不同构型的2’-O,4’-C-亚甲基桥双环核苷（锁核酸单体）的合成

Synthesis of 2’-O,4’-C-Methylene-Linked Bicyclic Ribonucleosides (LNA monomers) with Different Configurations

摘要:

分别以L-核糖(3a)和D-核糖(3b)为原料，经过甲磺酰基化、脱异丙叉保护基、乙酰基化得到L-五呋喃糖衍生物(4a)和D-五呋喃糖衍生物(4b)，然后分别与3-羟基吡嗪-2-酰胺进行Vorbruggen偶合，再经过闭环、脱甲磺酰基、脱苄基等合成了两种不同构型的锁核酸单体1-羟甲基-3[4-(3-氧代吡嗪-2-酰胺)基]-7-羟基-2,5-二氧二环[2.2.1]庚烷(2a,2b)，总收率分别高达24.6%，31.5%。对闭环、脱除甲磺酰基以及脱除苄基等步骤的反应条件进行了优化，收率分别达到83.5%，62.5%，86.9%。目标产物的结构经过红外光谱、核磁共振氢谱、质谱、元素分析等进行确证。

Abstract:

L-pentofuranose derivative(4a) and D-pentofuranose derivative(4b) were synthesized via mesylation, removing isopropylidene group and acetylation with L-ribofuranose (3a) and D-ribofuranose((3b) as starting materials, respectively. Subsequent Vorbruggen coupling with 3-oxo-5,6-dihydropyrazine-2-carboxamide, cyclization, demesylation and debenzylation afforded 7-Hydroxy-1-(hydroxymethyl)-3-[4-(3-oxo-3,4-dihydropyrazine-2-carboxamide)-yl]-2,5-dioxabicyclo[2.2.1] heptane with two different configurations (2a, 2b) in yields 24.6% and 31.5% , respectively. The reaction conditions of ring-closing, demesylation and debenzylation were optimized with yields 83.5%, 62.5% and 86.9%. The chemical structures of target compounds were finely identified by IR, 1H NMR, MS and elementary analysis.