danДоклады Национальной академии наук БеларусиDoklady of the National Academy of Sciences of Belarus1561-83232524-2431The Republican Unitary Enterprise Publishing House "Belaruskaya Navuka"dan-390Research ArticleХИМИЯCHEMISTRYСИНТЕЗ 2′-ДЕЗОКСИ-2′-ФТОР-D-АРАБИНОНУКЛЕОЗИДОВ 6-ЗАМЕЩЕННОГО ТИМИНАSYNTHESIS OF 6-SUBSTITUTED THYMINE 2′-DEOXY-2′-FLUORO-D-ARABINOFURANOSYL NUCLEOSIDESБожокТ. С.BozhokT. S.

науч. сотрудник

Researcher

tboshok@tut.byКалиниченкоЕ. Н.KalinichenkoE. N.

член-корреспондент, д-р хим. наук, заместитель директора

Corresponding Member, D. Sc. (Chemistry), Deputy Director

kalinichenko@iboch.bas-net.byИнститут биоорганической химии НАН БеларусиInstitute of Bioorganic Chemistry of the National Academy of Sciences of Belarus2017020320176116167Copyright © Божок Т.С., Калиниченко Е.Н., 20172017Божок Т.С., Калиниченко Е.Н.Bozhok T.S., Kalinichenko E.N.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://doklady.belnauka.by/jour/article/view/390

Исследования в области химии фторнуклеозидов являются актуальным направлением современной биоорганической и медицинской химии компонентов нуклеиновых кислот. Настоящая работа посвящена синтезу 2′-дезокси-2′-фтор-D-арабинофуранозил нуклеозидов 6-замещенного тимина с целью изучения их биологической активности. Конвергентный синтез пиримидиновых C(2′)-α/β-фторзамещенных нуклеозидов осуществлен путем конденсации 2,4-бис-О-триметилсилильного производного 6-фтортимина с 3,5-ди-O-бензоил-2-дезокси-2-фтор-α-D-арабино-фуранозил бромидом. Конденсация 1-α-бромсахара и персилильного производного 6-фтортимина при кипячении в хлороформе приводила к образованию смеси блокированных N(1)-α/β-D-нуклеозидов 6-фтортимина, которые выделены колоночной хроматографией на силикагеле с выходом 29 и 5  % соответственно. Стандартная процедура деблокирования индивидуальных бензоилированных α/β-нуклеозидов 6-фтортимина аммиаком в метаноле приводилак замещению атома фтора в 6-положении гетероцикла с образованием 2′-дезокси-2′-фтор-β/α-D-арабинозидов 6-амино- и 6-метокситимина. Показано, что дебензоилирование промежуточного С(2′)-β-арабинозида 6-фтортиминапод действием моногидрата гидроксида лития в смеси ацетонитрил–вода приводило к целевому нуклеозиду с высоким выходом (82  %). Разработан подход к синтезу 2′-фтор-6,3′-O-α-D-ангидронуклеозидов путем реакции внутримолекулярной  циклизации в результате удаления защитных групп бензоильного производного 2′-фтор-α-D-арабинофуранозил-6-фтортимина в основных условиях. Структура синтезированных нуклеозидов установлена на основании данных УФ-, ЯМР-, КД- и масс-спектроскопии.

New 6-fluorothymine 2′-deoxy-2′-fluoro-D-arabinofuranosyl nucleosides were prepared by the silyl method starting from persilylated 6-fluorothymine and 3,5-di-O-benzoyl-2-deoxy-2-fluoro-α-D-arabinofuranosyl bromide. A mixture of benzoylated N(1)-β- and α-anomeric 6-fluorothymine 2′-fluorodeoxy arabinonucleosides was obtained by refluxing in CHCl3 witha 34  % yield. 6-Substituted (OMe, NH2) thymine 2′-deoxy-2′-fluoro-D-arabinonucleosides were prepared by the treatment of individually protected N(1)-α/β-D-arabinosides with methanolic ammonia. It is shown that mild deprotection of the benzoyl groups of intermediate 6-fluorothymine β-nucleoside using LiOH monohydrate in a mixture of acetonitrile-water resulted in the target nucleoside in good yields (82  %). An approach to the synthesis of 2′-fluoro-6,3′-O-α-D-anhydronucleosides was developed as a result of the intramolecular substitution reaction of the fluorine atom at the C(6)-position of the heterocycle by the C(3′)-hydroxyl group of an intermediate deprotected nucleoside during the removal of the protective groups of 6-fluorothymine N(1)-α-arabinonucleoside under the basic reaction conditions. The structures of all synthesized nucleosides were proved by UV-, NMR-, CD- and mass-spectroscopy.

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The authors declare that there are no conflicts of interest present.