Synthesis of 2,3-Dideoxy-2-fluoro-2,3-endo-methylene- and 2,3-Dideoxy-2-fluoro-3‑C‑hydroxymethyl-2,3-endo-methylene-pentofuranoses and Their Use in the Preparation of Conformationally Locked Bicyclic Nucleosides
Construction of protected 2,3-dideoxy-2-fluoro-2,3-endo-methylene-pentofuranoses from d-glyceraldehyde and 2,3-dideoxy-2-fluoro-3-C-hydroxymethyl-2,3-endo-methylene-pentofuranoses from d-isoascorbic acid, via Simmons–Smith-type stereoselective cyclopropanations on the respective fluoroallyl alcoh...
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Veröffentlicht in: | Journal of organic chemistry 2015-02, Vol.80 (4), p.2198-2215 |
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creator | Clarkson, Rob Komsta, Zofia Mayes, Benjamin A Moussa, Adel Shelbourne, Montserrat Stewart, Alistair Tyrrell, Andrew J Wallis, Laura L Weymouth-Wilson, Alexander C |
description | Construction of protected 2,3-dideoxy-2-fluoro-2,3-endo-methylene-pentofuranoses from d-glyceraldehyde and 2,3-dideoxy-2-fluoro-3-C-hydroxymethyl-2,3-endo-methylene-pentofuranoses from d-isoascorbic acid, via Simmons–Smith-type stereoselective cyclopropanations on the respective fluoroallyl alcohols, is described. Synthesis of the corresponding conformationally locked sugar modified uridine and guanosine nucleosides was achieved via Vorbrüggen or Mitsunobu methodologies. Stereochemical confirmation of the novel nucleosides was performed on the basis of 2D NOESY NMR experiments. Analysis of 2′,3′-dideoxy-2′-fluoro-3′-C-hydroxymethyl-2′,3′-endo-methylene-uridine by X-ray crystallography yielded the principal conformational parameters and indicated that the furanoid ring adopted an oE/oT1, East pucker. The uridine and guanosine nucleosides were found to be inactive in the hepatitis C virus (HCV) cell-based replicon assay, which was corroborated on examination of the corresponding nucleoside triphosphates against the HCV NS5B polymerase. |
doi_str_mv | 10.1021/jo502712g |
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Synthesis of the corresponding conformationally locked sugar modified uridine and guanosine nucleosides was achieved via Vorbrüggen or Mitsunobu methodologies. Stereochemical confirmation of the novel nucleosides was performed on the basis of 2D NOESY NMR experiments. Analysis of 2′,3′-dideoxy-2′-fluoro-3′-C-hydroxymethyl-2′,3′-endo-methylene-uridine by X-ray crystallography yielded the principal conformational parameters and indicated that the furanoid ring adopted an oE/oT1, East pucker. The uridine and guanosine nucleosides were found to be inactive in the hepatitis C virus (HCV) cell-based replicon assay, which was corroborated on examination of the corresponding nucleoside triphosphates against the HCV NS5B polymerase.</description><identifier>ISSN: 0022-3263</identifier><identifier>EISSN: 1520-6904</identifier><identifier>DOI: 10.1021/jo502712g</identifier><identifier>PMID: 25615008</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><ispartof>Journal of organic chemistry, 2015-02, Vol.80 (4), p.2198-2215</ispartof><rights>Copyright © 2015 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a230t-a09e3d3f52bb52c5eecd30d310f8103a65deacc298e0a9f96cc86ab93774b4a73</citedby><cites>FETCH-LOGICAL-a230t-a09e3d3f52bb52c5eecd30d310f8103a65deacc298e0a9f96cc86ab93774b4a73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jo502712g$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jo502712g$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25615008$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Clarkson, Rob</creatorcontrib><creatorcontrib>Komsta, Zofia</creatorcontrib><creatorcontrib>Mayes, Benjamin A</creatorcontrib><creatorcontrib>Moussa, Adel</creatorcontrib><creatorcontrib>Shelbourne, Montserrat</creatorcontrib><creatorcontrib>Stewart, Alistair</creatorcontrib><creatorcontrib>Tyrrell, Andrew J</creatorcontrib><creatorcontrib>Wallis, Laura L</creatorcontrib><creatorcontrib>Weymouth-Wilson, Alexander C</creatorcontrib><title>Synthesis of 2,3-Dideoxy-2-fluoro-2,3-endo-methylene- and 2,3-Dideoxy-2-fluoro-3‑C‑hydroxymethyl-2,3-endo-methylene-pentofuranoses and Their Use in the Preparation of Conformationally Locked Bicyclic Nucleosides</title><title>Journal of organic chemistry</title><addtitle>J. Org. Chem</addtitle><description>Construction of protected 2,3-dideoxy-2-fluoro-2,3-endo-methylene-pentofuranoses from d-glyceraldehyde and 2,3-dideoxy-2-fluoro-3-C-hydroxymethyl-2,3-endo-methylene-pentofuranoses from d-isoascorbic acid, via Simmons–Smith-type stereoselective cyclopropanations on the respective fluoroallyl alcohols, is described. Synthesis of the corresponding conformationally locked sugar modified uridine and guanosine nucleosides was achieved via Vorbrüggen or Mitsunobu methodologies. Stereochemical confirmation of the novel nucleosides was performed on the basis of 2D NOESY NMR experiments. Analysis of 2′,3′-dideoxy-2′-fluoro-3′-C-hydroxymethyl-2′,3′-endo-methylene-uridine by X-ray crystallography yielded the principal conformational parameters and indicated that the furanoid ring adopted an oE/oT1, East pucker. The uridine and guanosine nucleosides were found to be inactive in the hepatitis C virus (HCV) cell-based replicon assay, which was corroborated on examination of the corresponding nucleoside triphosphates against the HCV NS5B polymerase.</description><issn>0022-3263</issn><issn>1520-6904</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><recordid>eNptkc1u1DAUhS1ERYfCghdA3iBRCYN_xk6yhCm0SCNAol1Hjn3DuDj21E4ksuMVeDr2fRI8ndLVWLqy7vV3j458EHrB6FtGOXt3HSXlFeM_HqEFk5wS1dDlY7SglHMiuBLH6GnO17QcKeUTdMylYpLSeoH-fp_DuIHsMo495m8EOXMW4q-ZcNL7KaZIdkMINpIBxs3sIQDBOtjDsLj9_WdVajPbVB72K4ckthDG2E9Jh5gh3wlebsAlfJUBu4CLKfwtwVYnPboYdu5WMfQxDXe99n7G62h-gsUfnJmNdwZ_mYyHmIun_Awd9dpneH5_n6CrTx8vVxdk_fX88-r9mmgu6Eg0bUBY0UvedZIbCWCsoFYw2teMCq2kBW0Mb2qguukbZUytdNeIqlp2S12JE_R6r7tN8WaCPLaDywa81wHilFumZCWYUrUo6OkeNSnmnKBvt8kNOs0to-0ux_Yhx8K-vJedugHsA_k_uAK82gPa5LI3pfIj-YDQP1fBqSM</recordid><startdate>20150220</startdate><enddate>20150220</enddate><creator>Clarkson, Rob</creator><creator>Komsta, Zofia</creator><creator>Mayes, Benjamin A</creator><creator>Moussa, Adel</creator><creator>Shelbourne, Montserrat</creator><creator>Stewart, Alistair</creator><creator>Tyrrell, Andrew J</creator><creator>Wallis, Laura L</creator><creator>Weymouth-Wilson, Alexander C</creator><general>American Chemical Society</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20150220</creationdate><title>Synthesis of 2,3-Dideoxy-2-fluoro-2,3-endo-methylene- and 2,3-Dideoxy-2-fluoro-3‑C‑hydroxymethyl-2,3-endo-methylene-pentofuranoses and Their Use in the Preparation of Conformationally Locked Bicyclic Nucleosides</title><author>Clarkson, Rob ; Komsta, Zofia ; Mayes, Benjamin A ; Moussa, Adel ; Shelbourne, Montserrat ; Stewart, Alistair ; Tyrrell, Andrew J ; Wallis, Laura L ; Weymouth-Wilson, Alexander C</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a230t-a09e3d3f52bb52c5eecd30d310f8103a65deacc298e0a9f96cc86ab93774b4a73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Clarkson, Rob</creatorcontrib><creatorcontrib>Komsta, Zofia</creatorcontrib><creatorcontrib>Mayes, Benjamin A</creatorcontrib><creatorcontrib>Moussa, Adel</creatorcontrib><creatorcontrib>Shelbourne, Montserrat</creatorcontrib><creatorcontrib>Stewart, Alistair</creatorcontrib><creatorcontrib>Tyrrell, Andrew J</creatorcontrib><creatorcontrib>Wallis, Laura L</creatorcontrib><creatorcontrib>Weymouth-Wilson, Alexander C</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of organic chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Clarkson, Rob</au><au>Komsta, Zofia</au><au>Mayes, Benjamin A</au><au>Moussa, Adel</au><au>Shelbourne, Montserrat</au><au>Stewart, Alistair</au><au>Tyrrell, Andrew J</au><au>Wallis, Laura L</au><au>Weymouth-Wilson, Alexander C</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis of 2,3-Dideoxy-2-fluoro-2,3-endo-methylene- and 2,3-Dideoxy-2-fluoro-3‑C‑hydroxymethyl-2,3-endo-methylene-pentofuranoses and Their Use in the Preparation of Conformationally Locked Bicyclic Nucleosides</atitle><jtitle>Journal of organic chemistry</jtitle><addtitle>J. Org. Chem</addtitle><date>2015-02-20</date><risdate>2015</risdate><volume>80</volume><issue>4</issue><spage>2198</spage><epage>2215</epage><pages>2198-2215</pages><issn>0022-3263</issn><eissn>1520-6904</eissn><abstract>Construction of protected 2,3-dideoxy-2-fluoro-2,3-endo-methylene-pentofuranoses from d-glyceraldehyde and 2,3-dideoxy-2-fluoro-3-C-hydroxymethyl-2,3-endo-methylene-pentofuranoses from d-isoascorbic acid, via Simmons–Smith-type stereoselective cyclopropanations on the respective fluoroallyl alcohols, is described. Synthesis of the corresponding conformationally locked sugar modified uridine and guanosine nucleosides was achieved via Vorbrüggen or Mitsunobu methodologies. Stereochemical confirmation of the novel nucleosides was performed on the basis of 2D NOESY NMR experiments. Analysis of 2′,3′-dideoxy-2′-fluoro-3′-C-hydroxymethyl-2′,3′-endo-methylene-uridine by X-ray crystallography yielded the principal conformational parameters and indicated that the furanoid ring adopted an oE/oT1, East pucker. The uridine and guanosine nucleosides were found to be inactive in the hepatitis C virus (HCV) cell-based replicon assay, which was corroborated on examination of the corresponding nucleoside triphosphates against the HCV NS5B polymerase.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>25615008</pmid><doi>10.1021/jo502712g</doi><tpages>18</tpages></addata></record> |
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title | Synthesis of 2,3-Dideoxy-2-fluoro-2,3-endo-methylene- and 2,3-Dideoxy-2-fluoro-3‑C‑hydroxymethyl-2,3-endo-methylene-pentofuranoses and Their Use in the Preparation of Conformationally Locked Bicyclic Nucleosides |
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