Intermediates and methods for making zearalenone macrolide analogs

A method for making a compound of formula (VI):

• wherein R1 and R2 are each independently selected from the group consisting of hydrogen, C1-6 alkyl, C3-6 unconjugated alkenyl and C3-6 unconjugated alkynyl;
• R3 is selected from the group consisting of hydrogen and a base stable oxygen protecting group;
• R4 is selected from the group consisting of hydrogen and a base stable oxygen protecting group;
• R8 is selected from the group consisting of hydrogen and —ORg wherein Rg is hydrogen or a base stable oxygen protecting group,
• R9 is selected from the group consisting of hydrogen, halogen, —ORb, C1-6 alkyl, C3-6 unconjugated alkenyl, C3-6 unconjugated alkynyl, C1-6 haloalkyl, —SRd and —NReRf wherein Rb is hydrogen or a base stable oxygen protecting group, wherein Rd is selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6heteroalkyl, 5-7 membered heteroaryl comprising 1, 2 or 3 heteroatoms, and C5-7 aryl and wherein Re and Rf are each independently selected from the group consisting of hydrogen,
• C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6heteroalkyl, 5-7 membered heteroaryl comprising 1, 2 or 3 heteroatoms, and C5-7 aryl or a base stable nitrogen protecting group;
• R10 is selected from the group consisting of hydrogen, halogen, —ORc, C1-6 alkyl, C3-6 unconjugated alkenyl, C3-6 unconjugated alkynyl, C1-6 haloalkyl and C1-6 alkoxy, wherein Rc is hydrogen or a base stable oxygen protecting group;
• and
• R11 and R12 are each independently selected from the group consisting of hydrogen and a base stable oxygen protecting group;
• or R11 and R12 are taken together to form a 5 membered heterocyclyldiyl of structure (a):
• wherein R19 and R20 are each independently selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy and phenyl, or R19 and R20 together represent a fluorenyl moiety of structure (b):
• comprising reacting a compound of formula (I):
• with a compound of formula (III):
• wherein Y is a halogen or —O—SO2CF3,
• under suitable basic conditions, such that a compound of formula (VI) is formed.

A method for making a compound of formula (IV):

• wherein R1 and R2 are each independently selected from the group consisting of hydrogen, C1-6 alkyl, C3-6 unconjugated alkenyl and C3-6 unconjugated alkynyl;
• R5 and R6 are each independently selected from the group consisting of hydrogen, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, phenyl and benzyl, wherein the phenyl or benzyl are substituted with 0, 1, 2, or 3 substituents independently selected from halogen, hydroxyl, C1-3 alkyl, and NH2;
• or R5 and R6 are taken together with the carbons on which they are attached to form a 5-6 membered unconjugated carbocyclic ring;
• R7 is selected from the group consisting of hydrogen and —ORa wherein Ra is hydrogen or a base stable oxygen protecting group;
• R8 is selected from the group consisting of hydrogen and —ORg wherein Rg is hydrogen or a base stable oxygen protecting group;
• R9 is selected from the group consisting of hydrogen, halogen, —ORb, C1-6 alkyl, C3-6 unconjugated alkenyl, C3-6 unconjugated alkynyl, C1-6 haloalkyl, —SRd and —NReRf wherein Rb is hydrogen or a base stable oxygen protecting group, wherein Rd is selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 heteroalkyl, 5-7 membered heteroaryl comprising 1, 2 or 3 heteroatoms, and C5-7 aryl and wherein Re and Rf are each independently selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 heteroalkyl, 5-7 membered heteroaryl comprising 1, 2 or 3 heteroatoms, and C5-7 aryl or a base stable nitrogen protecting group;
• R10 is selected from the group consisting of hydrogen, halogen, —ORc, C1-6 alkyl, C3-6 unconjugated alkenyl, C3-6 unconjugated alkynyl, C1-6 haloalkyl and C1-6 alkoxy, wherein Rc is hydrogen or a base stable oxygen protecting group;
• and
• R11 and R12 are each independently selected from the group consisting of hydrogen and a base stable oxygen protecting group;
• or R11 and R12 are taken together to form a 5 membered heterocyclyldiyl of structure (a):
• wherein R19 and R20 are each independently selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy and phenyl, or R19 and R20 together represent a fluorenyl moiety of structure (b):
• comprising combining a compound of formula (I):
• wherein
• R3 is selected from the group consisting of hydrogen and a base stable oxygen protecting group;
• and
• R4 is selected from the group consisting of hydrogen and a base stable oxygen protecting group;
• with a compound of formula (II):
• wherein
• X is a halogen;
• and
• R13 is selected from the group consisting of hydrogen and a base stable oxygen protecting group;
• and a compound of formula (III):
• wherein Y is a halogen or —O—SO2CF3,
• under suitable conditions, such that an alpha-intermediate and a compound of formula (IV) are formed.

A method for making a compound of formula (IV):

• wherein R1 and R2 are each independently selected from the group consisting of hydrogen, C1-6 alkyl, C3-6 unconjugated alkenyl and C3-6 unconjugated alkynyl;
• R5 and R6 are each independently selected from the group consisting of hydrogen, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, phenyl and benzyl, wherein the phenyl or benzyl are substituted with 0, 1, 2, or 3 substituents independently selected from halogen, hydroxyl, C1-3 alkyl, and NH2;
• or R5 and R6 are taken together with the carbons on which they are attached to form a 5-6 membered unconjugated carbocyclic ring;
• R7 is selected from the group consisting of hydrogen and —ORa wherein Ra is hydrogen or a base stable oxygen protecting group;
• R8 is selected from the group consisting of hydrogen and —ORg wherein Rg is hydrogen or a base stable oxygen protecting group;
• R9 is selected from the group consisting of hydrogen, halogen, —ORb, C1-6 alkyl, C3-6 unconjugated alkenyl, C3-6 unconjugated alkynyl, C1-6 haloalkyl, —SRd and —NReRf wherein Rb is hydrogen or a base stable oxygen protecting group, wherein Rd is selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 heteroalkyl, 5-7 membered heteroaryl comprising 1, 2 or 3 heteroatoms, and C5-7 aryl and wherein Re and Rf are each independently selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 heteroalkyl, 5-7 membered heteroaryl comprising 1, 2 or 3 heteroatoms, and C5-7 aryl or a base stable nitrogen protecting group;
• R10 is selected from the group consisting of hydrogen, halogen, —ORc, C1-6 alkyl, C3-6 unconjugated alkenyl, C3-6 unconjugated alkynyl, C1-6 haloalkyl and C1-6 alkoxy, wherein Rc is hydrogen or a base stable oxygen protecting group;
• and
• R11 and R12 are each independently selected from the group consisting of hydrogen and a base stable oxygen protecting group;
• or R11 and R12 are taken together to form a 5 membered heterocyclyldiyl of structure (a):
• wherein R19 and R20 are each independently selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy and phenyl, or R19 and R20 together represent a fluorenyl moiety of structure (b):
• comprising reacting a compound of formula (I):
• wherein R3 is selected from the group consisting of hydrogen and a base stable oxygen protecting group;
• and
• R4 is selected from the group consisting of hydrogen and a base stable oxygen protecting group;
• with a compound of formula (II):
• wherein X is a halogen;
• and
• R13 is selected from the group consisting of hydrogen and a base stable oxygen protecting group;
• under suitable basic conditions to form a compound of formula (V):
• and reacting the compound of formula (V) with a compound of formula (III):
• wherein Y is a halogen or —O—SO2CF3;
• under suitable basic conditions, such that a compound of formula (IV) is formed.

A method for making a compound of formula (IV):

• wherein R1 and R2 are each independently selected from the group consisting of hydrogen, C1-6 alkyl, C3-6 unconjugated alkenyl and C3-6 unconjugated alkynyl;
• R5 and R6 are each independently selected from the group consisting of hydrogen, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, phenyl and benzyl, wherein the phenyl or benzyl are substituted with 0, 1, 2, or 3 substituents independently selected from halogen, hydroxyl, C1-3 alkyl, and NH2;
• or R5 and R6 are taken together with the carbons on which they are attached to form a 5-6 membered unconjugated carbocyclic ring;
• R7 is selected from the group consisting of hydrogen and —ORa wherein Ra is hydrogen or a base stable oxygen protecting group;
• R8 is selected from the group consisting of hydrogen and —ORg wherein Rg is hydrogen or a base stable oxygen protecting group;
• R9 is selected from the group consisting of hydrogen, halogen, —ORb, C1-6 alkyl, C3-6 unconjugated alkenyl, C3-6 unconjugated alkynyl, C1-6 haloalkyl, —SRd and —NReRf wherein Rb is hydrogen or a base stable oxygen protecting group, wherein Rd is selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 heteroalkyl, 5-7 membered heteroaryl comprising 1, 2 or 3 heteroatoms, and C5-7 aryl and wherein Re and Rf are each independently selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 heteroalkyl, 5-7 membered heteroaryl comprising 1, 2 or 3 heteroatoms, and C5-7 aryl or a base stable nitrogen protecting group;
• R10 is selected from the group consisting of hydrogen, halogen, —ORc, C1-6 alkyl, C3-6 unconjugated alkenyl, C3-6 unconjugated alkynyl, C1-6 haloalkyl and C1-6 alkoxy, wherein Rc is hydrogen or a base stable oxygen protecting group;
• and
• R11 and R12 are each independently selected from the group consisting of hydrogen and a base stable oxygen protecting group;
• or R11 and R12 are taken together to form a 5 membered heterocyclyldiyl of structure (a):
• wherein R19 and R20 are each independently selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy and phenyl, or R19 and R20 together represent a fluorenyl moiety of structure (b):
• comprising reacting a compound of formula (I):
• wherein R3 is selected from the group consisting of hydrogen and a base stable oxygen protecting group;
• and
• R4 is selected from the group consisting of hydrogen and a base stable oxygen protecting group;
• with a compound of formula (III):
• wherein Y is a halogen or —O—SO2CF3;
• under suitable basic conditions to form a compound of formula (VI):
• and reacting the compound of formula (VI)
• with a compound of formula (II):
• wherein X is a halogen;
• and
• R13 is selected from the group consisting of hydrogen and a base stable oxygen protecting group;
• under suitable basic conditions, such that a compound of formula (IV) is formed.

A method for making a composition comprising a compound of formula (IV):

• comprising combining a compound of formula (I):
• with a compound of formula (II):
• and a compound of formula (III):
• wherein Y is a halogen or —O—SO2CF3;
• R1 and R2 are each independently selected from the group consisting of hydrogen, C1-6 alkyl, C3-6 unconjugated alkenyl and C3-6 unconjugated alkynyl;
• R3 is selected from the group consisting of hydrogen and a base stable oxygen protecting group;
• and
• R4 is selected from the group consisting of hydrogen and a base stable oxygen protecting group;
• R5 and R6 are each independently selected from the group consisting of hydrogen, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, phenyl and benzyl, wherein the phenyl or benzyl are substituted with 0, 1, 2, or 3 substituents independently selected from halogen, hydroxyl, C1-3 alkyl, and NH2;
• or R5 and R6 are taken together with the carbons on which they are attached to form a 5-6 membered unconjugated carbocyclic ring;
• R7 is selected from the group consisting of hydrogen and —ORa wherein Ra is hydrogen or a base stable oxygen protecting group;
• R8 is selected from the group consisting of hydrogen and —ORg wherein Rg is hydrogen or a base stable oxygen protecting group;
• R9 is selected from the group consisting of hydrogen, halogen, —ORb, C1-6 alkyl, C3-6 unconjugated alkenyl, C3-6 unconjugated alkynyl, C1-6 haloalkyl, —SRd and —NReRf wherein Rb is hydrogen or a base stable oxygen protecting group, wherein Rd is selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 heteroalkyl, 5-7 membered heteroaryl comprising 1, 2 or 3 heteroatoms, and C5-7 aryl and wherein Re and Rf are each independently selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 heteroalkyl, 5-7 membered heteroaryl comprising 1, 2 or 3 heteroatoms, and C5-7 aryl or a base stable nitrogen protecting group;
• R10 is selected from the group consisting of hydrogen, halogen, —ORc, C1-6 alkyl, C3-6 unconjugated alkenyl, C3-6 unconjugated alkynyl, C1-6 haloalkyl and C1-6 alkoxy, wherein Rc is hydrogen or a base stable oxygen protecting group;
• and
• R11 and R12 are each independently selected from the group consisting of hydrogen and a base stable oxygen protecting group;
• or R11 and R12 are taken together to form a 5 membered heterocyclyldiyl of structure (a):
• wherein R19 and R20 are each independently selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy and phenyl, or R19 and R20 together represent a fluorenyl moiety of structure (b):
• R13 is selected from the group consisting of hydrogen and a base stable oxygen protecting group;
• and
• X is a halogen;
• under suitable conditions, such that a composition comprising a compound of formula (IV) is formed, wherein the composition is purity-enhanced, yield-enhanced and/or substantially free of organic impurities.