Process for production of macrolide compounds

Abstract

Disclosed herein are a method for producing pirandolide D and a crystal of a solvate of pirandolide D, the method comprising a step of reacting a compound represented by Formula (A1) with a compound represented by Formula (B1) in the presence of a metal catalyst to obtain a compound represented by Formula (C1) (in these formulae, (In the formula, X represents hydrogen, an optionally substituted boron group, an optionally substituted stannyl group, or an optionally substituted silyl group, R4 is hydrogen or the like, R5 is an optionally substituted benzoyl group or the like, and R1 and R2 are each independently hydrogen or the like). # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a method for producing pladienolide D, which is a macrolide-based natural product having antitumor activity, and a crystal of pladienolide D. Background Art

[0002] Pradinolide D represented by the following formula (1): It is a 12-membered ring compound based on macrolides with antitumor activity. The example of the main production method includes fermentation production using strains such as Streptomyces species Mer-11107 (patent document 1). However, in the production by fermentation, there are still problems in purification from the culture, it is difficult to separate high-purity pradinolide D, and the production volume is limited, which is not suitable for large-scale production. On the other hand, research by chemical total synthesis has also been carried out, and several reports have been carried out on the total synthesis of pradinolide D so far, but it is hoped that the production method will be further improved so as to carry out large-scale synthesis (patent document 2 and non-patent document 1). Pradinolide D is also used as a starting material for conversion into analogs having various antitumor activities (Patent Document 3). Therefore, it is expected to establish a production method that combines a synthetic route capable of synthesis with high yield and a purification method capable of stable quality control without using a silica gel column, and to establish a production method for pranolide D suitable for large-scale synthesis. Reference List Patent Literature

[0003] Patent document 1: WO 02 / 060890 A Patent Document 2: WO 2007 / 043621 A Patent Document 3: WO 2015 / 175594 A Non-patent literature

[0004] Non-patent document 1: Regina M. Kanada et al., "Total Synthesis of the Potent Antitumor Macrolides Pladienolide B and D", Angew. Chem. Int. Ed. [German Angewandte Chemie] 2007, 46, 4350-4355 Summary of the invention Technical issues

[0005] An object of the present invention is to provide an effective method for synthesizing pranolide D which has antitumor activity and is useful as a synthetic intermediate for antitumor agents. Solution to the problem

[0006] The present invention is as follows. [1] A method for producing pranidolactone D represented by formula (1): or a salt thereof, or a solvate thereof, The method comprises the following steps: Step 1-1) allows a compound represented by formula (A1): wherein X is hydrogen, optionally substituted boronyl, optionally substituted stannyl, or optionally substituted silyl, R 4 is hydrogen or a silyl protecting group, and R 5 is hydrogen, optionally substituted benzoyl, or a silyl protecting group, Reaction with a compound represented by formula (B1) in the presence of a metal catalyst: Where R 1 and R 2 are each independently hydrogen or a silyl protecting group, To obtain a compound represented by formula (C1): Where R 1 , R 2 and R 4 are each independently hydrogen or a silyl protecting group, and R 5 is hydrogen, optionally substituted benzoyl or a silyl protecting group; and Optionally, step 1-3) converting pranidolactone D into a solvate, Provided that when R in the compound represented by formula (C1) obtained in step 1-1 is 1 , R 2 , R 4 and R 5 When any one or more of is not hydrogen, the method further comprises the following steps: Step 1-2) One or more protecting groups of the compound represented by formula (C1) obtained in Step 1-1 are removed to obtain pranidolactone D after Step 1-1. [2] A method for producing pranidolactone D represented by formula (1): or a salt thereof, or a solvate thereof, The method comprises the following steps: Step 2-1) a compound represented by formula (A2): wherein X is hydrogen or an optionally substituted boron group, R 4 is hydrogen or a silyl protecting group, and R 5 is hydrogen or optionally substituted benzoyl, Reaction with a compound represented by formula (B1) in the presence of a metal catalyst: Where R 1 and R 2 are each independently hydrogen or a silyl protecting group, To obtain a compound represented by formula (C2): Where R 1 , R 2 and R 4 are each independently hydrogen or a silyl protecting group, and R 5 is hydrogen or optionally substituted benzoyl; Step 2-2) removing the protecting group of the compound represented by formula (C2) obtained in Step 2-1 to obtain pranidolactone D; and Optionally, step 2-3) converting the pranidolactone D obtained in step 2-2 into a solvate. [3] The method according to [2], wherein R 5 It's hydrogen. [4] The method according to [2] or [3], wherein R 5 It is 2,4-dinitrobenzoyl. [5] The method according to [2] or [3], wherein R 5 It is 3,5-dinitrobenzoyl. [6] The method according to any one of [2] to [5], wherein R 4 It's hydrogen. [7] The method according to any one of [2] to [6], wherein R 2 It's hydrogen. [8] The method according to any one of [2] to [7], wherein R 1 It's hydrogen. [9] The method according to any one of [2] to [7], wherein R 1 is a silyl protecting group.

[10] The method according to any one of [2] to [7], wherein R 1 By SiR 6 R 7 R 8 represents a silyl group, and R 6 , R 7 and R 8 Each is independently selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl and phenyl.

[11] The method according to any one of [2] to [7], wherein R 1 It is tert-butyl(dimethyl)silyl.

[12] The method according to any one of [2] to

[11] , wherein X is hydrogen.

[13] The method according to any one of [2] to

[11] , wherein X is an optionally substituted boron group.

[14] The method according to any one of [2] to

[11] , wherein X is boronic acid, pinacol borate or trifluoroborate.

[15] The method according to any one of [2] to

[14] , wherein the metal catalyst is a palladium catalyst.

[16] The method according to any one of [2] to

[14] , wherein the metal catalyst is palladium (II) acetate.

[17] The method according to any one of [2] to

[14] , wherein the metal catalyst is tris(dibenzylideneacetone)dipalladium(0).

[18] The method according to any one of [2] to

[14] , wherein the metal catalyst is (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II).

[19] The method according to any one of [2] to

[18] , wherein the step of removing the protecting group includes removal using an acid and removal using a base.

[20] The method according to any one of [2] to

[18] , wherein the step of removing the protecting group includes removal using fluoride ions and removal using a base.

[21] The method according to any one of [2] to

[18] , wherein the step of removing the protecting group comprises removal using a base.

[22] The method according to any one of [2] to

[18] , wherein the step of removing the protecting group comprises removal using fluoride ions.

[23] The method according to any one of [2] to

[18] , wherein the step of removing the protecting group comprises removing using lithium hydroxide.

[24] The method according to any one of [2] to

[18] , wherein the step of removing the protecting group comprises removing using tetrabutylammonium fluoride.

[25] The method according to any one of [2] to

[18] , wherein the step of removing the protecting group includes removal using tetrabutylammonium fluoride and removal using lithium hydroxide.

[26] A method for producing pranololide D represented by formula (1): or a salt thereof, or a solvate thereof, The method comprises the following steps: Step 3-1) allows a compound represented by formula (A1): wherein X is hydrogen, optionally substituted boronyl, optionally substituted stannyl, or optionally substituted silyl, R 4 and R 5 are each independently hydrogen, an optionally substituted benzoyl or a silyl protecting group, Reaction with a compound represented by formula (B2) in the presence of a metal catalyst: Where R 1 and R 2 are each independently hydrogen or a silyl protecting group, To obtain a compound represented by formula (C3): Where R 1 , R 2 and R 4 are each independently hydrogen or a silyl protecting group, and R 5 is hydrogen, optionally substituted benzoyl or a silyl protecting group; and Step 3-2) Acetylation of the hydroxyl group of the compound represented by formula (C3) obtained in step 3-1 to obtain a compound represented by formula (C1): Where R 1 , R 2 and R 4 are each independently hydrogen or a silyl protecting group, and R 5 is hydrogen, an optionally substituted benzoyl or a silyl protecting group, The condition is that when R 1 , R 2 , R 4 and R 5 When any one or more of is not hydrogen, The method further comprises the following steps: Step 3-3) One or more protecting groups of the compound represented by formula (C1) obtained in Step 3-2 are removed to obtain pranidolactone D.

[27] A method for producing pranololide D represented by formula (1): or a salt thereof, or a solvate thereof, The method comprises the following steps: Step 4-1) allows a compound represented by formula (A2): wherein X is hydrogen or an optionally substituted boron group, R 4 is hydrogen or a silyl protecting group, and R 5 is hydrogen or optionally substituted benzoyl, Reaction with a compound represented by formula (B2) in the presence of a metal catalyst: Where R 1 and R 2 are each independently hydrogen or a silyl protecting group, To obtain a compound represented by formula (C4): Where R 1 , R 2 and R 4 are each independently hydrogen or a silyl protecting group, and R 5 is hydrogen or optionally substituted benzoyl; Step 4-2) Acetylation of the hydroxyl group of the compound represented by formula (C4) obtained in step 4-1 to obtain a compound represented by formula (C2): Where R 1 , R 2 and R 4 are each independently hydrogen or a silyl protecting group, and R 5 is optionally substituted benzoyl; step 4-3) removing one or more protecting groups of the compound represented by formula (C2) obtained in step 4-2 to obtain pranidolactone D; and Optionally, step 4-4) converting the pranidolactone D obtained in step 4-3 into a solvate.

[28] The method according to

[27] , wherein R 5 It's hydrogen.

[29] The method according to

[27] or

[28] , wherein R 5It is 2,4-dinitrobenzoyl.

[30] The method according to

[27] or

[28] , wherein R 5 It is 3,5-dinitrobenzoyl.

[31] The method according to any one of

[27] to

[30] , wherein R 4 It's hydrogen.

[32] The method according to any one of

[27] to

[31] , wherein R 2 It's hydrogen.

[33] The method according to any one of

[27] to

[32] , wherein R 1 It's hydrogen.

[34] The method according to any one of

[27] to

[32] , wherein R 1 is a silyl protecting group.

[35] The method according to any one of

[27] to

[32] , wherein R 1 By SiR 6 R 7 R 8 represents a silyl group, and R 6 , R 7 and R 8 Each is independently selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl and phenyl.

[36] The method according to any one of

[27] to

[32] , wherein R 1 It is tert-butyl(dimethyl)silyl.

[37] The method according to any one of

[27] to

[36] , wherein X is hydrogen.

[38] The method according to any one of

[27] to

[36] , wherein X is an optionally substituted boron group.

[39] The method according to any one of

[27] to

[36] , wherein X is boronic acid, pinacol borate or trifluoroborate.

[40] The method according to any one of

[27] to

[39] , wherein the metal catalyst is a palladium catalyst.

[41] The method according to any one of

[27] to

[39] , wherein the metal catalyst is palladium (II) acetate.

[42] The method according to any one of

[27] to

[39] , wherein the metal catalyst is tris(dibenzylideneacetone)dipalladium(0).

[43] The method according to any one of

[27] to

[39] , wherein the metal catalyst is (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II).

[44] The method according to any one of

[27] to

[43] , wherein the step of removing one or more protecting groups comprises removal using an acid and removal using a base.

[45] The method according to any one of

[27] to

[43] , wherein the step of removing one or more protecting groups comprises removal using fluoride ions and removal using a base.

[46] The method according to any one of

[27] to

[43] , wherein the step of removing one or more protecting groups comprises removal using a base.

[47] The method according to any one of

[27] to

[43] , wherein the step of removing one or more protecting groups comprises removal using fluoride ions.

[48] ​​The method according to any one of

[27] to

[43] , wherein the step of removing one or more protecting groups comprises removal using lithium hydroxide.

[49] The method according to any one of

[27] to

[43] , wherein the step of removing one or more protecting groups comprises removing using tetrabutylammonium fluoride.

[50] The method according to any one of

[27] to

[43] , wherein the step of removing one or more protecting groups comprises removal using tetrabutylammonium fluoride and removal using lithium hydroxide.

[51] The method according to any one of [1] to

[50] , wherein the pranidolactone D or its salt or solvate is pranidolactone D 2-methyltetrahydrofuran solvate.

[52] A method for producing a compound represented by formula (B3): or a salt thereof, Where R 1 and R 2 are each independently a silyl protecting group, The method comprises the following steps: Step 5-1) In a compound represented by formula (D1): and a compound represented by formula (D2): Where R 1 and R 2 are each independently a silyl protecting group, To obtain a compound represented by formula (D3): Where R 1 and R 2 each independently is a silyl protecting group; Step 5-2) The p-methoxybenzyl (MPM) group is removed from the compound represented by formula (D3) obtained in step 5-1 to obtain a compound represented by formula (D4): Where R 1 and R 2 are each independently a silyl protecting group; and Step 5-3) The compound represented by the formula (D4) obtained in Step 5-2 is reacted in the presence of a ruthenium catalyst to obtain a compound represented by the formula (B3).

[53] A compound represented by formula (C5): or a salt thereof, Where R 1 , R 2 and R 4 Each is independently hydrogen or a silyl protecting group.

[54] A compound represented by formula (C6): or a salt thereof, Where R 1 , R 2 and R 4 Each is independently hydrogen or a silyl protecting group.

[55] A compound represented by formula (C7): or a salt thereof, wherein X is hydrogen or an optionally substituted boron group and R 4 is hydrogen or a silyl protecting group.

[56] A compound represented by formula (C8): or a salt thereof, wherein X is hydrogen or an optionally substituted boron group and R 4 is hydrogen or a silyl protecting group.

[57] A crystal of pranidolactone D toluene solvate represented by formula (1a):

[58] The crystal according to

[57] , which has one or more diffraction peaks in powder X-ray diffraction at a diffraction angle (2θ±0.2°) selected from the following group, the group consisting of: 3.6°, 6.8°, 7.8°, 8.7°, 15.4°, 16.6°, 17.8° and 18.3°.

[59] A crystal of prandilactone D chlorobenzene solvate represented by formula (1b):

[60] The crystal according to

[59] , which has one or more diffraction peaks in powder X-ray diffraction at a diffraction angle (2θ±0.2°) selected from the following group, the group consisting of: 3.6°, 7.8°, 15.4°, 16.2°, 16.6°, 17.9°, 18.3°, 20.4°, 21.3° and 21.7°.

[61] A crystal of pranidolactone D tetrahydrofuran solvate represented by formula (1c):

[62] The crystal according to

[61] , which has one or more diffraction peaks in powder X-ray diffraction at a diffraction angle (2θ±0.2°) selected from the following group, the group consisting of: 9.4°, 10.8°, 11.2°, 14.5°, 15.1°, 18.1°, 19.3°, 19.8°, 21.6° and 22.8°.

[63] A crystal of 2-methyltetrahydrofuran solvate of pranidolactone D represented by formula (1d):

[64] The crystal according to

[63] , which has one or more diffraction peaks in powder X-ray diffraction at a diffraction angle (2θ±0.2°) selected from the following group, the group consisting of: 10.3°, 10.7°, 11.7°, 13.3°, 14.4°, 17.2°, 18.9°, 21.2°, 22.5° and 23.4°.

[65] The crystal according to

[63] , which has a diffraction peak at a diffraction angle (2θ±0.2°) of 18.9° in powder X-ray diffraction.

[66] The crystal according to

[63] , which has diffraction peaks at diffraction angles (2θ±0.2°) of 10.7°, 14.4° and 18.9° in powder X-ray diffraction.

[67] The crystal according to

[63] , which has diffraction peaks at diffraction angles (2θ±0.2°) of 10.7°, 14.4°, 17.2°, 18.9° and 21.2° in powder X-ray diffraction.

[68] The crystal according to

[63] , which has diffraction peaks at diffraction angles (2θ±0.2°) of 10.3°, 10.7°, 11.7°, 13.3°, 14.4°, 17.2°, 18.9°, 21.2°, 22.5° and 23.4° in powder X-ray diffraction.

[69] The crystal according to

[63] , wherein the powder X-ray pattern of the crystal in powder X-ray diffraction is substantially the same as Figure 4 The powder X-ray diffraction pattern is the same as shown in .

[70] A crystal according to any one of

[63] to

[69] , wherein the crystal is in the solid state 13 In the CNMR spectrum, there is one or more peaks at a chemical shift (δ±0.5ppm) selected from the group consisting of: 9.1ppm, 10.0ppm, 10.5ppm, 16.2ppm, 21.4ppm, 23.9ppm, 24.2ppm, 25.4ppm, 26.8ppm, 28.0ppm, 28.5ppm, 33.3ppm, 33.7ppm, 35.9ppm, 39.9ppm, 41.1ppm , 42.7ppm, 45.7ppm, 56.0ppm, 59.3ppm, 67.9ppm, 70.4ppm, 72.6ppm, 76.5ppm, 77.7ppm, 83.0ppm, 124. 0ppm, 124.4ppm, 128.0ppm, 130.2ppm, 134.4ppm, 139.1ppm, 141.0ppm, 141.3ppm, 166.9ppm and 170.4ppm.

[71] The crystal according to any one of

[63] to

[69] , which is in the solid state 13 In the CNMR spectrum, there is a peak at a chemical shift (δ±0.5 ppm) of 72.6 ppm.

[72] A crystal according to any one of

[63] to

[69] , wherein the crystal is in the solid state 13 In the CNMR spectrum, there are peaks at chemical shifts (δ±0.5 ppm) of 72.6 ppm, 134.4 ppm, and 170.4 ppm.

[73] The crystal according to any one of

[63] to

[69] , which is in the solid state 13 In the CNMR spectrum, there are peaks at chemical shifts (δ±0.5 ppm) of 21.4 ppm, 70.4 ppm, 72.6 ppm, 134.4 ppm, and 170.4 ppm.

[74] The crystal according to any one of

[63] to

[69] , which is in the solid state 13 In the CNMR spectrum, there are peaks at chemical shifts (δ±0.5 ppm) of 16.2 ppm, 21.4 ppm, 67.9 ppm, 70.4 ppm, 72.6 ppm, 76.5 ppm, 77.7 ppm, 134.4 ppm, 166.9 ppm, and 170.4 ppm.

[75] The crystal according to any one of

[63] to

[69] , which is in the solid state 13 In the CNMR spectrum, there are peaks at chemical shifts (δ±0.5ppm) of 10.0ppm, 16.2ppm, 21.4ppm, 56.0ppm, 59.3ppm, 67.9ppm, 70.4ppm, 72.6ppm, 76.5ppm, 77.7ppm, 83.0ppm, 128.0ppm, 130.2ppm, 134.4ppm, 139.1ppm, 166.9ppm and 170.4ppm.

[76] A crystal according to any one of

[63] to

[69] , wherein the crystal is in the solid state 13 In the C NMR spectrum, there are peaks at chemical shifts (δ±0.5ppm) of 9.1ppm, 10.0ppm, 10.5ppm, 16.2ppm, 21.4ppm, 23.9ppm, 24.2ppm, 25.4ppm, 26.8ppm, 28.0ppm, 28.5ppm, 33.3ppm, 33.7ppm, 35.9ppm, 39.9ppm, 41.1ppm, 42.7ppm, 45.7ppm, 56.0ppm, 59.3ppm, 67.9ppm, 70.4ppm, 72.6ppm, 76.5ppm, 77.7ppm, 83.0ppm, 124.0ppm, 124.4ppm, 128.0ppm, 130.2ppm, 134.4ppm, 139.1ppm, 141.0ppm, 141.3ppm, 166.9ppm and 170.4ppm.

[77] The crystal according to any one of

[63] to

[69] , which is in the solid state 13 In the CNMR spectrum, its solid state 13 CNMR spectrum is basically Figure 5 The solid state shown 13 The C NMR spectra were identical. Advantageous Effects of the Invention

[0007] The present invention provides a method for producing a macrolide-based compound pradinolide D having antitumor activity, a synthetic intermediate for producing pradinolide D, and a crystal of a solvate of pradinolide D. The production method of the present invention can provide high-quality pradinolide D with good reproducibility and is also suitable for large-scale production. In the production method of the present invention, pradinolide D or a solvate thereof can be obtained as a solid due to the synthetic intermediate, and thus purification by crystallization becomes possible, so that high-purity pradinolide D or a solvate thereof can be produced by removing impurities. BRIEF DESCRIPTION OF THE DRAWINGS

[0008] Figure 1 This is a powder X-ray diffraction pattern of the crystals of pranidolactone D toluene solvate obtained in Example D-2. The horizontal axis represents the diffraction angle (2θ), and the vertical axis represents the peak intensity. Figure 2 This is a powder X-ray diffraction pattern of the crystal of pradinolide D chlorobenzene solvate obtained in Example D-3. The horizontal axis represents the diffraction angle (2θ), and the vertical axis represents the peak intensity. Figure 3 This is a powder X-ray diffraction pattern of the crystals of pranidolactone D tetrahydrofuran solvate obtained in Example D-4. The horizontal axis represents the diffraction angle (2θ), and the vertical axis represents the peak intensity. Figure 4 This is a powder X-ray diffraction pattern of the crystals of pranidolactone D 2-methyltetrahydrofuran solvate obtained in Example D-6. The horizontal axis represents the diffraction angle (2θ), and the vertical axis represents the peak intensity. Figure 5 It is the solid state of the crystals of pranidolactone D 2-methyltetrahydrofuran solvate obtained in Example D-6 13 CNMR spectrum. The horizontal axis represents chemical shift (δ), and the vertical axis represents peak intensity. Figure 6 This is a thermal analysis TG-DTA chart of the crystals of pradinolide D toluene solvate obtained in Example D-2. The horizontal axis represents temperature, the left vertical axis represents weight change in TG, and the right vertical axis represents heat flow in DTA. Figure 7 This is a thermal analysis TG-DTA chart of the crystals of pradinolide D chlorobenzene solvate obtained in Example D-3. The horizontal axis represents temperature, the left vertical axis represents weight change in TG, and the right vertical axis represents heat flow in DTA. Figure 8 This is a thermal analysis TG-DTA chart of the crystals of pranidolactone D tetrahydrofuran solvate obtained in Example D-4. The horizontal axis represents temperature, the left vertical axis represents weight change in TG, and the right vertical axis represents heat flow in DTA. Fig. 9 This is a thermal analysis TG-DTA chart of the crystals of pranidolactone D 2-methyltetrahydrofuran solvate obtained in Example D-6. The horizontal axis represents temperature, the left vertical axis represents weight change in TG, and the right vertical axis represents heat flow in DTA. DETAILED DESCRIPTION

[0009] Hereinafter, the meanings of symbols, terms, etc. described in this specification will be described, and the present invention will be described in detail.

[0010] In this specification, for convenience, the structural formula of the compound is not limited to the description of the formula, and a salt may be formed or may be a solvate. In addition, there may be a crystal polymorph, but the crystal form is not limited in the same manner and may be any single crystal form or a mixture of crystal forms, and may partially contain an amorphous form. These are all covered by the present invention.

[0011] In the present specification, examples of the “salt” of the compound include alkali metal salts (such as lithium salts, sodium salts and potassium salts) and alkaline earth metal salts (such as magnesium salts and calcium salts).

[0012] In this specification, "solvate" refers to a molecular species formed by combining a compound or its salt with a solvent molecule, and includes hydrates. Examples of solvents forming solvates include water, hexane, heptane, methyl acetate, ethyl acetate, isopropyl acetate, 1,4-dioxane, methylene chloride, ethylene dichloride, chloroform, carbon tetrachloride, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, acetonitrile, acetone, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, benzene, toluene, anisole, cumene, chlorobenzene and trifluorobenzene. The number of solvent molecules relative to the compound or its salt is not particularly limited, and can be, for example, one molecule or two molecules.

[0013] The present invention also encompasses isotopically labeled compounds of the compounds described herein and methods of production using these compounds. Isotopically labeled compounds are identical to the compounds described herein except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Isotopes that can be incorporated into the compounds according to the present invention are isotopes of hydrogen, carbon, nitrogen, oxygen and fluorine that make up the compound, and include 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 O. 18 F, etc.

[0014] In the present specification, "optionally substituted boron group" includes boric acid, boric acid ester, trifluoroborate, triol borate, etc. Trifluoroborate and triol borate can be stabilized with a counter cation. Examples of the optionally substituted boron group include groups having the following structures. In the chemical formulae in the present specification, preferred examples of the "optionally substituted boron group" in X include boric acid, pinacol borate and trifluoroborate, and more preferred examples include pinacol borate.

[0015] In the present specification, "optionally substituted stannyl" refers to a substituted or unsubstituted stannyl group, including tin (IV). Examples of the optionally substituted stannyl group include tri(n-butyl)stannyl.

[0016] In the present specification, "optionally substituted silyl" refers to a substituted or unsubstituted silyl group. Examples of the optionally substituted silyl include hydroxy(dimethyl)silyl, benzyl(dimethyl)silyl and trimethoxysilyl.

[0017] In the present specification, "optionally substituted benzoyl" refers to a benzoyl group which may have a substituent on the benzene ring. The optionally substituted benzoyl group serves as a protective group for the hydroxyl group in the synthesis step and can be removed by hydrolysis using a base. Examples of the optionally substituted benzoyl group include substituents having the following structures. In the chemical formulae of this specification, R 5 Preferred examples of the "optionally substituted benzoyl group" include 2,4-dinitrobenzoyl and 3,5-dinitrobenzoyl. The optionally substituted benzoyl group may be 2,4-dinitrobenzoyl on one hand, and 3,5-dinitrobenzoyl on the other hand. When the optionally substituted benzoyl group is 3,5-dinitrobenzoyl, it is easy to obtain a synthetic intermediate for producing pranolide D as a solid, so that a high-purity intermediate and pranolide D can be easily obtained by recrystallization, crystallization, etc.

[0018] In this specification, a "silyl protecting group" refers to a protecting group for a hydroxyl group in which silicon is directly bonded to the hydroxyl group, and may be any group commonly used in organic synthesis. For example, the silyl protecting groups for hydroxyl groups described in Greene's Protective Groups In Organic Synthesis (4th edition, Wuts Peter GM et al.) may be used. A silyl protecting group is, for example, a hydroxyl protecting group consisting of SiR 6 R 7 R 8 represents a silyl group, and R 6 , R 7 and R 8Each independently selected from the group consisting of: methyl, ethyl, isopropyl, tert-butyl and phenyl. The example of silyl protecting group includes trimethylsilyl (TMS), triethylsilyl (TES), diethyl (isopropyl) silyl (DEIPS), triisopropylsilyl (TIPS), tert-butyl (dimethyl) silyl (TBS) and tert-butyl (diphenyl) silyl (TBDPS). In the chemical formulae of this specification, R 1 The "silyl protecting group" in R may preferably be TES, DEIPS, TBS, TIPS or TBDPS, and may preferably be TBS, TIPS or TBDPS. 1 The silyl protecting group in can be TES in one aspect, TBS in another aspect, TIPS in another aspect, and TBDPS in still another aspect. In the chemical formulae of this specification, R 2 The "silyl protecting group" in R may preferably be TMS, TES, DEIPS, TBS or TIPS, and may more preferably be TES, TBS or TIPS. 2 The silyl protecting group in can be TMS in one aspect, TES in another aspect, TBS in another aspect, and TIPS in still another aspect. In the chemical formulae of this specification, R 4 The "silyl protecting group" in R may preferably be TES, TBS, TIPS or TBDPS, and may more preferably be TES, TBS or TIPS. 4 The silyl protecting group in can be TES in one aspect, TBS in another aspect, TIPS in another aspect, and TBDPS in still another aspect.

[0019] The conditions and reagents that can be used to remove the protecting group in the method of the present disclosure depend on the type of protecting group, and for example, the conditions and reagents for removing various protecting groups described in Greene's Protective Groups In Organic Synthesis (4th edition, Wuts Peter G. M. et al.) can be used. As the conditions and reagents for removing the protecting group, a plurality of conditions and reagents can be used simultaneously or in stages according to different protecting groups.

[0020] When the protecting group to be removed is a "silyl protecting group", for example, an acid such as hydrochloric acid, bromic acid, trifluoroacetic acid (TFA), p-toluenesulfonic acid, pyridinium p-toluenesulfonate (PPTS) or camphorsulfonic acid (CSA) can be used, or a fluoride ion can be used to remove the protecting group, and as a fluoride ion source, for example, tetrabutylammonium fluoride (TBAF), pyridine hydrofluoride, triethylamine trihydrogen fluoride, tris(dimethylamino)sulfonium difluorotrimethylsilicic acid (TASF), ammonium fluoride, potassium fluoride, cesium fluoride, etc. can be used. Preferred examples of acids include hydrochloric acid, p-toluenesulfonic acid, and pyridinium p-toluenesulfonate (PPTS). The fluoride ion source can preferably be tetrabutylammonium fluoride (TBAF).

[0021] When the protecting group to be removed is an "optionally substituted benzoyl group", the protecting group can be removed using, for example, a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate, and can be removed by hydrolysis using a base. The base may preferably be lithium hydroxide or sodium hydroxide.

[0022] When the protecting group to be removed is a "dinitrobenzoyl group" and is selected from the group consisting of R 1 , R 2 and R 4 When one or more of the group consisting of is a silyl protecting group, in addition to the removal using a base, tetrabutylammonium fluoride can be used to simultaneously remove the dinitrobenzoyl group and the one or more silyl protecting groups. Examples of the dinitrobenzoyl group include a 2,4-dinitrobenzoyl group, a 3,5-dinitrobenzoyl group, and a 2,5-dinitrobenzoyl group.

[0023] In the case of removing the silyl protecting group and optionally substituted benzoyl, in the step of removing the protecting group, the removal using the acid or fluoride ion for removing the silyl protecting group and the removal using the base can be carried out simultaneously or in stages. One aspect of the multiple removals that can be carried out in stages can be to remove using acid and to remove using base. One aspect of the multiple removals that can be carried out simultaneously or in stages can be to remove using fluoride ions and to remove using base. Another specific aspect can be to remove using tetrabutylammonium fluoride and to remove using lithium hydroxide, and still another specific aspect can be to remove using tetrabutylammonium fluoride and to remove using sodium hydroxide.

[0024] In the method of the present disclosure, the acetylation step can be carried out by any method capable of acetylation of hydroxyl groups, and examples of reagents that can be used for acetylation (hereinafter also referred to as "acetylation reagents") include reagents capable of acetylation alone, reagents capable of causing reaction with a base, and reagents capable of acetylation by condensation. Examples of acetylation reagents include acetic acid, acetic anhydride, acetyl chloride and acetyl bromide, and the acetylation reagent may preferably be acetic anhydride or acetyl chloride, and the acetylation reagent may preferably be acetic anhydride.

[0025] Examples of the "base" that can be used together with the "acetylating agent" include triethylamine, diisopropyl(ethyl)amine, pyridine and 4-(dimethylamino)pyridine.

[0026] In this specification, "metal catalyst" refers to a transition metal catalyst used in a coupling reaction such as a Suzuki coupling reaction, a Heck reaction, a Stiller coupling reaction or a Hiama coupling reaction, and can also be used together with a ligand. Examples of "metal catalysts" include palladium catalysts, nickel catalysts, iron catalysts, copper catalysts, rhodium catalysts, iridium catalysts and gold catalysts. The metal catalyst can be any metal catalyst commonly used in organic synthesis, and commercially available metal catalysts can be used.

[0027] In the present specification, examples of the “palladium catalyst” include tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), palladium(II) acetate, palladium(II) chloride, bis(triphenylphosphine)palladium(II) dichloride, dichlorobis(benzonitrile)palladium(II), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II), and [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)dichloropalladium(II).

[0028] Examples of "ligands" that can be used together with the "metal catalyst" include XPhos (2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl), Amphos (di-tert-butyl(4-dimethylaminophenyl)phosphine), SPhos (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl), Xantphos (4,5'-bis(diphenylphosphino)-9,9'-dimethylxanthene), BrettPhos (2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl) and RuPhos (2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl). Catalysts in which such ligands are combined with transition metals (e.g., palladium) are commercially available and can be used as the "metal catalyst".

[0029] The coupling reaction using a "metal catalyst" can be carried out together with a "base". Examples of the "base" used in the coupling reaction include sodium carbonate, potassium carbonate, cesium carbonate, silver (I) carbonate, trisodium phosphate, tripotassium phosphate, sodium acetate, potassium acetate, silver (I) acetate, silver (I) oxide, triethylamine, diisopropyl (ethyl) amine, sodium hydroxide, sodium tert-butoxide, and potassium tert-butoxide.

[0030] In this specification, "ruthenium catalyst" refers to a ruthenium catalyst used for performing a cross metathesis reaction or a ring-closing metathesis reaction. Examples of ruthenium catalysts include Grubbs-II ((1,3-bis (2,4,6-trimethylphenyl) -2-imidazolidinylidene) dichloro (phenylmethylene) (tricyclohexylphosphine) ruthenium) and Hoveyda-Grubbs-II ((1,3-bis- (2,4,6-trimethylphenyl) -2-imidazolidinylidene) dichloro (o-isopropoxyphenylmethylene) ruthenium). The ruthenium catalyst can be Grubbs-II ((1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium) on the one hand and Hoveyda-Grubbs-II ((1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)ruthenium) on the other hand.

[0031] Step 1-1, step 2-1, step 3-1 and step 4-1 are steps of coupling reaction under a metal catalyst. The above-mentioned metal catalyst can be used, and the amount of the metal catalyst is not particularly limited, and relative to the compound represented by formula (B1) or formula (B2) as the starting material, for example, 0.01 to 0.2 equivalents can be used. In addition, the reaction can be carried out with a ligand, and for the ligand, the above-mentioned ligand can be used, and the amount of the ligand is not particularly limited, and relative to the compound represented by formula (B1) or formula (B2) as the starting material, for example, 0.01 to 0.2 equivalents can be used. In addition, the reaction can be carried out with a base, and the above-mentioned base can be used as a base, and the amount of the base is not particularly limited, and relative to the compound represented by formula (B1) or formula (B2) as the starting material, for example, 1 to 5 equivalents can be used. The solvent in the coupling reaction is not particularly limited, as long as it dissolves the starting material and does not inhibit the reaction, and can use, for example, water, acetonitrile, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, toluene, etc., or a mixed solvent thereof. The reaction temperature generally varies depending on the starting material, the solvent, and other reagents used in the reaction, and ranges from room temperature to the boiling point of the solvent, preferably from room temperature to 100 ° C. When the reaction temperature exceeds the boiling point of the solvent, heating under reflux can be performed. The reaction time can be set to the time when the starting material disappears by stirring, and can be, for example, 1 hour to 24 hours.

[0032] In the compounds represented by formula (A1) and formula (A2), when X is hydrogen, the metal catalyst may preferably be palladium (II) acetate. The base may preferably be silver carbonate (I) or silver acetate (I), and may more preferably be silver carbonate (I). On the one hand, the metal catalyst is palladium (II) acetate and the base is silver carbonate (I), and on the other hand, the metal catalyst is palladium (II) acetate and the base is silver acetate (I). The reaction temperature is preferably 40°C to 100°C, and more preferably 60°C to 80°C.

[0033] In the compounds represented by formula (A1) and (A2), when X is an optionally substituted boron group, the metal catalyst may preferably be (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) or tris(dibenzylideneacetone)dipalladium(0), and may more preferably be (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II). The base may be silver(I) oxide. In one aspect, the metal catalyst is (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) and the base is silver(I) oxide, and in another aspect, the metal catalyst is tris(dibenzylideneacetone)dipalladium(0) and basic silver(I) oxide. The reaction temperature is preferably room temperature to 60°C, and more preferably room temperature.

[0034] Step 1-2, step 2-2, step 3-3 and step 4-3 are steps for removing protecting groups, and are steps for removing silyl protecting groups and optionally substituted benzoyl groups. The above conditions and reagents can be used for removing protecting groups. Depending on the type of protecting groups of starting materials, protecting groups can be removed simultaneously or in stages. When the suitable conditions and reagents for removing between the optionally substituted benzoyl and the silyl protecting groups are different, this step can also be carried out in stages, and the silyl protecting groups can be removed after removing the optionally substituted benzoyl, and the optionally substituted benzoyl can be removed after removing the silyl protecting groups. When removing protecting groups in stages, after completing the removal of one of the optionally substituted benzoyl and silyl protecting groups, the reaction can be carried out by adding acid, alkali, fluoride ion source etc., and the reaction corresponds to the conditions for removing another protecting group in the reaction system, and after the removal of a protecting group is completed, the reaction is stopped to separate the crude product containing the synthetic intermediate, and purified as required, and then another protecting group can be removed. When the optionally substituted benzoyl and silyl protecting groups are simultaneously removable, the desired product can be obtained by subjecting them to one reaction condition.

[0035] In the case of removing the silyl protecting group, the above-mentioned acid or fluoride ion source can be used to remove the protecting group. In the case of using an acid, relative to the compound represented by formula (C1) or formula (C2) as starting material, for example 0.05 to 5 equivalents can be used, although this depends on the number of silyl protecting groups and changes. In the case of using a fluoride ion source, relative to the compound represented by formula (C1) or formula (C2) as starting material, for example 1 to 10 equivalents can be used, although this depends on the number of silyl protecting groups and changes. The acid can preferably be hydrochloric acid, p-toluenesulfonic acid or pyridinium p-toluenesulfonate (PPTS), and the fluoride ion source can preferably be tetrabutylammonium fluoride. The solvent in the removal of the silyl protecting group is not particularly limited as long as it dissolves the starting material and does not inhibit the reaction, and can use, for example, water, methanol, ethanol, acetonitrile, methylene chloride, chloroform, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, toluene, etc., or a mixed solvent thereof. The reaction temperature generally varies depending on the starting material, the solvent, and other conditions and reagents used in the reaction, and ranges from room temperature to the boiling point of the solvent, preferably from room temperature to 40°C, and more preferably room temperature. The reaction time can be set to the time when the starting material disappears by stirring, and can be, for example, 1 hour to 24 hours.

[0036] In the case of removing an optionally substituted benzoyl group, the base mentioned in the above conditions for removing an optionally substituted benzoyl group can be used to remove the protective group, and the amount of the base is not particularly limited, and can be used, for example, in an amount of 1 to 5 equivalents relative to the compound represented by formula (C1) or formula (C2) as a starting material. The base may preferably be lithium hydroxide or sodium hydroxide. The solvent in removing the optionally substituted benzoyl group is not particularly limited as long as it dissolves the starting material and does not inhibit the reaction, and can use, for example, water, methanol, ethanol, acetonitrile, methylene chloride, chloroform, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, toluene, etc., or a mixed solvent thereof. The reaction temperature generally varies depending on the starting material, the solvent, and other conditions and reagents used in the reaction, and ranges from room temperature to the boiling point of the solvent, preferably from room temperature to 40°C, and more preferably room temperature. The reaction time can be set to the time when the starting material disappears by stirring, and can be, for example, 1 hour to 24 hours.

[0037] When the silyl protecting group and the optionally substituted benzoyl are removed in stages, in one aspect of the step of removing the protecting group, an acid is used for removal and then a base is used for removal, and in another aspect, a fluoride ion is used for removal and then a base is used for removal, and in another aspect, a base is used for removal and then an acid is used for removal, and in still another aspect, a base is used for removal and then a fluoride ion is used for removal. In another aspect, tetrabutylammonium fluoride is used for removal and then lithium hydroxide is used for removal, and in still another aspect, lithium hydroxide is used for removal and then tetrabutylammonium fluoride is used for removal. In another aspect, tetrabutylammonium fluoride is used for removal and then sodium hydroxide is used for removal, and in still another aspect, sodium hydroxide is used for removal and then tetrabutylammonium fluoride is used for removal.

[0038] Step 3-2 and step 4-2 are steps of acetylation of hydroxyl groups. In acetylation, the above-mentioned acetylating agent can be used, and the amount of the acetylating agent is not particularly limited, and for example, 1 to 5 equivalents can be used relative to the compound represented by formula (C3) or formula (C4) as the starting material. The acetylating agent may preferably be acetic anhydride. The acetylating agent may be used together with a base. For the base, a bond that can be used together with the above-mentioned acetylating agent can be used, and the amount of the base is not particularly limited, and for example, 1 to 5 equivalents can be used relative to the compound represented by formula (C3) or formula (C4) as the starting material. The base may preferably be triethylamine, and triethylamine and 4-(dimethylamino)pyridine may also be used simultaneously. The solvent in the acetylation is not particularly limited as long as it dissolves the starting material and does not inhibit the reaction, and for example acetonitrile, methylene chloride, chloroform, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, toluene, pyridine, etc., or a mixed solvent thereof can be used. The reaction temperature generally varies depending on the starting material, the solvent, and other conditions and reagents used in the reaction, and ranges from room temperature to the boiling point of the solvent, preferably from room temperature to 40°C, and more preferably room temperature. The reaction time can be set to the time when the starting material disappears by stirring, and can be, for example, 1 hour to 24 hours.

[0039] Step 5-1 is a step of performing ester formation. Ester formation can be performed by a method commonly used in organic synthesis, and for example, carboxylic acid chloride as a synthetic intermediate can be prepared with a chlorinating agent, and the resulting carboxylic acid chloride can be used, or a commercially available condensing agent can be used. Examples of chlorinating agents or condensing agents include thionyl chloride, oxalyl chloride, 2,4,6-trichlorobenzoyl chloride, 2-methyl-6-nitrobenzoic anhydride (MNBA), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (WSC), N,N'-dicyclohexylcarbodiimide (DCC), N,N'-carbonyldiimidazole (CDI), 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) and O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU). Chlorinating agent or condensing agent can be preferably 2,4,6-trichlorobenzoyl chloride. The amount of chlorinating agent or condensing agent can be, for example, 1 to 3 equivalents, relative to the compound represented by formula (D2) as its actual material. For ester formation, in addition to chlorinating agent or condensing agent, base can also be used, and the amount of base is not particularly limited, and relative to the compound represented by formula (D2) as starting material, for example, 1 to 5 equivalents can be used. Base can preferably be triethylamine, diisopropyl (ethyl) amine, pyridine or 4- (dimethylamino) pyridine. The solvent in the ester formation is not particularly limited, as long as it dissolves the starting material and does not inhibit the reaction, and can use, for example, acetonitrile, methylene chloride, chloroform, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, toluene, etc., or a mixed solvent thereof. The reaction temperature generally varies depending on the starting material, the solvent, and other conditions and reagents used in the reaction, and ranges from room temperature to the boiling point of the solvent, preferably from room temperature to 40 ° C, and more preferably room temperature. When the ester formation is carried out in stages, in the stage where the compound represented by formula (D2) forms anhydride as a starting material with a condensing agent, the reaction temperature is preferably 60 ° C to 100 ° C, and when the temperature exceeds the boiling point of the solvent, heating and reflux can be performed. The reaction time can be set to the time when the starting material disappears by stirring, and can be, for example, 1 hour to 24 hours.

[0040] Step 5-2 is a step of removing the p-methoxybenzyl group. Removal can be performed according to the method described in Greene's Protective Groups In Organic Synthesis (4th edition, Wuts Peter GM et al.), but for example, 2,3-dichloro-5,6-dicyano-p-benzoquinone can be used for removal. The amount of 2,3-dichloro-5,6-dicyano-p-benzoquinone is not particularly limited, and 1 to 5 equivalents can be used, for example, relative to the compound represented by formula (D3) as the starting material. The solvent in removing the p-methoxybenzyl group is not particularly limited as long as it dissolves the starting material and does not inhibit the reaction, and for example acetonitrile, methylene chloride, chloroform, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, toluene, etc., or a mixed solvent thereof can be used. The reaction temperature generally varies depending on the starting material, the solvent, and other conditions and reagents used in the reaction, and ranges from room temperature to the boiling point of the solvent, preferably from room temperature to 40°C, and more preferably room temperature. The reaction time can be set to the time when the starting material disappears by stirring, and can be, for example, 1 hour to 24 hours.

[0041] Step 5-3 is a step of performing a ring-closing metathesis reaction using a ruthenium catalyst. The above-mentioned ruthenium catalyst can be used, and the amount of the ruthenium catalyst is not particularly limited, and for example, 0.01 to 0.1 equivalents can be used relative to the compound represented by formula (D4) as the starting material. The ruthenium catalyst may preferably be Grubbs-II ((1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinyl) dichloro (o-isopropoxyphenylmethylene) ruthenium). The solvent in the ring-closing metathesis reaction using a ruthenium catalyst is not particularly limited, as long as it dissolves the starting material and does not inhibit the reaction, and for example acetonitrile, methylene chloride, chloroform, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, toluene, etc., or a mixed solvent thereof may be used. The reaction temperature generally varies depending on the starting material, the solvent, and other reagents used in the reaction, and ranges from room temperature to the boiling point of the solvent, preferably from 80°C to 120°C. When the reaction temperature exceeds the boiling point of the solvent, heating under reflux may be performed. The reaction time may be set to the time when the starting material disappears by stirring, and may be, for example, 1 hour to 24 hours.

[0042] In the compound represented by formula (C5), in one aspect, R 1 is hydrogen, R 2 is hydrogen, and R 4 is hydrogen, and on the other hand, R 1 is a silyl protecting group, R 2 is hydrogen, and R 4 is hydrogen, and on the other hand, R 1 is a silyl protecting group, R 2 is a silyl protecting group, and R 4 is hydrogen. 1 , R 2 and R 4 The silyl protecting group in can be selected from the above protecting groups, and examples thereof include TMS, TES, TBS, TIPS and TBDPS. The compound represented by formula (C5) is easily crystallized by having an optionally substituted benzoyl group, and thus can be purified by crystallization, recrystallization, etc.

[0043] In the compound represented by formula (C6), in one aspect, R 1 is hydrogen, R 2 is hydrogen, and R 4 is hydrogen, and on the other hand, R 1 is a silyl protecting group, R 2 is hydrogen, and R 4 is hydrogen, and on the other hand, R 1 is a silyl protecting group, R 2 is a silyl protecting group, and R 4 is hydrogen. 1 , R 2 and R 4 The silyl protecting group in can be selected from the above protecting groups, and examples thereof include TMS, TES, TBS, TIPS and TBDPS. The compound represented by formula (C6) is easily crystallized by having an optionally substituted benzoyl group, and thus can be purified by crystallization, recrystallization, etc.

[0044] In the compound represented by formula (C7), in one aspect, X is hydrogen and R 4 is hydrogen, and on the other hand, X is hydrogen and R 4 is a silyl protecting group, and in another aspect, X is an optionally substituted boron group and R 4 is hydrogen, and in yet another aspect, X is optionally substituted boryl and R 4 is a silyl protecting group. The optionally substituted boron group in X may be the optionally substituted boron group described above. 4 The silyl protecting group in the formula (C7) can be selected from the above protecting groups, and examples thereof include TMS, TES, DEIPS, TBS, TIPS and TBDPS. The compound represented by formula (C7) is easily crystallized by having an optionally substituted benzoyl group, and can therefore be purified by crystallization, recrystallization, etc.

[0045] In the compound represented by formula (C8), in one aspect, X is hydrogen and R 4 is hydrogen, and on the other hand, X is hydrogen and R 4 is a silyl protecting group, and in another aspect, X is an optionally substituted boron group and R 4 is hydrogen, and in yet another aspect, X is optionally substituted boryl and R 4 is a silyl protecting group. The optionally substituted boron group in X may be the optionally substituted boron group described above. 4 The silyl protecting group in the formula (C8) can be selected from the above protecting groups, and examples thereof include TMS, TES, DEIPS, TBS, TIPS and TBDPS. The compound represented by formula (C8) is easily crystallized by having an optionally substituted benzoyl group, and can therefore be purified by crystallization, recrystallization, etc.

[0046] Step 1-3, step 2-3 and step 4-4 are steps of converting pradinolide D into a solvate. The solvate obtained may be a crystal. For example, the crystal of the solvate of pradinolide D can be produced by dissolving pradinolide D in a solvent, heating the solution, and then cooling the solution under stirring to cause crystallization. In addition, for example, the crystal of the solvate of pradinolide D can also be produced in the following manner: dissolving pradinolide D in a solvent, adding a poor solvent to cause crystallization, or dissolving pradinolide D in a solvent, distilling out the solvent by reduced pressure distillation to cause crystallization. In addition, the crystal of the solvate of pradinolide D can also be produced by dissolving pradinolide D in a solvent, adding a seed of the desired crystal of the solvate of pradinolide D to cause crystallization. When using seed crystals, seed crystals can be added at room temperature or under heating.

[0047] In the present specification, the solvate of pranidinolide D or a salt thereof represented by formula (1) is not particularly limited as long as it is a solvate formed between pranidinolide D or a salt thereof and a solvent capable of forming a solvate therewith. The solvate of pranidinolide D or a salt thereof represented by formula (1) may be, in one aspect, a pranidinolide toluene solvate, or in another aspect, a pranidinolide D chlorobenzene solvate, or in another aspect, a pranidinolide D tetrahydrofuran solvate, or in still another aspect, a pranidinolide D 2-methyltetrahydrofuran solvate.

[0048] In this specification, the diffraction angle and diffraction pattern of powder X-ray diffraction refer to the diffraction angle and diffraction pattern obtained by irradiation with copper Kα rays. 13 The chemical shifts in the C NMR spectra refer to those based on glycine as an external standard (176.03 ppm).

[0049] In the present specification, pranidolactone D toluene solvate may exist as a crystal. The crystal of pranidolactone D toluene solvate may be, on the one hand, a crystal having one or more diffraction peaks at a diffraction angle (2θ±0.2°) selected from the group consisting of 3.6°, 6.8°, 7.8°, 8.7°, 15.4°, 16.6°, 17.8° and 18.3° in powder X-ray diffraction, or on the other hand, a crystal having a diffraction peak at a diffraction angle (2θ±0.2°) of 7.8° in powder X-ray diffraction, or on the other hand, a crystal having a diffraction peak at a diffraction angle (2θ±0.2°) of 1.5° in powder X-ray diffraction. The invention relates to a crystal having diffraction peaks at (2θ±0.2°)3.6°, 7.8° and 16.6°, or on the other hand, in powder X-ray diffraction, the crystal has diffraction peaks at diffraction angles (2θ±0.2°)3.6°, 7.8°, 15.4°, 16.6° and 18.3°, or on the other hand, in powder X-ray diffraction, the crystal has diffraction peaks at diffraction angles (2θ±0.2°)3.6°, 6.8°, 7.8°, 8.7°, 15.4°, 16.6°, 17.8° and 18.3°.

[0050] In the present specification, pranidolactone D chlorobenzene solvate may exist as a crystal. The crystal of pranidolactone D chlorobenzene solvate may be, on the one hand, a crystal having one or more diffraction peaks at a diffraction angle (2θ±0.2°) selected from the group consisting of 3.6°, 7.8°, 15.4°, 16.2°, 16.6°, 17.9°, 18.3°, 20.4°, 21.3° and 21.7° in powder X-ray diffraction, or on the other hand, a crystal having a diffraction peak at a diffraction angle (2θ±0.2°) of 7.8° in powder X-ray diffraction, or on the other hand, a crystal having a diffraction peak at a diffraction angle (2θ±0.2°) of 1.5° in powder X-ray diffraction. The invention relates to a crystal having diffraction peaks at (2θ±0.2°)3.6°, 7.8° and 16.6°, or on the other hand, in powder X-ray diffraction, the crystal has diffraction peaks at diffraction angles (2θ±0.2°)3.6°, 7.8°, 15.4°, 16.6° and 18.3°, or on the other hand, in powder X-ray diffraction, the crystal has diffraction peaks at diffraction angles (2θ±0.2°)3.6°, 7.8°, 15.4°, 16.2°, 16.6°, 17.9°, 18.3°, 20.4°, 21.3° and 21.7°.

[0051] In the present specification, pranidolactone D tetrahydrofuran solvate may exist as a crystal. The crystal of pranidolactone D tetrahydrofuran solvate may be, on the one hand, a crystal having one or more diffraction peaks at a diffraction angle (2θ±0.2°) selected from the group consisting of 9.4°, 10.8°, 11.2°, 14.5°, 15.1°, 18.1°, 19.3°, 19.8°, 21.6° and 22.8° in powder X-ray diffraction, or on the other hand, a crystal having a diffraction peak at a diffraction angle (2θ±0.2°) of 14.5° in powder X-ray diffraction, or on the other hand, a crystal having a diffraction peak at a diffraction angle (2θ±0.2°) of 14.5° in powder X-ray diffraction. The invention relates to a crystal having diffraction peaks at (2θ±0.2°)10.8°, 14.5° and 19.3°, or on the other hand, in powder X-ray diffraction, the crystal has diffraction peaks at diffraction angles of (2θ±0.2°)9.4°, 10.8°, 14.5°, 19.3° and 19.8°, or on the other hand, in powder X-ray diffraction, the crystal has diffraction peaks at diffraction angles of (2θ±0.2°)9.4°, 10.8°, 11.2°, 14.5°, 15.1°, 18.1°, 19.3°, 19.8°, 21.6° and 22.8°.

[0052] In the present specification, pranidolactone D 2-methyltetrahydrofuran solvate may exist as a crystal. The crystal of pranidolactone D 2-methyltetrahydrofuran solvate may be, on the one hand, a crystal having one or more diffraction peaks at a diffraction angle (2θ±0.2°) selected from the group consisting of 10.3°, 10.7°, 11.7°, 13.3°, 14.4°, 17.2°, 18.9°, 21.2°, 22.5° and 23.4° in powder X-ray diffraction, or on the other hand, a crystal having a diffraction peak at a diffraction angle (2θ±0.2°) of 18.9° in powder X-ray diffraction, or on the other hand, a crystal having a diffraction peak at a diffraction angle (2θ±0.2°) of 18.9° in powder X-ray diffraction. The invention relates to a crystal having diffraction peaks at diffraction angles (2θ±0.2°) of 10.7°, 14.4°, 17.2°, 18.9° and 21.2° in powder X-ray diffraction, or a crystal having diffraction peaks at diffraction angles (2θ±0.2°) of 10.3°, 10.7°, 11.7°, 13.3°, 14.4°, 17.2°, 18.9°, 21.2°, 22.5° and 23.4° in powder X-ray diffraction.

[0053] The crystals of pranidolactone D 2-methyltetrahydrofuran solvate can be, in one aspect, in the solid state 13 In the C NMR spectrum, a crystal having one or more peaks at a chemical shift (δ±0.5ppm) selected from the group consisting of 9.1ppm, 10.0ppm, 10.5ppm, 16.2ppm, 21.4ppm, 23.9ppm, 24.2ppm, 25.4ppm, 26.8ppm, 28.0ppm, 28.5ppm, 33.3ppm, 33.7ppm, 35.9ppm, 39.9ppm, 41.1ppm, 42. 7ppm, 45.7ppm, 56.0ppm, 59.3ppm, 67.9ppm, 70.4ppm, 72.6ppm, 76.5ppm, 77.7ppm, 83.0ppm, 124.0ppm, 124.4ppm, 128.0ppm, 130.2ppm, 134.4ppm, 139.1ppm, 141.0ppm, 141.3ppm, 166.9ppm and 170.4ppm, or in a solid state 13 In the C NMR spectrum, a crystal having a peak at a chemical shift (δ±0.5 ppm) of 72.6 ppm, or on the other hand, in the solid state 13In the C NMR spectrum, a crystal having peaks at chemical shifts (δ±0.5 ppm) of 72.6 ppm, 134.4 ppm and 170.4 ppm, or on the other hand, in the solid state 13 In the CNMR spectrum, a crystal having peaks at chemical shifts (δ±0.5 ppm) of 21.4 ppm, 70.4 ppm, 72.6 ppm, 134.4 ppm and 170.4 ppm, or on the other hand, in the solid state 13 In the CNMR spectrum, a crystal having peaks at chemical shifts (δ±0.5 ppm) of 16.2 ppm, 21.4 ppm, 67.9 ppm, 70.4 ppm, 72.6 ppm, 76.5 ppm, 77.7 ppm, 134.4 ppm, 166.9 ppm and 170.4 ppm, or on the other hand, in the solid state 13 In the C NMR spectrum, crystals having peaks at chemical shifts (δ±0.5 ppm) of 10.0 ppm, 16.2 ppm, 21.4 ppm, 56.0 ppm, 59.3 ppm, 67.9 ppm, 70.4 ppm, 72.6 ppm, 76.5 ppm, 77.7 ppm, 83.0 ppm, 128.0 ppm, 130.2 ppm, 134.4 ppm, 139.1 ppm, 166.9 ppm and 170.4 ppm.

[0054] In the crystals of prandinolide D 2-methyltetrahydrofuran solvate, the crystals having the above-mentioned powder X-ray diffraction peaks can be simultaneously in the above-mentioned solid state 13 The crystal of pranololide D 2-methyltetrahydrofuran solvate may be, in one aspect, having diffraction peaks at diffraction angles (2θ±0.2°) of 10.7°, 14.4° and 18.9° in the powder X-ray diffraction peak and having a peak at a chemical shift of 10.7°, 14.4° and 18.9° in the solid state. 13 A crystal having peaks at chemical shifts (δ±0.5ppm) of 72.6ppm, 134.4ppm and 170.4ppm in C NMR spectrum, or on the other hand, having diffraction peaks at diffraction angles (2θ±0.2°) of 10.7°, 14.4°, 17.2°, 18.9° and 21.2° in powder X-ray diffraction peaks and having peaks at chemical shifts (δ±0.5ppm) of 72.6ppm, 134.4ppm and 170.4ppm in C NMR spectrum, or on the other hand, having diffraction peaks at diffraction angles (2θ±0.2°) of 10.7°, 14.4°, 17.2°, 18.9° and 21.2° in solid state 13 A crystal having peaks at chemical shifts (δ±0.5ppm) of 21.4ppm, 70.4ppm, 72.6ppm, 134.4ppm and 170.4ppm in C NMR spectrum, or on the other hand, having diffraction peaks at diffraction angles (2θ±0.2°) of 10.3°, 10.7°, 11.7°, 13.3°, 14.4°, 17.2°, 18.9°, 21.2°, 22.5° and 23.4° in powder X-ray diffraction peaks and having peaks at chemical shifts (δ±0.5ppm) of 21.4ppm, 70.4ppm, 72.6ppm, 134.4ppm and 170.4ppm in C NMR spectrum, or on the other hand, having diffraction peaks at diffraction angles (2θ±0.2°) of 10.3°, 10.7°, 11.7°, 13.3°, 14.4°, 17.2°, 18.9°, 21.2°, 22.5° and 23.4° in solid state13 Crystals having peaks at chemical shifts (δ±0.5 ppm) of 16.2 ppm, 21.4 ppm, 67.9 ppm, 70.4 ppm, 72.6 ppm, 76.5 ppm, 77.7 ppm, 134.4 ppm, 166.9 ppm and 170.4 ppm in C NMR spectrum.

[0055] Diffraction peaks in powder X-ray diffraction and solid 13 The chemical shifts in the C NMR spectrum are characteristic peaks of pranidinolide D toluene solvate crystals, pranidinolide D chlorobenzene solvate crystals, pranidinolide D tetrahydrofuran solvate crystals and pranidinolide D 2-methyltetrahydrofuran solvate crystals.

[0056] Generally speaking, because the diffraction angle (2θ) in powder X-ray diffraction may appear in an error within the range of ±0.2°, the value of the diffraction angle needs to be understood as a numerical value included in the range of about ±0.2°. Therefore, in a specific compound or its salt or solvate, the present invention includes not only crystals in which the diffraction angles of the peaks in the powder X-ray diffraction completely coincide with each other, but also crystals in which the diffraction angles of the peaks coincide with each other with an error of about ±0.2°. Therefore, in this specification, for example, "having a diffraction peak at a diffraction angle of 14.4° (2θ±0.2°)" means "having a diffraction peak at a diffraction angle (2θ) of 14.2° to 14.6°", and the same applies to other diffraction angles.

[0057] In general, in each measurement, the peak intensity or half-width of the diffraction angle (2θ) in the powder X-ray diffraction is different due to the difference in measurement conditions or the change in the size or shape of each particle of the powder crystal used as the measurement sample (even if the crystal form is the same), and does not always show a constant peak intensity or half-width. Therefore, in the comparison of the powder X-ray diffraction pattern, even if there is a difference in peak intensity or half-width at the same diffraction angle (2θ), the difference does not mean that the difference originates from a different crystal form. Therefore, with respect to the diffraction peak characteristics of a specific crystal of the present invention, it is meant that the crystal whose powder X-ray diffraction pattern has such a difference has the same crystal form as the crystal of the present invention.

[0058] In this specification, the phrase "having Figure 4 The term "powder X-ray diffraction pattern having substantially the same powder X-ray diffraction pattern as shown" means that in a powder X-ray diffraction pattern having characteristic diffraction peaks, even if the peak intensity or half-width is different from that of Figure 4 The peak intensity or half width of the powder X-ray diffraction pattern shown is Figure 4 When the peak intensity or half width of the powder X-ray diffraction pattern shown is consistent within an error range of ±0.2°, the crystals are consistent with Figure 4 The crystals shown display a powder X-ray diffraction pattern of the same.

[0059] Usually, due to solid 13 The chemical shift δ in the C NMR spectrum may have an error within the range of ±0.5 ppm, so the value of the chemical shift needs to be understood as a value included in the range of about ±0.5 ppm. 13 The chemical shifts in the C NMR spectrum are completely consistent with each other, and include crystals in which the chemical shifts are consistent with each other with an error of about ±0.5 ppm. Therefore, in the present specification, for example, the phrase "having a peak at a chemical shift (δ ± 0.5 ppm) 72.6 ppm" means having a peak at a chemical shift (δ) in the range of 72.1 ppm to 73.1 ppm, and the same applies to other 13 Chemical shifts in C solid-state NMR spectra.

[0060] Generally speaking, in each measurement, the solid 13 The peak intensity or half width at the chemical shift δ in the C NMR spectrum varies due to differences in measurement conditions or changes in the size or shape of each particle of the powder crystal used as the measurement sample (even if the crystal form is the same), and does not always show a constant peak intensity or half width. 13 In comparison of C solid-state NMR spectra, even if there is a difference in peak intensity or half-width at the same chemical shift δ, the difference does not mean that the difference is caused by different crystal forms. Therefore, with respect to the peak characteristics of a specific crystal of the present invention, it means that its solid-state 13 The crystals having such a difference in C NMR spectrum have the same crystal form as the crystals of the present invention.

[0061] In this specification, the phrase "having Figure 5 The solid state shown 13 C NMR spectra are essentially the same solid state 13 C NMR spectrum" refers to the solid state with characteristic diffraction peaks. 13 In C NMR spectra, even if the peak intensity or half-width is Figure 5 The solid state shown 13 The peak intensity or half-width of the CNMR spectrum is different. Figure 5 The solid state shown 13 When the C NMR spectrum is consistent within an error range of ±0.5 ppm, the crystal is Figure 5 The display shown is solid 13 The CNMR spectra of the crystals were identical.

[0062] The pranidolactone D used for crystallization may be pranidolactone D produced by fermentation or pranidolactone D produced by chemical synthesis, and may also be produced by the above-mentioned method for producing pranidolactone D. The pranidolactone D used for crystallization may be in any form, may be an acid anhydride or a solvate, may be amorphous or crystalline (including those formed of a plurality of crystal polymorphs), or may be a mixture thereof.

[0063] The solvent used for crystallization is not particularly limited as long as it is a solvent that forms a solvate of pradinolide D, and examples thereof include alcohol-based solvents such as methanol, ethanol, isopropanol, and 1-propanol; acetonitrile; amide-based solvents such as N,N-dimethylformamide; ester-based solvents such as ethyl acetate and isopropyl acetate; saturated hydrocarbon-based solvents such as hexane and heptane; ketone-based solvents such as acetone and 2-butanone; ether-based solvents such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, and 2-methyltetrahydrofuran; unsaturated hydrocarbon solvents such as toluene and chlorobenzene; and water. These solvents may be used alone, or two or more thereof may be used in combination.

[0064] The amount of the solvent used can be appropriately selected, wherein the lower limit is an amount in which pradilactone D is dissolved by heating or an amount in which the suspension can be stirred, and the upper limit is an amount in which the yield of crystals does not significantly decrease.

[0065] The temperature when dissolving pranidolactone D by heating can be appropriately selected depending on the solvent, and is preferably in the range of 50°C to a temperature at which the recrystallization solvent starts to reflux, and more preferably 60°C to 80°C.

[0066] Since rapid cooling can produce crystals (polymorphs) having different aspects, cooling during crystallization can be desirably performed by appropriately adjusting the cooling rate in consideration of the influence on the quality of the crystal, grain size, etc., and is preferably performed at a rate of, for example, 5° C. / hour to 40° C. / hour. More preferably, cooling is performed at a rate of, for example, 5° C. / hour to 25° C. / hour.

[0067] The final crystallization temperature can be appropriately selected depending on the yield, quality, etc. of the crystal, and it is preferably -25°C to +30°C.

[0068] When the crystal of the solvate of pranolide D is obtained by crystallization, the crystal of the crystal can be separated, for example, by normal filtering operation, the separated crystal can be washed by filtering with a solvent as needed, and the crystal can be further dried to obtain the crystal of the solvate of pranolide D. As the solvent for washing the crystal, a solvent similar to the crystallization solvent can be used, and the crystal can also be washed with a solvent different from the crystallization solvent. Examples thereof include methanol, ethanol, isopropanol, 1-propanol, acetonitrile, ethyl acetate, isopropyl acetate, hexane, heptane, acetone, 2-butanone, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, toluene and chlorobenzene. These solvents can be used alone, or two or more thereof can be used in combination.

[0069] The crystals separated by the filtering operation may be suitably dried by leaving in the atmosphere or under a nitrogen stream or by heating.

[0070] For the drying time, the time until the amount of residual solvent drops below the predetermined amount can be appropriately selected according to the production volume, drying device, drying temperature, etc. Drying can be carried out under ventilation or reduced pressure. The degree of reduced pressure can be appropriately selected according to the production volume, drying device, drying temperature, etc. The crystals obtained after drying can also be left in the atmosphere as needed.

[0071] The pranidolactone D used for producing the crystal of the solvate of pranidolactone D according to the present disclosure may be pranidolactone D chemically synthesized according to, for example, the production method according to one aspect of the present disclosure, or may be pranidolactone D produced by fermentation. As a method for producing pranidolactone D by fermentation, for example, the production method described in Patent Document 1 can be used, and the method is incorporated herein by reference.

[0072] The crystals of the solvate of prandinolide D according to the present disclosure (e.g., crystals of prandinolide D 2-methyltetrahydrofuran solvate) may have high purity. In the crystals of the solvate of prandinolide D according to the present disclosure, high purity may mean, for example, that in the analysis using high performance liquid chromatography (HPLC), the ratio of the area of ​​the absorption peak of prandinolide D to the total area of ​​the absorption peak detected at 240 nm is 90.00% or more, 93.00% or more, 95.00% or more, or 96.00% or more. Another aspect of the present disclosure may be a composition containing the crystals of the solvate of prandinolide D according to one aspect of the present disclosure, wherein in the analysis using high performance liquid chromatography (HPLC), the ratio of the area of ​​the absorption peak of prandinolide D to the total area of ​​the absorption peak detected at 240 nm is 90.00% or more, 93.00% or more, 95.00% or more, or 96.00% or more. In these cases, the analysis conditions of HPLC may be, for example, those used in "Example E. Purity measurement" described later. Examples

[0073] Hereinafter, the present invention will be described in detail with reference to examples.

[0074] A compound described with a name of a reference or the like indicates that the compound was produced according to the reference or the like.

[0075] In addition, the abbreviations used herein are conventional abbreviations well known to those skilled in the art. In this specification, the following abbreviations are used. Ac:Acetyl AcOH: acetic acid Ac2O: acetic anhydride Ag2CO3: Silver carbonate Ag2O: Silver(I) oxide B2pin2: Bis(pinacol)diboron n-Bu3SnH: Tri-n-butyltin DCM: dichloromethane DDQ: 2,3-dichloro-5,6-dicyano-p-benzoquinone DIPEA: N,N-diisopropylethylamine DMAP: 4-dimethylaminopyridine DMF: N,N-dimethylformamide Et3N: triethylamine Grubbs-II: (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium Hoveyda-Grubbs-II: (1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)ruthenium K2CO3: Potassium carbonate Me:Methyl MeCN: Acetonitrile MeOH: Methanol MPM: p-methoxybenzyl MTBE: 2-methoxy-2-methylpropane PdCl2(PhCN)2: Dichlorobis(benzonitrile)palladium(II) PdCl2(PPh3)2: Bis(triphenylphosphine)palladium(II) dichloride Pd2(dba)3: tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride Pd(OAc)2: Palladium(II) acetate PPTS: Pyridinium p-toluenesulfonate TFA: trifluoroacetic acid TBAF: Tetrabutylammonium fluoride TBDPS: tert-butyldiphenylsilyl TBS-Cl: tert-butyldimethylsilyl chloride TBS-OTf: tert-Butyldimethylsilyl trifluoromethanesulfonate TES-Cl: triethylchlorosilane TES-OTf: triethylsilyl trifluoromethanesulfonate THF: Tetrahydrofuran XPhos: 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl Zhan Catalyst-1B: 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazole-2-ylidene[2-(isopropoxy)-5-(N,N-dimethylaminosulfonyl)phenyl]methylenedichloride ruthenium(II) n-: positive - s-: Zhong- t-: uncle- tert-: uncle- 1 H-NMR: Proton Nuclear Magnetic Resonance Spectroscopy

[0076] "Room temperature" in the following examples and production examples generally refers to about 10° C. to about 35° C. Unless otherwise specified, % means weight percentage.

[0077] In the measurement of proton nuclear magnetic resonance spectra, a nuclear magnetic resonance apparatus of model JNM-ECZ500R / S1 manufactured by JEOL Co., Ltd. or a nuclear magnetic resonance apparatus Avance Neo 700MHz manufactured by Bruker was used. The chemical shifts of the proton nuclear magnetic resonance spectra were recorded in δ units (ppm) relative to tetramethylsilane in CDCl3, in δ units in CD3OD, where methanol was set to 3.31ppm (3.30ppm for the solvate of pradilactone D), and in δ units in CD3CN, where acetonitrile was set to 1.93ppm. Coupling constants were recorded in Hertz (Hz). The abbreviations of the splitting modes are as follows. s: singlet, d: doublet, t: triplet, q: quartet, m: multiplet, br.s: broad singlet

[0078] For chromatography, silica gel 60 (70-230 mesh ASTM) manufactured by Merck, parallel preparative type {column: Hi-Flash manufactured by YAMAZEN TM As the silica gel, any one of a column (silica gel), size: any one of S (16×60 mm), M (20×75 mm), L (26×100 mm), 2L (26×150 mm), and 3L (46×130 mm)} or Isolera 1 manufactured by Biotage {column: Biotage Sfar 20 um (silica gel HC D) manufactured by Biotage, size: any one of 5 g (9 mL), 25 g (42 mL), 50 g (80 mL), 100 g (150 mL), 200 g (310 mL), and 350 g (530 mL)}. As NH silica gel, CHROMATOREX NH-DM2035 manufactured by Fuji Silysia Chemical Ltd., parallel preparation type {column: Hi-Flash manufactured by Yamazen Co., Ltd. TM Column (amino), size: any one of S (16×60 mm), M (20×75 mm), L (26×100 mm), 2L (26×150 mm), and 3L (46×130 mm)} and Isolera 1 manufactured by Biotage {column: Biotage Sfar 50 μm (amino D) manufactured by Biotage, size: any one of 5 g (9 mL) and 11 g (15 mL)}.

[0079] Powder X-ray crystal diffraction of the crystals produced in the following Examples was performed by placing the obtained crystals on a sample stage of a powder X-ray diffractometer and analyzing the crystals under the following conditions. (Conditions of the transmission method) X-ray source: Cu-Kα Voltage: 45kV Current: 200mA Optical system: focusing optical system Solar slit: 2.5° Detector: D / teX Ultra 250 (one-dimensional semiconductor detector) Scanning speed: 10° / min Step width: 0.01° Scanning range: 3° to 40° Membrane: Mylar film

[0080] In thermal analysis (TG-DTA), a sample was accurately weighed in an aluminum sample pan and measured under the following conditions. (Measurement conditions) Atmosphere: Nitrogen flow at 100 mL / min Control: Empty aluminum sample pan Heating speed: 10℃ / min Sampling interval: 1 second Measuring temperature range: room temperature to 200°C, room temperature to 150°C, or room temperature to 160°C

[0081] Solid State 13 C NMR spectrum was measured under the following conditions by sealing about 100 mg of a solid sample in a sample tube. (Measurement conditions) Device used: Avance Neo 400MHz (manufactured by Bruker) 4mm-CPMAS probe (manufactured by Bruker) Measurement core: 13 C (resonance frequency 100.6228298MHz) Measuring temperature: room temperature Pulse mode: CPTOSS measurement Rotation speed: 10,000Hz Pulse repetition time: 5 seconds Contact time: 2 milliseconds Number of points: 2048 times Reference material: 10% 15N glycine (external reference: 176.03 ppm)

[0082] As the nomenclature of the compounds shown below, except for commonly used reagents, the nomenclature shown in "E-Notebook" 18th edition (PerkinElmer, Inc.) is used.

[0083] Example A-1 Synthesis of (2R,3S)-2-((2R,3R)-3-((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxiran-2-yl)pentan-3-ol

[0084] A-1-(1) Synthesis of (3R,7S,8S,E)-1-(tert-butyldiphenylsilyl)-3,7-dimethyldec-5-ene-1-yne-3,8-diol At 25 ° C, PPTS (3.96 g, 15.8 mmol) was added to a solution of (3R, 7S, 8S, E) -8- ((tert-butyldimethylsilyl) oxy) -1- (tert-butyldiphenylsilyl) -3,7-dimethyldec-5-ene-1-yn-3-ol (CAS No. 2389978-00-9; Angew. Chem. Int. Ed. [German Applied Chemistry] 2019, 58, 18803-18807) (4.33 g, 7.89 mmol) in MeOH (86 mL) synthesized according to the method described in the literature. The reaction mixture was stirred at 50 ° C for 21 hours. The reaction mixture was allowed to cool to room temperature, and then ethyl acetate and water were added to the reaction mixture, and the organic layer was separated. The aqueous layer was re-extracted with ethyl acetate. The combined organic layers were washed with 0.5N hydrochloric acid, water, saturated sodium bicarbonate aqueous solution and saturated brine in sequence. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure.The residue was purified by silica gel column chromatography (10%-50% ethyl acetate / n-heptane) to obtain the title compound (2.97 g). 1 H-NMR (500MHz, CDCl3) δ (ppm): 0.93 (t, J = 7.5Hz, 3H), 1.02 (d, J = 6.9Hz, 3H), 1 .08(s,9H),1.33-1.45(m,2H),1.48-1.53(m,2H),1.59(s,3H),2.25-2.34(m,1 H),2.39-2.47(m,1H),2.56(dd,J=13.8,6.3Hz,1H),3.39(dt,J=8.7,4.5Hz,1H ),5.58-5.66(m,1H),5.69-5.79(m,1H),7.33-7.44(m,6H),7.75-7.81(m,4H).

[0085] A-1-(2) Synthesis of (2R,3S)-2-((2R,3R)-3-((R)-4-(tert-butyldiphenylsilyl)-2-hydroxy-2-methylbut-3-yn-1-yl)oxiran-2-yl)pentan-3-ol To a mixed solution of (3R,7S,8S,E)-1-(tert-butyldiphenylsilyl)-3,7-dimethyldec-5-ene-1-yne-3,8-diol (2.97 g, 6.83 mmol) obtained in Example A-1-(1) in 0.05 M aqueous sodium tetraborate solution (pH = 9; 50 mL) (containing MeCN (75 mL)) and 0.4 mM disodium ethylenediamine-N,N,N',N'-tetraacetate was added 1,2:4,5-di-O-isopropylidene-β-D-erythro-2,3-hexanedialdehyde-2,6-pyranose (Smith epoxidation catalyst; CAS No. 18422-53-2) (5.29 g, 20.5 mmol) at 30°C, and the mixture was stirred at room temperature for 15 minutes. The mixture was ice-cooled, and Oxone (registered trademark) powder (CAS No. 70693-62-8) (1.58 g, 2.56 mmol) and K2CO3 powder (708 mg, 5.12 mmol) were added 8 times at 15 minute intervals. The reaction mixture was then stirred for 150 minutes under ice cooling. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The aqueous layer was re-extracted with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15%-40% ethyl acetate / n-heptane). The fractions containing the desired product were collected and concentrated. Heptane was added to the resulting residue, and the mixture was then ultrasonically treated and stirred at room temperature for 30 minutes. The resulting solid was collected by filtration, washed with heptane and dried under reduced pressure to obtain the title compound (1.66 g). 1H-NMR (500MHz, CDCl3) δ (ppm): 0.90 (d, J = 6.9 Hz, 3H), 0.93 (t, J = 7.5 Hz, 3H), 1.08 (s, 9H), 1.4 6-1.51(m,2H),1.58(br.dd,J=6.6,3.2Hz,1H),1.66(s,3H),1.84(br.s,1H),1.96(dd,J=14. 3,7.5Hz,1H),2.08-2.14(m,1H),2.87(dd,J=6.3,2.3Hz,1H),3.03(br.s,1H),3.26(ddd,J=7 .2,4.9,2.3Hz,1H),3.58-3.64(m,1H),7.34-7.43(m,6H),7.77(ddd,J=7.9,3.3,1.4Hz,4H).

[0086] A-1-(3) Synthesis of (2R,3S)-2-((2R,3R)-3-((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxiran-2-yl)pentan-3-ol To a solution of (2R,3S)-2-((2R,3R)-3-((R)-4-(tert-butyldiphenylsilyl)-2-hydroxy-2-methylbut-3-yn-1-yl)oxiran-2-yl)pentane-3-ol (1.66 g, 3.68 mmol) obtained in Example A-1-(2) in THF (9.2 mL) was added a THF solution of TBAF (1 M; 9.2 mL, 9.2 mmol) at 25°C. The reaction mixture was then stirred at room temperature for 21.5 hours. Saturated aqueous ammonium chloride solution, ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (twice). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-50% ethyl acetate / n-heptane) to obtain the title compound (726 mg). 1 H-NMR (500MHz, CDCl3) δ (ppm): 0.94-1.00 (m, 6H), 1.50-1.56 (m, 5H), 1.57-1.64 (m, 1H), 1.79-1.91 (m, 2H), 1.96-2.03 (m, 1H), 2.52 (s, 1H), 2.84 (dd, J = 6.9, 2.3Hz, 1H), 2.93 (s, 1H), 3.20 (ddd, J = 7.2, 4.9, 2.3Hz, 1H), 3.67 (tt, J = 7.4, 3.5Hz, 1H).

[0087] Example A-2 Synthesis of (2R,3S)-2-((2R,3R)-3-((R)-2-hydroxy-2-methylbut-3-en-1-yl)oxiran-2-yl)pentan-3-ol To a solution of (2R, 3S)-2-((2R, 3R)-3-((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxiran-2-yl)pentane-3-ol (200 mg, 0.942 mmol) obtained in Example A-1-(3) in ethyl acetate (4 mL) was added Lindlar catalyst (20 mg) at 25 ° C. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 2.5 hours. The catalyst was filtered off and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30%-60% ethyl acetate / n-heptane) to obtain the title compound (183 mg). 1 H-NMR (500MHz, CDCl3) δ (ppm): 0.91 (d, J = 7.3Hz, 3H), 0.97 (t, J = 7.3Hz, 3H), 1.36 (s, 3H), 1. 48-1.54(m,2H),1.63(td,J=6.7,3.1Hz,1H),1.71-1.83(m,2H),2.06(br.d,J=4.3Hz,1H),2. 31(s,1H),2.76(dd,J=6.7,2.5Hz,1H),2.99(td,J=6.1,2.5Hz,1H),3.66(br.d,J=3.1Hz,1H ), 5.11 (dd, J = 11.0, 1.2 Hz, 1H), 5.31 ( dd, J = 17.1, 1.2 Hz, 1H), 5.98 ( dd, J = 17.1, 10.4 Hz, 1H).

[0088] Example A-3 Synthesis of triethyl(((R)-2-methyl-1-((2R,3R)-3-((2S,3S)-3-((triethylsilyl)oxy)pentan-2-yl)oxiran-2-yl)but-3-en-2-yl)oxy)silane To a solution of (2R,3S)-2-((2R,3R)-3-((R)-2-hydroxy-2-methylbut-3-en-1-yl)oxiran-2-yl)pentane-3-ol (91 mg, 0.425 mmol) and 2,6-dimethylarsine (0.20 mL, 1.7 mol) obtained in Example A-2 in THF (2 mL) was added TES-OTf (0.29 mL, 1.3 mmol) at 0°C over 3 minutes. The reaction mixture was stirred at the same temperature for 45 minutes. To the reaction mixture was added 2,6-dimethylarsine (0.10 mL, 0.86 mmol) at 0°C, followed by TES-OTf (0.15 mL, 0.66 mmol) over 2 minutes. Then, the reaction solution was stirred for 30 minutes. To the reaction solution was added water (1 mL) at 0°C, and the mixture was stirred for 5 minutes. Ethyl acetate and water were added to the mixture, and the organic layer was separated. The organic layer was washed with 0.5N hydrochloric acid, brine, saturated sodium bicarbonate aqueous solution and saturated brine in sequence. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0%-10% ethyl acetate / n-heptane) to obtain the title compound (155 mg). 1 H-NMR (500MHz, CDCl3) δ (ppm): 0.57-0.66 (m, 12H), 0.83 (t, J = 7.3Hz, 3H), 0.89 (d, J = 7.3Hz, 3H), 0 .93-1.01(m,18H),1.27-1.34(m,1H),1.39(s,3H),1.46-1.52(m,2H),1.61-1.66(m,1H),1.80(dd, J=14.1,5.5Hz,1H),2.60(dd,J=8.0,2.5Hz,1H),2.86(td,J=5.7,2.1Hz,1H),3.75(td,J=6.4,3.7 Hz, 1H), 5.02 (dd, J = 10.4, 1.2 Hz, 1H), 5.18 ( dd, J = 17.1, 1.2 Hz, 1H), 5.92 ( dd, J = 17.1, 11.0 Hz, 1H).

[0089] Example A-4 Synthesis of triethyl(((R,E)-2-methyl-4-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2R,3R)-3-((2S,3S)-3-((triethylsilyl)oxy)pentan-2-yl)oxiran-2-yl)but-3-en-2-yl)oxy)silane

[0090] A-4-(1) Synthesis of triethyl(((R)-2-methyl-1-((2R,3R)-3-((2S,3S)-3-((triethylsilyl)oxy)pentan-2-yl)oxiran-2-yl)but-3-yn-2-yl)oxy)silane To a solution of (2R,3S)-2-((2R,3R)-3-((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxiran-2-yl)pentane-3-ol (56 mg, 0.26 mmol) and 2,6-dimethylarsine (79 μL, 0.68 mmol) obtained in Example A-1-(3) in THF (1.9 mL) was added TES-OTf (0.14 mL, 0.62 mmol) at 0°C over 2 minutes. The reaction mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added 2,6-dimethylarsine (40 μL, 0.34 mmol) at 0°C. TES-OTf (70 μL, 0.31 mmol) was then added over 2 minutes. Then, the reaction mixture was stirred for 20 minutes. To the reaction mixture was added saturated aqueous sodium bicarbonate solution (1 mL) at 0°C, and the mixture was stirred for 5 minutes. Ethyl acetate and water are added to the mixture, and the organic layer is separated. The organic layer is washed with 0.5N hydrochloric acid, water, saturated sodium bicarbonate aqueous solution and saturated brine in sequence. The organic layer is dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue is purified by silica gel column chromatography (0%-10% ethyl acetate / n-heptane) to obtain the title compound (109mg). 1 H-NMR (500MHz, CDCl3) δ (ppm): 0.59-0.65 (m, 6H), 0.66-0.73 (m, 6H), 0.84 (t, J= 7.5Hz,3H),0.93(d,J=6.9Hz,3H),0.95-0.99(m,18H),1.27-1.36(m,1H),1.45-1 .54(m,5H),1.77(dd,J=13.8,6.3Hz,1H),2.03(dd,J=13.8,5.2Hz,1H),2.45(s, 1H), 2.71 (dd, J=8.0, 2.3Hz, 1H), 2.94-3.00 (m, 1H), 3.77 (td, J=6.3, 3.4Hz, 1H).

[0091] A-4-(2) Synthesis of triethyl(((R,E)-2-methyl-4-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2R,3R)-3-((2S,3S)-3-((triethylsilyl)oxy)pentan-2-yl)oxiran-2-yl)but-3-en-2-yl)oxy)silane At 25 ° C, to the triethyl (((R)-2-methyl-1-((2R, 3R)-3-((2S, 3S)-3-((triethylsilyl)oxy)pentane-2-yl)oxirane-2-yl)but-3-yn-2-yl)oxy)silane (46.8 mg, 106 μmol) obtained in Example A-4-(1) in DCM (1 mL) solution was added pinacol borane (CAS No. 25015-63-8) (23 μL, 0.16 mmol) and carbonyl bis (triphenylphosphine) rhodium chloride (I) (14.7 mg, 21 μmol). The reaction mixture was stirred at 40 ° C under a nitrogen atmosphere for 8 hours. The reaction mixture was allowed to cool. The reaction mixture was directly purified by silica gel column chromatography (0%-5% ethyl acetate / n-heptane) to obtain the title compound (32.2 mg). 1 H-NMR (500MHz, CDCl3) δ (ppm): 0.61 (q, J = 8.0Hz, 12H), 0.82 (t, J = 7.3Hz, 3H), 0.88 (d, J = 6.7H z,3H),0.96(td,J=8.0,3.7Hz,18H),1.19-1.23(m,1H),1.27(d,J=1.2Hz,12H),1.37(s,3H),1 .43-1.54(m,3H),1.93(dd,J=13.8,4.6Hz,1H),2.56(dd,J=8.3,2.1Hz,1H),2.84(ddd,J=6.9 ,4.7,2.5Hz,1H),3.73(td,J=6.4,3.1Hz,1H),5.64(d,J=18.3Hz,1H),6.61(d,J=17.7Hz,1H).

[0092] Example A-5 Synthesis of (2R,3S)-2-((2R,3R)-3-((R)-2-hydroxy-2-methylbut-3-en-1-yl)oxiran-2-yl)pentan-3-yl 3,5-dinitrobenzoate To a solution of (2R, 3S)-2-((2R, 3R)-3-((R)-2-hydroxy-2-methylbut-3-ene-1-yl)oxirane-2-yl)pentane-3-ol (50 mg, 0.23 mmol), Et3N (75 μL, 0.54 mmol) and DMAP (5.7 mg, 47 μmol) obtained in Example A-2 in DCM (2 mL) was added 3,5-dinitrobenzoyl chloride (81 mg, 0.35 mmol) at 0°C. The reaction mixture was stirred at 0°C for 10 minutes and at room temperature for 45 minutes. Water (1 mL) was added to the reaction mixture at 0°C, and the mixture was stirred for 10 minutes. Ethyl acetate and 1N hydrochloric acid were added to the mixture, and the organic layer was separated. The organic layer was washed with water, saturated sodium bicarbonate aqueous solution and saturated brine in sequence. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-40% ethyl acetate / n-heptane) to obtain the title compound (76 mg). 1 H-NMR (500MHz, CDCl3) δ (ppm): 0.97 (t, J = 7.6 Hz, 3H), 1.08 (d, J = 7.3 Hz, 3H), 1.3 3(s,3H),1.60-1.67(m,1H),1.68-1.76(m,1H),1.83-1.91(m,3H),2.02(s,1H),2 .62(dd,J=8.0,1.8Hz,1H),2.90-2.95(m,1H),5.11(d,J=10.4Hz,1H),5.26-5.34 (m,2H),5.95(dd,J=17.1,11.0Hz,1H),9.17(d,J=1.8Hz,2H),9.22-9.25(m,1H).

[0093] Example A-6 Synthesis of (2R,3S)-2-((2R,3R)-3-((R,E)-4-(Benzyldimethylsilyl)-2-hydroxy-2-methylbut-3-en-1-yl)oxiran-2-yl)pentan-3-ol A mixture of Ag2O (0.7 mg, 2.6 μmol), XPhos (CAS No. 564483-18-7) (2.7 mg, 5.7 μmol) and THF (0.75 mL) was stirred at 50 ° C for 30 minutes under a nitrogen atmosphere, and then the mixture was allowed to cool. At room temperature, a solution of (2R, 3S)-2-((2R, 3R)-3-((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxirane-2-yl)pentane-3-ol (20 mg, 94 μmol) obtained in Example A-1-(3) in THF (1 mL) and benzyldimethylsilane (CAS No. 1631-70-5) (40.2 μL, 0.236 mmol) were added to the mixture. The reaction mixture was stirred at 50 ° C for 130 minutes under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature. The reaction mixture was directly purified by silica gel column chromatography (20%-60% ethyl acetate / n-heptane) to obtain the title compound (32.2 mg). 1 H-NMR (500MHz, CDCl3) δ (ppm): 0.06 (s, 3H), 0.07 (s, 3H), 0.89 (d, J = 6.9Hz, 3H), 0.97 (t, J = 7.5Hz, 3H ),1.30(s,3H),1.50-1.54(m,2H),1.61-1.71(m,2H),1.74-1.81(m,1H),2.06-2.11(m,1H),2.14(s,2 H),2.32(s,1H),2.73(dd,J=6.3,2.3Hz,1H),2.92(td,J=6.3,2.3Hz,1H),3.61-3.70(m,1H),5.87(d ,J=18.9Hz,1H),6.05(d,J=18.9Hz,1H),6.97(d,J=7.5Hz,2H),7.03-7.09(m,1H),7.16-7.22(m,2H).

[0094] Example A-7 Synthesis of (2R,3S)-2-((2R,3R)-3-((R,E)-2-hydroxy-2-methyl-4-(tributylstannyl)but-3-en-1-yl)oxiran-2-yl)pentan-3-ol A THF solution (1.5 mL) of (2R, 3S)-2-((2R, 3R)-3-((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxirane-2-yl)pentane-3-ol (20.5 mg, 97 μmol) obtained in Example A-1-(3) was cooled in an ice-water bath. PdCl(PPh) (3.39 mg, 4.84 μmol) and n-BuSnH (31 μL, 116 μmol) were added thereto and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate aqueous solution. The organic layer was separated and dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0%-25% ethyl acetate / n-heptane) to obtain the title compound (16.3 mg). 1 H-NMR (500MHz, CDCl3) δ (ppm): 0.82-0.94 (m, 18H), 0.97 (t, J = 7.5Hz, 3H), 1.25-1.33 (m ,6H),1.34(s,3H),1.44-1.54(m,8H),1.62-1.75(m,2H),1.83(dd,J=14.0,6.6Hz,1H),2 .20(br.d,J=4.6Hz,1H),2.28(s,1H),2.76(dd,J=6.3,2.3Hz,1H),2.99(td,J=6.2,2.6 Hz, 1H), 3.66 (br.dd, J = 7.5, 3.4Hz, 1H), 6.08 (d, J = 19.5Hz, 1H), 6.20 (d, J = 19.5Hz, 1H).

[0095] Example A-8 Synthesis of (2R,3S)-2-((2R,3R)-3-((R,E)-2-hydroxy-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-yl)oxiran-2-yl)pentan-3-ol A solution of copper (II) trifluoromethanesulfonate (21.3 mg, 0.059 mmol), B2pin2 (359 mg, 1.41 mmol), sodium tert-butoxide (11.3 mg, 0.118 mmol) and 2,6-di(1-pyrazolyl)pyridine (24.9 mg, 0.118 mmol) in MeCN (8 mL) and MeOH (150 μL) was stirred at room temperature for 10 min (the mixture became solution B). The (2R, 3S)-2-((2R, 3R)-3-((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxirane-2-yl)pentane-3-ol (50 mg, 0.236 mmol) obtained in Example A-1-(3) was dissolved in solution B (1.6 ml). The resulting reaction mixture was stirred at room temperature for 2 hours and then stirred at 50 ° C for 4 hours. Solution B (1.6 ml) was added to the reaction mixture, and the reaction mixture was stirred at 50 ° C for 2 hours and then allowed to cool to room temperature. The reaction mixture was quenched with water. The resulting mixture was filtered. The filtrate was extracted with ethyl acetate (twice). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10%-100% ethyl acetate / n-heptane) to obtain the title compound (52.0 mg). 1 H-NMR (500MHz, CDCl3) δ (ppm): 0.89 (d, J = 7.3Hz, 3H), 0.96 (t, J = 7.3Hz, 3H), 1.24 (s, 12H), 1.3 5(s,3H),1.48-1.56(m,2H),1.60(ddd,J=10.2,6.9,3.7Hz,1H),1.71(br.dd,J=14.1,6.1Hz,1H )1.85(dd,J=14.1,6.1Hz,1H),1.98(br.s,1H),2.29-2.45(m,1H),2.72(dd,J=6.1,2.5Hz,1H), 2.98(td,J=6.1,2.5Hz,1H), 3.62-3.67(m,1H), 5.70(d,J=18.3Hz,1H), 6.69(d,J=18.3Hz,1H).

[0096] Example A-9 Synthesis of (2R,3S)-2-((2R,3R)-3-((R,E)-2-hydroxy-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-yl)oxiran-2-yl)pentan-3-ol To a solution of (2R,3S)-2-((2R,3R)-3-((R)-2-hydroxy-2-methylbut-3-en-1-yl)oxiran-2-yl)pentan-3-ol (50 mg, 0.233 mmol) obtained in Example A-2 in 1,2-dichloroethane (4 mL) were added p-benzoquinone (2.52 mg, 23 μmol), 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (108 mg, 0.70 mmol) and Zhan catalyst-1B (34.2 mg, 47 μmol) at room temperature. The reaction mixture was stirred at 70°C under a nitrogen atmosphere for 3 hours. To the reaction mixture was added 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (108 mg, 0.70 mmol), and the reaction mixture was stirred at 70°C for 3 hours. Zhan catalyst-1B (34.2 mg, 47 μmol) was then added to the reaction mixture, and the reaction mixture was stirred at 70°C overnight and then allowed to cool. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10%-50% ethyl acetate / n-heptane) to obtain the title compound (51.3 mg). The obtained compounds 1 The H-NMR spectrum (500 MHz, CDCl 3 ) was consistent with that of the compound obtained in Example A-8.

[0097] Example A-10 Synthesis of (2R,3S)-2-((2R,3R)-3-((R,E)-2-hydroxy-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-yl)oxiran-2-yl)pentan-3-yl 3,5-dinitrobenzoate To a solution of (2R,3S)-2-((2R,3R)-3-((R,E)-2-hydroxy-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)but-3-en-1-yl)oxirane-2-yl)pentane-3-ol (42 mg, 0.123 mmol) and DMAP (3.02 mg, 25 μmol) obtained in Example A-8 in DCM (2 mL) was added Et3N (39.6 μL, 0.284 mmol) and 3,5-dinitrobenzoyl chloride (42.7 mg, 0.185 mmol) at 0°C. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with saturated aqueous ammonium chloride. Ethyl acetate was added to the obtained mixture, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (10%-50% ethyl acetate / n-heptane) to obtain the title compound (43.9 mg). 1 H-NMR (500MHz, CDCl3) δ (ppm): 0.97 (t, J = 7.3Hz, 3H), 1.07 (d, J = 7.3Hz, 3H), 1. 27(s,12H),1.32(s,3H),1.65-1.72(m,2H),1.80-1.89(m,3H),2.59(dd,J=8.3, 2.1Hz,1H),2.90(ddd,J=6.9,4.7,2.5Hz,1H),5.25-5.30(m,1H),5.68(d,J=18 .3Hz, 1H), 6.65 (d, J = 18.3Hz, 1H), 9.17 (d, J = 2.5Hz, 2H), 9.23 (t, J = 2.1Hz, 1H).

[0098] Example A-11 Synthesis of (2R,3S)-2-((2R,3R)-3-((R,E)-2-hydroxy-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-yl)oxiran-2-yl)pentan-3-yl 3,5-dinitrobenzoate To a solution of (2R, 3S)-2-((2R, 3R)-3-((R)-2-hydroxy-2-methylbut-3-ene-1-yl)oxirane-2-yl)pentane-3-yl 3,5-dinitrobenzoate (15 mg, 37 μmol) in 1,2-dichloroethane (2 mL) obtained in Example A-5 was added p-benzoquinone (0.40 mg, 3.7 μmol), 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (19 μL, 0.11 mmol) and Zhan catalyst-1B (5.39 mg, 7.35 μmol) at room temperature. The reaction mixture was purged with N2 and then stirred at 70 °C for 6 hours. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography (0%-50% ethyl acetate / n-heptane) to obtain the title compound (19.4 mg). The obtained compounds 1 The H-NMR spectrum (500 MHz, CDCl 3 ) was consistent with that of the compound obtained in Example A-10.

[0099] Example A-12 Synthesis of (2R,3S)-2-((2R,3R)-3-((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxiran-2-yl)pentan-3-yl 3,5-dinitrobenzoate To a solution of (2R,3S)-2-((2R,3R)-3-((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxiran-2-yl)pentane-3-ol (50 mg, 0.236 mmol) and DMAP (5.75 mg, 47 μmol) obtained in Example A-1-(3) in DCM (2 mL) was added Et3N (76 μL, 0.542 mmol) and 3,5-dinitrobenzoyl chloride (81 mg, 0.353 mmol) at 0°C. The reaction mixture was stirred at room temperature for 5 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated brine in sequence. The organic layer was dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0%-50% ethyl acetate / n-heptane) to obtain the title compound (72.1 mg). 1H-NMR (500MHz, CDCl3) δ (ppm): 0.98 (t, J = 7.3Hz, 3H), 1.12 (d, J = 6.7Hz, 3H), 1. 54(s,3H),1.74-1.81(m,2H),1.89(dd,J=14.7,7.3Hz,2H),2.00(dd,J=14.1,4 .3Hz,1H),2.50(s,1H),2.65(s,1H),2.71(dd,J=8.3,2.1Hz,1H),3.14-3.19(m ,1H),5.30(dt,J=8.1,5.1Hz,1H),9.17(d,J=2.5Hz,2H),9.24(t,J=2.1Hz,1H).

[0100] Example A-13 Synthesis of (2R,3S)-2-((2R,3R)-3-((R,E)-2-hydroxy-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-yl)oxiran-2-yl)pentan-3-yl 3,5-dinitrobenzoate A solution of copper (II) trifluoromethanesulfonate (8.90 mg, 25 μmol), B2pin2 (150 mg, 0.591 mmol), sodium tert-butoxide (4.73 mg, 49 μmol) and 2,6-di(1-pyrazolyl)pyridine (10.4 mg, 49 μmol) in MeCN (4 mL) and MeOH (60 μL) was stirred at room temperature for 30 min (the mixture became solution A). The 3,5-dinitrobenzoic acid (2R, 3S)-2-((2R, 3R)-3-((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxirane-2-yl)pentane-3-yl ester (40 mg, 98 μmol) obtained in Example A-12 was dissolved in solution A (810 μL). The resulting reaction mixture was stirred at 50 ° C for 19 hours. Solution A (810 μL) was added to the reaction mixture, and the reaction mixture was stirred at 50 ° C for 4 hours. The mixture was cooled to room temperature. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with water and saturated brine in sequence. The organic layer was dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0%-50% ethyl acetate / n-heptane) to obtain the title compound (15.2 mg). The obtained compounds 1 The H-NMR spectrum (500 MHz, CDCl 3 ) was consistent with that of the compound obtained in Example A-10.

[0101] Example A-14 Synthesis of Potassium Trifluoro((R,E)-3-Hydroxy-4-((2R,3R)-3-((2R,3S)-3-Hydroxypentan-2-yl)oxirane-2-yl)-3-methylbut-1-en-1-yl)borate To a solution of (2R, 3S)-2-((2R, 3R)-3-((R, E)-2-hydroxy-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)but-3-ene-1-yl)oxirane-2-yl)pentane-3-ol (30.7 mg, 0.09 mmol) obtained in Example A-8 in MeOH (0.5 mL) was added 4.5 M aqueous potassium hydrogen fluoride solution (140 μL, 0.63 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. 4.5 M aqueous potassium hydrogen fluoride solution (140 μL, 0.63 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. Hot acetone was added to the residue, and the supernatant was decanted (3 times). The combined supernatant was filtered and the filtrate was concentrated under reduced pressure. The residue was triturated with diethyl ether. The obtained solid was collected by filtration, washed with diethyl ether and dried under reduced pressure to give the title compound (22.2 mg). 1 H-NMR (500MHz, CDCl3) δ (ppm): 0.84 (br.d, J = 3.7Hz, 3H), 0.89-0.97 (m, 3H), 1.32 (br.s, 3H), 1.42-1.61 (m, 3H), 1.64-1.82 (m, 2 H), 2.75 (br.s, 1H), 2.90 (br.s, 1H), 3.54-3.72 (m, 2H), 3.91 (br.s, 1H), 5.59 (br.d, J = 16.5Hz, 1H), 6.02 (br.d, J = 16.5Hz, 1H).

[0102] Example A-15 Synthesis of (2R,3S)-2-((2R,3R)-3-((R)-2-hydroxy-2-methylbut-3-en-1-yl)oxiran-2-yl)pentan-3-ol To a solution of (2R,3S)-2-((2R,3R)-3-((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxiran-2-yl)pentan-3-ol (680 mg, 3.20 mmol) obtained in Example A-1-(3) in MeOH (13.6 mL) was added diethylenetriamine (0.348 mL, 3.20 mmol) and 0.3% palladium / boron nitride (34.1 mg, 0.961 μmol; prepared according to Adv. Synth. Catal. 2012, 354, 1264-1268) at 25°C. The reaction mixture was stirred at room temperature for 7.25 hours under a hydrogen atmosphere (at standard pressure). Ethyl acetate (15 mL) was added to the reaction solution, and the catalyst was then filtered out through a microporous filter and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. Ethyl acetate and 5% brine were added to the residue, and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 times). The combined organic layers were dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30%-60% ethyl acetate / n-heptane) to obtain the title compound (654 mg). 1 The H-NMR spectrum (500 MHz, CDCl 3 ) was consistent with that of the compound obtained in Example A-2.

[0103] Example A-16 Synthesis of (2R,3S)-2-((2R,3R)-3-((R,E)-2-hydroxy-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-yl)oxiran-2-yl)pentan-3-yl 3,5-dinitrobenzoate

[0104] A-16-(1) Synthesis of (2R,3S)-2-((2R,3R)-3-((R,E)-2-hydroxy-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-yl)oxiran-2-yl)pentan-3-ol A mixture of (2R, 3S)-2-((2R, 3R)-3-((R)-2-hydroxy-2-methylbut-3-yn-1-yl)oxirane-2-yl)pentane-3-ol (880 mg, 4.15 mmol), [1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene] copper(I) chloride (16.7 mg, 0.041 mmol), B2pin2 (1.16 g, 4.56 mmol) and sodium hydroxide (8.29 mg, 0.207 mmol) obtained in Example A-1-(3) was purged with nitrogen. Cyclopentyl methyl ether (17.6 mL) and MeOH (335 μL) were added to the mixture. The resulting reaction mixture was stirred at room temperature for 3.4 hours. The reaction mixture was quenched with water and extracted with ethyl acetate (3 times). The combined organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (0%-50% ethyl acetate / n-heptane) to obtain the title compound (1.55 g, weight content by NMR: 71.0%). 1 The H-NMR spectrum (500 MHz, CDCl 3 ) was consistent with that of the compound obtained in Example A-8.

[0105] A-16-(2) Synthesis of (2R,3S)-2-((2R,3R)-3-((R,E)-2-hydroxy-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-yl)oxiran-2-yl)pentan-3-yl 3,5-dinitrobenzoate At 0°C, to a solution of (2R,3S)-2-((2R,3R)-3-((R,E)-2-hydroxy-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-yl)oxirane-2-yl)pentan-3-ol (1.55 g, weight content by NMR: 71.0%, 3.23 mmol), DMAP (79 mg, 647 μmol), and Et3N (0.901 mL, 6.47 mmol) obtained in Example A-16-(1) was added 3,5-dinitrobenzoyl chloride (1.04 g, 4.53 mmol), and the mixture was stirred at the same temperature for 1 hour. 3,5-dinitrobenzoyl chloride (155mg, 0.672mmol) was added to the reaction mixture, and the mixture was stirred at 0°C for 2 hours. Then 3,5-dinitrobenzoyl chloride (155mg, 0.672mmol) and Et3N (0.240mL, 1.72mmol) were added thereto, and the mixture was stirred at 0°C for 1 hour. The reaction mixture was returned to room temperature, stirred for 2 hours and 40 minutes, and then 3,5-dinitrobenzoyl chloride (155mg, 0.672mmol) and Et3N (0.470mL, 3.37mmol) were added thereto, and the mixture was stirred at room temperature for 15 minutes. Further, 3,5-dinitrobenzoyl chloride (155mg, 0.672mmol) was added thereto, and the mixture was stirred at room temperature for 15 minutes. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and the mixture was stirred at room temperature for 20 minutes. Ethyl acetate and water were added to the mixture obtained, and the organic layer was separated. The organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine in sequence, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0%-30% ethyl acetate / n-heptane) and concentrated under reduced pressure to obtain a residue (1.39 g) containing the title compound. Ethyl acetate (3.5 mL) and n-heptane (14 mL) were added to the residue, and the residue was dissolved at 100 ° C. The resulting solution was slowly cooled to room temperature. The precipitated solid was collected by filtration, washed with n-heptane, and dried under reduced pressure to obtain the title compound (920 mg, weight content of NMR: 96.3%) as a solid. The compound mentioned as the main component 1 The H-NMR spectrum (500 MHz, CDCl3) was consistent with that in Example A-10.

[0106] Example A-17 Synthesis of ((R,E)-4-((2R,3R)-3-((2R,3S)-3-((3,5-dinitrobenzoyl)oxy)pentan-2-yl)oxirane-2-yl)-3-hydroxy-3-methylbut-1-en-1-yl)boronic acid 3,5-dinitrobenzoic acid (2R, 3S)-2-((2R, 3R)-3-((R, E)-2-hydroxy-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-yl)oxiran-2-yl)pentane-3-yl ester (24.5 mg, 0.046 mmol), ammonium acetate (10.6 mg, 0.138 mmol) and sodium periodate (29.4 mg, 0.138 mmol) obtained in Example A-10 were dissolved in a mixed solution of acetone (1.0 mL) and water (0.5 mL). The reaction mixture was vigorously stirred at room temperature for 23 hours. Ammonium acetate (10.6mg, 0.138mmol), sodium periodate (29.4mg, 0.138mmol), acetone (1.0mL) and water (0.5mL) are added to the reaction mixture, and the mixture is further stirred for 6 hours. The reaction solution is filtered to remove solids, and the solids are washed with MTBE. The filtrate obtained is concentrated under reduced pressure. Ethyl acetate and water are added to the residue, and the organic layer is separated. The organic layer is washed with saturated brine and then concentrated under reduced pressure. The concentrated residue solution in acetonitrile (0.6mL) and water (0.3mL) is stirred at room temperature for 1 hour, and then stirred at 70°C for 1 hour. The reaction mixture is slowly cooled to 0°C and water (2.0mL) is added thereto. The mixture is concentrated under reduced pressure. Toluene is added to the concentrated residue, and the resulting mixture is concentrated under reduced pressure again to obtain the title compound (20.1mg). 1 H-NMR(500MHz,DMSO-d6)δ(ppm):0.89(t,J=7.3Hz,3H),1.00(d,J=7.3Hz,3H),1.16(s,3H ),1.47(dd,J=14.1,6.1Hz,1H),1.61-1.70(m,2H),1.79(q,J=7.2Hz,2H),2.63(dd,J=8.0 ,1.8Hz,1H),2.83(td,J=5.7,2.1Hz,1H),4.65(s,1H),5.14-5.20(m,1H),5.46(d,J=17.7 Hz,1H),6.45(d,J=18.3Hz,1H),7.49(s,2H),8.93(d,J=2.5Hz,2H),9.05(t,J=2.1Hz,1H)

[0107] Example B-1 Synthesis of (3S,4S,E)-1-iodo-2,4-dimethylhexa-1,5-dien-3-yl (3R,6R,7S)-3-((tert-butyldimethylsilyl)oxy)-7-((4-methoxybenzyl)oxy)-6-methyl-6-((triethylsilyl)oxy)non-8-enoate Under ice cooling, to a solution of (3R,6R,7S)-3-((tert-butyldimethylsilyl)oxy)-7-((4-methoxybenzyl)oxy)-6-methyl-6-((triethylsilyl)oxy)non-8-enoic acid (CAS No. 1399679-73-2; Org. Lett. [Org. Express] 2012, 14, 4730-4733) (261 mg, 0.46 mmol) and Et3N (90 μL, 0.645 mmol) in THF (10 mL), 2,4,6-trichlorobenzoyl chloride (86 μL, 0.552 mmol) was added, and the reaction mixture was stirred at room temperature for 80 minutes. Under ice cooling, Et3N (90 μL, 0.645mmol) and 2,4,6-trichlorobenzoyl chloride (86 μL, 0.552mmol) were added to the reaction mixture, and the reaction mixture was then stirred at room temperature for 2 hours. Under ice cooling, Et3N (90 μL, 0.645mmol) and 2,4,6-trichlorobenzoyl chloride (86 μL, 0.552mmol) were added to the reaction mixture, and the reaction mixture was then stirred at room temperature for 1 hour. The insoluble material in the reaction mixture was filtered out and the filtrate was concentrated under reduced pressure. Under ice water, to a solution of the concentrated residue in toluene (4 mL), (3S, 4S, E)-1-iodo-2,4-dimethylhexa-1,5-dien-3-ol (CAS No. 952487-46-6; Eur. J. Org. Chem. [European Journal of Organic Chemistry] 2016, 2110-2114) (348 mg, 1.38 mmol) and DMAP (197 mg, 1.61 mmol) in toluene (6 mL) were added over 5 minutes. The resulting reaction mixture was stirred at room temperature overnight. To the reaction mixture, add MTBE, water and 0.5N hydrochloric acid, and separate the organic layer.The organic layer is washed with saturated sodium bicarbonate aqueous solution and saturated brine successively.The organic layer is dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure.The gained residue is purified by silica gel column chromatography (0%-3% ethyl acetate / n-heptane), to obtain a mixture of title compound and impurity (520mg).The reaction mixture is further purified by silica gel column chromatography (0%-3% ethyl acetate / n-heptane), to obtain the title compound (323mg). 1 H-NMR (500MHz, CDCl3) δ (ppm): 0.02 (s, 3H), 0.04 (s, 3H), 0.50-0.61 (m, 6H), 0.86 (s, 9H), 0.88-0.96 (m, 12H), 1.16 (s, 3H), 1.1 9-1.25(m,1H),1.40-1.53(m,2H),1.69-1.78(m,1H),1.80(s,3H),2.29-2.57(m,3H),3.50(d,J=7.6Hz,1H),3.80(s,3H),3.95- 4.06(m,1H),4.23(d,J=11.7Hz,1H),4.50(d,J=11.7Hz,1H),4.97-5.08(m,2H),5.09-5.15(m,1H),5.22(br.d,J=17.2Hz,1H), 5.31(d,J=10.3Hz,1H),5.60-5.73(m,1H),5.76-5.89(m,1H),6.30(s,1H),6.86(br.d,J=6.9Hz,2H),7.24(br.d,J=6.9Hz,2H).

[0108] Example B-2 Synthesis of (3S,4S,E)-1-iodo-2,4-dimethylhexa-1,5-dien-3-yl (3R,6R,7S)-3-((tert-butyldimethylsilyl)oxy)-7-hydroxy-6-methyl-6-((triethylsilyl)oxy)non-8-enoate To a solution of (3S,4S,E)-1-iodo-2,4-dimethylhexa-1,5-dien-3-yl (3R,6R,7S)-3-((tert-butyldimethylsilyl)oxy)-7-((4-methoxybenzyl)oxy)-6-methyl-6-((triethylsilyl)oxy)non-8-enoate (311 mg, 0.388 mmol) obtained in Example B-1 in DCM (5 mL) were added 1 M phosphate buffer (pH=7.0, 0.5 mL) and DDQ (115 mg, 0.505 mmol) in sequence. The reaction mixture was stirred at room temperature for 100 minutes. DCM (3 mL), 1 M phosphate buffer (pH=7.0, 0.3 mL) and DDQ (115 mg, 0.505 mmol) were added to the reaction mixture and the reaction mixture was stirred at room temperature for 1 hour. Then DCM (1mL), 1M phosphate buffer (pH=7.0, 0.1mL) and DDQ (25mg, 0.11mmol) are added to the reaction mixture and the reaction mixture is stirred at room temperature for 40 minutes. MTBE, saturated sodium bicarbonate aqueous solution and water are added to the reaction mixture, and the organic layer is separated. The organic layer is washed with water and saturated brine in sequence. The organic layer is dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (0%-5% MTBE / n-heptane) to obtain the title compound (249mg). 1 H-NMR (500MHz, CDCl3) δ (ppm): 0.03 (s, 3H), 0.06 (s, 3H), 0.63 (q, J = 7.6Hz, 6H), 0.87 (s, 9H), 0.90-1.02 (m, 12H), 1.22 (s ,3H),1.28-1.33(m,1H),1.47-1.54(m,1H),1.55-1.61(m,1H),1.67-1.75(m,1H),1.81(d,J=1.4Hz,3H),2.33-2.55(m,3 H),2.60(d,J=3.4Hz,1H),3.78-3.90(m,1H),4.03(quin,J=5.9Hz,1H),4.96-5.10(m,2H),5.13(d,J=8.3Hz,1H),5.20(d d,J=10.3,1.4Hz,1H),5.31(dt,J=17.2,1.7Hz,1H),5.57-5.74(m,1H),5.84(ddd,J=17.2,10.7,6.5Hz,1H),6.32(s,1H).

[0109] Example B-3 Synthesis of (4R,7R,8S,11S,12S,E)-4-((tert-butyldimethylsilyl)oxy)-8-hydroxy-12-((E)-1-iodoprop-1-en-2-yl)-7,11-dimethyl-7-((triethylsilyl)oxacyclododec-9-en-2-one To p-benzoquinone (77 mg, 0.717 mmol) was added a toluene solution (1,200 mL) of (3R, 6R, 7S)-3-((tert-butyldimethylsilyl)oxy)-7-hydroxy-6-methyl-6-((triethylsilyl)oxy)non-8-enoic acid (3S, 4S, E)-1-iodo-2,4-dimethylhexa-1,5-dien-3-yl ester (4.88 g, 7.167 mmol) obtained in Example B-2. To the mixture heated to 100° C., a toluene solution (20 mL) of Grubbs-II (0.61 g, 0.717 mmol) was added dropwise over 70 minutes using a syringe pump. The reaction mixture was cooled to room temperature, and the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0%-5% ethyl acetate / n-heptane) to obtain the title compound (3.51 g). 1 H-NMR (500MHz, CDCl3) δ (ppm): 0.07 (s, 3H), 0.08 (s, 3H), 0.65 (q, J = 7.8Hz, 6H), 0.89-0.94 (m, 12H) ),0.95-1.02(m,9H),1.32(s,3H),1.34-1.43(m,2H),1.45-1.54(m,1H),1.57-1.64(m,1H),1.80(d ,J=1.2Hz,3H),2.38-2.56(m,3H),2.64(d,J=10.9Hz,1H),3.56(t,J=10.0Hz,1H),3.76-3.85(m,1H ), 5.12 (d, J = 10.9Hz, 1H), 5.36 (dd, J = 14.9, 9.7Hz, 1H), 5.60 (dd, J = 14.9, 9.7Hz, 1H), 6.45 (s, 1H).

[0110] Example B-4 Synthesis of (2S,3S,6S,7R,10R,E)-10-((tert-butyldimethylsilyl)oxy)-2-((E)-1-iodoprop-1-en-2-yl)-3,7-dimethyl-12-oxo-7-((triethylsilyl)oxy)oxacyclododec-4-en-6-yl acetate To a solution of (4R,7R,8S,11S,12S,E)-4-((tert-butyldimethylsilyl)oxy)-8-hydroxy-12-((E)-1-iodoprop-1-en-2-yl)-7,11-dimethyl-7-((triethylsilyl)oxacyclododecan-9-en-2-one (110 mg, 0.169 mmol) obtained in Example B-3 in pyridine (3 mL) was added Ac2O (1.45 mL, 15.3 mmol). The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0%-4% ethyl acetate / n-heptane) to obtain the title compound (113 mg). 1 H-NMR (500MHz, CDCl3) δ (ppm): 0.06 (s, 3H), 0.07 (s, 3H), 0.59-0.66 (m, 6H), 0.90 (s, 12H), 0 .99(t,J=7.6Hz,9H),1.21(s,3H),1.31-1.35(m,1H),1.37-1.49(m,2H),1.58-1.70(m,1H), 1.81(s,3H),2.06(s,3H),2.35-2.53(m,3H),3.66-3.89(m,1H),4.97(d,J=9.8Hz,1H),5.11 (d, J=11.0Hz, 1H), 5.56 (dd, J=15.3, 9.8Hz, 1H), 5.66 (dd, J=15.9, 9.8Hz, 1H), 6.45 (s, 1H).

[0111] Example B-5 Synthesis of (4R,7R,8S,11S,12S,E)-4-((tert-butyldimethylsilyl)oxy)-7,8-dihydroxy-12-((E)-1-iodoprop-1-en-2-yl)-7,11-dimethyloxacyclododec-9-en-2-one To a solution of (4R,7R,8S,11S,12S,E)-4-((tert-butyldimethylsilyl)oxy)-8-hydroxy-12-((E)-1-iodoprop-1-en-2-yl)-7,11-dimethyl-7-((triethylsilyl)oxacyclododec-9-en-2-one (260 mg, 0.398 mmol) obtained in Example B-3 in THF (10 mL) were added AcOH (30 μL, 0.518 mmol) and a THF solution of TBAF (1 M) in sequence under ice water. ; 0.518mL, 0.518mmol). The resulting mixture was stirred at room temperature for 3 hours and 30 minutes. Under ice cooling, the reaction mixture was quenched with saturated sodium bicarbonate aqueous solution. MTBE was added to the mixture, and the organic layer was separated. The aqueous layer was extracted with MTBE. The combined organic layers were washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0%-30% ethyl acetate / n-heptane) to obtain the title compound (208mg). 1 H-NMR (500MHz, CDCl3) δ (ppm): 0.07 (s, 3H), 0.08 (s, 3H), 0.85-0.94 (m, 12 H),1.30(s,3H),1.34-1.47(m,3H),1.58-1.65(m,1H),1.79(s,3H),1.85(d ,J=4.3Hz,1H),2.30-2.60(m,4H),3.72-3.91(m,2H),5.12(d,J=10.4Hz,1 H),5.43(dd,J=15.3,9.8Hz,1H),5.73(dd,J=15.3,9.8Hz,1H),6.45(s,1H)

[0112] Example B-6 Synthesis of (2S,3S,6S,7R,10R,E)-10-((tert-butyldimethylsilyl)oxy)-7-hydroxy-2-((E)-1-iodoprop-1-en-2-yl)-3,7-dimethyl-12-oxooxadecan-4-en-6-yl acetate Under ice cooling, to (4R, 7R, 8S, 11S, 12S, E) -4- ((tert-butyldimethylsilyl) oxy) -7, 8- dihydroxy -12- ((E) -1- iodoprop-1-ene-2-yl) -7, 11- dimethyloxacyclododec-9-ene-2-one (144mg, 0.268mmol) and DMAP (6.54mg, 54μmol) obtained in Example B-5, Et was added successively to a solution in DCM (4mL) N (0.112mL, 0.803mmol) and Ac O (27μL, 0.281mmol). The reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution. MTBE was added to the mixture obtained, and the organic layer was separated. The organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (0%-20% ethyl acetate / n-heptane) to obtain the title compound (149 mg). 1 H-NMR (500MHz, CDCl3) δ (ppm): 0.06 (s, 3H), 0.08 (s, 3H), 0.80-0.96 (m, 12H), 1.21 (s, 3H), 1. 30-1.48(m,3H),1.61-1.72(m,1H),1.78(d,J=1.2Hz,3H),2.08(s,1H),2.09(s,3H),2.35-2. 43(m,1H),2.43-2.56(m,2H),3.84(dq,J=8.3,4.2Hz,1H),5.06(d,J=9.8Hz,1H),5.09(d,J=1 0.4Hz, 1H), 5.60 (dd, J=15.3, 9.8Hz, 1H), 5.68 (dd, J=15.3, 9.8Hz, 1H), 6.46 (d, J=1.2Hz, 1H).

[0113] Example B-7 Synthesis of (4R,7R,8S,11S,12S,E)-4,7,8-trihydroxy-12-((E)-1-iodoprop-1-en-2-yl)-7,11-dimethyloxacyclododec-9-en-2-one To a solution of (4R,7R,8S,11S,12S,E)-4-((tert-butyldimethylsilyl)oxy)-8-hydroxy-12-((E)-1-iodoprop-1-en-2-yl)-7,11-dimethyl-7-((triethylsilyl)oxacyclododecan-9-en-2-one (600 mg, 0.919 mmol) obtained in Example B-3 in THF (6 mL) was added a THF solution of TBAF (1 M; 5.51 mL, 5.51 mmol) under ice water. The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride solution. Ethyl acetate and saturated brine were added to the obtained mixture, and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0%-80% ethyl acetate / n-heptane) to obtain the title compound (312 mg). 1 H-NMR (500MHz, CDCl3) δ (ppm): 0.92 (d, J = 6.7Hz, 3H), 1.15-1.27 (m, 1H), 1.31 (s, 3H), 1.35-1.5 2(m,2H),1.69(tt,J=13.3,3.8Hz,1H),1.80-1.87(m,4H),2.36(s,1H),2.46-2.59(m,2H),2.61- 2.69(m,1H),3.39(d,J=11.0Hz,1H),3.69-3.78(m,1H),3.81(dd,J=9.8,4.3Hz,1H),5.30(d,J= 10.4Hz, 1H), 5.39 (dd, J=15.0, 10.1Hz, 1H), 5.75 (dd, J=15.3, 9.8Hz, 1H), 6.48 (d, J=1.2Hz, 1H).

[0114] Example B-8 Synthesis of (2S,3S,6S,7R,10R,E)-7,10-dihydroxy-2-((E)-1-iodoprop-1-en-2-yl)-3,7-dimethyl-12-oxooxacyclodec-4-en-6-yl acetate Under ice cooling, to the solution of (4R, 7R, 8S, 11S, 12S, E) -4,7,8- trihydroxy -12- ((E) -1- iodoprop- 1- ene- 2-yl) -7,11- dimethyloxacyclo dodeca- 9-ene- 2- ketone (220mg, 0.519mmol) and DMAP (12.7mg, 0.104mmol) in DCM (5.5mL) were added Et3N (0.216mL, 1.56mmol) and Ac2O (51μL, 0.544mmol) successively. The reaction mixture was stirred at the same temperature for 1 hour. The reaction solution was quenched with saturated sodium bicarbonate aqueous solution. Ethyl acetate was added to the mixture obtained, and the organic layer was separated. The organic layer was washed with water three times. The combined water layer was re-extracted with ethyl acetate. The ethyl acetate layer obtained by re-extraction was washed with water and saturated brine successively. All combined organic layers were dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (30%-80% ethyl acetate / n-heptane) to obtain the title compound (200 mg). 1 H-NMR (500MHz, CDCl3) δ (ppm): 0.90 (d, J = 6.8Hz, 3H), 1.21 (s, 3H), 1.23-1.33 (m, 2H), 1.38 (t d,J=13.2,3.9Hz,1H),1.65-1.74(m,1H),1.83(d,J=1.0Hz,3H),2.07(s,1H),2.09(s,3H),2.4 4-2.69(m,3H),3.40(d,J=10.7Hz,1H),3.71-3.81(m,1H),5.07(d,J=9.3Hz,1H),5.31(d,J=1 0.7Hz, 1H), 5.58 (dd, J = 15.1, 9.3Hz, 1H), 5.69 (dd, J = 15.1, 9.3Hz, 1H), 6.48 (d, J = 1.5Hz, 1H).

[0115] Example B-9 Synthesis of (2S,3S,6S,7R,10R,E)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-((E)-penta-2,4-dien-2-yl)oxacyclododec-4-en-6-yl acetate

[0116] B-9-(1) Synthesis of Methyl (R)-3-((tert-butyldimethylsilyl)oxy)-5-((2S,4R,5S)-5-((1E,3S,4S,5E)-4-hydroxy-6-iodo-3,5-dimethylhexa-1,5-dien-1-yl)-4-methyl-2-phenyl-1,3-dioxolan-4-yl)pentanoate A solution of Hoveyda-Grubbs-II (24 mg, 38 μmol) in toluene (7.8 mL) was prepared. This was referred to as Liquid C. Liquid C (2.6 mL) was added to (R)-3-((tert-butyldimethylsilyl)oxy)-5-((2S,4R,5S)-4-methyl-2-phenyl-5-vinyl-1,3-dioxolan-4-yl)pentanoic acid methyl ester (CAS No. 934497-57-1; Angew. Chem. Int. Ed. [German Angewandte Chemie] 2007, 46, 4350-4350) synthesized according to the method described in the literature. 55) (178 mg, 0.410 mmol) and (3S,4S,E)-1-iodo-2,4-dimethylhexa-1,5-dien-3-ol (CAS No. 952487-46-6; Eur. J. Org. Chem. [European Journal of Organic Chemistry] 2016, 2110-2114) (206 mg, 0.819 mmol) synthesized according to the method described in the literature in toluene (13 mL). The reaction mixture was stirred at 110° C. for 4 hours under nitrogen bubbling. Liquid C (1.3 mL) was added to the reaction mixture, and the mixture was stirred under the same conditions for 2 hours. Then liquid C (1.3 mL) was added to the reaction mixture, and the mixture was stirred under the same conditions for 4 hours. Liquid C (2.6 mL) was further added to the reaction mixture, and the mixture was stirred at 100° C. for 13.5 hours under nitrogen bubbling. The reaction mixture was cooled to room temperature. The reaction mixture was directly purified by silica gel column chromatography (NH silica gel, 0%-30% ethyl acetate / n-heptane) to obtain the title compound (234 mg). 1H-NMR (500MHz, CDCl3) δ (ppm): 0.01 (s, 3H), 0.03 (s, 3H), 0.85 (s, 9H), 0.98 (d, J = 7.3Hz, 3H), 1.32 (s, 3H) ),1.56-1.75(m,4H),1.81(d,J=1.2Hz,3H),1.86(d,J=3.7Hz,1H),2.32-2.38(m,1H),2.40-2.46(m,2H) ,3.64(s,3H),3.93(dd,J=7.0,4.0Hz,1H),4.07-4.13(m,1H),4.27(d,J=7.3Hz,1H),5.62(dd,J=15.6,7 .6Hz,1H),5.80(dd,J=15.3,8.0Hz,1H),5.90(s,1H),6.26(s,1H),7.34-7.39(m,3H),7.47-7.49(m,2H).

[0117] B-9-(2) Synthesis of (R)-3-((tert-butyldimethylsilyl)oxy)-5-((2S,4R,5S)-5-((1E,3S,4S,5E)-4-hydroxy-6-iodo-3,5-dimethylhexa-1,5-dien-1-yl)-4-methyl-2-phenyl-1,3-dioxolan-4-yl)pentanoic acid Lithium hydroxide (149 mg, 3.55 mmol) was added to a solution of (R)-3-((tert-butyldimethylsilyl)oxy)-5-((2S, 4R, 5S)-5-((1E, 3S, 4S, 5E)-4-hydroxy-6-iodo-3,5-dimethylhexa-1,5-diene-1-yl)-4-methyl-2-phenyl-1,3-dioxolan-4-yl)pentanoic acid methyl ester (234 mg, 0.355 mmol) obtained in Example B-9-(1) in THF (5 mL) and water (2.5 mL). The reaction mixture was sonicated to dissolve lithium hydroxide. The mixture was stirred at room temperature for 3 days. 0.5 N hydrochloric acid and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The aqueous layer was re-extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (251 mg). The crude product was used in the subsequent reaction without further purification. 1H-NMR (500MHz, CDCl3) δ (ppm): 0.07 (s, 6H), 0.88 (s, 9H), 0.96 (d, J = 6.7Hz, 3H), 1.32 (s, 3H), 1.35-1.3 8(m,1H),1.59-1.66(m,3H),1.73-1.80(m,1H),1.82(d,J=1.2Hz,3H),2.39-2.46(m,1H),2.48(d,J=4. 9Hz,2H),3.93(d,J=7.3Hz,1H),4.03(quin,J=5.7Hz,1H),4.28(d,J=7.3Hz,1H),5.59(dd,J=15.3,7.3 Hz,1H),5.77(dd,J=15.9,8.0Hz,1H),5.91(s,1H),6.25(s,1H),7.34-7.39(m,3H),7.45-7.49(m,2H).

[0118] B-9-(3) Synthesis of (2S,3aS,6S,7S,11R,13aR,E)-11-((tert-butyldimethylsilyl)oxy)-7-((E)-1-iodoprop-1-en-2-yl)-6,13a-dimethyl-2-phenyl-3a,6,7,10,11,12,13,13a-octahydro-9H-[1,3]dioxol[4,5-f][1]oxacyclododecane-9-one To a solution of 2-methyl-6-nitrobenzoic anhydride (351 mg, 1.02 mmol) and DMAP (249 mg, 2.04 mmol) in toluene (40 mL) stirred at 120 ° C, a syringe pump was used to dropwise add a solution of (R)-3-((tert-butyldimethylsilyl)oxy)-5-((2S, 4R, 5S)-5-((1E, 3S, 4S, 5E)-4-hydroxy-6-iodo-3,5-dimethylhexa-1,5-diene-1-yl)-4-methyl-2-phenyl-1,3-dioxolan-4-yl)pentanoic acid (219 mg, 0.340 mmol) in toluene (10 mL) obtained in Example B-9-(2) over 5 hours. After the addition was completed, the reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was cooled to room temperature. The reaction mixture was directly purified twice by silica gel column chromatography (silica gel, 0%-15% ethyl acetate / n-heptane) to obtain the title compound (188 mg). 1H-NMR (500MHz, CDCl3) δ (ppm): 0.08 (s, 3H), 0.09 (s, 3H), 0.89 (s, 9H), 0.89-0.90 (m, 3H), 1.32-1.37 (m, 1H), 1.38 ( s,3H),1.40-1.47(m,1H),1.63(br.t,J=11.6Hz,1H),1.81(d,J=1.2Hz,3H),2.04(td,J=12.7,7.6Hz,1H),2.33(dd, J=14.4,10.1Hz,1H),2.53-2.63(m,2H),3.93-3,99(m,1H),4.18(d,J=9.8Hz,1H),5.10(d,J=10.4Hz,1H),5.38(dd ,J=15.0,9.5Hz,1H),5.65(dd,J=15.3,9.8Hz,1H),5.91(s,1H),6.47(s,1H),7.36-7.40(m,3H),7.48-7.51(m,2H).

[0119] B-9-(4) Synthesis of (2S,3aS,6S,7S,11R,13aR,E)-11-((tert-butyldimethylsilyl)oxy)-6,13a-dimethyl-7-((E)-penta-2,4-dien-2-yl)-2-phenyl-3a,6,7,10,11,12,13,13a-octahydro-9H-[1,3]dioxolo[4,5-f][1]oxacyclododecane-9-one (CAS No. 934497-98-0) To the (2S,3aS,6S,7S,11R,13aR,E)-11-((tert-butyldimethylsilyl)oxy)-7-((E)-1-iodoprop-1-en-2-yl)-6,13a-dimethyl-2-phenyl-3a,6,7,10,11,12,13,13a-octahydro-9H-[1,3]dioxol[4,5-f][1]oxy To a solution of heterocyclododecane-9-one (70.8 mg, 0.113 mmol) and 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (70.0 mg, 0.452 mmol) in THF (2 mL) and water (0.2 mL) was added Ag2O (131 mg, 0.565 mmol) and Pd(dppf)Cl2 (16.5 mg, 23 μmol). The reaction mixture was stirred at room temperature for 1 hour. The insoluble matter in the reaction mixture was passed through Celite TMFiltered off and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel, 0%-10% ethyl acetate / n-heptane) to obtain the title compound (57.4 mg). 1 H-NMR (500MHz, CDCl3) δ (ppm): 0.07 (s, 3H), 0.09 (s, 3H), 0.88 (s, 9H), 0.90 (s, 3H), 1.26-1.33 (m, 1H), 1.39 (s, 3H), 1.41 (br.d, J=8.0 Hz,1H),1.61-1.67(m,1H),1.74(s,3H),2.01-2.09(m,1H),2.31(dd,J=14.7,10.4Hz,1H),2.54-2.64(m,2H),3.94-4.02(m,1H),4.19 (d,J=9.2Hz,1H),4.98(d,J=10.4Hz,1H),5.17(dd,J=10.4,1.2Hz,1H),5.27(dd,J=16.8,1.5Hz,1H),5.42(dd,J=15.3,9.8Hz,1H),5. 64(dd,J=15.0,9.5Hz,1H),5.91(s,1H),6.13(d,J=11.0Hz,1H),6.54(dt,J=16.7,10.6Hz,1H),7.35-7.41(m,3H),7.48-7.53(m,2H).

[0120] B-9-(5) Synthesis of (4R,7R,8S,11S,12S,E)-4,7,8-trihydroxy-7,11-dimethyl-12-((E)-penta-2,4-dien-2-yl)oxacyclododec-9-en-2-one (CAS No. 934497-99-1) PPTS (180 mg, 0.717 mmol) was added to a solution of (2S, 3aS, 6S, 7S, 11R, 13aR, E) -11- ((tert-butyldimethylsilyl) oxy) -6, 13a- dimethyl -7- ((E) -penta-2, 4-dien-2-yl) -2-phenyl -3a, 6, 7, 10, 11, 12, 13, 13a- octahydro -9H- [1, 3] dioxol [4, 5-f] [1] oxacyclododecan-9-one (40.4 mg, 77 μmol) in MeOH (2 mL) obtained in Example B-9- (4). The reaction mixture was stirred at room temperature for 1 day. MeOH (6 mL) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 2 hours. MeOH (6 mL) was further added to the reaction mixture, and the mixture was stirred at room temperature for 4 days. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (silica gel, 0% to 100% ethyl acetate / n-heptane) to obtain the title compound (17.5 mg). 1 H-NMR (500MHz, CDCl3) δ (ppm) 0.92 (dd, J = 6.7, 1.2Hz, 3H), 1.31 (d, J = 1.2Hz, 3H), 1.40 (td, J = 13.5, 3.7Hz, 1H), 1.4 9(br.t,J=13.5Hz,1H),1.65-1.73(m,1H),1.76(s,3H),1.82(br.d,J=3.1Hz,1H),2.38(s,1H),2.50-2.58(m,2H),2 .60-2.66(m,1H),3.53(d,J=10.4Hz,1H),3.72-3.78(m,1H),3.82(br.dd,J=9.8,2.5Hz,1H),5.19(br.t,J=11.6Hz, 2H), 5.26 (s, 1H), 5.30 (s, 1H), 5.40-5.48 (m, 1H), 5.70-5.77 (m, 1H), 6.12 (br.d, J = 11.0Hz, 1H), 6.51-6.61 (m, 1H).

[0121] B-9-(6) Synthesis of (2S,3S,6S,7R,10R,E)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-((E)-penta-2,4-dien-2-yl)oxacyclododec-4-en-6-yl acetate (CAS No. 934498-00-7) Ac2O (2.3 μ L, 25 μ mol) is added to a solution of (4R, 7R, 8S, 11S, 12S, E) -4,7,8- trihydroxy -7,11- dimethyl -12- ((E) -penta-2,4- diene -2- base) oxacyclododec-9-ene-2-one (8.0 mg, 25 μ mol), triethylamine (3.4 μ L, 25 μ mol) and DMAP (0.6 mg, 5 μ mol) in DCM (1 ml) obtained in Example B-9- (5). The reaction mixture is stirred at room temperature for 1 day. The reaction solution is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (silica gel, 0% to 100% ethyl acetate / n-heptane) to obtain the title compound (5.4 mg). 1 H-NMR (500MHz, CDCl3) δ (ppm): 0.91 (d, J = 6.7Hz, 3H), 1.22 (s, 3H), 1.29-1.47 (m, 3H), 1.51-1.56 (m, 1H), 1. 67-1.75(m,1H),1.76(s,3H),2.10(s,3H),2.49-2.58(m,2H),2.64(dd,J=15.0,3.4Hz,1H),3.53(d,J=11.0H z,1H),3.76(ddt,J=10.9,7.3,3.4Hz,1H),5.10(d,J=9.2Hz,1H),5.16-5.23(m,2H),5.23-5.36(m,1H),5.6 2(dd,J=15.3,9.8,1H), 5.68(dd,J=15.3,9.2Hz,1H), 6.13(d,J=11.0Hz,1H), 6.56(dt,J=17.0,10.5Hz,1H). According to the method described in the literature (Angew. Chem. Int. Ed. [German Angewandte Chemie] 2007, 46, 4350-4355), pranidolactone D can be synthesized by cross-metathesis reaction of the obtained compound with the compound of Example A-2.

[0122] Example C-1 Synthesis of Pradinolide D A solution of (2S, 3S, 6S, 7R, 10R, E) -7, 10-dihydroxy -2- ((E) -1- iodoprop- 1- en-2-yl) -3, 7- dimethyl -12- oxooxacyclodec-4-en-6-yl ester (5.37 mg, 12 μmol) of acetic acid obtained in Example B-8 and (2R, 3S) -2- ((2R, 3R) -3- ((R) -2-hydroxy-2-methylbut- 3- en- 1-yl) oxiran- 2-yl) pentane-3-ol (4.94 mg, 23 μmol) obtained in Example A-2 in DMF (0.8 mL) was degassed and then replaced with a nitrogen atmosphere. Pd (OAc) 2 (0.65 mg, 2.9 μmol) and Ag 2 CO 3 (4.13 mg, 15 μmol) were added to the mixture at room temperature. The obtained reaction mixture was stirred at room temperature for 15 minutes, and then stirred at 60 ° C for 6 hours. After allowing the reaction mixture to cool, the insoluble material in the reaction mixture was filtered out by a microporous filter. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0%-5% MeOH / ethyl acetate) to obtain the title compound (4.7 mg). 1 H-NMR(500MHz,CD3OD)δ(ppm):0.88(d,J=6.9Hz,3H),0.90(d,J=6.9Hz,3H),0.94(t,J=7.5Hz,3H),1.19(s,3H),1.25-1.30(m,1H),1.34( s,3H),1.37-1.71(m,7H),1.78(d,J=1.2Hz,3H),1.87(dd,J=14.0,5.4Hz,1H),2.06(s,3H),2.50-2.55(m,2H),2.55-2.62(m,1H),2.67(d d,J=8.0,2.3Hz,1H),2.90(td,J=5.7,2.3Hz,1H),3.53(dt,J=8.7,4.5Hz,1H),3.79(br.dd,J=9.7,4.0Hz,1H),5.03-5.09(m,2H),5.57(d d,J=15.5,9.7Hz,1H),5.70(dd,J=14.9,9.7Hz,1H),5.87(d,J=14.9Hz,1H),6.14(dd,J=10.9,1.2Hz,1H),6.53(dd,J=15.5,10.9Hz,1H).

[0123] Example C-2 Synthesis of Pradinolide D

[0124] C-2-(1) Synthesis of (2S,3S,6S,7R,10R,E)-10-((tert-butyldimethylsilyl)oxy)-7-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl acetate A DMF solution (1 mL) of (2R, 3S)-2-((2R, 3R)-3-((R)-2-hydroxy-2-methylbut-3-en-1-yl)oxirane-2-yl)pentane-3-ol (10.8 mg, 50 μmol) obtained in Example A-2 and (2S, 3S, 6S, 7R, 10R, E)-10-((tert-butyldimethylsilyl)oxy)-7-hydroxy-2-((E)-1-iodoprop-1-en-2-yl)-3,7-dimethyl-12-oxoxodec-4-en-6-yl acetate (14.5 mg, 25 μmol) obtained in Example B-6 was degassed and then replaced with a nitrogen atmosphere. Pd(OAc)2 (1.4 mg, 6.25 μmol) and Ag2CO3 (8.96 mg, 33 μmol) were added to the mixture. The obtained reaction mixture was stirred at 80°C for 90 minutes. Ethyl acetate and water were added to the reaction mixture. The insoluble material in the mixture was filtered out. Then, the organic layer of the filtrate was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with 10% sodium chloride aqueous solution (twice), dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (0%-70% ethyl acetate / n-heptane) to obtain the title compound (12.5mg). 1H-NMR (500MHz, CDCl3) δ (ppm): 0.06 (s, 3H), 0.07 (s, 3H), 0.88-0.91 (m, 15H), 0.96 (t, J = 7.3Hz, 3H), 1.21 (s, 3H), 1.28-1.33 (m, 1H), 1.36 ( s,3H),1.37-1.54(m,5H),1.58-1.65(m,1H),1.72-1.77(m,4H),1.80-1.86(m,1H),2.02(br.s,1H),2.09(s,1H),2.10(s,3H),2.32(br.s,1 H),2.36-2.42(m,1H),2.42-2.60(m,2H),2.75(dd,J=6.1,2.5Hz,1H),2.98(td,J=6.1,2.5Hz,1H),3.65(br.s,1H),3.79-3.93(m,1H),4.96 (d,J=10.4Hz,1H),5.07(d,J=8.6Hz,1H),5.56-5.74(m,2H),5.81(d,J=15.3Hz,1H),6.14(d,J=11.0Hz,1H),6.50(dd,J=15.0,10.7Hz,1H).

[0125] C-2-(2) Synthesis of Pradinolide D To a THF solution (0.6 mL) of (2S, 3S, 6S, 7R, 10R, E)-10-((tert-butyldimethylsilyl)oxy)-7-hydroxy-2-((R, 2E, 4E)-6-hydroxy-7-((2R, 3R)-3-((2R, 3S)-3-hydroxypentane-2-yl)oxirane-2-yl)-6-methylhept-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-ene-6-yl ester (10.5 mg, 16 μmol) obtained in Example C-2-(1) was added a THF solution of TBAF (1 M; 47 μL, 47 μmol). The resulting reaction mixture was stirred at room temperature overnight. Ethyl acetate, saturated aqueous ammonium chloride solution and water were added to the ice-cooled reaction mixture, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure.The resulting residue was purified by silica gel column chromatography (0%-100% ethyl acetate / n-heptane) to obtain the title compound (7.5 mg). The obtained compounds 1 The H-NMR spectrum (500 MHz, CD3OD) was consistent with that in Example C-1.

[0126] Example C-3 Synthesis of Pradinolide D

[0127] C-3-(1) Synthesis of (2S,3S,6S,7R,10R,E)-10((tert-butyldimethylsilyl)oxy)-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxo-7-((triethylsilyl)oxy)oxacyclododec-4-en-6-yl acetate A solution of (2S,3S,6S,7R,10R,E)-10-((tert-butyldimethylsilyl)oxy)-2-((E)-1-iodoprop-1-en-2-yl)-3,7-dimethyl-12-oxo-7-((triethylsilyl)oxy)oxacyclododec-4-en-6-yl acetate (12.5 mg, 18 μmol) obtained in Example B-4 and (2R,3S)-2-((2R,3R)-3-((R)-2-hydroxy-2-methylbut-3-en-1-yl)oxiran-2-yl)pentan-3-ol (7.71 mg, 36 μmol) obtained in Example A-2 in DMF (1 mL) was degassed and replaced with a nitrogen atmosphere. At room temperature, Ag2CO3 (7.4 mg, 27 μmol) and Pd(OAc)2 (1.0 mg, 4.5 μmol) were added to the mixture. The resulting reaction mixture was stirred at room temperature for 20 minutes, and then stirred at 80 ° C for 2 hours. The reaction mixture was allowed to cool and concentrated under reduced pressure. The residue was suspended in ethyl acetate, and insoluble matter was filtered out by a microporous filter. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25%-50% ethyl acetate / n-heptane) to obtain the title compound (10.1 mg). 1H-NMR (500MHz, CDCl3) δ (ppm): 0.06 (s, 3H), 0.07 (s, 3H), 0.60-0.66 (m, 6H), 0.87-0.91 (m, 15H), 0.94-1.02 (m, 12H), 1.18-1.23 (m, 3H), 1.24 -1.35(m,2H),1.36(s,3H),1.40-1.47(m,2H),1.49-1.56(m,2H),1.59 -1.68(m,2H),1.73(br.d,J=6.1Hz,1H),1.75(s,3H),1.79-1.87(m,1H) ,2.06(s,3H),2.30-2.55(m,4H),2.75(dd,J=6.4,2.1Hz,1H),2.98(td,J=6.1,2.5Hz,1H),3.65(br.s,1H),3.76-3.86(m,1H),4.95-5.01(m, 2H), 5.59 (dd, J=15.3, 9.2Hz, 1H), 5.66 (dd, J=15.3, 9.2Hz, 1H), 5.81 (d, J=15.3Hz, 1H), 6.14 (d, J=11.0Hz, 1H) 6.50 (dd, J=15.3, 11.0Hz, 1H).

[0128] C-3-(2) Synthesis of Pradinolide D To a solution of (2S, 3S, 6S, 7R, 10R, E) -10 ((tert-butyldimethylsilyl) oxy) -2- ((R, 2E, 4E) -6-hydroxy-7- ((2R, 3R) -3- ((2R, 3S) -3-hydroxypentane-2-yl) oxiran-2-yl) -6-methylhept-2,4-dien-2-yl) -3,7-dimethyl-12-oxo-7- ((triethylsilyl) oxy) oxacyclododec-4-en-6-yl acetate (10.0 mg, 13 μmol) obtained in Example C-3- (1) in THF (0.3 mL) was added a THF solution of TBAF (1 M; 64 μL, 64 μmol). The reaction mixture was stirred at room temperature for 15 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and then ethyl acetate and water were added thereto, and the organic layer was separated. The organic layer was dried over magnesium sulfate, filtered and then concentrated under reduced pressure.The residue was purified by silica gel column chromatography (0%-5% MeOH / ethyl acetate) to obtain the title compound (6.2 mg). The obtained compounds 1The H-NMR spectrum (500 MHz, CD3OD) was consistent with that in Example C-1.

[0129] Example C-4 Synthesis of Pradinolide D To (2S,3S,6S,7R,10R,E)-7,10-dihydroxy-2-((E)-1-iodoprop-1-en-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl acetate (10 mg, 21 μmol) obtained in Example B-8 and (2R,3S)-2-((2R,3R)-3-((R,E)-2-hydroxy-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxocyclododec-4-en-6-yl)acetate (10 mg, 21 μmol) obtained in Example A-8 were added. To a solution of (10-(2-(heterocyclopentyl)borane-2-yl)but-3-ene-1-yl)oxirane-2-yl)pentane-3-ol (8.03 mg, 24 μmol) in THF (1 mL) and water (0.1 mL) was added Ag2O (24.9 mg, 0.107 mmol), Pd2(dba)3 (3.93 mg, 4.29 μmol) and Pd(dppf)Cl2 (3.14 mg, 4.29 μmol), and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0%-100% ethyl acetate / n-heptane) to obtain the title compound (3.0 mg). The obtained compounds 1 The H-NMR spectrum (500 MHz, CD3OD) was consistent with that in Example C-1.

[0130] Example C-5 Synthesis of (2S,3S,6S,7R,10R,E)-10-((tert-butyldimethylsilyl)oxy)-7-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl acetate To (2S,3S,6S,7R,10R,E)-10-((tert-butyldimethylsilyl)oxy)-7-hydroxy-2-((E)-1-iodoprop-1-en-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl acetate (10 mg, 17 μmol) obtained in Example B-6 and (2R,3S)-2-((2R,3R)-3-((R,E)-2-hydroxy-2-methyl-4-( To a solution of (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)but-3-ene-1-yl)oxirane-2-yl)pentane-3-ol (6.45 mg, 19 μmol) in THF (1 mL) and water (0.1 mL) was added Ag2O (20.0 mg, 86 μmol), Pd2(dba)3 (3.15 mg, 3.45 μmol) and Pd(dppf)Cl2 (2.52 mg, 3.45 μmol). The reaction mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0%-100% ethyl acetate / n-heptane) to obtain the title compound (7.4 mg). The obtained compounds 1 The H-NMR spectrum (500 MHz, CDCl3) was consistent with that in Example C-2-(1). According to the method of Example C-2-(2), pranidolactone D can be synthesized from the obtained compound.

[0131] Example C-6 Synthesis of Pradinolide D To a DMF solution (1 mL) of (2S,3S,6S,7R,10R,E)-7,10-dihydroxy-2-((E)-1-iodoprop-1-en-2-yl)-3,7-dimethyl-12-oxooxadecan-4-en-6-yl acetate (12.5 mg, 27 μmol) obtained in Example B-8, a THF solution (1 mL) of (2R,3S)-2-((2R,3R)-3-((R,E)-2-hydroxy-2-methyl-4-(tributylstannyl)but-3-en-1-yl)oxiran-2-yl)pentan-3-ol (16.2 mg, 32 μmol) obtained in Example A-7, PdCl2(PhCN)2 (3.08 mg, 8.04 μmol), and DIPEA (24 μL, 139 μmol) were added. The obtained mixture was stirred at 50 ° C for 5 hours and 30 minutes. The reaction mixture was cooled in an ice-water bath. Ethyl acetate and water were added to the reaction mixture to separate the organic layer. Ethyl acetate and saturated brine were added to the aqueous layer, and the mixture was then filtered, and the organic layer of the filtrate was separated. The combined organic layer was dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (0%-100% ethyl acetate / n-heptane) to obtain the title compound (4.39 mg). The obtained compounds 1 The H-NMR spectrum (500 MHz, CD3OD) was consistent with that in Example C-1.

[0132] Example C-7 Synthesis of Pradinolide D To a solution of (2R,3S)-2-((2R,3R)-3-((R,E)-4-(benzyldimethylsilyl)-2-hydroxy-2-methylbut-3-en-1-yl)oxiran-2-yl)pentan-3-ol (4.7 mg, 13 μmol) obtained in Example A-6 in 1,4-dioxane (0.5 mL) was added a THF solution of TBAF (1 M; 28 μL, 28 μmol) at 25°C, and the mixture was stirred at room temperature for 30 minutes. To the mixture was added acetic acid (2S, 3S, 6S, 7R, 10R, E) -7, 10- dihydroxy -2- ((E) -1- iodoprop- 1- ene-2-yl) -3, 7- dimethyl -12- oxooxacyclodec-4-ene-6-yl ester (5.3 mg, 11 μmol) in 1, 4- dioxane (0.5 mL) and Pd2(dba)3 (1.04 mg, 1.14 μmol). The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0% -2% MeOH / ethyl acetate) to obtain the title compound (2.9 mg). The obtained compounds 1 The H-NMR spectrum (500 MHz, CD3OD) was consistent with that in Example C-1.

[0133] Example C-8 Synthesis of Pradinolide D

[0134] C-8-(1) Synthesis of (2S,3S,6S,7R,10R,E)-7,10-dihydroxy-3,7-dimethyl-2-((R,2E,4E)-6-methyl-6-((triethylsilyl)oxy)-7-((2R,3R)-3-((2S,3S)-3-((triethylsilyl)oxy)pentan-2-yl)oxiran-2-yl)hept-2,4-dien-2-yl)-12-oxooxacyclododec-4-en-6-yl acetate To a mixture of (2S,3S,6S,7R,10R,E)-7,10-dihydroxy-2-((E)-1-iodoprop-1-en-2-yl)-3,7-dimethyl-12-oxoxadecan-4-en-6-yl acetate (5.03 mg, 10.8 μmol) obtained in Example B-8, Pd2(dba)3 (1.98 mg, 2.16 μmol) and Ag2O (12.5 mg, 54 μmol) was added A solution of triethyl (((R, E)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2R,3R)-3-((2S,3S)-3-((triethylsilyl)oxy)pentane-2-yl)oxirane-2-yl)but-3-ene-2-yl)oxy)silane (8.22 mg, 14 μmol) obtained in Example A-4-(2) in THF (1 mL). Water (0.1 mL) was added to the mixture, and the reaction mixture was then stirred at room temperature under a nitrogen atmosphere for 22 hours. After MeCN was added to the reaction mixture, the insoluble material in the mixture was filtered out through a microporous filter. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50%-75% ethyl acetate / n-heptane) to obtain the title compound (3.3 mg). 1 H-NMR (500MHz, CDCl3) δ (ppm): 0.57-0.65 (m, 12H), 0.79-0.85 (m, 6H), 0.88 (d, J = 6.3Hz, 3H), 0.96 (td, J = 8.0, 3.4Hz, 18H), 1.21 (s, 3H), 1.28 -1.38(m,3H),1.40(s,3H),1.42-1.54(m,4H),1.59(br.d,J=6.3Hz,1H),1.65-1.72(m,1H),1.74(d,J=1.2Hz,3H),1.90(dd,J=13.8,5.2Hz,1 H),2.10(s,3H),2.44-2.67(m,4H),2.80-2.86(m,1H),3.53(d,J=10.9Hz,1H),3.70-3.77(m,2H),5.09(d,J=9.2Hz,1H),5.18(d,J=10.3Hz,1 H), 5.61 (dd, J = 14.9, 9.2Hz, 1H), 5.67 (dd, J = 14.9, 9.2Hz, 1H), 5.76 (d, J = 14.9Hz, 1H), 6.09 (d, J = 10.9Hz, 1H), 6.43 (dd, J = 15.2, 11.2Hz, 1H).

[0135] C-8-(2) Synthesis of Pradinolide D To a solution of (2S,3S,6S,7R,10R,E)-7,10-dihydroxy-3,7-dimethyl-2-((R,2E,4E)-6-methyl-6-((triethylsilyl)oxy)-7-((2R,3R)-3-((2S,3S)-3-((triethylsilyl)oxy)pentan-2-yl)oxiran-2-yl)hept-2,4-dien-2-yl)-12-oxooxacyclododec-4-en-6-yl acetate (3.3 mg, 4.2 μmol) obtained in Example C-8-(1) in THF (0.5 mL) was added a THF solution of TBAF (1 M; 17 μL, 17 μmol). The reaction mixture was stirred at room temperature for 1 hour. Then add TBAF THF solution (1M; 17 μ L, 17 μ mol) to the reaction mixture, and stir the mixture for 2.5 hours. Saturated aqueous ammonium chloride solution is added to the reaction mixture, ethyl acetate and water are then added thereto, and the organic layer is separated. The organic layer is dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue is purified by silica gel column chromatography (0%-5% MeOH / ethyl acetate) to obtain the title compound (2.3 mg). The obtained compounds 1 The H-NMR spectrum (500 MHz, CD3OD) was consistent with that in Example C-1.

[0136] Example C-9 Synthesis of (2S,3S,6S,7R,10R,E)-7,10-dihydroxy-3,7-dimethyl-2-((R,2E,4E)-6-methyl-6-((triethylsilyl)oxy)-7-((2R,3R)-3-((2S,3S)-3-((triethylsilyl)oxy)pentan-2-yl)oxiran-2-yl)hept-2,4-dien-2-yl)-12-oxooxacyclododec-4-en-6-yl acetate A solution of (2S,3S,6S,7R,10R,E)-7,10-dihydroxy-2-((E)-1-iodoprop-1-en-2-yl)-3,7-dimethyl-12-oxooxadecan-4-en-6-yl acetate (6.45 mg, 14 μmol) obtained in Example B-8 and triethyl (((R)-2-methyl-1-((2R,3R)-3-((2S,3S)-3-((triethylsilyl)oxy)pentan-2-yl)oxiran-2-yl)but-3-en-2-yl)oxy)silane (12.3 mg, 28 μmol) obtained in Example A-3 in DMF (1 ml) was degassed and replaced with a nitrogen atmosphere. To the mixture, add Ag2CO3(4.96mg, 18μmol) and Pd(OAc)2(0.78mg, 3.5μmol). The resulting reaction mixture was stirred at room temperature for 15 minutes, stirred at 80°C for 2.5 hours, and then stirred at 60°C for 15 hours. Then, to the reaction mixture, add Ag2CO3(4.96mg, 18μmol) and Pd(OAc)2(0.78mg, 3.5μmol), and then the reaction mixture was stirred at 80°C for 2.5 hours. Allow the reaction mixture to cool and concentrate under reduced pressure. The residue is suspended in ethyl acetate, and insoluble matter is filtered out by microporous filter. The filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (50%-70% ethyl acetate / n-heptane) to obtain the title compound (4.4mg). The obtained compounds 1 The H-NMR spectrum (500 MHz, CDCl3) was consistent with that in Example C-8-(1). According to the method of Example C-8-(2), pranidolactone D can be synthesized from the obtained compound.

[0137] Example C-10 Synthesis of Pradinolide D

[0138] C-10-(1) Synthesis of (2S,3S,6S,7R,10R,E)-10-((tert-butyldimethylsilyl)oxy)-7-hydroxy-3,7-dimethyl-2-((R,2E,4E)-6-methyl-6-((triethylsilyl)oxy)-7-((2R,3R)-3-((2S,3S)-3-((triethylsilyl)oxy)pentan-2-yl)oxiran-2-yl)hept-2,4-dien-2-yl)-12-oxooxacyclododec-4-en-6-yl acetate A solution of triethyl(((R)-2-methyl-1-((2R,3R)-3-((2S,3S)-3-((triethylsilyl)oxy)pentan-2-yl)oxiran-2-yl)but-3-en-2-yl)oxy)silane (19.6 mg, 44 μmol) obtained in Example A-3 and (2S,3S,6S,7R,10R,E)-10-((tert-butyldimethylsilyl)oxy)-7-hydroxy-2-((E)-1-iodoprop-1-en-2-yl)-3,7-dimethyl-12-oxoxodecan-4-en-6-yl acetate (17 mg, 29 μmol) obtained in Example B-6 in DMF (1 mL) was degassed and then replaced with a nitrogen atmosphere. Pd(OAc)2(1.64mg, 7.32μmol) and Ag2CO3(10.5mg, 38μmol) were added to the mixture in sequence. The resulting reaction mixture was stirred at 80°C for 3 hours. Then, Pd(OAc)2(1.64mg, 7.32μmol) and Ag2CO3(10.5mg, 38μmol) were added to the reaction mixture, and the mixture was stirred at 80°C for 4 hours. Ethyl acetate and water were added to the ice-cooled reaction mixture. The insoluble material in the mixture was filtered out. Then, the organic layer of the filtrate was separated. The organic layer was washed with 10% sodium chloride aqueous solution (twice), dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0%-20% ethyl acetate / n-heptane) to obtain the title compound (8.6mg). 1H-NMR (500MHz, CDCl3) δ (ppm): 0.06 (s, 3H), 0.07 (s, 3H), 0.61 (q, J = 8.0Hz, 12H), 0.79-0.85 (m, 6H), 0.88 (br.d, J = 6.7Hz, 3H), 0.90 (s, 9H), 0.9 6(t,J=7.6Hz,18H),1.21(s,3H),1.38(s,3H),1.40-1.55(m,6H),1.57- 1.60(m,1H),1.67(br.s,1H),1.70(s,3H),1.89(dd,J=14.1,4.9Hz,1H), 2.09(d,J=1.2Hz,4H),2.33-2.54(m,3H),2.56(br.d,J=8.0Hz,1H),2.83(br.t,J=5.5Hz,1H),3.69-3.79(m,1H),3.84(br.d,J=3.7Hz,1H),4.9 7(d,J=10.4Hz,1H),5.08(d,J=8.0Hz,1H),5.60-5.68(m,2H),5.71(d,J=14.7Hz,1H),6.10(br.d,J=11.0Hz,1H),6.41(dd,J=15.3,11.0Hz,1H).

[0139] C-10-(2) Synthesis of Pradinolide D To a solution of (2S, 3S, 6S, 7R, 10R, E) -10- ((tert-butyldimethylsilyl) oxy) -7-hydroxy-3, 7-dimethyl-2- ((R, 2E, 4E) -6-methyl-6- ((triethylsilyl) oxy) -7- ((2R, 3R) -3- ((2S, 3S) -3- ((triethylsilyl) oxy) pentane-2-yl) oxiran-2-yl) hept-2, 4-dien-2-yl) -12-oxooxacyclododec-4-en-6-yl acetate (18.9 mg, 21 μmol) obtained in Example C-10- (1) in THF (1 mL) was added a THF solution of TBAF (1 M; 0.19 mL, 0.19 mmol). The resulting reaction mixture was stirred at room temperature overnight. 10% aqueous ammonium chloride solution and ethyl acetate are added to the ice-cooled reaction mixture, and then the organic layer is separated. The aqueous layer is extracted with ethyl acetate. The combined organic layer is dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (0%-100% ethyl acetate / n-heptane) to obtain the title compound (11.2 mg). The obtained compounds1 The H-NMR spectrum (500 MHz, CD3OD) was consistent with that in Example C-1.

[0140] Example C-11 Synthesis of Pradinolide D

[0141] C-11-(1) Synthesis of (2S,3S,6S,7R,10R,E)-10-((tert-butyldimethylsilyl)oxy)-3,7-dimethyl-2-((R,2E,4E)-6-methyl-6-((triethylsilyl)oxy)-7-((2R,3R)-3-((2S,3S)-3-((triethylsilyl)oxy)pentan-2-yl)oxiran-2-yl)hept-2,4-dien-2-yl)-12-oxo-7-((triethylsilyl)oxy)oxacyclododec-4-en-6-yl acetate To (2S,3S,6S,7R,10R,E)-10-((tert-butyldimethylsilyl)oxy)-2-((E)-1-iodoprop-1-en-2-yl)-3,7-dimethyl-12-oxo-7-((triethylsilyl)oxy)oxacyclododec-4-en-6-yl acetate (20 mg, 29 μmol) obtained in Example B-4 and triethyl (((R)-2- To a solution of methyl-1-((2R,3R)-3-((2S,3S)-3-((triethylsilyl)oxy)pentane-2-yl)oxirane-2-yl)but-3-ene-2-yl)oxy)silane (19.1 mg, 43 μmol) in DMF (2 mL) were added Ag2CO3 (10.3 mg, 37 μmol) and Pd(OAc)2 (1.62 mg, 7.20 μmol) in sequence. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 15 minutes and at 80°C for 5 hours. Then, Ag2CO3 (10.3 mg, 37 μmol) and Pd(OAc)2 (1.62 mg, 7.20 μmol) were added to the reaction mixture, and the reaction mixture was stirred at 80°C overnight. The reaction mixture was allowed to cool to room temperature. The insoluble material in the mixture was filtered out and washed with ethyl acetate. The filtrate was washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure.The residue was purified by silica gel column chromatography (0%-10% ethyl acetate / n-heptane) to obtain the title compound (10.1 mg). 1H-NMR (500MHz, CDCl3) δ (ppm): 0.06 (s, 3H), 0.07 (s, 3H), 0.58-0.66 (m, 18H), 0.81-0.85 (m, 6H), 0.87 (d, J = 6.7Hz, 3H), 0.90 (s, 9H), 0.94-1 .03(m,27H),1.21(s,3H),1.28-1.36(m,2H),1.39(s,3H),1.43-1.53(m,4H),1.58-1.69(m,2H),1.73(s,3H),1.89(dd,J=13.5,4.9Hz,1H), 2.06(s,3H),2.35-2.52(m,3H),2.57(dd,J=8.0,1.8Hz,1H),2.81-2.86(m,1H),3.71-3.76(m,1H),3.77-3.83(m,1H),4.96-5.02(m,2H),5. 59(dd,J=15.3,9.8Hz,1H), 5.65(dd,J=15.3,8.6Hz,1H), 5.72(d,J=15.3Hz,1H), 6.11(br.d,J=11.0Hz,1H), 6.41(dd,J=15.3,11.0Hz,1H).

[0142] C-11-(2) Synthesis of Pradinolide D To a solution of (2S, 3S, 6S, 7R, 10R, E) -10- ((tert-butyldimethylsilyl) oxy) -3,7-dimethyl-2- ((R, 2E, 4E) -6-methyl-6- ((triethylsilyl) oxy) -7- ((2R, 3R) -3- ((2S, 3S) -3- ((triethylsilyl) oxy) pentane-2-yl) oxiran-2-yl) hept-2,4-dien-2-yl) -12-oxo-7- ((triethylsilyl) oxy) oxacyclododec-4-ene-6-yl acetate (10.1 mg, 10.0 μmol) in THF (0.50 mL) was added a THF solution of TBAF (1M; 0.12 mL, 0.12 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (66%-100% ethyl acetate / n-heptane) to obtain the title compound (5.0 mg). The obtained compounds 1 The H-NMR spectrum (500 MHz, CD3OD) was consistent with that in Example C-1.

[0143] Example C-12 Synthesis of (2S,3S,6S,7R,10R,E)-7,10-dihydroxy-3,7-dimethyl-2-((R,2E,4E)-6-methyl-6-((triethylsilyl)oxy)-7-((2R,3R)-3-((2S,3S)-3-((triethylsilyl)oxy)pentan-2-yl)oxiran-2-yl)hept-2,4-dien-2-yl)-12-oxooxacyclododec-4-en-6-yl acetate

[0144] C-12-(1) Synthesis of (4R,7R,8S,11S,12S,E)-4,7,8-trihydroxy-7,11-dimethyl-12-((R,2E,4E)-6-methyl-6-((triethylsilyl)oxy)-7-((2R,3R)-3-((2S,3S)-3-((triethylsilyl)oxy)pentan-2-yl)oxiran-2-yl)hept-2,4-dien-2-yl)oxacyclododec-9-en-2-one A solution of (4R, 7R, 8S, 11S, 12S, E)-4,7,8-trihydroxy-12-((E)-1-iodoprop-1-en-2-yl)-7,11-dimethyloxacyclododecan-9-en-2-one (19.0 mg, 45 μmol) obtained in Example B-7 and triethyl(((R)-2-methyl-1-((2R, 3R)-3-((2S, 3S)-3-((triethylsilyl)oxy)pentane-2-yl)oxirane-2-yl)but-3-en-2-yl)oxy)silane (29.7 mg, 67 μmol) obtained in Example A-3 in DMF (1 ml) was degassed and replaced with a nitrogen atmosphere. To the mixture was added Ag2CO3 (16.1 mg, 58 μmol) and Pd(OAc)2 (2.51 mg, 11 μmol). The obtained reaction mixture was stirred at room temperature for 20 minutes, and then stirred at 80 ° C for 4 hours and 20 minutes. Allow the reaction mixture to cool and concentrate under reduced pressure. The residue is suspended in ethyl acetate, and insoluble matter is filtered out by a microporous filter. The filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (50%-75% ethyl acetate / n-heptane) to obtain the title compound (18.4mg). 1H-NMR (500MHz, CDCl3) δ (ppm): 0.58-0.67 (m, 12H), 0.79-0.85 (m, 6H), 0.90 (d, J = 6.7Hz, 3H), 0.97 (td, J = 8.0, 4.3Hz, 18H), 1.18-1.30 (m, 3H), 1. 30-1.34(m,3H),1.39-1.41(m,3H),1.42-1.54(m,4H),1.63-1.73(m,1H) ,1.75(s,3H),1.83(br.d,J=4.3Hz,1H),1.91(dd,J=14.1,4.9Hz,1H),2. 38(s,1H),2.48-2.58(m,3H),2.59-2.66(m,1H),2.84(ddd,J=6.6,4.7, 2.1Hz,1H),3.54(d,J=11.0Hz,1H),3.69-3.78(m,2H),3.82(dd,J=9.8,3 .7Hz,1H),5.17(d,J=10.4Hz,1H),5.43(dd,J=15.0,10.1Hz,1H),5.69-5.79(m,2H),6.08(dd,J=11.0,1.2Hz,1H),6.43(dd,J=15.3,11.0Hz,1H).

[0145] C-12-(2) Synthesis of (2S,3S,6S,7R,10R,E)-7,10-dihydroxy-3,7-dimethyl-2-((R,2E,4E)-6-methyl-6-((triethylsilyl)oxy)-7-((2R,3R)-3-((2S,3S)-3-((triethylsilyl)oxy)pentan-2-yl)oxiran-2-yl)hept-2,4-dien-2-yl)-12-oxooxacyclododec-4-en-6-yl acetate Under ice cooling, to a solution of (4R,7R,8S,11S,12S,E)-4,7,8-trihydroxy-7,11-dimethyl-12-((R,2E,4E)-6-methyl-6-((triethylsilyl)oxy)-7-((2R,3R)-3-((2S,3S)-3-((triethylsilyl)oxy)pentan-2-yl)oxiran-2-yl)hept-2,4-dien-2-yl)oxacyclododec-9-en-2-one (16.5 mg, 22 μmol), DMAP (0.55 mg, 4.5 μmol), and Et3N (9.3 μL, 67 μmol) obtained in Example C-12-(1) was added a DCM solution of Ac2O (1 M; 22 μL, 22 μmol). The reaction solution was stirred at the same temperature for 30 minutes.Then Ac2O's DCM solution (1M; 2 μL, 2 μmol) was added to the reaction mixture, and the resulting reaction mixture was stirred for 30 minutes under ice cooling. Saturated sodium bicarbonate aqueous solution, ethyl acetate and water were added to the reaction mixture, and the organic layer was separated. The resulting organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (46%-65% ethyl acetate / n-heptane) to obtain the title compound (14.9mg). The obtained compounds 1 The H-NMR spectrum (500 MHz, CDCl3) was consistent with that in Example C-8-(1). According to the method of Example C-8-(2), pranidolactone D can be synthesized from the obtained compound.

[0146] Example C-13 Synthesis of (2S,3S,6S,7R,10R,E)-10-((tert-butyldimethylsilyl)oxy)-7-hydroxy-3,7-dimethyl-2-((R,2E,4E)-6-methyl-6-((triethylsilyl)oxy)-7-((2R,3R)-3-((2S,3S)-3-((triethylsilyl)oxy)pentan-2-yl)oxiran-2-yl)hept-2,4-dien-2-yl)-12-oxooxacyclododec-4-en-6-yl acetate

[0147] C-13-(1) Synthesis of (4R,7R,8S,11S,12S,E)-4-((tert-butyldimethylsilyl)oxy)-7,8-dihydroxy-7,11-dimethyl-12-((R,2E,4E)-6-methyl-6-((triethylsilyl)oxy)-7-((2R,3R)-3-((2S,3S)-3-((triethylsilyl)oxy)pentan-2-yl)oxiran-2-yl)hept-2,4-dien-2-yl)oxacyclododec-9-en-2-one A solution of triethyl(((R)-2-methyl-1-((2R,3R)-3-((2S,3S)-3-((triethylsilyl)oxy)pentan-2-yl)oxiran-2-yl)but-3-en-2-yl)oxy)silane (30 mg, 68 μmol) obtained in Example A-3 and (4R,7R,8S,11S,12S,E)-4-((tert-butyldimethylsilyl)oxy)-7,8-dihydroxy-12-((E)-1-iodoprop-1-en-2-yl)-7,11-dimethyloxacyclododec-9-en-2-one (24.4 mg, 45 μmol) obtained in Example B-5 in DMF (1 mL) was degassed and then replaced with a nitrogen atmosphere. Pd(OAc)2(2.54mg, 11μmol) and Ag2CO3(16.2mg, 59μmol) were added to the mixture in sequence. The resulting reaction mixture was stirred at 80°C for 3 hours. Ethyl acetate and water were added to the reaction mixture, and the insoluble matter in the mixture was filtered out. Then, the organic layer of the filtrate was separated. The organic layer was washed with 10% sodium chloride aqueous solution (twice), dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0%-30% ethyl acetate / n-heptane) to obtain the title compound (18.7mg). 1H-NMR (500MHz, CDCl3) δ (ppm): 0.07 (s, 3H), 0.08 (s, 3H), 0.56-0.65 (m, 12H), 0.78-0.85 (m, 6H), 0.89 (d, J = 6, 7Hz, 3H), 0.90 (s, 9H), 0.96 (td,J=8.0,1.8Hz,18H),1.23(td,J=7,6,3.7Hz,1H),1.30(s,3H),1.39(s,3H),1.40-1.54(m,6H),1.58-1.65(m,1H),1.66-1.77(m,3H),1 .82(d,J=4.3Hz,1H),1.90(dd,J=13.8,4.6Hz,1H),2.35-2.60(m,5H),2.77-2.86(m,1H),3.73(td,J=6.4,3.1Hz,1H),3.81(dt,J=9.8,4. 9Hz, 2H), 5.00 (d, J = 10.4Hz, 1H), 5.47 (dd, J = 15.0, 10.1Hz, 1H), 5.66-5.77 (m, 2H), 6.10 (d, J = 11.0Hz, 1H), 6.42 (dd, J = 15.0, 11.3Hz, 1H).

[0148] C-13-(2) Synthesis of (2S,3S,6S,7R,10R,E)-10-((tert-butyldimethylsilyl)oxy)-7-hydroxy-3,7-dimethyl-2-((R,2E,4E)-6-methyl-6-((triethylsilyl)oxy)-7-((2R,3R)-3-((2S,3S)-3-((triethylsilyl)oxy)pentan-2-yl)oxiran-2-yl)hept-2,4-dien-2-yl)-12-oxooxacyclododec-4-en-6-yl acetate Under ice cooling, to the (4R,7R,8S,11S,12S,E)-4-((tert-butyldimethylsilyl)oxy)-7,8-dihydroxy-7,11-dimethyl-12-((R,2E,4E)-6-methyl-6-((triethylsilyl)oxy)-7-((2R,3R)-3-((2S,3S)-3-((triethylsilyl)oxy)-1,4-dihydroxy ...1,4-dihydroxy-7,8-dihydroxy-7,11-dimethyl-12-((R,2E,4E)-6-methyl-6-((triethylsilyl)oxy)-7-((2R,3R)-3-((2S,3S)-3-((triethylsilyl)oxy)-1 To a DCM solution (1mL) of (18.7mg, 22μmol) and DMAP (0.535mg, 4.4μmol) was added Et3N (9.2μL, 66μmol) and Ac2O (2.2μL, 23μmol). The reaction mixture was stirred at the same temperature for 1 hour. Ac2O (2.2μL, 23μmol) was added to the reaction mixture, and the mixture was stirred for 30 minutes. Ac2O (0.55μL, 5.8μmol) was added to the reaction mixture, and the mixture was stirred for 40 minutes. Ac2O (0.55μL, 5.8μmol) was then added to the reaction mixture, and the mixture was stirred for 15 minutes. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution. Ethyl acetate was added to the obtained mixture, and the organic layer was separated. The organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0%-20% ethyl acetate / n-heptane) to obtain the title compound (18.9 mg). The obtained compounds 1 The H-NMR spectrum (500 MHz, CDCl3) was consistent with that in Example C-10-(1). According to the method of Example C-10-(2), pranidolactone D can be synthesized from the obtained compound.

[0149] Example C-14 Synthesis of (2S,3S,6S,7R,10R,E)-10-((tert-butyldimethylsilyl)oxy)-3,7-dimethyl-2-((R,2E,4E)-6-methyl-6-((triethylsilyl)oxy)-7-((2R,3R)-3-((2S,3S)-3-((triethylsilyl)oxy)pentan-2-yl)oxiran-2-yl)hept-2,4-dien-2-yl)-12-oxo-7-((triethylsilyl)oxy)oxacyclododec-4-en-6-yl acetate

[0150] C-14-(1) Synthesis of (4R,7R,8S,11S,12S,E)-4-((tert-butyldimethylsilyl)oxy)-8-hydroxy-7,11-dimethyl-12-((R,2E,4E)-6-methyl-6-((triethylsilyl)oxy)-7-((2R,3R)-3-((2S,3S)-3-((triethylsilyl)oxy)pentan-2-yl)oxiran-2-yl)hept-2,4-dien-2-yl)-7-((triethylsilyl)oxy)oxacyclododec-9-en-2-one To (4R,7R,8S,11S,12S,E)-4-((tert-butyldimethylsilyl)oxy)-8-hydroxy-12-((E)-1-iodoprop-1-en-2-yl)-7,11-dimethyl-7-((triethylsilyl)oxy)oxacyclododec-9-en-2-one (30 mg, 46 μmol) obtained in Example B-3 and triethyl (((R)-2- To a solution of methyl-1-((2R,3R)-3-((2S,3S)-3-((triethylsilyl)oxy)pentane-2-yl)oxirane-2-yl)but-3-ene-2-yl)oxy)silane (30.5 mg, 69 μmol) in DMF (2 mL) was added AgCO (16.5 mg, 60 μmol) and Pd(OAc) (2.58 mg, 11 μmol) in sequence. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 15 minutes and at 80 ° C for 3 hours. The reaction mixture was allowed to cool to room temperature. The insoluble material in the mixture was filtered out and washed with ethyl acetate. The filtrate was washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0%-10% ethyl acetate / n-heptane) to obtain the title compound (15 mg). 1H-NMR (500MHz, CDCl3) δ (ppm): 0.07 (s, 3H), 0.08 (s, 3H), 0.58-0.66 (m, 18H), 0 .80-0.85(m,6H),0.89-0.91(m,12H),0.94-1.02(m,27H),1.32(s,3H),1.34-1 .38(m,1H),1.39(s,3H),1.41-1.44(m,1H),1.45-1.55(m,4H),1.58-1.66(m,2 H),1.72(d,J=1.2Hz,3H),1.89(dd,J=13.5,4.9Hz,1H),2.38-2.51(m,3H),2.56 (dd,J=8.3,2.1Hz,1H),2.66(d,J=10.4Hz,1H),2.84(br.t,J=4.6Hz,1H),3.57 (t,J=10.1Hz,1H),3.73(dt,J=6.6,3.1Hz,1H),3.81(dt,J=5.2,2.9Hz,1H),5.0 1(d,J=11.0Hz,1H),5.40(dd,J=15.3,9.8Hz,1H),5.58(dd,J=15.0,9.5Hz,1H) ,5.72(d,J=15.3Hz,1H), 6.10(d,J=11.0Hz,1H), 6.42(dd,J=15.3,11.0Hz,1H).

[0151] C-14-(2) Synthesis of (2S,3S,6S,7R,10R,E)-10-((tert-butyldimethylsilyl)oxy)-3,7-dimethyl-2-((R,2E,4E)-6-methyl-6-((triethylsilyl)oxy)-7-((2R,3R)-3-((2S,3S)-3-((triethylsilyl)oxy)pentan-2-yl)oxiran-2-yl)hept-2,4-dien-2-yl)-12-oxo-7-((triethylsilyl)oxy)oxacyclododec-4-en-6-yl acetate At room temperature, to a solution of (4R, 7R, 8S, 11S, 12S, E)-4-((tert-butyldimethylsilyl)oxy)-8-hydroxy-7, 11-dimethyl-12-((R, 2E, 4E)-6-methyl-6-((triethylsilyl)oxy)-7-((2R, 3R)-3-((2S, 3S)-3-((triethylsilyl)oxy)pentane-2-yl)oxirane-2-yl)hept-2,4-diene-2-yl)-7-((triethylsilyl)oxy)oxacyclododec-9-ene-2-one (15 mg, 16 μmol) obtained in Example C-14-(1) in pyridine (1 mL) was added Ac2O (0.5 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (0%-10% ethyl acetate / n-heptane) to obtain the title compound (16.1 mg). The obtained compounds 1 The H-NMR spectrum (500 MHz, CDCl3) was consistent with that in Example C-11-(1). According to the method of Example C-11-(2), pranidolactone D can be synthesized from the obtained compound.

[0152] Example C-15 Synthesis of (2S,3S,6S,7R,10R,E)-10-((tert-butyldimethylsilyl)oxy)-7-hydroxy-3,7-dimethyl-2-((R,2E,4E)-6-methyl-6-((triethylsilyl)oxy)-7-((2R,3R)-3-((2S,3S)-3-((triethylsilyl)oxy)pentan-2-yl)oxiran-2-yl)hept-2,4-dien-2-yl)-12-oxooxacyclododec-4-en-6-yl acetate At 25° C., (2S,3S,6S,7R,10R,E)-10-((tert-butyldimethylsilyl)oxy)-7-hydroxy-2-((E)-1-iodoprop-1-en-2-yl)-3,7-dimethyl-12-oxoxadecan-4-en-6-yl acetate (5.8 mg, 10 μmol) obtained in Example B-6, triethyl (((R,E)-2-methyl-4-(4,4,5,5,-tetramethyl-1,3 To a solution of ((2-dioxaborolan-2-yl)-1-((2R,3R)-3-((2S,3S)-3-((triethylsilyl)oxy)pentane-2-yl)oxirane-2-yl)but-3-ene-2-yl)oxy)silane (8.4 mg, 15 μmol), and Pd(dppf)Cl2 (1.46 mg, 2.0 μmol) in THF (0.9 mL) were added Ag2O (11.6 mg, 50 μmol) and water (0.1 ml) in sequence. The reaction mixture was stirred at room temperature for 130 minutes under a nitrogen atmosphere. After MeCN was added to the reaction mixture, the mixture was filtered through a microporous filter. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15%-37% ethyl acetate / n-heptane) to obtain the title compound (8.5 mg). The obtained compounds 1 The H-NMR (500 MHz, CDCl3) spectrum was consistent with that in Example C-10-(1). According to the method of Example C-10-(2), pranidolactone D can be synthesized from the obtained compound.

[0153] Example C-16 Synthesis of Pradinolide D

[0154] C-16-(1) Synthesis of (2R,3S)-2-((2R,3R)-3-((R,3E,5E)-6-((2S,3S,6S,7R,10R,E)-6-acetoxy-7,10-dihydroxy-3,7-dimethyl-12-oxooxacyclododec-4-en-2-yl)-2-hydroxy-2-methylhepta-3,5-dien-1-yl)oxiran-2-yl)pentan-3-yl 3,5-dinitrobenzoate To a solution of (2S,3S,6S,7R,10R,E)-7,10-dihydroxy-2-((E)-1-iodoprop-1-en-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl acetate (50 mg, 0.107 mmol) obtained in Example B-8 and (2R,3S)-2-((2R,3R)-3-((R)-2-hydroxy-2-methylbut-3-en-1-yl)oxiran-2-yl)pentan-3-yl 3,5-dinitrobenzoate (56.9 mg, 0.139 mmol) obtained in Example A-5 in DMF (3 mL) were added Ag2CO3 (38.4 mg, 0.139 mmol) and Pd(OAc)2 (6.02 mg, 27 μmol) at room temperature. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 15 minutes and at 80 ° C for 4 hours. The insoluble material in the mixture was filtered out and washed with ethyl acetate. The filtrate was washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (66%-100% ethyl acetate / n-heptane) to obtain the title compound (57mg). 1 H-NMR (500MHz, CDCl3) δ (ppm): 0.89 (d, J = 6.7 Hz, 3H), 0.97 (t, J = 7.3 Hz, 3H), 1. 06(d,J=6.7Hz,3H),1.21(s,3H),1.35(s,3H),1.36-1.42(m,1H),1.50-1.56(m, 2H),1.63-1.73(m,3H),1.76(s,3H),1.84(d,J=3.1Hz,1H),1.87-1.91(m,2H),2 .08(d,J=4.9Hz,2H),2.10(s,3H),2.48-2.58(m,2H),2.58-2.65(m,2H),2.91(d dd,J=7.2,4.4,2.5Hz,1H),3.49(d,J=11.0Hz,1H),3.76-3.80(m,1H),5.08(d,J =9.2Hz,1H),5.16(d,J=10.4Hz,1H),5.26-5.31(m,1H),5.61(dd,J=15.3,9.8Hz ,1H),5.68(dd,J=15.3,9.2Hz,1H),5.83(d,J=15.3Hz,1H),6.11(d,J=10.4Hz,1 H), 6.52 (dd, J = 15.3, 11.0Hz, 1H), 9.17 (d, J = 1.8Hz, 2H), 9.24 (t, J = 2.1Hz, 1H).

[0155] C-16-(2) Synthesis of Pradinolide D To a solution of (2R,3S)-2-((2R,3R)-3-((R,3E,5E)-6-((2S,3S,6S,7R,10R,E)-6-acetoxy-7,10-dihydroxy-3,7-dimethyl-12-oxooxacyclododec-4-ene-2-yl)-2-hydroxy-2-methylhept-3,5-diene-1-yl)oxirane-2-yl)pentane-3-yl 3,5-dinitrobenzoate (3.0 mg, 4.02 μmol) in THF (0.1 mL) was added a THF solution of TBAF (1 M; 20 μL, 20 μmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. Under ice cooling, saturated aqueous ammonium chloride solution, ethyl acetate and water were added to the reaction solution. The organic layer was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure.The resulting residue was purified by silica gel column chromatography (0%-100% ethyl acetate / n-heptane) to obtain the title compound (2.3 mg). The obtained compounds 1 The H-NMR spectrum (500 MHz, CD3OD) was consistent with that in Example C-1.

[0156] Example C-17 Synthesis of Pradinolide D

[0157] C-17-(1) Synthesis of (2R,3S)-2-((2R,3R)-3-((R,3E,5E)-6-((2S,3S,6S,7R,10R,E)-6-acetoxy-10-((tert-butyldimethylsilyl)oxy)-7-hydroxy-3,7-dimethyl-12-oxooxacyclododec-4-en-2-yl)-2-hydroxy-2-methylhepta-3,5-dien-1-yl)oxiran-2-yl)pentan-3-yl 3,5-dinitrobenzoate A solution of (2R,3S)-2-((2R,3R)-3-((R)-2-hydroxy-2-methylbut-3-en-1-yl)oxiran-2-yl)pentan-3-yl 3,5-dinitrobenzoate (58.0 mg, 142 μmol) obtained in Example A-5 and (2S,3S,6S,7R,10R,E)-10-((tert-butyldimethylsilyl)oxy)-7-hydroxy-2-((E)-1-iodoprop-1-en-2-yl)-3,7-dimethyl-12-oxoxooxadecan-4-en-6-yl acetate (55 mg, 95 μmol) obtained in Example B-6 in DMF (2 mL) was degassed and then replaced with a nitrogen atmosphere. To the mixture, Pd(OAc)2(5.32mg, 24μmol) and Ag2CO3(34mg, 0.123mmol) were added in sequence, and the resulting mixture was stirred at 80°C for 2 hours. Ethyl acetate and water were added to the ice-cooled reaction mixture. The insoluble material in the mixture was filtered out. Then, the organic layer of the filtrate was separated. The organic layer was washed with 10% sodium chloride aqueous solution (twice), dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0%-50% ethyl acetate / n-heptane) to obtain the title compound (55.4mg). 1H-NMR (500MHz, CDCl3) δ (ppm): 0.06 (s, 3H), 0.07 (s, 3H), 0.88-0.92 (m, 12H), 0. 97(t,J=7.3Hz,3H),1.06(d,J=6.7Hz,3H),1.21(s,3H),1.34(s,3H),1.36-1.48 (m,3H),1.63-1.74(m,6H),1.80-1.94(m,3H),2.02(s,1H),2.09(br.s,1H),2.1 0(s,3H),2.38(dd,J=14.1,4.9Hz,1H),2.46(dd,J=13.4,3.1Hz,1H),2.48-2.56 (m,1H),2.60(dd,J=8.0,1.8Hz,1H),2.91(ddd,J=6.9,4.4,2.1Hz,1H),3.84(br .d,J=3.7Hz,1H),4.94(d,J=11.0Hz,1H),5.07(d,J=8.6Hz,1H),5.28(dt,J=8.1 ,5.1Hz,1H),5.57-5.72(m,2H),5.80(d,J=15.3Hz,1H),6.13(br.d,J=10.4Hz,1 H), 6.49 (dd, J = 15.3, 11.0Hz, 1H), 9.17 (d, J = 2.5Hz, 2H), 9.24 (t, J = 1.8Hz, 1H).

[0158] C-17-(2) Synthesis of Pradinolide D To a THF solution (0.45 mL) of (2R, 3S)-2-((2R, 3R)-3-((R, 3E, 5E)-6-((2S, 3S, 6S, 7R, 10R, E)-6-acetoxy-10-((tert-butyldimethylsilyl)oxy)-7-hydroxy-3,7-dimethyl-12-oxooxacyclododecan-4-ene-2-yl)-2-hydroxy-2-methylhept-3,5-diene-1-yl)oxirane-2-yl)pentane-3-yl 3,5-dinitrobenzoate (15.1 mg, 18 μmol) was added a THF solution of TBAF (1 M; 105 μL, 105 μmol). The resulting mixture was stirred at room temperature overnight. A 10% aqueous ammonium chloride solution and ethyl acetate were added to the ice-cooled reaction mixture, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0%-100% ethyl acetate / n-heptane) to obtain the title compound (8.6 mg). The obtained compounds 1 The H-NMR spectrum (500 MHz, CD3OD) was consistent with that in Example C-1.

[0159] Example C-18 Synthesis of (2R,3S)-2-((2R,3R)-3-((R,3E,5E)-6-((2S,3S,6S,7R,10R,E)-6-acetoxy-10-((tert-butyldimethylsilyl)oxy)-7-hydroxy-3,7-dimethyl-12-oxooxacyclododec-4-en-2-yl)-2-hydroxy-2-methylhepta-3,5-dien-1-yl)oxiran-2-yl)pentan-3-yl 3,5-dinitrobenzoate

[0160] C-18-(1) Synthesis of (2R,3S)-2-((2R,3R)-3-((R,3E,5E)-6-((2S,3S,6S,7R,10R,E)-10-((tert-butyldimethylsilyl)oxy)-6,7-dihydroxy-3,7-dimethyl-12-oxooxacyclododec-4-en-2-yl)-2-hydroxy-2-methylhepta-3,5-dien-1-yl)oxiran-2-yl)pentan-3-yl 3,5-dinitrobenzoate A DMF solution (1 mL) of (2R,3S)-2-((2R,3R)-3-((R)-2-hydroxy-2-methylbut-3-en-1-yl)oxiran-2-yl)pentan-3-yl 3,5-dinitrobenzoate (22.8 mg, 56 μmol) obtained in Example A-5 and (4R,7R,8S,11S,12S,E)-4-((tert-butyldimethylsilyl)oxy)-7,8-dihydroxy-12-((E)-1-iodoprop-1-en-2-yl)-7,11-dimethyloxacyclododec-9-en-2-one (20 mg, 37 μmol) obtained in Example B-5 was degassed and replaced with a nitrogen atmosphere. Pd(OAc)2(2.1mg, 9.3μmol) and Ag2CO3(13.3mg, 48μmol) were added to the mixture. The resulting reaction mixture was stirred at room temperature for 15 minutes, and then stirred at 80°C for 2 hours. The reaction mixture was allowed to cool, and then concentrated under reduced pressure, and the resulting residue was suspended in ethyl acetate, and the insoluble material was filtered out by a microporous filter. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30%-65% ethyl acetate / n-heptane) to obtain the title compound (19.9mg). 1 H-NMR (500MHz, CDCl3) δ (ppm): 0.06 (s, 3H), 0.07 (br.s, 3H), 0.87-0.91 (m, 12H), 0.97 (br.t, J = 7.3Hz, 3H), 1.06 (d, J = 7.3Hz, 3H), 1.30 (s, 3H) ,1.34(s,3H),1.35-1.50(m,4H),1.58-1.71(m,3H),1.72(s,3H),1.78 -1.94(m,4H),2.34-2.41(m,2H),2.41-2.55(m,2H),2.60(dd,J=8.3,2. 1Hz,1H),2.91(td,J=4.7,2.1Hz,1H),3.74-3.87(m,2H),4.97(d,J=10.4Hz,1H),5.24-5.32(m,1H),5.46(dd,J=15.0,10.1Hz,1H),5.71(dd,J =15.0,9.5Hz,1H),5.80(d,J=15.3Hz,1H),6.12(br.d,J=10.4Hz,1H),6.50(dd,J=15.3,11.0Hz,1H),9.17(d,J=2.5Hz,2H),9.20-9.25(m,1H).

[0161] C-18-(2) Synthesis of (2R,3S)-2-((2R,3R)-3-((R,3E,5E)-6-((2S,3S,6S,7R,10R,E)-6-acetoxy-10-((tert-butyldimethylsilyl)oxy)-7-hydroxy-3,7-dimethyl-12-oxooxacyclododec-4-en-2-yl)-2-hydroxy-2-methylhepta-3,5-dien-1-yl)oxiran-2-yl)pentan-3-yl 3,5-dinitrobenzoate Under ice cooling, (2R,3S)-2-((2R,3R)-3-((R,3E,5E)-6-((2S,3S,6S,7R,10R,E)-10-((tert-butyldimethylsilyl)oxy)-6,7-dihydroxy-3,7-dimethyl-12-oxooxacyclododec-4-en-2-yl)-2-hydroxy-3,5-dinitrobenzoic acid obtained in Example C-18-(1) was added to the mixture. To a solution of 4-(2-methyl-3-heptyl-3,5-diene-1-yl)oxirane-2-yl)pentane-3-yl ester (17.0 mg, 21 μmol), DMAP (0.51 mg, 4.2 μmol) and Et3N (8.7 μL, 62 μmol) in DCM (1 ml) was added a DCM solution of Ac2O (1M; 21 μL, 21 μmol), and the mixture was stirred at 0 ° C for 40 minutes. Saturated aqueous sodium bicarbonate solution, ethyl acetate and water were added to the reaction mixture, and the organic layer was separated. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30%-65% ethyl acetate / n-heptane) to obtain the title compound (14.7 mg). The obtained compounds 1 The H-NMR spectrum (500 MHz, CDCl3) was consistent with that in Example C-17-(1). According to the method of Example C-17-(2), pranidolactone D can be synthesized from the obtained compound.

[0162] Example C-19 Synthesis of Pradinolide D

[0163] C-19-(1) Synthesis of (2R,3S)-2-((2R,3R)-3-((R,3E,5E)-6-((2S,3S,6S,7R,10R,E)-6-acetoxy-7,10-dihydroxy-3,7-dimethyl-12-oxooxacyclododec-4-en-2-yl)-2-hydroxy-2-methylhepta-3,5-dien-1-yl)oxiran-2-yl)pentan-3-yl 3,5-dinitrobenzoate To (2S,3S,6S,7R,10R,E)-7,10-dihydroxy-2-((E)-1-iodoprop-1-en-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl acetate (10 mg, 21 μmol) obtained in Example B-8 and (2R,3S)-2-((2R,3R)-3-((R,E)-2-hydroxy-2-methyl-4-(4,4, To a solution of (5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)but-3-ene-1-yl)oxirane-2-yl)pentane-3-yl ester (12.6 mg, 24 μmol) in THF (1 mL) and water (0.1 mL) was added Ag2O (24.9 mg, 0.107 mmol), Pd2(dba)3 (3.93 mg, 4.29 μmol) and Pd(dppf)Cl2 (3.14 mg, 4.29 μmol). The reaction mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0%-100% ethyl acetate / n-heptane) to obtain the title compound (10.4 mg). The obtained compounds 1 The H-NMR spectrum (500 MHz, CDCl3) was consistent with that in Example C-16-(1).

[0164] C-19-(2) Synthesis of Pradinolide D At 0°C, to a solution of (2R, 3S)-2-((2R, 3R)-3-((R, 3E, 5E)-6-((2S, 3S, 6S, 7R, 10R, E)-6-acetoxy-7,10-dihydroxy-3,7-dimethyl-12-oxooxacyclododec-4-ene-2-yl)-2-hydroxy-2-methylhept-3,5-diene-1-yl)oxirane-2-yl)pentane-3-yl 3,5-dinitrobenzoate (4.8 mg, 6.4 μmol) in THF (1 mL) was added 0.1N aqueous lithium hydroxide solution (64 μL, 6.4 μmol). The reaction mixture was stirred at 0°C for 30 minutes and then at room temperature for 2 hours. Saturated aqueous ammonium chloride solution, DCM and water were added to the reaction solution, and the organic layer was separated. The aqueous layer was extracted with DCM (twice). The combined organic layers were dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0%-100% ethyl acetate / n-heptane) to obtain the title compound (3.0 mg). The obtained compounds 1 The H-NMR spectrum (500 MHz, CD3OD) was consistent with that in Example C-1.

[0165] Example C-20 Synthesis of (2R,3S)-2-((2R,3R)-3-((R,3E,5E)-6-((2S,3S,6S,7R,10R,E)-6-acetoxy-10-((tert-butyldimethylsilyl)oxy)-7-hydroxy-3,7-dimethyl-12-oxooxacyclododec-4-en-2-yl)-2-hydroxy-2-methylhepta-3,5-dien-1-yl)oxiran-2-yl)pentan-3-yl 3,5-dinitrobenzoate At room temperature, (2S,3S,6S,7R,10R,E)-10-((tert-butyldimethylsilyl)oxy)-7-hydroxy-2-((E)-1-iodoprop-1-en-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl acetate (10 mg, 17 μmol) obtained in Example B-6 and (2R,3S)-2-((2R,3R)-3,5-dinitrobenzoic acid obtained in Example A-10 were added to a 1% ethyl acetate and a 2% ethyl acetate. To a solution of 3-((R,E)-2-hydroxy-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-ene-1-yl)oxirane-2-yl)pentane-3-yl ester (13 mg, 24 μmol) in THF (1 mL) and water (0.1 mL) was added Ag2O (20.0 mg, 86 μmol) and Pd(dppf)Cl2 (2.52 mg, 3.45 μmol). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours. Insoluble material was filtered off from the reaction mixture with filter paper and washed with ethyl acetate. The filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (0%-50% ethyl acetate / n-heptane) to obtain the title compound (13.3 mg). The obtained compounds 1 The H-NMR spectrum (500 MHz, CDCl3) was consistent with that in Example C-17-(1). According to the method of Example C-17-(2), pranidolactone D can be synthesized from the obtained compound.

[0166] Example C-21 Synthesis of (2R,3S)-2-((2R,3R)-3-((R,3E,5E)-6-((2S,3S,6S,7R,10R,E)-10-((tert-butyldimethylsilyl)oxy)-6,7-dihydroxy-3,7-dimethyl-12-oxooxacyclododec-4-en-2-yl)-2-hydroxy-2-methylhepta-3,5-dien-1-yl)oxiran-2-yl)pentan-3-yl 3,5-dinitrobenzoate To (4R,7R,8S,11S,12S,E)-4-((tert-butyldimethylsilyl)oxy)-7,8-dihydroxy-12-((E)-1-iodoprop-1-en-2-yl)-7,11-dimethyloxacyclododecan-9-en-2-one (13 mg, 24 μmol) obtained in Example B-5 and (2R,3S)-2-((2R,3R)-3-((R,E)-2-3,5-dinitrobenzoic acid obtained in Example A-11 were added. To a solution of hydroxy-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-ene-1-yl)oxirane-2-yl)pentane-3-yl ester (18 mg, 34 μmol) in THF (1 mL) were added Pd(dppf)Cl2 (3.53 mg, 4.83 μmol), Ag2O (28 mg, 0.121 mmol) and water (0.15 mL, 8.33 mmol) in sequence. The resulting reaction mixture was stirred at room temperature for 110 minutes. Ethyl acetate and water were added to the ice-cooled reaction mixture, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The resulting residue was purified with (0%-60% ethyl acetate / n-heptane) to obtain the title compound (18.9 mg). The obtained compounds 1 The H-NMR (500 MHz, CDCl3) spectrum was consistent with that in Example C-18-(1). Pradinolide D can be synthesized from the obtained compound according to the method of Example C-18-(2), followed by the method of Example C-17-(2).

[0167] Example C-22 Synthesis of (2S,3S,6S,7R,10R,E)-10-((tert-butyldimethylsilyl)oxy)-7-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl acetate To (2S,3S,6S,7R,10R,E)-10-((tert-butyldimethylsilyl)oxy)-7-hydroxy-2-((E)-1-iodoprop-1-en-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl acetate (6.5 mg, 11 μmol) obtained in Example B-6 and trifluoro((R,E)-3-hydroxy-4-((tert-butyldimethylsilyl)oxy)-7-hydroxy-2-((E)-1-iodoprop-1-en-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl)acetate (6.5 mg, 11 μmol) obtained in Example A-14 were added. To a solution of potassium -((2R,3R)-3-((2R,3S)-3-hydroxypentane-2-yl)oxirane-2-yl)-3-methylbut-1-ene-1-yl)borate (5.38 mg, 17 μmol) in THF (1 mL) and water (0.1 mL) was added Ag2O (13.0 mg, 56 μmol) and Pd(dppf)Cl2 (1.64 mg, 2.24 μmol). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours. The reaction mixture was filtered through a glass microfiber filter paper. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0%-50% ethyl acetate / n-heptane) to obtain the title compound (5.3 mg). The obtained compounds 1 The H-NMR spectrum (500 MHz, CDCl3) was consistent with that in Example C-2-(1). According to the method of Example C-2-(2), pranidolactone D can be synthesized from the obtained compound.

[0168] Example C-23 Synthesis of Pradinolide D

[0169] C-23-(1) Synthesis of (2R,3S)-2-((2R,3R)-3-((R,3E,5E)-6-((2S,3S,6S,7R,10R,E)-6-acetoxy-10-((tert-butyldimethylsilyl)oxy)-7-hydroxy-3,7-dimethyl-12-oxooxacyclododec-4-en-2-yl)-2-hydroxy-2-methylhepta-3,5-dien-1-yl)oxiran-2-yl)pentan-3-yl 3,5-dinitrobenzoate A solution of (2R,3S)-2-((2R,3R)-3-((R)-2-hydroxy-2-methylbut-3-en-1-yl)oxiran-2-yl)pentan-3-yl 3,5-dinitrobenzoate (158 mg, 388 μmol) obtained in Example A-5 and (2S,3S,6S,7R,10R,E)-10-((tert-butyldimethylsilyl)oxy)-7-hydroxy-2-((E)-1-iodoprop-1-en-2-yl)-3,7-dimethyl-12-oxoxooxadecan-4-en-6-yl acetate (150 mg, 258 μmol) obtained in Example B-6 in DMF (3 mL) was replaced with a nitrogen atmosphere. To the mixture, Pd(OAc)2 (14.5 mg, 65 μmol) and Ag2CO3 (93 mg, 336 μmol) were added in sequence, and the resulting mixture was stirred at 60°C for 24 hours under a nitrogen atmosphere, and then at 80°C for 2 hours. Ethyl acetate and water were added to the reaction mixture at room temperature. The insoluble matter in the mixture was filtered out through glass fiber filter paper, and the filtrate was separated into multiple layers. A 5% sodium chloride aqueous solution was added to the organic layer obtained by layer separation, the mixture was filtered through diatomaceous earth, and the organic layer was separated from the filtrate and washed with a 5% sodium chloride aqueous solution. The water layer obtained by layer separation was extracted with ethyl acetate, and the organic layer was washed with a 5% sodium chloride aqueous solution. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (35%-65% ethyl acetate / n-heptane) to obtain the title compound (142 mg). The obtained compound 1 The H-NMR spectrum (500 MHz, CDCl3) was consistent with that of the compound obtained in Example C-17-(1).

[0170] C-23-(2) Synthesis of Pradinolide D To a solution of (2R,3S)-2-((2R,3R)-3-((R,3E,5E)-6-((2S,3S,6S,7R,10R,E)-6-acetoxy-10-((tert-butyldimethylsilyl)oxy)-7-hydroxy-3,7-dimethyl-12-oxooxacyclododec-4-en-2-yl)-2-hydroxy-2-methylhept-3,5-dien-1-yl)oxiran-2-yl)pentan-3-yl 3,5-dinitrobenzoate (100 mg, 116 μmol) obtained in THF (2 ml) was added a THF solution of TBAF (1 M; 0.70 mL, 700 μmol). The resulting mixture was stirred at room temperature for 20 hours. The ice-cooled reaction mixture was quenched with saturated aqueous ammonium chloride solution, and ethyl acetate and water were added to the resulting mixture, and then the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (50%-100% ethyl acetate / n-heptane) to obtain the title compound (49.4 mg). The obtained compound 1 The H-NMR spectrum (500 MHz, CD3OD) was consistent with that in Example C-1.

[0171] Example C-24 Synthesis of (2R,3S)-2-((2R,3R)-3-((R,3E,5E)-6-((2S,3S,6S,7R,10R,E)-6-acetoxy-10-((tert-butyldimethylsilyl)oxy)-7-hydroxy-3,7-dimethyl-12-oxooxacyclododec-4-en-2-yl)-2-hydroxy-2-methylhepta-3,5-dien-1-yl)oxiran-2-yl)pentan-3-yl 3,5-dinitrobenzoate To (2S,3S,6S,7R,10R,E)-10-((tert-butyldimethylsilyl)oxy)-7-hydroxy-2-((E)-1-iodoprop-1-en-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl acetate (10 mg, 17 μmol) obtained in Example B-6 and ((R,E)-4-((2R,3R)-3-( To a solution of (2R,3S)-3-((3,5-dinitrobenzoyl)oxy)pentane-2-yl)oxirane-2-yl)-3-hydroxy-3-methylbut-1-ene-1-yl)boric acid (9.35 mg, 21 μmol) in THF (1 mL) and water (0.1 mL) was added Ag2O (4.0 mg, 17 μmol) and Pd(dppf)Cl2 (2.52 mg, 3.45 μmol). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0%-50% ethyl acetate / n-heptane) to obtain the title compound (14.8 mg). The obtained compounds 1 The H-NMR (500 MHz, CDCl3) spectrum is consistent with the NMR spectrum in Example C-17-(1). This compound can be used to obtain pranidolactone D by the method of Example C-17-(2).

[0172] Example D-1 Pradinolide D powder Ethyl acetate and water were added to a mixed solution of pradilactone D in n-butyl acetate and DMF obtained by fermentation according to the method described in Patent Document 1 (content: 38.1% w / w; 11.3 g, 7.79 mmol) and the organic layer was separated. The organic layer was washed with water and a 5% sodium chloride aqueous solution in sequence. The obtained organic layer was dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to obtain the title compound (4.64 g; containing 9.16 wt% of n-butyl acetate as a residual solvent) as a pale yellow powder. 1 The H-NMR spectrum (500 MHz, CD3OD) was consistent with that in Example C-1.

[0173] Example D-2 Production of pranidolactone D toluene solvate In a 4 mL vial, weigh the pradilactone D (200 mg) obtained in Example D-1, and add toluene (1 mL). Stir with a stirrer at room temperature for 12 days. Loosen the lid of the vial and stir with a stirrer for 2 days while the solvent is splashed. The resultant is dried under reduced pressure at room temperature for 1 day to obtain the crystals of the toluene solvate mentioned. 1 H-NMR (700MHz, CD3OD) δ (ppm): 0.88 (3H, d, J = 6.8Hz), 0.89 (3H, d, J = 7.0Hz), 0.9 3(3H,t,J=7.4Hz),1.18(3H,s),1.22-1.27(1H,m),1.33(3H,s),1.35-1.40(1H,m ),1.44-1.59(3H,m),1.60-1.69(3H,m),1.77(3H,d,J=0.6Hz),1.85(1H,dd,J=13 .9,5.6Hz),2.05(3H,s),2.31(1.5H,s),2.46-2.54(2H,m),2.54-2.60(1H,m),2. 66(1H,dd,J=8.1,2.1Hz),2.89(1H,td,J=5.6,2.1Hz),3.52(1H,dt,J=8.5,4.2Hz ),3.74-3.81(1H,m),4.99-5.11(2H,m),5.56(1H,dd,J=15.0,10.0Hz),5.69(1H, dd,J=15.0,9.7Hz),5.86(1H,d,J=15.3Hz),6.13(1H,d,J=10.8Hz),6.52(1H,dd, J=15.3,10.8Hz),7.08-7.12(0.5H,m),7.14(1H,d,J=7.6Hz),7.17-7.22(1H,m).

[0174] Example D-3 Production of chlorobenzene solvate of pradinolide D In a 4 mL vial, weigh the pradinolide D (200 mg) obtained in Example D-1, and add chlorobenzene (0.5 mL). Stir with a stirrer at room temperature for 1 day. Remove the lid of the vial and stir with a stirrer for 2 days while the solvent is splashed. The resultant is dried under reduced pressure at room temperature for 1 day to obtain the crystals of the chlorobenzene solvate mentioned. 1H-NMR (700MHz, CD3OD) δ (ppm): 0.88 (3H, d, J = 6.8Hz), 0.89 (3H, d, J = 7.2Hz), 0.93 (3H, t, J = 7.4Hz), 1.18 (3H, s), 1.22-1.25 (1H, m), 1.33 (3H, s), 1. 35-1.42(1H,m),1.43-1.60(3H,m),1.60-1.69(3H,m),1.77(3H,d,J=1.1H z),1.86(1H,dd,J=14.0,5.5Hz),2.05(3H,s),2.48-2.54(2H,m),2.54-2. 60(1H,m),2.66(1H,dd,J=7.8,2.4Hz),2.89(1H,td,J=5.5,2.4Hz),3.52( 1H,dt,J=8.5,4.4Hz),3.74-3.80(1H,m),5.00-5.08(2H,m),5.56(1H,dd, J=15.3,10.0Hz),5.69(1H,dd,J=15.3,9.7Hz),5.86(1H,d,J=15.3Hz),6.13(1H,brd,J=11.1Hz),6.52(1H,dd,J=15.3,11.1Hz),7.25-7.37(3H,m).

[0175] Example D-4 Production of pradinolide D tetrahydrofuran solvate In a 4 mL vial, weigh the pradinolide D (200 mg) obtained in Example D-1, and add tetrahydrofuran (0.2 mL) and n-heptane (0.8 mL). Stir with a stirrer at room temperature for 1 day. Remove the lid of the vial and stir with a stirrer for 1 day while the solvent is splashed. The resulting product is dried under reduced pressure at room temperature for 1 day to obtain the crystals of the tetrahydrofuran solvate mentioned. 1H-NMR (700MHz, CD3CN) δ (ppm): 0.80 (3H, d, J = 6.9Hz), 0.83 (3H, d, J = 6.8Hz), 0.88 (3H, t, J = 7.2Hz), 1.11(3H,s),1.21-1.27(1H,m),1.26-1.31(1H,m),1.27(3H,s),1.28-1.34(1H,m),1.37-1.48(2H, m),1.46-1.52(1H,m),1.50-1.56(1H,m),1.56(1H,dd,J=14.0,6.8Hz),1.74(3H,d,J=1.1Hz),1.76 -1.81(3H,m),1.82(1H,dd,J=14.0,5.5Hz),2.01(3H,s),2.46(1H,dd,J=14.6,4.0Hz),2.49(1H,dd, J=14.6,3.4Hz),2.54-2.59(1H,m),2.60(1H,dd,J=7.4,2.3Hz),2.79-2.84(1H,m),2.81(1H,d,J=5 .5Hz),2.99(1H,s),3.22(1H,s),3.25(1H,d,J=8.7Hz),3.45-3.50(1H,m),3.58-3.66(3H,m),3.66 -3.73(1H,m),4.98(1H,d,J=9.7Hz),5.03(1H,d,J=10.6Hz),5.51(1H,dd,J=15.2,9.9Hz),5.64(1H ,dd,J=15.2,9.7Hz), 5.86(1H,d,J=15.2Hz), 6.10(1H,d,J=10.6Hz), 6.46(1H,dd,J=15.2,10.6Hz).

[0176] Example D-5 Production of 2-methyltetrahydrofuran solvate of pranidolactone D Pradinolide D (300 mg) obtained in Example D-1 was dissolved in 2-methyltetrahydrofuran (1.2 mL), and n-heptane (0.3 mL) was added dropwise thereto at room temperature, and then the mixture was stirred at room temperature for 10 minutes. The resulting mixture was stirred at 40° C. for 25 minutes, at room temperature for 2 hours, and further at 0° C. for 21 hours. The precipitated crystals were collected by filtration, washed with a 2:1 mixed solution of n-heptane and 2-methyltetrahydrofuran, and dried under an air stream to obtain the crystals of the tetrahydrofuran solvate mentioned (157 mg). 1H-NMR (500MHz, CD3OD) δ (ppm): 0.89 (d, J = 6.9 Hz, 3H), 0.90 (d, J = 7.5 Hz, 3H), 0.94 (t, J = 7.5 Hz, 3H), 1.19 (s, 3H), 1. 21(d,J=6.3Hz,3H),1.23-1.28(m,1H),1.34(s,3H),1.36-1.39(m,1H),1.39-1.70(m,7H),1.78(s,3H),1.87(dd,J= 14.3,5.7Hz,1H),1.89-1.98(m,2H),1.99-2.04(m,1H),2.06(s,3H),2.51-2.54(m,2H),2.55-2.61(m,1H),2.67(d d,J=7.5,2.3Hz,1H),2.90(td,J=6.0,2.3Hz,1H),3.53(dt,J=8.3,4.4Hz,1H),3.70(td,J=8.0,6.3Hz,1H),3.79(br dd,J=9.7,3.4Hz,1H),3.84-3.90(m,1H),3.95(dt,J=7.7,6.2Hz,1H),5.05(dd,J=10.0,6.6Hz,2H),5.57(dd,J=15 .2,10.0Hz,1H),5.67-5.74(m,1H),5.87(d,J=15.5Hz,1H),6.14(d,J=10.9Hz,1H),6.53(dd,J=15.2,11.2Hz,1H).

[0177] Example D-6 Production of 2-methyltetrahydrofuran solvate of pranidolactone D

[0178] D-6-(1) Synthesis of (2R,3S)-2-((2R,3R)-3-((R,3E,5E)-6-((2S,3S,6S,7R,10R,E)-6-acetoxy-10-((tert-butyldimethylsilyl)oxy)-7-hydroxy-3,7-dimethyl-12-oxooxacyclododec-4-en-2-yl)-2-hydroxy-2-methylhepta-3,5-dien-1-yl)oxiran-2-yl)pentan-3-yl 3,5-dinitrobenzoate To (2S,3S,6S,7R,10R,E)-10-((tert-butyldimethylsilyl)oxy)-7-hydroxy-2-((E)-1-iodoprop-1-en-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl acetate (802 mg, 1.38 mmol) obtained in Example B-6 and (2R,3S)-2-((2R,3R)-3-((R,E)-2-hydroxy-2-((E)-1-iodoprop-1-en-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl) acetate obtained in Example A-16-(2) were added. To a solution of -methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-yl)oxirane-2-yl)pentane-3-yl ester (920 mg, weight content by NMR: 96.3%, 1.66 mmol) in THF (80 mL) and water (8 mL) were added Ag2O (1.60 g, 6.91 mmol) and Pd(dppf)Cl2 (202 mg, 0.276 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction solution was filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated. Water and ethyl acetate were added to the residue, and the organic layer was separated. The aqueous layer was re-extracted with ethyl acetate. The combined organic layer was washed with a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The resultant was purified by silica gel column chromatography (0%-50% ethyl acetate / n-heptane) to obtain the title compound (1.40 g, crude weight). 1 The H-NMR spectrum was consistent with that of the compound obtained in Example C-17-(1).

[0179] D-6-(2) Synthesis of Pradinolide D To a solution of (2R,3S)-2-((2R,3R)-3-((R,3E,5E)-6-((2S,3S,6S,7R,10R,E)-6-acetoxy-10-((tert-butyldimethylsilyl)oxy)-7-hydroxy-3,7-dimethyl-12-oxooxacyclododec-4-en-2-yl)-2-hydroxy-2-methylhepta-3,5-dien-1-yl)oxiran-2-yl)pentan-3-yl 3,5-dinitrobenzoate (1.40 g, crude weight) obtained in Example D-6-(1) in THF (14 ml) was added a THF solution of TBAF (1 M; 9.76 mL, 9.76 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. Subsequently, a THF solution of TBAF (1M; 9.76 mL, 9.76 mmol) was added to the reaction mixture, and the reaction mixture was stirred for another 25 hours. The reaction mixture was quenched with a saturated aqueous ammonium chloride solution. Ethyl acetate and water were added to the obtained mixture, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the resultant was washed with a saturated aqueous ammonium chloride solution (twice) and a saturated aqueous sodium bicarbonate solution (twice) in sequence. The combined aqueous layers were extracted with ethyl acetate (twice). The combined ethyl acetate layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate), and then repurified by NH silica gel column chromatography (0%-100% MeOH / ethyl acetate) to obtain the title compound (504 mg, weight content of NMR: 96.3%). The compound mentioned 1 The H-NMR spectrum (500 MHz, CD3OD) was consistent with that in Example C-1.

[0180] D-6-(3) Production of 2-methyltetrahydrofuran solvate of pranidolactone D At room temperature, over 10 minutes, to a solution of pranolide D (98.7 mg, weight content of NMR: 96.3%, 172 μmol) obtained in Example D-6-(2) in 2-methyltetrahydrofuran (0.5 mL), n-heptane (0.5 mL) was added in 5 batches of 0.1 ml, and the mixture was stirred for 30 minutes. Then, seed crystals of pranolide D 2-methyltetrahydrofuran solvate obtained in Example D-5 were added to the mixture, and the mixture was stirred at room temperature for 15 minutes. The crystals adhering to the wall were added dropwise with ultrasonic waves, and the mixture was further stirred at room temperature for 45 minutes. Thereafter, the mixture was gradually cooled to 0°C over 40 minutes, and further stirred at 0°C overnight. The precipitated crystals were collected by filtration, washed with a 2:1 mixed solution (2 mL) of n-heptane and 2-methyl-THF, and dried under reduced pressure to obtain the title compound (98.9 mg). 1H-NMR (700MHz, CD3OD) δ (ppm): 0.87 (3H, d, J = 6.6Hz), 0.89 (3H, d, J = 7.0Hz), 0.93 (3H, t, J = 7.5Hz), 1.18 (3H,brs),1.20(3H,d,J=6.2Hz),1.21-1.26(1H,m),1.33(3H,s)1.34-1.39(1H,m),1.41-1.46(1H,m),1. 46-1.51(1H,m),1.51-1.55(1H,m),1.54-1.59(1H,m),1.60-1.66(1H,m),1.60-1.64(1H,m),1.65(1H,dd ,J=14.1,6.6Hz),1.77(3H,s),1.86(1H,dd,J=14.1,5.7Hz),1.88-1.97(2H,m),2.00-2.04(1H,m),2.05( 3H,s),2.50-2.53(2H,m),2.54-2.60(1H,m),2.66(1H,dd,J=7.9,2.2Hz),2.89(1H,ddd,J=6.6,5.7,2.2 Hz),3.52(1H,dt,J=8.4,4.4Hz),3.69(1H,td,J=8.3,6.6Hz),3.75-3.80(1H,m),3.86(1H,td,J=7.9,6.6 Hz),3.92-3.97(1H,m),5.04(1H,d,J=9.6Hz),5.06(1H,d,J=10.2Hz),5.56(1H,dd,J=15.4,10.1Hz),5.6 9(1H,dd,J=15.4,9.6Hz), 5.86(1H,d,J=15.4Hz), 6.13(1H,d,J=10.6Hz), 6.52(1H,dd,J=15.4,10.6Hz).

[0181] Example E. Measurement of Purity The pranolide D obtained in Example D-6-(2) and the pranolide D2-methyltetrahydrofuran solvate obtained in Example D-6-(3) were dissolved in water / acetonitrile (1 / 1, v / v) to prepare a solution having a concentration of 0.5 mg / mL. The measurement was performed under the following high performance liquid chromatography (HPLC) conditions, and the HPLC purity was evaluated. The results are shown in Table 2. [HPLC conditions] Column: Sun Armor C18, 4.6 mm × 250 mm, 3 μm Mobile phase A: water / acetonitrile (77 / 23, v / v) Mobile phase B: acetonitrile Flow rate: 0.9 mL / min Column temperature: 30°C Detection wavelength: 240nm Injection volume: 10 μL Gradient conditions [Table 1]

[0182] [Table 2]

[0183] The retention time of pranidolactone D and pranidolactone D 2-methyltetrahydrofuran solvate was 75.5 minutes. In the pranidolactone D 2-methyltetrahydrofuran solvate obtained in Example D-6-(3), the proportion of impurities was reduced by crystallization and washing, and improvement in purity was confirmed.

Claims

1. A method for producing pranololide D represented by formula (1): or a salt thereof, or a solvate thereof, The method comprises the following steps: Step 2-1) a compound represented by formula (A2): wherein X is hydrogen or an optionally substituted boron group, R 4 is hydrogen or a silyl protecting group, and R 5 is hydrogen or optionally substituted benzoyl, Reaction with a compound represented by formula (B1) in the presence of a metal catalyst: Where R 1 and R 2 are each independently hydrogen or a silyl protecting group, To obtain a compound represented by formula (C2): Where R 1 , R 2 and R 4 are each independently hydrogen or a silyl protecting group, and R 5 is hydrogen or optionally substituted benzoyl; Step 2-2) removing the protecting group of the compound represented by formula (C2) obtained in Step 2-1 to obtain pranidolactone D; as well as Optionally, step 2-3) converting the pranidolactone D obtained in step 2-2 into a solvate.

2. The method according to claim 1, wherein R 5 It's hydrogen.

3. The method according to claim 1, wherein R 5 It is 2,4-dinitrobenzoyl.

4. The method according to claim 1, wherein R 5 It is 3,5-dinitrobenzoyl.

5. The method according to any one of claims 1 to 4, wherein R 4 It's hydrogen.

6. The method according to any one of claims 1 to 5, wherein R 2 It's hydrogen.

7. The method according to any one of claims 1 to 6, wherein R 1 It's hydrogen.

8. The method according to any one of claims 1 to 6, wherein R 1 is a silyl protecting group.

9. The method according to any one of claims 1 to 6, wherein R 1 It is tert-butyl(dimethyl)silyl.

10. The process according to any one of claims 1 to 9, wherein X is hydrogen.

11. The method according to any one of claims 1 to 9, wherein X is an optionally substituted boron group.

12. The method according to any one of claims 1 to 9, wherein X is boronic acid, pinacol borate or trifluoroborate.

13. The method according to any one of claims 1 to 12, wherein the pranidolactone D or a salt thereof or a solvate thereof is pranidolactone D 2-methyltetrahydrofuran solvate.

14. The process according to any one of claims 1 to 13, wherein the metal catalyst is a palladium catalyst.

15. The process according to any one of claims 1 to 13, wherein the metal catalyst is palladium (II) acetate.

16. The process according to any one of claims 1 to 13, wherein the metal catalyst is tris(dibenzylideneacetone)dipalladium(0).

17. The process according to any one of claims 1 to 13, wherein the metal catalyst is (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II).

18. The method according to any one of claims 1 to 17, wherein the step of removing the protecting group comprises removal using an acid and removal using a base.

19. The method according to any one of claims 1 to 17, wherein the step of removing the protecting group comprises removal using fluoride ions and removal using a base.

20. The method according to any one of claims 1 to 17, wherein the step of removing the protecting group comprises removal using a base.

21. The method according to any one of claims 1 to 17, wherein the step of removing the protecting group comprises removal using fluoride ions.

22. The method according to any one of claims 1 to 17, wherein the step of removing the protecting group comprises removal using lithium hydroxide.

23. The method according to any one of claims 1 to 17, wherein the step of removing the protecting group comprises removal using tetrabutylammonium fluoride.

24. The method according to any one of claims 1 to 17, wherein the step of removing the protecting group comprises removal using tetrabutylammonium fluoride and removal using lithium hydroxide.

25. A compound represented by formula (C5): or a salt thereof, Where R 1 , R 2 and R 4 Each is independently hydrogen or a silyl protecting group.

26. A compound represented by formula (C7): or a salt thereof, wherein X is hydrogen or an optionally substituted boron group and R 4 is hydrogen or a silyl protecting group.

27. A crystal of pranidolactone D 2-methyltetrahydrofuran solvate represented by formula (1d):

28. The crystal according to claim 27, which has one or more diffraction peaks in powder X-ray diffraction at a diffraction angle (2θ±0.2°) selected from the group consisting of 10.3°, 10.7°, 11.7°, 13.3°, 14.4°, 17.2°, 18.9°, 21.2°, 22.5° and 23.4°.

29. The crystal according to claim 27 or 28, wherein the crystal is 13 In the C NMR spectrum, there are one or more peaks at a chemical shift (δ±0.5 ppm) selected from the group consisting of: 9.1ppm, 10.0ppm, 10.5ppm, 16.2ppm, 21.4ppm, 23.9ppm, 24.2ppm, 25.4ppm, 26.8ppm, 28. 0ppm, 28.5ppm, 33.3ppm, 33.7ppm, 35.9ppm, 39.9ppm, 41.1ppm, 42.7ppm, 45.7ppm, 56.0p pm, 59.3ppm, 67.9ppm, 70.4ppm, 72.6ppm, 76.5ppm, 77.7ppm, 83.0ppm, 124.0ppm, 124.4p pm, 128.0ppm, 130.2ppm, 134.4ppm, 139.1ppm, 141.0ppm, 141.3ppm, 166.9ppm and 170.4ppm.

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