Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary.
Institute of Healthcare Industry, University of Debrecen, Nagyerdei krt 98, 4032 Debrecen, Hungary.
Org Biomol Chem. 2023 Mar 8;21(10):2213-2219. doi: 10.1039/d3ob00154g.
Herein, we report a stereoselective synthesis of a novel type of conformationally constrained nucleoside analogue in which the sugar part is replaced by a new symmetrical tricycle consisting of a morpholine ring condensed with two imidazolidines. 1,5-Dialdehydes obtained from trityl- and dimethoxytrityl-protected uridine, ribothymidine, inosine, cytidine, adenosine and guanosine by metaperiodate oxidation were reacted with ,-dibenzyl-1,2,3-triaminopropane; the latter reactant was produced using a new method that avoids explosive intermediates. Reactions of dialdehydes with propane-triamine cascade tricyclization resulted in the corresponding triaza-tricyclic derivatives bearing three new stereogenic centers in high yields. Out of the eight possible diastereoisomers, one stereoisomer was formed in each case due to the chiral control of the starting nucleoside-dialdehydes and the steric constraint of the condensed ring system. The absolute configuration of the new stereotriad was determined by X-ray diffraction and NMR experiments. A mechanistic study performed under reductive conditions to trap the presumed bicyclic intermediate showed that the triamine reactant first attacks the 2'-aldehyde group, followed by a rapid bicyclization to form the imidazolidino-morpholine unit.
本文报道了一种新型的立体选择性核苷类似物的全合成方法，其中糖部分被一个新的对称三环所取代，该三环由一个吗啉环与两个咪唑烷环缩合而成。通过高碘酸盐氧化，从三苯甲基和二甲氧基三苯甲基保护的尿苷、胸苷、肌苷、胞苷、腺苷和鸟苷中得到的 1,5-二醛与β,β-二苄基-1,2,3-三氨基丙烷反应；后者通过一种新的方法合成，避免了爆炸中间体的产生。二醛与丙烷三胺的反应进行级联三环化，以高产率得到了相应的三氮杂三环衍生物，这些衍生物带有三个新的手性中心。在八种可能的非对映异构体中，由于起始核苷二醛的手性控制和缩合环系的空间位阻，每种情况下都形成了一个立体异构体。新的立体三单元的绝对构型通过 X 射线衍射和 NMR 实验确定。在还原条件下进行的机理研究表明，三胺反应物首先攻击 2'-醛基，然后快速进行双环化反应，形成咪唑烷并吗啉单元。
