- 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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- 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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- 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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- 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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- 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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- 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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