CN109956936B

CN109956936B - Preparation method of Psymberin

Info

Publication number: CN109956936B
Application number: CN201910244201.9A
Authority: CN
Inventors: 叶涛; 郭益安; 余杰; 杨明泽
Original assignee: Shenzhen Qianyan Pharmaceutical R&d Technology Co ltd; Peking University Shenzhen Graduate School
Current assignee: Shenzhen Qianyan Pharmaceutical R&d Technology Co ltd; Peking University Shenzhen Graduate School
Priority date: 2019-03-28
Filing date: 2019-03-28
Publication date: 2021-01-05
Anticipated expiration: 2039-03-28
Also published as: CN109956936A

Abstract

The invention belongs to the field of synthetic chemistry, and particularly relates to a preparation method of psymberin. The preparation method of the psymberin comprises the following steps: derivatizing the compound 2 to obtain an acyl chloride compound 14; connecting a compound 3 with an acyl chloride compound 14, and then removing a protecting group to obtain a compound 1, wherein the compound 1 is psymberin; wherein, the structural formula of the compound is shown in the specification. The preparation method of the psymberin, provided by the invention, is constructed by utilizing an imido ester formation-acylation-reduction method based on the instability of N, O-hemiaminal, and has the characteristics of simple process, low cost and high yield compared with the prior art.

Description

Preparation method of Psymberin

Technical Field

The invention belongs to the field of synthetic chemistry, and particularly relates to a preparation method of psymberin.

Background

Marine polyketone natural products psymberin with excellent anti-cancer activity are respectively and independently selected from two different Phillip Crews subject groups (Cichewicz, R.H., et al. org.Lett.2004,6,1951.) and George R.Pettit subject groups (Pettit, G.R., et al. J.Med.chem.2004,47,1149.) in 2005Separated from sponge organism. Structurally, the psymberin comprises a polysubstituted trans 2, 6-tetrahydropyran ring, the psymberic acid fragment and the pyran fragment are joined by an unstable N, O-hemiaminal structure, and the dihydroisocoumarin structure in the molecule renders the psymberin uniquely present in a wide range of molecules within its family. Since the 2005 isolation, studies around the synthesis and activity of this star molecule have been uninterrupted. Psymberin has significant inhibitory activity against multiple tumor cell lines, particularly against a portion of the melanoma cell lines (MALME-3M, SK-MEL-5 and UACC-62) and breast cancer cell line (MIDA-MB-435) at nanomolar concentration Levels (LC)₅₀<2.5x 10^-9M), the inhibitory activity on the colon cancer cell line HCC-2998 reaches micromolar Level (LC)₅₀ 3.76x 10^-7M)。

Since the psymberin is a natural anticancer small molecule with a broad spectrum and certain selectivity, the intensive synthesis and structure-activity relationship research aiming at the psymberin has important significance for the development of new anticancer drugs.

Disclosure of Invention

The invention aims to overcome the defects in the prior art and provide a preparation method of psymberin, aiming at solving the technical problem that the existing synthesis method of psymberin is limited.

In order to achieve the purpose, the invention adopts the following technical scheme:

the invention provides a preparation method of psymberin, which comprises the following steps:

derivatizing the compound 2 to obtain an acyl chloride compound 14;

connecting a compound 3 with an acyl chloride compound 14, and then removing a protecting group to obtain a compound 1, wherein the compound 1 is psymberin;

wherein, the structural formula of the compound is as follows:

the preparation method of the psymberin, provided by the invention, is constructed by utilizing an imido ester formation-acylation-reduction method based on the instability of N, O-hemiaminal, and has the characteristics of simple process, low cost and high yield compared with the prior art.

Detailed Description

In order to make the technical problems, technical solutions and advantageous effects to be solved by the present invention more clearly apparent, the present invention is further described in detail below with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

The embodiment of the invention provides a preparation method of psymberin, which comprises the following steps:

s01: derivatizing the compound 2 to obtain an acyl chloride compound 14;

s02: connecting a compound 3 with an acyl chloride compound 14, and then removing a protecting group to obtain a compound 1, wherein the compound 1 is psymberin;

wherein, the structural formula of the compound is as follows:

the preparation method of the psymberin provided by the embodiment of the invention is constructed by utilizing an imido ester formation-acylation-reduction method based on the instability of N, O-hemiaminal, has the characteristics of simple process, low cost and high yield, and has a very strong application prospect in the medical industry. In order to complete the total synthesis of psymberin, the examples of the present invention have been intensively studied, and a great deal of creative work has been performed to realize the present invention.

Specifically, the synthesis of a polyketone natural product psymberin is analyzed by using classical reverse synthetic analysis, the natural product psymberin is successfully synthesized, and the reverse synthetic analysis of the psymberin is as follows:

due to the instability of the N, O-hemiaminal, the present example chose to construct this structure at the end by an imidate (imidate) formation-acylation-reduction method, and thus could be retro-pushed to compound 2 and primary amide main fragment compound 3; for a dihydroisocoumarin structure in a key fragment, a polysubstituted aryl mother nucleus can be constructed by a later Diels-Alder/aromatization reaction, and an unsaturated alkyne ester compound 4 is used as a dienophile in the key reaction; the introduction of three consecutive chiral centers at positions C-15 to C-17 in compound 4 is achieved by Brown mutagenesis and iodine-induced electrophilic cyclization reactions, respectively, and thus can be retro-extrapolated to compound 5; the key trans-tetrahydropyran fragment compound 5 was obtained starting from compound 7 by a trans-ring Michael addition/lactone reduction strategy. The unsaturated lactone structure in the compound 7 can be constructed by Still-Gennari modified HWE olefination reaction, and can be finally retrograded to the known aldehyde compound 8.

The specific synthetic route is as follows:

(1) synthesis of psymberic acid fragment compound 2: carrying out addition reaction on the compound 10 and the compound 9 to obtain a compound 11; introducing a methyl group into the compound 11, removing ketal protection, and then carrying out hydroxyl protection to obtain a compound 13; the compound 13 is subjected to Dess-Martin oxidation reaction and Pinnick oxidation reaction to obtain a compound 2. In one embodiment, the specific reaction process is as follows:

starting from the known compound 10 in Zn, SnCl₂And (3) under the conditions of (1), carrying out an addition reaction with the compound 9 to obtain an addition product compound 11 in a stereoselective manner. Subsequently, the compound 11 is introduced with methyl under the condition of NaH and MeI, and the ketal protection is further removed under the condition of PTSA (p-toluenesulfonic acid) to obtain the diol compound 12. Further, the primary hydroxyl group in compound 12 is optionally protected with TBS, then a Bz protecting group is introduced to the secondary hydroxyl group, and finally the TBS protection is removed under the condition of 3N hydrochloric acid to obtain compound 13. The compound 13 undergoes Dess-Martin oxidation reaction(in DMP, NaHCO)₃In the presence), and the Pinnick oxidation reaction (in NaClO)₂，NaH₂PO₄2-methyl-2-butene, i.e., 2-methyl-2-butene) to yield psymberic acid fragment compound 2. The compound 2 may be in (COCl)₂Derivatization under DMF conditions gives the acid chloride compound 14, which can be used directly for subsequent fragment docking.

(2) Synthesis of trans tetrahydropyran fragment compound 5: after the compound 8 and isopentenyl bromide are subjected to addition reaction, oxidizing a double bond at the tail end of a product, and then performing alkenylation and lactonization reaction with a phosphate compound 19 to obtain a compound 7; removing the compound 7 ketal and carrying out a trans-ring oxaMichael addition reaction to obtain a compound 6; protecting the primary hydroxyl of the compound 6 to obtain a compound 20; the lactone structure of compound 20 is reduced to give compound 5. In one embodiment, the specific reaction process is as follows:

starting from the known compound 8 in Zn, NH₄And reacting with isopentenyl bromide 15 under the condition of Cl to obtain a pair of addition products, namely a compound 16 and a compound 17, wherein the stereoselectivity is 1.7:1, and the compound 17 is a target compound. Subsequently, the terminal double bond in the compound 17 is oxidatively cleaved under ozone conditions to obtain an aldehyde compound 18. Further, in the presence of KHMDS (potassium hexamethyldisilazide), 18-crown-6 (18-crown-6), the aldehyde compound 18 undergoes a Still-Gennari modified HWE olefination reaction one-pot method to complete the olefination reaction with the phosphate compound 19 and the lactonization reaction to obtain the unsaturated lactone compound 7. Under the condition of catalytic amount of PPTS (compound of pyridine and 4-toluenesulfonic acid), the compound 7 is subjected to one-pot ketal removal and trans-ring oxaMichael addition reaction to obtain a bridged ring compound 6. Further under the conditions of 4-methoxybenzyl-2,2,2-trichloroacetimidate (4-methoxybenzyl-2, 2, 2-trichloroiminoacetate), PTSA, the primary hydroxyl group of compound 6 is protected by PMB to give compound 20, which is finally treated with LiBH₄Reduction reactionThe lactone structure in the bridged ring compound 20 should be reduced to give the target trans tetrahydropyran fragment compound 5.

(3) Synthesis of alkyne ester compound 26: protecting hydroxyl in the compound 5 to obtain a compound 21; oxidizing the protected primary hydroxyl group in compound 21 to obtain compound 22; subjecting compound 22 to asymmetric Brown mutagenesis to obtain compound 23; introducing a Boc group to the secondary hydroxyl group of compound 23 to give compound 24; carrying out cyclization reaction on the compound 24, and then hydrolyzing to obtain a compound 25; introducing a compound 25 into ethyl propiolate to obtain a compound 4, and protecting a hydroxyl group of the compound 4 to obtain a compound 26. In one embodiment, the specific reaction process is as follows:

firstly, two hydroxyl groups in a trans-tetrahydropyran compound 5 are protected under the condition of TESOTF, 2,6-lutidine to obtain a compound 21. Subsequently, one of the TES protected hydroxyl groups in compound 21 was selectively oxidized by Swern oxidation to give aldehyde compound 22. The construction of two consecutive chiral centers can be achieved by an asymmetric Brown mutagenesis reaction starting from aldehyde compound 22 to give compound 23. Under the conditions of NaHMDS, Boc2O, a Boc group can be introduced to the newly generated secondary hydroxyl group to give compound 24. Subsequently, under the conditions of the active substance IBr, the compound 24 can undergo iodine-induced cyclization reaction, and further hydrolysis can obtain the epoxy compound 25. The introduction of ethyl propiolate can be realized in the compound 25 under the conditions of n-BuLi and boron trifluoride diethyl etherate to obtain the alkyne ester compound 4. Finally, two naked hydroxyls in the compound 4 are protected under the condition of TESOTF, 2,6-lutidine to obtain the compound 26.

(4) Construction of dihydroisocoumarin structural Compound 32: carrying out Diels-Alder/aromatization reaction on the compound 26 and the compound 27 to obtain a compound 28; protecting the phenolic hydroxyl group of compound 28, and then introducing a bromine atom to compound 30 on the aryl group; exchanging said compound 30 with lithium halide, followed by alkylation with MeI to provide compound 31; the compound 31 is deprotected and lactonized to give compound 32, then the bare hydroxyl groups are protected again with TES. In one embodiment, the specific reaction process is as follows:

the alkyne ester compound 26 and the diene compound 27 undergo a Diels-Alder/aromatization reaction under the heating condition to obtain a compound 28. The two phenolic hydroxyl groups of compound 28 were then protected under MOMCl and DIPEA to afford compound 29. Further, under the condition of NBS, a bromine atom is introduced to the aryl group of the compound 29 to the compound 30. Alkylation of compound 30 with MeI by lithium halide exchange under butyllithium conditions at low temperature gives compound 31. Finally, under the condition of TBAF, the compound 31 is lactonized while being subjected to three TES protecting groups removal, and then the other two naked hydroxyl groups are protected again under the condition of TESOTF, 2,6-lutidine to obtain the dihydroisocoumarin compound 32.

(5) Synthesis of Psymberin:

starting from compound 32, firstly in Pd (OH)₂/C，H₂Under conditions of (2) removing the PMB protecting group, followed by removal in AZADO, NaClO₂The newly obtained primary hydroxyl group is oxidized to the acid in one step under the condition of AcOH/NaOAc buffer solution to obtain compound 33. In TBTU, DIPEA and NH₄Under Cl conditions, the acid compound 33 can be converted to the primary amide compound 34. Subsequently, in the presence of B-bromothecol, two MOM and two TES protecting groups were removed from compound 34, and subsequently Ac₂Deprotection of all hydroxyl groups under pyridine conditions gives compound 3, protected with a peracetyl group. Finally, docking of the psymberic acid fragment compound 14 with compound 3 can be achieved using an imidate formation-acylation-reduction strategy, and finally removal of all protecting groups under LiOH conditions, i.e.The final product psymberin (1) was obtained.

The invention is described in further detail with reference to a part of the test results, which are described in detail below with reference to specific examples.

Example 1

To a mixture of a known aldehyde compound 10(3.0g,17.2mmol,1.0equiv.) and SnCl at room temperature₂(3.26g,17.2mmol,1.0equiv.) to an aqueous suspension (10mL) was added activated zinc dust (2.24g,34.4mmol,2.0 equiv.). After stirring for 5 minutes, compound 9(2.1mL,20.7mmol,1.2equiv.) was slowly added dropwise to the reaction system. Stirring was continued for 10 minutes at room temperature, then the reaction was filtered through celite, and the resulting filtrate was extracted repeatedly with ethyl acetate (4X 30 mL). The organic phase was collected and washed with anhydrous Na₂SO₄And (5) drying. The filtrate was dried by evaporation and isolated on silica gel column to give compound 11(3.75g, 87%) as a colorless oily addition product.

NaH (1.5g,37.4mmol,1.3equiv., 60% in mineral oil) was added to dry THF (140mL) to make a suspension, after cooling to 0 deg.C, a solution of compound 11(5.35g,28.2mmol,1.0equiv.) in THF (30mL) was slowly added. After stirring vigorously for 30 minutes, MeI (2.2mL,43.2mmol,1.5equiv.) was added slowly to the reaction and the reaction was allowed to warm to room temperature and stirring was continued for 3 hours. After the reaction is finished, adding saturated NH into the system₄The reaction was quenched with aqueous Cl (5mL), the reaction was extracted with ethyl acetate (3 × 150mL), and the combined organic phases were washed with water (15mL) followed by saturated brine (20mL) and dried over anhydrous sodium sulfate solid. After filtration, the filtrate was concentrated under reduced pressure by means of a vacuum pump and the resulting crude product was dissolved again in MeOH (125mL), and TsOH. H was added to the system at room temperature₂O (500mg,2.6mmol,0.11equiv.) was reacted for 12 h. After the reaction is complete, Et is added₃The reaction was quenched with N (2 mL). Concentrating the reaction solution directly by a vacuum water pump under reduced pressure, and separating the obtained crude product by silica gel column chromatography to obtain colorless oily diol compound 12(3.5g,76％)。

[α]_D ²²＝+16.4(c 1.0,CHCl₃)；¹H NMR(300MHz,CDCl₃)4.85–4.74(m,2H),3.80–3.60(m,3H),3.48(ddd,J＝11.3,7.4,4.2Hz,1H),3.40(s,3H),3.08(d,J＝5.1Hz,1H),2.87(brs,1H),2.34(dd,J＝14.3,7.1Hz,1H),2.17(dd,J＝14.2,5.9Hz,1H),1.77(s,3H).¹³C NMR(75MHz,CDCl₃)142.3,113.4,81.8,72.5,63.2,58.4,38.8,22.8.HRMS(m/z):calculated for C₈H₁₆NaO₃ ⁺[M+Na]⁺:183.0997,found 183.0996.

Example 2

Diol compound 12(2g,12.5mmol,1.0equiv.) was dissolved in dichloromethane (5.0mL), cooled to 0 ℃, and imidazole (2.55g,37.5mmol,3.0equiv.) and TBSCl (2.83g,15.1mmol,1.5equiv.) were added, respectively. The temperature was maintained and stirring was continued for 5 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution (10 mL). The reaction was then extracted with ethyl acetate (3X 50mL), the organic phases combined and washed successively with saturated ammonium chloride solution (15mL), water (15mL) and saturated brine (20mL), and the anhydrous sodium sulfate solid dried. After filtration, the filtrate was concentrated under reduced pressure by a vacuum pump and separated by flash column chromatography (ethyl acetate/n-hexane ═ 1:20) to give compound 12-1(3.2g, 93%) as a colorless oil.

[α]_D ²²＝+16.5(c 1.0,CHCl₃)；¹H NMR(400MHz,CDCl₃)4.82–4.75(m,2H),3.74–3.58(m,3H),3.40(dd,J＝7.5,5.0Hz,1H),3.37(s,3H),2.53(d,J＝3.8Hz,1H),2.35–2.16(m,2H),1.76(d,J＝1.2Hz,3H),0.88(s,9H),0.06(s,3H),0.05(s,3H).¹³C NMR(101MHz,CDCl₃)142.9,112.8,80.1,72.8,63.5,58.2,38.5,26.0,23.0,18.3,-5.3.HRMS(m/z):calculated for C₁₄H₃₀NaO₃Si⁺[M+Na]⁺:297.1862,found 297.1862.

Example 3

Compound 12-1(3.8g,13.9mmol,1.0equiv.) is dissolved in dichloromethane (150mL) and Et is added sequentially under zero conditions₃N (19.2mL,139mmol,10.0equiv.) and BzCl (8.0mL,69.5mmol,5.0equiv.), followed by warming the reaction to room temperature and stirring continued for 2 hours. BzCl (3.2mL,17mmol,2.0equiv.) was added to the reaction again, stirring was continued for 2 hours and then saturated NaHCO was added₃The reaction was quenched (5 mL). The reaction mixture was extracted with dichloromethane (2X 200mL), the organic phases were combined and washed successively with 1N hydrochloric acid (50mL), water (50mL), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was dissolved in THF (30mL) again, and 3N hydrochloric acid solution (6mL) was slowly added dropwise to the solution. After stirring for 2 hours, the reaction was cooled to zero and solid NaHCO was added₃(2.0g) the reaction was quenched. The reaction mixture was extracted with methylene chloride (3X 100mL), the organic phases were combined and washed successively with water (50mL) and saturated brine (50mL), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to give compound 13(3.3g, 88%) as a colorless oily substance.

[α]_D ²³＝-13.94(c 1.0,CHCl₃)；¹H NMR(400MHz,CDCl₃)8.09–8.04(m,2H),7.60–7.53(m,1H),7.47–7.41(m,2H),5.14(dt,J＝5.0,3.7Hz,1H),4.87–4.78(m,2H),4.01(dd,J＝12.4,5.0Hz,1H),3.92(dd,J＝12.4,3.6Hz,1H),3.79(ddd,J＝7.5,5.7,3.9Hz,1H),3.48(s,3H),2.87(brs,1H),2.47–2.37(m,1H),2.35–2.24(m,1H),1.80(t,J＝1.1Hz,3H).¹³C NMR(101MHz,CDCl₃)166.5,141.8,133.3,130.1,129.9,128.6,113.6,80.3,76.4,61.9,59.0,39.8,22.8.HRMS(m/z):calculated for C₁₅H₂₀NaO₄ ⁺[M+Na]⁺:287.1259,found 287.1265.

Example 4

Compound 13(2.95g,11.2mmol,1.0equiv.) is dissolved in dichloromethane (30mL), cooled to zero degrees and then NaHCO is added in sequence₃(2.81g,33.5mmol,3.0equiv.) and Dess-Martin oxidant (7.13g,16.7mmol,1.5 equiv.). After the reaction system is stirred for 1 hour at room temperature, the reaction liquid is directly separated by silica gel column chromatography to obtain an aldehyde intermediate compound.

The aldehyde intermediate compound of the previous step was dissolved in a t-butanol-water (36mL, v/v ═ 4:1) mixed solvent, and 2-methyl-2-butene (5mL), sodium dihydrogen phosphate (8.4g,54mmol,5.0equiv.) and sodium chlorite (4.8g,54mmol,5.0equiv.) were added in this order under zero temperature conditions, followed by warming the reaction system to room temperature and continued stirring for 1 hour. After completion of the reaction, the reaction mixture was extracted directly with ethyl acetate (3X 100mL), and the organic phases were combined and washed successively with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure to remove low-boiling components. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate/n-hexane ═ 1:5) to obtain carboxylic acid compound 2(2.1g, 70%).

[α]_D ²³＝+0.2(c 1.0,CHCl₃)；¹H NMR(400MHz,CDCl₃)8.14–8.03(m,2H),7.63–7.55(m,1H),7.51–7.40(m,2H),5.59(d,J＝2.5Hz,1H),4.92–4.83(m,2H),3.94(ddd,J＝8.0,5.3,2.5Hz,1H),3.52(s,3H),2.56(ddd,J＝14.7,8.2,1.1Hz,1H),2.44(dd,J＝14.6,5.3Hz,1H),1.80(d,J＝1.1Hz,3H).¹³C NMR(101MHz,CDCl₃)173.4,165.9,141.4,133.7,130.1,129.3,128.7,128.6,113.9,79.7,73.2,58.5,39.1,22.7.HRMS(m/z):calculated for C₁₅H₁₈NaO₅ ⁺[M+Na]⁺:301.1052,found 301.1055.

Example 5

Carboxylic acid compound 2(56mg,0.2mmol,1.0equiv.) was dissolved in dry DCM (1mL) and cooled to zero degrees before adding oxalyl chloride (2mL,2mmol,1M in DCM,10.0equiv.) and catalytic amount of DMF. The reaction was then warmed to room temperature and stirring continued for 2 hours. After the reaction is finished, the solvent in the reaction bottle is dried by nitrogen, and the obtained crude product is dried under the condition of a vacuum pump. The resulting acid chloride compound 14 was dissolved in dry DCM (1mL) to make a 0.2M solution in dichloromethane which was used to dock the immediately subsequent fragment.

Example 6

The known aldehyde compound 8(20.7g,117mmol,1.0equiv.) was dissolved in a tetrahydrofuran/saturated aqueous ammonium chloride solution (1:5) mixed solvent (180mL), cooled to 0 ℃, and at that temperature isopentenyl bromide 15(14mL,149mmol,1.05equiv.) and newly activated zinc powder (7.9g,123mmol,1.05equiv.) were added successively to the reaction system, followed by warming the reaction system to room temperature and stirring at that temperature for 0.5 hour. After the reaction was completed, ethyl acetate (100mL) and saturated NH were added successively to the system₄The reaction was quenched with aqueous Cl (20mL), the organic and aqueous phases were then separated, the resulting aqueous phase was extracted with ethyl acetate (3 × 100mL), and the combined organic phases were washed with water (50mL) followed by saturated brine (50mL) and dried over anhydrous sodium sulfate solid. After filtration, the filtrate was concentrated under reduced pressure using a vacuum pump, and the crude product was separated by silica gel column chromatography (ethyl acetate/n-hexane ═ 1:5) to give a pair of diastereomers with a total yield of 76%, d.r. ═ 1.7:1, respectively compound 16 in the S configuration (19.7g, 74%) and compound 17 in the target R configuration (9.9g, 28%).

Compound 16: [ alpha ] to]_D ²⁷＝-11.0(c 0.7,CHCl₃)；¹H NMR(500MHz,CDCl₃)5.80(dd,J＝17.5,10.8Hz,1H),5.06(dd,2H),4.31–4.25(m,1H),4.08(dd,J＝8.0,6.0Hz,1H),3.52(t,J＝7.9Hz,2H),1.96(d,J＝3.9Hz,1H),1.79(ddd,J＝14.2,7.1,1.8Hz,1H),1.48(ddd,J＝13.9,10.7,5.0Hz,1H),1.01(s,3H),1.00(s,3H),0.91–0.86(m,6H).¹³C NMR(126MHz,CDCl₃)145.2,113.6,112.5,75.0,74.7,70.5,41.5,35.1,30.1,29.8,23.1,22.1,8.4,8.1.HRMS(m/z):calculated for C₁₄H₂₆NaO₃ ⁺[M+Na]⁺:265.1780,found 265.1779.

Compound 17: [ alpha ] to]_D ²⁷＝+14.4(c 1.4,CHCl₃)；¹H NMR(500MHz,CDCl₃)5.86(dd,J＝17.5,10.9Hz,1H),5.07–4.98(m,2H),4.27–4.19(m,1H),4.10(dd,J＝7.9,6.0Hz,1H),3.53–3.45(m,2H),3.22(d,J＝1.7Hz,1H),1.73(ddd,J＝14.0,3.6,1.5Hz,1H),1.63(dq,J＝12.6,7.2Hz,4H),1.50(ddd,J＝14.1,10.5,9.3Hz,1H),1.03(s,6H),0.93–0.85(m,6H).¹³C NMR(126MHz,CDCl₃)145.4,113.5,112.6,77.8,76.8,70.4,41.2,35.0,30.0,29.6,23.3,22.1,8.2,8.1.HRMS(m/z):calculated for C₁₄H₂₆NaO₃ ⁺[M+Na]⁺:265.1780,found 265.1779.

Example 7

The alkenyl compound 17(1.45g, 6mmol, 1.0equiv.) was dissolved in dichloromethane (20mL), cooled to-78 ℃, followed by passing ozone gas through the reaction system for about 2 hours until the reaction solution became blue, and no raw material remained as confirmed by thin layer chromatography. After the reaction was completed, triphenylphosphine solid (1.9g, 7.2mmol, 1.2equiv.) was added to the system at the same temperature, and the reaction was slowly warmed to room temperature and stirred for 2 h. The reaction mixture was directly concentrated under reduced pressure using a vacuum pump, and the resulting crude product was separated by silica gel column chromatography (ethyl acetate/n-hexane ═ 1:4) to give compound 18(1.3g, 90%) as a colorless oil.

[α]_D ²¹＝+7.6(c 2.0,CHCl₃)；¹H NMR(400MHz,CDCl₃)9.56(s,1H),4.30–4.18(m,1H),4.10(dd,J＝8.0,6.0Hz,1H),3.92(dt,J＝10.5,1.6Hz,1H),3.54(d,J＝1.6Hz,1H),3.49(t,J＝7.9Hz,1H),1.75–1.43(m,6H),1.05(s,3H),1.02(s,3H),0.89–0.78(m,6H).¹³C NMR(100MHz,CDCl₃)206.0,113.6,76.5,74.9,70.2,49.9,34.5,29.7,29.4,18.6,16.6,8.0,7.9.HRMS(m/z):calculated for C₁₃H₂₄NaO₄ ⁺[M+Na]⁺:267.1572,found 267.1577.

Example 8

Phosphate compound 19(3.46g, 10.9mmol, 1.6equiv.) and 18-crown-6 (3.23g, 12.2mmol, 1.8equiv.) were dissolved in dry THF (60mL) under argon, cooled to-78 ℃ and KHMDS (10mL, 10mmol, 1.0M in THF, 1.5equiv.) was slowly added dropwise to the system, with constant stirring at this temperature for 0.5 h. A solution of aldehyde compound 18(1.45g, 6mmol, 1.0equiv.) in tetrahydrofuran (10mL) was slowly added dropwise to the above reaction system, and after holding at this temperature for about 20 minutes, the reaction system was slowly warmed to zero (6 hours) and held at zero for 2 hours. After completion of the reaction, the reaction was quenched by addition of saturated ammonium chloride solution, the reaction solution was extracted with ethyl acetate (3 × 50mL), the organic phases were combined and washed with saturated brine (10mL), and the anhydrous sodium sulfate solid was dried. After filtration, the filtrate was concentrated under reduced pressure by means of a vacuum pump. The crude product was subjected to silica gel column chromatography (ethyl acetate/n-hexane ═ 1:3) to give unsaturated lactone compound 7(1.7g, 92%).

[α]_D ²⁴＝-14.5(c 1.0,CHCl₃)；¹H NMR(500MHz,CDCl₃)6.59(d,J＝9.7Hz,1H),5.82(d,J＝9.7Hz,1H),4.44–4.33(m,1H),4.09(dd,J＝7.8,5.9Hz,1H),4.02(dd,J＝10.7,2.1Hz,1H),3.50(t,J＝7.9Hz,1H),2.14(ddd,J＝14.5,10.7,3.9Hz,1H),1.68(ddd,J＝14.2,8.9,2.1Hz,1H),1.64–1.40(m,4H),1.06(s,3H),1.01(s,3H),0.84(q,J＝7.3Hz,6H).¹³C NMR(125MHz,CDCl₃)163.8,156.8,118.4,112.7,82.1,72.7,69.3,35.0,32.9,29.8,29.4,24.6,19.4,8.3,8.0.HRMS(m/z):calculated for C₁₅H₂₄NaO₄ ⁺[M+Na]⁺:291.1572,found 291.1579.

Example 9

Compound 7(3.9g, 14.6mmol, 1.0equiv.) was dissolved in toluene (40mL), PPTS (375mg,1.5mmol,0.1equiv.) and a small amount of water (about 0.2mL) were added at room temperature, the reaction was warmed to 80 ℃ and stirred for 2 hours, and after confirming no starting material remained by thin layer chromatography, the reaction was continued to warm to 100 ℃ and continued to react for 10 hours. After completion of the reaction, the reaction mixture was returned to room temperature, and the reaction mixture was directly concentrated under reduced pressure by a vacuum pump and subjected to flash column chromatography (ethyl acetate/n-hexane ═ 2:1) to obtain the intended bridged compound 6(2.6g, 88%).

[α]_D ²⁴＝-30.7(c 1.0,CHCl₃)；¹H NMR(500MHz,CDCl₃)4.39(q,J＝2.8Hz,1H),3.84–3.77(m,2H),3.74(dd,J＝11.7,2.9Hz,1H),3.57(dd,J＝11.6,5.2Hz,1H),2.92(dd,J＝19.6,5.4Hz,1H),2.81(dd,J＝19.5,1.2Hz,1H),2.12(ddd,J＝14.5,12.0,2.6Hz,1H),1.80(dt,J＝14.4,3.6Hz,1H),1.19(s,3H),1.08(s,3H).¹³C NMR(126MHz,CDCl₃)169.7,81.5,74.0,65.7,65.2,34.0,32.80,28.9,23.0,22.9.HRMS(m/z):calculated for C₁₀H₁₆NaO₄ ⁺[M+Na]⁺:223.0946,found223.0941.

Example 10

Compound 6(731mg, 3.6mmol, 1.0equiv.) was dissolved in dichloromethane (20mL), and 4-methoxybenzyl-2,2,2-trichloroacetimidate (1.6mL, 7.3mmol, 2.0equiv.) and TsOH. H.were added to the reaction system at room temperature₂O (62mg, 0.36mmol, 0.1equiv.), and the reaction was heated to 40 ℃ with stirring overnight. After the reaction was completed, triethylamine (0.5mL) was added to the reaction system to quench the reaction, and the reaction solution was directly concentrated under reduced pressure by a vacuum pump and subjected to flash column chromatography (ethyl acetate/n-hexane ═ 1:2) to give compound 20(1.1g, 91%) as a colorless viscous oil.

[α]_D ²⁰＝-9.4(c 0.5,CHCl₃)；¹H NMR(500MHz,CDCl₃)7.24(d,J＝8.6Hz,2H),6.87(d,J＝8.6Hz,2H),4.50(s,1H),4.35(dd,J＝2.8Hz,1H),3.95–3.85(m,1H),3.80(s,4H),3.66–3.26(m,2H),2.89(dd,J＝19.5,5.3Hz,1H),2.82(dd,J＝19.7,1.5Hz,1H),2.09–1.99(m,1H),1.81(dt,J＝14.4,3.5Hz,1H),1.19(s,3H),1.06(s,3H).¹³C NMR(126MHz,CDCl₃)169.8,159.5,130.3,129.4,114.0,81.6,74.0,73.4,72.3,64.7,55.4,33.8,32.8,29.7,23.0.HRMS(m/z):calculated for C₁₈H₂₄NaO₅ ⁺[M+Na]⁺:343.1521,found 343.1515.

Example 11

PMB-protected endocyclic lactone compound 20(283mg, 0.88mmol, 1.0equiv.) was dissolved in dry tetrahydrofuran (8mL) at room temperature. Reacting LiBH₄(1.3mL, 2.7mmol, 2M in THF,3.0equiv.) and MeOH (0,14mL, 3.5mmol, 4.0equiv.) were added slowly dropwise in that order to the reaction system (with a large amount of bubbles), followed by continued stirring at room temperature overnight. After the reaction was completed, the reaction system was cooled to 0 ℃ and then H was dropwise added₂The reaction was quenched with O (2mL), extracted with ethyl acetate (3 × 20mL) after stirring for about 30min, the organic phases combined and washed with saturated brine (20mL), dried over anhydrous sodium sulfate solid. After filtration, the filtrate was concentrated under reduced pressure by means of a vacuum pump. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate/n-hexane ═ 1:1) to give compound 5(264mg, 91%) as a colorless oil.

[α]_D ²⁶＝+25.5(c 1.0,CHCl₃)；¹H NMR(400MHz,CDCl₃)7.26(d,J＝8.6Hz,2H),6.88(d,J＝8.7Hz,2H),4.49(d,J＝1.6Hz,2H),4.30–4.09(m,1H),3.80(s,3H),3.78–3.76(m,1H),3.76–3.72(m,1H),3.68(ddd,J＝11.1,7.0,4.0Hz,1H),3.53(dd,J＝10.3,4.7Hz,1H),3.48(dd,J＝11.0,2.6Hz,1H),3.32(dd,J＝10.3,4.6Hz,1H),1.84–1.70(m,2H),1.69–1.58(m,2H),0.92(s,3H),0.89(s,3H).¹³C NMR(101MHz,CDCl₃)159.5,129.9,129.6,114.0,72.9,72.5,69.7,69.2,61.8,55.4,38.8,30.9,30.3,23.3,13.8.HRMS(m/z):calculated for C₁₈H₂₈NaO₅ ⁺[M+Na]⁺:347.1834,found 347.1836.

Example 12

Compound 5(354mg, 1.3mmol, 1.0equiv.) was dissolved in dichloromethane (10mL) and 2,6-lutidine (0.35mL, 4.1mmol, 3.2equiv) was added, TESOTf (0.31mL, 1.9mmol, 1.5equiv.) was added at-78 ℃, stirring was continued for 1 hour and the reaction was quenched with saturated ammonium chloride solution (10 mL). The reaction mixture was returned to room temperature, extracted with ethyl acetate (2X 30mL), the organic phases were combined and washed successively with 10% aqueous citric acid (30mL), saturated aqueous sodium bicarbonate (30mL) and saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure to remove low-boiling components. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate/n-hexane ═ 1:50) to obtain compound 21(428mg, 85%) as a colorless oil.

[α]_D ²⁷＝+15.8(c 1.0,CHCl₃)；¹H NMR(400MHz,CDCl₃)7.26(d,J＝8.6Hz,2H),6.87(d,J＝8.6Hz,2H),4.53–4.43(m,2H),4.13–4.02(m,1H),3.80(s,3H),3.75(ddd,J＝10.0,8.1,4.4Hz,1H),3.67–3.57(m,2H),3.55(dd,J＝9.6,5.9Hz,1H),3.49(dd,J＝9.8,5.7Hz,1H),3.40(dd,J＝10.9,2.2Hz,1H),2.03–1.86(m,1H),1.74(ddd,J＝13.4,5.1,4.3Hz,1H),1.70–1.59(m,2H),0.95(t,J＝7.9Hz,17H),0.92(s,3H),0.86(s,3H),0.63–0.53(m,12H).¹³C NMR(101MHz,CDCl₃)159.3,130.7,129.3,113.9,76.4,73.2,73.1,71.7,68.5,61.0,55.4,38.5,32.3,32.1,24.7,16.4,7.1,7.0,5.2,4.6.HRMS(m/z):calculated for C₃₀H₅₆NaO₅Si₂ ⁺[M+Na]⁺:575.3564,found 575.3559.

Example 13

Dry dichloromethane (10mL) was added to a well dried round bottom flask, cooled to-78 ℃ and added with oxalyl chloride (0.43mL,0.85mmol, 2M in DCM, 5.0equiv.) and DMSO in dichloromethane (0.06mL, 0.85mmol, 5.0equiv.) with a lot of gas evolved, stirring was continued until no bubbles evolved, and a solution of compound 21(94mg,0.17mmol, 1.0equiv.) in dichloromethane (1mL) was slowly added to the reaction. After keeping the reaction system under stirring at-78 ℃ for about 2 hours, excess triethylamine (2mL) was added slowly while the reaction system was slowly raised to 0 ℃ and stirring at this temperature was continued for 1 hour. The reaction was quenched by the addition of saturated ammonium chloride solution (10mL) and the separated aqueous phase was extracted with ethyl acetate (2 × 30 mL). All organic phases were combined, washed successively with a saturated ammonium chloride solution and a saturated brine, and dried by adding anhydrous sodium sulfate. The solid was removed by filtration, the low boiling point fraction was distilled off at low temperature under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (ethyl acetate/n-hexane ═ 1:20) to obtain compound 22(65mg, 88%) as a pale yellow oil.

[α]_D ²⁷＝+5.3(c 1.0,CHCl₃)；¹H NMR(300MHz,CDCl₃)9.76(dd,J＝3.4,1.6Hz,1H),7.27(d,J＝8.3Hz,2H),6.90(d,J＝8.6Hz,2H),4.49(s,2H),4.18–4.06(m,1H),4.01(dd,J＝10.6,3.2Hz,1H),3.82(s,3H),3.68(dd,J＝7.7,4.0Hz,1H),3.55(qd,J＝10.1,5.5Hz,2H),2.93(ddd,J＝16.2,10.6,3.4Hz,1H),2.49(ddd,J＝16.3,3.3,1.7Hz,1H),1.81(ddd,J＝13.6,6.1,4.0Hz,1H),1.66(ddd,J＝13.4,7.7,5.0Hz,2H),1.02–0.96(m,9H),0.95(s,3H),0.90(s,3H),0.60(q,J＝7.8Hz,6H).¹³C NMR(75MHz,CDCl₃)202.9,159.3,130.5,129.3,113.9,75.2,73.1,73.0,71.8,68.1,55.4,43.6,38.1,31.9,24.7,17.4,7.1,5.1.HRMS(m/z):calculated for C₂₄H₄₀NaO₅Si⁺[M+Na]⁺:459.2543,found 459.2543.

Example 14

Potassium tert-butoxide (263mg, 2.6mmol, 5.0equiv.) was dissolved in tetrahydrofuran (15mL) and cooled to-78 ℃. Cis-2-butene (208mg, 3.7mmol, 7.0equiv.) was added at-78 deg.C, and after 15 minutes, nBuLi (1.1mL, 2.6mmol, 2.4M in Hexene, 5.0equiv.) was slowly added dropwise. The reaction was then warmed to-45 ℃ and stirring continued at this temperature for 30 minutes. Cooled again to-78 ℃, and (+) -Ipc is slowly dripped into the reaction system₂A solution of BOMe (1g, 3.2mmol, 6.0equiv.) in tetrahydrofuran (8mL) and stirring continued for 30 min. Then, boron trifluoride ether solution (0.6mL, 4.2mmol,8.0equiv.) was slowly added dropwise to the system, and stirring was continued. After 30 minutes, a solution of compound 22(230mg, 0.53mmol, 1.0equiv.) in THF (3mL) was slowly added to the system. After stirring at-78 ℃ for 10 hours, the reaction was slowly raised to zero. Finally the reaction was again cooled to-78 ℃ and quenched by addition of MeOH (2 mL).

After the reaction solution obtained after quenching was returned to room temperature, the reaction solution was directly concentrated by a vacuum pump under reduced pressure, the obtained crude product was dissolved again in a tetrahydrofuran-water (10mL, v/v ═ 3:2) mixed solvent, sodium perborate tetrahydrate (567mg, 3.7mmol, 7.0equiv.) was added at room temperature, and the reaction system was vigorously stirred at room temperature for 5 hours. After completion of the reaction, ethyl acetate (20mL) was added to dilute the reaction solution, the reaction solution was extracted with ethyl acetate (3 × 20mL), the combined organic phases were washed with saturated brine (100mL), and the organic phases were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure using a vacuum pump, and the resulting crude product was subjected to silica gel column chromatography (ethyl acetate/n-hexane ═ 1:10) to give compound 23(243mg, 93%).

[α]_D ²⁷＝+4.1(c 1.0,CHCl₃)；¹H NMR(500MHz,CDCl₃)7.28(d,J＝8.3Hz,2H),6.88(d,J＝8.2Hz,2H),5.83(ddd,J＝17.6,10.4,7.5Hz,1H),5.17–4.93(m,2H),4.49(s,2H),4.28–4.10(m,1H),3.80(s,3H),3.65–3.56(m,1H),3.56(t,J＝6.2Hz,1H),3.48(d,J＝10.6Hz,1H),3.42(dd,J＝10.0,4.7Hz,1H),2.31–2.16(m,1H),1.78–1.49(m,4H),1.05(d,J＝6.8Hz,3H),0.94(t,J＝7.9Hz,9H),0.88(s,3H),0.86(s,3H),0.56(q,J＝7.9Hz,6H).¹³C NMR(126MHz,CDCl₃)159.4,141.8,130.4,129.4,114.3,114.0,81.2,76.6,73.1,72.8,70.8,69.2,55.4,44.3,39.2,32.3,31.6,24.3,15.8,15.4,7.0,5.3.HRMS(m/z):calculated for C₂₈H₄₈NaO₅Si⁺[M+Na]⁺:515.3169,found 515.3165.

Example 15

Compound 23(320mg, 0.65mmol, 1.0equiv.) was dissolved in anhydrous tetrahydrofuran (2mL) and cooled to 0 ℃. NaHMDS (1mL, 2mmol, 2M in THF,3.0equiv.) was slowly added dropwise to the reaction and stirring continued at this temperature for 0.5 h. Subsequently, Boc dissolved in tetrahydrofuran (2mL)₂A solution of O (212mg, 1mmol,1.5equiv.) was slowly added dropwise to the reaction system, and the reaction system was warmed to room temperature and stirred for 2 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution (2 mL). The reaction was then extracted with ethyl acetate (3 × 20mL), and the organic phases were combined and washed with water (10mL) and saturated brine (20mL), and the anhydrous sodium sulfate solid was dried. After filtration, the filtrate was concentrated under reduced pressure by a vacuum pump, and the resulting crude product was subjected to silica gel column chromatography (ethyl acetate/n-hexane ═ 1:25) to give compound 24(352mg, 91%) as a colorless oil.

[α]_D ¹⁹＝+1.5(c 0.7,CHCl₃)；¹H NMR(500MHz,CDCl₃)7.26(d,J＝8.6Hz,2H),6.86(d,J＝8.5Hz,2H),5.80(ddd,J＝17.4,10.4,7.0Hz,1H),5.09–4.96(m,2H),4.82–4.71(m,1H),4.47(d,J＝2.1Hz,2H),4.14–4.07(m,1H),3.80(s,3H),3.61(dd,J＝8.2,4.0Hz,1H),3.56(d,J＝5.5Hz,2H),3.40(dd,J＝10.4,2.6Hz,1H),2.50(q,J＝6.5Hz,1H),2.06(d,J＝11.8Hz,1H),1.85–1.72(m,2H),1.65(ddd,J＝13.4,8.1,5.0Hz,1H),1.46(s,9H),1.01(d,J＝6.9Hz,3H),0.94(t,J＝7.9Hz,9H),0.90(s,3H),0.85(s,3H),0.56(q,J＝7.9Hz,6H)ppm.¹³C NMR(126MHz,CDCl₃)159.3,153.6,140.7,130.9,129.3,115.0,113.9,81.4,79.0,77.5,73.3,73.1,72.1,68.2,55.4,40.1,38.8,32.0,30.9,28.5,28.1,24.8,14.1,7.1,5.3ppm.HRMS(m/z):calculated for C₃₃H₅₆NaO₇Si⁺[M+Na]⁺:615.3693,found615.3690.

Example 16

The Boc protected compound 24(234mg, 0.4mmol, 1.0equiv.) was dissolved in freshly distilled toluene (20mL) and cooled to-78 ℃. Iodine bromide (0.8mL, 0.8mmol, 1M in DCM, 2.0equiv.) was then added slowly dropwise to the reaction, with stirring at that temperature for 1 hour. After the reaction was completed, the reaction was quenched by adding a saturated sodium bicarbonate solution (3mL) and a saturated sodium thiosulfate solution (3mL), and the reaction was allowed to warm to room temperature. The reaction was extracted with ethyl acetate (3 × 20mL), the combined organic phases were washed with saturated sodium bicarbonate solution (10mL) followed by saturated brine (10mL), and the anhydrous sodium sulfate solid was dried. After filtration, the filtrate was concentrated under reduced pressure using a vacuum pump to give a crude cyclized intermediate.

The crude product from the previous step was dissolved in MeOH (15mL) and K was added at room temperature₂CO₃(60mg, 1.6mmol, 4.0equiv.) and the reaction was warmed to 35 ℃ with continued stirring for 20 hours. After the reaction was completed, a saturated ammonium chloride solution (10mL) was added to quench the reaction, and the low boiling point components were removed by vacuum pump. The residue was extracted with ethyl acetate (3 × 30mL) and washed with water (10mL) and saturated brine (20mL), and the anhydrous sodium sulfate solid was dried. After filtration, the filtrate was concentrated under reduced pressure using a vacuum pump and subjected to flash column chromatography (ethyl acetate/n-hexane ═ 1:5) to give the targeted epoxy compound 25(156mg, 78%) with a diastereoselectivity of 5: 1.

[α]_D ²¹＝+19.4(c 0.3,CHCl₃)；¹H NMR(400MHz,CDCl₃)7.28(d,J＝8.6Hz,2H),6.87(d,J＝8.7Hz,2H),4.49(s,2H),4.26–4.17(m,1H),4.08(brs,1H),3.80(s,3H),3.75(ddd,J＝10.1,4.1,1.7Hz,1H),3.62(dd,J＝9.9,8.1Hz,1H),3.56(dd,J＝7.9,5.1Hz,1H),3.50(dd,J＝11.0,1.9Hz,1H),3.40(dd,J＝10.0,4.4Hz,1H),2.95(ddd,J＝6.9,4.0,2.7Hz,1H),2.76(dd,J＝5.0,4.0Hz,1H),2.61(dd,J＝5.1,2.8Hz,1H),1.90(q,J＝11.7,10.9Hz,1H),1.73–1.60(m,2H),1.52(dt,J＝14.7,1.9Hz,1H),1.38(qt,J＝6.8,3.5Hz,1H),1.06(d,J＝6.9Hz,3H),0.94(t,J＝7.9Hz,9H),0.90(s,3H),0.87(s,3H),0.56(q,J＝8.1Hz,6H).¹³C NMR(101MHz,CDCl₃)159.4,130.2,129.4,113.9,81.2,77.4,74.8,73.1,72.7,70.7,69.0,55.4,54.9,47.0,42.3,39.0,32.2,31.6,24.4,11.7,7.1,5.2.HRMS(m/z):calculated for C₂₈H₄₈NaO₆Si⁺[M+Na]⁺:531.3118,found 531.3113.

Example 17

Ethyl propiolate (50mg, 0.6mmol, 10.0equiv.) was dissolved in tetrahydrofuran (5mL) followed by slow addition of nBuLi (0.24mL, 0.6mmol, 2.5M in hexane, 10.0eq.) at-78 ℃ and stirring for 30min maintaining this temperature. Then BF was slowly added dropwise₃·Et₂O (0.08mL, 0.6mmol, 10.0equiv.), and stirred for 10 minutes while maintaining this temperature. TES-protected epoxy compound 25(30mg, 0.06mmol, 1.0equiv.) was dissolved in THF (1mL) and slowly added dropwise to the reaction, and stirring was continued at that temperature for 12 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution (2 mL). The reaction was then extracted with ethyl acetate (3X 30mL), the organic phases combined and washed successively with water (10mL) and saturated brine (10mL), and the anhydrous sodium sulfate solid dried. After filtration, the filtrate was concentrated under reduced pressure using a vacuum pump, and subjected to flash column chromatography (ethyl acetate/n-hexane ═ 1:5) to obtain the objective alkyne ester compound 4(20mg, 54%).

[α]_D ²⁵＝+12.9(c 0.5,CHCl₃)；¹H NMR(300MHz,CDCl₃)7.26(d,J＝8.6Hz,2H),6.89(d,J＝8.6Hz,2H),4.48(s,2H),4.28–4.16(m,3H),4.12(ddd,J＝9.0,5.9,1.6Hz,1H),3.99(d,J＝9.9Hz,1H),3.81(s,3H),3.64(t,J＝9.5Hz,1H),3.59–3.48(m,2H),3.37(dd,J＝9.9,3.7Hz,1H),2.61(dd,J＝17.2,5.9Hz,1H),2.47(dd,J＝17.1,8.8Hz,1H),2.11(q,J＝11.7Hz,1H),1.77–1.49(m,7H),1.39(d,J＝14.4Hz,1H),1.35–1.23(m,4H),1.03–0.84(m,18H),0.57(q,J＝7.8Hz,6H).¹³C NMR(75MHz,CDCl₃)159.5,153.9,129.9,129.4,113.9,86.6,81.4,78.6,74.5,74.4,73.3,72.8,70.9,68.1,62.1,55.5,40.6,38.8,33.2,31.5,24.8,24.4,14.2,7.1,5.2,4.6.HRMS(m/z):calculated for C₁₈H₃₆NaO₆Si⁺[M+Na]⁺:629.3486,found 629.3480.

Example 18

Compound 4(12mg, 0.02mmol, 1.0equiv.) was dissolved in dichloromethane (2mL) and 2,6-lutidine (34 μ L, 0.3mmol, 15.0equiv.) was added, TESOTf (44 μ L,0.2 mmol,10.0equiv.) was added at-78 ℃, followed by continued stirring at that temperature for 1 hour. After the reaction was completed, the reaction was quenched with a saturated ammonium chloride solution (3mL), and the reaction solution was extracted with ethyl acetate (2 × 20mL) and the organic phases were combined, and the organic phases were combined and washed successively with a 10% aqueous citric acid solution (10mL), a saturated sodium bicarbonate solution (10mL) and a saturated saline solution (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure to remove low-boiling components. The residue was subjected to silica gel column chromatography (ethyl acetate/n-hexane ═ 1:30) to give compound 26(11mg, 67%) as a colorless oil.

[α]_D ²¹＝+2.3(c 0.33,CHCl₃)；¹H NMR(500MHz,CDCl₃)7.25(d,J＝8.9Hz,2H),6.87(d,J＝8.5Hz,2H),4.49–4.41(m,2H),4.19(q,J＝7.1Hz,2H),4.04(p,J＝5.5Hz,1H),3.91(dt,J＝9.3,3.2Hz,1H),3.87(ddd,J＝7.7,6.3,3.6Hz,1H),3.80(s,3H),3.59(dd,J＝8.6,4.6Hz,1H),3.55(dd,J＝9.6,5.8Hz,1H),3.50(dd,J＝9.7,5.7Hz,1H),3.28(dd,J＝11.0,2.0Hz,1H),2.62(dd,J＝17.4,3.7Hz,1H),2.44(dd,J＝17.4,6.3Hz,1H),1.84(t,J＝12.4Hz,1H),1.78–1.57(m,4H),1.27(t,J＝7.1Hz,3H),1.01–0.92(m,27H),0.89–0.87(m,6H),0.83(s,3H),0.69–0.63(m,6H),0.61–0.53(m,12H).¹³C NMR(126MHz,CDCl₃)159.3,153.9,130.8,129.4,113.9,88.3,75.9,74.7,73.1,72.4,72.0,69.8,69.0,61.6,55.4,41.7,38.7,34.2,32.1,26.1,24.6,15.7,14.2,9.3,7.1,7.1,5.6,5.4,5.2.HRMS(m/z):calculated for C₄₅H₈₂NaO₈Si₃ ⁺[M+Na]⁺:857.5215,found 857.5210.

Example 19

Compound 26(200mg, 0.038mmol, 1.0equiv.) was dissolved in excess compound 27(2mL) under argon, the tube was sealed and the reaction was warmed to 170 ℃ for 72 hours. After the reaction is finished, after the reaction tube is cooled to room temperature, dichloromethane (2mL), methanol (4mL) and SiO are added into the reaction system in sequence₂(60mg) was vigorously stirred at 35 ℃ for 10 hours. Subsequently, solid SiO was removed by filtration₂And directly distilling the filtrate under reduced pressure to remove low-boiling components. The resulting crude product was isolated by silica gel column chromatography (ethyl acetate/n-hexane ═ 1:5) to give compound 28(140mg, 64%) as a light yellow oil Diels-Alder product.

[α]_D ²³＝+14.0(c 0.3,CHCl₃)；¹H NMR(400MHz,CDCl₃)11.46(brs,1H),7.21(d,J＝8.5Hz,2H),6.92(brs,1H),6.86–6.79(m,2H),6.38(d,J＝2.6Hz,1H),6.26(d,J＝2.4Hz,1H),4.52–4.33(m,4H),4.18–4.08(m,2H),4.07–4.00(m,1H),3.78(s,3H),3.61–3.48(m,3H),3.42(d,J＝9.8Hz,1H),3.36(dd,J＝15.0,6.0Hz,1H),2.97(dd,J＝15.0,6.4Hz,1H),2.00(t,J＝12.7Hz,1H),1.87(q,J＝5.5Hz,1H),1.81–1.55(m,3H),1.40(t,J＝7.1Hz,3H),0.99–0.92(m,22H),0.91–0.84(m,15H),0.66–0.53(m,12H),0.49–0.40(m,6H).¹³C NMR(101MHz,CDCl₃)171.6,164.8,160.7,159.4,144.4,129.9,129.7,113.9,112.2,106.3,101.8,75.7,74.2,73.4,73.3,71.4,71.1,68.2,61.3,55.4,40.5,39.8,38.6,33.6,32.2,25.2,17.5,14.5,9.8,7.3,7.2,7.1,5.7,5.4,5.2.HRMS(m/z):calculated for C₄₉H₈₆NaO₁₀Si₃ ⁺[M+Na]⁺:941.5426,found 941.5413.

Example 20

Diels-Alder product compound 28(160mg, 0.17mmol, 1.0equiv.) was dissolved in freshly distilled dichloromethane (5mL), cooled to zero degrees, DIPEA (0.55mL, 3.4mmol, 20equiv.) and MOMCl (0.13mL, 1.7mmol, 10equiv.) were added sequentially, and the reaction was allowed to warm to room temperature and continued stirring for 6 hours. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate solution (5mL) under zero temperature conditions, then the reaction was extracted with ethyl acetate (2X 20mL), the organic phases were combined and washed with water (20mL) and saturated brine (20mL) in order, and the anhydrous sodium sulfate solid was dried. After filtration, the filtrate was concentrated under reduced pressure using a vacuum pump and subjected to flash column chromatography (ethyl acetate/n-hexane ═ 1:5) to give compound 29(145mg, 83%) as a pale yellow oil.

[α]_D ²³＝+4.6(c 0.3,CHCl₃)；¹H NMR(400MHz,CDCl₃)7.23(d,J＝8.6Hz,2H),6.84(d,J＝8.6Hz,2H),6.67(d,J＝2.2Hz,1H),6.63(d,J＝2.2Hz,1H),5.19–5.09(m,4H),4.47–4.37(m,2H),4.34(q,J＝7.1Hz,2H),4.10–4.00(m,2H),4.00–3.93(m,1H),3.79(s,3H),3.58(dd,J＝9.1,4.4Hz,1H),3.52(dd,J＝9.4,6.8Hz,1H),3.45(d,J＝0.7Hz,7H),3.28(dd,J＝9.8,2.2Hz,1H),2.90(dd,J＝14.1,3.9Hz,1H),2.64(dd,J＝14.0,8.9Hz,1H),1.84–1.57(m,4H),1.34(t,J＝7.1Hz,3H),0.95(td,J＝7.9,6.6Hz,18H),0.90–0.80(m,18H),0.60(dt,J＝17.0,7.9Hz,12H),0.37(qd,J＝7.9,1.8Hz,6H).¹³C NMR(101MHz,CDCl₃)168.1,159.2,158.4,155.3,140.5,130.9,129.2,120.1,113.8,111.9,101.6,94.9,94.5,76.1,75.0,73.1,73.1,71.8,70.1,69.0,60.9,56.1,55.4,42.3,38.8,38.7,34.5,31.9,24.5,15.4,14.4,9.7,7.2,7.2,7.1,5.7,5.2,5.1.HRMS(m/z):calculated for C₅₃H₉₄NaO₁₂Si₃ ⁺[M+Na]⁺:1029.5951,found 1029.5045.

Example 21

MOM-protected compound 29(20mg, 20 μmol,1.0equiv.) was dissolved in dichloromethane (3.6mL), NBS (11mg, 0.06mmol, 3.0equiv.) was added to the reaction system at room temperature, and stirring was continued for 1.5 hours under light-shielding conditions. After the reaction was completed, a saturated sodium bicarbonate solution (2mL) and a saturated sodium thiosulfate solution (2mL) were added to the reaction system in this order to quench the reaction. The reaction was then extracted with ethyl acetate (3X 20mL), the organic phases combined and washed successively with saturated sodium bicarbonate solution (20mL) and saturated brine (20mL), and the anhydrous sodium sulfate solid dried. After filtration, the filtrate was concentrated under reduced pressure using a vacuum pump and subjected to flash column chromatography (ethyl acetate/n-hexane ═ 1:4) to give compound 30(21mg, 99%) as a pale yellow oil.

[α]_D ²⁵＝+10.8(c 0.25,CHCl₃)；¹H NMR(400MHz,CDCl₃)7.23(d,J＝8.6Hz,2H),6.86(s,1H),6.84(d,J＝8.6Hz,2H),5.23(s,2H),5.16–5.09(m,2H),4.53–4.38(m,2H),4.38–4.29(m,2H),4.24–4.16(m,1H),4.10–4.02(m,1H),3.99–3.89(m,1H),3.57(td,J＝7.5,7.0,3.9Hz,2H),3.50(s,4H),3.45(s,3H),3.33–3.26(m,1H),3.02(d,J＝6.3Hz,2H),1.83–1.70(m,1H),1.70–1.63(m,1H),1.35(t,J＝7.1Hz,3H),0.99–0.92(m,18H),0.89(d,J＝6.9Hz,3H),0.87(s,3H),0.85–0.78(m,12H),0.66–0.50(m,16H),0.35(q,J＝7.9Hz,6H).¹³C NMR(101MHz,CDCl₃)168.1,159.2,158.4,155.3,140.5,130.9,129.2,120.1,113.8,111.9,101.6,94.9,94.5,76.1,75.0,73.1,73.1,71.8,70.1,69.0,60.9,56.1,55.4,42.3,38.8,38.7,34.5,31.9,24.5,15.4,14.4,9.7,7.2,7.2,7.1,5.7,5.2,5.1.HRMS(m/z):calculated for C₅₃H₉₃BrNaO₁₂Si₃ ⁺[M+Na]⁺:1107.5056,found 1107.5056.

Example 22

Bromo compound 30(20mg, 0.018mmol, 1.0equiv.) was dissolved in freshly distilled tetrahydrofuran (3mL), cooled to-100 ℃, to which nBuLi (0.036mL, 2.1mmol, 2.5M in hexane, 20.0equiv.) was slowly added, the reaction turned from colorless to pale red. After stirring was continued for 10 minutes, MeI (20mg, 0.018mmol, 1.0equiv.) was slowly added dropwise to the reaction system, and the red color of the reaction system immediately disappeared to colorless. After the end of the dropwise addition, the reaction was slowly raised to zero and stirring was continued for 20 minutes. After completion of the reaction, the reaction was quenched by adding saturated ammonium chloride solution (2mL), the reaction solution was extracted with ethyl acetate (3X 20mL), the organic phases were combined and washed with water (10mL) and saturated brine (10mL) in this order, and the anhydrous sodium sulfate solid was dried. After filtration, the filtrate was concentrated under reduced pressure using a vacuum pump and subjected to flash column chromatography (ethyl acetate/n-hexane ═ 1:5) to give compounds 2 to 31(18mg, 97%) as colorless oils.

[α]_D ²⁰＝+6.8(c 1.0,CHCl₃)； ¹H NMR(500MHz,CDCl₃)7.23(d,J＝8.5Hz,2H),6.85(d,J＝8.6Hz,2H),6.76(s,1H),5.17(d,J＝1.3Hz,2H),5.11(s,1H),4.49–4.39(m,2H),4.38–4.28(m,1H),4.13(d,J＝8.5Hz,1H),4.07–3.97(m,2H),3.79(s,3H),3.61–3.55(m,1H),3.58–3.52(m,1H),3.52(dd,J＝9.6,4.9Hz,1H),3.46(s,3H),3.45(s,3H),3.27(d,J＝9.8Hz,1H),2.87(dd,J＝14.2,9.9Hz,1H),2.79(dd,J＝14.1,3.6Hz,1H),2.20(s,3H),1.82–1.74(m,2H),1.75–1.61(m,3H),1.34(t,J＝7.2Hz,3H),0.95(t,J＝8.0Hz,9H),0.95(t,J＝7.9Hz,9H),0.88(d,J＝6.4Hz,4H),0.83(s,2H),0.79(t,J＝8.0Hz,9H),0.61(q,4H),0.58(q,4H),0.37–0.23(m,4H).13C NMR(126MHz,CDCl₃)168.7,159.3,156.5,152.6,138.3,130.9,129.2,121.9,121.0,113.9,100.67,95.3,94.8,76.4,75.4,73.2,71.8,70.0,68.8,60.9,56.1,56.1,55.4,43.3,38.8,34.9,32.0,24.6,15.8,14.4,12.5,10.1,7.3,7.1,7.1,5.9,5.3,5.0.HRMS(m/z):calculated for C₅₄H₉₆NaO₁₂Si₃ ⁺[M+Na]⁺:1043.6107,found 1043.6102.

Example 23

Compound 31(20mg, 0.02mmol, 1.0equiv.) was dissolved in dry dimethylformamide (2mL) and tetrabutylammonium fluoride solution (0.2mL, 0.2mmol, 1M in THF, 10equiv.) was added slowly at 0 ℃. The reaction was allowed to warm to room temperature and stirring was continued for 2 hours. After completion of the reaction, the reaction was quenched by addition of a saturated solution of ammonium chloride (5mL), followed by extraction of the reaction solution with ethyl acetate (3 × 20mL), and the combined organic phases were washed with a saturated brine (10mL), and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure by a vacuum pump, and the resulting crude product was subjected to silica gel column chromatography (ethyl acetate/n-hexane ═ 2:1) to give compound 31-1(12mg, 97%) as a colorless oil.

[α]_D ²⁷＝+27.1(c 0.3,CHCl₃)；¹H NMR(500MHz,CDCl₃)7.25(d,J＝8.9Hz,2H),6.88(s,1H),6.79(d,J＝8.6Hz,2H),5.31–5.21(m,4H),4.48(d,J＝2.6Hz,2H),4.38(ddd,J＝12.2,5.5,2.6Hz,1H),4.27–4.21(m,1H),4.08(dt,J＝10.1,2.2Hz,1H),3.99(brs,1H),3.75–3.68(m,4H),3.58–3.50(m,5H),3.48(s,3H),3.35(dd,J＝10.1,4.5Hz,1H),2.98(dd,J＝16.6,2.7Hz,1H),2.85(dd,J＝16.6,12.1Hz,1H),2.07(s,3H),1.96–1.88(m,1H),1.87–1.72(m,2H),1.67(ddd,J＝13.4,4.7,3.0Hz,1H),1.55(dt,J＝14.3,1.8Hz,1H),1.11(d,J＝7.0Hz,3H),0.95(s,3H),0.91(s,3H).¹³C NMR(126MHz,CDCl₃)163.4,159.7,159.5,158.8,142.2,130.1,129.4,117.8,114.0,109.6,102.2,96.1,94.7,79.9,79.1,73.2,72.3,72.3,70.2,69.6,56.7,56.5,55.3,42.6,39.1,32.8,30.9,29.4,23.5,14.0,11.2,10.0.HRMS(m/z):calculated for C₃₄H₄₈NaO₁₁ ⁺[M+Na]⁺:655.3094,found 655.3088.

Example 24

Compound 31-1(50mg, 0.08mmol, 1.0equiv.) was dissolved in dichloromethane 10mL) and 2,6-lutidine (0.1mL, 0.8mmol, 10.0equiv.) was added followed by TESOTf (0.09mL, 0.4mmol, 5.0equiv.) at-78 ℃, stirred at this temperature for 1 hour and quenched with saturated ammonium chloride solution (3 mL). The organic phases were combined and extracted with ethyl acetate (3X 20mL) and washed successively with combined organic phases and successively with 10% aqueous citric acid (10mL), saturated aqueous sodium bicarbonate (10mL) and saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure to remove low-boiling components. The residue was subjected to silica gel column chromatography (ethyl acetate/n-hexane ═ 1:4) to give compound 32(61mg, 90%) as a colorless oil.

[α]_D ²⁶＝+41.23(c 1.0,CHCl₃)；¹H NMR(400MHz,CDCl₃)7.20(d,J＝8.6Hz,1H),6.86(s,1H),6.74(d,J＝8.6Hz,1H),5.32–5.16(m,4H),4.42(d,J＝2.5Hz,2H),4.25–4.14(m,2H),4.08(t,J＝7.8Hz,1H),3.67(s,3H),3.62(dd,J＝9.9,7.0Hz,1H),3.58–3.52(m,4H),3.49(s,3H),3.38(dd,J＝9.8,4.8Hz,1H),3.31(dd,J＝11.2,2.1Hz,1H),2.94(dd,J＝16.4,2.6Hz,1H),2.43(dd,J＝16.4,12.0Hz,1H),2.00(s,3H),1.99–1.95(m,1H),1.87(d,J＝12.0Hz,1H),1.77–1.59(m,4H),1.06(d,J＝6.7Hz,3H),0.99–0.87(m,21H),0.85(s,3H),0.64–0.44(m,12H).¹³C NMR(101MHz,CDCl₃)163.5,159.5,159.2,158.7,141.8,130.3,129.3,117.5,113.7,109.6,102.0,96.0,94.6,79.7,75.0,73.2,73.1,71.2,69.9,69.1,56.7,56.5,55.2,39.8,39.0,33.5,32.2,29.5,24.2,14.8,11.2,9.0,7.1,7.1,5.6,5.2.HRMS(m/z):calculated for C₄₆H₇₆NaO₁₁Si₂ ⁺[M+Na]⁺:883.4824,found 883.4821.

Example 25

Compound 32(200mg, 0.23mmol, 1.0equiv.) is dissolved in tetrahydrofuran (15mL) and a catalytic amount of Pd (OH) is added at room temperature₂C (10 wt.%), and then a small amount of the reaction system was pumped through a vacuum pumpThe air was replaced three times with hydrogen and stirred under hydrogen balloon conditions for 24 hours. After the reaction was completed, insoluble materials in the reaction system were filtered off by a short column filled with celite, and the filtrate was concentrated under reduced pressure by a vacuum pump to obtain a crude product, compound 32-1, which was used in the next reaction without further purification (155mg, 90%).

The crude product compound 32-1(35mg, 0.047mmol, 1.0equiv.) from the previous step was dissolved in a mixed solvent of dichloromethane/2-methyl-2-butene (v/v ═ 5:1) (2.4mL), and to the reaction system were added an acetic acid/sodium acetate buffer solution (2mL), AZADO (3.5mg, 0.03mmol, 0.5equiv.) and sodium chlorite (42mg, 0.47mmol, 10.0equiv.) in succession at room temperature, and the reaction was stirred for 24 hours. After the reaction was complete, the reaction was extracted with ethyl acetate (3X 20mL), the organic phases were combined and washed successively with water (15mL) and saturated sodium chloride solution (15 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure to remove low-boiling components. The residue was subjected to silica gel column chromatography (ethyl acetate/n-hexane ═ 1:4) to give compound 33(34mg, 97%) as a colorless oil.

[α]_D ²⁶＝+31.72(c 1.0,CHCl₃)；¹H NMR(400MHz,CDCl₃)6.79(s,1H),5.26–5.16(m,4H),4.39(dd,J＝6.7,1.3Hz,1H),4.32(dt,J＝10.3,2.8Hz,1H),4.24(ddd,J＝11.0,7.9,2.8Hz,1H),3.52(s,3H),3.48(s,3H),3.43(dd,J＝11.5,4.7Hz,1H),3.16(dd,J＝10.6,1.5Hz,1H),2.99(dd,J＝16.6,2.9Hz,1H),2.72(dd,J＝16.7,11.3Hz,1H),2.21–2.11(m,2H),2.05(s,3H),1.88–1.76(m,1H),1.75–1.70(m,1H),1.59(ddd,J＝13.9,10.6,3.2Hz,1H),1.03(d,J＝6.8Hz,3H),0.98–0.89(m,18H),0.84(s,3H),0.82(s,3H),0.67–0.47(m,12H).¹³C NMR(101MHz,CDCl₃)173.5,165.1,159.9,158.7,141.6,117.8,108.7,102.0,95.9,94.6,80.3,72.9,72.7,68.6,56.7,56.6,39.7,39.1,34.3,31.4,28.7,22.9,12.3,11.1,8.6,7.1,7.0,5.6,5.2.HRMS(m/z):calculated for C₃₈H₆₆NaO₁₁Si₂ ⁺[M+Na]⁺:777.4041,found 777.4048.

Example 26

Compound 33(128mg, 0.17mmol, 1.0equiv.) was dissolved in freshly distilled dichloromethane (6mL), diisopropylethylenediamine (0.2mL, 1.7mmol, 10.0equiv.), TBTU (273mg, 0.85mmol, 5.0equiv.) and ammonium acetate (65mL, 0.86mmol, 5.0equiv.) were added to the reaction successively at 0 ℃, the reaction was warmed to room temperature, and stirring was continued for 12 hours. After completion of the reaction, the reaction was quenched by addition of a saturated solution of ammonium chloride (10mL), followed by extraction of the reaction solution with ethyl acetate (3 × 50mL), and the combined organic phases were washed with a saturated brine (20mL), and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure by a vacuum pump, and the resulting crude product was subjected to silica gel column chromatography (ethyl acetate/n-hexane ═ 1:5) to give compound 34(103mg, 81%) as a colorless oil.

[α]_D ²⁶＝+23.7(c 1.0,CHCl₃)；¹H NMR(500MHz,CDCl₃)6.89(s,1H),6.85(brs,1H),5.79(brs,1H),5.32–5.20(m,4H),4.40(dt,J＝10.0,2.8Hz,1H),4.36(dd,J＝6.2,2.4Hz,1H),4.32(ddd,J＝8.3,6.8,4.1Hz,1H),3.53(s,3H),3.49(s,3H),3.40(dd,J＝10.7,4.3Hz,1H),3.23(dd,J＝10.1,2.4Hz,1H),2.92–2.87(m,2H),2.34(ddd,J＝13.1,4.6,2.5Hz,1H),2.20–2.13(m,1H),2.11(s,3H),1.87–1.69(m,3H),1.02(d,J＝7.1Hz,3H),0.97(q,J＝7.9Hz,15H),0.87–0.84(m,6H),0.66–0.58(m,12H).¹³C NMR(126MHz,CDCl₃)173.8,163.1,160.0,159.1,142.1,117.7,109.1,102.1,95.9,94.7,79.8,77.8,73.1,72.9,68.0,56.7,56.6,39.4,38.8,34.6,30.0,28.4,23.6,13.6,11.2,9.0,7.1,7.0,5.9,5.3.HRMS(m/z):calculated for C₃₈H₆₇NaO₁₀Si₂ ⁺[M+Na]⁺:776.4201,found 776.4197.

Example 27

The amide compound 34(45mg, 0.05mmol, 1.0equiv.) was dissolved in freshly distilled dichloromethane (5mL) and the reaction system was cooled to zero, bromopyrocatechol borane (200mg, 1.0mmol, 20.0equiv.) was dissolved in dichloromethane (1mL) and the solution was added slowly dropwise to the above reaction system, after which the reaction system was kept vigorously stirred at zero for about 1 hour. After completion of the reaction, the reaction was quenched by adding a saturated tetrahydrofuran solution of sodium hydrogencarbonate to the reaction system, followed by addition of water (5mL), extraction of the mixture with ethyl acetate (5 × 20mL), and the combined organic phases were washed with saturated brine (20mL), and then the organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure by a vacuum pump, and the resulting crude product was subjected to silica gel column chromatography (ethyl acetate/n-hexane ═ 4:1) to give a colorless oily compound.

The compound obtained in the previous step was again dissolved in freshly distilled dichloromethane (2mL), cooled to 0 ℃ and pyridine (1mL) and acetic anhydride (0.5mL) were added to the reaction system, after which the reaction system was warmed to room temperature and stirred for 24 hours. After the reaction was completed, the reaction system was cooled to 0 ℃ and saturated sodium bicarbonate solution (3mL) was slowly added dropwise thereto to quench the reaction and continue stirring for 15 minutes. The mixture was then extracted with ethyl acetate (3 × 20mL), the organic phases combined and washed successively with water (10mL), dilute hydrochloric acid (20mL, 1N) and saturated brine (20mL), and the organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure using a vacuum pump, and the resulting crude product was subjected to silica gel column chromatography (ethyl acetate/n-hexane ═ 4:1) to give compound 3(31mg, 75%) as a white foam.

[α]_D ²⁴＝+32.9(c 0.5,CHCl₃)；¹H NMR(400MHz,CDCl₃)6.83(s,1H),6.82(brs,1H),5.58(brs,1H),5.29(ddd,J＝6.3,5.1,2.8Hz,1H),4.82(dd,J＝8.5,4.0Hz,1H),4.43–4.30(m,2H),3.46(dd,J＝11.4,2.5Hz,1H),3.05(dd,J＝16.4,2.8Hz,1H),2.78(dd,J＝16.4,11.9Hz,1H),2.35(s,3H),2.33(s,3H),2.25(ddd,J＝13.5,5.8,4.1Hz,1H),2.19–2.10(m,2H),2.10(s,3H),2.08(s,3H),2.06(s,3H),1.90(ddd,J＝13.6,8.5,5.1Hz,1H),1.79(ddd,J＝15.1,5.2,2.6Hz,1H),1.66(s,1H),1.16(d,J＝7.0Hz,3H),0.94(s,3H),0.93(s,3H).¹³C NMR(101MHz,CDCl₃)173.5,171.2,170.1,169.7,168.4,161.7,153.3,150.7,141.3,125.8,117.1,115.9,79.7,78.5,73.6,72.4,70.6,40.7,37.1,30.8,28.9,27.6,24.4,21.6,21.3,21.1,20.9,16.9,12.3,9.6.HRMS(m/z):calculated for C₃₀H₃₉NaO₁₂ ⁺[M+Na]⁺:628.2370,found 628.2364.

Example 28

Compound 3(10mg, 15. mu. mol,1.0equiv.) and poly (4-vinylpyridine) (40mg, 380. mu. mol,25.0equiv.) were dissolved in dry DCM (1.5mL) under argon and Me was added at room temperature₃OBF₄(16mg, 110. mu. mol,7.0equiv.) and stirring was continued for 2 hours. After completion of the reaction, dehydrated ether (3mL) was added to the reaction system and stirring was continued for 5 minutes, followed by filtration to remove insoluble materials from the reaction system and drying of the solvent in the filtrate by nitrogen gas. The resulting residue was redissolved in dry toluene (2mL) and cooled to zero degrees. DIPEA (0.1mL,140 μmol,9.0equiv.) and the acid chloride compound 14(0.6mL,0.2M dichloromethane solution) were added to the above reaction system, followed by heating the reaction system to 40 ℃ and continued stirring for 2 hours; to the reaction was again added acid chloride compound 14(0.4mL,0.2M dichloromethane solution) and stirring was continued for 40 minutes. Cooling the reaction system to zero degree, and adding NaBH in turn₄(45mg, 115. mu. mol,7.7equiv.) and ethanol (2mL), maintaining the temperature and stirring for 2 hours. After completion of the reaction, the reaction system was diluted with ethyl acetate (30mL), the reaction solution was washed with water (5Ml), the organic phase was dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure using a vacuum pump, the resulting crude product was dissolved in methanol (3mL) again, 1N LiOH (0.6mL) was added, and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (5mL) and 0.05N NaHSO₄The solution adjusted the pH of the reaction solution to 6. Subsequently, ethyl acetate (4 in yield)20mL) was extracted repeatedly, the organic phases were combined and successively treated with NaHCO₃(10mL), washed with water (10mL) and saturated brine (15mL), and dried over anhydrous sodium sulfate. After spin-drying, the crude product was first isolated on silica gel plates to yield psymberin (1) (2.2mg, 22%).

[α]_D ²⁴＝+21.1(c 0.10,MeOH)；¹H NMR(600MHz,CDCl₃)11.15(brs,1H),7.07(d,J＝10.4Hz,1H),6.58(brs,1H),6.30(s,1H),5.45(dd,J＝10.3,8.5Hz,1H),4.83–4.78(m,2H),4.54(ddd,J＝12.2,4.8,3.3Hz,1H),4.40(d,J＝2.9Hz,1H),4.35(brs,1H),4.15(brs,1H),3.97–3.92(m,1H),3.91–3.86(m,1H),3.73(ddd,J＝8.8,4.4,3.0Hz,1H),3.67(dd,J＝10.7,4.5Hz,1H),3.53(d,J＝10.7Hz,1H),3.38(s,3H),3.37(s,3H),2.90(dd,J＝16.6,3.4Hz,1H),2.82(dd,J＝16.6,12.2Hz,1H),2.37(dd,J＝14.6,8.8Hz,1H),2.18(dd,J＝14.5,4.4Hz,1H),2.08–2.05(m,1H),2.04(s,3H),1.88(ddd,J＝7.6,4.6,3.1Hz,1H),1.81(ddd,J＝13.6,10.6,5.9Hz,1H),1.75(d,J＝1.1Hz,3H),1.64–1.58(m,1H),1.10(d,J＝7.0Hz,3H),0.97(s,3H),0.92(s,3H).¹³C NMR(151MHz,CDCl₃)173.6,170.5,162.3,161.0,142.0,139.7,113.2,113.1,101.6,101.3,81.9,80.6,79.5,78.3,73.9,73.1,71.4,57.9,56.3,42.7,38.8,37.6,32.2,29.7,28.4,23.1,22.7,13.6,10.5,9.3.HRMS(m/z):calculated for C₃₁H₄₇NNaO₁₁ ⁺[M+Na]⁺:632.3047,found 632.3049.

The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.

Claims

1. A method for preparing psymberin, comprising the steps of:

carrying out Diels-Alder/aromatization reaction on the compound 26 and the compound 27 to obtain a compound 28; protecting the phenolic hydroxyl group of the compound 28, and then introducing a bromine atom to the compound 30 on the aryl group; exchanging said compound 30 with lithium halide, followed by alkylation with MeI to provide compound 31; TES protection is removed from the compound 31, lactonization is achieved, and then exposed hydroxyl is protected by TES to obtain a compound 32;

removing the PMB protecting group from the compound 32, and oxidizing the obtained hydroxyl group to acid to obtain a compound 33; converting said compound 33 to a primary amide compound 34; removing MOM protecting group and TES protecting group in the amide compound 34, and protecting hydroxyl group with acetyl to obtain a compound 3;

derivatizing the compound 2 to obtain an acyl chloride compound 14;

wherein, the structural formula of the compound is as follows:

2. the process for preparing psymberin according to claim 1, wherein the process for preparing compound 2 comprises the steps of:

carrying out addition reaction on the compound 10 and the compound 9 to obtain a compound 11;

introducing a methyl group into the compound 11, removing ketal protection, and then carrying out hydroxyl protection to obtain a compound 13;

carrying out Dess-Martin oxidation reaction and Pinnick oxidation reaction on the compound 13 to obtain a compound 2;

wherein, the structural formula of the compound is as follows:

3. the process for preparing psymberin according to claim 2, wherein compound 10 is subjected to a stereoselective addition reaction with compound 9 to give compound 11; and/or the presence of a gas in the gas,

the compound 11 introduces methyl under the conditions of NaH and MeI.

4. The method of preparing psymberin of claim 2, wherein the step of introducing compound 11 to the methyl group followed by removal of the ketal protection and subsequent hydroxy protection comprises: first hydroxyl group is protected by TBS, then second hydroxyl group is protected by Bz, and finally TBS protection is removed.

5. The process for preparing psymberin according to claim 1, wherein said compound 32 is in Pd (OH)₂C and H₂Removing the PMB protecting group under the condition (1); and/or the presence of a gas in the gas,

in AZADO, NaClO₂Oxidizing the obtained hydroxyl group to an acid to obtain a compound 33 under the condition of an AcOH/NaOAc buffer solution; and/or the presence of a gas in the gas,

in TBTU, DIPEA and NH₄Converting said compound 33 to a primary amide compound 34 under Cl conditions; and/or the presence of a gas in the gas,

the MOM protecting group and the TES protecting group in the amide compound 34 are removed in the presence of bromopyrocatechol borane.

6. The method of preparing psymberin according to claim 1, wherein the method of preparing compound 26 comprises the steps of:

protecting hydroxyl in the compound 5 to obtain a compound 21;

oxidizing the protected primary hydroxyl group in compound 21 to obtain compound 22;

subjecting compound 22 to asymmetric Brown mutagenesis to obtain compound 23;

introducing a Boc group to the secondary hydroxyl group of compound 23 to give compound 24;

carrying out cyclization reaction on the compound 24, and then hydrolyzing to obtain a compound 25;

introducing a compound 25 into ethyl propiolate to obtain a compound 4, and protecting hydroxyl of the compound 4 to obtain a compound 26;

wherein, the structural formula of the compound is as follows:

7. the method of preparing psymberin according to claim 6, wherein the method of preparing compound 5 comprises:

removing the compound 7 ketal and carrying out a trans-ring oxaMichael addition reaction to obtain a compound 6;

protecting the primary hydroxyl of the compound 6 to obtain a compound 20;

reducing the lactone structure of the compound 20 to obtain a compound 5;

wherein, the structural formula of the compound is as follows:

8. the method of preparing psymberin according to claim 7, wherein the method of preparing compound 7 comprises:

after the compound 8 and isopentenyl bromide are subjected to addition reaction, oxidizing a double bond at the tail end of a product, and then performing alkenylation and lactonization reaction with a phosphate compound 19 to obtain a compound 7;

wherein, the structural formula of the compound is as follows: