Title:
IMPROVED SYNTHESIS OF [2.2.1]BICYCLO NUCLEOSIDES
Document Type and Number:
WIPO Patent Application WO2000056746
Kind Code:
A3
Abstract:
A synthesis of [2.2.1]bicyclo nucleosides which is shorter and provides higher overall yields proceeds via the key intermediate of general formula (III), wherein R4 and R5 are, for instance, sulfonates and R7 is, for instance, a halogen or an acetate. From compounds in general formula (II), such as 3-O-aryl-4-C-hydroxymethyl-1,2-O- isopropylidene- alpha -D-ribofuranose, intermediates of general formula (III) are suitable for coupling with silylated nucleobases. Upon one-pot base-induced ring-closure and desulfonation of the formed [2.2.1]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'-sulfonated ring-closed intermediate also allows for synthesis of 5'-amino- and thio-LNAs.
Inventors:
KOCHKINE ALEXEI (DK)
FENSHOLDT JEF (DK)
PFUNDHELLER HENRIK M (DK)
FENSHOLDT JEF (DK)
PFUNDHELLER HENRIK M (DK)
Application Number:
PCT/DK2000/000141
Publication Date:
October 18, 2001
Filing Date:
March 24, 2000
Export Citation:
Assignee:
EXIQON AS (DK)
KOCHKINE ALEXEI (DK)
FENSHOLDT JEF (DK)
PFUNDHELLER HENRIK M (DK)
KOCHKINE ALEXEI (DK)
FENSHOLDT JEF (DK)
PFUNDHELLER HENRIK M (DK)
International Classes:
C07H17/04; C07H19/00; C07H19/06; C07H19/16; C07H15/18; (IPC1-7): C07H9/04; C07H15/203
Domestic Patent References:
| WO1999014226A2 | 1999-03-25 |
Other References:
TIM FAT TAM ET AL: "A synthetic Route to 4-C-methyl-xylo-furanose", CAN. J. CHEM., vol. 57, 1979, pages 2818 - 2822, XP002901162
NIELSEN P ET AL: "Synthesis and chemoselective activation of phenyl 3,5-di-O-benzyl-2-O,4-C-methylene-1-thio-beta-D-ribofuranoside: a key synthon towards alpha-LNA", CHEM. COMMUN., 1998, pages 2645 - 2646, XP002901163
NIELSEN P ET AL: "A new synthetic approach towards alpha- and beta-LNA (locked nucleic acids)", NUCLEOSIDES & NUCLEOTIDES, vol. 18, no. (4&5), 1999, pages 701 - 702, XP002901164
SINGH S K ET AL: "LNA (locked nucleic acids): synthesis and high-affinity nucleic acid recognition", CHEM. COMMUN., 1998, pages 455 - 456, XP002094303
NIELSEN P ET AL: "Synthesis and chemoselective activation of phenyl 3,5-di-O-benzyl-2-O,4-C-methylene-1-thio-beta-D-ribofuranoside: a key synthon towards alpha-LNA", CHEM. COMMUN., 1998, pages 2645 - 2646, XP002901163
NIELSEN P ET AL: "A new synthetic approach towards alpha- and beta-LNA (locked nucleic acids)", NUCLEOSIDES & NUCLEOTIDES, vol. 18, no. (4&5), 1999, pages 701 - 702, XP002901164
SINGH S K ET AL: "LNA (locked nucleic acids): synthesis and high-affinity nucleic acid recognition", CHEM. COMMUN., 1998, pages 455 - 456, XP002094303
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