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WO2016011130A1 - Compositions et procédés pour la préparation de composés 4-oxy-2-cyclohexénone et 6-oxy-2-cyclohexénone - Google Patents

Compositions et procédés pour la préparation de composés 4-oxy-2-cyclohexénone et 6-oxy-2-cyclohexénone Download PDF

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WO2016011130A1
WO2016011130A1 PCT/US2015/040530 US2015040530W WO2016011130A1 WO 2016011130 A1 WO2016011130 A1 WO 2016011130A1 US 2015040530 W US2015040530 W US 2015040530W WO 2016011130 A1 WO2016011130 A1 WO 2016011130A1
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compound
formula
optionally substituted
alkyl
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Jim-Min Fang
Che-Sheng HSU
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National Taiwan University NTU
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National Taiwan University NTU
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
    • C07C45/30—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with halogen containing compounds, e.g. hypohalogenation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
    • C07C45/511—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups
    • C07C45/515—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups the singly bound functional group being an acetalised, ketalised hemi-acetalised, or hemi-ketalised hydroxyl group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/69—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by addition to carbon-to-carbon double or triple bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • A. cinnamomea is used as a precious traditional Chinese herbal prescription.
  • the natural analogous compounds of 4-hydroxycyclohexenone type include antroquinonol B (2) and antroquinonol C (3) with modification at the fifteen-carbon substituent, antroquinonol D (4) having the structure without a methoxy substituent at the C-3 position, compound 5 and its acetate 6 having a lactone moiety at the aliphatic chain.
  • A. cinnamomea active medicinal substances are only obtained in small quantities by isolation from natural sources or the culture media of A.
  • the present invention relates to methods for the chemical synthesis of A. cinnamomea active medicinal substances and intermediate compounds thereto.
  • A. cinnamomea active medicinal substances include, but not limited to, antroquinonol (1), antroquinonol B (2), antroquinonol C (3), antroquinonol D (4), compound 5 and its acetate 6.
  • the method of the invention allows for a reliable and scalable synthesis of A. cinnamomea active medicinal substances and related compounds bearing a sensitive core structure of 4-hydroxycyclohex-2-en- 1-one. The synthesis is conducted in suitable conditions to avoid aromatization of this core structure that may be resulted from oxidation or elimination of water molecule .
  • the present invention provides a compound of formula (C):
  • a compound of formula (C) can be used in the synthesis of cyclohexenone compounds A. cinnamomea active medicinal substances) useful for treatment of cancers and/or diseases.
  • the present invention provides a compound of formula (I): (I) or a salt thereof,
  • a compound of formula (I) can be used in the synthesis of cyclohexenone compounds (A. cinnamomea active medicinal substances) useful for treatment of cancers and/or diseases.
  • the present invention provides a compound of formula (II):
  • a compound of formula (II) can be used in the synthesis of cyclohexenone compounds (A. cinnamomea active medicinal substances) useful for treatment of cancers and/or diseases.
  • the present invention provides a compound of formula (IV):
  • the present invention provides a compound of formula (VI):
  • the present invention provides a compound of formula (VII):
  • a compound of formulae (IV) or (V) is an A. cinnamomea active medicinal substance for treatment of cancers and/or diseases.
  • the compound of formula (IV) is antroquinonol (compound 1).
  • the compound of formula (IV) is antroquinonol B (compound
  • the compound of formula (IV) is antroquinonol C (compound
  • the compound of formula (IV) is antroquinonol D (compound
  • the compound of formula (IV) is compound 5 having a lactone moiety at the aliphatic chain.
  • the compound of formula (V) is compound 6.
  • the present invention provides a method for synthesizing a compound of formula (IV).
  • the converting comprises the formation of an intermediate having the formula (III).
  • the formation of the intermediate (III) takes place in the presence of a reducing agent.
  • the converting of (II) to (IV) takes place in the presence of a reducing agent followed by hydrolysis.
  • the hydrolysis takes place in acidic conditions.
  • the compound of formula (II) is prepared by treating a compound of formula (I) with an electrophilic reagent in basic conditions.
  • the compound of formula (I) is prepared by treating a compound of formula (C) with a nucleophilic reagent under suitable conditions.
  • the nucleophilic reagent is an organometallic reagent, a metal alkoxide, a metal thiolate, or a metal amide.
  • the compound of formula (C) is generated from a compound of formula (B):
  • the compound of formula (B) is generated from a compound of formula (A):
  • the present invention provides a method for synthesizing a compound of formula (V). the method comprising:
  • the converting of (IV) to (V) takes place in the presence of an alkylating or acylating agent.
  • the present invention provides a method for synthesizing a compound of formula (VI). the method comprising:
  • the hydrolysis takes place in acidic conditions.
  • the present invention provides a method for synthesizing a compound of formula (VII):
  • Figure 1 General method for the synthesis of compounds (IV), (V), (VI) and (VII) via key intermediates (I), (II) and (III).
  • the compounds of the present invention may exist in particular geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis- and trara-isomers, R- and /S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • Isomeric mixtures containing any of a variety of isomer ratios may be utilized in accordance with the present invention. For example, where only two isomers are combined, mixtures containing 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 isomer ratios are all contemplated by the present invention. Those of ordinary skill in the art will readily appreciate that analogous ratios are contemplated for more complex isomer mixtures.
  • a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
  • an isomer/enantiomer may, in some embodiments, be provided substantially free of the corresponding enantiomer, and may also be referred to as "optically enriched.”
  • “Optically enriched,” as used herein, means that the compound is made up of a significantly greater proportion of one enantiomer.
  • the compound of the present invention is made up of at least about 90% by weight of a preferred enantiomer. In other embodiments the compound is made up of at least about 95%, 98%, or 99% by weight of a preferred enantiomer.
  • Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts or prepared by asymmetric syntheses.
  • HPLC high pressure liquid chromatography
  • Jacques, et al Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H., et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).
  • an "alkyl group having from 1 to 6 carbons” (also referred to herein as "Ci_6 alkyl”) is intended to encompass 1 (Ci alkyl), 2 (C 2 alkyl), 3 (C 3 alkyl), 4 (C 4 alkyl), 5 (C 5 alkyl) and 6 (C 6 alkyl) carbons, and a range of 1 to 6 ( ⁇ _ 6 alkyl), 1 to 5 (C ⁇ alkyl), 1 to 4 (C ⁇ alkyl), 1 to 3 (d_ 3 alkyl), 1 to 2 (d_ 2 alkyl), 2 to 6 (C 2 _ 6 alkyl), 2 to 5 (C 2 _ 5 alkyl), 2 to 4 (C 2 ⁇ alkyl), 2 to 3 (C 2 _ 3 alkyl), 3 to 6 (C 3 _ 6 alkyl), 3 to 5 (C 3 _ 5 alkyl), 3 to 6 (C 3 _ 6 alkyl), 3 to 5 (C 3 _ 5 alkyl), 3 to
  • aliphatic refers to a monoradical of a non-aromatic, saturated or unsaturated, unbranched (“straight-chain”) or branched, substituted or unsubstituted, acyclic hydrocarbon having 1-50 carbon atoms (i.e., C ⁇ s aliphatic).
  • the term “aliphatic” encompasses the groups “alkyl”, “alkenyl”, and “alkynyl” as defined herein.
  • aliphatic refers to a C 2 -C 30 aliphatic group.
  • aliphatic refers to a C 5 -C 25 aliphatic group.
  • aliphatic refers to a Cr-C t o aliphatic group. In certain embodiments, aliphatic refers to a C 10 -C 2 o aliphatic group. In certain embodiments, aliphatic refers to a Cn-C 15 aliphatic group. Unless otherwise specified, each instance of aliphatic is independently unsubstituted ("unsubstituted aliphatic") or substituted (“substituted aliphatic”) with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more substituents as described herein. Aliphatic group substituents include, but are not limited to, any of the monovalent or divalent substituents described herein, that result in the formation of a stable moiety.
  • alkyl is given its ordinary meaning in the art and refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • the alkyl group may be a lower alkyl group, i.e., an alkyl group having 1 to 10 carbon atoms (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl).
  • a straight-chain or branched-chain alkyl may have 30 or fewer carbon atoms in its backbone, and, in some cases, 20 or fewer.
  • a straight-chain or branched-chain alkyl may have 12 or fewer carbon atoms in its backbone (e.g., Ci-Cn for straight chain, C 3 -C 12 for branched chain), 6 or fewer, or 4 or fewer.
  • cycloalkyls may have from 3-10 carbon atoms in their ring structure, or 5, 6 or 7 carbons in the ring structure.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, t-butyl, cyclobutyl, hexyl, and cyclochexyl.
  • alkylene refers to a bivalent alkyl group.
  • An "alkylene” group is a polymethylene group, i.e., -(CH 2 ) Z -, wherein z is a positive integer, e.g., from 1 to 20, from 1 to 10, from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
  • a substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described herein for a substituted aliphatic group.
  • alkenyl and alkynyl are given their ordinary meaning in the art and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • the alkyl, alkenyl and alkynyl groups employed in the invention contain 1-20 aliphatic carbon atoms. In certain other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-10 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-8 aliphatic carbon atoms. In still other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-6 aliphatic carbon atoms.
  • the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-4 carbon atoms.
  • Illustrative aliphatic groups thus include, but are not limited to, for example, methyl, ethyl, n- propyl, isopropyl, allyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl, sec-pentyl, isopentyl, t- pentyl, n-hexyl, sec-hexyl, moieties and the like, which again, may bear one or more substituents.
  • Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1- methyl-2-buten-l-yl, and the like.
  • Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl and the like.
  • substituents of the above-described aliphatic (and other) moieties of compounds of the invention include, but are not limited to aliphatic; heteroaliphatic; aryl;
  • heteroaryl alkylaryl; alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; CI; Br; I; -OH; -N0 2 ; -CN; -CF 3 ; -CHF 2 ; -CH 2 F; - CH 2 CF 3 ; -CHC1 2 ; -CH 2 OH; -CH 2 CH 2 OH; -CH 2 NH 2 ; -CH 2 S0 2 CH 3 ; -C(0)R x ; -C0 2 (R x ); - CON(R x ) 2 ; -OC(0)R x ; -OC0 2 R x ; -OCON(R x ) 2 ; -N(R X ) 2 ; -S(0) 2 R x ; -NR x (CO)R x
  • heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl wherein any of the aliphatic, heteroaliphatic, alkylaryl, or alkylheteroaryl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substituents described above and herein may be substituted or
  • carbocyclic groups optionally substituted, having a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), or multiple fused rings in which at least one is aromatic (e.g., 1,2,3,4- tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl). That is, at least one ring may have a conjugated pi electron system, while other, adjoining rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.
  • the aryl group may be optionally substituted, as described herein.
  • Substituents include, but are not limited to, any of the previously mentioned substitutents, i.e., the substituents recited for aliphatic moieties, or for other moieties as disclosed herein, resulting in the formation of a stable compound.
  • an aryl group is a stable mono- or polycyclic unsaturated moiety having preferably 3-14 carbon atoms, each of which may be substituted or unsubstituted.
  • Carbocyclic aryl groups refer to aryl groups wherein the ring atoms on the aromatic ring are carbon atoms.
  • Carbocyclic aryl groups include monocyclic carbocyclic aryl groups and polycyclic or fused compounds (e.g., two or more adjacent ring atoms are common to two adjoining rings) such as naphthyl groups. It will be appreciated that an aryl group may be attached via an alkyl moiety to form an "aralkyl” (or “alkylaryl”) group.
  • alkoxy refers to an alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom or through a sulfur atom.
  • the alkyl group contains 1-20 aliphatic carbon atoms.
  • the alkyl group contains 1-10 aliphatic carbon atoms.
  • the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-8 aliphatic carbon atoms.
  • the alkyl group contains 1-6 aliphatic carbon atoms.
  • the alkyl group contains 1-4 aliphatic carbon atoms.
  • alkoxy include but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n- butoxy, t-butoxy, neopentoxy and n-hexoxy.
  • thioalkyl include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and the like.
  • aliphatic e.g., alkyl, alkenyl, alkynyl
  • heteroaliphatic e.g., heteroalkyl, heteroalkenyl, heteroalkynyl
  • carbocyclyl, heterocyclyl, aryl and heteroaryl groups, as defined herein, are optionally substituted (e.g., "substituted” or “unsubstituted” aliphatic, "substituted” or “unsubstituted” alkyl, "substituted” or “unsubstituted” alkenyl, "substituted” or “unsubstituted” alkynyl, "substituted” or “unsubstituted” heteroaliphatic, "substituted” or “unsubstituted” heteroalkyl, "substituted” or “unsubstituted” heteroalkenyl, "substituted” or "substituted”
  • unsubstituted heteroaryl group means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom etc.) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • a "substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
  • each instance of R is, independently, selected from the group consisting of hydrogen, Ci- ! o alkyl, ⁇ _ 10 fluoroalkyl, C 2 _ 10 alkenyl, C 2 _ 10 alkynyl, C 3 _ 10 carbocyclyl, 3-14 membered heterocyclyl, C 6 _ 14 aryl, and 5-14 membered heteroaryl, or two R groups attached to an N atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each aliphatic, heteroaliphatic, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R D groups; and
  • Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary and quarternary nitrogen atoms.
  • nitrogen atom substituents are also referred to as "amino protecting groups” or “nitrogen protecting groups”.
  • Amino protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 M edition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference.
  • Exemplary amino protecting groups include, but are not limited to, methyl carbamate, ethyl carbamante, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl- [9-( 10, 10-dioxo- 10,10,10,10- tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), l-(l-adamantyl)-l-methylethyl carbamate (Adpoc), l,l-dimethyl-2-halo
  • dimethylthiophosphinamide Mpt
  • diphenylthiophosphinamide Ppt
  • dialkyl phosphoramidates dibenzyl phosphoramidate
  • diphenyl phosphoramidate diphenyl phosphoramidate
  • benzenesulfenamide o- nitrobenzenesulfenamide (Nps)
  • 2,4-dinitrobenzenesulfenamide pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, 3 -nitropyridinesulfenamide (Npys), >-toluenesulfonamide (Ts)
  • benzenesulfonamide 2,3,6,-trimethyl-4- methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4- methoxybenzen
  • oxygen atom substituents are also referred to as "hydroxyl protecting groups” or “oxygen protecting groups”.
  • Hydroxyl protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference.
  • Exemplary hydroxyl protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl,
  • IPDMS dimethylisopropylsilyl
  • DEIPS diethylisopropylsilyl
  • TDMS t-butyldimethylsilyl
  • TDPS t-butyldiphenylsilyl
  • tribenzylsilyl tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS)
  • formate benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, >-chlorophenoxyacetate, 3- phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate
  • the protecting groups include methylene acetal, ethylidene acetal, 1-t-butylethylidene ketal, 1-phenylethylidene ketal, (4-methoxyphenyl)ethylidene acetal, 2,2,2- trichloroethylidene acetal, acetonide, cyclopentylidene ketal, cyclohexylidene ketal,
  • cycloheptylidene ketal benzylidene acetal, >-methoxybenzylidene acetal, 2,4- dimethoxybenzylidene ketal, 3,4-dimethoxybenzylidene acetal, 2-nitrobenzylidene acetal, methoxymethylene acetal, ethoxymethylene acetal, dimethoxymethylene ortho ester, 1- methoxyethylidene ortho ester, 1-ethoxyethylidine ortho ester, 1,2-dimethoxyethylidene ortho ester, a-methoxybenzylidene ortho ester, l-(N,N-dimethylamino)ethylidene derivative, -(N - dimethylamino)benzylidene derivative, 2-oxacyclopentylidene ortho ester, di-t-butylsilylene group (DTBS), l,3-(l,l,3,3-tet
  • a compound of the present invention is provided as a salt.
  • Salts are well known in the art. For example, Berge et ah, describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • Salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples include salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, pers
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C ⁇ alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further salts include, when appropriate, ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower-alkyl sulfonate and aryl sulfonate.
  • leaving group refers to any atom or moiety that is capable of being displaced by another atom or moiety in a chemical reaction. More specifically, in some embodiments, “leaving group” refers to the atom or moiety that is displaced in a nucleophilic substitution reaction. In some embodiments, “leaving groups” are any atoms or moieties that are conjugate bases of strong acids. Examples of suitable leaving groups include, but are not limited to, chloride, bromide, iodide, tosyl, triflate, sulfonate, mesylate, dimethyl sulfonate,
  • Any of the compounds described herein may be in a variety of forms, such as, but not limited to, salts, solvates, hydrates, tautomers, and isomers.
  • the compound described herein may exist in various tautomeric forms.
  • tautomer as used herein includes two or more interconvertable compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency ⁇ e.g., a single bond to a double bond, a triple bond to a double bond, or vice versa).
  • the exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations ⁇ i.e., the reaction providing a tautomeric pair) may be catalyzed by acid or base.
  • Exemplary tautomerizations include keto-to-enol; amide-to-imide; lactam-to-lactim; enamine- to-imine; and enamine-to-(a different) enamine tautomerizations.
  • the compounds described herein may exist in various isomeric forms.
  • the term "isomer” as used herein includes any and all geometric isomers and
  • stereoisomers e.g., enantiomers, diastereomers, etc.
  • “isomer” includes cis- and trara-isomers, E- and Z-isomers, R- and /S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • an isomer/enantiomer may, in some embodiments, be provided substantially free of the corresponding enantiomer, and may also be referred to as "optically enriched.”
  • “Optically- enriched,” as used herein, means that the compound is made up of a significantly greater proportion of one enantiomer.
  • the compound of the present invention is made up of at least about 90% by weight of a preferred enantiomer. In other embodiments the compound is made up of at least about 95%, 98%, or 99% by weight of a preferred enantiomer.
  • Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts or prepared by asymmetric syntheses.
  • HPLC high pressure liquid chromatography
  • Jacques, et ah Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H., et ah, Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).
  • Antroquinonol (compound 1)
  • antroquinonol B compound 2
  • antroquinonol C compound 3
  • compound 3 antroquinonol D (compound 4), compound 5, and compound 6 are natural products isolated from A. cinnamomea and possess biological activities for treatment of cancer, male infertility, Parkinsonism and cardiovascular diseases. These active medicinal substances bear the same core structure of 4-oxy-2-cyclohexen-l-one.
  • the present invention relates to a new synthetic route to 4-oxy-2-cyclohexenone and 6- oxy-2-cyclohexenone compounds useful for treatment of cancers and/or diseases, and the intermediates thereto.
  • the cyclohexenone compounds include, but not limited to, A. cinnamomea active medicinal substances such as antroquinonol, antroquinonol B, antroquinonol C, antroquinonol D, compound 5, and compound 6.
  • the intermediates include the compounds of formulae (I), (II) and (III), and the cyclohexenone compounds have the structures of formulae (IV), (V), (VI) and (VII).
  • the present invention provides a compound of formula (I): (I) or a salt thereof, wherein:
  • R and R 1 are independently optionally substituted alkyl
  • R 2 is hydrogen, optionally substituted C ⁇ alkyl, halogen, cyano, acyl, -OR A , -SR A or -N(R B ) 2 , wherein each R A is independently hydrogen, an oxygen or a sulfur protecting group, optionally substituted C 1-6 alkyl, optionally substituted aryl, optionally substituted acyl, or optionally substituted imidoyl; and each R B is independently hydrogen or an amino protecting group;
  • R is hydrogen, optionally substituted C 2 _0 alkyl, halomethyl, trifluoromethyl, halogen, cyano, acyl, -OR A , -SR A or -N(R B ) 2 , wherein each R A is independently hydrogen, an oxygen or a sulfur protecting group, optionally substituted C 1-6 alkyl, optionally substituted aryl, optionally substituted acyl, or optionally substituted imidoyl; and each R B is independently hydrogen or an amino protecting group;
  • R 6 is hydrogen, optionally substituted C ⁇ alkyl, halogen, cyano, acyl, -OR A , -SR A or -N(R B ) 2 , wherein each R A is independently hydrogen, an oxygen or a sulfur protecting group, optionally substituted C 1-6 alkyl, optionally substituted aryl, optionally substituted acyl, or optionally substituted imidoyl; and each R B is independently hydrogen or an amino protecting group.
  • R 2 and R 3 are not taken together with their intervening atoms to form a carbocycle or heterocycle; R and OR are not taken together with their intervening atoms
  • R and OR are not taken together with their intervening atoms to form a carbocycle or heterocycle.
  • R is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, halogen, haloalkyl, trifluoromethyl, cyano, acyl, alkoxycarbonyl, aminocarbonyl, alkoxy, silyloxy, aralkyloxy, acyloxy, alkylthio, aralkylthio, amino, nitro, amido, and sulfonamido groups.
  • R is selected from the group consisting of hydrogen, optionally substituted C 2-6 alkyl, halogen, haloalkyl, tnfluoromethyl, cyano, acyl, alkoxycarbonyl, aminocarbonyl, hydroxy, alkoxy, silyloxy, aralkyloxy, acyloxy, alkylthio, aralkylthio, amino, nitro, amido, and sulfonamido groups.
  • R 6 is an alkyl (C1-C6), alkyl with substituents of nitro, cyano and ester groups, alkenyl (C2-C6), alkynyl (C2-C6), aryl, alkoxy, silyloxy, alkylthio,
  • alkylamino haloalkyl, tnfluoromethyl, cycloalkyl (C3-C8), cycloalkenyl (C5-C8), heterocyclyl, and heteroaryl.
  • R 1 is optically active chiral alkyl.
  • R and R 1 are optionally substituted C ⁇ alkyl.
  • R and R 1 are the same.
  • R and R 1 are taken together with their intervening atoms to form a carbocycle or heterocycle. In certain embodiments, R and R 1 are taken together with their intervening atoms to form an optionally substituted 1,3-dioxacycle.
  • R and R 1 are taken together with their intervening atoms to form 1,3-dioxacyclopentane, 1,3-dioxacyclohexane or an optically active variant thereof.
  • R is halogen, haloalkyl, trifluoromethyl, cyano, acyl, alkoxycarbonyl, aminocarbonyl, alkoxy, silyloxy, aralkyloxy, acyloxy, alkylthio, aralkylthio, optionally substituted amino, nitro, amido, or sulfonamido group.
  • R 2 is -OR A , wherein R A is hydrogen, an oxygen or sulfur protecting group, optionally substituted C 1-10 alkyl, optionally substituted aryl, optionally substituted acyl, or optionally substituted imidoyl.
  • R is -OH.
  • R 2 is -0(protecting group).
  • R 2 is -OR A , wherein R A is unsubstituted C 1-10 alkyl.
  • R 2 is -OR A , wherein R A is substituted C 1-10 alkyl.
  • R 2 is -OR A , wherein R A is unsubstituted aryl.
  • R 2 is -OR A , wherein R A is substituted aryl. In some embodiments, R 2 is -OR A , wherein R A is unsubstituted acyl. In some embodiments, R 2 is -OR A , wherein R A is substituted acyl. In some embodiments, R 2 is -OR A , wherein R A is unsubstituted imidoyl. In some embodiments, R 2 is -OR A , wherein R A is substituted imidoyl. 2 2
  • R is alkoxy. In certain embodiments, R is methoxy.
  • R is halogen. In certain embodiments, R is chlorine atom. In certain embodiments, R is bromine atom.
  • R is halogen, haloalkyl, trifluoromethyl, cyano, acyl, alkoxycarbonyl, aminocarbonyl, alkoxy, silyloxy, aralkyloxy, acyloxy, alkylthio, aralkylthio, optionally substituted amino, nitro, amido, or sulfonamido group.
  • R 3 is -OR 3 , wherein R B is hydrogen, an oxygen or sulfur protecting group, optionally substituted C 1-10 alkyl, optionally substituted aryl, optionally substituted acyl, or optionally substituted imidoyl.
  • R is -OH.
  • R 3 is -0(protecting group).
  • R 3 is -OR 3 , wherein R B is unsubstituted C 1-10 alkyl.
  • R 3 is -OR 3 , wherein R 3 is substituted C 1-10 alkyl.
  • R 3 is -OR 3 , wherein R 3 is unsubstituted aryl.
  • R is -OR , wherein R is substituted aryl. In some embodiments, R is -OR , wherein R 3 is unsubstituted acyl. In some embodiments, R 3 is -OR 3 , wherein R 3 is substituted acyl. In some embodiments, R 3 is -OR 3 , wherein R 3 is unsubstituted imidoyl. In some embodiments, R 3 is -OR 3 , wherein R 3 is substituted imidoyl.
  • R is alkoxy. In certain embodiments, R is methoxy. [0099] In certain embodiments, R is hydrogen.
  • R is halogen. In certain embodiments, R is chlorine atom. In certain embodiments, R is bromine atom.
  • R and R are the same. In some embodiments, R and R are
  • R and R are each methoxy.
  • R is methoxy and R is chlorine atom.
  • R 6 is alkyl (optionally with substituent of nitro, cyano and ester group), alkenyl (C2-C6), alkynyl (C2-C6), aryl, alkoxy, silyloxy, alkylthio, alkylamino, haloalkyl, trifluoromethyl, cycloalkyl (C3-C8), cycloalkenyl (C5-C8), heterocyclyl, or heteroaryl.
  • R 6 is methyl. [00105] In certain embodiments, R 6 is methoxy.
  • a compound of formula (I) is useful in the synthesis of A. cinnamomea active medicinal substances.
  • the present invention provides a compound of formula (II):
  • R and R 1 are independently optionally substituted alkyl
  • R 2 is hydrogen, optionally substituted ⁇ _ 6 alkyl, halogen, cyano, acyl, -OR A , -SR A or -N(R B ) 2 , wherein each R A is independently hydrogen, an oxygen or a sulfur protecting group, optionally substituted C 1-6 alkyl, optionally substituted aryl, optionally substituted acyl, or optionally substituted imidoyl; and each R B is independently hydrogen or an amino protecting group;
  • R is hydrogen, optionally substituted C 2 _0 alkyl, halomethyl, trifluoromethyl, halogen, cyano, acyl, -OR A , -SR A or -N(R B ) 2 , wherein each R A is independently hydrogen, an oxygen or a sulfur protecting group, optionally substituted C 1-6 alkyl, optionally substituted aryl, optionally substituted acyl, or optionally substituted imidoyl; and each R B is independently hydrogen or an amino protecting group;
  • R 5 is optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl;
  • R 6 is hydrogen, optionally substituted C ⁇ alkyl, halogen, cyano, acyl, -OR A , -SR A or -N(R B ) 2 , wherein each R A is independently hydrogen, an oxygen or a sulfur protecting group, optionally substituted C 1-6 alkyl, optionally substituted aryl, optionally substituted acyl, or optionally substituted imidoyl; and each R is independently hydrogen or an amino protecting group.
  • R 2 and R 3 are not taken together with their intervening atoms to form a carbocycle or heterocycle; R and OR are not taken together with their intervening atoms
  • R and OR are not taken together with their intervening atoms to form a carbocycle or heterocycle.
  • R is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, halogen, haloalkyl, trifluoromethyl, cyano, acyl, alkoxycarbonyl, aminocarbonyl, alkoxy, silyloxy, aralkyloxy, acyloxy, alkylthio, aralkylthio, amino, nitro, amido, and sulfonamido groups.
  • R is selected from the group consisting of hydrogen, optionally substituted C 2-6 alkyl, halogen, haloalkyl, trifluoromethyl, cyano, acyl, alkoxycarbonyl, aminocarbonyl, hydroxy, alkoxy, silyloxy, aralkyloxy, acyloxy, alkylthio, aralkylthio, amino, nitro, amido, and sulfonamido groups.
  • R 6 is an alkyl (C1-C6), alkyl with substituents of nitro, cyano and ester groups, alkenyl (C2-C6), alkynyl (C2-C6), aryl, alkoxy, silyloxy, alkylthio,
  • alkylamino haloalkyl, trifluoromethyl, cycloalkyl (C3-C8), cycloalkenyl (C5-C8), heterocyclyl, and heteroaryl.
  • R 1 is optically active chiral alkyl.
  • R and R 1 are optionally substituted C ⁇ alkyl.
  • R and R 1 are the same.
  • R and R 1 are taken together with their intervening atoms to form a carbocycle or heterocycle. In certain embodiments, R and R 1 are taken together with their intervening atoms to form an optionally substituted 1,3-dioxacycle.
  • R and R 1 are taken together with their intervening atoms to form 1,3-dioxacyclopentane, 1,3-dioxacyclohexane or an optically active variant thereof.
  • R is halogen, haloalkyl, trifluoromethyl, cyano, acyl, alkoxycarbonyl, aminocarbonyl, alkoxy, silyloxy, aralkyloxy, acyloxy, alkylthio, aralkylthio, optionally substituted amino, nitro, amido, or sulfonamido group.
  • R 2 is -OR A , wherein R A is hydrogen, an oxygen or sulfur protecting group, optionally substituted C 1-10 alkyl, optionally substituted aryl, optionally substituted acyl, or optionally substituted imidoyl.
  • R is -OH.
  • R 2 is -0(protecting group).
  • R 2 is -OR A , wherein R A is unsubstituted C 1-10 alkyl.
  • R 2 is -OR A , wherein R A is substituted C 1-10 alkyl.
  • R 2 is -OR A , wherein R A is unsubstituted aryl.
  • R 2 is -OR A , wherein R A is substituted aryl. In some embodiments, R 2 is -OR A , wherein R A is unsubstituted acyl. In some embodiments, R 2 is -OR A , wherein R A is substituted acyl. In some embodiments, R 2 is -OR A , wherein R A is unsubstituted imidoyl. In some embodiments, R 2 is -OR A , wherein R A is substituted imidoyl.
  • R is alkoxy. In certain embodiments, R is methoxy.
  • R is halogen. In certain embodiments, R is chlorine atom. In
  • R is bromine atom
  • R is halogen, haloalkyl, trifluoromethyl, cyano, acyl, alkoxycarbonyl, aminocarbonyl, alkoxy, silyloxy, aralkyloxy, acyloxy, alkylthio, aralkylthio, optionally substituted amino, nitro, amido, or sulfonamido group.
  • R 3 is -OR 3 , wherein R B is hydrogen, an oxygen or sulfur protecting group, optionally substituted C 1-10 alkyl, optionally substituted aryl, optionally substituted acyl, or optionally substituted imidoyl.
  • R is -OH.
  • R 3 is -0(protecting group).
  • R 3 is -OR 3 , wherein R B is unsubstituted C 1-10 alkyl.
  • R 3 is -OR 3 , wherein R 3 is substituted C 1-10 alkyl.
  • R 3 is -OR 3 , wherein R 3 is unsubstituted aryl.
  • R is -OR , wherein R is substituted aryl. In some embodiments, R is -OR , wherein R 3 is unsubstituted acyl. In some embodiments, R 3 is -OR 3 , wherein R 3 is substituted acyl. In some embodiments, R 3 is -OR 3 , wherein R 3 is unsubstituted imidoyl. In some embodiments, R 3 is -OR 3 , wherein R 3 is substituted imidoyl. [00124] In certain embodiments, R is alkoxy. In certain embodiments, R is methoxy. [00125] In certain embodiments, R is hydrogen.
  • R is halogen. In certain embodiments, R is chlorine atom. In certain embodiments, R is bromine atom.
  • R and R are the same. In some embodiments, R and R are
  • R and R are each methoxy.
  • R is methoxy and R is chlorine atom.
  • R 5 is an optionally substituted alkyl (C1-C45), an optionally substituted alkenyl (C2-C45) and an optionally substituted alkynyl (C2-C45).
  • R 5 is substituted alkyl (C3-C45) bearing heterocycle with a 5- or 6-membered lactone.
  • R 5 is substituted alkenyl (C3-C45) bearing heterocycle with a 5- or 6-membered lactone.
  • R 5 is substituted alkynyl (C3-C45) bearing heterocycle with a 5- or 6-membered lactone.
  • R 5 is benzyl
  • R is
  • R is
  • R is wherein saccharide is D-glucoside, D-mannoside, D-galactoside, D-xylose, N-acetyl-D- glucosamine, or N-acetyl-D-galactosamine.
  • R 5 is
  • R 6 is alkyl (optionally with substituent of nitro, cyano and ester group), alkenyl (C2-C6), alkynyl (C2-C6), aryl, alkoxy, silyloxy, alkylthio, alkylamino, haloalkyl, trifluoromethyl, cycloalkyl (C3-C8), cycloalkenyl (C5-C8), heterocyclyl, or heteroaryl.
  • R 6 is methyl. [00145] In certain embodiments, R 6 is methoxy.
  • R 6 is substituted C 1-6 alkyl bearing an alkoxy, a silyloxy, an alkylthio or an alkylamino group.
  • the compound of formula (II) is selected from the group consisting of:
  • the compound of formula (II) can be used in the synthesis of A. cinnamomea active medicinal substances such as antroquinonol, antroquinonol B, antroquinonol C, antroquinonol D, compound 5 and compound 6.
  • the present invention features an intermediate of formula (III):
  • the compound of formula (IV) is selected from the group consisting of:
  • the compound of formula (IV) has substituents in cis or trans configurations.
  • the compound of formula (IV) is a racemic mixture or an optically active compound.
  • the compound of formula (IV) is selected from the group consisting of:
  • the present invention provides a compound of formula (V):
  • R is selected from the group consisting of optionally substituted C 1-6 alkyl
  • R , R , R and R are as described herein.
  • R 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is allyl. In some embodiments, R 4 is benzyl.
  • R 4 is acetyl. In certain embodiments, R 4 is chloroacetyl. In certain embodiments, R 4 is methoxyacetyl. In certain embodiments, R 4 is trichloroacetyl. In certain embodiments, R 4 is benzoate. In certain embodiments, R 4 is 4-bromobenzoate.
  • R 4 is -C(0)R D , wherein R D is alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl. In certain embodiments, R D is alkyl (C1-C8) or cycloalkyl (C3-C8).
  • R 4 is selected from the group consisting of -C(0)CH 3 , - C(0)C 2 H 5 , -C(0)C 3 H 7 , -C(0)(t-Bu), -C(0)CF 3 , -C(0)CH 2 Ph, -C(0)C 6 H 5 , and optionally substituted benzoyl.
  • R 4 is -C(0)CH 3 .
  • R 4 is 4- bromobenzoyl.
  • the compound of formula (V) is selected from the group consisting of:
  • the compound of formula (V) has substituents in cis or trans configurations.
  • the compound of formula (V) is a racemic mixture or an optically active compound.
  • the compound of formula (V) is compound 6.
  • the present invention provides a compound of formula (VI): (VI) or a salt thereof,
  • the compound of formula (VI) is selected from the group consisting of:
  • the compound of formula (VI) has substituents in cis or trans configurations.
  • the compound of formula (VI) is a racemic mixture or an optically active compound.
  • the compound of formula (VI) is:
  • the present invention provides a compound of formula (VII): (VII) or a salt thereof,
  • R 2 , R 4 , R 5 and R 6 are as described herein.
  • the compound of formula (VII) is selected from the group consisting of:
  • the compound of formula (VII) has substituents in cis or trans configurations.
  • the compound of formula (VII) is a racemic mixture or an optically active compound.
  • the compound of formula (VI) is selected from the group consisting of:
  • Table 2 lists exemplary compounds of formula (II). Table 2.
  • Table 3 lists exemplary compounds of formula (III). Table 3.
  • Table 4 lists exemplary compounds of formula (IV). Table 4.
  • Table 5 lists exemplary compounds of formula (V). Table 5.
  • Table 6 lists exem lary compounds of formula (VI).
  • the present invention relates to a new synthetic route to 4-oxy-2-cyclohexenone and 6- oxy-2-cyclohexenone compounds useful for treatment of cancers and/or diseases, and the intermediates thereto.
  • the cyclohexenone compounds include the compounds of formulae (IV), (V), (VI) and (VII).
  • the intermediates include the compounds of formulae (I), (II) and (III).
  • the general synthetic route is summarized in Figure 1.
  • the present invention provides a method of synthesizing the compound of formula (IV).
  • the method of the invention comprises the conversion of a compound of formula (II) under suitable conditions to form a compound of formula (IV) in one or more steps.
  • the conversion of the compound of formula (II) to the compound of formula (IV) comprises the formation of an intermediate of formula (III).
  • the conversion of the compound (II) to the intermediate (III) is performed by reduction:
  • Examples of the reducing agent include, but not limited to, lithium aluminumhydride (LiAlH 4 ), diisobutylaluminum hydride (DIBAL), lithium tri-tert-butoxyalminum hydride (LiAl(Ot-Bu) 3 H), NaBH 4 -CeCl 3 , lithium triethylborohydride (LiEt 3 BH, Superhydride), lithium tri-sec-butylborohydride (L-Selectride), or lithium trisiamylborohydride (LS-Selectride).
  • the stereochemical outcome is dependent on the substrate, reducing agent, and reaction conditions.
  • the conversion of the intermediate (III) to the compound (IV) is performed by the hydrolysis in acidic conditions:
  • the compound of formula (II) is prepared by treating a compound of formula (I) with an electrophilic reagent in basic conditions:
  • the conversion of the compound of formula (I) to the compound of formula (II) can be performed by using an electrophilic reagent (R 5 X) in the presence of a base.
  • a base include, but not limited to, sodium hydride (NaH), potassium tert-butoxide (t-BuOK), lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LHMDS), sodium
  • X is a leaving group. Examples of the leaving group include, but not limited to, CI, Br, I, OS0 2 CH 3 (mesylate), OS0 2 CF 3 (triflate), or OS0 2 C 6 H4-p-CH 3 (tosylate).
  • the stereochemistry of alkylation product is controlled by the nature of substrate and the reaction conditions including the size of R 6 , temperature, solvent, cosolvent, base, and additive.
  • the addition reaction and alkylation is performed in a one-pot procedure.
  • the compound of formula (I) is prepared by treating a compound of formula (C) with a nucleophilic reagent under suitable conditions:
  • the preparation of the compound (I) from the compound (C) can be performed by Michael reaction using a nucleophilic reagent (R 6 M).
  • the nucleophilic reagent is organometallic reagent, metal alkoxide, metal thiolate, and metal amide.
  • R 6 M examples include, but not limited to, (CH 3 ) 2 CuLi, (n-C 4 H 9 ) 2 CuLi, CH 3 MgBr-CuCl, CH 3 MgCl-CuBr, CH 3 MgBr-CuBr, CH 3 MgBr-CuI, CH 3 MgBr-Cu(OCOCH 3 ), CH 3 MgBr-CuSPh, CH 3 MgBr-CuCN, CH 3 MgI- CuBr, CH 3 MgI-CuCN, CH 3 Li-CuBr, C 2 H 5 MgBr-CuBr, PhMgl-CuSPh, PhCH 2 MgCl-CuI, (CH 3 ) 2 Zn, (CH 3 ) 3 A1, (CH 3 ) 4 Sn, CH 3 ONa, (CH 3 ) 2 CHONa, CH 3 SNa, C 2 H 5 SNa, (C 2 H 5 ) 2 NNa, or [PhCH 2 ] 2 NLi.
  • the asymmetric Michael reaction is performed when one of R and R 1 is chiral.
  • chiral ligand and metal salt are also used as additives to produce the optically active compound of formula (I).
  • the metal salt include, but not limited to, CuCl, CuBr, Cul, Cu(OCOCH 3 ), Cu(OCOCF 3 ), Cu(OCOCF 3 ) 2 , CuSPh, CuCN, and copper(I) thiophene-2-carboxylate.
  • the chiral ligands belong to several structural categories.
  • chiral ligand examples include, but not limited to, ephedrine-based ligand, sparteine, oxazolino-based ligand, ferrocene-based ligand, 2,2'-bis(diphenylphosphanyl)-l, -binaphthyl (BINAP), BINAP- based ligands, binaphthol-based ligand, amino acid-based ligand, tartaric acid-based ligand, 1,2- diamine-based ligand, camphor-based ligand, saccharide-based ligand, peptide-based ligand, or iV-heterocyclic carbene (1,3-disubstituted imidazoles). See, for example, (1) Lopez, F. et al.
  • the compound of formula (C) is generated from a compound of formula (B) by oxidation in the presence of an alcohol compound (ROH):
  • Examples of the oxidizing agent for generating compound (C) from compound (B) include, but not limited to, 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ), potassium hexacyanoferrate(III), hypervalent iodine reagents [e.g. iodobenzene diacetate C 6 H 5 I(0 2 CCH 3 ) 2 , or iodobenzene di(trifluoroacetate) C 6 H 5 I(0 2 CCF 3 ) 2 )].
  • DDQ 2,3-dichloro-5,6-dicyano-l,4-benzoquinone
  • K hexacyanoferrate(III) potassium hexacyanoferrate(III)
  • hypervalent iodine reagents e.g. iodobenzene diacetate C 6 H 5 I(0 2 CCH 3 ) 2 , or iodobenzen
  • the compound of formula (B) is generated from a compound of formula (A) by Baeyer-Villiger oxidation:
  • Examples of the oxidizing agent for generating compound (B) from compound (A) include, but not limited to, peroxy acids (e.g. m-ClC 6 H 4 C0 3 H), hydrogen peroxide (e.g. H 2 0 2 - H 2 S0 4 ), or tert-butyl hydroperoxide (e.g. t-BuOOH-V 2 0 5 ).
  • peroxy acids e.g. m-ClC 6 H 4 C0 3 H
  • hydrogen peroxide e.g. H 2 0 2 - H 2 S0 4
  • tert-butyl hydroperoxide e.g. t-BuOOH-V 2 0 5
  • the present invention provides a method of synthesizing the compound of formula (V).
  • the method of the invention comprises alkylation or acylation of the compound (IV):
  • the compound of formula (II) can be the compound of formula (Il-a):
  • the present invention provides a method of synthesizing the compound (VI):
  • the method comprises the reduction of the compound of formula (II-a) under suitable conditions to form a compound of formula (VI) in one or more steps.
  • the present invention provides a method of synthesizing the compound of formula (VII).
  • the method of the invention comprises alkylation or acylation of the compound (VI):
  • the C-5 and C-6 substituents R 5 and R 6 in the compound (IV) exist in the cis disposition; epimerization at C-6 is conducted by the catalysis of a base to give the 5,6-trans isomer.
  • the present invention provides a method of synthesizing a racemic mixture of ( ⁇ )-antroquinonol (compound 1).
  • Figure 2 is an exemplary synthetic route for making a racemic mixture of ( ⁇ )-antroquinonol (compound 1).
  • the present invention provides a method of synthesizing (4/?,5/?,6/?)-(+)-antroquinonol D (compound 4).
  • Figure 3 is an exemplary synthetic route for making (4/?,5/?,6/?)-(+)-antroquinonol D.
  • the present invention provides a method of the invention for synthesizing (4/?,5/?,6/?)-(+)-antroquinonol (compound 1).
  • Figure 4 is an exemplary synthetic route for making (4/?,5/?,6/?)-(+)-antroquinonol.
  • Compounds in the present invention are tested for their anticancer activities against H1975 gefinitib-resistant non-small lung cancer cells and MDA-MB-231 triple negative breast cancer cells.
  • Some compounds of formulae (IV) and (VI) include, but not limited to,
  • antroquinonol (1) and its stereoisomers antroquinonol D (4) and its stereoisomers, 3-chloro-6- farnesyl-4-hydroxy-2-methoxy-5-methylcyclohex-2-en-l-one and its stereoisomers, as well as 5- farnesyl-6-hydroxy-2,3-dimethoxy-4-methylcyclohex-2-en-l-one and its stereoisomers showing the IC 5 o values in micromolar or submicromolar range.
  • alkyl refers to a saturated aliphatic hydrocarbon radical including straight chain and branched chain groups of 1 to 20 carbon atoms unless otherwise stated.
  • a lower alkyl refers to that having 1 to 4 carbon atoms e.g., methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, or tert-butyl, and the like.
  • the alkyl group may be substituted or unsubstituted.
  • the substituent group(s) is preferably one or more selected from the group consisting of halo, hydroxy, unsubstituted lower alkoxy, aryl optionally substituted with one or more groups, alkoxy groups, aryloxy optionally substituted with one or more groups, 6-member heteroaryl having from 1 to 3 nitrogen atoms in the ring, the carbons in the ring being optionally substituted with one or more groups, 5-member heteroaryl having from 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, the carbon and the nitrogen atoms in the group being optionally substituted with one or more groups, which are independently of each other halo, hydroxy, unsubstituted lower alkyl or unsubstituted lower alkoxy groups, 5- or 6-member heterocyclic group having from 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, the carbon and nitrogen (if present) atoms in the group being optionally substituted with one or more groups, which are independently of each other
  • substitution refers to a compound having a substituent comprising at least one carbon, nitrogen, oxygen, or sulfur atom that is bonded to one or more hydrogen atoms. If a substituent is described as being “substituted,” a non-hydrogen substituent is in the place of a hydrogen on a carbon, nitrogen, oxygen, or sulfur of the substituent. Thus, for example, a substituted alkyl substituent is an alkyl substituent wherein at least one non-hydrogen substituent is in the place of a hydrogen on the alkyl substituent.
  • monofluoroalkyl is alkyl substituted with a fluorine
  • difluoroalkyl is alkyl substituted with two fluorines. It should be recognized that if there are more than one substitutions on a substituent, each non- hydrogen substituent may be identical or different (unless otherwise stated).
  • a substituent is described as being “optionally substituted", the substituent is either (1) substituted, or (2) not substituted.
  • any atom capable of substitution in each member of such group may be (1) substituted, or (2) not substituted.
  • Atoms capable of substitution include, for example, carbon bonded to at least one hydrogen, oxygen bonded to at least one hydrogen, sulfur bonded to at least one hydrogen, or nitrogen bonded to at least one hydrogen.
  • halogen refers to a fluorine substituent (-F), chlorine substituent (-C1), bromine substituent (-Br), or iodine substituent (-1).
  • hydroxy refers to an -OH group.
  • alkoxy refers to both an -0-(unsubstituted alkyl) and an -O- (unsubstituted cycloalkyl) group.
  • Representative examples include, but are not limited to, e.g., methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,
  • amino refers to an -NH 2 , an -N-alkyl and an -N-dialkyl group. Representative examples include, but are not limited to, e.g., methylamino, ethylamino, propylamino, butylamino, cyclopropylamino, dimethylamino, diethylamino, diisopropylamino, and the like.
  • cycloalkyl refers to a 3 to 8 member all-carbon monocyclic ring, an all-carbon 5-member/6-member or 6-member/6-member fused bicyclic ring or a multicyclic fused ring (a "fused" ring system means that each ring in the system shares an adjacent pair of carbon atoms with each other ring in the system) group wherein one or more of the rings may contain one or more double bonds but none of the rings has a completely conjugated pi-electron system.
  • Examples, without limitation, of cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexadiene, adamantane, cycloheptane, cycloheptatriene, and the like.
  • a cycloalkyl group may be substituted or unsubstituted. When substituted, the substituent groups are defined above.
  • alkenyl refers to an alkyl group consisting of at least two carbon atoms and at least one carbon-carbon double bond. Representative examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like.
  • alkynyl refers to an alkyl group consisting of at least two carbon atoms and at least one carbon-carbon triple bond. Representative examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like.
  • aryl refers to an all-carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups of 1 to 14 carbon atoms having a completely conjugated pi-electron system. Examples, without limitation, of aryl groups are phenyl, naphthalenyl and anthracenyl. The aryl group may be substituted or unsubstituted. When substituted, the substituent groups are defined above.
  • aryloxy refers to both an -O-aryl and an -O-heteroaryl group, as defined herein. Representative examples include, but are not limited to, phenoxy, pyridinyloxy, furanyloxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy, and the like, and derivatives thereof.
  • heteroaryl refers to a monocyclic or fused ring (i.e., rings which share an adjacent pair of atoms) group of 5 to 14 ring atoms containing one, two, or three ring heteroatoms selected from N, O, or S, the remaining ring atoms being C, and, in addition, having a completely conjugated pi-electron system. Examples, without limitation, of
  • unsubstituted heteroaryl groups are pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline, purine and carbazole.
  • the heteroaryl group may be substituted or unsubstituted. When substituted, the substituent groups are defined above.
  • heterocyclyl refers to a monocyclic or fused ring group having in the ring(s) of 5 to 9 ring atoms in which one or two ring atoms are heteroatoms selected from N, O, S, SO or S0 2 , the remaining ring atoms being C.
  • the rings may also have one or more double bonds. However, the rings do not have a completely conjugated pi-electron system. Examples, without limitation, of unsubstituted heterocyclic groups are pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, homopiperazino, and the like.
  • the heterocyclic ring may be substituted or unsubstituted. When substituted, the substituent groups are defined above.
  • Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl,
  • heteroaryl refers to an aromatic heterocyclyl typically containing from 5 to 14 ring atoms.
  • a heteroaryl may be a single ring or multiple (typically 2 or 3) fused rings.
  • Such moieties include, for example, 5-membered rings such as furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiodiazolyl, oxadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxathiazolyl, and oxatriazolyl; 6-membered rings such as pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and oxathiazinyl; 7-membered rings such as oxepinyl and thiepinyl; 6/5-membered fused-ring systems such as benzofuranyl, isobenzofuranyl, benzoxazolyl, benzoisoxazolyl, anthranilyl, benzothienyl, isobenz
  • the 5-membered rings include furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, pyrazolyl, and imidazolyl;
  • the 6-membered rings include pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl;
  • the 6/5-membered fused- ring systems include benzoxazolyl, benzoisoxazolyl, anthranilyl, benzothienyl, isobenzothienyl, and purinyl; and the 6/6-membered fused-ring systems include quinolinyl, isoquinolinyl, and benzodiazinyl.
  • Distortionless enhancement polarization transfer (DEPT) spectra were taken to determine the types of carbon signals.
  • the ESI-MS experiments were conducted on a Bruker Daltonics BioTOF III high-resolution mass spectrometer.
  • the MALDI-MS measurements were performed on a Bruker Daltonics Ultraflez II MALDI-TOF/TOF 2000 mass spectrometer.
  • DHB 2,5-dihydroxybenzoic acid
  • Chiral Iigand was used to induce the asymmetric Michael reaction.
  • An example of chiral Iigand is binaphthol-derived chiral Iigand, (1 lb5)-N ⁇ -bis((/?)-l-phenylethyl)dinaphtho[2,l-c/:l',2'- /][l,3,2]dioxaphosphepin-4-amine. [Imbos, R.; et al. Org. Lett. 1999, 1, 623.] Under an atmosphere of argon, a solution of a metal salt (0.024 mmol) and an (5)-chiral Iigand (0.048 mmol) was stirred at room temperature for 1 h.
  • Example 9 Asymmetric Michael reaction of formula (C) to formula (I) Synthesis of (5)-3,4,4-trimethoxy-5-methylcyclohex-2-en-l-one Under an atmosphere of argon, a solution of a metal salt (0.024 mmol) and a K)-chiral ligand (0.048 mmol) was stirred at room temperature for 1 h. The colorless solution was cooled, and a solution of 3,4,4-trimethoxycyclohexa-2,5-dien-l-one (88 mg, 0.48 mmol) and a methylmetal reagent (2.4 mmol) was added.
  • Example 14 Asymmetric Michael reaction of formula (C) to formula (I) Synthesis of (5)-2,3,4,4-tetramethoxy-5-methylcyclohex-2-en-l-one
  • a solution of 2,3,4,4-tetramethoxycyclohexa-2,5-dien-l-one (100 mg, 0.48 mmol) and a methylmetal reagent (2.4 mmol) was treated with a metal salt (0.024 mmol) and a K)-chiral ligand (0.048 mmol) for 12 h to give (5)-2,3,4,4-tetramethoxy-5-methylcyclohex-2-en-l-one.
  • the methansulfonate of (l/?)-(-)-myrtenol was prepared and reacted with 4-hydroxy-3- methoxybenzaldehyde, followed by Baeyer-Villiger oxidation to give 3-methoxy-4- (myrtenyloxy)phenol.
  • 3-methoxy-4-(myrtenyloxy)phenol was oxidized with PIFA in anhydrous MeOH to give 3,4-dimethoxy-4-(myrtenyloxy) cyclohexa-2,5-dien-l-one.
  • Example 22 Alkylation reaction of formula (I) to formula (II) Synthesis of (5/?,6/?/S)-6-allyl-4,4-dimethoxy-5-methylcyclohex-2-en-l-one Under an atmosphere of nitrogen, LDA (5.88 mmol, 3.0 mL of 2.0 M solution in THF/n- heptane/ethylbenzene) was added to a solution of (5/?)-4,4-dimethoxy-5-methylcyclohex-2-en-l- one (0.5 g, 2.94 mmol) in THF (5.0 mL) at -78 °C.
  • LDA 5.88 mmol, 3.0 mL of 2.0 M solution in THF/n- heptane/ethylbenzene
  • Example 29 Reduction and hydrolysis of formula (II) to formulae (IV) and (VI)
  • translcis 1 :1
  • Li(Ot-Bu) 3 AlH in THF at 0 °C for 5 h followed by hydrolysis with oxalic acid, gave 5-farnesyl-4-hydroxy-2,3-dimethoxy-6-methylcyclohex-2-en-l-one (containing stereoisomers, 26% yield) and 5-farnesyl-6-hydroxy-2,3-dimethoxy-4-methylcyclohex-2-en-l- one (containing stereoisomers, 64% yield).
  • the 4,5-cis-5,6-cis compound (4/?,5/?,6/S)-3-chloro-5-farnesyl-4-hydroxy-2-methoxy-6/S'- methylcyclohex-2-en-l-one (40 mg, 0.1 mmol) was dissolved in MeOH (2.0 mL), and K 2 C0 3 (41 mg, 0.3 mmol) was added. The mixture was stirred at room temperature for 12 h, quenched with saturated aqueous NH 4 C1 (5.0 mL), and then extracted with CH 2 C1 2 (3 x 20 mL). The organic phase was washed with brine (30 mL), dried over MgS0 4 , and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with elution of EtOAc/CH 2 Cl 2 (2:98) to give (+)-antroquinonol in the 4,5-cis-5,6-trans configuration.
  • HI 975 gefinitib-resistant non-small lung cancer cells or MDA-MB-231 triple negative breast cancer cells were seeded in 96-well plate for 24 h. Then, the test compound was dosed into the well in triplicate for 72 h incubation. Finally, cell viability was measured using the CellTiter 96 ® AQueous Non-Radioactive Cell Proliferation Assay reagent (Promega Corporation, Madison, WI, USA) according to the manufacturer's instructions. The absorbance was measured using
  • Inhibitor IC 50 values i.e. the concentrations of the compound required for 50% cell viability were determined from dose-response curves by plotting the percent inhibition of cell viability versus inhibitor concentrations using Prism 5 (GraphPad Software, Inc., San Diego, CA, USA).
  • camphorata and its bioactive compounds evidence-Based Complem. Alt. Med. 2011, art. no. 212641.
  • Antroquinonol inhibits NSCLC proliferation by altering PI3K/mTOR proteins and miRNA expression profiles. Mutat. Res., 2011, 707, 42-52.

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Abstract

La présente invention concerne une nouvelle voie de synthèse des composés 4-oxy-2-cyclohexénone et 6-oxy-2-cyclohexénone utiles pour le traitement de cancers et/ou de maladies, et leurs intermédiaires. Des exemples de ces composés cyclohexénone comprennent, mais non exclusivement, des substances médicinales actives provenant de A. cinnamomea telles que l'antroquinonol, l'antroquinonol B, l'antroquinonol C, et l'antroquinonol D. Lesdits intermédiaires comprennent les composés de formules (I), (II) et (III), et lesdits composés cyclohexénone ont les structures de formules (IV), (V), (VI) et (VII).
PCT/US2015/040530 2014-07-17 2015-07-15 Compositions et procédés pour la préparation de composés 4-oxy-2-cyclohexénone et 6-oxy-2-cyclohexénone Ceased WO2016011130A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160237012A1 (en) * 2015-02-17 2016-08-18 Golden Biotechnology Corporation Anticancer agents and process of making thereof
WO2018094122A1 (fr) * 2016-11-18 2018-05-24 Golden Biotechnology Corporation Procédés et compositions pour le traitement de la dermatite atopique
CN111018686A (zh) * 2019-11-19 2020-04-17 南通大学 6-苄亚基-2-芳基乙炔基环己烯酮衍生物及其制备方法和医药用途

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4057851A (en) * 1974-06-12 1977-11-08 Wisconsin Alumni Research Foundation Chiral 2-substituted-4-hydroxy-2-cyclopenten-1-one
US4837352A (en) * 1986-06-09 1989-06-06 Stauffer Chemical Company 3-chloro-2-(2'-substituted benzoyl)-cyclohex-2-enone intermediate compounds
US20060088904A1 (en) * 2004-10-01 2006-04-27 Lockwood Samuel F Methods for the synthesis of astaxanthin
US20120071426A1 (en) * 2010-09-20 2012-03-22 Golden Biotechnology Corporation Methods and compositions for treating lung cancer
US20120178623A1 (en) * 2009-07-16 2012-07-12 Syngenta Crop Protection Llc Novel herbicides

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4057851A (en) * 1974-06-12 1977-11-08 Wisconsin Alumni Research Foundation Chiral 2-substituted-4-hydroxy-2-cyclopenten-1-one
US4837352A (en) * 1986-06-09 1989-06-06 Stauffer Chemical Company 3-chloro-2-(2'-substituted benzoyl)-cyclohex-2-enone intermediate compounds
US20060088904A1 (en) * 2004-10-01 2006-04-27 Lockwood Samuel F Methods for the synthesis of astaxanthin
US20120178623A1 (en) * 2009-07-16 2012-07-12 Syngenta Crop Protection Llc Novel herbicides
US20120071426A1 (en) * 2010-09-20 2012-03-22 Golden Biotechnology Corporation Methods and compositions for treating lung cancer

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
BLANCHARD ET AL.: "5-Methyl-2-Cyclohexenone", J. AM. CHEM. SOC., vol. 73, no. 12, 1951, pages 5863 - 5864 *
CORMA ET AL.: "One-pot synthesis of phenols from aromatic aldehydes by Baeyer-Villiger oxidation with H202 using water-tolerant Lewis acids in molecular sieve", JOURNAL OF CATALYSIS, vol. 221, 2004, pages 67 - 76, XP004474935, DOI: doi:10.1016/S0021-9517(03)00291-4 *
DATABASE PUBCHEM 14 January 2008 (2008-01-14), Database accession no. 23642504 *
DATABASE PUBCHEM 23 October 2008 (2008-10-23), Database accession no. 24978363 *
MENDELSOHN ET AL.: "Approach to Tetrodotoxin via the Oxidative Amidation of a Phenol", ORGANIC LETTERS, vol. 11, 2009, pages 4736 - 4739 *
WIPF ET AL.: "Pi- Facial Selectivity in Nucleophilic Additions to 4,4-Disubstituted Dienones: Experimental Support for Electrostatic Control", J.AM.CHEM.SOC, vol. 116, 1994, pages 11678 - 11688 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160237012A1 (en) * 2015-02-17 2016-08-18 Golden Biotechnology Corporation Anticancer agents and process of making thereof
WO2018094122A1 (fr) * 2016-11-18 2018-05-24 Golden Biotechnology Corporation Procédés et compositions pour le traitement de la dermatite atopique
CN110088073A (zh) * 2016-11-18 2019-08-02 国鼎生物科技股份有限公司 用于治疗特应性皮炎的方法和组合物
US11364209B2 (en) 2016-11-18 2022-06-21 Golden Biotechnology Corporation Methods and compositions for treating atopic dermatitis
CN110088073B (zh) * 2016-11-18 2023-01-10 国鼎生物科技股份有限公司 用于治疗特应性皮炎的方法和组合物
CN111018686A (zh) * 2019-11-19 2020-04-17 南通大学 6-苄亚基-2-芳基乙炔基环己烯酮衍生物及其制备方法和医药用途
CN111018686B (zh) * 2019-11-19 2020-09-22 南通大学 6-苄亚基-2-芳基乙炔基环己烯酮衍生物及其制备方法和医药用途

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