Total synthesis of conolidine and apparicine

Takanashi, Noriyuki; Suzuki, Kenta; Kitajima, Mariko; Takayama, Hiromitsu

doi:10.1016/j.tetlet.2015.12.029

Cited by 24 publications

(15 citation statements)

References 42 publications

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“…It was found to be even more potent than conolidine while also showing no mu-opioid receptor activity. Several other groups have also been successful in synthesizing derivatives of conolidine ( 64 , 65 ). This study aimed to produce conolidine derivatives with an even greater analgesic effect and oral bioavailability.…”

Section: Evidence Acquisitionmentioning

confidence: 99%

Conolidine: A Novel Plant Extract for Chronic Pain

et al. 2021

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: Pain, the most common symptom reported among patients in the primary care setting, is complex to manage. Opioids are among the most potent analgesics agents for managing pain. Since the mid-1990s, the number of opioid prescriptions for the management of chronic non-cancer pain (CNCP) has increased by more than 400%, and this increased availability has significantly contributed to opioid diversion, overdose, tolerance, dependence, and addiction. Despite the questionable effectiveness of opioids in managing CNCP and their high rates of side effects, the absence of available alternative medications and their clinical limitations and slower onset of action has led to an overreliance on opioids. Conolidine is an indole alkaloid derived from the bark of the tropical flowering shrub Tabernaemontana divaricate used in traditional Chinese, Ayurvedic, and Thai medicine. Conolidine could represent the beginning of a new era of chronic pain management. It is now being investigated for its effects on the atypical chemokine receptor (ACK3). In a rat model, it was found that a competitor molecule binding to ACKR3 resulted in inhibition of ACKR3’s inhibitory activity, causing an overall increase in opiate receptor activity. Although the identification of conolidine as a potential novel analgesic agent provides an additional avenue to address the opioid crisis and manage CNCP, further studies are necessary to understand its mechanism of action and utility and efficacy in managing CNCP.

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Section: Evidence Acquisitionmentioning

confidence: 99%

Conolidine: A Novel Plant Extract for Chronic Pain

et al. 2021

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“…Starting from known chiral diol 79, 61) keto-amine 80 was prepared in four steps (Chart 24). Then, 80 was alkylated with alkyne derivative 81 to afford alkyne-ketone 82.…”

Section: Monoterpenoid Indole Alkaloidsmentioning

confidence: 99%

Total Syntheses of <i>Lycopodium</i> and Monoterpenoid Indole Alkaloids Based on Biosynthesis-Inspired Strategies

Takayama

2020

Chem. Pharm. Bull.

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“…Due to their unique structure and potentially useful biological activity, the total synthesis of 5-nor stemmadenine alkaloids has been reported by Bennasar et al [ 39 , 40 ], Micalizio [ 37 ], and Takayama [ 41 ] (Scheme 2 ). In addition, synthetic work on the 1-azabicyclo[4.2.2]decane skeleton core has been published by Joule [ 42 , 43 ] and Weinreb’s group [ 44 ] (Scheme 3 ).…”

Section: Synthesis Studiesmentioning

confidence: 99%

“…A recent report of the total synthesis of (±)-apparicine ( 2 ) by Bennasar and co-workers [ 39 , 40 ] detailed an approach which utilized an intramolecular Heck reaction. Micalizio and Takayama [ 37 , 41 ] reported the total syntheses of conolidine ( 6 ), which could be derived from an iminium ion under intramolecular Mannich reaction. In addition, Micalizio and co-workers [ 37 ] clarified the absolute stereochemistry of 6 .…”

Section: Synthesis Studiesmentioning

confidence: 99%

Synthesis and stereochemical determination of an antiparasitic pseudo-aminal type monoterpene indole alkaloid

et al. 2016

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5-Nor stemmadenine alkaloids, isolated from the genus Tabernaemontana, display a range of bioactivity. 16-Hydroxy-16,22-dihydroapparicine, the active component of an extract from the Tabernaemontana sp. (dichotoma, elegans, and divaricate), exhibited potent antimalarial activity, representing the first such report of the antimalarial property of 5-nor stemmadenine alkaloids. We, therefore, decided to attempt the total synthesis of the compound to explore its antimalarial activity and investigate structure and bioactivity relationships. As a result, we completed the first total synthesis of 16-hydroxy-16,22-dihydroapparicine, by combining a phosphine-mediated cascade reaction, diastereoselective nucleophilic addition of 2-acylindole or methylketone via a Felkin–Anh transition state, and chirality transferring intramolecular Michael addition. We also clarified the absolute stereochemistries of the compound. Furthermore, we evaluated the activity of the synthetic compound, as well as that of some intermediates, all of which showed weak activity against chloroquine-resistant Plasmodium falciparum (K1 strain) malaria parasites.

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Total synthesis of conolidine and apparicine

Cited by 24 publications

References 42 publications

Conolidine: A Novel Plant Extract for Chronic Pain

Conolidine: A Novel Plant Extract for Chronic Pain

Total Syntheses of <i>Lycopodium</i> and Monoterpenoid Indole Alkaloids Based on Biosynthesis-Inspired Strategies

Synthesis and stereochemical determination of an antiparasitic pseudo-aminal type monoterpene indole alkaloid

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