Chemical Synthesis of a 5‘-Terminal TMG-Capped Triribonucleotide m32,2,7G5‘pppAmpUmpA of U1 RNA

Authors:
  • MKMichinori Kadokura
    Michinori Kadokura
  • TSTakahiko Satoh
    Takahiko Satoh
  • TWTakeshi Wada
    Takeshi Wada
  • VSVicki Sumpter
    Vicki Sumpter
  • RLReinhard Lührmann
    Reinhard Lührmann
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Abstract
The 5‘-terminal TMG-capped triribonucleotide, m32,2,7G5‘pppAmpUmpA, has been synthesized by condensation of an appropriately protected triribonucleotide derivative of ppAmpUmpA with a new TMG-capping reagent. During this total synthesis, it was found that the regioselective 2‘-O-methylation of 3‘,5‘-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-N-(4-monomethoxytrityl)adenosine was achieved by use of MeI/Ag2O without affecting the base moiety. A new route to 2-N,2-N-dimethylguanosine from guanosine via a three-step reaction has also been developed by reductive methylation using paraformaldehyde and sodium cyanoborohydride. These key intermediates were used as starting materials for the construction of a fully protected derivative of pAmpUmpA and a TMG-capping reagent of Im-pm32,2,7G. The target TMG-capped tetramer, m32,2,7G5‘pppAmpUmpA, was synthesized by condensation of a partially protected triribonucleotide 5‘-terminal diphosphate species, ppAMMTrmpUmpA, with Im-pm32,2,7G followed by treatment with 80% acetic acid. The structure of m32,2,7G5‘pppAmpUmpA was characterized by 1H and 31P NMR spectroscopy as well as enzymatic assay using snake venom phosphodiesterase, calf intestinal phosphatase, and nuclease P1.

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