A class of seven-membered ring pseudo-saccharide compounds, their preparation methods and applications

Abstract

This application relates to a class of seven-membered ring mimetic sugar compounds, their preparation methods, and applications. The compounds have the structure shown in Formula I. #imgabs0# This application synthesizes the compounds shown in Formula I and their pharmaceutically acceptable salts using D-arabinose as a raw material. The compounds and their pharmaceutically acceptable salts exhibit strong glycosidase inhibitory activity and are used to treat diseases caused by coronaviruses, influenza viruses, and the like.

Description

Technical Field

[0001] The present invention relates to a class of seven-membered ring pseudo-sugar molecular compounds (including seven-membered ring oxygen sugars and seven-membered ring azasugars) and a synthesis method of pharmaceutically acceptable salts of seven-membered ring azasugars, as well as their use as glycosidase inhibitors for treating diseases caused by the new coronavirus and the like, belonging to the fields of carbohydrate chemistry and medicinal chemistry. Background Art

[0002] Glycoplasmids can be seven- or eight-membered oxysugars, as opposed to the five- or six-membered oxysugars found in nature. They can also be compounds in which the oxygen atoms in the sugar ring are replaced by heteroatoms, such as nitrogen atoms. These structures primarily consist of single five- or six-membered rings, but some also have fused rings of five- and five-membered, or five- and six-membered, rings called azasugars, also known as iminosugars. Using a six-membered ring structure as an example, oxysugars and glycoplasmids are shown below.

[0003]

[0004] Glycoside mimetics, as glycosidase inhibitors, are often used to treat diseases caused by glucose metabolism disorders, such as antiviral infection (including anti-AIDS), anti-tumor, anti-cancer, anti-diabetes and immunosuppression (Ye Xinshan et al., Chinese Journal of Medicinal Chemistry, 2015, 25, 397-406).

[0005] In 2014, Sergio D. Rosenzweig et al. discovered that two siblings with a deficiency in the enzyme mannooligosaccharidase (MANOG) glucosidase showed reduced susceptibility to viral infection compared to their normal peers despite their hypogammaglobulinemia. Combined with treatment with glycosidase inhibitors, these individuals showed impaired viral replication and entry. Rosenzweig et al. proposed using glycosidase inhibitors as a novel antiviral strategy to protect the immune system and reduce susceptibility to infection in viral patients (Sergio D. Rosenzweig et al., Engl. J. Med. 2014, 370, 1615–1625). Subsequently, British scientists, targeting the process by which viruses require the host endoplasmic reticulum protein folding machinery to properly fold one or more glycoproteins into the complete viral form, employed glycosidase inhibitors to mitigate viral damage by disrupting viral replication in the human body. These antiviral strategies employed glycosidase inhibitors, which mimic the stereochemical properties of glucose. DNJ is the natural azasugar deoxynojirimycin. MON-DNJ targets α-glucosidases I and II (α-glu I and α-glu II) in the endoplasmic reticulum, thereby affecting the folding of viral glycoproteins. It exhibits activity against dengue virus, influenza viruses H1N1 and H3N2, hepatitis C virus, and human immunodeficiency virus, and is currently under clinical investigation as a candidate drug for the treatment of dengue virus (Nicole Zitzmann et al., Biochemical Society Transactions, 2017, 45, 571–582). The following are alkylated modified saccharide mimetics.

[0006]

[0007] Since 2019, the novel coronavirus (COVID-19) has caused millions of deaths worldwide. Vaccines developed in my country have effectively prevented the spread of COVID-19 both domestically and internationally, achieving remarkable results. The development of small-molecule anti-COVID-19 drugs remains an essential complement to vaccines for the treatment of COVID-19. Based on the effects of glycosidase inhibitors on viral replication, the potential for glycomimetic compounds to serve as lead compounds for further, systematic research into their anti-COVID-19 activity is of great practical significance.

[0008] Its main features are interference with viral glycoproteins and blocking the synthesis of N-linked glycosylation of the viral S protein. The biological mechanism of glycoprotein synthesis and correct folding in the endoplasmic reticulum involves the addition of the precursor glycan Glc3Man9GlcNAc2 to peptides for translation. The product, cleaved by α-glucosidase-I (α-glu-I) at the terminal glucose residue, can either bind to butyl maleate and be transported out of the endoplasmic reticulum or be further modified by α-glucosidase-II (α-glu-II) to become a substrate for calnexin / calreticulin. α-glu-II can scavenge residual glucose when releasing calnexin / calreticulin. At this point, correctly folded proteins are exported to the Golgi apparatus for further processing, while misfolded proteins can undergo epiglycosylation during their "second chance" folding by uridine diphosphate glucose:glycoprotein glucosyltransferase (UGGT). Alternatively, they can be directed to the endoplasmic reticulum-associated degradation (ERAD) pathway by endoplasmic reticulum-mannosidase I (ER-Man I), which removes mannose residues from the B arm of the glycan. ER degradation-promoting α-mannosidase-like stress proteins 1-3 (EDEM1-3) then act on the C arm of the glycan. Subsequently, through interaction with the membrane-forming adaptor protein Lin-12-like suppressor / enhancer of sel1l (SEL1L), the substrate is mediated by endoplasmic reticulum cohesin-9 / X protein transactivator gene (OS-9 / XTP3-B), delivering the complex to ubiquitin ligase (HRD1) for ubiquitination. PNGase then separates the glycan from the protein, and both fragments, glycan and protein, are degraded. There are many documents in the prior art that record this. For example, Elizabeth C. Clarke et al. The iminosugars celgosivir, castanospermine and UV-4 inhibit SARS-CoV-2 replication, Glycobiology, 2020, 1–7; Dominic S. Alonzi et al. Iminosugar antivirals: the therapeutic sweet spot, Biochemical Society Transactions (2017) 45 571–582; Aitor Casas-Sanchez et al. Protein glycosylation is essential for SARS-CoV-2

[0009] infection (https: / / doi.org / 10.1101 / 2021.02.05.429940). Therefore, the glycosidase inhibition mechanism may become a potential drug for the prevention and / or treatment of COVID-19

[0010] As an artificially synthesized mimetic sugar molecule, seven-membered epoxy sugar has a very significant inhibitory effect on the lectin FimHLD (Beat Ernst et al. Chemical Science, 2018, 9, 646–654), but its biological activity as a glycosidase inhibitor has not yet been recognized. The biological activity of inhibiting glycosidases has been widely reported (a. Somsak, L. et al. Current pharmaceutical design 2003, 9, 1177–1189; b. Stutz, AE et al. Current Topics in Medicinal Chemistry 2003, 3, 513–523; c. Zhang Yongmin et al. Journal of the American Chemical Society, 2009, 131, 5390–5392; d. Journal of the American Chemical Society, 2010, 132, 1804–1806; e. Organic & Biomolecular Chemistry, 2015, 13, 3446–3456). However, the related activity of seven-membered ring azasugar alkyl-substituted derivatives has not been reported so far.

[0011] There are many reported synthetic methods for seven-membered ring pseudosaccharides (a. Wong C.-H. et al. Angew. Chem., Int. Ed., 1999, 38, 2300–2324; b. Le Merrer Yves et al. Tetrahedron letters, 1998, 385–388; c. Bleriot Yves et al. Heterocycles, 2004, 64, 65–74; Organic & Biomolecular Chemistry, 2004, 2, 1492–1499; Tetrahedron: Asymmetry, 2005, 16, 313–319; Organic & Biomolecular Chemistry, 2006, 4, 1653–1662; d. Beat Ernst et al. Chemical Science, 2018, 9, 646–654). All the reported synthetic methods require multi-step synthesis. Almost all of these known synthetic methods have disadvantages such as harsh operating conditions, lengthy experimental steps, and low selectivity and yield. Summary of the Invention

[0012] One of the objects of the present invention is to provide a compound or its stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, metabolite or prodrug and a preparation method thereof.

[0013] Another object of the present invention is to provide a method for preparing the above compound.

[0014] Another object of the present invention is to provide a composition containing the above-mentioned compound or its stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, metabolites or prodrugs.

[0015] Another object of the present invention is to provide the use of the above-mentioned compound or its stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, metabolites or prodrugs for preventing and treating viruses.

[0016] To achieve the above object, the present invention provides the following technical solutions:

[0017] A compound having the general formula I:

[0018]

[0019] The stereo configurations of carbons at positions 2, 5, and 6 of the compound of formula I are 2R, 5R, 6R, 2S, 5R, 6R, 2R, 5S, 6S, 2S, 5S, 6S.

[0020] X is N, O or S. When X is O or S, R3 represents no substitution;

[0021] R1 and R2 are each independently selected from hydrogen, deuterium, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted aryl, optionally substituted or unsubstituted heteroaryl, One or more of, R4 represents an alkyl group;

[0022] R3 is selected from one or more of hydrogen, deuterium, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted aryl, and optionally substituted or unsubstituted heteroaryl.

[0023] The term "alkyl" as used herein includes both branched and straight chain saturated hydrocarbon groups having the specified number of carbon atoms. For example, "C 1-10 "alkyl" (or alkylene) refers to C1, C2, C3, C4, C5, C6, C7, C8, C9 and C10 alkyl. In addition, for example, "C 1-6"Alkyl" means an alkyl group having 1 to 6 carbon atoms. The alkyl group may be unsubstituted or substituted such that one or more of its hydrogen atoms are replaced by other chemical groups. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl) and the like. Unless otherwise specified, a reference to a specific alkyl group includes all isomers thereof.

[0024] "Alkenyl" is a hydrocarbon group, including straight or branched chain structures, having one or more carbon-carbon double bonds occurring at any stable point in the chain. For example, "C 2-6 "Alkenyl" (or alkenylene) is intended to include C2, C3, C4, C5, and C6 alkenyl groups. Examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like.

[0025] As used herein, the term "substituted" refers to the replacement of any one or more hydrogen atoms on a designated atom or group with a selected designated group, provided that the general valence of the designated atom is not exceeded. Unless otherwise specified, substituents are named relative to the central structure. For example, it is understood that when (cycloalkyl)alkyl is a possible substituent, the point of attachment of the substituent to the central structure is in the alkyl portion. A ring double bond, as used herein, is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N). When referring to substitution, particularly polysubstitution, it is meant that multiple substituents are substituted at various positions on the designated group, e.g., dichlorobenzyl refers to 2,3-dichlorobenzyl, 2,4-dichlorobenzyl, 2,5-dichlorobenzyl, 2,6-dichlorobenzyl, 3,4-dichlorobenzyl, and 3,5-dichlorobenzyl.

[0026] Combinations of substituents and variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates.A stable compound or stable structure implies that the compound is sufficiently stable when isolated to a useful degree of purity from a reaction mixture, and then formulated into an efficacious therapeutic agent.

[0027] The term "heteroaryl" refers to substituted and unsubstituted aromatic 5- or 6-membered monocyclic groups, 9- or 10-membered bicyclic groups, and 11- to 14-membered tricyclic groups having at least one heteroatom (O, S, or N) in at least one ring, preferably one, two, or three heteroatoms selected from O, S, and N. Each ring of a heteroaryl group containing a heteroatom may contain one or two oxygen or sulfur atoms and / or from one to four nitrogen atoms, provided that the total number of heteroatoms in each ring is four or fewer and each ring has at least one carbon atom. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen may optionally be oxidized and quaternized. A bicyclic or tricyclic heteroaryl group must include at least one fully aromatic ring; the nitrogen and other fused rings may be aromatic or non-aromatic. The heteroaryl group may be attached at any available nitrogen or carbon atom in any ring.

[0028] Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, furanyl, thienyl, oxadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and the like.

[0029] Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothiophenyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzofuranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzofuranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridinyl, fluoropyridinyl, dihydroisoindolyl, tetrahydroquinolinyl, and the like.

[0030] If not otherwise indicated, the compounds of the present invention are understood to include both the free form and salts thereof. The term "salt" refers to acidic and / or basic salts formed with inorganic and / or organic acids and bases. In addition, the term "salt" may include zwitterions (inner salts), such as when the compound of formula I contains a basic fragment such as an amine or a pyridine or imidazole ring, and an acidic fragment such as a carboxylic acid. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, such as acceptable metal and amine salts, in which the cation does not significantly contribute to the toxicity or biological activity of the salt. However, other salts may be useful, such as when separation or purification steps are employed during the preparation process, and are therefore also included in the scope of the present invention.

[0031] Preferably, C1-C 10 Alkyl refers to methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and isomers thereof; C2-C5 alkenyl refers to ethenyl, propenyl, allyl, butenyl, pentenyl and isomers thereof.

[0032] When a substituent is referred to as an alkenyl, alkyl, aryl, benzyl, or cycloalkyl group, or when these substituents are specifically alkenyl, alkyl, aryl, benzyl, or cycloalkyl groups, it refers to one to three of the above substituents. For example, chlorobenzyl refers to one to three chlorine-substituted benzyl groups.

[0033] The present application also provides a method for preparing the compound, comprising the following steps:

[0034] Compound 1 (D-arabinose) is reacted with acetyl chloride and methanol to generate compound 2 in which the anomeric carbon of D-arabinose is protected by a hydroxymethyl group. Compound 2 is then reacted with benzyl bromide under the catalysis of sodium hydride to generate compound 3 in which the hydroxyl group is protected by a benzyl group.

[0035]

[0036] Compound 3 reacts with acetic acid and sulfuric acid solution to generate compound 4 with a free anomeric carbonyl group.

[0037] Compound 4 undergoes a Wittig-Hornal reaction to generate compound 5 having a terminal olefin.

[0038]

[0039] Compound 5 reacts with allyl bromide under sodium hydride catalysis to generate compound 6 with two terminal olefins. Compound 6 undergoes olefin metathesis to generate compound 7 with an intracyclic double bond and a seven-membered epoxy sugar structure.

[0040]

[0041] Compound 7 is dihydroxylated to generate compound 8 having a seven-membered epoxy sugar structure with two hydroxyl groups. Compound 8 is deprotected with a deprotection reagent to generate compound 9;

[0042] The deprotection reagent is palladium carbon / hydrogen, and the mass ratio of the palladium carbon to the intermediate is in the range of 5:100-20:100;

[0043] R1 and R2 in the compound 9 are hydrogen;

[0044]

[0045] Compound 8 is acetylated and then deprotected using a deprotection reagent to generate compound 11;

[0046] The deprotection reagent is palladium carbon / hydrogen, and the mass ratio of the palladium carbon to the intermediate is in the range of 5:100-20:100;

[0047] R1 and R2 in the compound 11 are acetyl groups.

[0048]

[0049] Compound 8 and C 1-18 The linear alkyl halide (RX) was catalyzed by sodium hydride and then deprotected by a deprotection reagent to generate compound 13;

[0050] The deprotection reagent is palladium carbon / hydrogen, and the mass ratio of the palladium carbon to the intermediate is in the range of 5:100-20:100;

[0051] In the compound 13, R1 and R2 are C 1-18 of straight-chain alkyl;

[0052] In the compound 13, R1 is hydrogen, R2 is C 1-18 of straight-chain alkyl;

[0053] R1 in the compound 13 is C 1-18 A straight chain alkyl group, R2 is hydrogen.

[0054]

[0055] Compound 5 was subjected to Mitsunobu reaction to generate compound 14 with inverted hydroxyl configuration.

[0056]

[0057] Compound 5 was oxidized with pyridinium chlorochromate to generate compound 15 with a ketocarbonyl group. Compound 15 was then subjected to reductive amination with allylamine to generate compound 16 with two terminal olefins.

[0058]

[0059] Compound 16 reacts with benzyl chloroformate to produce compound 17. Compound 17 undergoes olefin metathesis to produce compound 18, which has an intracyclic double bond and a seven-membered azasugar structure.

[0060]

[0061] Compound 18 was dihydroxylated to generate compound 19 with a seven-membered azasugar structure containing two hydroxyl groups. 1-18 The linear alkyl halide (RX) is catalyzed by sodium hydride to produce compound 20.

[0062]

[0063] Compound 20 is deprotected by a deprotection reagent to generate compound 21;

[0064] The deprotection reagent is palladium carbon / hydrogen, and the mass ratio of the palladium carbon to the intermediate is in the range of 5:100-20:100;

[0065] R1 in the compound 21 is C 1-18 of a straight chain alkyl group.

[0066]

[0067] Compound 16 and C 1-18 The linear alkyl halide (RX) is catalyzed by sodium hydride to generate compound 22;

[0068] R3 in the compound 22 is C 1-18 of a straight chain alkyl group.

[0069]

[0070] Compound 22 was subjected to olefin metathesis to generate compound 23, which has an intracyclic double bond and a seven-membered azasugar structure;

[0071] In the compound 23, R3 is C 1-18 of a straight chain alkyl group.

[0072]

[0073] Compound 23 was dihydroxylated to generate compound 24 having a seven-membered azasugar structure with two hydroxyl groups, which was then deprotected by a deprotection reagent to generate compound 25.

[0074] The deprotection reagent is palladium carbon / hydrogen, and the mass ratio of the palladium carbon to the intermediate is in the range of 5:100-20:100;

[0075] In the compound 25, R3 is C 1-18 of a straight chain alkyl group.

[0076]

[0077] The reaction in each step is carried out in at least one solvent including dichloromethane, chloroform, tetrahydrofuran, ether, ethyl acetate, acetic acid, water, dioxane, methanol, ethanol, acetonitrile, formamide and N,N-dimethylformamide. The solvent, except water, can be an anhydrous grade solvent according to the requirements of the reaction conditions; the reaction temperature is -40°C to 140°C.

[0078] Any of the above compounds represented by Formula I and pharmaceutically acceptable salts thereof also fall within the scope of protection of the present invention.

[0079] The above salts are pharmaceutically acceptable salts.

[0080] The pharmaceutical composition of the present invention comprises a pharmaceutically acceptable carrier (such as a diluent, an excipient) and optionally other additives. The preparation method of the pharmaceutical composition is a conventional pharmaceutical method.

[0081] The compounds of the present invention or their pharmaceutically acceptable salts can be administered by various routes of administration, including but not limited to oral, inhalation, rectal, transdermal, transmucosal enteral administration, and subcutaneous, intramuscular or intravenous injection.

[0082] The compounds of the present invention or their pharmaceutically acceptable simple derivatives can be administered alone and / or together with other known antiviral drugs. Example

[0083] The present invention is further illustrated by the following examples. It should be understood that the methods described in the examples are merely illustrative of the present invention and are not intended to limit the present invention. Simple modifications to the preparation methods of the present invention, based on the concepts of the present invention, fall within the scope of the present invention. All raw materials and solvents used in the examples are commercially available products of corresponding purity.

[0084] Synthesis route 1 of the compound represented by general formula I of the present invention:

[0085]

[0086] Synthesis route 2 of the compound represented by general formula I of the present invention:

[0087]

[0088] Synthesis route 3 of the compound represented by general formula I of the present invention:

[0089]

[0090] It should be noted that the synthetic route for the compound of formula I of the present invention selects representative alkyl groups for the alkylated oxysugars and azasugars. For example, when R1, R2, R3, and R4 are linear or branched substituents containing only carbon chains, those skilled in the art, after reading this specification, can easily obtain substituents for oxygen atoms or nitrogen atoms with carbon chains of different lengths (e.g., 1-18 carbon atoms) according to the operating methods of this embodiment. These are all achievable by those skilled in the art without any creative effort, so the scope of protection of the present invention is by no means limited to the scope disclosed in this embodiment.

[0091] [Intermediate Preparation Example 1] Synthesis of Compound 4

[0092] Acetyl chloride (0.12 mL, 1.66 mmol) was dissolved in methanol (5 mL) and added dropwise to a stirred reaction flask containing a suspension of D-arabinose (0.5 g, 3.38 mmol) and methanol (10 mL) at room temperature under nitrogen. Stirring was continued until the starting material disappeared as detected by thin-layer chromatography (dichloromethane / methanol 2:1). The reaction mixture was neutralized to pH 7 with solid sodium bicarbonate, filtered, and concentrated under reduced pressure. The resulting residue was then diluted with acetone (30 mL), the resulting suspension was filtered to remove excess sodium bicarbonate, and concentrated under reduced pressure to afford crude compound 2. The crude compound 2 (0.55 g, 3.38 mmol) was placed in a reaction flask, anhydrous tetrahydrofuran (12 mL) was added, and the mixture was stirred and dissolved. The reaction solution was kept at 0°C in an ice bath, and sodium hydride (0.81 g, 20.3 mmol) was added in portions, followed by a catalytic amount of tetrabutylammonium iodide (15 mg). Maintaining the reaction temperature at 0°C, benzyl bromide (1.4 ml, 10.6 mmol) was added dropwise. After the addition was complete, the reaction was naturally warmed to room temperature and stirred overnight. After the reaction was completed, methanol (5 mL) was added dropwise to quench the reaction. The reaction solution was concentrated and extracted with dichloromethane (150 mL) and water (150 mL). The dichloromethane layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound 3. The crude compound 3 was dissolved in acetic acid (20 mL) and 1M sulfuric acid (10 mL) and stirred at 100°C for 5 h. The reaction mixture was then cooled to room temperature, neutralized with solid sodium bicarbonate, and filtered. The resulting solution was extracted with dichloromethane (2×50 mL), and the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (petroleum ether / ethyl acetate 4:1) gave compound 4 (1.2 g, 48%) as a colorless oil. The spectral data were the same as those reported in the literature (Bleriot Yves et al. Tetrahedron: Asymmetry., 2002, 13, 2553–2565).

[0093] 1 H NMR (400MHz, CDCl3) δ7.44-7.22(m,30H,6×Ph),5.45-5.26(m,2H),4.66(d,J=11.6Hz,1H),4.61-4.44(m,11H),4.16(t,J=4.6Hz,1H),4. 09(q,J=4.2Hz,1H),4.02(t,J=4.6Hz,1H),3.98(d,J=1.7Hz,1H),3.94(d,J=2.7Hz,1H),3.83(d,J=9.4Hz,1H),3.55(dddd,J=14.1,10.1,

[0094] 9.3,4.9Hz,4H),3.12(s,1H).

[0095] [Intermediate Preparation Example 2] Synthesis of Compound 5

[0096] Under nitrogen, n-butyllithium (13.1 mL, 2.5 M hexane solution, 32.8 mmol) was added dropwise to a stirred reaction flask containing methyltriphenylphosphonium bromide (11.7 g, 32.8 mmol) and anhydrous tetrahydrofuran (150 mL) at 0°C in an ice bath. After the addition was complete, stirring was continued for 0.5 h. Then, a solution of compound 4 (6.9 g, 16.4 mmol) in anhydrous tetrahydrofuran (70 mL) was added dropwise to the reaction flask at 0.5°C. After the addition was complete, the reaction system was heated to 90°C and refluxed for 3 hours. After the reaction was complete, water was slowly added at 0°C to quench the reaction. The resulting solution was extracted with ethyl acetate (2 × 100 mL). The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (petroleum ether / ethyl acetate 6:1) afforded compound 5 (6.24 g, 91%) as a colorless oil. The spectral data were the same as those reported in the literature (Bleriot Yves et al. Org. Biomol. Chem., 2004, 2, pp. 1492-1499).

[0097] 1 H NMR (400MHz, CDCl3) δ7.43-7.18 (m, 15H, 3×Ph), 5.96 (ddd, J=16.7, 11.0, 7.5Hz, 1H), 5.41-5 .25(m,2H),4.74-4.46(m,5H),4.37(d,J=11.9Hz,1H),4.16-3.97(m,2H),3.72-3.54(m,3H).

[0098] [Intermediate Preparation Example 3] Synthesis of Compound 6

[0099] Compound 5 (1.3 g, 3.11 mmol), tetrabutylammonium iodide (0.3 g, 0.31 mmol), and anhydrous N,N-dimethylformamide (50 mL) were added to a reaction flask. Sodium hydride (0.49 g, 12.44 mmol) was added portionwise with stirring at 0°C. Stirring was continued for 0.5 hours after the addition. 3-Propylene bromide (1.07 mL, 12.44 mmol) was added dropwise at 0°C. After the addition was complete, the reaction was stirred at room temperature overnight. After completion of the reaction, methanol (40 mL) was added at 0°C to quench the reaction, and the resulting solution was extracted with ethyl acetate (2 × 100 mL). The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (petroleum ether / ethyl acetate 10:1) afforded compound 6 (1.48 g, 100%) as a colorless oil.

[0100] 1H NMR (600MHz, CDCl3) δ7.41–7.27(m,15H),5.97–5.89(m,1H),5.88–5.79(m,1H),5.33(d,J=17.3Hz,1H),5.31–5.27(m, 1H),5.22(ddd,J=12.6,3.3,1.6Hz,1H),5.11(dd,J=10.4,1.6Hz,1H),4.70(d,J=11.3Hz,1H),4.66(d,J=8.2Hz,1H),4 .64(d,J=8.7Hz,1H),4.57(d,J=12.2Hz,1H),4.55(d,J=2.6Hz,1H),4.53–4.47(m,1H),4.37(d,J=11.8Hz,1H),4.14–4 .04(m,2H),3.92–3.84(m,1H),3.78(dt,J=4.8,2.7Hz,1H),3.73(dd,J=6.1,4.2Hz,1H),3.67(dd,J=11.2,5.5Hz,1H). 13 C NMR (151MHz, CDCl3) δ138.69, 138.65, 138.53 (3×Cipso), 136.24 (=CH), 135.31 (=CH), 128.42, 128.42, 128.35, 128.35,128.29,128.29,128.22,128.22,128.11,128.11,127.82,127.82,127.62,127.60,127.55(15aromatic C),118.57(=CH2),116.62(=CH2),81.47(-CH),80.59(-CH),78.18(-CH),74.93( -CH2),73.38(-CH2),71.26(-CH2),70.68(-CH2),69.24(-CH2).ESI-HRMS:Calcd forC 30 H 34 O4Na(M+Na + ):481.2349.Found:481.2340.

[0101] [Intermediate Preparation Example 4] Synthesis of Compound 7

[0102] In a reaction flask, compound 6 (1.3 g, 2.84 mmol) was dissolved in dichloromethane (500 mL) and degassed by bubbling nitrogen for 30 min. Grubbs catalyst 1st (10% mol, 0.5 g) was added and the reaction was stirred at reflux at 45°C under nitrogen until the starting material disappeared completely by thin-layer chromatography (petroleum ether / ethyl acetate 5:1). Excess lead acetate was added to quench the reaction. The reaction mixture was concentrated under reduced pressure and purified by flash column chromatography (petroleum ether / ethyl acetate 15:1) to afford compound 7 (1.03 g, 86%) as a colorless oil.

[0103] 1 H NMR (600MHz, CDCl3) δ7.42–7.15(m,15H),5.86–5.76(m,2H),4.76(d,J=11.2Hz,1H ),4.72(d,J=12.0Hz,1H),4.67(d,J=11.9Hz,1H),4.56(s,2H),4.46(dd,J=13.9,6. 4Hz,1H),4.46–4.38(m,1H),4.35(ddd,J=6.5,3.7,1.3Hz,1H),4.21–4.11(m,1H),3 .80(ddd,J=7.7,6.5,2.9Hz,1H),3.69(ddd,J=15.6,9.8Hz,2H),3.64–3.56(m,1H). 13 CNMR(151MHz, CDCl3)δ138.69,138.35,138.33(3×Cipso),131.45(=CH),129.24(=CH),128.46,128.46,128.46, 128.46,128.44,128.44,128.11,128.11,127.88,127.88,127.86,127.86,127.76,127.68,127.67(15aromatic C),80.81(-CH),80.68(-CH),78.85(-CH),73.89(-CH2),73.41(-CH2),72.14(-CH2),70.61(-CH2),67.79(-CH2).ESI-HRMS:Calcd forC 28 H 30 O4Na(M+Na + ):453.2036.Found:453.2029.

[0104] [Intermediate Preparation Example 5] Synthesis of Compound 8

[0105] Compound 7 (0.68 g, 1.58 mmol) was dissolved in a reaction flask with an acetone / water solution of 8:1 (5 mL), and N-methylmorpholine oxide (0.74 g, 6.33 mmol) and OsO4 (0.25 mL, 2.5% wt tert-butanol solution) were added. The reaction was stirred at room temperature overnight. After the reaction was completed, an excess of sodium thiosulfate (500 mg) was added to terminate the reaction. The reaction mixture was extracted with ethyl acetate (2 × 150 mL) and washed with brine (150 mL). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (petroleum ether / ethyl acetate 2:1) gave compound 8A (110 mg, 16%) as a colorless oil. Further elution gave compound 8B (196 mg, 27%) as a colorless oil.

[0106] Compound 8A 1 H NMR (600MHz, CDCl3) δ7.52–7.00(m,15H),4.92(d,J=11.5Hz,1H),4.78(d,J=11.1Hz,1H),4.65(d,J=11.5Hz,1H),4.62–4.51(m,4H), 4.24–4.16(m,2H),4.03–3.97(m,1H),3.91(dd,J=8.5,2.3Hz,1H),3.78–3.71(m,2H),3.70–3.60(m,2H),3.24(br,1H),2.67(br,1H). 13 C NMR(151MHz, CDCl3)δ138.14,137.98,137.90(3×Cipso),128.79,128.79,128.58,128.58,128.5 1,128.51,128.20,128.19,128.02,127.99,127.99,127.97,127.97,127.80,127.80(15aromatic C),80.59(-CH),80.56(-CH),80.44(-CH),75.23(-CH),74.43(-CH2),73.59(-CH2),72.13(-CH2),71.10(-CH2),70.65(-CH2),70.08(-CH).ESI-HRMS:Calcd for C 28 H 32 O6Na(M+Na + ):487.2091.Found:487.2087.

[0107] Compound 8B 1H NMR (600MHz, CDCl3) δ7.52–6.98(m,15H),4.61–4.52(m,3H),4.49(d,J=12.1Hz,1H),4.45(d,J =11.7Hz,1H),4.38(d,J=11.7Hz,1H),4.17(dd,J=13.2,2.9Hz,1H),4.09(d,J=4.8Hz,1H),4.05 (s,1H),3.88(s,1H),3.79(dd,J=10.5,5.5Hz,1H),3.73(t,J=4.7Hz,1H),3.68(br,1H),3.64( dd,J=13.1,0.8Hz,1H),3.55(dd,J=9.9,6.1Hz,1H),3.43(dd,J=9.9,5.4Hz,1H),3.24(br.1H). 13 C NMR(151MHz, CDCl3)δ138.17,137.63,137.53(3×Cipso),128.70,128.70,128.54,128.54,128.4 9,128.49,128.25,128.19,128.19,128.03,128.00,128.01,128.01,127.94,127.82(15aromatic C),85.55(-CH),84.61(-CH),75.73(-CH),74.91(-CH),74.44(-CH2),73.40(-CH2),72.42(-CH2),72.25(-CH2),71.55(-CH2),69.98(-CH).ESI-HRMS:Calcd for C 28 H 32 O6Na(M+Na + ):487.2091.Found:487.2087.

[0108] [Intermediate Preparation Example 6] Synthesis of Compound 10

[0109] Compound 8B (232 mg, 0.43 mmol) was dissolved in pyridine (4 ml) in a reaction flask. Excess acetic anhydride (2 ml) was added and the mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was concentrated under reduced pressure. Purification by flash column chromatography (petroleum ether / ethyl acetate 10:1) afforded compound 10 (143 mg, 47%) as a colorless oil.

[0110] 1H NMR (600MHz, CDCl3) δ7.35–7.22(m,13H),7.15–7.10(m,2H),5.73(t,J=1.9Hz,1H ),5.22–5.17(m,1H),4.76(d,J=11.3Hz,1H),4.69(d,J=11.1Hz,1H),4.57–4.52(m ,3H),4.40(d,J=11.1Hz,1H),3.95(dd,J=12.7,6.7Hz,1H),3.79(ddd,J=15.6,9. 8,6.5Hz,3H),3.63(t,J=5.2Hz,2H),3.60–3.54(m,1H),2.13(s,3H),2.05(s,3H). 13 C NMR(151MHz, CDCl3)δ170.57(C=O),170.50(C=O),138.22,138.14,137.86(3×Cipso),128.47–127.71(15aromatic C),81.61(-CH),80.68(-CH),77.76(-CH),74.35(-CH),73.49(-CH2),72.81(-CH2)),71.02( -CH2),70.75(-CH2),70.45(-CH2),67.81(-CH),21.14(-CH3),21.03(-CH3).ESI-HRMS:Calcd for C 32 H 36 O8Na(M+Na + ):571.2302.Found:571.2294.

[0111] [Intermediate Preparation Example 7] Synthesis of Compound 12

[0112] Compound 8A (196 mg, 0.422 mmol), tetrabutylammonium iodide (15.6 mg, 0.1 mmol), and anhydrous N,N-dimethylformamide (50 mL) were added to a reaction flask. Sodium hydride (11 mg, 0.465 mmol) was added portionwise with stirring at 0°C. After 0.5 hours, n-heptane bromide (66.3 L, 0.422 mmol) was added dropwise at 0°C. After complete addition, the reaction was stirred at room temperature overnight. After completion of the reaction, methanol (5 mL) was added at 0°C to quench the reaction, and the resulting solution was extracted with ethyl acetate (2 × 50 mL). The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (petroleum ether / ethyl acetate 5:1) afforded compound 12A (50 mg) as a yellow oil. Further elution afforded compounds 12B (52 mg) and 12C (38 mg) as yellow oils.

[0113] Compound 12A 1 H NMR (600MHz, CDCl3) δ7.41–7.23(m,13H),7.17(d,J=6.8Hz,2H),4.79(dd,J=11.3,6.8Hz,1H),4.7 1(t,J=10.9Hz,1H),4.67(d,J=11.0Hz,1H),4.61–4.49(m,2H),4.49–4.40(m,1H),4.00(t,J=6.0H z,1H),3.93(td,J=9.9,4.7Hz,1H),3.80–3.73(m,4H),3.69(d,J=10.2Hz,1H),3.67–3.50(m,4H), 3.50–3.43(m,2H),1.55(dd,J=13.4,6.8Hz,4H),1.42–1.20(m,16H),0.89(dt,J=9.5,6.0Hz,6H). 13 C NMR(151MHz,CDCl3)δ138.87,138.68,138.51(3×Cipso),128.69–127.57(15aromatic C),82.30,82.09,80.22,78.78,78.48,77.61,73.84,73.55,72.98,71.66,71.20,70.85,70.66,70.10,32.17–22.78(-CH2 aliph),14.25(-CH3 aliph),14.22(-CH3 aliph).ESI-HRMS:Calcd for C 42 H 60 O6Na(M+Na +):683.4282.Found:683.4257.

[0114] Compound 12B 1 H NMR(600MHz,CDCl3)δ7.55–7.10(m,15H),4.91(d,J=11.5Hz,1H),4.73(d,J=11.0Hz,1H),4.71–4.65(m,1H),4.57(dt,J=16.9,9.6Hz,3H),4.02(dd,J=13.7,5.5Hz,2H),3.87–3.80(m,1H),3.76(dd,J=12.7,3.5Hz,1H),3.72–3.66(m,1H),3.64(dd,J=10.2,4.6Hz,1H),3.60–3.53(m,1H),3.46(dd,J=6.8,2.5Hz,1H),2.73(br,1H),1.59–1.47(m,2H),1.40–1.20(m,10H),0.89(t,J=6.9Hz,3H). 13 C NMR(151MHz,CDCl3)δ138.33–138.24(3×Cipso),128.71–127.09(15aromatic C),82.41(-CH),81.37(-CH),79.51(-CH),78.30(-CH),75.04(-CH2),74.19(-CH2),73.64(-CH2),71.69(-CH),71.49(-CH2),70.97(-CH2),70.71(-CH2),31.96,30.20,29.25,26.24,22.76(-CH2 aliph),14.23(-CH3 aliph).ESI-HRMS:Calcd for C 35 H 46 O6Na(M+Na + ):585.3187.Found:585.3181.

[0115] Compound 12C 1H NMR (600MHz, CDCl3) δ7.42–7.00(m,15H),4.66(t,J=4.2Hz,2H),4.58(d,J=12.2Hz,1H),4.55–4.48(m,2H), 4.34(d,J=11.1Hz,1H),4.20–4.15(m,1H),4.08(d,J=5.9Hz,1H),4.06(d,J=5.8Hz,1H),3.99(dd,J=7.0,3.9 Hz,1H),3.83–3.79(m,1H),3.78–3.75(m,1H),3.70–3.51(m,2H),3.38(dd,J=15.5,6.8Hz,1H),2.23(br,1H) ,1.63(dd,J=14.3,7.2Hz,2H),1.52(dd,J=8.9,4.9Hz,2H),1.40–1.16(m,8H),0.87(dd,J=14.3,7.3Hz,3H). 13 C NMR(151MHz, CDCl3)δ138.46,138.41,138.21(3×Cipso),128.57–127.65(15aromatic C),81.69(-CH),81.19(-CH),81.02(-CH),79.06(-CH),73.52(-CH2),73.44(-CH2),73.36(-CH2) ,71.95(-CH2),71.38(-CH),71.21(-CH2),69.22(-CH2),31.90,30.19,29.25,26.16,22.73(-CH2 aliph),14.22(-CH3 aliph).ESI-HRMS:Calcd forC 35 H 46 O6Na(M+Na + ):585.3187.Found:585.3184.

[0116] [Intermediate Preparation Example 8] Synthesis of Compound 14

[0117] Compound 5 (100 mg, 0.239 mmol), 4-nitrobenzoic acid (160 mg, 0.957 mmol), and triphenylphosphine (251 mg, 0.957 mmol) were added to a reaction flask and dissolved in anhydrous tetrahydrofuran (5 mL). Under nitrogen protection, diethyl azodicarboxylate (140 mg, 0.957 mmol) was added dropwise at 0°C. After the reaction was completed, the solvent was removed under reduced pressure, and the resulting crude product was dissolved in a mixed solvent of methanol / water (4 mL / 0.4 mL). Sodium hydroxide (29 mg, 0.719 mmol) was added, and the reaction solution was refluxed for 1 h. After cooling, it was extracted with dichloromethane (2×20 mL). The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain compound 14 (39 mg, 91%) as a colorless oil.

[0118] 1 H NMR (400MHz, CDCl3): 7.39-7.28 (m, 15H, 3×Ph), 5.91 (ddd, J=17.5, 10.3, 7.4Hz, 1H), 5.40 (dd, J=1 7.5,10.3Hz,2H),4.91(d,J=11.2Hz,1H,CHPh),4.64(dd,J=11.8,11.2Hz,2H,2×CHPh),4.47(dd,J =11.9Hz,2H,2×CHPh),4.43(d,J=11.8Hz,1H,CHPh),4.15(t,J=7.4,6.5Hz,1H),3.97(ddd,J=5.5, 3.5, 2.6Hz, 1H), 3.66 (dd, J=6.5, 2.6Hz, 1H), 3.48 (ddd, J=6.2, 5.5, 3.4Hz, 2H), 2.51 (br, 1H, OH).

[0119] [Intermediate Preparation Example 9] Synthesis of Compound 15

[0120] Compound 14 (5.71 g, 13.66 mmol) and Molecular sieves (9.3 g) and anhydrous dichloromethane (230 mL) were added under nitrogen protection. Pyridinium chlorochromate (8.84 g, 41 mmol) was added and the reaction was stirred at room temperature. After the reaction, flash column chromatography (petroleum ether / ethyl acetate 6:1) was used to elute the mixture to obtain compound 15 (4.95 g, 90%) as a colorless oil. Spectral data were consistent with those reported in the literature (Bleriot Yves et al., Org. Biomol. Chem., 2004, 2, pp. 1492–1499).

[0121] 1H NMR (400MHz, CDCl3) δ7.41-7.14(m,15H,3×Ph),5.99-5.82(m,1H),5.45-5.24(m,2H),4.58(dd,J=11.8,3.0Hz,2H),4.54-4.48(m,2 H), 4.43 (d, J = 11.9Hz, 1H), 4.34 (d, J = 4.9Hz, 2H), 4.30 (dd, J = 11.6, 3.5Hz, 1H), 4.18 (dd, J = 7.8, 3.5Hz, 1H), 4.00 (d, J = 3.6Hz, 1H).

[0122] [Intermediate Preparation Example 10] Synthesis of Compound 16

[0123] Compound 15 (3.83 g, 9.21 mmol) and Molecular sieves (9 g), anhydrous dichloromethane (80 mL). Under nitrogen protection, allylamine (8 mL, 105.81 mmol) and acetic acid (2.8 mL, 48.81 mmol) were added with stirring at room temperature. After 0.5 h of reaction, sodium cyanoborohydride (3.1 g, 48.81 mmol) was added in batches and stirred at room temperature overnight. After the reaction was completed, 1 M sodium hydroxide (55 mL) was added dropwise to quench the reaction. The resulting solution was extracted with dichloromethane (2 × 100 ml). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The colorless oily compound 16A (2.04 g, 42%) and the colorless oily compound 16B (2.16 g, 51%) were purified by flash column chromatography (petroleum ether / ethyl acetate 10:1). The spectral data were the same as those reported in the literature (Bleriot Yves et al. Org. Biomol. Chem., 2004, 2, pp. 1492-1499).

[0124] Compound 16A 11H NMR (400 MHz, CDCl3) δ 7.38 - 7.30 (m, 15H, 3×Ph), 5.94 - 5.82 (m, 2H), 5.41 (m,), 5.37 (m, 1H), 5.16 (ddd, J = 17.1, 3.3, 1.6 Hz, 1H), 5.06 (ddd, J = 10.0, 2.8, 1.4 Hz, 1H), 4.93 (d, J = 11.2 Hz, 1H, CHPh), 4.66 (d, J = 11.6 Hz, 1H, CHPh), 4.60 (d, J = 11.2 Hz, 1H, CHPh), 4.47 (d, J = 12.0 Hz, 1H, CHPh), 4.43 (d, J = 12.0 Hz, 1H, CHPh), 4.42 (d, J = 11.6 Hz, 1H, CHPh), 4.25 (dd, J = 7.5, 7.0 Hz, 1H), 3.77 (dd, J = 7.0, 3.3 Hz, 1H), 3.53 (dd, J = 9.2, 5.0 Hz, 1H), 3.48 (dd, J = 9.2, 7.3 Hz, 1H), 3.37 (ddt, J = 12.6, 6.0, 1.4 Hz, 1H), 3.20 (ddt, J = 13.7, 6.0, 1.4 Hz, 1H), 2.98 (ddd, J = 7.3, 5.0, 3.3 Hz, 1H).

[0125] Compound 16B 1 1H NMR (400 MHz, CDCl3) δ 7.38 - 7.30 (m, 15H, 3×Ph), 5.95 (m, J = 18.1, 10.5, 7.5 Hz, 1H), 5.83 (m, 1H), 5.35 (m, 1H), 5.32 (m, 1H), 5.14 (app.dq, J = 17.1, 1.6 Hz, 1H), 5.06 (app.dq, J = 10.2, 1.4 Hz, 1H), 4.81 (d, J = 11.4 Hz, 1H, CHPh), 4.68 (d, J = 11.4 Hz, 1H, CHPh), 4.67 (d, J = 11.8 Hz, 1H, CHPh), 4.57 (d, J = 12.0 Hz, 1H, CHPh), 4.49 (d, J = 12.0 Hz, 1H, CHPh), 4.42 (d, J = 11.8 Hz, 1H, CHPh), 4.22 (dd, J = 7.5, 4.8 Hz, 1H), 3.69 (dd, J = 9.6, 4.1 Hz, 1H), 3.65 (m, 2H), 3.23 (ddt, J = 15.1, 6.2, 1.4 Hz, 1H), 3.13 (ddt, J = 13.9, 5.6, 1.4 Hz, 1H), 3.03 (m, 1H).

[0126] [Intermediate Preparation Example 11] Synthesis of Compound 17

[0127] At 0°C, benzyl chloroformate (2 mL, 14.54 mmol) was added dropwise to a reaction flask containing compound 16A (5.54 g, 12.12 mmol) and potassium bicarbonate (21.8 g, 218.16 mmol) dissolved in a water / ethyl acetate mixture (800 mL, 1:1, v / v). The mixture was stirred overnight at room temperature. The organic phase was separated and washed with 1M hydrochloric acid solution and brine, respectively. The organic phase was dried over anhydrous magnesium sulfate, filtered under reduced pressure, and the filtrate was concentrated. Purification by flash column chromatography (petroleum ether / ethyl acetate 15:1) gave compound 17A (6.35 g, 89%) as a colorless oil. The same reaction procedure was used to synthesize compound 16B (4.08 g, 8.92 mmol) to give compound 17B (4.6 g, 87%) as a colorless oil. The spectral data were the same as those reported in the literature (Bleriot Yves et al. Org. Biomol. Chem., 2004, 2, pp. 1492-1499).

[0128] Compound 17A 1 H NMR (400MHz, CDCl3) δ7.38-7.29(m,40H,8×Ph),6.00-5.73(m,4H),5.37-4.98(m,12H),4.90-4.32(m,14H),4.15-3.51(m,12H).

[0129] Compound 17B 1 H NMR (400MHz, CDCl3) δ7.41-7.30(m,40H,8×Ph),6.02-5.78(m,4H),5.40-5.01(m,12H),4.88-4.33(m,14H),4.10-3.68(m,12H).

[0130] [Intermediate Preparation Example 12] Synthesis of Compound 18

[0131] In a reaction flask, compound 17A (330 mg, 0.558 mmol) was dissolved in dichloromethane (140 mL) and degassed by bubbling nitrogen for 30 min. Grubbs catalyst 1st (10% mol, 140 mg) was added and the reaction was stirred under reflux at 45°C under nitrogen protection until the starting material disappeared completely after thin-layer chromatography (petroleum ether / ethyl acetate 5:1). An excess of lead acetate was added to quench the reaction. The reaction mixture was concentrated under reduced pressure and purified by flash column chromatography (petroleum ether / ethyl acetate 15:1) to give compound 18A (306 mg, 98%) as a colorless oil. The same reaction procedure was used to synthesize compound 17B (0.98 g, 1.66 mmol) to give compound 18B (0.91 g, 98%) as a colorless oil. The spectral data were the same as those reported in the literature (Bleriot Yves et al. Org. Biomol. Chem., 2004, 2, pp. 1492-1499).

[0132] Compound 18A 1 H NMR (400MHz, CDCl3) δ7.38-7.25(m,40H,8×Ph),5.79-5.68(m,4H),5.17(m,4H,2×CH2Ph),4.98(d,J=11.3Hz,1H,CHPh),4.95(d, J=11.1Hz,1H,CHPh),4.82(d,J=11.6Hz,1H,CHPh),4.75(d,J=11.7Hz,1H,CHPh),4.70(d,J=11.6Hz,1H,CHPh),4.68(d,J=11.7H z,1H,CHPh),4.60(m,1H),4.54(d,J=11.3Hz,1H,CHPh),4.51(d,J=11.1Hz,1H,CHPh),4.50(d,J=12.0Hz,1H,CHPh),4.49(d,J=1 2.0Hz,1H,CHPh),4.47(m,1H),4.34-4.26(m,4H),3.92-3.73(m,6H),3.65(dd,J=10.2,2.9Hz,1H),3.58(dd,J=10.2,3.2Hz,1H).

[0133] Compound 18B 1H NMR (400MHz, CDCl3) δ7.37-7.25(m,40H,8×Ph),6.06(ddd,J=11.5,6.1,2.1Hz,1H),5.92(ddd,J=11.7,6.1,2.2Hz,1H),5.77(m, 2H),5.18(s,2H,CH2Ph),5.14(d,J=12.4Hz,1H,CHPh),5.02(d,J=12.4Hz,1H,CHPh),5.01(m,1H,),4.86(m,1H),4.65-4.50(m,12 H,6×CH2Ph),4.40(m,1H),4.30(m,1H),4.27(m,1H),4.23(m,1H),4.08(dd,J=4.3,6.9Hz,1H),4.05(dd,J=4.4,6.8Hz,1H),3.90 -3.80(m,2H),3.87(dd,J=7.0,9.6Hz,1H),3.83(dd,J=7.3,9.4Hz,1H),3.74(dd,J=8.2,9.6Hz,1H),3.67(dd,J=7.6,9.4Hz,1H).

[0134] [Intermediate Preparation Example 13] Synthesis of Compound 19

[0135] Compound 18A (2.0 g, 3.54 mmol) was dissolved in an 8:1 acetone / water solution (20 mL) in a reaction flask. N-methylmorpholine oxide (1.7 g, 14.16 mmol) and OsO4 (0.7 mL, 2.5% wt tert-butanol solution) were added and stirred at room temperature overnight. After completion, the reaction was terminated by the addition of an excess of sodium thiosulfate (500 mg). The reaction mixture was extracted with ethyl acetate (2 × 150 mL) and washed with brine (150 mL). The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (petroleum ether / ethyl acetate 2:1) afforded compound 19A (1.58 g, 75%) as a colorless oil. Further elution afforded compound 19B (210 mg, 15%) as a colorless oil. The same reaction procedures were used to synthesize compound 18B (1.22 g, 2.16 mmol) as a colorless oil, compound 19C (660 mg, 51%) and compound 19D (340 mg, 26%). The spectral data were consistent with those reported in the literature (Bleriot Yves et al., Org. Biomol. Chem., 2006, 4, pp. 1653–1662).

[0136] Compound 19A 11H NMR (C400 MHz, DCl3) δ 7.40 - 7.27 (m, 40H, 8×Ph), 5.27 (d, J = 12.5 Hz, 1H, CHPh), 5.21 (d, J = 12.5 Hz, 1H, CHPh), 5.17 (d, J = 12.4 Hz, 1H, CHPh), 5.13 (d, J = 12.4 Hz, 1H, CHPh), 4.74 (m, 1H), 4.74 (d, J = 10.5 Hz, 2H, 2×CHPh), 4.69 (d, J = 8.6 Hz, 1H, CHPh), 4.66 - 4.48 (m, 7H), 4.38 (app.t, 1H), 4.30 (app.t, J = 6.1 Hz, 1H), 4.18 (d, J = 8.8 Hz, 1H), 4.09 - 4.01 (m, 4H), 3.93 (m, 2H), 3.88 - 3.78 (m, 3H), 3.71 (dd, J = 9.0, 5.5 Hz, 1H), 3.62 (dd, J = 9.1, 5.6 Hz, 1H), 3.32 - 3.22 (m, 2H), 2.98 (d, J = 8.8 Hz, 1H), 2.96 (d, J = 8.8 Hz, 1H).

[0137] Compound 19B 1 1H NMR (400 MHz, CDCl3) δ 7.37 - 7.24 (m, 40H, 8×Ph), 5.22 (d, J = 12.4 Hz, 1H, CHPh), 5.17 (d, J = 12.4 Hz, 1H, CHPh), 5.16 (d, J = 12.3 Hz, 1H, CHPh), 5.08 (d, J = 12.3 Hz, 1H, CHPh), 4.75 (m, J = 4.6 Hz, 1H), 4.66 - 4.50 (m, 9H), 4.46 (d, J = 12.0 Hz, 1H, CHPh), 4.41 (d, J = 1十二.0 Hz, 1H, CHPh), 4.27 (m, 1H), 4.19 (m, 1H), 4.18 (dd, J = 7.4, 5.2 Hz, 1H), 4.14 (m, 2H), 4.11 (dd, J = 7.4, 5.1 Hz, 1H), 4.03 (m, 3H), 3.93 (m, 1H), 3.79 (dd, J = 9.7, 8.7 Hz, 1H), 3.73 (dd, J = 9.5, 8.9 Hz, 1H), 3.64 (dd, J = 8.7, 5.0 Hz, 1H), 3.50 (dd, J = 8.9, 5.3 Hz, 1H), 3.35 - 3.28 (m, 3H), 2.81 (d, J = 11.4 Hz, 1H).

[0138] Compound 19C 11H NMR (400 MHz, CDCl3) δ 7.39 - 7.26 (m, 40H, 8×Ph), 5.24 (d, J = 12.3 Hz, 1H, CHPh), 5.22 (d, J = 12.5 Hz, 1H, CHPh), 5.18 (d, J = 12.5 Hz, 1H, CHPh), 5.16 (d, J = 12.3 Hz, 1H, CHPh), 5.06 (d, J = 11.1 Hz, 1H, CHPh), 5.04 (d, J = 11.1 Hz, 1H, CHPh), 4.98 (d, J = 10.9 Hz, 1H, CHPh), 4.96 (d, J = 11.2 Hz, 1H, CHPh), 4.64 (d, J = 11.1 Hz, 1H, CHPh), 4.58 (d, J = 11.2 Hz, 1H, CHPh), 4.53 (d, J = 11.2 Hz, 1H, CHPh), 4.48 (d, J = 12.0 Hz, 1H, CHPh), 4.47 (d, J = 10.9 Hz, 1H, CHPh), 4.43 (d, J = 11.7 Hz, 1H, CHPh), 4.38 (dd, J = 4.8 Hz, J = 15.9 Hz, 1H), 4.36 (d, J = 10.7 Hz, 1H, CHPh), 4.35 (m, 1H), 4.33 (d, J = 12.0 Hz, 1H, CHPh), 4.25 (dd, J = 15.7, 5.1 Hz, 1H), 4.13 (app.t, J = 4.1 Hz, 1H), 4.09 (dt, J = 9.2, 2.4, 2.1 Hz, 1H), 4.01 (app.t, J = 4.0 Hz, 1H), 3.83 (dd, J = 9.8, 2.9 Hz, 1H), 3.86 - 3.73 (m, 5H), 3.68 (dd, J = 9.8, 2.6 Hz, 1H), 3.62 - 3.55 (m, 3H), 3.31 (d, J = 16.4 Hz, 1H), 3.27 (dd, J = 15.7 Hz, 1H).

[0139] Compound 19D 1H NMR (400MHz, CDCl3) δ7.39-7.23(m,40H,8×Ph),5.17(s,2H,CH2Ph),5.16(d,J=12.3Hz,1H,CHPh),5.10(d,J=12.3Hz,1H,CHPh),4.89(d,J=10.9Hz,1H ,CHPh),4.88(d,J=11.2Hz,1H,CHPh),4.83(d,J=11.3Hz,2H,2×CHPh),4.65(d,J=11.6Hz,1H,CHPh),4.60(d,J=11.3Hz,1H,CHPh),4.52(d,J=11.2Hz,1 H,CHPh),4.52(d,J=10.9Hz,1H,CHPh),4.47(d,J=12.2Hz,1H,CHPh),4.46(d,J=10.9Hz,1H,CHPh),4.40(d,J=12.1Hz,1H,CHPh),4.38(d,J=12.2Hz,1 H,CHPh),4.28-4.23(m,3H),4.23-4.20(m,3H),4.15(m,1H),3.83-3.66(m, 6H),3.65(dd,1H),3.61(m,1H),3.55(dd,1H),3.37(dd,1H),3.29(dd,1H).

[0140] [Intermediate Preparation Example 14] Synthesis of Compound 20

[0141] Compound 19A (64 mg, 0.093 mmol), tetrabutylammonium iodide (3 mg, 0.009 mmol), and anhydrous N,N-dimethylformamide (3 mL) were added to a reaction flask. Sodium hydride (11 mg, 0.279 mmol) was added portionwise with stirring at 0°C. After 0.5 hours, n-heptane bromide (16 L, 0.1 mmol) was added dropwise at 0°C. After complete addition, the mixture was stirred at room temperature overnight. Another portion of NaH (11 mg, 0.279 mmol) was added at 0°C. After 0.5 hours, BnBr (22 L, 0.188 mmol) was added dropwise at 0°C. The mixture was stirred at room temperature overnight. The reaction was quenched by the addition of methanol (4 mL) at 0°C, and the resulting solution was extracted with dichloromethane (2 x 50 mL). The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (petroleum ether / ethyl acetate 6:1) gave compound 20A (59 mg, 81%) as a yellow oil. Following the same reaction procedure, compounds 19B (28 mg, 0.04 mmol), 19C (50 mg, 0.072 mmol), and 19D (27 mg, 0.04 mmol) were synthesized to give compound 20B (7 mg, 23%), compound 20C (12 mg, 21%), and compound 19D (28 mg, 89%) as yellow oils, respectively.

[0142] Compound 20A 1 H NMR(600MHz, CDCl3)δ7.55–7.04(m,50H),5.21(d,J=12.3Hz,1H),5.18–5.07(m,3H),4.92–4.84(m,1H),4.74 –4.37(m,18H),4.17(d,J=11.4Hz,1H),4.08(dt,J=22.7,9.8Hz,2H),3.97(d,J=12.7Hz,1H),3.79(d,J=11.0H z,2H),3.75–3.59(m,7H),3.56–3.42(m,5H),3.39(ddd,J=13.2,11.4,6.8Hz,3H),3.32–3.24(m,1H),1.61–1. 52(m,4H),1.45(dd,J=12.9,7.8Hz,3H),1.30(ddd,J=36.0,19.3,10.4Hz,20H),0.88(dt,J=14.8,6.7Hz,6H). 1313C NMR (151 MHz, CDCl3) δ 156.22, 156.20 (2×C=O), 138.70–136.68 (10×Cipso), 128.61–127.61 (50 aromatic C), 82.03 (-CH), 81.88 (-CH), 81.58 (-CH), 81.45 (-CH), 80.54 (-CH), 80.40 (-CH), 78.74 (-CH), 78.13 (-CH), 73.67 (-CH2), 73.56 (-CH2), 73.48 (-CH2), 73.37 (-CH2), 73.15 (-CH2), 73.12 (-CH2), 72.94 (-CH2), 72.81 (-CH2), 71.10 (-CH2), 70.37 (-CH2), 70.09 (-CH2), 67.71 (-CH2), 67.67 (-CH2), 65.34 (-CH2), 64.83 (-CH2), 54.85 (-CH), 54.61 (-CH), 40.89 (-CH2), 40.49 (-CH2), 31.99, 31.97, 30.23, 30.08, 29.92, 29.83, 29.50), 29.30, 29.22, 26.31, 26.17, 22.77, 22.76 (-CH2 aliph), 14.25 (-CH3 aliph). ESI-HRMS: Calcd for C 50 H 60 NO7 (M+H + ): 786.4364. Found: 786.4366.

[0143] Compound 20B 1 1H NMR (600 MHz, CDCl3) δ 7.58–7.00 (m, 50H), 5.20 (d, J=12.3 Hz, 1H), 5.16 (d, J=12.3 Hz, 1H), 5.11 (dd, J=12.2, 7.6 Hz, 1H), 4.87 (s, 1H), 4.74–4.34 (m, 12H), 4.20 (d, J=10.7 Hz, 1H), 4.04 (ddd, J=31.4, 20.9, 11.0 Hz, 2H), 3.74–3.60 (m, 6H), 3.57–3.38 (m, 5H), 1.50–1.39 (m, 3H), 1.36–1.17 (m, 20H), 0.88 (dd, J=8.6, 5.5 Hz, 6H). 1313C NMR (151 MHz, CDCl3) δ 156.24, 156.17 (2×C=O), 138.91–136.69 (10×Cipso), 128.70–127.29 (50 aromatic C), 82.06 (-CH), 82.04 (-CH), 81.84 (-CH), 81.68 (-CH), 81.58 (-CH), 81.33 (-CH), 77.75 (-CH), 77.26 (-CH), 73.55 (-CH2), 73.39 (-CH2), 73.08 (-CH2), 73.04 (-CH2), 72.98 (-CH2), 72.85 (-CH2), 72.04 (-CH2), 71.92 (-CH2), 71.60 (-CH2), 67.75 (-CH2), 67.71 (-CH2), 65.38 (-CH2), 64.82 (-CH2), 54.97 (-CH), 54.75 (-CH), 32.00, 30.25, 30.20, 29.85, 29.29, 26.35, 22.79 (-CH2 aliph), 14.25 (-CH3 aliph). ESI-HRMS: Calcd for C 50 H 60 NO7 (M + H + ): 786.4364. Found: 786.4344.

[0144] Compound 20C 1 1H NMR (600 MHz, CDCl3) δ 7.39–7.18 (m, 30H), 7.18–7.03 (m, 2H), 4.98–4.91 (m, 1H), 4.88 (d, J=12.4 Hz, H), 4.73–4.63 (m, 2H), 4.57 (d, J=10.9 Hz, 1H), 4.53–4.41 (m, 3H), 4.38–4.23 (m, 3H), 4.05 (s, 1H), 4.00 (s, 1H), 3.91 (d, J=6.7 Hz, 2H), 3.82 (d, J=6.4 Hz, 1H), 3.74 (dd, J=19.5, 9.9 Hz, 1H), 3.61 (d, J=7.0 Hz, 1H), 3.54–3.48 (m, 1H), 3.44 (t, J=7.6 Hz, 1H), 3.35–3.23 (m, 2H), 1.43 (dd, J=13.2, 6.9 Hz, 2H), 1.37–1.14 (m, 14H), 0.94–0.81 (m, 5H). ESI-HRMS: Calcd for C 50 H 59 NO7Na (M + Na+ ):808.4184.Found:808.4156.

[0145] Compound 20D 1 H NMR(600MHz,CDCl3)δ7.45(dd,J=11.1,7.3Hz,2H),7.40–7.19(m,21H),7.15(ddd,J=9.1,7.2,2.8Hz,2H),5.19(dd,J=26.7,12.3Hz,1H),5.09(t,J=11.7Hz,1H),4.98–4.76(m,4H),4.59(dd,J=11.8,3.1Hz,1H),4.44(dd,J=21.3,11.4Hz,2H),4.37(d,J=12.3Hz,1H),4.34–4.17(m,3H),4.09(d,J=26.4Hz,1H),3.81(d,J=12.8Hz,1H),3.69–3.56(m,2H),3.55–3.43(m,2H),3.37–3.11(m,3H),1.66–1.54(m,3H),1.48–1.41(m,1H),1.39–1.17(m,9H),0.94–0.87(m,3H). 13 C NMR(151MHz,CDCl3)δ156.28,156.15(2×C=O),139.44–136.53(10×Cipso),128.66–127.38(50aromatic C),82.46(-CH),82.34(-CH),79.40(-CH),79.32(-CH),78.84(-CH),77.97(-CH),74.88(-CH),74.80(-CH2),74.77(-CH2),74.70(-CH2),74.43(-CH2),74.19(-CH2),74.14(-CH2),72.88(-CH2),72.78(-CH2),69.87(-CH2),69.64(-CH2),69.44(-CH2),69.33(-CH2),67.71(-CH2),67.49(-CH2),58.65(-CH),58.47(-CH),41.35(-CH2),31.99,31.96,30.24,30.06,29.30,29.23,26.25,26.12,22.76(-CH2 aliph),14.26(-CH3 aliph).ESI-HRMS:Calcd for C 50 H 59 NO7Na(M+Na+ ):808.4184.Found:808.4165.

[0146] [Intermediate Preparation Example 15] Synthesis of Compound 22

[0147] To a reaction flask, compound 16A (268 mg, 0.586 mmol), tetrabutylammonium iodide (15.6 mg, 0.1 mmol), and anhydrous N,N-dimethylformamide (50 mL) were added. Sodium hydride (14 mg, 0.586 mmol) was added portionwise with stirring at 0°C. After 0.5 hours, n-butyl bromide (368 L, 4.105 mmol) was added dropwise at 0°C. After complete addition, the reaction was stirred at room temperature overnight. After completion of the reaction, methanol (5 mL) was added at 0°C to quench the reaction, and the resulting solution was extracted with ethyl acetate (2 × 50 mL). The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (petroleum ether / ethyl acetate 5:1) afforded compound 22A (209 mg, 70%) as a colorless oil. The same reaction procedure was used to synthesize compound 22B (137 mg, 28%) as a colorless oil using compound 16B (435 mg, 0.951 mmol).

[0148] Compound 22A 1 H NMR (600MHz, CDCl3) δ7.49–7.20(m,15H),5.99(ddd,J=17.4,10.4,7.0Hz,1H),5.93–5.76(m,1H),5.48(d,J=17.3Hz,1H),5.39(d,J=10.5 Hz,1H),5.17(d,J=17.1Hz,1H),5.13–5.05(m,2H),4.74(d,J=11.8Hz,1H),4.67(d,J=11.5Hz,1H),4.52(d,J=11.8Hz,1H),4.47(s,2H),4 .37(t,J=7.3Hz,1H),3.84–3.76(m,2H),3.72(dd,J=9.0,4.9Hz,1H),3.65(dd,J=14.5,4.9Hz,1H),3.16(dd,J=14.5,7.6Hz,1H),3.11(dd ,J=7.8,4.1Hz,1H),2.96–2.88(m,1H),2.55–2.48(m,1H),1.51–1.41(m,2H),1.32(ddd,J=18.6,14.6,7.2Hz,2H),0.96(t,J=7.3Hz,3H). 1313C NMR (151 MHz, CDCl3) δ 139.83, 138.91, 138.57 (3×Cipso), 138.37 (=CH), 135.96 (=CH), 128.37–127.08 (15 aromatic C), 118.14 (=CH2), 115.52 (=CH2), 83.39 (-CH), 82.67 (-CH), 75.74 (-CH2), 73.20 (-CH2), 70.81 (-CH2), 66.49 (-CH2), 60.57 (-CH), 55.43 (-CH2), 51.75 (-CH2), 31.16, 20.62 (-CH2 aliph), 14.22 (-CH3 aliph). ESI-HRMS: Calcd for C 34 H 43 NO3 (M+H + ): 514.3316. Found: 514.3311.

[0149] Compound 22B 1 1H NMR (600 MHz, CDCl3) δ 7.42–7.17 (m, 20H), 6.00–5.85 (m, 1H), 5.83–5.68 (m, 1H), 5.29 (t, J=7.3 Hz, 2H), 5.11 (dd, J=17.2, 1.4 Hz, 1H), 5.02–4.93 (m, 1H), 4.82 (dd, J=11.2, 7.4 Hz, 1H), 4.67–4.53 (m, 3H), 4.48 (d, J=13.0 Hz, 2H), 4.38 (dd, J=11.5, 3.8 Hz, 2H), 4.30–4.20 (m, 1H), 3.79 (dd, J=10.1, 3.8 Hz, 1H), 3.73–3.65 (m, 3H), 3.31–3.15 (m, 3H), 2.59–2.48 (m, 3H), 1.36 (ddd, J=17.2, 12.9, 8.4 Hz, 4H), 1.29–1.13 (m, 4H), 0.85 (dt, J=7.4, 5.4 Hz, 6H). 13C NMR (151MHz, CDCl3) δ139.18–138.89 (3×Cipso), 138.50 (=CH), 137.02 (=CH), 128.41–127.37 (15aromatic C),118.37(=CH2),115.65(=CH2),82.04(-CH),81.94(-CH),74.37(-CH2),73.17(-CH2), 70.84(-CH2),68.15(-CH2),59.46(-CH),54.87(-CH2),51.31(-CH2),31.26,20.65(-CH2 aliph),14.23(-CH3 aliph).ESI-HRMS:Calcd for C 34 H 43 NO3(M+H + ):514.3316.Found:514.3306.

[0150] [Intermediate Preparation Example 16] Synthesis of Compound 23

[0151] In a reaction flask, compound 22A (200 mg, 0.389 mmol) was dissolved in dichloromethane (100 mL) and degassed by bubbling nitrogen for 30 min. Grubbs' catalyst 1st (10% mol, 80 mg) was added and the reaction was stirred under reflux at 45°C under nitrogen until the starting material disappeared completely as determined by thin-layer chromatography (petroleum ether / ethyl acetate 5:1). Excess lead acetate was added to quench the reaction. The reaction mixture was concentrated under reduced pressure and purified by flash column chromatography (petroleum ether / ethyl acetate 15:1) to afford compound 23A (71 mg, 37%) as a colorless oil. The same reaction procedure was followed to obtain compound 23B (43 mg, 33%) as a colorless oil using compound 22B (137 mg, 0.267 mmol).

[0152] Compound 23A 11H NMR (600 MHz, CDCl3) δ 7.43–7.25 (m, 15H), 5.70 (s, 2H), 4.75 (d, J = 11.7 Hz, 1H), 4.65 (t, J = 7.6 Hz, 3H), 4.53 (t, J = 7.5 Hz, 2H), 4.23 (d, J = 7.7 Hz, 1H), 3.94 (dd, J = 7.7, 3.5 Hz, 1H), 3.78 (dd, J = 9.6, 5.6 Hz, 1H), 3.71 (t, J = 8.8 Hz, 1H), 3.58 (d, J = 16.7 Hz, 1H), 3.46–3.39 (m, 1H), 3.33–3.23 (m, 1H), 2.83–2.67 (m, 2H), 1.40 (dt, J = 13.1, 6.6 Hz, 2H), 1.35–1.25 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H). 13 13C NMR (151 MHz, CDCl3) δ 139.06, 138.89, 138.72 (3×Cipso), 130.59 (=CH), 128.56 (=CH), 128.39–127.52 (15 aromatic C), 81.55 (-CH), 79.26 (-CH), 73.48 (-CH2), 73.12 (-CH2), 72.10 (-CH2), 68.09 (-CH2), 60.74 (-CH), 54.77 (-CH2), 49.63 (-CH2), 31.09, 20.51 (-CH2 aliph), 14.20 (-CH3 aliph). ESI-HRMS: Calcd for C 32 H 39 NO3 (M + H + ): 486.3003. Found: 486.2990.

[0153] Compound 23B 1H NMR(600MHz, CDCl3)δ7.58–7.13(m,15H),5.63(dd,J=11.7,1.9Hz,1H),5.54–5.46(m,1H),4.81 (ddd,J=11.6,9.0,6.9Hz,2H),4.73(q,J=11.7Hz,2H),4.58(d,J=11.5Hz,1H),4.48(q,J=12.0H z,2H),3.76(dd,J=9.5,7.5Hz,1H),3.53–3.39(m,3H),3.22(ddd,J=19.6,11.4,9.5Hz,2H),2.7 9–2.68(m,1H),2.67–2.59(m,1H),1.51–1.42(m,2H),1.39–1.29(m,2H),0.91(t,J=7.3Hz,3H). 13 C NMR(151MHz, CDCl3)δ139.22,139.15,138.68(3×Cipso),130.78(=CH),129.07(=CH),128.43–127.45(15aromaticC),83.41(-CH), 80.34(-CH),73.48(-CH2),73.17(-CH2),73.06(-CH2),70.11(-CH2),65.39(-CH),57.19(-CH2),50.49(-CH2),31.30,20.38(-CH2 aliph),14.19(-CH3 aliph).ESI-HRMS:Calcd for C 32 H 39 NO3(M+H + ):486.3003.Found:486.3004.

[0154] [Intermediate Preparation Example 17] Synthesis of Compound 24

[0155] Compound 23A (140 mg, 0.19 mmol) was dissolved in an 8:1 acetone / water solution (20 mL) in a reaction flask. N-methylmorpholine oxide (88 mg, 0.76 mmol) and OsO4 (0.1 mL, 2.5% wt tert-butanol solution) were added and stirred at room temperature overnight. After completion, the reaction was terminated by the addition of an excess of sodium thiosulfate (200 mg). The reaction mixture was extracted with ethyl acetate (2 × 50 mL) and washed with brine (50 mL). The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (petroleum ether / ethyl acetate 2:1) afforded compound 24A (54 mg, 54%) as a colorless oil. The same reaction procedure was followed with compound 23B (110 mg, 0.182 mmol) to afford compound 24B (58 mg, 61%) as a colorless oil.

[0156] Compound 24A 1 H NMR(600MHz, CDCl3)δ7.42–7.20(m,15H),4.70(dd,J=17.8,11.3Hz,2H),4.60(d,J=11.3Hz,2H), 4.56–4.45(m,2H),4.00–3.92(m,2H),3.89(dd,J=7.8,4.5Hz,1H),3.81(dd,J=5.1,3.1Hz,1H),3. 72(dd,J=9.5,6.5Hz,1H),3.65(dd,J=9.6,4.7Hz,1H),3.10–2.97(m,2H),2.85(dd,J=14.8,3.5H z,1H),2.74–2.56(m,2H),1.49–1.31(m,2H),1.24(td,J=14.7,7.4Hz,2H),0.87(t,J=7.3Hz,3H). 13 C NMR(151MHz, CDCl3)δ138.27,138.24,138.09(3×Cipso),128.55–127.74(15aromatic C),80.64(-CH),79.18(-CH),74.76(-CH),74.50(-CH2),74.00(-CH2),73.26(-CH2),6 9.02(-CH2),68.40(-CH),61.20(-CH),54.97(-CH2),52.77(-CH2),30.40,20.39(-CH2 aliph),14.11(-CH3 aliph).ESI-HRMS:Calcd for C 32 H 42 NO5(M+H +):520.3057.Found:520.3052.

[0157] Compound 24B 1 H NMR (600MHz, CDCl3) δ7.47–7.15(m,15H),4.74–4.60(m,2H),4.54(dd,J=11.4,8.1Hz,2H),4.46 –4.35(m,2H),4.10(s,1H),4.04(dd,J=7.6,4.8Hz,1H),3.96(d,J=7.6Hz,1H),3.72–3.64(m,1H) ,3.59(d,J=5.0Hz,2H),3.04(dd,J=9.6,4.7Hz,1H),2.93(dd,J=14.4,8.6Hz,1H),2.85–2.77(m ,1H),2.72–2.56(m,2H),1.50–1.33(m,2H),1.25(dd,J=17.1,7.7Hz,3H),0.88(t,J=7.3Hz,3H). 13 C NMR(151MHz, CDCl3)δ138.58,138.52,138.35(3×Cipso),128.55–127.69(15aromatic C),83.62(-CH),75.90(-CH),74.30(-CH2),73.22(-CH2),71.94(-CH),71.37(-CH),70 .10(-CH2),65.61(-CH),56.17(-CH2),51.70(-CH2),30.48(-CH2),29.83,20.40(-CH2 aliph),14.16(-CH3 aliph).ESI-HRMS:Calcd for C 32 H 42 NO5(M+H + ):520.3057.Found:520.3049.

[0158] [Example 1] Synthesis of Compound 9

[0159] In a hydrogenation reaction flask, compound 8A (22 mg, 0.047 mmol) was dissolved in methanol (3 mL) and 10% palladium-on-carbon catalyst (10 mg) was added. The reaction mixture was stirred at room temperature under hydrogen for 4 h. After completion of the reaction, the filtrate was filtered, collected, and concentrated under reduced pressure to obtain compound 9A (11 mg, 100%) as a colorless oil. The same reaction procedure was used to synthesize compound 8B (36 mg, 0.078 mmol) to obtain compound 9B (8.3 mg, 55%) as a colorless oil.

[0160] Compound 9A 1 H NMR (600MHz, MeOD) δ4.10(ddd,J=5.7,3.9,2.0Hz,1H),4.04(dd,J=12.7,5.7Hz,1H),3.89–3.85(t,J=8.4,7.8Hz,1H),3.82(dd,J=11.6,2.6Hz,1H),3. 73(dd,J=8.8,1.9Hz,1H),3.65(dd,J=12.7,3.9Hz,1H),3.60(ddd,J=7.8,7 .3,2.6Hz,1H),3.52(dd,J=11.6,7.2Hz,1H),3.32–3.27(dd,J=7.8Hz,1H). 13 C NMR(151MHz,MeOD)δ82.04(-CH),75.56(-CH),75.47(-CH),73.91(-CH),73.39(-CH2),72.93(-CH),64.52(-CH2).ESI-HRMS:Calcd for C7H 14 O6Na(M+Na + ):217.0683.Found:217.0681.

[0161] Compound 9B 1 H NMR (600MHz, MeOD) δ4.02(s,1H),3.93–3.88(m,2H),3.76–3.70(m,2H),3.67–3.57(m,3H),3.36–3.32(m,1H). 13 C NMR(151MHz,MeOD)δ85.24(-CH),78.73(-CH),74.02(-CH),73.28(-CH),71.41(-CH2),71.31(-CH),64.23(-CH2).ESI-HRMS:Calcdfor C7H 14 O6Na(M+Na + ):217.0683.Found:217.0679.

[0162] [Example 2] Synthesis of Compound 11

[0163] In a hydrogenation reaction flask, compound 10 (39 mg, 0.068 mmol) was dissolved in methanol (3 mL) and 10% palladium-on-carbon catalyst (10 mg) was added. The reaction mixture was stirred at room temperature under hydrogen for 4 h. After completion of the reaction, the filtrate was filtered, collected, and concentrated under reduced pressure to afford compound 11 (18 mg, 95%) as a colorless oil.

[0164] 1 H NMR(600MHz,MeOD)δ5.57(t,J=2.4Hz,1H),5.19(ddd,J=6.9,5.8,2.7Hz,1H),3.87–3.79(m,3H),3.78( dd,J=8.5,2.0Hz,1H),3.66–3.59(m,2H),3.38(ddd,J=9.1,7.4,2.8Hz,1H),2.10(s,3H),1.99(s,3H). 13 C NMR(151MHz,MeOD)δ172.63(C=O),171.76(C=O),83.69(-CH),75.03(-CH),74.62(-CH),72.08 (-CH),71.68(-CH),68.20(-CH2),64.15(-CH2),20.83(-CH3),20.75(-CH3).ESI-HRMS:Calcd for C 11 H 18 O8(M+Na + ):301.0899.Found:301.0885.

[0165] [Example 3] Synthesis of Compound 13

[0166] In a hydrogenation reaction flask, compound 12A (39 mg, 0.068 mmol) was dissolved in methanol (3 mL) and 10% palladium-on-carbon catalyst (10 mg) was added. The reaction mixture was stirred at room temperature under hydrogen for 4 h. After completion of the reaction, the filtrate was filtered, collected, and concentrated under reduced pressure to obtain compound 13A (22 mg, 76%) as a colorless oil. Following the same reaction procedure, compound 12B (31 mg, 0.055 mmol) was used to obtain compound 13B (9 mg, 56%) as a colorless oil; and compound 12C (52 mg, 0.092 mmol) was used to obtain compound 13C (28 mg, 100%) as a colorless oil.

[0167] Compound 13A 1 H NMR(600MHz,MeOD)δ3.94–3.90(m,2H),3.85–3.80(m,2H),3.69–3.65(m,2H),3.64–3.59(m,2H),3 .59–3.45(m,4H),3.31–3.27(m,1H),1.67–1.49(m,4H),1.47–1.23(m,16H),0.92(t,J=6.8Hz,6H). 13¹³C NMR (151 MHz, MeOD) δ 82.41 (-CH), 80.23 (-CH), 79.82 (-CH), 76.24 (-CH), 75.96 (-CH), 71.99 (-CH₂), 71.95 (-CH₂), 71.84 (-CH₂), 64.63 (-CH₂), 33.07 (-CH₂), 33.04, 31.16, 31.14, 30.31, 30.29, 27.36, 27.32, 23.71 (-CH₂ aliph), 14.46 (-CH₃ aliph). ESI-HRMS: Calcd for C 21 H 43 O₆ (M + H + ): 391.3054. Found: 391.3046.

[0168] Compound 13B 1 ¹H NMR (600 MHz, MeOD) δ 4.18 (td, J = 5.3, 1.5 Hz, 1H), 4.01–3.96 (m, 1H), 3.85 (dd, J = 11.6, 2.8 Hz, 1H), 3.77–3.72 (m, 2H), 3.70–3.58 (m, 4H), 3.58–3.48 (m, 2H), 1.68 (ddd, J = 9.3, 8.8, 4.7 Hz, 2H), 1.49–1.26 (m, 8H), 0.96 (t, J = 7.0 Hz, 3H). 13 ¹³C NMR (151 MHz, MeOD) δ 83.71 (-CH), 81.70 (-CH), 76.48 (-CH), 75.42 (-CH), 73.03 (-CH₂), 72.19 (-CH₂), 70.53 (-CH), 64.62 (-CH₂), 33.02, 31.12, 30.35, 27.23, 23.70 (-CH₂ aliph), 14.43 (-CH₃ aliph). ESI-HRMS: Calcd for C 14 H 28 O₆Na (M + Na + ): 315.1784. Found: 315.1769.

[0169] Compound 13C 1H NMR(600MHz,MeOD)δ3.95(dd,J=12.7,5.4Hz,1H),3.86–3.78(m,5H),3.66–3.62(m,1H),3.61–3.58(m,1H),3.55–3.53(m,1 H),3.48(dd,J=11.6,7.3Hz,1H),3.27(dd,J=9.7,7.6Hz,1H),1.68–1.59(m,2H),1.48–1.31(m,8H),0.96(t,J=6.9Hz,3H). 13 C NMR(151MHz,MeOD)δ82.66(-CH),80.26(-CH),76.36(-CH),75.77(-CH),73.26(-CH),72.23(- CH2),71.71(-CH2),64.58(-CH2),33.01,31.21,30.32,27.31,23.70(-CH2aliph),14.43(-CH3 aliph).ESI-HRMS:Calcd for C 14 H 28 O6Na(M+Na + ):315.1784.Found:315.1770.

[0170] [Example 4] Synthesis of Compound 21

[0171] In a hydrogenation reaction flask, compound 20A (25 mg, 0.031 mmol) was dissolved in methanol (3 mL) and 10% palladium-on-carbon catalyst (10 mg) was added. The reaction mixture was stirred at room temperature under hydrogen for 4 h. After completion of the reaction, the filtrate was filtered, collected, and concentrated under reduced pressure to obtain compound 21A (11 mg, 100%) as a colorless oil. Following the same reaction procedure, compound 20B (7 mg, 0.009 mmol) was used to obtain compound 21B (3.3 mg, 100%) as a colorless oil; compound 20C (12 mg, 0.015 mmol) was used to obtain compound 21C (2 mg, 50%) as a colorless oil; and compound 20D (28 mg, 0.035 mmol) was used to obtain compound 21D (10 mg, 83%) as a colorless oil.

[0172] Compound 21A 11H NMR (600 MHz, MeOD) δ 4.11 (d, J = 5.0 Hz, 1H), 3.99 (dd, J = 9.0, 4.0 Hz, 1H), 3.98–3.95 (m, 1H), 3.84 (d, J = 3.4 Hz, 1H), 3.79–3.68 (m, 2H), 3.55 (ddt, J = 19.1, 13.0, 7.8 Hz, 4H), 3.27 (dd, J = 12.9, 4.0 Hz, 1H), 1.62–1.54 (m, 2H), 1.42–1.23 (m, 8H), 0.90 (t, J = 6.9 Hz, 3H). 13 13C NMR (151 MHz, MeOD) δ 76.53 (-CH), 74.61 (-CH), 72.44 (-CH), 72.18 (-CH), 71.46 (-CH2), 62.05 (-CH2), 58.66 (-CH), 45.15 (-CH2), 32.98, 30.88, 30.24, 27.10, 23.66 (-CH2 aliph), 14.40 (-CH3 aliph). ESI-HRMS: Calcd for C 14 1 30 1 + NO5 (M + H

[0173] Compound 21B 1 1H NMR (600 MHz, MeOD) δ 4.36 (dd, J = 8.1, 2.6 Hz, 1H), 4.03 (dd, J = 4.9, 3.5 Hz, 1H), 3.79 (d, J = 3.3 Hz, 1H), 3.74–3.65 (m, 4H), 3.62 (dt, J = 9.1, 6.7 Hz, 1H), 3.50 (dd, J = 8.3, 6.3 Hz, 1H), 3.43 (dd, J = 13.1, 8.1 Hz, 1H), 3.24 (dd, J = 13.1, 3.5 Hz, 1H), 1.68–1.57 (m, 2H), 1.45–1.21 (m, 8H), 0.91 (t, J = 6.9 Hz, 3H). 13 13C NMR (151 MHz, MeOD) δ 87.43 (-CH), 72.52 (-CH2), 72.16 (-CH), 71.99 (-CH), 66.21 (-CH), 61.89 (-CH2), 48.55 (-CH2), 59.43 (-CH), 33.01, 31.02, 30.31, 27.11, 23.69 (-CH2 aliph), 14.41 (-CH3 aliph). ESI-HRMS: Calcd for C14 H 30 NO5(M+H + ):292.2118.Found:292.2111.

[0174] Compound 21C 1 H NMR(600MHz,MeOD)δ3.98(dd,J=11.8,3.6Hz,1H),3.95–3.92(m,1H),3.91–3.88(m,1H),3.87–3.81(m,2H),3.70(dt,J=9.2,6.6Hz,1H),3.67–3.61(m,2H),3.58–3.52(m,1H),3.43(dd,J=13.6,7.4Hz,1H),3.30(dd,J=13.6,3.2Hz,1H),1.69–1.62(m,2H),1.47–1.31(m,8H),0.96(t,J=7.0Hz,3H). 13 C NMR(151MHz,MeOD)δ76.03(-CH),75.87(-CH),74.80(-CH),72.25(-CH2),72.19(-CH),61.45(-CH),60.45(-CH2),44.90(-CH2),32.99,30.93,30.27,27.13,23.68(-CH2aliph),14.41(-CH3 aliph).ESI-HRMS:Calcdfor C 14 H 30 NO5(M+H + ):292.2118.Found:292.2112.

[0175] Compound 21D 1 H NMR(600MHz,MeOD)δ4.25(s,1H),3.99(dd,J=11.7,3.9Hz,1H),3.88–3.84(m,1H),3.82(d,J=8.7Hz,1H),3.73(dd,J=11.6,7.9Hz,1H),3.62(dd,J=8.5,1.6Hz,1H),3.61–3.55(m,1H),3.49(dt,J=9.1,6.6Hz,1H),3.39(dd,J=13.3,5.9Hz,1H),3.31–3.26(m,1H),3.18(td,J=8.3,3.9Hz,1H),1.62–1.55(m,2H),1.35(ddd,J=20.3,10.1,4.4Hz,8H),0.90(t,J=6.9Hz,3H).13 C NMR(151MHz,MeOD)δ77.30(-CH),75.73(-CH),73.95(-CH),71.22(-CH2),70.27(-CH),62.70( -CH),60.85(-CH2),46.91(-CH2),32.98,30.91,30.25,27.13,23.66(-CH2aliph),14.40(-CH3 aliph).ESI-HRMS:Calcd forC 14 H 30 NO5(M+H + ):292.2118.Found:292.2111.

[0176] [Example 5] Synthesis of Compound 25

[0177] In a hydrogenation reaction flask, compound 24A (12 mg, 0.023 mmol) was dissolved in methanol (3 mL) and 10% palladium-on-carbon catalyst (10 mg) was added. The reaction mixture was stirred at room temperature under hydrogen for 4 h. After completion of the reaction, the filtrate was filtered, collected, and concentrated under reduced pressure to obtain compound 25A (2.5 mg, 42%) as a colorless oil. The same reaction procedure was used to synthesize compound 24B (10 mg, 0.019 mmol) to obtain compound 25B (5.5 mg, 100%) as a colorless oil.

[0178] Compound 25A 1 H NMR (600MHz, MeOD) δ3.49–3.30(m,5H),3.17(dd,J=6.5,2.9Hz,1H),2.60(dd,J=14.4,7.2Hz,1H),2.53(dd,J=10.6,4.7Hz,1H ),2.39(d,J=12.9Hz,1H),2.28(t,J=7.6Hz,2H),1.13–0.96(m,2H),0.87(dt,J=14.7,7.3Hz,2H),0.49(dd,J=9.5,5.3Hz,3H). 13 C NMR(151MHz,MeOD)δ78.17(-CH),74.21(-CH),73.07(-CH),69.94(-CH),64.55(-CH),61.76(-CH2),56.14(-CH2),52.48(-CH2),30.82,21.36(-CH2 aliph),14.42(-CH3 aliph).ESI-HRMS:Calcd for C 11 H 24 NO5(M+H+ ):250.1649.Found:250.1643.

[0179] Compound 25B 1 H NMR(600MHz,MeOD)δ4.09(s,1H),3.88–3.77(m,2H),3.74(d,J=5.5Hz,2H),3.68(dt,J=10.7,3.4Hz,1H),3.05(dd,J=14.5,10.8Hz,1H),2 .88–2.75(m,2H),2.70(dd,J=12.1,5.8Hz,1H),2.47(dd,J=14.5,2.9Hz,1H),1.52–1.42(m,2H),1.42–1.30(m,2H),0.96(t,J=7.3Hz,3H). 13 C NMR(151MHz,MeOD)δ75.27(-CH),73.56(-CH),70.59(-CH),69.71(-CH),68.99(-CH),62.84(-CH2),56.89(-CH2),32.67,21.16(-CH2aliph),14.37(-CH3 aliph).ESI-HRMS:Calcd for C 11 H 24 NO5(M+H + ):250.1649.Found:250.1644.

[0180] Biological activity test: glycosidase activity test

[0181] Preparation of enzyme reaction solution: α-glucosidase lyophilized powder was prepared into 0.1% solution with phosphate-buffered saline (PBS), aliquoted, and stored at -20°C until use. α-glucosidase was derived from bovine serum albumin (BSA) and purchased from Sigma.

[0182] Preparation of substrate: Prepare 4-nitrophenyl-α-glucoside into a 0.1 mol / L working solution using phosphate buffer.

[0183] Preparation of test samples: The test compounds were prepared with phosphate buffer to a concentration of 1.0×10 -4 mmol / L solution was diluted 1000, 10000, and 100000 times with phosphate buffer respectively and set aside.

[0184] Mix 10 μL of diluted sample with 50 μL of phosphate buffer and 20 μL of enzyme solution, incubate at 37°C for 10 min, then add 20 μL of substrate and react at 37°C for 10 min. After adding the reaction terminator, measure the OD value at 405 nm. Acarbose was used as a positive control. The experiment was repeated twice, with triplicate wells each time. Results are expressed as mean ± SD.

[0185]

[0186] .

Claims

1. A compound as follows:

2. A composition, characterized in that: The composition comprises the compound according to claim 1 and a pharmaceutically acceptable auxiliary agent.

3. Use of the compound according to claim 1 in the preparation of a medicament for treating diseases caused by α-glucosidase.

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