Intermediates, preparation methods and uses of pregnanediol P57 and its derivatives, and pregnanediol P57 derivatives.

Abstract

This invention relates to intermediates, preparation methods, and uses of pregnanediol P57 and its derivatives as shown in Formula I, as well as pregnanediol P57 derivatives. The method employs a convergent synthesis strategy to synthesize P57 and its derivatives, resulting in a short synthetic route, high yield, and suitability for industrial production. The definitions of each substituent in Formula I are the same as those in the claims.

Description

Technical Field

[0001] This invention relates to intermediates, preparation methods and uses of pregnanediol P57 and its derivatives, and pregnanediol P57 derivatives. Background Technology

[0002] In 2005, a research report by the World Health Organization (WHO) indicated that the number of overweight adults worldwide had reached 1.6 billion, with 400 million of them being obese. That same year, a health survey of children found that over 20 million children under the age of five were overweight. Besides causing inconvenience in movement and disproportionate body shape, obesity, more importantly, can induce various diseases, such as diabetes, cardiovascular disease, hypertension, and sleep apnea syndrome. Therefore, obesity is a significant public health problem facing humanity in the 21st century and has been defined as a disease by the WHO. In addition to a balanced diet, cultivating healthy lifestyle habits, and increasing physical activity, drug treatment is increasingly favored in addressing obesity. The search for weight-loss drugs with natural sources and no side effects has become urgent.

[0003] Studies have found that pregnanediol P57, isolated from the South African plant Hoodia Gordonii, has a significant appetite-reducing effect. Although research on the efficacy and reliability of Hoodia Gordonii is limited, its safety has been confirmed by years of use by local people, leading to the development of a series of products based on it. With attention from media outlets such as CBS, a global surge in the consumption of Hoodia Gordonii products has emerged. Pregnanediol P57 holds promise for development as a new anti-obesity drug. However, the content of P57 in natural plants is extremely low, only 0.003–0.02%. [(a) Phytochemistry 2007, 68, 2545-2553; (b) Planta Med 2011, 77, 1149-1160.]. Due to the diversity and microscopic heterogeneity of saponins in plants, obtaining pure pregnanediol P57 through isolation and purification is very difficult, and obtaining a sufficient quantity of P57 for activity testing is even more challenging. This has become a bottleneck for further in-depth research on the bioactivity of P57 and for the use of pure P57 as a weight-loss drug.

[0004]

[0005] In 1998, Professor van Heerden and colleagues at the University of Natal in South Africa pioneered the total synthesis of pregnanediol P57 using progesterone and glucose as raw materials. The main problems with this method are: the first step of the progesterone conversion reaction takes too long and has a low yield; subsequent chemical conversions require highly toxic solvents; the stepwise glycosylation of the aglycone Hoodigogenin A with the sugar is very inefficient; and the double bond on the 12-tigrate ester is affected during the final removal of the 2-position phenylthio group from the sugar.

[0006] In 2011, Professor Miesch and colleagues at the University of Strasbourg synthesized the p57 aglycone hoedogogenin A in 11 steps with an overall yield of 0.04%, starting from commercially available pregnane derivatives. The drawbacks of this method are the high cost of the starting materials, resulting in a high overall cost, and the critical Norrish I-Prins reaction yielded only 25%, with difficult separation, hindering industrial production.

[0007] In 2012, Dr. Zhang Jian synthesized P57 using digoxin as a starting material in a 20-step linear process with an overall yield of 2.4%. The drawbacks of this method are: the starting material is the natural extract digoxin, resulting in high costs; it also requires degradation to obtain digoxin aglycone, leading to significant waste; separation and purification are also cumbersome; subsequent chemical transformations require highly toxic solvents; and the stepwise glycosylation of the P57 aglycone, Hoodigogenin A, and the sugar resulted in low yields in both glycosylation processes. The overall industrialization economics of this route are poor.

[0008] In summary, there is currently a lack of a suitable method for industrial-scale synthesis of P57 in this field. Summary of the Invention

[0009] This invention provides intermediates, preparation methods, and uses for pregnanediol P57 and its derivatives, as well as pregnanediol P57 derivatives. Starting from the inexpensive starting material dehydroepiandrosterone (DHEA), this invention employs a stepwise reaction strategy using the Norrish I reaction and Prins reaction to synthesize the aglycone Hooodigogenin A. A convergent synthesis strategy is then used to achieve a one-step glycosylation assembly of the P57 aglycone and its trisaccharide. The synthetic route is short, yields high, and is easily scaled up for industrial applications.

[0010] In a first aspect, the present invention provides a compound represented by Formula I.

[0011]

[0012] in,

[0013] n is 0 or 1;

[0014] R1 is selected from the following group: hydrogen, C2-C6 alkyl, unsubstituted or para-substituted benzoyl, tris(C3-C9)silyl, tris(C9-C6)silyl, etc. 16 Aryl)silyl, allyl, or substituted or unsubstituted benzyl;

[0015] R2 is selected from hydrogen, hydroxyl, and halogen; wherein the hydroxyl group may have a protecting group, and the protecting group is selected from the group consisting of: C2-C6 alkyl acyl, unsubstituted or para-substituted benzoyl, tris(C3-C9)silyl, tris(C9-C6)silyl, and tris(C3-C9)silyl. 16 Aryl)silyl, allyl, or substituted or unsubstituted benzyl;

[0016] Wherein, the substituents of the benzoyl group are selected from the group consisting of: methoxy, nitro, azide, and halogen; and the substituents on the benzyl group are selected from the group consisting of: naphthylmethylene, p-methoxyphenyl, p-methylphenyl, p-nitrobenzyl, and para-halogen-substituted benzyl.

[0017] In another preferred embodiment, R1 is selected from the group consisting of acetyl, unsubstituted benzoyl, or para-methoxy-substituted benzoyl.

[0018] In another preferred embodiment, the compound is not P57:

[0019]

[0020] In another preferred embodiment, the compound is selected from the group consisting of:

[0021]

[0022]

[0023] A second aspect of the present invention provides a method for preparing a compound of Formula I as described in the first aspect of the present invention, the method comprising the steps of:

[0024] (1) React the polysaccharide shown in Formula II or Formula III with the aglycone shown in Formula IV to obtain the compound of Formula I.

[0025]

[0026] Wherein, the definitions of R1 and R2 are the same as those described in the first aspect of the present invention;

[0027] R3 is selected from the group consisting of C1-C10 alkyl groups, C3-C10 cycloalkyl groups, or C6-C10 aryl groups; preferably, R3 is a C4 alkyl group or a C3 cycloalkyl group.

[0028] In another preferred embodiment, the method includes the steps of: performing a ring-closing reaction with a compound of formula V, followed by a tigrate condensation reaction to obtain a compound of formula IV.

[0029]

[0030] R4 is selected from the group consisting of: C2-C6 alkyl, benzoyl or para-substituted benzoyl, tri(C3-C9)silyl, tri(C9-C6)silyl, and tri(C6-C6)silyl. 16 Aryl)silyl, allyl, benzyl, or benzyl or hydrogen substituted on the benzene ring;

[0031] The para-substituent of the benzoyl group is selected from the group consisting of: methoxy, nitro, azide, and halogen.

[0032] The benzyl group substituted on the benzene ring is selected from the group consisting of: naphthylmethylene, p-methoxyphenyl, p-methylphenyl, p-nitrobenzyl, and para-halogenated benzyl.

[0033] In another preferred embodiment, the R4 is selected from the group consisting of benzyl, p-methoxybenzyl, and naphthylmethylene.

[0034] In another preferred embodiment, the method further includes: performing a Norrish type I and Prins reaction with a compound of formula VI to convert it into intermediate V:

[0035]

[0036] In another preferred embodiment, the method further includes: performing a 20-position carbonylation and a Prins reaction using formula VII to obtain intermediate VI:

[0037]

[0038] Alternatively, the method may include the step of: oxidizing with formula IX to convert into intermediate VI:

[0039]

[0040] R4 and R5 are each independently selected from C2-C6 alkyl acyl, benzoyl or para-substituted benzoyl, tris(C3-C9)silyl, tris(C9-C6)silyl, and tris(C6-C6)silyl. 16 The benzoyl group is aryl, silyl, allyl, benzyl, or has a substituted benzyl group or hydrogen on the benzene ring; the para-substituted benzoyl group is methyl methoxyphenyl, methyl phenyl, nitrobenzyl, or halogen; the substituted benzyl group on the benzene ring is naphthylene, p-methoxyphenyl, p-methylphenyl, p-nitrobenzyl, or para-halogen-substituted benzyl. Preferably, R4 is benzyl, p-methoxybenzyl, or naphthylene; R5 is tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or hydrogen.

[0041] In another preferred embodiment, the method further includes: performing a Norrish type I reaction using formula VIII to obtain intermediate VII.

[0042]

[0043] The definitions of R4 and R5 are the same as above.

[0044] In another preferred embodiment, the method further includes: oxidizing with formula IX to convert into intermediate VIII:

[0045]

[0046] The definitions of R4 and R5 are the same as above.

[0047] In another preferred embodiment, the method further includes: performing a hydroboration oxidation reaction using formula X to obtain intermediate IX:

[0048]

[0049] R4 is defined as above.

[0050] A third aspect of the present invention provides a method of compound formula I as described in the first aspect of the present invention, characterized by comprising the steps of:

[0051] (1) Construction of the β-hydroxyl group at position 12: Using dehydroepiandrosterone (DHEA) as the starting material, the β-hydroxyl group at position 12 is introduced by three known steps: protecting the hydroxyl group at position 3, forming an enamine at position 17, and activating the CH bond at position 12.

[0052]

[0053] (2) Introduction of hydroxyl group at position 20: Compound 3 with vinyl group at C17 is obtained by reacting with compound 2, and then compound 4 with hydroxyl group at position 20 is prepared by hydroboration oxidation reaction.

[0054]

[0055] (3) Preparation of Norrish Type I reaction precursor: The hydroxyl groups at positions 12 and 17 are simultaneously oxidized to ketone carbonyl groups by oxidation; or the hydroxyl group at position 12 is selectively oxidized to ketone carbonyl groups by protecting group operation, while the hydroxyl group at position 17 is either exposed or protected by a protecting group.

[0056]

[0057] (4) Construction of the 14-position hydroxyl group: The 20-position of the compound was converted to a carbonyl group via the Norrish type I reaction, and then the desired 14-position β-hydroxyl group was constructed via the Prins reaction:

[0058]

[0059] (5) Protection of the 12-hydroxyl group with tigric acid: The ester condensation reaction of the 12-hydroxyl group with tigric acid was carried out under Yamaguchi ester condensation conditions:

[0060]

[0061] (6) Preparation of aglycone Hoodigogenin A: The protecting group at position 3 of compound 9 was removed to prepare aglycone Hoodigogenin A:

[0062]

[0063] (7) Glycosylation reaction: The trisaccharide is prepared into a suitable donor and glycosylated with the aglycone Hoodigogenin A under suitable glycosylation conditions to prepare the compound of formula I;

[0064] And optional step: (8) Remove the protecting group from the compound of formula I.

[0065] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0066] Through long-term and in-depth research, the inventors have developed a method for preparing compound P57 using dehydroepiandrosterone as a raw material:

[0067]

[0068] In the method described, the introduction of the 14-hydroxyl group of the aglycone Hoodigogenin A is efficiently constructed using the Norrish type I reaction and the Prins reaction, while the construction of the basic structural skeleton of P57 is achieved through a convergent strategy, using a one-step glycosylation of the glycosyl donor and the aglycone Hoodigogenin A for high efficiency. Subsequently, pregnaneposide P57 and its derivatives can be prepared through a simple protecting group removal operation. Based on the above findings, the inventors completed this invention.

[0069] Preparation method of compound P57

[0070] The steps of the preparation method of compound P57 of the present invention are as follows:

[0071]

[0072] Step (1): Construction of the 12-position β-hydroxyl group: Referring to (Angew. Chem. Int. Ed. 2009, 48, 7911-7914; J. Am. Chem. Soc. 2015, 137, 13776-13779.), it was prepared from dehydroepiandrosterone (DHEA) via a three-step known reaction (protection of the 3-position hydroxyl group, formation of an enamine from the 17-position carbonyl group, and activation of the 12-position hydroxyl group by a remote CH bond). R4 is selected from C1-C6 alkyl acyl, benzoyl or para-substituted benzoyl, tris(C3-C9)silyl, tris(C9-C6)silyl, and tris(C6-C6)silyl groups. 16 The benzoyl group is aryl, silyl, allyl, benzyl, or has a substituted benzyl group or hydrogen atom on the benzene ring; the para-substituted benzoyl group is methyl methoxyphenyl, methyl phenyl, nitrobenzyl, or halogen; the substituted benzyl group on the benzene ring refers to naphthylene, p-methoxyphenyl, p-methylphenyl, p-nitrobenzyl, or para-halogen-substituted benzyl. Preferably, R4 is benzyl, p-methoxybenzyl, or naphthylene.

[0073]

[0074] Step (2.1): Introduction of the 20-position hydroxyl group: Carbon addition is performed via the Wittigreck reaction to introduce a vinyl group at C17; the 20-position hydroxyl group is introduced via hydroboration oxidation. Compound 2 is dissolved in an organic solvent, and then a Wittigreck reagent (prepared by pre-mixing a base and a Wittigreck reagent precursor) is added to it, and the reaction yields compound 3. The base used can be one or any mixture of sodium hydride, lithium diisopropylamino, potassium di(trimethylsilylamino), sodium di(trimethylsilylamino), lithium di(trimethylsilylamino), potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, or n-butyllithium, preferably potassium tert-butoxide; the Wittish reagent precursor used can be ethyltriphenylphosphine bromide or ethylphenyl sulfide, preferably ethyltriphenylphosphine bromide; the molar ratio of compound 2, base, and Wittish reagent precursor can be 1:1 to 6:1 to 6, preferably 1:2 to 4:2 to 4; the organic solvent can be one or any mixture of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, toluene, dioxane, N,N-dimethylformamide, dimethyl sulfoxide, etc., preferably tetrahydrofuran; the reaction temperature is 0℃ to 100℃, preferably 40℃ to 70℃; the reaction time is 1 to 20 hours, preferably 4 to 8 hours.

[0075] Step (2.2): In an organic solvent, compound 3 first undergoes a hydroboration reaction with a borane reagent to obtain an alkylborane, and then an oxidant is added to oxidize the alkylborane to obtain compound 4. The borane used in the hydroboration reaction can be one or a mixture of any number of monosubstituted and disubstituted boranes such as borane tetrahydrofuran, 9-boron bicyclo[3.3.1]nonane (9-BBN), borane dimethyl sulfide, and diisopinepineborane, preferably 9-boron bicyclo[3.3.1]nonane; the molar ratio of compound 3 to the borane reagent can be 1:1 to 8, preferably 1:2 to 5; the organic solvent can be one or a mixture of any number of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, toluene, and dioxane, preferably tetrahydrofuran; the reaction temperature is 0℃ to 100℃, preferably 30℃ to 80℃; the reaction time is 1 to 20 hours, preferably 4 to 8 hours. When oxidizing the above-obtained borane with an oxidant, the oxidant can be a mixture of hydrogen peroxide and sodium hydroxide or sodium perborate, preferably a mixture of hydrogen peroxide and sodium hydroxide; the molar ratio of compound 3 to the oxidant can be 1:10 to 200, preferably 1:60 to 150; the reaction temperature is 0℃ to 60℃, preferably 0℃ to 30℃; the reaction time is 1 to 10 hours, preferably 1 to 4 hours. R4 is selected from C1-C6 alkyl acyl, benzoyl or para-substituted benzoyl, tris(C3-C9)silyl, tris(C9-C6)silyl, etc. 16 The benzoyl group is aryl, silyl, allyl, benzyl, or has a substituted benzyl group or hydrogen atom on the benzene ring; the para-substituted benzoyl group is methyl methoxyphenyl, methyl phenyl, nitrobenzyl, or halogen; the substituted benzyl group on the benzene ring refers to naphthylene, p-methoxyphenyl, p-methylphenyl, p-nitrobenzyl, or para-halogen-substituted benzyl. Preferably, R4 is benzyl, p-methoxybenzyl, or naphthylene.

[0076]

[0077] Step (3): Oxidation of the 12-position hydroxyl group to the ketone carbonyl group: Through appropriate protecting group operation, the 12-position hydroxyl group is selectively oxidized to the ketone carbonyl group, while the 17-position hydroxyl group is either exposed or protected by a protecting group.

[0078] Compound 4 is dissolved in a first organic solvent, and then, in the presence of a base, the hydroxyl group at carbon 20 reacts with a hydroxyl protecting agent to form a hydroxyl protecting group, yielding the hydroxyl-protected compound. Next, the hydroxyl-protected compound is dissolved in a second organic solvent, and an oxidizing agent is added to oxidize the hydroxyl group at carbon 12, yielding compound 5. The base used for protecting the hydroxyl group can be one or any mixture of sodium hydride, sodium hydroxide, triethylamine, imidazole, pyridine, or 4-dimethylaminopyridine, preferably imidazole; the hydroxyl protecting agent can be tert-butyldimethylchlorosilane, trimethylchlorosilane, tert-butyldiphenylchlorosilane, triisopropylchlorosilane, chloromethyl methyl ether, benzyl chloride, benzyl bromide, p-methoxybenzyl chloride, p-methoxybenzyl bromide, acetic anhydride, acetyl chloride, acetyl bromide, trifluoroacetyl chloride, trifluoroacetyl bromide, benzoyl chloride, benzoic anhydride, chloroacetyl chloride, or chloroacetic acid. The anhydride is preferably tert-butyldimethylchlorosilane; the molar ratio of the base and the hydroxyl protecting agent in compound 4 can be 1:1 to 6:1 to 4, preferably 1:2 to 4:1 to 2; the first organic solvent can be one or any mixture of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, toluene, dioxane, N,N-dimethylformamide, dimethyl sulfoxide, etc., preferably N,N-dimethylformamide; the reaction temperature is 0℃ to 80℃, preferably 10℃ to 40℃; the reaction time is 2 to 30 hours, preferably 10 to 20 hours. The oxidizing agents used for oxidizing the hydroxyl group at the 12th carbon position can be Dys-Martin oxidant (DMP), chromium trioxide, chromium trioxide-sulfuric acid-acetone (Jones' reagent), dichromates, chromium oxide-pyridine coordination compounds (Collins' reagent), pyridinium chlorochromate (PCC), pyridinium fluorochromate (PFC), nitrium dichromate (NDC), pyridinium dichromate (PDC), dimethyl sulfoxide-acetic anhydride system (DMSO-Ac2O), and dimethyl sulfoxide-dicyclohexylcarbonyl dihydrogen oxidant. The compound can be an imine system (DMSO-DCC), a dimethyl sulfoxide-oxalyl chloride system (DMSO-(COCl)2), silver carbonate, hypochlorite, or chlorate, or any mixture thereof, preferably Dysmartin oxidant (DMP); the molar ratio of the compound protected at the C20 hydroxyl position to the oxidant can be 1:1 to 10, preferably 1:2 to 6; the second organic solvent can be a mixture of one or more of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, toluene, dioxane, etc., preferably dichloromethane. R4 and R5 are each independently selected from C1-C6 alkyl acyl, benzoyl or para-substituted benzoyl, tris(C3-C9)silyl, tris(C9-C6)silyl, etc. 16The benzoyl group is aryl, silyl, allyl, benzyl, or a benzyl group substituted on the benzene ring, or hydrogen; the para-substituted benzoyl group is methyl methoxyphenyl, p-methylphenyl, p-nitrobenzyl, or para-halogenated benzyl. Preferably, R4 is benzyl, p-methoxybenzyl, or naphthyl methylene; R5 is tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or hydrogen. When R5 is a hydrogen atom, the hydroxyl group is deprotected using conventional methods for removing the hydroxyl protecting group in the art to obtain a compound with a hydroxyl group exposed at carbon 20; then, the hydroxyl-exposed compound is dissolved in a second organic solvent, an oxidizing agent is added, and the hydroxyl group at carbon 20 is oxidized to obtain compound 7. For example, when R5 is tert-butyldimethylsilyl or tert-butyldiphenylsilyl, the deprotecting agent used can be one or any mixture of tetrabutylammonium fluoride, potassium fluoride, cesium fluoride, or ammonium fluoride, preferably tetrabutylammonium fluoride; the first organic solvent can be one or any mixture of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, toluene, dioxane, N,N-dimethylformamide, dimethyl sulfoxide, preferably tetrahydrofuran; the molar ratio of compound 6 to the deprotecting agent can be 1:1 to 6, preferably 1:2 to 4; the reaction temperature is 0℃ to 80℃, preferably 40℃ to 70℃; the reaction time is 1 to 30 hours, preferably 10 to 20 hours.

[0079]

[0080] Step (4.1): Construction of the 14-hydroxyl group: The 20-hydroxyl group is oxidized to a carbonyl group via a Norrish type I reaction, and the 14-hydroxyl group is constructed via a Prins reaction. Compound 5 is dissolved in an organic solvent and reacted for a period of time under the illumination of a high-pressure mercury lamp or a photoreactor with a specific wavelength light source. The solvent is then removed by rotation, and acid is added and reacted for a period of time to obtain compound 6 (when R6 is a hydrogen atom, acid can be omitted). The organic solvent may be one or any mixture of dichloromethane, 1,2-dichloroethane, acetonitrile, carbon tetrachloride, tetrahydrofuran, benzene, toluene, carbon disulfide, nitrobenzene, dioxane, N,N-dimethylformamide, dimethyl sulfoxide, etc., preferably dioxane and dichloromethane; the high-pressure mercury lamp power may be one or more high-pressure mercury lamp light sources with power ranging from 50W to 400W, preferably 125W; the mass-volume ratio of compound 5 to organic solvent may be 1mg / ml to 100mg / ml, preferably 10mg / ml to 40mg / ml; the reaction temperature may be -30℃ to 80℃, preferably -20℃ to 30℃; the high-pressure mercury lamp irradiation time may be 0.5 to 20 hours, preferably 1 to 4 hours. The photoreactor light source can be one or more ultraviolet lamps with power ranging from 185nm to 350nm, preferably one or more ultraviolet lamps with power ranging from 280nm to 320nm; the mass-to-volume ratio of compound 5 to organic solvent can be 1mg / ml to 100mg / ml, preferably 10mg / ml to 40mg / ml; the reaction temperature is -30℃ to 80℃, preferably 0℃ to 30℃; the irradiation time is 0.5 to 20 hours, preferably 1 to 6 hours. The acid can be one or any mixture of sulfuric acid, hydrochloric acid, phosphoric acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, or camphorsulfonic acid, preferably a 75% aqueous acetic acid solution; the volume ratio of the added acid to the organic solvent can be 0.5 to 5:1, preferably 0.5 to 1.5:1; the reaction temperature after adding the acid is 0℃ to 60℃, preferably 0℃ to 30℃; the reaction time after adding the acid is 0.5 to 5 hours, preferably 0.5 to 1.5 hours. R4 and R5 are each independently selected from C1-C6 alkyl acyl, benzoyl or para-substituted benzoyl, tris(C3-C9)silyl, tris(C9-C6)silyl, and tris(C6-C6)silyl. 16 The benzoyl group is aryl, silyl, allyl, benzyl, or has a substituted benzyl group or hydrogen on the benzene ring; the para-substituted benzoyl group is methyl methoxyphenyl, methyl phenyl, nitrobenzyl, or halogen; the substituted benzyl group on the benzene ring is naphthylene, p-methoxyphenyl, p-methylphenyl, p-nitrobenzyl, or para-halogen-substituted benzyl. Preferably, R4 is benzyl, p-methoxybenzyl, or naphthylene; R5 is tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or hydrogen.

[0081] Step (4.2): Compound 6 is dissolved in a first organic solvent, and its hydroxyl protecting group is deprotected using conventional methods in the art to obtain a compound with the hydroxyl protecting group exposed at carbon 20; then, the hydroxyl protecting compound is dissolved in a second organic solvent, an oxidant is added, and the hydroxyl protecting group at carbon 20 is oxidized to obtain compound 7. For example, when R6 is silicon-based, the deprotecting agent used can be one or any mixture of tetrabutylammonium fluoride, potassium fluoride, cesium fluoride, or ammonium fluoride, preferably tetrabutylammonium fluoride; the first organic solvent can be one or any mixture of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, toluene, dioxane, N,N-dimethylformamide, dimethyl sulfoxide, preferably tetrahydrofuran; the molar ratio of compound 6 to the deprotecting agent can be 1:1 to 6, preferably 1:2 to 4; the reaction temperature is -20℃ to 80℃, preferably 40℃ to 70℃; the reaction time is 1 to 30 hours, preferably 10 to 20 hours. The oxidation reaction conditions for the hydroxyl group at the 20th carbon are exactly the same as the oxidation conditions in step 3 described above.

[0082] Step (4.3): After dissolving compound 7 in an organic solvent, an acid is added to carry out the Prins reaction to obtain compound 8. The acid can be one or any mixture of sulfuric acid, hydrochloric acid, phosphoric acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, or camphorsulfonic acid, preferably a mixture of acetic acid / water / trifluoroacetic acid (2.5 / 1 / 0.6); the organic solvent can be one or any mixture of dichloromethane, 1,2-dichloroethane, methanol, ethanol, tetrahydrofuran, toluene, dioxane, etc., preferably tetrahydrofuran; the mass-to-volume ratio of compound 7 to organic solvent can be 1 mg / ml to 50 mg / ml, preferably 1 mg / ml to 20 mg / ml; the volume ratio of organic solvent to added acid can be 0.5 to 5, preferably 0.5 to 1.5; the reaction temperature is -20℃ to 60℃, preferably -10℃ to 30℃; the reaction time is 1 to 40 hours, preferably 10 to 20 hours.

[0083]

[0084] Step (5): Condensation reaction of 12-position tigoester: Compound 8 is dissolved in an organic solvent, and tigoyl reagent, condensation reagent and organic base are added. After reaction, compound 9 is obtained. The organic solvent can be one or any mixture of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, toluene, N,N-dimethylformamide, dimethyl sulfoxide, dioxane, etc., preferably toluene; the tigoyl reagent can be one or any mixture of maleic anhydride, tigoic acid or tigoyl chloride, preferably tigoic acid; the condensation reagent can be one or any mixture of 2,4,6-trichlorobenzoyl chloride, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) or dicyclohexylcarbodiimide (DCC), preferably 2,4,6-Trichlorobenzoyl chloride is selected; the organic base can be one or any mixture of 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, diisopropylamine, pyridine, dimethylpyridine, or trimethylpyridine, preferably triethylamine and 4-dimethylaminopyridine; the molar ratio of compound 8, tiglyl reagent, condensing agent, and organic base can be 1:1 to 5:1 to 5:1 to 10, preferably 1:1 to 3:1 to 3:2 to 6; the reaction temperature is 0℃ to 120℃, preferably 60℃ to 100℃; the reaction time is 1 to 20 hours, preferably 2 to 8 hours. R4 is selected from C1-C6 alkyl acyl, benzoyl or para-substituted benzoyl, tri(C3-C9 alkyl)silyl, tri(C9-C6 alkyl)silyl, tri(C6 ... 16 The benzoyl group is aryl, silyl, allyl, benzyl, or has a substituted benzyl group or hydrogen atom on the benzene ring; the para-substituted benzoyl group is methyl methoxyphenyl, methyl phenyl, nitrobenzyl, or halogen; the substituted benzyl group on the benzene ring refers to naphthylene, p-methoxyphenyl, p-methylphenyl, p-nitrobenzyl, or para-halogen-substituted benzyl. Preferably, R4 is benzyl, p-methoxybenzyl, or naphthylene.

[0085]

[0086] Step (6): Removal of the 3-position protecting group to prepare the aglycone Hoodigogenin A: Compound 9 is dissolved in a first organic solvent, and its hydroxyl group is deprotected using conventional methods in the art to obtain a compound with the hydroxyl group exposed at the carbon 3 position. R4 is selected from C1-C6 alkyl acyl, benzoyl or para-substituted benzoyl, tris(C3-C9)silyl, tris(C9-C6)silyl, etc. 16The benzoyl group is aryl, silyl, allyl, benzyl, or has a substituted benzyl group or hydrogen atom on the benzene ring; the para-substituted benzoyl group has a para-substituent of methyl methoxyphenyl, methyl phenyl, nitrobenzyl, or para-halogenated benzyl. Preferably, R4 is benzyl, methyl methoxybenzyl, or methyl methoxyphenyl. For example, when R4 is benzyl, compound 9 is dissolved in a solvent, and a debenzylating agent is added, resulting in the P57 aglycone Hoodigogenin A. The debenzylidene reagent may be one or any mixture of several of the following: palladium on carbon / hydrogen, palladium hydroxide on carbon / hydrogen, Raney nickel, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), aluminum trichloride, lithium / naphthalene reagent, dimethyl boron bromide, lithium / di-tert-butylbiphenyl, etc., preferably 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ); the solvent may be water, various pH buffer solutions, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, toluene, N,N-dimethylformyl The reaction mixture comprises one or any mixture of amines, dimethyl sulfoxide, dioxane, etc., preferably a mixture of 1,2-dichloroethane and pH=7.0 phosphate buffer; the molar ratio of compound 9 to the debenzylidene reagent can be 1:1 to 10, preferably 1:3 to 6; the mass-volume ratio of compound 9 to solvent can be 1 mg / ml to 200 mg / ml, preferably 1 mg / ml to 80 mg / ml; the reaction temperature is 0℃ to 80℃, preferably 30℃ to 60℃; the reaction time is 1 to 10 hours, preferably 1 to 3 hours.

[0087] In addition to the above-mentioned route, compound 7 can also be obtained from intermediate 4 through step (7):

[0088]

[0089] In step (7), the hydroxyl groups at positions 12 and 20 are oxidized to ketone carbonyl groups: referring to step (3), the hydroxyl groups on the carbons at positions 12 and 20 are oxidized to obtain compound 10; the photolysis reaction of compound 10 is carried out completely according to the reaction conditions in step 4 above to obtain compound 7. Wherein, R4 is selected from C1-C6 alkyl acyl, benzoyl or para-substituted benzoyl, tris(C3-C9)silyl, tris(C9-C6)silyl, and tris(C3-C9)silyl. 16 The benzoyl group is aryl, silyl, allyl, benzyl, or has a substituted benzyl group or hydrogen atom on the benzene ring; the para-substituted benzoyl group is methyl methoxyphenyl, methyl phenyl, nitrobenzyl, or halogen; the substituted benzyl group on the benzene ring refers to naphthylene, p-methoxyphenyl, p-methylphenyl, p-nitrobenzyl, or para-halogen-substituted benzyl. Preferably, R4 is benzyl, p-methoxybenzyl, or naphthylene.

[0090] After obtaining the aglycone Hoodigogenin A, steroidal saponin P57 can be obtained through the following synthetic steps 9-10:

[0091]

[0092] R1 is selected from C1-C6 alkyl acyl, benzoyl or para-substituted benzoyl, tri(C3-C9)silyl, tri(C9-C6)silyl, and tri(C6-C6)silyl. 16 The benzoyl group is aryl, silyl, allyl, benzyl, or a benzyl group substituted on the benzene ring, or hydrogen; the para-substituted benzoyl group is a methyl methoxy, nitro, azide, or halogen; the benzyl group substituted on the benzene ring refers to naphthylene, p-methoxyphenyl, p-methylphenyl, p-nitrobenzyl, or para-halogen-substituted benzyl. Preferably, R1 is independently selected from acetyl, benzoyl, or a benzoyl group substituted on the benzene ring. R2 is selected from hydrogen, hydroxyl, halogen, or a hydroxyl group with a protecting group (the protecting group is similar to R1). R6 is selected from C1-C6. 10 Alkyl group, C3-C 10 The cycloalkyl or aryl group, preferably R6 is a C4 alkyl or a C3 cycloalkyl group.

[0093] (9) Trisaccharide 11 was prepared by referring to known literature [Chem.Comm.2012,48,8679-8681; Proc.Natl.Acad.Sci.USA2014,111,14571-14576.], dissolved in an organic solvent, and esterified with o-alkynylbenzoic acid under the action of condensing reagent and base. The organic solvent may be one or any mixture of several of the following: dichloromethane, 1,2-dichloroethane, acetonitrile, ethyl acetate, tetrahydrofuran, toluene, etc., preferably dichloromethane; the condensing agent may be one or any mixture of several of the following: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), dicyclohexylcarbodiimide (DCC), 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), 1-hydroxybenzotri(HOBt), etc., preferably 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI); the base may be one or any mixture of several of the following: the condensing agent itself, triethylamine, pyridine, N,N-diisopropylethylamine (DIPEA), etc., preferably the condensing agent itself and N,N-diisopropylethylamine (DIPEA). The molar ratio of trisaccharide, substituted benzoic acid, condensing agent, and base can be 1:1 to 5:1 to 5:1 to 200, preferably 1:1 to 1.5:1.5 to 3:1 to 6; the reaction temperature is 0℃ to 50℃, preferably 10℃ to 30℃; and the reaction time is 1 to 20 hours, preferably 2 to 8 hours.

[0094] P57 aglycone Hoodigogenin A and trisaccharide 12 were glycosylated to obtain compound 13. P57 aglycone Hoodigogenin A and compound 12 were dissolved in an organic solvent, a drying agent was added, and then a Lewis acid was added for glycosylation to obtain compound 13. The drying agent can be... Molecular sieves Molecular sieves Molecular sieves, acid-washed Molecular sieves, acid-washed Molecular sieves, acid-washed Molecular sieves, anhydrous sulfates, etc., one or any mixture thereof, preferably Molecular sieves and Molecular sieve; the mass ratio of the desiccant to compound 11 can be 1-8, preferably 2-5; the organic solvent can be one or any mixture of dichloromethane, 1,2-dichloroethane, acetonitrile, ethyl acetate, tetrahydrofuran, toluene, chlorobenzene, etc., preferably dichloromethane or chlorobenzene; the Lewis acid can be one or any mixture of gold monochloride, gold trichloride, mercuric trifluoromethanesulfonate, gold triphenylphosphine trifluoromethanesulfonate (Ph3PAuOTf), gold triphenylphosphine (I) bis(trifluoromethanesulfonyl)imine salt (Ph3PAuNTf2), etc., preferably gold triphenylphosphine trifluoromethanesulfonate (Ph3PAuOTf) or gold triphenylphosphine (I) bis(trifluoromethanesulfonyl)imine salt (Ph3PAuNTf2); P57 aglycone Hoodigogenin The molar ratio of A to the Lewis acid can be 1:0.001 to 1, preferably 1:0.01 to 0.3; the molar ratio of P57 aglycone Hoodigogenin A to compound 11 can be 1:1 to 8, preferably 1:1 to 2; the reaction temperature is -70℃ to 50℃, preferably -30℃ to 30℃; the reaction time is 1 to 20 hours, preferably 1 to 5 hours.

[0095]

[0096] Compound 12 was deprotected under alkaline conditions to obtain P57(1). Compound 12 was dissolved in an organic solvent, and under the action of an alkali, the acyl protecting group was removed to obtain compound P57(1). The alkali can be one or any mixture of sodium methoxide, sodium ethoxide, potassium tert-butoxide, ammonia, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc., preferably potassium hydroxide; the organic solvent can be one or any mixture of dichloromethane, 1,2-dichloroethane, acetonitrile, methanol, ethanol, tetrahydrofuran, toluene, etc., preferably a mixture of methanol and toluene; the molar ratio of compound 12 to the alkali can be 1:1 to 50, preferably 1:5 to 20; the reaction temperature is 0℃ to 60℃, preferably 0℃ to 30℃; the reaction time is 1 to 20 hours, preferably 1 to 4 hours.

[0097]

[0098] Compound 13 can also be obtained from intermediate 11 via synthetic steps 13 and 14. R1 is selected from C1-C6 alkyl acyl, benzoyl or para-substituted benzoyl, tris(C3-C9)silyl, tris(C9-C6)silyl, etc. 16 The benzoyl group is aryl, silyl, allyl, benzyl, or a benzyl group substituted on the benzene ring, or hydrogen; the para-substituted benzoyl group refers to methyl methoxyphenyl, p-methoxyphenyl, p-methylphenyl, p-nitrobenzyl, or para-halogenated benzyl. Preferably, R1 is selected from acetyl, benzoyl, or a benzoyl group substituted on the benzene ring. R2 is selected from hydrogen, hydroxyl, halogen, or a hydroxyl group with a protecting group (the protecting group is similar to R1).

[0099] Preparation of trisaccharide glycoene donors: Trisaccharide 11 is reacted with an acid anhydride or acyl chloride under alkaline conditions using an organic solvent to prepare the glycoene donor. The organic solvent can be one or any mixture of dichloromethane, 1,2-dichloroethane, acetonitrile, ethyl acetate, tetrahydrofuran, toluene, etc., preferably dichloromethane; the acid anhydride can be acetic anhydride, benzoic anhydride, trifluoromethanesulfonic anhydride, methanesulfonic anhydride, p-toluenesulfonic anhydride, etc.; the acyl chloride can be acetyl chloride, benzoic acid chloride, p-toluenesulfonyl chloride, methanesulfonyl chloride, etc., preferably trifluoromethanesulfonic anhydride; the base can be one or any mixture of triethylamine, pyridine, N,N-diisopropylethylamine (DIPEA), etc., preferably triethylamine. The molar ratio of trisaccharide, acid anhydride or acyl chloride, and base can be 1:1 to 20:1 to 30, preferably 1:2 to 5:3 to 10; the reaction temperature is -20℃ to 50℃, preferably -10℃ to 30℃; and the reaction time is 1 to 40 hours, preferably 8 to 20 hours.

[0100] P57 aglycone Hoodigogenin A and trisaccharide glycoene donor 14 were glycosylated to obtain compound 13. P57 aglycone Hoodigogenin A and compound 13 were dissolved in an organic solvent, a drying agent was added, and then an acid was added for glycosylation to obtain compound 13. The drying agent can be... Molecular sieves Molecular sieves Molecular sieves, acid-washed Molecular sieves, acid-washed Molecular sieves, acid-washed Molecular sieves, anhydrous sulfates, etc., one or any mixture thereof, preferably Molecular sieves and Molecular sieve; the mass ratio of the desiccant to compound 11 can be 1-8, preferably 2-5; the organic solvent can be one or any mixture of dichloromethane, 1,2-dichloroethane, acetonitrile, ethyl acetate, tetrahydrofuran, toluene, chlorobenzene, etc., preferably chlorobenzene; the acid can be one or any mixture of triphenylphosphine hydroiodide (TPHI), triphenylphosphine hydrobromide (TPHB), various phosphine hydrohalides, various chiral and non-chiral phosphoric acids, etc., preferably triphenylphosphine hydrobromide (TPHB); the molar ratio of P57 aglycone Hoodigogenin A to the Lewis acid can be 1:0.001-1, preferably 1:0.05-0.3; the molar ratio of P57 aglycone Hoodigogenin A to compound 14 can be 1:0.5-8, preferably 1:0.5-2; the reaction temperature is -70℃ to 50℃, preferably -30℃ to 30℃; the reaction time is 1-20 hours, preferably 4-10 hours.

[0101] Compared with the prior art, the main advantages of the present invention include:

[0102] 1. A method for the industrial production of P57 with a short synthetic route is provided. The method uses inexpensive dehydroepiandrosterone as a raw material to efficiently construct a 14-hydroxyl group through the Norrish I reaction and Prins reaction, which facilitates the large-scale acquisition of the P57 aglycone Hoodigogenin A; trisaccharide and tetrasaccharide fragments are prepared with high selectivity using inexpensive and readily available glucose as a raw material; then a one-step "glycosylation" reaction and deprotection operation are performed to prepare gram-scale pregnanediol P57 and its derivatives.

[0103] 2. A series of compounds with P57-like structures were provided.

[0104] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0105] The following examples will help to further understand the present invention, but do not limit the scope of the invention.

[0106] Example 1: Synthesis of Compounds 2-4

[0107]

[0108] Following the method described in the literature (Angew. Chem. Int. Ed. 2009, 48, 7911-7914; J. Am. Chem. Soc. 2015, 137, 13776-13779.), compound 2-2 was prepared from dehydroepiandrosterone (DHEA) via a three-step reaction. Compound 2-2: 1 H NMR (400MHz, CDCl3) δ7.36-7.24(m,5H),5.37(brs,1H),4.56(s,2H),3.80(dd ,J=11.3,4.7Hz,1H),3.31-3.23(m,1H),3.10(s,1H),2.50-2.43(m,2H),2.31 -2.26(m,1H),2.15-2.08(m,2H),2.04-1.94(m,2H),1.89-1.78(m,2H),1.68- 1.40(m,5H),1.27-1.20(m,1H),1.13-1.00(m,2H),1.03(s,3H),0.95(s,3H); 13 C NMR (100MHz, CDCl3) δ141.2,139.0,128.4,127.6,127.5,120.7,78.3,72.7,70.0,51 .4,49.6,49.2,39.1,37.2,37.2,35.8,30.6,30.5,28.3,28.3,21.7,19.4,8.1; ESIMS 417.5[M+Na] + .

[0109] Ph3PEtBr (28.5 g, 76.8 mmol) and t-BuOK (8.60 g, 76.8 mmol) were added to a dry three-necked flask, followed by THF (200 mL). The mixture was stirred at room temperature for 40 min, yielding a blood-red turbid liquid. Compound 2-2 (10.1 g dissolved in 100 mL of THF, 25.6 mmol) was added, and the mixture was heated to 70 °C and stirred for 5 h. After cooling, a saturated ammonium chloride solution was added and stirred for 30 min. The mixture was separated, and the aqueous phase was extracted three times with n-hexane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The solution was then subjected to column chromatography (PE / EtOAc = 10:1) to give a white solid 2-3 (8.8 g, 85%). Compound 2-3: [α] 25 D = -47.5 (c = 1.4, CHCl3); 1HNMR(400MHz, CDCl3)δ7.36-7.31(m,4H),7.28-7.24(m,1H),5.36(brs,1H),5.27-5.20(m,1 H),4.56(s,2H),3.78(dt,J=10.4,4.9Hz,1H),3.27(tt,J=11.3,4.5Hz,1H),2.48-2.41(m,2H ),2.32-2.16(m,2H),2.06-1.95(m,2H),1.89-1.79(m,5H),1.69(d,J=5.3Hz,1H),1.67-1.5 9(m,1H),1.57-1.37(m,4H),1.32-1.26(m,1H),1.13-1.04(m,2H),1.03(s,3H),0.89(s,3H); 13 C NMR (100MHz, CDCl3) δ148.6,140.9,139.1,128.5,127.6,127.5,121.5,115.1,78.5,74.7,70.0,55.0 ,49.3,48.9,39.1,37.2,37.0,33.3,31.9,31.4,30.4,28.4,23.5,19.4,14.6,11.8; HRMS(ESI)calcd for C 28 H 38 O2Na[M+Na] + 429.2764, found 429.2768.

[0110] Compound 2-3 (7.10 g, 17.5 mmol) was dissolved in 100 mL of THF, and 9-BBN (100 mL, 0.5 M in THF, 50.0 mmol) was added. The mixture was heated to 60 °C and reacted for 5 h. After cooling to room temperature, the mixture was transferred to an ice bath for further cooling. 10% NaOH (100 mL) and 30% H2O2 (200 mL) were added slowly in sequence, and the mixture was heated to room temperature and stirred for another 2 h. TLC showed that the reaction was complete. After dilution with ethyl acetate, the aqueous layer was separated, extracted three times with ethyl acetate, and the organic phases were combined. The solutions were washed successively with saturated Na2S2O3 solution and saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE / EtOAc = 2:1) to give a white solid 2-4 (6.70 g, 91%). Compound 2-4: [α] 25 D = -53.7 (c = 1.0, CHCl3); 1H NMR(400MHz, CDCl3)δ7.34-7.31(m,4H),7.28-7.26(m,1H),5.35(brs,1H),4.56(s,2H),4.11 -3.05(m,1H),3.36(dd,J=11.2,4.5Hz,1H),3.31-3.23(m,1H),2.43(ddd,J=13.1,4.6,2.1Hz, 1H),2.31-2.24(m,1H),2.04-1.95(m,2H),1.90-1.85(m,1H),1.79-1.66(m,4H),1.58-1.38( m,6H),1.26(d,J=6.8Hz,3H),1.08-1.00(m,2H),1.03(s,3H),0.98-0.93(m,1H),0.79(s,3H); 13 C NMR (100MHz, CDCl3) δ141.1,139.1,128.5,127.7,127.5,121.5,78.6,78.3,70.0,68.9,56.7,55.1 ,49.6,48.2,39.2,37.3,37.1,31.6,30.3,29.3,28.5,24.3,23.7,20.5,19.4,9.2; HRMS(ESI)calcd forC 28 H 40 O3Na[M+Na] + 447.2870, found 447.2875.

[0111] Example 2: Synthesis of Compounds 2-5

[0112]

[0113] Compounds 2-4 (6.70 g, 15.8 mmol) were dissolved in dry DMF (150 mL), and imidazole (3.23 g, 47.4 mmol) and tert-butyldimethylchlorosilane (3.57 g, 23.7 mmol) were added. The mixture was stirred at room temperature for 20 h. TLC showed that the reaction was complete. The solution was diluted with ethyl acetate, washed successively with saturated sodium bicarbonate aqueous solution and saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE / EtOAc = 12:1) to give a white solid (8.2 g, 96%).

[0114] The above-mentioned white solid (9.20 g, 17.1 mmol) was dissolved in dry CH₂Cl₂ (5 mL), and Dysmartin oxidant (DMP) (18.1 g, 42.7 mmol) and NaHCO₃ (5.0 g, 59.9 mmol) were added at room temperature. The mixture was stirred for 2 h. TLC showed that the reaction was complete. The mixture was diluted with EtOAc and washed successively with saturated Na₂SO₃ solution, saturated sodium bicarbonate aqueous solution, and saturated brine. After drying with anhydrous sodium sulfate, the mixture was concentrated and subjected to column chromatography (PE / EtOAc = 15:1) to give white solid 5 (8.4 g, 92%). Compound 5: [α] 25 D = +21.9 (c = 0.68, CHCl3); 1 H NMR (400MHz, CDCl3) δ7.36-7.29(m,4H),7.28-7.22(m,1H),5.37(brs,1H),4.55(s,2H),3.91-3.85(m, 1H),3.33-3.21(m,1H),2.59(t,J=13.2Hz,1H),2.47(ddd,J=13.3,4.6,2.1Hz,1H),2.27(t,J=11.2Hz,1 H),2.22-2.11(m,2H),2.10-1.93(m,2H),1.90-1.64(m,5H),1.62-1.49(m,2H),1.48-1.30(m,3H),1.1 6(d,J=6.2Hz,3H),1.13-1.07(m,1H),1.10(s,3H),1.04(s,3H),0.87(s,9H),0.05(s,3H),0.02(s,3H); 13 C NMR (100MHz, CDCl3) δ215.0,140.7,139.0,128.4,127.6,127.5,121.4,78.3,70.1,57.5,56.1,53.4,49.4,39 .1,37.9,37.7,37.0,31.5,31.3,28.3,26.1,24.4,24.0,23.5,19.1,18.1,13.0,-3.3,-4.5; HRMS(ESI)calcd for C 34 H 53 O3Si[M+H] + 537.3758, found 537.3767.

[0115] Example 3 Synthesis of compounds 2-6

[0116]

[0117] Compound 2-5 (2.0 g, 3.72 mmol) was dissolved in 1,4-dioxane (80 mL), cooled in a liquid nitrogen bath, and purged three times. The reaction solution was irradiated with a 125 W high-pressure mercury lamp for 2.5 h in an ice bath. After removing the solvent by rotary evaporation, 75% acetic acid (100 mL) was added and stirred for 1 h. The mixture was washed once with ice water, and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed successively with saturated sodium bicarbonate aqueous solution and saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE / EtOAc = 15:1) to give a colorless oily liquid 2-6 (1.68 g, 84%). Compound 2-6: [α] 24 D = –4.9 (c = 1.1, CHCl3); 1 H NMR(400MHz, CDCl3)δ9.54(s,1H),7.39-7.31(m,4H),7.30-7.23(m,1H),5.43(brs,1H),4.57( s,2H),3.98(dd,J=6.2,2.4Hz,1H),3.38-3.24(m,1H),2.68(dt,J=16.2,8.0Hz,1H),2.53-2.36 (m,2H),2.34-2.16(m,4H),2.14-1.94(m,3H),1.93-1.80(m,2H),1.75-1.70(m,2H),1.65(s,3 H),1.62-1.49(m,2H),1.19-1.12(m,1H),1.05(s,6H),0.83(s,9H),0.01(s,3H),-0.04(s,3H); 13 C NMR (100MHz, CDCl3) δ201.9,139.7,139.0,138.9,136.2,128.5,127.7,127.6,122.2,78.4,70.2,68.9,57.4,45. 3,43.1,39.1,38.1,37.7,34.2,31.5,30.1,28.3,25.9,22.2,21.7,19.3,18.1,13.6,-4.2,-4.8; HRMS(ESI)calcd for C 34 H 52 O3SiNa[M+Na] + 559.3578, found 559.3580.

[0118] Example 4 Synthesis of compounds 2-8

[0119]

[0120] Compound 2-6 (1.30 g, 2.42 mmol) was dissolved in THF (8 mL), and TBAF (7.3 mL, 1.0 M in THF, 7.3 mmol) was added. The mixture was heated to 65 °C and reacted for 18 h. TLC showed that the reaction was complete. After cooling, the mixture was diluted with dichloromethane, washed once with water, and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE / EtOAc = 4:1) to give a colorless oily liquid 2-7 (923 mg, 91%).

[0121] The above-mentioned colorless oily liquid 2-7 (1.35 g, 3.19 mmol) was dissolved in dry CH2Cl2 (20 mL). At room temperature, Dysmartin oxidant (DMP) (3.39 g, 7.99 mmol) and NaHCO3 (938 mg, 11.2 mmol) were added, and the mixture was stirred for 1 h. TLC showed that the reaction was complete. The solution was diluted with EtOAc, washed successively with saturated Na2SO3 solution, saturated sodium bicarbonate aqueous solution, and saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE / EtOAc = 6:1) to give a white solid 2-8 (1.23 g, 92%). Compound 2-8: [α] 30 D = -129.2 (c = 1.6, CHCl3); 1 H NMR (500MHz, CDCl3) δ9.60 (d, J = 1.3Hz, 1H), 7.38-7.30 (m, 4H), 7.29-7.25 (m, 1H), 5.43 (brs, 1H),4.56(s,2H),3.36-3.26(m,2H),2.69(td,J=11.2,5.0Hz,1H),2.53-2.39(m,2H),2.32-2 .18(m,3H),2.15-2.07(m,3H),2.06(s,3H),2.03-1.96(m,1H),1.94-1.83(m,3H),1.71(dt,J =13.1,3.5Hz,1H),1.65(s,3H),1.61-1.50(m,1H),1.16(td,J=13.6,3.7Hz,1H),1.05(s,3H); 13 C NMR (125MHz, CDCl3) δ211.0,201.4,142.0,139.9,138.9,133.5,128.4,127.6,127.6,121.6,78.2,70.1 ,64.2,44.5,43.3,39.0,38.1,37.5,34.5,31.7,30.1,28.2,27.3,25.5,19.2,13.6; HRMS(ESI)calcdfor C28 H 36 O3Na[M+Na] + 443.2557, found 443.2559.

[0122] Example 5: Synthesis of P57 aglycone Hoodigogenin A

[0123]

[0124] Compound 2-8 (1.15 g, 2.73 mmol) was dissolved in THF (80 mL), and a mixture of acetic acid / water / trifluoroacetic acid (2.5 / 1 / 0.6) (80 mL) was added. The reaction was carried out at room temperature for 18 h. TLC showed that the reaction was complete. The solution was diluted with dichloromethane, washed once with ice water, and extracted twice with dichloromethane. The organic phases were combined, washed successively with saturated sodium bicarbonate aqueous solution and saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE / EtOAc = 1.5:1) to give a white solid 2-9 (890 mg, 75%). Compound 2-9: [α] 27 D = +11.9 (c = 1.0, CHCl3); 1 H NMR (500MHz, CDCl3) δ7.38-7.30(m,4H),7.29-7.25(m,1H),5.40(brs,1H),4.58(d,J=11.9Hz,1H) ,4.55(d,J=11.9Hz,1H),4.39(s,1H),3.60(dd,J=7.8,6.3Hz,1H),3.35-3.23(m,2H),2.49-2.41( m,1H),2.35-2.27(m,2H),2.27(s,3H),2.01-1.79(m,6H),1.78-1.68(m,3H),1.61-1.50(m,1H),1 .45(q,J=12.5Hz,1H),1.20(td,J=12.3,4.1Hz,1H),1.08-1.02(m,1H),1.01(s,3H),0.93(s,3H); 13 C NMR (125MHz, CDCl3) δ218.3,139.2,139.0,128.5,127.7,127.6,122.2,85.8,78.4,73.5,70.1,57.0 ,55.2,43.6,39.0,37.4,37.2,35.8,34.6,33.2,30.0,28.5,27.5,24.5,19.5,8.4; HRMS(ESI)calcd forC 28 H 38 O4Na[M+Na]+ 461.2662, found 461.2665.

[0125] Tiragic acid (346 mg, 3.45 mmol) was dissolved in toluene (15 mL), followed by the addition of Et3N (1.3 mL, 9.2 mmol) and 2,4,6-trichlorobenzoyl chloride (0.54 mL, 3.45 mmol). The mixture was stirred at room temperature for 2 h. Then, a toluene (10 mL) solution containing 2-9 (1.01 g, 2.30 mmol) and DMAP (140 mg, 1.15 mmol) was added, and the mixture was stirred at 80 °C for 2 h. After cooling to room temperature, the mixture was diluted with EtOAc, washed with saturated sodium bicarbonate aqueous solution and saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE / EtOAc = 6:1) to give a white solid 2-10 (1.08 g, 90%). Compound 2-10: [α] 28 D = +15.9 (c = 0.73, CHCl3); 1 H NMR (500MHz, CDCl3) δ7.38-7.29(m,4H),7.28-7.24(m,1H),6.95-6.91(m,1H),5.40(brs,1H),4.64(d d,J=12.0,4.4Hz,1H),4.55(s,2H),4.25(s,1H),3.33-3.22(m,1H),3.18-3.09(m,1H),2.45(ddd,J=13 .2,4.7,2.3Hz,1H),2.38-2.23(m,2H),2.20(s,3H),2.03-1.92(m,4H),1.89(s,3H),1.84(d,J=8.1Hz ,3H),1.83-1.71(m,4H),1.60(s,1H),1.54-1.44(m,2H),1.32-1.26(m,1H),1.07(s,3H),1.00(s,3H); 13 C NMR (125MHz, CDCl3) δ217.2,167.8,139.2,139.1,138.0,128.9,128.5,127.7,127.6,122.1,85.8,78.4,76.1,70.1, 57.3,53.9,43.2,39.0,37.4,37.3,35.9,34.6,33.3,28.4,27.5,26.2,24.5,19.5,14.7,12.3,10.1; HRMS(ESI)calcd for C 33 H 48 O5N[M+NH4] +538.3527, found 538.3530.

[0126] Compound 2-10 (1.08 g, 2.07 mmol) was dissolved in a mixture of 1,2-dichloroethane (20 mL) and phosphate buffer (pH 7.0) (2.4 mL). 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (2.35 g, 10.4 mmol) was added, and the mixture was reacted at room temperature to 50 °C for 1.5 h. TLC showed the reaction was complete. The mixture was cooled to room temperature, diluted with dichloromethane, washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE / EtOAc = 2:1) to give a white solid, Hoodigogenin A (721 mg, 81%). Hoodigogenin A: [α] 27 D = +16.8 (c = 0.40, CHCl3); 1 H NMR (500MHz, CDCl3) δ6.97-6.89(m,1H),5.41(m,1H),4.64(dd,J=12.0,4.4Hz,1H),4.27(s,1H), 3.52(ddd,J=15.8,11.2,4.5Hz,1H),3.17-3.10(m,1H),2.32(ddd,J=13.1,5.1,2.4Hz,2H),2.26- 2.21(m,1H),2.20(s,3H),2.04-1.93(m,3H),1.89(s,3H),1.84(d,J=8.0Hz,3H),1.82-1.72(m,5 H),1.53-1.43(m,2H),1.33-1.28(m,2H),1.12(dd,J=14.2,4.3Hz,1H),1.07(s,3H),0.99(s,3H); 13 C NMR (125MHz, CDCl3) δ217.2,167.8,139.1,138.0,128.9,122.2,85.9,76.1,71.7,57.3,53.9, 43.2,42.1,37.3,37.0,35.9,34.6,33.3,31.6,27.5,26.2,24.5,19.5,14.7,12.3,10.1; ESIMS 453.5[M+Na] + .

[0127] Example 6 Synthesis of Compound 10

[0128]

[0129] Compound 2-4 (1.50 g, 3.53 mmol) was dissolved in dichloromethane (60 mL), and Dysmartin oxidant (DMP) (6.0 g, 14.1 mmol) and NaHCO3 (1.50 g, 17.9 mmol) were added at room temperature. The mixture was stirred for 3 h. TLC showed that the reaction was complete. The solution was diluted with EtOAc, washed successively with saturated Na2SO3 solution, saturated sodium bicarbonate aqueous solution, and saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE / EtOAc = 4:1) to give a white solid 2-11 (1.4 g, 93%). Compound 2-11: [α] 25 D = +74.2 (c = 1.2, CHCl3); 1 H NMR (400MHz, CDCl3) δ7.36-7.31(m,4H),7.30-7.24(m,1H),5.37(brs,1H),4.56(s,2H),3.34( dd,J=9.8,8.7Hz,1H),3.31-3.23(m,1H),2.63(t,J=13.2Hz,1H),2.48(ddd,J=13.3,4.7,2.3Hz ,1H),2.34-2.27(m,2H),2.26(s,3H),2.24-2.17(m,1H),2.16-2.04(m,1H),1.99(dt,J=12.9, 3.4Hz,1H),1.94-1.66(m,4H),1.65-1.42(m,5H),1.11(s,3H),1.06-1.02(m,1H),0.98(s,3H); 13 C NMR (100MHz, CDCl3) δ213.5,209.6,140.7,138.9,128.4,127.6,127.5,121.1,78.1,70.0,57.9,57.8 ,54.2,53.2,39.0,37.7,37.7,36.9,31.4,31.4,31.3,28.2,24.2,22.6,19.0,13.4; HRMS(ESI)calcd forC 28 H 36 O3Na[M+Na] + 443.2557, found 443.2562.

[0130] Example 7 Synthesis of compounds 2-8

[0131]

[0132] Compound 2-11 (1.0 g, 2.38 mmol) was dissolved in dichloromethane (50 mL), cooled in a liquid nitrogen bath, and the atmosphere was evacuated three times. The reaction solution was irradiated with a 125 W high-pressure mercury lamp for 20 min under ice bath conditions. After removing the solvent by rotary evaporation, column chromatography (PE / EtOAc = 6:1) was performed to give a white solid 2-8 (370 mg, 37%), while recovering the starting material 2-11 (600 mg). If the recovered starting material 2-11 (600 mg) was used to repeat the same reaction, a total of white solid 2-8 (640 mg, 64%) could be obtained, while recovering the starting material 2-11 (250 mg).

[0133] Example 8 Synthesis of compounds 2-7

[0134]

[0135] Compound 2-5 (14 g, 26.1 mmol) was dissolved in 140 mL of THF. TBAF (78.2 mL, 1.0 min THF, 78.2 mmol) was added under ice bath conditions, and the mixture was heated to 65 °C and reacted for 18 h. TLC showed the reaction was complete. After cooling, the mixture was diluted with dichloromethane, washed once with water, and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (PE / EtOAc = 5:1) to give a white solid 2-12 (10.7 g, 97%). Compound 2-12: 1 H NMR(500MHz, CDCl3)δ7.37-7.30(m,4H),7.28-7.24(m,1H),5.38(brs,1H) ,4.56(s,2H),3.88(dd,J=6.2,2.4Hz,1H),3.32-3.23(m,1H),2.61(dt,J=1 6.2,8.0Hz,1H),2.51-2.44(m,1H),2.34-2.16(m,4H),2.14-1.94(m,3H),1 .89-1.80(m,2H),1.76-1.68(m,2H),1.22(d,2H),1.11(s,3H),1.08(s,3H; 13 C NMR (500MHz, CDCl3) δ215.3,140.8,139.0,138.9,136.2,128.5,127.7,127.6,121.3,78.3,70.1,69.4 ,57.3,53.4,48.7,39.1,38.2,37.9,37.8,37.0,31.5,31.3,28.3,24.0,23.7,23.0,19.1,18.1,13.0.

[0136] Compound 2-12 (2.1 g, 4.97 mmol) was dissolved in 1,4-dioxane (70 mL) in a quartz tube, cooled in a liquid nitrogen bath, and purged three times. The solution was then placed in a photoreactor for illumination. After 5 hours, TLC showed that most of the feedstock had been converted. The solution was directly evaporated to dryness and then subjected to column chromatography (PE / EtOAc = 5:1) to give a white solid 2-7 (1.28 g, 61%, recovered feedstock 245 mg, BRSM 69%). Compound 2-7: 1 H NMR(500MHz, CDCl3)δ9.56(s,1H),7.37-7.30(m,4H),7.29-7.25(m,1H),5.43(b rs,1H),4.56(s,2H),4.03(dd,J=6.2,2.4Hz,1H),3.34-3.27(m,1H),2.72(dt,J =16.2,8.0Hz,1H),2.51-2.45(m,1H),2.34-2.16(m,4H),2.10-1.93(m,3H),1.8 0-1.70(m,2H),1.68(s,3H),1.62-1.49(m,2H),1.19-1.12(d,4H),1.05(s,3H); 13 C NMR (500MHz, CDCl3) δ201.8,141.0,139.9,139.0,135.1,128.5,127.7,127.6,121.8,78.3,7 0.2,67.2,56.8,44.8,43.2,39.0,38.2,37.7,34.3,31.3,30.4,28.3,21.1,20.5,19.3,13.0.

[0137] Example 9 Synthesis of compounds 2-17

[0138]

[0139] The preparation of compound 2-13 was performed according to reference (Chem. Commun. 2012, 48, 8679-8681), and the preparation of compound 2-14 was performed according to reference (Nat. Commun. 2015, 6, 5879-5888, DOI: 10.1038 / ncomms6879 and its cited references). Compounds 2-13 (1.14 mg, 2.00 mmol) and 2-14 (340 mg, 0.82 mmol) were mixed and dissolved in toluene (4 mL), and activated [agent / concentrate / etc.] was added. Molecular sieves were used, and the mixture was stirred at room temperature for 30 min. Ph3PAuNTf2 (180 mg, 0.25 mmol) was added at 20 °C, and the reaction was allowed to proceed naturally for 3 h. The reaction was quenched with triethylamine, filtered, and concentrated. Column chromatography (PE / EtOAc = 3:1) gave a white solid 2-15 (550 mg, 86%). Compound 2-15: [α] 24 D = –9.2 (c = 1.2, CHCl3); 1 H NMR (500MHz, CDCl3) δ8.10-8.01(m,4H),7.62-7.55(m,2H),7.48-7.43(m,4H ),6.94(d,J=9.1Hz,2H),6.79(d,J=9.1Hz,2H),5.34(dd,J=9.6,7.9Hz,1H), 5.28(d,J=8.3Hz,1H),5.16(t,J=9.5Hz,1H),4.77(dd,J=9.7,2.1Hz,1H),4. 70(d,J=7.9Hz,1H),3.97(dd,J=9.4,6.3Hz,1H),3.87-3.76(m,4H),3.75(s,3 H),3.71(dd,J=9.6,6.2Hz,1H),3.48(s,3H),3.39(s,3H),3.35(s,3H),3.26 (dd,J=9.4,3.0Hz,1H),3.22(dd,J=9.5,2.8Hz,1H),2.30-2.24(m,1H),2.17 -2.09(m,1H),1.78(ddd,J=13.6,9.5,2.4Hz,1H),1.65(ddd,J=12.4,9.7,2. 4Hz, 1H), 1.32 (d, J = 6.1Hz, 3H), 1.25 (d, J = 6.7Hz, 3H), 0.97 (d, J = 6.2Hz, 3H); 13 C NMR (125MHz, CDCl3) δ165.4,164.9,154.9,151.5,133.5,133.3,129.9,129.9,129.8,129.7,128.7,128.6,117.7,114.5,102.7,99.6, 96.9,84.1,82.1,81.7,76.7,76.6,74.6,73.5,70.6,69.0,68.1,59.2,58.7,57.8,55.8,36.0,34.7,18.4,18.1,17.8; HRMS(ESI)calcd forC 42 H 52 O 14 Na[M+Na]+ 803.3249, found 803.3246.

[0140] Dissolve 2-15 (500 mg, 0.64 mmol) in CH3CN (40 mL) and H2O (40 mL), and add Ag(DPAH)2 (650 mg, 1.4 mmol) under ice bath conditions. Stir the reaction mixture at room temperature for 1 h. Filter, dilute with dichloromethane, wash with saturated sodium bicarbonate aqueous solution and saturated brine, dry to anhydrous sodium sulfate, and concentrate. Column chromatography (PE:EA = 1:1) gives a white solid hemiacetal 2-16 (390 mg, 91%).

[0141] The hemiacetal 2-16 (390 mg, 0.58 mmol) was dissolved in dichloromethane (30 mL), and 2-(cyclopropylethynyl)benzoic acid (220 mg, 1.2 mmol), 4-dimethylaminopyridine (DMAP) (14 mg, 0.12 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (280 mg, 1.5 mmol) were added sequentially. The reaction was carried out at room temperature for 4 h. The mixture was then diluted with dichloromethane, washed with saturated sodium bicarbonate aqueous solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated. Column chromatography (PE:EA = 2:1) yielded colorless syrup 2-17 (430 mg, 90%, β / α = 6.5 / 1). Compound 2-17β:[α] 27 D = +11.6 (c = 0.98, CHCl3); 1H NMR (500MHz, CDCl3) δ8.09-8.04 (m, 4H), 7.90 (ddd, J = 7.9, 1.4, 0.6Hz, 1H), 7.6 2-7.54(m,2H),7.51-7.42(m,5H),7.39(td,J=7.6,1.4Hz,1H),7.28-7.24(m,1H ),6.20(dd,J=9.4,2.3Hz,1H),5.34(dd,J=9.6,7.9Hz,1H),5.16(t,J=9.5Hz,1H ),4.77(dd,J=9.7,2.0Hz,1H),4.69(d,J=7.9Hz,1H),4.13-4.04(m,1H),3.88-3 .76(m,4H),3.72(dd,J=9.6,6.2Hz,1H),3.48(s,3H),3.41(s,3H),3.35(s,3H), 3.28(dd,J=9.2,3.0Hz,1H),3.23(dd,J=9.5,2.8Hz,1H),2.33-2.27(m,1H),2.1 7-2.10(m,1H),1.79-1.72(m,1H),1.70-1.63(m,1H),1.53-1.46(m,1H),1.32(d ,J=6.2Hz,3H),1.25(d,J=6.3Hz,3H),0.96(d,J=6.2Hz,3H),0.90-0.84(m,4H); 13 C NMR (125MHz, CDCl3) δ165.4,164.9,164.5,134.3,133.5,133.3,131.9,131 .3,130.7,129.9,129.9,129.8,129.7,128.7,128.6,127.0,125.0,102.7, 99.7,99.6,92.0,84.2,81.8,81.7,76.7,76.1,74.6,73.5,70.6,70.1,68. 1,59.2,58.7,57.6,35.9,33.3,18.3,18.1,17.8,9.0,0.8; HRMS(ESI)calcd for C 47 H 54 O 14 Na[M+Na] + 865.3406, found 865.3410.

[0142] Example 10 Synthesis of compounds 2-18

[0143]

[0144] Compound 2-17 (1.95 g, 2.3 mmol) and Hoodigogenin A (900 mg, 2.1 mmol) were mixed and dissolved in dichloromethane (40 mL), and activated [the solution] was added. Molecular sieves were used, and the mixture was stirred at room temperature for 30 min. Ph3PAuOTf (125 mg, 0.21 mmol) was added at 10 °C, and the reaction was allowed to proceed naturally for 2 h. The reaction was quenched with triethylamine, filtered, and concentrated. Column chromatography (PE / EtOAc = 2:1) yielded colorless syrups 2-18β (1275 mg, 56%) and 2-18α (925 mg, 40%). Compound 2-18β:[α] 29 D = +4.0 (c = 1.1, CHCl3); 1 H NMR (500MHz, CDCl3) δ8.06-8.04(m,4H),7.62-7.53(m,2H),7.48-7.42(m,4H),6.95-6.89 (m,1H),5.39(brs,1H),5.32(dd,J=9.6,7.9Hz,1H),5.15(t,J=9.5Hz,1H),4.81(dd,J=9. 6,2.0Hz,1H),4.71(dd,J=9.6,2.0Hz,1H),4.68(d,J=7.9Hz,1H),4.63(dd,J=12.0,4.4Hz ,1H),4.25(s,1H),3.84-3.75(m,4H),3.75-3.66(m,2H),3.55-3.49(m,1H),3.47(s,3H),3 .37(s,3H),3.34(s,3H),3.20(dd,J=9.5,2.8Hz,1H),3.17-3.10(m,2H),2.38-2.27(m,2H ),2.19(s,3H),2.14-2.08(m,1H),2.07-1.91(m,5H),1.88(s,3H),1.83(d,J=7.1Hz,3H),1 .80-1.72(m,3H),1.67-1.60(m,2H),1.56-1.45(m,3H),1.30(d,J=6.2Hz,3H),1.18(d,J= 6.2Hz,3H),1.09(dd,J=13.7,3.6Hz,1H),1.05(s,3H),0.97(s,3H),0.94(d,J=6.2Hz,3H); 13C NMR (125MHz, CDCl3) δ217.2,167.8,165.4,164.9,139.1,137.9,133.5,133.3,129.9,129.9,129. 8,129.8,128.9,128.7,128.6,122.1,102.7,99.7,96.0,85.8,84.2,82.6,81.7,77.6,76.7,76.0 ,74.6,73.4,70.6,68.6,68.1,59.2,58.7,57.9,57.3,53.9,43.2,38.8,37.4,37.2,36.0,35.8,3 5.5,34.5,33.3,29.6,27.5,26.2,24.5,19.4,18.3,18.1,17.8,14.6,12.3,10.0; HRMS(ESI)calcd for C 61 H 86 O 17 N[M+NH4] + 1104.5890, found 1104.5890. Compound 2-18α:[α] 29 D = +44.9 (c = 0.60, CHCl3); 1HNMR(500MHz,CDCl3)δ8.07-8.04(m,4H),7.62-7.54(m,2H),7.50-7.40(m,4H),6.96-6.87(m,1H),5.36(brs,1H),5.33(dd,J=9.6,7.9Hz,1H),5.15(t,J=9.5Hz,1H),4.85(d,J=3.4Hz,1H),4.76(dd,J=9.6,2.0Hz,1H),4.68(d,J=7.9Hz,1H),4.63(dd,J=11.9,4.4Hz,1H),4.23(s,1H),4.19(dd,J=9.2,6.4Hz,1H),3.83-3.75(m,3H),3.73-3.64(m,2H),3.46(s,3H),3.41-3.37(m,1H),3.36(s,3H),3.35(s,3H),3.25(dd,J=9.2,3.0Hz,1H),3.22(dd,J=9.5,2.8Hz,1H),3.15-3.10(m,1H),2.35-2.25(m,3H),2.19(s,3H),2.17-2.06(m,2H),2.02-1.93(m,3H),1.88(s,3H),1.83(d,J=7.1Hz,3H),1.80-1.73(m,4H),1.70-1.64(m,2H),1.53-1.42(m,2H),1.31(d,J=6.2Hz,3H),1.16(d,J=6.4Hz,3H),1.06(s,3H),1.03-1.00(m,1H),0.96(s,3H),0.94(d,J=6.2Hz,3H); 13 C NMR(100MHz,CDCl3)δ217.2,167.8,165.4,165.0,139.6,137.9,133.5,133.3,130.0,129.9,129.8,129.8,128.9,128.7,128.6,121.7,102.7,99.5,93.9,85.9,84.2,81.7,76.6,76.1,75.7,75.6,74.6,73.4,70.6,68.1,63.1,59.2,58.5,57.3,53.9,43.1,40.0,37.3,37.2,35.9,35.7,34.5,33.3,32.8,27.6,27.4,26.2,24.5,19.5,18.0,17.8,17.8,14.7,12.3,10.1;HRMS(ESI)calcd for C 61 H86 O 17 N[M+NH4] + 1104.5890, found 1104.5885.

[0145] Example 11 Synthesis of compound P57

[0146]

[0147] Compound 2-18β (1.20 g, 0.11 mmol) was dissolved in toluene (100 mL), and a methanol (10 mL) solution of potassium hydroxide (110 mg) was added. The reaction was allowed to proceed at room temperature for 1.0 h. The solution was neutralized to pH 7.0 with acidic resin, filtered, and concentrated. Column chromatography (CH₂Cl₂ / MeOH = 30:1) gave a white solid, P57 (950 mg, 98%). Compound P57: [α] 27 D = +6.5 (c = 0.48, CHCl3); 1HNMR(500MHz,CDCl3)δ6.95-6.89(m,1H),5.41(d,J=5.1Hz,1H),4.84(dd,J=9.6,2.0Hz,1H),4.76(dd,J=9.5,2.0Hz,1H),4.64(dd,J=12.0,4.4Hz,1H),4.30(d,J=7.7Hz,1H),4.25(s,1H),3.91(dd,J=9.6,6.2Hz,1H),3.84(dd,J=9.6,6.3Hz,1H),3.81-3.77(m,2H),3.65(s,3H),3.57-3.48(m,2H),3.44(s,3H),3.43(s,3H),3.37(dd,J=9.2,6.1Hz,1H),3.27(dd,J=9.5,3.0Hz,1H),3.23-3.16(m,2H),3.15-3.07(m,2H),2.37-2.30(m,4H),2.19(s,3H),2.15(ddd,J=13.8,3.7,2.1Hz,1H),2.09(ddd,J=13.7,3.6,2.0Hz,1H),2.03-1.90(m,4H),1.88(s,3H),1.83(d,J=8.0Hz,3H),1.79-1.75(m,3H),1.65(ddd,J=13.8,9.6,2.5Hz,1H),1.54-1.41(m,3H),1.31(d,J=6.1Hz,3H),1.27(d,J=6.2Hz,3H),1.21(d,J=6.2Hz,3H),1.10(dd,J=13.7,3.8Hz,1H),1.06(s,3H),0.98(s,3H); 13 C NMR(125MHz,CDCl3)δ217.2,167.8,139.1,137.9,128.9,122.1,104.5,99.8,96.0,85.9,85.4,82.9,82.7,77.6,77.1,76.1,74.9,74.8,71.8,68.7,68.4,60.8,58.1,58.1,57.3,53.9,43.2,38.8,37.4,37.2,35.9,35.7,35.3,34.6,33.3,29.6,27.5,26.2,24.5,19.5,18.6,18.4,18.0,14.7,12.3,10.1;HRMS(ESI)calcd for C 47 H 74 O 15 Na[M+Na] +901.4920, found 901.4916.

[0148] Example 12 Synthesis of compounds 2-19

[0149]

[0150] Hemiacetal 2-16 (110.3 mg, 0.1634 mmol) was dissolved in toluene with water under vacuum for three separate drying cycles under Ar protection. The solution was then dissolved in redistilled DCM (2.0 mL). The system was cooled to 0 °C, and DIPEA (55 μL, 0.3268 mmol) and (CF3CO)2O (162 μL, 0.9804 mmol) were added sequentially. After reacting for 13 h, TLC showed unreacted compounds at the starting site. Additional DCM was then added. i Pr2NEt (110 μL, 0.6536 mmol), (CF3CO)2O (324 μL, 1.9608 mmol). The reaction was continued for 7 h. The system was quenched with a saturated NaHCO3 solution, diluted with EA, and washed successively with saturated NaHCO3 solution and saturated NaCl solution. The mixture was dried over anhydrous Na2SO4. After filtration and concentration, the solution was wet-loaded onto a column (PE / EA = 10:1, 5:1, 3:1, 2:1, 1:1 up to DCM / MeOH = 15:1) to obtain trisaccharide 2-19 (47.4 mg, 44%), and the hemiacetal (59.9 mg, 97% brsm) was recovered. [α] D 28 =82.5 (C=0.17, CHCl3); 1 H NMR(500MHz,Chloroform-d)δ8.11–7.99(m,5H),7.64–7.52(m,2H),7.52–7.43(m,5H),6.33(d,J=5.9Hz,1H),5.40–5.2 5(m,1H),5.16(t,J=9.5Hz,1H),4.87(t,J=5.8Hz,1H),4.79(dd,J=9.7,2.1Hz,1H),4.70(d,J=7.9Hz,1H),4.16–4.04(m, 2H),3.85–3.75(m,4H),3.75–3.67(m,2H),3.51–3.44(m,5H),3.40(s,3H),3.35(s,4H),3.23(dd,J=9.6,2.8Hz,1H),2. 16(ddd,J=13.8,3.6,2.1Hz,1H), 1.66(ddd,J=13.8,9.7,2.6Hz,1H), 1.30(dd,J=9.9,6.2Hz,7H), 0.96(d,J=6.2Hz,4H); 13C NMR(126MHz,Chloroform-d)δ164.45,163.95,145.15,132.51,132.31,128.96,128.89,128.82,128.76,127.67,127.58,101.73,98.88, 98.06,83.20,80.74,79.87,75.65,73.64,72.46,70.80,69.61,68.76,67.22,58.19,57.67,56.41,34.84,17.05,16.83,16.58; ESI-HRMS calcd for C 35 H 48 NO 12 [M+NH4] + m / z=674.3171,found:674.3167.

[0151] Raw material 2-19 (28.2 mg, 0.04294 mmol) was mixed with Hoodigogenin A (28.5 mg, 0.06619 mmol), and the mixture was dried under vacuum after three applications of toluene to remove water. Then, under Ar protection, [the mixture was] added... MS, TPHB (7.4 mg, 0.02147 mmol), and PhCl (1.0 mL) were dissolved by sonication and reacted at room temperature. The reaction was allowed to proceed for 8 h. The reaction was complete upon TLC, quenched with Et3N, diluted with DCM, and filtered through diatomaceous earth. The sample was washed successively with saturated NaHCO3 and NaCl solutions, and dried over anhydrous Na2SO4. After filtration and concentration, wet loading onto a column (PE / EA = 10:1, 5:1, 4:1, 3:1, 2:1) did not separate the components. Preparative TLC separated 2-18β (9.6 mg, 21%) and 2-18α (1.4 mg, 3%), with HPLC selectivity of 2-18β / α = 7.7:1.0.

[0152] Example 13 Synthesis of compounds 2-23

[0153]

[0154] Raw materials 2-20 (1.00 g, 2.52 mmol) and 2-21 (1.30 g, 3.03 mmol) were dissolved three times with toluene (without water) in 33 mL of freshly distilled diethyl ether, and then freshly activated... 3.3 g of molecular sieve was stirred at room temperature for half an hour. PPh3AuNTf2 (186 mg, 0.252 mmol) was added at 0 °C, and the reaction was carried out at this temperature for 17 h. The reaction was quenched with triethylamine, diluted with DCM, and washed successively with saturated NaHCO3 solution and saturated NaCl solution. The mixture was dried over anhydrous Na2SO4. After filtration and concentration, the sample was loaded onto a column using a wet column chromatography method to give 1.08 g of a white solid 2-22, yield 67%. [α] D 22 = +0.91(C 1.0, CHCl3) 1 H NMR (500MHz, CDCl3) δ7.35–7.29(m,4H),7.28–7.22(m,1H),4.99(m,1H),4.87(dd,J=11.9,1.5Hz,1H),4.83–4.73(m, 3H),4.51(dd,J=11.9,1.4Hz,1H),4.42(dd,J=7.9,1.0Hz,1H),3.92–3.82(m,2H),3.80(q,J=3.2Hz,1H),3.74(q,J=3 .1Hz,1H),3.48–3.40(m,5H),3.39(s,3H),3.36(s,3H),3.24(dd,J=9.5,3.1Hz,1H),3.17(dd,J=9.5,2.8Hz,1H),2.1 5(m,2H),2.09(m,4H),2.06(s,3H),1.62(m,2H),1.25(d,J=6.3Hz,3H),1.20(d,J=6.2Hz,3H),1.16(d,J=6.2Hz,3H); 13 C NMR (126MHz, CDCl3) δ169.70,169.05,137.99,128.40,127.95,127.66,102.44,99.62,97.46,83.93,82.49,81.21,76.80,76. 57,73.61,72.42,70.68,70.18,68.80,68.05,58.56,58.28,57.78,35.88,34.89,21.02,20.96,18.27,18.04,17.59; ESI-HRMS calcd forC 32 H 48 NaO 13 [M+Na] + m / z=663.2987,found:663.2998.

[0155] Raw material 2-22 (2.5 g, 3.90 mmol) was dissolved in EA / MeOH (75 / 25 mL), and dried triethylamine (0.27 mL, 1.95 mmol) and 20% palladium hydroxide on carbon (containing 50% water) (2.74 g, 1.95 mmol) were added. The mixture was purged with hydrogen three times and reacted at 50 °C under normal hydrogen pressure for 48 h. The mixture was filtered through diatomaceous earth, washed with methanol, concentrated, and then loaded onto a column for chromatography, yielding 1.68 g of a white, foamy solid.

[0156] The obtained white solid (2.15 g, 3.90 mmol) and acetic acid (1.18 g, 5.86 mmol) were dissolved in 27 mL of dry DCM. DMAP (476 mg, 3.90 mmol), EDCI (1.495 g, 7.80 mmol), and DIPEA (1.3 mL, 7.80 mmol) were added, and the reaction was carried out at room temperature for 12 h. The DCM was diluted and washed successively with saturated NaHCO3 solution and saturated NaCl solution, and dried over anhydrous Na2SO4. The solution was filtered and concentrated, and then wet-pressed onto a column to give a white solid 2-23, 2.87 g, with a two-step yield of 78%. The main β configuration is [α]. D 22 = -95.84 (C 1.0, CHCl3); 1 H NMR(500MHz,Chloroform-d)δ7.90(d,J=7.9Hz,1H),7.47(dd,J=7.8,1.4Hz,1H),7.38(d,J=7.7Hz,1H),7.29–7.24(m,1H),6.20(dd,J=9.4,2. 3Hz,1H),4.98(m,J=9,1H),4.82–4.76(m,2H),4.42(d,J=8.2Hz,1H),4 .12–4.04(m,1H),3.91–3.83(m,2H),3.74(q,J=3.1Hz,1H),3.48–3.38( m,7H),3.35(s,3H),3.31(dd,J=9.2,2.9Hz,1H),3.17(dd,J=9.5,2.8Hz,1H),2.45(m,2H),2.30(m,1H),2.11(m,1H),2.08(s,3H),2.06(s,3H) ,1.78(m,1H),1.68–1.56(m,3H),1.52–1.43(m,2H),1.24(d,J=6.3Hz,3 H),1.20(d,J=6.1Hz,3H),1.17(d,J=6.3Hz,3H),0.92(t,J=7.4Hz,3H); 13C NMR(126MHz,cdcl3)δ169.71,169.10,164.51,134.43,131.84,131.21,130.53 ,127.08,125.07,102.44,99.52,96.49,91.92,83.89,81.63,81.22,79.24,76 .53,76.12,73.61,72.44,70.17,70.06,68.09,58.48,58.33,57.55,35.71,33 .34,30.79,22.17,21.01,20.96,19.62,18.28,18.04,17.57,13.75;ESI-HRMS calcd for C 38 H 54 NaO 14 [M+Na] + m / z=757.3406,found:754.3409.

[0157] Example 14 Synthesis of compounds 2-24

[0158]

[0159] Raw materials 2-33 (2.05 g, 2.787 mmol) and 2-17 (1.0 g, 2.322 mmol) were dissolved three times with toluene (with water) in 34 mL of freshly distilled ethylene glycol dimethyl ether, and then added to freshly activated... 3.4 g of molecular sieve was stirred at room temperature for half an hour. PPh3AuNTf2 (85.8 mg, 0.1161 mmol) was added at -10 °C, and the reaction was slowly allowed to return to room temperature for 1.5 h. The system was quenched with triethylamine and triphenylphosphine. The mixture was diluted with DCM, washed successively with saturated NaHCO3 solution and saturated NaCl solution, and dried over anhydrous Na2SO4. The solution was filtered, concentrated, and column-passed to give 1.56 g of a white solid 2-24β (70% yield) and 131 mg of 2-24α (5.9% yield), with a β:α ratio of 11.9:1. 2-24β[α] D 22 = +12.56 (C 1.0, CHCl3); 1H NMR(500MHz, CDCl3)δ6.91(qd,J=7.1,1.6Hz,1H),5.40(m,1H),4.99(dd,J=9.7,7.9Hz,1H),4 .86–4.78(m,2H),4.75(dd,J=9.6,2.0Hz,1H),4.63(dd,J=12.0,4.4Hz,1H),4.43(d,J=7.9Hz ,1H),4.25(s,1H),3.89–3.80(m,2H),3.78(q,J=3.2Hz,1H),3.74(q,J=3.0Hz,1H),3.52(m,1 H),3.47–3.38(m,7H),3.36(s,3H),3.21-3.16(m,2H),3.14–3.11(m,1H),2.40–2.25(m,2H); 13 C NMR (126MHz, CDCl3) δ217.20,169.75,169.11,167.81,139.15,137.93,128.85,122.09,102.51,99.7 2,95.99,85.85,84.00,82.67,81.25,77.60,76.66,76.03,73.64,72.45,70.24,68.65,68.09,58.64 ,58.25,57.94,57.32,53.88,43.18,38.79,37.39,37.21,35.96,35.85,35.55,34.54,33.28,29.83, 29.61,27.49,26.21,24.51,21.07,21.01,19.45,18.34,18.10,17.64,14.63,12.29,10.03;ESI-HRMS calcd for C 51 H 78 NaO 17 [M+Na] + m / z=985.5131,found:985.5104.

[0160] Example 15 Synthesis of compound P57

[0161]

[0162] The starting material 2-24β (1.6 g, 1.661 mmol) was dissolved in 283 mL of dry toluene. A solution of KOH (326 mg, 5.814 mmol) in 27.8 mL of MeOH was added dropwise under ice bath conditions. The reaction was allowed to return to room temperature for 2 h. TLC showed complete reaction. The solution was acidified to approximately pH 7 using acidic resin, filtered, and subjected to rotary evaporation and column chromatography to obtain 1.326 g of a white, foamy solid P57, with a yield of 91%. [α] 27 D = +6.5 (c = 0.48, CHCl3); 1 H NMR (500MHz, CDCl3) δ6.97-6.86(m,1H),5.41(d,J=4.8Hz,1H),4.84(d,J=8.2Hz,1H),4.76(d,J=8.1Hz ,1H),4.64(dd,J=11.9,4.3Hz,1H),4.30(d,J=7.7Hz,1H),4.25(s,1H),3.95-3.75(m,4H),3.65(s,3H), 3.52(dd,J=15.4,6.0Hz,2H),3.44(s,3H),3.43(s,3H),2.35(t,J=18.0Hz,4H),2.19(s,3H),1.87(d,J =7.3Hz,3H),1.31(d,J=6.1Hz,4H),1.29-1.24(m,6H),1.21(d,J=6.2Hz,3H),1.06(s,3H),0.98(s,3H); 13 C NMR (126MHz, CDCl3) δ217.0,167.8,139.0,137.7,128.8,122.0,104.4,99.6,95. 9,85.7,85.3,82.8,82.6,77.0,76.9,75.9,74.7,74.7,71.7,68.5,68.3,60.6,58 .0,57.9,57.2,53.8,43.1,38.7,37.3,37.1,35.7,35.6,35.2,34.4,33.1,29.7, 29.5,27.4,26.1,24.4,19.31,18.4,18.2,17.8,14.5,12.1,9.9.HRMS(ESI)calcd for C 47 H 74 O 15 Na[M+Na] + 901.4920, found 901.4916.

[0163] Example 16 Synthesis of compound α / β-6-69

[0164] Compound α / β-6-69 was prepared by following the procedures in Examples 1-12 (similar steps to the synthesis of compound P57):

[0165]

[0166] HRMS(ESI)Calcd for C 54 H 86 O 17 Na[M+Na] + :1029.5757,found 1029.575.1

[0167] Example 17 Synthesis of compounds 6-69

[0168] Compounds 6-69 were prepared by following the procedures in Examples 1-12 (similar steps to the synthesis of compound P57):

[0169]

[0170] [α] D 22 =25.1 (c 0.6, CHCl3); 1 H NMR (400MHz, CDCl3) δ6.96–6.89(m,1H),5.41(d,J=4.9Hz,1H),4.84(dd,J=9.6,1.6Hz,1H),4.74(d dd,J=9.3,5.2,1.6Hz,2H),4.68(dd,J=9.6,1.6Hz,1H),4.66–4.60(m,1H),3.84(ddd,J=14.0,11.6 ,5.1Hz,7H),3.64–3.60(m,1H),3.65–3.60(m,1H),3.58–3.49(m,2H),3.58–3.49(m,2H),3.43(d,J =4.9Hz,12H),3.22(t,J=10.2Hz,4H),3.13(t,J=5.5Hz,1H),2.20(s,3H),1.06(s,3H),0.98(s,3H); 13C NMR (101MHz, CDCl3) δ217.1,167.7,139.0,137.8,128.7,122.0,99.7,99.7,99.5,9 5.9,85.7,82.5,82.5,82.4,77.2,76.9,75.9,72.4,70.7,68.6,68.4,58.1,58.0,57 .2,57.2,53.8,53.5,43.0,38.7,37.3,37.1,35.7,35.6,35.3,35.2,34.4,33.7,33 .2,29.7,29.5,27.4,26.1,24.4,19.3,18.3,18.2,14.5,12.2,9.9.HRMS(ESI)Calcd for C 54 H 86 O 17 Na[M+Na] + :1029.5757,found 1029.575.

[0171] Example 18 Synthesis of compounds 6-70

[0172] Compounds 6-70 were prepared by following the procedures in Examples 1-12 (similar steps to the synthesis of compound P57):

[0173]

[0174] [α] D 27 =6.1(c 2.1,CHCl3); 1 H NMR (400MHz, CDCl3) δ6.93(q,J=6.8Hz,1H),5.41(brs,1H),4.84(d,J=8.4Hz,1H),4.76(d,J=7.6Hz,1 H),4.74(d,J=8.0Hz,1H),4.64(dd,J=12.0,4.0Hz,1H),4.50(d,J=8.4Hz,1H),4.26(brs,1H),3.92-3 .78(m,6H),3.58-3.48(m,1H),3.45(s,6H),3.44(s,6H),3.39(s,3H),3.32-3.10(m,7H),2.59(brs,1 H),2.40-2.26(m,3H),2.20(s,3H),2.14-2.09(m,1H),1.33-1.12(m,12H),1.06(s,3H),0.98(s,3H); 13C NMR (100MHz, CDCl3) δ217.0,167.6,138.9,137.7,128.7,121.9,101.4,99.7,99.6,95.8,8 5.6,82.5,82.42,82.38,80.5,77.2,76.9,75.8,75.3,71.5,68.5,68.3,68.2,58.1,58.0,5 7.9,57.1,56.2,53.7,43.0,38.6,37.2,37.0,35.6,35.5,35.4,35.3,35.2,34.3,33.1,29. 6,29.4,27.3,26.0,24.3,19.2,18.2,18.14,18.11,17.9,14.4,12.1,9.8; HRMS(MALDI)m / z calcd C 54 H 86 O 17 Na[M+Na] + 1029.5757, found 1029.5758.

[0175] Example 19 Synthesis of Compound 3-2 Molecule 1

[0176] Compound 3-2 Molecule 1 was prepared by following the procedures in Examples 1-12 (similar steps to the synthesis of compound P57):

[0177]

[0178] [α] D 22 =7.0 (c 0.9, CHCl3); 1H NMR (400MHz, CDCl3) δ6.95–6.87(m,1H),5.40(d,J=5.0Hz,1H),4.84(dd,J=9.6,1.5Hz,2H),4.73(dd,J=9.5,1.5Hz,1H) ,4.63(dd,J=11.9,4.3Hz,1H),4.63(dd,J=11.9,4.3Hz,1H),4.55(dd,J=9.6,1.4Hz,1H),4.55(d,J=8.3Hz,1H),4.27(s, 1H),4.23(d,J=2.8Hz,1H),3.88–3.75(m,6H),3.59–3.47(m,1H),3.41(d,J=13.5Hz,9H),3.32(dq,J=12.2,6.1Hz,1H), 3.26–3.08(m,8H),2.86(s,1H),2.51(s,1H),2.33(ddd,J=10.5,9.6,2.9Hz,4H),2.19(s,3H),1.05(s,3H),0.97(s,3H); 13 C NMR (101MHz, CDCl3) δ217.1,167.7,139.0,137.8,128.7,122.0,100.3,99.7,99.5,95. 9,85.8,82.6,82.5,80.5,77.4,77.3,75.9,75.3,71.8,68.6,68.4,67.8,66.6,58.0,5 7.9,57.2,56.5,53.8,43.0,38.6,37.3,37.1,36.8,35.7,35.5,35.3,35.3,34.4,33.2 ,29.7,29.5,27.4,26.1,24.4,19.3,18.3,18.2,18.0,14.5,12.2,9.9.HRMS(ESI)Calcd for C 53 H 84 O 17 Na[M+Na] + :1015.5601,found 1015.5590.

[0179] Example 20 Synthesis of compounds 6-72

[0180] Compounds 6-72 were prepared by following the procedures in Examples 1-12 (similar steps to the synthesis of compound P57):

[0181]

[0182] [α] D23 =22.7(c 0.9,CHCl3); 1H NMR (500MHz, CDCl3) δ6.93(d,J=7.0Hz,1H),5.41(d,1H),4.96(d,J=8.7Hz,1H),4.75(dd,J=19.4,9.4H z,3H),4.65(dd,J=11.9,4.1Hz,1H),4.51(d,J=9.3Hz,2H),4.27(s,2H),4.27(s,2H),3.92–3.85(m,2H) ,3.82(d,J=12.3Hz,5H),3.55(dd,J=25.5,14.5Hz,2H),3.45(s,3H),3.43(s,3H),3.39(s,3H),3.30(d t,J=12.2,6.1Hz,2H),3.24(d,J=9.5Hz,2H),3.15(dt,J=30.7,13.3Hz,9H),0.08(d,J=10.0Hz,6H).13C NMR (101MHz, CDCl3) δ217.2,139.1,137.8,128.7,122.0,101.5,99.8,99.7,95.8,94.9,85.8,85.8,83.0 ,82.7,82.4,80.6,76.3,76.0,75.9,75.4,71.6,69.5,68.4,68.3,68.1,68.1,58.1,58.0,57.9,57.2,56 .3,53.8,53.5,43.1,40.2,38.7,37.8,37.3,37.1,37.0,35.7,35.4,35.3,35.1,34.4,33.2,29.7,29.4, 27.3,26.1,25.9,25.9,24.4,19.3,18.3,18.2,18.1,18.0,14.5,12.2,9.9,-4.1,-5.3.HRMS(ESI)Calcd forC 59 H 98 O 17 NaSi[M+Na] + :1129.6465,found 1129.6464.

[0183] Example 21 Synthesis of Compounds 17-99

[0184] Compounds 17-99 were prepared by following the procedures in Examples 1-12 (similar steps to the synthesis of compound P57):

[0185]

[0186] [α] 25 D =+20.1(c=0.48,CHCl3); 1 H NMR(400MHz,CDCl3)δ6.94-6.90(m,1H),5.41(brs,1H),5.08(dd,J=9.8,7.9Hz,1H),4.84(dd,J=9.6,2.0Hz,1H),4.76(d,J=10.1Hz,1H),4.73(d,J=10.2Hz,1H),4.63(dd,J=11.8,4.3Hz,1H),4.38(d,J=8.0Hz,1H),4.26(s,1H),3.92-3.75(m,7H),3.62-3.49(m,2H),3.44(s,3H),3.43(s,3H),3.42(s,3H),3.41(s,3H),3.27(dd,J=9.8,3.3Hz,1H),3.22-3.10(m,4H),2.40-2.27(m,3H),2.19(s,3H),2.07(s,3H),2.01-1.92(m,4H),1.88(s,3H),1.83(d,J=7.3Hz,3H),1.69-1.52(m,7H),1.37(d,J=6.4Hz,3H),1.21(d,J=3.6Hz,3H),1.19(d,J=3.6Hz,3H),1.17(d,J=6.2Hz,3H),1.06(s,3H),0.97(s,3H); 13 C NMR(125MHz,CDCl3)δ217.2,169.6,167.8,139.2,137.9,128.9,122.1,102.6,99.8,99.8,96.1,85.9,83.8,82.7,82.6,81.7,77.6,76.7,76.1,71.0,70.5,68.7,68.5,68.2,68.1,58.7,58.1,58.1,57.5,57.3,53.9,43.2,38.8,37.4,37.2,36.1,35.9,35.7,35.4,34.6,33.3,29.6,27.5,26.2,24.5,21.1,19.5,18.4,18.4,18.1,16.7,14.6,12.3,10.1;HRMS(ESI)calcd for C 56 H 88 O 19 Na[M+Na] + 1087.5812,found1087.5813.

[0187] Example 22 Synthesis of Compounds 17-100

[0188] Compounds 17-100 were prepared by following the procedures in Examples 1-12 (similar steps to the synthesis of compound P57):

[0189]

[0190] [α] 25 D = +69.8 (c = 0.24, CHCl3); 1 H NMR (400MHz, CDCl3) δ6.94-6.90(m,1H),5.36(m,1H),5.08(dd,J=9.8,8.0Hz, 1H),4.87(d,J=4.1Hz,1H),4.78(dd,J=5.4,2.1Hz,1H),4.76(dd,J=5.6,1.9H z,1H),4.63(dd,J=12.0,4.4Hz,1H),4.38(d,J=8.0Hz,1H),4.24(s,1H),3.90 -3.71(m,6H),3.58(dd,J=6.5,1.2Hz,1H),3.44(s,3H),3.42(s,3H),3.41(s,6 H),3.33-3.25(m,2H),3.22(dd,J=9.6,3.0Hz,1H),3.18(dd,J=9.6,2.8Hz,1H ),3.14-3.11(m,1H),2.32-3.29(m,3H),2.19(s,3H),2.07(s,3H),2.00-1.95( m,3H),1.88(s,3H),1.84(d,J=7.1Hz,3H),1.79-1.72(m,4H),1.37(d,J=6.4H z,3H),1.19(d,J=7.7Hz,6H),1.17(d,J=6.3Hz,3H),1.06(s,3H),0.97(s,3H); 13C NMR (100MHz, CDCl3) δ217.2,169.6,167.8,139.6,138.0,128.8,121.7,102.6,99.8,99.6,94 .0,85.9,83.8,82.5,81.7,81.7,76.6,76.1,75.7,75.7,70.9,70.5,68.6,68.2,68.0,63.0,5 8.7,57.9,57.7,57.5,57.3,53.9,43.1,40.0,37.3,37.2,36.0,35.8,35.1,34.5,33.3,33.0, 27.5,27.4,26.2,24.5,21.2,19.5,18.3,18.1,17.8,16.7,14.7,12.3,10.1; HRMS(ESI)calcd for C 56 H 88 O 19 Na[M+Na] + 1087.5812, found 1087.5814.

[0191] Example 23 Synthesis of compound α-3-20-175

[0192] Compound α-3-20-175 was prepared by following the procedures in Examples 1-12 (similar steps to those used for compound P57):

[0193]

[0194] [α] D 28 =44.1 (c 1.3, CHCl3); 1 H NMR (400MHz, CDCl3) δ6.93(q,J=6.8Hz,1H),5.37(brs,1H),4.88(d,J=4.0Hz,1H),4.79(d,J=8.8H z,1H),4.76(d,J=8.8Hz,1H),4.67-4.62(m,2H),4.51(d,J=8.4Hz,1H),4.28-4.17(m,2H),3.91-3 .71(m,5H),3.45(s,3H),3.43(s,3H),3.42(s,3H),3.39-3.29(m,6H),3.23(dd,J=9.6,2.4Hz,1H) ,3.16-3.10(m,1H),2.38-2.26(m,4H),2.20(s,3H),1.26-1.18(m,12H),1.06(s,3H),0.98(s,3H); 13C NMR (100MHz, CDCl3) δ216.9,170.1,167.6,139.4,137.7,128.7,121.5,101.3,99.6,99.4,93.8, 85.7,82.6,82.3,81.5,77.7,77.2,76.9,75.9,75.5,75.2,69.9,68.4,68.2,62.8,58.3,57.8,5 7.4,57.1,56.4,53.7,42.9,39.8,37.1,37.0,36.1,35.64,35.56,35.0,34.3,33.0,32.8,29.6, 27.4,27.2,26.0,24.3,21.0,19.3,18.14,18.11,17.62,17.60,14.4,12.1,9.8; HRMS(MALDI)m / z calcd C 56 H 88 O 18 Na[M+Na] + 1071.5863, found 1071.5869.

[0195] Example 24 Synthesis of compound 2,74-157-α

[0196] Compound 2,74-157-α was prepared by following the procedures in Examples 1-12 (similar steps to the synthesis of compound P57):

[0197]

[0198] [α] D 25 = +56.0 (c 0.55, CHCl3); 1H NMR (400MHz, CDCl3) δ6.92 (br d,J=7.6Hz,1H),5.40(br,1H),4.91(d,J=4Hz,1H),4.85(dd,J=1.6,9.6Hz,1H),4.64(dd,J=11.6,4.4Hz,1H),4.33(d,J= 7.6z,1H),4.27(s,1H),4.22(dd,J=6.8,9.2Hz,1H),3.83-3.86(m,2H),3.75(d,J=3.6Hz,1H),3.64(s,3H),3.52-3.58(m, 2H),3.40(s,3H),3.39(s,3H),3.40-3.52(m,3H),3.19(t,J=9.2Hz,1H),3.08-3.15(m,2H),2.53(s,1H),2.45(s,1H),2. 27-2.34(m,2H),2.19-2.24(m,1H)2.19(s,1H),1.88(s,3H),1.27-1.31(m,7H),1.22-1.25(m,5H),1.05(3H)0.98(s,3H); 13 C NMR (100MHz, CDCl3) δ217.1,167.7,138.0,137.8,128.7,122.0,104.2,95.7,91. 2,85.7,85.2,77.0,76.9,75.9,75.1,74.7,74.5,74.4,72.4,71.7,68.9,63.3,6 0.6,57.4,57.2,56.6,53.7,43.0,38.6,37.2,37.1,35.7,34.6,34.4,33.1,31.2 ,29.5,27.3,26.0,24.4,19.3,18.5,17.8,17.7,14.5,12.1,9.9; LR-ESIMSCalcd for C47H74O15Na(M+Na + )901.5, found 901.2.

[0199] Example 25 Bioactivity Experiment

[0200] 1. Materials

[0201] 1.1 Prostaglandin E2 (PGE2), compounds 6-70 and 2-74-157.

[0202]

[0203] 1.2 solution

[0204] 1.2.1 PGE2 solution: Dissolve PGE2 in physiological saline to 2M.

[0205] 1.3 Method:

[0206] Fever model: Healthy mice implanted with a micro-drug delivery system two weeks prior were randomly assigned to either the PGE2 group or the compound treatment + PGE2 group. Mouse weight was measured and recorded. Body temperature was recorded using a metabolic cage one hour before drug treatment. The compound treatment + PGE2 group received an intraperitoneal injection of the compound treatment (25 mg / kg), while the PEG2 group received an injection of the solvent. One hour later, both groups received a hypothalamic injection of PGE2 (2 μL).

[0207] 1.4 Results

[0208] A dual-tube micro-drug delivery system was implanted in the hypothalamus region of male adult C57BL / 6J mice. Two weeks later, the compound or solvent of this application was injected into the hypothalamus. One hour later, PGE2 was injected to induce fever. The core temperature of the mice was monitored. The results showed that, compared with the control group injected with the carrier, the injection of the compound of this application could keep the core temperature of the animals in a mild and sustained low temperature state.

[0209] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A method for preparing a compound of Formula I, ###0001### wherein, n is 0 or 1; R1 is selected from the group consisting of hydrogen, C2-C6 alkanoyl, unsubstituted or para-substituted benzoyl; R2 is selected from the group consisting of hydrogen, hydroxyl, halogen; wherein said hydroxyl optionally has a protecting group selected from the group consisting of C2-C6 alkanoyl, unsubstituted or para-substituted benzoyl; wherein said para-substituent of said benzoyl is selected from the group consisting of methoxy, nitro, azido, halogen; said method comprising the steps of: (1) reacting a polysaccharide of Formula II or III with an aglycone of Formula IV to obtain a compound of Formula I, ###0002### ###0003### ###0004### R3 is selected from the group consisting of C1-C10 alkyl, C3-C10 cycloalkyl, or C6-C10 aryl; and said method further comprising the steps of: (1) construction of a β-hydroxyl group at position 12: using dehydroepiandrosterone (DHEA) as a starting material, introducing a β-hydroxyl group at position 12 by a three-step reaction of 3-hydroxyl protecting group manipulation, 17-ketone enamine formation, and C-H bond activation; (2) introduction of a hydroxyl group at position 20: reacting with compound 2 to obtain compound 3 with a vinyl group at C17, and then preparing compound 4 with a hydroxyl group at position 20 by borohydride oxidation; (3) preparation of a Norrish Type I reaction precursor: oxidizing both hydroxyl groups at positions 12 and 17 to ketone carbonyl groups, or selectively oxidizing the hydroxyl group at position 12 to a ketone carbonyl group and leaving the hydroxyl group at position 17 bare or protected by a protecting group; (4) construction of a hydroxyl group at position 14: converting the hydroxyl group at position 20 to a carbonyl group by a Norrish Type I reaction, and then constructing the desired β-hydroxyl group at position 14 by a Prins reaction; (5) tiglic acid protection of the hydroxyl group at position 12: performing an ester condensation reaction of the hydroxyl group at position 12 with tiglic acid using Yamaguchi ester condensation conditions; (6) preparation of aglycone Hoodigogenin A: removing the protecting group at position 3 of compound 9 to obtain aglycone Hoodigogenin A; R5 is selected from the group consisting of C2-C6 alkanoyl, benzoyl or para-substituted benzoyl, or hydrogen; wherein said para-substituent of said benzoyl is selected from the group consisting of methoxy, nitro, azido, halogen. said R1 is selected from the group consisting of acetyl, unsubstituted benzoyl, or para-methoxy substituted benzoyl. said compound of Formula I is selected from the group consisting of: ###0005### comprising the steps of: (1) construction of a β-hydroxyl group at position 12: using dehydroepiandrosterone (DHEA) as a starting material, introducing a β-hydroxyl group at position 12 by a three-step reaction of 3-hydroxyl protecting group manipulation, 17-ketone enamine formation, and C-H bond activation; (2) introduction of a hydroxyl group at position 20: reacting with compound 2 to obtain compound 3 with a vinyl group at C17, and then preparing compound 4 with a hydroxyl group at position 20 by borohydride oxidation; ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ R4is selected from the group consisting of C2-C6alkanoyl, benzoyl or p-substituted benzoyl, tri(C3-C9alkyl)silyl, tri(C9-C 16 aryl)silyl, allyl, benzyl, naphthylmethylene, p-methoxyphenyl, p-methylphenyl, p-nitrobenzyl, p-halogen substituted benzyl, or hydrogen; ​ 2. The method of claim 1, wherein, ​ 3. The method of claim 1, wherein, ​ 4. A process for the preparation of a compound of formula I according to claim 1, characterized in that, ​ ​ ​ (3) Preparation of the Norrish Type I reaction precursor: by oxidation, the hydroxyl groups at 12 and 17 positions are oxidized to ketone carbonyl groups simultaneously; or by protection group manipulation, the hydroxyl group at 12 position is selectively oxidized to ketone carbonyl group, and the hydroxyl group at 17 position is left bare or protected by a protecting group; (4) Construction of the hydroxyl group at 14 position: by Norrish Type I reaction, the compound 20 position is converted to carbonyl group, and then by Prins reaction, the desired β-type hydroxyl group at 14 position is constructed: (5) Tiglic acid protection of the hydroxyl group at 12 position: by Yamaguchi ester condensation condition, the ester condensation reaction between the hydroxyl group at 12 position and tiglic acid is carried out: (6) Preparation of the aglycone Hoodigogenin A: by removing the protecting group at 3 position of compound 9, the aglycone Hoodigogenin A is prepared: (7) Glycosidation reaction: the polysaccharide shown in formula II or formula III is reacted with the aglycone shown in formula IV, so as to prepare the compound of formula I as claimed in claim 1; and optionally, step (8): removing the protecting group from the compound of formula I; wherein R4, R5 are each independently selected from C2-C6 alkanoyl, benzoyl or para-substituted benzoyl, or hydrogen; the para-substituted benzoyl is substituted at para position with methoxy, nitro, azido, halogen.

5. The method of claim 1, wherein, In step (2), it comprises: (2.1) after compound 2 is dissolved in organic solvent, Wittig reagent is added thereto, and after reaction, compound 3 is obtained; (2.2) compound 3 is first subjected to borohydration reaction with borane reagent to obtain alkyl boron, and then the alkyl boron is subjected to oxidation reaction by adding oxidant, so as to obtain compound 4.

6. The method of claim 5, wherein, The borane used in the borohydration reaction is selected from the group consisting of borane tetrahydrofuran, 9-borabicyclo[3.3.1]nonane, borane dimethyl sulfide, diisopinocamphylborane, or a combination thereof.

7. The method of claim 1, wherein, In step (3), when the hydroxyl group is protected by a protecting group, the hydroxyl protecting reagent used is selected from the group consisting of tert-butyldimethylchlorosilane, trimethylchlorosilane, tert-butyldiphenylchlorosilane, triisopropylchlorosilane, chloromethyl methyl ether, benzyl chloride, benzyl bromide, p-methoxybenzyl chloride, p-methoxybenzyl bromide, acetic anhydride, acetyl chloride, acetyl bromide, trifluoroacetyl chloride, trifluoroacetyl bromide, benzoyl chloride, benzoyl anhydride, chloroacetyl chloride or chloroacetic anhydride.

8. The method of claim 1, wherein, In step (3), when the hydroxyl group at 12 position carbon is oxidized, the oxidant used is selected from the group consisting of one or a mixture of any number of the following: Dess-Martin oxidant, chromium trioxide, chromium trioxide-sulfuric acid-acetone, dichromate, chromium oxide-pyridine coordination compound, pyridinium chlorochromate, pyridinium fluorochromate, nitrosonium dichromate, pyridinium dichromate, dimethyl sulfoxide-acetic anhydride system, dimethyl sulfoxide-dicyclohexyl carbodiimide system, dimethyl sulfoxide-oxalyl chloride system, silver carbonate, hypochlorite or chlorate.

9. The method of claim 1, wherein, In step (4), it comprises: (4.1) after compound 5 is dissolved in organic solvent, it is irradiated under the irradiation of high-pressure mercury lamp or specific wavelength light source of photo-reactor for a period of time, so as to obtain compound 6; (4.2): deprotection of the hydroxyl group of compound 6 to obtain a compound with a free hydroxyl group at carbon 20; then adding an oxidizing agent to oxidize the hydroxyl group at carbon 20 to obtain compound 7; (4.3): Prins reaction of compound 7 after dissolving in an organic solvent and adding an acid to obtain compound 8.

10. The method of claim 1, wherein, In step (5), the condensation is carried out in the presence of a condensing agent selected from the group consisting of 2,4,6-trichlorobenzoyl chloride, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) or dicyclohexylcarbodiimide (DCC), or a combination thereof.

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