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US 2008/0306145 A1Published application
Preparation Of Ginkgolide And F-Seco-Ginkgolide Lactols
AssigneeThe Trustees of Columbia University in the City of New York
InventorsKoji Nakanishi, Nina Berova, Katsunori Tanaka
Life of this patent
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Abstract
The present invention relates to synthesis of C11 natural ginkgolide derivatives and C11 f-seco-gingkolide derivatives from the corresponding lactols which are selectively obtained using NaBH4.
Claims27
A compound having the structure:
- wherein R1 is H or —OR8,
- where R8 is H, or —C(O)R9, where R9 is alkyl, aryl, or amino;
- wherein R2 is H, OH, —O(CH3), —OC(O)CH3, (C1-C10) alkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, -A-Ar, -A-Z-Ar, —SO2—Ar, -A-NR10, —O-A-Ar, or —R10,
- where A is (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, which is unsubstituted or substituted by a straight or branched alkyl chain group having 1 to 5 carbon atoms;
- Z is carbon, oxygen, sulfur or nitrogen;
- Ar is a phenyl group, a pyridyl group, a naphthyl group, a pyrimidyl group, or a quinolyl group, each of which is unsubstituted or substituted by one to five substituents selected from the group consisting of hydrogen, halogen, a hydroxy group, a carboxylic acid group, substituted or unsubstituted (C1-C10) alkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, (C1-C10) haloalkyl, (C1-C10) alkoxy, (C2-C10) alkenyloxy, (C2-C10) alkynyloxy, (C1-C10) haloalkoxy, a phenyl group, a phenoxy group, an aralkyl group, an aralkyloxy group, a substituted phenyl group, a substituted phenoxy group, a substituted aralkyl group, a substituted aralkyloxy group, —C(O)R10, C(O)NR10R10, —C(O)OR10, —N(H)COR10—NH(OH), —N(OH)COR10, —CH2OR10, —OCH2CO2R10, —CH2CO2R10, —CH2SR10, —CH2NR10R10, —CH2CONR10R10, —SR10—OSR10, —N(R10)(R10) or —NR10SO2R10,
- where each R10 is independently selected from hydrogen, (C1-C10) alkyl, (C3-C10) cycloalkyl, —SCX3 in which X is a halogen, —CN, —NO2 or -Z-A-Z′- in which Z and A are as defined above and Z′ represents carbon, oxygen, sulfur, or nitrogen;
- wherein R4 is H, OH, halide, unsubstituted or substituted, straight or branched (C1-C5) alkyl group, (C2-C5) alkenyl, or a (C2-C5) alkynyl, (C1-C5) alkoxy, (C2-C5) alkenyloxy, or (C2-C5) alkynyloxy, —N3, —C(O)R11, —C(O)NR11R12, —C(O)OR11, —OC(O)R11, —OC(O)OR11, —NH(OH), —N(R11)(R12), —N(H)COR11, —N(OH)COR11, —CH2OR11, —OCH2CO2R11, —CH2SR11, —CH2N(R11)(R12), —SR11, —OSR11, —N(R11)SO2R12, —OR13, or triethylsiloxy,
- where R13 is H, —C(O)—O—R14, or —C(O)(R14), where R14 is alkyl, aryl, or amino, and where R11 and R12 are each, independently, hydrogen, substituted or unsubstituted (C1-C5) alkyl, (C2-C5) alkenyl, (C2-C5) alkynyl, or cycloalkyl or aryl group having 3 to 10 carbon atoms;
- wherein R6 is H or —OR8,
- where R8 is H, or —C(O)R9, where R9 is alkyl, aryl, or amino;
- wherein R7 is —CH3;
- wherein R3 is O and R5 is selected from H, OH, —C(CH3)—C(O)—O(CH3), (C1-C10) alkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, heterocyclic, amino, amido, alkoxy, alkenyloxy, alkynyloxy, —O-aryl, —O-(alkyl)(C1-C10), (—NH-alkyl, —N(alkyl)2, —NH2, -alkyl-C(O)(OH), -alkyl-OH, -alkyl-(NH2), halide, CX3 where X is a halide, indole radical, -A-Ar, -A-Z-Ar, —SO2—Ar, -A-NR10, —O-A-Ar, or —R10, where A, Z, Ar and R10 are defined as above, or
- wherein R5 is O and R3 is selected from OH, —C(CH3)—C(O)—O(CH3), (C1-C10) alkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, heterocyclic, amino, amido, alkoxy, alkenyloxy, alkynyloxy, —O-aryl, —O—(C2-C10 alkyl) (C1-C10), (—NH-alkyl, —N(alkyl)2, —NH2, -alkyl-C(O)(OH), -alkyl-OH, -alkyl-(NH2), halide, CX3 where X is a halide, indole radical, -A-Ar, -A-Z-Ar, —SO2—Ar, -A-NR10, —O-A-Ar, or —R10, where A, Z, Ar and R10 are defined as above,
- or an optically pure enantiomer, diastereomer, tautomer or salt thereof.
12 more elements
A process for preparing the compound of claim comprising:
- (a) exposing a compound having the structure:
- wherein R1 is H or —OR8,
- where R8 is H, or —C(O)R9, where R9 is alkyl, aryl, or amino;
- wherein R2 is H, OH, —O(CH3), —OC(O)CH3, (C1-C10) alkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, -A-Ar, -A-Z-Ar, —SO2—Ar, -A-NR10, O-A-Ar, or —R10,
- where A is (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, which is unsubstituted or substituted by a straight or branched alkyl chain group having 1 to 5 carbon atoms;
- Z is carbon, oxygen, sulfur or nitrogen;
- Ar is a phenyl group, a pyridyl group, a naphthyl group, a pyrimidyl group, or a quinolyl group, each of which is unsubstituted or substituted by one to five substituents selected from the group consisting of hydrogen, halogen, a hydroxy group, a carboxylic acid group, substituted or unsubstituted (C1-C10) alkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, (C1-C10) haloalkyl, (C1-C10) alkoxy, (C2-C10) alkenyloxy, (C2-C10) alkynyloxy, (C1-C10) haloalkoxy, a phenyl group, a phenoxy group, an aralkyl group, an aralkyloxy group, a substituted phenyl group, a substituted phenoxy group, a substituted aralkyl group, a substituted aralkyloxy group, —C(O)R10, —C(O)NR10R10, —C(O)OR10, —N(H)COR10—NH(OH), —N(OH)COR10, —CH2OR10, —OCH2CO2R10, —CH2CO2R10, —CH2SR10, —CH2NR10R10, —CH2CONR10R10, —SR10, —OSR10, —N(R10)(R10), or —NR10SO2R10,
- where each R10 is independently selected from hydrogen, (C1-C10) alkyl, (C3-C10) cycloalkyl, —SCX3 in which X is a halogen, —CN, —NO2 or -Z-A-Z′- in which Z and A are as defined above and Z′ represents carbon, oxygen, sulfur, or nitrogen;
- wherein R4 is H, OH, halide, unsubstituted or substituted, straight or branched (C1-C5) alkyl group, (C2-C5) alkenyl, or a (C2-C5) alkynyl, (C1-C5) alkoxy, (C2-C5) alkenyloxy, or (C2-C5) alkynyloxy, —N3, —C(O)R11, —C(O)NR11R12, —C(O)OR11, —OC(O)R11, —OC(O)OR11, —NH(OH), —N(R11)(R12), —N(H)CR11, —N(OH)COR11, —CH2OR11, —OCH2CO2R11, —CH2SR11, —CH2N(R11)(R12), —SR11, —OSR11, —N(R11)SO2R12, —OR13 or triethylsiloxy,
- where R13 is H, —C(O)—O—R14, or —C(O)(R14), where R14 is alkyl, aryl, or amino, and where R11 and R12 are each, independently, hydrogen, substituted or unsubstituted (C1-C5) alkyl, (C2-C5) alkenyl, or (C2-C5) alkynyl, or a cycloalkyl or aryl group having 3 to 10 carbon atoms;
- wherein R6 is H or —OR8,
- where R8 is H, or —C(O)R9, where R9 is alkyl, aryl, or amino;
- and
- wherein R7 is —CH3,
- to NaBH4 in a suitable solvent to produce a lactol derivative;
- and
- (b) reacting the lactol derivative product of step (a) with an agent suitable to produce the compound.
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A process for preparing a compound having the structure:
- comprising reacting
- wherein R1 is H or —OR8,
- wherein R2 is H, OH, —O(CH3), —OC(O)CH3, (C1-C10) alkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, -A-Ar, -A-Z-Ar, —SO2—Ar, -A-NR10, —O-A-Ar, or —R10,
- where A is (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, which is unsubstituted or substituted by a straight or branched alkyl chain group having 1 to 5 carbon atoms;
- Z is carbon, oxygen, sulfur or nitrogen;
- Ar is a phenyl group, a pyridyl group, a naphthyl group, a pyrimidyl group, or a quinolyl group, each of which is unsubstituted or substituted by one to five substituents selected from the group consisting of hydrogen, halogen, a hydroxy group, a carboxylic acid group, substituted or unsubstituted (C1-C10) alkyl, (C2-C10) alkenyl, (C2-C10) alkynyl, (C1-C10) haloalkyl, (C1-C10) alkoxy, (C2-C10) alkenyloxy, (C2-C10) alkynyloxy, (C1-C10) haloalkoxy, a phenyl group, a phenoxy group, an aralkyl group, an aralkyloxy group, a substituted phenyl group, a substituted phenoxy group, a substituted aralkyl group, a substituted aralkyloxy group, —C(O)R10, —C(O)NR10R10, —C(O)OR10, —N(H)COR10—NH(OH), —N(OH)COR10, —CH2OR10, —OCH2CO2R10, —CH2CO2R10, —CH2SR10, —CH2NR10R10, —CH2CONR10R10, —SR10, —OSR10, —N(R10)(R10), or —NR10SO2R10,
- where each R10 is independently selected from hydrogen, (C1-C10) alkyl, (C3-C10) cycloalkyl, —SCX3 in which X is a halogen, —CN, —NO2 or -Z-A-Z′- in which Z and A are as defined above and Z′ represents carbon, oxygen, sulfur, or nitrogen;
- wherein R4 is H, OH, halide, unsubstituted or substituted, straight or branched (C1-C5) alkyl group, (C2-C5) alkenyl, or a (C2-C5) alkynyl, (C1-C5) alkoxy, (C2-C5) alkenyloxy, or (C2-C5) alkynyloxy, —N3, —C(O)R11, —C(O)NR11R12, —C(O)OR11, —OC(O)R11, —OC(O)OR11, —NH(OH), —N(R11)(R12), —N(H)COR11, —N(OH)COR11, —CH2OR11, —OCH2CO2R11, —CH2SR11, —CH2N(R11)(R12), —SR11, —OSR11, —N(R11)SO2R12, —OR13, or triethylsiloxy,
- where R13 is H, —C(O)—O—R14, or —C(O)(R14), where R14 is alkyl, aryl, or amino, and where R11 and R12 are each, independently, hydrogen, substituted or unsubstituted (C1-C5) alkyl, (C2-C5) alkenyl, (C2-C5) alkynyl, or cycloalkyl or aryl group having 3 to 10 carbon atoms;
- and
- wherein R15 is H or halide, and R16 is —C(CH3)—C(O)—OCH3,
- with NaBH4 in a suitable solvent.
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A process for preparing a compound having the structure:
- comprising:
- a) exposing a compound having the structure:
- to p-phenylbenzoic acid, DEC, DMAP, at a suitable temperature so as to produce a compound having the structure:
- b) separating the compounds produced in step a);
- and
- c) exposing the products of step b) to a suitable hydrolyzing agent so as to produce the compound.
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Dependencies are inferred from the claim text.