An efficient synthesis of fluoro-neplanocin A analogs using electrophilic fluorination and palladium-catalyzed dehydrosilylation

Jarhad, Dnyandev B.; Jang, Min Hwan; Shin, Young Sup; Kim, Gyudong; Kim, Hong Rae; Hyun, Young Eum; Yoon, Jong‐Won; Jeong, Lak Shin

doi:10.1039/c9qo00099b

Cited by 4 publications

(10 citation statements)

References 27 publications

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“…Ketone 6 was derived from D-cyclopentenone 7, using a Michael reaction as a key step. Intermediate 7 was efficiently derived from D-ribose according to our previously published procedure with a minor modification [16,17].…”

Section: Resultsmentioning

confidence: 99%

“…Key intermediate 6 was synthesized according to our previously published procedure, as shown in Scheme 2 [17]. Briefly, D-ribose was converted to diene 8 in four steps without purification in a 64% yield.…”

Section: Resultsmentioning

confidence: 99%

“…The removal of the TBDPS group of 11 with tetra-n-butylammonium fluoride (TBAF) yielded diol 12, in which the primary hydroxyl group was selectively protected with a TBDPS group to afford 13. Oxidation of the remaining secondary alcohol in 13 with tetra-n-propylammonium perruthenate (TPAP) and Nmethylmorpholine N-oxide (NMO) afforded ketone 6 [17], which served as the key starting material for the electrophilic fluorination.…”

Section: Resultsmentioning

confidence: 99%

“…Ketone 6 was treated with lithium bis(trimethylsilyl)amide (LiHMDS), followed by trapping the resulting enolate with chlorotriethylsilane (TESCl) to produce silyl enol ether. The silyl enol ether was treated with electrophilic fluorine, octane ditetrafluoroborate) to produce desired 6-b-fluoro-cyclopentanone 14 as the single stereoisomer, which was equilibrated to geminal diol because of the electronegative fluorine atom [14,16,17]. The b stereochemistry of fluorine was obtained because of the steric hindrance by the 2,3-isopropylidene group, which was confirmed by long-range coupling between H-8 and 6 0 -b-F and Xray crystallography after conversion to adenosine derivative 3a.…”

Section: Resultsmentioning

confidence: 99%

“…Here, we report the synthesis of enantiomerically pure 6 0 -fluorinated-5 0 -homoaristeromycin analogues 3aee via the electrophilic fluorination [14,16,17] of the silyl enol ether with Selectfluor as the key step and assessment of their antiviral activity.…”

Section: Introductionmentioning

confidence: 99%

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Identification of 6′-β-fluoro-homoaristeromycin as a potent inhibitor of chikungunya virus replication

Shin

Jarhad

Jang

et al. 2020

European Journal of Medicinal Chemistry

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a b s t r a c tWe have reported on aristeromycin (1) and 6 0 -fluorinated-aristeromycin analogues (2), which are active against RNA viruses such as Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV), Zika virus (ZIKV), and Chikungunya virus (CHIKV). However, these exhibit substantial cytotoxicity. As this cytotoxicity may be attributed to 5 0 -phosphorylation, we designed and synthesized one-carbon homologated 6 0 -fluorinated-aristeromycin analogues. This modification prevents 5 0 -phosphorlyation by cellular kinases, whereas the inhibitory activity towards S-adenosyl-L-homocysteine (SAH) hydrolase will be retained. The enantiomerically pure 6 0 -fluorinated-5 0 -homoaristeromycin analogues 3a-e were synthesized via the electrophilic fluorination of the silyl enol ether with Selectfluor, using a base-build up approach as the key steps. All synthesized compounds exhibited potent inhibitory activity towards SAH hydrolase, among which 6 0 -b-fluoroadenosine analogue 3a was the most potent (IC 50 ¼ 0.36 mM). Among the compounds tested, 6 0 -b-fluoro-homoaristeromycin 3a showed potent antiviral activity (EC 50 ¼ 0.12 mM) against the CHIKV, without noticeable cytotoxicity up to 250 mM. Only 3a displayed anti-CHIKV activity, whereas both3a and 3b inhibited SAH hydrolase with similar IC 50 values (0.36 and 0.37 mM, respectively), which suggested that 3a's antiviral activity did not merely depend on the inhibition of SAH hydrolase. This is further supported by the fact that the antiviral effect was specific for CHIKV and some other alphaviruses and none of the homologated analogues inhibited other RNA viruses, such as SARS-CoV, MERS-CoV, and ZIKV. The potent inhibition and high selectivity index make 6 0 -b-fluoro-homoaristeromycin (3a) a promising new template for the development of antivirals against CHIKV, a serious re-emerging pathogen that has infected millions of people over the past 15 years.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification of 6′-β-fluoro-homoaristeromycin as a potent inhibitor of chikungunya virus replication

Shin

Jarhad

Jang

et al. 2020

European Journal of Medicinal Chemistry

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Design, Synthesis, and Molecular Docking Analysis of Fluorinated MLN4924 Derivatives as Antiviral Agents

Sung,

Hyeon,

Kim

et al. 2023

Asian J Org Chem

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MLN4924 is known for its potential in cancer treatment and antiviral activity as a NEDD8‐activating enzyme (NAE) inhibitor. We designed and synthesized fluorinated MLN4924 derivatives by electrophilic fluorination at the 6′‐position and nucleophilic fluorination at the 2′‐position of the sugar moiety, respectively. The compounds were then evaluated for their anti‐HCMV activity, and compound 2 a exhibited the most potent HCMV inhibitory activity, showing similar results to MLN4924 but with no toxicity at a high concentration. Docking studies highlighted the importance of the sugar conformation in the binding interaction with the target protein. This research offers critical insights into the optimization of MLN4924 derivatives and provides a promising pathway towards the development of effective antiviral agents.

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Chemical Approaches to Carbocyclic Nucleosides

Ojeda‐Porras

Roy

Agrofoglio

2022

The Chemical Record

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Nucleoside analogues are at the forefront of antiviral therapy for last decades. To circumvent some of their limitations, based on their metabolism, and in order to improve their anti‐viral potency and selectivity, several families of nucleoside analogues have been described through structural modifications at the sugar and heterocycles. The replacement of the oxygen of the nucleoside by a methylene has led to the family of carbocyclic (or cyclopentane) nucleoside analogues. Various potent anti‐HIV and anti‐HBV drugs belong to this family. Main syntheses of carbocyclic analogues of nucleosides used Diels‐Alder reactions (in racemic or asymmetric series), but also started from carbohydrates (ribose, glucose), as a source of optically active compounds, which then had to be transformed into carbacycles under various conditions. The growing interest in carbocyclic nucleosides has led several groups, including ours, to develop new analogues and to explore novel routes. This article will review some of the recent chemistry developed on selected five‐membered ring carbocyclic nucleosides.

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An efficient synthesis of fluoro-neplanocin A analogs using electrophilic fluorination and palladium-catalyzed dehydrosilylation

Abstract: An alternative and efficient approach to neplanocin A analogs 1b and 1d has been developed using electrophilic fluorination and Pd-catalyzed dehydrosilylation.

Cited by 4 publications

References 27 publications

Identification of 6′-β-fluoro-homoaristeromycin as a potent inhibitor of chikungunya virus replication

Identification of 6′-β-fluoro-homoaristeromycin as a potent inhibitor of chikungunya virus replication

Design, Synthesis, and Molecular Docking Analysis of Fluorinated MLN4924 Derivatives as Antiviral Agents

Chemical Approaches to Carbocyclic Nucleosides

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