{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:59:48Z","timestamp":1760241588303,"version":"build-2065373602"},"reference-count":29,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2018,6,15]],"date-time":"2018-06-15T00:00:00Z","timestamp":1529020800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Halogen substitution at various positions of canonical nucleosides has generated a number of bioactive structural variants. Herein, the synthesis of two unique series of sugar modified nucleosides bearing a gem-dichloro group is presented. The synthetic plan entails the controlled addition of phosphorus pentachloride to suitably protected 2\u2032- or 3\u2032-ketodeoxynucleoside intermediates as the key step, facilitating the rapid construction of such functionalized molecules. Under the same reaction conditions, the highest chemoselectivity was observed for the formation of 2\u2032,2\u2032-dichloro-2\u2032,3\u2032-dideoxynucleosides, while a competing 2\u2032,3\u2032-elimination process occurred in the case of the 3\u2032,3\u2032-dichloro counterparts.<\/jats:p>","DOI":"10.3390\/molecules23061457","type":"journal-article","created":{"date-parts":[[2018,6,15]],"date-time":"2018-06-15T11:21:20Z","timestamp":1529061680000},"page":"1457","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Phosphorus Pentachloride Promoted gem-Dichlorination of 2\u2032- and 3\u2032-Deoxynucleosides"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2735-7216","authenticated-orcid":false,"given":"Fabio","family":"Da Paixao Soares","sequence":"first","affiliation":[{"name":"Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Herestraat 49, 3000 Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8866-2265","authenticated-orcid":false,"given":"Elisabetta","family":"Groaz","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Herestraat 49, 3000 Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3589-8503","authenticated-orcid":false,"given":"Piet","family":"Herdewijn","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Herestraat 49, 3000 Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,6,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1038\/nrd4010","article-title":"Advances in the development of nucleoside and nucleotide analogues for cancer and viral diseases","volume":"12","author":"Jordheim","year":"2013","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2529","DOI":"10.1021\/jm1013693","article-title":"Synopsis of some recent tactical application of bioisosteres in drug design","volume":"54","author":"Meanwell","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2854","DOI":"10.1021\/jm9000133","article-title":"Halogen bonding\u2014A novel interaction for rational drug design?","volume":"52","author":"Lu","year":"2009","journal-title":"J. Med. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Uesugi, S., Miki, H., Ikehara, M., Iwahashi, H., and Kyogoku, Y. (1979). Linear relationship between electronegativity of 2\u2032-substituents and conformation of adenine nucleosides. Tetrahedron Lett., 4073\u20134076.","DOI":"10.1016\/S0040-4039(01)86507-2"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2781","DOI":"10.1021\/ci400257k","article-title":"Halogen interactions in protein-ligand complexes: Implications of halogen bonding for rational drug design","volume":"53","author":"Sirimulla","year":"2013","journal-title":"J. Chem. Inf. Model."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1021\/ci400539q","article-title":"Halogen bond: Its role beyond drug-target binding affinity for drug discovery and development","volume":"54","author":"Xu","year":"2014","journal-title":"J. Chem. Inf. Model."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3468","DOI":"10.1016\/j.bmcl.2017.05.075","article-title":"Discovery of beta-D-2\u2032-deoxy-2\u2032-dichlorouridine nucleotide prodrugs as potent inhibitors of hepatitis C virus replication","volume":"27","author":"Pinho","year":"2017","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"5424","DOI":"10.1021\/acs.jmedchem.7b00067","article-title":"2\u2032-Chloro,2\u2032-fluoro ribonucleotide prodrugs with potent pan-genotypic activity against hepatitis C virus replication in culture","volume":"60","author":"Zhou","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"5416","DOI":"10.1021\/acs.orglett.5b02769","article-title":"Seven-membered ring nucleoside analogues: Stereoselective synthesis and studies on their conformational properties","volume":"17","author":"Habibian","year":"2015","journal-title":"Org. Lett."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2463","DOI":"10.1016\/S0040-4020(01)90749-5","article-title":"Nucleosides of fluoro sugars 6. Synthesis and reactivity of 3\u2032-fluoro-3\u2032-desoxythymidine and 3\u2032-chloro-3\u2032-desoxythymidine","volume":"27","author":"Etzold","year":"1971","journal-title":"Tetrahedron"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2695","DOI":"10.1016\/S0960-894X(02)00551-6","article-title":"Synthesis and evaluation of thymidine-5\u2032-O-monophosphate analogues as inhibitors of mycobacterium tuberculosis thymidylate kinase","volume":"12","author":"Vanheusden","year":"2002","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Kikugawa, K., and Ichino, M. (1971). Direct halogenation of sugar moiety of nucleosides. Tetrahedron Lett., 87\u201390.","DOI":"10.1016\/S0040-4039(01)96366-X"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1021\/jm00106a028","article-title":"4\u2032,5\u2032-Unsaturated 5\u2032-halogenated nucleosides\u2014Mechanism-based and competitive inhibitors of S-adenosyl-l-homocysteine hydrolase","volume":"34","author":"Jarvi","year":"1991","journal-title":"J. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4130","DOI":"10.1021\/jm100165w","article-title":"3\u2032-Bromo analogues of pyrimidine nucleosides as a new class of potent inhibitors of mycobacterium tuberculosis","volume":"53","author":"Shakya","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1862","DOI":"10.1021\/jm5017279","article-title":"Discovery of 4\u2032-chloromethyl-2\u2032-deoxy-3\u2032,5\u2032-di-O-isobutyryl-2\u2032-fluorocytidine (ALS-8176), a first-in-class RSV polymerase inhibitor for treatment of human respiratory syncytial virus infection","volume":"58","author":"Wang","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Ohuchi, S., Singh, R.K., Wada, T., and Hata, T. (1992). Facile chlorination of sugar moiety of nucleosides by use of tris(2,4,6-tribromophenoxy)dichlorophosphorane. Chem. Lett., 1505\u20131506.","DOI":"10.1246\/cl.1992.1505"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2289","DOI":"10.1021\/jo00979a018","article-title":"Halo sugar nucleosides 3. Reactions for chlorination and bromination of nucleoside hydroxyl groups","volume":"37","author":"Verheyden","year":"1972","journal-title":"J. Org. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1021\/jm00356a007","article-title":"Nucleosides 123. Synthesis of antiviral nucleosides\u20135-Substituted 1-(2-deoxy-2-halogeno-beta-D-arabinofuranosyl)cytosines and-uracils\u2013Some structure activity relationships","volume":"26","author":"Watanabe","year":"1983","journal-title":"J. Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"6190","DOI":"10.1021\/ja00772a043","article-title":"Protection of hydroxyl groups as tert-butyldimethylsilyl derivatives","volume":"94","author":"Corey","year":"1972","journal-title":"J. Am. Chem. Soc."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Larsen, E., Kofoed, T., and Pedersen, E.B. (1995). Synthesis of 2,3\u2032-anhydro-2\u2032-deoxyuridines and 2\u2032,3\u2032-didehydro-2\u2032,3\u2032-dideoxyuridines using polymer-supported fluoride. Synthesis, 1121\u20131125.","DOI":"10.1055\/s-1995-4070"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1080\/00397919808005101","article-title":"Acetyl chloride-methanol as a convenient reagent for: (A) quantitative formation of amine hydrochlorides (B) carboxylate ester formation (C) mild removal of N-t-Boc-protective group","volume":"28","author":"Nudelman","year":"1998","journal-title":"Synth. Commun."},{"key":"ref_22","first-page":"845","article-title":"Highly reactive magnesium for the preparation of grignard-reagents\u20131-Norbornanecarboxylic acid","volume":"50\u201359","author":"Rieke","year":"1988","journal-title":"Org. Synth."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1002\/cber.19761090103","article-title":"General reaction of phosphines and carbon-tetrachloride on nucleophiles 29. Reactions in system triphenylphosphine-carbon tetrachloride","volume":"109","author":"Appel","year":"1976","journal-title":"Chem. Ber. Recl."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1016\/S0040-4039(00)92342-6","article-title":"Chemistry of the Wittig reaction 4. Simple conversion of aldehydes to 1,1-dichloroalkane and 1,1-dichloro-1-alkene derivatives, useful intermediates for the synthesis of acetylenic compounds","volume":"33","author":"Vinczer","year":"1992","journal-title":"Tetrahedron Lett."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4023","DOI":"10.1080\/00397910802271271","article-title":"Facile conversion of aldehydes and ketones to gem-dichlorides using chlorodiphenylphosphine\/N-chlorosuccinimide as a new and neutral system","volume":"38","author":"Aghapour","year":"2008","journal-title":"Synth. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3044","DOI":"10.1021\/jo00409a024","article-title":"Synthesis of 3\u2032-azido-2\u2032,3\u2032-dideoxyribofuranosylpurines","volume":"43","author":"Imazawa","year":"1978","journal-title":"J. Org. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/0008-6215(94)00165-0","article-title":"One-pot synthesis of 1,2-O-isopropylidene-alpha-D-xylofuranose","volume":"263","author":"Moravcova","year":"1994","journal-title":"Carbohydr. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/0040-4020(84)85111-X","article-title":"Nucleic-acid related-compounds 44. 2\u2032 and 3\u2032-Ketonucleosides and their arabino and xylo reduction products\u2013Convenient access via selective protection and oxidation of ribonucleosides","volume":"40","author":"Hansske","year":"1984","journal-title":"Tetrahedron"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1021\/jm00106a034","article-title":"Synthesis and anticancer activity of various 3\u2032-deoxy pyrimidine nucleoside analogs and crystal-structure of 1-(3-deoxy-beta-D-threo-pentofuranosyl)cytosine","volume":"34","author":"Lin","year":"1991","journal-title":"J. Med. Chem."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/23\/6\/1457\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:08:55Z","timestamp":1760195335000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/23\/6\/1457"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,6,15]]},"references-count":29,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2018,6]]}},"alternative-id":["molecules23061457"],"URL":"https:\/\/doi.org\/10.3390\/molecules23061457","relation":{},"ISSN":["1420-3049"],"issn-type":[{"type":"electronic","value":"1420-3049"}],"subject":[],"published":{"date-parts":[[2018,6,15]]}}}