C4'-CF₃-α-L-脱氧胸苷亚磷酰胺单体的合成

Synthesis of C4'-CF₃-α-L-Deoxythymidine Phosphoramidite

摘要: 化学修饰是改善反义核酸成药性的重要手段。在本文的研究中，采用化学合成的方法，以已知的化合物(S)-1,3-二(苄氧基)-4-(1,3-二噻烷-2-基)丁-2-酮为原料，经过4步反应，得到苄基保护的C4'-CF₃-β-L-脱氧胸苷5a和C4'-CF₃-α-L-脱氧胸苷5b。然后通过氯化钯催化氢化脱除5b的苄基保护基，制得C4'-CF₃-α-L-脱氧胸苷6。通过核磁共振¹H谱、¹³C谱、¹⁹F谱和二维NOESY谱，确认了5a，5b和6的结构以及C4'和C1'的构型。经过两步常规反应，将6转化为C4'-CF₃-α-L-脱氧胸苷亚磷酰胺8，并使用¹H谱，³¹P谱，ESI-MS高分辨率质谱确定了最终目标产物8的结构正确性。

Abstract: Chemical modification is an essential approach to make antisense oligonucleotides drug-like mol-ecules. In this paper, we report the synthesis of C4'-CF₃-α-L-deoxythymidine phosphoramidite. The synthesis started from the known compound 1, which was efficiently transformed to benzylation protected C4'-CF₃-β-L-deoxythymidine 5a and C4'-CF₃-α-L-deoxythymidine 5b in four steps. Debenzylation of 5b using PdCl₂/H₂ afforded C4'-CF₃-α-L-deoxythymidine 6. Based on 1D ¹H, ¹³C, ¹⁹F and 2D NOESY NMR spectra, the structures of 5a, 5b and 6 were unambiguously characterized. Compound 6 was converted to the phosphoramidite in two routine reaction steps, and the structure of target product 8 was confirmed by ¹H NMR spectrum, ¹³¹P NMR spectrum, and ESI-MS high resolution mass spectrometry.