Department of Pharmaceutical Chemistry, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary.
Org Biomol Chem. 2018 Jan 17;16(3):393-401. doi: 10.1039/c7ob02296d.
A novel type of nucleoside analogue in which the sugar part is replaced by a new tricycle, 3,7,10-trioxa-11-azatricyclo[5.3.1.0]undecane has been prepared by substrate-controlled asymmetric synthesis. 1,5-Dialdehydes obtained from properly protected or unprotected uridine, ribothymidine, cytidine, inosine, adenosine and guanosine by metaperiodate oxidation reacted readily with tris(hydroxymethyl)aminomethane to provide the corresponding tricyclic derivatives with three new stereogenic centers. Through a double cyclisation cascade process the tricyclic compounds were obtained in good to high yields, with very high diastereoselectivity. Formation of one stereoisomer, out of the eight possible, was observed in all cases. The absolute configuration of the new stereotriad-containing tricyclic systems was aided by conventional NMR experiments followed by chemical shift calculations using an X-ray crystal structure as reference that was in good agreement with H-H distances obtained from a new ROESY NMR method. The synthesis was compatible with silyl, trityl and dimethoxytrityl protecting groups. A new reagent mixture containing ZnCl, EtSiH and hexafluoroisopropanol was developed for detritylation of the acid-sensitive tricyclano nucleosides.
一种新型核苷类似物，其中糖部分被一个新的三环替换，3,7,10-三氧-11-氮杂三环[5.3.1.0]十一烷通过底物控制的不对称合成制备。通过高碘酸盐氧化，从适当保护或未保护的尿嘧啶、胸苷、胞苷、肌苷、腺苷和鸟苷中得到的 1,5-二醛与三羟甲基氨基甲烷反应，很容易得到具有三个新的立体中心的相应三环衍生物。通过双环化级联反应，以良好到高产率获得了三环化合物，具有非常高的非对映选择性。在所有情况下，都观察到了从八个可能的立体异构体中一种立体异构体的形成。通过常规 NMR 实验和使用 X 射线晶体结构作为参考的化学位移计算来辅助新型含三立体中心的三环系统的绝对构型，这与从新的 ROESY NMR 方法获得的 H-H 距离非常吻合。该合成与硅基、三苯甲基和二甲氧基三苯甲基保护基相容。开发了一种含有 ZnCl、EtSiH 和六氟异丙醇的新试剂混合物，用于脱除酸敏感的三环核苷。
