A method for synthesizing the trabectedin pentacyclic core framework

Abstract

This application relates to the field of medicinal chemistry, and specifically to a method for synthesizing the pentacyclic core skeleton of trabectedine. The method described in this application first completes the connection of the AE ring system through a condensation reaction, then constructs the D ring through a Pictet-Spengler reaction, followed by the C ring through a azira-Michael reaction, and finally constructs the B ring through a SOMO small molecule catalytic reaction. This method achieves the large-scale preparation of the pentacyclic skeleton of trabectedine and reserves construction sites for the derivative rings, providing a more convenient preparation method for the total synthesis of trabectedine and its derivatives, and providing a material basis for the activity study of this drug.

Description

Technical Field

[0001] This application relates to the field of medicinal chemistry technology, and in particular to a method for synthesizing the pentacyclic core skeleton of trabectedine. Background Technology

[0002] Trabectin (Ecteinascidin 743) is a tetrahydroisoquinoline alkaloid isolated from Caribbean sea squirts. It possesses excellent antitumor activity and was approved by the European Union in 2007 as the first marine-derived antitumor drug for second-line treatment of advanced soft tissue sarcoma. In 2015, it was approved by the US Food and Drug Administration (FDA) for second-line treatment of unresectable or metastatic liposarcoma or leiomyosarcoma. Currently, trabectin's application has expanded to treat platinum-sensitive recurrent ovarian cancer. The yield of naturally extracted trabectin is extremely low; only 1 gram of trabectin can be extracted from every ton of sea squirts, far from meeting market demand. Currently, trabectin is mainly obtained through semi-synthesis; however, even semi-synthesis requires 21 reaction steps to obtain trabectin with a total yield of only 1.0%, making it very expensive. Therefore, developing new and efficient synthetic methods for trabectin is urgent and has significant application value.

[0003]

[0004] Trabectedin comprises a core pentacyclic ring (A, B, C, D, E) and derived rings (F, G, H). The construction strategy of the core pentacyclic ring determines the efficiency of total synthesis. From a molecular structure perspective, rings A and B are fully substituted tetrahydroisoquinoline ring systems, and ring B has a transcyclic ten-membered thiolactone ring, which is a major challenge in synthesis. The CDE ring system contains an aza[3.3.1] bridged ring system, and stereoscopically, rings DE are almost parallel to ring F, which is another major challenge in synthesis. Therefore, in the development of the method, it is necessary not only to consider the construction of the pentacyclic ring, but also to provide active sites for further generation of derived rings.

[0005] Since the A and E rings in the pentacyclic ring are mainly substituted benzene rings, almost all reported syntheses have used the corresponding commercially available benzene ring compounds as starting materials. The reported methods for constructing the five-ring system include: Corey's group (JACS, 1996, 118, 9202-9203): A→AB→ABE→ABCDE; Fukuyama's group (first generation, JACS, 2002, 124, 6552-6554): A→AE→ACE→ACDE→ABCDE; Fukuyama's group (second generation, JACS 2013, 135, 13684-13687): A→ACDE→ABCDCE; Zhu's group (JACS, 2006, 128, 87-89): A→ADE→ACDE→ABCDE; Ma's group (ACIEE 2019, 58, 3972-3975): A→AB→ABDE→ABCDE; Danishefsky's group (ACIEE, 2006, 45, 1754-1759): A→AB→ABE→ABCDE; Williams' group (JOC 2008, 73, 9594-9600): A→AB→ABE→ABCDE. All the above synthetic routes introduce a ten-membered thiolactone bridge ring (F ring), as well as G and H rings at the end. The main difference lies in how the ABCDE pentacyclic skeletal structure is synthesized. The above synthetic routes still need further simplification, and the overall yield needs further improvement.

[0006] Based on this, the technical solution of this application is proposed. Summary of the Invention

[0007] To further simplify the synthetic route, this application proposes a method for synthesizing the ABCDE pentacyclic core skeleton of trabectedine. This method enables the large-scale preparation of the ABCDE pentacyclic skeleton of trabectedine, reducing the synthetic steps to ten and achieving a yield of 12.5%.

[0008] The technical solution of this application includes the following:

[0009] A method for synthesizing the trabectedine pentacyclic core framework includes the following steps:

[0010]

[0011] Compound I and compound II were subjected to a condensation reaction to obtain compound III;

[0012] Compound III was deactivated by removing the Boc group in an acidic solution to obtain compound IV;

[0013] Compound IV was dissolved in a mixed solution of dichloromethane and trifluoroethanol, and then tert-butyldimethylsiloxane, acetic acid, and [other ingredients] were added at -15°C to -5°C. The molecular sieves were mixed and stirred for 3-5 hours to obtain compound V;

[0014] Compound V was subjected to an amino protection reaction with di-tert-butyl dicarbonate to prepare compound VI;

[0015] Compound VII was prepared by subjecting compound VI and 3-bromopropene to hydroxyl protection reaction.

[0016] Compound VII was de-TBS-grouped in a tetrabutylammonium fluoride solution to obtain compound VIII;

[0017] Compound VIII was oxidized to obtain compound IX;

[0018] Compound X was prepared by mixing the compound IX with (formylmethylene)triphenylphosphine and stirring at 30℃~40℃ for 10h~20h.

[0019] Compound X was dissolved in tetrahydrofuran, and then mixed with a bis(trimethylsilylamine)lithium solution at -80°C to -70°C. The mixture was then stirred at 20°C to 40°C for 10 to 20 hours to obtain compound XI.

[0020] Compound XI was dissolved in ethylene glycol dimethyl ether, and then (2R,5R)-(+)-2-tert-butyl-3-methyl-5-benzyl-4-imidazolinone, trifluoroacetic acid, cerium ammonium nitrate and water were added at -80℃ to -70℃ and mixed. The mixture was then stirred at 20℃ to 40℃ for 10h to 20h to obtain compound XII.

[0021] In some embodiments, compound I and compound II are subjected to a condensation reaction to obtain compound III, comprising:

[0022] Compound I and Compound II were dissolved in tetrahydrofuran, and N,N-diisopropylethylamine, 1-hydroxybenzotriazole and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added and mixed. The mixture was stirred for 10 h to 20 h to obtain Compound II.

[0023] Optionally, the molar ratio of compound I to compound II is 1:(1 to 1.5);

[0024] Optionally, the molar ratio of compound I to N,N-diisopropylethylamine, 1-hydroxybenzotriazole and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride is 1:(2-3):(1-1.3):(1-1.3).

[0025] In some embodiments, the Boc group of compound III is removed in an acidic solution to obtain compound IV, comprising:

[0026] A dioxane solution of hydrogen chloride was added to a methanol solution of compound III at -5℃ to 5℃. After the addition was complete, the temperature was raised to 20℃ to 40℃ and stirred for 10h to 20h to obtain compound IV.

[0027] Optionally, the molar concentration of the dioxane solution of hydrogen chloride is 3M to 5M;

[0028] Optionally, the molar ratio of compound III to hydrogen chloride is 1:(5-6).

[0029] In some embodiments, the volume ratio of the dichloromethane to the trifluoroethanol is (6-8):1; and / or,

[0030] The molar ratio of compound IV to tert-butyldimethylsiloxane acetaldehyde is 1:(1–1.5); and / or,

[0031] The molar ratio of compound IV to acetic acid is 1:(0.2–0.4); and / or,

[0032] The above The mass-to-volume ratio of the molecular sieve to the mixed solution of dichloromethane and trifluoroethanol is 5–15 g: 100 mL.

[0033] In some embodiments, compound V and di-tert-butyl dicarbonate are subjected to an amino protection reaction to obtain compound VI, comprising:

[0034] Compound V was dissolved in dichloromethane, and N,N-diisopropylethylamine and ditert-butyl dicarbonate were added and mixed. The mixture was stirred for 10-20 hours to obtain compound VI.

[0035] Optionally, the molar ratio of compound V to ditert-butyl dicarbonate is 1:(1.5-2);

[0036] Optionally, the molar ratio of compound V to N,N-diisopropylethylamine is 1:(1 to 1.5).

[0037] In some embodiments, compound VI and 3-bromopropene are subjected to a hydroxyl protection reaction to prepare compound VII, comprising:

[0038] Compound VI and cesium carbonate were dissolved in acetonitrile, and then 3-bromopropene was added and mixed. The mixture was stirred at 30°C to 40°C for 10 to 20 hours to obtain compound VII.

[0039] Optionally, the molar ratio of compound VI to cesium carbonate is 1:(1 to 1.5);

[0040] Optionally, the molar ratio of compound VI to 3-bromopropene is 1:(1 to 1.5).

[0041] In some embodiments, compound VII is de-TBS-grouped in a tetrabutylammonium fluoride solution to obtain compound VIII, comprising:

[0042] Add tetrabutylammonium fluoride tetrahydrofuran solution to the tetrahydrofuran solution of compound VII, and stir at 20℃~40℃ for 1h~3h after the addition is complete to obtain compound VIII;

[0043] Optionally, the molar ratio of compound VII to tetrabutylammonium fluoride is 1:(1.2-1.6);

[0044] Optionally, the molar concentration of the tetrabutylammonium fluoride tetrahydrofuran solution is 0.5M to 1.5M.

[0045] In some embodiments, compound VIII is subjected to a hydroxyl oxidation reaction to obtain compound IX, comprising:

[0046] Compound VIII was dissolved in dichloromethane and mixed with iodophenyl diacetic acid and 9-azabicyclo[3.3.1]nonane-N-oxide. The mixture was stirred at 20°C to 40°C for 10 to 20 hours to obtain compound IX.

[0047] Optionally, the molar ratio of compound VIII, iodophenyl diacetic acid, and 9-azabicyclo[3.3.1]nonane-N-oxide is 1:(1.5-2):(0.1-0.12).

[0048] In some embodiments, compound X is prepared by Wittig addition reaction of compound IX and (formylmethylene)triphenylphosphine, comprising:

[0049] Compound IX was dissolved in acetonitrile and mixed with (formylmethylene)triphenylphosphine, and then stirred at 30℃~40℃ for 10h~20h to obtain compound X;

[0050] The molar ratio of compound IX to (formylmethylene)triphenylphosphine is 1:(1 to 1.5).

[0051] In some embodiments, the solution of lithium bis(trimethylsilylamine) comprises a tetrahydrofuran solution of lithium bis(trimethylsilylamine); and / or,

[0052] The molar concentration of the tetrahydrofuran solution of the bis(trimethylsilylamine) lithium is 0.5 M to 1.5 M; and / or,

[0053] The molar ratio of compound X to the bis(trimethylsilylamine)lithium is 1:(1.5–2.5); and / or,

[0054] The molar ratio of compound XI, (2R,5R)-(+)-2-tert-butyl-3-methyl-5-benzyl-4-imidazolinone, trifluoroacetic acid, cerium ammonium nitrate, and water is 1:(0.15-0.25):(0.15-0.25):(1.5-2.5):(1.5-2.5).

[0055] The method for synthesizing the trabectedine pentacyclic skeleton in this application follows the ring system construction sequence of A→AE→ADE→ACDE→ABCDE. Specifically, after large-scale synthesis of ring A and ring E fragments, the AE ring system is linked by an EDCI-mediated condensation reaction. Then, the D ring is constructed by a Pictet-Spengler reaction, followed by the C ring via a azira-Michael reaction, and finally the B ring is constructed by a SOMO small molecule catalytic reaction. This method achieves the large-scale preparation of the ABCDE pentacyclic skeleton of trabectedine and reserves construction sites for the derivative rings, providing a more convenient preparation method for the total synthesis of trabectedine and its derivatives, and providing a material basis for the activity study of this drug. Attached Figure Description

[0056] To more clearly illustrate the technical solutions in the specific embodiments of this application or the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of this application. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0057] Figure 1 Synthetic route for constructing the trabectedin pentacyclic skeleton according to an embodiment of this application. Detailed Implementation

[0058] The present application is further described below with reference to embodiments and examples. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the application. Furthermore, it should be understood that after reading the teachings of this application, those skilled in the art can make various alterations or modifications to this application, and these equivalent forms also fall within the protection scope of the appended claims.

[0059] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application.

[0060] the term

[0061] Unless otherwise stated or in case of contradiction, the terms or phrases used herein shall have the following meanings:

[0062] The term "and / or" as used herein includes any one of two or more related listed items, as well as any and all combinations of the related listed items. These arbitrary and all combinations encompass any two related listed items, any more related listed items, or a combination of all related listed items. It should be noted that when at least three items are connected using at least two conjunctions selected from "and / or," "or / and," or "and / or," it should be understood that, in this application, the technical solution undoubtedly includes solutions connected by "logical AND," and also undoubtedly includes solutions connected by "logical OR." For example, "A and / or B" includes three parallel solutions: A, B, and A+B. For example, the technical solution of "A, and / or, B, and / or, C, and / or, D" includes any one of A, B, C, and D (that is, a technical solution that is connected by "logical OR"), as well as any and all combinations of A, B, C, and D, that is, combinations of any two or three of A, B, C, and D, and also combinations of all four of A, B, C, and D (that is, a technical solution that is connected by "logical AND").

[0063] In this document, terms such as "preferred," "better," and "more preferred" are merely descriptions of implementation methods or examples that achieve better results, and should be understood as not constituting a limitation on the scope of protection of this application.

[0064] In this application, terms such as "further," "even further," and "particularly" are used to describe purposes and indicate differences in content, but should not be construed as limiting the scope of protection of this application.

[0065] In this application, the terms "first aspect," "second aspect," "third aspect," "fourth aspect," etc., are used for descriptive purposes only and should not be construed as indicating or implying relative importance or quantity, nor should they be construed as implicitly indicating the importance or quantity of the indicated technical features. Moreover, "first," "second," "third," "fourth," etc., serve only as a non-exhaustive enumeration and should be understood not to constitute a closed limitation on quantity.

[0066] In this application, the technical features described in an open-ended manner include both closed technical solutions consisting of the listed features and open technical solutions that include the listed features.

[0067] In this application, numerical intervals (i.e., numerical ranges) are involved. Unless otherwise specified, optional numerical distributions within the aforementioned numerical intervals are considered continuous and include the two endpoints (i.e., the minimum and maximum values) of the numerical range, as well as every value between these two endpoints. Unless otherwise specified, when a numerical interval refers only to integers within that interval, it includes the two endpoint integers of the numerical range, as well as every integer between the two endpoints. Furthermore, when multiple ranges are provided to describe features or characteristics, these ranges can be merged. In other words, unless otherwise specified, the ranges disclosed herein should be understood to include any and all subranges to which they are included.

[0068] Unless otherwise specified, the temperature parameters in this application are permitted to be either constant-temperature treatment or variations within a certain temperature range. It should be understood that the constant-temperature treatment allows temperature fluctuations within the precision range of the instrument control. Fluctuations are permitted within ranges such as ±1℃, ±0.8℃, ±0.5℃, ±0.4℃, ±0.3℃, ±0.2℃, and ±0.1℃.

[0069] In this application, weight can be a well-known unit of mass in the chemical industry, such as μg, mg, g, or kg.

[0070] In this application, the concentration unit M refers to mol / L. For example, 1M of sodium chloride solution means that 1 mole of sodium chloride is dissolved in 1 liter of solution.

[0071] One or more embodiments of this application provide a method for synthesizing the trabectedin pentacyclic skeleton, which achieves the preparation of the ABCDE pentacyclic skeleton of trabectedin in only ten steps, and reserves construction sites for the derived rings, providing a more convenient preparation method for the total synthesis of trabectedin and its derivatives, and providing a material construction basis for the activity study of this drug.

[0072] The synthesis method of the trabectedin pentacyclic skeleton includes the following steps:

[0073]

[0074] S1: Compound I and compound II are subjected to a condensation reaction to obtain compound III;

[0075] S2: The Boc group of compound III was removed in an acidic solution to obtain compound IV;

[0076] S3: After dissolving compound IV in a mixed solution of dichloromethane and trifluoroethanol, tert-butyldimethylsiloxane acetaldehyde, acetic acid, and... are added at -15°C to -5°C. The molecular sieves were mixed and stirred for 3-5 hours to obtain compound V;

[0077] S4: Compound V and ditert-butyl dicarbonate are subjected to an amino protection reaction to obtain compound VI;

[0078] S5: Compound VI and 3-bromopropene are subjected to a hydroxyl protection reaction to obtain compound VII;

[0079] S6: Compound VII was de-TBS-grouped in tetrabutylammonium fluoride solution to obtain compound VIII;

[0080] S7: Compound VIII is subjected to hydroxyl oxidation to obtain compound IX;

[0081] S8: Compound IX and (formylmethylene)triphenylphosphine were subjected to a Wittig addition reaction to obtain compound X;

[0082] S9: After dissolving the compound X in tetrahydrofuran, add a solution of bis(trimethylsilylamine)lithium at -80℃ to -70℃ and mix, then stir at 20℃ to 40℃ for 10h to 20h to obtain compound XI;

[0083] S10: After dissolving the compound XI in ethylene glycol dimethyl ether, add (2R,5R)-(+)-2-tert-butyl-3-methyl-5-benzyl-4-imidazolinone, trifluoroacetic acid, cerium ammonium nitrate and water at -80℃ to -70℃, and then stir at 20℃ to 40℃ for 10h to 20h to obtain compound XII.

[0084] refer to Figure 1 The method for synthesizing the pentacyclic skeleton of trabectedine in this application follows the ring system construction sequence of A→AE→ADE→ACDE→ABCDE. Specifically, the synthesis strategy is as follows: after synthesizing the A and E ring fragments on a large scale, the AE ring system is connected by a condensation reaction (refer to step S1). After a suitable group protection strategy, the D ring is constructed by the Pictet-Spengler reaction (refer to steps S2-S3). After a suitable group protection strategy and chain lengthening strategy, the C ring is constructed by the aza-Michael reaction (refer to steps S4-S9). Finally, the B ring is constructed by the SOMO small molecule catalytic reaction (refer to S10).

[0085] The following is a detailed explanation of each step:

[0086] Step S1: In this step, compound I and compound II undergo a condensation reaction to obtain compound III.

[0087] In one embodiment, compound I and compound II are subjected to a condensation reaction to obtain compound III, comprising:

[0088] Compound I and Compound II were dissolved in tetrahydrofuran, and N,N-diisopropylethylamine, 1-hydroxybenzotriazole and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added and mixed. The mixture was stirred for 10 h to 20 h to obtain Compound II.

[0089] Optionally, the molar ratio of compound I to compound II is 1:(1-1.5); for example, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, etc. Optionally, the molar ratio of compound I to N,N-diisopropylethylamine, 1-hydroxybenzotriazole and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride is 1:(2-3):(1-1.3):(1-1.3); for example, 1:2:1:1, 1:2.5:1.2:1.2, 1:3:1.2:1.2, etc.

[0090] Step S2: In this step, compound III is deactivated by removing the Boc group in an acid solution to obtain compound IV;

[0091] In one embodiment, compound III is deactivated by removing the Boc group in an acidic solution to obtain compound IV, comprising:

[0092] A dioxane solution of hydrogen chloride was added to a methanol solution of compound III at -5℃ to 5℃. After the addition was complete, the temperature was raised to 20℃ to 40℃ and stirred for 10h to 20h to obtain compound IV.

[0093] Optionally, the molar concentration of the dioxane solution of hydrogen chloride is 3M to 5M;

[0094] Optionally, the molar ratio of compound III to hydrogen chloride is 1:(5-6); for example, 1:5, 1:5.5, 1:6, etc.

[0095] Step S3: In this step, the D ring is constructed using the Pictet-Spengler reaction.

[0096] In one embodiment, compound IV was dissolved in a mixed solution of dichloromethane and trifluoroethanol, and then tert-butyldimethylsiloxane, acetic acid, and [other ingredients] were added at -15°C to -5°C. The molecular sieves were mixed and stirred for 3 to 5 hours to obtain compound V.

[0097] Optionally, the volume ratio of the dichloromethane to the trifluoroethanol is (6-8):1; for example, 6:1, 7:1, 8:1, etc.

[0098] Optionally, the molar ratio of compound IV to tert-butyldimethylsiloxane acetaldehyde is 1:(1 to 1.5); for example, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, etc.

[0099] Optionally, the molar ratio of compound IV to acetic acid is 1:(0.2 to 0.4); for example, 1:0.2, 1:0.3, 1:0.4, etc.

[0100] Optionally, the The mass-to-volume ratio of the molecular sieve to the mixed solution of dichloromethane and trifluoroethanol is 5–15 g: 100 mL; for example, 5 g: 100 mL, 8 g: 100 mL, 10 g: 100 mL, 12 g: 100 mL, 15 g: 100 mL, etc.

[0101] Step S4: In this step, compound V and ditert-butyl dicarbonate are subjected to an amino protection reaction to obtain compound VI.

[0102] In one embodiment, compound V and di-tert-butyl dicarbonate are subjected to an imino protection reaction to prepare compound VI, comprising:

[0103] Compound V was dissolved in dichloromethane, and N,N-diisopropylethylamine and ditert-butyl dicarbonate were added and mixed. The mixture was stirred for 10-20 hours to obtain compound VI.

[0104] Optionally, the molar ratio of compound V to ditert-butyl dicarbonate is 1:(1.5-2); for example, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, etc.

[0105] Optionally, the molar ratio of compound V to N,N-diisopropylethylamine is 1:(1 to 1.5); for example, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, etc.

[0106] Step S5: In this step, compound VI and 3-bromopropene are subjected to a hydroxyl protection reaction to obtain compound VII.

[0107] In one embodiment, compound VI and 3-bromopropene are subjected to a hydroxyl protection reaction to prepare compound VII, comprising:

[0108] Compound VI and cesium carbonate were dissolved in acetonitrile, and then 3-bromopropene was added and mixed. The mixture was stirred at 30°C to 40°C for 10 to 20 hours to obtain compound VII.

[0109] Optionally, the molar ratio of compound VI to cesium carbonate is 1:(1 to 1.5); for example, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, etc.

[0110] Optionally, the molar ratio of compound VI to 3-bromopropene is 1:(1 to 1.5); for example, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, etc.

[0111] Step S6: In this step, compound VII is de-TBS-grouped in tetrabutylammonium fluoride solution to obtain compound VIII.

[0112] In one embodiment, compound VII is de-TBS-grouped in a tetrabutylammonium fluoride solution to obtain compound VIII, comprising:

[0113] Add tetrabutylammonium fluoride tetrahydrofuran solution to the tetrahydrofuran solution of compound VII, and stir at 20℃~40℃ for 1h~3h after the addition is complete to obtain compound VIII;

[0114] Optionally, the molar ratio of compound VII to tetrabutylammonium fluoride is 1:(1.2 to 1.6); for example, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, etc.

[0115] Optionally, the molar concentration of the tetrabutylammonium fluoride tetrahydrofuran solution is 0.5M to 1.5M.

[0116] Step S7: In this step, compound VIII is subjected to a hydroxyl oxidation reaction to obtain compound IX.

[0117] In one embodiment, compound VIII is subjected to a hydroxyl oxidation reaction to obtain compound IX, comprising:

[0118] Compound VIII was dissolved in dichloromethane and mixed with iodophenyl diacetic acid and 9-azabicyclo[3.3.1]nonane-N-oxide. The mixture was stirred at 20°C to 40°C for 10 to 20 hours to obtain compound IX.

[0119] Optionally, the molar ratio of compound VIII, iodophenyl diacetic acid, and 9-azabicyclo[3.3.1]nonane-N-oxide is 1:(1.5-2):(0.1-0.12); for example, 1:1.5:0.1, 1:1.8:0.11, 1:2:0.12, etc.

[0120] Step S8: In this step, compound IX and (formylmethylene)triphenylphosphine are subjected to a Wittig addition reaction to obtain compound X.

[0121] In one embodiment, compound IX and (formylmethylene)triphenylphosphine are subjected to a Wittig addition reaction to prepare compound X, comprising:

[0122] Compound IX was dissolved in acetonitrile and mixed with (formylmethylene)triphenylphosphine, and then stirred at 30℃~40℃ for 10h~20h to obtain compound X;

[0123] The molar ratio of compound IX to (formylmethylene)triphenylphosphine is 1:(1 to 1.5); for example, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, etc.

[0124] Step S9: In this step, the C ring is prepared by aza-Michael reaction to obtain compound XI.

[0125] In one embodiment, compound X was dissolved in tetrahydrofuran, and then a solution of bis(trimethylsilylamine)lithium was added and mixed at -80°C to -70°C, and then stirred at 20°C to 40°C for 10 to 20 hours to obtain compound XI.

[0126] Optionally, the molar ratio of compound X to the bis(trimethylsilylamine)lithium is 1:(1.5 to 2.5); for example, 1:1.5, 1:1.8, 1:2, 1:2.2, 1:2.5, etc.

[0127] Optionally, the molar concentration of the tetrahydrofuran solution of bis(trimethylsilylamine)lithium is 0.5 M to 1.5 M.

[0128] Step S10: In this step, a B ring is constructed by SOMO small organic molecule catalytic reaction to obtain compound XII.

[0129] In one embodiment, compound XI was dissolved in ethylene glycol dimethyl ether, and then (2R,5R)-(+)-2-tert-butyl-3-methyl-5-benzyl-4-imidazolinone, trifluoroacetic acid, cerium ammonium nitrate and water were added at -80°C to -70°C and stirred at 20°C to 40°C for 10 to 20 hours to obtain compound XII.

[0130] Optionally, the molar ratio of compound XI, (2R,5R)-(+)-2-tert-butyl-3-methyl-5-benzyl-4-imidazolinone, trifluoroacetic acid, cerium ammonium nitrate, and water is 1:(0.15-0.25):(0.15-0.25):(1.5-2.5):(1.5-2.5); for example, 1:0.15:0.15:1.5:1.5, 1:0.2:0.2:2:2, 1:0.25:0.25:2.5:2.5, etc.

[0131] The following are some specific examples.

[0132] For experimental parameters not specified in the following specific embodiments, please refer to the guidelines given in this application document first, or refer to experimental manuals or other experimental methods known in the art, or refer to the experimental conditions recommended by the manufacturer.

[0133] The raw materials and reagents involved in the following specific embodiments can be obtained commercially or prepared by those skilled in the art using known methods.

[0134] Example 1

[0135] 1. Synthesis of Compound 2

[0136]

[0137] Substrate 1 (30 g, 169.5 mmol, 1.0 equiv.) and potassium carbonate (46.8 g, 338.9 mmol, 2.0 equiv.) were dissolved in DMF (200 mL). 3-bromopropene (16.1 mL, 186.4 mmol, 1.1 equiv.) was added at room temperature, and the mixture was stirred overnight. The solution was then quenched with saturated ammonium chloride solution (200 mL). The organic phase was removed by rotary evaporation under reduced pressure, followed by extraction with ethyl acetate (200 mL × 3). The combined organic phases were washed once with saturated brine (300 mL), dried over Na₂SO₄, filtered, and rotary evaporated under reduced pressure to obtain a concentrated crude product. This crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate 10:1) to give a pale yellow solid 2 (34.6 g, yield 94%).

[0138] R f =0.6 (petroleum ether / ethyl acetate = 8 / 1); 1 H NMR (400MHz, CDCl3) δ6.34 (s, 1H), 6.05 (s, 2H), 6.09–5.93 (m, 1H), 5.41 (dq, J = 17.3 ,1.6Hz,1H),5.30(dq,J=10.6,1.5Hz,1H),4.46(dt,J=5.1,1.6Hz,2H),2.14(s,3H);13 C NMR (101MHz, CDCl3) δ152.47,147.49,144.53,132.63,117.71,115.79,115.18,104.08,102.52,88.84,69.77,9.30.

[0139] 2. Synthesis of Compound 3

[0140]

[0141] Substrate 2 (30 g, 138.2 mmol, 1.0 equiv.) was dissolved in dichloromethane (200 mL). A 1.5 M diisobutylaluminum hydride solution in toluene (110.6 mL, 165.8 mmol, 1.2 equiv.) was added at 0 °C. After stirring for 2 hours, the mixture was quenched with a saturated potassium sodium tartrate solution (200 mL) at the same temperature. The mixture was then brought to room temperature and stirred overnight until the system was clear. The mixture was then extracted with dichloromethane (200 mL × 3). The combined organic phases were washed once with saturated brine (300 mL), dried over Na₂SO₄, filtered, and rotary evaporated under reduced pressure. The crude product obtained was concentrated from the organic phase. This crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate 10:1) to give a pale yellow solid 3 (27.7 g, yield 91%).

[0142] R f =0.6 (petroleum ether / ethyl acetate = 8 / 1); 1 H NMR(600MHz, CDCl3)δ10.07(s,1H),6.65(s,1H),6.08(s,2H),6.02-6.07(m,1H),5.42(dq, J=17.3,1.7Hz,1H),5.29(dq,J=10.5,1.5Hz,1H),4.52(dt,J=5.1,1.6Hz,2H),2.18(s,3H); 13 C NMR (151MHz, CDCl3) δ191.0,152.5,149.4,143.9,130.5,125.2,118.7,104.1,103.5,89.3,70.1,9.8.

[0143] 3. Synthesis of Compound 4

[0144]

[0145] Substrate 3 (30.0 g, 136.3 mmol, 1.0 equiv.) and S-tert-butylsulfinamide (19.8 g, 163.6 mmol, 1.2 equiv.) were dissolved in tetrahydrofuran (200 mL). Tetraethyl titanate (57.2 mL, 272.6 mmol, 2.0 equiv.) was added at room temperature, and the mixture was stirred overnight. The mixture was then quenched with saturated ammonium chloride solution (200 mL). After removing the organic phase by rotary evaporation under reduced pressure, the mixture was extracted with ethyl acetate (200 mL × 3). The combined organic phases were washed once with saturated brine (300 mL), dried over Na₂SO₄, filtered, and rotary evaporated under reduced pressure. The crude product obtained was a concentrated organic phase. This crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate 5:1) to give a pale yellow solid 4 (41.0 g, yield 93%).

[0146] R f =0.3 (petroleum ether / ethyl acetate = 8 / 1); 1 H NMR(600MHz, CDCl3)δ9.17(s,1H),7.79(s,1H),6.63–6.53(m,3H),5.96(dq,J=17.3,1.7Hz ,1H),5.81(dq,J=10.5,1.5Hz,1H),5.04(dt,J=5.2,1.6Hz,2H),2.69(s,3H),1.78(s,9H); 13 C NMR (151MHz, CDCl3) δ157.17,152.52,147.48,142.70,133.23,117.32,114.54,112.88,102.00,100.51,69.60,57.72,22.56,9.32.

[0147] 4. Synthesis of Compound 6

[0148]

[0149] Substrate 5 (15.0 mL, 54.1 mmol, 1.0 equiv.) was dissolved in tetrahydrofuran (100 mL). A 2M solution of lithium diisopropylamino in tetrahydrofuran / n-heptane / ethylbenzene (29.7 mL, 59.5 mmol, 1.1 equiv.) was added at 0 °C. After stirring for 1 hour, the mixture was cooled to -78 °C. Then, BOMCl (8.7 mL, 59.5 mmol, 1.1 equiv.) was added, and the mixture was stirred and allowed to heat naturally for 4 hours. The mixture was then quenched with saturated ammonium chloride solution (100 mL). After removing the organic phase by rotary evaporation under reduced pressure, the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed once with saturated brine (300 mL), dried over Na₂SO₄, filtered, and rotary evaporated under reduced pressure. The crude product obtained was a concentrated organic phase. This crude product was purified by silica gel column chromatography (pure petroleum ether) to give a pale yellow liquid 6 (16.0 g, yield 72%).

[0150] R f =0.7 (pure petroleum ether); 1 H NMR(600MHz, CDCl3)δ7.31–7.17(m,5H),4.35(s,2H),3.68(s,

[0151] 2H),1.51–1.37(m,6H),1.27-1.19(m,6H),0.93–0.77(m,15H); 13 C NMR (151MHz, CDCl3) δ138.91,128.18,127.50,127.28,77.20,61.48,29.13,27.31,13.70,8.98.

[0152] 5. Synthesis of Compound 7

[0153]

[0154] Substrate 6 (17.9 g, 40.2 mmol, 2.6 equiv.) was dissolved in tetrahydrofuran (100 mL). A 2.5 M n-butyllithium solution in n-hexane (14.2 mL, 35.6 mmol, 2.3 equiv.) was added at -78 °C, and the mixture was stirred for 1.5 hours. At this temperature, substrate 4 (5 g, 15.5 mmol, 1.0 equiv., dissolved in 50 mL of tetrahydrofuran) was slowly added, and the mixture was stirred for 4 hours. The mixture was then quenched with saturated ammonium chloride solution (100 mL) and brought to room temperature. The organic phase was removed by rotary evaporation under reduced pressure, followed by extraction with ethyl acetate (100 mL × 3). The combined organic phases were washed once with saturated brine (300 mL), dried over Na₂SO₄, filtered, and rotary evaporated under reduced pressure. The crude product, a concentrated organic phase, was purified by silica gel column chromatography (petroleum ether:ethyl acetate 5:1) to give a yellow liquid (R)-7 (5.3 g, 77% yield).

[0155] R f =0.4 (petroleum ether / ethyl acetate = 2 / 1); 1 H NMR (600MHz, CDCl3) δ7.38–7.19(m,5H),6.53(s,1H),6.07(m,1H),5.91(s,2H),5.42(dd,J=17.3,1.8Hz,1H) ,5.22(dd,J=10.6,1.7Hz,1H),4.67(m,1H),4.53(s,2H)4.47(d,2H),3.74(m,2H),2.07(s,6H),1.16(s,9H); 13 CNMR (151MHz, CDCl3) δ152.2,146.3,138.7,134.1,128.3,128.1,127.8,127.4,127.3,1 19.0,116.2,108.1,103.5,101.0,73.1,72.5,69.5,55.6,54.1,22.0,8.11; HRMS(ESI)C 24 H 32 NO5S + [M+H] + Calculated molecular weight: 446.1996; Actual molecular weight: 446.1993.

[0156] 6. Synthesis of Compound 10

[0157]

[0158] Substrate 7 (6.5 g, 14.6 mmol, 1.0 equiv.) was dissolved in methanol (300 mL), and a 4 M dioxane solution of hydrogen chloride (14.6 mL, 58.4 mmol, 4.0 equiv.) was added at 0 °C. After stirring for 1 hour, the organic phase was removed by rotary evaporation under reduced pressure. Ethyl acetate (100 mL) and 10% sodium hydroxide solution (100 mL) were added, and the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed once with 10% sodium hydroxide solution (300 mL), dried over Na₂SO₄, filtered, and rotary evaporated under reduced pressure. The resulting crude product, a brownish-yellow liquid (R)-8, was obtained after organic phase concentration. This crude product was not purified.

[0159] Crude product 8 (1.0 equiv.) and substrate (S)-9 (5.7 g, 17.6 mmol, 1.2 equiv.) were dissolved in tetrahydrofuran (200 mL). DIPEA (7.7 mL, 44.0 mmol, 3.0 equiv.), HOBt (2.4 g, 17.6 mmol, 1.2 equiv.), and EDCI (3.4 g, 17.6 mmol, 1.2 equiv.) were added at room temperature. After stirring overnight, the mixture was quenched with saturated ammonium chloride solution (100 mL). The organic phase was removed by rotary evaporation under reduced pressure, followed by extraction with ethyl acetate (100 mL × 3). The combined organic phases were washed once with saturated sodium chloride solution (300 mL), dried over Na₂SO₄, filtered, and rotary evaporated under reduced pressure. The resulting concentrated organic phase was the crude product. This crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate 3:1) to give a yellow solid (R,R)-10 (8.5 g, 2-step yield 89%).

[0160] R f =0.8 (petroleum ether / ethyl acetate = 1 / 1); 1H NMR (600MHz, CDCl3) δ9.52 (s, 1H), 8.73 (d, J = 9.5Hz, 1H), 7.31-7.23 (m, 5H), 6.76 (s, 1H), 6.46 (s, 1H), 6.40 (s,1H),6.17-6.10(m,1H),5.90(dd,J=12.7,1.5Hz,2H),5.54–5.44(m,1H),5.44–5.39(m,2H),5.31–5.23( m,2H),4.74–4.61(m,2H),4.61–4.54(m,2H),4.51–4.40(m,2H),4.11–3.96(m,1H),3.85(s,3H),3.84–3.73 (m,2H),3.04(dd,J=15.3,5.1Hz,1H),2.50(dd,J=15.3,5.1Hz,1H),2.28(s,3H),2.12(s,3H),1.17(s,9H); 13 C NMR (151MHz, CDCl3) δ152.35,148.76,148.71,146.54,144.31,138.25,137.92,133.89,133.59,129.90,129.47,128.30,128.28,127.63,123. 29,116.94,116.54,113.86,109.12,103.32,100.94,72.85,69.83,60. 48,38.17,29.31,28.26,27.21,22.68,15.63,14.11,8.74; HRMS(ESI)C 36 H 45 N2O9 + [M+H] + Calculated molecular weight: 649.3120; Actual molecular weight: 649.3116; Chiral purity: 99% ee.

[0161] 7. Synthesis of Compound 12

[0162]

[0163] Substrate 10 (5.9 g, 9.1 mmol, 1.0 equiv.) was dissolved in methanol (300 mL). A 4 M dioxane solution of hydrogen chloride (11.4 mL, 45.5 mmol, 5.0 equiv.) was added at 0 °C. The mixture was allowed to heat naturally and stirred overnight. After removing the organic phase by rotary evaporation under reduced pressure, ethyl acetate (100 mL) and 10% sodium hydroxide solution (100 mL) were added. The mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed once with 10% sodium hydroxide solution (300 mL), dried over Na₂SO₄, filtered, and rotary evaporated under reduced pressure to obtain crude product 11, a concentrated organic phase.

[0164] Crude product 11 (1.0 equiv.) was dissolved in a dichloromethane / trifluoroethanol mixed solvent (50 mL, 7:1), and tert-butyldimethylsiloxane acetaldehyde (12.0 mL, 11.0 mmol, 1.2 equiv.), acetic acid (0.15 mL, 2.8 mmol, 0.3 equiv.), and [other components] were added at -20 °C. Molecular sieve (5 g, 100% wt.) was stirred for 4 hours, then quenched with saturated sodium carbonate solution (50 mL) at this temperature and brought to room temperature. Extraction was performed with dichloromethane (50 mL × 3). The combined organic phases were washed once with saturated sodium chloride solution (200 mL), dried over Na₂SO₄, filtered, and evaporated under reduced pressure to obtain a concentrated crude product. This crude product was purified by silica gel column chromatography (dichloroethane:ethyl acetate 7:1) to give a yellow solid (1R, 11S, 13S)-12 (5.2 g, 2-step yield 81%).

[0165] R f =0.3 (dichloromethane / methanol = 10 / 1); 1 H NMR(600MHz, CDCl3)δ7.30(d,J=9.3Hz,1H),7.21–7.13(m,5H),6.42(s,1H),6.23(s,1H),5.97–5.9 3(m,1H),5.87–5.79(m,2H),5.55–5.49(m,1H),5.32(dq,J=17.3,1.7Hz,1H),5.17(dq,J=10.6,1.5H z,1H),4.45(s,2H),4.36(dt,J=5.5,1.6Hz,2H),4.08–4.03(m,1H),3.86(d,J=5.1Hz,2H),3.78–3.7 1(m,2H),3.70(s,3H),3.67–3.58(m,2H),2.96–2.87(m,2H),2.19(s,3H),2.03(s,3H),1.07(s,9H); 13C NMR (151MHz, CDCl3) δ172.40,154.57,151.32,145.77,144.15,143.20,13 7.66,137.14,132.46,128.83,128.26,127.18,126.43,125.34,119.61,11 9.27,116.19,115.98,108.23,103.51,99.90,80.11,71.60,70.76,68.98, 65.17,57.56,51.09,30.64,26.71,24.95,17.62,14.70,7.70; HRMS(ESI)C 39 H 53 N2O8Si + [M+H] + Calculated molecular weight: 705.3566; Actual molecular weight: 705.3559; Chiral purity: 99% ee.

[0166] 8. Synthesis of Compound 13

[0167]

[0168] Substrate 12 (5 g, 7.1 mmol, 1.0 equiv.) was dissolved in dichloromethane (50 mL). N,N-diisopropylethylamine (1.5 mL, 8.5 mmol, 1.2 equiv.) and di-tert-butyl dicarbonate (2.5 mL, 10.6 mmol, 1.5 equiv.) were added at room temperature. The mixture was stirred overnight, and then rotary evaporated under reduced pressure to obtain a crude product with concentrated organic phase. This crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate 3:1) to give a yellow solid 13 (5.3 g, yield 93%).

[0169] R f =0.7 (petroleum ether / ethyl acetate = 2 / 1); 1H NMR(600MHz, CDCl3)δ7.30(d,J=9.3Hz,1H),7.21–7.13(m,5H),6.42(s,1H),6.23(s,1H),5.97–5.93(m,1H ),5.87–5.79(m,2H),5.55–5.49(m,1H),5.32(dq,J=17.3,1.7Hz,1H),5.17(dq,J=10.6,1.5Hz,1H),4.45(s ,2H),4.36(dt,J=5.5,1.6Hz,2H),4.08–4.03(m,1H),3.86(d,J=5.1Hz,2H),3.78–3.71(m,2H),3.70(s,3H ),3.67–3.58(m,2H),2.96–2.87(m,2H),2.19(s,3H),2.03(s,3H),1.07(s,9H),0.74(s,9H),-0.10(s,6H); 13 C NMR (151MHz, CDCl3) δ172.40,154.57,151.32,145.77,144.15,143.20,137.66,13 7.14,132.46,128.83,128.26,127.18,126.43,125.34,119.61,119.27,116.19,1 15.98,108.23,103.51,99.90,80.11,71.60,70.76,68.98,65.17,59.57,51.09,5 0.58,48.63,30.64,26.71,24.95,17.62,14.70,7.70,-1.03,-6.57.; HRMS(ESI)C 44 H 61 N2O 10 Si + [M+H] + Calculated molecular weight: 805.4090; Actual molecular weight: 805.4086; Chiral purity: 99% ee.

[0170] 9. Synthesis of Compound 14

[0171]

[0172] Substrate 13 (5 g, 6.2 mmol, 1.0 equiv.) and cesium carbonate (2.5 g, 7.4 mmol, 1.2 equiv.) were dissolved in acetonitrile (50 mL). 3-bromopropene (0.7 mL, 7.4 mmol, 1.2 equiv.) was added at room temperature, and the mixture was heated to 35 °C and stirred overnight. The mixture was then cooled to room temperature, quenched with saturated ammonium chloride solution (50 mL), and the organic phase was removed by rotary evaporation under reduced pressure. The mixture was then extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed once with saturated brine (150 mL), dried over Na₂SO₄, filtered, and rotary evaporated under reduced pressure. The resulting crude product was a concentrated organic phase. This crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate 5:1) to give a yellow solid 14 (3.9 g, yield 73%).

[0173] R f =0.7 (petroleum ether / ethyl acetate = 3 / 1); 1 H NMR(600MHz, CDCl3)δ7.43(d,J=9.5Hz,1H),7.22–7.12(m,5zzzH),6.63(s,1H),6.27(s,1H),6.08–6.00( m,1H),6.00–5.93(m,1H),5.81(d,J=28.1Hz,2H),5.55(s,1H),5.32(dq,J=17.3,1.7Hz,2H),5.20–5.11( m,2H),4.57–4.50(m,1H),4.45(s,2H),4.36(d,J=5.2Hz,2H),4.07(s,1H),3.87(d,J=10.4Hz,1H),3.71( s,3H),3.68–3.59(m,2H),2.97(s,2H),2.16(s,3H),2.03(s,3H),1.06(s,9H),0.74(s,9H),-0.07(s,6H); 13C NMR (151MHz, CDCl3) δ172.69,154.59,151.30,148.58,146.77,137.22,133.17,132.50, 130.48,128.93,127.16,126.46,126.38,125.96,123.44,116.69,116.29,115.96,108.2 7,103.85,99.85,79.86,72.87,71.53,70.48,69.08,65.42,59.02,57.63,51.37,48.50, 30.60,28.67,26.67,25.04,21.66,17.69,14.69,13.09,7.70,-1.04,-6.46; HRMS(ESI)C 47 H 65 N2O 10 Si + [M+H] + Calculated molecular weight: 845.4403; Actual molecular weight: 845.4394; Chiral purity: 99% ee.

[0174] 10. Synthesis of Compound 15

[0175]

[0176] Substrate 14 (3 g, 3.5 mmol, 1.0 equiv.) was dissolved in tetrahydrofuran (30 mL), and a 1 M tetrabutylammonium fluoride tetrahydrofuran solution (5.0 mL, 5.0 mmol, 1.4 equiv.) was added at room temperature. After stirring for 2 hours, the mixture was rotary evaporated under reduced pressure to obtain a crude product with concentrated organic phase. This crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate 2:1) to give a yellow solid 15 (2.34 g, 90% yield).

[0177] R f =0.3 (petroleum ether / ethyl acetate = 3 / 1); 1H NMR (600MHz, CDCl3) δ7.74(d,J=9.0Hz,1H),7.31-7.23(m,5H),6.71(s,1H),6.32(d,J=17.9Hz,1H),6.14–6.07(m,1H) ,6.07–6.00(m,1H),5.92–5.83(m,2H),5.79–5.59(m,1H),5.44–5.36(m,2H),5.24(ddd,J=10.4,8.3,1.7Hz,2H),4.64– 4.54(m,2H),4.54–4.47(m,2H),4.47–4.38(m,2H),4.28–3.85(m,1H),3.79(s,3H),3.78-3.70(m,2H),3.45(d,J=13.8 Hz,1H),3.21(d,J=13.8Hz,1H),3.11(d,J=13.7Hz,1H),2.92(d,J=13.9Hz,1H),2.23(s,3H),2.10(s,3H),1.21(s,9H); 13 C NMR (151MHz, CDCl3) δ173.60,156.21,152.50,149.77,147.91,146.62,138.67,138. 01,134.03,133.63,131.87,129.06,128.31,127.73,127.67,126.77,124.84,118.0 0,116.94,116.75,109.17,103.50,100.98,81.30,74.11,72.96,71.96,69.83,64.7 9,60.07,57.72,51.39,48.67,31.03,29.71,28.35,27.88,15.74,8.77; HRMS(ESI)C 41 H 51 N2O 10 + [M+H] + Calculated molecular weight: 731.3538; Actual molecular weight: 731.3530; Chiral purity: 99% ee.

[0178] 11. Synthesis of Compound 16

[0179]

[0180] Substrate 15 (2 g, 2.7 mmol, 1.0 equiv.) was dissolved in dichloromethane (20 mL). Iodophenyl diacetic acid (1.3 g, 4.1 mmol, 1.5 equiv.) and ABNO (0.04 g, 0.3 mmol, 0.1 equiv.) were added at room temperature. After stirring overnight, the mixture was quenched with saturated sodium sulfite solution (20 mL). Extraction was performed with dichloromethane (20 mL × 3). The combined organic phases were washed once with saturated sodium chloride solution (80 mL), dried over Na2SO4, filtered, and rotary evaporated under reduced pressure. The crude product obtained was concentrated from the organic phase. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate 4:1) to give yellow solid 16 (1.4 g, yield 69%).

[0181] R f =0.4 (petroleum ether / ethyl acetate = 3 / 1); 1 H NMR(600MHz, CDCl3)δ9.52(s,1H),8.73(d,J=9.5Hz,1H),7.23-7.31(m,5H),6.76(s,1H),6.46(s,1H),6.40(s,1 H),6.17-6.10(m,1H),6.09-6.03(m,1H),5.90(dd,J=12.7,1.5Hz,2H),5.54–5.44(m,1H),5.44–5.39(m,2H),5. 31–5.23(m,2H),4.74–4.61(m,2H),4.61–4.54(m,2H),4.51–4.40(m,2H),4.11–3.96(m,1H),3.85(sf,3H),3.84 –3.73(m,2H),3.04(dd,J=15.3,5.1Hz,1H),2.50(dd,J=15.3,5.1Hz,1H),2.28(s,3H),2.12(s,3H),1.17(s,9H); 13 C NMR (151MHz, CDCl3) δ197.57,172.31,154.96,152.35,149.91,148.03,146.58,138. 74,138.32,133.57,133.49,133.45,130.65,128.07,127.56,127.49,127.26,124.7 5,120.65,118.68,116.84,116.82,108.90,103.45,100.95,81.89,72.69,71.95,69 .64,60.23,60.04,59.17,48.52,31.78,28.01,27.55,15.78,8.70,8.64; HRMS(ESI)C41 H 49 N2O 10 + [M+H] + Calculated molecular weight: 729.3382; Actual molecular weight: 729.3378; Chiral purity: 99% ee.

[0182] 12. Synthesis of Compound 17

[0183]

[0184] Substrate 16 (2 g, 2.7 mmol, 1.0 equiv.) was dissolved in acetonitrile (20 mL). (Formylmethylene)triphenylphosphine (1.0 g, 3.3 mmol, 1.2 equiv.) was added at room temperature. The mixture was heated to 35 °C and stirred overnight. After cooling to room temperature, the mixture was quenched with saturated ammonium chloride solution (20 mL). The organic phase was removed by rotary evaporation under reduced pressure. The mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed once with saturated brine (60 mL), dried over Na₂SO₄, filtered, and rotary evaporated under reduced pressure. The crude product obtained was a concentrated organic phase. This crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate 3:1) to give a yellow solid 17 (1.7 g, yield 81%).

[0185] R f =0.4 (petroleum ether / ethyl acetate = 3 / 1); 1 H NMR (600MHz, CDCl3) δ9.40(s,1H),8.10(s,1H),7.34–7.23(m,5H),7.01(d,J=8.7Hz,1H),6.95(dd,J=15.6 ,5.3Hz,1H),6.76(s,1H),6.45(s,1H),6.27-6.18(m,1H),6.06-6.0z(m,1H),5.92(dd,J=12.7,1.5Hz,2H) ,5.39(dq,J=17.2,1.7Hz,1H),5.36(s,2H),5.27–5.19(m,4H),4.67-4.48(m,2H),4.44-4.42(m,2H),3.80 (s,3H),3.79-3.71(m,2H),3.65(s,2H),2.91(s,1H),2.73(s,1H),2.25(s,3H),2.10(s,3H),1.25(s,9H); 13C NMR (151MHz, CDCl3) δ193.61,155.68,154.99,152.48,150.00,147.75,146.81,138. 51,137.88,133.77,133.45,132.54,132.23,131.90,129.07,128.36,128.28,127.65 ,124.78,118.28,117.00,109.35,103.61,101.02,100.86,81.78,74.00,72.97,72. 37,72.21,69.80,60.13,58.63,48.95,31.49,29.68,22.68,15.79,8.74; HRMS(ESI)C 43 H 51 N2O 10 + [M+H] + Calculated molecular weight: 755.3538; Actual molecular weight: 755.3539; Chiral purity: 99% ee.

[0186] 13. Synthesis of Compound 18

[0187]

[0188] Substrate 17 (2 g, 2.7 mmol, 1.0 equiv.) was dissolved in tetrahydrofuran (20 mL). A 1 M solution of bis(trimethylsilylamino)lithium in tetrahydrofuran (5.3 mL, 5.3 mmol, 2.0 equiv.) was added at -78 °C. The mixture was allowed to heat naturally and stirred overnight. The solution was then quenched with saturated ammonium chloride solution (20 mL). The organic phase was removed by rotary evaporation under reduced pressure. The mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed once with saturated brine (60 mL), dried over Na₂SO₄, filtered, and rotary evaporated under reduced pressure. The crude product obtained was a concentrated organic phase. This crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate 2:1) to give a yellow solid diastereomer 18 (1.5 g, yield 76%, dr = 1:1).

[0189] R f =0.5 (petroleum ether / ethyl acetate = 3 / 1); 1H NMR(600MHz,CDCl3)δ9.68–9.56(m,1H),7.42–7.05(m,5H),6.57–6.47(m,1H),6.24–6.13(m,1H),6.12(d,J=7.0Hz,1H),6.04–5.96(m,1H),5.84–5.79(m,2H),5.41–5.36(m,2H),5.36–5.27(m,1H),5.25(dt,J=9.0,1.5Hz,2H),5.24–5.16(m,1H),4.91–4.77(m,1H),4.71–4.61(m,1H),4.59–4.47(m,1H),4.32–4.26(m,2H),4.25(s,1H),4.20(s,1H),3.67(d,J=7.2Hz,3H),3.65–3.52(m,2H),3.15–3.02(m,1H),2.97(dd,J=16.3,1.7Hz,1H),2.73–2.61(m,1H),2.38–2.21(m,1H),2.11(d,J=2.4Hz,3H),2.04(d,J=1.2Hz,3H),1.48–1.37(m,9H); 13C NMR (151MHz, CDCl3) δ198.90,198.78,168.88,168.74,153.12,152.65,152.58,149 .45,149.36,147.96,147.55,146.41,146.19,139.84,139.61,138.10,138.08,134 .34,134.06,133.44,133.42,131.98,131.87,129.20,128.77,128.54,128.17,128.14,127.62,127.41,127.39,127.36,127.29,126.95,126.07,125.83,125.43,125. 25,118.30,117.68,116.99,116.97,113.82,113.35,109.88,109.75,104.23,104.10,100.87,100.78,81.14,81.02,73.85,73.58,72.74,72.69,69.60,69.58,68.40, 68.34,65.35,59.88,59.83,56.51,56.26,55.18,54.91,53.72,52.18,50.25,49.2 5,47.16,47.05,32.72,32.28,29.67,28.30,28.23,15.71,15.70,8.75; HRMS(ESI)C 43 H 51 N2O 10 + [M+H] + Calculated molecular weight: 755.3538; Measured molecular weight: 755.3537; Diasteremeric isomer dr = 1:1.

[0190] 14. Synthesis of Compound 19

[0191]

[0192] Substrate 18 (1 g, 1.33 mmol, 1.0 equiv.) was dissolved in ethylene glycol dimethyl ether (10 mL). (2R,5R)-(+)-2-tert-butyl-3-methyl-5-benzyl-4-imidazolinone (0.065 g, 0.27 mmol, 0.2 equiv.), trifluoroacetic acid (0.02 mL, 0.27 mmol, 0.2 equiv.), cerium ammonium nitrate (1.41 g, 2.65 mmol, 2.0 equiv.), and water (0.05 mL, 2.65 mmol, 2.0 equiv.) were added at -78 °C. After naturally heating and stirring overnight, the mixture was quenched with saturated ammonium chloride solution (10 mL). The organic phase was removed by rotary evaporation under reduced pressure. The mixture was then extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed once with saturated brine (30 mL), dried over Na₂SO₄, filtered, and rotary evaporated under reduced pressure to obtain the concentrated crude organic phase. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate 3:1) to give a yellow solid diastereomer 19 (0.67 g, yield 67%, dr = 3:3:1:1).

[0193] R f =0.5 (petroleum ether / ethyl acetate = 3 / 1); 1 H NMR (600MHz, CDCl3) δ9.62–9.46(m,1H),7.25–7.02(m,5H),6.49–6.40(m,1H),6.18–6.07(m,1H),6.04(s, 1H),5.94(ddq,J=16.0,10.5,5.8Hz,2H),5.86–5.81(m,1H),5.73(s,2H),5.32(d,J=17.8Hz,2H),5.27–5. 15(m,4H),4.87–4.67(m,1H),4.65–4.38(m,3H),4.27–4.00(m,6H),3.60(s,3H),3.49(dd,J=11.3,5.0Hz, 2H),3.10–2.94(m,2H),2.90(d,J=16.4Hz,1H),2.67–2.53(m,1H),2.04(s,3H),1.97(s,3H),1.36(s,9H); 13C NMR (151MHz, CDCl3) δ197.92,197.78,167.88,152.12,151.59,148.45,146.96,145.42,137.09,133. 35,133.06,132.43,130.87,128.21,127.18,127.05,126.39,126.29,125.08,125.07,124.26,117.32 ,116.68,116.00,112.33,108.88,103.22,99.79,80.15,76.20,72.86,72.58,71.70,68.59,67.39,5 8.84,55.50,55.24,54.18,53.89,51.18,49.25,46.17,28.68,27.31,27.24,14.72,7.76; HRMS(ESI)C 43 H 49 N2O 10 + [M+H] + Calculated molecular weight: 755.3382; Measured molecular weight: 755.3383; Diasteremeric isomer dr = 3:3:1:1.

[0194] All references to this application are incorporated herein by reference as if each document were individually incorporated herein by reference. Unless they conflict with the purpose and / or technical solution of this application, all cited references are incorporated herein by reference in their entirety and for all purposes. When references are cited in this application, the definitions of relevant technical features, terms, nouns, phrases, etc., are also incorporated herein by reference. Examples and preferred embodiments of the cited technical features may also be incorporated herein by reference, but only to the extent that they enable the implementation of this application. It should be understood that when the cited content conflicts with the description in this application, this application shall prevail or modifications shall be made adaptably to the description in this application.

[0195] The technical features of the above-described embodiments and examples can be combined in any suitable manner. For the sake of brevity, not all possible combinations of the technical features in the above-described embodiments and examples are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0196] The embodiments described above merely illustrate several implementation methods of this application and should not be construed as limiting the scope of the patent application. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of this application, and these all fall within the protection scope of this application. Furthermore, it should be understood that after reading the above teachings, those skilled in the art can make various alterations or modifications to this application, and the equivalent forms obtained also fall within the protection scope of this application. It should also be understood that technical solutions obtained by those skilled in the art based on the technical solutions provided in this application through logical analysis, reasoning, or limited experimentation are all within the protection scope of the appended claims. Therefore, the protection scope of this patent application should be determined by the appended claims, and the specification can be used to interpret the content of the claims.

Claims

1. A method for synthesizing the pentacyclic skeleton of trabectedine, characterized in that, Includes the following steps: Compound I and compound II were subjected to a condensation reaction to obtain compound III; Compound III was deactivated by removing the Boc group in an acidic solution to obtain compound IV; Compound IV was dissolved in a mixed solution of dichloromethane and trifluoroethanol, and then tert-butyldimethylsiloxane, acetic acid, and [other ingredients] were added at -15°C to -5°C. The molecular sieves were mixed and stirred for 3-5 hours to obtain compound V; Compound V was subjected to an amino protection reaction with di-tert-butyl dicarbonate to prepare compound VI; Compound VII was prepared by subjecting compound VI and 3-bromopropene to hydroxyl protection reaction. Compound VII was de-TBS-grouped in a tetrabutylammonium fluoride solution to obtain compound VIII; Compound VIII was subjected to a hydroxyl oxidation reaction to obtain compound IX; Compound IX was subjected to a Wittig addition reaction with (formylmethylene)triphenylphosphine to prepare compound X; Compound X was dissolved in tetrahydrofuran, and then mixed with a solution of bis(trimethylsilylamine)lithium at -80°C to -70°C. The mixture was then stirred at 20°C to 40°C for 10 to 20 hours to obtain compound XI. Compound XI was dissolved in ethylene glycol dimethyl ether, and then (2R,5R)-(+)-2-tert-butyl-3-methyl-5-benzyl-4-imidazolinone, trifluoroacetic acid, cerium ammonium nitrate and water were added at -80℃ to -70℃ and mixed. The mixture was then stirred at 20℃ to 40℃ for 10h to 20h to obtain compound XII.

2. The method for synthesizing the trabectedin pentacyclic skeleton according to claim 1, characterized in that, Compound I and compound II were subjected to a condensation reaction to prepare compound III, which includes: Compound I and Compound II were dissolved in tetrahydrofuran, and N,N-diisopropylethylamine, 1-hydroxybenzotriazole and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added and mixed. The mixture was stirred for 10 h to 20 h to obtain Compound II. Optionally, the molar ratio of compound I to compound II is 1:(1 to 1.5); Optionally, the molar ratio of compound I to N,N-diisopropylethylamine, 1-hydroxybenzotriazole and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride is 1:(2-3):(1-1.3):(1-1.3).

3. The method for synthesizing the trabectedin pentacyclic skeleton according to claim 1 or 2, characterized in that, Compound III was deactivated by removing the Boc group in an acidic solution to obtain compound IV, comprising: A dioxane solution of hydrogen chloride was added to a methanol solution of compound III at -5℃ to 5℃. After the addition was complete, the temperature was raised to 20℃ to 40℃ and stirred for 10h to 20h to obtain compound IV. Optionally, the molar concentration of the dioxane solution of hydrogen chloride is 3M to 5M; Optionally, the molar ratio of compound III to hydrogen chloride is 1:(5-6).

4. The method for synthesizing the trabectedin pentacyclic skeleton according to claim 1, characterized in that, The volume ratio of the dichloromethane to the trifluoroethanol is (6-8):1; and / or, The molar ratio of compound IV to tert-butyldimethylsiloxane acetaldehyde is 1:(1–1.5); and / or, The molar ratio of compound IV to acetic acid is 1:(0.2–0.4); and / or, The above The mass-to-volume ratio of the molecular sieve to the mixed solution of dichloromethane and trifluoroethanol is 5–15 g: 100 mL.

5. The method for synthesizing the trabectedin pentacyclic skeleton according to any one of claims 1, 2, and 4, characterized in that, Compound V and ditert-butyl dicarbonate were subjected to an amino protection reaction to prepare compound VI, comprising: Compound V was dissolved in dichloromethane, and N,N-diisopropylethylamine and ditert-butyl dicarbonate were added and mixed. The mixture was stirred for 10-20 hours to obtain compound VI. Optionally, the molar ratio of compound V to ditert-butyl dicarbonate is 1:(1.5-2); Optionally, the molar ratio of compound V to N,N-diisopropylethylamine is 1:(1 to 1.5).

6. The method for synthesizing the trabectedin pentacyclic skeleton according to any one of claims 1, 2, and 4, characterized in that, Compound VII is prepared by subjecting compound VI and 3-bromopropene to a hydroxyl protection reaction, comprising: Compound VI and cesium carbonate were dissolved in acetonitrile, and then 3-bromopropene was added and mixed. The mixture was stirred at 30°C to 40°C for 10 to 20 hours to obtain compound VII. Optionally, the molar ratio of compound VI to cesium carbonate is 1:(1 to 1.5); Optionally, the molar ratio of compound VI to 3-bromopropene is 1:(1 to 1.5).

7. The method for synthesizing the trabectedin pentacyclic skeleton according to any one of claims 1, 2, and 4, characterized in that, Compound VII was de-TBS-grouped in a tetrabutylammonium fluoride solution to obtain compound VIII, comprising: Add tetrabutylammonium fluoride tetrahydrofuran solution to the tetrahydrofuran solution of compound VII, and stir at 20℃~40℃ for 1h~3h after the addition is complete to obtain compound VIII; Optionally, the molar ratio of compound VII to tetrabutylammonium fluoride is 1:(1.2-1.6); Optionally, the molar concentration of the tetrabutylammonium fluoride tetrahydrofuran solution is 0.5M to 1.5M.

8. The method for synthesizing the trabectedin pentacyclic skeleton according to claims 1, 2 and 4, characterized in that, Compound VIII is subjected to a hydroxyl oxidation reaction to obtain compound IX, comprising: Compound VIII was dissolved in dichloromethane and mixed with iodophenyl diacetic acid and 9-azabicyclo[3.3.1]nonane-N-oxide. The mixture was stirred at 20°C to 40°C for 10 to 20 hours to obtain compound IX. Optionally, the molar ratio of compound VIII, iodophenyl diacetic acid, and 9-azabicyclo[3.3.1]nonane-N-oxide is 1:(1.5-2):(0.1-0.12).

9. The method for synthesizing the trabectedin pentacyclic skeleton according to claim 1, characterized in that, Compound X was prepared by reacting compound IX with (formylmethylene)triphenylphosphine via a Wittig addition reaction, comprising: Compound IX was dissolved in acetonitrile and mixed with (formylmethylene)triphenylphosphine, and then stirred at 30℃~40℃ for 10h~20h to obtain compound X; The molar ratio of compound IX to (formylmethylene)triphenylphosphine is 1:(1 to 1.5).

10. The method for synthesizing the trabectedin pentacyclic skeleton according to any one of claims 1, 2, 4, and 9, wherein the solution of bis(trimethylsilylamino)lithium comprises a tetrahydrofuran solution of bis(trimethylsilylamino)lithium; and / or, The molar concentration of the tetrahydrofuran solution of the bis(trimethylsilylamine) lithium is 0.5 M to 1.5 M; and / or, The molar ratio of compound X to the bis(trimethylsilylamine)lithium is 1:(1.5–2.5); and / or, The molar ratio of compound XI, (2R,5R)-(+)-2-tert-butyl-3-methyl-5-benzyl-4-imidazolinone, trifluoroacetic acid, cerium ammonium nitrate, and water is 1:(0.15-0.25):(0.15-0.25):(1.5-2.5):(1.5-2.5).

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