Branched multi-hydroxyl-protecting oligomer, linked body bonded therewith, and branched multi-hydroxyl oligomer obtained by deprotecting said linked body

Abstract

The present invention makes it possible to inexpensively provide a branched multi-hydroxyl-protecting oligomer that is represented by formula (1), can be synthesized via few reaction steps with a good yield by means of a simple method, and is extremely effective in improving the solubility in water of a target compound. In formula (1), X is a reactive group, Ya to Yd are at least one item selected from the group consisting of P, T, G, and A represented by formula (3), m is 1, m' is an integer of 1-3, n is an integer of 0-9, and n' is an integer of 0-27 (except in cases in which the compound represented by formula (1) is X-G1G1, X-G1G2, X-G1A1, or X-G1A2).

Description

Branched multi-hydroxyl-protected oligomer, a linker bonded thereto, and a branched multi-hydroxyl-protected oligomer obtained by deprotecting the linker

[0001] The present invention relates to a branched multi-hydroxyl-protected oligomer, a linker formed by binding to the branched multi-hydroxyl-protected oligomer, and a branched multi-hydroxyl-protected oligomer formed by deprotecting the linker.

[0002] Pterostilbene, resveratrol, and other polyphenols are known to have antioxidant and anti-inflammatory properties, as well as to improve skin elasticity. However, they are poorly water-soluble, and suffer from problems such as inconsistent mixing and precipitation over time. Glycosylation, in which sugar components are chemically linked to aglycones, is known as a method for improving the water solubility of poorly water-soluble compounds. However, this requires combining multiple monosaccharides to achieve sufficient water solubility, and the hydroxyl groups of the monosaccharides must also be protected, which can be costly.

[0003] Also known is a method of improving water solubility by introducing multiple hydroxyl groups into a polymer. Examples of multi-hydroxylation include polyethylene glycol (PEG), polyglycerol (PGL), and branched oligomer (BGL). These multi-hydroxylation methods offer significant advantages over glycosylation in terms of raw material availability and cost. As shown in the formula below, there is only one type of PEG, but PGL is known to be of linear and semi-linear types, and BGL comes in multiple varieties depending on the number of branches.

[0004] [wherein X is a general representation of a functional group that links to a poorly water-soluble target, and n is an integer of 1 or greater.]

[0005] PEG monomers and dimers are highly toxic, and only oligomers exceeding several dozen in number can fully exhibit water solubility. PGL contains numerous uncontrollable asymmetric carbon atoms, making it difficult to maintain reproducibility in compound production, homogeneity, and quality assurance. Furthermore, because both PEG and PGL are produced by polymerization reactions, molecular weight variation is also an issue. Furthermore, glycosylation often results in mixtures due to the lack of control over the stereochemistry at the sugar linkage (anomeric position). On the other hand, BGL does not contain asymmetric carbon atoms, and a production method that allows molecular weight control has been established. BGL production is highly reproducible, enabling the production of quality-assured derivatives. However, the drawback of BGL is the labor-intensive process of selectively producing 1,3-protected glycerin at the first stage of production (Patent Document 1). Additionally, the production of oligomers exceeding heptamers requires multiple steps and results in low yields (Non-Patent Document 1).

[0006] WO2020 / 255741A1

[0007] Hisao Nemoto et al., Bioorg. Med. Chem. Lett. 2011, 21, 4724-4727.

[0008] The present invention has been made to solve the above-mentioned problems, and aims to provide a branched multi-hydroxyl-protected oligomer at low cost that can be synthesized in good yield by a simple method with fewer reaction steps and that is highly effective in improving the water solubility of target compounds.

[0009] The above-mentioned problems can be solved by providing a branched multi-hydroxyl-protected oligomer represented by the following formula (1):

[0010] [In formula (1), X is at least one selected from the group consisting of groups represented by formula (2) below, and Y ａ ~Y ｄ is at least one selected from the group consisting of P, T, G, and A represented by the following formula (3), m is 1, m' is an integer of 1 to 3, n is an integer of 0 to 9, and n' is an integer of 0 to 27 (provided that the compound represented by formula (1) is X-G １ G １ , X-G １ G２ , X-G １ A １ and X-G １ A ２ (Except when

[0011]

[0012] [In formula (3), Z is at least one selected from the group consisting of a hydrogen atom, a protecting group, and a carbon skeleton; R ａ is at least one selected from the group consisting of a hydrogen atom and an alkyl group.

[0013] A branched multi-hydroxyl-protected oligomer represented by the following formula (1a) is a preferred embodiment.

[0014] [In formula (1a), X is at least one selected from the group consisting of groups represented by formula (2) below, and Y ｂ ~Y ｄ is at least one selected from the group consisting of P, T, G, and A represented by the following formula (3), Z is at least one selected from the group consisting of a hydrogen atom, a protecting group, and a carbon skeleton, m is 1, m' is an integer of 1 to 3, n is an integer of 0 to 9, and n' is an integer of 0 to 27.

[0015]

[0016] [In formula (3), Z is at least one selected from the group consisting of a hydrogen atom, a protecting group, and a carbon skeleton; R ａ is at least one selected from the group consisting of a hydrogen atom and an alkyl group.

[0017] A branched multi-hydroxyl-protected oligomer represented by the following formula (1c) is also a preferred embodiment.

[0018] [In formula (1c), X is at least one selected from the group consisting of groups represented by the following formula (2), and Y ｂ ~Y ｄis at least one selected from the group consisting of P, T, G, and A represented by the following formula (3), Z is at least one selected from the group consisting of a hydrogen atom, a protecting group, and a carbon skeleton, m is 1, m' is an integer of 1 to 3, n is an integer of 0 to 9, and n' is an integer of 0 to 27 (provided that the compound represented by formula (1c) is X-G １ G １ , X-G １ G ２ , X-G １ A １ and X-G １ A ２ (Except when

[0019]

[0020] [In formula (3), Z is at least one selected from the group consisting of a hydrogen atom, a protecting group, and a carbon skeleton; R ａ is at least one selected from the group consisting of a hydrogen atom and an alkyl group.

[0021] In this case, a preferred embodiment is a conjugate formed by binding the branched multi-hydroxyl-protected oligomer to a target compound. It is preferred that the branched multi-hydroxyl-protected oligomer is deprotected, and that the target compound is a poorly water-soluble compound. A preferred embodiment is a water-solubility improver formed from the branched multi-hydroxyl-protected oligomer.

[0022] According to the present invention, a branched multi-hydroxyl-protected oligomer that can be synthesized in good yield using a simple method with fewer reaction steps and that is highly effective in improving the water solubility of target compounds can be provided at low cost.

[0023] 1 shows the results of evaluating the water solubility of pterostilbene, pterostilbene glycoside, and a deprotected pterostilbene conjugate. 2 shows the results of evaluating the water solubility of a deprotected pterostilbene conjugate.

[0024] The branched multi-hydroxyl-protected oligomer of the present invention is represented by the following formula (1):

[0025] [In formula (1), X is at least one selected from the group consisting of groups represented by formula (2) below, and Y ａ ~Y ｄ is at least one selected from the group consisting of P, T, G, and A represented by the following formula (3), m is 1, m' is an integer of 1 to 3, n is an integer of 0 to 9, and n' is an integer of 0 to 27 (provided that the compound represented by formula (1) is X-G １ G １ , X-G １ G ２ , X-G １ A １ and X-G １ A ２ (Except when

[0026]

[0027] [In formula (3), Z is at least one selected from the group consisting of a hydrogen atom, a protecting group, and a carbon skeleton; R ａ is at least one selected from the group consisting of a hydrogen atom and an alkyl group.

[0028] The branched multi-hydroxyl-protected oligomer of the present invention can be synthesized using a simple method with fewer reaction steps, and can be provided at low cost. Furthermore, as is clear from the water solubility evaluation results in the Examples described below, the branched multi-hydroxyl-protected oligomer of the present invention has the excellent advantage of being highly effective in improving the water solubility of target compounds, which are poorly water-soluble compounds. In contrast, glycosylation can be costly because it requires combining multiple monosaccharides to achieve sufficient water solubility and protecting the hydroxyl groups of the monosaccharides. Furthermore, with branched oligomers (BGL), the first step in the production requires a laborious process of selectively producing glycerin protected at the 1,3-positions, which can be costly. Therefore, it can be seen that the adoption of the present invention is highly significant.

[0029] In the above formula (1), X is at least one selected from the group consisting of groups represented by the following formula (2), and is a reactive group used for bonding to a target compound. A substituent of the target compound reacts with X, and a linked compound formed by bonding the branched multi-hydroxyl-protected oligomer represented by formula (1) to the target compound can be suitably obtained.

[0030]

[0031] In particular, from the viewpoint of good reactivity with the target compound, X is preferably at least one selected from the group consisting of groups represented by the following formula (2a):

[0032]

[0033] In the above formula (1), Y ａ ~Y ｄ is at least one selected from the group consisting of P, T, G, and A represented by the following formula (3), m is 1, m' is an integer of 1 to 3, n is an integer of 0 to 9, and n' is an integer of 0 to 27.

[0034] [In formula (3), Z is at least one selected from the group consisting of a hydrogen atom, a protecting group, and a carbon skeleton; R ａ is at least one selected from the group consisting of a hydrogen atom and an alkyl group.

[0035] Y in the above formula (1) ａ ~Y ｄ is at least one selected from the group consisting of P, T, G, and A represented by the above formula (3), and Y ａ ~Y ｄ may be the same or different. ａ ~Y ｄ are connected to each other via Z in the above formula (3), and Z used for the connection is a carbon skeleton. That is, Z in -OZ is a carbon skeleton, and Y ａ ~Y ｄ are connected to each other by an ether bond (—O—). The carbon skeleton is preferably a covalent bond, and may be a divalent hydrocarbon group.

[0036] In the above formula (1), m is 1 and m' is an integer of 1 to 3. Y, which is at least one selected from the group consisting of P, T, G, and A represented by the above formula (3), ａ The number of Z's is Y ｂ For example, Y ａ All Z's and Y's ｂ may be bonded, or Y ａ One or more Zs and Ys ｂ are combined to form Y ａ The remaining Z may be at least one selected from the group consisting of a hydrogen atom and a protecting group. ａ When is P, there are three Z's, so the maximum number of m' is 3. In the above formula (1), n ​​is an integer of 0 to 9, and n' is an integer of 0 to 27. Y, which is at least one selected from the group consisting of P, T, G, and A represented by the above formula (3), ｂ The number of Z's is Y ｃ and Y is at least one selected from the group consisting of P, T, G, and A represented by the formula (3). ｃ The number of Z's is Y ｄ For example, Y ｂ All Z's and Y's ｃ may be bonded, or Y ｃ All Z's and Y's ｄ may be bonded to Y ｂ One or more Zs and Ys ｃ are combined to form Y ｂ The remaining Z may be at least one selected from the group consisting of a hydrogen atom and a protecting group, ｃ One or more Zs and Ys ｄ are combined to form Y ｃ The remaining Z may be at least one selected from the group consisting of a hydrogen atom and a protecting group. ｂ If all are P, there are nine Zs, so the maximum number of n is 9. Similarly, if n is 9 and Y ｃ If all are P, there are 27 Zs, so the maximum number of n' is 27. Note that if both n and n' are 0, Y ｃ and Y ｄ This results in a structure in which

[0037] In the above formula (3), Z is at least one selected from the group consisting of a hydrogen atom, a protecting group, and a carbon skeleton, and as described above, Y ａ ~Y ｄ are mutually linked via Z. The Z not used in the linkage is preferably at least one selected from the group consisting of a hydrogen atom and a protecting group. From the viewpoint of deprotecting the linked compound after obtaining the linked compound bound to the target compound, it is a preferred embodiment that the Z not used in the linkage is a protecting group. In particular, it is a preferred embodiment that the end of the branched multi-hydroxyl group-protected oligomer represented by the above formula (1) is a protecting group. The protecting group is not particularly limited as long as it is a substituent that protects a hydroxyl group. Examples include an acyl group, an alkoxymethyl group, an alkoxycarbonyl group, an alkenyl group, an alkylsilyl group, an arylmethyl group, a tetrahydropyranyl group, and a group in which multiple Zs form a cyclic structure. Furthermore, in the above formula (3), R ａ is at least one selected from the group consisting of a hydrogen atom and an alkyl group. Examples of the alkyl group include linear or branched alkyl groups having 1 to 10 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, an n-hexyl group, an isohexyl group, a 2-ethylhexyl group, an n-heptyl group, an n-octyl group, an n-nonyl group, and an n-decyl group. Among these, the preferred alkyl group is a methyl group or an ethyl group.

[0038] Examples of the acyl group include a linear or branched alkylcarbonyl group having 2 to 10 carbon atoms, an arylcarbonyl group, etc. The linear or branched alkylcarbonyl group having 2 to 10 carbon atoms is not particularly limited as long as it has a structure in which a carbonyl group is bonded to any carbon atom of an alkyl group, and examples of the alkyl group include a linear or branched alkyl group having 1 to 10 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, an n-hexyl group, an isohexyl group, a 2-ethylhexyl group, an n-heptyl group, an n-octyl group, an n-nonyl group, and an n-decyl group. Specific examples of the acyl group include an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a benzoyl group, a dodecanoyl group, and a crotonoyl group. Of these, the preferred acyl group is an acetyl group.

[0039] The alkoxymethyl group is not particularly limited as long as it has a structure in which an alkoxy group having 1 to 7 carbon atoms is bonded to a methyl group, and examples thereof include a methoxymethyl group, an ethoxymethyl group, and a benzyloxymethyl group.

[0040] Examples of the alkoxycarbonyl group include linear, branched, and cyclic alkoxycarbonyl groups having 2 to 10 carbon atoms, such as a methoxycarbonyl group, an ethoxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, an n-propoxycarbonyl group, an isopropoxycarbonyl group, an allyloxycarbonyl group, an n-butoxycarbonyl group, an isobutoxycarbonyl group, a sec-butoxycarbonyl group, a tert-butoxycarbonyl group, a pentyloxycarbonyl group, a hexyloxycarbonyl group, a heptyloxycarbonyl group, an octyloxycarbonyl group, and a benzyloxycarbonyl group.

[0041] The alkenyl group may be a straight-chain or branched alkenyl group having 2 to 6 carbon atoms, such as a vinyl group, an allyl group, a methylvinyl group, a propenyl group, a butenyl group, a pentenyl group, or a hexenyl group.

[0042] Examples of the alkylsilyl group include a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a tert-butyldimethylsilyl group, and a tert-butyldiphenylsilyl group.

[0043] The arylmethyl group is not particularly limited as long as it has a structure in which an aryl group is bonded to a methyl group, and examples thereof include a benzyl group and a 4-methoxybenzyl group.

[0044] As the group in which a plurality of Z's form a cyclic structure, in the case of P, T, G, and A represented by the above formula (3), structures represented by the following formulas (3a) to (3d) are preferably adopted, respectively.

[0045] [In formula (3a), R ｂ is an alkyl group.

[0046] [In formula (3b), R ａ , R ｃ and R ｄ is at least one selected from the group consisting of a hydrogen atom and an alkyl group.

[0047] [In formula (3c), R ｃ and R ｄ is at least one selected from the group consisting of a hydrogen atom and an alkyl group.

[0048] [In formula (3d), R ｃ and R ｄ is at least one selected from the group consisting of a hydrogen atom and an alkyl group.

[0049] In the above formula (3a), R ｂ is an alkyl group, and R ｂ is R in formula (3) ａ The alkyl groups described above can be used in the same manner. ａ , R ｃ and R ｄ is at least one selected from the group consisting of a hydrogen atom and an alkyl group. ａ is R in formula (3).ａ and R of formula (3) ａ The alkyl groups described above can be used in the same manner. ｃ and R ｄ is at least one selected from the group consisting of a hydrogen atom and an alkyl group. ｃ and R ｄ In a preferred embodiment, both of R are alkyl groups, and one is a hydrogen atom and the other is an alkyl group. ｃ and R ｄ The alkyl group used in formula (3) is R ａ The alkyl groups described above can be used in the same manner.

[0050] The above-mentioned protecting group may further have a substituent, and examples of such a substituent include halogen atoms such as fluorine atom, chlorine atom, bromine atom, and iodine atom; alkyl groups such as methyl group, ethyl group, and n-propyl group; alkenyl groups such as vinyl group, allyl group, methylvinyl group, and propenyl group; alkynyl groups such as ethynyl group, propynyl group, and propargyl group; aryl groups such as phenyl group and naphthyl group; alkoxy groups such as methoxy group, ethoxy group, propoxy group, isopropoxy group, and butoxy group; alkylthio groups such as methylthio group, ethylthio group, propylthio group, and butylthio group; arylthio groups such as phenylthio group and naphthylthio group; acyloxy groups such as acetoxy group, propanoyloxy group, butanoyloxy group, pivaloyloxy group, and benzoyloxy group; heteroaromatic ring groups such as pyridyl group, thienyl group, furyl group, imidazolyl group, and oxazolyl group; amino group; hydroxyl group; cyano group; and nitro group.

[0051] Since m in the above formula (1) is 1, the branched multi-hydroxyl-protected oligomer of the present invention has Y ａ are P, T, G, or A. Among them, a branched multi-hydroxyl-protected oligomer represented by the following formula (1a) or formula (1c) is preferred.

[0052] [In formula (1a), X, Y ｂ ~Yｄ , Z, m, m', n, and n' are defined as in formula (1).

[0053] [In formula (1b), X, Y ｂ ~Y ｄ , Z, m, m′, n, and n′ are the same as those in formula (1), and R ａ has the same meaning as in formula (3).

[0054] [In formula (1c), X, Y ｂ ~Y ｄ , Z, m, m', n and n' are the same as those in the formula (1) (provided that the compound represented by the formula (1c) is X-G １ G １ , X-G １ G ２ , X-G １ A １ and X-G １ A ２ (Except when

[0055] [In formula (1d), X, Y ｂ ~Y ｄ , Z, m, m', n, and n' are defined as in formula (1).

[0056] In the above formula (1a), for example, m′ is 1, n and n′ are 0, and Y ｂ is P, T, G or A represented by the above formula (3), １ P １ ,X-P １ T １ ,X-P １ G １ ,X-P １ A １ ) is one of the simplest structures for the branched multi-hydroxyl-protected oligomer of the present invention. The branched multi-hydroxyl-protected oligomer of the present invention is not limited to this structure.

[0057] [In formula (1a′), X has the same meaning as in formula (1), and Z and R ａ has the same meaning as in formula (3).

[0058] The method for producing the branched multi-hydroxyl-protected oligomer of the present invention is not particularly limited. For example, as shown in the following reaction formula (I), ａ =Br) and an alcohol R represented by the following formula (4): １ As shown in the following reaction formula (II), tribromide (X ａ =Br) and an alcohol R represented by the following formula (4): １ It can be produced by an etherification reaction with —OH. ｂ = Cl) and an alcohol R represented by the following formula (4) １ The branched multi-hydroxyl-protected oligomer can also be produced by a linkage reaction with —OH. Known methods are suitably employed for these reactions. The halogen atom in Xa is preferably a bromine atom, a chlorine atom, or an iodine atom. The substituent X in the obtained branched multi-hydroxyl-protected oligomer is at least one selected from the group consisting of groups represented by formula (2), and can be converted to the desired substituent X by appropriately carrying out a tosylation reaction, a deallylation reaction, or the like.

[0059] [In formula (I), X has the same meaning as in formula (1), ａ is a halogen atom, and R １ is at least one alcohol R selected from the group consisting of the following formula (4): １ It is a group obtained by removing —OH from —OH.]

[0060] [In formula (II), X has the same meaning as in formula (1), ａ is a halogen atom, and R １ is at least one alcohol R selected from the group consisting of the following formula (4): １ It is a group obtained by removing —OH from —OH.]

[0061] [In formula (I), X has the same meaning as in formula (1), ｂ is a halogen atom, and R １ —OH is at least one selected from the group consisting of alcohols represented by the following formula (4):

[0062]

[0063] The obtained branched multi-hydroxyl-protected oligomer can be conjugated to a target compound. For example, when the substituent X in the branched multi-hydroxyl-protected oligomer represented by formula (1) is -Br or -OTs, a conjugate can be obtained by reacting it with the hydroxyl group of the target compound, pterostilbene, as shown in the following reaction formula (IV). That is, a conjugate formed by conjugating a branched multi-hydroxyl-protected oligomer to a target compound is a preferred embodiment. The target compound is preferably a water-insoluble compound, and preferred examples of the water-insoluble compound include polyphenol compounds having hydroxyl groups, such as pterostilbene and resveratrol.

[0064] [In formula (IV), Y ａ , Y ｂ , Y ｃ , Y ｄ , m, m', n, and n' are defined as in formula (1).

[0065] The branched multi-hydroxyl-protected oligomer to be bonded to the target compound may be a deprotected branched multi-hydroxyl-protected oligomer. However, from the viewpoint of efficient reaction, it is preferred to obtain a linker bonded to the target compound and then deprotect the linker. Known methods can be used for deprotection. As shown in the examples below, the protecting groups in the linker are deprotected to generate a large number of hydroxyl groups. As is clear from the water solubility evaluation results in the examples below, the branched multi-hydroxyl-protected oligomer of the present invention has a very high effect of improving the water solubility of the target compound, which is a poorly water-soluble compound. Therefore, a water solubility improver comprising a branched multi-hydroxyl-protected oligomer is a preferred embodiment.

[0066] The present invention will be described in more detail below using examples. The reagents and solvents used were commercially available and used as they were without any purification process. The organic solvents used in the mixing are all in volume ratios. 1 H NMR and 13C NMR was measured using a JEOL JNN-ECS400 at 400 MHz and 100 MHz, respectively.

[0067] [Raw material compound]

[0068]

[0069] A1: (1-methyl-2,6,7-trioxabicyclo[2.2.2]octan-4-yl)methanol is a known substance, the preparation of which is described in T. Jeffrey Dunn, William L. Neumann, Milorad M. Rogic, and Steven R. Woulfe J. Org. Chem., 1990, 55, 6368-6373.

[0070]

[0071] A2: (2s,5s)-2-methyl-1,3-dioxan-5-ol can be obtained by the known method of WO2020 / 255741A1.

[0072]

[0073] A3: (2,2-dimethyl-1,3-dioxolan-4-yl)methanol is available from TCI (Tokyo Chemical Industry Co., Ltd.).

[0074]

[0075] A4: (2,2,5-trimethyl-1,3-dioxan-5-yl)methanol is commercially available from Merck-Aldrich.

[0076]

[0077] A22: 1,3-bis((2,2-dimethyl-1,3-dioxan-5-yl)oxy)propan-2-ol can be synthesized by a known method described in Nemoto, Hisao; Kamiya, Masaki; Nakamoto, Aki; Katagiri, Ayato; Yoshitomi, Kohsuke; Kawamura, Tomoyuki; Hattori, Hatsuhiko. Chem. Lett. 2010, 39, 856-857.

[0078]

[0079] A23: 1,3-bis((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)propan-2-ol is commercially available from Synnovator Products.

[0080]

[0081] B1: 5,5-bis(bromomethyl)-2,2-dimethyl-1,3-dioxane is commercially available from Fujifilm Wako Pure Chemical Industries, Ltd.

[0082]

[0083] C1: 3-(3-bromo-2,2-bis(bromomethyl)propoxy)prop-1-ene is commercially available from Chemhere, Hong Kong.

[0084]

[0085] D1: 2-(3-bromo-2,2-bis(bromomethyl)propoxy)tetrahydro-2H-pyran can be produced by the known method described in JP 2022-14977 A.

[0086]

[0087] E1: 1,3-dibromo-2-(bromomethyl)-2-((methoxymethoxy)methyl)propane can be produced in 80% yield by the equilibrium transacetal reaction of 3-bromo-2,2-bis(bromomethyl)propan-1-ol with 20 equivalents of dimethoxymethane in the absence of a solvent and under acid catalysis for 12 hours. 1 H NMR (CDCl3, 400 MHz): δ 4.64 (s, 2H), 3.58 (s, 2H), 3.54 (s, 6H), 3.40 (s, 3H) 13 C NMR (CDCl3, 100 MHz): δ 97.0 (CH2), 66.8(CH2), 55.7(CH3), 43.6, (C), 34.6 (CH 2 x 3)

[0088]

[0089] F1: (E)-4-(3,5-dimethoxystyryl)phenol (pterostilbene) is commercially available from TCI (Tokyo Chemical Industry Co., Ltd.).

[0090] Synthesis Example 1 [Dibromide B1 and alcohol R 1 -OH Etherification Reaction]

[0091]

[0092] Alcohol R 1To a solution (2-10 mL) of 1,3-dimethylimidazolidin-2-one (DMI) containing -OH (10 mmol), sodium hydride (60% in paraffin) (10-20 mmol) was added at room temperature and stirred for 5 min. B1 (30-40 mmol) was added to the suspension and stirred at 100 °C for 20 h. The suspension was then returned to room temperature, deionized water (30-40 mL) was added, and the mixture was extracted with ethyl acetate / toluene (1 / 1) (60-100 mL). The resulting organic layer was washed with deionized water (30-40 mL x 2-3 times) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (toluene / ethyl acetate = 10 / 1-2 / 1) to obtain the desired compounds as colorless liquids or solids (3.7-7.0 mmol, 37-70% yield).

[0093] Synthesis Example 2 [Tribromide C1 and Alcohol R 2 -OH Etherification Reaction]

[0094]

[0095] Alcohol R 2 A solution (2-10 mL) of 1,3-dimethylimidazolidin-2-one (DMI) with -OH (40-60 mmol) was added to sodium hydride (60% paraffin) (R 2 C1 (30-40 mmol) was added to the suspension at room temperature and stirred for 5 minutes. C1 (30-40 mmol) was added to the suspension and stirred at 100°C overnight. The suspension was then cooled to room temperature, deionized water (30-40 mL) was added, and the mixture was extracted with ethyl acetate / toluene (1 / 1) (60-100 mL). The resulting organic layer was washed with deionized water (30-40 mL, 2-3 times) and concentrated under reduced pressure. DMI (<1 mmHg, boiling point = ∼100°C) and excess starting alcohol R were extracted from the residue using vacuum distillation. 2The resulting residue was purified by silica gel column chromatography (toluene / ethyl acetate = 4 / 1-1 / 1) to obtain the target compound as a colorless liquid (6.50-7.40 mmol, R 2 (65-74% yield based on conversion to -OH).

[0096] Synthesis Example 3 [Deallylation reaction of the compound obtained in Synthesis Example 2]

[0097]

[0098] Potassium carbonate (30-40 mmol) was added to a solution of allyl ether (10 mmol) in methanol (40-60 ml). The resulting suspension was stirred under an argon atmosphere, and tetrakis(triphenylphosphine)palladium(0) (0.1-0.2 mmol) was added at room temperature. The mixture was stirred at 65 °C for 8-20 hours. The suspension was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the target compound. This compound was used in the next reaction without further purification.

[0099] Synthesis Example 4 [Epichlorohydrin and Alcohol R 3 -OH ligation reaction]

[0100]

[0101] Alcohol R 3Potassium hydroxide (130 mmol) was added to a solution (30 mL) of 1,3-dimethylimidazolidin-2-one (DMI) containing -OH (156 mmol), and the mixture was stirred at 80°C for 30 minutes. The resulting suspension was then heated to 55°C, and a solution (5 mL) of epichlorohydrin (4.6 g, 50 mmol) in 1,3-dimethylimidazolidin-2-one (DMI) was added dropwise. The resulting suspension was stirred at 55°C for 45 hours and then at 80°C for an additional 22 hours. Ion-exchanged water (50-80 mL) was poured into the suspension at room temperature, and the mixture was extracted with ethyl acetate (200-300 mL). The resulting organic layer was washed with ion-exchanged water (50-80 mL, 2-3 times) and concentrated under reduced pressure. The residue was then purified under reduced pressure with DMI (<1 mmHg, ∼100°C) and excess starting alcohol R. 3 After collecting -OH (<1 mmHg, 140-150°C, ~56 mmol), the target compound was obtained as a colorless solid or liquid by distillation (<1 mmHg, 200-210°C) (21.2-29.1 mmol, R 3 (42.5-58.4% yield based on conversion to -OH).

[0102] Synthesis Example 5 [Tosylation reaction of alcohols obtained in Synthesis Examples 3 and 4]

[0103]

[0104] Alcohol R 4 To a pyridine solution (28.0 mmol) of -OH (1.4 mmol), 4-dimethylaminopyridine (0.28 mmol) and then tosyl chloride (2.8 mmol) were added at room temperature and stirred for 8-20 hours. Saturated aqueous sodium bicarbonate (20 mL) and ethyl acetate (40 mL) were added to the resulting reaction mixture and stirred for 2 hours. The resulting organic layer was washed with ion-exchanged water (30-40 mL, 2-3 times) and then concentrated under reduced pressure. The resulting mixture was used in the next reaction without further purification.

[0105] Synthesis Example 6 [Etherification reaction of the compound obtained in Synthesis Example 1 or Synthesis Example 5 with the target compound]

[0106]

[0107] (1) When X=OTs, pterostilbene F1 (8.68 mmol) was dissolved in N,N-dimethylformamide (15 mL) with anhydrous potassium carbonate (17.36 mmol) and tosylate R 5 -OTs (7.23 mmol) was added at room temperature and stirred at 90 °C for 11 hours. The suspension was then returned to room temperature, ion-exchanged water (40 mL) was added, and the mixture was extracted with ethyl acetate / toluene (1 / 1) (100 mL). The resulting organic layer was washed with ion-exchanged water (40 mL x 2) and saturated aqueous sodium bicarbonate (20 mL) in that order, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (toluene / ethyl acetate = 5 / 1 - 2 / 1) to obtain the desired conjugate as a colorless liquid (6.07-6.13 mmol, 70-84% yield).

[0108] (2) When X=Br, a solution of pterostilbene F1 (15-20 mmol) in DMI (10-20 mL) is added with potassium hydroxide (15-20 mmol) and bromide R 5 -Br (10 mmol) was added at room temperature and stirred at 100 °C for 20 hours. The suspension was then returned to room temperature, ion-exchanged water (30-40 mL) was poured into it, and the mixture was extracted with ethyl acetate / toluene (1 / 1) (60-100 mL). The resulting organic layer was washed with ion-exchanged water (30-40 mL, 2-3 times) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (toluene / ethyl acetate = 10 / 1-3 / 1) to obtain the desired conjugates as colorless liquids or solids (6.1-8.0 mmol, 61-80% yield).

[0109] Synthesis Example 7 [Deprotection reaction of the linked compound obtained in Synthesis Example 6]

[0110]

[0111] (1) Reaction conditions when the structure does not contain an orthoester (n=0): To a methanol solution (10 mL) of the compound (10 mmol) obtained in Synthesis Example 6 was added hydrochloric acid (1-3 mol / L, 10 mL) while stirring at room temperature, and the mixture was stirred for 2 hours. The resulting mixture was concentrated under reduced pressure. This procedure was repeated 2-3 times.

[0112] (2) Reaction conditions when the structure contains an orthoester (n≠0): To a methanol solution (10 mL) of the compound (10 mmol) obtained in Synthesis Example 6, hydrochloric acid (1-3 mol / L, 10 mL) was added with stirring at room temperature for 2 hours, and the resulting mixture was concentrated under reduced pressure. This procedure was repeated 2-3 times. Then, 1.2-2.0 equivalents of sodium hydroxide (based on the orthoester moiety of the raw material) were added. After confirming that the product had converged to one point by thin-layer chromatography, the mixture was concentrated under reduced pressure.

[0113] (3) Purification method when the target compound has sufficiently high water solubility The residue was purified using a Diaion resin column (2-propanol / water = 1 / 4-1 / 1) to obtain the target compound, the deprotected conjugate (8.5-9.8 mmol, yield 85-98%). This purification method was used in Examples 1 to 4, 8, 14, and 18.

[0114] (4) Purification method for when the target compound is not sufficiently water-soluble: The crude target compound was dissolved in 2-propanol to prepare a solution, and sodium bicarbonate was added to the solution until the pH reached 7 or higher. The resulting suspension was filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound, the deprotected conjugate (8.5-9.8 mmol, 85-98% yield). This purification method was used in Examples 5, 6, 10, 11, 13, and 15-17.

[0115] Example 1 [Synthesis of Compound G117: P １ P １ ]

[0116]

[0117] In Synthesis Example 1, R 1 Using A1 as -OH, the target compound G117 was obtained. Chemical Formula: C 15 H25 BrO6 4-(((5-(bromomethyl)-2,2-dimethyl-1,3-dioxan-5-yl)methoxy)methyl)-1-methyl-2,6,7-trioxabicyclo[2.2.2]octane 1 H NMR (CDCl3, 400 MHz): δ 4.00 (s, 6H), 3.73 (d, J = 12.0 Hz, 2H), 3.69 (d, J = 12.0 Hz, 2H),3.47 (s, 2H), 3.42 (s, 2H), 3.23 (s, 2H), 1.46 (s, 3H), 1.41 (s, 3H), 1.40 (s, 3H). 13 C NMR (CDCl3, 100 MHz): δ 108.6 (C), 98.7 (C), 71.2 (CH2), 69.9 (CH2), 69.4 (CH2×3), 63.7 (CH2×2), 38.5 (C), 35.4 (CH2) 35.1 (C), 23.8 (CH3), 23.5 (CH3), 23.4 (CH3).

[0118] [Synthesis of compound G118]

[0119]

[0120] In Synthesis Example 6 (2), R 5 Using G117 as -X, the target compound G118 was obtained. Chemical Formula: C 31 H 40 O9 (E)-4-(((5-((4-(3,5-dimethoxystyryl)phenoxy)methyl)-2,2-dimethyl-1,3-dioxan-5-yl)methoxy)methyl)-1-methyl-2,6,7-trioxabicyclo[2.2.2]octane 1H NMR (CDCl3, 400 MHz): δ 7.44 (d, J = 8.8 Hz, 2H), 7.04 (d, J = 16.0 Hz, 1H), 6.91 (d, J = 16.0 Hz, 1H), 6.88 (d, J = 8.8 Hz, 2H), 6.65 (d, J = 2.4 Hz, 2H), 6.38 (brt, J = 2.4 Hz, 1H), 3.95 (s, 8H), 3.87-3.75 (m, 10H), 3.48 (s, 2H), 3.18 (s, 2H), 1.47-1.40 (m, 9H). 13 C NMR (CDCl3, 100 MHz): δ 161.1 (C×2), 158.8 (C), 139.7 (C), 130.4 (C), 128.7 (CH), 128.0 (CH×2), 126.9 (CH), 114.8 (CH×2), 108.6 (C),104.4 (CH×2), 99.8 (CH), 98.6 (C), 71.0 (CH2), 70.0 (CH2), 69.5 (CH2×3), 67.3 (CH2), 62.6 (CH2×2), 55.5 (CH3×2), 39.0 (C), 35.2 (C), 24.1 (CH3), 23.6 (CH3×2).

[0121] [Synthesis of compound G119]

[0122]

[0123] In Synthesis Example 7 (2), G118 was used as the compound obtained in Synthesis Example 6 to obtain the target compound G119. Chemical Formula: C 26 H 36 O9 (E)-2-((3-(4-(3,5-dimethoxystyryl)phenoxy)-2,2-bis(hydroxymethyl)propoxy)methyl)-2-(hydroxymethyl)propane-1,3-diol 1H NMR (CD3OD, 400 MHz): δ 7.48 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 16.0 Hz, 1H), 6.95 (d, J = 16.0 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.68 (d, J = 2.4 Hz, 2H), 6.37 (brt, J = 2.4 Hz, 1H), 3.98 (s, 2H), 3.80 (s, 6H), 3.70 (s, 4H), 3.57 (s, 6H), 3.52 (2H), 3.43 (2H). 13 C NMR (CD3OD, 100 MHz): δ 162.4 (C×2), 160.5 (C), 141.2 (C), 131.5 (C), 129.7 (CH), 128.8 (CH×2), 127.5 (CH), 115.8 (CH×2), 105.3 (CH×2), 100.4 (CH), 71.8 (CH2), 71.5 (CH2), 67.9 (CH2), 63.1 (CH2×3), 62.4 (CH2×2), 55.7 (CH3×2), 47.1(C), 47.0 (C).

[0124] Example 2 [Synthesis of Compound G127: P １ G １ ]

[0125]

[0126] In Synthesis Example 1, R 1 Using A2 as -OH, the target compound G127 was obtained. Chemical Formula: C 13 H 23 BrO5 5-(bromomethyl)-2,2-dimethyl-5-((((2s,5s)-2-methyl-1,3-dioxan-5-yl)oxy)methyl)-1,3-dioxane 1H NMR (CDCl3, 400 MHz): δ 4.71 (q, J = 5.0 Hz, 1H), 4.18, (brd, J = 13.6 Hz, 2H), 3.86 (d, J = 12.0 Hz, 2H), 3.83 (m, 2H), 3.80 (d, J = 12.0 Hz, 2H), 3.64 (s, 2H), 3.56 (s, 2H), 3.18 (m, 1H), 1.42 (s, 3H), 1.42 (s, 3H), 1.34 (d, J = 5.2 Hz, 3H). 13 C NMR (CDCl3, 100 MHz): δ 99.1 (CH) , 98.6 (C), 71.3 (CH), 68.4 (CH2×2), 68.1 (CH2), 63.9 (CH2×2), 38.5 (C), 36.2 (CH2), 23.8 (CH3), 23.7 (CH3), 21.2 (CH3).

[0127] [Synthesis of compound G128]

[0128]

[0129] In Synthesis Example 6 (2), R 5 Using G127 as -Br, the target compound G128 was obtained. Chemical Formula: C 29 H 38 O8 5-((4-((E)-3,5-dimethoxystyryl)phenoxy)methyl)-2,2-dimethyl-5-((((2s,5s)-2-methyl-1,3-dioxan-5-yl)oxy)methyl)-1,3-dioxane 1H NMR (CDCl3, 400 MHz): δ 7.41 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 16.0 Hz, 1H), 6.90 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 16.0 Hz, 1H), 6.63 (d, J = 2.4 Hz, 2H), 6.35 (brt, J = 2.4 Hz, 1H), 4.64 (q, J = 4.8 Hz, 1H), 4.10 (d, J = 11.6 Hz 2H), 4.05 (s, 2H), 3.90 (s, 4H), 3.78 (s, 6H), 3.72 (d, J = 11.6 Hz, 2H), 3.59 (s, 2H), 3.06 (m, 1H), 1.43 (s, 6H), 1.29 (d, J = 4.8 Hz, 3H). 13 C NMR (CDCl3, 100 MHz): δ 160.9 (C×2), 158.8 (C), 139.6 (C), 130.0 (C), 128.6 (CH), 127.7 (CH×2), 126.5 (CH), 114.8 (CH×2), 104.2 (CH×2), 99.6 (CH), 98.9 (CH), 98.2 (C), 71.3 (CH), 68.2 (CH2×2), 67.6 (CH2), 67.3 (CH2), 62.5 (CH2×2), 55.2 (CH3×2), 38.8 (C), 23.9 (CH3), 23.6 (CH3), 21.0 (CH3).

[0130] [Synthesis of compound G129]

[0131]

[0132] In Synthesis Example 7 (1), G128 was used as the compound obtained in Synthesis Example 6 to obtain the target compound G129. Chemical Formula: C 24 H 32 O8 (E)-2-(((1,3-dihydroxypropan-2-yl)oxy)methyl)-2-((4-(3,5-dimethoxystyryl)phenoxy)methyl)propane-1,3-diol1 H NMR (CD3OD, 400 MHz): δ 7.48 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 16.0 Hz, 1H), 6.95 (d, J = 16.0 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.68 (d, J = 2.0 Hz, 2H), 6.37 (brt, J = 2.0 Hz, 1H), 4.00 (s, 2H), 3.81 (s, 6H), 3.77-3.68 (m, 7H), 3.68-3.52 (m, 4H). 13 C NMR (CD3OD, 100 MHz): δ 162.4 (C×2), 160.4 (C), 141.1 (C), 131.4 (C), 129.7 (CH), 128.8 (CH×2), 127.5 (CH), 115.8 (CH×2), 105.3 (CH×2), 100.4 (CH), 83.1 (CH), 70.1 (CH2), 67.7 (CH2), 62.4 (CH2×4), 55.7 (CH3×2), 47.0 (C).

[0133] Example 3 [Synthesis of Compound G137: P １ A １ ]

[0134]

[0135] In Synthesis Example 1, R 1 Using A3 as -OH, the target compound G137 was obtained. Chemical Formula: C 14 H 25 BrO5 5-(bromomethyl)-5-(((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)methyl)-2,2-dimethyl-1,3-dioxane-methane (1 / 1) 1 H NMR (CDCl3, 400 MHz): δ 4.25 (m, 1H), 4.10-3.30 (m, 12H), 1.50-1.20 (m, 12H). 13C NMR (CDCl3, 100 MHz): δ 109.5 (C), 98.7 (C), 74.7 (CH), 72.4 (CH2), 71.2 (CH2), 66.8 (CH2), 63.9 (CH2×2), 38.6 (C), 36.0 (CH2), 26.9 (CH3), 25.6 (CH3), 24.2 (CH3), 23.2 (CH3).

[0136] [Synthesis of compound G138]

[0137]

[0138] In Synthesis Example 6 (2), R 5 Using G137 as -X, the target compound G138 was obtained. Chemical Formula: C 30 H 40 O8 1 H NMR (CDCl3, 400 MHz): δ 7.43 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 16.0 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 6.90 (d, J = 16.0 Hz, 2H), 6.65 (d, J = 2.4 Hz, 2H), 6.37 (brt, J = 2.4 Hz, 1H), 4.27-4.16 (m, 1H), 4.02 (s, 2H), 4.01-3.96 (m, 1H), 3.86 (s, 4H), 3.82 (s, 6H), 3.75-3.64 (m, 1H), 3.62-3.40 (m, 4H), 1.44 (s, 3H), 1.43 (s, 3H), 1.39 (s, 3H), 1.33 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ 161.1 (C×2), 158.9 (C), 139.8 (C), 130.2 (C), 128.8 (CH), 127.9 (CH×2), 126.7 (CH), 114.9 (CH×2), 109.4 (C),104.4 (CH×2), 99.7 (CH), 98.5 (C), 74.7 (CH), 72.4 (CH2), 71.0 (CH2), 67.3 (CH2), 66.8 (CH2), 62.7 (CH2), 62.7 (CH2), 55.5 (CH3×2), 39.0 (C), 26.8 (CH3), 25.6 (CH3), 24.6 (CH3), 23.1 (CH3).

[0139] [Synthesis of compound G139]

[0140]

[0141] In Synthesis Example 7 (1), G138 was used as the compound obtained in Synthesis Example 6 to obtain the target compound G139. Chemical Formula: C 24 H 32 O8 (E)-3-(3-(4-(3,5-dimethoxystyryl)phenoxy)-2,2-bis(hydroxymethyl)propoxy)propane-1,2-diol 1 H NMR (CD3OD, 400 MHz): δ 7.42 (d, J = 8.8 Hz, 2H), 7.04 (d, J = 16.4 Hz, 1H), 6.91 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 16.4 Hz, 1H), 6.65 (d, J = 2.0 Hz, 2H), 6.35 (brt, J = 2.0 Hz, 1H), 3.96 (s, 2H), 3.80-3.73 (m, 1H), 3.76 (s, 6H), 3.70 (s, 4H), 3.65-3.41 (m, 6H). 13C NMR (CD3OD, 100 MHz): δ 162.4 (C×2), 160.4 (C), 141.1 (C), 131.4 (C), 129.7 (CH), 128.8 (CH×2), 127.5 (CH), 115.8 (CH×2), 105.3 (CH×2), 100.4 (CH), 72.6 (CH2), 70.8 (CH), 70.1 (CH2), 66.5 (CH2), 63.1 (CH2), 61.1 (CH2×2), 54.5 (CH3×2), 46.8 (C).

[0142] Example 4 [Synthesis of Compound H115: P １ P ３ ]

[0143]

[0144] In Synthesis Example 2, R 2 Using A1 as -OH, the target compound H115 was obtained. Chemical Formula: C 29 H 46 O 13 4,4'-(((2-((allyloxy)methyl)-2-(((1-methyl-2,6,7-trioxabicyclo[2.2.2]octan-4-yl)methoxy)methyl)propane-1,3-diyl)bis(oxy))bis(methylene))bis(1-methyl-2,6,7-trioxabicyclo[2.2.2]octane) 1 H NMR (CDCl3, 400 MHz): δ 5.82 (ddt, J = 5.6, 10.4, 17.6 Hz, 1H), 5.28-5.14 (m, 2H), 4.00 (s, 18H) 3.90 (ddd, J = 1.2, 1.2, 5.6 Hz, 2H), 3.30-3.11(m, 14H), 1.46 (s, 9H). 13C NMR (CDCl3, 100 MHz): δ 134.6 (CH), 117.0 (CH2) 108.6 (C×3), 72.3 (CH2), 70.3 (CH2×3), 69.8 (CH2×3), 69.4 (CH2×9), 68.5 (CH2), 45.7 (C), 35.2 (C×3), 23.5 (CH3×3).

[0145] [Synthesis of Compound H116]

[0146]

[0147] A deallylation reaction was carried out in the same manner as in Synthesis Example 3 to obtain the target compound H116. Chemical Formula: C 26 H 42 O 13 3-((1-methyl-2,6,7-trioxabicyclo[2.2.2]octan-4-yl)methoxy)-2,2-bis(((1-methyl-2,6,7-trioxabicyclo[2.2.2]octan-4-yl)methoxy)methyl)propan-1-ol 1 H NMR (CDCl3, 400 MHz): δ 3.97 (s, 18H), 3.56 (d, J = 5.6 Hz, 2H), 3.30 (s, 6H), 3.16 (s, 6H), 1.98 (t, J = 5.6 Hz, 1H), 1.45 (s, 9H). 13 C NMR (CDCl3, 100 MHz): δ 108.7 (C×3), 71.2 (CH2×2), 70.1 (CH2×2), 69.5 (CH2×11), 63.7 (CH2), 45.7 (C), 35.2 (C×3), 23.5 (CH3×3).

[0148] [Synthesis of compound H117]

[0149]

[0150] In Synthesis Example 5, R 4 Using H116 as -OH, the target compound H117 was obtained. The crude H117 was used in the next reaction.

[0151] [Synthesis of compound H118]

[0152]

[0153] In Synthesis Example 6 (1), R 5 Using H117 as -OTs, the target compound H118 was obtained. The crude H118 was used in the next reaction.

[0154] [Synthesis of compound H119]

[0155]

[0156] In Synthesis Example 7 (2), H118 was used as the compound obtained in Synthesis Example 6 to obtain the target compound H119. Chemical Formula: C 36 H 56 O 15 (E)-2,2'-(((2-((4-(3,5-dimethoxystyryl)phenoxy)methyl)-2-((3-hydroxy-2,2-bis(hydroxymethyl)propoxy)methyl)propane-1,3-diyl)bis(oxy))bis(methylene))bis(2-(hydroxymethyl)propane-1,3-diol) 1 H NMR (CD3OD, 400 MHz): δ 7.47 (d, J = 8.8 Hz, 2H), 7.08 (d, J = 16.0 Hz, 1H), 6.94 (d, J = 16.0 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 6.67 (d, J = 2.0 Hz, 2H), 6.36 (brt, J = 2.0 Hz, 1H), 4.00 (s, 2H), 3.80 (s, 6H), 3.65-3.50 (m, 24H), 3.47-3.40 (m, 6H). 13C NMR (CD3OD, 100 MHz): δ 162.4 (C×2), 160.6 (C), 141.1 (C), 131.3 (C), 129.7 (CH), 128.9 (CH×2), 127.5 (CH), 115.9 (CH×2), 105.3 (CH×2), 100.5 (CH), 72.6 (CH2×2), 72.0 (CH2×2), 68.0 (CH2), 63.5 (CH2×7), 63.3 (CH2×2), 63.0 (CH2×2), 55.8 (CH3×2), 47.1 (C), 46.9 (C×3).

[0157] Example 5 [Synthesis of Compound H123: P １ G ３ ]

[0158]

[0159] In Synthesis Example 2, R 2 Using A2 as -OH, the target compound H123 was obtained. Chemical Formula: C 23 H 40 O 10 (2S,2'S,5s,5's)-5,5'-((2-((allyloxy)methyl)-2-((((2S,5s)-2-methyl-1,3-dioxan-5-yl)oxy)methyl)propane-1,3-diyl)bis(oxy))bis(2-methyl-1,3-dioxane) 1H NMR (CDCl3, 400 MHz): δ 5.89 (ddt, J = 5.6, 10.4, 17.2 Hz, 1H), 5.24 (ddd, J = 1.6, 1.6, 17.2 Hz, 1H, one of CH2), 5.11 (ddd, J = 1.6, 1.6, 10.4 Hz, 1H, one of CH2), 4.68 (q, J = 4.8 Hz, 3H),4.14 (dd, J = 1.6, 12.4 Hz, 6H), 3.97 (ddd, J = 1.6, 1.6, 5.6 Hz, 2H), 3.77 (dd, J = 1.6, 12.4 Hz, 6H), 3.62-3.57 (m, 8H), 3.19 (m, 3H), 1.31 (d, J = 4.8 Hz, 9H). 13 C NMR (CDCl3, 100 MHz): δ 135.5 (CH), 116.1 (CH2), 99.0 (CH×3), 72.3 (CH2), 71.2 (CH×3), 69.3 (CH2), 68.6 (CH2×6), 67.7 (CH2×3), 45.7 (C), 21.2 (CH3×3).

[0160] [Synthesis of Compound H123′]

[0161]

[0162] In Synthesis Example 2, D1 and R 2 Using A2 as -OH, the target compound H123' was obtained. Chemical Formula: C 25 H 44 O 11 1H NMR (CDCl3, 400 MHz) d 4.68 (q, J = 4.8 Hz, 3H), 4.62 (t, J = 4.8 Hz, 1H), 4.13 (brd, J = 12.0 Hz, 6H), 3.87 (d, J = 9.2 Hz, 2H), 3.77 (brd, J = 12.0 Hz, 6H), 3.62 (s, 6H), 3.90-3.33 (m, 1H), 3.51 (d, J = 9.2 Hz, 1H), 3.53-3.44 (m, 1H), 3.21-3.19 (m, 3H), 1.75-1.42 (m, 6H), 1.29 (d, J = 4.8 Hz, 9H). 13 C NMR (CDCl3, 100 MHz) d 98.8 (CH), 98.7 (CH × 3), 70.9 (CH × 3), 68.4 (CH 2 × 3), 68.2 (CH 2 × 3), 67.5 (CH 2 × 3), 66.4 (CH2), 61.6 (CH2), 45.1 (C), 30.4 (CH2), 25.3 (CH2), 20.9 (CH3 × 3), 19.2 (CH2)

[0163] [Synthesis of compound H123″]

[0164]

[0165] In Synthesis Example 2, E1 and R 2 Using A2 as -OH, the target compound H123'' was obtained. Chemical Formula: C 22 H 40 O 11 (2S,2'S,5s,5's)-5,5'-((2-((methoxymethoxy)methyl)-2-((((2S,5s)-2-methyl-1,3-dioxan-5-yl)oxy)methyl)propane-1,3-diyl)bis(oxy))bis(2-methyl-1,3-dioxane) 1H NMR (CDCl3, 400 MHz): δ 4.69 (q, J = 5.2 Hz, 3H), 4.62 (s, 2H), 4.14 (brd, J = 12.4 Hz, 6H), 3.78 (brd, J = 12.4 Hz, 6H), 3.68 (s, 2H), 3.60 (s, 6H), 3.35 (s, 3H), 3.23-3.17 (m, 3H), 1.30 (d, J = 5.2 Hz, 9H). 13 C NMR (CDCl3, 100 MHz): δ 99.0 (CH×3), 97.1 (CH2), 71.3 (CH×3), 68.6 (CH2×6), 67.5 (CH2×3), 67.0 (CH2), 55.2 (CH3), 45.4 (C), 21.2 (CH3×3).

[0166] [Synthesis of compound H124]

[0167]

[0168] A deallylation reaction was carried out in the same manner as in Synthesis Example 3 to obtain the target compound H124. Chemical Formula: C 20 H 36 O 10 3-(((2S,5s)-2-methyl-1,3-dioxan-5-yl)oxy)-2,2-bis((((2S,5s)-2-methyl-1,3-dioxan-5-yl)oxy)methyl)propan-1-ol 1 H NMR (CDCl3, 400 MHz): δ 4.70 (q, J = 5.2 Hz, 3H), 4.20-4.10 (m, 6H), 3.85-3.74 (m, 8H), 3.64 (s, 6H), 3.26-3.21 (m, 3H), 3.20 (t, J = 5.2 Hz, 1H), 1.31 (d, J = 5.2 Hz, 9H). 13 C NMR (CDCl3, 100 MHz): δ 99.0 (CH×3), 71.0 (CH×3), 68.5 (CH2×3) ,68.3 (CH2×6), 65.2 (CH2), 45.4 (C), 21.1 (CH3×3).

[0169] [Synthesis of Compound H127′]

[0170]

[0171] In Synthesis Example 5, R 4 Using H124 as the -OH, the target compound H127' was obtained. The crude H127' was used in the next reaction.

[0172] [Synthesis of Compound H128']

[0173]

[0174] In Synthesis Example 6 (1), R 5 Using H127' as -OTs, the target compound H128' was obtained. Chemical Formula: C 36 H 50 O 12 (2S,2'S,5s,5's)-5,5'-((2-((4-((E)-3,5-dimethoxystyryl)phenoxy)methyl)-2-((((2S,5s)-2-methyl-1,3-dioxan-5-yl)oxy)methyl)propane-1,3-diyl)bis(oxy))bis(2-methyl-1,3-dioxane) 1 H NMR (CDCl3, 400 MHz): δ 7.43 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 16.0 Hz, 1H), 6.91 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 16.0 Hz, 1H), 6.65 (d, J = 2.4 Hz, 2H), 6.37 (brt, J = 2.4 Hz, 1H), 4.68 (q, J = 5.2 Hz, 3H), 4.18 (s, 2H), 4.17-4.09 (m, 6H), 3.83 (s, 6H), 3.81-3.70 (m, 12H), 3.21 (m, 3H), 1.30 (d, J = 5.2 Hz, 9H). 13C NMR (CDCl3, 100 MHz): δ 161.0 (C×2), 159.0 (C), 139.9 (C), 129.9 (C), 129.1 (CH), 127.8 (CH×2), 126.5 (CH), 115.1 (CH×2), 104.4 (CH×2), 99.8 (CH), 99.1 (CH×3), 71.4 (CH×3), 68.7 (CH2×6), 67.6 (CH2×3), 67.5 (CH2), 55.5 (CH3×2), 45.7 (C), 21.3 (CH3×3).

[0175] [Synthesis of compound H125]

[0176]

[0177] To a suspension of H124 (9.5 mmol) in water (9.5 mL), amberlyst-15 (Merck-Aldrich, sulfonic acid content 2 mmol / g) (48 mg) was added and stirred at 100 °C overnight. The suspension was filtered, and the filtrate was concentrated under reduced pressure to give the target compound, H125, which was used in the next reaction without further purification.

[0178]

[0179]

[0180] Furthermore, the synthesis of H125 from H123' and the synthesis of H125 from H123'' were also carried out according to the above scheme.

[0181] [Synthesis of compound H126]

[0182]

[0183] To a toluene suspension (20 mL) of H125 (8.12 mmol), 2,2-dimethoxypropane (73.08 mmol) and amberlyst-15 (Merck-Aldrich, sulfonic acid content 2 mmol / g) (81.2 mg) were added, and the mixture was stirred at 85 °C for 2 hours while distilling off the methanol. The resulting suspension was filtered at room temperature, and triethylamine (1 mL) was added to the filtrate, followed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (toluene / ethyl acetate = 1 / 1-1 / 4) to obtain the desired compound H126 as a colorless liquid (5.28 mmol, 52.8% yield over three steps from H122). Chemical Formula: C23H42O10 3-((2,2-dimethyl-1,3-dioxan-5-yl)oxy)-2,2-bis(((2,2-dimethyl-1,3-dioxan-5-yl)oxy)methyl)propan-1-ol 1 H NMR (CDCl3, 400 MHz): δ 3.95 (dd, J = 4.0, 12.0 Hz, 6H), 3.74 (dd, 6.0, 12.0 Hz, 6H), 3.69 (brd, J = 4.0 Hz, 2H), 3.51 (s, 6H), 3.4-3.30 (m, 3H), 2.99 (brt, 1H), 1.41 (s, 9H), 1.40 (s, 9H). 13 C NMR (CDCl3, 100 MHz): δ 98.3 (C×3), 70.9 (CH×3), 68.4 (CH2×3), 64.5 (CH2), 62.6 (CH2×6), 45.2 (C), 23.9 (CH3×3), 23.5 (CH3×3).

[0184] [Synthesis of compound H127]

[0185]

[0186] In Synthesis Example 5, R 4 Using H126 as -OH, the target compound H127 was obtained. The crude H127 was used as is in the next reaction.

[0187] [Synthesis of compound H128]

[0188]

[0189] In Synthesis Example 6 (1), R 5 Using H127 as -OTs, the target compound H128 was obtained. Chemical Formula: C 39 H 56 O 12 (E)-5,5'-((2-((4-(3,5-dimethoxystyryl)phenoxy)methyl)-2-(((2,2-dimethyl-1,3-dioxan-5-yl)oxy)methyl)propane-1,3-diyl)bis(oxy))bis(2,2-dimethyl-1,3-dioxane) 1 H NMR (CDCl3, 400 MHz): δ 7.42 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 16.4 Hz, 1H), 6.90 (d, J = 16.4 Hz, 1H), 6.89 (d, J = 8.8 Hz, 2H), 6.65 (d, J = 2.4 Hz, 2H), 6.38 (brt, J = 2.4 Hz, 1H), 3.98 (s, 2H), 3.93 (dd, J = 4.4, 12.0 Hz, 6H), 3.83 (s, 6H), 3.68 (dd, J = 6.4, 12.0 Hz, 6H), 3.57 (s, 6H), 3.44-3.34 (m, 3H), 1.40 (s, 9H), 1.38 (s, 9H). 13 C NMR (CDCl3, 100 MHz): δ 161.1 (C×2), 159.1 (C), 139.8 (C), 130.1 (C), 128.9 (CH), 127.9 (CH×2), 126.6 (CH), 115.0 (CH×2), 104.4 (CH×2), 99.7 (CH), 98.3 (C×3), 71.0 (CH×3), 67.2 (CH2×3), 66.7 (CH2), 62.7 (CH2×6), 55.5 (CH3×2), 45.4 (C), 24.6 (CH3×3), 22.9 (CH3×3).

[0190] [Synthesis of compound H129]

[0191]

[0192] In Synthesis Example 7 (1), H128 was used as the compound obtained in Synthesis Example 6 to obtain the target compound H129. Chemical Formula: C30H44O12 (E)-2,2'-((2-(((1,3-dihydroxypropan-2-yl)oxy)methyl)-2-((4-(3,5-dimethoxystyryl)phenoxy)methyl)propane-1,3-diyl)bis(oxy))bis(propane-1,3-diol) 1 H NMR (CD3OD, 400 MHz): δ 7.46 (d, J = 8.8 Hz, 2H), 7.08 (d, J = 16.0 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 16.0 Hz, 1H), 6.67 (d, J = 2.0 Hz, 2H), 6.36 (brt, J = 2.0 Hz, 1H), 4.07 (s, 2H), 3.80 (s, 6H), 3.76-3.69 (m, 6H), 3.67-3.52 (m, 12H), 3.44-3.35 (m, 3H). 13 C NMR (CD3OD, 100 MHz): δ 162.5 (C×2), 160.5 (C), 141.2 (C), 131.5 (C), 129.7 (CH), 128.8 (CH×2), 127.5 (CH), 115.9 (CH×2), 105.3 (CH×2), 100.4 (CH), 83.0 (CH×3), 69.6 (CH2×3), 68.0 (CH2), 62.4 (CH2×6), 55.7 (CH3×2), 46.9 (C).

[0193] Example 6 [Synthesis of Compound H135: P １ A ３ ]

[0194]

[0195] In Synthesis Example 2, R 2Using A3 as -OH, the target compound H135 was obtained. Chemical Formula: C 26 H 46 O 10 4,4'-(((2-((allyloxy)methyl)-2-(((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)methyl)propane-1,3-diyl)bis(oxy))bis(methylene))bis(2,2-dimethyl-1,3-dioxolane)--methane (1 / 1) 1 H NMR (CDCl3, 400 MHz): δ 5.93-5.80 (m, 1H), 5.28-5.10 (m, 2H), 4.26-4.17 (m, 3H), 4.03 (dd, J = 6.4, 8.0 Hz, 3H), 3.95-3.90 (m, 2H), 3.75 (dd, J = 6.4, 8.0 Hz, 3H), 3.53-3.37 (m, 14H), 1.41 (s, 9H), 1.36 (s, 9H). 13 C NMR (CDCl3, 100 MHz): δ 135.0 (CH), 116.1 (CH2) 109.1 (C×3), 74.5 (CH×4), 72.2 (CH2×3), 70.2 (CH2×3), 68.8 (CH2), 66.8 (CH2×3), 45.6 (C), 26.7 (CH3×3), 25.5 (CH3×3).

[0196] [Synthesis of compound H136]

[0197]

[0198] A deallylation reaction was carried out in the same manner as in Synthesis Example 3 to obtain the target compound H136. Chemical Formula: C23H42O10 3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2,2-bis(((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)methyl)propan-1-ol 1H NMR (CDCl3, 400 MHz): δ 4.28-4.14 (m, 3H), 4.10-3.98 (m, 4H), 3.78-3.60 (m, 4H), 3.54-3.40 (m, 12H), 3.25-2.84 (m, 1H), 1.40 (s, 6H), 1.40 (s, 3H), 1.34 (s, 9H). 13 C NMR (CDCl3, 100 MHz): δ 109.5 (C×2), 109.4 (C), 74.7 (CH×3), 72.5 (CH2×2), 71.9 (CH2), 70.2 (CH2), 66.9 (CH2), 66.7 (CH2×2), 65.4 (CH2), 45.5 (C), 26.9 (CH3×3), 25.5 (CH3×3).

[0199] [Synthesis of compound H137]

[0200]

[0201] In Synthesis Example 5, R 4 Using H136 as -OH, the target compound H137 was obtained. The crude H137 was used in the next reaction.

[0202] [Synthesis of compound H138]

[0203]

[0204] In Synthesis Example 6 (1), R 5 Using H137 as -OTs, the target compound H138 was obtained. Chemical Formula: C 39 H 56 O 12 (E)-4,4'-(((2-((4-(3,5-dimethoxystyryl)phenoxy)methyl)-2-(((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)methyl)propane-1,3-diyl)bis(oxy))bis(methylene))bis(2,2-dimethyl-1,3-dioxolane) 1H NMR (CDCl3, 400 MHz): δ 7.42 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 16.0 Hz, 1H), 6.90 (d, J = 16.0 Hz, 1H), 6.89 (d, J = 8.8 Hz, 2H), 6.65 (d, J = 2.4 Hz, 2H), 6.38 (brt, J = 2.4 Hz, 1H), 4.27-4.13 (m, 3H), 4.12-3.98 (m, 4H), 3.97 (s, 2H), 3.83 (s, 6H), 3.78-3.65 (m, 4H), 3.57 (s, 6H), 3.54-3.34 (m, 4H), 1.40 (s, 9H), 1.34 (s, 9H). 13 C NMR (CDCl3, 100 MHz): δ 161.1 (C×2), 159.1 (C), 139.8 (C), 130.0 (C), 128.9 (CH), 127.9 (CH×2), 126.6 (CH), 114.9 (CH×2), 109.4 (C×3), 104.4 (CH×2), 99.7 (CH), 74.7 (CH×3), 72.5 (CH2×3), 70.2 (CH2×3), 67.0 (CH2), 66.9 (CH2×3), 55.5 (CH3×2), 45.7 (C), 26.9 (CH3×3), 25.6 (CH3×3).

[0205] [Synthesis of compound H139]

[0206]

[0207] In Synthesis Example 7 (1), H138 was used as the compound obtained in Synthesis Example 6 to obtain the target compound H139. Chemical Formula: C 30 H 44 O 12 (E)-3,3'-((2-((2,3-dihydroxypropoxy)methyl)-2-((4-(3,5-dimethoxystyryl)phenoxy)methyl)propane-1,3-diyl)bis(oxy))bis(propane-1,2-diol) 1H NMR (CD3OD, 400 MHz): δ 7.47 (d, J = 8.8 Hz, 2H), 7.08 (d, J = 16.0 Hz, 1H), 6.93 (d, J = 16.0 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.68 (d, J = 2.4 Hz, 2H), 6.36 (brt, J = 2.4 Hz, 1H), 4.02 (s, 2H), 3.80 (s, 6H), 3.79-3.70 (m, 4H), 3.68-3.98 (m, 17). 13 C NMR (CD3OD, 100 MHz): δ 162.5 (C×2), 160.5 (C), 141.2 (C), 131.5 (C), 129.7 (CH), 128.8 (CH×2), 127.5 (CH), 115.9 (CH×2), 105.2 (CH×2), 100.4 (CH), 74.0 (CH2×2), 73.9 (CH2), 72.2 (CH2×3), 71.1 (CH×3), 68.2 (CH2), 64.5(CH2×2), 64.4 (CH2), 55.7 (CH3×2), 46.7 (C).

[0208] Example 7 [Synthesis of Compound H145: P １ T ３ ]

[0209]

[0210] In Synthesis Example 2, R 2 Using A4 as -OH, the target compound H145 was obtained. Chemical Formula: C 32 H 58 O 10 5,5'-(((2-((allyloxy)methyl)-2-(((2,2,5-trimethyl-1,3-dioxan-5-yl)methoxy)methyl)propane-1,3-diyl)bis(oxy))bis(methylene))bis(2,2,5-trimethyl-1,3-dioxane) 1H NMR (CDCl3, 400 MHz): δ 5.87 (ddt, J = 5.6, 10.4, 17.6 Hz, 1H), 5.26 (ddd, J = 1.6, 3.2, 17.6 Hz, 1H, one of CH2), 5.14 (ddd, J = 1.6, 3.2, 10.6 Hz, 1H, one of CH2), 3.93 (ddd, J = 1.6, 1.6, 5.6 Hz, 2H), 3.75-3.59 (m, 6H), 3.55-3.29 (m, 20H), 1.42 (s, 9H), 1.39 (s, 9H), 0.89 (s, 9H). 13 C NMR (CDCl3, 100 MHz): δ 135.3 (CH), 116.4 (CH2) 97.9 (C×3), 74.4 (CH2×3), 72.5 (CH2), 70.4 (CH2×3), 69.6 (CH2), 66.8 (CH2×6), 46.2 (C), 34.7 (C×3), 25.6 (CH3×3), 22.2 (CH3×3), 18.7 (C×3).

[0211] [Synthesis of compound H146]

[0212]

[0213] A deallylation reaction was carried out in the same manner as in Synthesis Example 3 to obtain the target compound H146. Chemical Formula: C 29 H 54 O 10 3-((2,2,5-trimethyl-1,3-dioxan-5-yl)methoxy)-2,2-bis(((2,2,5-trimethyl-1,3-dioxan-5-yl)methoxy)methyl)propan-1-ol 1 H NMR (CDCl3, 400 MHz): δ 3.80-3.64 (m, 8H), 3.60-3.45 (m, 10H), 3.41-3.44 (m, 8H), 2.80 (t, J = 6.4 Hz, 1H),1.43 (s, 9H), 1.40 (s, 9H), 0.90 (s, 3H), 0.88 (s, 6H). 13C NMR (CDCl3, 100 MHz): δ 98.0 (C×2), 97.9 (C), 74.8 (CH2×2), 74.4 (CH2),72.0 (CH2×2), 70.2 (CH2), 66.8 (CH2×2), 66.7 (CH2×4), 66.3 (CH2), 45.8 (C), 34.7 (C×3), 26.4 (CH3×2), 25.9 (CH3), 22.0 (CH3), 21.5 (CH3×2) 18.7 (CH3), 18.5 (CH3×2).

[0214] Example 8 [Synthesis of Compound H216: G １ P ２ ]

[0215]

[0216] In Synthesis Example 4, R 3 Using A1 as -OH, the target compound H216 was obtained. Chemical Formula: C 17 H 28 O9 1,3-bis((1-methyl-2,6,7-trioxabicyclo[2.2.2]octan-4-yl)methoxy)propan-2-ol 1 H NMR (CDCl3, 400 MHz): δ 4.00 (s, 12H), 3.93-3.84 (m, 1H), 3.42 (dd, J = 4.4, 9.6 Hz, 2H), 3.38 (dd, J = 6.0, 10.0 Hz, 2H), 3.27 (d, J = 10.0 Hz, 2H), 3.24 (d, J = 9.6 Hz, 2H), 2.21 (m, 1H), 1.46 (s, 6H).

[0217] [Synthesis of compound H217]

[0218]

[0219] In Synthesis Example 5, R 4 Using H216 as -OH, the target compound H217 was obtained. The crude H217 was used as is in the next reaction.

[0220] [Synthesis of compound H218]

[0221]

[0222] In Synthesis Example 6 (1), R 5 Using H217 as -OTs, the target compound, H218, was obtained. Chemical Formula: C 33 H 42 O 11 1 H NMR (CDCl3, 400 MHz): δ 7.44 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 16.0 Hz, 1H), 6.92 (d, J =16.4 Hz, 2H), 6.89 (d, J = 8.8 Hz, 1H), 6.65 (d, J = 2.4 Hz, 2H), 6.39 (brt, J = 2.4 Hz, 1H), 4.50-4.42 (m, 1H), 4.05-3.90 (m, 14H), 3.83 (s, 6H), 3.60-3.53 (m, 2H), 3.24 (s, 4H), 1.45 (s, 6H). 13 C NMR (CDCl3, 100 MHz): δ 161.1 (C×2), 157.7 (C), 139.7 (C), 131.1 (C), 128.5 (CH), 128.0 (CH×2), 127.4 (CH), 116.4 (CH×2), 108.7 (C×2), 104.5 (CH×2), 100.0 (CH), 71.0 (CH2×2), 70.4 (CH2×2), 69.5 (CH2×7), 55.5 (CH3×2), 35.2 (C×2), 23.6 (CH3×2).

[0223] [Synthesis of compound H219]

[0224]

[0225] In Synthesis Example 7 (2), H218 was used as the compound obtained in Synthesis Example 6 to obtain the target compound H219. Chemical Formula: C 29 H 42 O 11(E)-2,2'-(((2-(4-(3,5-dimethoxystyryl)phenoxy)propane-1,3-diyl)bis(oxy))bis(methylene))bis(2-(hydroxymethyl)propane-1,3-diol) 1 H NMR (CD3OD, 400 MHz): δ 7.43 (d, J = 8.8 Hz, 2H), 7.04 (d, J = 16.4 Hz, 1H), 6.98 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 16.4 Hz, 1H), 6.65 (d, J = 2.0 Hz, 2H), 6.35 (brt, J = 2.0 Hz, 1H), 4.65-4.57 (m, 1H), 3.77 (s, 6H), 3.72-3.63 (m, 2H), 3.64-3.52 (m, 16H), 3.52-3.43 (m, 2H). 13 C NMR (CD3OD, 100 MHz): δ 162.4 (C×2), 159.3 (C), 141.0 (C), 131.9 (C), 129.5 (CH), 128.9 (CH×2), 127.8 (CH), 117.5 (CH×2), 105.3 (CH×2), 100.5 (CH), 77.7 (CH), 72.6 (CH2), 71.9 (CH2). 63.2 (CH2×8), 55.8 (CH2×2), 46.9 (C×2).

[0226] Example 9 [Synthesis of Compound H246: G １ T ２ ]

[0227]

[0228] In Synthesis Example 4, R 3 Using A4 as -OH, the target compound H246 was obtained. Chemical Formula: C 19 H 36 O7 1,3-bis((2,2,5-trimethyl-1,3-dioxan-5-yl)methoxy)propan-2-ol 1H NMR (CDCl3, 400 MHz): δ 4.03-3.93 (m, 1H), 3.80-3.30 (m, 16H), 2.57 (d, J = 4.8 Hz, 1H), 1.43 (s, 6H), 1.40 (s, 6H), 0.86 (s, 6H). 13 C NMR (CDCl3, 100 MHz): δ 98.1 (C×2), 74.3 (CH2×2), 72.8 (CH2×2), 69.6 (CH), 66.6 (CH2×4), 34.6 (C×2), 27.0 (CH3×2), 20.8 (CH3×2), 18.4 (CH3×2).

[0229] Example 10 [Synthesis of Compound J117: P １ P １ P ３ ]

[0230]

[0231] In Synthesis Example 1, R 1 Using H116 as -OH, the target compound J117 was obtained. Chemical Formula: C 34 H 55 BrO 15 4,4'-(((2-(((5-(bromomethyl)-2,2-dimethyl-1,3-dioxan-5-yl)methoxy)methyl)-2-(((1-methyl-2,6,7-trioxabicyclo[2.2.2 ]octan-4-yl)methoxy)methyl)propane-1,3-diyl)bis(oxy))bis(methylene))bis(1-methyl-2,6,7-trioxabicyclo[2.2.2]octane) 1 H NMR (CDCl3, 400 MHz): δ 3.97 (s, 18H), 3.70 (s, 4H), 3.50 (s, 2H), 3.36 (s, 2H), 3.28 (s, 2H), 3.23 (s, 6H), 3.13 (s, 6H), 1.45 (s, 9H), 1.41 (s, 6H). 13C NMR (CDCl3, 100 MHz): δ 108.7 (C×3), 98.9 (C), 70.9 (CH2), 70.1 (CH2×2), 70.0 (CH2×3), 69.7 (CH2), 69.5 (CH2×10), 64.0 (CH2×2), 46.0 (C), 38.7 (C), 35.7 (CH3), 35.3 (C×3), 24.0 (CH3), 23.6 (CH3×3), 23.5 (CH3).

[0232] [Synthesis of compound J118]

[0233]

[0234] In Synthesis Example 6 (2), R 5 The target compound J118 was obtained using J117 as -X. J118 was not purified by column chromatography, and the crude product was used directly in the next reaction.

[0235] [Synthesis of compound J119]

[0236]

[0237] In Synthesis Example 7 (2), J118 was used as the compound obtained in Synthesis Example 6 to obtain the target compound J119. Chemical Formula: C 41 H 66 O 18 (E)-2,2'-(((2-((3-(4-(3,5-dimethoxystyryl)phenoxy)-2,2-bis(hydroxymethyl)propoxy)methyl)-2-((3-hydroxy-2,2-bi s(hydroxymethyl)propoxy)methyl)propane-1,3-diyl)bis(oxy))bis(methylene))bis(2-(hydroxymethyl)propane-1,3-diol) 1H NMR (CD3OD, 400 MHz): δ 7.48 (d, J = 8.8 Hz, 2H), 7.08 (d, J = 16.0 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 16.0 Hz, 1H), 6.67 (d, J = 2.4 Hz, 2H), 6.36 (brt, J = 2.4 Hz, 1H), 3.98 (s, 2H), 3.80 (s, 6H), 3.71 (s, 4H), 3.60-3.55 (m, 18H), 3.38-3.34 (m, 16H). 13 C NMR (CD3OD, 100 MHz): δ 162.4 (C×2), 160.6 (C), 141.1 (C), 131.3 (C), 129.7 (CH), 128.9 (CH×2), 127.5 (CH), 115.7 (CH×2), 105.2 (CH×2), 100.5 (CH), 72.6 (CH2×2), 72.1 (CH2×2), 71.6 (CH2), 68.5 (CH2), 63.5 (CH2×10), 63.3 (CH2×2), 63.0 (CH2×2), 55.8 (CH3×2), 47.1 (C×2), 46.9 (C×3).

[0238] Example 11 [Synthesis of Compound J127: P １ P １ G ３ ]

[0239]

[0240] In Synthesis Example 1, R 1 Using H126 as -OH, the target compound J127 was obtained. Chemical Formula: C 31 H 55 BrO 125,5'-((2-(((5-(bromomethyl)-2,2-dimethyl-1,3-dioxan-5-yl)methoxy)methyl)-2-(((2,2-dimethyl-1,3-dioxan-5-yl)oxy)methyl)propane-1,3-diyl)bis(oxy))bis(2,2-dimethyl-1,3-dioxane) 1 H NMR (CDCl3, 400 MHz): δ 4.00-3.88 (m, 6H), 3.80-3.64 (m, 10H), 3.56 (s, 2H), 3.46 (m, 13H), 1.42 (s, 9H), 1.40 (s, 6H), 1.39 (s, 9H). 13 C NMR (CDCl3, 100 MHz): δ 98.7 (C), 98.2 (C×3), 70.9 (CH×3), 69.8 (CH2), 67.4 (CH2×2), 63.9 (CH2×2), 62.6 (CH2×8), 45.6 (C), 38.6 (C), 36.1 (CH2), 24.6 (CH3), 24.5 (CH3×3), 23.0 (CH3×3), 22.8 (CH3).

[0241] [Synthesis of compound J128]

[0242]

[0243] In Synthesis Example 6 (2), R 5 Using J127 as -X, the target compound J128 was obtained. Chemical Formula: C 47 H 70 O 15 (E)-5,5'-((2-(((5-((4-(3,5-dimethoxystyryl)phenoxy)methyl)-2,2-dimethyl-1,3-dioxan-5-yl)methoxy)methyl )-2-(((2,2-dimethyl-1,3-dioxan-5-yl)oxy)methyl)propane-1,3-diyl)bis(oxy))bis(2,2-dimethyl-1,3-dioxane) 1H NMR (CDCl3, 400 MHz): δ 7.43 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 16.0 Hz, 1H), 6.89 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 16.0 Hz, 1H), 6.63 (brd, J = 2.4 Hz, 2H), 6.38 (brt, J = 2.4 Hz, 1H), 3.99 (s, 2H), 3.88-3.80 (m, 8H), 3.79 (s, 6H), 3.74-3.58 (m, 8H), 3.46-3.30 (m, 10H), 3.25 (m, 3H), 1.43 (s, 3H), 1.41 (s, 3H), 1.38 (s, 9H), 1.35 (s, 9H). 13 C NMR (CDCl3, 100 MHz): δ 160.9 (C×2), 158.8 (C), 139.6 (C), 130.0 (C), 128.6 (CH), 127.7 (CH×2), 126.6 (CH), 114.7 (CH×2), 104.2 (CH×2), 99.5 (CH), 98.3 (C), 97.9 (C×3), 70.7 (CH×3), 69.6 (CH2), 67.8 (CH2), 67.2 (CH2×2), 67.0 (CH2), 62.6 (CH2), 62.5 (CH2×2) 62.4 (CH2×6), 55.2 (CH3×2), 45.5 (C), 38.8 (C), 24.2(CH3), 24.0 (CH3×3), 23.1 (CH3×3), 23.0 (CH3).

[0244] [Synthesis of compound J129]

[0245]

[0246] In Synthesis Example 7 (1), J128 was used as the compound obtained in Synthesis Example 6 to obtain the target compound J129. Chemical Formula: C 35 H 54 O 15(E)-2,2'-((2-(((1,3-dihydroxypropane-2-yl)oxy)methyl)-2-((3-(4-(3,5-dimethoxystyryl)phenoxy)-2,2-bis(hydroxymethyl)propoxy)methyl)propane-1,3-diyl)bis(oxy))bis(propane-1,3-diol) 1 H NMR (CD3OD, 400 MHz): δ 7.46 (d, J = 8.8 Hz, 2H), 7.08 (d, J = 16.4 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 16.4 Hz, 1H), 6.67 (d, J = 2.4 Hz, 2H), 6.36 (brt, J = 2.4 Hz, 1H), 3.97 (s, 2H), 3.78 (s, 6H), 3.70 (s, 4H), 3.78-3.44 (m, 22H), 3.42-3.33 (m, 3H). 13 C NMR (CD3OD, 100 MHz): δ 162.4 (C×2), 160.4 (C), 141.1 (C), 131.4 (C), 129.7 (CH), 128.8 (CH×2), 127.5 (CH), 115.7 (CH×2), 105.2 (CH×2), 100.4 (CH), 82.9 (CH×3), 70.0 (CH2), 69.8 (CH2×2), 69.7 (CH2), 67.7 (CH2), 62.5 (CH2×2), 62.3 (CH2×7), 55.7 (CH3×2), 47.1 (C), 46.9 (C).

[0247] Example 12 [Synthesis of Compound J127': P １ P １ G ３ ]

[0248]

[0249] In Synthesis Example 1, R 1 Using H124 as -OH, the target compound J127' was obtained. Chemical Formula: C 28 H 49BrO 12 (2S,2'S,5s,5's)-5,5'-((2-(((5-(bromomethyl)-2,2-dimethyl-1,3-dioxan-5-yl)methoxy)methyl)-2-((( (2S,5s)-2-methyl-1,3-dioxan-5-yl)oxy)methyl)propane-1,3-diyl)bis(oxy))bis(2-methyl-1,3-dioxane) 1 H NMR (CDCl3, 400 MHz): δ 4.71 (q, J = 5.2 Hz, 3H), 4.18-4.08 (m, 6H), 3.83-3.68 (m, 10H), 3.60 (s, 2H), 3.59 (s, 8H), 3.39 (s, 2H), 3.20 (m, 3H), 1.40 (s, 3H), 1.40 (s, 3H), 1.34-1.28 (m, 9H). 13 C NMR (CDCl3, 100 MHz): δ 98.8 (CH×3), 98.4 (C), 71.1 (CH×3), 70.8 (CH2), 70.2 (CH2), 68.4 (CH2×7), 67.6 (CH2×2), 63.8 (CH2×2), 45.7 (C), 38.4 (C), 36.2 (CH2), 25.0 (CH3), 22.2 (CH3), 21.1 (CH3×3).

[0250] [Synthesis of compound J128']

[0251]

[0252] In Synthesis Example 6 (2), R 5 Using J127' as -X, the target compound J128' was obtained. Chemical Formula: C 44 H 64 O 15(2S,2'S,5s,5's)-5,5'-((2-(((5-((4-((E)-3,5-dimethoxystyryl)phenoxy)methyl)-2,2-dimethyl-1,3-dioxan-5-yl)methoxy)methyl)-2-((((2S,5s)-2-methyl-1,3-dioxan-5-yl)oxy)methyl)propane-1,3-diyl)bis(oxy))bis(2-methyl-1,3-dioxane) 1 1H NMR (CDCl3, 400 MHz): δ 7.42 (d, J = 8.8 Hz, 2H), 7.04 (d, J = 16.0 Hz, 1H), 6.91 (d, J = 16.0 Hz, 1H), 6.89 (d, J = 8.8 Hz, 2H), 6.66 (d, J = 2.4 Hz, 2H), 6.38 (brt, J = 2.4 Hz, 1H), 4.64 (q, J = 5.2 Hz, 3H), 4.12 - 4.04 (m, 6H), 4.03 (s, 2H), 3.83 (s, 10H), 3.72 - 3.64 (m, 6H), 3.56 (s, 2H), 3.54 (s, 6H), 3.46 (s, 2H), 3.11 - 3.04 (m, 3H), 1.44 (s, 3H), 1.42 (s, 3H), 1.29 (d, J = 5.2 Hz, 9H). 13 13C NMR (CDCl3, 100 MHz): δ 161.0 (C×2), 159.0 (C), 139.8 (C), 130.3 (C), 129.2 (CH), 127.9 (CH×2), 126.6 (CH), 114.8 (CH×2), 104.4 (CH×2), 99.7 (CH), 99.0 (CH×3), 98.5 (C), 71.3 (CH×3), 70.5 (CH2), 70.3 (CH2), 68.6 (CH2×8), 67.8 (CH2×3), 67.1 (CH2), 62.9 (CH2×2), 55.5 (CH3×2), 25.5 (CH3), 22.2 (CH3), 21.2 (CH3×3).

[0253] Example 13 [Synthesis of Compound J137: P１ P １ A ３ ]

[0254]

[0255] In Synthesis Example 1, R 1 Using H136 as -OH, the target compound J137 was obtained. Chemical Formula: C 31 H 55 BrO 12 5-(bromomethyl)-5-((3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2,2-bis(((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)methyl)propoxy)methyl)-2,2-dimethyl-1,3-dioxane--methane (1 / 1) 1 H NMR (CDCl3, 400 MHz): δ 4.23 (quin, J = 6.0 Hz, 3H), 4.03 (dd, J = 6.4 Hz, 3H), 3.84-3.64 (m, 8H), 3.62-3.30 (m, 17H), 1.41 (s, 16H), 1.36 (s, 8H). 13 C NMR (CDCl3, 100 MHz): δ 109.3 (C×3), 98.6 (C), 74.7 (CH×3), 72.4 (CH2×2), 70.9 (CH2), 70.4 (CH2×2), 70.2 (CH2), 66.9 (CH2×4), 63.9 (CH2×2), 63.7 (CH2), 45.9 (C), 38.6 (C), 36.0 (CH2), 26.8 (CH3×3), 25.6 (CH3×3), 24.6 (CH3), 22.7 (CH3).

[0256] [Synthesis of compound J138]

[0257]

[0258] In Synthesis Example 6 (2), R 5 Using J137 as -X, the target compound J138 was obtained. Chemical Formula: C47 H 70 O 15 (E)-5-((4-(3,5-dimethoxystyryl)phenoxy)methyl)-5-((3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2,2-bis(((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)methyl)propoxy)methyl)-2,2-dimethyl-1,3-dioxane 1 H NMR (CDCl3, 400 MHz): δ 7.43 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 16.0 Hz, 1H), 6.91 (d, J = 16.0 Hz, 1H), 6.90 (d, J = 8.8 Hz, 2H), 6.63 (brd, J = 2.4 Hz, 2H), 6.38 (brt, J = 2.4 Hz, 1H), 4.20-4.12 (m, 3H), 4.02 (s, 2H), 4.02-3.95 (m, 3H), 3.88-3.79 (m, 10H), 3.73-3.65 (m, 3H), 3.48-3.30 (m, 16H), 1.45 (s, 3H), 1.42 (s, 3H), 1.39 (s, 9H), 1.34 (s, 9H). 13 C NMR (CDCl3, 100 MHz): δ 161.1 (C×2), 159.0 (C), 139.8 (C), 130.2 (C), 128.8 (CH), 127.9 (CH×2), 126.7 (CH), 114.8 (CH×2), 109.4 (C×3), 104.2 (CH×2), 99.8 (CH), 98.5 (C), 74.7 (CH×3), 72.4 (CH2×3), 70.8 (CH2), 70.5 (CH2×3), 70.2 (CH2), 67.3 (CH2), 66.9 (CH2×4), 62.8 (CH2), 55.5 (CH3×2), 46.0 (C), 39.0 (C), 26.9 (CH3×3), 25.6 (CH3×3), 25.3 (CH3), 22.5 (CH3).

[0259] [Synthesis of compound J139]

[0260]

[0261] In Synthesis Example 7 (1), J138 was used as the compound obtained in Synthesis Example 6 to obtain the target compound J139. Chemical Formula: C 35 H 54 O 15 (E)-3,3'-((2-((2,3-dihydroxypropoxy)methyl)-2-((3-(4-(3,5-dimethoxystyryl)phenoxy)-2,2-bis(hydroxymethyl)propoxy)methyl)propane-1,3-diyl)bis(oxy))bis(propane-1,2-diol) 1 H NMR (CD3OD, 400 MHz): δ 7.47 (d, J = 8.8 Hz, 2H), 7.08 (d, J = 16.0 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 16.0 Hz, 1H), 6.67 (d, J = 2.4 Hz, 2H), 6.36 (brt, J = 2.4 Hz, 1H), 3.97 (s, 2H), 3.79 (s, 6H), 3.76-3.65 (m, 6H), 3.64-3.33 (m, 23H). 13 C NMR (CD3OD, 100 MHz): δ 162.4 (C×2), 160.5 (C), 141.1 (C), 131.4 (C), 129.7 (CH), 128.9 (CH×2), 127.5 (CH), 115.7 (CH×2), 105.2 (CH×2), 100.4 (CH), 73.9 (CH2×4), 72.0 (CH×3), 71.7 (CH2×2), 71.5 (CH2), 67.8 (CH2), 64.5 (CH2×4), 62.6 (CH2×2), 55.8 (CH3×2), 46.8 (C), 46.8 (C).

[0262] Example 14 [Synthesis of Compound J147: P １ P １ T ３]

[0263]

[0264] In Synthesis Example 1, R 1 Using H146 as -OH, the target compound J147 was obtained. Chemical Formula: C 37 H 67 BrO 12 5,5'-(((2-(((5-(bromomethyl)-2,2-dimethyl-1,3-dioxan-5-yl)methoxy)methyl)-2-(((2,2,5-trimethyl-1,3- dioxan-5-yl)methoxy)methyl)propane-1,3-diyl)bis(oxy))bis(methylene))bis(2,2,5-trimethyl-1,3-dioxane) 1 H NMR (CDCl3, 400 MHz): δ 3.73-3.63 (m, 12H), 3.57-3.49 (m, 10H),3.47 (s, 6H), 3.39 (s, 6H), 1.42 (s, 12H), 1.39 (s, 12H), 0.87 (s, 9H). 13 C NMR (CDCl3, 100 MHz): δ 98.0 (C×4), 74.6 (CH2×4), 71.8 (CH2×4), 66.6 (CH2×8), 65.9 (CH2), 63.3 (CH2), 45.7 (C), 35.1 (CH2), 34.6 (C×3), 26.4 (CH3×4), 21.3 (CH3×4), 18.5 (CH3×3).

[0265] [Synthesis of compound J148]

[0266]

[0267] In Synthesis Example 6 (2), R 5 Using J147 as -X, the target compound J148 was obtained. Chemical Formula: C 53 H 82 O 15(E)-5,5'-(((2-(((5-((4-(3,5-dimethoxystyryl)phenoxy)methyl)-2,2-dimethyl-1,3-dioxan-5-yl)methoxy)methyl)-2-(((2,2,5-trimethyl-1,3-dioxan-5-yl)methoxy)methyl)propane-1,3-diyl)bis(oxy))bis(methylene))bis(2,2,5-trimethyl-1,3-dioxane) 1 H NMR (CDCl3, 400 MHz): δ 7.43 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 16.0 Hz, 1H), 6.91 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 16.0 Hz, 1H), 6.63 (d, J = 2.4 Hz, 2H), 6.38 (brt, J = 2.4 Hz, 1H), 4.05 (s, 2H), 3.91-3.78 (m, 4H), 3.83 (s, 6H), 3.66 (d, J = 11.6 Hz, 6H), 3.48 (d, J = 11.6 Hz, 6H), 3.42 (s, 2H), 3.39 (s, 2H), 3.35 (s, 6H), 3.27 (s, 6H), 1.45 (s, 3H), 1.42 (s, 3H), 1.41 (s, 9H), 1.38 (s, 9H), 0.85 (s, 9H). 13C NMR (CDCl3, 100 MHz): δ 161.1 (C×2), 159.1 (C), 139.8 (C), 130.1 (C), 128.9 (CH), 127.9 (CH×2), 126.7 (CH), 114.9 (CH×2), 104.2 (CH×2), 99.8 (CH), 98.5 (C), 97.9 (C×3), 74.4 (CH2×3), 71.0 (CH2), 70.7 (CH2), 70.5 (CH2×3), 67.4 (CH2), 66.7 (CH2×6), 62.8 (CH2×2), 55.5 (CH3×2), 46.5 (C), 39.0 (C), 34.7 (C×3), 25.9 (CH3×3), 25.7 (CH3), 22.2 (CH3), 22.0 (CH3×3), 18.6 (CH3×3).

[0268] [Synthesis of compound J149]

[0269]

[0270] In Synthesis Example 7 (1), J148 was used as the compound obtained in Synthesis Example 6 to obtain the target compound J149. Chemical Formula: C 41 H 66 O 15 (E)-2,2'-(((2-((3-(4-(3,5-dimethoxystyryl)phenoxy)-2,2-bis(hydroxymethyl)propoxy)methyl)-2-((3-hydroxy-2-(h ydroxymethyl)-2-methylpropoxy)methyl)propane-1,3-diyl)bis(oxy))bis(methylene))bis(2-methylpropane-1,3-diol) 1H NMR (CD3OD, 400 MHz): δ 7.48 (d, J = 8.8 Hz, 2H), 7.08 (d, J = 16.0 Hz, 1H), 6.94 (d, J = 16.0 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 6.67 (d, J = 2.0 Hz, 2H), 6.36 (brt, J = 2.0 Hz, 1H), 3.98 (s, 2H), 3.79 (s, 6H), 3.70 (s, 4H), 3.51-3.33 (m, 22H), 3.21 (s, 6H), 0.84 (s, 9H). 13 C NMR (CD3OD, 100 MHz): δ 162.4 (C×2), 160.5 (C), 141.1 (C), 131.4 (C), 129.7 (CH), 128.9 (CH×2), 127.6 (CH), 115.8 (CH×2), 105.3 (CH×2), 100.4 (CH), 75.5 (CH2×3), 71.9 (CH2), 71.8 (CH2×2), 71.4 (CH2), 67.8 (CH2), 66.5 (CH2×7), 62.5 (CH2×2), 55.7 (CH3×2), 47.1 (C), 47.0 (C), 42.6 (C×3), 17.2 (CH3×3).

[0271] Example 15 [Synthesis of Compound J217: P １ G １ P ２ ]

[0272]

[0273] In Synthesis Example 1, R 1 Using H216 as -OH, the target compound J217 was obtained. Chemical Formula: C 25 H 41 BrO 11 1,3-bis((1-methyl-2,6,7-trioxabicyclo[2.2.2]octan-4-yl)methoxy)propan-2-ol 1H NMR (CDCl3, 400 MHz): δ 3.99 (s, 12H), 3.71 (dd, J = 12.0, 18.8 Hz, 4H), 3.56 (s, 2H), 3.53 (quin, J = 4.8 Hz, 1H), 3.50 (s, 2H), 3.40 (s, 2H), 3.39 (s, 2H), 3.21 (s, 4H), 1.46 (s, 6H), 1.41 (s, 3H), 1.40 (s, 3H). 13 C NMR (CDCl3, 100 MHz): δ 108.7 (C×2), 98.8 (C), 78.3 (CH), 71.3 (CH2×2), 70.1 (CH2×2), 69.5 (CH2×6), 69.4 (CH2), 63.9 (CH2×2), 38.5 (C), 35.7 (CH2), 35.1 (C×2), 24.2 (CH3), 23.6 (CH3×2), 23.3 (CH3).

[0274] [Synthesis of compound J218]

[0275]

[0276] In Synthesis Example 6 (2), R 5 Using J217 as -X, the target compound J218 was obtained. Chemical Formula: C 41 H 56 O 14 1H NMR (CDCl3, 400 MHz): δ 7.43 (d, J = 8.8 Hz, 2H), 7.04 (d, J = 16.0 Hz, 1H), 6.91 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 16.0 Hz, 1H), 6.65 (d, J = 2.4 Hz, 2H), 6.37 (brt, J = 2.4 Hz, 1H), 4.05 (s, 2H), 3.92-3.78 (m, 10H), 3.70-3.63 (m, 6H), 3.60 (quin, J = 5.2 Hz, 1H), 3.54-3.43 (m, 8H), 3.43-3.34 (m, 4H), 1.44 (s, 3H), 1.42 (s, 3H), 1.41 (s, 6H), 1.38 (s, 6H), 0.83 (s, 6H). 13 C NMR (CDCl3, 100 MHz): δ 161.0 (C×2), 159.0 (C), 139.8 (C), 130.0 (C), 128.9 (CH), 127.8 (CH×2), 126.6 (CH), 114.9 (CH×2), 104.4 (CH×2), 99.7 (CH), 98.4 (C), 97.9 (C×2), 78.7 (CH), 74.4 (CH2×2), 71.3 (CH2×2), 69.8 (CH2), 67.3 (CH2), 66.6 (CH2×2), 66.6 (CH2×2), 62.7 (CH2×2), 55.5 (CH3×2), 38.9 (C), 34.5 (C×2), 26.5 (CH3×2), 25.2 (CH3), 22.6 (CH3), 21.3 (CH3×2), 18.4 (CH3×2).

[0277] [Synthesis of compound J219]

[0278]

[0279] In Synthesis Example 7 (2), J218 was used as the compound obtained in Synthesis Example 6 to obtain the target compound J219. Chemical Formula: C 34 H 52 O 14(E)-2,2'-(((2-(3-(4-(3,5-dimethoxystyryl)phenoxy)-2,2-bis(hydroxymethyl)propoxy)propane-1,3-diyl)bis(oxy))bis(methylene))bis(2-(hydroxymethyl)propane-1,3-diol) 1 H NMR (CD3OD, 400 MHz): δ 7.48 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 16.4 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 16.4 Hz, 1H), 6.67 (d, J = 2.0 Hz, 2H), 6.36 (brt, J = 2.0 Hz, 1H), 3.99 (s, 2H), 3.80 (s, 6H), 3.76-3.72 (m, 2H), 3.72-3.69 (m, 4H), 3.62-3.54 (m, 13H), 3.54-3.48 (m, 4H),3.47-3.42 (m, 4H). 13 C NMR (CD3OD, 100 MHz): δ 162.4 (C×2), 160.4 (C), 141.1 (C), 131.4 (C), 129.7 (CH), 128.8 (CH×2), 127.5 (CH), 115.8 (CH×2), 105.3 (CH×2), 100.4 (CH), 79.6 (CH), 72.3 (CH2×2), 72.1 (CH2×2), 63.1 (CH2×8), 62.7 (CH2×2), 55.8 (CH3×2), 46.8 (C×2), 46.8 (C).

[0280] Example 16 [Synthesis of Compound J227: P １ G １ G ２ ]

[0281]

[0282] In Synthesis Example 1, R 1 Using A22 as -OH, the target compound J227 was obtained. Chemical Formula: C 23 H 41BrO9 5,5'-((2-((5-(bromomethyl)-2,2-dimethyl-1,3-dioxan-5-yl)methoxy)propane-1,3-diyl)bis(oxy))bis(2,2-dimethyl-1,3-dioxane) 1 H NMR (CDCl3, 400 MHz): δ 3.96 (dd, J = 4.0, 12.0 Hz, 4H), 3.82-3.68 (m, 8H), 3.63-3.50 (m, 9H), 3.44 (m, 2H), 1.44-1.39 (m, 18H). 13 C NMR (CDCl3, 100 MHz): δ 98.5 (C), 98.2 (C×2), 78.8 (CH), 71.0 (CH×2), 69.9 (CH), 68.7 (CH2×2), 63.8 (CH2×2), 62.6 (CH2×2), 62.5 (CH2×2), 38.5 (C), 36.0 (CH2), 24.2 (CH3×2), 24.2 (CH3), 23.1 (CH3), 23.1 (CH3×2).

[0283] [Synthesis of compound J228]

[0284]

[0285] In Synthesis Example 6 (2), R 5 Using J227 as -X, the target compound J228 was obtained. Chemical Formula: C 39 H 56 O 12 (E)-5,5'-((2-((5-((4-(3,5-dimethoxystyryl)phenoxy)methyl)-2,2-dimethyl-1,3-dioxan-5-yl)methoxy)propane-1,3-diyl)bis(oxy))bis(2,2-dimethyl-1,3-dioxane) 1H NMR (CDCl3, 400 MHz): δ 7.43 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 16.4 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 6.90 (d, J = 16.4 Hz, 2H), 6.64 (d, J = 2.4 Hz, 2H), 6.37 (brt, J = 2.4 Hz, 1H), 4.02 (s, 2H), 3.92-3.76 (m, 14H), 3.72-3.60 (m, 6H), 3.58-3.44 (m, 5H), 3.40-3.31 (m, 2H), 1.44 (s, 3H), 1.42 (s, 3H), 1.39 (s, 6H), 1.36 (s, 6H). 13 C NMR (CDCl3, 100 MHz): δ 161.0 (C×2), 158.9 (C), 139.8 (C), 130.2 (C), 128.8 (CH), 127.9 (CH×2), 126.7 (CH), 114.8 (CH×2), 104.4 (CH×2), 99.7 (CH), 98.5 (C), 98.3 (C×2), 79.1 (CH), 71.1 (CH×2), 69.6 (CH2), 68.6 (CH2×2), 67.1 (CH2), 62.7 (CH2×2), 62.7 (CH2×2), 62.6 (CH2×2), 55.4 (CH3×2), 39.0 (C), 24.7 (CH3), 24.2 (CH3×2), 23.2 (CH3×2), 23.1 (CH3).

[0286] [Synthesis of compound J229]

[0287]

[0288] In Synthesis Example 7 (1), J228 was used as the compound obtained in Synthesis Example 6 to obtain the target compound J229. Chemical Formula: C 30 H 44 O 12(E)-2,2'-((2-(3-(4-(3,5-dimethoxystyryl)phenoxy)-2,2-bis(hydroxymethyl)propoxy)propane-1,3-diyl)bis(oxy))bis(propane-1,3-diol) 1 H NMR (CD3OD, 400 MHz): δ 7.42 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 16.0 Hz, 1H), 6.95 (d, J = 16.0 Hz, 1H), 6.94 (d, J = 8.4 Hz, 2H), 6.67 (d, J = 2.0 Hz, 2H), 6.36 (brt, J = 2.0 Hz, 1H), 3.98 (s, 2H), 3.79 (s, 6H), 3.78-3.37 (m, 21H). 13 C NMR (CD3OD, 100 MHz): δ 162.3 (C×2), 160.3 (C), 140.9 (C), 131.3 (C), 129.6 (CH), 128.8 (CH×2), 127.4 (CH), 115.7 (CH×2), 105.3 (CH×2), 100.4 (CH), 82.9 (CH×2), 80.4 (CH), 70.5 (CH2×2), 70.3 (CH2), 67.6 (CH2), 63.1 (CH2×3), 62.4 (CH2×3), 55.7 (CH3×2), 47.8 (C).

[0289] Example 17 [Synthesis of Compound J237: P １ G １ A ２ ]

[0290]

[0291] In Synthesis Example 1, R 1 Using A23 as -OH, the target compound J237 was obtained. Chemical Formula: C 23 H 41BrO9 5-(((1,3-bis((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)propan-2-yl)oxy)methyl)-5-(bromomethyl)-2,2-dimethyl-1,3-dioxane 1 H NMR (CDCl3, 400 MHz): δ 4.30-4.20 (s, 2H), 4.09-4.01 (m, 2H), 3.83-3.43 (m, 19H), 1.42 (s, 6H), 1.41 (s, 6H), 1.36 (s, 6H). 13 C NMR (CDCl3, 100 MHz): δ 109.5 (C×2), 98.7 (C), 78.8 (CH), 74.8 (CH2×2), 72.6 (CH2×2), 71.7 (CH2), 71.5 (CH2), 70.0 (CH2), 66.9 (CH2×2), 63.9 (CH2×2), 38.7 (C), 36.2 (CH2), 26.9 (CH3×2), 25.6 (CH3×2), 24.4 (CH3), 23.1 (CH3).

[0292] [Synthesis of compound J238]

[0293]

[0294] In Synthesis Example 6 (2), R 5 Using J237 as -X, the target compound J238 was obtained. Chemical Formula: C 39 H 56 O 12 (E)-5-(((1,3-bis((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)propan-2-yl)oxy)methyl)-5-((4-(3,5-dimethoxystyryl)phenoxy)methyl)-2,2-dimethyl-1,3-dioxane 1H NMR (CDCl3, 400 MHz): δ 7.43 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 16.8 Hz, 1H), 6.91 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 16.8 Hz, 1H), 6.64 (d, J = 2.4 Hz, 2H), 6.37 (brt, J = 2.4 Hz, 1H), 4.24-4.13 (m, 2H), 4.03 (s, 2H), 4.01-3.94 (m, 2H), 3.88-3.77 (m, 12H), 3.72-3.62 (m, 3H), 3.62-3.36 (m, 8H), 1.44 (s, 3H), 1.43 (s, 3H), 1.40 (s, 6H), 1.34 (s,6H). 13 C NMR (CDCl3, 100 MHz): δ 161.0 (C×2), 159.0 (C), 139.7 (C), 130.1 (C), 128.8 (CH), 127.8 (CH×2), 126.7 (CH), 114.8 (CH×2), 109.4 (C×2), 104.4 (CH×2), 99.7 (CH), 98.4 (C), 78.8 (CH), 74.7 (CH×2), 72.6 (CH2×2), 71.6 (CH2), 71.4 (CH2), 69.6 (CH2), 67.1 (CH2), 66.7 (CH2×4), 62.7 (CH2×2), 55.5 (CH3×2), 39.0 (C), 26.9 (CH3×2), 25.5 (CH3×2), 24.9 (CH3), 22.9 (CH3).

[0295] [Synthesis of compound J239]

[0296]

[0297] In Synthesis Example 7 (1), J238 was used as the compound obtained in Synthesis Example 6 to obtain the target compound J239. Chemical Formula: C 30 H 44 O 12(E)-3,3'-((2-(3-(4-(3,5-dimethoxystyryl)phenoxy)-2,2-bis(hydroxymethyl)propoxy)propane-1,3-diyl)bis(oxy))bis(propane-1,2-diol) 1 H NMR (CD3OD, 400 MHz): δ 7.46 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 16.0 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 16.0 Hz, 1H), 6.67 (d, J = 2.0 Hz, 2H), 6.36 (brt, J = 2.0 Hz, 1H), 3.98 (s, 2H), 3.79 (s, 6H), 3.77-3.66 (m, 6H), 3.65-3.40 (m, 15H). 13 C NMR (CD3OD, 100 MHz): δ 162.4 (C×2), 160.4 (C), 141.1 (C), 131.4 (C), 129.7 (CH), 128.8 (CH×2), 127.5 (CH), 115.8 (CH×2), 105.3 (CH×2), 100.5 (CH), 79.9 (CH×2), 73.8 (CH2×2), 72.1 (CH2×2), 70.6 (CH), 67.7 (CH2), 64.4 (CH2×3), 62.6 (CH2×2), 55.8 (CH3×2), 46.8 (C).

[0298] Example 18 [Synthesis of Compound J247: P １ G １ T ２ ]

[0299]

[0300] In Synthesis Example 1, R 1 Using H246 as -OH, the target compound J247 was obtained. Chemical Formula: C 27 H 49BrO9 5,5'-(((2-((5-(bromomethyl)-2,2-dimethyl-1,3-dioxan-5-yl)methoxy)propane-1,3-diyl)bis(oxy))bis(methylene))bis(2,2,5-trimethyl-1,3-dioxane) 1 H NMR (CDCl3, 400 MHz): δ 3.81 (d, J = 12.4 Hz, 2H), 3.72 (d, J = 12.4 Hz, 2H), 3.73-3.39 (m, 21H), 1.43 (s, 6H), 1.40 (s, 6H), 1.39 (s, 6H), 0.87 (s, 6H). 13 C NMR (CDCl3, 100 MHz): δ 98.3 (C), 97.7 (C×2), 78.5 (CH), 74.2 (CH2×2), 71.5 (CH2×2), 69.8 (CH2), 66.4 (CH2×4), 63.7 (CH2×2), 38.4 (C), 36.1 (CH2), 34.3 (C×2), 26.4 (CH3×2), 24.6 (CH3), 22.6 (CH3), 21.1 (CH3×2), 18.2 (CH3×2).

[0301] [Synthesis of compound J248]

[0302]

[0303] In Synthesis Example 6 (2), R 5 Using J247 as -X, the target compound J248 was obtained. Chemical Formula: C 43 H 64 O 12 1H NMR (CDCl3, 400 MHz): δ 7.43 (d, J = 8.8 Hz, 2H), 7.04 (d, J = 16.0 Hz, 1H), 6.91 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 16.0 Hz, 1H), 6.65 (d, J = 2.4 Hz, 2H), 6.37 (brt, J = 2.4 Hz, 1H), 4.05 (s, 2H), 3.92-3.78 (m, 10H), 3.70-3.63 (m, 6H), 3.60 (quin, J = 5.2 Hz, 1H), 3.54-3.43 (m, 8H), 3.43-3.34 (m, 4H), 1.44 (s, 3H), 1.42 (s, 3H), 1.41 (s, 6H), 1.38 (s, 6H), 0.83 (s, 6H). 13 C NMR (CDCl3, 100 MHz): δ 161.0 (C×2), 159.0 (C), 139.8 (C), 130.0 (C), 128.9 (CH), 127.8 (CH×2), 126.6 (CH), 114.9 (CH×2), 104.4 (CH×2), 99.7 (CH), 98.4 (C), 97.9 (C×2), 78.7 (CH), 74.4 (CH2×2), 71.3 (CH2×2), 69.8 (CH2), 67.3 (CH2), 66.6 (CH2×2), 66.6 (CH2×2), 62.7 (CH2×2), 55.5 (CH3×2), 38.9 (C), 34.5 (C×2), 26.5 (CH3×2), 25.2 (CH3), 22.6 (CH3), 21.3 (CH3×2), 18.4 (CH3×2).

[0304] [Synthesis of compound J249]

[0305]

[0306] In Synthesis Example 7 (1), J248 was used as the compound obtained in Synthesis Example 6 to obtain the target compound J249. Chemical Formula: C 34 H 52 O 12(E)-2,2'-(((2-(3-(4-(3,5-dimethoxystyryl)phenoxy)-2,2-bis(hydroxymethyl)propoxy)propane-1,3-diyl)bis(oxy))bis(methylene))bis(2-methylpropane-1,3-diol) 1 H NMR (CD3OD, 400 MHz): δ 7.46 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 16.4 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 16.4 Hz, 1H), 6.67 (d, J = 2.0 Hz, 2H), 6.36 (brt, J = 2.0 Hz, 1H), 3.99 (s, 2H), 3.79 (s, 6H), 3.76-3.69 (m, 6H), , 3.66-3.54 (m, 1H), 3.51-3.46 (m, 4H), 3.46-3.41 (m, 8H), 3.33-3.30 (m, 4H), 0.85 (s, 6H). 13 C NMR (CD3OD, 100 MHz): δ 162.4 (C×2), 160.5 (C), 141.1 (C), 131.4 (C), 129.7 (CH), 128.8 (CH×2), 127.5 (CH), 115.8 (CH×2), 105.3 (CH×2), 100.4 (CH), 79.8 (CH), 75.4 (CH2×2), 72.3 (CH2×2), 70.7 (CH2), 67.7 (CH2), 66.4 (CH2×3), 66.3 (CH2×3), 55.7 (CH3×2), 46.8 (C), 42.5 (C×2), 17.1 (CH3×2).

[0307] Example 19 [Evaluation of Water Solubility] The deprotected pterostilbene conjugates obtained in the examples were evaluated for water solubility by the following method. The results are summarized in Figures 1 and 2. In Figures 1 and 2, the numbers in the ellipses for each compound represent the degree of water solubility as a molar ratio, with the water solubility of F1 (pterostilbene) (21 mg (0.0819 mmol) dissolved in 1 L) being taken as 1.0. The water solubility of F1 (pterostilbene) was determined using the value described in Sarah J. Bethune et al., Cryst. Growth Des. 2011, 11, 2817-2823. The water solubility of F1 glycoside (pterostilbene monoglycoside) was determined using the value described in Jose L. Gonzalez-Alfonso et al., Molecules 2018, 23, 1271.

[0308] [Compounds G119, G129, G139, H119, and H219] 1.0 g of the corresponding compound and 100 mL of ion-exchanged water were weighed into a round-bottom flask, and the mixture was heated with a heat gun for approximately 1 minute, taking care not to boil, and then allowed to stand at room temperature. After 24 hours, the residue was removed by filtration, and the filtrate was concentrated under reduced pressure. The water solubility of each compound was calculated from the weight of the compound recovered from the filtrate.

[0309] [Compounds H129, H139, J119, J129, J139, J219, J229, and J239] A solution was prepared in a round-bottom flask using the corresponding compound and the amount of ion-exchanged water shown in Figure 1, and the water solubility of the compound was calculated. Because the corresponding compounds were extremely water-soluble, the water solubility limit could not be measured, but compared to the poorly water-soluble F1, their water solubility was an order of magnitude higher at more than 2 x 10^4.

Claims

1. A branched multi-hydroxyl-protected oligomer represented by the following formula (1): [In formula (1), X is at least one selected from the group consisting of groups represented by the following formula (2), and Y ａ ~Y ｄ is at least one selected from the group consisting of P, T, G, and A represented by the following formula (3), m is 1, m' is an integer from 1 to 3, n is an integer from 0 to 9, and n' is an integer from 0 to 27 (provided that the compound represented by formula (1) is X-G １ G １ , X-G １ G ２ , X-G １ A １ and X-G １ A ２ (Except where [In formula (3), Z is at least one selected from the group consisting of a hydrogen atom, a protecting group, and a carbon skeleton; R ａ is at least one selected from the group consisting of a hydrogen atom and an alkyl group.

2. A branched multi-hydroxyl-protected oligomer represented by the following formula (1a): [In formula (1a), X is at least one selected from the group consisting of groups represented by the following formula (2), and Y ｂ ~Y ｄ is at least one selected from the group consisting of P, T, G, and A represented by the following formula (3), Z is at least one selected from the group consisting of a hydrogen atom, a protecting group, and a carbon skeleton, m is 1, m' is an integer from 1 to 3, n is an integer from 0 to 9, and n' is an integer from 0 to 27. [In formula (3), Z is at least one selected from the group consisting of a hydrogen atom, a protecting group, and a carbon skeleton; R ａ is at least one selected from the group consisting of a hydrogen atom and an alkyl group.

3. A branched multi-hydroxyl-protected oligomer represented by the following formula (1c): [In formula (1c), X is at least one selected from the group consisting of groups represented by the following formula (2), and Y ｂ ~Y ｄ is at least one selected from the group consisting of P, T, G, and A represented by the following formula (3), Z is at least one selected from the group consisting of a hydrogen atom, a protecting group, and a carbon skeleton, m is 1, m' is an integer of 1 to 3, n is an integer of 0 to 9, and n' is an integer of 0 to 27 (provided that the compound represented by formula (1c) is X-G １ G １ , X-G １ G ２ , X-G １ A １ and X-G １ A ２ (Except where [In formula (3), Z is at least one selected from the group consisting of a hydrogen atom, a protecting group, and a carbon skeleton; R ａ is at least one selected from the group consisting of a hydrogen atom and an alkyl group.

4. A linker comprising the branched multi-hydroxyl-protected oligomer according to any one of claims 1 to 3 and a target compound.

5. A linker obtained by deprotecting the branched multi-hydroxyl-protected oligomer according to claim 4.

6. A conjugate according to claim 4, wherein the target compound is a poorly water-soluble compound.

7. A water solubility enhancer comprising the branched multi-hydroxyl-protected oligomer according to any one of claims 1 to 3.

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