Enantioselective formal synthesis of ent-rhynchophylline and ent-isorhynchophylline

Amat, Mercedes; Ramos, Carlos; Pérez, Maria; Molins, Elı́es; Florindo, Pedro; Santos, Maria M. M.; Bosch, Joan

doi:10.1039/c2cc38540f

Cited by 39 publications

(16 citation statements)

References 36 publications

(7 reference statements)

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“…Following this procedure, tetracyclic oxindole 8 was obtained in 45% overall yield from aldehyde 5. The required bicyclic lactam 2 was prepared, as previously reported [28], by cyclocondensation of prochiral aldehyde-diester 1 with (S)-tryptophanol in a process that involves the stereoselective desymmetrization of two enantiotopic acetate chains. A subsequent bromination with pyridinium perbromide, with careful control of the reaction time (10 s) and operating under strictly anhydrous conditions to minimize the formation of the corresponding oxindole, afforded 2-bromoindole 3 in an improved yield (92%).…”

Section: Resultsmentioning

confidence: 99%

Studies on the Enantioselective Synthesis of E-Ethylidene-bearing Spiro[indolizidine-1,3′-oxindole] Alkaloids

et al. 2021

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A synthetic route for the enantioselective construction of the tetracyclic spiro[indolizidine-1,3′-oxindole] framework present in a large number of oxindole alkaloids, with a cis H-3/H-15 stereochemistry, a functionalized two-carbon substituent at C-15, and an E-ethylidene substituent at C-20, is reported. The key steps of the synthesis are the generation of the tetracyclic spirooxindole ring system by stereoselective spirocyclization from a tryptophanol-derived oxazolopiperidone lactam, the removal of the hydroxymethyl group, and the stereoselective introduction of the E-ethylidene substituent by acetylation at the α-position of the lactam carbonyl, followed by hydride reduction and elimination. Following this route, the 21-oxo derivative of the enantiomer of the alkaloid 7(S)-geissoschizol oxindole has been prepared.

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Section: Resultsmentioning

confidence: 99%

Studies on the Enantioselective Synthesis of E-Ethylidene-bearing Spiro[indolizidine-1,3′-oxindole] Alkaloids

et al. 2021

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“…The asymmetric synthesis of indoloquinolizidines was achieved starting from enantiopure tryptophanol, a methodology used previously by the groups of Allin [19,20] and Amat-Bosch [21,22,23,24,25,26,27] for the synthesis of several indole alkaloids. In this synthetic strategy, tryptophanol is used not only as the source of chirality, but is also used to incorporate the tryptamine moiety present in the target alkaloids [28,29].…”

Section: Resultsmentioning

confidence: 99%

Enantiopure Indolo[2,3-a]quinolizidines: Synthesis and Evaluation as NMDA Receptor Antagonists

et al. 2016

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Enantiopure tryptophanol is easily obtained from the reduction of its parent natural amino acid trypthophan (available from the chiral pool), and can be used as chiral auxiliary/inductor to control the stereochemical course of a diastereoselective reaction. Furthermore, enantiopure tryptophanol is useful for the syntheses of natural products or biological active molecules containing the aminoalcohol functionality. In this communication, we report the development of a small library of indolo[2,3-a]quinolizidines and evaluation of their activity as N-Methyl D-Aspartate (NMDA) receptor antagonists. The indolo[2,3-a]quinolizidine scaffold was obtained using the following key steps: (i) a stereoselective cyclocondensation of (S)-or (R)-tryptophanol with appropriate racemic δ-oxoesters; (ii) a stereocontrolled cyclization on the indole nucleus. The synthesized enantiopure indolo[2,3-a]quinolizidines were evaluated as NMDA receptor antagonists and one compound was identified to be 2.9-fold more potent as NMDA receptor blocker than amantadine (used in the clinic for Parkinson's disease). This compound represents a hit compound for the development of novel NMDA receptor antagonists with potential applications in neurodegenerative disorders associated with overactivation of NMDA receptors.

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“…[ 14 ] Studies have shown that Rhy has various beneficial effects, being anti-addictive, anti-arrhythmic, anticonvulsant, anti-anxiety, and anti-hypertensive, as well as exhibiting sedative and neuroprotective properties in various models. [ 15 16 17 18 ] Rhy can alleviate methamphetamine (METH)-induced neurotoxicity in rat cortical neurons[ 19 ] and inhibit Ca 2 + influx to prevent glutamate-induced neuronal death in vitro . [ 20 ] Thus, Rhy is widely used to treat central nervous system (CNS) disorders, including convulsions, numbness, and lightheadedness, as well as cardiovascular disease, such as hypertension.…”

Section: Introductionmentioning

confidence: 99%

Rhynchophylline downregulates phosphorylated camp response element binding protein, nuclear receptor-related-1, and brain-derived neurotrophic factor expression in the hippocampus of ketamine-induced conditioned place preference rats

Guo

Luo²,

Tu³

et al. 2018

Phcog Mag

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Background:Addiction to ketamine is becoming a serious public health issues, for which there exists no effective treatment. Rhynchophylline (Rhy) is an alkaloid extracted from certain Uncaria species that is well known for both its potent anti-addictive and neuroprotective properties. Increasing evidence supports the contributions of cAMP response element binding protein (CREB), nuclear receptor-related-1 (Nurr1), and brain-derived neurotrophic factor (BDNF) in modulating neural and behavioral plasticity which was induced by addictive drugs.Objective:To investigate the effects of Rhy on the behavior and the levels of phosphorylated CREB (p-CREB), Nurr1, and BDNF in the hippocampus of ketamine-induced conditioned place preference (CPP) rats.Materials and Methods:CPP paradigm was used to establish the model of ketamine-dependent rats and to evaluate the effect of Rhy on ketamine dependence. The expressions of p-CREB, Nurr1, and BDNF were tested by Western blotting and immunohistochemistry.Results:We observed that Rhy can reverse the behavior preference induced by ketamine CPP training. At the same time, expression of p-CREB, Nurr1, and BDNF, which was significantly increased by ketamine, was restored in the Rhy -treated group.Conclusion:This study indicates that Rhy can reverse the reward effect induced by ketamine in rats and the mechanism can probably be related to regulate the hippocampal protein expression of p-CREB, Nurr1, and BDNF.SUMMARY P-CREB, Nurr1 and BDNF play an important role in the formation of ketamine-induced place preference in ratsRhynchophylline reversed the expression of p-CREB, Nurr1 and BDNF which was activated by ketamine in the hippocampusRhynchophylline demonstrates the potential effect of mediates ketamine induced rewarding effect. Abbreviations used: Rhy: Rhynchophylline; CREB: cAMP response element binding protein; Nurr1: Nuclear receptor-related-1; BDNF: Brain-derived neurotrophic factor; CPP: Conditioned place preference; NMDA: N-methyl-D-aspartic acid; METH: Methamphetamine; CNS: Central nervous system; PFA: Paraformaldehyde; GAPDH: Glyceraldehyde-3-phosphate dehydrogenase; LTP: long-term potentiation.

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Enantioselective formal synthesis of ent-rhynchophylline and ent-isorhynchophylline

Cited by 39 publications

References 36 publications

Studies on the Enantioselective Synthesis of E-Ethylidene-bearing Spiro[indolizidine-1,3′-oxindole] Alkaloids

Studies on the Enantioselective Synthesis of E-Ethylidene-bearing Spiro[indolizidine-1,3′-oxindole] Alkaloids

Enantiopure Indolo[2,3-a]quinolizidines: Synthesis and Evaluation as NMDA Receptor Antagonists

Rhynchophylline downregulates phosphorylated camp response element binding protein, nuclear receptor-related-1, and brain-derived neurotrophic factor expression in the hippocampus of ketamine-induced conditioned place preference rats

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