Production of bridged artificial nucleosides

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

• wherein X, R1, R2 and R5 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;
• R1 and R2 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(R3)R4 (wherein R3 and R4 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
• R5 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.

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

• wherein X, R1, R2 and R5 are as defined below, and R5′ is independently as defined for R5,
• the method comprising cyclopropanating a compound represented by formula (II):
• 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;
• R1 and R2 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(R3)R4 (wherein R3 and R4 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
• R5 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,
• wherein the cyclopropanation comprises post-treatment of a reaction mixture with ammonia.

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

• wherein X, R1, R2 and R5 are as defined below, and R5′ is independently as defined for R5,
• the method comprising at least cyclopropanating, in the presence of an organic acid, a compound represented by formula (II):
• 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;
• R1 and R2 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(R3)R4 (wherein R3 and R4 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
• R5 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.

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

• wherein X, R1, R2 and R5 are as defined below, and R5′ is independently as defined for R5,
• 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;
• R1 and R2 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(R3)R4 (wherein R3 and R4 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
• R5 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, R1, R2 and R5 are as defined above, and
• cyclopropanating the compound represented by formula (II).

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;
• R1 and R2 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(R3)R4 (wherein R3 and R4 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);
• R5 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
• R6 represents a protecting group for a hydroxy group used in nucleic acid synthesis;
• with the exception of the case where X is a 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl group, R1 and R2 are benzyl groups, and R6 is an acetyl group;
• and the case where X is a 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl group, and R1, R2 and R6 are acetyl groups.

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;
• R1 and R2 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(R3)R4 (wherein R3 and R4 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
• R5 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;
• with the exception of the case where X is a 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl group, and R1 and R2 are benzyl groups;
• and the case where X is a 2-oxo-4-amino-1,2-dihydropyrimidin-1-yl group, and R1 and R2 are hydrogen atoms.

A compound represented by formula (II):

• 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;
• R1 and R2 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(R3)R4 (wherein R3 and R4 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
• R5 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;
• with the exception of the case where X is a 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl group, R1 is a naphthyl group, and R2 is a benzyl group;
• and the case where X is a 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl group, R1 is a naphthyl group, and R2 is a hydrogen atom.