Method for producing a spirooxindole derivative

A method of stereoselectively producing a compound of formula (IV):

• or a salt thereof, comprising:
• reacting a compound of formula (I):
• and a compound of formula (V):
• in a solvent using an asymmetric catalyst prepared from a Lewis acid and a chiral ligand,
• wherein
• R1 is a hydrogen atom, a C1-C6 alkylcarbonyl group optionally substituted with 1 to 3 substituents independently selected from group A, or a C1-C6 alkoxycarbonyl group optionally substituted with 1 to 3 substituents independently selected from group A,
• R2 is a 5- or 6-membered heteroaryl group containing, in the ring, 1 to 3 heteroatoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom;
• a phenyl group;
• a C3-C6 cycloalkyl group;
• or a C3-C6 cycloalkenyl group, wherein
• the 5- or 6-membered heteroaryl group, the phenyl group, the C3-C6 cycloalkyl group, and the C3-C6 cycloalkenyl group are each optionally substituted with 1 to 3 substituents independently selected from the group consisting of a halogen atom, a vinyl group, an ethynyl group, a cyano group, a hydroxy group, an amino group, a carboxy group, an aminocarbonyl group, a C1-C6 alkyl group optionally substituted with 1 to 3 substituents independently selected from group A, a C3-C4 cycloalkyl group optionally substituted with 1 to 3 substituents independently selected from group A, a C1-C6 alkoxy group optionally substituted with 1 to 3 substituents independently selected from group A, a C3-C4 cycloalkoxy group optionally substituted with 1 to 3 substituents independently selected from group A, a C1-C6 alkylamino group optionally substituted with 1 to 3 substituents independently selected from group A, a di-C1-C6 alkylamino group optionally substituted with 1 to 3 substituents independently selected from group A, a 4- to 7-membered saturated heterocyclic group containing one nitrogen atom in the ring and optionally substituted with 1 to 3 substituents independently selected from group B, a C1-C6 alkoxycarbonyl group optionally substituted with 1 to 3 substituents independently selected from group A, a C3-C4 cycloalkoxycarbonyl group optionally substituted with 1 to 3 substituents independently selected from group A, a C1-C6 alkylaminocarbonyl group optionally substituted with 1 to 3 substituents independently selected from group A, and a C3-C4 cycloalkylaminocarbonyl group optionally substituted with 1 to 3 substituents independently selected from group A,
• R3 and R4 are each independently a C1-C6 alkyl group optionally substituted with 1 to 3 substituents independently selected from group C, or
• R3 and R4 together form a C4-C6 cycloalkyl ring, a tetrahydrofuran ring, a tetrahydropyran ring, or a piperidine ring, wherein
• the C4-C6 cycloalkyl ring, the tetrahydrofuran ring, the tetrahydropyran ring, and the piperidine ring is each optionally substituted with 1 to 8 substituents independently selected from group D,
• R5 is a C1-C6 alkoxy group optionally substituted with 1 to 3 substituents independently selected from group E, a C3-C8 cycloalkoxy group optionally substituted with 1 to 3 substituents independently selected from group E, a C2-C6 alkenyloxy group, or —NR51R52,
• R51 and R52 are each independently a hydrogen atom, a C1-C6 alkyl group optionally substituted with 1 to 3 substituents independently selected from group E, a C3-C8 cycloalkyl group optionally substituted with 1 to 3 substituents independently selected from group E, or a 3- to 6-membered saturated heterocyclic group containing, in the ring, one heteroatom independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom and optionally substituted with 1 to 3 substituents independently selected from group E,
• ring Z is a benzene ring optionally substituted with 1 to 4 substituents independently selected from group E, a pyridine ring optionally substituted with 1 to 3 substituents independently selected from group E, or a pyrimidine ring optionally substituted with 1 or 2 substituents independently selected from group E,
• group A:
• a halogen atom, a hydroxy group, a C1-C6 alkyl group, an amino group, and a phenyl group,
• group B:
• a C1-C6 alkyl group and a hydroxy group,
• group C:
• a halogen atom, a hydroxy group, a phenyl group, a pyridyl group, and an amino group,
• group D:
• a halogen atom and a C1-C6 alkyl group optionally substituted with 1 to 3 halogen atoms,
• group E:
• a halogen atom, a hydroxy group, a vinyl group, an ethynyl group, a cyano group, a C1-C6 alkoxy group, an aminocarbonyl group, and a C1-C6 alkyl group optionally substituted with 1 to 3 halogen atoms,
• the Lewis acid is selected from the group consisting of a Zn(II) Lewis acid, a Ag(I) Lewis acid, a Ni(II) Lewis acid, a Co(II) Lewis acid, a Ru(I) Lewis acid, a Cu(I) Lewis acid, and a Cu(II) Lewis acid, and
• the chiral ligand is selected from the group consisting of
• a compound of formula (VI):
• a compound of formula (VII):
• a compound of formula (VIII):
• a compound of formula (IX):
• a compound of formula (X):
• a compound of formula (XI):
• and a compound of formula (XII):
• wherein
• R6 is a phenyl group optionally substituted with 1 to 3 substituents independently selected from group F,
• ring Y is a benzene ring, a cyclohexane ring, or a dioxolane ring optionally substituted with 1 to 4 halogen atoms,
• R7 is a phenyl group optionally substituted with 1 to 3 substituents independently selected from group G, or a furanyl group optionally substituted with 1 to 3 substituents independently selected from group G,
• R8 is a hydrogen atom or a C1-C6 alkoxy group,
• R9 is a C1-C6 alkoxy group, or
• two R9 moieties together form a 7- to 12-membered heterocyclic ring containing two oxygen atoms in the ring,
• X is CH, CR10, or a nitrogen atom,
• R10 is a C1-C6 alkoxy group,
• V is P(R11)2 or a phenyl group substituted with a substituent selected from P(R11)2 and PH(O)R12,
• R11 is a C1-C6 alkyl group, a cyclohexyl group, or a phenyl group optionally substituted with two trifluoromethyl groups,
• R12 is a C1-C6 alkyl group or a phenyl group,
• W is a C1-C6 alkylthio group, a dihydrooxazolyl group optionally substituted with one C1-C6 alkyl group, CH(CH3)P(R13)2, or CHR14R15,
• R13 is a cyclohexyl group, a C1-C6 alkyl group, or a phenyl group optionally substituted with 1 or 2 substituents independently selected from group H,
• R14 is a phenyl group optionally substituted with one P(R16)2,
• R15 is a C1-C6 alkyl group or a di-C1-C6 alkylamino group,
• R16 is a phenyl group or a cyclohexyl group,
• U is any one of the following:
• R17 is a phenyl group optionally substituted with 1 to 3 substituents independently selected from group F,
• R18 is a C1-C6 alkyl group or a phenyl group,
• R19 is a hydrogen atom or a C1-C6 alkyl group,
• R20 and R21 are each independently a C1-C6 alkyl group,
• group F:
• a C1-C6 alkyl group and a C1-C6 alkoxy group,
• group G:
• a C1-C6 alkyl group, a C1-C6 alkoxy group, and a di-C1-C6 alkylamino group, and
• group H:
• a C1-C6 alkyl group and a C1-C6 alkyl group optionally substituted with three halogen atoms.