Dual-Face Nucleoside Scaffold Featuring a Stereogenic All-Carbon Quaternary Center. Intramolecular Silicon Tethered Group-Transfer Reaction

Tambutet, Guillaume; Becerril-Jiménez, Fabiola; Dostie, Starr; Simard, Ryan D.; Prévost, Michel; Mochirian, Philippe; Guindon, Yvan

doi:10.1021/ol502777r

Cited by 11 publications

(20 citation statements)

References 30 publications

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“…OEt2. 7 Treatment of the crude reaction mixture with HF-pyridine was necessary to remove undesired TMS protection of the oxygen at C3. The vinyldimethylchlorosilane moiety was then installed on the resulting free alcohols to provide the 3,4-anti (8a,b) and 3,4-syn (11a,b) bromides in a 10:1 ratio and excellent yield (52%) over the three steps.…”

Section: Resultsmentioning

confidence: 99%

“…Preference for the 3,4-anti stereochemistry has been proposed to occur through a Felkin-Ahn transition state. 7,[18][19][20][21] The steric hindrance imposed by the isopropylidene moiety of aldehyde 9 is likely to prohibit chelate formation between the aldehyde and α-oxygen.…”

Section: Resultsmentioning

confidence: 99%

“…4 We have initiated the syntheses of novel nucleoside analogues possessing an all-carbon quaternary stereogenic center at C3'. [5][6][7] It is proposed that this chiral center could enhance target specificity in addition to providing opportunities for the incorporation of different pharmacophores. As illustrated in Figure 1, the hydroxymethyl substituent at C3' can have either a xylo/lyxo-(β-face) or ribo/arabino-(α-face) like orientation.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis of nucleoside analogues using acyclic diastereoselective reactions

Lussier¹,

Waltz²,

Freure³

et al. 2019

Arkivoc

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The design of novel xylo-like nucleoside analogues bearing a C3' all-carbon quaternary center and a C2'hydroxy substituent is described. Synthesis of this scaffold makes use of highly diastereoselective transformations on acyclic substrates. Central to the approach is formation of a 2,4-syn cyanohydrin from cyanide addition onto an aldehyde through a proposed seven-membered ring chelate using a bidentate Lewis acid. In addition, a highly diastereoselective Mukaiyama aldol reaction, an intramolecular radical atom cyclization, and thioaminal formation are used to generate this novel molecule. A series of related nucleoside analogues are being tested as antiviral and anticancer agents.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Synthesis of nucleoside analogues using acyclic diastereoselective reactions

Lussier¹,

Waltz²,

Freure³

et al. 2019

Arkivoc

Self Cite

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show abstract

“…In parallel, we have been studying carbon-centered free radicals on acyclic molecules and their reactivity in atom transfer reactions, leading to the generation of all carbon stereogenic quaternary centers. Together, these findings [10][11][12][13][14][15][16] led to the conceptualization and synthesis of novel nucleoside analogues bearing a quaternary all-carbon stereogenic center at C3 or C2 [16][17][18].…”

Section: Introductionmentioning

confidence: 99%

Nucleotide Analogues Bearing a C2′ or C3′-Stereogenic All-Carbon Quaternary Center as SARS-CoV-2 RdRp Inhibitors

et al. 2022

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The design of novel nucleoside triphosphate (NTP) analogues bearing an all-carbon quaternary center at C2′ or C3′ is described. The construction of this all-carbon stereogenic center involves the use of an intramoleculer photoredox-catalyzed reaction. The nucleoside analogues (NA) hydroxyl functional group at C2′ was generated by diastereoselective epoxidation. In addition, highly enantioselective and diastereoselective Mukaiyama aldol reactions, diastereoselective N-glycosylations and regioselective triphosphorylation reactions were employed to synthesize the novel NTPs. Two of these compounds are inhibitors of the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2, the causal virus of COVID-19.

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“…The stereogenic all-carbon quaternary center would be generated by photoredox initiated radical cylizations of α-bromo esters 8a and 8b bearing a β-silicon tethered allyl moiety. 7,13 These reactions were observed to proceed through the 7-endo-trig pathway. Density functional theory (DFT) calculations were performed to elucidate the origin of this preference.…”

Section: ■ Introductionmentioning

confidence: 99%

Diastereoselective Synthesis of Arabino- and Ribo-like Nucleoside Analogues Bearing a Stereogenic C3′ All-Carbon Quaternary Center

et al. 2019

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The synthesis of novel nucleoside analogues bearing a C3′ all-carbon quaternary center and a C2′-hydroxy substituent is described. The all-carbon stereogenic center was generated through an intramolecular 7-endo attack of a silyltethered allyl moiety on a tertiary radical using photoredox catalysis. Subsequent allylic oxidation and diastereoselective hydride reductions provided the hydroxy substituent at C2′, which then controls the stereoselective introduction of pyrimidine nucleobases on the corresponding furanose scaffold. Density functional theory (DFT) calculations provided insights into the origin of the high syn diastereoselectivity resulting from the radical cyclization. This original methodology grants access to a wide range of 1′,2′-cis and 1′,2′-trans arabino-and ribo-like analogues bearing an all-carbon quaternary center at C3′. These molecules are currently being tested for their antiviral and anticancer properties.

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Dual-Face Nucleoside Scaffold Featuring a Stereogenic All-Carbon Quaternary Center. Intramolecular Silicon Tethered Group-Transfer Reaction

Cited by 11 publications

References 30 publications

Synthesis of nucleoside analogues using acyclic diastereoselective reactions

Synthesis of nucleoside analogues using acyclic diastereoselective reactions

Nucleotide Analogues Bearing a C2′ or C3′-Stereogenic All-Carbon Quaternary Center as SARS-CoV-2 RdRp Inhibitors

Diastereoselective Synthesis of Arabino- and Ribo-like Nucleoside Analogues Bearing a Stereogenic C3′ All-Carbon Quaternary Center

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