Process for preparation of (-)-epicatechin

Abstract

Provided herein are process steps for the synthesis of (-)-epicatechin. The synthesis method provided by the invention is divided into two stages: (1) synthesizing an epoxide intermediate and (2) synthesizing the (-)-epicatechin.

Description

Cross-referencing related applications

[0001] This application claims priority to U.S. Provisional Application Serial No. 63 / 461,058, filed April 21, 2023, the contents of which are incorporated herein by reference in their entirety. Technical Field

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

[0003] Catechins and epicatechins are naturally occurring polyphenols widely distributed throughout plant systems. They are found in cocoa, tea leaves, fruits, vegetables, and pine bark. (+)-Catechin and (-)-Epicatechin are the most abundant naturally occurring epimers. For example, green tea leaves contain both (-)-epitaphthenic and (+)-catechins. The reported bioactivities of these compounds include antitumor, antimutagenic, and antioxidant activities. However, the isolation of stereospecific catechin derivatives, such as (-)-epitaphthenic, 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 using commercially available materials to achieve the required purity levels. Summary of the Invention

[0004] The purposes and advantages of the disclosed subject matter will be set forth in the following description and will be apparent, and will be understood through practice of the disclosed subject matter. Further advantages of the disclosed subject matter will be realized and obtained through the means expressly pointed out in this specification and its claims.

[0005] In order to achieve these and other advantages, and in accordance with the purposes of the disclosed subject matter, as implemented and broadly described, the disclosed subject matter includes various methods for preparing (-)-epicatechin.

[0006] In some embodiments, this disclosure provides a method for preparing (-)-epicatechin. In some embodiments, the method includes providing a compound of formula V, wherein X is O or S, R3 is Ph, Bn, or CH(CH3)2, and R4 is Ph or H:

[0007] Equation V.

[0008] In some embodiments, the method further includes providing a compound of formula II, wherein R1 is MOM or Bn:

[0009] Formula II.

[0010] In some embodiments, the method includes coupling the compound of formula II and the compound of formula V to form a first intermediate, wherein the first intermediate comprises a secondary alcohol. In some embodiments, the method includes protecting the secondary alcohol in the first intermediate to form a second intermediate. In some embodiments, the method includes reducing the second intermediate to form a third intermediate, wherein the third intermediate comprises a primary alcohol. In some embodiments, the method includes removing the Bn group of formula V to form a fourth intermediate. In some embodiments, the method includes selectively forming a sulfonate ester from the primary alcohol of the fourth intermediate to form a fifth intermediate. In some embodiments, the method includes epoxidizing the fifth intermediate to form a sixth intermediate. In some embodiments, the method includes alkylating the sixth intermediate to form a seventh intermediate, wherein the seventh intermediate comprises a primary alcohol. In some embodiments, the method includes protecting the primary alcohol of the seventh intermediate to form an eighth intermediate. In some embodiments, the method includes cyclizing the eighth intermediate to form a ninth intermediate. In some embodiments, the method includes deprotecting the ninth intermediate to form a tenth intermediate. In some embodiments, the method includes deprotecting the tenth intermediate to form (-)-epicatechin.

[0011] In some embodiments, X is S, and R3 is Ph. In a particular embodiment, R1 is MOM.

[0012] In some embodiments, the alcohol in the first intermediate is protected with a silicon group. In a specific embodiment, the silicon group is tert-butyldimethylsilyl.

[0013] In some embodiments, the sulfonate ester is -OTs, -OMes, or -OTf. In a specific embodiment, the sulfonate ester is -OTs.

[0014] In some embodiments, the sixth intermediate is alkylated with a compound of formula VII, wherein X is F, Br, I, Cl, N, S, or B, and R3 is a Bn or MOM protecting group to form the seventh intermediate:

[0015] Equation VII.

[0016] In a specific embodiment, X is F, and R3 is Bn.

[0017] In some embodiments, the seventh intermediate is protected with a MOM or Bn protecting group. In a specific embodiment, the seventh intermediate is protected with a MOM protecting group.

[0018] In some embodiments, the deprotection of the ninth intermediate is debenzylation. In a specific embodiment, the sixth intermediate is a syn-epoxide intermediate.

[0019] In some embodiments, this disclosure provides a method for preparing (-)-epicatechin. In some embodiments, the method includes providing (S)-2-(benzyloxy)-1-(4-phenyl-2-thiooxazolidine-3-yl)ethyl-1-one and 3,4-bis(methoxymethoxy)benzaldehyde. In some 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-thiooxazolidine-3-yl)prop-1-one. In some embodiments, the method includes protecting (2S,3R)-2-(benzyloxy)-3-(3,4-bis(methoxymethoxy)phenyl)-3-hydroxy-1-((S)-4-phenyl-2-thiooxazolidine-3-yl)prop-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-thiooxazolidine-3-yl)prop-1-one. In some embodiments, the method includes reducing (2S,3R)-2-(benzyloxy)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)-1-((S)-4-phenyl-2-thiooxazolidine-3-yl)prop-1-one with LiBH4 to produce (2R,3R)-2-(benzyloxy)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)prop-1-ol. In some embodiments, the method includes deprotecting (2R,3R)-2-(benzyloxy)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)propane-1-ol under H2 with Pd / C to produce (2R,3R)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)propane-1,2-diol. In some embodiments, the method includes p-toluenesulfonating (2R,3R)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)propane-1,2-diol with p-toluenesulfonic acid to produce (2R,3R)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)-2-hydroxypropyl ester of 4-methylbenzenesulfonic acid. In some embodiments, the method includes epoxidizing 4-methylbenzenesulfonic acid (2R,3R)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)-2-hydroxypropyl ester in methanol using potassium carbonate to produce ((R)-(3,4-bis(methoxymethoxy)phenyl)((R)-ethyleneoxy-2-yl)methoxy)(tert-butyl)dimethylsilane.In some embodiments, the method includes using n-butyllithium to alkylate ((R)-(3,4-bis(methoxymethoxy)phenyl)((R)-ethyleneoxy-2-yl)methoxy)(tert-butyl)dimethylsilane with (((5-fluoro-1,3-phenylene)bis(oxy))bis(methylene))diphenyl to produce (1R,2R)-3-(2,4-bis(benzyloxy)-6-fluorophenyl)-1-(3,4-bis(methoxymethoxy)phenyl)-1-((tert-butyldimethylsilyl)oxy)prop-2-ol). In some embodiments, the method includes protecting (1R,2R)-3-(2,4-bis(benzyloxy)-6-fluorophenyl)-1-(3,4-bis(methoxymethoxy)phenyl)-1-((tert-butyldimethylsilyl)oxy)prop-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-silanedecane. In some embodiments, 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-silazane with TBAF to produce (1R,2R)-3-(2,4-bis(benzyloxy)-6-fluorophenyl)-1-(3,4-bis(methoxymethoxy)phenyl)-2-(methoxymethoxy)prop-1-ol. In some embodiments, the method includes cyclizing (1R,2R)-3-(2,4-bis(benzyloxy)-6-fluorophenyl)-1-(3,4-bis(methoxymethoxy)phenyl)-2-(methoxymethoxy)prop-1-ol with potassium hydride to produce (2R,3R)-5,7-bis(benzyloxy)-2-(3,4-bis(methoxymethoxy)phenyl)-3-(methoxymethoxy)chromane. In some embodiments, the method includes deprotecting (2R,3R)-5,7-bis(benzyloxy)-2-(3,4-bis(methoxymethoxy)phenyl)-3-(methoxymethoxy)chromane with HCl to produce 4-((2R,3R)-5,7-bis(benzyloxy)-3-hydroxychromane-2-yl)phenyl-1,2-diol. In some embodiments, the method includes deprotecting 4-((2R,3R)-5,7-bis(benzyloxy)-3-hydroxytryptane-2-yl)phenyl-1,2-diol with Pd / C under H2 to obtain (-)-epicatechin. Attached Figure Description

[0020] Figure 1 The general steps associated with the synthesis of (-) epicatechin derivatives, as disclosed herein, are shown.

[0021] Figure 2The general steps associated with the synthesis of (-) epicatechin derivatives, as disclosed herein, are shown.

[0022] Figure 3 The general steps associated with the synthesis of (-) epicatechin derivatives, as disclosed herein, are shown.

[0023] Figure 4 The general steps associated with the synthesis of (-) epicatechin derivatives, as disclosed herein, are shown.

[0024] Figure 5 The general steps associated with the synthesis of (-) epicatechin derivatives, as disclosed herein, are shown.

[0025] Figure 6 The general steps associated with the synthesis of (-) epicatechin derivatives, as disclosed herein, are shown.

[0026] Figure 7 The general steps associated with the synthesis of (-) epicatechin derivatives, as disclosed herein, are shown. Detailed Implementation

[0027] Stereospecific catechin derivatives, including (-)-epicatechin and (+)-epicatechin, have been reported to possess biological activities including antitumor, antimutagenic, and antioxidant activities. However, obtaining each of these compounds at the industrial scale and purity required for health applications (e.g., pharmaceutical applications) remains challenging. This disclosure provides a method for synthesizing stereopure catechin epimers from commercially available starting materials to address the aforementioned needs.

[0028] For clarity, but not as a limitation, the detailed description of the subject matter of this disclosure is divided into the following sections:

[0029] I. Definition;

[0030] II. Catechin epimers;

[0031] III. The synthesis process; and

[0032] IV. Consumer Products.

[0033] I. Definition

[0034] The terms used in this specification generally have their common meaning in the art, in the context of this disclosure, and in the specific context in which each term is used. Some terms are discussed below or in other parts of the specification to provide additional guidance to practitioners in describing the compositions and methods of this disclosure and how to prepare and use them.

[0035] For the purposes of interpreting this specification, the following definitions will apply, and where appropriate, terms used in the singular will also include the plural form, and vice versa. In the event of any conflict between any definition listed below and any document incorporated herein by reference, the definition listed below shall prevail.

[0036] As used herein, in the claims and / or specification, the use of the word “a” or “an” in conjunction with the term “comprising” may mean “a”, but this is also consistent with the meaning of “one or more”, “at least one” and “one or more”.

[0037] As used herein, the terms “comprise,” “include,” “having,” “has,” “can,” “contains,” and variations thereof are intended to be open-ended transitional phrases, terms, or words that do not exclude additional actions or structures. This disclosure also contemplates other embodiments, whether explicitly listed or not, which “comprise”, “consist of,” and “substantially constitute” the embodiments or elements presented herein.

[0038] As used herein, the terms “about” or “approximately” mean within an acceptable range of error for a particular value as determined by one of ordinary skill in the art, the acceptable range of error being to some extent dependent on how the value was measured or determined, i.e., the limitations of the measurement system. For example, according to practice in the art, “about” may mean within three or more standard deviations. Alternatively, “about” may mean a range up to 20%, preferably up to 10%, more preferably up to 5%, and still more preferably up to 1% of a given value.

[0039] The term "alkyl" refers to a straight-chain or branched C1-C alkyl group consisting only of carbon and hydrogen atoms, without any unsaturation, and connected to the rest of the molecule by single bonds. 20 Hydrocarbon groups, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl).

[0040] The term "alkenyl" refers to a C2-C group containing at least one carbon-carbon double bond, which can be straight-chain or branched. 20 Aliphatic hydrocarbon groups, such as vinyl groups.

[0041] The term "cycloalkyl" refers to an unsaturated, non-aromatic monocyclic or polycyclic hydrocarbon ring system (containing, for example, C3-C6), such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0042] The term "aryl" refers to an aromatic radical having approximately 6 to approximately 14 carbon atoms, such as phenyl or biphenyl.

[0043] The term "arylalkyl" refers to an aryl group as defined above directly bonded to an alkyl group as defined above, such as -CH2C6H5 and -C2H4C6H5. As used herein, the term "benzyl" or "Bn" generally refers to a phenyl group ("Ph") with a single alkyl group. As used herein, Bn is -CH2C6H6 or -CH2Ph.

[0044] As used herein, the term "chiral auxiliary" refers to a chemical compound used to control the stereochemical outcome of a reaction by incorporating the chiral auxiliary into the compound, and then removing the chiral auxiliary after the desired stereochemistry has been achieved during synthesis.

[0045] As used herein, the term “cyclization” refers to a chemical reaction in which atoms of one or more compounds are transformed into closed rings.

[0046] The term "heterocyclic" refers to a stable 3- to 15-membered ring radical consisting of a carbon atom and one or more (e.g., one to five) heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. For the purposes of this application, heterocyclic radicals can be monocyclic or bicyclic systems, which may include fused ring or bridged ring systems, and the nitrogen, carbon, oxygen, or sulfur atoms in the heterocyclic radical may optionally be oxidized to various oxidation states.

[0047] The term "heteroaryl" refers to a heterocyclic ring in which the aromatic ring is located.

[0048] As used herein, the term "ether" generally refers to two alkyl groups bonded to one oxygen atom.

[0049] As used herein, the term "intermediate" refers to a compound formed by a reaction in a multi-step synthesis and then used in a subsequent step of said multi-step synthesis. In some embodiments, the intermediate may be isolated and purified using methods known to those skilled in the art prior to its use in subsequent steps.

[0050] In some other embodiments, the intermediate can be used in subsequent steps without further purification. In some embodiments, the intermediate can be prepared in situ and then used in subsequent steps.

[0051] As used herein, the term "isomer" refers to different compounds having the same molecular formula but different atomic arrangements and configurations. Furthermore, as used herein, the term "stereoisomer" refers to any of the various stereoisomeric configurations that can exist for a given compound of the subject matter of this disclosure, including geometric isomers. It should be understood that the compounds of this disclosure contain double bonds, wherein the substituents can be E or Z configurations. Furthermore, as used herein, the term "epitaximer" refers to any one of two stereoisomers that differ in the group arrangement of a single asymmetric carbon atom (such as the first chiral center of a sugar carbon chain). For example, but not limited to, (-)-epicatechin and (+)-epicatechin are epimers. Furthermore, as used herein, the term "structural isomer" refers to different compounds having the same number and type of atoms but different atomic connections. As used herein, the term "optical isomer" refers to two compounds containing the same number and type of atoms and bonds (i.e., the same atomic connections), and different spatial arrangements of atoms, but which are non-overlapping mirror images. Each non-overlapping mirror image is called an enantiomer.

[0052] As used herein, the term "leaving group" refers to an atomic or molecular fragment that leaves with a pair of electrons during heterolytic bond cleavage. Leaving groups can be anions, cations, or neutral molecules. As is known to those skilled in the art, the more stable an atom or atomic group is in itself, the better it is as a leaving group. For example, a good leaving group can be a conjugated base of a strong acid. In some embodiments, the leaving group is a neutral molecule, such as water or ammonia.

[0053] As used herein, the term "organic lithium" refers to a compound in which at least one carbon atom is bonded to at least one lithium atom.

[0054] As used herein, the term “oxidation” or “oxidized” refers to a chemical reaction in which chemical species lose electrons.

[0055] As used herein, the term "protecting group" refers to a derivative that is reversibly formed from an existing functional group in the molecule. The protecting group is temporarily attached to reduce reactivity, thus preventing the protected functional group from reacting under the synthetic conditions (conditions the molecule undergoes in one or more subsequent steps). Once the selective synthetic steps are complete, the protecting group can be removed via a deprotection step.

[0056] As used herein, the terms “protected” and “protection” refer to a synthetic step in which a functional group is reversibly and temporarily derivatized to reduce the reactivity of said functional group. For example, but not limited to, “protecting a hydroxyl group” means performing a synthetic step in which a reagent, such as tert-butyldimethylsilyl chloride or chloromethyl methyl ether, is added to a compound containing a hydroxyl group to convert the hydroxyl group to tert-butyldimethylsilyl ether or methoxymethyl ether. As is known to those skilled in the art, other reagents that can introduce the same or different protecting groups can also be used to protect the functional group.

[0057] As used herein, the term “reduced” or “reduced” refers to a chemical reaction in which chemical species gain electrons.

[0058] As used herein, the term "sulfonate" generally refers to a sulfur atom bonded to two oxygen atoms by a double bond, to one oxygen atom by a single bond, and to another single group by a single bond. "Sulfonation" refers to the addition of a sulfonate group. Common sulfonate compounds include methanesulfonates ("Mes"), p-toluenesulfonates ("Ts"), or trifluoromethanesulfonates ("Tf"). As used herein, "mesyl" refers to methanesulfonyl, "trifyl" refers to trifluoromethanesulfonyl, and "tosyl" refers to p-toluenesulfonyl. As used herein, "tosylate" or "tosyl group" refers to p-toluenesulfonate, and "p-toluenesulfonation" refers to the addition of a p-toluenesulfonyl group. In some embodiments, the p-toluenesulfonyl group is added via p-toluenesulfonyl chloride (TsCl). As used herein, "sulfonate ester" generally refers to a sulfonate in which the oxygen atom, which is single-bonded to the sulfur atom, is bonded to another group. Common sulfonate compounds include "OMes", "OTs", or "OTf".

[0059] II. Catechin epimers

[0060] Catechins are natural phenolic compounds found in a variety of sources, including many herbs, fruits, vegetables, beverages, algae, and confectionery. Cocoa, tea, and certain pome fruits are major dietary sources of catechins.

[0061] Catechins are flavan-3-ols, belonging to the flavonoid family of chemistry. Catechins have two benzene rings (referred to as ring A and ring B) and a dihydropyran heterocycle (ring C) with a hydroxyl group at carbon 3, as shown in Formula I:

[0062]

[0063] Formula I: Catechins

[0064] The molecule has two chiral centers at carbons 2 and 3, and therefore has four diastereomers, referred to herein as epimers. These four epimers are (+)-catechin, (-)-epicatechin, (-)-catechin, and (+)-epicatechin, as shown in the following formulas IA-ID:

[0065]

[0066] Although the four epimers of catechins are structurally similar, they have been shown to possess some significantly different activities. For example, Tsuchiya has reported that the epimers exhibit a variety of biological activities through their interactions with the cell membrane. For instance, (-)-epicatechin and (+)-epicatechin have been shown to be more effective than (+)-catechin and (-)-catechin in reducing membrane fluidity. Reversed-phase chromatographic evaluation showed that (-)-epicatechin and (+)-epicatechin are more hydrophobic than (-)-catechin and (+)-catechin, although the hydrophobicity is indistinguishable between the optical isomers. See Tsuchiya, “Stereospecificity in membrane effects of catechins,” *Chem. Biol. Interact*, 2001, 134, 41-54, which is cited and incorporated herein by reference.

[0067] The isolation of stereospecific catechin epimers is typically very difficult. Therefore, the synthesis of (-)-epicatechin provided in this disclosure allows for the formation of a single epimer for use in a variety of consumer products.

[0068] III. Synthesis Process

[0069] This disclosure provides a method for synthesizing (-)-epicatechin. In some embodiments, the synthesis of (-)-epicatechin may include two stages: a first stage for preparing an epoxide intermediate, and a second stage for converting the epoxide intermediate into the desired (-)-epicatechin. Each of the stages will be further described below.

[0070] Stage 1: Preparation of epoxide intermediates

[0071] In some embodiments, the first stage includes the preparation of a syn-epoxide intermediate. In some embodiments, the first stage includes the preparation of an anti-epoxide intermediate. In some embodiments, the synthesis of the epoxide intermediate follows the method described above. Figure 1-5 The general steps outlined in the document are carried out and discussed further below.

[0072] In some embodiments, the commercially available starting material is 3,4-dihydroxybenzaldehyde. In specific embodiments, the hydroxyl group of the 3,4-dihydroxybenzaldehyde compound is first protected with one or more protecting groups commonly found in the literature, including methoxymethyl ether (OMOM), tetrahydropyranyl ether, tert-butyl ether, allyl ether, benzyl ether (OBn), triisopropylsilyl ether (OTIPS), or tert-butyldimethylsilyl ether (OTBS). In some specific embodiments, the protecting group is benzyl ether. In some specific embodiments, the protecting group is methoxymethyl ether. In specific embodiments, R1 is methoxymethyl (MOM) or benzyl (Bn). In some embodiments, chloromethylmethyl ether is used to protect the hydroxyl group of the compound of formula II.

[0073]

[0074] Formula II.

[0075] Stage 1.1: Synthesis of cis-epoxide intermediates

[0076] In some embodiments, a syn-epoxide intermediate is formed. The syn-epoxide intermediate is a compound of formula III, wherein R1 and R2 are H or protecting groups. In specific embodiments, R1 and R2 are the same. In specific embodiments, R1 and R2 are different. In some embodiments, R1 and R2 can be H, methoxymethyl, tetrahydropyranyl, tert-butyl, allyl, benzyl, triisopropylsilyl, or tert-butyldimethylsilyl. In specific embodiments, R2 is H or tert-butyldimethylsilyl, and R1 is methoxymethyl or benzyl.

[0077]

[0078] Formula III.

[0079] Stage 1.1.1: 7-step synthesis of Syn-epoxide intermediates

[0080] In some embodiments, Figure 1 The general synthesis of syn-epoxide intermediates is outlined in the document. For example... Figure 1As shown, the synthesis comprises seven steps. Specifically, the synthesis includes a coupling reaction to form a chiral auxiliary compound. The chiral auxiliary compound further undergoes an asymmetric aldol condensation reaction. Subsequently, a protecting group is added to the reaction product, and the chiral auxiliary is then removed from the compound by a reduction reaction. The resulting product then undergoes debenzylation followed by sulfonation. Finally, the desired syn-epoxide intermediate is formed.

[0081] In some embodiments, the second starting material used to synthesize (-)-epicatechin is a compound of formula III, wherein X is S or O, R3 is Ph, Bn or CH(CH3)2, and R4 is Ph or H.

[0082]

[0083] Formula IV.

[0084] In some embodiments, the compound of formula IV is converted into a chiral auxiliary compound. In some embodiments, the compound of formula I is coupled with benzyloxyacetic acid or benzyloxyacetyl chloride using a coupling agent. Specifically, the compound of formula I is coupled with benzyloxyacetic acid using a coupling agent. In some embodiments, the coupling agent is 3-{[(ethylimino)methylene]amino}-N,N-dimethylpropane-1-amine (EDCI), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate (HBTU), benzotriazol-1-yloxytris(dimethylamino)phosphonophosphate hexafluorophosphate (BOP), benzotriazol-1-yloxytripyrrolidinylphosphonium hexafluorophosphate (PyBOP), propylphosphonic anhydride (T3P), or N,N'-dicyclohexylcarbodiimide (DCC). In a specific embodiment, the coupling agent is EDCI. Scheme I illustrates the coupling reaction.

[0085]

[0086] Option I.

[0087] In some embodiments, the chiral auxiliary is a compound of formula V, wherein X is O or S, R3 is Ph, Bn or CH(CH3)2, and R4 is Ph or H. 。

[0088]

[0089] Formula V

[0090] In some embodiments, the protected 3,4-dihydroxybenzaldehyde is coupled with a chiral auxiliary agent in an asymmetric aldol condensation reaction. In some embodiments, a titanolate is formed from the chiral auxiliary agent. In a specific embodiment, the titanolate is formed by acting the chiral auxiliary agent on titanium tetrachloride. In some embodiments, the titanolate is reacted with a base and the protected 3,4-dihydroxybenzaldehyde to form an anti-aldol condensation product. In a specific embodiment, the base is triethylamine. Scheme II demonstrates an asymmetric aldol condensation reaction.

[0091]

[0092] Option II.

[0093] In some embodiments, the resulting compound is further protected with one or more silane-based protecting groups commonly found in the literature, including triisopropylsilyl ether, tert-butyldiphenylsilyl ether, or tert-butyldimethylsilyl ether. In a specific embodiment, the protecting group is tert-butyldimethylsilyl ether. In some embodiments, tert-butyldimethylsilyl chloride is used to protect the hydroxyl groups of the resulting compound. Scheme III illustrates the protection reaction.

[0094]

[0095] Option III.

[0096] In some embodiments, the resulting compound undergoes a reduction reaction to remove the chiral auxiliary agent. In some embodiments, the resulting compound is subjected to a reducing agent to form the resulting primary alcohol. Various reducing agents can be used to perform this reduction, such as, but not limited to, lithium borohydride. Scheme IV illustrates the reduction reaction.

[0097]

[0098] Option IV.

[0099] In some embodiments, the resulting compound further undergoes debenzylation. In some embodiments, debenzylation is carried out using a palladium catalyst in the presence of hydrogen. In some embodiments, the palladium catalyst may be carbon-supported palladium (Pd / C) or carbon-supported palladium hydroxide (Pd(OH)₂ / C). In a specific embodiment, the palladium catalyst is Pd(OH)₂ / C in the presence of hydrogen. Scheme V illustrates the debenzylation reaction.

[0100]

[0101] Option V.

[0102] In some embodiments, the primary alcohol of the above-described compound is then converted to a leaving group. In some embodiments, the leaving group is a methanesulfonate, p-toluenesulfonate, trifluoromethanesulfonate, bromide, or chloride. In some embodiments, the compound may be treated with methanesulfonyl chloride, p-toluenesulfonyl chloride, or trifluoromethanesulfonyl chloride in the presence of at least one catalyst and a base. In a specific embodiment, the compound is treated with p-toluenesulfonyl chloride in the presence of the catalyst dibutyltin oxide and 4-dimethylaminopyridine (DMAP) and the base triethylamine to obtain a sulfonate. Scheme VI illustrates a sulfonation reaction.

[0103]

[0104] Option VI.

[0105] In some embodiments, the resulting compounds undergo further epoxidation. In some embodiments, the compounds are treated with bases commonly found in the literature, including potassium carbonate, potassium hydroxide, sodium hydroxide, sodium methoxide, lithium bis(trimethylsilyl)amino, ammonium hydroxide, sodium carbonate, cesium carbonate, and potassium tert-butoxide. In a specific embodiment, the compounds are treated with potassium carbonate to obtain a syn-epoxide intermediate. Scheme VII illustrates epoxidation.

[0106]

[0107] Option VII.

[0108] Stage 1.1.2: Two-step synthesis of syn-epoxides

[0109] In some embodiments, Figure 2 The general synthesis of syn-epoxide intermediates is outlined in the document. For example... Figure 2 As shown, the synthesis comprises two steps. Specifically, the synthesis includes an asymmetric addition followed by epoxidation, thereby forming the desired syn-epoxide intermediate.

[0110] In some embodiments, the protected 3,4-dihydroxybenzaldehyde can undergo asymmetric addition with an olefin. In some embodiments, the asymmetric addition can be carried out with a vinyltrimethoxysilane in the presence of a bis-naphthyl catalyst. In a specific embodiment, the bis-naphthyl catalyst is (R)-DTBM-SEGPHOS. In some embodiments, the asymmetric addition can be further carried out in the presence of a copper catalyst. Scheme VIII illustrates the asymmetric addition.

[0111]

[0112] Option VIII.

[0113] In some embodiments, the resulting compound undergoes a further epoxidation reaction. In some embodiments, the compound is treated with a titanium catalyst and an oxidant. In a specific embodiment, the catalyst is titanium-salalen, and the peroxide is hydrogen peroxide, to obtain the syn-epoxide intermediate. Scheme IX illustrates epoxidation.

[0114]

[0115] Option IX.

[0116] Stage 1.2: Synthesis of anti-epoxide intermediates

[0117] In some embodiments, an anti-epoxide intermediate is formed. The anti-epoxide intermediate is a compound of formula VI, wherein R1 and R2 are H or protecting groups. In specific embodiments, R1 and R2 are the same. In specific embodiments, R1 and R2 are different. In some embodiments, R1 and R2 can be H, methoxymethyl, tetrahydropyranyl, tert-butyl, allyl, benzyl, triisopropylsilyl, or tert-butyldimethylsilyl. In specific embodiments, R2 is H or tert-butyldimethylsilyl, and R1 is methoxymethyl or benzyl.

[0118]

[0119] Formula VI.

[0120] Stage 1.2.1: Two-step synthesis of anti-epoxides

[0121] In some embodiments, Figure 3 The general synthesis of anti-epoxide intermediates is outlined in the document. For example... Figure 3 As shown, the synthesis comprises two steps. Specifically, the synthesis includes a Grignard reaction followed by epoxidation to form the desired anti-epoxide intermediate.

[0122] In some embodiments, the protected 3,4-dihydroxybenzaldehyde can undergo a Grignard reaction. In some embodiments, the Grignard reaction can be carried out using vinyl magnesium bromide to obtain the desired product. Scheme X illustrates the Grignard reaction.

[0123]

[0124] Option X.

[0125] In some embodiments, the resulting compound undergoes a Sharpless epoxidation reaction. In some embodiments, the compound is treated with a chiral catalyst and an oxidant. In a specific embodiment, the chiral catalyst is formed from tetraisopropoxide titanium and (+)-diisopropyl tartrate ((+)-DIPT). In a specific embodiment, the compound is further treated with the oxidant tert-butyl hydroperoxide (TBHP) to obtain an anti-epoxide intermediate. Scheme XI illustrates epoxidation.

[0126]

[0127] Option XI.

[0128] Stage 1.2.2: Five-step synthesis of anti-epoxides from 3,4-dihydroxybenzaldehyde

[0129] In some embodiments, Figure 4 The general synthesis of anti-epoxide intermediates is outlined in the document. For example... Figure 4 As shown, the synthesis comprises five steps. Specifically, the synthesis includes a Wittig reaction, followed by the reduction of the olefin. Subsequently, the product may undergo a protecting reaction, followed by the reduction of the ester. Finally, epoxidation is carried out to form the desired anti-epoxide intermediate.

[0130] In some embodiments, the protected 3,4-dihydroxybenzaldehyde can undergo a Wittig reaction. In some embodiments, the Wittig reaction is carried out using ethoxycarbonylmethyl (triphenyl)phosphine bromide to give the desired product. Scheme XII illustrates the Wittig reaction.

[0131]

[0132] Option XII.

[0133] In some embodiments, the resulting product may undergo olefin reduction. In some embodiments, the olefin is reduced using an organolithium reagent and an acid. In a specific embodiment, the olefin is reduced using the organolithium reagent lithium bromide and the acid sulfuric acid to give the desired product. Scheme XIII illustrates the reduction reaction.

[0134]

[0135] Option XIII.

[0136] In some embodiments, the resulting compound is further protected with one or more silane-based protecting groups commonly found in the literature, including triisopropylsilyl ether, tert-butyldiphenylsilyl ether, or tert-butyldimethylsilyl ether. In some specific embodiments, the protecting group is tert-butyldimethylsilyl ether. In some embodiments, tert-butyldimethylsilyl chloride is used to protect the hydroxyl groups of the resulting compound. Scheme XIV illustrates the protecting reaction.

[0137]

[0138] Option XIV.

[0139] In some embodiments, the resulting product may undergo a reduction reaction. In some embodiments, the ester is reduced using a borohydride reagent. In some embodiments, the borohydride reagent may be sodium borohydride or lithium borohydride. In specific embodiments, the ester may be reduced using an organolithium reagent, lithium bromide, and sulfuric acid to obtain the desired product. Scheme XV illustrates the reduction reaction.

[0140]

[0141] Option XV.

[0142] In some embodiments, the resulting compound undergoes an epoxidation reaction. In some embodiments, the compound is treated with a base. In some embodiments, the base is sodium hydroxide, sodium hydride, lithium hydroxide, potassium tert-butoxide, sodium carbonate, or potassium hydroxide. In a specific embodiment, the compound is treated with sodium hydroxide to obtain the desired anti-epoxide. Scheme XVI illustrates epoxidation.

[0143]

[0144] Option XVI.

[0145] Stage 1.2.3: Five-step synthesis of anti-epoxides from tartaric acid

[0146] In some embodiments, Figure 5 The general synthesis of anti-epoxide intermediates is outlined in the document. For example... Figure 5 As shown, the synthesis comprises five steps. Specifically, the synthesis includes cyclization, followed by an oxidation reaction. Subsequently, the product may undergo a protecting reaction, followed by ester reduction. Finally, epoxidation is performed to form the desired anti-epoxide intermediate.

[0147] In some embodiments, the starting material may be tartaric acid. In some embodiments, tartaric acid may undergo a cyclization reaction with an acid and acetone. In specific embodiments, tartaric acid may react with the acid p-toluenesulfonic acid and acetone to yield the desired product. Scheme XVII illustrates the reaction.

[0148]

[0149] Option XVII.

[0150] In some embodiments, the resulting product can then be oxidized. In some embodiments, the product is treated with an oxidizing agent. In a specific embodiment, the product is treated with the oxidizing agent sodium periodate to obtain the desired aldehyde. Scheme XVIII illustrates the reaction.

[0151]

[0152] Scheme XVIII.

[0153] In some embodiments, the resulting product undergoes a reaction with protected 4-bromocatechol to yield the desired secondary alcohol. Scheme XIX illustrates the reaction.

[0154]

[0155] Solution XIX.

[0156] In some embodiments, the resulting product may further undergo ring-opening followed by sulfonation. In some embodiments, the ring-opening reaction may be carried out using an acid. In a specific embodiment, the acid is p-toluenesulfonic acid. In some embodiments, the sulfonation reaction may be carried out by treating the resulting product with methanesulfonyl chloride, p-toluenesulfonyl chloride, or trifluoromethanesulfonyl chloride in the presence of at least one catalyst and a base. In a specific embodiment, the compound is treated with p-toluenesulfonyl chloride to give a sulfonate ester. Scheme XX illustrates the sulfonation reaction.

[0157]

[0158] Option XX.

[0159] In some embodiments, the resulting compound undergoes an epoxidation reaction. In some embodiments, the compound is treated with a base. In some embodiments, the base is sodium hydroxide, sodium hydride, or potassium hydroxide. In a specific embodiment, the compound is treated with sodium hydroxide to obtain the desired anti-epoxide. Scheme XXI demonstrates epoxidation.

[0160]

[0161] Solution XXI.

[0162] In some embodiments, the resulting compound is further protected with one or more silane-based protecting groups commonly found in the literature, including triisopropylsilyl ether, tert-butyldiphenylsilyl ether, or tert-butyldimethylsilyl ether. In a specific embodiment, the protecting group is tert-butyldimethylsilyl ether. In some embodiments, tert-butyldimethylsilyl chloride is used to protect the hydroxyl groups of the resulting compound. Scheme XXII illustrates the protecting reaction.

[0163]

[0164] Option XXII.

[0165] Stage 2: Synthesis of (-)-epicatechin

[0166] In some embodiments, the second stage includes the synthesis of (-)-epicatechin. In specific embodiments, (-)-epicatechin can be synthesized from syn-epoxide. In specific embodiments, (-)-epicatechin can be synthesized from anti-epoxide. In some embodiments, the synthesis of (-)-epicatechin is performed according to... Figure 6 and 7 The general steps outlined in the document are carried out and discussed further below.

[0167] Stage 2.1: Synthesis of (-)-epicatechin from Syn-epoxide intermediates

[0168] In some embodiments, Figure 6 The text outlines the general synthesis of (-)-epicatechin from syn-epoxide intermediates. For example... Figure 6 As shown, the synthesis comprises at least five steps. Specifically, the synthesis includes an epoxide ring-opening reaction. Subsequently, the product undergoes a protecting reaction, followed by a deprotecting reaction. Then, the resulting product undergoes a cyclization reaction. Finally, one or more deprotecting reactions produce the desired (-)-epicatechin product.

[0169] In some embodiments, the starting material for synthesizing (-)-epicatechin from syn-epoxide is a compound of formula VII, wherein X is F, Br, I, Cl, N, S or B, and R3 is Bn or MOM.

[0170]

[0171] Equation VII.

[0172] In some embodiments, the syn-epoxide intermediate undergoes an epoxide ring-opening reaction. In some embodiments, the compound of formula VII is 1,3-bis(benzyloxy)-5-fluorobenzene, wherein X is F and R3 is benzyl. In specific embodiments, the compound of formula VI is treated with an organolithium reagent. In some embodiments, the organolithium reagent is n-butyllithium, methyllithium, or tert-butyllithium. In specific embodiments, the organolithium reagent is n-butyllithium. In some 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 in the presence of a Lewis acid known in the literature, wherein X is Br, I, Cl, N, S, or B. Scheme XXIII illustrates epoxide ring-opening.

[0173]

[0174] Option XXIII.

[0175] In some embodiments, the resulting compound is further protected with one or more protecting groups commonly found in the literature, including methoxymethyl ethers, tetrahydropyranyl ethers, tert-butyl ethers, allyl ethers, benzyl ethers, triisopropylsilyl ethers, or tert-butyldimethylsilyl ethers. In some embodiments, the protecting group differs from the group at R2. In some specific embodiments, the protecting group is tert-methoxymethyl. In some embodiments, methoxymethyl chloride is used to protect the hydroxyl group of the resulting compound. Scheme XXIV illustrates the protecting reaction.

[0176]

[0177] Plan XXIV.

[0178] In some embodiments, the protected compound further undergoes selective deprotection of the protecting group at R2. In a specific embodiment, R2 is tert-butyldimethylsilyl. In some embodiments, the protected compound is treated with a suitable acid or fluoride known in the literature to achieve deprotection of the silyl ether. In a specific embodiment, the protected compound is treated with tetrabutylammonium fluoride (TBAF) to obtain the desired deprotected compound. Scheme XXV illustrates the deprotection reaction.

[0179]

[0180] Solution XXV.

[0181] In some embodiments, the resulting product undergoes a cyclization reaction. In some embodiments, the resulting product is treated with a strong base. In some embodiments, the strong base is potassium hydride, sodium hydride, or potassium tert-butoxide. In a specific embodiment, X is F, and the strong base is potassium hydride, to obtain the desired cyclized product. Scheme XXVI demonstrates a deprotection reaction.

[0182]

[0183] Option XXVI.

[0184] 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 cyclized product.

[0185] In some embodiments, the cyclized product further undergoes one or more deprotection reactions. In some embodiments, the methoxymethyl ether group is removed using methods known in the literature. In some embodiments, the methoxymethyl ether group is removed using an acid. In a specific embodiment, the acid is hydrochloric acid.

[0186] In some embodiments, the benzyl ether group is removed using a debenzylation reaction. In some embodiments, debenzylation is carried out using a palladium catalyst in the presence of hydrogen. In some embodiments, the palladium catalyst may be carbon-supported palladium (Pd / C) or carbon-supported palladium hydroxide (Pd(OH)₂ / C). In a specific embodiment, the palladium catalyst is Pd(OH)₂ / C in the presence of hydrogen. In a specific embodiment, the one or more deprotection reactions produce the desired (-)-epicatechin product. Scheme XXVII illustrates the deprotection reaction.

[0187]

[0188] Option XXVII.

[0189] Stage 2.2: Synthesis of (-)-epicatechin from anti-epoxide intermediates

[0190] In some embodiments, Figure 7 The text outlines the general synthesis of (-)-epicatechin from anti-epoxide intermediates. For example... Figure 7 As shown, the synthesis comprises at least five steps. Specifically, the synthesis includes a first reaction. Subsequently, the product undergoes a protection reaction, followed by a deprotection reaction. Then, the resulting product undergoes a cyclization reaction. Finally, the deprotection reaction yields the desired (-)-epicatechin product.

[0191] In some embodiments, the anti-epoxide undergoes a first reaction. Scheme XXVIII demonstrates the conversion.

[0192]

[0193] Solution XXVIII.

[0194] In some embodiments, the resulting compound further undergoes one or more deprotection reactions. In a specific embodiment, R2 is tert-butyldimethylsilyl. In some embodiments, the protected compound is treated with a suitable acid or fluoride known in the literature to achieve deprotection of the silyl ether. In a specific embodiment, the protected compound is treated with tetrabutylammonium fluoride (TBAF) to obtain the desired deprotected compound.

[0195] In some embodiments, R1 and R3 are different. In a specific embodiment, R1 is benzyl and R3 is a methoxymethyl group. In some embodiments, the methoxymethyl ether group is removed using methods known in the literature. In some embodiments, the methoxymethyl ether group is removed using an acid. In a specific embodiment, the acid is hydrochloric acid. Scheme XXIX demonstrates a deprotection reaction.

[0196]

[0197] Solution XXIX.

[0198] In some embodiments, the resulting product undergoes a cyclization reaction. In some embodiments, the resulting product is treated with triethyl orthopropionate. In some embodiments, the reaction mixture is further treated with an acid. In a specific embodiment, the reaction mixture is treated with p-toluenesulfonic acid to obtain the desired cyclized product. Scheme XXX illustrates the cyclization reaction.

[0199]

[0200] Plan XXX.

[0201] In some embodiments, the resulting product undergoes a deprotection reaction. In specific embodiments, the benzyl ether group is removed using a debenzylation reaction. In some embodiments, debenzylation is carried out using a palladium catalyst in the presence of hydrogen. In some embodiments, the palladium catalyst may be carbon-supported palladium (Pd / C) or carbon-supported palladium hydroxide (Pd(OH)₂ / C). In specific embodiments, the palladium catalyst is Pd(OH)₂ / C in the presence of hydrogen. In specific embodiments, the deprotection reaction yields the desired (-)-epicatechin product. Scheme XXXI illustrates the deprotection reaction.

[0202]

[0203] Plan XXXI.

[0204] IV. Consumer Products

[0205] In some embodiments, this disclosure further relates to consumer products comprising one or more catechin epimers disclosed herein. In some embodiments, the consumer product comprises (-)-epicatechin, wherein each of the compounds is prepared by the methods disclosed herein.

[0206] In some embodiments, the stereospecific catechin epimers provided herein can be used in a variety of edible products. Non-limiting examples of suitable food products include chocolate, chewing gum compositions, hard and soft confectionery products, dairy products, snack food products, food products belonging to the beverage category (where the product has approximately a neutral pH), food products belonging to the frozen food category (including frozen dairy products), nutritional products, nutritional supplements and pharmaceuticals, and the food categories described herein.

[0207] As used herein, “beverage category” can refer to beverages, beverage mixtures, and concentrates, including but not limited to ready-to-drink beverages and powdered beverages, both alcoholic and non-alcoholic, wherein the beverage has an approximately neutral pH. Other non-limiting examples of beverages may include carbonated and non-carbonated beverages, such as soda water, fruit or vegetable juices.

[0208] As used herein, the “frozen food category” refers to refrigerated or frozen food products having a neutral pH. Non-limiting examples of food products in the frozen food category may include ice cream, ready-to-eat ice cream, single-serving dairy ice cream, single-serving water ice cream, multi-serving dairy ice cream, multi-serving water ice cream, family-sized ice cream, family-sized dairy ice cream, ice cream desserts, bulk ice cream, family-sized water ice cream, frozen yogurt, artisanal ice cream, frozen ready-to-eat meals, 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 baked goods, and frozen desserts.

[0209] As used herein, the “snack food category” refers to any food that can be served as a light, informal meal, including but not limited to sweet and savory snacks and snack bars, wherein the food has a neutral pH. Examples of snack foods include, but are not limited to, fruit snacks, potato chips, puffed snacks, tortilla chips, popcorn, pretzels, nuts, and other sweet and savory snacks. Examples of snack bars include, but are not limited to, granola bars, breakfast bars, energy bars, fruit bars, and other snack bars.

[0210] As used herein, “nutritional product” means any product capable of providing desired nutritional value, including but not limited to nutrition bars and nutritional beverages. In some embodiments, nutritional products are medical foods and / or complementary nutritional therapies. Non-limiting examples of nutrition bars include protein bars (e.g., RXBAR®, LÄRABAR®, CLIF BAR®), nut bars (e.g., KIND® bars), energy bars, fiber bars, meal replacement bars, or other nutrition bars. Non-limiting examples of nutritional beverages include protein drinks (e.g., BOOST® beverages), meal replacement shakes and / or beverages (e.g., Ensure® nutritional shakes), diabetic shakes and / or beverages (e.g., Glucerna® shakes), immune support beverages, children's supplement beverages, or other nutritional beverages.

[0211] As used herein, “nutritional supplement” means a supplement that provides the desired nutrition. Nutritional supplements may be administered orally, for example, in the form of tablets, chewable tablets, gummies, or powders. Non-limiting examples of nutritional supplements include vitamin supplements, mineral supplements, herbal supplements, other nutritional supplements, or combinations thereof. As used herein, “medicine” means a medicinal product. Non-limiting examples of medicines include prescription drugs, over-the-counter drugs (e.g., aspirin, acetaminophen, or ibuprofen), herbal medicines, or other medicines.

[0212] In some embodiments, effective amounts of (-)-epicatechin can be added to consumer products that do not naturally contain flavanols to provide consumers with the desired health benefits. These amounts can be determined based on existing, ongoing clinical trials. Flavanol monomers can also be added to foods and beverages that already contain flavanols to further enrich the product and thus provide improved health benefits.

[0213] Medicinal products containing (-)-epicatechin of this disclosure can be administered in several ways, such as orally, nasally, buccally, intravenously, and topically. Those skilled in the art will be able to determine appropriate delivery modalities to maximize the effectiveness of the catechin compounds.

[0214] Example

[0215] This disclosure will be better understood by referring to the following examples, which are provided as examples of this disclosure and not as limitations.

[0216] Example 1: Synthesis of (-)-epicatechin

[0217] Example 1 provides a twelve-step synthesis of (-)-epicatechin. Chiral auxiliary agent 1 and 3,4-bis(methoxymethoxy)benzaldehyde 2 were used as starting materials. Scheme XXXII illustrates the steps of this synthesis and is further described below.

[0218]

[0219] Reagents and conditions: (a) Et3N, 4 h; (b) 2,6-dimethylpyridine, TBSCl, dichloromethane; (c) LiBH4, ether, 0 °C, 1 h; (d) H2, Pd-C, ethyl acetate; (e) TsCl, dichloromethane; (f) K2CO3, methanol, 0 °C; (g) nBuLi, (((5-fluoro-1,3-phenylene)bis(oxy))bis(methylene))diphenyl, THF; (h) MOMCl, dichloromethane; (i) TBAF, THF; (j) KH, DMF; (k) HCl, dioxane; (l) H2, Pd-C, ethyl acetate.

[0220] Plan XXXII.

[0221] Chiral auxiliaries 1 and 3,4-bis(methoxymethoxy)benzaldehyde 2 undergo an asymmetric aldol condensation reaction with titanium tetrachloride and triethylamine to yield the desired product (2S,3R)-2-(benzyloxy)-3-(3,4-bis(methoxymethoxy)phenyl)-3-hydroxy-1-((S)-4-phenyl-2-thiooxazolidine-3-yl)prop-1-one 3. The product is then protected with tert-butyldimethylsilyl chloride (TBSCl) to produce the desired tert-butyldimethylsilyl ether, namely (2S,3R)-2-(benzyloxy)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)-1-((S)-4-phenyl-2-thiooxazolidine-3-yl)prop-1-one 4. The chiral auxiliary is removed in a reduction reaction at 0 °C in the presence of lithium borohydride (LiBH4) to produce (2R,3R)-2-(benzyloxy)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)propane-1-ol 5. The benzyl group is then removed by hydrogenation under H2 using Pd / C to produce the desired alcohol, namely (2R,3R)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)propane-1,2-diol 6. Alcohol 6 then undergoes selective p-toluenesulfonation of a primary alcohol to produce the desired p-toluenesulfonate, namely (2R,3R)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)-2-hydroxypropyl 4-methylbenzenesulfonic acid 7. p-Toluenesulfonate 7 is further treated in methanol with potassium carbonate to produce the desired epoxide, namely ((R)-(3,4-bis(methoxymethoxy)phenyl)((R)-ethyleneoxy-2-yl)methoxy)(tert-butyl)dimethylsilane 8. Then, epoxide 8 is alkylated in THF with n-butyllithium and (((5-fluoro-1,3-phenylene)bis(oxy))bis(methylene))diphenyl alkylate to produce the desired alcohol, namely (1R,2R)-3-(2,4-bis(benzyloxy)-6-fluorophenyl)-1-(3,4-bis(methoxymethoxy)phenyl)-1-((tert-butyldimethylsilyl)oxy)prop-2-ol 9. Then, the free hydroxyl group of alcohol 9 is protected with chloromethyl methoxy ether (MOMCl) to give the desired product, namely (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-silazane 10. The desired product is then deprotected with tetrabutylammonium fluoride (TBAF) to produce the desired alcohol, namely (1R,2R)-3-(2,4-bis(benzyloxy)-6-fluorophenyl)-1-(3,4-bis(methoxymethoxy)phenyl)-2-(methoxymethoxy)prop-1-ol 11.Then, alcohol 11 undergoes potassium hydride treatment to produce the desired protected (-)-epicatechin, namely (2R,3R)-5,7-bis(benzyloxy)-2-(3,4-bis(methoxymethoxy)phenyl)-3-(methoxymethoxy)tryptane 12. Finally, methoxymethyl ether is deprotected using HCl to produce the selectively deprotected product, namely 4-((2R,3R)-5,7-bis(benzyloxy)-3-hydroxytryptane-2-yl)phenyl-1,2-diol 13. Following this deprotection, benzyl ether is deprotected using Pd / C under H2 gas to produce (-)-epicatechin 14 as a grayish-white solid.

[0222] Example 2: Synthesis of (S)-2-(benzyloxy)-1-(4-phenyl-2-thiooxazolidine-3-yl)ethyl-1-one (1)

[0223]

[0224] Under nitrogen atmosphere, a solution of (4S)-4-phenyl-1,3-oxazolidine-2-thione (1 eq., 5.5 g, 30.69 mmol), benzyloxyacetic acid (1 eq., 5.099 g, 4.39 mL, 30.69 mmol), and DMAP (0.25 eq., 0.94 g, 7.67 mmol) in methylene chloride (100 mL) was cooled to 0 °C and treated with EDCI (1.1 eq., 5.24 g, 33.75 mmol). After stirring at 0 °C for 4 hours, 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 x 50 mL). The separated organic layer was washed successively with 1 N HCl aqueous solution (50 mL), water (50 mL), 1 M NaOH aqueous solution (2 x 50 mL), water (50 mL), and brine (20 mL). The resulting organic phase was dried with sodium sulfate, filtered, and concentrated. The resulting crude solid was crystallized from a mixture of ethyl acetate and hexane to give 2-(benzyloxy)-1-[(4S)-4-phenyl-2-thio-1,3-oxazolidine-3-yl]ethyl-1-one (8.52 g, 26.023 mmol, 84.8%) as a grayish-white needle-like substance. 1 H NMR (400 MHz, CDCl3) ẟ 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).

[0225] Example 3: Synthesis of 3,4-bis(methoxymethoxy)benzaldehyde (2)

[0226]

[0227] Under nitrogen atmosphere, a stirred solution of 3,4-dihydroxybenzaldehyde (1 eq., 1 g, 7.24 mmol) in DMF (20 mL) was cooled to 0 °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 overnight at room temperature. The reaction mixture was filtered and thoroughly washed with ethyl acetate. The filtrate was diluted with water (200 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with water (2 x 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 light brown oil. The material was used in subsequent steps without requiring further purification.

[0228] Example 4: Synthesis of (2S,3R)-2-(benzyloxy)-3-(3,4-bis(methoxymethoxy)phenyl)-3-hydroxy-1-((S)-4-phenyl-2-thiooxazolidine-3-yl)prop-1-one (3)

[0229]

[0230] Under argon atmosphere, a solution of 2-(benzyloxy)-1-[(4S)-4-phenyl-2-thio-1,3-oxazolidine-3-yl]ethyl-1-one (1 eq., 723 mg, 2.208 mmol) in anhydrous dichloromethane (20 mL) was cooled to -10 °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 °C. After 5 minutes, triethylamine (2 eq., 446.93 mg, 0.61 mL, 4.42 mmol) was added dropwise. With the addition of triethylamine, the solution color changed from amber to deep purple. After stirring for 75 minutes, 3,4-bis(methoxymethoxy)benzaldehyde (2 eq., 999.16 mg, 4.42 mmol) was added from dichloromethane (5 mL). After the addition was complete, stirring was continued at -78 °C for 2 hours. Once the reaction was complete, the mixture was diluted with brine (30 mL) and slowly heated to 0 °C. The quenched reaction mixture was extracted with 1 M HCl aqueous solution (2 x 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 / hexane) to produce (2S,3R)-2-(benzyloxy)-3-[3,4-bis(methoxymethoxy)phenyl]-3-hydroxy-1-[(4S)-4-phenyl-2-thio-1,3-oxazolidin-3-yl]prop-1-one (760 mg, 1.37 mmol, 62.16%), which was a pale yellow foam. 1 H NMR (400 MHz, CDCl3) ẟ 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 = 8Hz, 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).

[0231] Example 5: Synthesis of (2S,3R)-2-(benzyloxy)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)-1-((S)-4-phenyl-2-thiooxazolidine-3-yl)prop-1-one (4)

[0232]

[0233] Under nitrogen atmosphere, a stirred solution of 2,6-dimethylpyridine (2.4 eq., 353.038 mg, 0.38 mL, 3.29 mmol) in dichloromethane (10 mL) was cooled to -78 °C, and tert-butyldimethylsilyltrifluoromethanesulfonate (2.2 eq., 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-thio-1,3-oxazolidine-3-yl]prop-1-one (1 eq., 760 mg, 1.37 mmol) were added dropwise to dichloromethane (5 mL). After stirring at -78°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 / hexane) to yield (2S,3R)-2-(benzyloxy)-3-[3,4-bis(methoxymethoxy)phenyl]-3-[(tert-butyldimethylsilyl)oxy]-1-[(4S)-4-phenyl-2-thio-1,3-oxazolidine-3-yl]propyl-1 (440 mg, 0.66 mmol) as a colorless oil. 1HNMR (400 MHz, CDCl3) ẟ -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).

[0234] Example 6: Synthesis of (2R,3R)-2-(benzyloxy)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)prop-1-ol (5)

[0235]

[0236] A solution of (2S,3R)-2-(benzyloxy)-3-[3,4-bis(methoxymethoxy)phenyl]-3-[(tert-butyldimethylsilyl)oxy]-1-[(4S)-4-phenyl-2-thio-1,3-oxazolidine-3-yl]propyl-1 (1 eq., 440 mg, 0.66 mmol) in diethyl ether (10 mL) and MeOH (2 mL) was cooled to 0 °C and treated once with lithium borohydride (1.5 eq., 20.805 mg, 0.96 mmol). After stirring at 0 °C for 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 x 15 mL). The combined extracts were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash column chromatography (15%-30% ethyl acetate / hexane) to produce (2R,3R)-2-(benzyloxy)-3-[3,4-bis(methoxymethoxy)phenyl]-3-[(tert-butyldimethylsilyl)oxy]prop-1-ol (298 mg, 0.605 mmol, 91.81%) as a colorless oil.1 H NMR (400 MHz, CDCl3) ẟ -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).

[0237] Example 7: Synthesis of (2R,3R)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)propane-1,2-diol (6)

[0238]

[0239] A heterogeneous solution of (2R,3R)-2-(benzyloxy)-3-[3,4-bis(methoxymethoxy)phenyl]-3-[(tert-butyldimethylsilyl)oxy]propane-1-ol (300 mg, 0.609 mmol) and palladium hydroxide (300 mg, 2.14 mmol) (20% loaded on carbon) was evacuated and filled with hydrogen three times, then stirred for 15 hours under a hydrogen atmosphere (balloon method). The mixture was filtered and washed with ethyl acetate. The combined filtrates were concentrated under reduced pressure and purified by silica gel flash column chromatography (20%–60% ethyl acetate / hexane) to yield (2R,3R)-3-[3,4-bis(methoxymethoxy)phenyl]-3-[(tert-butyldimethylsilyl)oxy]propane-1,2-diol (200 mg, 0.5 mmol, 81.59%) as a colorless, viscous oil. 1H NMR (400 MHz, CDCl3) ẟ -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, 4H), 6.89 (dd, J = 8, 4 Hz, 1H), 7.09 (d, J = 8 Hz, 1H), 7.16 (d, J = 4 Hz,1H).

[0240] Example 8: Synthesis of 4-methylbenzenesulfonic acid (2R,3R)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)-2-hydroxypropyl ester (7)

[0241]

[0242] Under nitrogen atmosphere, a stirred solution of (2R,3R)-3-[3,4-bis(methoxymethoxy)phenyl]-3-[(tert-butyldimethylsilyl)oxy]propane-1,2-diol (1 eq., 200 mg, 0.5 mmol) in anhydrous dichloromethane (4 mL) was cooled to 0 °C and treated with dibutyltin oxide (0.02 eq., 2.47 mg, 0.0099 mmol), p-toluenesulfonyl chloride (1.2 eq., 113.66 mg, 0.6 mmol), DMAP (0.1 eq., 6.07 mg, 0.05 mmol), and triethylamine (1.2 eq., 60.33 mg, 0.083 mL, 0.6 mmol). After stirring for 5 hours, the reaction mixture was quenched with water (5 mL). After layer separation, the aqueous layer was extracted with dichloromethane (2 x 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 / hexane) to yield a colorless oil, [(1R,2R)-1-[3,4-bis(methoxymethoxy)phenyl]-2-hydroxy-3-[(4-methylbenzenesulfonyl)oxy]propoxy](tert-butyl)-dimethylsilane (260 mg, 0.47 mmol, 94%). 1H NMR (400 MHz, CDCl3) ẟ -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).

[0243] Example 9: Synthesis of ((R)-(3,4-bis(methoxymethoxy)phenyl)((R)-ethyleneoxy-2-yl)methoxy)(tert-butyl)dimethylsilane (8)

[0244]

[0245] Under nitrogen atmosphere, a solution of [(1R,2R)-1-[3,4-bis(methoxymethoxy)phenyl]-2-hydroxy-3-[(4-methylbenzenesulfonyl)oxy]propoxy](tert-butyl)dimethylsilane (1 eq., 260 mg, 0.47 mmol) in MeOH (2.5 mL) and dioxane (1 mL) was cooled to 0 °C (ice bath) and treated with potassium carbonate (2 eq., 129.085 mg, 0.93 mmol). After stirring at 0 °C for 1.0 hour, 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 / hexane) to produce a colorless oily substance, [(R)-[3,4-bis(methoxymethoxy)phenyl][(2R)-ethylene oxide-2-yl]methoxy](tert-butyl)dimethylsilane (148 mg, 0.38 mmol, 82.41%). 1H NMR (400 MHz, CDCl3) ẟ 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).

[0246] Example 10: Synthesis of (1R,2R)-3-(2,4-bis(benzyloxy)-6-fluorophenyl)-1-(3,4-bis(methoxymethoxy)phenyl)-1-((tert-butyldimethylsilyl)oxy)prop-2-ol (9)

[0247]

[0248] Under argon atmosphere, a solution of 1,3-bis(benzyloxy)-5-fluorobenzene (2 eq., 232.54 mg, 0.75 mmol) in anhydrous THF (5 mL) was cooled to -78 °C and carefully treated dropwise with n-butyllithium (2.09 eq., 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)-ethyleneoxy-2-yl]methoxy](tert-butyl)dimethylsilane (1 eq., 145 mg, 0.38 mmol) in anhydrous THF (2 mL) was slowly added, followed by a solution of boron trifluoride ether (2 eq., 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 x 15 mL), and the combined extracts were 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 / hexane) to yield (1R,2R)-3-[2,4-bis(benzyloxy)-6-fluorophenyl]-1-[3,4-bis(methoxymethoxy)phenyl]-1-[(tert-butyldimethylsilyl)oxy]prop-2-ol (125 mg, 0.18 mmol, 47.84%) as a colorless oil. 1H NMR (400MHz, CDCl3) ẟ - 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) -114.52.

[0249] 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-silazane (10)

[0250]

[0251] Under nitrogen atmosphere, a solution of (1R,2R)-3-[2,4-bis(benzyloxy)-6-fluorophenyl]-1-[3,4-bis(methoxymethoxy)phenyl]-1-[(tert-butyldimethylsilyl)oxy]prop-2-ol (1 eq., 125 mg, 0.18 mmol) and diisopropylethylamine (12 eq., 279.8 mg, 0.38 mL, 2.16 mmol) in dichloromethane (3 mL) was cooled to 0 °C and treated with chloromethyl methyl ether (6 eq., 87.15 mg, 0.082 mL, 1.082 mmol) and tetrabutylammonium iodide (0.05 eq., 3.33 mg), with stirring continued overnight at room temperature. After completion, the reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate (10 mL) and extracted with ethyl acetate (3 x 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 / hexane) to yield (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-silanedecane (110 mg, 0.15 mmol, 82.74%). 1 H NMR (400 MHz, CDCl3) ẟ -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, 10H). 19 F NMR (376 MHz, CDCl3) -114.08.

[0252] Example 12: Synthesis of (1R,2R)-3-(2,4-bis(benzyloxy)-6-fluorophenyl)-1-(3,4-bis(methoxymethoxy)phenyl)-2-(methoxymethoxy)prop-1-ol (11)

[0253]

[0254] 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-silazanedecane (1 eq., 110 mg, 0.15 mmol) in THF (3 mL) was cooled to 0 °C (ice bath) and treated with tetrabutylammonium fluoride (1.5 eq., 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 / hexane) to produce (1R,2R)-3-[2,4-bis(benzyloxy)-6-fluorophenyl]-1-[3,4-bis(methoxymethoxy)phenyl]-2-(methoxymethoxy)prop-1-ol (90 mg, 0.14 mmol, 96.83%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) ẟ 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) -114.07.

[0255] Example 13: Synthesis of (2R,3R)-5,7-bis(benzyloxy)-2-(3,4-bis(methoxymethoxy)phenyl)-3-(methoxymethoxy)chromane (12)

[0256]

[0257] Under argon atmosphere, a stirred solution of (1R,2R)-3-[2,4-bis(benzyloxy)-6-fluorophenyl]-1-[3,4-bis(methoxymethoxy)phenyl]-2-(methoxymethoxy)prop-1-ol (1 eq., 90 mg, 0.14 mmol) in anhydrous DMF (3 mL) was cooled to 0°C (ice bath) and treated with potassium hydride (5 eq., 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 cooled again to 0°C and quenched with water (30 mL), and extracted with ethyl acetate (3 x 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 / hexane) to produce (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. 1 H NMR (400 MHz, CDCl3)ẟ 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 = 2.3Hz, 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).

[0258] Example 14: Synthesis of 4-((2R,3R)-5,7-bis(benzyloxy)-3-hydroxytryptane-2-yl)phenyl-1,2-diol (13)

[0259]

[0260] A solution of (2R,3R)-5,7-bis(benzyloxy)-2-[3,4-bis(methoxymethoxy)phenyl]-3-(methoxymethoxy)-3,4-dihydro-2H-1-benzopyran (1 eq., 70 mg, 0.12 mmol) in MeOH (2 mL) and dichloromethane (2 mL) was cooled to 0 °C and treated with HCl (68.88 eq., 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 / hexane) to produce 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. 1 H NMR(400 MHz, CDCl3) ẟ 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).

[0261] Example 15: Synthesis of (-)-epicatechin

[0262]

[0263] A solution of 4-[(2R,3R)-5,7-bis(benzyloxy)-3-hydroxy-3,4-dihydro-2H-1-benzopyran-2-yl]phenyl-1,2-diol (1 eq., 25 mg, 0.053 mmol) in THF-MeOH-water (1:1:1) (3 mL) was evacuated with carbon-supported palladium hydroxide (4.021 eq., 30 mg, 0.21 mmol) (20% loaded on carbon) and filled with hydrogen (3 times). This heterogeneous solution was stirred overnight at room temperature under a hydrogen atmosphere (balloon method). The catalyst was removed by filtration and the filtrate was concentrated. The aqueous residue was then lyophilized to produce (2R,3R)-2-(3,4-dihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3,5,7-triol (9 mg, 0.031 mmol, 58.35%).

[0264] Example 16: Alternative Synthesis of Syn-Epoxide Intermediates

[0265] Compound 3,4-bis(benzyloxymethoxy)benzaldehyde 15 can be used as a starting material to achieve the syn-epoxide intermediate. Scheme XXXIII illustrates the steps of this synthesis and is further described below.

[0266]

[0267] Option XXXIII.

[0268] Compound 3,4-bis(benzyloxymethoxy)benzaldehyde 15 can undergo asymmetric addition with vinyltrimethoxysilane in the presence of catalyst CuF∙2H2O and (R)-DTBM-SEGPHOS to yield the desired olefin (S)-1-(3,4-bis(benzyloxy)phenyl)prop-2-en-1-ol 16. Olefin 16 can then be further epoxidized with hydrogen peroxide using titanium-Salalen. The additional steps can be the same as steps 7-12 of scheme XXXII in Example 1.

[0269] Example 17: Alternative synthesis of (-)-epicatechin using anti-epoxide intermediates

[0270] Example 17 provides a seven-step synthesis of (-)-epicatechin. Compound 3,4-bis(benzyloxymethoxy)benzaldehyde 15 can be used as a starting material. Scheme XXXIV illustrates the steps of this synthesis and is further described below.

[0271]

[0272] Option XXXIV.

[0273] Compound 3,4-bis(benzyloxymethoxy)benzaldehyde 15 can undergo a Grignard reaction using a Grignard reagent, vinyl magnesium bromide, to yield the desired olefin (S)-1,1-(3,4-bis(benzyloxy)phenyl)prop-2-en-1-ol 18. Olefin 18 can then be further reacted with titanium isopropoxide (Ti(O) iPr)4) and tert-butyl hydroperoxide (TBHP) undergo epoxidation to produce the desired epoxide, namely (S)-(3,4-bis(benzyloxy)phenyl)((R)-ethyleneoxy-2-yl)methanol 19. Epoxide 19 can then be converted to the product, namely (1S,2R)-1-(3,4-bis(benzyloxy)phenyl)-1-((tert-butyldimethylsilyl)oxy)-3-(2,4,6-tris(methoxymethoxy)phenyl)prop-2-ol 20. Product 20 can then undergo deprotection to remove tert-butyl dimethyl ether under deprotection conditions, thereby producing the desired alcohol, namely 2-((2R,3S)-3-(3,4-bis(benzyloxy)phenyl)-2,3-dihydroxypropyl)benzene-1,3,5-triol 21. Alcohol 21 can then undergo cyclization using triethyl orthopropionate and p-toluenesulfonation using p-toluenesulfonic acid to produce the protected (-)-epicatechin, namely 2-((2R,3S)-3-(3,4-bis(benzyloxy)phenyl)-2,3-dihydroxypropyl)-phenyl-1,3,5-triol 22. The protected product 22 can then be deprotected by debenzylation to give the desired (-)-epicatechin 14.

[0274] Example 18: Alternative Synthesis of Anti-Epoxide Intermediates

[0275] Compound 3,4-bis(benzyloxymethoxy)benzaldehyde 15 can be used as a starting material to achieve the desired anti-epoxide intermediate. Scheme XXXV illustrates the steps of this synthesis and is further described below.

[0276]

[0277] Solution XXXV.

[0278] Compound 3,4-bis(benzyloxymethoxy)benzaldehyde 15 undergoes a Wittig reaction using a suitable ylide to produce the desired alkene, ethyl(E)-3-(3,4-bis(benzyloxy)phenyl)acrylate 23. Alkene 23 can then undergo an addition reaction to achieve the desired alcohol, ethyl(2R,3R)-3-(3,4-bis(benzyloxy)phenyl)-2-bromo-3-hydroxypropionate 24. The desired alcohol 24 can be protected with tert-butyldimethylsilyl ether using TBSCl to produce the desired protected product, ethyl(2R,3R)-3-(3,4-bis(benzyloxy)phenyl)-2-bromo-3-((tert-butyldimethylsilyl)oxy)propionate 25. The product can be further treated in THF with lithium borohydride (LiBH4) to produce the desired primary alcohol, namely (2R,3R)-3-(3,4-bis(benzyloxy)phenyl)-2-bromo-3-((tert-butyldimethylsilyl)oxy)prop-1-ol 26. Finally, compound 26 can undergo an epoxidation reaction using sodium hydroxide (NaOH) to give the anti-epoxide intermediate, namely (S)-(3,4-bis(benzyloxy)phenyl)((R)-epoxyethylene-2-yl)methanol 19. The additional steps can be the same as steps 3-8 of scheme XXXIV in Example 17.

[0279] Example 19: Alternative Synthesis of Anti-Epoxide Intermediates

[0280] Tartaric acid can be used as a starting material to achieve the desired anti-epoxide intermediate. Scheme XXXVI illustrates the steps of this synthesis and is further described below.

[0281]

[0282] Option XXXVI.

[0283] The compound tartaric acid can be reacted with p-toluenesulfonic acid and acetone to produce the desired dimer, 1,2-bis((S)-2,2-dimethyl-1,3-dioxolane-4-yl)ethane-1,2-diol 26. Dimer 23 can then be oxidized in water using sodium periodate to give the desired aldehyde, (S)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde 27. Aldehyde 27 can then undergo an addition reaction with (S)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde to produce the desired secondary alcohol, (R)-(3,4-bis(benzyloxy)phenyl)((S)-2,2-dimethyl-1,3-dioxolane-4-yl)methanol 28. The secondary alcohol can then undergo p-toluenesulfonic acid, followed by p-toluenesulfonyl chloride, to produce the desired p-toluenesulfonated product, namely 4-methylbenzenesulfonic acid (2S,3R)-3-(3,4-bis(benzyloxy)phenyl)-2,3-dihydroxypropyl ester 29. Finally, compound 29 can undergo an epoxidation reaction using sodium hydroxide (NaOH) to give the anti-epoxide intermediate, namely (R)-(3,4-bis(benzyloxy)phenyl)((S)-epoxyethylene-2-yl)methanol 30. The remaining steps can be the same as steps 3-8 of scheme XXXIV in Example 17.

[0284] ***

[0285] Although the subject matter and advantages of this disclosure have been described in detail, it should be understood that various changes, substitutions, and alternatives can be made herein without departing from the spirit and scope of this disclosure. Furthermore, the scope of this application is not intended to be limited to the specific embodiments of the processes, material compositions, methods, and procedures described herein. As will be readily understood by those skilled in the art from the disclosed subject matter, existing or subsequently developed processes, material compositions, methods, or steps that perform substantially the same functions as those in the corresponding embodiments described herein or achieve substantially the same results as those in the corresponding embodiments described herein can be utilized based on this disclosure. Therefore, the appended claims are intended to cover such processes, machines, manufactures, material compositions, methods, or steps within their scope.

[0286] All patents, patent applications, publications, product descriptions, solutions and serial numbers cited in the entirety of this application are incorporated herein by reference for all purposes.

Claims

1. A method for preparing (-)-epicatechin, the method comprising: a) Provides compound V: Formula V Where X is O or S, R3 is Ph, Bn or CH(CH3)2, and R4 is Ph or H, and further provided are compounds of formula II: Formula II Where R1 is MOM or Bn; b) Couple the compound of formula II and the compound of formula V to form a first intermediate, wherein the first intermediate comprises a secondary alcohol; c) Protect the secondary alcohol in the first intermediate to form a second intermediate; d) Reduce the second intermediate to form a third intermediate, wherein the third intermediate comprises a primary alcohol; e) Remove the Bn group of formula V to form a fourth intermediate; f) Selectively forming a sulfonate from the primary alcohol of the fourth intermediate to form a fifth intermediate; g) Epoxidize the fifth intermediate to form the sixth intermediate; h) Alkylating the sixth intermediate to form a seventh intermediate, wherein the seventh intermediate comprises a primary alcohol; i) Protect the primary alcohol of the seventh intermediate to form the eighth intermediate; j) Cyclocyclize the eighth intermediate to form the ninth intermediate; k) Deprotect the ninth intermediate to form the tenth intermediate; l) Deprotect the tenth intermediate to form (-)-epicatechin.

2. The method according to claim 1, wherein X is S and R3 is Ph.

3. The method according to claim 1, wherein R1 is MOM.

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

5. The method according to claim 4, wherein the silicon-based group is tert-butyldimethylsilyl.

6. The method according to claim 1, wherein the sulfonate in (f) is -OTs, -OMes or -OTf.

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

8. The method according to claim 1, wherein the sixth intermediate is alkylated with a compound of formula VII: Equation VII Wherein X is F, Br, I, Cl, N, S or B, and R3 is a Bn or MOM protecting group to form the seventh intermediate.

9. The method of claim 8, wherein X is F and R3 is Bn.

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

11. The method of claim 10, wherein the seventh intermediate is protected with a 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 a syn-epoxide intermediate.

14. A method for preparing (-)-epicatechin, the method comprising: a) Provides (S)-2-(benzyloxy)-1-(4-phenyl-2-thiooxazolidine-3-yl)ethyl-1-one and 3,4-bis(methoxymethoxy)benzaldehyde; b) Add chloromethyl methyl ether to produce (2S,3R)-2-(benzyloxy)-3-(3,4-bis(methoxymethoxy)phenyl)-3-hydroxy-1-((S)-4-phenyl-2-thiooxazolidine-3-yl)prop-1-one; c) Protect (2S,3R)-2-(benzyloxy)-3-(3,4-bis(methoxymethoxy)phenyl)-3-hydroxy-1-((S)-4-phenyl-2-thiooxazolidine-3-yl)prop-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-thiooxazolidine-3-yl)prop-1-one; d) Reduce (2S,3R)-2-(benzyloxy)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)-1-((S)-4-phenyl-2-thiooxazolidine-3-yl)prop-1-one with LiBH4 to produce (2R,3R)-2-(benzyloxy)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)prop-1-ol; e) Deprotecting (2R,3R)-2-(benzyloxy)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)propane-1-ol with Pd / C under H2 gas to produce (2R,3R)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)propane-1,2-diol; f) P-toluenesulfonate (2R,3R)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)propane-1,2-diol with p-toluenesulfonic acid to produce (2R,3R)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)-2-hydroxypropyl 4-methylbenzenesulfonic acid; g) In methanol, potassium carbonate is used to epoxidize (2R,3R)-3-(3,4-bis(methoxymethoxy)phenyl)-3-((tert-butyldimethylsilyl)oxy)-2-hydroxypropyl ester of 4-methylbenzenesulfonic acid to produce ((R)-(3,4-bis(methoxymethoxy)phenyl)((R)-ethylene oxide-2-yl)methoxy)(tert-butyl)dimethylsilane; h) Using n-butyllithium, ((R)-(3,4-bis(methoxymethoxy)phenyl)((R)-ethyleneoxy-2-yl)methoxy)(tert-butyl)dimethylsilane is alkylated with (((5-fluoro-1,3-phenylene)bis(oxy))bis(methylene))diphenyl to produce (1R,2R)-3-(2,4-bis(benzyloxy)-6-fluorophenyl)-1-(3,4-bis(methoxymethoxy)phenyl)-1-((tert-butyldimethylsilyl)oxy)prop-2-ol; i) Protect (1R,2R)-3-(2,4-bis(benzyloxy)-6-fluorophenyl)-1-(3,4-bis(methoxymethoxy)phenyl)-1-((tert-butyldimethylsilyl)oxy)prop-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-silazdecane; k) Deprotect (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-silazanedecane with TBAF to produce (1R,2R)-3-(2,4-bis(benzyloxy)-6-fluorophenyl)-1-(3,4-bis(methoxymethoxy)phenyl)-2-(methoxymethoxy)prop-1-ol; l) Using potassium hydride, (1R,2R)-3-(2,4-bis(benzyloxy)-6-fluorophenyl)-1-(3,4-bis(methoxymethoxy)phenyl)-2-(methoxymethoxy)prop-1-ol is cyclized to produce (2R,3R)-5,7-bis(benzyloxy)-2-(3,4-bis(methoxymethoxy)phenyl)-3-(methoxymethoxy)chromane; m) Deprotecting (2R,3R)-5,7-bis(benzyloxy)-2-(3,4-bis(methoxymethoxy)phenyl)-3-(methoxymethoxy)chromane with HCl to produce 4-((2R,3R)-5,7-bis(benzyloxy)-3-hydroxychromane-2-yl)phenyl-1,2-diol; and n) Deprotecting 4-((2R,3R)-5,7-bis(benzyloxy)-3-hydroxytryptane-2-yl)phenyl-1,2-diol with Pd / C under H2 to give (-)-epicatechin.

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