Method for preparing (-)-epicatechin

Abstract

Method steps for the synthesis of (-)-epicatechin are provided herein. The synthesis method is provided in two steps: (1) synthesis of an epoxide intermediate, and (2) synthesis of (-)-epicatechin.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 461,058, filed on 21 April 2023, the contents of which are incorporated herein by reference in their entirety.

[0002] This disclosure relates to the synthesis of (-)-epicatechin. [Background technology]

[0003] Catechins and epicatechins are naturally occurring polyphenols widely distributed in plant systems. They are found in cocoa, tea, fruits, vegetables, and pine bark. (+)-catechin and (-)-epicatechin are the most abundant naturally occurring epimers. For example, green tea leaves contain (-)-epicatechin and (+)-catechin. Reported biological activities of these compounds include antitumor activity, antimutagenic activity, and antioxidant activity. However, the isolation of stereospecific catechin derivatives, such as (-)-epicatechin, often requires difficult purification steps to separate the compound of interest from other epimers and / or structurally similar compounds present in natural extracts. Therefore, there is a need for efficient synthetic methods to produce catechin and epicatechin monomers on a large scale from commercially available materials at the purity levels required for scale-up synthesis. [Overview of the project]

[0004] The objectives and merits of the disclosed subject matter are described below and are evident therefrom, and will be learned through the implementation of the disclosed subject matter. Further merits of the subject matter of this disclosure will be realized and achieved through the written description herein and the devices specifically pointed out in the claims.

[0005] To achieve these and other advantages, and in accordance with the purpose of the disclosed subject matter, the disclosed subject matter includes various methods for preparing (-)-epicatechin.

[0006] In certain embodiments, the subject of the present disclosure provides a method for preparing (-)-epicatechin. In certain embodiments, the method comprises providing a compound of formula V, where X is O or S, R3 is Ph, Bn, or CH(CH3)2, and R4 is Ph or H. [ka] Formula V In certain embodiments, the method further comprises providing a compound of formula II, where R1 is MOM or Bn. [ka] Formula II

[0007] In certain embodiments, the method comprises coupling the compounds of Formulas II and V to form a first intermediate, the first intermediate comprising a secondary alcohol. In certain embodiments, the method comprises protecting the secondary alcohol in the first intermediate to form a second intermediate. In certain embodiments, the method comprises reducing the second intermediate to form a third intermediate, the third intermediate comprising a primary alcohol. In certain embodiments, the method comprises removing the Bn group of Formula V to form a fourth intermediate. In certain embodiments, the method comprises selectively forming a sulfonate ester from the primary alcohol of the fourth intermediate to form a fifth intermediate. In certain embodiments, the method comprises epoxidizing the fifth intermediate to form a sixth intermediate. In certain embodiments, the method comprises alkylating the sixth intermediate to form a seventh intermediate, the seventh intermediate comprising a primary alcohol. In certain embodiments, the method comprises protecting the primary alcohol of the seventh intermediate to form an eighth intermediate. In certain embodiments, the method comprises cyclizing the eighth intermediate to form a ninth intermediate. In certain embodiments, the method comprises deprotecting the ninth intermediate to form a tenth intermediate. In certain embodiments, the method comprises deprotecting the tenth intermediate to form (−)-epicatechin.

[0008] In certain embodiments, X is S and R3 is Ph. In certain embodiments, R1 is MOM.

[0009] In certain embodiments, the alcohol of the first intermediate is protected with a silyl group. In certain embodiments, the silyl group is t-butyldimethylsilyl.

[0010] In certain embodiments, the sulfonate ester is -OTs, -OMes, or -OTf. In certain embodiments, the sulfonate ester is -OTs.

[0011] In certain embodiments, the sixth intermediate is alkylated with a compound of Formula VII to form a seventh intermediate, where X is F, Br, I, Cl, N, S, or B, and R3 is Bn or a MOM protecting group. [Chemical formula] Formula VII In certain embodiments, X is F and R3 is Bn.

[0012] In certain embodiments, the seventh intermediate is protected with a MOM or Bn protecting group. In certain embodiments, the seventh intermediate is protected with a MOM protecting group.

[0013] In certain embodiments, the deprotection of the ninth intermediate is debenzylation. In certain embodiments, the sixth intermediate is a syn-epoxide intermediate.

[0014] In certain embodiments, the subject of this disclosure provides a method for preparing (-)-epicatechin. In certain embodiments, the method includes providing (S)-2-(benzyloxy)-1-(4-phenyl-2-thioxoxazolidine-3-yl)ethane-1-one and 3,4-bis(methoxymethoxy)-benzaldehyde. In certain embodiments, the method includes adding chloromethyl methyl ether to produce (2S,3R)-2-(benzyloxy)-3-(3,4-bis(methoxymethoxy)phenyl)-3-hydroxy-1-((S)-4-phenyl-2-thioxoxazolidine-3-yl)propan-1-one. In a particular embodiment, the method includes protecting (2S,3R)-2-(benzyloxy)-3-(3,4-bis(methoxymethoxy)phenyl)-3-hydroxy-1-((S)-4-phenyl-2-thioxoxazolidine-3-yl)propan-1-one with TBSCl to produce (2S,3R)-2-(benzyloxy)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)-1-((S)-4-phenyl-2-thioxoxazolidine-3-yl)propan-1-one. In a particular embodiment, the method includes reducing (2S,3R)-2-(benzyloxy)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)-1-((S)-4-phenyl-2-thioxoxazolidine-3-yl)propan-1-one with LiBH4 to produce (2R,3R)-2-(benzyloxy)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)propan-1-ol. In a particular embodiment, the method includes deprotecting (2R,3R)-2-(benzyloxy)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)propane-1-ol with Pd / C under H2 to produce (2R,3R)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)propane-1,2-diol.In certain embodiments, the method comprises tosylation of (2R,3R)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)propane-1,2-diol with tosylic acid to produce (2R,3R)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)-2-hydroxypropyl 4-methylbenzenesulfonate. In certain embodiments, the method comprises epoxidizing (2R,3R)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)-2-hydroxypropyl 4-methylbenzenesulfonate using potassium carbonate in methanol to produce (R)-(3,4-bis(methoxymethoxy)phenyl)((R)-oxiran-2-yl)methoxy)(tert-butyl)dimethylsilane. In a particular embodiment, the method involves alkylating ((R)-(3,4-bis(methoxymethoxy)phenyl)((R)-oxiran-2-yl)methoxy)(tert-butyl)dimethylsilane with (((5-fluoro-1,3-phenylene)bis(oxy))bis(methylene))dibenzene using n-butyllithium to produce (1R,2R)-3-(2,4-bis(benzyloxy)-6-fluorophenyl)-1-(3,4-bis(methoxymethoxy)phenyl)-1-((tert-butyldimethylsilyl)oxy)propan-2-ol. In a particular embodiment, the method includes protecting (1R,2R)-3-(2,4-bis(benzyloxy)-6-fluorophenyl)-1-(3,4-bis(methoxymethoxy)phenyl)-1-((tert-butyldimethylsilyl)oxy)propan-2-ol with MOMCl to produce (5R,6R)-5-{[2,4-bis(benzyloxy)-6-fluorophenyl]methyl}-6-[3,4-bis(methoxymethoxy)phenyl]-8,8,9,9-tetramethyl-2,4,7-trioxa-8-siladecane.In a particular embodiment, the method includes deprotecting (5R,6R)-5-{[2,4-bis(benzyloxy)-6-fluorophenyl]methyl}-6-[3,4-bis(methoxymethoxy)phenyl]-8,8,9,9-tetramethyl-2,4,7-trioxa-8-siladecane with TBAF to produce (1R,2R)-3-(2,4-bis(benzyloxy)-6-fluorophenyl)-1-(3,4-bis(methoxymethoxy)phenyl)-2-(methoxymethoxy)propan-1-ol. In certain embodiments, the method includes cyclizing (1R,2R)-3-(2,4-bis(benzyloxy)-6-fluorophenyl)-1-(3,4-bis(methoxymethoxy)phenyl)-2-(methoxymethoxy)propan-1-ol using potassium hydride to produce (2R,3R)-5,7-bis(benzyloxy)-2-(3,4-bis(methoxymethoxy)phenyl)-3-(methoxymethoxy)chroman. In certain embodiments, the method includes deprotecting (2R,3R)-5,7-bis(benzyloxy)-2-(3,4-bis(methoxymethoxy)phenyl)-3-(methoxymethoxy)chroman with HCl to produce 4-((2R,3R)-5,7-bis(benzyloxy)-3-hydroxychroman-2-yl)benzene-1,2-diol. In a particular embodiment, the method includes deprotecting 4-((2R,3R)-5,7-bis(benzyloxy)-3-hydroxychroman-2-yl)benzene-1,2-diol with Pd / C under H2 to obtain (-)-epicatechin. [Brief explanation of the drawing]

[0015] [Figure 1] The general steps related to the synthesis of the (-) epicatechin derivatives disclosed herein are shown. [Figure 2] The general steps related to the synthesis of the (-) epicatechin derivatives disclosed herein are shown. [Figure 3] The general steps related to the synthesis of the (-) epicatechin derivatives disclosed herein are shown. [Figure 4]The general steps related to the synthesis of the (-) epicatechin derivatives disclosed herein are shown. [Figure 5] The general steps related to the synthesis of the (-) epicatechin derivatives disclosed herein are shown. [Figure 6] The general steps related to the synthesis of the (-) epicatechin derivatives disclosed herein are shown. [Figure 7] The general steps related to the synthesis of the (-) epicatechin derivatives disclosed herein are shown.

[0016] [Detailed description of the invention] Stereospecific catechin derivatives, including (-)-epicatechin and (+)-epicatechin, have been reported to possess biological activities including antitumor activity, antimutagenic activity, antioxidant activity, and others. However, obtaining each of these compounds at the industrial scale and purity required for health applications, such as pharmaceutical applications, remains challenging. This disclosure provides the synthesis of sterically pure epimers of catechins from commercially available starting materials to address the aforementioned needs.

[0017] For clarity, a detailed description of the subject matter of this disclosure, though not limited to this scope, is divided into the following subsections. I. Definition; II. Catechin epimers; III. Synthesis process; and IV. Consumer goods

[0018] I. Definition The terms used herein generally have the common meaning in the art within the context of this disclosure and in the specific context in which each term is used. Certain terms are discussed below or elsewhere in this specification to provide additional guidance to practitioners when describing the compositions and methods of this disclosure and how they are prepared and used.

[0019] For the purposes of interpreting this Spec., the following definitions apply, and where appropriate, a term used in the singular also includes the plural, and vice versa. In the event of any conflict between any of the following definitions and any document incorporated herein by reference, the following definition shall prevail.

[0020] As used herein, the terms “a” or “an,” when used in the claims and / or in conjunction with the term “comprising,” may mean “one,” but also coincide with the meanings of “one or more,” “at least one,” and “one or more than one.”

[0021] As used herein, the terms “comprise(s),” “include(s),” “having,” “has,” “can,” and “contain(s),” and their variations, are intended to be open-ended transitional phrases, terms, or words that do not exclude additional acts or structures. This disclosure also contemplates other embodiments, whether expressly described or otherwise, that are “comprise,” “consist of,” and “essentially consist of,” the elements presented herein.

[0022] As used herein, the terms “about” or “approximately” mean an acceptable range of error for a particular value as determined by those skilled in the art, which depends in part on how the value is measured or determined, i.e., on the limitations of the measuring system. For example, “about” may mean within three standard deviations or greater than three standard deviations, according to the practice of the art. Alternatively, “about” may mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and even more preferably up to 1% of a given value.

[0023] The term "alkyl" refers to a linear or branched C1-C chain consisting only of carbon and hydrogen atoms, which are unsaturated and bonded to the rest of the molecule by single bonds. 20 This refers to hydrocarbon groups, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl).

[0024] The term "alkenyl" refers to a compound containing at least one carbon-carbon double bond, which can be a straight or branched chain, C2-C 20 This refers to an aliphatic hydrocarbon group, such as the ethenyl group.

[0025] The term "cycloalkyl" refers to unsaturated, non-aromatic, monocyclic or polycyclic hydrocarbon ring systems (e.g., containing C3-C6) such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0026] The term "aryl" refers to aromatic groups, such as phenyl or biphenyl, that have approximately 6 to 14 carbon atoms.

[0027] The term "arylalkyl" refers to an aryl group directly bonded to an alkyl group as defined above, e.g., -CH2C6H5 and -C2H4C6H5. As used herein, the term "benzyl" or "Bn" generally refers to a phenyl group ("Ph") having a single alkyl group. As used herein, Bn is -CH2C6H6 or -CH2Ph.

[0028] As used herein, the term “chiral auxiliary” refers to a compound used to control the stereochemical outcome of a reaction by integrating a chiral auxiliary into the compound and then removing the chiral auxiliary after the desired stereochemistry has been achieved during synthesis.

[0029] As used herein, the term "cyclization" refers to a chemical reaction in which one or more atoms of a compound form a ring.

[0030] The term "heterocyclic" refers to a stable 3- to 15-membered ring group consisting of a carbon atom and one or more heteroatoms selected from the group consisting of, for example, nitrogen, oxygen, and sulfur. For the purposes of this application, the heterocyclic group may be monocyclic or bicyclic ring systems, which may include condensed or bridging ring systems, and the nitrogen, carbon, oxygen, or sulfur atoms in the heterocyclic group may be optionally oxidized to various oxidation states.

[0031] The term "heteroaryl" refers to a heterocyclic ring in which the ring is aromatic.

[0032] As used herein, the term "ether" generally refers to two alkyl groups bonded to an oxygen atom.

[0033] As used herein, the term “intermediate” refers to a compound formed by a reaction in a multi-step synthesis and subsequently used in a subsequent step of the multi-step synthesis. In certain embodiments, the intermediate may be isolated and purified using methods known to those skilled in the art before being used in a subsequent step.

[0034] In certain other embodiments, the intermediate may be used in subsequent steps without further purification. In certain embodiments, the intermediate may be prepared in situ and then used in subsequent steps.

[0035] As used herein, the term “isomer” refers to different compounds having the same molecular formula but differing in the arrangement and composition of atoms. Also as used herein, the term “stereoisomer” refers to any of the various stereoisomer configurations, including geometric isomers, that may exist for a given compound of the subject matter of this disclosure. It is understood that the compounds of this disclosure contain double bonds and substituents may be in E or Z configurations. Furthermore, as used herein, the term “epimer” refers to any two stereoisomers having different arrangements of groups on a single asymmetric carbon atom (e.g., the first chiral center of a sugar's carbon chain). For example, but not limited to, (-)-epicatechin and (+)-epicatechin are epimers. Also as used herein, the term “structural isomer” refers to different compounds having the same number of atoms and types of atoms but with atoms connected in different ways. As used herein, the term “optical isomer” refers to two compounds that have mirror images of the same number and type of atoms, as well as the same bonding (i.e., the same interatomic connections), and different spatial arrangements of atoms, but which are not superimposed. Each mirror image that is not superimposed is called an enantiomer.

[0036] As used herein, the term “leaving group” refers to an atom or molecular fragment that leaves with an electron pair in an anisotropic bond cleavage. The leaving group may be an anion, a cation, or a neutral molecule. As is known to those skilled in the art, an atom or group of atoms may be more stable on its own than a leaving group. For example, a good leaving group may be the conjugate base of a strong acid. In certain embodiments, the leaving group may be a neutral molecule such as water or ammonia.

[0037] As used herein, the term “organolithium” refers to a compound having at least one carbon atom bonded to at least one lithium atom.

[0038] As used herein, the terms “oxidation” or “oxidized” refer to a chemical reaction in which a chemical species loses electrons.

[0039] As used herein, the term “protecting group” refers to a reversibly formed derivative of an existing functional group in a molecule. The protecting group temporarily binds to and reduces the reactivity of the protected functional group, thereby preventing it from reacting under the synthetic conditions the molecule is subjected to in one or more subsequent steps. The protecting group can be removed through a deprotection step once the selective synthetic steps are complete.

[0040] As used herein, the terms “protect” and “to protect” refer to a synthetic step in which a functional group is reversibly and transiently derivatized to reduce the reactivity of the functional group. For example, “protection of a hydroxyl group” means, for example, carrying out a synthetic step in which a reagent such as tert-butyldimethylsilyl chloride or chloromethyl methyl ether is added to a compound having a hydroxyl group to convert the hydroxyl group to tert-butyldimethylsilyl or methoxymethyl ether. Functional groups can also be protected using other reagents that can introduce the same or different protecting groups, as is known to those skilled in the art.

[0041] As used herein, the terms “reduction” or “reduced” refer to a chemical reaction in which a chemical species gains electrons.

[0042] As used herein, the term “sulfonate” generally refers to a sulfur atom that is double-bonded to two oxygen atoms, single-bonded to one oxygen atom, and single-bonded to a further group. “Sulfonylation” refers to the addition of a sulfonic acid group. Common sulfonate compounds include mesylate ("Mes"), tosylate ("Ts"), or triflate ("Tf"). As used herein, “mesyl” refers to methanesulfonyl, “trefuryl” refers to trifluoromethanesulfonyl, and “tosyl” refers to p-toluenesulfonyl. As used herein, “tosylate” or “tosyl group” refers to p-toluenesulfonate, and “tosylation” refers to the addition of a tosyl group. In certain embodiments, the tosyl group is added with tosyl chloride (TsCl). As used herein, “sulfonic acid ester” generally refers to a sulfonate in which an oxygen single-bonded to a sulfur atom is bonded to a further group. Common sulfonic acid ester compounds include "OMes," "OTs," or "OTf."

[0043] II. Catechin Epimers Catechins are naturally occurring phenols found in a variety of sources, including many herbs, fruits, vegetables, beverages, algae, and confectionery items. Cocoa, tea, and certain stone fruits are major sources of catechins in the diet.

[0044] Catechin is a flavan-3-ol and belongs to the chemical family of flavonoids. As shown by formula I, catechin has two benzene rings (called ring A and ring B) and a dihydropyran heterocycle (ring C) with a hydroxyl group on carbon 3. [ka] Formula I: Catechin

[0045] The molecule has two chiral centers on carbons 2 and 3, and as such, the molecule has four diastereomers, which are referred to herein as epimers. These four epimers are (+)-catechin, (-)-epicatechin, (-)-catechin, and (+)-epicatechin, shown below as formulas IA~ID: [ka] The four epimers of catechins, while structurally similar, have been shown to possess specific and remarkably different activities. For example, Tsuchiya reports that epimers exhibit diverse biological activities through interactions with cell membranes. For instance, both (-)-epicatechin and (+)-epicatechin were shown to be more effective than (+)-catechin and (-)-catechin in reducing membrane fluidity. Reverse-phase chromatography evaluation showed that (-)-epicatechin and (+)-epicatechin were more hydrophobic than (-)-catechin and (+)-catechin, although hydrophobicity could not be distinguished between optical isomers. See Tsuchiya, “Stereospecificity in membrane effects of catechins,” Chem. Biol. Interact 2001, 134, 41-54 (which is incorporated herein by reference).

[0046] The isolation of stereospecific catechin epimers is often extremely difficult. Therefore, the synthesis of (‐)-epicatechin provided in this disclosure enables the formation of a single epimer for application in various consumer goods.

[0047] III. Synthesis Process This disclosure provides a method for synthesizing (-)-epicatechin. In certain embodiments, the synthesis of (-)-epicatechin may comprise two steps: a first step of preparing an epoxide intermediate, and a second step of converting the epoxide intermediate to the desired (-)-epicatechin. Each step is further described below.

[0048] Step 1: Preparation of Epoxy Intermediate In certain embodiments, the first step includes the preparation of a syn-epoxide intermediate. In certain embodiments, the first step includes the preparation of an anti-epoxide intermediate. In certain embodiments, the synthesis of the epoxide intermediate proceeds according to general steps outlined in Figures 1-5 and further described below.

[0049] In certain embodiments, the commercially available starting material is 3,4-dihydroxybenzaldehyde. In certain embodiments, the hydroxyl group of the compound 3,4-dihydroxybenzaldehyde is first protected with one or more protecting groups commonly known in the literature, including methoxymethyl ether (OMOM), tetrahydropyranyl ether, t-butyl ether, allyl ether, benzyl ether (OBn), triisopropylsilyl ether (OTIPS), or t-butyldimethylsilyl ether (OTBS). In certain embodiments, the protecting group is benzyl ether. In certain embodiments, the protecting group is methoxymethyl ether. In certain embodiments, R1 is methoxymethyl (MOM) or benzyl (Bn). In certain embodiments, chloromethyl methyl ether is used to protect the hydroxyl group of the compound of formula II. [ka] Formula II

[0050] Step 1.1: Synthesis of the Syn-Epoxy Intermediate In certain embodiments, a syn-epoxide intermediate is formed. The syn-epoxide intermediate is a compound of formula III, where R1 and R2 are H or a protecting group. In certain embodiments, R1 and R2 are the same. In certain embodiments, R1 and R2 are different. In certain embodiments, R1 and R2 may be H, methoxymethyl, tetrahydropyranyl, t-butyl, allyl, benzyl, triisopropylsilyl, or t-butyldimethylsilyl groups. In certain embodiments, R2 is H or t-butyldimethylsilyl, and R1 is methoxymethyl or benzyl. [ka] Formula III

[0051] Step 1.1.1: Seven-step synthesis of the syn-epoxide intermediate. In a particular embodiment, the general synthesis of a syn-epoxide intermediate is outlined in Figure 1. As shown in Figure 1, the synthesis comprises seven steps. In particular, the synthesis includes a coupling reaction to form a chiral auxiliary compound. The chiral auxiliary compound then undergoes an asymmetric aldol reaction. Subsequently, a protecting group is added to the reaction product, and then the chiral auxiliary is removed from the compound by a reduction reaction. The resulting product then undergoes a debenzylate reaction, followed by a sulfonation reaction. Finally, the desired syn-epoxide intermediate is formed.

[0052] In a particular embodiment, the second starting material for the synthesis of (-)-epicatechin is the compound of formula III, where X is S or O, R3 is Ph, Bn, or CH(CH3)2, and R4 is Ph or H. [ka] Formula IV

[0053] In certain embodiments, the compound of formula IV is converted into a chiral auxiliary compound. In certain embodiments, the compound of formula I is coupled with benzyloxyacetic acid or benzyloxyacetyl chloride using a coupling agent. In particular, the compound of formula I is coupled with benzyloxyacetic acid using a coupling agent. In certain embodiments, the coupling agent is 3-{[(ethylimino)methylidene]amino}-N,N-dimethylpropan-1-amine (EDCI), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), propylphosphonic anhydride (T3P), or N,N'-dicyclohexylcarbodiimide (DCC). In certain embodiments, the coupling agent is EDCI. The coupling reaction is shown in Scheme I. [ka] Scheme I.

[0054] In certain embodiments, the chiral auxiliary is a compound of formula V, where X is O or S, R3 is Ph, Bn, or CH(CH3)2, and R4 is Ph or H. [ka] Formula V

[0055] In certain embodiments, protected 3,4-dihydroxybenzaldehyde and a chiral auxiliary are bonded in an asymmetric aldol reaction. In certain embodiments, the titanium enolate is formed from the chiral auxiliary. In certain embodiments, the titanium enolate is formed by providing a chiral auxiliary to titanium tetrachloride. In certain embodiments, the titanium enolate is subjected to a base and protected 3,4-dihydroxybenzaldehyde to form an anti-aldol product. In certain embodiments, the base is triethylamine. The asymmetric aldol reaction is shown in Scheme II. [ka] Scheme II.

[0056] In certain embodiments, the resulting compound is further protected using one or more silyl protecting groups commonly known in the literature, including triisopropylsilyl ether, t-butyldiphenylsilyl ether, or t-butyldimethylsilyl ether. In certain embodiments, the protecting group is t-butyldimethylsilyl ether. In certain embodiments, t-butyldimethylsilyl chloride is used to protect the hydroxyl group of the resulting compound. The protection reaction is shown in Scheme III. [ka] Scheme III.

[0057] In certain embodiments, the resulting compound is subjected to a reduction reaction to remove the chiral auxiliary group. In certain embodiments, the resulting compound is subjected to a reducing agent to form a primary alcohol. This reduction can be carried out using various reducing agents, including but not limited to lithium borohydride. The reduction reaction is shown in Scheme IV. [ka] Scheme IV.

[0058] In certain embodiments, the resulting compound undergoes further debenzylation. In certain embodiments, a palladium catalyst is used for debenzylation in the presence of hydrogen gas. In certain embodiments, the palladium catalyst may be carbon-supported palladium (Pd / C) or carbon-supported palladium hydroxide (Pd(OH)2 / C). In certain embodiments, the palladium catalyst is Pd(OH)2 / C in the presence of hydrogen gas. The debenzylation reaction is shown in scheme V. [ka] Scheme V.

[0059] In certain embodiments, the primary alcohol of the above compound is then converted to a leaving group. In certain embodiments, the leaving group is a mesylate, tosylate, triflate, bromide, or chloride. In certain embodiments, the compound can be treated with mesyl chloride, tosyl chloride, or trifuryl chloride in the presence of at least one catalyst and a base. In certain embodiments, the compound is treated with tosyl chloride in the presence of the catalyst dibutyltin oxide and 4-dimethylaminopyridine (DMAP) and the base triethylamine to obtain a sulfonic acid ester. The sulfonation reaction is shown in Scheme VI. [ka] Scheme VI.

[0060] In certain embodiments, the resulting compound undergoes a further epoxidation reaction. In certain embodiments, the compound is treated with a base commonly known in the literature, including potassium carbonate, potassium hydroxide, sodium hydroxide, sodium methoxide, lithium bis(trimethylsilyl)amide, ammonium hydroxide, sodium carbonate, cesium carbonate, and potassium tert-butoxide. In certain embodiments, the compound is treated with potassium carbonate to obtain a syn-epoxide intermediate. The epoxidation is shown in Scheme VII. [ka] Scheme VII.

[0061] Step 1.1.2: Two-step synthesis of thin epoxides In a particular embodiment, the general synthesis of a syn-epoxide intermediate is outlined in Figure 2. As shown in Figure 2, the synthesis involves two steps. In particular, the synthesis involves asymmetric addition followed by epoxidation, resulting in the formation of the desired syn-epoxide intermediate.

[0062] In certain embodiments, protected 3,4-dihydroxybenzaldehyde can undergo asymmetric addition with an alkene. In certain embodiments, the asymmetric addition can be carried out using vinyltrimethoxysilane in the presence of a binaphthyl catalyst. In certain embodiments, the binaphthyl catalyst is (R)-DTBM-SEGPHOS. In certain embodiments, the asymmetric addition can be further completed in the presence of a copper catalyst. The asymmetric addition is shown in Scheme VIII. [ka] Scheme VIII.

[0063] In certain embodiments, the resulting compound undergoes a further epoxidation reaction. In certain embodiments, the compound is treated with a titanium catalyst and an oxidizing agent. In certain embodiments, the catalyst is titanium salane and the peroxide is hydrogen peroxide, yielding a syn-epoxide intermediate. The epoxidation is shown in Scheme IX. [ka] Scheme IX.

[0064] Step 1.2 Synthesis of anti-epoxide intermediates In certain embodiments, an anti-epoxide intermediate is formed. The anti-epoxide intermediate is a compound of formula VI, where R1 and R2 are H or a protecting group. In certain embodiments, R1 and R2 are the same. In certain embodiments, R1 and R2 are different. In certain embodiments, R1 and R2 may be H, methoxymethyl, tetrahydropyranyl, t-butyl, allyl, benzyl, triisopropylsilyl, or t-butyldimethylsilyl. In certain embodiments, R2 is H or t-butyldimethylsilyl, and R1 is methoxymethyl or benzyl. [ka] Equation VI

[0065] Step 1.2.1: Two-step synthesis of anti-epoxides In a particular embodiment, the general synthesis of an anti-epoxide intermediate is outlined in Figure 3. As shown in Figure 3, the synthesis involves two steps. In particular, the synthesis involves a Grignard reaction followed by epoxidation, which leads to the formation of the desired anti-epoxide intermediate.

[0066] In certain embodiments, protected 3,4-dihydroxybenzaldehyde can undergo a Grignard reaction. In certain embodiments, the Grignard reaction is carried out using magnesium vinyl bromide to obtain the desired product. The Grignard reaction is shown in scheme X. [ka] Scheme X.

[0067] In certain embodiments, the resulting compound undergoes a Sharpless epoxidation reaction. In certain embodiments, the compound is treated with a chiral catalyst and an oxidizing agent. In certain embodiments, the chiral catalyst is formed from titanium tetraisopropoxide and (+)-diisopropyl tartrate ((+)-DIPT). In certain embodiments, the compound is further treated with the oxidizing agent tert-butyl hydroperoxide (TBHP) to obtain an anti-epoxide intermediate. The epoxidation is shown in Scheme XI. [ka] Scheme XI.

[0068] Step 1.2.2: Five-step synthesis of anti-epoxides from 3,4-dihydroxybenzaldehyde In a particular embodiment, the general synthesis of an anti-epoxide intermediate is outlined in Figure 4. As shown in Figure 4, the synthesis comprises five steps. In particular, the synthesis involves a Wittig reaction followed by the reduction of the alkene. The product can then undergo a protection reaction and then ester reduction. Finally, this is followed by epoxidation, resulting in the formation of the desired anti-epoxide intermediate.

[0069] In certain embodiments, protected 3,4-dihydroxybenzaldehyde can undergo the Wittig reaction. In certain embodiments, the Wittig reaction is carried out using ethoxycarbonylmethyl(triphenyl)phosphonium bromide to obtain the desired product. The Wittig reaction is shown in Scheme XII. [ka] Scheme XII.

[0070] In certain embodiments, the obtained product can undergo alkene reduction. In certain embodiments, the alkene is reduced using an organolithium reagent and an acid. In certain embodiments, the alkene is reduced with lithium bromide, which is an organolithium reagent, and sulfuric acid, which is an acid, to obtain the desired product. The reduction reaction is shown in Scheme XIII. [ka] Scheme XIII.

[0071] In certain embodiments, the resulting compound is further protected using one or more silyl protecting groups commonly known in the literature, including triisopropylsilyl ether, t-butyldiphenylsilyl ether, or t-butyldimethylsilyl ether. In certain embodiments, the protecting group is t-butyldimethylsilyl ether. In certain embodiments, t-butyldimethylsilyl chloride is used to protect the hydroxyl group of the resulting compound. The protection reaction is shown in Scheme XIV. [ka] Scheme XIV.

[0072] In certain embodiments, the obtained product can undergo a reduction reaction. In certain embodiments, the ester is reduced using a boron hydride reagent. In certain embodiments, the boron hydride reagent may be sodium borohydride or lithium borohydride. In certain embodiments, the ester is reduced with lithium bromide, an organolithium reagent, and sulfuric acid, an acid, to obtain the desired product. The reduction reaction is shown in Scheme XV. [ka] Scheme XV.

[0073] In certain embodiments, the resulting compound undergoes an epoxidation reaction. In certain embodiments, the compound is treated with a base. In certain embodiments, the base is sodium hydroxide, sodium hydride, lithium hydroxide, potassium tert-butoxide, sodium carbonate, or potassium hydroxide. In certain embodiments, the compound is treated with sodium hydroxide to obtain the desired anti-epoxide. The epoxidation is shown in scheme XVI. [ka] Scheme XVI.

[0074] Step 1.2.3: Five-step synthesis of anti-epoxides from tartaric acid In a particular embodiment, the general synthesis of an anti-epoxide intermediate is outlined in Figure 5. As shown in Figure 5, the synthesis comprises five steps. In particular, the synthesis involves cyclization and subsequent oxidation reactions. The product can then undergo a protection reaction and then esterification. Finally, this is followed by epoxidation, resulting in the formation of the desired anti-epoxide intermediate.

[0075] In certain embodiments, the starting material may be tartaric acid. In certain embodiments, tartaric acid can undergo a cyclization reaction with an acid and acetone. In certain embodiments, tartaric acid can be reacted with tosylic acid, which is an acid, and acetone to obtain the desired product. The reaction is shown in Scheme XVII. [ka] Scheme XVII.

[0076] In certain embodiments, the resulting product may then be oxidized. In certain embodiments, the product is treated with an oxidizing agent. In certain embodiments, the product is treated with sodium periodate, which is an oxidizing agent, to obtain the desired aldehyde. The reaction is shown in scheme XVIII. [ka] Scheme XVIII.

[0077] In a particular embodiment, the resulting product is reacted with protected 4-bromocatechol to obtain a desired secondary alcohol. The reaction is shown in Scheme XIX. [ka] Scheme XIX.

[0078] In certain embodiments, the resulting product can undergo further ring-opening and subsequent sulfonylation. In certain embodiments, the ring-opening reaction can be achieved using an acid. In certain embodiments, the acid is tosylic acid. In certain embodiments, the sulfonylation reaction can proceed by treating the resulting product with mesyl chloride, tosyl chloride, or trifuryl chloride in the presence of at least one catalyst and a base. In certain embodiments, the compound is treated with tosyl chloride to obtain a sulfonate. The sulfonation reaction is shown in scheme XX. [ka] Scheme XX.

[0079] In certain embodiments, the resulting compound undergoes an epoxidation reaction. In certain embodiments, the compound is treated with a base. In certain embodiments, the base is sodium hydroxide, sodium hydride, or potassium hydroxide. In certain embodiments, the compound is treated with sodium hydroxide to obtain the desired anti-epoxide. The epoxidation is shown in Scheme XXI. [ka] Scheme XXI.

[0080] In certain embodiments, the resulting compound is further protected using one or more silyl protecting groups commonly known in the literature, including triisopropylsilyl ether, t-butyldiphenylsilyl ether, or t-butyldimethylsilyl ether. In certain embodiments, the protecting group is t-butyldimethylsilyl ether. In certain embodiments, t-butyldimethylsilyl chloride is used to protect the hydroxyl group of the resulting compound. The protection reaction is shown in Scheme XXII. [ka] Scheme XXII.

[0081] Step 2: Synthesis of (-)-epicatechin In certain embodiments, the second step involves the synthesis of (-)-epicatechin. In certain embodiments, (-)-epicatechin may be synthesized from a syn-epoxide. In certain embodiments, (-)-epicatechin may be synthesized from an anti-epoxide. In certain embodiments, the synthesis of (-)-epicatechin proceeds according to general steps outlined in Figures 6 and 7, as will be discussed further below.

[0082] Step 2.1: Synthesis of (-)-epicatechin from syn-epoxide intermediates In a particular embodiment, the general synthesis of (-)-epicatechin from a syn-epoxide intermediate is outlined in Figure 6. As shown in Figure 6, the synthesis comprises at least five steps. In particular, the synthesis involves an epoxide ring-opening reaction. The product is then protected and subsequently deprotected. The resulting product then undergoes a cyclization reaction. Finally, one or more deprotection reactions yield the desired (-)-epicatechin product.

[0083] In a particular embodiment, the starting material for the synthesis of (-)-epicatechin from syn-epoxides is the compound of formula VII, where X is F, Br, I, Cl, N, S, or B, and R3 is Bn or MOM. [ka] Formula VII

[0084] In certain embodiments, the syn-epoxide intermediate undergoes an epoxide ring-opening reaction. In certain embodiments, the compound of formula VII is 1,3-bis(benzyloxy)-5-fluorobenzene, where X is F and R3 is benzyl. In certain embodiments, the compound of formula VI is treated with an organolithium reagent. In certain embodiments, the organolithium reagent is n-butyllithium, methyllithium, or tert-butyllithium. In certain embodiments, the organolithium reagent is n-butyllithium. In certain embodiments, the syn-epoxide intermediate is further added to the reaction mixture to obtain the desired product. In alternative embodiments, the syn-epoxide intermediate can undergo epoxide ring-opening using the compound of formula VI, where X is Br, I, Cl, N, S, or B in the presence of a Lewis acid known in the literature. The epoxide ring-opening is shown in scheme XXIII. [ka] Scheme XXIII.

[0085] In certain embodiments, the resulting compound is further protected using one or more protecting groups commonly known in the literature, including methoxymethyl ether, tetrahydropyranyl ether, t-butyl ether, allyl ether, benzyl ether, triisopropylsilyl ether, or t-butyldimethylsilyl ether. In certain embodiments, the protecting group is different from the R2 group. In certain embodiments, the protecting group is t-methoxymethyl. In certain embodiments, methoxymethyl chloride is used to protect the hydroxyl group of the resulting compound. The protection reaction is shown in Scheme XXIV. [ka] Scheme XXIV.

[0086] In certain embodiments, the protected compound undergoes further selective deprotection of the protecting group at R2. In certain embodiments, R2 is t-butyldimethylsilyl. In certain embodiments, the protected compound is treated with a suitable acid or fluoride known in the literature for deprotection of the silyl ether. In certain embodiments, the protected compound is treated with tetrabutylammonium fluoride (TBAF) to obtain the desired deprotected compound. The deprotection reaction is shown in scheme XXV. [ka] Scheme XXV.

[0087] In certain embodiments, the obtained product is subjected to a cyclization reaction. In certain embodiments, the obtained product is treated with a strong base. In certain embodiments, the strong base is potassium hydride, sodium hydride, or potassium tert-butoxide. In certain embodiments, X is F, and the strong base is potassium hydride, and the desired cyclization product is obtained. The deprotection reaction is shown in scheme XXVI. [ka] Scheme XXVI.

[0088] In alternative embodiments where X is Br, I, Cl, N, S, or B, the cyclization reaction is carried out in the presence of a copper catalyst to obtain the desired cyclization product.

[0089] In certain embodiments, the cyclization product undergoes one or more further deprotection reactions. In certain embodiments, the methoxymethyl ether group is removed using methods known in the literature. In certain embodiments, the methoxymethyl ether group is removed using an acid. In certain embodiments, the acid is hydrochloric acid.

[0090] In certain embodiments, the benzyl ether group is removed using a debenzylation reaction. In certain embodiments, a palladium catalyst is used for debenzylation in the presence of hydrogen gas. In certain embodiments, the palladium catalyst may be carbon-supported palladium (Pd / C) or carbon-supported palladium hydroxide (Pd(OH)2 / C). In certain embodiments, the palladium catalyst is Pd(OH)2 / C in the presence of hydrogen gas. In certain embodiments, one or more deprotection reactions yield the desired (-)-epicatechin product. The deprotection reactions are shown in Scheme XXVII. [ka] Scheme XXVII.

[0091] Step 2.2: Synthesis of (-)-epicatechin from anti-epoxide intermediates In a particular embodiment, the general synthesis of (-)-epicatechin from an anti-epoxide intermediate is outlined in Figure 7. As shown in Figure 7, the synthesis comprises at least five steps. In particular, the synthesis comprises a first reaction. The product is then protected and subsequently deprotected. The resulting product then undergoes a cyclization reaction. Finally, the deprotection reaction yields the desired (-)-epicatechin product.

[0092] In a particular embodiment, the anti-epoxide undergoes a first reaction. The transformation is shown in scheme XXVIII. [ka] Scheme XXVIII.

[0093] In certain embodiments, the resulting compound undergoes one or more deprotection reactions. In certain embodiments, R2 is t-butyldimethylsilyl. In certain embodiments, the protected compound is treated with a suitable acid or fluoride known in the literature for deprotection of the silyl ether. In certain embodiments, the protected compound is treated with tetrabutylammonium fluoride (TBAF) to obtain the desired deprotected compound.

[0094] In certain embodiments, R1 and R3 are different. In certain embodiments, R1 is benzyl and R3 is a methoxymethyl group. In certain embodiments, the methoxymethyl ether group is removed using a method known in the literature. In certain embodiments, the methoxymethyl ether group is removed using an acid. In certain embodiments, the acid is hydrochloric acid. The deprotection reaction is shown in scheme XXIX. [ka] Scheme XXIX.

[0095] In certain embodiments, the obtained product is subjected to a cyclization reaction. In certain embodiments, the obtained product is treated with triethyl orthopropionate. In certain embodiments, the reaction mixture is further treated with acid. In certain embodiments, the reaction mixture is treated with tosylic acid to obtain the desired cyclization product. The cyclization reaction is shown in scheme XXX. [ka] Scheme XXX.

[0096] In certain embodiments, the resulting product undergoes a deprotection reaction. In certain embodiments, the benzyl ether group is removed using a debenzylation reaction. In certain embodiments, a palladium catalyst is used for debenzylation in the presence of hydrogen gas. In certain embodiments, the palladium catalyst may be carbon-supported palladium (Pd / C) or carbon-supported palladium hydroxide (Pd(OH)2 / C). In certain embodiments, the palladium catalyst is Pd(OH)2 / C in the presence of hydrogen gas. In certain embodiments, the deprotection reaction yields the desired (-)-epicatechin product. The deprotection reaction is shown in Scheme XXXI. [ka] Scheme XXXI.

[0097] IV. Consumer goods In certain embodiments, the disclosure further relates to a consumer product comprising one or more catechin epimers disclosed herein. In certain embodiments, the consumer product comprises (-)-epicatechin, and each of the compounds is prepared by a method disclosed herein.

[0098] In certain embodiments, the stereospecific catechin epimers provided herein can be used in a wide variety of food products. Non-limiting examples of suitable foods include chocolate, chewing gum compositions, hard and soft confectionery products, dairy products, snack foods, foods in the beverage category where the product has a nearly neutral pH, foods in the frozen food category including frozen dairy products, nutritional products, dietary supplements, and pharmaceuticals, as well as foods in the food categories described herein.

[0099] As used herein, the “beverage category” may refer to beverages, beverage mixtures, and concentrates, including, but not limited to, instant alcoholic and non-alcoholic beverages, as well as dry powder beverages, where the beverage has a near-neutral pH. Additional non-limiting examples of beverages include carbonated and non-carbonated beverages, such as soda, fruit juice, or vegetable juice.

[0100] As used herein, “Frozen Food Category” refers to chilled or frozen foods having a neutral pH. Non-exclusive examples of foods in the Frozen Food Category may include ice cream, impulse ice cream, single serving dairy ice cream, single serving water ice cream, multi-pack dairy ice cream, multi-pack water ice cream, takeaway ice cream, takeaway dairy ice cream, ice cream desserts, bulk ice cream, takeaway water ice cream, frozen yogurt, homemade ice cream, frozen cooked foods, frozen pizza, chilled pizza, frozen soup, frozen pasta, frozen processed red meat, frozen processed poultry, frozen processed fish / seafood, frozen vegetables, frozen processed vegetables, frozen meat substitutes, frozen potatoes, frozen bakery products, and frozen desserts.

[0101] As used herein, the “snack food category” refers to any food that may be a light, formless meal, but which includes sweet and flavored snacks and snack bars, having a neutral pH. Examples of snack foods include, but are not limited to, fruit snacks, chips / crisps, extruded snacks, tortilla / corn chips, popcorn, pretzels, nuts, and other sweet and flavored snacks. Examples of snack bars include, but are not limited to, granola / muesli bars, breakfast bars, energy bars, fruit bars, and other snack bars.

[0102] As used herein, “nutritional product” means any product that can provide desirable nutritional value, including, but not limited to, nutritional bars and nutritional beverages. In certain embodiments, a nutritional product is a medical food and / or nutritional therapy. Non-limiting examples of nutritional bars include protein bars (e.g., RXBAR®, LARABAR®, CLIF BAR®), nut bars (e.g., KIND® bars), energy bars, fiber bars, meal replacement bars, or other nutritional bars. Non-limiting examples of nutritional beverages include protein drinks (e.g., BOOST® Drinks), meal replacement shakes and / or beverages (e.g., Enure® Nutritional Shakes), diabetes shakes and / or beverages (e.g., Glucerna® Shakes), immune support beverages, pediatric supplement beverages, or other nutritional beverages.

[0103] As used herein, “nutritional supplement” means a supplement that can provide desired nutrition. Nutritional supplements may be administered orally, for example, in the form of pills, chews, gummies, or powders. Non-limiting examples of nutritional supplements include vitamin supplements, mineral supplements, botanical supplements, other nutritional supplements, or combinations thereof. As used herein, “pharmaceutical” means a medical drug. Non-limiting examples of pharmaceuticals include prescription drugs, over-the-counter drugs (e.g., aspirin, acetaminophen, or ibuprofen), botanical drugs, or other pharmaceuticals.

[0104] In certain embodiments, an effective amount of (-)-epicatechin can be added to consumer goods that do not naturally contain flavanols to provide consumers with desired health benefits. These amounts may be determined from existing ongoing clinical trials. Alternatively, flavanol monomers can be added to foods and beverages that already contain flavanols to further enhance the nutritional value of the product and provide improved health benefits.

[0105] The pharmaceuticals containing (-)-epicatechin as disclosed herein may be administered by several means, including orally, nasally, buccally, intravenously, and topically. Those skilled in the art will be able to determine the appropriate mode of delivery to maximize the efficacy of the catechin compound. [Examples]

[0106] The subject matter of this disclosure will be better understood by referring to the following embodiments, which are provided as examples and not limiting to the subject matter of this disclosure.

[0107] Example 1: Synthesis of (-)-epicatechin Example 1 provides a 12-step synthesis of (-)-epicatechin. Chiral auxiliary group 1 and 3,4-bis(methoxymethoxy)benzaldehyde 2 are used as starting materials. The steps of this synthesis are shown in Scheme XXXII and are further described below. [ka] Reagents and conditions: (a) Et3N, 4 hours; (b) 2,6-Lutidine, TBSCl, Dichloromethane; (c) LiBH4, Ether 0 o C, 1 hour; (d) H2, Pd-C, ethyl acetate; (e) TsCl, dichloromethane; (f) K2CO3, methanol, 0 o C;(g)nBuLi, (((5-fluoro-1,3-phenylene)bis(oxy))bis(methylene)dibenzene, THF;(h)MOMCl, dichloromethane;(i)TBAF, THF;(j)KH, DMF;(k)HCl, dioxane;(l)H2, Pd-C, ethyl acetate. Scheme XXXII.

[0108] Chiral auxiliary group 1 and 3,4-bis(methoxymethoxy)benzaldehyde 2 were subjected to an asymmetric aldol reaction using titanium tetrachloride and triethylamine to obtain the desired product, (2S,3R)-2-(benzyloxy)-3-(3,4-bis(methoxymethoxy)phenyl)-3-hydroxy-1-((S)-4-phenyl-2-thioxoxazolidine-3-yl)propan-1-one 3. The product was then protected with t-butyldimethylsilyl chloride (TBSCl) to obtain the desired t-butyldimethylsilyl ether, (2S,3R)-2-(benzyloxy)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)-1-((S)-4-phenyl-2-thioxoxazolidine-3-yl)propan-1-one 4. The chiral auxiliary group was formed in the presence of lithium borohydride (LiBH4) at 0 oIn a reduction reaction at C, the benzyl group was removed to produce (2R,3R)-2-(benzyloxy)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)propan-1-ol 5. The benzyl group was then removed by hydrogenation under H2 with Pd / C to obtain the desired alcohol, (2R,3R)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)propan-1,2-diol 6. Alcohol 6 was then subjected to selective tosylation of a primary alcohol to obtain the desired tosylate, (2R,3R)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)-2-hydroxypropyl 4-methylbenzenesulfonate 7. Tosilate 7 was further treated with potassium carbonate in methanol to obtain the desired epoxide, ((R)-(3,4-bis(methoxymethoxy)phenyl)((R)-oxiran-2-yl)methoxy)(tert-butyl)dimethylsilane 8. Then, epoxide 8 was alkylated with (((5-fluoro-1,3-phenylene)bis(oxy))bis(methylene))dibenzene using n-butyllithium in THF to obtain the desired alcohol, (1R,2R)-3-(2,4-bis(benzyloxy)-6-fluorophenyl)-1-(3,4-bis(methoxymethoxy)phenyl)-1-((tert-butyldimethylsilyl)oxy)propan-2-ol 9. Next, the free hydroxyl group of alcohol 9 was protected with chloromethyl methoxy ether (MOMCl) to obtain the desired product (5R,6R)-5-{[2,4-bis(benzyloxy)-6-fluorophenyl]methyl}-6-[3,4-bis(methoxymethoxy)phenyl]-8,8,9,9-tetramethyl-2,4,7-trioxa-8-siladecane 10. Then, the desired product was deprotected with tetrabutylammonium fluoride (TBAF) to obtain the desired alcohol (1R,2R)-3-(2,4-bis(benzyloxy)-6-fluorophenyl)-1-(3,4-bis(methoxymethoxy)phenyl)-2-(methoxymethoxy)propan-1-ol 11.Next, alcohol 11 was subjected to potassium hydride to obtain the desired protected (-)-epicatechin, (2R,3R)-5,7-bis(benzyloxy)-2-(3,4-bis(methoxymethoxy)phenyl)-3-(methoxymethoxy)chroman 12. Finally, methoxymethyl ether was deprotected with HCl to obtain the selectively deprotected product, 4-((2R,3R)-5,7-bis(benzyloxy)-3-hydroxychroman-2-yl)benzene-1,2-diol 13. Following this deprotection, benzyl ether was deprotected with Pd / C under H2 gas to obtain (-)-epicatechin 14 as an off-white solid.

[0109] Example 2: Synthesis of (S)-2-(benzyloxy)-1-(4-phenyl-2-thioxoxazolidine-3-yl)ethane-1-one (1) [ka]

[0110] Under nitrogen, solutions of (4S)-4-phenyl-1,3-oxazolidine-2-thion (1 equivalent, 5.5 g, 30.69 mmol), benzyloxyacetic acid (1 equivalent, 5.099 g, 4.39 mL, 30.69 mmol), and DMAP (0.25 equivalents, 0.94 g, 7.67 mmol) in methylene chloride (100 mL) were cooled to 0°C and treated with EDCI (1.1 equivalents, 5.24 g, 33.75 mmol). oAfter stirring for 4 hours in 1C, the ice bath was removed and stirring was continued for 16 hours. The reaction mixture was diluted with methylene chloride (100 mL) and washed with water (2 × 50 mL). The separated organic layer was successively washed with 1 N aqueous HCl (50 mL), water (50 mL), 1 M aqueous NaOH (2 × 50 mL), water (50 mL), and brine (20 mL). The resulting organic phase was dried over sodium sulfate, filtered, and concentrated. The resulting crude solid was crystallized from a mixture of ethyl acetate and hexane to obtain 2-(benzyloxy)-1-[(4S)-4-phenyl-2-sulfanylidene-1,3-oxazolidine-3-yl]ethane-1-one (8.52 g, 26.023 mmol, 84.8%) as an off-white needle-shaped substance. 1 H NMR (400 MHz, CDCl3) δ 4.53 (dd, J = 8, 4 Hz, 1H), 4.60 (s, 2H), 4.86 (t, J = 8 Hz, 1H), 5.04 (dd, J = 36, 16 Hz, 2H), 5.71 (dd, J = 8, 4 Hz, 1H), 7.29-7.41 (m, 10H).

[0111] Example 3: Synthesis of 3,4-bis(methoxymethoxy)benzaldehyde (2) [ka]

[0112] Under nitrogen, a stirred solution of 3,4-dihydroxybenzaldehyde (1 equivalent, 1 g, 7.24 mmol) in DMF (20 mL) was prepared. oCooled to C (ice bath) and treated with potassium carbonate (9 eq., 9.005 g, 65.16 mmol). After stirring for 15 minutes, chloromethyl methyl ether (4.5 eq., 2.62 g, 32.58 mmol) was added dropwise. After the addition was complete, the thick slurry was stirred at room temperature overnight. The reaction mixture was filtered and washed thoroughly with ethyl acetate. The filtrate was diluted with water (200 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with water (2 × 15 mL), dried over sodium sulfate, and concentrated to give 3,4-bis(methoxymethoxy)benzaldehyde (1.5 g, 6.63 mmol, 91.58%) as a pale brown oil. This material was used in the subsequent step without further purification.

[0113] Example 4: Synthesis of (2S,3R)-2-(benzyloxy)-3-(3,4-bis(methoxymethoxy)phenyl)-3-hydroxy-1-((S)-4-phenyl-2-thioxooxazolidin-3-yl)propan-1-one (3)

Chemical formula

[0114] Under argon, a solution of 2-(benzyloxy)-1-[(4S)-4-phenyl-2-sulfanylidene-1,3-oxazolidin-3-yl]ethan-1-one (1 eq., 723 mg, 2.208 mmol) in anhydrous dichloromethane (20 mL) was cooled to -10 o C and treated dropwise with titanium tetrachloride (1.1 eq., 2.43 mL, 2.43 mmol) (1.0 M in dichloromethane). After stirring for 30 minutes, the solution was cooled to -78 o C. After 5 minutes, triethylamine (2 eq., 446.93 mg, 0.61 mL, 4.42 mmol) was added dropwise. The color of the solution changed from amber to deep purple upon addition of triethylamine. After stirring for 75 minutes, 3,4-bis(methoxymethoxy)benzaldehyde (2 eq., 999.16 mg, 4.42 mmol) in dichloromethane (5 mL) was added. After the addition was complete, -78 oStirring continued at C for 2 hours. Once completed, the mixture was diluted with brine (30 mL) and 0 o The mixture was gently warmed in C. The quenched reaction was extracted with 1 M aqueous HCl (2 × 30 mL) and water (30 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (20-40% ethyl acetate in hexane) to obtain (2S,3R)-2-(benzyloxy)-3-[3,4-bis(methoxymethoxy)phenyl]-3-hydroxy-1-[(4S)-4-phenyl-2-sulfanylidene-1,3-oxazolidine-3-yl]propan-1-one (760 mg, 1.37 mmol, 62.16%) as a pale yellow foam. 1 H NMR (400 MHz, CDCl3) δ 2.97 (brs, 1H), 3.52 (s, 6H), 4.29-4.35 (m, 2H), 4.51 (dd, J = 12, 8 Hz, 2H), 4.98 (d, J = 8 Hz, 1H), 5.19 (d, J = 8 Hz, 1H), 5.21 (d, J = 8 Hz, 1H), 5.26 (dd, J = 4, 2 Hz, 2H), 5.33 (dd, J = 4, 2 Hz, 1H), 6.50 (d, J = 4 Hz, 1H), 7.12 (d, J = 8 Hz, 1H), 7.14 -7.24 (m, 7H), 7.31(d, J = 4 Hz, 1H), 7.34-7.41 (m, 3H).

[0115] Example 5: Synthesis of (2S,3R)-2-(benzyloxy)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)-1-((S)-4-phenyl-2-thioxoxazolidine-3-yl)propan-1-one (4) [ka]

[0116] Under nitrogen, a stirred solution of 2,6-lutidine (2.4 equivalents, 353.038 mg, 0.38 mL, 3.29 mmol) in dichloromethane (10 mL) was heated to -78°C. o The mixture was cooled to 1°C and filled drop by drop with tert-butyldimethylsilyl trifluoromethanesulfonate (2.2 equivalents, 798.29 mg, 0.69 mL, 3.02 mmol) and (2S,3R)-2-(benzyloxy)-3-[3,4-bis(methoxymethoxy)phenyl]-3-hydroxy-1-[(4S)-4-phenyl-2-sulfanylidene-1,3-oxazolidine-3-yl]propan-1-one (1 equivalent, 760 mg, 1.37 mmol) in 5 mL of dichloromethane. -78 o After stirring in C for 2 hours, the reaction mixture was quenched with 50% saturated sodium bicarbonate, heated to room temperature, and diluted with dichloromethane (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (10-20% ethyl acetate in hexane) to obtain (2S,3R)-2-(benzyloxy)-3-[3,4-bis(methoxymethoxy)phenyl]-3-[(tert-butyldimethylsilyl)oxy]-1-[(4S)-4-phenyl-2-sulfanylidene-1,3-oxazolidine-3-yl]propane-1 (440 mg, 0.66 mmol) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ -0.09 (s, 3H), 0.03 (s, 3H), 0.85 (s, 9H), 3.52 (s, 6H), 4.00 (t, J = 8 Hz, 1H), 4.15 (dd, J = 12, 4 Hz, 1H), 4.58 (d, J = 12 Hz, 1H), 4.67 (d, J = 12 Hz, 1H), 4.88 (d, J = 4 Hz, 1H), 5.06 (dd, J = 8, 4 Hz, 1H), 5.18 (t, J = 8 Hz, 2 H), 5.26 (d, J = 8 Hz, 1H), 5.31 (d, J = 4 Hz,1H).6.56 (d, J = 8 Hz, 1H), 6.91 (dd, J = 8, 2 Hz, 1H), 7.06 (d, J = 8 Hz, 1H), 7.09-7.11 (m, 2H), 7.19-7.25 (m, 5H), 7.30-7.34 (m, 3H).

[0117] Example 6: Synthesis of (2R,3R)-2-(benzyloxy)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)propan-1-ol (5) [ka]

[0118] A solution of (2S,3R)-2-(benzyloxy)-3-[3,4-bis(methoxymethoxy)phenyl]-3-[(tert-butyldimethylsilyl)oxy]-1-[(4S)-4-phenyl-2-sulfanylidene-1,3-oxazolidine-3-yl]propane-1 (1 equivalent, 440 mg, 0.66 mmol) in diethyl ether (10 mL) and MeOH (2 mL) is prepared. o It was cooled to C and treated in one go with lithium borohydride (1.5 equivalents, 20.805 mg, 0.96 mmol). oAfter stirring in 1 hour, the mixture was quenched with a saturated aqueous solution of NaHCO3. The mixture was extracted with ethyl acetate and hexane (10:1) (3 × 15 mL). The combined extract was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash column chromatography (15-30% ethyl acetate in hexane) to obtain (2R,3R)-2-(benzyloxy)-3-[3,4-bis(methoxymethoxy)phenyl]-3-[(tert-butyldimethylsilyl)oxy]propan-1-ol (298 mg, 0.605 mmol, 91.81%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ -0.11 (s, 3H), 0.04 (s, 3H), 0.88 (s, 9 H), 1.94 (t, J = 8 Hz, 1H), 3.31 (dd, J = 12, 8 Hz, 1H), 3.47-3.56 (m, 1H), 3.49 (s, 3H), 3.52 (s, 3H), 3.57-3.61 (m, 1H), 4.63 (d, J = 12 Hz, 1H), 4.77 (d, J = 8 Hz, 1H), 4.83 (d, J = 12 Hz, 1H), 5.19-5.22 (m, 4H), 6.90 (dd, J = 8, 4 Hz, 1H), 7.08 (d, J = 8 Hz, 1H), 7.19 (d, J = 4 Hz, 1H).

[0119] Example 7: Synthesis of (2R,3R)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)propane-1,2-diol (6) [ka]

[0120] A heterogeneous solution of (2R,3R)-2-(benzyloxy)-3-[3,4-bis(methoxymethoxy)phenyl]-3-[(tert-butyldimethylsilyl)oxy]propan-1-ol (300 mg, 0.609 mmol) and palladium hydroxide (300 mg, 2.14 mmol) (20% carbon-supported) was evacuated, packed three times with hydrogen, and then stirred under a hydrogen atmosphere (balloon) for 15 hours. The mixture was filtered and washed with ethyl acetate. The combined filtrate was concentrated under reduced pressure and purified by silica gel flash column chromatography (20-60% ethyl acetate in hexane) to obtain (2R,3R)-3-[3,4-bis(methoxymethoxy)phenyl]-3-[(tert-butyldimethylsilyl)oxy]propan-1,2-diol (200 mg, 0.5 mmol, 81.59%) as a colorless, concentrated oil. 1 H NMR (400 MHz, CDCl3) δ -0.15 (s, 3H), 0.05 (s, 3H), 0.90 (s, 9H), 1.95 (t, J = 8 Hz, 1H), 2.82 (d, J = 4 Hz, 1H), 3.43-3.53 (m, 1H), 3.50 (s, 3H), 3.52 (s, 3H), 3.56-3.64 (m, 2H), 4.60 (d, J = 8 Hz, 1H), 5.21-5.24 (m, 4 H), 6.89 (dd, J = 8, 4 Hz, 1H), 7.09 (d, J = 8 Hz, 1H), 7.16 (d, J = 4 Hz, 1H).

[0121] Example 8: Synthesis of (2R,3R)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)-2-hydroxypropyl 4-methylbenzenesulfonate (7) [ka]

[0122] Under nitrogen, a stirred solution of (2R,3R)-3-[3,4-bis(methoxymethoxy)phenyl]-3-[(tert-butyldimethylsilyl)oxy]propane-1,2-diol (1 equivalent, 200 mg, 0.5 mmol) in anhydrous dichloromethane (4 mL) is prepared. o The mixture was cooled to 10°C and treated with dibutyltin oxide (0.02 equivalents, 2.47 mg, 0.0099 mmol), p-toluenesulfonyl chloride (1.2 equivalents, 113.66 mg, 0.6 mmol), DMAP (0.1 equivalents, 6.07 mg, 0.05 mmol), and triethylamine (1.2 equivalents, 60.33 mg, 0.083 mL, 0.6 mmol). After stirring for 5 hours, the reaction mixture was quenched with water (5 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2 × 10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (15-30% ethyl acetate in hexane) to obtain [(1R,2R)-1-[3,4-bis(methoxymethoxy)phenyl]-2-hydroxy-3-[(4-methylbenzenesulfonyl)oxy]propoxy](tert-butyl)-dimethylsilane (260 mg, 0.47 mmol, 94%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ -0.17 (s, 3H), 0.02 (s, 3H), 0.86 (s, 9 H), 2.44 (s, 3 H), 2.60 (d, J = 4 Hz, 1H), 3.49 (s, 3 H), 3.52 (s, 3H), 3.72-3.76 (m, 1H), 3.84 (dd, J = 12, 8 Hz, 1H), 4.02 (dd, J = 12. 4Hz, 1H), 4.61 (d, J = 4 Hz, 1H), 5.20-5.22 (m, 4H), 6.81 (dd, J = 8, 4 Hz, 1H), 7.06 (d, J = 8 Hz, 1H), 7.12 (d, J = 4 Hz, 1H), 7.33 (d, J = 8 Hz, 2H), 7.78 (d, J = 8 Hz, 2H).

[0123] Example 9: Synthesis of ((R)-(3,4-bis(methoxymethoxy)phenyl)((R)-oxiran-2-yl)methoxy)(tert-butyl)dimethylsilane (8) [ka]

[0124] Under nitrogen, a solution of [(1R,2R)-1-[3,4-bis(methoxymethoxy)phenyl]-2-hydroxy-3-[(4-methylbenzenesulfonyl)oxy]propoxy](tert-butyl)dimethylsilane (1 equivalent, 260 mg, 0.47 mmol) in MeOH (2.5 mL) and dioxane (1 mL) was prepared. o It was cooled in an ice bath (C) and treated with potassium carbonate (2 equivalents, 129.085 mg, 0.93 mmol). o After stirring for 1.0 hour in C, the ice bath was removed and stirring was continued for 2 hours. Upon completion, the reaction mixture was diluted with ethyl acetate (10 mL), filtered, and thoroughly washed with ethyl acetate. The filtrate was concentrated under reduced pressure and purified by silica gel flash column chromatography (20% ethyl acetate in hexane) to obtain [(R)-[3,4-bis(methoxymethoxy)phenyl][(2R)-oxiran-2-yl]methoxy](tert-butyl)dimethylsilane (148 mg, 0.38 mmol, 82.41%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 0.00 (s, 3 H), 0.11 (s, 3H), 0.91 (s, 9H), 2.65 (dd, J = 8, 4 Hz, 1H), 2.75 (t, J = 8 Hz, 1H), 3.04-3.07 (m, 1H), 3.51 (s, 3H), 3.52 (3H), 4.29 (d, J = 4 Hz, 1H), 5.21-5.23 (m, 4 H), 6.90 (dd, J = 8, 4 Hz, 1H), 7.11 (d, J = 8 Hz, 1H), 7.22 (s, 1H).

[0125] Example 10: Synthesis of (1R,2R)-3-(2,4-bis(benzyloxy)-6-fluorophenyl)-1-(3,4-bis(methoxymethoxy)phenyl)-1-((tert-butyldimethylsilyl)oxy)propan-2-ol (9) [ka]

[0126] Under argon conditions, a solution of 1,3-bis(benzyloxy)-5-fluorobenzene (2 equivalents, 232.54 mg, 0.75 mmol) in anhydrous THF (5 mL) was heated to -78 o The mixture was cooled to 1°C and carefully treated dropwise with n-butyllithium (2.09 equivalents, 0.38 mL, 0.79 mmol, 2.3 M in hexane). After stirring for 1 hour, a solution of [(R)-[3,4-bis(methoxymethoxy)phenyl][(2R)-oxiran-2-yl]methoxy](tert-butyl)dimethylsilane (1 equivalent, 145 mg, 0.38 mmol) in anhydrous THF (2 mL), followed by a solution of boron trifluoride etherate (2 equivalents, 107.035 mg, 0.096 mL, 0.75 mmol) in anhydrous THF (2 mL). After stirring for 30 minutes, the reaction was quenched with MeOH (3 mL) and brine (10 mL). The mixture was extracted with ethyl acetate (3 × 15 mL), the combined extract was washed with brine (15 mL), dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel flash column chromatography (5-15% ethyl acetate in hexane) to obtain (1R,2R)-3-[2,4-bis(benzyloxy)-6-fluorophenyl]-1-[3,4-bis(methoxymethoxy)-phenyl]-1-[(tert-butyldimethylsilyl)oxy]propan-2-ol (125 mg, 0.18 mmol, 47.84%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ - 0.16 (s, 3H), 0.06 (s, 3H), 0.89 (s, 9H), 2.50 (d, J = 4 Hz, 1H), 2.51-2.72 (m, 2H), 3.47 (s, 3H), 3.52 (s, 3H), 3.82-3.89 (m, 1H), 4.50 (d, 4 Hz, 1H), 4.95 (s, 2H), 4.96 (s, 2H), 5.14 (s, 2H), 5.20 (s, 2H), 6.28-6.33 (m, 2H), 6.83 (dd, J = 8, 2 Hz, 1H), 7.02 (d, J = 8 Hz, 1H), 7.16 (d, J = 2 Hz, 1H), 7.26-7.36 (m, 10 Hz). 19 F NMR (376 MHz, CDCl3) δ -114.52.

[0127] Example 11: Synthesis of (5R,6R)-5-{[2,4-bis(benzyloxy)-6-fluorophenyl]methyl}-6-[3,4-bis(methoxymethoxy)phenyl]-8,8,9,9-tetramethyl-2,4,7-trioxa-8-siladecane (10) [ka]

[0128] Under nitrogen, a solution of (1R,2R)-3-[2,4-bis(benzyloxy)-6-fluorophenyl]-1-[3,4-bis(methoxymethoxy)phenyl]-1-[(tert-butyldimethylsilyl)oxy]propan-2-ol (1 equivalent, 125 mg, 0.18 mmol) and diisopropylethylamine (12 equivalents, 279.8 mg, 0.38 mL, 2.16 mmol) in dichloromethane (3 mL) was prepared. oThe mixture was cooled to 1°C and treated with chloromethyl methyl ether (6 equivalents, 87.15 mg, 0.082 mL, 1.082 mmol) and tetrabutylammonium iodide (0.05 equivalents, 3.33 mg). Stirring was continued overnight at room temperature. Upon completion, the reaction mixture was poured into saturated sodium bicarbonate aqueous solution (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash column chromatography (5-15% ethyl acetate in hexane) to obtain (5R,6R)-5-{[2,4-bis(benzyloxy)-6-fluorophenyl]methyl}-6-[3,4-bis(methoxymethoxy)phenyl]-8,8,9,9-tetramethyl-2,4,7-trioxa-8-siladecane (110 mg, 0.15 mmol, 82.74%). 1 H NMR (400 MHz, CDCl3) δ -0.13(s, 3H), 0.040 (s, 3H), 0.87 (s, 9H), 2.50 (d, J = 8 Hz, 1H), 2.68 (dd, J = 8, 4 Hz, 1 H), 3.46 (s, 3H), 3.51 (s, 3H), 4.02-4.07 (m, 1H), 4.35 (d, J = 8 Hz, 1H), 4.61 (dd, J = 12, 8 Hz, 2H), 4.95 (s, 2H), 4.98 (s, 2H), 5.15 (s, 2H), 5.20 (s, 2H), 6.26 (d, J = 12 Hz, 1H), 6.31 (brs, 1H), 6.83 (d, J = 8 Hz, 1H), 7.02 (d, 8 Hz, 1H), 7.13 (s, 1H), 7.30-7.43 (m, 10 H). 19 F NMR (376 MHz, CDCl3) δ -114.08.

[0129] Example 12: Synthesis of (1R,2R)-3-(2,4-bis(benzyloxy)-6-fluorophenyl)-1-(3,4-bis(methoxymethoxy)phenyl)-2-(methoxymethoxy)propan-1-ol (11) [ka]

[0130] A stirred solution of (5R,6R)-5-{[2,4-bis(benzyloxy)-6-fluorophenyl]methyl}-6-[3,4-bis(methoxymethoxy)phenyl]-8,8,9,9-tetramethyl-2,4,7-trioxa-8-siladecane (1 equivalent, 110 mg, 0.15 mmol) in THF (3 mL) is prepared by 0 o The mixture was cooled in an ice bath and treated with tetrabutylammonium fluoride (1.5 equivalents, 0.22 mL, 0.22 mmol) (1.0 M in THF). The reaction mixture was stirred at room temperature, concentrated, and purified by silica gel flash column chromatography (15-40% ethyl acetate in hexane) to obtain (1R,2R)-3-[2,4-bis(benzyloxy)-6-fluorophenyl]-1-[3,4-bis(methoxymethoxy)phenyl]-2-(methoxymethoxy)propan-1-ol (90 mg, 0.14 mmol, 96.83%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 2.72 (dd, J = 16, 8 Hz, 1H), 2.88 (dd, J = 16, 8 Hz, 1H), 3.09 (s, 3H), 3.47 (s, 3H), 3.49 (s, 3H), 3.35 (d, J = 4 Hz, 1H), 3.94-3.99 (m, 1H), 4.37 (dd, J = 12, 8 Hz, 2H), 4.49 (t, J = 4 Hz, 1H), 4.97-5.00 (m, 4H), 5.15-5.20 (m, 4H), 6.32 (dd, J = 12, 4Hz, 1H), 6.37 (brs, 1H), 6.85 (dd, J = 8, 4 Hz, 1 H), 7.02 (d, J = 8 Hz, 1H), 7.14 (d, J = 4 Hz, 1H), 7.32-7.41 (m, 10 H). 19 F NMR (376 MHz, CDCl3) δ -114.07.

[0131] Example 13: Synthesis of (2R,3R)-5,7-bis(benzyloxy)-2-(3,4-bis(methoxymethoxy)phenyl)-3-(methoxymethoxy)chroman(12) [ka]

[0132] Under argon, a stirred solution of (1R,2R)-3-[2,4-bis(benzyloxy)-6-fluorophenyl]-1-[3,4-bis(methoxymethoxy)phenyl]-2-(methoxymethoxy)propan-1-ol (1 equivalent, 90 mg, 0.14 mmol) in anhydrous DMF (3 mL) was prepared. o The mixture was cooled in an ice bath and treated with potassium hydride (5 equivalents, 96.61 mg, 0.72 mmol, 30% in paraffin oil). After the addition was complete, the ice bath was removed. After stirring for 2 hours, the reaction mixture was 0 o The mixture was recooled to 14C, quenched with water (30 mL), and extracted with ethyl acetate (3 × 10 mL). The organic layer was washed with water (10 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash column chromatography (15-40% ethyl acetate in hexane) to obtain (2R,3R)-5,7-bis(benzyloxy)-2-[3,4-bis(methoxymethoxy)phenyl]-3-(methoxymethoxy)-3,4-dihydro-2H-1-benzopyran (70 mg, 0.12 mmol, 80.36%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 2.84 (dd, J = 17.3, 4 Hz, 1H), 2.94 (s, 3H), 3.03 (dd, J = 17.3, 4 Hz, 1H), 4.22 (brs, 1H), 4.30 (d, J = 7 Hz, 1H), 4.61 (d, J = 7 Hz, 1H), 4.98 (s, 3H), 5.01 (s, 2H), 5.21-5.25 (m, 4H), 6.23 (d, J = 2.3 Hz, 1H), 6.28 (d, J = 2.3 Hz, 1H), 7.09 (dd, J = 8.5, 2 Hz, 1 H), 7.15 (d, J = 8.4 Hz, 1H), 7.28-7.41 (m, 10H).

[0133] Example 14: Synthesis of 4-((2R,3R)-5,7-bis(benzyloxy)-3-hydroxychroman-2-yl)benzene-1,2-diol (13) [ka]

[0134] A solution of (2R,3R)-5,7-bis(benzyloxy)-2-[3,4-bis(methoxymethoxy)phenyl]-3-(methoxymethoxy)-3,4-dihydro-2H-1-benzopyran (1 equivalent, 70 mg, 0.12 mmol) in MeOH (2 mL) and dichloromethane (2 mL) is prepared. o The mixture was cooled to 1°C and treated with HCl (68.88 equivalents, 2 mL, 8 mmol) in dioxane. After 1 hour, the ice bath was removed and stirring was continued for 1 hour. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash chromatography (50-100% ethyl acetate in hexane) to obtain 4-[(2R,3R)-5,7-bis(benzyloxy)-3-hydroxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzene-1,2-diol (28 mg, 0.06 mmol, 51.24%) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 2.94 (dd, J = 16, 4 Hz, 1H), 3.02 (d, J = 16 Hz, 1H), 4.25 (brs, 1H), 4.92 (s, 1H), 5.00 (s, 2H), 5.02 (s, 2H), 6.27 (s, 2H), 6.87-6.90 (m, 2H), 7.07 (s, 1H), 7.30-7.41 (m, 10H).

[0135] Example 15: Synthesis of (-)-epicatechin [ka]

[0136] A solution of 4-[(2R,3R)-5,7-bis(benzyloxy)-3-hydroxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzene-1,2-diol (1 equivalent, 25 mg, 0.053 mmol) and carbon-supported palladium hydroxide (4.021 equivalents, 30 mg, 0.21 mmol) (20% carbon-supported) in THF-MeOH-water (1:1:1) (3 mL) was evacuated and filled with hydrogen (3 times). This heterogeneous solution was stirred overnight at room temperature under a hydrogen atmosphere (balloon). The catalyst was removed by filtration, and the filtrate was concentrated. Next, the aqueous solution of the residue was freeze-dried to obtain (2R,3R)-2-(3,4-dihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3,5,7-triol (9 mg, 0.031 mmol, 58.35%).

[0137] Example 16: Alternative synthesis of syn-epoxide intermediates Compound 3,4-bis(benzyloxymethoxy)benzaldehyde 15 can be used as a starting material to reach the syn-epoxide intermediate. The steps of this synthesis are shown in Scheme XXXIII and are further described below. [ka] Scheme XXXIII.

[0138] Compound 3,4-bis(benzyloxymethoxy)benzaldehyde 15 can be subjected to asymmetric addition of vinyltrimethoxysilane in the presence of catalyst CuF·2H2O and (R)-DTBM-SEGPHOS to obtain the desired alkene (S)-1-(3,4-bis(benzyloxy)phenyl)propa-2-en-1-ol 16. Alkene 16 can then be further subjected to epoxidation with titanium-salarene using hydrogen peroxide. Further steps can be the same as steps 7-12 of scheme XXXII in Example 1.

[0139] Example 17: Alternative synthesis of (-)-epicatechin using an anti-epoxide intermediate Example 17 provides a seven-step synthesis of (-)-epicatechin. Compound 3,4-bis(benzyloxymethoxy)benzaldehyde 15 can be used as a starting material. The steps of this synthesis are shown in Scheme XXXIV and are further described below. [ka] Scheme XXXIV.

[0140] Compound 3,4-bis(benzyloxymethoxy)benzaldehyde 15 undergoes a Grignard reaction with the Grignard reagent vinylmagnesium bromide to obtain the desired alkene (S)-1 1-(3,4-bis(benzyloxy)phenyl)propa-2-en-1-ol 18. Then, alkene 18 is converted to titanium isopropoxide (Ti(O) iThe epoxide can be further epoxidized with Pr)4) and t-butyl hydroperoxide (TBHP) to obtain the desired epoxide (S)-(3,4-bis(benzyloxy)phenyl)((R)-oxiran-2-yl)methanol 19. The epoxide 19 can then be converted to the product (1S,2R)-1-(3,4-bis(benzyloxy)phenyl)-1-((tert-butyldimethylsilyl)oxy)-3-(2,4,6-tris(methoxymethoxy)phenyl)propan-2-ol 20. The product 20 can then be deprotected using deprotection conditions to remove t-butyldimethyl ether to obtain the desired alcohol 2-((2R,3S)-3-(3,4-bis(benzyloxy)phenyl)-2,3-dihydroxypropyl)benzene-1,3,5-triol 21. Next, alcohol 21 is cyclized with triethyl orthopropionate and tosylated with tosylic acid to obtain protected (-)-epicatechin 2-((2R,3S)-3-(3,4-bis(benzyloxy)phenyl)-2,3-dihydroxypropyl)-benzene-1,3,5-triol 22. Then, the protected product 22 is deprotected via a debenzyl reaction to obtain the desired (-)-epicatechin 14.

[0141] Example 18: Alternative synthesis of anti-epoxide intermediates Compound 3,4-bis(benzyloxymethoxy)benzaldehyde 15 can be used as a starting material to reach the desired anti-epoxide intermediate. The steps of this synthesis are shown in Scheme XXXV and are further described below. [ka] Scheme XXXV.

[0142] Compound 3,4-bis(benzyloxymethoxy)benzaldehyde 15 can undergo a Wittig reaction with a suitable ylide to obtain the desired alkene, ethyl(E)-3-(3,4-bis(benzyloxy)phenyl)acrylate 23. Alkene 23 can then undergo an addition reaction to reach the desired alcohol, ethyl(2R,3R)-3-(3,4-bis(benzyloxy)phenyl)-2-bromo-3-hydroxypropanoate ethyl 24. The desired alcohol 24 can be protected with t-butyldimethylsilyl ether using TBSCl to obtain the desired protected product, (2R,3R)-3-(3,4-bis(benzyloxy)phenyl)-2-bromo-3-((tert-butyldimethylsilyl)oxy)propanoate ethyl 25. The product is further treated with lithium borohydride (LiBH4) in THF to obtain the desired primary alcohol, (2R,3R)-3-(3,4-bis(benzyloxy)phenyl)-2-bromo-3-((tert-butyldimethylsilyl)oxy)propan-1-ol 26. Finally, compound 26 undergoes an epoxidation reaction with sodium hydroxide (NaOH) to obtain the anti-epoxide intermediate, (S)-(3,4-bis(benzyloxy)phenyl)((R)-oxiran-2-yl)methanol 19. Further steps can be the same as steps 3-8 of scheme XXXIV in Example 17.

[0143] Example 19: Alternative synthesis of anti-epoxide intermediates Tartaric acid, a compound, can be used as a starting material to reach the desired anti-epoxide intermediate. The steps of this synthesis are shown in Scheme XXXVI and are further described below. [ka] Scheme XXXVI.

[0144] The compound tartaric acid reacts with tosylic acid and acetone to obtain the desired dimer, 1,2-bis((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethane-1,2-diol 26. The dimer 23 is then oxidized with sodium periodate in water to obtain the desired aldehyde, (S)-2,2-dimethyl-1,3-dioxolan-4-carbaldehyde 27. The aldehyde 27 then undergoes an addition reaction with (S)-2,2-dimethyl-1,3-dioxolan-4-carbaldehyde to obtain the desired secondary alcohol, (R)-(3,4-bis(benzyloxy)phenyl)((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methanol 28. Next, the secondary alcohol is subjected to tosylic acid, and then to tosyl chloride to obtain the desired tosylation product, (2S,3R)-3-(3,4-bis(benzyloxy)phenyl)-2,3-dihydroxypropyl 4-methylbenzenesulfonate 29. Finally, compound 29 undergoes an epoxidation reaction with sodium hydroxide (NaOH) to obtain the anti-epoxide intermediate, (R)-(3,4-bis(benzyloxy)phenyl)((S)-oxiran-2-yl)methanol 30. Further steps can be the same as steps 3-8 of scheme XXXIV in Example 17.

[0145] While the subject matter of this disclosure and its merits have been described in detail, various changes, substitutions, and modifications can naturally be made herein without departing from the spirit and scope of the subject matter of this disclosure. Furthermore, the scope of this application is not intended to be limited to specific embodiments of the process, as well as the materials, methods, and process configurations described herein. As those skilled in the art will readily understand from the disclosed subject matter of the subject matter, process, material composition, method, or step, it is possible to use the subject matter of this disclosure to perform substantially the same function or achieve substantially the same results as the corresponding embodiment described herein, whether currently existing or to be developed in the future. Accordingly, the appended claims are intended to include within their scope such as the process, machine, manufacture, material composition, method, or step.

[0146] Various patents, patent applications, publications, product descriptions, protocols, and sequence acceptance numbers are cited throughout this application, and their inventions are incorporated herein by reference in their entirety for all purposes.

Claims

1. A method for preparing (-)-epicatechin, wherein the method is a) Compounds of formula V: 【Chemistry 1】 Formula V (In the formula, X is O or S, and R 3 is Ph, Bn, or CH(CH 3 ) 2 And R 4 The purpose is to provide a compound of formula II (where is Ph or H), and further, a compound of formula II: 【Chemistry 2】 Formula II (In the formula, R 1 This is to provide (which is MOM or Bn), b) Coupling compounds of formulas II and V to form a first intermediate, wherein the first intermediate contains a secondary alcohol. c) Protecting the secondary alcohol in the first intermediate to form a second intermediate, d) Reducing the second intermediate to form a third intermediate, wherein the third intermediate contains a primary alcohol, e) Removing the Bn group from formula V to form a fourth intermediate, f) Selectively forming a sulfonic acid ester from the primary alcohol of the fourth intermediate to form a fifth intermediate, g) Ephexizing the fifth intermediate to form a sixth intermediate, h) alkylating the sixth intermediate to form a seventh intermediate, wherein the seventh intermediate contains a primary alcohol, and the alkylation is performed. i) protecting the primary alcohol of the seventh intermediate to form the eighth intermediate, j) Cyclizing the eighth intermediate to form the ninth intermediate, k) Deprotecting the ninth intermediate to form a tenth intermediate, l) Deprotecting the above-mentioned intermediate to form (-)-epicatechin, Methods that include...

2. X is S, R 3 The method according to claim 1, wherein the pH is [value].

3. R 1 The method according to claim 1, wherein the device is MOM.

4. The method according to claim 1, wherein the alcohol of the first intermediate is protected with a silyl group.

5. The method according to claim 4, wherein the silyl group is t-butyldimethylsilyl.

6. The method according to claim 1, wherein the sulfonic acid ester of (f) is -OTs, -OMes, or -OTf.

7. The method according to claim 6, wherein the sulfonic acid ester in (f) is -OTs.

8. The sixth intermediate is the compound of formula VII: 【Transformation 3】 Formula VII (wherein X is F, Br, I, Cl, N, S, or B, R 3 The method according to claim 1, wherein is alkylated with Bn or a MOM protecting group to form the seventh intermediate.

9. where X is F and R 3 is Bn, the method according to claim 8.

10. The method according to claim 1, wherein the seventh intermediate is protected with MOM or a Bn protecting group.

11. The method according to claim 10, wherein the seventh intermediate is protected with an MOM protecting group.

12. The method according to claim 1, wherein the deprotection in (k) is debenzylation.

13. The method according to claim 1, wherein the sixth intermediate is the syn-epoxide intermediate.

14. A method for preparing (-)-epicatechin, wherein the method is a) To provide (S)-2-(benzyloxy)-1-(4-phenyl-2-thioxoxazolidine-3-yl)ethane-1-one and 3,4-bis(methoxymethoxy)benzaldehyde, b) Adding chloromethyl methyl ether to produce (2S,3R)-2-(benzyloxy)-3-(3,4-bis(methoxymethoxy)phenyl)-3-hydroxy-1-((S)-4-phenyl-2-thioxoxazolidine-3-yl)propan-1-one, c) Protecting (2S,3R)-2-(benzyloxy)-3-(3,4-bis(methoxymethoxy)phenyl)-3-hydroxy-1-((S)-4-phenyl-2-thioxoxazolidine-3-yl)propan-1-one with TBSCl to produce (2S,3R)-2-(benzyloxy)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)-1-((S)-4-phenyl-2-thioxoxazolidine-3-yl)propan-1-one, d) (2S,3R)-2-(benzyloxy)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)-1-((S)-4-phenyl-2-thioxoxazolidine-3-yl)propan-1-one, LiBH 4 By reduction, (2R,3R)-2-(benzyloxy)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)propan-1-ol is produced, e) (2R,3R)-2-(benzyloxy)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)propan-1-ol, H 2 Deprotection with Pd / C under gaseous conditions yields (2R,3R)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)propane-1,2-diol, f) Tosylation of (2R,3R)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)propane-1,2-diol with tosylic acid to produce (2R,3R)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)-2-hydroxypropyl 4-methylbenzene sulfonate, g) Eccluting (2R,3R)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)-2-hydroxypropyl 4-methylbenzene sulfonate with potassium carbonate in methanol to produce ((R)-(3,4-bis(methoxymethoxy)phenyl)((R)-oxiran-2-yl)methoxy)(tert-butyl)dimethylsilane, h) Alkylating ((R)-(3,4-bis(methoxymethoxy)phenyl)((R)-oxiran-2-yl)methoxy)(tert-butyl)dimethylsilane with n-butyllithium using (((5-fluoro-1,3-phenylene)bis(oxy))bis(methylene))dibenzene to produce (1R,2R)-3-(2,4-bis(benzyloxy)-6-fluorophenyl)-1-(3,4-bis(methoxymethoxy)phenyl)-1-((tert-butyldimethylsilyl)oxy)propan-2-ol, i) Protecting (1R,2R)-3-(2,4-bis(benzyloxy)-6-fluorophenyl)-1-(3,4-bis(methoxymethoxy)phenyl)-1-((tert-butyldimethylsilyl)oxy)propan-2-ol with MOMCl to produce (5R,6R)-5-{[2,4-bis(benzyloxy)-6-fluorophenyl]methyl}-6-[3,4-bis(methoxymethoxy)phenyl]-8,8,9,9-tetramethyl-2,4,7-trioxa-8-siladecane, k) Deprotecting (5R,6R)-5-{[2,4-bis(benzyloxy)-6-fluorophenyl]methyl}-6-[3,4-bis(methoxymethoxy)phenyl]-8,8,9,9-tetramethyl-2,4,7-trioxa-8-siladecane with TBAF to produce (1R,2R)-3-(2,4-bis(benzyloxy)-6-fluorophenyl)-1-(3,4-bis(methoxymethoxy)phenyl)-2-(methoxymethoxy)propan-1-ol, l) Cyclization of (1R,2R)-3-(2,4-bis(benzyloxy)-6-fluorophenyl)-1-(3,4-bis(methoxymethoxy)phenyl)-2-(methoxymethoxy)propan-1-ol using potassium hydride to produce (2R,3R)-5,7-bis(benzyloxy)-2-(3,4-bis(methoxymethoxy)phenyl)-3-(methoxymethoxy)chroman, Deprotecting m)(2R,3R)-5,7-bis(benzyloxy)-2-(3,4-bis(methoxymethoxy)phenyl)-3-(methoxymethoxy)chroman with HCl to produce 4-((2R,3R)-5,7-bis(benzyloxy)-3-hydroxychroman-2-yl)benzene-1,2-diol, n) 4-((2R,3R)-5,7-bis(benzyloxy)-3-hydroxychroman-2-yl)benzene-1,2-diol, H 2 Below, deprotection with Pd / C is performed to obtain (-)-epicatechin, Methods that include...

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