Exiqon A/s

Alexei Kochkine

Jef Fensholdt

Henrik M Pfundheller

A synthesis of &lsqb;2.2.1&rsqb;bicyclo nucleosides which is shorter and provides higher overall yields proceeds via the key intermediate of the general formula III, wherein R and R are, for instance, sulfonates and R is, for instance, a halogen or an acetate. From compounds of the general formula II, such as 3-O-aryl-4-C-hydroxymethyl-1,2-O-isopropylidene-&agr;-D-ribofuranose, intermediates of the general formula III are suitable for coupling with silylated nucleobases. Upon one-pot base-induced ring-closure and desulfonation of the formed &lsqb;2.2.1&rsqb;bicyclo nucleoside, a short route to each the LNA (Locked Nucleic Acid) derivatives of adenosine, cytosine, uridine, thymidine and guanidine is demonstrated. The use of the 5&prime;-sulfonated ring-closed intermediate also allows for synthesis of 5&prime;-amino- and thio-LNAs

Synthesis of &lsqb;2.2.1&rsqb;bicyclo nucleosides

A synthesis of &lsqb;2.2.1&rsqb;bicyclo nucleosides which is shorter and provides higher overall yields proceeds via the key intermediate of the general formula III, wherein R and R are, for instance, sulfonates and R is, for instance, a halogen or an acetate. From compounds of the general formula II, such as 3-O-aryl-4-C-hydroxymethyl-1,2-O-isopropylidene-&agr;-D-ribofuranose, intermediates of the general formula III are suitable for coupling with silylated nucleobases. Upon one-pot base-induced ring-closure and desulfonation of the formed &lsqb;2.2.1&rsqb;bicyclo nucleoside, a short route to each the LNA (Locked Nucleic Acid) derivatives of adenosine, cytosine, uridine, thymidine and guanidine is demonstrated. The use of the 5&prime;-sulfonated ring-closed intermediate also allows for synthesis of 5&prime;-amino- and thio-LNAs.

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Alexei Kochkine