277. The synthesis of emetine and related compounds. Part V. A stereochemically favourable synthesis of emetine

Openshaw, Harry; Whittaker, Norman

doi:10.1039/jr9630001461

Cited by 51 publications

(25 citation statements)

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“…As an alternative strategy, we envisioned that pseudo-allylic strain in the ene-ester product of a Horner-Wadsworth-Emmons (HWE) reaction, or in the corresponding transition state, might be used to perturb the equilibrium away from the equatorial alignment. 58 Therefore, ketone 6 S was treated with the carbanion formed from methyl diethylphosphonoacetate, and partial epimerization was indeed observed (Scheme 2A). The ene-ester with the desired axial ethyl group was obtained as a mixture of E and Z isomers, 8 E and 8 Z (55 mol% of total product by NMR), while the ene-ester with retention of configuration at the ethyl group, 9 , was obtained exclusively as the E isomer (45 mol% of total product by NMR).…”

Section: Resultsmentioning

confidence: 99%

Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators

et al. 2016

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Mu-opioid receptor agonists represent mainstays of pain management. However, the therapeutic use of these agents is associated with serious side effects, including potentially lethal respiratory depression. Accordingly, there is a longstanding interest in the development of new opioid analgesics with improved therapeutic profiles. The alkaloids of the Southeast Asian plant Mitragyna speciosa, represented by the prototypical member mitragynine, are an unusual class of opioid receptor modulators with distinct pharmacological properties. Here we describe the first receptor-level functional characterization of mitragynine and related natural alkaloids at the mu-, kappa-, and delta-opioid receptors. These results show that mitragynine and the oxidized analog 7-hydroxymitragynine, are partial agonists of the human mu-opioid receptor and competitive antagonists at the kappa- and delta-opioid receptors. We also show that mitragynine and 7-hydroxymitragynine are G-protein-biased agonists of the mu-opioid receptor, which do not recruit β-arrestin following receptor activation. Therefore, the Mitragyna alkaloid scaffold represents a novel framework for the development of functionally biased opioid modulators, which may exhibit improved therapeutic profiles. Also presented is an enantioselective total synthesis of both (-)-mitragynine and its unnatural enantiomer, (+)-mitragynine, employing a proline-catalyzed Mannich-Michael reaction sequence as the key transformation. Pharmacological evaluation of (+)-mitragynine revealed its much weaker opioid activity. Likewise, the intermediates and chemical transformations developed in the total synthesis allowed the elucidation of previously unexplored structure-activity relationships (SAR) within the Mitragyna scaffold. Molecular docking studies, in combination with the observed chemical SAR, suggest that Mitragyna alkaloids adopt a binding pose at the mu-opioid receptor that is distinct from that of classical opioids.

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Section: Resultsmentioning

confidence: 99%

Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators

et al. 2016

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“…Based on the premise of the existence of an interconversion between benzo[a]quinolizine and isoquinolinium upon exposure to an acid [20], we hypothesized that (±)- 1 could be recovered from the resolution mother liquid upon acid-catalyzed racemization, and then resolved again. As expected, after adding additional (+)-CSA to the resolution mother liquid and refluxing overnight, complete racemization took place, and when the reaction mixture was cooled to 15 °C with stirring, the camphorsulfonate salt of (+)- 1 was formed as crystals with a moderate ee value.…”

Section: Resultsmentioning

confidence: 99%

Preparation and evaluation of tetrabenazine enantiomers and all eight stereoisomers of dihydrotetrabenazine as VMAT2 inhibitors

Yao

Xue-ying

et al. 2011

European Journal of Medicinal Chemistry

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Tetrabenazine (TBZ) ((±)-1) and dihydrotetrabenazines (DHTBZ) are potent inhibitors of VMAT2. Herein, a practical chemical resolution of (±)-1 and stereoselective synthesis of all eight DHTBZ stereoisomers are described. The result of VMAT2 binding assay revealed that (+)-1 (Ki = 4.47 nM) was 8000-fold more potent than (−)-1 (Ki = 36,400 nM). Among all eight DHTBZ stereoisomers, (2R,3R,11bR)-DHTBZ ((+)-2: Ki = 3.96 nM) showed the greatest affinity for VMAT2. The (3R,11bR)-configuration appeared to play a key role for VMAT2 binding. In summary, (+)-1, (+)-2, and their derivatives warrant further studies in order to develop more potent and safer drugs for the treatment of chorea associated with Huntington’s disease and other hyperkinetic disorders.

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“…been synthesized by many groups[214][215][216][217][218][219][220]. Openshaw[215] obtained the (−)-benzoquinolizidine 218 by the reaction of the 3,4-dihydroisoquinoline 216 and the Mannich base 217 followed by treatment with (−)-camphor-10-sulfonic acid.…”

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confidence: 99%

“…Openshaw[215] obtained the (−)-benzoquinolizidine 218 by the reaction of the 3,4-dihydroisoquinoline 216 and the Mannich base 217 followed by treatment with (−)-camphor-10-sulfonic acid. The ketone 218 was transformed into emetine (213) via the unsaturated ester 219.…”

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confidence: 99%

Alkaloids

Hoshino¹,

Murakata²,

Ishizaki³

et al. 2000

Ullmann's Encyclopedia of Industrial Chemistry

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277. The synthesis of emetine and related compounds. Part V. A stereochemically favourable synthesis of emetine

Cited by 51 publications

References 0 publications

Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators

Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators

Preparation and evaluation of tetrabenazine enantiomers and all eight stereoisomers of dihydrotetrabenazine as VMAT2 inhibitors

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