- Total Synthesis of (-)-Canadine, (-)-Rotundine, (-)-Sinactine, and (-)-Xylopinine Using a Last-Step Enantioselective Ir-Catalyzed Hydrogenation
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A concise asymmetric total synthesis of a group of tetrahydroprotoberberine alkaloids, (-)-canadine, (-)-rotundine, (-)-sinactine, and (-)-xylopinine, has been accomplished in three steps from the commercially available corresponding disubstituted phenylethylamine and disubstituted benzaldehyde. Our synthesis toward these four alkaloids took advantage of the following strategy: In the first step, we achieved an efficient and sustainable synthesis of secondary amine hydrochlorides via a fully continuous flow; in the second step, we developed a Pictet-Spengler reaction/Friedel-Crafts hydroxyalkylation/dehydration cascade for the construction of the dihydroprotoberberine core structure (ABCD-ring); and in the last step, Ir-catalyzed enantioselective hydrogenation was employed for the introduction of the desired stereochemistry at the C-14 position in the tetrahydroprotoberberine alkaloids. This work significantly expedites the asymmetric synthesis of the entire tetrahydroprotoberberine alkaloid family as well as a more diverse set of structurally related non-natural analogues.
- Chen, Fener,Chen, Wenchang,Chen, Yu,Jiang, Meifen,Li, Weijian,Tang, Pei,Yang, Zhi
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p. 8143 - 8153
(2021/06/28)
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- Method for synthesizing tetrahydroberberine and derivatives thereof
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The invention provides a method for synthesizing tetrahydroberberine and derivatives thereof. Specifically, in the presence of an iridium metal catalyst precursor, a chiral diphosphine ligand, an acid and a halogen-containing additive, in a hydrogen atmosphere, a compound (II) is subjected to an asymmetric catalytic hydrogenation reaction in an organic solvent so as to prepare the compound (I).
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Paragraph 0094-0099
(2021/07/08)
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- A General, Concise Strategy that Enables Collective Total Syntheses of over 50 Protoberberine and Five Aporhoeadane Alkaloids within Four to Eight Steps
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A concise, catalytic, and general strategy that allowed efficient total syntheses of 22 natural 13-methylprotoberberines within four steps for each molecule is reported. This synthesis represents the most efficient and shortest route to date, featuring three catalytic processes: CuI-catalyzed redox-A3 reaction, Pd-catalyzed reductive carbocyclization, and PtO2-catalyzed hydrogenation. Importantly, this new strategy to the tetracyclic framework has also been applied to the collective concise syntheses of >30 natural protoberberines (without 13-methyl group) and five aporhoeadane alkaloids.
- Zhou, Shiqiang,Tong, Rongbiao
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supporting information
p. 7084 - 7089
(2016/05/19)
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- Asymmetric total synthesis and identification of tetrahydroprotoberberine derivatives as new antipsychotic agents possessing a dopamine D1, D2 and serotonin 5-HT1A multi-action profile
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An effective and rapid method for the microwave-assisted preparation of the key intermediate for the total synthesis of tetrahydroprotoberberines (THPBs) including l-stepholidine (l-SPD) was developed. Thirty-one THPB derivatives with diverse substituents on A and D ring were synthesized, and their binding affinity to dopamine D1, D2 and serotonin 5-HT 1A and 5-HT2A receptors were determined. Compounds 18k and 18m were identified as partial agonists at the D1 receptor with Ki values of 50 and 6.3 nM, while both compounds act as D2 receptor antagonists (Ki = 305 and 145 nM, respectively) and 5-HT1A receptor full agonists (Ki = 149 and 908 nM, respectively). These two THPBs compounds exerted antipsychotic actions in animal models. Further electrophysiological studies employing single-unit recording in intact animals demonstrated that 18k-excited dopaminergic (DA) neurons are associated with its 5-HT1A receptor agonistic activity. These results suggest that these two compounds targeted to multiple neurotransmitter receptors may present novel lead drugs with new pharmacological profiles for the treatment of schizophrenia.
- Sun, Haifeng,Zhu, Liyuan,Yang, Huicui,Qian, Wangke,Guo, Lin,Zhou, Shengbin,Gao, Bo,Li, Zeng,Zhou, Yu,Jiang, Hualiang,Chen, Kaixian,Zhen, Xuechu,Liu, Hong
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p. 856 - 868
(2013/03/13)
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- Asymmetric synthesis of (S)-(-)-tetrahydropalmatine and (S)-(-)-canadine via a sulfinyl-directed Pictet-Spengler cyclization
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(S)-(-)-Tetrahydropalmatine 2 and (S)-(-)-canadine 4 were synthesized in three steps from (S)-6, in 33% and 34% overall yield, respectively. Thus, condensation of the (S)-(E)-sulfinylimines 10 and 11 with the carbanion derived from (S)-6 gave the tetrahydroisoquinolines 12 and 13, respectively, which upon TFA induced N-desulfinylation, and subsequent microwave assisted Pictet-Spengler cyclization effected both cyclization and C-desulfinylation producing (S)-(-)-tetrahydropalmatine 2 and (S)-(-)-canadine 4 in optically pure form.
- Mastranzo, Virginia M.,Olivares Romero, José Luis,Yuste, Francisco,Ortiz, Benjamín,Sánchez-Obregón, Rubén,García Ruano, José L.
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p. 1266 - 1271
(2012/02/15)
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- Asymmetric synthesis of tetrahydropalmatine via tandem 1,2-addition/ cyclization
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The enantioselective synthesis of both enantiomers of tetrahydropalmatine (2) (ee = 98%), a natural alkaloid belonging to the tetrahydroprotoberberine family, is described. The key step of this total synthesis is based on our tandem 1,2-addition/ring-closure methodology employing lithiated methylbenzamide and benzaldehyde SAMP or RAMP hydrazones as substrates. An initial route was investigated for the formation of N- and 3-substituted dihydroisoquinolones starting from 2-substituted benzaldehyde SAMP hydrazones, but although high diastereoselectivity was achieved, only disappointing yields were obtained. In our subsequent synthetic strategy, 2,3-dimethoxy-6-methylbenzamide 6 and 3,4-dimethoxybenzaldehyde SAMP or RAMP hydrazone 19 gave the dihydroisoquinolones 20 in high diastereomeric purity (de ≥ 96%) and reasonable yield (54-55%), taking into account the complex functionalities established in one step. Cleavage of the N-N bond of the chiral auxiliary and reduction of the carbonyl group of the amide moiety were performed in the same step, and the resulting tetrahydroisoquinolines 22 (ee = 99%) were N-functionalized by treatment with various electrophiles to investigate the ring closure by Pummerer, Friedel-Crafts, and Pomeranz-Fritsch reactions. The Pummerer cyclization led to the formation of (S)-(-)-2 with slight racemization (ee = 89%), whereas the Friedel-Crafts reaction proved to be unsuccessful. Finally, Pomeranz-Fritsch-type cyclization afforded the desired title compound (R)-(+)-2 in excellent enantioselectivity in 9% overall yield over seven steps and after optimization of the last step (S)-(-)-2 in 17% overall yield.
- Boudou, Marine,Enders, Dieter
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p. 9486 - 9494
(2007/10/03)
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- Convenient synthesis of 2,3,9,10-tetraoxygenated protoberberine alkaloids and their 13-methyl alkaloids
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New and convenient synthesis of 2,3,9,10-tetraoxygenated protoberberine alkaloids and their 13-methyl alkaloids through the same intermediates was developed. Acylation of the brominated benzylphenethylamine (13) with α- chloro-α-(methylthio)acetyl chloride, followed by cyclization with stannic chloride, furnished the key intermediates 4-methylthio-3- phenethylisoquinolin-3-ones (14), which were methylated to provide their methyl derivatives (17). Both isoquinolin-3-ones (14, 17) were easily transformed into protoberberine alkaloids (16) and their 13-methyl alkaloids (21) in good yield.
- Hanaoka, Miyoji,Hirasawa, Taeko,Cho, Won Jea,Yasuda, Shingo
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p. 399 - 404
(2007/10/03)
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- Aryl radical cyclizations: One-pot syntheses of protoberberine and pavine alkaloids
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(equation presented) Treatment of 2-(2′-bromo-β-phenethyl)isocarbostyrils 7 with AIBN Bu3SnH in boiling benzene gave 8-oxoberbines 3 in good yields. A similar treatment of 2-(2′-bromo-β-phenethyl)isoquinolinium bromides 6 and their nor- and hom
- Orito, Kazuhiko,Satoh, Yoshitaka,Nishizawa, Hidetoshi,Harada, Rika,Tokuda, Masao
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p. 2535 - 2537
(2007/10/03)
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- Synthesis of phthalideisoquinoline and protoberberine alkaloids and indolo[2,1-α]isoquinolines in a divergent route involving palladium(0)- catalyzed carbonylation
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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
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p. 6583 - 6596
(2007/10/03)
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- Aberrant Biosynthesis of (±)-, (+)- and (-)-12-Bromotetrahydropalmatines
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The incorporation of 2′-bromodidehydro[N-14CH3]reticulinium iodide (1) into (±)-12-bromotetrahydropalmatine (4), (+)-12-bromotetrahydropalmatine (9) and (-)-12-bromotetrahydropalmatine (7) in Cocculus laurifolius DC (Menispermaceae) has been studied and stereospecific reduction of 1 into (+)-9 and (-)-7 and (±)-(4), 12-bromotetrahydropalmatines demonstrated.
- Bhakuni, Dewan S.,Jain, Sudha
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p. 548 - 551
(2007/10/03)
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- Sulfur-controlled 6-exo aryl radical cyclisation of N-ethenyl-2-(2-bromophenyl)acetamides: Synthesis of (±)-tetrahydropalmatine and saulatine
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Bu3SnH-mediated aryl radical cyclisation of 2-(2-bromophenyl)-N-[2,2-bis(phenylsulfanyl)ethenyl]-acetamide 7 takes place in a 6-exo-trig manner to give the isoquinolinone 9. The method has been applied to the synthesis of (±)-tetrahydropalmatine 16 and saulatine 24.
- Ishibashi, Hiroyuki,Kawanami, Hirotaka,Nakagawa, Hiroko,Ikeda, Masazumi
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p. 2291 - 2295
(2007/10/03)
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- Total synthesis of (-)-tetrahydropalmatine via chiral formamidine carbanions: Unexpected behavior with certain ortho-substituted electrophiles
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A method has been developed by alkylation of chiral lithioformamidines to construct protoberberine alkaloids with a C(9) and C(10) D-ring substitution pattern. This ring pattern was established using an ortho-substituted hydroxymethylbenzene electrophile protected as a silyl ether to ultimately provide (-)-tetrahydropalmatine in 88% ee. Additionally, we have discovered limitations with ortho-substituted electrophiles in the asymmetric formamidine alkylation. These electrophiles have the potential to disrupt the lithium formamidine chelate and cause the selectivity in the alkylation to be uncharacteristically low. The total synthesis of (±)-canadine and (-)-tetrahydropalmatine along with the limitations to the formamidine alkylation technology are delineated herein.
- Matulenko, Mark A.,Meyers
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p. 573 - 580
(2007/10/03)
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- Studies on Mannich Reaction of 1-Benzyltetrahydroisoquinolines
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The effect of substituents in Mannich cyclisation reaction of 1-benzyltetrahydroisoquinolines has been studied.Both para- and ortho-cyclisation products are formed when hydroxyl groups are present in the benzene ring of the benzylic moiety whereas only pa
- Bhakuni, D. S.,Kumar, Praveen
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p. 417 - 421
(2007/10/02)
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- A NEW AND CONVENIENT SYNTHESIS OF PROTOBERBERINE ALKALOIDS: (+/-)-TETRAHYDROPALMATINE, (+/-)-SINACTINE, (+/-)-CANADINE AND-)-STYLOPINE
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2,3,9,10-Tetraoxygenated protoberberine alkaloids (14) were efficiently synthesized from the readily available benzaldehyde (2 or 10) via the benzylphenethylamines (11) and 2-phenethylisoquinolin-3-ones (12 or 13).
- Yasuda, Shingo,Hirasawa, Taeko,Hanaoka, Miyoji
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p. 2399 - 2402
(2007/10/02)
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- Rearrangement of Isoindolobenzazepinium to Dibenzoquinolizinium Ions: Application to the Total Synthesis of (+/-)-Tetrahydropalmatine
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(+/-)-Tetrahydropalmatine (17) has been synthesized in 16percent yield from 6,7-dimethoxy-3-(3,4-dimethoxybenzylidene)phthalide (4) as follows.Reaction of compound (4) with glycine afforded 6,7-dimethoxy-3-(3,4-dimethoxybenzylidene)phthalimidin-2-ylacetic
- Napolitano, Elio,Fiaschi, Rita,Scartoni, Valerio,Marsili, Antonio
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p. 781 - 784
(2007/10/02)
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- Syntheses of (+/-)-Tetrahydropalmatine and Spirobenzylisoquinolines by Thermolysis of Benzocyclobutene Derivatives
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The tetrahydroprotoberberine alkaloid, (+/-)-tetrahydropalmatine (1) was synthesized by heating the 1-benzocyclobutenyl-3,4-dihydroisoquinoline (16), followed by reduction of the dehydro compound (20) with sodium borohydride.Ochotensine type spirobenzylis
- Kametani, Tetsuji,Yukawa, Hirotaka,Suzuki, Yukio,Honda, Toshio
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p. 2151 - 2154
(2007/10/02)
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- Chemical Transformation of Protoberberines. VIII. A Novel Synthesis of (+/-)-Fumaricine and a Formal Synthesis of (+/-)-Alpinigenine
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Berberine (1) was transformed stereoselectively into either the trans- or cis-hydroxyspirobenzylisoquinoline (9 or 10) via the 8,14-cycloberbine (3).This method was applied to a first transformation of the protoberberine (22) into a spirobenzylisoquinolin
- Hanaoka, Miyoji,Nagami, Kazuyoshi,Hirai, Yuriko,Sakurai, Shun-Ichiro,Yasuda, Shingo
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p. 2273 - 2280
(2007/10/02)
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- SYNTHESIS OF 2,3,9,10-TETRAOXYGENATED PROTOBERBERINE ALKALOID, TETRAHYDROPALMATINE
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Tetrahydropalmatine (15) was synthesized from the 3,4-dihydroisoquinoline derivative (13) by thermal electrocyclic reaction and subsequent reduction.An intermolecular Diels-Alder type reaction of the benzocyclobutane (6) with the 3,4-dihydroisoquinoline afforded the 13-cyanoprotoberberine (9) regioselectively.
- Kametani, Tetsuji,Yukawa, Hirotaka,Suzuki, Yukio,Yamaguchi, Ryoji,Honda, Toshio
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p. 1067 - 1069
(2007/10/02)
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- BIOSYNTHESIS OF (+)-, (-)- AND (+/-)-TETRAHYDROPALMATINES
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Specific incorporation of didehydroreticuline and reticuline into (+/-)-, (+)-, and (-)-tetrahydropalmatines in Cocculus laurifolius and of (R)- and (S)-reticulines into (R)- and (S)-tetrahydropalmatines respectively has been demonstrated.Feeding of 3H,4'-methoxy-14C>reticuline suggested that reticuline was not converted in the plants into didehydroreticuline and racemisation of optically active forms of tetrahydropalmatine did not take place via dehydrotetrahydropalmatine.
- Bhakuni, Dewan S.,Jain, Sudha,Gupta, Sandeep
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p. 1591 - 1594
(2007/10/02)
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- Synthesis of (+/-)-Scoulerine, (+/-)-Coreximine, (+/-)-Tetrahydropalmatine and Their Monobromo and Dibromo Derivatives
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(+/-)-Scoulerine (14), (+/-)-tetrahydropalmatine (15), (+/-)-coreximine (17) and their 1-bromo derivatives (13a), (12b) and (16) and 1,12-dibromo derivatives (13c) and (13d) respectively have been synthesized.Condensation of substituted benzaldehyde (1) w
- Bhakuni, D. S.,Kumar, P.
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- SYNTHETIC APPLICATION OF LITHIATION REACTIONS - XVI: SYNTHESES OF (+/-)TETRAHYDROPALMATINE, (+/-)CANADINE, (+/-)STYLOPINE AND (+/-)SINACTINE
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N,N-Dimethyl-3,4-dimethoxy- and methylenedioxybenzylamines were lithiated and the organolithium intermediates treated with paraformaldehyde to give the 2-hydroxymethyl derivatives.The latter were converted to 7,8-dimethoxy- and methylenedioxyisochroman-3-ones through successive reaction with ClCOOEt, KCN and KOH.The isochromanones on condensation with homoveratrylamine or homopiperonylamine, followed by cyclisation and reduction furnished the protoberberine alkaloids.
- Narasimhan, N. S.,Mali, R. S.,Kulkarni, B. K.
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p. 1975 - 1982
(2007/10/02)
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- SYNTHESES OF 7,8-DIMETHOXY AND 7,8-METHYLENEDIOXY ISOCHROMAN-3-ONES AN EFFICIENT SYNTHESIS OF (+/-) TETRAHYDROPALMATINE AND (+) CANADINE
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Efficient syntheses of the title compounds, using heteroatom directed lithiation reaction, is described.
- Narasimhan, N.S.,Mali, R.S.,Kulkarni, B.K.
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p. 2797 - 2798
(2007/10/02)
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- Synthetic Applications of Lithiation Reactions : Part XV - New Syntheses of Isochinolines and a Novel Synthesis of Tetrahydropalmatine
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New syntheses of the isoquinoline ring system, involving organometallic intermediates, are described.This is illustrated by a novel synthesis of the alkaloid, tetrahydropalmatine, in simple steps.
- Narasimhan, N. S.,Ranade, A. C.,Bhide, B. H.
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p. 439 - 440
(2007/10/02)
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- A regiospecific synthesis of protoberberine alkaloids
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The protoberberine skeleton has been prepared in two steps from N-benzyl-3,4-dihydroisoquinolinium salts.Treatment of the salts with the anion of methyl methylthiomethylsulfoxide yields mixtures of diastereomeric adducts that cyclize on heating with concentrated hydrochloric acid to dihydroprotoberberines.The latter compounds may be reduced to their tetrahydro analogues with sodium borohydride, oxidized to protoberberinium salts with iodine, or converted to 13-methyltetrahydroprotoberberines by treatment with formaldehyde according to an established procedure.The method has been applied successfully to the synthesis of (+/-)-tetrahydropalmatine, palmatine iodide, (+/-)-xylopinine, (+/-)-sinactine, and (+/-)-corydaline.N-Benzylisoquinolinium salts may be used in place of their dihydro analogues as starting materials in this synthesis, thereby extending the range of substitution patterns potentially available.
- Kiparissides, Zinovia,Fichtner, Robert H.,Poplawski, Janusz,Nalliah, Bala C.,MacLean, David B.
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p. 2770 - 2779
(2007/10/02)
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- THE ALKALOIDS OF Hydrastis canadensis L. (RANUNCULACEAE). TWO NEW ALKALOIDS: HYDRASTIDINE AND ISOHYDRASTIDINE
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Ten alkaloids have been isolated from rhizomes and roots of Hydrastis canadensis L.Four of them, viz. berberine, 1, β-hydrastine, 2, canadine, 3, and canadaline, 4, had been previously isolated.Two are new phthalideisoquinoline alkaloids, viz. 3'-O-demethyl-β-hydrastine, named hydrastidine, 5, and 4'-O-demethyl-β-hydrastine, named isohydrastidine, 6.Two are (-)-(S)-corypalmine, 7, and (-)-(S)-isocorypalmine, 8, known mono-O-demethyl derivatives of (-)-(S)-tetrahydropalmatine, 9.One, 10, is a bis-O,O'-demethyl derivative of 9, whose hydroxy groups were not located, whereas the structure of the tenth alkaloid is still unknown. 1H NMR data for 1-8 and 10, and 13C NMR data for 5, 6, and 8 are reported.
- Messana, Irene,La Bua, Roberto,Galeffi, Corrado
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p. 539 - 544
(2007/10/02)
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