Analogues of LNA (Locked Nucleic Acid): Synthesis of the 2′-Thio-LNA Ribothymidine and 5-Methylcytidine Phosphoramidites

Abstract

The bicyclic 2′-thio-LNA ribothymidine phosphoramidite (13) has been synthesised using a strategy making the synthesis of 2′-thio-LNA convergent with the syntheses of LNA and 2′-amino-LNA. The key step was the formation of anhydro-nucleoside 4 that prevented unwanted oxetane (3) formation during debenzylation of the 3′-OBn group, while concomitantly furnishing the necessary inversion of configuration at the C2′ position. No oxetane was observed even under basic conditions. We believe that this is due to the rigid tricyclic anhydro-nucleoside limiting the conformational freedom of the furanose, thereby preventing the formation of a strained tetracyclic system. After removal of the benzyl protection group the liberated 3′-OH group (5) was easily benzoylated (6) and the anhydro-nucleoside ring opened to give the threo configured nucleoside 7. The 2′-thio-LNA ribothymidine phosphoramidite was synthesised in 9 steps from anhydro-nucleoside 4 in 30% yield. The 2′-thio-LNA 5-methylcytidine phosphoramidite was synthesised from nucleoside 12 using standard protocols.

nucleosides - bicyclic compounds - antisense agents - hydrogenations - bioorganic chemistry

References

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New address: Daniel Sejer Pedersen, Cambridge University, University Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, UK.

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LNA is defined as an oligonucleotide containing one or more 2′-O,4′-C-methylene-β-d-ribofuranosyl nucleotide mono-mers (LNA monomers). [3] [5] For clarity the terms 2′-amino-LNA and 2′-thio-LNA are used herein for the LNA analogues, where the 2′-oxygen has been substituted by a nitrogen atom or a sulfur atom.

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