Zhang Xingang, Xia Hairong, Dong XiCheng, Jin Jing, Meng Wei-Dong, Qing Feng-Ling
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, 354 Fenglin Lu, Shanghai 200032, China.
J Org Chem. 2003 Nov 14;68(23):9026-33. doi: 10.1021/jo034512i.
The design and synthesis of gem-difluorinated sugar nucleosides were described. The key intermediate, 3-deoxy-3,3-difluoro-d-arabinofuranose 9, was first stereoselectively prepared from the chiral gem-difluorohomoallyl alcohol 12. The kinetic formation of single anti-14 in the benzylation of 12 could be accomplished by controlling the amount of sodium hydride used. The dihydroxylation of 14 (a mixture of anti and syn isomers) followed by deprotection and oxidation stereoselectively afforded furanose 9 with the arabino configuration at the C2 position. N(1)-(3-Deoxy-3,3-difluoro-beta-D-arabinofuranosyl)cytosine 6 was prepared from 9 by the glycosylation reaction. 4'-Thiofuranose 25 was easily synthesized from 9. The oxidation of 25 followed by the condensation with silylated N(4)-benzoylcytosine (Pummerer reaction) failed to give our desired protected nucleoside l-3'-deoxy-3',3'-difluoro- 4'-thiocytidine 27', but the regioisomer 27 was obtained. The regiochemistry of the Pummerer reaction was determined by the kinetic acidity of the alpha-proton of 4'-thiofuranose 25.
描述了偕二氟代糖核苷的设计与合成。关键中间体3-脱氧-3,3-二氟-D-阿拉伯呋喃糖9首先由手性偕二氟高烯丙醇12立体选择性制备。通过控制氢化钠的用量，可以实现12苄基化过程中单一反式-14的动力学形成。14（反式和顺式异构体的混合物）经双羟基化、脱保护和氧化后，立体选择性地得到在C2位具有阿拉伯糖构型的呋喃糖9。通过糖基化反应由9制备了N(1)-(3-脱氧-3,3-二氟-β-D-阿拉伯呋喃糖基)胞嘧啶6。4'-硫代呋喃糖25由9很容易合成。25氧化后与甲硅烷基化的N(4)-苯甲酰胞嘧啶缩合（普默勒反应）未能得到我们所需的保护核苷1-3'-脱氧-3',3'-二氟-4'-硫代胞苷27'，而是得到了区域异构体27。普默勒反应的区域化学由4'-硫代呋喃糖α-质子的动力学酸度决定。
