Synthesis of (—)-Talaumidin, a Neurotrophic 2,5-Biaryl-3,4-dimethyltetrahydrofuran Liganan, and Its Stereoisomers

(-)-Talaumidin (1), a 2,5-biaryl-3,4-dimethyltetrahydrofuran lignan isolated from Aristolochia arcuata Masters, shows significant neurite-outgrowth promotion and neuroprotection in primary cultured rat cortical neurons and in NGF-differentiated PC12 cells. The four stereogenic centers on the tetrahydrofuran moiety in 1 result in the presence of seven diastereomers except for their enantiomers. In order to investigate the stereochemistry-activity relationships of the stereoisomers, the systematic synthesis of all stereoisomers of 1 was accomplished by employing Evans aldol, diastereoselective hydroboration, reductive deoxygenation, and Mitsunobu reactions as key steps. The ability of all of the synthesized stereoisomers to promote neurite-outgrowth in PC12 and neuronal cells was evaluated. All stereoisomers exhibited moderate to potent neurotrophic activities in NGF-differentiated PC12 cells at 30 μM and in primary cultured rat cortical neuronal cells at 0.01 μM. In particular, 1e bearing all cis substituents resulted in the most potent neurite-outgrowth promotion.

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“…13,25 Diastereoselective hydroboration of 8a and 8b proceeded smoothly, giving 9a and 9b with >99%de. 26,27 …”

Section: Scheme 2 Evans Syn-and Anti-selective Aldol Reactions Of 2 mentioning

confidence: 98%

“…13,28 (Scheme 4) A series of oxidation/Grignard reaction/re-oxidation reactions of 9a gave a ketone 10 in 71%…”

Section: Scheme 3 Preparation Of 9a and 9bmentioning

confidence: 99%

Systematic Asymmetric Synthesis of All Diastereomers of (−)-Talaumidin and Their Neurotrophic Activity

et al. 2015

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“…In this review, we focus and summarize neuriteoutgrowth promotion activities in primary cultured rat cortical neurons (Zhai et al, 2004) and in NGF-differentiated PC12 cells. Additionally, we describe the synthesis of 1 and all stereoisomers of 1 (Esumi et al, 2006;Fukuyama et al, 2008), and discuss structure-activity relationships between 1 and its analogs on PC12 cells (Harada et al, 2015). Furthermore, we report their regenerative activity toward mouse optic nerves as a neurotrophic activity in vivo, reinforcing their potential as therapeutic agents for neurodegenerative disease (Harada et al, 2018).…”

Section: Introductionmentioning

confidence: 83%

“…To date, six syntheses have been reported. In 2006, we reported the first total synthesis of (2S,3S,4S,5S)talaumidin via a flexible and stereo-controlled synthetic strategy (Esumi et al, 2006;Fukuyama et al, 2008). In addition, we determined the absolute configuration of (-)-talaumidin to be (2S,3S,4S,5S) during the course of the synthetic study.…”

Section: Total Syntheses Of (-)-Talaumidinmentioning

confidence: 99%

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Chemistry and Neurotrophic Activities of (–)-Talaumidin and Its Derivatives

Harada

Kubo

2020

Front. Chem.

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Talaumidin (1), a 2,5-biaryl-3,4-dimethyltetrahydrofuran lignan isolated from Aristolochia arcuata Masters, exhibits significant neurite-outgrowth promotion and neuroprotection in primary cultured rat cortical neurons and in NGF-differentiated PC12 cells. The first enantioselective total synthesis of 1 was achieved by a flexible and reliable synthetic pathway involving an Evans asymmetric aldol reaction, as well as a stereocontrolled hydroboration and Friedel-Crafts arylation, to construct the four contiguous chiral centers on the tetrahydrofuran (THF) ring of 1. In order to investigate the stereochemistry-activity relationship of 1, a systematic synthesis of all diastereomers of 1 was accomplished by applying the synthetic strategy used for natural product 1. The evaluation of neurite-outgrowth promotion by all of the synthesized diastereomers indicated that the (-)-(1S,2R,3S,4R)-isomer 1e was significantly more active than naturally occurring 1. Additionally, we established a synthetic methodology for talaumidin derivatives that could be used to prepare a variety of analogs in a few steps and on a large scale. The synthesized racemic analog rac-1e (56a) exhibited neurite-outgrowth promoting activity in NGF-differentiated PC12 cells to the same degree as the optically active (-)-1e, revealing that a relative configuration bearing all-cis-substituents is important for potent neurotrophic activity, whilst the absolute configuration does not affect activity. Fourteen analogs based on (±)-56a were prepared via the same synthetic methodology. Among them, 56b with a methylenedioxy group on both benzene rings was found to exhibit the most significant neurite outgrowth promotion. In addition, 56a and 56b induced regeneration of the mouse optic nerve in vivo, and their activity was higher than that of talaumidin, as well as their in vitro measured activity. Furthermore, the structure-activity relationship of 56b indicated that the two benzene rings were essential structures, and that the methyl groups on the THF ring could enhance the neurotrophic activity. This result suggests that the two benzene rings of the talaumidin derivatives are essential structures for neurotrophic activity, while the two methyl groups on the THF ring can enhance neurite-outgrowth activity. Finally, it was observed that 1 and derivatives 56a and 56b exhibited potent regenerative activity in the injured mouse optic nerve in vivo.

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Neurotrophe Naturstoffe – ihre Chemie und Biologie

Lacoske

Theodorakis

2013

Angewandte Chemie

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Neurodegenerative Erkrankungen und Rückenmarksverletzungen betreffen weltweit etwa 50 Millionen Menschen und verursachen Gesundheitskosten von insgesamt mehr als 600 Milliarden Dollar pro Jahr. Nervenwachstumsfaktoren, d. h. Neurotrophine, sind potenzielle Therapeutika für diese Erkrankungen, denn sie können die Regeneration von Nerven fördern. Durchschnittlich 500 Publikationen jährlich belegen die Bedeutung der Neurotrophine in den biomedizinischen Wissenschaften und ihr Potenzial für therapeutische Anwendungen. Allerdings ist die klinische Verwendung von Neurotrophinen wegen ihres schlechten pharmakokinetischen Profils stark eingeschränkt. Niedermolekulare Verbindungen, die die neurotrophe Aktivität modulieren, bieten hingegen einen vielversprechenden Therapieansatz bei neurologischen Erkrankungen. Die Natur hat für eine beeindruckende Zahl von Naturstoffen mit starken neurotrophen Wirkungen gesorgt. Die aktuellen Strategien zur Synthese dieser Verbindungen sowie deren Fähigkeit, das Wachstum und die Erneuerung von Nervenzellen zu induzieren, bilden den Schwerpunkt dieses Aufsatzes. Es ist davon auszugehen, dass neurotrophe Naturstoffe nicht nur als Leitstrukturen in der Wirkstoffentwicklung genutzt werden können, sondern auch für das nächste große Projekt der Biomedizin: die Kartierung der Hirnaktivität (BAM, Brain Activity Map).

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Synthesis of (—)-Talaumidin, a Neurotrophic 2,5-Biaryl-3,4-dimethyltetrahydrofuran Liganan, and Its Stereoisomers

Cited by 16 publications

References 14 publications

Systematic Asymmetric Synthesis of All Diastereomers of (−)-Talaumidin and Their Neurotrophic Activity

Systematic Asymmetric Synthesis of All Diastereomers of (−)-Talaumidin and Their Neurotrophic Activity

Chemistry and Neurotrophic Activities of (–)-Talaumidin and Its Derivatives

Neurotrophe Naturstoffe – ihre Chemie und Biologie

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