- 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 0084-0093
(2021/07/08)
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- Asymmetric total synthesis of tetrahydroprotoberberine derivatives and evaluation of their binding affinities at dopamine receptors
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Cocaine addiction remains a serious challenge for clinical and medical research because there is no effective pharmacological treatment. L-THP, a natural product isolated from Corydalis yanhusuo W.T. Wang, is one of the most frequently used traditional herbs to treat drug addiction in China. Our laboratory first reported that its demethylated metabolites L-ICP, L-CD, and L-CP had high affinity at dopamine D1, D2, and D5 receptors. Here we report the chemical synthesis of these metabolites and other derivatives and their binding affinities at dopamine receptors. The synthesis of these bioactive metabolites will allow further in vivo study of their potential in treating cocaine addiction.
- Lee, David Y.W.,Liu, Jing,Zhang, Shuzhen,Huang, Peng,Liu-Chen, Lee-Yuan
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p. 1437 - 1440
(2017/03/08)
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- Compositions and methods for producing benzylisoquinoline alkaloids
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The present invention relates to host cells that produce compounds that are characterized as benzylisoquinolines, as well as select precursors and intermediates thereof. The host cells comprise one, two or more heterologous coding sequences wherein each of the heterologous coding sequences encodes an enzyme involved in the metabolic pathway of a benzylisoquinoline, or its precursors or intermediates from a starting compound. The invention also relates to methods of producing the benzylisoquinoline, as well as select precursors and intermediates thereof by culturing the host cells under culture conditions that promote expression of the enzymes that produce the benzylisoquinoline or precursors or intermediates thereof.
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Page/Page column 3; 14
(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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- Formation and conformation of baicalin-berberine and wogonoside-berberine complexes
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It is well-known that baicalin-berberine complex (1) precipitates in the water decoction of numerous Chinese Medicinal formulae containing Radix Scutellariae and Rhizoma Coptidis or Cortex Phellodendri. In the current study, ionic interaction between the carboxylate ion of baicalin and the quaternary ammonium ion of berberine was revealed to be responsible for the formation of 1 and wogonoside-berberine (2) by using FAB-MS and NMR titration experiments. In addition, nuclear Overhauser effect spectroscopy (NOESY) correlations observed in 1 and 2 suggested quite different conformation of the two complexes, which was further supported by the fact that the [a]D of the canadine obtained by reduction of 1 is of an opposite sign to that obtained from 2. Partition coefficients (n-octanol/water) determination demonstrated 12-20 times larger partition coefficient of each complex (1, 2) than that of each single compound (baicalin, wogonoside, and berberine), indicating the significant role of the formation of the complex in the bioavailability enhancement of these pharmacologically active constituents.
- Wang, Jing-Rong,Tanaka, Takashi,Zhang, Hong,Kouno, Isao,Jiang, Zhi-Hong
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experimental part
p. 706 - 711
(2012/10/07)
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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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- Characterization of two methylenedioxy bridge-forming cytochrome P450-dependent enzymes of alkaloid formation in the Mexican prickly poppy Argemone mexicana
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Formation of the methylenedioxy bridge is an integral step in the biosynthesis of benzo[c]phenanthridine and protoberberine alkaloids in the Papaveraceae family of plants. This reaction in plants is catalyzed by cytochrome P450-dependent enzymes. Two cDNAs that encode cytochrome P450 enzymes belonging to the CYP719 family were identified upon interrogation of an EST dataset prepared from 2-month-old plantlets of the Mexican prickly poppy Argemone mexicana that accumulated the benzo[c]phenanthridine alkaloid sanguinarine and the protoberberine alkaloid berberine. CYP719A13 and CYP719A14 are 58% identical to each other and 77% and 60% identical, respectively, to stylopine synthase CYP719A2 of benzo[c]phenanthridine biosynthesis in Eschscholzia californica. Functional heterologous expression of CYP719A14 and CYP719A13 in Spodoptera frugiperda Sf9 cells produced recombinant enzymes that catalyzed the formation of the methylenedioxy bridge of (S)-cheilanthifoline from (S)-scoulerine and of (S)-stylopine from (S)-cheilanthifoline, respectively. Twenty-seven potential substrates were tested with each enzyme. Whereas CYP719A14 transformed only (S)-scoulerine to (S)-cheilanthifoline (Km 1.9 ± 0.3; kcat/Km 1.7), CYP719A13 converted (S)-tetrahydrocolumbamine to (S)-canadine (Km 2.7 ± 1.3; kcat/Km 12.8), (S)-cheilanthifoline to (S)-stylopine (Km 5.2 ± 3.0; kcat/Km 2.6) and (S)-scoulerine to (S)-nandinine (Km 8.1 ± 1.9; k cat/Km 0.7). These results indicate that although CYP719A14 participates in only sanguinarine biosynthesis, CYP719A13 can be involved in both sanguinarine and berberine formation in A. mexicana.
- Diaz Chavez, Maria Luisa,Rolf, Megan,Gesell, Andreas,Kutchan, Toni M.
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experimental part
p. 186 - 193
(2012/02/14)
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- Preparation and structural elucidation of (-)-tetrahydroberberine-(+)-2,3-di(p-toluyl) tartaric acid complex
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A new (2:1) complex of (-)-13aS-tetrahydroberberine [(-)-13aS-THB] with (+)-2,3-di(p-toluyl) tartaric acid (DTTA), i.e. 5,8,13,13a-tetrahydro-9,10-dimethoxy-2,3-methylenedioxy-6H dibenzo[a,g] quinolizine·2,3-di(p-toluyl) tartaric acid [2C20H20NO4·C20H18O8], as well as its optical active component (-)-THB, has been obtained from the resolution process of (±)-THB in methanol. The structures of this complex and an enantiomer (-)-13aS-THB have been characterized by CD, IR and NMR spectroscopy as well as by X-ray single crystal diffraction.
- Gao, Jin-Ming,Liu, Wei-Tao,Li, Man-Lin,Liu, Han-Wei,Zhang, Xing-Chang,Li, Zong-Xiao
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experimental part
p. 466 - 469
(2009/03/12)
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- Difference between Enzymatic and Chemical N-methylations of Protoberberine-Type Alkaloid, Dependent on the Stereoisomer of (-)-N-methyl-7,8,13,13a-tetrahydroberberinium salt
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A possible relation between the stereostructure of (-)-(13aS)-tetrahydroberberine (1) and its enzymatic/chemical N-methylation, an important biosynthetic reaction to isoquinoline alkaloids in plants, was examined by CD spectroscopic, X-ray crystallographic, and energy calculation methods. The CD measurements indicated that 1 has two conformers (cis and trans) concerning the ring junction of the quinolizidine skeleton, and exist with a cis/trans ratio of about 1/4 in a diethyl ether : 2-methylbutane : ethanol (5:5:2) mixture. The dimensional/conformational difference between these cis and trans conformers was clarified by the X-ray crystal-structure analyses of two stereoisomers of N-methylated 1 (3 and 4). By using these structural parameters, the progress of N-methylation was simulated by energy profile calculations, suggesting that the cis and trans conformers are the major substrate for the enzymatic and chemical N-methylation reactions, respectively. Taking these results and the simulation of N-methylation of 1 by S-adenosyl-L-methionine at the binding pocket of N-methyltransferase into consideration, different pathways for chemical and enzymatic N-methylations of 1 have been proposed.
- Kamigauchi, Miyoko,Yoshida, Mayumi,Noda, Yuko,Nishijo, Jujiro,In, Yasuko,Tomoo, Koji,Ohishi, Hirofumi,Ishida, Toshimasa
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p. 587 - 594
(2007/10/03)
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- The Polonovski-Potier reaction of berbine N-oxides. Synthesis of 8-hydroxymethyl and 8-methylberbines
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The Polonovski-Potier reaction of trans and cis berbines N-oxides was studied. The 8-cyano derivative obtained from trans N-oxides were used to synthesize 8-hydroxymethyl and 8-methyl berbines. This procedure was applied to the stereocontroled synthesis of (8R, 14S)-(-)-8-methylcanadine from (14S)-(-)-canadine. (C) 2000 Elsevier Science Ltd.
- Suau, Rafael,Nájera, Francisco,Rico, Rodrigo
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p. 9713 - 9723
(2007/10/03)
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- THE STEREOSPECIFIC SYNTHESIS OF (-)-(8R) AND (-)-(8S)-METHYLCANADINE
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Regioselective complexation of the dimethoxy arene ring of canadine to the Cr(CO)3,moiety gives two diastereoisomers which are separated by flash chromatography.Deprotonation of either diastereoisomer with n-butyllithium followed by addition of methyl iodide or trimethylsilyl chloride gives C11-methyl- or -trimethylsilylcanadine after decomplexation.Each diastereoisomer of the C11-trimethylsilylcanadine complex may be treated with base and methyl iodide to give, after desilylation and decomplexation, the enantiomerically pure (-)-(8R) and (-)-(8S) methyl canadines; racemic samples of C8-methylcanadines are prepared via an independent route.
- Baird, Peter D.,Blagg, Julian,Davies, Stephen G.,Sutton, Kevin H.
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p. 171 - 186
(2007/10/02)
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- INTRAMOLECULAR ADDITION OF AMINES TO CHIRAL VINYL SULFOXIDES, TOTAL SYNTHESIS OF (R)-(+)-CANADINE
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The intramolecular conjugate addition of an amine to the chiral vinyl sulfoxides 3 and 4 to give chiral isoquinolines 5 and 6 is reported.Isoquinoline 5 is converted to (R)-(+)-Canadine via an intramolecular Pummerer reaction.
- Pyne, Stephen G.
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p. 4737 - 4740
(2007/10/02)
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