Chemical synthesis and NMR spectroscopy of long stable isotope labelled RNAElectronic supplementary information (ESI) available. See DOI: 10.1039/c7cc06747j

We showcase the high potential of the 2′-cyanoethoxymethyl (CEM) methodology to synthesize RNAs with naturally occurring modified residues carrying stable isotope (SI) labels for NMR spectroscopic applications. The method was applied to synthesize RNAs with sizes ranging between 60 to 80 nucleotides. The presented approach gives the possibility to selectively modify larger RNAs (>60 nucleotides) with atom-specifically 13 C/ 15 N-labelled building blocks. The method harbors the unique potential to address structural as well as dynamic features of these RNAs with NMR spectroscopy but also using other biophysical methods, such as mass spectrometry (MS), or small angle neutron/X-ray scattering (SANS, SAXS). A synthetic access to stable isotope modified large RNAs for structural biology is introduced.