阅读说明：本技术 表儿茶素及相关多酚 (Epicatechin and related polyphenols ) 是由 松迪普·杜加尔 迪内希·马哈詹 库马尔·桑托什·拉伊 萨布吉特·辛格 伊什瓦·拉凯什·帕蒂尔 于 2014-04-04 设计创作，主要内容包括：本申请涉及表儿茶素及相关多酚的新类似物。本发明提供了表儿茶素及相关多酚的新类似物、其多种官能化衍生物、其制备方法、包含这些化合物的组合物、及其使用方法。(The present application relates to novel analogues of epicatechin and related polyphenols. The present invention provides novel analogues of epicatechin and related polyphenols, their various functionalized derivatives, methods of making them, compositions containing these compounds, and methods of using them.)

1. Novel epicatechin-polyphenol analogues of formula (I):

wherein

A is independently deuterium, hydrogen, alkyl, F, Cl;

b is independently A OR hydroxy, OR¹¹、NR¹¹R¹²；

R¹To R¹⁰Independently of each other hydrogen, deuterium, NH₂F, Cl, hydroxy, alkoxy, lower acyclic OR cyclic alkyl, lower acyclic OR cyclic acyl, -CO-OR₁₁、-OCO-OR₁₁、-CO-NR₁₁R₁₂、-COR₁₁、-CR₁₁R₁₂、-O-CO-R₁₁、-CR₁₁R₁₂、-O-CO-NR₁₁R₁₂、OCONHCHR¹¹R¹²、-OCR₁₁R₁₂、-O-CO-R₁₁R₁₂-a CO-amino acid or-CO-hydroxy acid; which may optionally be substituted by lower alkyl, acyl, alkoxy, OR¹¹、NR¹¹R¹²、COOR¹¹、CONR¹¹R¹²、OCOR¹¹R¹²、OCONR¹¹R¹²、OSO₃R¹¹、OSO₂NR¹¹R¹²、NR¹¹SO₂NR¹²、NR¹¹SO₃R¹²Substitution;

when any two adjacent R¹To R¹⁰Is OH or NHR¹¹When it additionally passes CR¹¹R¹²、-(C＝O)_n、-CO(CH₂)_n-、-C＝S、C＝NR¹²or-OSO₃-are connected together; wherein n is 1 to 2;

R¹¹and R¹²Independently of one another hydrogen, OH, halogen, C_1-6Alkyl, aryl, alkaryl, arylalkyl, substituted alkyl which may be linear, branched or cyclic, C which may be linear, branched or cyclic_1-6Alkoxy radical, COOR₁₃，CH₂COOR₁₃，C(R¹³)₂OCOR¹³，C(R¹³)₂OCOOR¹³，C(R¹³)₂OCON(R¹³)₂，C(R¹³)₂N(R¹³)COOR¹³Or haloalkyl, aryl, substituted aryl, or R¹¹And R¹²Together with the atoms to which they may be attached form a 5 to 7 membered ring optionally incorporating one or two ring heteroatoms selected from N, O or S, which is optionally substituted with further substituents;

or A and R⁶Oximes can be formed;

R¹³independently is hydrogen, lower straight or branched chain alkyl, substituted or unsubstituted aryl or benzyl when two R are¹³Groups, when present on the same atom, may be linked to form a 3 to 6 membered ring;

wherein the substitution at the pyran rings C2 and C3 is always cis (+) or cis (-) or a mixture of both, in other words, the absolute configuration at the pyran rings C2 and C3 may have RR or SS stereochemistry or a racemic mixture of RR and SS.

2. An analogue according to claim 1 and according to formula (II),

wherein

A is independently deuterium, hydrogen, alkyl, F, Cl;

b is independently A OR hydroxy, OR¹¹、NR¹¹R¹²；

R₁To R₇And R₉Independently H, D, NH₂F, Cl, hydroxy, -CO-OR₁₁、-CO-NR₁₁R₁₂、OCONHCHR¹¹R¹²、-COR₁₁、-CR₁₁R₁₂、-O-CO-R₁₁、-CR₁₁R₁₂、-O-CO-NR₁₁-R₁₂、-OCR₁₁R₁₂、-O-CO-R₁₁R₁₂；

R¹¹And R¹²Independently of one another hydrogen, OH, halogen, C_1-6Alkyl, aryl, alkaryl, arylalkyl, substituted alkyl which may be linear, branched or cyclic, C which may be linear, branched or cyclic_1-6Alkoxy radical, COOR₁₃，CH₂COOR₁₃，C(R¹³)₂OCOR¹³，C(R¹³)₂OCOOR¹³，C(R¹³)₂OCON(R¹³)₂，C(R¹³)₂N(R¹³)COOR¹³Or haloalkyl, aryl, substituted aryl, or R¹¹And R¹²Together with the atoms to which they may be attached form a 5 to 7 membered ring optionally incorporating one or two ring heteroatoms selected from N, O or S, which is optionally substituted with further substituents;

or A and R⁶Oximes can be formed;

R¹³independently is hydrogen, lower straight or branched chain alkyl, substituted or unsubstituted aryl or benzyl when two R are¹³Groups, when present on the same atom, may be linked to form a 3 to 6 membered ring;

wherein the substitution at the pyran rings C2 and C3 is always cis (+) or cis (-) or a mixture of both, in other words, the absolute configuration at the pyran rings C2 and C3 may have RR or SS stereochemistry or a racemic mixture of RR and SS.

3. The compound of claim 1, wherein the compound is any one of:

(R, E) -2- (3, 4-dihydroxyphenyl) -5, 7-dihydroxychroman-3-one oxime;

cis (±) 3-hydroxytryptan-2-yl) benzene-1, 2-diol;

cis (±)2- (3, 4-dihydroxyphenyl) chromane-3, 7-diol;

cis (±)2- (4-hydroxyphenyl) chromane-3, 7-diol;

v. cis (±)2- (3-hydroxyphenyl) chromane-3, 5-diol;

cis (±)2- (4-hydroxyphenyl) chromane-3, 5-diol;

cis (±)2- (3-hydroxyphenyl) chromane-3, 7-diol;

cis (±)2- (4-hydroxyphenyl) chromane-3, 5, 7-triol;

(2R, 3S) -2- (3, 4-dihydroxyphenyl) -3-aminochroman-5, 7-diol;

x. (2R, 3R) -2- (3, 4-dihydroxyphenyl) -3-fluorochromane-5, 7-diol;

cis (±)2- (3-hydroxyphenyl) chromane-3-ol;

cis (±)2- (4-hydroxyphenyl) chromane-3-ol;

cis (±)2- (3, 4-dihydroxyphenyl) chromane-3, 5-diol;

cis (±)2- (3-hydroxyphenyl) chromane-3, 5, 7-triol;

XV. cis (±) 2-phenylchromane-3, 5, 7-triol;

cis (±)2- (4-hydroxyphenyl) -3-methoxychroman-7-ol;

cis (±)2- (3-methoxyphenyl) chromane-3, 7-diol;

cis (±)2- (3-hydroxyphenyl) -7-methoxychroman-3-ol;

cis (±) 7-methoxy-2- (3-methoxyphenyl) chroman-3-ol;

XX. cis (±)3, 7-dimethoxy-2- (4-methoxyphenyl) chromane;

xxi, cis (±) 7-hydroxy-2- (4-hydroxyphenyl) chroman-3-yl acetate;

xxii, cis (±)4- (3, 7-dihydroxychroman-2-yl) phenylacetate;

xxiii cis (±) 3-hydroxy-2- (3-hydroxyphenyl) chroman-7-yl acetate;

xxiv, cis (±)4- (7-acetoxy-3-hydroxytryptan-2-yl) phenylacetate;

xxv, cis (±)2- (4-acetoxyphenyl) chromane-3, 7-diyl diacetate;

xxvi.2- (3-methoxy-4-methylphenyl) chromane-3, 7-diol;

xxvii.2- (3-hydroxy-4-methylphenyl) chromane-3, 7-diol;

xxviii.2- (4-fluoro-3-methoxyphenyl) chromane-3, 7-diol;

xxix.2- (4-fluoro-3-hydroxyphenyl) chromane-3, 7-diol;

xxx.2- (3-hydroxyphenyl) -3-propoxychroman-7-ol;

xxxi, cis (±)2- (3, 4-dihydroxy-2-methylphenyl) chromane-3, 5, 7-triol;

xxxii, cis (±)2- (2-fluoro-3, 4-dihydroxyphenyl) chromane-3, 5, 7-triol;

xxxiii. cis (±)2- (2-fluoro-4, 5-dihydroxyphenyl) chromane-3, 5, 7-triol;

xxxiv, cis (±)2- (3-fluoro-4-hydroxyphenyl) chromane-3, 5, 7-triol;

xxxv, cis (±) (2- (3, 4-dihydroxy-5-methylphenyl) chromane-3, 5, 7-triol;

XXXVI (2R, 3R) -2- (3, 4-dihydroxyphenyl) chromane-4, 4-d2-3, 5, 7-triol;

XXXVII (2R, 3R) -2- (3, 4-dihydroxyphenyl) chromane-2-d-3, 5, 7-triol;

XXXVIII (2R, 3R) -2- (3, 4-dihydroxyphenyl) chromane-2, 4-d2-3, 5, 7-triol;

XXXIX (2R, 3R) -2- (3, 4-dihydroxyphenyl) -5, 7-dihydroxychroman-3-yl isobutyl carbonate;

XL. tert-butylneopentyl (4- ((2R, 3R) -3, 5, 7-trihydroxychroman-2-yl) -1, 2-phenylene) bis (carbonate);

xli.3- ((((2R, 3R) -2- (3, 4-dihydroxyphenyl) -5, 7-dihydroxychroman-3-yl) oxy) carbonyl) -1-methylpyridin-1-ium;

xlii 2-hydroxy-5- ((2R, 3R) -3, 5, 7-trihydroxychroman-2-yl) phenyl neopentyl carbonate;

xliii 2-hydroxy-4- ((2R, 3R) -3, 5, 7-trihydroxychroman-2-yl) phenyloctanoate;

xliv.4- ((2R, 3R) -3, 5, 7-trihydroxychroman-2-yl) -1, 2-phenylenebis (isopropyl carbamate);

XLV (2R, 3R) -2- (3, 4-dihydroxyphenyl) -5, 7-dihydroxychroman-3-yl neopentyl carbonate;

XLVI (2R, 3R) -2- (3, 4-dihydroxyphenyl) -5, 7-dihydroxychroman-3-yl-isopropyl carbamate;

XLVII (2R, 3R) -2- (3, 4-dihydroxyphenyl) -5, 7-dihydroxychroman-3-yl dimethylcarbamate;

xlviii dibenzyl (4- ((2R, 3R) -3, 5, 7-trihydroxychroman-2-yl) -1, 2-phenylene) bis (carbonate);

xlix dimethyl (4- ((2R, 3R) -3, 5, 7-trihydroxychroman-2-yl) -1, 2-phenylene) bis (carbonate);

l. (2R, 3R) -2- (3, 4-dihydroxyphenyl) -3-hydroxytryptane-5, 7-diyldiisobutylbis (carbonate);

li.4- ((2R, 3R) -5, 7-bis ((benzylcarbamoyl) oxy) -3-hydroxychroman-2-yl) -1, 2-phenylenebis (benzylcarbamate);

lii. dibenzyl (4- ((2R, 3R) -5, 7-bis (((benzyloxy) carbonyl) oxy) -3-hydroxytryptan-2-yl) -1, 2-phenylene) bis (carbonate);

LIII (2R, 3R) -2- (3, 4-dihydroxyphenyl) -5, 7-dihydroxychroman-3-ylethylcarbonate;

LIV (2R, 3R) -2- (3, 4-dihydroxyphenyl) -3-hydroxytryptane-5, 7-diyldiisobutylbis (carbonate);

LV (2R, 3R) -2- (3, 4-dihydroxyphenyl) -5, 7-dihydroxychroman-3-yl isopropyl carbonate;

lvi methyl ((((2R, 3R) -2- (3, 4-dihydroxyphenyl) -5, 7-dihydroxychroman-3-yl) oxy) carbonyl) glycinate;

LVII (2R, 3R) -2- (3, 4-dihydroxyphenyl) -3-hydroxytryptane-5, 7-diyldiethylbis (carbonate);

LVIII (2R, 3R) -2- (3, 4-dihydroxyphenyl) -3-hydroxytryptane-5, 7-diyldimethyl bis (carbonate);

lix.4- ((2R, 3R) -3, 5, 7-trihydroxychroman-2-yl) -1, 2-phenylenebis (benzylcarbamate);

LX. dibenzyl (4- ((2R, 3R) -3-hydroxy-5, 7-bis ((isobutoxycarbonyl) oxy) chroman-2-yl) -1, 2-phenylene) bis (carbonate);

(2R, 3R) -2- (3, 4-dihydroxyphenyl) -3, 7-dihydroxychroman-5-ylheptanoate;

(2R, 3R) -2- (3, 4-dihydroxyphenyl) -3, 5-dihydroxychroman-7-ylheptanoate;

LXIII (2R, 3R) -2- (3, 4-dihydroxyphenyl) -3-hydroxytryptane-5, 7-diyl diheptanoate;

LXIV (2R, 3R) -2- (3, 4-dihydroxyphenyl) -3, 7-dihydroxychroman-5-yl octanoate;

LXV (2R, 3R) -2- (3, 4-dihydroxyphenyl) -3, 5-dihydroxychroman-7-yl octanoate;

lxvi dibenzyl (4- ((2R, 3R) -3-hydroxy-5, 7-bis ((methoxycarbonyl) oxy) chroman-2-yl) -1, 2-phenylene) bis (carbonate);

LXVII (2R, 3R) -7-methoxy-2- (3-methoxyphenyl) -3-propoxychroman;

(2R, 3R) -2- (3-methoxyphenyl) -3-propoxychroman-7-ol;

(2R, 3R) -2- (3-hydroxy-4-methylphenyl) chromane-3, 7-diol;

(2R, 3R) -7-methoxy-2- (4-methoxyphenyl) chroman-3-ol;

LXXI (2R, 3R) -2- (3, 4-dihydroxyphenyl) -5, 7-dihydroxychroman-3-yl nicotinate;

lxxii. dineopentyl (4- ((2R, 3R) -3, 5, 7-trihydroxychroman-2-yl) -1, 2-phenylene) bis (carbonate);

tert-butyl ((2R, 3R) -2- (3, 4-dihydroxyphenyl) -5, 7-dihydroxychroman-3-yl) carbonate lxxiii;

(2R, 3R) -2- (3, 4-dihydroxyphenyl) -5, 7-dihydroxychroman-3-yl (R) -3-hydroxybutyrate;

lxxv, diisopropyl (4- ((2R, 3R) -3, 5, 7-trihydroxychroman-2-yl) -1, 2-phenylene) bis (carbonate);

dineopentyl (4- ((2R, 3R) -3, 5, 7-trihydroxychroman-2-yl) -1, 2-phenylene) bis (carbonate).

4. The compound of claim 1, which is present as a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

5. A process for the preparation of a novel polyphenol analogue of claim 1 comprising the steps of:

I. protecting a hydroxyl group of acetophenone of formula 1 with a protecting agent in the presence of a base and a solvent;

reacting the compound of formula 2 obtained from step (i) with the compound of formula 3 in the presence of a base and a solvent to obtain the chalcone of formula 4;

converting the chalcone of formula 4 to compound 5 in the presence of an epoxidizing agent or a base;

optionally protecting the hydroxy group of the compound obtained in step III;

reducing the compound of step III or step IV in the presence of a chiral/achiral reducing agent to obtain a mixture of 4H-chromene and 2H-chromene compounds of formula 6 and formula 7;

deprotecting the 4H-chromene and 2H-chromene compounds obtained in step V to obtain the polyphenol analogue of the invention.

6. A process for the preparation of a novel polyphenol analogue of claim 1 comprising the steps of:

I. protecting the hydroxyl group of the flavan-3-ol of formula 8 with a protecting agent;

treating the protected flavan-3-ol of step I with an oxidizing agent to obtain a compound of formula 9;

functionalizing the oxo group of compound 9 to obtain a compound of formula 10;

deprotecting the compound obtained in step III to obtain a polyphenol analogue of the invention.

7. A process for the preparation of a novel polyphenol analogue of claim 1 comprising the steps of:

i. optionally protecting the hydroxyl group of the flavan-3-ol of formula 11 with a protecting agent;

functionalizing the protected/unprotected hydroxyl group of compound 11 to obtain a compound of formula 12;

deprotecting the compound obtained in step ii to obtain a polyphenol analogue of the invention.

8. A process for the preparation of a novel polyphenol analogue of claim 1 comprising the steps of:

i. treating the chalcone of formula 4 with a reducing agent in the presence of a solvent at a temperature from ambient temperature to reflux temperature to obtain a compound of formula 13;

converting the compound of formula 13 to the compound of formula 14 in the presence of a hydroxylating agent with or without a chiral co-catalyst and a suitable solvent at a temperature from ambient to reflux;

functionalizing a hydroxyl group of the compound of formula 14 with a suitable reagent in the presence of a suitable solvent to obtain a compound of formula 15;

treating the compound of formula 14 with an oxidizing agent to obtain a compound of formula 16;

reducing the compound obtained from step iv in the presence of a chiral reducing agent at a temperature of-78 ℃ to room temperature in the presence of a suitable solvent to obtain the polyphenol analogue.

9. A pharmaceutical composition comprising a compound as claimed in any of claims 1 to 3, together with a pharmaceutically or nutraceutically acceptable excipient.

10. A compound according to claim 1 for use in the treatment of a disease associated with mitochondrial dysfunction.

11. The compound of claim 1 for use as a supplement and medicament to meet increased energy needs in meeting the muscle needs of athletes/exercise muscles.

12. A method of testing a compound for AMPK activation potential, comprising:

a. liver cancer (Hep G2) hepatocytes were maintained in T75 culture flasks containing 25mM DMEM + 10% fetal bovine serum; upon reaching 70% to 80% confluence, cells were seeded at a density of 40,000 cells/well in 25mM DMEM + 10% FCS medium in 96-well plates, which were then plated at 37 ℃ with 5% CO₂Incubating for 24 hours;

b. various concentrations of the compounds were prepared in DMSO, diluted to the desired concentration with medium and incubated with 5% CO at 37 deg.C₂Incubation; cells were fixed with 4% formaldehyde for 30 minutes and washed three times with PBS containing 0.1% Triton X-100 at room temperature;

c. with 1% H in PBS-T₂O₂(0.1% Tween 20) endogenous peroxidase was quenched for 30 minutes and washed three times in PBS-T; cells were blocked with 1% BSA in PBS-T for 1 hour; cells were incubated overnight at 4 ℃ with a 1: 1000 dilution of primary antibody (phospho-AMPK α (Thrl72) rabbit mAb, Cell Signaling) in PBS-T containing 5% BSA;

d. cells were washed three times with PBS-T over 5 minutes and incubated with a 1: 1000 dilution of secondary antibody (anti-rabbit IgG, HRP-binding antibody, Cell Signaling) in PBS-T containing 1% BSA for 1 hour at room temperature; cells were washed three times with PBS-T within 5 minutes; cells were incubated with 100. mu.l TMB substrate solution for 30 min and 100. mu.l 2N H₂SO₄Stopping the reaction;

e. plates were read at 450nM using an ELISA plate reader and absorbance was recorded,% activity was calculated using DMSO control as 100%.

Technical Field

The present invention provides novel analogues of epicatechin and related polyphenols, their various functionalized derivatives, methods of making them, compositions containing these compounds, and methods of using them.

Background

Polyphenolic natural products are currently of interest due to their various biological activities, their presence in food, and their consequent relevance to human health. The polyphenol natural products have two or more hydroxyl groups on the aromatic ring thereof.

Representative examples include: (-) -epicatechin ((-) -epifzelechin), (+) -catechin, (-) -epicatechin, (-) -gallocatechin, (-) -epigallocatechin, their respective 3-gallate esters and two 3- (30-methyl) -gallate esters, which are collectively referred to herein as "catechins". (+) -catechin, (-) -catechin, (+) -epicatechin and (-) -epicatechin are flavan-3-ols.

These flavonols are present in the human diet chocolate, fruits, vegetables and wine and have found their use in the treatment of: acute coronary syndromes, including but not limited to myocardial infarction and angina pectoris; acute ischemic events in other organs and tissues, renal injury, renal ischemia, and diseases of the aorta and its branches; injuries resulting from medical interventions, including but not limited to Coronary Artery Bypass Grafting (CABG) and aneurysm repair; cancer; as well as metabolic diseases, diabetes and other such diseases.

Although such polyphenols (including catechins and epicatechins) are widely used, they have some disadvantages such as low potency, undesirable pharmacokinetic and pharmacokinetic profiles. Thus, there is a need to improve the potency, pharmacodynamic and pharmacokinetic profile of polyphenols.

One way to achieve this effect is to obtain new analogues of epicatechin. Analogs of polyphenols may be used to reduce or eliminate metabolites, increase the half-life of the parent drug, reduce the number of administrations required to achieve a desired effect, and/or create a more efficacious and/or safe drug.

Object of the Invention

The object of the present invention is to provide novel polyphenol analogues and a process for their preparation.

Disclosure of Invention

The present invention relates to novel polyphenol analogues of formula (I).

Wherein the content of the first and second substances,

a is independently deuterium, hydrogen, alkyl, F, Cl;

b is independently A OR hydroxy, OR¹¹、NR¹¹R¹²；

R¹To R¹⁰Independently of each other hydrogen, deuterium, NH₂F, Cl, hydroxy, alkoxy, lower acyclic OR cyclic alkyl, lower acyclic OR cyclic acyl, -CO-OR₁₁、-OCO-OR₁₁、 -CO-NR₁₁R₁₂、-COR₁₁、-CR₁₁R₁₂、-O-CO-R₁₁、-CR₁₁R₁₂、-O-CO-NR₁₁R₁₂、 OCONHCHR¹¹R¹²、-OCR₁₁R₁₂、-O-CO-R₁₁R₁₂-a CO-amino acid or-CO-hydroxy acid; which may optionally be substituted by lower alkyl, acyl, alkoxy, OR¹¹、NR¹¹R¹²、COOR¹¹、 CONR¹¹R¹²、OCOR¹¹R¹²、OCONR¹¹R¹²、OSO₃R¹¹、OSO₂NR¹¹R¹²、 NR¹¹SO₂NR¹²、NR¹¹SO₃R¹²Substitution;

when any two adjacent R¹To R¹⁰Is OH or NHR¹¹When it is additionally passed through CR¹¹R¹²、-(C＝O)_n、-CO(CH₂)_n-、-C＝S、C＝NR¹²or-OSO₃-are connected together; wherein n is 1 to 2;

R¹¹and R¹²Independently of one another hydrogen, OH, halogen, C_1-6Alkyl, aryl, alkaryl, arylalkyl, substituted alkyl which may be linear, branched or cyclic, C which may be linear, branched or cyclic_1-6Alkoxy radical, COOR₁₃，CH₂COOR₁₃，C(R¹³)₂OCOR¹³，C(R¹³)₂OCOOR¹³， C(R¹³)₂OCON(R¹³)₂，C(R¹³)₂N(R¹³)COOR¹³Or haloalkyl, aryl, substituted aryl, or R¹¹And R¹²Together with the atoms to which they may be attached form a 5 to 7 membered ring optionally incorporating one or two ring heteroatoms selected from N, O or S, which is optionally substituted with further substituents;

or A and R⁶Oximes can be formed;

R¹³independently is hydrogen, lower straight or branched chain alkyl, substituted or unsubstituted aryl or benzyl when two R are¹³Groups, when present on the same atom, may be linked to form a 3 to 6 membered ring;

wherein the substitution at the pyran rings C2 and C3 is always cis (+) or cis (-) or a mixture of both. In other words, the absolute configuration at the pyran rings C2 and C3 may have RR or SS stereochemistry or a racemic mixture of RR and SS.

Detailed Description

Accordingly, the present invention relates to novel polyphenol analogues of formula (I).

Wherein the content of the first and second substances,

a is independently deuterium, hydrogen, alkyl, F, Cl;

b is independently A OR hydroxy, OR¹¹、NR¹¹R¹²；

R¹To R¹⁰Independently of each other hydrogen, deuterium, NH₂F, Cl, hydroxy, alkoxy, lower acyclic OR cyclic alkyl, lower acyclic OR cyclic acyl, -CO-OR₁₁、-OCO-OR₁₁、 -CO-NR₁₁R₁₂、-COR₁₁、-CR₁₁R₁₂、-O-CO-R₁₁、-CR₁₁R₁₂、-O-CO-NR₁₁R₁₂、 OCONHCHR¹¹R¹²、-OCR₁₁R₁₂、-O-CO-R₁₁R₁₂-a CO-amino acid or-CO-hydroxy acid; which may optionally be substituted by lower alkyl, acyl, alkoxy, OR¹¹、NR¹¹R¹²、COOR¹¹、 CONR¹¹R¹²、OCOR¹¹R¹²、OCONR¹¹R¹²、OSO₃R¹¹、OSO₂NR¹¹R¹²、 NR¹¹SO₂NR¹²、NR¹¹SO₃R¹²Substitution;

when any two adjacent R¹To R⁶Is OH or NHR¹¹Which may additionally pass CR¹¹R¹²、-(C＝O)_n、-CO(CH₂)_n-、-C＝S、C＝NR¹²or-OSO₃-are connected together; wherein n is 1 to 2.

R¹¹And R¹²Independently are hydrogen, OH,halogen, C_1-6Alkyl, aryl, alkaryl, arylalkyl, substituted alkyl which may be linear, branched or cyclic, C which may be linear, branched or cyclic_1-6Alkoxy radical, COOR₁₃，CH₂CooR₁₃，C(R¹³)₂OCOR¹³，C(R¹³)₂OCOOR¹³， C(R¹³)₂OCON(R¹³)₂，C(R¹³)₂N(R¹³)COOR¹³Or haloalkyl, aryl, substituted aryl, or R¹¹And R¹²Together with the atoms to which they may be attached form a 5 to 7 membered ring optionally incorporating one or two ring heteroatoms selected from N, o or S, which is optionally substituted with further substituents;

or A and R⁶Oximes can be formed;

R¹³independently is hydrogen, lower straight or branched chain alkyl, substituted or unsubstituted aryl or benzyl when two R are¹³Groups, when present on the same atom, may be linked to form a 3 to 6 membered ring;

wherein the substitution at the pyran rings C2 and C3 is always cis (+) or cis (-) or a mixture of both. In other words, the absolute configuration at the pyran rings C2 and C3 may have RR or SS stereochemistry or a racemic mixture of RR and SS.

The novel polyphenol analogues of the invention of formula I may also be represented by compounds of formula II;

wherein

A is independently deuterium, hydrogen, alkyl, F, Cl;

b is independently A OR hydroxy, OR¹¹、NR¹¹R¹²；

R₁To R₇And R₉Independently H, D, NH₂F, Cl, hydroxy, -CO-OR₁₁、 -CO-NR₁₁R₁₂、OCONHCHR¹¹R¹²、-COR₁₁、-CR₁₁R₁₂、-O-CO-R₁₁、 -CR₁₁R₁₂、-O-Co-NR₁₁-R₁₂、-OCR₁₁R₁₂、-O-CO-R₁₁R₁₂；

R¹¹And R¹²Independently of one another hydrogen, OH, halogen, C_1-6Alkyl, aryl, alkaryl, arylalkyl, substituted alkyl which may be linear, branched or cyclic, C which may be linear, branched or cyclic_1-6Alkoxy radical, COOR₁₃，CH₂COOR₁₃，C(R¹³)₂OCOR¹³，C(R¹³)₂OCOOR¹³， C(R¹³)₂OCON(R¹³)₂，C(R¹³)₂N(R¹³)COOR¹³Or haloalkyl, aryl, substituted aryl, or R¹¹And R¹²Together with the atoms to which they may be attached form a 5 to 7 membered ring optionally incorporating one or two ring heteroatoms selected from N, o or S, which is optionally substituted with further substituents;

or A and R⁶Oximes can be formed;

R¹³independently is hydrogen, lower straight or branched chain alkyl, substituted or unsubstituted aryl or benzyl when two R are¹³Groups, when present on the same atom, may be linked to form a 3 to 6 membered ring;

wherein the substitution at the pyran rings C2 and C3 is always cis (+) or cis (-) or a mixture of both. In other words, the absolute configuration at the pyran rings C2 and C3 may have RR or SS stereochemistry or a racemic mixture of RR and SS.

Compounds of the invention

The compounds of the present invention are shown by way of example and not limitation as provided in table 1.

Table 1: exemplary Compounds of the invention

The compounds of the present invention include:

(R, E) -2- (3, 4-dihydroxyphenyl) -5, 7-dihydroxychroman-3-one oxime;

cis (±) 3-hydroxytryptan-2-yl) benzene-1, 2-diol;

cis (±)2- (3, 4-dihydroxyphenyl) chromane-3, 7-diol;

cis (±)2- (4-hydroxyphenyl) chromane-3, 7-diol;

v. cis (±)2- (3-hydroxyphenyl) chromane-3, 5-diol;

cis (±)2- (4-hydroxyphenyl) chromane-3, 5-diol;

cis (±)2- (3-hydroxyphenyl) chromane-3, 7-diol;

cis (±)2- (4-hydroxyphenyl) chromane-3, 5, 7-triol;

(2R, 3S) -2- (3, 4-dihydroxyphenyl) -3-aminochroman-5, 7-diol;

x. (2R, 3R) -2- (3, 4-dihydroxyphenyl) -3-fluorochromane-5, 7-diol;

cis (±)2- (3-hydroxyphenyl) chromane-3-ol;

cis (±)2- (4-hydroxyphenyl) chromane-3-ol;

cis (±)2- (3, 4-dihydroxyphenyl) chromane-3, 5-diol;

cis (±)2- (3-hydroxyphenyl) chromane-3, 5, 7-triol;

XV. cis (±) 2-phenylchromane-3, 5, 7-triol;

cis (±)2- (4-hydroxyphenyl) -3-methoxychroman-7-ol;

cis (±)2- (3-methoxyphenyl) chromane-3, 7-diol;

cis (±)2- (3-hydroxyphenyl) -7-methoxychroman-3-ol;

cis (±) 7-methoxy-2- (3-methoxyphenyl) chroman-3-ol;

XX. cis (±)3, 7-dimethoxy-2- (4-methoxyphenyl) chromane;

xxi, cis (±) 7-hydroxy-2- (4-hydroxyphenyl) chroman-3-yl acetate;

xxii, cis (±)4- (3, 7-dihydroxychroman-2-yl) phenylacetate;

xxiii cis (±) 3-hydroxy-2- (3-hydroxyphenyl) chroman-7-yl acetate;

xxiv, cis (±)4- (7-acetoxy-3-hydroxytryptan-2-yl) phenylacetate;

xxv, cis (±)2- (4-acetoxyphenyl) chromane-3, 7-diyl diacetate;

xxvi.2- (3-methoxy-4-methylphenyl) chromane-3, 7-diol;

xxvii.2- (3-hydroxy-4-methylphenyl) chromane-3, 7-diol;

xxviii.2- (4-fluoro-3-methoxyphenyl) chromane-3, 7-diol;

xxix.2- (4-fluoro-3-hydroxyphenyl) chromane-3, 7-diol;

xxx.2- (3-hydroxyphenyl) -3-propoxychroman-7-ol;

xxxi, cis (±)2- (3, 4-dihydroxy-2-methylphenyl) chromane-3, 5, 7-triol;

xxxii, cis (±)2- (2-fluoro-3, 4-dihydroxyphenyl) chromane-3, 5, 7-triol;

xxxiii. cis (±)2- (2-fluoro-4, 5-dihydroxyphenyl) chromane-3, 5, 7-triol;

xxxiv, cis (±)2- (3-fluoro-4-hydroxyphenyl) chromane-3, 5, 7-triol;

xxxv, cis (±) (2- (3, 4-dihydroxy-5-methylphenyl) chromane-3, 5, 7-triol;

XXXVI (2R, 3R) -2- (3, 4-dihydroxyphenyl) chromane-4, 4-d2-3, 5, 7-triol;

XXXVII (2R, 3R) -2- (3, 4-dihydroxyphenyl) chromane-2-d-3, 5, 7-triol;

XXXVIII (2R, 3R) -2- (3, 4-dihydroxyphenyl) chromane-2, 4-d2-3, 5, 7-triol;

XXXIX (2R, 3R) -2- (3, 4-dihydroxyphenyl) -5, 7-dihydroxychroman-3-yl isobutyl carbonate;

XL. tert-butylneopentyl (4- ((2R, 3R) -3, 5, 7-trihydroxychroman-2-yl) -1, 2-phenylene) bis (carbonate);

xli.3- ((((2R, 3R) -2- (3, 4-dihydroxyphenyl) -5, 7-dihydroxychroman-3-yl) oxy) carbonyl) -1-methylpyridin-1-ium;

xlii 2-hydroxy-5- ((2R, 3R) -3, 5, 7-trihydroxychroman-2-yl) phenyl neopentyl carbonate;

xliii 2-hydroxy-4- ((2R, 3R) -3, 5, 7-trihydroxychroman-2-yl) phenyloctanoate;

xliv.4- ((2R, 3R) -3, 5, 7-trihydroxychroman-2-yl) -1, 2-phenylenebis (isopropyl carbamate);

XLV (2R, 3R) -2- (3, 4-dihydroxyphenyl) -5, 7-dihydroxychroman-3-yl neopentyl carbonate;

XLVI (2R, 3R) -2- (3, 4-dihydroxyphenyl) -5, 7-dihydroxychroman-3-yl-isopropyl carbamate;

XLVII (2R, 3R) -2- (3, 4-dihydroxyphenyl) -5, 7-dihydroxychroman-3-yl dimethylcarbamate;

xlviii dibenzyl (4- ((2R, 3R) -3, 5, 7-trihydroxychroman-2-yl) -1, 2-phenylene) bis (carbonate);

xlix dimethyl (4- ((2R, 3R) -3, 5, 7-trihydroxychroman-2-yl) -1, 2-phenylene) bis (carbonate);

l. (2R, 3R) -2- (3, 4-dihydroxyphenyl) -3-hydroxytryptane-5, 7-diyldiisobutylbis (carbonate);

li.4- ((2R, 3R) -5, 7-bis ((benzylcarbamoyl) oxy) -3-hydroxychroman-2-yl) -1, 2-phenylenebis (benzylcarbamate);

lii. dibenzyl (4- ((2R, 3R) -5, 7-bis (((benzyloxy) carbonyl) oxy) -3-hydroxytryptan-2-yl) -1, 2-phenylene) bis (carbonate);

LIII (2R, 3R) -2- (3, 4-dihydroxyphenyl) -5, 7-dihydroxychroman-3-ylethylcarbonate;

LIV (2R, 3R) -2- (3, 4-dihydroxyphenyl) -3-hydroxytryptane-5, 7-diyldiisobutylbis (carbonate);

LV (2R, 3R) -2- (3, 4-dihydroxyphenyl) -5, 7-dihydroxychroman-3-yl isopropyl carbonate;

lvi methyl ((((2R, 3R) -2- (3, 4-dihydroxyphenyl) -5, 7-dihydroxychroman-3-yl) oxy) carbonyl) glycinate;

LVII (2R, 3R) -2- (3, 4-dihydroxyphenyl) -3-hydroxytryptane-5, 7-diyldiethylbis (carbonate);

LVIII (2R, 3R) -2- (3, 4-dihydroxyphenyl) -3-hydroxytryptane-5, 7-diyldimethyl bis (carbonate);

lix.4- ((2R, 3R) -3, 5, 7-trihydroxychroman-2-yl) -1, 2-phenylenebis (benzylcarbamate);

LX. dibenzyl (4- ((2R, 3R) -3-hydroxy-5, 7-bis ((isobutoxycarbonyl) oxy) chroman-2-yl) -1, 2-phenylene) bis (carbonate);

(2R, 3R) -2- (3, 4-dihydroxyphenyl) -3, 7-dihydroxychroman-5-ylheptanoate;

(2R, 3R) -2- (3, 4-dihydroxyphenyl) -3, 5-dihydroxychroman-7-ylheptanoate;

LXIII (2R, 3R) -2- (3, 4-dihydroxyphenyl) -3-hydroxytryptane-5, 7-diyl diheptanoate;

LXIV (2R, 3R) -2- (3, 4-dihydroxyphenyl) -3, 7-dihydroxychroman-5-yl octanoate;

LXV (2R, 3R) -2- (3, 4-dihydroxyphenyl) -3, 5-dihydroxychroman-7-yl octanoate;

lxvi dibenzyl (4- ((2R, 3R) -3-hydroxy-5, 7-bis ((methoxycarbonyl) oxy) chroman-2-yl) -1, 2-phenylene) bis (carbonate);

LXVII (2R, 3R) -7-methoxy-2- (3-methoxyphenyl) -3-propoxychroman;

(2R, 3R) -2- (3-methoxyphenyl) -3-propoxychroman-7-ol;

(2R, 3R) -2- (3-hydroxy-4-methylphenyl) chromane-3, 7-diol;

(2R, 3R) -7-methoxy-2- (4-methoxyphenyl) chroman-3-ol;

LXXI (2R, 3R) -2- (3, 4-dihydroxyphenyl) -5, 7-dihydroxychroman-3-yl nicotinate;

lxxii. dineopentyl (4- ((2R, 3R) -3, 5, 7-trihydroxychroman-2-yl) -1, 2-phenylene) bis (carbonate);

tert-butyl ((2R, 3R) -2- (3, 4-dihydroxyphenyl) -5, 7-dihydroxychroman-3-yl) carbonate lxxiii;

(2R, 3R) -2- (3, 4-dihydroxyphenyl) -5, 7-dihydroxychroman-3-yl (R) -3-hydroxybutyrate;

lxxv, diisopropyl (4- ((2R, 3R) -3, 5, 7-trihydroxychroman-2-yl) -1, 2-phenylene) bis (carbonate);

dineopentyl (4- ((2R, 3R) -3, 5, 7-trihydroxychroman-2-yl) -1, 2-phenylene) bis (carbonate).

In another embodiment, the invention also discloses a process for preparing compounds of formula (I) and formula (II),

synthesis scheme 1:

scheme 1 includes the following steps:

step 1: protecting a hydroxyl group of the acetophenone of formula 1 optionally with a protecting agent in the presence of a base and a solvent;

the protecting agent is preferably a benzylating agent (e.g. benzyl bromide) and the compound of formula 1 can be converted to a compound having a protected hydroxy group at ambient temperature in the presence of a suitable base (e.g. potassium carbonate) in the presence of a suitable solvent (e.g. dimethylformamide or acetone). Further conversion of the protected compound to the chalcone of formula [3] in the presence of a suitable base (e.g. NaOH, KOH or piperidine) in the presence of a suitable solvent (e.g. MeOH, EtOH, THF) at ambient temperature;

step 2: in the presence of a suitable base (e.g., NaOH), in the presence of a suitable epoxidizing agent (e.g., hydrogen peroxide) and in the presence of a suitable solvent (e.g., MEOH or EtOH), formula [3 [)]The chalcone of (a) may be converted into a compound [ 4]]。

Step 3: formula [4]The compound(s) can be converted to the compound having a protected hydroxyl group [ 5] by treating with a protecting agent to protect the hydroxyl group, if present, preferably with a benzylating agent (e.g., benzyl bromide) at ambient temperature in the presence of a suitable base (e.g., potassium carbonate) in the presence of a suitable solvent (e.g., dimethylformamide or acetone)]；

Step 4: compound [ 5] in a solvent (such as THF or ether) in the presence of a chiral/achiral reducing agent (such as lithium aluminum hydride/deuteride) at temperatures from ambient to reflux]Can be converted into a compound [ 6]]And compound [7]A mixture of (a).

Step 5: after deprotection, the compound [6]And compound [7]Can be converted into a compound [ 8]]And compound [9]. When the hydrogenation is carried out in the presence of palladium on carbon in the presence of a hydrogen atmosphere or palladium hydroxide at a temperature of from ambient to 60 ℃, the 4H-chromene and 2H-chromene compounds obtained in step 4 are converted into the polyphenol analogue of the present invention.

Synthesis scheme 2:

scheme 2 includes the following steps:

step 1: chalcone 3 (which can be synthesized as described in scheme 1) is treated with a reducing agent (such as NaBH) in the presence of a suitable solvent (such as EtOH or MeOH) at temperatures ranging from ambient to reflux₄) After treatment, it can be converted into 10.

Step 2: at ambient to reflux temperature in a suitable reagent (e.g. OsO)₄) In the presence or absence of a chiral cocatalyst (e.g., AD-mix-. alpha.or AD-mix-. beta.) in a suitable solvent (II)Such as THF), compound 10 can be converted to a compound of formula 11.

Step 3: when using a suitable reducing agent (e.g., NaCNBH) in the presence of a suitable solvent (e.g., AcOH or THF) at ambient temperature₃) Upon treatment, compound 11 can be converted to compound 12.

Step 4: compound 12 can be converted to compound 13 in the presence of a suitable oxidant, such as dess-martin periodinane, in the presence of a suitable solvent, such as THF or DCM.

Step 5: compound [13] in the presence of a suitable reducing agent, such as lithium tri-sec-butylborohydride (l-selectride), in the presence of a suitable solvent, such as THF, at a temperature of-78 deg.C to room temperature]Can be converted into compound 8.

Synthesis scheme 3:

any flavan-3-ols (12) (such as catechins) with or without suitable protecting groups (e.g., benzyl on the phenolic hydroxyl group) may be converted to compounds [13] in the presence of a suitable oxidizing agent (such as dess-martin periodinane) in the presence of a suitable solvent (such as THF or DCM). Compound [13] can be further functionalized to compound 14 with or without diastereoselectivity using different transformations of the keto group known in the literature, such as, but not limited to, cyanohydrin, oxime synthesis or halogenation, or when treated with different Grignard reagents to obtain tertiary alcohols.

Synthesis scheme 4:

any flavan-3-ols (15) (such as epicatechin) with or without suitable protecting groups (e.g., benzyl on phenolic hydroxyl group) may be functionalized to compounds of formula [16] in the presence of a suitable solvent (such as THF, DCM), in the presence of a suitable nucleophile such as an alkylating agent (such as alkyl iodide or alkyl bromide) or an acylating agent (such as acetyl chloride or alkyl chloroformate reagent) in the presence of a suitable base (such as NaH, pyridine). The protecting group (if present) may then be removed or retained to provide the final compound.

Synthesis scheme 5:

in a suitable reducing agent (e.g., NaCNBD)₄) Any flavan-3-ol intermediate (e.g., anthocyanidin [17 ]) with or without a suitable protecting group (e.g., benzyl on phenolic hydroxyl group) in the presence of a suitable solvent (e.g., THF or DCM)]) Can be converted into a compound [18A ]]And the compound [18B]. When using Pd (OH) under hydrogen atmosphere₂Upon treatment, Compound [18A ]]And the compound [18B]Further reduction and deprotection can be carried out in a single step to obtain the final product with or without diastereoselectivity.

It is submitted that the synthetic schemes disclosed herein are not intended to limit the scope of the invention, but are intended as representative general synthetic schemes for synthesizing all analogs of the invention.

Salts and isomers and counterions

The present invention includes within its scope salts and isomers. The compounds of the invention, after being novel, may in some cases form salts, which are also within the scope of the invention. All stereoisomers of the compounds of the present invention (such as those that may exist due to an asymmetric carbon on the substituent of compound R), including enantiomeric and diastereomeric forms, are also contemplated within the invention.

Compositions comprising novel entities of the invention

The invention also contemplates compositions or formulations comprising the compounds of the invention. The composition or formulation may be used for cosmetic or nutraceutical or pharmaceutical purposes. In addition, the compounds of the present invention may be used in combination with other pharmaceutical or nutraceutical agents.

In another aspect, the invention also relates to the use of the compounds for indications where epicatechin and other polyphenols are found to be useful. The compounds of the invention are useful for inducing mitochondrial biogenesis. The compounds of the invention may be used as supplements/medicaments to meet increased energy requirements in meeting the muscle needs of athletes/exercising muscles. The compounds of the invention are useful for the treatment of diseases associated with mitochondrial dysfunction.

Without being bound by theory, it is proposed that the novel analogs of the present invention exhibit significantly different pharmacokinetic, pharmacodynamic and acute and long-term toxicity profiles compared to other polyphenols. Furthermore, they exhibit rapid oxidation and often produce detectable kinetic isotope effects (kinetic isotope effects) that affect the pharmacokinetic, pharmacological and/or toxicological characteristics of the compound.

Examples

The following examples are representative of the present disclosure and provide detailed methods for preparing compounds of the present disclosure, including preparing intermediate compounds. The preparation of specific compounds of the embodiments is described in detail in the examples below, but the skilled person will appreciate that the chemical reactions can be readily adapted to prepare a variety of other reagents of various embodiments. For example, the synthesis of non-exemplified compounds can be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications to reaction conditions.

For all the following examples, standard procedures (work-up) and purification methods known to those skilled in the art may be employed. Unless otherwise indicated, all temperatures are expressed in degrees Celsius (C.). All reactions were carried out at room temperature unless otherwise indicated. The synthetic methods described herein are intended to illustrate the chemistry available through the use of specific examples and are not intended to indicate the scope of the disclosure.

Example 1: synthesis of (R, E) -2- (3, 4-dihydroxyphenyl) -5, 7-dihydroxychroman-3-one oxime [1001]

Step 1: synthesis of Tetrabenzylated Catechin [20] from Catechin [19]

At 0 ℃ under nitrogen atmosphere to [19]](1.0g, 3.4mmol) of DMF in stirring was added anhydrous K₂CO₃(2.3g, 17.0 mmol). After stirring at the same temperature for an additional 15 minutes, benzyl bromide (2.0ml, 17.0mmol) was added dropwise. The reaction temperature was raised to 25 ℃ and stirring was continued overnight. [19]Consumption was monitored by TLC. In [19]]After complete consumption, water (50ml) was added and the organic layer was extracted with ethyl acetate (3X 100 ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. The organic layer was concentrated to give a light brown viscous material, which was further purified by silica gel column chromatography using 8% ethyl acetate in hexane as eluent to give [20] as a white powder](1.5g，68％)；ESIMS：651[M⁺+1]

Step 2: synthesis of [21] from Tetrabenzylated Catechin [20]

At room temperature to [20]](1.0g, 1.53mmol) in dry DCM was added all at once with dess-Martin periodinane (0.98g, 2.3 mmol). After stirring for an additional 6 to 7 hours, saturated NaH was added₂CO₃(20ml) and extracted with DCM (3X 100 ml). The combined organic layers were washed with water and dried over sodium sulfate. The organic layer was concentrated to give a pale pink viscous material, which was further purified by flash chromatography on silica gel using DCM as eluent to give [21] as a white-pink solid powder](0.65g，71％)；ESIMS：649[M⁺+1]

And step 3: synthesis of [22] from [21]

At room temperature to [21]](0.20g, 0.30mmol) to a stirred solution in a mixture of acetonitrile (2ml) and methanol (5ml) was added ammonium acetate (0.03g, 0.36mmol) in one portion. After stirring at this temperature for an additional 10 minutes, hydroxylamine hydrochloride (0.02g, 0.36mmol) was added. [21]Consumption was monitored by TLC. In [21]]After complete consumption, the reaction mixture was concentrated and water (50ml) was added. The organic layer was then extracted with ethyl acetate (2X 100 ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. The organic layer was concentrated to give [22] as a off-white sticky solid]It was used as such in the next step (0.12g, 68%); ESIMS: 664[ M ]⁺+1]

And 4, step 4: synthesis of 1001 from [22]

At room temperature to [22]](0.15g, 0.22mmol) to a stirred solution in a mixture of ethyl acetate and methanol (1: 1, 5ml) was added a slurry of 10% Pd/C (0.02 g). Hydrogen balloon pressure was applied and the reaction mixture was stirred at room temperature for 1 hour, followed by additional stirring at 50 ℃ to 55 ℃ overnight. The reaction was monitored by TLC. The reaction mass was filtered through celite and excess solvent was removed under vacuum to give a light brown viscous material, which was further purified using silica gel column and 6% methanol in dichloromethane as eluent to give [1001] as an off-white viscous material](0.02 g，25％)；ESIMS：304[M⁺+1]

Example 2: synthesis of (2R, 3R) -2- (2, 3-dihydroxyphenyl) -3-fluorochromane-5, 7-diol [1010]

Step 1: synthesis of [1010] from Catechin [19]

At-10 ℃ to [19]](0.10g, 0.34mmol) of dry DCM to stir a solution DAST (0.20ml, 1.0mmol) dissolved in DCM was added to form a solution. Stirring was continued for 2 hours and then saturated NaHCO was added₃Then extracted with DCM (2X 50 ml). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to give a light brown viscous material. The crude reaction mixture was purified using a flash silica gel column and 1% MeOH in DCM as eluent to give 1014(0.01g, 10%) as a light yellow viscous material; ESIMS: 293[ M ]⁺+1]

Example 3: synthesis of (2R, 3S) -2- (3, 4-dihydroxyphenyl) -3-aminochroman-5, 7-diol [1009]

Step 1: synthesis of [23(A + B) ]from [21]

Under nitrogen atmosphere at room temperature to [21]]To a stirred solution of (0.50g, 0.77mmol) in anhydrous THF was added benzylamine (0.18ml, 1.5 mmol). After stirring at the same temperature for another 15 minutes, acetic acid (3 to 4 drops) was added dropwise. Stirred at this temperature for an additional 1 hour, NaCNBH was added₃(0.09g，1.5mmol)。[21]Consumption was monitored by TLC. After the starting material was completely consumed, water (50ml) was added and the organic layer was extracted with ethyl acetate (3X 100 ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. The organic layer was concentrated to give a light brown viscous material, which was further purified by silica gel column chromatography using 5% ethyl acetate in hexane as eluent to give [23 ]](0.21g, 36%) and 15 as a pale yellow viscous material (0.07g, 13%). ESIMS: 740[ M ]⁺+1]

Step 2: synthesis from [23A ] 1009

At room temperature to [23A ]](0.10g, 0.13mmol) to a stirred solution in a mixture of ethyl acetate and methanol (1: 1, 5ml) was added a slurry of 10% Pd/C (0.02 g). Hydrogen balloon pressure was applied and the reaction mixture was stirred at room temperature overnight. The reaction was monitored by TLC. The reaction mass was filtered through celite and excess removed under vacuum at low temperatureSolvent to give light brown viscous material, which was further purified using preparative HPLC to give [1009 as light brown viscous material] (0.01g，27％)。ESIMS：290[M⁺+1]

Example 4: synthesis of cis (±)2- (4-hydroxyphenyl) chromane-3, 7-diol [1004]

Step 1: synthesis of 1- (4-benzyloxy) -2-hydroxyphenyl) ethanone from 1- (2, 4-dihydroxyphenyl) ethanone

At 0 ℃ under nitrogen atmosphere to [24 ]](10.0g, 65.78mmol) in DMF (60ml) was added K₂CO₃(27.2g, 197 mmol). After stirring at this temperature for 15 minutes, benzyl bromide (7.2ml, 65.7mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred overnight. TLC showed [24]Is completely consumed. The reaction mixture was quenched with water (500ml) and extracted with ethyl acetate (2X 500 ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. The organic layer was subjected to rotary evaporation to give a light brown viscous material. The crude product was loaded on a silica gel column and eluted with 8% ethyl acetate/hexanes to give [25] as a brown powder](12g， 75％)；ESIMS：242[M⁺+1]

Step 2: synthesis of [27] from 1- (4-benzyloxy) -2-hydroxyphenyl) ethanone and [26]

To [25]](3.0g, 12.3mmol) in EtOH (30mL) stirred solution was added [26]](3.1g, 14.8mmol) and the reaction mixture was heated to 50 ℃ and then 50% aqueous NaOH (9.0ml) was added dropwise to the reaction mixture under constant stirring at 50 ℃ and allowed to stir at room temperature overnight. Completion of the reaction was monitored by checking TLC. TLC shows [25]Is completely consumed. The reaction mixture was poured into crushed ice and neutralized with 5% HCl solution to obtain the crude product as a yellow precipitate, which was obtained byFiltration through a buchner funnel and recrystallization of the crude product with aqueous EtOH to obtain the pure product as a yellow powder [27]. The pure product [27]](3.5g, 64%) was used in the next step. ESIMS: 436[ M ]⁺+1]

And step 3: synthesis of [28] from [27]

To [27]](3.0g, 6.88mmol) of methanol (40ml) to a stirred solution was added 20% aqueous NaOH (7.0 ml). The reaction mixture was kept in an ice bath at 0 ℃ and 30% H was added dropwise with constant stirring₂O₂(3.2ml) the reaction temperature was then raised to room temperature and stirred at that temperature overnight. Completion of the reaction was monitored by TLC. TLC showed [27]Is completely consumed. The reaction mixture was acidified with cold 5% HCl solution. The yellow precipitate formed was filtered through a buchner funnel and the crude product recrystallized from aqueous EtOH to obtain the pure product [28] as a yellow powder]. The pure product [28]](1.7g, 56%) was used for the next step; ESIMS: 450[ M ]⁺+1]

And 4, step 4: synthesis of [29] from [28]

At 0 ℃ under nitrogen atmosphere to [28]](1.6g, 3.55mmol) of DMF in stirring was added K₂CO₃(0.588g, 4.26 mmol). After stirring at this temperature for 15 minutes, benzyl bromide (0.42ml, 3.55mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred overnight. TLC shows [28]Is completely consumed. The reaction mixture was quenched with water (500ml) and extracted with ethyl acetate (2X 200 ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. The organic layer was rotary evaporated to give a yellow solid. The crude product was washed with diethyl ether to give a pale yellow powder [29]](1.5g，78％)。ESIMS：540[M⁺+1]

And 5: synthesis of [30] and [31] from [29]

At 40 ℃ under nitrogen atmosphere to [29]](1.5g, 2.77mmol) of MTBE (20ml) was stirred and LAH (0.422g, 11.1mmol) was added. After stirring at this temperature for 5 minutes, the temperature of the reaction mixture was raised to 80 ℃ for 2 hours. Reaction completion as monitored by TLC indicated [29]Is completely consumed. The reaction mixture was quenched with water (50ml) and extracted with ethyl acetate (2X 100 ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. The organic layer was subjected to rotary evaporation to give a dark brown viscous material. The crude product was loaded on a silica gel column and eluted with 100% DCM to give as [30]]And [31]]A light brown viscous material of the mixture (0.90g, 61%). Will [30]]And [31]]The mixture of (a) is used in the next step; ESIMS: 526[ M ]⁺+1]。

Step 6: synthesis of [1004] from [30] and [31]

At room temperature to [30]]And [31]](0.750g, 1.42mmol) to a stirred solution of a 1: 1 mixture of ethyl acetate and methanol (10ml) was added a slurry of 10% Pd/C (0.075 g). Hydrogen balloon pressure was applied and the reaction mixture was stirred at this temperature for 1 hour, then the reaction temperature was raised to 50 ℃ to 55 ℃ and stirred at this temperature overnight. The reaction mass was filtered through celite and the solvent was removed under a rotary evaporator to give a light brown viscous material. The crude product was purified by preparative HPLC to give cis-rac [1004 as off-white powder](0.035g, 10%) and its trans isomer [32 ] as a white-like powder](0.013g，4％)；ESIMS：258[M⁺+1]。

Example 5: synthesis of cis (. + -.) 2- (3, 4-dihydroxyphenyl) chromane-3, 7-diol [1003] was carried out by the method described for [1004] using [25] and 3, 4-bis (benzyloxy) benzaldehyde as starting materials.

Example 6: synthesis of cis (. + -.) 2- (3-hydroxyphenyl) chromane-3, 7-diol [1007] was carried out by the method described for [1004] using [25] and 3- (benzyloxy) benzaldehyde as starting materials.

Example 7: synthesis of cis (±) 3-hydroxytryptan-2-yl) benzene-1, 2-diol

Step 1: (E) synthesis of-3- (3, 4-bis- (benzyloxy) phenyl) -1- (2-hydroxyphenyl) prop-2-en-1-one [35 ]:

to compound [33]](2.0g, 14.68mmol) and the Compound [34](1.75g, 8.28mmol) in EtOH (20ml) was added aqueous NaOH (2g dissolved in 10ml water). The reaction mixture was stirred at 50 ℃ for 30 minutes and then at room temperature overnight. [33]And [34 ]]Consumption was monitored by TLC. The reaction mixture was acidified to pH 4 with 2N HCl, water (50ml) was added and the organic layer was extracted with ethyl acetate (2X 100 ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. The organic layer was concentrated to give a pale yellow viscous material, which was further purified by recrystallization using EtOH to give [35] as a pale yellow solid](3.04g， 55％)。ESIMS：437[M⁺+1]

Step 2: synthesis of 2- (3, 4-bis (benzyloxy) phenyl) -3-hydroxy-4H-chromen-4-one (36):

the compound [35] is reacted at 0 DEG C](2.5g, 5.77mmol) was stirred in EtOH (20ml) for 10 min. Then 20% NaOH solution (8ml) was added to the reaction mixture followed by 30% H₂O₂(10ml) and stirred at 0 ℃ for 4 to 5 hours. Then, the reaction mixture was kept at 4 deg.CThe mixture was kept frozen overnight. [35]Consumption was monitored by TLC. The reaction mixture was acidified to pH 3 with 2N HCl and the organic layer was extracted with ethyl acetate (2X 100 ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. The organic layer was concentrated to give a pale yellow viscous material, which was further purified by recrystallization using EtOH to give [36 ] as a pale yellow solid] (1.56g，62％)。ESIMS：451[M⁺+1]

And step 3: synthesis of 3- (benzyloxy) -2- (3, 4-bis (benzyloxy) phenyl) -4H-chromen-4-one [37 ]:

under nitrogen atmosphere at room temperature to [36 ]](1.40g, 3.11mmol) of DMF in stirring was added anhydrous K₂CO₃(0.865g, 6.22 mmol). After stirring at the same temperature for another 15 minutes, benzyl bromide (0.57ml, 4.66mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for an additional 2 to 3 hours. [36]Consumption was monitored by TLC. In [36 ]]After complete consumption, water (20ml) was added and the organic layer was extracted with ethyl acetate (2 × 50 ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. The organic layer was concentrated to give a light brown viscous material, which was further purified by crystallization using EtOH to give [37] as a pale yellow solid](1.70g，90％)。ESIMS：541[M⁺+1]

And 4, step 4: synthesis of Compound [38] and Compound [39]

Under nitrogen atmosphere at room temperature to [37]](1.30g, 2.41mmol) of MTBE (30ml) was stirred and LAH (0.366g, 9.647mmol) was added. The reaction mixture temperature was increased to 70 ℃ and stirred at this temperature for 1 hour. [37]Consumption was monitored by TLC. In [37]]After complete consumption, the reaction mixture was cooled to 0 ℃ and then passed over NH₄Cl (25ml) quench. Additive for foodWater (20ml) was added and the organic layer was extracted with ethyl acetate (2X 50 ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. Concentrating the organic layer to obtain compound [38]And compound [39]Was used directly in the next step (1.20g, 80%). ESIMS: 527[ M⁺+1]

And 5: 1002 Synthesis of

At room temperature under nitrogen atmosphere to [38]And [39]](0.500g, 9.53mmol) to a stirred solution in a mixture of ethyl acetate and methanol (1: 1, 20ml) was added a slurry of 10% Pd/C (0.05 g). Hydrogen balloon pressure was applied and the reaction mixture was stirred at room temperature for 1 hour, followed by additional stirring at 50 ℃ to 55 ℃ overnight. The reaction was monitored by using TLC. The reaction mass was filtered through a celite bed and excess solvent was removed under vacuum to give a light brown viscous material, which was further purified using silica gel column and 2% methanol in dichloromethane as eluent to give cis-rac 1002(0.090g, 40%) and 1002A (0.010g, 10%) as off-white solids. ESIMS: 259[ M⁺+1]

Example 8: the synthesis of cis (. + -.) 2- (3-hydroxyphenyl) chroman-3-ol [1011] was carried out by the method described for 1002 using [33] and 3- (benzyloxy) benzaldehyde as starting materials.

Example 9: the synthesis of cis (. + -.) 2- (4-hydroxyphenyl) chroman-3-ol [1012] was carried out by the method described for 1002 using [33] and 4- (benzyloxy) benzaldehyde as starting materials.

Example 10: synthesis of cis (. + -.) 2- (4-hydroxyphenyl) chromane-3, 5-diol [1006]

Step 1: synthesis of 1- (2- (benzyloxy) -6-hydroxyphenyl) -ethanone [41]

Under nitrogen atmosphere at room temperature to [40 ]](2.0g, 1.34mmol) of DMF in stirring was added anhydrous K₂CO₃(2.17g, 15.77 mmol). After stirring at the same temperature for an additional 15 minutes, benzyl bromide (1.92ml, 15.77mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight. [40]Consumption was monitored by TLC. In [40 ]]After complete consumption, water (50ml) was added and the organic layer was extracted with ethyl acetate (2 × 100 ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. The organic layer was concentrated to give a light brown viscous material, which was further purified by silica gel column chromatography using 5% ethyl acetate in hexane as eluent to give [41] as a white powder](2.1g，80％)。ESIMS：243[M⁺+1]

Step 2: (E) -synthesis of 1- (2- (benzyloxy) -6-hydroxyphenyl) -3- (4- (benzyloxy) -phenyl) -prop-2-en-1-one (43):

to compound [41](2.0g, 8.28mmol) and a compound [42 [](1.75g, 8.28mmol) of EtOH (20ml) to a stirred solution aqueous NaOH (1g dissolved in 6ml of water) was added. The reaction mixture was stirred at 50 ℃ for 30 minutes and then at room temperature overnight. [41]And [42 ]]Consumption was monitored by TLC. The reaction mixture was acidified to pH 4 with 2N HCl, water (50ml) was added and the organic layer was extracted with ethyl acetate (2X 100 ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. The organic layer was concentrated to give a pale yellow viscous material, which was further purified by recrystallization using EtOH to give [43 ] as a pale yellow solid](2.0g， 50％)。ESIMS：437[M⁺+1]

And step 3: synthesis of 5- (benzyloxy) -2- (4- (benzyloxy) -phenyl) -3-hydroxy-4H-chromen-4-one (44):

the compound [43 ] is reacted at 0 DEG C](1.5g, 3.44mmol) in EtOH (20ml)Stirred for 10 minutes. A solution of 20% NaOH (10ml) was then added to the reaction mixture followed by 30% H₂O₂(10ml) and stirred at 0 ℃ for 4 to 5 hours. The reaction mixture was then kept frozen overnight at 4 ℃. [43]Consumption was monitored by TLC. The reaction mixture was acidified to pH 3 with 2N HCI and the organic layer was extracted with ethyl acetate (2X 100 ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. The organic layer was concentrated to give a pale yellow viscous material, which was further purified by recrystallization using EtOH to give [44 as a pale yellow solid]And [45 ]](890mg，50％)。ESIMS：451[M⁺+1]

And 4, step 4: synthesis of 3, 5-bis- (benzyloxy) -2- (4- (benzyloxy) -phenyl) -4H-chromen-4-one (46):

at room temperature under nitrogen atmosphere to [44](0.6g, 1.33mmol) of DMF in stirring was added anhydrous K₂CO₃(0.36g, 2.66 mmol). After stirring at the same temperature for an additional 15 minutes, benzyl bromide (0.325ml, 2.66mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for an additional 2 to 3 hours. [44]Consumption was monitored by TLC. In [44 ]]After complete consumption, water (20ml) was added and the organic layer was extracted with ethyl acetate (2 × 50 ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. The organic layer was concentrated to give a light brown viscous material, which was further purified by crystallization using EtOH to give [46 ] as a pale yellow solid](0.3g，52％)。ESIMS：541[M⁺+1]

And 5: synthesis of Compound 62(A) +62(B) from [61]

Under nitrogen atmosphere at room temperature to [46 ]](0.5g, 9.25mmol) of MTBE (20ml) to a stirred solution LAH (0.140g, 37.03 mmol) was addedl). The reaction mixture temperature was increased to 70 ℃ and stirred at this temperature for 1 hour. [46]Consumption was monitored by TLC. In [46 ]]After complete consumption, the reaction mixture was cooled to 0 ℃ and then passed over NH₄Cl (25ml) quench. Water (20ml) was added and the organic layer was extracted with ethyl acetate (2X 50 ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. The organic layer was concentrated to give off-white viscous material of compound 47(a + B) (0.4g, 80%) which was used directly in the next step. ESIMS: 527[ M⁺+1]

Step 6: synthesis of 2- (4-hydroxyphenyl) -chromane-3, 5-diol (1006):

to a stirred solution of 47(A + B) (0.400g, 0.76mmol) in a mixture of ethyl acetate and methanol (1: 1, 20ml) was added a slurry of 10% Pd/C (0.04 g) at room temperature under nitrogen. Hydrogen balloon pressure was applied and the reaction mixture was stirred at room temperature for 1 hour, followed by additional stirring at 50 ℃ to 55 ℃ overnight. The reaction was monitored by using TLC. The reaction mass was filtered through a celite bed and excess solvent was removed under vacuum to give a light brown viscous material, which was further purified using silica gel column and 2% methanol in dichloromethane as eluent to give cis-rac 1006(0.028g, 30%) as an off-white solid. ESIMS: 259[ M⁺+1]

Example 11: the synthesis of cis (. + -.) 2- (3-hydroxyphenyl) chromane-3, 5-diol [1005] was carried out by the method described for 1006 using [41] and 3- (benzyloxy) benzaldehyde as starting materials.

Example 12: the synthesis of cis (. + -.) 2- (3, 4-dihydroxyphenyl) chromane-3, 5-diol [1013] was carried out by the method described for 1006 using [41] and 3, 4-bis (benzyloxy) benzaldehyde as starting materials.

Example 13: 2- (3-methoxy-4-methylphenyl) chromane-3, 7-diol [1026 [ ]]And 2- (3-hydroxy-4-methylphenyl) chromane-3, 7-diol [1027]For synthesis of [25]And 3-methoxy-4-methylbenzaldehyde as starting materials byThe method described with respect to 1004. [1026]ESIMS：287[M⁺+1][1027] ESIMS：272[M⁺+1]

Example 14: 2- (4-fluoro-3-methoxyphenyl) chromane-3, 7-diol [1028]And 2- (4-fluoro-3-hydroxyphenyl) chromane-3, 7-diol [1029]For synthesis of [25]And 4-fluoro-3-methoxybenzaldehyde as starting materials were carried out by the method described with respect to 1004. [1028]ESIMS：290[M⁺+1][1029] ESIMS：276[M⁺+1]

Example 15: synthesis of cis (. + -.) 2- (3-methoxyphenyl) chromane-3, 7-diol, cis (. + -.) 2- (3-hydroxyphenyl) -7-methoxychromane-3-ol, cis (. + -.) 7-methoxy-2- (3-methoxyphenyl) chromane-3-ol [1017, 1018 and 1019]

Step 1: synthesis of [1017], [1018] and [1019] from [1007]

Under nitrogen atmosphere at 0 deg.C to [1007]](0.12g, 0.46mmol) of DMF stirred solution was added with anhydrous K₂CO₃(0.12g, 0.93 mmol). After stirring for another 15 minutes at the same temperature, methyl iodide (0.05ml, 0.93mmol) was added dropwise. The reaction temperature was increased to 25 ℃ and stirring was continued for 4 hours. [1007]Consumption was monitored by TLC. In [1007]After complete consumption, water (50ml) was added and the organic layer was extracted with ethyl acetate (2 × 50 ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. The organic layer was concentrated to give a light brown viscous material, which was further purified by silica gel column chromatography using 5% ethyl acetate/hexane as eluent to give [1017] as a pale green viscous material](0.05g, 37%) as a pale yellow viscous material [1018]]And [1019]](0.02g，16％)。[1019]ESIMS：287[M⁺+1][1017]And [1018]]ESIMS：272[M⁺+1]

Example 16: synthesis of cis (+/-) 4- (3, 7-dihydroxychroman-2-yl) phenylacetate [1022], cis (+/-) 3-hydroxy-2- (4-hydroxyphenyl) chroman-7-yl acetate [1023] and cis (+/-) 4- (7-acetoxy-3-hydroxychroman-2-yl) phenylacetate [1024]

Step 1: synthesis of [1022], [1023] and [1024] from [1007]

Under nitrogen atmosphere at 0 deg.C to [1007]](0.2g, 0.77mmol) of DMF to a stirred solution was added pyridine (0.12ml, 1.5 mmol). After stirring for another 5 minutes at the same temperature, acetic anhydride (0.15ml, 1.5mmol) was added dropwise. The reaction temperature was increased to 25 ℃ and stirring was continued for 1 hour. [1007]Consumption was monitored by TLC. In [1007]After complete consumption, water (50ml) was added and the organic layer was extracted with ethyl acetate (2 × 50 ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. The organic layer was concentrated to give a light brown viscous material, which was further purified by silica gel column chromatography using 5% ethyl acetate/hexane as eluent to give [1024] as a pale yellow viscous material](0.08g, 30%) as yellow viscous material [ 1022%]And [1023](0.04g，17％)。[1024]ESIMS：343[M⁺+1][1022]And [1023]ESIMS：301[M⁺+1]

Example 17: synthesis of 2- (3-hydroxyphenyl) -3-propoxychroman-7-ol [1030]

Step 1: synthesis of [48] from [1007]

Under nitrogen atmosphere at room temperature to [1007](0.15g, 0.58mmol) of DMF in stirring was added anhydrous K₂CO₃(0.24g, 1.14 mmol). After stirring for another 15 minutes at the same temperature, benzyl bromide (0.13ml, 1.16mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature overnight. [1007]Consumption was monitored by TLC. In [1007]After complete consumption, water (20ml) was added and the organic layer was extracted with ethyl acetate (2X 50 ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. The organic layer was concentrated to give a light brown viscous material, use 5%It was further purified by silica gel column chromatography using ethyl acetate/hexane as eluent to give [48 as off-white viscous material](0.17g，67％)。 [81]ESIMS：439[M⁺+1]

Step 2: synthesis of [49] from [48]

Under nitrogen atmosphere at room temperature to [48]]To a stirred solution of (0.25g, 0.57mmol) in DMF was added sodium hydride (0.45g, 1.1 mmol). After stirring at the same temperature for another 15 minutes, propyl bromide (0.13ml, 1.1mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature overnight. [48]Consumption was monitored by TLC. In [ 48)]After complete consumption, water (20ml) was added and the organic layer was extracted with ethyl acetate (2 × 50 ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. The organic layer was concentrated to give a light brown viscous material, which was further purified by silica gel column chromatography using 7% ethyl acetate/hexane as eluent to give [49] as an off-white viscous material](0.20g，73％)。[49]ESIMS：481[M⁺+1]

And step 3: synthesis of [1030] from [49]

Under nitrogen atmosphere at room temperature to [49]](0.20g, 0.4mmol) to a stirred solution in a mixture of ethyl acetate and methanol (1: 1, 20ml) was added a slurry of 10% Pd/C (0.02 g). Hydrogen balloon pressure was applied and the reaction mixture was stirred at room temperature for 1 hour, followed by additional stirring at 50 ℃ to 55 ℃ overnight. The reaction was monitored by using TLC. The reaction mass was filtered through a celite bed and excess solvent was removed under vacuum to give a light brown viscous material, which was further purified using a silica gel column and 2% methanol in dichloromethane as eluent to give [1030] as an off-white solid](0.90g，72％)。ESIMS：301[M⁺+1]

Example 18: synthesis of cis (±)2- (4-hydroxyphenyl) chromane-3, 5, 7-triol [1008]

Step 1: synthesis of 1- (2, 4-bis (benzyloxy) -6-hydroxyphenyl) -ethanone:

at 0 ℃ under nitrogen atmosphere to [50 ]](3.0g, 16.19mmol) of DMF in stirring was added anhydrous K₂CO₃(5.56g, 40.32 mmol). After stirring at the same temperature for an additional 15 minutes, benzyl bromide (4.92ml, 40.32mmol) was added dropwise. The reaction temperature was increased to 25 ℃ and stirring was continued overnight. [50]Consumption was monitored by TLC. In [50 ]]After complete consumption, water (50ml) was added and the organic layer was extracted with ethyl acetate (2X 100 ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. The organic layer was concentrated to give a light brown viscous material, which was further purified by silica gel column chromatography using 5% ethyl acetate/hexane as eluent to give [51] as a white powder](3.2g，70％)。ESIMS：349[M⁺+1]

Step 2: (E) synthesis of-3- (4- (benzyloxy) phenyl) -1- (2, 4-bis (benzyloxy) -6-hydroxyphenyl) -prop-2-en-1-one:

to compound [51](2.0g, 5.74mmol) and Compound [26]To a stirred solution of (1.21g, 5.74mmol) in EtOH (20ml) was added aqueous NaOH (2g dissolved in 10ml of water). The reaction mixture was stirred at 50 ℃ for 30 minutes and then at room temperature overnight. [51]And [26]]Consumption was monitored by TLC. The reaction mixture was acidified to pH 4 with 2N HCl, water (50ml) was added and the organic layer was extracted with ethyl acetate (2X 100 m). The combined organic layers were washed with water, brine and dried over sodium sulfate. The organic layer was concentrated to give a pale yellow viscous material, which was further purified by recrystallization using EtOH to give [52 ] as a pale yellow solid](2.0g， 65％)。ESIMS：543[M⁺+1]

And step 3: synthesis of 5, 7-bis (benzyloxy) -2- (4- (benzyloxy) phenyl) -3-hydroxy-4H-chromen-4-one:

the compound [52 ] is reacted at 0 DEG C](1.8g, 3.32mmol) was stirred in EtOH (20ml) for 10 min. Then 20% NaOH solution (8ml) was added to the reaction mixture followed by 30% H₂O₂(20ml) and stirred at 0 ℃ for 4 to 5 hours. The reaction mixture was then kept frozen overnight at 4 ℃. [52]Consumption was monitored by TLC. The reaction mixture was acidified to pH 3 with 2N HCl and the organic layer was extracted with ethyl acetate (2X 100 ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. The organic layer was concentrated to give a pale yellow viscous material, which was further purified by recrystallization using EtOH to give [53] as a pale yellow solid](1.3g，60％)。ESIMS：557[M⁺+1]

And 4, step 4: synthesis of 3, 5, 7-tris (benzyloxy) -2- (4- (benzyloxy) phenyl) -4H-chromen-4-one:

at room temperature under nitrogen atmosphere to [53]](1.25g, 2.24mmol) of DMF in stirring was added anhydrous K₂CO₃(0.370g, 2.69 mmol). After stirring at the same temperature for an additional 15 minutes, benzyl bromide (0.330ml, 2.69mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for an additional 2 to 3 hours. [53]Consumption was monitored by TLC. In [53]]After complete consumption, water (20ml) was added and the organic layer was extracted with ethyl acetate (2 × 50 ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. The organic layer was concentrated to give a light brown viscous material, which was further purified by crystallization using EtOH to give [54 ] as a pale yellow solid](0.900g，60％)。ESIMS：646[M⁺+1]

And 5: synthesis of compound 55(a) +55 (B):

at room temperature under nitrogen atmosphere to [54 ]](0.950g, 1.47mmol) of MTBE (20ml) to a stirred solution LAH (0.223g, 5.82mmol) was added. The reaction mixture temperature was increased to 70 ℃ and stirred at this temperature for 1 hour. [54]Consumption was monitored by TLC. In [54 ]]After complete consumption, the reaction mixture was cooled to 0 ℃ and then passed over NH₄Cl (25ml) quench. Water (20ml) was added and the organic layer was extracted with ethyl acetate (2X 50 ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. The organic layer was concentrated to give compound [55(A + B)]Was used directly in the next step (0.590g, 70%). ESIMS: 633[ M ]⁺+1]

Step 6: 1011 synthesized from 55(A) and 55(B)

To a stirred solution of 55(A + B) (0.300g, 4.7mmol) in a mixture of ethyl acetate and methanol (1: 1, 20ml) was added a slurry of 10% Pd/C (0.05g) at room temperature under a nitrogen atmosphere. Hydrogen balloon pressure was applied and the reaction mixture was stirred at room temperature for 1 hour, followed by additional stirring at 50 ℃ to 55 ℃ overnight. The reaction was monitored by using TLC. The reaction mass was filtered through a celite bed and excess solvent was removed under vacuum to give a light brown viscous material, which was further purified using silica gel column and 2% methanol in dichloromethane as eluent to give cis-rac 1008 as an off-white solid (0.040g, 35%). ESIMS: 275[ M ]⁺+1]

Example 19: the synthesis of cis (±)2- (3-hydroxyphenyl) chromane-3, 5, 7-triol [1014] was carried out by the method described for 1008 using [51] and 3- (benzyloxy) benzaldehyde as starting materials.

Example 20: the synthesis of cis (±) 2-phenylchromane-3, 5, 7-triol [1015] was carried out using [51] and benzaldehyde as starting materials by the method described with respect to 1008.

Example 21: synthesis of cis (±)2- (3, 4-dihydroxy-2-methylphenyl) chromane-3, 5, 7-triol [1035]

Step 1: from 50 to 51

At 0 ℃ under nitrogen atmosphere to [50 ]](5.0g, 26.8mmol) of DMF (50ml) was stirred and K was added₂CO₃(11.1g, 80.6 mmol). After stirring at this temperature for 15 minutes, benzyl bromide (6.42ml, 53.7mmol) was added dropwise. The temperature of the reaction mixture was allowed to rise to room temperature and stirred overnight. TLC showed [50]Is completely consumed. The reaction mixture was quenched with water (500ml) and extracted with ethyl acetate (2X 400 ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. The organic layer was rotary evaporated to give a light brown solid. The crude product was loaded onto a silica gel column and eluted with 10% ethyl acetate/hexane as an off-white powder [51]](3.3g, 35%). This pure product [51]]For the next step. ESIMS: 348[ M ]⁺+1]

Step 2: synthesis of [53] from [51] and [56 ].

To [51]](3.3.g, 9.48mmol) in EtOH (35.0mL) stirred solution was added [56 [ ]](3.6g, 11.3mmol) and the reaction mixture was heated to 50 ℃ then 50% aqueous NaOH (10.0ml) was added dropwise to the reaction mixture under constant stirring at 50 ℃ and stirred at room temperature overnight. Completion of the reaction was monitored by TLC. TLC shows [56]Is completely consumed. The reaction mixture was poured into crushed ice and neutralized with 5% HCl solution to obtain crude product as yellow precipitate, which was filtered through buchner funnel and recrystallized from aqueous EtOHCrude product to obtain pure product as yellow powder [57]. This pure product [57]](4.2g, 68%) was used in the next step. ESIMS: 663[ M ]⁺+1]

And step 3: synthesis of [58] from [57 ].

To [57]]To a stirred solution (35ml) of (3.0g, 5.53mmol) in methanol was added a 20% aqueous NaOH solution (5.0 ml). The reaction mixture was kept in an ice bath at 0 ℃ and 30% H was added dropwise with constant stirring₂O₂(2.5ml) the reaction temperature was then raised to room temperature and stirred at that temperature overnight. Completion of the reaction was monitored by detection TLC. The reaction mixture was acidified with a chilled 5% HCl solution. The yellow precipitate formed was filtered through a buchner funnel and the crude product recrystallized from aqueous EtOH to obtain the pure product as a yellow powder [58]]. This pure product [58]](0.4g, 10%) was used in the next step. ESIMS: 677[ M⁺+1]

And 4, step 4: synthesis of [59] from [58 ].

At 0 ℃ under nitrogen atmosphere to [58]](0.4g, 0.59mmol) of DMF in stirring was added K₂CO₃(0.12g, 0.86 mmol). After stirring at this temperature for 15 minutes, benzyl bromide (0.10ml, 0.88mmol) was added dropwise. The reaction temperature was allowed to rise to room temperature and stirred overnight. TLC showed [58]]Was completely consumed and the reaction mixture was quenched with water (500ml) and extracted with ethyl acetate (2X 200 ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. The organic layer was rotary evaporated to give a yellow solid. The crude product was washed with diethyl ether to give a pale yellow powder [59]](0.4g，88％)。ESIMS：767[M⁺+1]

And 5: synthesis of [60] and [61] from [59]

At 40 ℃ under nitrogen atmosphere to [59]](0.4g, 0.52mmol) of MTBE (10ml) was stirred and LAH (0.05g, 1.56mmol) was added. After stirring at this temperature for 5 minutes, the temperature of the reaction mixture was raised to 80 ℃ for 2 hours. Completion of the reaction was monitored by detection TLC. TLC shows [59]Is completely consumed. The reaction mixture was quenched with water (50ml) and extracted with ethyl acetate (2X 100 ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. The organic layer was subjected to rotary evaporation to give a dark brown viscous material. The crude product was loaded on a silica gel column and eluted with 100% DCM to give as [60]]And [61]]A light brown viscous material of the mixture (0.25g, 67%). Will [60]]And [61]]The mixture of (a) was used in the next step. ESIMS: 727[ M ]⁺+1]

Step 6: 1031 was synthesized from [60] and [61 ].

To a stirred solution of [60] and [61] (0.25g, 0.34mmol) in a 1: 1 mixture of ethyl acetate and methanol (10ml) was added a slurry of 10% Pd/C (0.03 g) at room temperature under a nitrogen atmosphere. Hydrogen balloon pressure was applied and the reaction mixture was stirred at this temperature for 1 hour, then the reaction temperature was raised to 50 ℃ to 55 ℃ and stirred at this temperature overnight. The reaction mass was filtered through celite and the solvent was removed under a rotary evaporator to give a light brown viscous material. The crude product was purified by preparative HPLC to give cis-rac [1031A ] (0.02g, 20%) as an off-white powder and trans-rac [1031B ] (0.01g, 9%) as an off-white powder.

Example 22: cis (±)2- (2-fluoro-3, 4-dihydroxyphenyl) chromane-3, 5, 7-triol [1032]For synthesis of [51]And 3, 4-bis (benzyloxy) -2-fluorobenzaldehyde as a starting material by the method described for 1031. ESIMS: 309[ M ]⁺+1]

Practice ofExample 23: cis (±)2- (2-fluoro-4, 5-dihydroxyphenyl) chromane-3, 5, 7-triol [1033]For synthesis of [51]And 4, 5-bis (benzyloxy) -2-fluorobenzaldehyde as a starting material by the method described for 1031. ESIMS: 309[ M ]⁺+1]

Example 24: synthesis of cis (±)2- (3-fluoro-4-hydroxyphenyl) chromane-3, 5, 7-triol [1034]

Step 1: synthesis of [63] from [51] and [62]

To [51]](2.2g, 6.32mmol) in EtOH (35.0mL) stirred solution was added [62](1.7g, 7.58mmol) and the reaction mixture was heated to 50 ℃ and then 50% aqueous NaOH (10.0ml) was added dropwise to the reaction mixture under constant stirring at 50 ℃ and stirred at room temperature overnight. Completion of the reaction was monitored by TLC. TLC shows [62]Is completely consumed. The reaction mixture was poured into crushed ice and neutralized with 5% HCl solution to obtain the crude product as a yellow precipitate, which was filtered through a buchner funnel and recrystallized from aqueous EtOH to obtain the pure product as a yellow powder [63]]. This pure product [63]](2.0g, 55%) was used in the next step. ESIMS: 560[ M ]⁺+1]

Step 2: synthesis of [64] from [63]

To [63]](2.0g, 3.57mmol) to a stirred solution of a mixture of EtOH (20.0ml) and THF (10ml) NaBH was added₄(0.3g, 7.14mmol) and the reaction mixture was heated to 80 ℃ for 2 hours, then the reaction mixture was rotary evaporated to dryness and a 1: 2 mixture of AcOH and water (20ml) was added at 0 ℃. The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was again subjected to rotary evaporation to dryness and poured over Na₂CO₃Was added to the saturated solution and extracted with DCM (200 ml). The combined organic layers were washed with water, brine and sulfurAnd (5) drying the sodium salt. The organic layer was subjected to rotary evaporation to give a light brown viscous material. This crude product was loaded on a silica gel flash column and eluted with 100% DCM to give a pale yellow viscous material [64]](1.0g， 51％)。ESIMS：545[M⁺+1]

And step 3: synthesizing [65] from [64 ].

At room temperature to [64]](1.0g, 1.8mmol) in dry THF was added OsO in N-methylmorpholine oxide (0.2g, 2.29mmol), t-BuOH (3%, 2ml) and water (3ml)₄And the resulting solution was stirred at that temperature for 6 hours. The reaction was monitored by TLC. In [64]]After complete consumption, a saturated solution of sodium thiosulfate was added and extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated to give the desired material [65]](0.9g, 86%) which was used as such in the next reaction. ESIMS: 579[ M ]⁺+1]

And 4, step 4: synthesis of [66] from [65]

At 0 ℃ under constant stirring [65]](0.9g, 1.55mmol) of AcOH to a stirred solution NaCNBH was added in one portion₃(1.4g, 23.3 mmol). The resulting solution was stirred at 0 ℃ for 1 hour, and then the temperature of the reaction mixture was returned to room temperature. The reaction was monitored by TLC. In [65]]After complete consumption, saturated NaHCO was added₃And extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated to give the desired material, trans [66]](0.60g, 68%) which was used as such in the next reaction. ESIMS: 563[ M⁺+1]

And 5: synthesis of [67] from [66]

At room temperature to [66]](0.6g, 1.0mmol) was added all at once to a stirred solution of anhydrous DCM with dess-Martin periodinane (1.2g, 3.0 mmol). After stirring for an additional 6 to 7 hours, saturated NaHCO was added₃(20ml) and extracted with DCM (3X 100 ml). The combined organic layers were washed with water and dried over sodium sulfate. The organic layer was concentrated to give a pale pink viscous material, which was further purified by flash column chromatography on silica gel using DCM as eluent to give [67] as a white-pink solid powder](0.40g，71％)ESIMS：561[M⁺+1]

Step 6: synthesis of [68] from [67]

At-78 ℃ under nitrogen atmosphere [67]](0.2g, 0.35mmol) of anhydrous THF to a stirred solution was added dropwise lithium tri-sec-butylborohydride (1.78 ml). The resulting solution was stirred at-78 ℃ for 5 hours, and then the temperature of the reaction mixture was returned to room temperature. The reaction was monitored by TLC. In [67]]After complete consumption, saturated NaHCO was added₃And extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated to give the desired material cis [68]](0.10g，51％)。 ESIMS：563[M⁺+1]

And 7: synthesis of [1034] from [68]

At room temperature to [68]](0.10g, 0.17mmol) to a stirred solution in a 1: 1 mixture of ethyl acetate and methanol (10ml) was added a slurry of 10% Pd/C (0.010 g). Hydrogen balloon pressure was applied and the reaction mixture was stirred at this temperature for 1 hour, then the reaction temperature was raised to 50 ℃ to 55 ℃ and stirred at this temperature overnight. The reaction mass was filtered through celite and the solvent was removed under a rotary evaporator to give a light brown viscous material. The crude product was loaded onto a silica gel column and washed with 4% methanol in dichloromethaneRemoving to obtain white powder [1034](0.028，57％)。 ESIMS：293[M⁺+1]

Example 25: cis (±) (2- (3, 4-dihydroxy-5-methylphenyl) chromane-3, 5, 7-triol [1035]For synthesis of [51]And 3, 4-bis (benzyloxy) -5-methylbenzaldehyde as starting materials were carried out by the methods described for 1031. ESIMS: 305[ M ]⁺+1]

Example 26: synthesis of (2R, 3R) -2- (3, 4-dihydroxyphenyl) chromane-4, 4-d2-3, 5, 7-triol [1036]

Step 1: synthesis of [84 and 85] from [86]

To a stirred suspension of [69] (2.5g) in methyl tert-butyl ether (75.0ml, 30 volumes) was added a small portion of lithium aluminum deuteride (0.251mg, 3.6 equiv) at room temperature under a nitrogen atmosphere. After stirring at this temperature for 10 minutes, the reaction temperature was increased from 65 ℃ to 70 ℃. After stirring at the same temperature for 1 hour, the reaction mass was quenched with 1N HCl (10ml) solution at 0 ℃ to-5 ℃ and then the reaction temperature was raised to room temperature. Ethyl acetate (10ml) was added to the reaction and stirred for 30 minutes. The organic layer was decanted and removed. To the aqueous layer was added ethyl acetate. The mixture was filtered through a celite bed and the aqueous and organic layers were separated. The organic layers were combined and concentrated under reduced pressure to give an off-white solid (2.5 g). The crude compound was triturated with ethyl acetate (10ml) at room temperature for 4 hours then filtered, washed with ethyl acetate and dried under vacuum to give an off-white solid (1.0g, 40% yield) [70 ].

In separation [70]]After that, the mother liquor was concentrated under reduced pressure to obtain a pale yellow residue. The resulting semi-solid was reacted at room temperature with 50% ethyl acetate: hexane (250ml) was ground for 30 minutes, thereby obtaining a solid. The solid was filtered and washed with 50% ethyl acetate: hexane (200ml) wash. The resulting solid was dried under vacuum to give an off-white solid (0.250g, 10% yield) [71]]。ESIMS：741[M⁺+1]

Step 2: synthesis of [1036] from [71]

At room temperature to [71]](0.3g, 0.404mmol) to a stirred solution (10ml) of a 1: 1 mixture of ethyl acetate and methanol was added Pd (oH)₂Slurry (0.030 g). The reaction mixture was stirred at room temperature for 1 hour, then the reaction temperature was raised to 50 ℃ to 55 ℃ and stirred at that temperature overnight. The reaction was filtered through celite. The collected solvent was removed on a rotary evaporator to give a light brown viscous material. The crude product was loaded onto a silica gel column and eluted with 4% methanol/dichloromethane to give a pale pink powder (0.055g, 46% yield) [ 1036%]。ESIMS：293[M⁺+1]

And step 3: synthesis of [1038] from [70]

At room temperature to [70]](0.18g, 0.24mmol) in a stirred solution of a 1: 1 mixture of ethyl acetate and methanol (8ml) Pd (OH) was added₂(0.020g) of a slurry. The reaction mixture was stirred at this temperature for 1 hour, then the reaction temperature was raised to 50 ℃ to 55 ℃ and stirred at this temperature overnight. The reaction was filtered through celite. The collected solvent was removed on a rotary evaporator to give a light brown viscous material. The crude product was loaded on a silica gel column and eluted with 4% methanol/dichloromethane to give an off-white powder, which was then separated on preparative HPLC to give [ 1038%](0.045 g, 64% yield). ESIMS: 293[ M ]⁺+1]

Example 27: synthesis of (2R, 3R) -2- (3, 4-dihydroxyphenyl) chromane-2-d-3, 5, 7-triol [1037] step 1: synthesis of [73] and [74] from [72]

At room temperature under nitrogen atmosphere to [72]](0.2g，0.25mmol) of anhydrous dichloromethane into a stirred solution, adding NaCNBD into the solution at one time₃(0.02g, 0.25 mmol). The reaction mixture was stirred at this temperature for 15 minutes. After completion of the reaction, the reaction mixture was quenched with water under cooling. The reaction mixture was further diluted with dichloromethane, the organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure to give [73] as a light pink viscous material]And [74]](0.16g，85％)。 ESIMS：740[M⁺+1]

Step 2: synthesis of [1037] from [73]

At room temperature to [73]](0.150g, 0.20mmol) in a stirred solution of a 1: 1 mixture of ethyl acetate and methanol (8ml) Pd (OH) was added₂Slurry (0.020 g). Hydrogen balloon pressure was applied and the reaction mixture was stirred at this temperature for 1 hour, then the reaction temperature was raised to 50 ℃ to 55 ℃ and stirred at this temperature overnight. The reaction was filtered through celite. The collected solvent was removed on a rotary evaporator to give a light brown viscous material. The crude product was loaded on a silica gel column and eluted with 4% methanol/dichloromethane to give an off-white powder, which was then separated on preparative HPLC to give cis-rac [1037]]And minor amounts of the trans isomer. ESIMS: 292[ M ]⁺+1]

Example 28: synthesis of dibenzyl (4- (3, 5, 7-trihydroxychroman-2-yl) -1, 2-phenylene) bis (carbonate) [1048]

At 0 ℃ in the direction of [75]](1.0 equiv., 0.15gm, 0.5mmol) to a suspension in 10ml acetonitrile triethylamine (2.0 equiv., 0.14ml, 1.0mol) was added dropwise and stirred for 10 min. To this suspension was added benzyl chloroformate (2.0 equiv., 0.16ml, 1.0mol) dropwise over a period of 5 minutes. The resulting solution was stirred at 0 ℃ for an additional 10 minutes. The progress of the reaction was monitored by TLC. Reaction mixture with acetic acidThe ethyl ester was diluted and washed with water. The ethyl acetate layer was separated and washed with Na₂SO₄Dried, filtered and evaporated to give a colourless gel which was subjected to column chromatography on silica gel and eluted with 2% MeOH in dichloromethane to give [1048] as a colourless solid][0.135gm，46％]。 ESIMS：740[M⁺+1]

The compounds [1043], [1044] and [1049] were synthesized in a similar manner.

Example 29: synthesis of 4- (3, 5, 7-trihydroxychroman-2-yl) -1, 2-phenylenebis (benzylcarbamate) [1059]

At 0 ℃ in the direction of [75]]To a suspension of (1.0 equiv., 0.2gm, 0.68mmol) in 10ml acetonitrile triethylamine (2.0 equiv., 0.14ml, 1.4mol) was added dropwise and stirred for 10 min. To this suspension was added dropwise benzyl isocyanate [2.0 equivalent, 0.17ml, 1.4mol over a period of 5 minutes]. The resulting solution was stirred at 0 ℃ for 10 minutes. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was separated and washed with Na₂SO₄Dried, filtered and evaporated to give a colourless gel which is filtered through silica gel [100 to 200 mesh size]Was subjected to column chromatography and the compound was eluted with 2% MeOH/dichloromethane to give [1059 as a colorless solid] (0.08gm，20％)。ESIMS：556[M⁺+1]

Example 30: synthesis of (2R, 3R) -2- (3, 4-dihydroxyphenyl) -5, 7-dihydroxychroman-3-yl isopropyl carbamate [1046]

Step 1: synthesis of tetrabenzylated racemic epicatechin [76] from racemic epicatechin [75]

At 0 ℃ under nitrogen atmosphere to [75]](1.0gm, 3.4mmol) of DMF in stirring was added K₂CO₃(2.3gm, 17.0 mmol). Stirred at this temperature for 15 minutesThereafter, benzyl bromide was added dropwise. The reaction temperature was allowed to rise to room temperature and stirred overnight. TLC showed [75]Is completely consumed. The reaction mixture was quenched with water (50ml) and extracted with ethyl acetate (2X 100 ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. The organic layer was subjected to rotary evaporation to give a light brown viscous material. The crude product was loaded onto a silica gel column and eluted with 8% ethyl acetate/hexanes to give a white powder [76]](1.5gm，68％)。ESIMS：651[M⁺+1]

Step 2: synthesis of [77] from [76]

At 0 ℃ under nitrogen atmosphere to [76]](0.20gm, 0.30mmol) of NaH (0.017gm, 0.46mmol) was added dropwise to a stirred solution of DMF. After stirring at this temperature for 1 hour, 4-nitrophenyl isopropyl carbamate (0.10gm, 0.46mmol) was added in portions. The reaction temperature was allowed to rise to room temperature and stirred for 2 hours. TLC shows [76]Is completely consumed. The reaction mixture was quenched with water (50ml) and extracted with ethyl acetate (2X 100 ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. The organic layer was subjected to rotary evaporation to give a light brown viscous material, which was purified on a silica gel column with 8% EtoAc/hexane as eluent to give [77] as a light yellow powder](0.07gm，35％)。ESIMS：736[M⁺+1]

And step 3: synthesis of [1046] from [77]

At room temperature to [77]](0.070g, 0.09mmol) to a stirred solution (10ml) of a 1: 1 mixture of ethyl acetate and methanol was added a slurry of 10% Pd/C (0.070 g). Hydrogen balloon pressure was applied and the reaction mixture was stirred at this temperature for 4 hours. The reaction mass was filtered through celite and the solvent was removed under a rotary evaporator to give a light brown viscous material. The crude product was eluted with 4% MeOH in dichloromethanePurification of the agent on silica gel column to give [1046] as off-white powder (0.005g, 74%)](0.02g，10％)。ESIMS：376[M⁺+1]

Compounds [1045], [1047], [1053], [1055] and [1056] were synthesized in a similar manner.

Example 31: synthesis of dibenzyl (4- ((2R, 3R) -5, 7-bis (((benzyloxy) carbonyl) oxy) -3-hydroxytryptan-2-yl) -1, 2-phenylene) bis (carbonate) [1052]

At 0 ℃ in the direction of [75]](1.0 equiv., 1.0gm, 3.5mmol) to a suspension in 10ml acetonitrile triethylamine (2.9 m) was added dropwise]21.0mol) and stirred for 10 minutes. To the suspension was added dropwise benzyl chloroformate (3.61ml, 21.0mmol) over a period of 5 minutes. The resulting solution was stirred at 0 ℃ for an additional 10 minutes. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was separated and washed with Na₂SO₄Drying, filtering and evaporating to obtain [1052] as a transparent viscous material](2.70g，94％)。ESIMS：827[M⁺+1]

In a similar manner [1051] was synthesized.

Example 32: synthesis of dibenzyl (4- ((2R, 3R) -5, 7-bis (((benzyloxy) carbonyl) oxy) -3-hydroxytryptan-2-yl) -1, 2-phenylene) bis (carbonate) [1066]

Step 1: synthesis of [1066] from [1048]

At 0 deg.C down [1048]]To a suspension of (0.1gm, 0.17mmol) in 10ml acetonitrile was added triethylamine (0.02ml, 0.17mmol) dropwise and stirred for 10 min. Methyl chloroformate (0.01ml, 0.17mmol) was added dropwise over a period of 5 minutes to the suspension. The resulting solution was stirred at 0 ℃ for an additional 30 minutes. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was separated and washed with Na₂SO₄Dried, filtered and evaporated to give a colourless gel which was subjected to column chromatography on silica gel and eluted with 20% ethyl acetate/hexane to give [1066] as an off-white solid][0.04gm，35％]。ESIMS：675[M⁺+1]

Synthesized in a similar manner [1060 ].

Step 2: synthesis of [1058] from [1066]

At room temperature, to [1066]](0.10g, 0.14mmol) to a stirred solution of a 1: 1 mixture of ethyl acetate and methanol (10ml) was added a slurry of 10% Pd/C (0.01 g). Hydrogen balloon pressure was applied and the reaction mixture was stirred at this temperature for 1 hour. The reaction mass was filtered through celite and the solvent was removed under a rotary evaporator to give a light brown viscous material. The crude product was purified on a silica gel column with 4% MeOH/dichloromethane as eluent to give [1058] as a light brown powder (0.05g, 74%)](0.05g，83％)。ESIMS：407[M⁺+1]

[1050], [1054] and [1057] were synthesized in a similar manner.

Example 33: [1061] synthesis of [1062] and [1063]

Step 1: synthesis of [78], [79] and [80] from [1048]

At 0 deg.C down [1048]](0.5gm, 0.89mmol) to a suspension in20 ml acetonitrile triethylamine (0.12ml, 0.89mmol) was added dropwise and stirred for 10 min. To the suspension was added heptanoyl chloride (0.13g, 0.89mmol) dropwise over a period of 5 minutes. The resulting solution was stirred at 0 ℃ for an additional 30 minutes. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was separated and washed with Na₂SO₄Drying, filtering and evaporating to give a colorless gel on silica gelSubjected to column chromatography and eluted with 2% MeOH/dichloromethane to give [78] as an off-white solid](0.07g, 11%), as a pale green viscous material [79]](0.05, 9%) and [80]](0.18g，25％)。[78]And [79]]：ESIMS：671[M⁺+1][80]：ESIMS：783[M⁺+1]

Step 2:

the synthesis of [1061], [1062] and [1063] was carried out as described in [1058] from [78], [79] and [80 ].

In a similar manner, [1064] and [1065] were synthesized.

Example 34: AMPK activation potential of test compounds:

compounds were evaluated for AMPK activation potential using a cell-based ELISA. Liver cancer (Hep G2) hepatocytes were maintained in T75 culture flasks containing 25mM DMEM + 10% fetal bovine serum. Cells were maintained in T75 flasks containing medium (DMEM + 10% fetal bovine serum). Upon reaching 70% to 80% confluence, cells were seeded at a density of 40,000 cells/well in 25mM DMEM + 10% FCS medium in 96-well plates. The plates were then incubated at 37 ℃ with 5% CO₂Incubate for 24 hours. The drugs were prepared in DMSO at various concentrations, diluted to the desired concentration with medium and incubated with 5% CO at 37 deg.C₂Incubations were performed for 30 minutes and 1 hour for epicatechin analog and 11-BHP analog, respectively. Metformin was used as a positive control. Cells were fixed with 4% formaldehyde for 30 minutes and washed three times with PBS containing 0.1% Triton X-100 at room temperature. With 1% H in PBS-T₂O₂(0.1% Tween 20) endogenous peroxidase was quenched for 30 minutes and washed three times in PBS-T. Cells were blocked with 1% BSA in PBS-T for 1 hour. Cells were incubated overnight at 4 ℃ with a 1: 1000 dilution of primary antibody (phospho-AMPK α (Thrl72) rabbit mAb, Cell Signaling) in PBS-T containing 5% BSA. Cells were then washed three times with PBS-T over 5 minutes and incubated with a 1: 1000 dilution of secondary antibody (anti-rabbit IgG, HRP-binding antibody, Cell Signaling) in PBS-T containing 1% BSA at room temperature for 14 hours. Cells were washed three times with PBS-T over 5 minutes. Cells were incubated with 100. mu.l TMB substrate solution for 30 min and 100. mu.l 2N H₂SO₄Stopping the reaction. Plates were then read at 450nM using an ELISA plate reader and absorbance recorded. The% activity was calculated using DMSO control as 100%. All compounds of the invention as exemplified and included were found to be active. For illustrative purposes, the activation potential of the compounds at a concentration of 10nm is provided in table 2.

Table 2: the activation potential of the compound.