Stereoselective Synthesis of (<i>S</i>)- and (<i>N</i>)-Cyclopropyl-Fused Carbocyclic Nucleosides Using Stereoselective Cyclopropanation

Hyun, Young Eum; Kim, Hong Rae; Jeong, Lak Shin

doi:10.1021/acs.joc.1c00705

Cited by 7 publications

(9 citation statements)

References 48 publications

(46 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Chemistry. We first synthesized conformationally restricted 1′-homologated (S)-methanocarba nucleosides employing diastereoselective cyclopropanation 10 to construct the bicyclo[3.1.0]hexane core, as shown in Scheme 1.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…The resulting crude residue was purified by flash column chromatography (hexanes/EtOAc, 5:1) to afford 8 (2.16 g, 87%) as a colorless oil whose spectroscopic and physical data was identical to those of known compounds. 10 6 -C h l o r o -9 -( ( ( 3 a S , 3 b S , 4 a S , 5 a R ) -2 , 2dimethyltetrahydrocyclopropa [3,4]cyclopenta [1,2-d][1,3] (12). To a stirred solution of 9 (50 mg, 0.27 mmol, 1.0 equiv) in THF (3 mL) were added triphenylphosphine (PPh 3 , 141 mg, 0.54 mmol, 2.0 equiv) and 6chloro-2-iodopurine (152 mg, 0.54 mmol, 2.0 equiv) at rt.…”

Section: ■ Conclusionmentioning

confidence: 99%

See 1 more Smart Citation

Structure–Activity Relationships of Truncated 1′-Homologated Carbaadenosine Derivatives as New PPARγ/δ Ligands: A Study on Sugar Puckering Affecting Binding to PPARs

Hyun

Kim

et al. 2023

J. Med. Chem.

Self Cite

View full text Add to dashboard Cite

Peroxisome proliferator-activated receptors (PPARs) are associated with the regulation of metabolic homeostasis. Based on a previous report that 1′-homologated 4′-thionucleoside acts as a dual PPARγ/δ modulator, carbocyclic nucleosides 2–5 with various sugar conformations were synthesized to determine whether sugar puckering affects binding to PPARs. (S)-conformer 2 was synthesized using Charette asymmetric cyclopropanation, whereas (N)-conformer 3 was synthesized using stereoselective Simmons–Smith cyclopropanation. All synthesized nucleosides did not exhibit binding affinity to PPARα but exhibited significant binding affinities to PPARγ/δ. The binding affinity of final nucleosides to PPARγ did not differ significantly based on their conformation, but their affinity to PPARδ depended greatly on their conformation, correlated with adiponectin production. (N)-conformer 3h was discovered to be the most potent PPARδ antagonist with good adiponectin production, which exhibited the most effective activity in inhibiting the mRNA levels of LPS-induced IL-1β expression in RAW 264.7 macrophages, implicating its anti-inflammatory activity.

show abstract

Section: ■ Results and Discussionmentioning

confidence: 99%

Section: ■ Conclusionmentioning

confidence: 99%

Structure–Activity Relationships of Truncated 1′-Homologated Carbaadenosine Derivatives as New PPARγ/δ Ligands: A Study on Sugar Puckering Affecting Binding to PPARs

Hyun

Kim

et al. 2023

J. Med. Chem.

Self Cite

View full text Add to dashboard Cite

show abstract

“…It was expected that the fusion to a cyclopropane would impart a significant rigidity to the resulting nucleosides similar to that of the cyclohexene moiety but should be less prone to hydrolytic processes and have more lipophilicity. Limiting flexible conformation with a fused cyclopropane is a useful strategy to increase the potency and selectivity of a nucleoside. ,, …”

Section: Introductionmentioning

confidence: 99%

“…Limiting flexible conformation with a fused cyclopropane is a useful strategy to increase the potency and selectivity of a nucleoside. 16 , 17 , 27 …”

Section: Introductionmentioning

confidence: 99%

Conformationally Locked Carbocyclic Nucleosides Built on a 4′-Hydroxymethyl-3′-hydroxybicyclo[4.1.0]heptane Template. Stereoselective Synthesis and Antiviral Activity

et al. 2022

View full text Add to dashboard Cite

Two new families of enantiomerically pure carbocyclic nucleoside analogues based on a cyclohexane moiety with five chiral centers and a fused cyclopropyl ring have been synthesized. A highly regio-and stereoselective synthetic approach for the modular construction of the functionalized bicyclo[4.1.0]heptyl azide intermediate 6 has been established. Key steps to achieve this asymmetric synthesis involved highly diastereoselective allylic oxidation and hydroboration reactions. The first family of compounds, 1a,b and 2, presents different natural nucleobases, whereas the second one 3a−e bears functionalized 1,2,3-triazoles. These derivatives have been tested as antiviral agents, and compound 3d has shown to display moderate activity against coxsackie B4 virus.

show abstract

“…Hence, we focused on designing a synthetic route that establishes positions C2−C4 in an early stage and utilizes different chemistry for the cyclopropyl installation. While the presence of four continuous stereocenters in ribonucleosides imposes a greater challenge in chemical synthesis compared to deoxy or truncated analogues, our recent publication of cyclopropyl-fused truncated nucleosides 12 provided insight into the utility of Charette's asymmetric cyclopropanation reaction toward the synthesis of (S)-MC ribonucleosides.…”

mentioning

confidence: 99%

Synthesis of Enantiomerically Pure Pyrimidine Ribonucleosides Locked in the South Conformation

et al. 2022

Self Cite

View full text Add to dashboard Cite

The conformation of the central five-membered ring of a nucleoside plays an important role in enzyme recognition. Bicyclo[3.1.0]hexane, also known as the methanocarba (MC), serves as a template that can mimic the locked forms of the two distinctive conformations, namely, the north and south conformations. While modified nucleosides locked in the north conformation have been actively investigated, the south counterpart remains largely unexplored because it is difficult to synthesize. Herein, we report a concise synthetic route that can provide the key amino sugar intermediate essential for the synthesis of (S)-MC ribonucleosides in a 100% stereoselective manner. Also, through the proposed synthetic approach, we report the first synthesis of enantiomerically pure (S)-MC cytidine 1. We believe our findings would greatly contribute to the field of nucleoside chemistry and provide opportunities for novel nucleoside discovery.

show abstract

Stereoselective Synthesis of (S)- and (N)-Cyclopropyl-Fused Carbocyclic Nucleosides Using Stereoselective Cyclopropanation

Cited by 7 publications

References 48 publications

Structure–Activity Relationships of Truncated 1′-Homologated Carbaadenosine Derivatives as New PPARγ/δ Ligands: A Study on Sugar Puckering Affecting Binding to PPARs

Structure–Activity Relationships of Truncated 1′-Homologated Carbaadenosine Derivatives as New PPARγ/δ Ligands: A Study on Sugar Puckering Affecting Binding to PPARs

Conformationally Locked Carbocyclic Nucleosides Built on a 4′-Hydroxymethyl-3′-hydroxybicyclo[4.1.0]heptane Template. Stereoselective Synthesis and Antiviral Activity

Synthesis of Enantiomerically Pure Pyrimidine Ribonucleosides Locked in the South Conformation

Contact Info

Product

Resources

About