Yugandhar Kothapalli, Chung K. Chu and Uma S. Singh*,
{"title":"通过手性纯 l-二氧戊环对β-l-5-[(E)-2-溴乙烯基)-1-((2S,4S)-2-(羟甲基)-1,3-(二氧戊环-4-基)Uracil)] (l-BHDU) 进行对映选择性合成。","authors":"Yugandhar Kothapalli, Chung K. Chu and Uma S. Singh*, ","doi":"10.1021/acs.joc.4c00399","DOIUrl":null,"url":null,"abstract":"<p >β-<span>l</span>-5-((<i>E</i>)-2-Bromovinyl)-1-((2<i>S</i>,4<i>S</i>)-2-(hydroxymethyl)-1,3-(dioxolane-4-yl) uracil (<span>l</span>-BHDU, <b>17</b>) is a potent and selective inhibitor of the varicella-zoster virus (VZV). <span>l</span>-BHDU (<b>17</b>) has demonstrated excellent <i>anti</i>-VZV activity and is a preclinical candidate to treat chickenpox, shingles (herpes zoster), and herpes simplex virus 1 (HSV-1) infections. Its monophosphate prodrug (POM-<span>l</span>-BHDU-MP, <b>24</b>) demonstrated an enhanced pharmacokinetic and antiviral profile. POM-<span>l</span>-BHDU-MP (<b>24</b>), <i>in vivo</i>, effectively reduced the VZV viral load and was effective for the topical treatment of VZV and HSV-1 infections. Therefore, a viable synthetic procedure for developing POM-<span>l</span>-BHDU-MP (<b>24</b>) is needed. In this article, an efficient approach for the synthesis of <span>l</span>-BHDU (<b>17</b>) from a readily available starting material is described in 7 steps. An efficient and practical methodology for both chiral pure <span>l</span>- & <span>d</span>-dioxolane <b>11</b> and <b>13</b> were developed <i>via</i> diastereomeric chiral amine salt formation. Neutralization of the amine carboxylate salt of <span>l</span>-dioxolane <b>10</b> provides enantiomerically pure <span>l</span>-dioxane <b>11</b> (ee ≥ 99%). Optically pure <b>11</b> was utilized to construct the final nucleoside <span>l</span>-BHDU (<b>17</b>) and its monophosphate ester prodrug (POM-<span>l</span>-BHDU-MP, <b>24</b>). Notably, the reported process eliminates expensive chiral chromatography for the synthesis of chiral pure <span>l</span>- & <span>d</span>-dioxolane, which offers avenues for the development and structure–activity relationship studies of <span>l</span>- & <span>d</span>-dioxolane-derived nucleosides.</p>","PeriodicalId":57,"journal":{"name":"The Journal of Organic Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3000,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.joc.4c00399","citationCount":"0","resultStr":"{\"title\":\"Enantioselective Synthesis of β-l-5-[(E)-2-Bromovinyl)-1-((2S,4S)-2-(hydroxymethyl)-1,3-(dioxolane-4-yl) Uracil)] (l-BHDU) via Chiral Pure l-Dioxolane\",\"authors\":\"Yugandhar Kothapalli, Chung K. Chu and Uma S. Singh*, \",\"doi\":\"10.1021/acs.joc.4c00399\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >β-<span>l</span>-5-((<i>E</i>)-2-Bromovinyl)-1-((2<i>S</i>,4<i>S</i>)-2-(hydroxymethyl)-1,3-(dioxolane-4-yl) uracil (<span>l</span>-BHDU, <b>17</b>) is a potent and selective inhibitor of the varicella-zoster virus (VZV). <span>l</span>-BHDU (<b>17</b>) has demonstrated excellent <i>anti</i>-VZV activity and is a preclinical candidate to treat chickenpox, shingles (herpes zoster), and herpes simplex virus 1 (HSV-1) infections. Its monophosphate prodrug (POM-<span>l</span>-BHDU-MP, <b>24</b>) demonstrated an enhanced pharmacokinetic and antiviral profile. POM-<span>l</span>-BHDU-MP (<b>24</b>), <i>in vivo</i>, effectively reduced the VZV viral load and was effective for the topical treatment of VZV and HSV-1 infections. Therefore, a viable synthetic procedure for developing POM-<span>l</span>-BHDU-MP (<b>24</b>) is needed. In this article, an efficient approach for the synthesis of <span>l</span>-BHDU (<b>17</b>) from a readily available starting material is described in 7 steps. An efficient and practical methodology for both chiral pure <span>l</span>- & <span>d</span>-dioxolane <b>11</b> and <b>13</b> were developed <i>via</i> diastereomeric chiral amine salt formation. Neutralization of the amine carboxylate salt of <span>l</span>-dioxolane <b>10</b> provides enantiomerically pure <span>l</span>-dioxane <b>11</b> (ee ≥ 99%). Optically pure <b>11</b> was utilized to construct the final nucleoside <span>l</span>-BHDU (<b>17</b>) and its monophosphate ester prodrug (POM-<span>l</span>-BHDU-MP, <b>24</b>). Notably, the reported process eliminates expensive chiral chromatography for the synthesis of chiral pure <span>l</span>- & <span>d</span>-dioxolane, which offers avenues for the development and structure–activity relationship studies of <span>l</span>- & <span>d</span>-dioxolane-derived nucleosides.</p>\",\"PeriodicalId\":57,\"journal\":{\"name\":\"The Journal of Organic Chemistry\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2024-06-20\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://pubs.acs.org/doi/epdf/10.1021/acs.joc.4c00399\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"The Journal of Organic Chemistry\",\"FirstCategoryId\":\"1\",\"ListUrlMain\":\"https://pubs.acs.org/doi/10.1021/acs.joc.4c00399\",\"RegionNum\":2,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, ORGANIC\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"The Journal of Organic Chemistry","FirstCategoryId":"1","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acs.joc.4c00399","RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, ORGANIC","Score":null,"Total":0}
Enantioselective Synthesis of β-l-5-[(E)-2-Bromovinyl)-1-((2S,4S)-2-(hydroxymethyl)-1,3-(dioxolane-4-yl) Uracil)] (l-BHDU) via Chiral Pure l-Dioxolane
β-l-5-((E)-2-Bromovinyl)-1-((2S,4S)-2-(hydroxymethyl)-1,3-(dioxolane-4-yl) uracil (l-BHDU, 17) is a potent and selective inhibitor of the varicella-zoster virus (VZV). l-BHDU (17) has demonstrated excellent anti-VZV activity and is a preclinical candidate to treat chickenpox, shingles (herpes zoster), and herpes simplex virus 1 (HSV-1) infections. Its monophosphate prodrug (POM-l-BHDU-MP, 24) demonstrated an enhanced pharmacokinetic and antiviral profile. POM-l-BHDU-MP (24), in vivo, effectively reduced the VZV viral load and was effective for the topical treatment of VZV and HSV-1 infections. Therefore, a viable synthetic procedure for developing POM-l-BHDU-MP (24) is needed. In this article, an efficient approach for the synthesis of l-BHDU (17) from a readily available starting material is described in 7 steps. An efficient and practical methodology for both chiral pure l- & d-dioxolane 11 and 13 were developed via diastereomeric chiral amine salt formation. Neutralization of the amine carboxylate salt of l-dioxolane 10 provides enantiomerically pure l-dioxane 11 (ee ≥ 99%). Optically pure 11 was utilized to construct the final nucleoside l-BHDU (17) and its monophosphate ester prodrug (POM-l-BHDU-MP, 24). Notably, the reported process eliminates expensive chiral chromatography for the synthesis of chiral pure l- & d-dioxolane, which offers avenues for the development and structure–activity relationship studies of l- & d-dioxolane-derived nucleosides.
期刊介绍:
The Journal of Organic Chemistry welcomes original contributions of fundamental research in all branches of the theory and practice of organic chemistry. In selecting manuscripts for publication, the editors place emphasis on the quality and novelty of the work, as well as the breadth of interest to the organic chemistry community.