Production of bridged artificial nucleosides

1 . A method for producing a compound represented by formula (II):

wherein X, R 1 , R 2 and R 5 are as defined below,

the method comprising at least intramolecularly cyclizing a compound represented by formula (I):

wherein

X represents a nucleic acid base moiety optionally having one or more substituents selected from a group α consisting of a hydroxy group, a hydroxy group protected by a protecting group for nucleic acid synthesis, an alkyl group of 1 to 5 carbon atoms, an alkoxy group of 1 to 5 carbon atoms, a mercapto group, a mercapto group protected by a protecting group for nucleic acid synthesis, an alkylthio group of 1 to 5 carbon atoms, an amino group, an amino group protected by a protecting group for nucleic acid synthesis, an amino group substituted with an alkyl group of 1 to 5 carbon atoms, and a halogen atom;

R 1 and R 2 each independently represent a hydrogen atom, a protecting group for a hydroxy group used in nucleic acid synthesis, an optionally branched or cyclic alkyl group of 1 to 7 carbon atoms, an optionally branched or cyclic alkenyl group of 2 to 7 carbon atoms, an aryl group of 3 to 10 carbon atoms optionally having one or more substituents selected from the group α and optionally containing a heteroatom, an aralkyl group having an aryl moiety of 3 to 12 carbon atoms optionally having one or more substituents selected from the group α and optionally containing a heteroatom, an acyl group optionally having one or more substituents selected from the group α, a silyl group optionally having one or more substituents selected from the group α, a phosphate group optionally having one or more substituents selected from the group α, a phosphate group protected by a protecting group for nucleic acid synthesis, or —P(R 3 )R 4 (wherein R 3 and R 4 each independently represent a hydroxy group, a hydroxy group protected by a protecting group for nucleic acid synthesis, a mercapto group, a mercapto group protected by a protecting group for nucleic acid synthesis, an amino group, an alkoxy group of 1 to 5 carbon atoms, an alkylthio group of 1 to 5 carbon atoms, a cyanoalkoxy group of 1 to 6 carbon atoms, or an amino group substituted with an alkyl group of 1 to 6 carbon atoms); and

R 5 represents a hydrogen atom, a halogen atom, an optionally branched or cyclic alkyl group of 1 to 7 carbon atoms optionally substituted with an aryl group of 3 to 12 carbon atoms optionally containing a heteroatom, an aralkyl group having an aryl moiety of 3 to 12 carbon atoms optionally containing a heteroatom, or a silyl group.

2 . The production method according to claim 1 , wherein the intramolecular cyclization is performed in the presence of a base.

3 . The production method according to claim 2 , wherein the base is an alkoxide.

4 . The production method according to claim 1 , further comprising producing a compound represented by formula (I) by deprotecting R 6 of a compound represented by formula (IV):

wherein

X represents a nucleic acid base moiety optionally having one or more substituents selected from a group α consisting of a hydroxy group, a hydroxy group protected by a protecting group for nucleic acid synthesis, an alkyl group of 1 to 5 carbon atoms, an alkoxy group of 1 to 5 carbon atoms, a mercapto group, a mercapto group protected by a protecting group for nucleic acid synthesis, an alkylthio group of 1 to 5 carbon atoms, an amino group, an amino group protected by a protecting group for nucleic acid synthesis, an amino group substituted with an alkyl group of 1 to 5 carbon atoms, and a halogen atom;

R 1 and R 2 each independently represent a hydrogen atom, a protecting group for a hydroxy group used in nucleic acid synthesis, an optionally branched or cyclic alkyl group of 1 to 7 carbon atoms, an optionally branched or cyclic alkenyl group of 2 to 7 carbon atoms, an aryl group of 3 to 10 carbon atoms optionally having one or more substituents selected from the group α and optionally containing a heteroatom, an aralkyl group having an aryl moiety of 3 to 12 carbon atoms optionally having one or more substituents selected from the group α and optionally containing a heteroatom, an acyl group optionally having one or more substituents selected from the group α, a silyl group optionally having one or more substituents selected from the group α, a phosphate group optionally having one or more substituents selected from the group α, a phosphate group protected by a protecting group for nucleic acid synthesis, or —P(R 3 ) R 4 (wherein R 3 and R 4 each independently represent a hydroxy group, a hydroxy group protected by a protecting group for nucleic acid synthesis, a mercapto group, a mercapto group protected by a protecting group for nucleic acid synthesis, an amino group, an alkoxy group of 1 to 5 carbon atoms, an alkylthio group of 1 to 5 carbon atoms, a cyanoalkoxy group of 1 to 6 carbon atoms, or an amino group substituted with an alkyl group of 1 to 6 carbon atoms);

R 5 represents a hydrogen atom, a halogen atom, an optionally branched or cyclic alkyl group of 1 to 7 carbon atoms optionally substituted with an aryl group of 3 to 12 carbon atoms optionally containing a heteroatom, an aralkyl group having an aryl moiety of 3 to 12 carbon atoms optionally containing a heteroatom, or a silyl group; and

R 6 represents a protecting group for a hydroxy group used in nucleic acid synthesis.

5 . The production method according to claim 4 , wherein R 6 is an acetyl group.

6 . The production method according to claim 1 , further comprising producing a compound represented by formula (I) using, as a starting material, a compound represented by formula (V):

wherein

R 1 and R 2 each independently represent a hydrogen atom, a protecting group for a hydroxy group used in nucleic acid synthesis, an optionally branched or cyclic alkyl group of 1 to 7 carbon atoms, an optionally branched or cyclic alkenyl group of 2 to 7 carbon atoms, an aryl group of 3 to 10 carbon atoms optionally having one or more substituents selected from a group α and optionally containing a heteroatom (wherein the group α consists of a hydroxy group, a hydroxy group protected by a protecting group for nucleic acid synthesis, an alkyl group of 1 to 5 carbon atoms, an alkoxy group of 1 to 5 carbon atoms, a mercapto group, a mercapto group protected by a protecting group for nucleic acid synthesis, an alkylthio group of 1 to 5 carbon atoms, an amino group, an amino group protected by a protecting group for nucleic acid synthesis, an amino group substituted with an alkyl group of 1 to 5 carbon atoms, and a halogen atom), an aralkyl group having an aryl moiety of 3 to 12 carbon atoms optionally having one or more substituents selected from the group α and optionally containing a heteroatom, an acyl group optionally having one or more substituents selected from the group α, a silyl group optionally having one or more substituents selected from the group α, a phosphate group optionally having one or more substituents selected from the group α, a phosphate group protected by a protecting group for nucleic acid synthesis, or —P(R 3 ) R 4 (wherein R 3 and R 4 each independently represent a hydroxy group, a hydroxy group protected by a protecting group for nucleic acid synthesis, a mercapto group, a mercapto group protected by a protecting group for nucleic acid synthesis, an amino group, an alkoxy group of 1 to 5 carbon atoms, an alkylthio group of 1 to 5 carbon atoms, a cyanoalkoxy group of 1 to 6 carbon atoms, or an amino group substituted with an alkyl group of 1 to 6 carbon atoms); and

R 6 and R 7 each independently represent a protecting group for a hydroxy group used in nucleic acid synthesis, an optionally branched or cyclic alkyl group of 1 to 7 carbon atoms, an optionally branched or cyclic alkenyl group of 2 to 7 carbon atoms, an aryl group of 3 to 10 carbon atoms optionally having one or more substituents selected from the group α and optionally containing a heteroatom, an aralkyl group having an aryl moiety of 3 to 12 carbon atoms optionally having one or more substituents selected from the group α and optionally containing a heteroatom, an acyl group optionally having one or more substituents selected from the group α, a silyl group optionally having one or more substituents selected from the group α, a phosphate group optionally having one or more substituents selected from the group α, or a phosphate group protected by a protecting group for nucleic acid synthesis, or

R 6 and R 7 are joined together to form-C(R 8 ) (R 9 )-(wherein R 8 and R 9 each independently represent a hydrogen atom, an optionally branched or cyclic alkyl group of 1 to 7 carbon atoms optionally substituted with an aryl group of 3 to 12 carbon atoms optionally containing a heteroatom, or an aralkyl group having an aryl moiety of 3 to 12 carbon atoms optionally containing a heteroatom).

7 . The production method according to claim 6 , wherein R 1 and R 2 are benzyl groups.

8 . A method for producing a compound represented by formula (III):

wherein X, R 1 , R 2 and R 5 are as defined below, and R 5 ′ is independently as defined for R 5 , the method comprising at least

intramolecularly cyclizing a compound represented by formula (I):

wherein

X represents a nucleic acid base moiety optionally having one or more substituents selected from a group α consisting of a hydroxy group, a hydroxy group protected by a protecting group for nucleic acid synthesis, an alkyl group of 1 to 5 carbon atoms, an alkoxy group of 1 to 5 carbon atoms, a mercapto group, a mercapto group protected by a protecting group for nucleic acid synthesis, an alkylthio group of 1 to 5 carbon atoms, an amino group, an amino group protected by a protecting group for nucleic acid synthesis, an amino group substituted with an alkyl group of 1 to 5 carbon atoms, and a halogen atom;

R 1 and R 2 each independently represent a hydrogen atom, a protecting group for a hydroxy group used in nucleic acid synthesis, an optionally branched or cyclic alkyl group of 1 to 7 carbon atoms, an optionally branched or cyclic alkenyl group of 2 to 7 carbon atoms, an aryl group of 3 to 10 carbon atoms optionally having one or more substituents selected from the group α and optionally containing a heteroatom, an aralkyl group having an aryl moiety of 3 to 12 carbon atoms optionally having one or more substituents selected from the group α and optionally containing a heteroatom, an acyl group optionally having one or more substituents selected from the group α, a silyl group optionally having one or more substituents selected from the group α, a phosphate group optionally having one or more substituents selected from the group α, a phosphate group protected by a protecting group for nucleic acid synthesis, or —P(R 3 ) R 4 (wherein R 3 and R 4 each independently represent a hydroxy group, a hydroxy group protected by a protecting group for nucleic acid synthesis, a mercapto group, a mercapto group protected by a protecting group for nucleic acid synthesis, an amino group, an alkoxy group of 1 to 5 carbon atoms, an alkylthio group of 1 to 5 carbon atoms, a cyanoalkoxy group of 1 to 6 carbon atoms, or an amino group substituted with an alkyl group of 1 to 6 carbon atoms); and

R 5 represents a hydrogen atom, a halogen atom, an optionally branched or cyclic alkyl group of 1 to 7 carbon atoms optionally substituted with an aryl group of 3 to 12 carbon atoms optionally containing a heteroatom, an aralkyl group having an aryl moiety of 3 to 12 carbon atoms optionally containing a heteroatom, or a silyl group, to produce a compound represented by formula (II):

wherein X, R 1 , R 2 and R 5 are as defined above, and

cyclopropanating the compound represented by formula (II).

9 . The production method according to claim 8 , further comprising producing a compound represented by formula (I) by deprotecting R 6 of a compound represented by formula (IV):

wherein

X represents a nucleic acid base moiety optionally having one or more substituents selected from a group α consisting of a hydroxy group, a hydroxy group protected by a protecting group for nucleic acid synthesis, an alkyl group of 1 to 5 carbon atoms, an alkoxy group of 1 to 5 carbon atoms, a mercapto group, a mercapto group protected by a protecting group for nucleic acid synthesis, an alkylthio group of 1 to 5 carbon atoms, an amino group, an amino group protected by a protecting group for nucleic acid synthesis, an amino group substituted with an alkyl group of 1 to 5 carbon atoms, and a halogen atom;

R 1 and R 2 each independently represent a hydrogen atom, a protecting group for a hydroxy group used in nucleic acid synthesis, an optionally branched or cyclic alkyl group of 1 to 7 carbon atoms, an optionally branched or cyclic alkenyl group of 2 to 7 carbon atoms, an aryl group of 3 to 10 carbon atoms optionally having one or more substituents selected from the group α and optionally containing a heteroatom, an aralkyl group having an aryl moiety of 3 to 12 carbon atoms optionally having one or more substituents selected from the group α and optionally containing a heteroatom, an acyl group optionally having one or more substituents selected from the group α, a silyl group optionally having one or more substituents selected from the group α, a phosphate group optionally having one or more substituents selected from the group α, a phosphate group protected by a protecting group for nucleic acid synthesis, or —P(R 3 ) R 4 (wherein R 3 and R 4 each independently represent a hydroxy group, a hydroxy group protected by a protecting group for nucleic acid synthesis, a mercapto group, a mercapto group protected by a protecting group for nucleic acid synthesis, an amino group, an alkoxy group of 1 to 5 carbon atoms, an alkylthio group of 1 to 5 carbon atoms, a cyanoalkoxy group of 1 to 6 carbon atoms, or an amino group substituted with an alkyl group of 1 to 6 carbon atoms);

R 5 represents a hydrogen atom, a halogen atom, an optionally branched or cyclic alkyl group of 1 to 7 carbon atoms optionally substituted with an aryl group of 3 to 12 carbon atoms optionally containing a heteroatom, an aralkyl group having an aryl moiety of 3 to 12 carbon atoms optionally containing a heteroatom, or a silyl group; and

R 6 represents a protecting group for a hydroxy group used in nucleic acid synthesis.

10 . The production method according to claim 8 , wherein the intramolecular cyclization is performed in the presence of a base.

11 . The production method according to claim 8 , wherein the cyclopropanation comprises post-treatment of a reaction mixture with ammonia.

12 . The production method according to claim 1 , wherein X is a purine or pyrimidine base optionally having one or more substituents selected from the above-mentioned group α.

13 . The production method according to claim 1 , wherein X is a group having a uracil skeleton optionally having a substituent, a group having a cytosine skeleton optionally having a substituent, or a group having a purine skeleton optionally having a substituent.

14 . The production method according to claim 8 , wherein X is a purine or pyrimidine base optionally having one or more substituents selected from the above-mentioned group α.

15 . The production method according to claim 8 , wherein X is a group having a uracil skeleton optionally having a substituent, a group having a cytosine skeleton optionally having a substituent, or a group having a purine skeleton optionally having a substituent.