Process for producing pyripyropene derivatives and intermediates for the production thereof

A process for producing compound B2a represented by formula B2a:

• wherein
• R1a represents optionally substituted straight chain C2-4 alkylcarbonyl;
• group —SiR3R4R5 optionally substituted by halogen atom wherein R3, R4, and R5 each independently represent straight chain or branched chain C1-6 alkyl or phenyl;
• C1-6 alkyloxy-C1-6 alkyl optionally substituted by halogen atom;
• C1-6 alkylthio-C1-6 alkyl optionally substituted by halogen atom;
• straight chain, branched chain, or cyclic C1-4 alkyl optionally substituted by halogen atom, provided that, when alkyl in the C1-4 alkyl group is of a branched chain or cyclic type, the alkyl group is C3-4 alkyl;
• C2-6 alkenyl optionally substituted by halogen atom;
• C2-6 alkynyl optionally substituted by halogen atom;
• optionally substituted benzyl;
• or an optionally substituted saturated or unsaturated five- or six-membered heterocyclic group,
• wherein, in R1a, the substituent optionally possessed by alkylcarbonyl is selected from the group consisting of halogen atoms, C1-4 alkyloxy, C1-4 haloalkyloxy, C1-4 alkylcarbonyl, C1-4 haloalkylcarbonyl, C1-4 alkylcarbonyloxy, and C1-4 haloalkylcarbonyloxy, and the substituent optionally possessed by the heterocyclic group and benzyl is selected from the group consisting of halogen atoms, C1-4 alkyl, C1-4 alkyloxy, C1-4 haloalkyloxy, C1-4 alkylthio, C1-4 haloalkyl, C1-4 alkylcarbonyl, C1-4 haloalkylcarbonyl, C1-4 alkylcarbonyloxy, C1-4 haloalkylcarbonyloxy, nitro, and cyano, and
• R′ represents cyclic C3-6 alkylcarbonyl, the process comprising:
• hydrolyzing acetyl at the 7-position of compound A1 represented by formula A1:
• wherein Ac represents acetyl,
• with a base to selectively deacylate compound A1, then protecting hydroxyl at the 7-position to give compound B1 represented by formula B1:
• wherein Ac and R1a are as defined above,
• then hydrolyzing acetyl at the 1- and 11-positions of compound B1 with a base to deacylate compound B1 and thus to give compound Fa represented by formula Fa:
• wherein R1a is as defined above,
• and then acylating hydroxyl at the 1- and 11-positions of compound Fa with an acylating agent corresponding to contemplated R′.

A process for producing compound B2b represented by formula B2b:

• wherein
• R1b represents formyl;
• optionally substituted straight chain C1-4 alkylcarbonyl;
• optionally substituted benzyl;
• group —SiR3R4R5 optionally substituted by halogen atom wherein R3, R4, and R5 each independently represent straight chain or branched chain C1-6 alkyl or phenyl;
• C1-6 alkyloxy-C1-6 alkyl optionally substituted by halogen atom;
• C1-6 alkylthio-C1-6 alkyl optionally substituted by halogen atom;
• straight chain, branched chain, or cyclic C1-4 alkyl optionally substituted by halogen atom, provided that, when alkyl in the C1-4 alkyl group is of a branched chain or cyclic type, the alkyl group represents C3-4 alkyl;
• C2-6 alkenyl optionally substituted by halogen atom;
• C2-6 alkynyl optionally substituted by halogen atom;
• or an optionally substituted saturated or unsaturated five- or six-membered heterocyclic group,
• wherein, in R1b, the substituent optionally possessed by alkylcarbonyl is selected from the group consisting of halogen atoms, C1-4 alkyloxy, C1-4 haloalkyloxy, C1-4 alkylcarbonyl, C1-4 haloalkylcarbonyl, C1-4 alkylcarbonyloxy, and C1-4 haloalkylcarbonyloxy, and the substituent optionally possessed by the heterocyclic group and benzyl is selected from the group consisting of halogen atoms, C1-4 alkyl, C1-4 alkyloxy, C1-4 haloalkyloxy, C1-4 alkylthio, C1-4 haloalkyl, C1-4 alkylcarbonyl, C1-4 haloalkylcarbonyl, C1-4 alkylcarbonyloxy, C1-4 haloalkylcarbonyloxy, nitro, and cyano, and
• R′ represents cyclic C3-6 alkylcarbonyl, the process comprising:
• hydrolyzing acyl at the 1-, 7-, and 11-positions of compound A4 represented by formula A4:
• wherein A1, A7, and A11, which may be the same or different, represent acetyl or propionyl,
• with a base to deacylate compound A4, then protecting hydroxyl at the 1- and 11-positions to give compound D represented by formula D:
• wherein two R2s together represent a group selected from groups represented by formulae D-1, D-2, D-3, and D-4:
• wherein Y1 represents a hydrogen atom or C1-4 alkyl;
• Xs, which may be the same or different, represent a hydrogen atom, C1-4 alkoxy, or nitro;
• and n is 0 to 5,
• then protecting hydroxyl at the 7-position of compound D to give compound E represented by formula E:
• wherein R1b and R2 are as defined above,
• and further removing the protective group at the 1- and 11-positions of compound E to give compound Fb represented by formula Fb:
• wherein R1b is as defined above,
• and then acylating hydroxyl at the 1- and 11-positions of compound Fb with an acylating agent corresponding to R′.

A process for producing compound C represented by formula C:

• wherein R′ represents cyclic C3-6 alkylcarbonyl, the process comprising:
• acylating hydroxyl at the 1- and 11-positions of compound Fb represented by formula Fb:
• wherein
• R1b represents formyl;
• optionally substituted straight chain C1-4 alkylcarbonyl;
• optionally substituted benzyl;
• group —SiR3R4R5 optionally substituted by halogen atom wherein R3, R4, and R5 each independently represent straight chain or branched chain C1-6 alkyl or phenyl;
• C1-6 alkyloxy-C1-6 alkyl optionally substituted by halogen atom;
• C1-6 alkylthio-C1-6 alkyl optionally substituted by halogen atom;
• straight chain, branched chain, or cyclic C1-4 alkyl optionally substituted by halogen atom, provided that, when alkyl in the C1-4 alkyl group is of a branched chain or cyclic type, the alkyl group is C3-4 alkyl;
• C2-6 alkenyl optionally substituted by halogen atom;
• C2-6 alkynyl optionally substituted by halogen atom;
• or an optionally substituted saturated or unsaturated five- or six-membered heterocyclic group,
• wherein, in R1b, the substituent optionally possessed by alkylcarbonyl is selected from the group consisting of halogen atoms, C1-4 alkyloxy, C1-4 haloalkyloxy, C1-4 alkylcarbonyl, C1-4 haloalkylcarbonyl, C1-4 alkylcarbonyloxy, and C1-4 haloalkylcarbonyloxy, and the substituent optionally possessed by the heterocyclic group and benzyl is selected from the group consisting of halogen atoms, C1-4 alkyl, C1-4 alkyloxy, C1-4 haloalkyloxy, C1-4 alkylthio, C1-4 haloalkyl, C1-4 alkylcarbonyl, C1-4 haloalkylcarbonyl, C1-4 alkylcarbonyloxy, C1-4 haloalkylcarbonyloxy, nitro, and cyano,
• with an acylating agent corresponding to R′ to give compound B2b represented by formula B2b:
• wherein R1b and R′ are as defined above,
• and then removing the protective group at the 7-position of compound B2b.

A process for producing compound C represented by formula C:

• wherein R′ represents straight chain, branched chain, or cyclic C2-6 alkylcarbonyl, provided that, when the alkyl moiety in the C2-6 alkylcarbonyl group is of a branched chain or cyclic type, the alkyl moiety is C3-6 alkylcarbonyl, the process comprising:
• hydrolyzing acyl at the 1-, 7-, and 11-positions of compound A4 represented by formula A4:
• wherein A1, A7, and A11, which may be the same or different, represent acetyl or propionyl,
• with a base to deacylate compound A4, then protecting hydroxyl at the 1- and 11-positions to give compound D represented by formula D:
• wherein two R2s together represent a group selected from groups represented by formulae D-1, D-2, D-3, and D-4:
• wherein Y1 represents a hydrogen atom or C1-4 alkyl;
• Xs, which may be the same or different, represent a hydrogen atom, C1-4 alkoxy, or nitro;
• and n is 0 to 5,
• then protecting hydroxyl at the 7-position of compound D to give compound E represented by formula E:
• wherein
• R1b represents formyl;
• optionally substituted straight chain C1-4 alkylcarbonyl;
• optionally substituted benzyl;
• group —SiR3R4R5 optionally substituted by halogen atom wherein R3, R4, and R5 each independently represent straight chain or branched chain C1-6 alkyl or phenyl;
• C1-6 alkyloxy-C1-6 alkyl optionally substituted by halogen atom;
• C1-6 alkylthio-C1-6 alkyl optionally substituted by halogen atom;
• straight chain, branched chain, or cyclic C1-4 alkyl optionally substituted by halogen atom, provided that, when alkyl in the C1-4 alkyl group is of a branched chain or cyclic type, the alkyl group is C3-4 alkyl;
• C2-6 alkenyl optionally substituted by halogen atom;
• C2-6 alkynyl optionally substituted by halogen atom;
• or an optionally substituted saturated or unsaturated five- or six-membered heterocyclic group,
• wherein, in R1b, the substituent optionally possessed by alkylcarbonyl is selected from the group consisting of halogen atoms, C1-4 alkyloxy, C1-4 haloalkyloxy, C1-4 alkylcarbonyl, C1-4 haloalkylcarbonyl, C1-4 alkylcarbonyloxy, and C1-4 haloalkylcarbonyloxy, and the substituent optionally possessed by the heterocyclic group and benzyl is selected from the group consisting of halogen atoms, C1-4 alkyl, C1-4 alkyloxy, C1-4 haloalkyloxy, C1-4 alkylthio, C1-4 haloalkyl, C1-4 alkylcarbonyl, C1-4 haloalkylcarbonyl, C1-4 alkylcarbonyloxy, C1-4 haloalkylcarbonyloxy, nitro, and cyano, and
• R2 is as defined above,
• and further removing the protective groups at the 1- and 11-positions of compound E to give compound Fb represented by formula Fb:
• wherein R1b is as defined above,
• then acylating hydroxyl at the 1- and 11-positions of compound Fb with an acylating agent corresponding to R′ to give compound B2b represented by B2b:
• wherein R1b and R′ are as defined above,
• and then removing the protective group at the 7-position of compound B2b.

A compound represented by formula B2b:

• wherein
• R1b represents formyl;
• optionally substituted straight chain C1-4 alkylcarbonyl;
• optionally substituted benzyl;
• group —SiR3R4R5 optionally substituted by halogen atom wherein R3, R4, and R5 each independently represent straight chain or branched chain C1-6 alkyl or phenyl;
• C1-6 alkyloxy-C1-6 alkyl optionally substituted by halogen atom;
• C1-6 alkylthio-C1-6 alkyl optionally substituted by halogen atom;
• straight chain, branched chain, or cyclic C1-4 alkyl optionally substituted by halogen atom, provided that, when alkyl in the C1-4 alkyl group is of a branched chain or cyclic type, the alkyl group is C3-4 alkyl;
• C2-6 alkenyl optionally substituted by halogen atom;
• C2-6 alkynyl optionally substituted by halogen atom;
• or an optionally substituted saturated or unsaturated five- or six-membered heterocyclic group,
• wherein, in R1b, the substituent optionally possessed by alkylcarbonyl is selected from the group consisting of halogen atoms, C1-4 alkyloxy, C1-4 haloalkyloxy, C1-4 alkylcarbonyl, C1-4 haloalkylcarbonyl, C1-4 alkylcarbonyloxy, and C1-4 haloalkylcarbonyloxy, and the substituent optionally possessed by the heterocyclic group and benzyl is selected from the group consisting of halogen atoms, C1-4 alkyl, C1-4 alkyloxy, C1-4 haloalkyloxy, C1-4 alkylthio, C1-4 haloalkyl, C1-4 alkylcarbonyl, C1-4 haloalkylcarbonyl, C1-4 alkylcarbonyloxy, C1-4 haloalkylcarbonyloxy, nitro, and cyano, and
• R′ represents cyclic C3-6 alkylcarbonyl.