
-
- An Acid-Catalyzed Epoxide Ring-Opening/Transesterification Cascade Cyclization to Diastereoselective Syntheses of (±)-β-Noscapine and (±)-β-Hydrastine
-
An acid-catalyzed stereoselective epoxide ring-opening/intramolecular transesterification cascade cyclization reaction and N-Boc deprotection was found to be a successful strategy to construct the phthalide tetrahydroisoquinoline skeleton in one pot. Based on this strategy, the unified and highly diastereoselective routes for the total syntheses of (±)-β-Noscapine and (±)-β-Hydrastine were exploited.
- Li, Jihui,Liu, Yongxiang,Song, Xinjing,Wu, Tianxiao,Meng, Jiaxin,Zheng, Yang,Qin, Qiaohua,Zhao, Dongmei,Cheng, Maosheng
-
supporting information
p. 7149 - 7153
(2019/09/30)
-
- A new total synthesis of (±)-α-noscapine
-
A new, convergent total synthesis of (±)-α-noscapine was developed on a grams scale through the condensation of 3-trimethylsilyl-meconin derivative 9 and the iodized salt cotarnine derivative 20 as the key step. Staring from simple 2,3-dimethoxybenzoic acid, piperonal and 2,2-dimethoxyethanamine, through the traditional chemical processes to give the final product in 11.6% yield over 14 steps.
- Mao, Yongjun,Song, Shuai,Zhao, Dongmei,Cheng, Maosheng
-
p. 2633 - 2640
(2014/01/06)
-
- Short synthesis of noscapine, bicuculline, egenine, capnoidine, and corytensine alkaloids through the addition of 1-siloxy-isobenzofurans to imines
-
A concise diastereotioselective strategy for the synthesis of noscapine, bicuculline, and egenine (1a-c), as well as capnoidine and corytensine (2a,b), was developed using diastereoselective addition of 1-siloxy-isobenzofurans 4a and 4b to iminium ion 5 in a one-pot approach. The synthesis features the use of imine 13 obtained through Bischler-Napieralsky reaction from amine 11. The addition of ionic liquids as addictives in the reactions afforded erythro configuration in major adduct compounds. The synthetic route can also be applied in the total synthesis of promising tubulin binding agent EM105 (3).
- Soriano, Maria Del Pilar C.,Shankaraiah, Nagula,Santos, Leonardo Silva
-
experimental part
p. 1770 - 1773
(2010/05/18)
-
- Synthesis of phthalideisoquinoline and protoberberine alkaloids and indolo[2,1-α]isoquinolines in a divergent route involving palladium(0)- catalyzed carbonylation
-
6,7,3',4'-Alkoxy-substituted 1-(2'-bromobenzoyl)-3,4-dihydroisoquinoline methiodides 17 were treated with sodium borohydride in methanol or acetic acid to give erythro-1-(2'-bromo-α-hydroxybenzyl)-2-methyl-1,2,3,4- tetrahydroisoquinolines 19. Treatment of 17 with lithium aluminum hydride in tetrahydrofuran gave the threo-isomer 20 in preference to the erythro 19. On the basis of studies on palladium(0)-catalyzed carbonylation of 2-bromo-3,4- dimethoxybenzyl alcohol to 6,7-dimethoxyphthalide, amino alcohol 19 or 20 was treated with a catalytic amount of palladium(II) acetate and triphenylphosphine in an atmosphere of carbon monoxide in the presence of chlorotrimethylsilane and potassium carbonate in boiling toluene to give the corresponding erythro- or threo-types of phthalideisoquinoline alkaloids 1 or 2, respectively. One-pot cyclization of the erythro-amino alcohols 19 was achieved by heating in N,N-dimethylformamide containing potassium carbonate to give 2,3,8,9- or 2,3,9,10-alkoxy-substituted 5,6-dihydroindolo[2,1- α]isoquinolines 3, which have a unique tetracyclic skeleton characteristic of dibenzopyrrocoline alkaloids. Similarly, palladium-(0)-catalyzed carbonylation of 1-(2'-bromobenzyl)tetrahydroisoquinolines 21 in the presence of excess potassium carbonate was found to give 8-oxoberbines 22, which on reduction with lithium aluminum hydride can be converted to protoberberine alkaloids 4.
- Orito, Kazuhiko,Miyazawa, Mamoru,Kanbayashi, Ryo,Tokuda, Masao,Suginome, Hiroshi
-
p. 6583 - 6596
(2007/10/03)
-
- Studies on Carboxylation of Alkoxy-Substituted Benzyl Alcohols via Direct Lithiation and Bromine-Lithium Exchange: Synthesis of Phthalides and Phthalideisoquinoline Alkaloids
-
Conversion of alkoxy-substituted benzyl alcohols to the corresponding phthalides by carboxylation via ortho lithiation and bromine-lithium exchange was studied.The method was applied to the key step in the synthesis of phthalideisoquinoline alkaloids.
- Orito, Kazuhiko,Miyazawa, Mamoru,Suginome, Hiroshi
-
p. 2489 - 2496
(2007/10/02)
-
- A New Synthesis of Phthalides by Internal Trapping in Ortho-Lithiated Carbamates Derived from Benzylic Alcohols
-
The addition of t-BuLi to a low-temperature THF solution of o-bromocarbamates 2 leads to ortho-lithiated intermediates 3, in which internal trapping by the electrophile on the side chain then takes place.This novel Parham-type anionic cyclization procedure affords the variously substituted phthalides 5 in high yields and can also be used for the preparation of lactones 8, which are useful for the synthesis of aristocularine alkaloids.
- Paleo, M. Rita,Lamas, Carlos,Castedo, Luis,Dominguez, Domingo
-
p. 2029 - 2033
(2007/10/02)
-
- Ring-cleavage of phthalidisoquinoline alkaloids by ethyl chloroformate
-
Degradation of (-)-α-narcotine (5), (-)-β-narcotine (6), and (-)-β-hydrastine (7) with ethyl chloroformate (ECF) affords the chloro-urethans 9 and 18, respectively. Diastereomer 9-I is easily hydrolyzed to the hydroxy-urethan 10, whilst 18 is converted to the methoxy-analogue 19. The stilbene lactone 11 is obtained from 9-I by treatment with DBU, the analogous stilbene 17 arises already when 7 is reacted with ECF. - Hydroxy-urethan 10 - a phenylogous aldol - is split by OH- to aldehyde 13 and to meconine (14). LiAlH4-reduction of 10 yields the stereochemically homogenous triol 15, which is cyclized to diastereomers of the 3-phenyl-isochroman 16 under acidic conditions.
- Von Angerer,Von Angerer,Ambros,Wiegrebe
-
p. 425 - 431
(2007/10/02)
-
- Directed ortho metalation of n,n-diethyl benzamides. Methodology and regiospecific synthesis of useful contiguously tri- and tetra-substituted oxygenated aromatics, phthalides and phthalic anhydrides
-
Full experimental details for the directed ortho metalation approch to a variety of simple ortho-substituted N,N-diethyl benzamides (Table 1) and contiguously 1,2,3- and 1,2,3,4-substituted benzamides (Tables 2) are given. The efficient conversion of these benzamides (6, 10, 12, 13, 18, 19) into phthalides (9a-b, 16b-c, 17) and phthalic anhydrides (8,16a), compounds previously available by demanding, classical methods, is detailed. A short synthesis of iso-ochracinic acid (27) is described.
- De Silva,Reed,Billedeau,Wang,Norris,Snieckus
-
p. 4863 - 4878
(2007/10/02)
-
- NEW SHORT STEP GENERAL SYNTHESIS OF ISOBENZOFURAN-1(3H)-ONES (PHTALIDES) BASED ON A SINGLE OR DOUBLE β-SCISSION OF ALKOXYL RADICALS GENERATED FROM 1-ETHYL-BENZOCYCLOBUTEN-1-OLS AND FROM 1,3-DIHYDROISOBENZOFURAN-1-OLS; SYNTHESIS OF SOME NATURAL PHTHALIDES
-
New general methods are described for the synthesis of phthalides, 3-monosubstituted, and 3,3-disubstituted phthalides including naturally-occuring phthalides such as pierardine based on a regioselective single or double β-scission of the alkoxyl radicals generated by the photolysis of the hypoiodites of 1-ethyl-benzocyclobuten-1-ols or 1,2-catacondensed benzocyclobuten-1-ols or 1,3-dihydro-1,3-alkanoisobenzofuran-1-ols.The formation paths of the phthalides, which involve a regioselective single or double β-scission of the alkoxyl radicals generated from 1-alkylbenzocyclobuten-1-ols and from catacondensed benzocyclobuten-1-ols, are discussed.Key Words: Synthesis of Phthalides; Alkoxy Radicals; Mercury(II)oxide-Iodine Reagent; Photolysis; Double β-Scission
- Kobayashi, Kazuhiro,Itoh, Masahito,Sasaki, Akiyoshi,Suginome, Hiroshi
-
p. 5437 - 5452
(2007/10/02)
-
- SYNTHESIS OF (Z)-3-BUTYLIDENE-6,7-DIHYDROXYPHTHALIDE
-
(Z)-3-Butylidene-6,7-dihydroxyphthalide (2) was first synthesized from 6,7-dimethoxyphthalide (4) and its structure was synthetically confirmed.
- Ogawa, Yoshimitsu,Hosaka, Kunio,Chin, Masao,Mitsuhashi, Hiroshi
-
p. 1737 - 1744
(2007/10/02)
-
- A NEW SYNTHESIS OF PHTHALIDES THROUGH β-SCISSION OF BENZOCYCLOBUTENOL HYPOIODITES
-
A simple new method for the synthesis of phthalides and their 3-alkyl 3,3'-spiroalkyl derivatives including (+/-)-3-butylphthalide, a racemic form of a constituent of celery oil, through the β-scission of alkoxyl radicals generated from hypoiodites of benzocyclobutenols by the photolysis, is described.
- Kobayashi, Kazuhiro,Itoh, Masahito,Suginome, Hiroshi
-
p. 3369 - 3372
(2007/10/02)
-
- Determination of Neutral Manufacturing Impurities in Heroin by Capillary Gas Chromatography with Electron Capture Detection after Reduction with Lithium Aluminum Hydride and Derivatization with Heptafluorobutyric Anhydride
-
Neutral byproducts associated with the manufacture of illicit heroin are many and include meconin, 4-acetoxy-3,6-dimethoxyphenanthrene, N,O6-diacetylnorcodeine, 4-acetoxy-3,6-dimethoxy-5-phenanthrene, N,O3,O6-triacetylnormorphine, and 4-acetoxy-3,6-dimethoxy-8-phenanthrene.These N- and O-acetylated impurities, and meconin, are easily isolated from the bulk heroin matrix, after which they are subjected to reduction with lithium aluminum hydride (LiAlH4) followed by derivatization with heptafluorobutyric anhydride (HFBA) in the presence of pyridine.The resultant haptafluorobutyryl (HFB) electrophiles are detected on-column at picogram (pg) levels by using capillary column gas chromatography/electron capture detection (CC/GC/ECD) in the splitless mode.The method is applicable for the in-depth analyses of crudely processed and highly refined heroin samples.
- Moore, James M.,Allen, Andrew C.,Cooper, Donald A.
-
p. 1003 - 1007
(2007/10/02)
-
- General Method for the Synthesis of Phthalaldehydic Acids and Phthalides from o-Bromobenzaldehydes via Ortho-Lithiated Aminoalkoxides
-
A general method for the synthesis of phthalaldehydic acids and phthalides, many of which are key intermediates in natural product synthesis, has been developed. o-Bromobenzaldehydes 1a-f were first protected in situ as α-morpholinoalkoxides by reaction with lithium morpholide.Treatment of the α-morpholinoalkoxides 3a-f with n-butyllithium (to exchange bromine with lithium) followed by sequential treatment with solid CO2 and dilute acid afforded the phthalaldehydic acids 6a-f, respectively.Reduction of 6a-f with NaBH4 in EtOH furnished the phthalides 7a-f, respectively, in nearly quantitative yields.Efficient methods for the synthesis of the o-bromobenzaldehydes 1a-d, which were not readily available, are also described.
- Sinhababu, Achintya K.,Borchardt, Ronald T.
-
p. 2356 - 2360
(2007/10/02)
-
- Synthetic Applications of Lithiation Reactions: Part XIX - A Facile Synthesis of 7-Methoxyphthalide & Meconine
-
7-Methoxyphthalide (3a) and meconine (3b) have been synthesised by the lithiation of appropriate N,N-dimethylbenzylamines (1a and 1b) followed by the reaction of the lithium derivatives with ethylchloroformate.
- Narasimhan, N. S.,Mali, R. S.,Kulkarni, B. K.,Gupta, P. K.
-
p. 1257 - 1258
(2007/10/02)
-
- Influence of Alkoxyalkyl Substituents in the Regioselective Lithiation of the Benzene Ring
-
The concomitant presence of an alkoxyalkyl group (α-alkoxyalkyl, α- or β-dialkoxyalkyl) and of an alkoxy group in the relative positions 1 and 3 in a benzene ring generally permits an easy lithiation of position 2 by proton-metal exchange with n-butyllithium; the only aromatic compound tested, bearing a β-alkoxyalkyl group, gave, however, extensive decomposition in the metalation step.Reaction of the metalated species with an electrophile (such as carbon dioxide or ethyl chloroformate) leads to the corresponding substituted products in good to excellent yields.The following transformations are described: 3,4-dimethoxybenzyl α-ethoxyethyl ether (1) into 6,7-dimethoxyphthalide (15); 3,4-(methylenedioxy)benzyl α-ethoxyethyl ether (2) into 6,7-(methylenedioxy)phthalide (16); 3,4-dimethoxybenzyl methyl ether (3) into ethyl 2-(methoxymethyl)-5,6-dimethoxybenzoate (18) and into ethyl 2-(chloromethyl)-5,6-dimethoxybenzoate (20); 3,4-(methylenedioxy)benzyl methyl ether (4) into ethyl 2-(methoxymethyl)-5,6-(methylenedioxy)benzoate (19) and into ethyl 2-(chloromethyl)-5,6-(methylenedioxy)benzoate (21); 3,4-dimethoxybenzaldehyde dimethyl acetal (5) into 5,6-dimethoxyphthalaldehydic acid (22); 3,4-(methylenedioxy)benzaldehyde dimethyl acetal (6) into 5,6-(methylenedioxy)phthalaldehydic acid (23); (3,4-dimethoxyphenyl)acetaldehyde dimethyl acetal (7) into ethyl 2-(2,2-dimethoxyethyl)-5,6-dimethoxybenzoate (25); 3,4,4'-trimethoxydeoxybenzoin ethylene acetal (10) into 2-(ethoxycarbonyl)-3,4,4'-trimethoxydeoxybenzoin (26); 4,3',4'-trimethoxydeoxybenzoin ethylene acetal (11) into 2'-(ethoxycarbonyl)-4,3',4'-trimethoxydeoxybenzoin (27); 3,4,3',4'-tetramethoxydeoxybenzoin ethylene acetal (12) into a mixture of 3-(3,4-dimethoxybenzylidene)-6,7-dimethoxyphthalide (28) and 3-(3,4-dimethoxyphenyl)-7,8-dimethoxyisocoumarin (29).The dioxole ring of methylenedioxy-substituted benzenes is sometimes unstable under these metalation conditions, and partial decomposition usually causes the yields to be lower than those in the case of the corresponding methoxy-substituted benzenes.Many of the products listed above, which have been already prepared by other methods, are more conveniently obtained by the present approach.
- Napolitano, Elio,Giannone, Enrico,Fiaschi, Rita,Marsili, Antonio
-
p. 3653 - 3657
(2007/10/02)
-
- Some Reactions of β-Hydrastine
-
β-Hydrastine (I) is an erythro compound, the chiral centres at C-1 and C-9 having R and S configurations respectively.Its conversion into the hitherto unknown threo-isomer by the reduction of the corresponding immonium derivative (II) with zinc and acetic acid has met with failure.Surprisingly, II with Zn/ AcOH regenerates β-hydrastine.During this reduction II rather suffers reductive cleavage yielding the non-nitrogenous lactone, meconine (IV).Sodium borohydride and catalytic reductions of II also fail to afford the threo-isomer.The latter is found to be extremely unstable as revealed from Dreiding model because of the severe steric interaction between the axial hydrogen at C-4 and the C1'-C2'bond.Benzylic oxidation of β-hydrastine (I) with MnO2, instead of producing the desired 4-oxo derivative (VI), gives 6,7-methylenedioxyisoquinoline arising out of cleavage at C1-C9 bond.
- Chatterjee, A.,Bhattacharyya, S.,Bhattacharyya, S.
-
-