WO2016011130A1

WO2016011130A1 - Compositions and methods for the preparation of 4-oxy-2-cyclohexenone and 6-oxy-2-cyclohexenone compounds

Info

Publication number: WO2016011130A1
Application number: PCT/US2015/040530
Authority: WO
Inventors: Jim-Min Fang; Che-Sheng HSU
Original assignee: National Taiwan University; WO, Andrew, Man Chung
Priority date: 2014-07-17
Filing date: 2015-07-15
Publication date: 2016-01-21
Also published as: TW201619112A

Abstract

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. Examples of these cyclohexenone compounds include, but not limited to, A. cinnamomea active medicinal substances such as antroquinonol, antroquinonol B, antroquinonol C, and antroquinonol D. 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).

Description

COMPOSITIONS AND METHODS FOR THE PREPARATION OF 4-OXY-2- CYCLOHEXENONE AND 6-OXY-2-CYCLOHEXENONE COMPOUNDS

RELATED APPLICATION

[0001] The present application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 62/025,508, filed July 17, 2014, which is herein incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

[0002] Unlike ubiquinones, compounds having the skeletons of 4-oxy-2-cyclohexenone or 6- oxy-2-cyclohexenone are rare. A natural product, antroquinonol (1), was isolated from the cultured mycelia of a Taiwanese medicinal mushroom, Antrodia cinnamomea, and found to have the structure of 4-hydroxy-5-farnesyl-6-methyl-2,3-dimethoxycyclohex-2-en-l-one. [Lee T.-H.; et al. Planta Med. 2007, 73, 1412. Ao, Z.-H.; et al. J. Ethnopharmacol. 2009, 121, 194.

Geethangili, M. & Tzeng Y.-M. Evidence-Based Complem. Alt. Med. 2011, art. no. 212641.] 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. [Liu, S.-Y.; et al. US patent 2008/0119565 Al. Lin, Y.-W.; et al. J. Sci. FoodAgric. 2010, 90, 1739. Yang, S.-S.; et al. Planta Med. 2009, 75, 512. Wang, S.-C; et al, J. Agric. Food Chem. 2014, 62, 5625.]

[0003] These natural products isolated from A. cinnamomea showed various biological activities, for example, acting as inflammatory agents, antioxidants and free-radical scavengers. These natural products are also applicable to prevention of hepatotoxicity and potentially used in treatment of cancer, male infertility, Parkinsonism and cardiovascular diseases. A function of antroquinonol is to block Ras and Rho processing via inhibition of isoprenyltransferases to cause associated cell death. [Ho, C.-L.; et al. Biomed Pharmacother. 2014, 68, 1007.] This anticancer agent is currently under clinical evaluation in patients with non-small cell lung cancer. [V. B. Kumar, et al. Mutat. Res., 2011, 707, 42.] A. cinnamomea active medicinal substances are only obtained in small quantities by isolation from natural sources or the culture media of A.

cinnamomea. Thus, there is a need for an alternative method to obtain these natural products in substantial quantity. [Sulake, R. S.; et al. J. Org. Chem. 2014, 79, 10820. Sulake, R. S. & Chen, C. Org. Lett. 2015, 17, 1138. Hsu, C.-S.; et al. Org. Biomol. Chem. 2015, 13, 5510.]

SUMMARY OF THE INVENTION

[0004] The present invention relates to methods for the chemical synthesis of A. cinnamomea active medicinal substances and intermediate compounds thereto. Examples of 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 .

[0005] In one aspect, the present invention provides a compound of formula (C):

(C) or a salt thereof,

1 2 3

wherein R, R , R and R are as described herein. In certain embodiments, 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.

[0006] In another aspect, the present invention provides a compound of formula (I):

(I) or a salt thereof,

1 2 3 6

wherein R, R , R , R and R are as described herein. In certain embodiments, 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.

[0007] In another aspect, the present invention provides a compound of formula (II):

(II) or a salt thereof,

1 2 3 5 6

wherein R, R , R , R , R and R are as described herein. In certain embodiments, 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.

[0008] In another aspect, the present invention involves an intermediate of formula (III):

(III) or a salt thereof, wherein R, R 1 , R 2 , R 3 , R 5 and R 6 are as described herein. In certain embodiments, an

intermediate of formula (III) can be used in the synthesis of cyclohexenone compounds (A. cinnamomea active medicinal substances) useful for treatment of cancers and/or diseases.

[0009] In another aspect, the present invention provides a compound of formula (IV):

(IV) or a salt thereof, wherein R , R , R and R are as described herein. [0010] In another aspect, the present invention provides a compound of formula (V):

(V) or a salt thereof, wherein R², R³, R⁴, R⁵ and R⁶ are as described herein.

[0011] In another aspect, the present invention provides a compound of formula (VI):

(VI) or a salt thereof,

2 5 6

wherein R , R and R are as described herein.

[0012] In another aspect, the present invention provides a compound of formula (VII):

(VII) or a salt thereof, wherein R², R⁴, R⁵ and R⁶ are as described herein.

[0013] In certain embodiments, a compound of formulae (IV) or (V) is an A. cinnamomea active medicinal substance for treatment of cancers and/or diseases.

[0014] In certain embodiments, the compound of formula (IV) is antroquinonol (compound 1).

[0015] In certain embodiments, the compound of formula (IV) is antroquinonol B (compound

2) ·

[0016] In certain embodiments, the compound of formula (IV) is antroquinonol C (compound

3) .

[0017] In certain embodiments, the compound of formula (IV) is antroquinonol D (compound

4) · [0018] In certain embodiments, the compound of formula (IV) is compound 5 having a lactone moiety at the aliphatic chain.

[0019] In certain embodiments, the compound of formula (V) is compound 6.

[0020] In another aspect, the present invention provides a method for synthesizing a compound of formula (IV).

(IV) or a salt thereof, the method comprising: converting a compound of formula (II) under suitable conditions to form a compound of formula

(IV).

[0021] In certain embodiments, the converting comprises the formation of an intermediate having the formula (III).

[0022] In certain embodiments, the formation of the intermediate (III) takes place in the presence of a reducing agent.

[0023] In certain embodiments, the converting of (II) to (IV) takes place in the presence of a reducing agent followed by hydrolysis.

[0024] In certain embodiments, the hydrolysis takes place in acidic conditions.

[0025] In certain embodiments, the compound of formula (II) is prepared by treating a compound of formula (I) with an electrophilic reagent in basic conditions.

[0026] In certain embodiments, the compound of formula (I) is prepared by treating a compound of formula (C) with a nucleophilic reagent under suitable conditions.

[0027] In certain embodiments, the nucleophilic reagent is an organometallic reagent, a metal alkoxide, a metal thiolate, or a metal amide.

[0028] In certain embodiments, the compound of formula (C) is generated from a compound of formula (B):

by oxidation in the presence of an alcohol compound (ROH).

[0029] In certain embodiments, the compound of formula (B) is generated from a compound of formula (A):

by Baeyer-Villiger oxidation.

[0030] In another aspect, the present invention provides a method for synthesizing a compound of formula (V). the method comprising:

converting a compound of formula (IV) under suitable conditions to form a compound of formula (V).

[0031] In certain embodiments, the converting of (IV) to (V) takes place in the presence of an alkylating or acylating agent.

[0032] In another aspect, the present invention provides a method for synthesizing a compound of formula (VI). the method comprising:

converting a compound of formula (II- a :

under suitable conditions to form a compound of formula (VI). [0033] In certain embodiments, the converting of (Il-a) to (VI) takes place in the presence of a reducing agent followed by hydrolysis.

[0034] In certain embodiments, the hydrolysis takes place in acidic conditions.

[0035] In another aspect, the present invention provides a method for synthesizing a compound of formula (VII):

the method comprising:

converting a compound of formula (VI) to form a compound of formula (VII) by alkylation or acylation.

[0036] Also within the scope of this disclosure are the compounds synthesized according to the method of the invention.

[0037] The details of one or more embodiments of the invention are set forth in the description below. Other features or advantages of the present invention will be apparent from the following drawings and detailed description of several embodiments, and also from the appending claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0038] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present disclosure, the inventions of which can be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

[0039] Figure 1. General method for the synthesis of compounds (IV), (V), (VI) and (VII) via key intermediates (I), (II) and (III).

[0040] Figure 2. Synthesis of (±)-antroquinonol (compound 1 as a racemic mixture).

[0041] Figure 3. Synthesis of (4/?,5/?,6/?)-(+)-antroquinonol D (compound 3 in the optically active form).

[0042] Figure 4. Synthesis of (4/?,5/?,6/?)-(+)-antroquinonol (compound 1 in the optically active form). DEFINITIONS

[0043] Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^th Ed., inside cover, and specific functional groups are generally defined as described therein.

Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March 's Advanced Organic Chemistry, 5^th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3^rd Edition, Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference.

[0044] 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.

[0045] 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.

[0046] If, for instance, a particular enantiomer of a compound of the present invention is desired, it 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. Alternatively, where 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. [0047] Where an isomer/enantiomer is preferred, it 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. In certain embodiments 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. See, for example, 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).

[0048] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, 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 (C₂ alkyl), 3 (C₃ alkyl), 4 (C₄ alkyl), 5 (C₅ alkyl) and 6 (C₆ 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 (C₂_₆ alkyl), 2 to 5 (C₂_₅ alkyl), 2 to 4 (C₂^ alkyl), 2 to 3 (C₂_₃ alkyl), 3 to 6 (C₃_₆ alkyl), 3 to 5 (C₃_₅ alkyl), 3 to 4 (C₃^ alkyl), 4 to 6 (C₄-₆ alkyl), 4 to 5 (C4_₅ alkyl), and 5 to 6 (C₅_0 alkyl) carbons.

[0049] The term "aliphatic," as used herein, 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). Thus, as used herein, the term "aliphatic" encompasses the groups "alkyl", "alkenyl", and "alkynyl" as defined herein. In certain embodiments, aliphatic refers to a C₂-C₃₀ aliphatic group. In certain embodiments, aliphatic refers to a C₅-C₂₅ aliphatic group. In certain embodiments, aliphatic refers to a Cr-C_to aliphatic group. In certain embodiments, aliphatic refers to a C₁₀-C₂o aliphatic group. In certain embodiments, aliphatic refers to a Cn-C₁₅ 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.

[0050] As used herein, the term "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. In some cases, 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). In some embodiments, a straight-chain or branched-chain alkyl may have 30 or fewer carbon atoms in its backbone, and, in some cases, 20 or fewer. In some

embodiments, a straight-chain or branched-chain alkyl may have 12 or fewer carbon atoms in its backbone (e.g., Ci-Cn for straight chain, C₃-C₁₂ for branched chain), 6 or fewer, or 4 or fewer. Likewise, cycloalkyls may have from 3-10 carbon atoms in their ring structure, or 5, 6 or 7 carbons in the ring structure. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, t-butyl, cyclobutyl, hexyl, and cyclochexyl.

[0051] The term "alkylene" as used herein refers to a bivalent alkyl group. An "alkylene" group is a polymethylene group, i.e., -(CH₂)_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.

[0052] The terms "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.

[0053] In certain embodiments, 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. In yet other embodiments, 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.

[0054] Some examples of 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; -N0₂; -CN; -CF₃; -CHF₂; -CH₂F; - CH₂CF₃; -CHC1₂; -CH₂OH; -CH₂CH₂OH; -CH₂NH₂; -CH₂S0₂CH₃; -C(0)R_x; -C0₂(R_x); - CON(R_x)₂; -OC(0)R_x; -OC0₂R_x; -OCON(R_x)₂; -N(R_X)₂; -S(0)₂R_x; -NR_x(CO)R_x wherein each occurrence of R_x independently includes, but is not limited to, aliphatic, alycyclic,

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

unsubstituted. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.

[0055] The term "aryl" is given its ordinary meaning in the art and refers to aromatic

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. In some cases, 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.

[0056] The term "alkoxy" (or "alkyloxy"), or "thioalkyl" as used herein refers to an alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom or through a sulfur atom. In certain embodiments, the alkyl group contains 1-20 aliphatic carbon atoms. In certain other embodiments, the alkyl group contains 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 group contains 1-6 aliphatic carbon atoms. In yet other embodiments, the alkyl group contains 1-4 aliphatic carbon atoms. Examples of alkoxy, include but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n- butoxy, t-butoxy, neopentoxy and n-hexoxy. Examples of thioalkyl include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and the like.

[0057] The term "imidoyl" as used herein refers to a group of formula -C(=NR*)R*, wherein each occurrence of R^* is optionally substituted alkyl, aryl, or heteroaryl.

[0058] In some embodiments, 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 "unsubstituted" heteroalkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl, or "substituted" or

"unsubstituted" heteroaryl group). In general, the term "substituted" 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. Unless otherwise indicated, 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.

[0059] Exemplary monovalent carbon atoms substituents include, but are not limited to, halo/halogen (i.e., -F, -Br, -CI, -I), -NC, -CN, -N0₂, -N₃, -C0₂H, -CHO, -S0₂H, -S0₃H, - S(=0)OH, acyl (e.g., -C(=0)R^A, -C0₂R^A, -C(=0)-0-C(=0)R^A, -C(=0)SR^A, -C(=0)N(R^B)₂, - C(=0)NR^BS0₂R^A,— C(=NR^B)R^A, -C(=NR^B)OR^A, -C(=NR^B)N(R^B)₂, -C(=S)R^A, - C(=S)N(R^A)₂, -C(=S)SR^A), amino (e.g., -NH₂,— N(OR^B)R^B, -N(R^B)₂,— NR^BS0₂R^A, - NR^BC(=0)R^A, -NR^BC0₂R^A, -NR^BC(=0)N(R^B)₂,— NR^BC(=NR^B)N(R^B)₂), thio (e.g., -SH, - SR^A, -SSR^B), oxy (e.g., -OH, -OR^A, -ON(R^B)₂, -OS0₂R^A, -OS(=0)R^A, -OC(=0)R^A, - OC0₂R^A, -OC(=0)N(R^B)₂, -OC(=NR^B)R^A, -OC(=NR^B)OR^A, -OC(=NR^B)N(R^B)₂), sulfonyl (e.g., -S0₂R^A, -S0₂OR^A, -S0₂N(R^B)₂), sulfinyl (e.g., -S(=0)R^A), silyl (e.g. , -Si(R^A)₃), C,.₁₀ alkyl, ^_₁₀ fluoroalkyl, C₂_₁₀ alkenyl, C₂_₁₀ alkynyl, C₃_₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆_₁₄ aryl, and 5-14 membered heteroaryl, wherein each aliphatic, heteroaliphatic, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^D groups; each instance of R^A is, independently, selected from the group consisting of C_\-_\ alkyl, Ci-_!o fluoroalkyl, C₂_₁₀ alkenyl, C₂_₁₀ alkynyl, C₃_₁₀ carbocyclyl, 3-14 membered heterocyclyl, C -u aryl, and 5-14 membered heteroaryl, wherein each aliphatic, heteroaliphatic, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^D groups; each instance of R^B is, independently, selected from the group consisting of hydrogen, - OH, -OR^A, -N(R^C)₂, -CN, -C(=0)R^A, -C(=0)N(R^c)₂, -C0₂R^A, -S0₂R^A, -C(=NR^c)OR^A, - C(=NR^C)N(R^C)₂, -S0₂N(R^c)₂, -S0₂R^c, -S0₂OR^c, -SOR^A, -C(=S)N(R^C)₂, -C(=0)SR^c, - C(=S)SR , Ci-io alkyl, Ci-w fluoroalkyl, C₂_₁₀ alkenyl, C₂_₁₀ alkynyl, C₃_₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆_₁₄ aryl, and 5-14 membered heteroaryl, or two R^B 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;

each instance of R is, independently, selected from the group consisting of hydrogen, Ci-_!o alkyl, ^_₁₀ fluoroalkyl, C₂_₁₀ alkenyl, C₂_₁₀ alkynyl, C₃_₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆_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

each instance of R^D is, independently, halogen, -CN, -N0₂, -N₃, -S0₂H, -S0₃H, - OH, -Od_₆ alkyl, -ON(d_₆ alkyl)₂, -N(d_₆ alkyl)₂, -N(Od_₆ alkyl)(d_₆ alkyl), -N(OH)(d_ 6 alkyl), -NH(OH), -SH, -Sd_₆ alkyl, -SS(d_₆ alkyl), -C(=0)(d_₆ alkyl), -C0₂H, -C0₂(d_₆ alkyl), -OC(=0)(d_₆ alkyl), -OC0₂(d_₆ alkyl), -C(=0)NH₂, -C(=0)N(d_₆ alkyl)₂, - OC(=0)NH(d_₆ alkyl), -NHC(=0)(d^ alkyl), -N(Ci_6 alkyl)C(=0)(d^ alkyl), -NHC0₂(d_₆ alkyl), -NHC(=0)N(d_₆ alkyl)₂, -NHC(=0)NH(d_₆ alkyl), -NHC(=0)NH₂, -C(=NH)0(d^ alkyl), -OC(=NH)(d_₆alkyl), -OC(=NH)Od_₆alkyl, -C(=NH)N(d_₆alkyl)₂, -C(=NH)NH(d^ alkyl), -C(=NH)NH₂, -OC(=NH)N(d^ alkyl)₂, -OC(NH)NH(d_₆ alkyl), -OC(NH)NH₂, - NHC(NH)N(d_₆ alkyl)₂, -NHC(=NH)NH₂, -NHS0₂(d^ alkyl), -S0₂N(d_₆ alkyl)₂, - S0₂NH(d_₆ alkyl), -S0₂NH₂,-S0₂d_₆ alkyl, -S0₂0d_₆ alkyl, -OS0₂d_₆ alkyl, -S(=0)d_₆ alkyl, d_₆ alkyl, d_₆ fluoroalkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₁₀ carbocyclyl, C₆_₁₀ aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal R^D substituents are joined to form =0, =S or =NR^B.

[0060] Exemplary divalent carbon atom substituents include, but are not limited to =0, =S, and =NR^B, wherein R^B is as defined herein.

[0061] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary and quarternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, =NR^B, -CHO, -C(=0)R^A, -C0₂R^A, -C(=0)SR^A, - C(=0)N(R^B)₂, -C(=0)NR^BS0₂R^A,— C(=NR^B)R^A, -C(=NR^B)OR^A, -C(=NR^B)N(R^B)₂, - C(=S)R^A, -C(=S)N(R^A)₂, -C(=S)SR^A, -NH₂,— N(OR^B)R^B, -N(R^B)₂,— NR^BS0₂R^A, - NR^BC(=0)R^A, -NR^BC0₂R^A, -NR^BC(=0)N(R^B)₂, -NR^BC(=NR^B)N(R^B)₂,-OH, -OR^A, -S0₂R^A, - S0₂OR^A, -S0₂N(R^B)₂, -S(=0)R^A), -Si(R^A)₃, d_₁₀ alkyl, d_₁₀ fluoroalkyl, C₂_₁₀ alkenyl, C₂_₁₀ alkynyl, C₃_₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆_₁₄ aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^D groups.

[0062] In certain embodiments, nitrogen atom substituents, as described above, 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.

[0063] 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-haloethyl carbamate, l,l-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), l,l-dimethyl-2,2,2- trichloroethyl carbamate (TCBOC), 1 -methyl- l-(4-biphenylyl)ethyl carbamate (Bpoc), l-(3,5-di- t-butylphenyl)-l-methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC), 1- adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p- methoxybenzyl carbamate (Moz), »-nitobenzyl carbamate, ^-bromobenzyl carbamate, p- chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2- methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(l,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), l,l-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p- (dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6- chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, phenothiazinyl-(10)-carbonyl derivative, AT-p-toluenesulfonylaminocarbonyl derivative, AT-phenylaminothiocarbonyl derivative, t-amyl carbamate, S-benzyl thiocarbamate, />-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, />-decyloxybenzyl carbamate, 2,2-dimethoxycarbonylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, l,l-dimethyl-3-(N,N- dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, >-(p'-methoxyphenylazo)benzyl carbamate, 1- methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1 -methyl- 1-cyclopropylmethyl carbamate, l-methyl-l-(3,5-dimethoxyphenyl)ethyl carbamate, 1 -methyl- l-(p- phenylazophenyl)ethyl carbamate, 1 -methyl- 1-phenylethyl carbamate, 1 -methyl- 1 -(4- pyridyl)ethyl carbamate, phenyl carbamate, />-(phenylazo)benzyl carbamate, 2,4,6-tri-t- butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, 2,4,6-trimethylbenzyl carbamate, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N- benzoylphenylalanyl derivative, benzamide, />-phenylbenzamide, o-nitophenylacetamide, o- nitrophenoxyacetamide, acetoacetamide, (N¹-dithiobenzyloxycarbonylamino)acetamide, 3-(p- hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o- nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivative, o-nitrobenzamide, o-(benzoyloxymethyl)benzamide, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N- dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N- 1,1, 4,4- tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted l,3-dimethyl-l,3,5- triazacyclohexan-2-one, 5-substituted l,3-dibenzyl-l,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(l -isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5- dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4- methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,1- dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino TV- oxide, N-l,l-dimethylthiomethyleneamine, N-benzylideneamine, N- »-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-( V ,Λ - dimethylaminomethylene)amine, N^V-isopropylidenediamine, N-^-nitrobenzylideneamine, N- salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2- hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5 ,5 -dimethyl-3-oxo- 1 - cyclohexenyl)amine, N-borane derivative, N-diphenylborinic acid derivative, N- [phenyl(pentacarbonylchromium- or tungsten)carbonyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp),

dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl 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- methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6- dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9- anthracenesulfonamide, 4-(4 ' , 8 ' -dimethoxynaphthylmethyl)benzenesulfonamide (DNMB S), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

[0064] Exemplary oxygen substituents include, but are not limited to, -C(=0)R^A, -C0₂R^A, - C(=0)-0-C(=0)R^A, -C(=0)SR^A, -C(=0)N(R^B)₂, -C(=0)NR^BS0₂R^A,— C(=NR^B)R^A, - C(=NR^B)OR^A, -C(=NR^B)N(R^B)₂, -C(=S)R^A, -C(=S)N(R^A)₂, -C(=S)SR^A, -S0₂R^A, -S0₂OR^A, - S0₂N(R^B)₂, -S(=0)R^A, -Si(R^A)₃, Ci_io alkyl, Ci_i₀ fluoroalkyl, C₂_₁₀ alkenyl, C₂_₁₀ alkynyl, C₃_₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆_₁₄ aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^D groups.

[0065] In certain embodiments, oxygen atom substituents, as described above, 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.

[0066] Exemplary hydroxyl protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl,

(phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), »- methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1- methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4- methoxytetrahydrothiopyranyl

1 - [(2-chloro-4-methyl)phenyl] -4-methoxypiperidin- 4-yl (CTMP), l,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a- octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1 -ethoxyethyl, 1 -(2-chloroethoxy)ethyl, 1 -methyl- 1 -methoxyethyl, 1 -methyl- 1 -benzyloxyethyl, 1 -methyl- 1 -benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, >-chlorophenyl, »-methoxyphenyl, 2,4-dinitrophenyl, benzyl, >-methoxybenzyl, 3,4-dimethoxybenzyl, o- nitrobenzyl, >-nitrobenzyl, >-halobenzyl, 2,6-dichlorobenzyl, »-cyanobenzyl, »-phenylbenzyl, 2- picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, », »'-dinitrobenzhydryl, 5- dibenzosuberyl, triphenylmethyl, a-naphthyldiphenylmethyl, »-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'- bromophenacyloxyphenyl)diphenylmethyl, 4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4 ' ,4 " -tris(levulinoyloxyphenyl)methyl, 4,4 ' ,4 " -tris(benzoyloxyphenyl)methyl, 3 -(imidazol- 1 - yl)bis(4',4"-dimethoxyphenyl)methyl, l,l-bis(4-methoxyphenyl)-l '-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, l,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS),

dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t- butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), 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

(levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, ?- phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, ^-nitrophenyl carbonate, benzyl carbonate, >-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, ^-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-l-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o- (dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4- (methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4- methylphenoxyacetate, 2,6-dichloro-4-( 1 , 1 ,3 ,3-tetramethylbutyl)phenoxyacetate, 2,4-bis( 1 , 1 - dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2- methyl-2-butenoate, o-(methoxycarbonyl)benzoate, a-naphthoate, N VJfJf- tetramethylphosphorodiamidate, N-phenylcarbamate, dimethylphosphinothioyl, 2,4- dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). For protecting 1,2- or 1,3-diols, 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-tetraisopropyldisiloxanylidene) derivative (TIPDS), tetra-t- butoxydisiloxane-l,3-diylidene derivative (TBDS), cyclic carbonates, cyclic boronates, ethyl boronate, and phenyl boronate.

[0067] In certain embodiments, 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. Other 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, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, ^-toluenesulfonate, undecanoate, valerate salts, and the like. 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.

[0068] The term "leaving group," as used herein, 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,

fluorosulfonate, methyl tosylate, brosylate, nosylate, or -S-tolyl. Non-limiting characteristics and examples of leaving groups can be found, for example in Organic Chemistry, 2d ed., Francis Carey (1992), pages 328-331; Introduction to Organic Chemistry, 2d ed., Andrew John

McMurry (2000), pages 398 and 408; each of which are incorporated herein by reference for the limited purpose of disclosing characteristics and examples of leaving groups.

[0069] 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.

[0070] In certain embodiments, the compound described herein may exist in various tautomeric forms. The term "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.

[0071] In certain embodiments, 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.). For example, "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. For instance, 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. In certain embodiments 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. See, for example, 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).

[0072] Before the present invention is further described, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0073] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0074] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned hereunder are incorporated herein by reference. Unless mentioned otherwise, the techniques employed herein are standard methodologies well known to one of ordinary skill in the art.

[0075] It must be noted that as used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a biomarker" includes a plurality of such biomarkers and reference to "the sample" includes reference to one or more samples and equivalents thereof known to those skilled in the art, and so forth. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as "solely," "only" and the like in connection with the recitation of claim elements, or use of a "negative" limitation. Moreover any positively recited element of the disclosure provides basis for a negative limitation to exclude that element from the claims.

[0076] All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

[0077] Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

DETAILED DESCRIPTION OF THE INVENTION

[0078] The terms used in this specification generally have their ordinary meanings in the art, within the context of the invention, and in the specific context where each term is used. Certain terms that are used to describe the invention are discussed below, or elsewhere in the

specification, to provide additional guidance to the practitioner regarding the description of the invention. For convenience, certain terms may be highlighted, for example using italics and/or quotation marks. The use of highlighting has no influence on the scope and meaning of a term; the scope and meaning of a term is the same, in the same context, whether or not it is highlighted. It will be appreciated that same thing can be said in more than one way. Consequently, alternative language and synonyms may be used for any one or more of the terms discussed herein, nor is any special significance to be placed upon whether or not a term is elaborated or discussed herein. Synonyms for certain terms are provided. A recital of one or more synonyms does not exclude the use of other synonyms. The use of examples anywhere in this specification including examples of any terms discussed herein is illustrative only, and in no way limits the scope and meaning of the invention or of any exemplified term. Likewise, the invention is not limited to various embodiments given in this specification.

[0079] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In the case of conflict, the present document, including definitions will control.

[0080] Antroquinonol (compound 1), antroquinonol B (compound 2), antroquinonol C

(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.

Description of Compounds

[0081] 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. Examples of 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).

[0082] In one aspect, the present invention provides a compound of formula (I):

(I) or a salt thereof, wherein:

R and R¹ are independently optionally substituted alkyl;

R² 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 C₂_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;

R⁶ 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.

[0083] In certain embodiments, 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

2 1

to form a carbocycle or heterocycle; and R and OR are not taken together with their intervening atoms to form a carbocycle or heterocycle.

[0084] In certain embodiments, 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. [0085] In certain embodiments, 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.

[0086] In certain embodiments, R⁶ 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.

[0087] In certain embodiments, R¹ is optically active chiral alkyl.

[0088] In certain embodiments, R and R¹ are optionally substituted C^ alkyl.

[0089] In certain embodiments, R and R¹ are the same.

[0090] In certain embodiments, R and R¹ are taken together with their intervening atoms to form a carbocycle or heterocycle. In certain embodiments, R and R¹ are taken together with their intervening atoms to form an optionally substituted 1,3-dioxacycle.

[0091] In certain embodiments, R and R¹ are taken together with their intervening atoms to form 1,3-dioxacyclopentane, 1,3-dioxacyclohexane or an optically active variant thereof.

[0092] In certain embodiments, R is halogen, haloalkyl, trifluoromethyl, cyano, acyl, alkoxycarbonyl, aminocarbonyl, alkoxy, silyloxy, aralkyloxy, acyloxy, alkylthio, aralkylthio, optionally substituted amino, nitro, amido, or sulfonamido group.

[0093] In some embodiments, R² 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. In some embodiments, R is -OH. In some embodiments, R² is -0(protecting group). In some embodiments, R² is -OR^A, wherein R^A is unsubstituted C_1-10 alkyl. In some embodiments, R² is -OR^A, wherein R^A is substituted C_1-10 alkyl. In some embodiments, R² is -OR^A, wherein R^A is unsubstituted aryl. In some

embodiments, R² is -OR^A, wherein R^A is substituted aryl. In some embodiments, R² is -OR^A, wherein R^A is unsubstituted acyl. In some embodiments, R² is -OR^A, wherein R^A is substituted acyl. In some embodiments, R² is -OR^A, wherein R^A is unsubstituted imidoyl. In some embodiments, R² is -OR^A, wherein R^A is substituted imidoyl. 2 2

[0094] In certain embodiments, R is alkoxy. In certain embodiments, R is methoxy.

2 2

[0095] In certain embodiments, R is halogen. In certain embodiments, R is chlorine atom. In certain embodiments, R is bromine atom.

[0096] In certain embodiments, R is halogen, haloalkyl, trifluoromethyl, cyano, acyl, alkoxycarbonyl, aminocarbonyl, alkoxy, silyloxy, aralkyloxy, acyloxy, alkylthio, aralkylthio, optionally substituted amino, nitro, amido, or sulfonamido group.

[0097] In some embodiments, R³ is -OR³, 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. In some embodiments, R is -OH. In some embodiments, R³ is -0(protecting group). In some embodiments, R³ is -OR³, wherein R^B is unsubstituted C_1-10 alkyl. In some embodiments, R³ is -OR³, wherein R³ is substituted C_1-10 alkyl. In some embodiments, R³ is -OR³, wherein R³ is unsubstituted aryl. In some

3 B B 3 B embodiments, R is -OR , wherein R is substituted aryl. In some embodiments, R is -OR , wherein R³ is unsubstituted acyl. In some embodiments, R³ is -OR³, wherein R³ is substituted acyl. In some embodiments, R³ is -OR³, wherein R³ is unsubstituted imidoyl. In some embodiments, R³ is -OR³, wherein R³ is substituted imidoyl.

[0098] In certain embodiments, R is alkoxy. In certain embodiments, R is methoxy. [0099] In certain embodiments, R is hydrogen.

[00100] In certain embodiments, R is halogen. In certain embodiments, R is chlorine atom. In certain embodiments, R is bromine atom.

2 3 2 3

[00101] In some embodiments, R and R are the same. In some embodiments, R and R are

2 3

each alkoxy. In some embodiments, R and R are each methoxy.

2 3

[00102] In some embodiments, R is methoxy and R is chlorine atom.

[00103] In certain embodiments, R⁶ 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.

[00104] In certain embodiments, R⁶ is methyl. [00105] In certain embodiments, R⁶ is methoxy.

[00106] In certain embodiments, a compound of formula (I) is useful in the synthesis of A. cinnamomea active medicinal substances.

[00107] The compound of formula (I) described herein can be made either by methods described in the art or by methods described herein.

[00108] In another aspect, the present invention provides a compound of formula (II):

(II) or a salt thereof, wherein:

R and R¹ are independently optionally substituted alkyl;

R² 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;

R⁵ is optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl;

R⁶ 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.

[00109] In certain embodiments, 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

2 1

[00110] In certain embodiments, 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.

[00111] In certain embodiments, 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.

[00112] In certain embodiments, R⁶ 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.

[00113] In certain embodiments, R¹ is optically active chiral alkyl.

[00114] In certain embodiments, R and R¹ are optionally substituted C^ alkyl.

[00115] In certain embodiments, R and R¹ are the same.

[00116] In certain embodiments, R and R¹ are taken together with their intervening atoms to form a carbocycle or heterocycle. In certain embodiments, R and R¹ are taken together with their intervening atoms to form an optionally substituted 1,3-dioxacycle.

[00117] In certain embodiments, R and R¹ are taken together with their intervening atoms to form 1,3-dioxacyclopentane, 1,3-dioxacyclohexane or an optically active variant thereof. 2

[00118] In certain embodiments, R is halogen, haloalkyl, trifluoromethyl, cyano, acyl, alkoxycarbonyl, aminocarbonyl, alkoxy, silyloxy, aralkyloxy, acyloxy, alkylthio, aralkylthio, optionally substituted amino, nitro, amido, or sulfonamido group.

[00119] In some embodiments, R² 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. In some embodiments, R is -OH. In some embodiments, R² is -0(protecting group). In some embodiments, R² is -OR^A, wherein R^A is unsubstituted C_1-10 alkyl. In some embodiments, R² is -OR^A, wherein R^A is substituted C_1-10 alkyl. In some embodiments, R² is -OR^A, wherein R^A is unsubstituted aryl. In some embodiments, R² is -OR^A, wherein R^A is substituted aryl. In some embodiments, R² is -OR^A, wherein R^A is unsubstituted acyl. In some embodiments, R² is -OR^A, wherein R^A is substituted acyl. In some embodiments, R² is -OR^A, wherein R^A is unsubstituted imidoyl. In some embodiments, R² is -OR^A, wherein R^A is substituted imidoyl.

2 2

[00120] In certain embodiments, R is alkoxy. In certain embodiments, R is methoxy.

2 2

[00121] In certain embodiments, R is halogen. In certain embodiments, R is chlorine atom. In

2

certain embodiments, R is bromine atom.

[00122] In certain embodiments, R is halogen, haloalkyl, trifluoromethyl, cyano, acyl, alkoxycarbonyl, aminocarbonyl, alkoxy, silyloxy, aralkyloxy, acyloxy, alkylthio, aralkylthio, optionally substituted amino, nitro, amido, or sulfonamido group.

[00123] In some embodiments, R³ is -OR³, 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. In some embodiments, R is -OH. In some embodiments, R³ is -0(protecting group). In some embodiments, R³ is -OR³, wherein R^B is unsubstituted C_1-10 alkyl. In some embodiments, R³ is -OR³, wherein R³ is substituted C_1-10 alkyl. In some embodiments, R³ is -OR³, wherein R³ is unsubstituted aryl. In some

3 B B 3 B embodiments, R is -OR , wherein R is substituted aryl. In some embodiments, R is -OR , wherein R³ is unsubstituted acyl. In some embodiments, R³ is -OR³, wherein R³ is substituted acyl. In some embodiments, R³ is -OR³, wherein R³ is unsubstituted imidoyl. In some embodiments, R³ is -OR³, wherein R³ is substituted imidoyl. [00124] In certain embodiments, R is alkoxy. In certain embodiments, R is methoxy. [00125] In certain embodiments, R is hydrogen.

[00126] In certain embodiments, R is halogen. In certain embodiments, R is chlorine atom. In certain embodiments, R is bromine atom.

2 3 2 3

[00127] In some embodiments, R and R are the same. In some embodiments, R and R are

2 3

each alkoxy. In some embodiments, R and R are each methoxy.

2 3

[00128] In some embodiments, R is methoxy and R is chlorine atom.

[00129] In certain embodiments, R⁵ is an optionally substituted alkyl (C1-C45), an optionally substituted alkenyl (C2-C45) and an optionally substituted alkynyl (C2-C45).

[00130] In certain embodiments, R⁵ is substituted alkyl (C3-C45) bearing halogen, hydroxy, alkoxy, silyloxy, aralkyloxy, acyloxy, alkylthio, aralkylthio, oxo (=0), carboxylic acid, ester, amino, cyano, nitro, amido, sulfonamide, aryl, saccharide, or heterocycle.

[00131] In some embodiments, R⁵ is substituted alkyl (C3-C45) bearing heterocycle with a 5- or 6-membered lactone.

[00132] In certain embodiments, R⁵ is substituted alkenyl (C3-C45) bearing halogen, hydroxy, alkoxy, silyloxy, aralkyloxy, acyloxy, alkylthio, aralkylthio, oxo (=0), carboxylic acid, ester, amino, cyano, nitro, amido, sulfonamide, aryl, saccharide, and heterocycle.

[00133] In some embodiments, R⁵ is substituted alkenyl (C3-C45) bearing heterocycle with a 5- or 6-membered lactone.

[00134] In certain embodiments, R⁵ is substituted alkynyl (C3-C45) bearing halogen, hydroxy, alkoxy, silyloxy, aralkyloxy, acyloxy, alkylthio, aralkylthio, oxo (=0), carboxylic acid, ester, amino, cyano, nitro, amido, sulfonamide, aryl, saccharide, and heterocycle.

[00135] In some embodiments, R⁵ is substituted alkynyl (C3-C45) bearing heterocycle with a 5- or 6-membered lactone.

[00136] In certain embodiments, R⁵ is benzyl.

[00137] In certain embodiments, R⁵ is

wherein n = 0-8.

[00138] In certain embodiments, R is

wherein n = 0-8.

[00139] In certain embodiments, R is

, wherein n = 0-8.

[00140] In certain embodiments, R is

[00141] In certain embodiments, R is

[00142] In certain embodiments, R is

wherein saccharide is D-glucoside, D-mannoside, D-galactoside, D-xylose, N-acetyl-D- glucosamine, or N-acetyl-D-galactosamine. In certain embodiments, R⁵ is

[00143] In certain embodiments, R⁶ 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.

[00144] In certain embodiments, R⁶ is methyl. [00145] In certain embodiments, R⁶ is methoxy.

[00146] In certain embodiments, R⁶ is substituted C_1-6 alkyl bearing an alkoxy, a silyloxy, an alkylthio or an alkylamino group.

[00147] In certain embodiments of the invention, the compound of formula (II) is selected from the group consisting of:

[00148] In certain embodiments of the invention, 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.

[00149] The compound of formula (II) described herein can be made either by methods described in the art or by methods described herein.

[00150] In another aspect, the present invention features an intermediate of formula (III):

(III) or a salt thereof, wherein R, R 1 , R2 , R 3 , R 5 and R 6 are as described herein. [00151] In another aspect, the present invention provides a compound of formula (IV):

(IV) or a salt thereof, wherein R 2 , R 3 , R 5 and R 6 are as described herein.

[00152] In certain embodiments, the compound of formula (IV) is selected from the group consisting of:

[00153] In certain embodiments, the compound of formula (IV) has substituents in cis or trans configurations.

[00154] In certain embodiments, the compound of formula (IV) is a racemic mixture or an optically active compound.

[00155] In certain embodiments, the compound of formula (IV) is selected from the group consisting of:

[00156] In another aspect, the present invention provides a compound of formula (V):

or a salt thereof, wherein R is selected from the group consisting of optionally substituted C_1-6 alkyl, and

2 3 5 6

acyl group. R , R , R and R are as described herein.

[00157] In some embodiments, R⁴ is methyl. In some embodiments, R⁴ is ethyl. In some embodiments, R⁴ is allyl. In some embodiments, R⁴ is benzyl.

[00158] In certain embodiments, R⁴ is acetyl. In certain embodiments, R⁴ is chloroacetyl. In certain embodiments, R⁴ is methoxyacetyl. In certain embodiments, R⁴ is trichloroacetyl. In certain embodiments, R⁴ is benzoate. In certain embodiments, R⁴ is 4-bromobenzoate.

[00159] In certain embodiments, R⁴ 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).

[00160] In certain embodiments, R⁴ is selected from the group consisting of -C(0)CH₃, - C(0)C₂H₅, -C(0)C₃H₇, -C(0)(t-Bu), -C(0)CF₃, -C(0)CH₂Ph, -C(0)C₆H₅, and optionally substituted benzoyl. In certain embodiments, R⁴ is -C(0)CH₃. In certain embodiments, R⁴ is 4- bromobenzoyl.

[00161] In certain embodiments, the compound of formula (V) is selected from the group consisting of:

[00162] In certain embodiments, the compound of formula (V) has substituents in cis or trans configurations.

[00163] In certain embodiments, the compound of formula (V) is a racemic mixture or an optically active compound.

[00164] In certain embodiments, the compound of formula (V) is compound 6.

[00165] In another aspect, the present invention provides a compound of formula (VI):

(VI) or a salt thereof,

wherein ², R⁵ and R⁶ are as described herein.

[00166] In certain embodiments, the compound of formula (VI) is selected from the group consisting of:

[00167] In certain embodiments, the compound of formula (VI) has substituents in cis or trans configurations.

[00168] In certain embodiments, the compound of formula (VI) is a racemic mixture or an optically active compound.

[00169] In certain embodiments, the compound of formula (VI) is:

[00170] In another aspect, the present invention provides a compound of formula (VII):

(VII) or a salt thereof,

wherein R², R⁴, R⁵ and R⁶ are as described herein.

[00171] In certain embodiments, the compound of formula (VII) is selected from the group consisting of:

[00172] In certain embodiments, the compound of formula (VII) has substituents in cis or trans configurations.

[00173] In certain embodiments, the compound of formula (VII) is a racemic mixture or an optically active compound.

[00174] In certain embodiments, the compound of formula (VI) is selected from the group consisting of:

[00175] Table 1 lists exemplary compounds of formula (I).

Table 1.

[00176] Table 2 lists exemplary compounds of formula (II). Table 2.

[00177] Table 3 lists exemplary compounds of formula (III). Table 3.

[00178] Table 4 lists exemplary compounds of formula (IV). Table 4.

[00179] Table 5 lists exemplary compounds of formula (V). Table 5.



Table 6. Table 6 lists exem lary compounds of formula (VI).

Description of Chemical Synthesis

[00180] 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.

[00181] In some embodiments, 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.

[00182] In certain embodiments, the conversion of the compound of formula (II) to the compound of formula (IV) comprises the formation of an intermediate of formula (III).

[00183] In preferred embodiments, the conversion of the compound (II) to the intermediate (III) is performed by reduction:

[00184] Examples of the reducing agent include, but not limited to, lithium aluminumhydride (LiAlH₄), diisobutylaluminum hydride (DIBAL), lithium tri-tert-butoxyalminum hydride (LiAl(Ot-Bu)₃H), NaBH₄-CeCl₃, lithium triethylborohydride (LiEt₃BH, 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.

[00185] In certain embodiments, the conversion of the intermediate (III) to the compound (IV) is performed by the hydrolysis in acidic conditions:

[00186] In certain embodiments, the compound of formula (II) is prepared by treating a compound of formula (I) with an electrophilic reagent in basic conditions:

(I) (I")

[00187] The conversion of the compound of formula (I) to the compound of formula (II) can be performed by using an electrophilic reagent (R⁵X) in the presence of a base. Examples of the base include, but not limited to, sodium hydride (NaH), potassium tert-butoxide (t-BuOK), lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LHMDS), sodium

hexamethyldisilazide (NHMDS), or potassium hexamethyldisilazide (KHMDS). X is a leaving group. Examples of the leaving group include, but not limited to, CI, Br, I, OS0₂CH₃ (mesylate), OS0₂CF₃ (triflate), or OS0₂C₆H4-p-CH₃ (tosylate). The stereochemistry of alkylation product (cis versus trans isomers) is controlled by the nature of substrate and the reaction conditions including the size of R⁶, temperature, solvent, cosolvent, base, and additive.

[00188] In certain embodiments, the addition reaction and alkylation is performed in a one-pot procedure.

[00189] In certain embodiments, the compound of formula (I) is prepared by treating a compound of formula (C) with a nucleophilic reagent under suitable conditions:

[00190] The preparation of the compound (I) from the compound (C) can be performed by Michael reaction using a nucleophilic reagent (R⁶M). The nucleophilic reagent is organometallic reagent, metal alkoxide, metal thiolate, and metal amide. Examples of R⁶M include, but not limited to, (CH₃)₂CuLi, (n-C₄H₉)₂CuLi, CH₃MgBr-CuCl, CH₃MgCl-CuBr, CH₃MgBr-CuBr, CH₃MgBr-CuI, CH₃MgBr-Cu(OCOCH₃), CH₃MgBr-CuSPh, CH₃MgBr-CuCN, CH₃MgI- CuBr, CH₃MgI-CuCN, CH₃Li-CuBr, C₂H₅MgBr-CuBr, PhMgl-CuSPh, PhCH₂MgCl-CuI, (CH₃)₂Zn, (CH₃)₃A1, (CH₃)₄Sn, CH₃ONa, (CH₃)₂CHONa, CH₃SNa, C₂H₅SNa, (C₂H₅)₂NNa, or [PhCH₂]₂NLi.

[00191] In certain embodiments, the asymmetric Michael reaction is performed when one of R and R¹ is chiral. Otherwise, chiral ligand and metal salt are also used as additives to produce the optically active compound of formula (I). Examples of the metal salt include, but not limited to, CuCl, CuBr, Cul, Cu(OCOCH₃), Cu(OCOCF₃), Cu(OCOCF₃)₂, CuSPh, CuCN, and copper(I) thiophene-2-carboxylate. The chiral ligands belong to several structural categories. Examples of the chiral ligand 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.

Catalytic enantioselective conjugate addition with Grignard reagents. Acc. Chem. Res. 2007, 40, 179-188; (2) Harutyunyan, S. R. et al. Catalytic asymmetric conjugate addition and allylic alkylation with Grignard reagents. Chem. Rev. 2008, 108, 2824-2852; and (3) Jerphagnon, T. et al. Recent advances in enantioselective copper-catalyzed 1,4-addition. Chem. Soc. Rev. 2009, 38, 1039-1075.

[00192] In certain embodiments, the compound of formula (C) is generated from a compound of formula (B) by oxidation in the presence of an alcohol compound (ROH):

[00193] 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 C₆H₅I(0₂CCH₃)₂, or iodobenzene di(trifluoroacetate) C₆H₅I(0₂CCF₃)₂)].

[00194] In certain embodiments, the compound of formula (B) is generated from a compound of formula (A) by Baeyer-Villiger oxidation:

[00195] Examples of the oxidizing agent for generating compound (B) from compound (A) include, but not limited to, peroxy acids (e.g. m-ClC₆H₄C0₃H), hydrogen peroxide (e.g. H₂0₂- H₂S0₄), or tert-butyl hydroperoxide (e.g. t-BuOOH-V₂0₅).

[00196] In some embodiments, 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):

(IV) (V) wherein R is an optionally substituted C_1-6 alkyl or acyl group as described herein.

[00197] In certain embodiments, the compound of formula (II) can be the compound of formula (Il-a):

[00198] In some embodiments, 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.

[00199] In some embodiments, 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):

(VI) (VII)

[00200] In certain embodiments, the C-5 and C-6 substituents R⁵ and R⁶ 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.

[00201] In some embodiments, 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).

[00202] The method described in Figure 2 involves in the following steps:

(a) converting the compound of formula (B)-a to the compound of formula (C)-a by oxidation with iodobenzene di(trifluoroacetate) in the presence of methanol.

(b) converting the compound (C)-a to the compound of formula (I)-a by Michael reaction with a nucleophilic reagent CH₃MgBr-CuCl;

(c) converting the compound (I)-a to an enolate ion for the alkylation with farnesyl bromide, and further treating the product with a small quantity of base to give the compound of formula cis- (II)-a; and

(d) converting the compound cis-(H)-b to compound (±)-l by reduction with LS-Selectride, followed by hydrolysis of the acetal group and epimerization at the C6 position.

[00203] In some embodiments, 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.

[00204] The method described in Figure 3 involves in the following steps:

(a) converting the compound of formula (C)-b to the compound of formula (I)-b in the (5)- configuration by asymmetric Michael reaction with an appropriate nucleophilic reagent in the presence of an optically active chiral ligand;

(b) converting the chiral compound (5)-(I)-b to an enolate ion for the alkylation with farnesyl bromide, and further treating the product with a small quantity of base to give the cis enriched chiral compound of formula (S,R)-(lT)-c; and

(c) converting the chiral compound (S,R)-(ll)-c by reduction with LS-Selectride, followed by hydrolysis of the acetal group and epimerization at the C6 position to the compound (4R,5R,6R)- (+)-3. [00205] In some embodiments, 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.

[00206] The method described in Figure 4 involves in the following steps:

(a) converting the compound of formula (C)-a to the compound of formula (I)-a or in the (5)- configuration by asymmetric Michael reaction with an appropriate nucleophilic reagent in the presence of an optically active chiral ligand;

(b) converting the chrial compound (5)-(I)-a to an enolate ion for the alkylation with farnesyl bromide, and further treating the product with a small quantity of base to give the cis enriched chiral compound of formula (5',/?)-(II)-b; and

(c) converting the chiral compound (5',/?)-(II)-b by reduction with LS-Selectride, followed by hydrolysis of the acetal group and epimerization at the C6 position, to the compound (4R,5R,6R)- (+)-l.

[00207] 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 IC₅o values in micromolar or submicromolar range.

EXAMPLES

[00208] Without intent to limit the scope of the invention, exemplary instruments, apparatus, methods and their related results according to the embodiments of the present invention are given below. Note that titles or subtitles may be used in the examples for convenience of a reader, which in no way should limit the scope of the invention. Moreover, certain theories are proposed and disclosed herein; however, in no way they, whether they are right or wrong, should limit the scope of the invention so long as the invention is practiced according to the invention without regard for any particular theory or scheme of action. [00209] As used herein, the term "alkyl" (alone or in combination with another term(s)) 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. When substituted, 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 halo, hydroxy, unsubstituted lower alkyl or unsubstituted lower alkoxy groups, mercapto, (unsubstituted lower alkylthio, arylthio optionally substituted with one or more groups which are independently of each other halo, hydroxy, unsubstituted lower alkyl or alkoxy groups, cyano, acyl, thioacyl, O-carbamyl, N-carbamyl, O- thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, nitro, N-sulfonamido, S-sulfonamido, RS(O)-, RS(0)₂-, -C(0)OR, RC(0)0-, and— NR^ER^F, wherein R^E and R^F are independently selected from the group consisting of hydrogen, unsubstituted lower alkyl, trihalomethyl, cycloalkyl, heterocyclic and aryl optionally substituted with one or more groups, which are independently of each other halo, hydroxy, unsubstituted lower alkyl or unsubstituted lower alkoxy groups.

[00210] As used herein, the term "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. To illustrate, monofluoroalkyl is alkyl substituted with a fluorine, and 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).

[00211] If a substituent is described as being "optionally substituted", the substituent is either (1) substituted, or (2) not substituted. When the members of a group of substituents are described generally as being optionally substituted, any atom capable of substitution in each member of such group may be (1) substituted, or (2) not substituted. Such a characterization contemplates that some members of the group are not substitutable. 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. On the other hand, hydrogen alone, halogen, oxo (=0), and cyano do not fall within the definition of being capable of substitution.

[00212] As used herein, the term "halogen" (alone or in combination with another term(s)) refers to a fluorine substituent (-F), chlorine substituent (-C1), bromine substituent (-Br), or iodine substituent (-1).

[00213] As used herein, the term "hydroxy" refers to an -OH group.

[00214] As used herein, the term "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,

cyclohexyloxy, and the like.

[00215] As used herein, the term "amino" refers to an -NH₂, 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.

[00216] As used herein, the term "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.

[00217] 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.

[00218] As used herein, the term "alkenyl" (alone or in combination with another term(s)) 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.

[00219] As used herein, the term "alkynyl" (alone or in combination with another term(s)) 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.

[00220] As used herein, the term "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.

[00221] As used herein, the term "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.

[00222] As used herein, the term "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.

[00223] As used herein, the term "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 S0₂, 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.

[00224] 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, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-l,l-dioxothienyl, triazolyl, triazinyl, and the like.

[00225] As used herein, the term "heteroaryl" (alone or in combination with another term(s)) 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, isobenzothienyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, pyranopyrrolyl, benzoxadiazolyl, indolyl, isoindazolyl, benzoimidazolyl, benzotriazolyl, purinyl, imidazopyrazinyl, and imidazolopyridazyl; and 6/6-membered fused-ring systems such as quinolinyl, isoquinolinyl, pyridopyridinyl, phthalazinyl, quinoxalinyl, benzodiazinyl, pteridinyl, pyridazinotetrazinyl, pyrazinotetrazinyl, pynmidinotetrazinyl, benzoimidazothiazolyl, carbazolyl, and acridinyl. In some embodiments, 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.

[00226] Example 1. Instrumentation:

Melting points were recorded on a Yanaco or Electrothermal MEL-TEMP 110 ID apparatus in open capillaries and are not corrected. Optical rotations were measured on digital polarimeter of Japan JASCO Co. DIP- 1000. [a]_D values are given in units of 10 deg cm g . Infrared (IR) spectra were recorded on Nicolet Magna 550-11 or Thermo Nicolet 380 FT-IR spectrometers. UV- visible spectra were measured on a Perkin Elmer Lambda 35 spectrophotometer. Nuclear magnetic resonance (NMR) spectra were obtained on Bruker Advance-400 (400 MHz) or Bruker A VIII (500 MHz) spectrometer. Chemical shifts (δ) are given in parts per million (ppm) relative to δ_Η 7.24 / 6c 77.0 (central line of t) for CHC1₃/CDC1₃, δ_Η 4.80 for H₂0/D₂0, δ_Η 3.31 / 6_C 48.2 for CD₃OD, or δκ 2.49 / 6c 39.5 for DMSO-<¾. The splitting patterns are reported as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (double of doublets) and br (broad). Coupling constants (J) are given in Hz. 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. The 2,5-dihydroxybenzoic acid (DHB), as MALDI matrix, was photoionized at different irradiances of a UV laser with λ_ιηαχ at 337 nm and 355 nm.

[00227] Example 2. Materials and methods:

All the reagents and solvents were reagent grade and were used without further purification unless otherwise specified. All solvents were anhydrous grade unless indicated otherwise.

CH₂C1₂ was distilled from CaH₂. All non-aqueous reactions were carried out in oven-dried glassware under a slight positive pressure of argon unless otherwise noted. Reactions were magnetically stirred and monitored by thin-layer chromatography on silica gel using aqueous p- anisaldehyde as visualizing agent. Silica gel (0.040-0.063 mm particle sizes) and LiChroprep RP-18 (0.040-0.063 mm particle sizes) were used for column chromatography. Flash

chromatography was performed on silica gel of 60-200 μπι particle size. Molecular sieves were activated under high vacuum at 220 °C over 6 hours.

[00228] Example 3. Baeyer-Villiger oxidation of formula (A) to formula (B)

Synthesis of 2,3,4-trimethoxyphenol

A solution of 2,3,4-trimethoxybenzaldehyde (5.0 g, 36.7 mmol) and 31% aqueous H₂0₂ (5.3 g, 48 mmol) in methanol (50 mL) was stirred with sulfuric acid (0.5 mL) at room temperature for 24 h, the reaction was quenched with water, and extracted with CH₂C1₂. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with EtOAc/hexane (15:85) to yield a pure product of 2,3,4-trimethoxyphenol (6.3 g, 95% yield). C₉H₁₂0₄; 1H NMR (400 MHz, CDC1₃) δ 6.57 (1 H, d, J= 8.0 Hz), 6.50 (1 H, d, J= 8.0 Hz), 3.87 (3 H, br s), 3.83 (3 H, br s), 3.74 (3 H, br s). ¹³C NMR (100 MHz, CDC1₃) δ 146.7, 143.3, 142.2, 140.5, 108.7, 107.6, 61.0, 60.7, 56.4. HRMS (negative mode) calcd for C₉H„0₄: 183.0657, found: mlz 183.0661 [M- H]^".

[00229] Example 4. Phenol oxidation of formula (B) to formula (C)

Synthesis of 2,3,4,4-tetramethoxycyclohexa-2,5-dien-l-one

To a stirred solution containing 2,3,4-trimethoxyphenol (7, 2.0 g, 10.9 mmol) and powdered K₂C0₃ (3.0 g, 21.7 mmol) in anhydrous MeOH (45 mL) was added a solution of iodobenzene di(trifluoroacetate) (PIFA, 4.7 g, 10.9 mmol) in CH₃CN (22 mL) at 0 °C. The mixture was stirred for 10 min at 0 °C to room temperature, diluted with water, and extracted with CH₂C1₂. The organic layer was washed with brine, dried over MgS0₄, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with elution of EtOAc/hexane (20:80) to yield cyclohexadienone 9 (1.9 g, 81% yield). C₁₀H₁₄O₅; IR v_max(neat) 2994 2948, 2834, 1672, 1607, 1313, 1210, 1076, 951, 833, 740 cm^-1. 1H NMR (400 MHz, CDC1₃) δ 6.48 (1 H, d, J= 10.4 Hz), 6.25 (1 H, d, J= 10.4 Hz), 4.16 (3 H, s), 3.74 (3 H, s), 3.31 (6 H, s). ¹³C NMR (100 MHz, CDC1₃) δ 182.9, 155.1, 140.0, 138.4, 129.9, 96.8, 60.9, 60.2, 51.1 (2 x). HRMS calcd for C₁₀H₁₅O₅: 215.0919, found: mlz 215.0913 [M + H]⁺.

[00230] Example 5. Phenol oxidation of formula (B) to formula (C) Synthesis of 2-chloro-3,4,4-trimethoxycyclohexa-2,5-dien-l-one

A solution of 2-chloro-3-methoxyphenol (0.8 g, 5.0 mmol) and PIFA (4.3 g, 10.0 mmol) in anhydrous MeOH (45 n L) was stirred for 10 min at 0 °C to room temperature. The mixture was diluted with water, and extracted with CH₂C1₂. The organic layer was washed with brine, dried over MgS0₄, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with elution of EtOAc/hexane (10:90) to yield 2-chloro-3,4,4- trimethoxycyclohexa-2,5-dien-l-one (709 mg, 65% yield). C₉H„C10₄; 1H NMR (400 MHz, CDC1₃) δ 6.45 (1 H, d, J= 12 Hz), 6.37 (1 H, d, J= 12 Hz), 4.23 (3 H, s), 3.29 (6 H, s). ¹³C NMR (100 MHz, CDC1₃) δ 179.3, 161.8, 139.8, 130.3, 115.1, 97.5, 60.0, 51.5 (2 x). HRMS calcd for C₉H₁₂C10₄: 219.0424, found: 219.0432 [M + H]⁺.

[00231] Example 6. Michael reaction of formula (C) to formula (I)

Synthesis of 2,3-dichloro-4,4,5-trimethoxycyclohex-2-en-l-one

A solution of 2,3-dichloro-4,4-dimethoxycyclohex-2,5-dien-l-one (30 mg, 0.14 mmol) in MeOH (4.0 mL) was stirred with K₂C0₃ (56 mg, 0.41 mmol) at room temperature for 2 h. The mixture was quenched with water (5.0 mL), and then extracted with CH₂C1₂ (20 mL x 3). The organic phase was washed with brine (30 mL), dried over MgS0₄, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with elution of EtOAc/hexane (10:90) to yield the Michael addition product 2,3-dichloro-4,4,5- trimethoxycyclohex-2-en-l-one (28 mg, 80% yield). C₉H₁₂C1₂0₄; 1H NMR (400 MHz, CDC1₃) δ 3.95 (1 H, m), 3.40 (3 H, s), 3.39 (3 H, s), 3.37 (3 H, s), 2.98 (2 H, dd, J=17.5, 3.0 Hz). ¹³C NMR (100 MHz, CDC1₃) δ 186.4, 149.7, 134.1, 98.1, 76.3, 57.1, 51.1, 49.1, 38.1.

[00232] Example 7. Michael reaction of formula (C) to formula (I)

Synthesis of 2,3,4,4-tetramethoxy-5-methylcyclohex-2-en-l-one

Under an atmosphere of nitrogen, a solution of CuCl (99.0 mg, 1.0 mmol) in THF (4 mL) was cooled to -50 °C, and MeMgBr (2.0 mmol, 2.0 mL of 1.0 M solution in THF) was added. The mixture was stirred for 1 h, and a solution of 2,3,4,4-tetramethoxycyclohexa-2,5-dien-l-one (214.0 mg, 1.0 mmol) in THF (1 mL) was added dropwise. The mixture was stirred at -50 °C for 6 h, quenched with saturated aqueous NH₄C1 (5.0 mL), and then extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with 0.5 M NaOH (30 mL) and brine (30 mL). The organic phase was dried over MgS0₄, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with EtOAc/hexane (15:85) to yield a pure compound of 2,3,4,4-tetramethoxy-5-methylcyclohex-2-en-l-one (115 mg, 50% yield). CnH₁₈0₅; IR v_max (neat) 2940, 2833, 1675, 1609, 1306, 1227, 1066, 994 cm^"1. 1H NMR (400 MHz, CDC1₃) δ 4.09 (3 H, s), 3.64 (3 H, s), 3.28 (3 H, s), 3.26 (3 H, s), 2.72 (1 H, dd, J= 16.8, 4.3 Hz), 2.47 (1 H, td, J= 7.0, 4.3 Hz), 2.27 (1 H, dd, J= 16.8, 3.8 Hz), 0.97 (3 H, d, J= 7.0 Hz). ¹³C NMR (100 MHz, CDC1₃) δ 194.5, 158.9, 138.3, 101.1, 60.9, 60.4, 51.0, 48.2, 41.1, 33.9, 14.5. HRMS calcd for C„H₁₉0₅: 231.1232, found: mlz 231.1234 [M + H]⁺.

[00233] Example 8. Asymmetric Michael reaction of formula (C) to formula (I) Synthesis of (7?)-4,4-dimethoxy-5-methylcyclohex-2-en-l-one

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. The colorless solution was cooled to -25 °C. A solution of 4,4-dimethoxycyclohexa-2,5-dien-l-one (150.0 mg, 1.0 mmol) and methylmetal reagent (1.5 mmol) was added. The mixture was stirred at -25 °C for 16 h, quenched with saturated aqueous NH₄C1 (5.0 mL), and then extracted with Et₂0 (3 x 20 mL). The combined organic layers were washed with 2.0 M KOH (30 mL) and brine (30 mL), dried over MgS0₄, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with elution of EtOAc/CH₂Cl₂ (20:80) to yield (/?)-4,4-dimethoxy-5- methylcyclohex-2-en-l-one (119 mg, 70% yield). C₉H₁₄0₃; [a]²⁵ _D -1.4 (c 10.9, CHC1₃); 1H NMR (400 MHz, CDC1₃) δ 6.64 (2 H, d, J= 10.4 Hz), 6.01(2 H, d, J= 10.4 Hz), 3.27 (3 H, s), 3.26 (3 H, s), 2.83 (1 H, dd, J= 16.8, 4.4 Hz), 2.47 (1 H, td, J= 6.4, 4.4 Hz), 2.27 (1 H, dd, J = 16.8, 2.8 Hz), 0.98 (3 H, d, J= 6.4 Hz). ¹³C NMR (100 MHz, CDC1₃) δ 199.0, 146.6, 130.6, 99.2, 49.8, 47.7, 42.3, 35.6, 14.9.

[00234] 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. The mixture was stirred for 12 h, poured into ice-cold saturated aqueous NH₄C1 (5 mL), and then extracted with Et₂0 (3 x 20 mL). The combined organic layers were washed with 1.0 M NaOH (30 mL) and brine (30 mL), dried over MgS0₄, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with elution of EtOAc/hexane (15:85) to yield (5)-5-methyl-3,4,4-trimethoxycyclohex-2-en-l-one (77.8 mg, 81% yield). C₁₀H₁₆O₄; [a]²⁴ _D +13.8 (c 2.0, CHC1₃); IR v_max (neat) 2972, 2941, 2837, 1659, 1608, 1458, 1223, 1074, 1028, 772 cm^-1; 1H NMR (400 MHz, CDC1₃) δ 5.34 (1 H, s), 3.73 (3 H, s), 3.31 (3 H, s), 3.26-3.20 (3 H, m), 2.78 (1 H, dd, J= 17.1, 5.0 Hz), 2.63-2.52 (1 H, m), 2.24 (1 H, dd, J= 17.1, 3.0 Hz), 0.98 (3 H, d, J= 7.0 Hz); ¹³C NMR (100 MHz, CDC1₃) δ 198.1, 171.3, 103.3, 99.9, 55.9, 48.1, 41.7, 34.8, 14.6. HRMS calcd for C₁₀H₁₇O₄: 201.1127, found: 201.1137 [M + H]⁺.

[00235] Example 10. Asymmetric Michael reaction of formula (C) to formula (I)

Synthesis of (5)-3-chloro-4,4-dimethoxy-5-methylcyclohex-2-en- 1 -one

A solution of 3-chloro-4,4-dimethoxycyclohexa-2,5-dien-l-one (100 mg, 0.53 mmol) and a methylmetal reagent (2.7 mmol) was treated with a metal salt (0.027 mmol) and a K)-chiral ligand (0.053 mmol) for 12 h to give (5)-3-chloro-4,4-dimethoxy-5-methylcyclohex-2-en-l-one (83.3 mg, 77% yield). C₉H₁₃C10₃; [a]²⁵ _D +3.6, c 4.25, CHC1₃; IR v_max (neat) 2968, 2942, 2836, 1684, 1604, 1457, 1253, 1074, 1054, 937 cm^-1. 1H NMR (500 MHz, CDC1₃) δ 6.28 (1 H, s), 3.34 (3 H, s), 3.33 (3 H, s), 2.86 (1 H, dd, J= 17.1, 4.9 Hz), 2.68 - 2.61 (1 H, m), 2.33 (1 H, dd, J= 17.1, 3.1 Hz), 0.98 (3 H, d, J= 6.7 Hz). ¹³C NMR (125 MHz, CDC1₃) δ 196.0, 155.3, 130.3, 99.2, 51.3, 48.3, 42.0, 35.8, 14.6. HRMS calcd for C₉H₁₃ClNa0₃: 227.0445, found: 227.0455 [M + Na]⁺.

[00236] Example 11. Asymmetric Michael reaction of formula (C) to formula (I)

Synthesis of (5)-3-bromo-4,4-dimethoxy-5-methylcyclohex-2-en- 1 -one

A solution of 3-bromo-4,4-dimethoxycyclohexa-2,5-dien-l-one (100 mg, 0.43 mmol) and a methylmetal reagent (2.1 mmol) was treated with a metal salt (0.022 mmol) and a K)-chiral ligand (0.043 mmol) for 12 h to give (5)-3-bromo-4,4-dimethoxy-5-methylcyclohex-2-en-l-one (79.2 mg, 74% yield). C₉H₁₃Br0₃; [a]²⁵ _D +0.9 (c 3.0, CHC1₃); IR v_max (neat) 2967, 2941, 2835, 1690, 1604, 1248, 1129, 1054, 934, 772 cm^-1; 1H NMR (500 MHz, CDC1₃) δ 6.58 (1 H, s), 3.38 (3 H, s), 3.33 (3 H, s), 2.87 (1 H, dd, J= 17.1, 4.9 Hz), 2.70-2.63 (1 H, m), 2.33 (1 H, dd, J=

17.1, 3.1 Hz), 0.98 (3 H, d, J= 6.7 Hz). ¹³C NMR (125 MHz, CDC1₃) δ 195.7, 148.6, 134.6, 98.7,

51.2, 48.4, 41.9, 35.7, 14.7.

[00237] Example 12. Asymmetric Michael reaction of formula (C) to formula (I) Synthesis of (5)-4,4-dimethoxy-3,5-dimethylcyclohex-2-en-l-one

A solution of 4,4-dimethoxy-3-methylcyclohexa-2,5-dien-l-one (100 mg, 0.60 mmol) and a methylmetal reagent (3.0 mmol) was treated with a metal salt (0.03 mmol) and a K)-chiral ligand (0.06 mmol) for 12 h to give (5)-4,4-dimethoxy-3,5-dimethylcyclohex-2-en-l-one.

C₁₀H₁₆O₃; [a]²⁵ _D -2.0 (c 1.43, CHC1₃); IR v_max (neat) 2965, 1677, 1457, 1437, 1256, 1123, 1075, 1053, 946 cm^"1; 1H NMR (500 MHz, CDC1₃) δ 5.88 (1 H, s), 3.25 (3 H, s), 3.21 (3 H, s), 2.85 (1 H, dd, J= 17.7, 4.9 Hz), 2.59 (1 H, m), 2.21 (1 H, d, J= 17.7 Hz), 2.00 (3 H, d, J= 1.8 Hz), 0.91 (3 H, d, J= 6.7 Hz); ¹³C NMR (125 MHz, CDC1₃) δ 198.6, 158.4, 128.7, 100.5, 50.6, 47.4, 42.1, 35.2, 21.0, 14.9. HRMS calcd for C₁₀H₁₆NaO₃: 217.0991, found: 217.0998 [M + Na]⁺.

[00238] Example 13. Asymmetric Michael reaction of formula (C) to formula (I)

Synthesis of (5)-2,3-dichloro-4,4-dimethoxy-5-methylcyclohex-2-en- 1 -one

A solution of 2,3-dichloro-4,4-dimethoxycyclohexa-2,5-dien-l-one (100 mg, 0.45 mmol) and a methylmetal reagent (2.2 mmol) was treated with a metal salt (0.023 mmol) and a K)-chiral ligand (0.045 mmol) at -5 °C for 12 h to give (5)-2,3-dichloro-4,4-dimethoxy-5-methylcyclohex- 2-en-l-one (76.3 mg, 71% yield). C₉H₁₂C1₂0₃; [a]²⁵ _D -0.9 (c 1.23, CHC1₃); IR v_max (neat) 2969, 2942, 2841, 1701, 1577, 1458, 1240, 1052, 947, 784 cm^-1; 1H NMR (500 MHz, CDC1₃) δ 3.33 (3 H, s), 3.31 (3 H, s), 2.96 (1 H, dd, J= 17.4, 4.6 Hz), 2.70-2.62 (1 H, m), 2.52 (1 H, dd, J= 17.4, 4.0 Hz), 0.97 (3 H, d, J= 7.3 Hz); ¹³C NMR (125 MHz, CDC1₃) δ 188.2, 151.2, 133.9, 100.1, 51.3, 48.6, 41.4, 35.3, 14.4.

[00239] 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. C„H₁₈0₅; [a]²⁵ _D +88.0 (c 2.0, CHC1₃); 1H NMR (400 MHz, CDC1₃) δ 4.09 (3 H, s), 3.64 (3 H, s), 3.28 (3 H, s), 3.26 (3 H, s), 2.72 (1 H, dd, J= 16.8, 4.3 Hz), 2.47 (1 H, td, J= 7.0, 4.3 Hz), 2.27 (1 H, dd, J= 16.8, 3.8 Hz), 0.97 (3 H, d, J= 7.0 Hz); ¹³C NMR (100 MHz, CDC1₃) δ 194.5, 158.9, 138.3, 101.1, 60.9, 60.4, 51.0, 48.2, 41.1, 33.9, 14.5. HRMS , calcd for C„H₁₉0₅:

231.1232, found mlz 231.1234 [M + H]⁺.

[00240] Example 15. Asymmetric Michael reaction of formula (C) to formula (I)

Synthesis of (5)-2-chloro-3,4,4-trimethoxy-5-methylcyclohex-2-en-l-one

A solution of 2-chloro-3,4,4-trimethoxycyclohexa-2,5-dien-l-one (100 mg, 0.46 mmol) and a methylmetal reagent (2.3 mmol) was treated with a metal salt (0.023 mmol) and a K)-chiral ligand (0.046 mmol) for 12 h to give (5)-2-chloro-3,4,4-trimethoxy-5-methylcyclohex-2-en-l- one. C₁₀H₁₅ClO₄; [a]²⁵ _D +52.9 (c 3.5, CHC1₃); IR v_max (neat) 2943, 2837, 1689, 1590, 1459, 1213, 1052, 1033, 805 cm^"1; 1H NMR (500 MHz, CDC1₃) 6 4.11 (3 H, s), 3.31 (3 H, s), 3.28 (3 H, s), 2.88 (1 H, dd, J= 17.1, 4.3 Hz), 2.55 (1 H, m), 2.45 (1 H, dd, J= 17.1, 3.7 Hz), 0.99 (3 H, d, J=6.7 Hz); ¹³C NMR (125 MHz, CDC1₃) δ 191.2, 167.3, 118.0, 101.8, 61.3, 51.4, 48.3, 41.5, 34.1, 14.4. HRMS calcd for C₁₀H₁₅ClNaO₄: 257.0557, found: mlz 257.0552 [M + Na]⁺.

[00241] Example 16. Asymmetric Michael reaction of formula (C) to formula (I)

Synthesis of (4/?,55)-4-(4-bromobenzyloxy)-3,4-dimethoxy-5-methylcyclohex-2-en-l-one and the (45',55)-isomer

By the method of phenol oxidation, 4-(4-bromobenzyloxy)-3-methoxyphenol was oxidized with PIFA in anhydrous MeOH to give 4-(4-bromobenzyloxy)-3,4-dimethoxycyclohexa-2,5-dien-l- one. A solution of 4-(4-bromobenzyloxy)-3,4-dimethoxycyclohexa-2,5-dien-l-one (100 mg, 0.30 mmol) and a methylmetal reagent (1.5 mmol) was treated with a K)-chiral ligand (0.030 mmol) and a promoter of metal salt (0.015 mmol) to give (4/?,55)-4-(4-bromobenzyl)-3,4-dimethoxy-5- methylcyclohex-2-en-l-one and the (45^,,55)-isomer in a ratio of 1:1.

(4/?,55)-Isomer: C₁₆H₁₉Br0₄: 1H NMR (500 MHz, CDC1₃) δ 7.45 (2 H, d, J= 8.5 Hz), 7.23 (2 H, d, J= 8.5 Hz), 5.36 (1 H, s), 4.60^1.53 (2 H, m), 3.71 (3 H, s), 3.25 (3 H, s), 2.73 (1 H, dd, J = 17.1, 4.9 Hz), 2.64 (1 H, dt, J= 6.7, 4.9 Hz), 2.35 (1 H, dd, J= 16.8, 4.9 Hz), 1.05 (3 H, d, J = 6.7 Hz). ¹³C NMR (125 MHz, CDC1₃) δ 198.0, 171.7, 137.0, 131.5 (2 x), 128.8 (2 x), 121.3, 103.9, 100.1, 62.3, 55.9, 51.5, 41.9, 35.4, 14.4.

(4S,5S)-Isomer: C₁₆H₁₉Br0₄: 1H NMR (500 MHz, CDC1₃) δ 7.43 (2 H, d, J= 7.9 Hz), 7.15 (2 H, d, J= 7.9 Hz), 5.31 (1 H, s), 4.58 (1 H, d, J= 11.6 Hz), 4.36 (1 H, d, J= 11.6 Hz), 3.68 (3 H, s), 3.36 (3 H, s), 2.88 (1 H, dd, J= 17.1, 4.7 Hz), 2.67 (1 H, ddd, J= 6.7, 4.7, 3.1 Hz), 2.29 (1 H, dd, J= 17.1, 3.1 Hz), 1.02 (3 H, d, J= 6.7 Hz). ¹³C NMR (125 MHz, CDC1₃) δ 197.8, 170.8, 136.8, 131.5 (2 x), 129.0 (2 x), 121.6, 103.5, 100.0, 64.7, 56.0, 48.3, 41.7, 35.0, 14.6.

[00242] Example 17. Asymmetric Michael reaction of formula (C) to formula (I)

Synthesis of (4/?,5/S)-3,4-dimethoxy-5-methyl-4-(myrtenyloxy)cyclohex-2-en-l-one and the (45',55)-isomer

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. By the method of phenol oxidation, 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. A solution of 3,4-dimethoxy-4-(4-myrtenyloxy) cyclohexa-2,5-dien- 1-one (100 mg, 0.33 mmol) and a methylmetal reagent (1.6 mmol) was treated with a K)-chiral ligand (0.033 mmol) and a promoter of metal salt (0.016 mmol) to give (4/?,55)-3,4-dimethoxy- 5-methyl-4-(myrtenyloxy)cyclohex-2-en-l-one and the (45^,,55)-isomer in a ratio of 1:1.

(4/?,55)-Isomer: C₁₉H₂₈0₄; 1H NMR (500 MHz, CDC1₃) δ 5.54 (1 H, br s), 5.34 (1 H, s), 3.91 (2 H, d, J= 1.8 Hz), 3.72 (3 H, s), 3.24 (3 H, s), 2.67 (1 H, dd, J= 16.8, 4.6 Hz), 2.58-2.49 (1 H, m), 2.40-2.26 (3 H, m), 2.26-2.17 (1 H, m), 2.12-2.06 (1 H, m), 2.06-2.00 (1 H, m), 1.26 (3 H, s), 1.18 (1 H, d, J= 8.5 Hz), 1.02 (3 H, d, J= 6.7 Hz), 0.83 (3 H, s). ¹³C NMR (125 MHz, CDC1₃) δ 198.2, 172.5, 144.6, 118.2, 103.7, 99.7, 63.7, 55.8, 51.3, 43.6, 42.0, 41.0, 38.1, 35.6, 31.4, 31.2, 26.2, 21.0, 14.4.

(4S,5S)-Isomer: C₁₉H₂₈0₄; 1H NMR (500 MHz, CDC1₃) δ 5.44 (1 H, d, J= 1.2 Hz), 5.33 (1 H, s), 3.94 (1 H, dd, J= 12.2, 1.2 Hz), 3.73 (3 H, s), 3.66 (1 H, dd, J= 12.2, 1.2 Hz), 3.31 (3 H, s), 2.85 (1 H, dd, J= 17.1, 4.7 Hz), 2.62 (1 H, ddd, J= 7.2, 4.7, 2.7 Hz), 2.35 (1 H, dt, J= 8.5, 5.5 Hz), 2.31-2.14 (3 H, m), 2.06 (1 H, d, J= 3.1 Hz), 2.04-1.98 (1 H, m), 1.25 (3 H, s), 1.14 (1 H, d, J = 8.5 Hz), 0.98 (3 H, d, J= 7.2 Hz), 0.79 (3 H, s). ¹³C NMR (125 MHz, CDC1₃) δ 198.3, 171.4, 144.5, 118.8, 103.2, 99.5, 66.1, 55.9, 48.1, 43.6, 41.8, 40.9, 38.0, 35.0, 31.5, 31.2, 26.2, 21.0, 14.6.

[00243] Example 18. Alkylation reaction of formula (I) to formula (II)

Synthesis of 6-farnesyl-2,3,4,4-tetramethoxy-5-methylcyclohex-2-en-l-one

Under an atmosphere of nitrogen, to a solution of 2,3,4,4-tetramethoxy-5-methylcyclohex-2-en- 1-one (0.5 g, 2.17 mmol) in THF (5.0 mL) at -78 °C was added lithium hexamethyldisilazide (LHMDS, 4.34 mmol, 4.3 mL of 1.0 M solution in THF). The mixture was stirred for 2 h, and a solution of farnesyl bromide (1.2 g, 4.34 mmol) in THF (3.0 mL) was added at -78 °C. The dry- ice cooling bath was removed, and the mixture was allowed to warm to room temperature and stirred for 5 h, quenched with water (5.0 mL), and then extracted with EtOAc (3 x 20 mL). The organic phase was washed with brine (30 mL), dried over MgS0₄, and concentrated under reduced pressure. The residue was purified by column chromatography on A1₂0₃ with EtOAc/ hexane (8:92) to yield 6-farnesyl-2,3,4,4-tetramethoxy-5-methylcyclohex-2-en-l-one as a mixture of trans and cis isomers (800 mg, 85% yield). HRMS calcd for C₂₆H₄₃0₅: 435.3110, found: mlz 435.3104 [M + H]⁺. C₂₆H₄₂0₅; IR v_max (neat) 2965, 2927, 2853, 1673, 1615, 1450, 1265, 1087, 1025, 970, 873, 833 cm^"1. 1H NMR (1 :1 isomers, 400 MHz, CDC1₃) δ 5.05 (6 H, d, J = 6.0 Hz, olefinic protons), 4.09 (3 H, s, trans), 4.05 (3 H, s, cis), 3.63 (6 H, s), 3.28 (3 H, s, cis), 3.27 (3 H, s, trans), 3.24 (3 H, s, trans), 3.22 (3 H, s, cis), 2.80 (1 H, dt, J= 9.7, 4.4 Hz, cis), 2.69-2.51 (2 H, m), 2.40 (1 H, qd, J= 7.0, 4.4 Hz, cis), 2.35-2.23 (3 H, m, trans), 2.09-1.88 (17 H, m), 1.63 (6 H, s), 1.60 (6 H, s) 1.55 (12 H, s), 0.94 (3 H, d, J= 6.5 Hz, trans), 0.78 (3 H, d, J = 7.0 Hz, cis). ¹³C NMR (1 :1 isomers, 100 MHz, CDC1₃) δ 196.4, 196.2, 158.8, 157.3, 145.0, 138.4, 137.2, 136.9, 135.0, 134.9, 131.2, 131.1, 124.4, 124.3, 124.2, 124.1, 124.0, 121.5, 121.4, 101.2, 101.1, 60.8, 60.7, 60.3, 60.2, 51.0, 50.9, 50.7, 49.2, 47.5, 47.0, 42.0, 39.9, 39.8, 39.7 (2 x), 37.5, 35.7, 28.9, 26.7, 26.6, 26.5, 25.6 (2 x), 24.5, 17.6 (2 x), 16.1, 16.0, 15.9, 14.6, 9.4. HRMS calcd for C₂₆H₄₃0₅: 435.3110, found: mlz 435.3104 [M + H]⁺.

[00244] Example 19. Alkylation reaction of formula (I) to formula (II)

Synthesis of 6-allyl-4,4-tetramethoxy-5-methylcyclohex-2-en- 1 -one Under an atmosphere of nitrogen, 4,4-dimethoxy-5-methylcyclohex-2-en-l-one was treated with lithium diisopropylamide (LDA) and allyl bromide to give the alkylation product 6-allyl-4,4- tetramethoxy-5-methylcyclohex-2-en-l-one as a mixture of cis and trans isomers.

Os-isomer: 1H NMR (400 MHz, C₆D₆) δ 6.24 (1 H, d, J= 10.0 Hz), 5.90 (1 H, d, J= 10.0 Hz), 5.28-5.68 (1 H, m), 5.13^1.97 (2 H, m), 3.01 (2 H, br s), 2.98 (3 H, s), 2.93 (3 H, s), 2.48 (1 H, tt, J= 6.7, 3.4 Hz), 2.03 (1 H, dt, J= 15.8, 9.9 Hz), 0.75 (3 H, d, J= 7.0 Hz). ¹³C NMR (100 MHz, C₆D₆) δ 198.8, 144.2, 136.7, 130.9, 116.5, 100.2, 49.3, 48.2, 46.8, 39.1, 31.0, 9.5.

Trans-isomer. 1H NMR (400 MHz, C₆D₆) δ 6.26 (1 H, d, J= 10.5 Hz), 5.96-5.81 (2 H, m), 5.19-5.04 (2 H, m), 3.00 (3 H, s), 2.88 (3 H, s), 2.80-2.68 (1 H, m), 2.58-2.47 (1 H, m), 2.41 (1 H, d, J= 7.0 Hz), 2.36-2.27 (1 H, m), 0.93 (3 H, d, J= 7.0 Hz). ¹³C NMR (100 MHz, C₆D₆) δ 199.1, 145.8, 136.6, 130.9, 116.9, 99.2, 52.0, 49.2, 48.1, 37.6, 35.1, 15.1.

[00245] Example 20. Alkylation reaction of formula (I) to formula (II)

Synthesis of 6-benzyl-2,3,4,4-tetramethoxy-5-methylcyclohex-2-en-l-one

[00246] Under an atmosphere of nitrogen, 2,3,4,4-tetramethoxy-5-methylcyclohex-2-en-l-one (0.5 g, 2.17 mmol) was treated with LHMDS (4.34 mmol, 4.3 mL of 1.0 M solution in THF) and benzyl bromide (0.7 g, 4.34 mmol) to give the desired alkylation product (trans/cis = 1 :1) as shown in the 1H NMR spectrum. HRMS calcd for C₁₈H₂₅0₅: 321.1702, found: mlz 321.1692 [M + H]⁺. The structure of cw-6-benzyl-2,3,4,4-tetramethoxy-5-methylcyclohex-2-en-l-one was confirmed by X-ray diffraction analysis (IC 17004, deposit CCDC 1036453).

[00247] Example 21. Alkylation reaction of formula (I) to formula (II)

Synthesis of 2,3,4,4-tetramethoxy-5-methyl-6-prenylcyclohex-2-en-l-one

Under an atmosphere of nitrogen, 2,3,4,4-tetramethoxy-5-methylcyclohex-2-en-l-one was treated with LHMDS and prenyl bromide to give the desired alkylation product (a mixture of trans and cis isomers) as shown in the ^!H NMR spectrum. HRMS calcd for C₁₆H₂₇0₅: 299.1858, found: mlz 299.1859 [M + H]⁺.

[00248] 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. The mixture was stirred for 2 h, and a solution of allyl bromide (0.7 g, 5.88 mmol) in THF (3.0 mL) was added at -78 °C. The dry-ice cooling bath was removed, and the mixture was allowed to warm to room temperature over a period of 5-12 h, quenched with water (5.0 mL), and then extracted with EtOAc (3 x 20 mL). The organic phase was washed with brine (30 mL), dried over MgS0₄, and concentrated under reduced pressure. The residue was purified by column chromatography on aluminum oxide with elution of EtOAc/hexane (8:92) to yield the alkylation product 6-allyl-5-methyl-4,4- dimethoxycyclohex-2-en-l-one (890 mg, 95% yield as a mixture of cis and trans isomers). The diastereomers were separated by chromatography.

(5R,6S)-isomer: [a]²⁰ _D -31.1 (c 2.3, CHC1₃). 1H NMR (400 MHz, C₆D₆) δ 6.24 (1 H, d, J= 10.0 Hz), 5.90 (1 H, d, J= 10.0 Hz), 5.28-5.68 (1 H, m), 5.13^1.97 (2 H, m), 3.01 (2 H, br s), 2.98 (3 H, s), 2.93 (3 H, s), 2.48 (1 H, tt, J= 6.7, 3.4 Hz), 2.03 (1 H, dt, J= 15.8, 9.9 Hz), 0.75 (3 H, d, J = 7.0 Hz). ¹³C NMR (100 MHz, C₆D₆) δ 198.8, 144.2, 136.7, 130.9, 116.5, 100.2, 49.3, 48.2, 46.8, 39.1, 31.0, 9.5.

(5/?,6/?)-isomer: [a]²⁰ _D -3.6 (c 2.0, CHC1₃). 1H NMR (400 MHz, C₆D₆) δ 6.26 (1 H, d, J= 10.5 Hz), 5.96-5.81 (2 H, m), 5.19-5.04 (2 H, m), 3.00 (3 H, s), 2.88 (3 H, s), 2.80-2.68 (1 H, m), 2.58-2.47 (1 H, m), 2.41 (1 H, d, J= 7.0 Hz), 2.36-2.27 (1 H, m), 0.93 (3 H, d, J= 7.0 Hz). ¹³C NMR (100 MHz, C₆D₆) δ 199.1, 145.8, 136.6, 130.9, 116.9, 99.2, 52.0, 49.2, 48.1, 37.6, 35.1, 15.1.

[00249] Example 23. Alkylation reaction of formula (I) to formula (II)

Synthesis of (55^,,6/?/S)-2-chloro-6-farnesyl-3,4,4-trimethoxy-5-methylcyclohex-2-en-l-one

Under an atmosphere of nitrogen, LHMDS (0.86 mmol, 0.9 mL of 1.0 M solution in THF) was added to a solution of (5)-2-chloro-3,4,4-trimethoxy-5-methylcyclohex-2-en-l-one (100 mg, 0.43 mmol) in THF (2.0 mL) at -78 °C. The mixture was stirred for 2 h, and a solution of farnesyl bromide (245 mg, 0.86 mmol) in THF (1.0 mL) was added at -78 °C. The dry-ice cooling bath was removed, and the mixture was allowed to warm to room temperature over a period of 12 h, quenched with water (5.0 mL), and then extracted with EtOAc (3 x 20 mL). The organic phase was washed with brine (30 mL), dried over MgS0₄, and concentrated under reduced pressure. The residue was purified by column chromatography on aluminum oxide with elution of

EtOAc/hexane (5:95) to yield the alkylation product (170 mg, 90% yield) as a mixture of trans and cis isomers (1 :1). This sample (170 mg, 0.39 mmol) containing trans and cis isomers (1 :1) was subjected to epimerization by treatment with NaH (2.0 mg, 0.04 mmol) in DMF (3.0 mL) at 25 °C for 24 h, giving the trans and cis isomers in a ratio of 1 :4. HRMS calcd for C₂₅H₃₉ClNa0₄: 416.2429, found: 416.2430 [M + Na]⁺.

[00250] Example 24. Alkylation reaction of formula (I) to formula (II)

Synthesis of (55^,,6/?/S)-6-farnesyl-3,4,4-trimethoxy-5-methylcyclohex-2-en-l-one

Under an atmosphere of nitrogen, LHMDS (1.0 mmol, 1.0 mL of 1.0 M solution in THF) was added to a solution of (5)-3,4,4-trimethoxy-5-methylcyclohex-2-en-l-one (100 mg, 0.5 mmol) in THF (2.0 mL) at -78 °C. The mixture was stirred for 2 h, and a solution of farnesyl bromide (285 mg, 1.0 mmol) in THF (1.0 mL) was added at -78 °C. The dry- ice cooling bath was removed, and the mixture was allowed to warm to room temperature over a period of 2 h, quenched with water (5.0 mL), and then extracted with EtOAc (3 x 20 mL). The organic phase was washed with brine (30 mL), dried over MgS0₄, and concentrated under reduced pressure. The residue was purified by column chromatography on aluminum oxide with elution of EtOAc/ hexane (10:90) to yield the alkylation product (192 mg, 95% yield) as a mixture of trans and cis isomers (1 :1). This sample (192 mg, 0.48 mmol) containing trans and cis isomers (1 :1) was subjected to epimerization by treatment with NaH (2.0 mg, 0.05 mmol) in DMF (3.0 mL) at 25 °C for 24 h, giving the trans and cis isomers in a ratio of 1 :4. HRMS calcd for C₂₅H₄₁0₄: 405.3005, found: mlz 405.3004 [M + H]⁺.

[00251] Example 25. Reduction and hydrolysis of formula (II) to formulae (IV) and (VI)

Synthesis of 5-farnesyl-4-hydroxy-2,3-dimethoxy-6-methylcyclohex-2-en-l-one and 5-farnesyl- 6-hydroxy-2,3-dimethoxy-4-methylcyclohex-2-en- 1 -one

Under an atmosphere of nitrogen, a solution of 6-farnesyl-2,3,4,4-tetramethoxy-5- methylcyclohex-2-en-l-one (0.9 g, 2.07 mmol) containing trans and cis isomers (1 :1) in THF (5.0 mL) was stirred at -40 °C for 15 min, and Li(s-Bu)₃BH (L-Selectride, 4.14 mmol, 4.2 mL of 1.0 M solution in THF) was added dropwise. The mixture was stirred at -40 °C for 5 h, quenched with water (5.0 mL), and then extracted with EtOAc (3 x 20 mL) and brine (30 mL). The organic phase was dried over MgS0₄, and concentrated under reduced pressure. The residue was dissolved in CHC1₃ (5.0 n L), and oxalic acid (0.2 g, 2.17 mmol) was added at room temperature. The mixture was stirred for 10 min, quenched with water (5.0 mL), and then extracted with CH₂C1₂ (3 x 20 mL). The organic phase was washed with brine (30 mL), dried over MgS0₄, and concentrated under reduced pressure. The residue was purified by column chromatography on Si0₂ with EtOAc/hexane (15:85) to yield 5-farnesyl-4-hydroxy-2,3- dimethoxy-6-methylcyclohex-2-en-l-one (containing stereoisomers) and 5-farnesyl-6-hydroxy- 2,3-dimethoxy-4-methylcyclohex-2-en- 1 -one (containing stereoisomers).

5-Farnesyl-4-hydroxy-2,3-dimethoxy-6-methylcyclohex-2-en-l-one, formula (IV):

(4,5-c£s-5,6-fra/w)-Isomer (antroquinonol): C₂₄H₃₈0₄; 1H NMR (500 MHz, CDC1₃) δ 5.14 (1 H, t, J= 7.3 Hz), 5.07 (2 H, t, J= 6.7 Hz), 4.34 (1 H, d, J= 3.1 Hz), 4.05 (3 H, s), 3.65 (3 H, s), 2.52 (1 H, qd, J= 6.7, 11.0 Hz), 2.22 (2 H, t, J= 7.3 Hz), 2.12-1.92 (8 H, m), 1.74 (1 H, dtd, J= 10.9, 7.5, 3.4 Hz), 1.66 (3 H, s), 1.64 (3 H, s), 1.58 (6 H, s), 1.16 (3 H, d, J= 6.7 Hz). ¹³C NMR (125 MHz, CDC1₃) δ 197.1, 160.4, 138.1, 135.9, 135.4, 131.1, 124.3, 123.9, 121.0, 68.0, 60.6, 59.2, 43.4, 40.3, 39.8, 39.7, 27.0, 26.8, 26.4, 25.7, 17.7, 16.1, 16.0, 12.3. HRMS calcd for C₂₄H₃₈0₄: 391.2848, found: mlz 391.2854 [M + H]⁺.

(4,5-trara-5,6-trara)-Isomer: C₂₄H₃₈0₄; IR v_max (neat) 3439, 2967, 2851, 1666, 1614, 1450, 1280, 1073, 994, 791, 747 cm^"1. 1H NMR (500 MHz, CDC1₃) δ 5.11 (1 H, t, J= 7.3 Hz), 5.05 (2 H, t, J = 6.4 Hz), 4.25 (1 H, d, J = 8.5 Hz), 4.10 (3 H, s), 3.64 (3 H, s), 2.60 (1 H, br s), 2.58-2.51 (1 H, m), 2.24-2.17 (1 H, m), 2.17-1.89 (9 H, m), 1.84-1.77 (1 H, m), 1.65 (6 H, s), 1.57 (6 H, s), 1.19 (3 H, d, J= 6.7 Hz). ¹³C NMR (125 MHz, CDC1₃) δ 197.1, 160.3, 138.7, 135.2, 135.2, 131.3, 124.3, 124.0, 118.8, 69.2, 60.7, 60.3, 45.9, 42.0, 40.0, 39.7, 26.7, 26.5, 26.3, 25.7, 17.7, 16.3, 16.0, 13.1. HRMS calcd for C₂₄H₃₉0₄: 391.2848, found: mlz 391.2854 [M + H]⁺.

(4,5-cw-5,6-cw)-Isomer: C₂₄H₃₈0₄; IR v_max (neat) 3424, 2922, 2850, 1737, 1612, 1450, 1231, 1043, 1012, 773 cm^"1. 1H NMR (500 MHz, CDC1₃) δ 5.15-5.03 (3 H, m), 4.40 (1 H, br s), 4.07 (3 H, s), 3.65 (3 H, s), 2.46 (1 H, qd, J= 7.3, 4.3 Hz), 2.38-2.28 (1 H, m), 2.15-1.91 (11 H, m), 1.65 (3 H, s), 1.63 (3 H, s), 1.57 (6 H, s), 1.23 (3 H, d, J= 7.3 Hz). ¹³C NMR (125 MHz, CDC1₃) δ 199.2, 160.6, 137.4, 135.3, 135.2, 131.3, 124.3, 123.9, 121.5, 69.7, 60.5, 59.6, 44.1, 40.3, 39.8, 39.7, 26.8, 26.5, 25.7, 25.6, 17.7, 16.2, 16.0, 14.8. HRMS calcd for C₂₄H₃₈0₄: 391.2848, found: mlz 391.2854 [M + H]⁺. (4,5-trara-5,6-cw)-Isomer: C₂₄H₃₈0₄; IR v_max (neat) 3431, 2976, 2919, 2849, 1667, 1614, 1451, 1234, 1039, 969, 781, 750 cm^-1. 1H NMR (400 MHz, CDC1₃) δ 5.13-5.02 (3 H, m), 4.29 (1 H, d, J= 4.4 Hz), 4.05 (3 H, s), 3.65 (3 H, s), 2.88 (1 H, qd, J= 6.8, 3.8 Hz), 2.38 (1 H, br s), 2.13- 1.90 (11 H, m), 1.65 (3 H, s), 1.57 (6 H, s), 1.54 (3 H, s), 1.08 (3 H, d, J= 6.8 Hz). ¹³C NMR (100 MHz, CDC1₃) δ 197.6, 158.9, 137.8, 135.5, 135.2, 131.3, 124.3, 123.9, 121.2, 69.6, 60.6, 59.5, 44.8, 40.2, 39.8, 39.7, 26.7, 26.5, 25.7, 25.5, 17.7, 16.1, 16.0, 11.8. HRMS calcd for C₂₄H₃₈0₄: 391.2848, found: mlz 391.2854 [M + H]⁺.

5-Farnesyl-6-hydroxy-2,3-dimethoxy-4-methylcyclohex-2-en- 1 -one, formula (VI) :

(4,5-cw-5,6-trara)-Isomer: C₂₄H₃₈0₄; IR v_max (neat) 3468, 2961, 2920, 1666, 1610, 1456, 1280, 1044, 994, 800, 790 cm^-1. 1H NMR (500 MHz, CDC1₃) δ 5.10^.99 (3 H, m), 4.42 (1 H, d, J = 5.5 Hz), 4.01 (3 H, s), 3.65 (3 H, s), 3.57 (1 H, s), 2.61 (1 H, qd, J= 7.3, 1.6 Hz), 2.25-2.19 (1 H, m), 2.11-1.90 (9 H, m), 1.79-1.69 (1 H, m), 1.66 (3 H, s), 1.57 (6 H, s), 1.50 (3 H, s), 1.29 (3 H, d, J= 7.3 Hz). ¹³C NMR (125 MHz, CDC1₃) δ 194.9, 166.7, 138.0, 135.1, 133.5, 131.3, 124.3, 123.9, 121.9, 70.8, 60.6, 59.2, 44.9, 39.8, 39.7, 34.6, 26.7, 26.5, 25.7, 24.0, 17.7, 17.6, 16.1, 16.0. HRMS calcd for C₂₄H₃₈0₄: 391.2848, found: mlz 391.2854 [M + H]⁺.

(4,5-trara-5,6-trara)-Isomer: C₂₄H₃₈0₄; IR v_max (neat) 3470, 2961, 2927, 1666, 1601, 1454, 1301, 1201, 1046, 984, 963, 802 cm^"1. 1H NMR (400 MHz, CDC1₃) δ 5.18 (1 H, t, J= 7.5 Hz), 5.05 (2

H, t, J= 6.3 Hz), 4.04 (3 H, s), 3.84 (1 H, d, J= 12.5 Hz), 3.72 (1 H, s), 3.63 (3 H, s), 2.56-2.40 (2 H, m), 2.37-2.25 (1 H, m), 2.13-1.88 (8 H, m), 1.66 (3 H, s), 1.65 (3 H, s), 1.63-1.60 (1 H, m),

I.59 (3 H, s), 1.57 (3 H, s), 1.19 (3 H, d, J= 7.0 Hz). ¹³C NMR (100 MHz, CDC1₃) δ 196.2, 167.4, 138.4, 135.1, 133.5, 131.3, 124.3, 124.1, 118.7, 72.2, 60.6, 60.6, 46.1, 40.1, 39.8, 35.3, 26.8, 26.4, 25.7, 25.2, 17.7, 16.3, 16.0, 15.4. HRMS calcd for C₂₄H₃₈0₄: 391.2848, found: mlz 391.2854 [M + H]⁺.

(4,5-cw-5,6-cw)-Isomer: C₂₄H₃₈0₄; IR v_max (neat) 3458, 2966, 2921, 2852, 1665, 1597, 1451, 1309, 1027, 975, 935, 775 cm^"1. 1H NMR (400 MHz, CDC1₃) δ 5.14-5.01 (3 H, m), 4.12 (1 H, d, J= 2.0 Hz), 4.07 (3 H, s), 3.64 (3 H, s), 3.54 (1 H, br s), 2.86 (1 H, qd, J= 7.0, 4.5 Hz), 2.25 (1 H, m), 2.10-1.89 (10 H, m), 1.66 (3 H, s), 1.58 (3 H, s), 1.56 (3 H, s), 1.55 (3 H, s), 1.20 (3 H, d, J= 7.0 Hz). ¹³C NMR (100 MHz, CDC1₃) δ 195.5, 166.8, 135.4, 135.0, 134.3, 131.2, 124.4, 124.1, 123.5, 75.3, 60.7, 60.4, 45.1, 39.8, 39.7, 37.1, 26.7, 26.5, 25.7, 22.1, 17.7, 16.0, 16.0, 15.0. HRMS calcd for C₂₄H₃₈0₄: 391.2848, found: mlz 391.2854 [M + H]⁺. (4,5-trara-5,6-czV)-Isomer: C₂₄H₃₈0₄; IR v_max (neat) 3450, 2967, 2920, 1666, 1600, 1450, 1280, 1073, 994, 791, 770 cm^"1. 1H NMR (500 MHz, CDC1₃) δ 5.08-5.05 (3 H, m), 4.05 (3 H, s), 3.91 (1 H, d, J= 12.2 Hz), 3.65 (3 H, s), 2.62-2.57 (2 H, m), 2.13-1.88 (10 H, m), 1.66 (3 H, s), 1.64 (3 H, s), 1.58 (6 H, br s), 1.11 (3 H, d, J= 7.3 Hz). ¹³C NMR (125 MHz, CDC1₃) δ 195.7, 170.2, 137.5, 135.2, 133.6, 131.3, 124.4, 123.9, 120.3, 71.6, 60.8, 59.5, 43.4, 39.8, 39.7, 34.4, 26.8, 26.4 (2 x), 25.7, 17.7, 16.3, 16.0, 11.9. HRMS calcd for C₂₄H₃₈0₄: 391.2848, found: mlz 391.2854 [M + H]⁺.

[00252] Example 26. Reduction and hydrolysis of formula (II) to formulae (IV) and (VI)

By a similar procedure, a THF solution of trans-6-farnesyl-2,3,4,4-tetramethoxy-5- methylcyclohex-2-en-l-one (0.9 g, 2.17 mmol) was reduced with LiAlH₄ (0.2 g, 4.34 mmol, 1.0 M in THF) at -40 °C for 5 h, followed by hydrolysis with oxalic acid, to give (4,5-tr n-s-5,6- tran-s^,)-5-farnesyl-4-hydroxy-2,3-dimethoxy-6-methylcyclohex-2-en-l-one (139 mg, 17% yield) and (4,5-tran-s^,-5,6-tran-s^,)-5-farnesyl-6-hydroxy-2,3-dimethoxy-4-methylcyclohex-2-en-l-one (589 mg, 73% yield).

[00253] Example 27. Reduction and hydrolysis of formula (II) to formulae (IV) and (VI)

By a similar procedure, a THF solution of 6-farnesyl-2,3,4,4-tetramethoxy-5-methylcyclohex-2- en-l-one {translcis = 1 :1, 0.9 g, 2.17 mmol) was reduced with LiAlH (0.2 g, 4.34 mmol, 1.0 M in THF) at -40 °C for 5 h, followed by hydrolysis with oxalic acid, to give 5-farnesyl-4- hydroxy-2,3-dimethoxy-6-methylcyclohex-2-en-l-one (containing stereoisomers, 34% yield) and 5-farnesyl-6-hydroxy-2,3-dimethoxy-4-methylcyclohex-2-en- 1 -one (containing stereoisomers, 56% yield).

[00254] Example 28. Reduction and hydrolysis of formula (II) to formulae (IV) and (VI)

By a similar procedure, reduction of 6-farnesyl-2,3,4,4-tetramethoxy-5-methylcyclohex-2-en-l- one {translcis = 1 :1) with -Bu₂AlH in THF at -78 °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, 37% yield) and 5-farnesyl-6-hydroxy-2,3-dimethoxy-4-methylcyclohex-2-en-l- one (containing stereoisomers, 56% yield).

[00255] Example 29. Reduction and hydrolysis of formula (II) to formulae (IV) and (VI) By a similar procedure, reduction of 6-farnesyl-2,3,4,4-tetramethoxy-5-methylcyclohex-2-en-l- one (translcis = 1 :1) with Li(Ot-Bu)₃AlH 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).

[00256] Example 30. Reduction and hydrolysis of formula (II) to formulae (IV) and (VI)

By a similar procedure, reduction of 6-farnesyl-2,3,4,4-tetramethoxy-5-methylcyclohex-2-en-l- one (2.07 mmol, translcis = 1 :1) with NaBH₄ (4.14 mmol) and CeCl₃ ^»7H₂0 (4.14 mmol) in MeOH 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, 37% yield) and 5-farnesyl- 6-hydroxy-2,3-dimethoxy-4-methylcyclohex-2-en-l-one (containing stereoisomers, 55% yield).

[00257] Example 31. Reduction and hydrolysis of formula (II) to formulae (IV) and (VI)

By a similar procedure, reduction of 6-farnesyl-2,3,4,4-tetramethoxy-5-methylcyclohex-2-en-l- one {translcis = 1 :1) with LiEt₃BH (Super-Hydride) in THF at -78 °C for 5 h, followed by hydrolysis with oxalic acid, gave 5-farnesyl-4-hydroxy-2,3-dimethoxy-6-methylcyclohex-2-en- 1-one (containing stereoisomers, 31% yield) and 5-farnesyl-6-hydroxy-2,3-dimethoxy-4- methylcyclohex-2-en-l-one (containing stereoisomers, 57% yield).

[00258] Example 32. Reduction and hydrolysis of formula (II) to formulae (IV) and (VI)

By a similar procedure, reduction of 6-farnesyl-2,3,4,4-tetramethoxy-5-methylcyclohex-2-en-l- one (translcis = 1 :1) with Li(siamyl)₃BH (LS-Selectride) in THF at -40 °C for 5 h, followed by hydrolysis with oxalic acid, gave 5-farnesyl-4-hydroxy-2,3-dimethoxy-6-methylcyclohex-2-en- 1-one (containing stereoisomers, 28% yield) and 5-farnesyl-6-hydroxy-2,3-dimethoxy-4- methylcyclohex-2-en-l-one (containing stereoisomers, 66% yield).

[00259] Example 33. Reduction and hydrolysis of formula (II) to formulae (IV) and (VI)

Synthesis of 5-benzyl-4-hydroxy-2,3-dimethoxy-6-methylcyclohex-2-en-l-one and 5-benzyl-6- hydroxy-2,3-dimethoxy-4-methylcyclohex-2-en- 1 -one

By a similar procedure, a solution 6-benzyl-2,3,4,4-tetramethoxy-5-methylcyclohex-2-en-l-one containing trans and cis isomers was treated with an appropriate reducing agent (LiAlH₄, DIB AL, LiAl(Ot-Bu)₃H, NaBH₄-CeCl₃, Super-Hydride, L-Selectride or LS-Selectride), followed by hydrolysis with oxalic acid, to give 5-benzyl-4-hydroxy-2,3-dimethoxy-6-methylcyclohex-2-en- 1-one (containing stereoisomers) and 5-benzyl-6-hydroxy-2,3-dimethoxy-4-methylcyclohex-2- en- 1-one (containing stereoisomers).

5-Benzyl-4-hydroxy-2,3-dimethoxy-6-methylcyclohex-2-en- 1 -one, formula (IV) :

(4,5-cis-5,6-trans)-lsomer. C₁₆H₂₀O₄; IR v_max (neat) 3431, 3026, 2932, 1660, 1619, 1454, 1240, 1015, 942, 751, 703 cm^"1. 1H NMR (500 MHz, CDC1₃) δ 7.31-7.26 (2 H, m), 7.23-7.18 (3 H, m), 3.98 (4 H, br s), 3.64 (3 H, s), 2.90 (1 H, dd, J= 13.1, 5.2 Hz), 2.75 (1 H, dd, J= 13.1, 11.0 Hz), 2.59 (1 H, qd, J= 6.7, 11.0 Hz), 2.03-1.93 (2 H, m), 1.25 (3 H, d, J= 6.7 Hz). ¹³C NMR (125 MHz, CDC1₃) δ 196.8, 160.4, 139.2, 135.8, 129.2 (2 x), 128.6 (2 x), 126.4, 66.9, 60.7, 59.4, 45.0, 40.3, 34.4, 12.6. HRMS calcd for C₁₆H₂₁0₄: 277.1440, found: mlz 2Ί Π ^'.1439 [M + H]⁺.

(4,5-trans-5,6-trans)-Isomer: C₁₆H₂₀O₄; White solid, mp 75.5-77.3 °C; IR v_max (neat) 3427, 3026, 2935, 2880, 1660, 1614, 1454, 1234, 1011, 969, 750, 702 cm^-1. 1H NMR (400 MHz, CDC1₃) δ 7.33-7.15 (5 H, m), 4.20 (1 H, d, J= 7.5 Hz), 4.08 (3 H, s), 3.62 (3 H, s), 3.03 (1 H, dd, J= 14.1, 5.0 Hz), 2.84 (1 H, dd, J=14.1, 4.5 Hz), 2.65 (1 H, br s), 2.22-2.13 (1 H, m), 2.13-2.00 (1 H, m), 1.35 (3 H, d, J= 7.0 Hz). ¹³C NMR (100 MHz, CDC1₃) δ 196.8, 160.1, 138.0, 134.9, 129.9 (2 x), 128.4 (2 x), 126.4, 68.7, 60.7, 60.3, 46.5, 42.2, 34.9, 14.9. HRMS calcd for C₁₆H₂₁0₄: 277.1440, found: mlz 277.1439 [M + Hf. A sample was recrystallized from EtOAc/hexane. The 4,5-trans- 5,6-trans configuration was unambiguously determined by X-ray crystallography (IC 16470, deposit CCDC 1036448).

(4,5-cw-5,6-cw)-Isomer: C₁₆H₂₀O₄; White solid, mp 137.8-138.9; IR v_max (neat) 3420, 3025, 2980, 2835, 1665, 1614, 1454, 1204, 1023, 969, 754, 712 cm^-1. 1H NMR (500 MHz, CDC1₃) δ 7.32-7.15 (5 H, m), 4.23 (1 H, d, J= 3.7 Hz), 4.05 (3 H, s), 3.64 (3 H, s), 2.99 (1 H, dd, J= 13.4, 8.5 Hz), 2.67 (1 H, dd, J= 13.4, 6.1 Hz), 2.49 (1 H, qd, J=7.3, 4.3 Hz), 2.41-2.32 (1 H, m), 1.30 (3 H, d, J= 7.3 Hz). ¹³C NMR (125 MHz, CDC1₃) δ 199.1, 160.5, 139.6, 135.2, 129.0 (2 x), 128.6 (2 x), 126.3, 69.2, 60.6, 59.8, 44.3, 41.5, 33.6, 15.0. HRMS calcd for C₁₆H₂₁0₄: 277.1440, found: mlz 277.1439 [M + Hf. A sample was recrystallized from EtOAc/hexane. The 4,5-cis- 5,6-cis configuration was unambiguously determined by X-ray crystallography (IC 16707, deposit CCDC 1036452).

(4,5-trans-5,6-cis)-lsomer. C₁₆H₂₀O₄; White solid, mp 168.7-169.5 °C; IR v_max (neat) 3430, 3016, 2970, 2884, 1663, 1620, 1451, 1224, 1013, 959, 757, 700 cm^-1. 1H NMR (500 MHz, CDC1₃) δ 7.31-7.23 (2 H, m), 7.23-7.15 (1 H, m), 7.11 (2 H, d, J= 7.3 Hz), 4.23 (1 H, d, J= 5.5 Hz), 4.03 (3 H, s), 3.67 (3 H, s), 2.81 (1 H, qd, J= 7.3, 4.3 Hz), 2.77-2.69 (1 H, m), 2.69-2.60 (1 H, m), 2.34-2.25 (1 H, m), 1.17 (3 H, d, J= 7.3 Hz). ¹³C NMR (125 MHz, CDC1₃) δ 197.4, 158.9, 139.1, 135.6, 128.8 (2 x), 128.6 (2 x), 126.4, 68.9, 60.6, 59.6, 46.0, 40.0, 33.2, 11.8. HRMS calcd for C₁₆H₂₁0₄: 277.1440, found: mlz 277.1439 [M + H]⁺. A sample was recrystallized from

EtOAc/hexane. The 4,5-trans-5,6-cis configuration was unambiguously determined by X-ray crystallography (IC16473, deposit CCDC 1036450) .

5-Benzyl-6-hydroxy-2,3-dimethoxy-4-methylcyclohex-2-en- 1 -one, formula (VI)

(4,5-cw-5,6-trara)-Isomer: C₁₆H₂₀O₄; IR v_max (neat) 3465, 3025, 2928, 2852, 1667, 1606, 1454, 1260, 1008, 972, 748, 701 cm^-1. 1H NMR (500 MHz, CDC1₃) δ 7.30-7.22 (2 H, m), 7.21-7.16 (1

H, m), 7.08 (2 H, d, J= 7.3 Hz), 4.50 (1 H, d, J= 5.5 Hz), 3.98 (3 H, s), 3.69 (3 H, s), 3.05 (1 H, dd, J= 14.0, 3.1 Hz), 2.49 (1 H, qd, J= 7.3, 1.2 Hz), 2.44-2.35 (1 H, m), 2.18-2.05 (1 H, m),

I.21 (3 H, d, J= 7.3 Hz). ¹³C NMR (125 MHz, CDC1₃) δ 194.5, 166.7, 139.8, 133.6, 129.1 (2 x), 128.6 (2 x), 126.2, 70.7, 60.7, 59.1, 46.5, 33.8, 31.8, 17.7. HRMS calcd for C₁₆H₂₁0₄: 277.1440, found: mlz 277.1439 [M + H]⁺.

(4,5-trans-5,6-trans)-Isomer: C₁₆H₂₀O₄; Pale yellow solid, mp 59.5-61.2 °C; IR v_max (neat) 3460, 3027, 2937, 2881, 1746, 1602, 1454, 1259, 1040, 977, 753, 702 cm^"1. 1H NMR (400 MHz, CDC1₃) δ 7.32-7.26 (4 H, m), 7.26-7.17 (1 H, m), 3.98 (3 H, s), 3.83 (1 H, br s), 3.74 (1 H, d, J = 12.5 Hz), 3.60 (3 H, s), 3.16 (1 H, dd, J= 14.1, 4.5 Hz), 2.92 (1 H, dd, J= 14.1, 3.5 Hz), 2.37 (1 H, qd, J= 10.2, 6.5 Hz), 1.89-1.76 (1 H, m), 1.31 (3 H, d, J= 6.5 Hz). ¹³C NMR (100 MHz, CDC1₃) δ 195.8, 166.9, 137.2, 133.3, 130.5 (2 x), 128.3 (2 x), 126.4, 71.3, 60.6, 60.5, 46.3, 34.7, 32.7, 15.7. HRMS calcd for C₁₆H₂₁0₄: 277.1440, found: mlz 2Ί Π ^'.1439 [M + H]⁺. A sample was recrystallized from EtOAc/hexane. The 4,5-trans-5,6-trans configuration was unambiguously determined by X-ray crystallography (IC16451, deposit CCDC 1036447).

(4,5-cw-5,6-czV)-Isomer: C₁₆H₂₀O₄; White solid, mp 99.8-101.3 °C; IR v_max (neat) 3440, 2924, 2852, 1755, 1651, 1454, 1226, 1025, 959, 735, 701 cm^"1. 1H NMR (400 MHz, CDC1₃) δ 7.23- 7.10 (5 H, m), 4.12 (1 H, d, J= 4.5 Hz), 4.08 (3 H, s), 3.64 (3 H, s), 2.91-2.82 (1 H, m), 2.82- 2.71 (1 H, m), 2.59-2.47 (2 H, m), 1.17 (3 H, d, J= 7.0 Hz). ¹³C NMR (100 MHz, CDC1₃) δ 195.3, 167.2, 141.3, 134.4, 129.0 (2 x), 128.3 (2 x), 125.8, 74.9, 60.7, 60.3, 45.9, 37.3, 30.4, 15.3. HRMS calcd for C₁₆H₂₁0₄: 277.1440, found: mlz 277.1439 [M + H]⁺. A sample was recrystallized from EtOAc/hexane. The 4,5-cis-5,6-cis configuration was unambiguously determined by X-ray crystallography (IC 16471, deposit CCDC 1036449).

(4,5-trara-5,6-cw)-Isomer: C₁₆H₂₀O₄; IR v_max (neat) 3471, 2924, 2853, 1666, 1607, 1454, 1233, 1048, 955, 748, 701 cm^"1. 1H NMR (500 MHz, CDC1₃) δ 7.30-7.26 (2 H, m), 7.22-7.17 (3 H, m), 4.02 (1 H, d, J= 12.2 Hz), 3.97 (3 H, s), 3.69 (1 H, s), 3.65 (3 H, s), 3.35 (1 H, dd, J= 14.0, 3.7 Hz), 2.57 (1 H, dd, J= 14.0, 11.9 Hz), 2.34-2.22 (1 H, m), 1.19 (3 H, d, J= 6.7 Hz). ¹³C NMR (125 MHz, CDC1₃) δ 195.4, 170.2, 138.8, 133.6, 128.9 (2 x), 128.6 (2 x), 126.3, 71.3, 60.8, 59.5, 44.7, 33.7, 33.6, 12.1. HRMS calcd for C₁₆H₂₁0₄: 277.1440, found: mlz 277.1439 [M + H]⁺.

[00260] Example 34. Reduction and hydrolysis to formula (IV)

Synthesis of 5-allyl-4-hydroxy-6-methylcyclohex-2-en-l-one

By a similar procedure, a solution 6-allyl-4,4-tetramethoxy-5-methylcyclohex-2-en-l-one was treated with LiEt₃BH, followed by hydrolysis with oxalic acid, to give 5-allyl-4-hydroxy-6- methylcyclohex-2-en- 1 -one.

(4,5-cw-5,6-trara)-Isomer: 1H NMR (400 MHz, CDC1₃) δ 6.82 (1 H, d, J= 10.0 Hz), 5.99-5.81 (2 H, m), 5.26-5.12 (2 H, m), 4.42 (1 H, br s), 2.69-2.57 (1 H, m), 2.36-2.18 (2 H, m), 1.94- 1.87 (1 H, m), 1.18 (3 H, d, J= 7.0 Hz). ¹³C NMR (100 MHz, CDC1₃) δ 200.7, 151.6, 134.3, 128.3, 118.4, 69.6, 49.6, 43.4, 32.9, 11.7.

(4,5-cw-5,6-czV)-Isomer: 1H NMR (400 MHz, CDC1₃) δ 6.78 (1 H, d, J= 10.0 Hz), 5.96 (1 H, d, J = 10.0 Hz), 5.93-5.80 (1 H, m), 5.15^1.99 (2 H, m), 4.75^1.67 (1 H, m), 2.56 (1 H, qd, J= 6.9, 4.0 Hz), 2.41 (1 H, qd, J= 8.0, 4.0 Hz), 2.37-2.27 (1 H, m), 2.20-2.09 (1 H, m), 1.16 (3 H, d, J = 6.9 Hz). ¹³C NMR (100 MHz, CDC1₃) δ 201.4, 149.6, 138.0, 128.8, 116.5, 70.5, 46.1, 45.4, 29.4, 13.2.

[00261] Example 35. Reduction of formula (II) and hydrolysis to formula (IV)

Synthesis of 4-hydroxy-2,3-dimethoxy-6-methyl-5-prenylcyclohex-2-en-l-one

Under an atmosphere of nitrogen, 2,3,4,4-tetramethoxy-5-methyl-6-prenylcyclohex-2-en-l-one was reduced with NaBH₄/CeCl₃ ^»7H₂0, followed by hydrolysis with oxalic acid and

chromatographic separation on silica gel column (EtOAc/hexane = 10:90) to give 4-hydroxy-2,3- dimethoxy-6-methyl-5-prenylcyclohex-2-en-l-one. The 4,5-trans-5,6-trans isomer was isolated and recrystallized from EtOAc/hexane. C₁₄H₂₂0₄; white solid, mp 94.5-95.2 °C. 1H NMR (500 MHz, CDC1₃) δ 5.10 (1 H, t, J= 7.6 Hz), 4.26 (1 H, d, J= 8.5 Hz), 4.09 (3 H, s), 3.63 (3 H, s), 2.64 (1 H, s), 2.56-2.48 (1 H, m), 2.21 (1 H, dq, J= 11.0, 6.7 Hz), 2.16-2.09 (1 H, m), 1.83-1.76 (1 H, m), 1.70 (3 H, s), 1.64 (3 H, s), 1.19 (3 H, d, J= 6.7 Hz). ¹³C NMR (125 MHz, CDC1₃) δ 197.2, 160.3, 135.3, 135.1, 119.0, 69.2, 60.6, 60.3, 45.8, 42.1, 26.6, 26.0, 18.0, 13.3. The structure was confirmed by X-ray crystallography (IC16504, deposit CCDC 1036451).

[00262] Example 36. Reduction of formula (II) and hydrolysis to formula (IV)

Synthesis of (45',5/?,6/?)-5-allyl-4-hydroxy-6-methylcyclohex-2-en- 1 -one

Under an atmosphere of nitrogen, a solution of (5/?,6/?)-6-allyl -4,4-dimethoxy-5- methylcyclohex-2-en-l-one (0.9 g, 4.29 mmol) in THF (5.0 mL) was stirred at -78 °C for 15 min, and LiEt₃BH (8.57 mmol, 8.6 mL of 1.0 M solution in THF) was added dropwise. The mixture was stirred at -78 °C for 2 h, quenched with water (15.0 mL), and then extracted with EtOAc (3 x 20 mL) and brine (30 mL). The organic phase was dried over MgS0₄, and concentrated under reduced pressure. The residue was dissolved in acetone (5.0 mL), and ^-toluenesulfonic acid (0.8 g, 4.29 mmol) was added at 0 °C. The mixture was stirred for 30 min, quenched with water (5.0 mL), and then extracted with CH₂C1₂ (3 x 20 mL). The organic phase was washed with brine (30 mL), dried over MgS0₄, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with elution of EtOAc/hexane (15:85) to give (4S,5R,6R)- 5-allyl-4-hydroxy-6-methylcyclohex-2-en-l-one (0.5 g, 70% yield). C₁₀H₁₄O₂, [a]²⁰ _D -40.6 (c 4.0, CHC1₃); 1H NMR (400 MHz, CDC1₃) δ 6.82 (1 H, d, J= 10.0 Hz), 5.99-5.81 (2 H, m), 5.26- 5.12 (2 H, m), 4.42 (1 H, br s), 2.69-2.57 (1 H, m), 2.36-2.18 (2 H, m), 1.94-1.87 (1 H, m), 1.18 (3 H, d, J= 7.0 Hz); ¹³C NMR (100 MHz, CDC1₃) δ 200.7, 151.6, 134.3, 128.3, 118.4, 69.6, 49.6, 43.4, 32.9, 11.7.

[00263] Example 37. Reduction of formula (II) and hydrolysis to formula (IV) Synthesis of (45^,,55',6/?)-5-allyl-4-hydroxy-6-methylcyclohex-2-en- 1 -one

By a similar procedure, (5/?,65)-6-allyl-4,4-dimethoxy-5-methylcyclohex-2-en-l-one (0.9 g, 4.29 mmol) in THF was reduced with LiEt₃BH at -78 °C for 2 h, followed by acid-catalyzed hydrolysis in acetone, gave (45^,,55',6/?)-5-allyl-4-hydroxy-6-methylcyclohex-2-en-l-one (0.5 g, 70% yield). C₁₀H₁₄O₂, [a]²⁰ _D -74.9 (c 2.8, CHC1₃). 1H NMR (400 MHz, CDC1₃) δ 6.78 (1 H, d, J = 10.0 Hz), 5.96 (1 H, d, J= 10.0 Hz), 5.93-5.80 (1 H, m), 5.15^1.99 (2 H, m), 4.75^1.67 (1 H, m), 2.56 (1 H, qd, J= 6.9, 4.0 Hz), 2.41 (1 H, m), 2.37-2.27 (1 H, m), 2.20-2.09 (1 H, m), 1.16 (3 H, d, J= 6.9 Hz). ¹³C NMR (100 MHz, CDC1₃) δ 201.4, 149.6, 138.0, 128.8, 116.5, 70.5, 46.1, 45.4, 29.4, 13.2.

[00264] Example 38. Reduction of formula (II) and hydrolysis to formula (IV)

Synthesis of (4/?,5/?,6/S)-3-chloro-5-farnesyl-4-hydroxy-2-methoxy-6-methylcyclohex-2-en- 1 - one

Under an atmosphere of nitrogen, a solution of (55^,,6/?/S)-2-chloro-6-farnesyl-3,4,4-trimethoxy-5- methylcyclohex-2-en-l-one (100 mg, 0.23 mmol) containing trans and cis isomers (1 :4) in THF (3.0 mL) was stirred at -20 °C for 15 min, and LS-Selectride (0.5 mmol, 0.5 mL of 1.0 M solution in THF) was added dropwise. The mixture was stirred at -20 °C for 12 h, quenched with water (5.0 mL), and then extracted with EtOAc (3 x 20 mL) and brine (30 mL). The organic phase was dried over MgS0₄, and concentrated under reduced pressure to give a crude alcohol product of (l/?/S',5/S',6/?/S)-2-chloro-6-farnesyl-3,4,4-trimethoxy-5-methylcyclohex-2-en-l-ol as a mixture of diastereomers. Without further purification, this sample was subjected to acid- catalyzed hydrolysis at room temperature. The mixture was filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with elution of EtOAc/hexane (10:90) to give 3-chloro-5-farnesyl-4-hydroxy-2-methoxy-6-methylcyclohex- 2-en-l-one as a mixture of diastereomers. The (4R,5R,6S)-isomer was obtained by

chromatography. C₂₃H₃₅C10₃; [a]²⁵ _D +25.1 (c 1.0, CHC1₃); IR v_max (neat) 3491, 2972, 2938, 2852, 1694, 1683, 1380, 1223, 1010, 771 cm^-1. 1H NMR (500 MHz, CDC1₃) δ 5.14-5.03 (3 H, m), 4.48 (1 H, d, J= 4.3 Hz), 3.78 (3 H, s), 2.58 (1 H, qd, J= 7.3, 4.3 Hz), 2.38 (1 H, dt, J= 15.0, 7.3 Hz), 2.30-2.22 (1 H, m), 2.16-1.93 (10 H, m), 1.66 (3 H, s), 1.64 (3 H, s), 1.58 (6 H, s), 1.25 (3 H, d, J= 7.3 Hz). ¹³C NMR (125 MHz, CDC1₃) δ 196.6, 148.2, 140.6, 138.0, 135.4, 131.3, 124.3, 123.8, 121.1, 72.4, 59.9, 45.2, 41.7, 39.8, 39.7, 26.7, 26.4, 25.8, 25.7, 17.7, 16.2, 16.0, 14.2.

HRMS calcd for C₂₃H₃₅ClNa0₃: 417.2167, found: mlz 417.2160 [M + Na]⁺.

[00265] Example 39. Reduction of formula (II) and hydrolysis to formula (IV)

Synthesis of (4/?,5/?,6/S)-5-farnesyl-4-hydroxy-2-methoxy-6-methylcyclohex-2-en- 1 -one

Under an atmosphere of nitrogen, a solution of (55^,,6/?S)-6-farnesyl-3,4,4-trimethoxy-5- methylcyclohex-2-en-l-one (100 mg, 0.25 mmol) containing trans and cis isomers (1 :4) in THF (3.0 mL) was stirred at -20 °C for 15 min, and LS-Selectride (0.5 mmol, 0.5 mL of 1.0 M solution in THF) was added dropwise. The mixture was stirred at -20 °C for 12 h, quenched with water (5.0 mL), and then extracted with EtOAc (3 x 20 mL) and brine (30 mL). The organic phase was dried over MgS0₄, and concentrated under reduced pressure to give a crude alcohol product of (l/?/S',5/S',6/?/S)-6-farnesyl-3,4,4-trimethoxy-5-methylcyclohex-2-en-l-ol as a mixture of diastereomers. Without further purification, this sample was subjected to acid-catalyzed hydrolysis at room temperature. The mixture was filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with elution of EtOAc/hexane (10:90) to give 5-farnesyl-4-hydroxy-2-methoxy-6-methylcyclohex-2-en-l-one as a mixture of diastereomers. (4/?,5/?,6/S)-isomer was obtained by chromatography. C₂₃H₃₆0₃; [a]²⁵ _D +21.7 (c 0.53, CHC1₃); IR v_max (neat) 3474, 2972, 2926, 2855, 1687, 1631, 1451, 1378, 1220, 1080, 772 cm^"1. 1H NMR (500 MHz, CDC1₃) δ 5.68 (1 H, d, J= 3.7 Hz), 5.17 (1 H, br s), 5.06 (2 H, d, J= 6.7 Hz), 4.68^1.76 (1 H, m), 3.62 (3 H, s), 2.59 (1 H, dd, J= 7.3, 3.7 Hz), 2.29 (2 H, d, J= 4.3 Hz), 2.10-1.91 (10 H, m), 1.66 (3 H, s), 1.61 (3 H, s), 1.58 (6 H, s), 1.22 (3 H, d, J= 6.7 Hz). ¹³C NMR (125 MHz, CDC1₃) δ 196.7, 150.6, 137.5, 135.4, 131.3, 124.3, 123.8, 122.5, 115.2, 69.5, 55.1, 45.4, 39.7, 39.6, 29.7, 26.7, 26.4, 25.7, 24.1, 17.7, 16.2, 16.0, 13.8. HRMS calcd for C₂₃H₃₆Na0₃: 383.2557, found: mlz 383.2556 [M + Na]⁺.

[00266] Example 40. Epimerization at C-6

Synthesis of (±)-antroquinonol

The (4,5-cw-5,6-cw)-isomer of 5-farnesyl-4-hydroxy-6-methyl-2,3-dimethoxycyclohex-2-en-l- one (30 mg, 0.077 mmol) was dissolved in MeOH (4.0 mL). K₂C0₃ (32 mg, 0.23 mmol) was added. The mixture was stirred at room temperature for 12 h, quenched with water (5.0 mL), and then extracted with CH₂C1₂ (3 x 20 mL). The organic phase was washed with brine (30 mL), dried over MgS0₄, and concentrated under reduced pressure. The residue was purified by column chromatography on Si0₂ with EtOAc/CH₂Cl₂ (5:95) to yield the (4,5-cis-5,6-trans)- isomer (antroquinonol racemic mixture, 25 mg, 83% yield). HRMS calcd for C₂₄H₃₈0₄:

391.2848, found: mlz 391.2852 [M + H]⁺.

[00267] Example 41. Epimerization at C-6

Synthesis of (4/?,5/?,6/?)-(+)-antroquinonol D The 4,5-cis-5,6-cis compound (4/?,5/?,6/S)-5-farnesyl-4-hydroxy-2-methoxy-6-methylcyclohex-2- en-l-one (36 mg, 0.1 mmol) was dissolved in MeOH (2.0 mL), and K₂C0₃ (41 mg, 0.3 mmol) at room temperature for 12 h. The residue was purified by column chromatography on silica gel with elution of EtOAc/CH₂Cl₂ (5:95) to give (+)-antroquinonol D in the 4,5-cis-5,6-trans

configuration. C₂₃H₃₆0₃; [a]²⁴ _D +50.0 (c 0.25, CHC1₃); 1H NMR (500 MHz, CD₃OD) δ 5.91 (1 H, d, J= 6.1 Hz), 5.21 (1 H, t, J= 7.0 Hz), 5.13-5.04 (2 H, m), 4.54^1.45 (1 H, m), 3.59 (3 H, s), 2.73-2.61 (1 H, m), 2.32-2.21 (1 H, m), 2.21-2.00 (8 H, m), 2.00-1.91 (2 H, m), 1.85-1.76 (1 H, m), 1.66 (3 H, s), 1.62 (3 H, s), 1.60 (3 H, s), 1.59 (3 H, s), 1.16 (3 H, d, J= 7.0 Hz); ¹³C NMR (125 MHz, CD₃OD) δ 198.8, 152.1, 138.1, 136.0, 132.1, 125.5, 125.4, 123.3, 116.7, 65.1, 55.3, 47.5, 43.4, 40.9, 40.8, 28.1, 27.8, 27.4, 25.9, 17.8, 16.2, 16.1, 13.1. HRMS calcd for C₂₃H₃₆Na0₃: 383.2562, found: mlz 383.2556 [M + Na]⁺.

[00268] Example 42. Epimerization at C-6 and substitution at C-3

Synthesis of (4/?,5/?,6/?)-(+)-antroquinonol

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 K₂C0₃ (41 mg, 0.3 mmol) was added. The mixture was stirred at room temperature for 12 h, quenched with saturated aqueous NH₄C1 (5.0 mL), and then extracted with CH₂C1₂ (3 x 20 mL). The organic phase was washed with brine (30 mL), dried over MgS0₄, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with elution of EtOAc/CH₂Cl₂ (2:98) to give (+)-antroquinonol in the 4,5-cis-5,6-trans configuration.

C₂₄H₃₈0₄; [a]²⁵ _D +45.0 (c 0.48, CHC1₃); 1H NMR (500 MHz, CDC1₃) δ 5.14 (1 H, t, J= 7.3 Hz), 5.07 (2 H, t, J= 6.7 Hz), 4.34 (1 H, d, J= 3.1 Hz), 4.05 (3 H, s), 3.65 (3 H, s), 2.52 (1 H, qd, J = 6.7, 11.0 Hz), 2.22 (2 H, t, J= 7.3 Hz), 2.12-1.92 (8 H, m), 1.74 (1 H, dtd, J= 10.9, 7.5, 3.4 Hz), 1.66 (3 H, s), 1.64 (3 H, s), 1.58 (6 H, s), 1.16 (3 H, d, J= 6.7 Hz). ¹³C NMR (125 MHz, CDC1₃) δ 197.1, 160.4, 138.1, 135.9, 135.4, 131.1, 124.3, 123.9, 121.0, 68.0, 60.6, 59.2, 43.4, 40.3, 39.8, 39.7, 27.0, 26.8, 26.4, 25.7, 17.7, 16.1, 16.0, 12.3. HRMS calcd for C₂₄H₃₉0₄: 391.2848, found: mlz 391.2854 [M + H]⁺.

[00269] Example 43. Acylation of 4-OH of formula (IV) to formula (V)

Synthesis of 4-Bromobenzoyloxy-5-farnesyl-2,3-dimethoxy-6-methylcyclohex-2-en-l-one Under an atmosphere of nitrogen, a solution of compound 1 (4,5-trans-5,6-cis isomer, 100 mg, 0.25 mmol) and triethylamine (51 mg, 0.50 mmol) in THF (3.0 mL) was stirred at 0 °C for 15 min. A solution of 4-bromobenzoyl chloride (82 mg, 0.38 mmol) in THF (1.0 mL) was added dropwise. The mixture was stirred at room temperature for 12 h, quenched with water (5.0 mL), and then extracted with EtOAc (3 x 20 mL) and brine (30 mL). The organic phase was washed with brine (30 mL), dried over MgS0₄, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with elution of EtOAc/hexane (5:95) to yield the benzoate ester of compound 1 in the 4,5-trans-5,6-cis configuration (72 mg, 50% yield). C₃₁H₄₁Br0₅; 1H NMR (500 MHz, CDC1₃) δ 7.89 (2 H, d, J= 7.9 Hz), 7.58 (2 H, d, J= 7.9 Hz), 5.85 (1 H, d, J= 3.7 Hz), 5.19 (1 H, m), 5.11 (1 H, m), 5.05 (1 H, m), 3.91 (3 H, s), 3.72 (3 H, s), 2.94 (1 H, m), 2.27-2.20 (1 H, m), 2.15 (1 H, m), 2.09 (2 H, m), 2.06-1.99 (4 H, m), 1.99-1.89 (3 H, m), 1.64 (3 H, s), 1.58 (3 H, s), 1.56 (3 H, s), 1.55 (3 H, s), 1.13 (3 H, d, J= 7.3 Hz). ¹³C NMR (125 MHz, CDC1₃) δ 196.8, 165.0, 155.4, 138.4, 137.9, 135.3, 131.9(2x), 131.3(2x), 131.2, 128.6, 128.5, 124.4, 123.9, 120.6, 71.9, 60.7, 59.0, 42.8, 40.4, 39.8, 39.7, 26.7, 26.6, 25.7, 25.4, 17.7, 16.2, 16.0, 11.7.

[00270] Example 44. Alkylation of 4-OH of formula (IV) to formula (V)

Synthesis of 5-benzyl-2,3,4-trimethoxy-6-methylcyclohex-2-en-l-one

Under an atmosphere of nitrogen, a solution of 5-benzyl-2,3-dimethoxy-4-hydroxy-6- methylcyclohex-2-en-l-one (4,5-trans-5,6-cis isomer, 100 mg, 0.25 mmol) and 2,6-di-tert-butyl- 4-methylpydridine (103 mg, 0.50 mmol) in CH₂C1₂ (3.0 mL) was stirred at 0 °C for 15 min. A solution of methyl triflate (62 mg, 0.38 mmol) in CH₂C1₂ (1.0 mL) was added dropwise. The mixture was stirred at room temperature for 12 h, quenched with water (5.0 mL), and then extracted with CH₂C1₂ (20 mL x 3) and brine (30 mL). The organic phase was washed with brine (30 mL), dried over MgS0₄, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with elution of EtOAc/hexane (10:90) to yield 5-benzyl- 2,3,4-trimethoxy-6-methylcyclohex-2-en-l-one (22 mg, 30%yield). C₁₇H₂₂0₄; 1H NMR (500 MHz, CDC1₃) δ 7.28 (2 H, d, J= 7.3 Hz), 7.21 (1 H, m), 7.09 (2 H, d, J= 7.3 Hz), 3.93 (3 H, s), 3.69 (3 H, s), 3.62 (1 H, d, J= 3.1 Hz), 3.25 (3 H, s), 3.07-3.00 (1 H, m), 2.89-2.83 (1 H, m), 2.44-2.37 (1 H, m), 2.29-2.21 (1 H, m), 1.20 (3 H, d, J= 7.3 Hz). ¹³C NMR (125 MHz, CDC1₃) δ 196.6, 157.5, 139.4, 136.9, 128.7 (4 x), 126.5, 77.8, 60.5, 58.5, 57.6, 43.5, 39.6, 32.7, 11.9. [00271] Example 45. Acylation of 6-OH of formula (VI) to formula (VII)

Synthesis of 6-acetoxy-5-benzyl-2,3-dimethoxy-4-methylcyclohex-2-en-l-one

Under an atmosphere of nitrogen, a solution of 5-benzyl-6-hydroxy-2,3-dimethoxy-4- methylcyclohex-2-en-l-one (100 mg, 0.36 mmol) and 4-dimethylaminopydridine (5 mg, 0.04 mmol) in pyridine (3.0 mL) was stirred at 0 °C for 15 min, and acetic anhydride (73 mg, 0.72 mmol) was added dropwise. The mixture was stirred at room temperature for 5 h, quenched with water (5.0 mL), and then extracted with CH₂C1₂ (3 x 20 mL) and brine (30 mL). The organic phase was washed with brine (30 mL), dried over MgS0₄, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with elution of EtOAc/hexane (10:90) to yield the acetylation product (92 mg, 80% yield). C₁₈H₂₂0₅; 1H NMR (500 MHz, CDC1₃) δ 7.30-7.25 (2 H, m), 7.23-7.17 (1 H, m), 7.07 (2 H, d, J= 7.3 Hz), 5.08 (1 H, d, J= 11.6 Hz), 3.99 (3 H, s), 3.60 (3 H, s), 2.96-2.77 (2 H, m), 2.43 (1 H, qd, J= 8.9, 6.7 Hz), 2.26-2.16 (1 H, m), 2.11 (3 H, s), 1.31 (3 H, d, J= 6.7 Hz). ¹³C NMR (125 MHz, CDC1₃) δ

189.2, 170.2, 165.5, 137.6, 134.2, 129.6 (2 x), 128.6 (2 x), 126.6, 74.7, 60.5, 60.4, 43.1, 35.7, 35.0, 20.8, 17.0.

[00272] Example 46. Alkylation of 6-OH of formula (VI) to formula (VII) Synthesis of 5-benzyl-2,3,6-trimethoxy-4-methylcyclohex-2-en-l-one

A solution of 5-benzyl-6-hydroxy-2,3-dimethoxy-4-methylcyclohex-2-en-l-one (100 mg, 0.36 mmol) and KOH (81 mg, 1.45 mmol) in DMSO (2.0 mL) was stirred at room temperature for 15 min, and methyl iodide (102 mg, 0.72 mmol) was added dropwise. The mixture was stirred at room temperature for 5 h, quenched with water (5.0 mL), and then extracted with EtOAc (3 x 20 mL) and brine (30 mL). The organic phase was washed with brine (30 mL), dried over MgS0₄, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with elution of EtOAc/hexane (10:90) to yield the methylation product (89 mg, 85% yield). C₁₇H₂₂0₄; 1H NMR (500 MHz, CDC1₃) δ 7.31-7.26 (2 H, m), 7.23-7.18 (1 H, m), 7.13 (2 H, d, J= 7.3 Hz), 3.97 (3 H, s), 3.64 (3 H, s), 3.46 (3 H, s), 3.40 (1 H, d, J= 6.7 Hz), 2.74 (2 H, m), 2.42 (1 H, m), 2.21-2.13 (1 H, m), 1.33 (3 H, d, J= 6.7 Hz). ¹³C NMR (125 MHz, CDC1₃) δ

193.3, 165.8, 138.6, 134.5, 129.5 (2 x), 128.5 (2 x), 126.5, 82.6, 60.5, 59.7, 58.3, 44.2, 36.2, 36.0, 19.1. [00273] Example 47. Evaluation of anticancer activity

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

SpectraMax M5 (Molecular Devices, Sunnyvale, CA, USA) for formazan product at a

wavelength of 490 nm with a reference wavelength of 650 nm. The absorbance of each well was corrected with reference to the blank. Inhibitor IC₅₀ 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).

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Claims

CLAIMS We claim:

1. A compound of formula II):

(II) or a salt thereof;

wherein:

R and R¹ are independently optionally substituted alkyl;

R⁶ 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;

provided that 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 to form a carbocycle or heterocycle; and R 2 and OR 1 are not taken together with their intervening to form a carbocycle or heterocycle.

2. The compound of claim 1, wherein R is methyl, and R¹ is methyl.

3. The compound of claim 1, wherein R is methyl, and R¹ is 4-bromobenzyl.

4. The compound of claim 1, wherein R is methyl, and R¹ is chiral alkyl.

5. The compound of claim 4, wherein the chiral alkyl is optically active 1-phenylethyl, menthyl, 8-phenylmenthyl, myrtanyl, myrtenyl, or 2-phenylcyclohexyl.

6. The compound of claim 5, wherein the chiral alkyl is optically active myrtenyl.

The compound of any one of claims 1-6, wherein R² is alkoxy or halogen.

8. The compound of any one of claims 1-6, wherein R is hydrogen, alkoxy or halogen.

9. The compound of any one of claims 1-6, wherein R 2 and R 3 are each methoxy.

10. The compound of any one of claims 1-6, wherein R 2 is methoxy, and R 3 is halogen.

11. The compound of any one of claims 1-6, wherein R⁵ is selected from the group consisting of farnesyl, allyl, prenyl and optionally substituted benzyl.

12. The compound of claim 11, wherein R⁵ is unsaturated alkyl (C3-C45) substituted with hydroxyl, methoxy, carboxyl, or heterocycle.

13. The compound of claim 12, wherein R⁶ is methoxy.

14. The compound of claim 1, wherein the compound of formula (II) is selected from those listed in Table 2.

15. The compound of claim 1, wherein the compound of formula (II) is selected from the group consisting of:

16. Use of the compound of formula (II) for the synthesis of A. cinnamomea active medicinal substances.

17. A method for synthesizing a compound of formula (IV):

(IV) or a salt thereof; wherein:

R² 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 C₂_0 alkyl, haloalkyl, 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;

R⁶ 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;

the method comprising:

converting a compound of formula (II) according to claim 1 under suitable conditions to form a compound of formula (IV)

18. The method of claim 17, wherein the converting comprises the formation of an intermediate having the formula (III):

19. The method of claim 18, wherein the formation of the intermediate takes place in the presence of a reducing agent.

20. The method of claim 17, wherein the converting takes place in the presence of a reducing agent followed by hydrolysis.

21. The method of claim 20, wherein the hydrolysis takes place in acidic conditions.

22. The method of claim 17, wherein the compound of formula (II) is prepared by treating a compound of formula (I):

with an electrophilic reagent in basic conditions.

23. The method of claim 22, wherein the compound of formula (I) is prepared by treating a compound of formula (C):

with a nucleophilic reagent under suitable conditions.

24. The method of claim 23, wherein the nucleophilic reagent is an organometallic reagent, a metal alkoxide, a metal thiolate, or a metal amide.

25. The method of claim 23, wherein the compound of formula (C) is generated from a compound of formula (B):

by oxidation in the presence of an alcohol compound (ROH).

26. The method of claim 25, wherein the compound of formula (B) is generated from a compound of formula (A):

by Baeyer-Villiger oxidation.

27. The method of claim 17, wherein the compound of formula (IV) is selected from the group consisting of:

28. The method of claim 17 or 27, wherein the compound of formula (IV) has substituents in cis or trans configurations.

29. The method of claim 17 or 27, wherein the compound of formula (IV) is a racemic mixture or an optically active compound.

30. The method of claim 17, wherein the compound of formula (IV) is selected from the group consisting of:

31. A method for synthesizing a compound of formula (V):

(V) or a salt thereof;

the method comprising:

32. The method of claim 30, wherein the converting takes place in the presence of an alkylating or acylating agent.

33. The method of claim 30, wherein the compound of formula (V) is selected from the group consisting of:

34. The method of claim 33, wherein the compound of formula (V) has substituents in cis or trans configurations.

35. The method of claim 33, wherein the compound of formula (V) is a racemic mixture or an optically active compound.

36. A method for synthesizing a compound of formula (VI):

(VI) or a salt thereof;

the method comprising:

converting a compound of formula (II- a):

under suitable conditions to form a compound of formula (VI).

37. The method of claim 36, wherein the converting takes place in the presence of a reducing agent followed by hydrolysis.

38. The method of claim 37, wherein the hydrolysis takes place in acidic conditions.

The method of claim 36, wherein the compound of formula (VI) is selected from the consisting of:

40. A method for synthesizing a compound of formula (VII):

(VII) or a salt thereof;

wherein R⁴ is optionally substituted C_1-6 alkyl or acyl;

the method comprising: