CN116332932B - Process for the preparation of Ecteinasticidin 743 and several higher intermediates of similar alkaloids - Google Patents

Abstract

The invention provides a new synthetic route of a higher intermediate of an ectonascidin 743 alkaloid and a derivative. Two coupling fragment compounds 2 and 8 are prepared from the same raw material and route, cyclized coupling of the two compounds with high yield is realized, and then several known advanced five-ring intermediates can be obtained through rapid C-ring construction and A-ring modification. By this route, in combination with the literature final transformation step, the total synthesis of ecteinascidin 743 (trabectedin) and Lurbinectedin can be completed with a total of 25 steps starting from commercial L-N-Cbz-tyrosine. The method effectively reduces the production cost of the ecteinascidin 743, and has the advantages of less total reaction number, cheap raw material reagent, mild condition, ideal yield, easy realization of industrialization and the like.

Description

Preparation of several advanced intermediates of ecteinascidin 743 and similar alkaloids Methods

Technical Field

The present invention relates to a method for preparing several advanced intermediates for synthesizing ecteinascidin 743 and similar alkaloids.

Background technique

Ecteinascidin 743 (Et-743) is a marine tetrahydroisoquinoline alkaloid isolated from the sea squirt Ecteinascidia turbinata . It was approved by the European Committee for Medicinal Products for Human Use (CHMP) and the U.S. Food and Drug Administration (FDA) in 2007 and 2015, respectively, as a new drug for the treatment of various advanced soft tissue tumors (drug name: Trabectedin). It is currently used in nearly 80 countries and regions around the world. Studies have shown that in terms of inhibitory activity against a variety of human cancer cells, ecteinascidin 743 is 1-3 orders of magnitude higher than well-known anticancer drugs currently used in clinical practice, such as camptothecin, paclitaxel, doxorubicin, bleomycin, mitomycin C, cisplatin and etoposide, and has a unique multiple mechanism of action. Its analog Lurbinectedin (PM1183) was also approved by the FDA in 2020 for the treatment of metastatic small cell lung cancer. Some simplified analogs of Et-743 that only retain the basic five-ring skeleton (AE ring), such as Phthlascidin 650 (Pt-650) [ Proc. Natl. Acad. Sci. 1999, 96 , 3496] and zalypsis [ Blood , 2009, 113 , 3781; Molecules ., 2014, 19 , 12328], also exhibit nanomolar anticancer activity equivalent to that of Et-743.

Since the content of Et-743 in nature is extremely low, with the highest amount obtained being 0.0001%, it cannot meet the needs of clinical medication and pharmacological research, so it is very important and urgent to develop an effective synthesis method. Since the Corey group reported the first synthesis of Et 743 in 1996 [ J. Am. Chem. Soc. 1996, 118 , 9202], the Fukuyama group [ J. Am. Chem. Soc. 2002, 124 , 6552; J. Am. Chem. Soc. 2013, 135 , 13684], the Zhu group [ J. Am. Chem. Soc. 2006, 128 , 87] and the Ma group [ Angew. Chem., Int. Ed. 2019, 58 , 3972] have also completed the total synthesis of this molecule. In addition, the Danishefsky group [ Angew. Chem. Int. Ed. 2006, 45 , 1754], the Williams group [ J. Org. Chem. 2008, 73 , 9594] and the inventor's group [CN 201610489181.1; J. Org. Chem. 2019, 84 , 13696] also reported the formal total synthesis of Et-743.

However, since most of the existing total synthesis routes are long and costly, the current sources of Et-743 and its analogs mainly rely on the semi-synthetic route developed by the Cuevas group of PharmaMar in 2000. Starting from the alkaloid cyanosafracin B obtained by biological fermentation, Et-743 was obtained with a total yield of 1.0% after 21 steps of reaction [WO0187895; Org Lett. 2000, 2 , 2545]. Later, the Zhang group optimized and improved this semi-synthetic route [ Eur. J. Org. Chem. 2017, 975]. However, the source of the raw material cyanosafracin B in the semi-synthesis is also limited, and it is difficult to separate and purify it. It is still difficult to completely solve the supply problem of Et-743, resulting in a high price that patients cannot afford.

All the current total and semi-synthetic routes of Et-743 are completed by first constructing or modifying the key five-ring intermediate, and then building the sulfur-containing lactone bridge ring and the third tetrahydroisoquinoline unit on it, and all of them can be used for the synthesis of Lurbinectedin. There are currently only two types of five-ring intermediates used to close the sulfur bridge ring, one is the A-type five-ring intermediate containing a tertiary hydroxydienone structure, and the other is the B-type five-ring intermediate containing an o-benzylphenol structure. After the two intermediates are closed with the sulfur-containing lactone bridge ring by known methods, the synthesis of Et-743 is completed by a transformation similar to that of the Corey research group. Therefore, the advantages and disadvantages of these two types of five-ring intermediate synthesis routes fundamentally determine the production costs of anticancer alkaloids such as Et-743, Lurbinectedin, Pt-650 and zalypsis.

In the existing Et-743 total synthesis route, the synthesis of type A or type B pentacyclic intermediates all adopts a convergent strategy, involving the coupling of two or more fragments. However, in most routes, each coupling fragment is prepared using completely different routes and raw materials, resulting in the actual total number of reactions in the route (about 40-60 reactions) being much more than the longest linear step on the surface, which is much higher than the total number of reactions in semi-synthesis, thereby greatly increasing the costs of raw materials, reagents, and manual operations. This is also the reason why Et-743 is now mainly obtained through semi-synthesis. At present, only the two coupling fragments in the total synthesis of the Ma group are prepared through the same route, which effectively reduces the total number of reactions and production costs. At present, only the two coupling fragments in the total synthesis of the Ma group are prepared through the same route, which effectively reduces the total number of reactions and production costs, and has good practical value and potential. The synthetic routes of the Ma group [ Angew. Chem., Int. Ed. 2019, 58 , 3972] and the inventors' group [CN201610489181.1; J. Org. Chem. 2019, 84 , 13696] are based on the cyclocoupling reaction between compound 1 (aldehyde fragment on the left) and compound 2 (amine fragment on the right), so that the A-type pentacyclic intermediate can be constructed efficiently and quickly through the coupling product compound 3. The only drawback is that the yield of this coupling step is not high and is not stable enough and fluctuates greatly (55-70%), which affects the efficiency and industrialization of the entire synthesis. In the earlier synthesis of renieramycin-type tetrahydroisoquinoline alkaloids [ J. Nat. Prod. 2013, 76 , 1789; CN201310266099.5], the inventors used compound 4 as the aldehyde fragment to carry out cyclization coupling with compound 2, with milder conditions and good reproducibility of yield (85-90%).

In summary, although the existing synthetic routes have achieved good results, there are still some shortcomings. For example, some preparation and transformation routes are long and the total number of reactions is large; the yield of some steps is not ideal; some involve some expensive reagents and raw materials; some reaction conditions are demanding and difficult to operate, etc. These will lead to an increase in the cost of synthesis and make it difficult to carry out large-scale preparation. If we can continue to improve some of the shortcomings of the existing total synthesis routes based on the previous research results, and develop more practical, economical and mild routes to synthesize the above two types of advanced pentacyclic intermediates, it may make total synthesis truly an effective industrial production route for Et-743 and Lurbinectedin, reduce its cost and price, and benefit the people to obtain more adequate satisfaction of demand.

Summary of the invention

The purpose of the present invention is to provide a low-cost, easy-to-operate method for preparing several advanced five-ring intermediates. These five-ring intermediates can be conveniently converted into Et-743 and Lurbinectedin and other analogs according to the steps in the literature, so that the synthesis cost and industrialization potential of alkaloids such as Et-743 are significantly improved.

In the first aspect of the present invention, there is provided an Et-743 synthetic intermediate compound selected from the group consisting of:

in,

R is selected from the following groups: TBDPS, TIPS, TBS, TES, TMS;

R' is selected from the following groups: Boc, Alloc, Troc, Cbz.

The second aspect of the present invention provides a method for preparing the known five-ring intermediate compounds A and A' for synthesizing Et-743:

It is characterized by comprising the steps of:

(a) Compound 8 and compound 2 are subjected to a cyclocoupling reaction to obtain compound 9:

Compound 2 was prepared from commercial L- N -Cbz-tyrosine by 7 steps according to known steps [ Tetrahedron: Asymmetry 2010, 21 , 39]. Compound 2 was then converted to compound 8 by 4 steps according to the literature method [ J. Nat. Prod. 2013, 76 , 1789; Tetrahedron Lett. 2021, 86 , 153498].

(b) through the aminomethylation reaction of compound 9, compound 10 is obtained:

(c) Compound 10 is subjected to a primary alcohol oxidation reaction to obtain compound 11, which is then subjected to an intramolecular Strecker reaction under acidic conditions to obtain compound 12:

(d) Compound 13 is obtained by reacting the protected phenolic hydroxyl group of compound 12:

(e) through the deallyl reaction of compound 13, compound 6 is obtained:

(f1) Compound 7 is obtained by phenol oxidation reaction of compound 6:

(g1) Compound A is obtained by photoreaction of compound 7:

(h1) Compound A' is obtained by oxidation reaction of compound A:

In another preferred embodiment, in the step (a), the cyclocoupling reaction is carried out in an inert solvent (preferably CH ₂ Cl ₂ : TFE = 7:1) in the presence of AcOH and 4A MS at 50 ^° C. to react compound 8 with compound 2 to obtain compound 9.

In another preferred embodiment, in the step (b), the aminomethylation reaction is carried out in a MeCN/THF mixed solvent, and compound 9 is reacted in the presence of HCHO, NaBH ₃ CN, and AcOH to obtain compound 10.

In another preferred embodiment, in the step (c), the oxidized primary alcohol and the intramolecular Strecker reaction react under (1) Porikh-Doering oxidation conditions to obtain compound 11, and then compound 11 reacts with TMSCN in (2) TFA/CH ₂ Cl ₂ mixed solvent to obtain compound 12.

In another preferred embodiment, in the step (d), the protection of the phenolic hydroxyl group is carried out in THF, in the presence of NaH, and compound 12 reacts with MOMCl to obtain compound 13.

In another preferred embodiment, in the step (e), the deallyl reaction is carried out in CH ₂ Cl ₂ in the presence of AcOH, and the compound 13 reacts with Pd (PPh ₃ ) ₄ and Bu ₃ SnH to obtain the compound 6.

In another preferred embodiment, in the step (f1), the phenol oxidation reaction is carried out in MeCN, and compound 6 is oxidized with Salcomine reagent/ _O2 to obtain compound 7.

In another preferred embodiment, in the step (g1), the light irradiation reaction is carried out in an inert solvent (preferably THF or CH ₂ Cl ₂ ) under blue light or fluorescent light to react with compound 7 to obtain compound A.

In another preferred embodiment, in the step (h1), the oxidation reaction is carried out in CH ₂ Cl ₂ or THF, using compound A to react with (PhSeO) ₂ O to obtain compound A'.

In another preferred embodiment, the steps (g1) and (h1) can be carried out in THF or CH ₂ Cl ₂ in a one-pot process, where compound 7 is sequentially irradiated with light and oxidized with (PhSeO) ₂ O in one pot to directly obtain compound A'.

The third aspect of the present invention provides a method for preparing five-ring intermediate compounds B and B' for synthesizing Et-743:

Wherein, R is selected from the following groups: TBDPS, TIPS, TBS, TES, TMS.

It is characterized by comprising the steps of:

Starting from compound 8 and compound 2, compound 6 is obtained through the same five steps (a), (b), (c), (d) and (e) as in the preparation method of the second aspect of the present invention:

(f2) Compound 1 is obtained by protecting the primary alcohol silyl group of compound 6:

Wherein, R is selected from the following groups: TBDPS, TIPS, TBS, TES, TMS.

(g2) Compound II is obtained by phenol oxidation reaction of compound I:

Wherein, R is selected from the following groups: TBDPS, TIPS, TBS, TES, TMS.

(h2) Compound B is obtained by photoreaction of compound II:

Wherein, R is selected from the following groups: TBDPS, TIPS, TBS, TES, TMS.

(i2) through the oxidation reaction of compound B, to obtain compound B':

Wherein, R is selected from the following groups: TBDPS, TIPS, TBS, TES, TMS.

In another preferred embodiment, in the step (f2), the primary alcohol protection reaction is carried out in CH ₂ Cl ₂ in the presence of DMAP or imidazole, and compound 6 reacts with RCl or ROTf (R is selected from: TBDPS, TIPS, TBS, TES, TMS) to obtain compound I.

In another preferred embodiment, in the step (g2), the phenol oxidation reaction is carried out in MeCN, using Salcomine reagent/ _O2 to oxidize compound I to obtain compound II.

In another preferred embodiment, in the step (h2), the light irradiation reaction is carried out in an inert solvent (preferably THF or CH ₂ Cl ₂ ), and compound II is irradiated with blue light or fluorescent light to obtain compound B.

In another preferred embodiment, in the step (i2), the oxidation reaction is carried out in CH ₂ Cl ₂ or THF, using compound B to react with (PhSeO) ₂ O to obtain compound B'.

In another preferred embodiment, the steps (h2) and (i2) can be carried out in THF or CH ₂ Cl ₂ in a one-pot process, where compound II is sequentially irradiated with light and oxidized with (PhSeO) ₂ O in one pot to directly obtain compound B'.

The fourth aspect of the present invention provides a method for preparing a five-ring intermediate compound C for synthesizing Et-743:

It is characterized by comprising the steps of:

Starting from compound 8 and compound 2, compound 6 is obtained through the same five steps (a), (b), (c), (d) and (e) as in the preparation method of the second aspect of the present invention:

(f3) Compound III is obtained by esterification reaction of compound 6 and compound VI:

Wherein, R' is selected from the following groups: Boc, Alloc, Troc, Cbz.

(g3) Compound IV is obtained by phenol oxidation reaction of compound III:

Wherein, R' is selected from the following groups: Boc, Alloc, Troc, Cbz.

(h3) Compound V is obtained by photoreaction of compound IV:

Wherein, R' is selected from the following groups: Boc, Alloc, Troc, Cbz.

(i3) Compound C is obtained by oxidation reaction of compound V:

Wherein, R' is selected from the following groups: Boc, Alloc, Troc, Cbz.

In another preferred embodiment, in the step (f3), the esterification reaction is carried out in CH ₂ Cl ₂ in the presence of EDCI, HOBt, DMAP and Et ₃ N, and compound 6 reacts with compound VI to obtain compound III.

In another preferred embodiment, in the step (g3), the phenol oxidation reaction is carried out in MeCN, and compound III is oxidized with Salcomine reagent/ _O2 to obtain compound IV.

In another preferred embodiment, in the step (h3), the photoirradiation reaction is carried out in an inert solvent (preferably THF or CH ₂ Cl ₂ ), and compound IV is irradiated with blue light to obtain compound V.

In another preferred embodiment, in the step (i3), the oxidation reaction is carried out in CH ₂ Cl ₂ or THF, using compound V to react with (PhSeO) ₂ O to obtain compound C.

In another preferred embodiment, the steps (h3) and (i3) can be carried out in THF or CH ₂ Cl ₂ in a one-pot process, where compound IV is sequentially irradiated with light and oxidized with (PhSeO) ₂ O in one pot to directly obtain compound C.

The fifth aspect of the present invention provides a method for preparing five-ring intermediate compound A, compound B and compound V for synthesizing Et-743, characterized in that it comprises the steps of:

In an inert solvent, compound 7, compound II, and compound IV are irradiated with blue light or fluorescent light to obtain corresponding compound A, compound B, and compound V:

in,

R is selected from the following groups: TBDPS, TIPS, TBS, TES, TMS;

R' is selected from the following groups: Boc, Alloc, Troc, Cbz.

In another preferred embodiment, the inert solvent is selected from the group consisting of THF, CH ₂ Cl ₂ , Et ₂ O, MeCN, toluene, t -BuOH, DMF, acetone, or a combination thereof.

In another preferred embodiment, the blue light is light with a wavelength in the range of 400-500nm.

The sixth aspect of the present invention provides a method for preparing compound 9, characterized in that it comprises the steps of:

Compound 8 and compound 2 were subjected to cyclocoupling reaction to obtain compound 9:

In another preferred embodiment, the reaction is carried out in the presence of a catalyst (selected from TFA, BF ₃ ·OEt ₂ , HCOOH, AcOH, PrOH, Yb(OTf) ₃ ) and a molecular sieve, and the catalyst is preferably AcOH.

In another preferred embodiment, the reaction is carried out at 20-80 ^° C.

In another preferred embodiment, the reaction is carried out in a solvent selected from the group consisting of CH ₂ Cl ₂ , toluene, TFE, or a combination thereof; preferably, the reaction is carried out in a mixed solvent of CH ₂ Cl ₂ :TFE = 1-10:1 (preferably 5-9:1) (v:v).

The seventh aspect of the present invention provides a method for preparing compound 12, characterized in that it comprises the steps of:

Compound 11 was obtained by oxidation of the primary alcohol of compound 10, and then compound 12 was obtained by intramolecular Strecker reaction under acidic conditions:

In another preferred embodiment, the oxidation reaction is carried out in a solvent selected from the group consisting of DMSO and a DMSO/CH ₂ Cl ₂ mixed solvent; preferably, the reaction is carried out in a mixed solvent of CH ₂ Cl ₂ :DMSO = 0.5-10:1 (preferably 1:1) (v:v).

In another preferred embodiment, the oxidation reaction is carried out in the presence of SO ₃ ·Py and a base (selected from Et ₃ N and DIPEA).

In another preferred embodiment, the intramolecular Strecker reaction is carried out in a solvent selected from the group consisting of TFA and a CH ₂ Cl ₂ /TFA mixed solvent; preferably, the reaction is carried out in a mixed solvent of CH ₂ Cl ₂ :TFA = 0.5-10:1 (preferably 4:1) (v:v).

In another preferred embodiment, the intramolecular Strecker reaction is carried out in the presence of TMSCN.

The present invention provides a new preparation route for several alpha-pentacyclic advanced intermediates such as compounds A, A', B, B' and C, which is more practical and simple than the previous routes. Such advanced intermediates such as compounds A, A', B, B' and C can be conveniently converted into various ecteinascidin-type alkaloids and analogs including Et-743, Lurbinectedin, Pt-650 and zalypsis according to the steps in the literature. This new route for synthesizing intermediates A, A', B, B' and C via compound 6 is mainly characterized by the following three key reactions: (1) Compound 8 is used to replace compound 1 as the aldehyde fragment to carry out the key Pictet-Spengler cyclocoupling with compound 2 (amine fragment), which solves the shortcomings of low yield and large fluctuation of cyclocoupling in the past; and the two coupling fragments 8 and 2 are prepared by the same route, so that the total number of reactions in the synthesis is reduced, which is the same as the number of the longest linear steps, greatly reducing manpower and financial resources. (2) Through Porikh-Doering oxidation conditions, the oxidation of the primary alcohol in compound 10 was successfully achieved without protecting the free phenolic hydroxyl and amino groups, effectively reducing the operations of functional group protection and deprotection, and the five-ring skeleton can be constructed more quickly, shortening the synthetic route. (3) For the first time, a photocatalytic reaction was achieved on complex five-ring structure substrates such as compounds 7, II and IV, and the five-membered acetal ring was successfully closed. The A ring modification that previously required three steps was completed in one step with good yield and significantly reduced the difficulty of operation, making it suitable for large-scale preparation.

Based on this new route method for preparing pentacyclic intermediate compounds A, A', B, B' and C, the synthesis of ecteinascidin alkaloids has the following advantages:

(1) The present invention uses L-tyrosine as the only starting material and compounds 2 and 8 synthesized via the same route for cyclocoupling, thereby improving the yield and reproducibility of this key coupling reaction and significantly reducing the total number of reactions and the raw materials and reagents involved.

(2) The synthetic route of the method of the present invention is simple. Starting from cheap commercial L- N -Cbz-tyrosine, the five-ring intermediate compound A or A' (both are known intermediates in the synthetic route of Et-743 of Zhang's group) can be obtained through 19 steps of reaction, or the five-ring intermediate compound B or B' (when R = TBDPS, both are known intermediates in the synthetic route of Et-743 of Corey's group) and compound C (when R' = Boc, a known intermediate in the synthetic route of Et-743 of Zhang's group) can be obtained through 20 steps of reaction. According to the literature method, compound A' can be converted into Et-743 in 6 steps, and compound C (R' = Boc) can be converted into Et-743 in 5 steps. This means that the total synthesis of Et-743 can be completed in a total of 25 steps based on the present invention, which is the total synthetic route with the shortest steps and the least number of reactions (close to the total number of reactions of semi-synthesis).

(3) The routes for synthesizing compounds A, A', B, B' and C of the present invention have ideal yields, and the raw materials and reagents used are easy to obtain and have low costs.

(4) The reaction conditions of each step of the present invention for synthesizing compounds A, A', B, B' and C from L- N -Cbz-tyrosine are relatively mild. All reactions are completed within the range of -30 to 60 ^° C, and most reactions are completed at room temperature. There are few reactions that require very strict anhydrous and anaerobic conditions, and the operation is simple and easy to realize industrial production.

Therefore, compared with the existing synthesis of ecteinascidin alkaloids, the method effectively reduces the cost and improves the efficiency, avoids the problem of raw material source limitation in semi-synthesis, and has a good application prospect.

Detailed ways

The present invention is described in more detail with reference to the following examples, but the present invention is not limited to these examples.

1. Synthesis of known intermediates Compound A and Compound A':

12.4 mmol of compound 8 and 15.9 mmol of compound 2 were dissolved in 35 mL of a mixed solvent of CH ₂ Cl ₂ /TFE (v/v, 7:1) at room temperature. 4 Å molecular sieves (5.5 g) and glacial acetic acid (0.35 mL, 6.2 mmol) were added to the reaction solution in sequence. After stirring the reaction at 50 °C for 12 h, solid sodium bicarbonate was added to quench the reaction. The reaction was filtered and the filtrate was concentrated. The crude product was purified by column chromatography to obtain compound 9 with a yield of 90%. IR (neat) υ _{max 3347} , 2978, 2928, 2860, 2358, 1732, 1681, 1651, 1645, 1456, 1415, 1367,1330 , 1307, 1234, 1168, 1138, 1072, 999 _, 925 cm ^-1 ; ¹ H NMR ⁽ 400 MHz, CDCl ₃ ) δ 7.71(s, 1H), 6.63 (s, 0.7H), 6.60 (s, 0.3H), 6.45 (s, 1H), 6.12 (m, 1H), 5.96 5.85 (dd, J = 11.1, 4.1 Hz, 1H), 5.41 (dd, J = 41.1, 17.6 Hz, 2H), 5.25 (t, J = 11.8 Hz, 2H), 5.17 – 5.03 (m, 1H), 4.63 (dd, J = 11.5, 6.0 Hz, 2H), 4.56 –4.43 (m, 1H), 4.37 (dd, J = 12.5, 4.5 Hz, 1H), 4.13 – 3.96 (m, 2H), 3.81 (s,3H), 3.79 (s, 3H), 3.72 (d, J = 9.8 Hz, 1H), 3.54 – 3.46 3H), 1.52 (s, 9H); 13 C NMR (100 MHz, CDCl ³ ) δ 156.7,149.2, 147.5, 147.2, 147.1, 146.2, 144.2, _143.3 , 134.6, 134.3, 134.0, 133.0,132.3, 132.1 , 132.0, 131.5, 131.1, 129.2, 128.1, 127.4, 126.7, 125.7, 125.3,122.2, 121.4, 120.5, 119.8, 118.6, 117.8, 117.1, 116.9, 80.9, 80.1, 74.1,73.6, 71.3, 70.6, 67.8, 60.8, 60.4, 60.2, 57.4, 55.8, 54.3, 53.2, 52.6, 49.1,47.9, 33.0, 28.6, 27.1, 26.6, 25.5, 15.8, 15.8; HRMS (ESI) m/z calcd for C ₃₅ H ₄₉ N ₂ O ₈ [M + H] ⁺ 625.3483, Found 625.3485.

4.5 mmol of compound 9 was dissolved in 23 mL of a mixed solution of CH ₃ CN/THF (v/v, 4:1) at room temperature. After the raw material was dissolved, 3.4 mL of a 37% HCHO aqueous solution was added thereto. After stirring at room temperature for 20 minutes, 11.3 mmol of NaBH ₃ CN was added to the reaction solution. After stirring for another 20 minutes, 11.3 mmol of AcOH was added thereto. After stirring for 1 hour, a saturated NaHCO ₃ solution was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over sodium sulfate, and concentrated. The crude product was purified by column chromatography to obtain compound 10 with a yield of 86%. 3H 2 O 3 ; [α] ²⁵ _D = + 69.2 ( c = 0.5, CHCl ₃ ); IR (neat) υ _max 3256,2928, 1647, 1586, 1457, 1397, 1367, 1320, 1253, 1166, 1139, 1103, 1076, 1002,922, 855, 777, 579 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.00 (s, 1H), 6.62 (s, 1H),6.48 (s, 1H), 6.17 – 6.05 (m, 1H), 5.91 – 5.77 (m, 2H), 5.42 (dd, J = 5.4 – 5.73 (m, 2H), 3.81 (s, 1H) , 3.82 (s, 4H), 3.77 (s, 4H), 3.61 – 3.89 (m, 2H), 3.54 (t, J = 13.6 Hz,1H), 3.53 (t, J = 14.3 Hz, 1H), 3.25 (t, J = 15.8 Hz, 1H), 3.59 (t, J = 16.7 Hz, 1H), 3.30 (t, J = 18.8 Hz, 1H), 3.55 (t, J = 19.9 Hz, 1H), 3.44 (t, J = 11.2 Hz, 1H), 3.80 (t, J = 11.8 Hz, 1H), 3.53 (t, J = 11.9 Hz, 1H), 7.8 (m, 2H), 2.25 (s, 4H), 2.17 (s, 3H), 1.53 (s, 9H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 157.8, 149.4, 147.5,147.1, 145.0, 134.9, 134.3, 131.6, 131.44, 131.37, 130.3, 129.4, 128.7,127.1, 125.3, 120.1, 120.0, 117.1, 116.3, 81.7, 73.7, 73.1, 71.4, 64.2, 62.5,61.0, 60.2, 60.1, 51.2, 45.9, 33.2, 29.8, 28.5, 27.0, 15.9, 15.8; HRMS (ESI) m/z calcd for C ₃₆ H ₅₁ N ₂ O ₈ [M + H] ⁺ 639.3640, found 639.3645.

4.8 mmol of compound 10 was dissolved in 24 mL of a mixed solution of CH ₂ Cl ₂ /DMSO (v/v, 1:1). The mixture was placed in a -15 ^o C cold bath and 11.3 mmol of DIPEA was added dropwise. After the addition was completed, the mixture was stirred for 30 minutes, and then 12.1 mmol of SO ₃ ·Py in CH ₂ Cl ₂ /DMSO solution (v/v, 1:1, 6 mL) was added dropwise, and the mixture was reacted at this temperature for 1.5 h. The reaction was quenched by adding water, the phases were separated, and the organic phases were combined by extraction with CH ₂ Cl ₂ three times, dried over sodium sulfate, and concentrated. The crude product was dissolved in a mixed solution of CH ₂ Cl ₂ /TFA (v/v, 4:1), stirred at room temperature for 2 h, 20 mmol of TMSCN was added, and stirring was continued for 1 h. The reaction was quenched by adding water, and the organic phases were combined by extraction with CH ₂ Cl ₂ three times, dried over sodium sulfate, and concentrated. The crude product was purified by column chromatography to obtain compound 12, and the two-step yield was 92%. ] ²⁰ _D = +18.8 ( c = 1.19, CHCl ₃ ); IR (neat) υ _max 3394, 2929, 2867, 1618, 1584,1488, 1454, 1416, 1353, 1319, 1233, 1190, 1149, 1101, 1074, 997, 966, 926,869, 840,790, 726, 569 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.65 (s, 1H), 6.44 (s,1H), 6.13 (ddd, J = 16.2, 10.9, 5.7 Hz, 1H), 5.88 – 5.77 (m, 1H), 5.72 (s, 1H),5.40 (dd, J = 17.1, 1.5 Hz, 1H), 5.25 (dd, J = 10.4, 1.0 Hz, 1H), 5.16 (dd, J =17.3, 1.6 Hz, 1H), 5.10 (dd, J = 10.4, 1.3 Hz, 1H), 4.59 (dd, J = 12.4, 5.6 Hz,1H), 4.52 (dd, J = 12.4, 5.8 Hz,1H), 4.35 (d, J = 2.4 Hz, 1H), 4.18 (dd, J = 9.2,2.1 Hz, 1H), 4.03 (d, J = 9 Hz, 1H), 3.84 (dd, J = 12.9, 5.3 Hz, 1H), 3.76 (s,3H), 3.76 – 3.73 (m, 3H), 3.42 (dd, J = 8.8, 2.4 Hz, 1H), 3.27 (d, J = 2.3 Hz,1H), 3.24 (d, J = 6.2 Hz, 1H), 2.97 (dd, J = 17.7, 7.9 Hz, 1H), 2.82 (d, J = 2.2Hz, 1H), 2.80 – 2.65 (m, 3H), 2.30 (s, 3H), 2.26 (s, 3H), 2.19 (s, 3H), 2.28 (dd, J = 1.7, 5.3 Hz, 1H), 3 H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 149.54, 148.2, 146.5,142.6, 135.3, 134.4, 132.5, 132.0, 130.8, 128.2, 125.0, 124.8, 120.8, 119.2,117.7, 117.2, 116.4, 73.9, 72.1, 62.5, 60.9, 60.2, 58.0, 57.7, 57.0, 55.8,41.8, 32.2, 25.6, 15.9, 15.8; HRMS (ESI) m/z calcd for C ₃₂ H ₄₀ N ₃ O ₅ [M + H] ⁺ 546.2962, found 546.2965.

3.3 mmol of compound 12 was dissolved in 16 mL of anhydrous tetrahydrofuran, placed in an ice-water bath, 5.0 mmol of NaH was added, and then 6.6 mmol of MOMCl was slowly added dropwise, and the reaction bottle was moved to room temperature for 2 h. Ethyl acetate and saturated NH ₄ Cl solution were added to quench the reaction, and the liquids were separated. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 13 with a yield of 93%. 3 Hz, 1H), _6.82 (ddt, J = 16.1, 10.5, ^{5.7 Hz} , _1H ) , 5.98 ₍ ddt, J = 17.2, 10.7, 5.8 Hz, 1H), 3.2 (s, 1H), 3.5 (ddt, J = 18.4, 10.9, 5.7 Hz , 1H), 3.4 (ddt, J = 19.8, 10.6, 5.9 Hz, 1H), 3.5 (ddt, J = 18.4, 10.7, 5.8 Hz, 1H), 3.6 (ddt, J = 19.8 _, 10.9, 5.7 ^Hz , ^1H ), 3.8 (ddt, J = 18.4, 10.6, 5.7 Hz, 1H), 3.9 (ddt, J = 18.4, 10.7, 5.8 Hz, 1H), 3.6 (ddt, J = 18.4, 10.9, 5.7 Hz, 1H), 3.6 (ddt, J = 18.4, 10.6, 5.7 Hz, 1H), 5.5 Hz, 1H), 5.44 – 5.36 (m, 1H), 5.25 (dd, J = 10.4, 1.5 Hz, 1H), 5.20 –5.06 (m, 4H), 4.63 – 4.56 (m, 1H), 4.55 – 4.48 (m, 1H), 4.35 (d, J = 2.4 Hz,1H), 4.17 (dd, J = 11.5, 2.1 Hz, 2H), 3.84 (ddt, J = 12.9, 5.3, 1.4 Hz, 1H), 3.79 – 3.76 (m, 1H), 3.75 (s, 3H), 3.72 (s, 3H), 3.58 (d, J = 7.7 Hz, 3H), 3.41 (dd, J = 8.8, 2.5 Hz, 1H), 3.30 – 3.22 (m, 2H), 2.99 (dd, J = 17.7, 7.9 Hz, 1H), 2.82– 2.68 (m, 3H), 2.32 (s, 3H), 2.22 (s, 3H), 2.20 (s, 3H), 2.05 (dd, J = 14.8,12.1 Hz, 1H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 149.6, 148.5, 148.2, 148.1, 135.3,134.3, 132.4, 131.4, 132.9 HRMS (ESI) m/z calcd for C ₃₄ H ₄₄ N ₃ O ₆ [M + H] ⁺ 590.3225, found 590.3226.

Under argon protection, 1.7 mmol of compound 13 was dissolved in 17 mL of anhydrous dichloromethane, and 0.32 mmol Pd(PPh ₃ ) ₄ , 27.2 mmol AcOH and 13.6 mmol Bu ₃ SnH were added to the reaction solution in sequence at room temperature. After reacting at room temperature for 1 h, a saturated NaHCO ₃ solution was added to quench the reaction. The liquid was separated, and the aqueous phase was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 6 with a yield of 91%. 968, 929 cm -1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ _6.71 (s, 1H), 6.48 ₍ s , 1H), 5.98 (s, 1H), 5.15 (d, J = 5.9 ^Hz , 1H), 5.10 (d, J = 5.9 Hz, 1H), 4.23 (d, J = 4.7 Hz, 1H), ^4.77 ( d, J = 4.1 Hz, 1H), 4.10 (d, _J = 4.9 Hz, 1H), 4.81 (d, J = 4.8 Hz, 1H), 4.65 (d, J = 4.9 Hz, 1H), 4.44 (d, J = 4.8 Hz, 1H), 4.23 (d, J = 4.7 Hz, 1H), 4.83 (d, J = 4.8 = 2.2 Hz, 1H), 4.10 (t, J = 3.4 Hz, 1H), 4.07 (d, J = 2.4 Hz,1H), 3.72 (s, 3H), 3.71 (s, 3H), 3.65 – 3.60 (m, 1H), 3.59 (s, 3H), 3.47 –3.33 (m, 3H), 3.11 (dd, J = 18.4, 8.0 Hz, 1H), 2.78 (dd, J = 15.5, 2.5 Hz, 1H),2.53 (d, J = 18.0 Hz, 1H), 2.37 (s, 3H), 2.26 (s, 3H), 2.24 (s, 3H), 2.19 (s, 3H), 2.23 (s, 3H), 2.19 (dd, J = 18.4, 8.0 Hz, 1H 3H), 1.86 (dd, J = 9.6, 2.7 Hz, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ148.7, 148.6, 145.0, 143.7, 131.8, 131.2, 129.8, 128.9, 125.2, 124.0, 121.1,118.4, 118.1, 99.4,64.2, 60.8, 60.5, 60.1, 58.3, 57.9, 57.1, 56.9, 55.6,41.7, 31.9, 25.9, 15.8, 15.7; HRMS (ESI) m/z calcd for C ₂₈ H ₃₆ N ₃ O ₆ [M + H] ⁺ 510.2599, found 510.2600.

0.38 mmol of compound 6 was dissolved in 3.8 mL of anhydrous acetonitrile at room temperature, and 0.13 mmol of salcomine was added to the reaction solution. The reaction solution was stirred at room temperature for 3 h under an oxygen atmosphere, filtered and concentrated. The crude product was purified by column chromatography to obtain compound 7 with a yield of 72%. 3H), ^4.26 (d, J =2.0 Hz, 1H), 4.03 ₍ d, J = 2.4 Hz, _1H ) , _3.94 (s, 3H), 3.82 ( ^s , 7H), 3.18 (s, 1H), 3.57 ( s, 2H), 3.54 (s, 1H), 3.55 (s, 3H), 3.54 (s, 1H), 3.53 (s, 2H), 3.62 (s, 7H) , 3.43 (s, 1H), ^3.57 (s, 3H ₎ , 3.61 (s, 1H), 3.10 (s, 2H), 3.53 (s, 7H), 3.61 (s, 1H), 3.90 (s, 3H), 3.83 (s, 7H), 3 . 3H), 3.69 (s,3H), 3.64 (d, J = 3.4 Hz, 1H), 3.56 (s, 3H), 3.46 – 3.35 (m, 2H), 3.24 (dt, J =11.3, 2.9 Hz ,1H), 3.15 – 3.02 (m, 2H), 2.45 (d, J = 18.1 Hz, 1H), 2.35 (s,3H), 2.18 (s, 3H), 1.91 (s, 3H), 1.63 – 1.53 (m, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 186.0, 181.4, 155.5, 148.8, 148.8, HRMS (ESI) m/z calcd for C ₂₈ H ₃₄ N ₃ O ₇ [M + H] ⁺ 524.2379, found 524.2379.

Under argon protection, 0.11 mmol of compound 7 was dissolved in 2 mL of anhydrous tetrahydrofuran, and the reaction solution was irradiated under blue light for 30 min at room temperature to obtain compound A. The blue light was turned off, and 0.11 mmol (PhSeO) ₂ O was added to the reaction solution containing compound A at -10 ^o C. After reacting at -10 ^o C for 20 min, saturated NaHCO ₃ solution and dichloromethane were added. The liquids were separated, and the aqueous phase was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to obtain compound A' with a yield of 53%. Less polar isomer: [ α ] ²⁰ _D = + 81.7 ( c = 0.14, CHCl ₃ ); IR (neat) υ _max 3349, 2926, 2853, 2361, 1635, 1484, 1446, 1417, 1378, 1344, 1233, 1143,1087, 1048, 997, 926, 892, 812 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.72 (s, 1H),5.87 (d, J = 6.6 Hz, 2H), 5.12 (s, 2H), 4.12 (d, J = 4.6 Hz, 2H), 3.93 3.88 (t, J = 3.2 Hz, 1H), 3.80 (dd, J = 11.7, 3.8 Hz, 1H), 3.65 – 3.59 (m, 1H),3.51 (s, 3H), 3.39 – 3.32 (m, 2H), 3.04 (dd, J = 17.9, 7.8 Hz, 1H), 2.62 (d, J =17.9 Hz, 1H), 2.32 (s, 3H), 2.24 (s, 3H), 2.20 (dd, J = 10.1, 5.3 Hz, 1H), 1.99(dd, J = 15.4, 8.2 Hz, 1H), 1.80 (s, 3H); ¹³ C 34.8, 29.9, 25.8,15.9, 7.4; HRMS (ESI) m/z calcd for C 28 H 33 N 3 O 8 [M + H] ₊ 530.2340, found 34.7; NMR (100 MHz, CDCl ₃ ) δ 198.9, 159.1,149.0, 148.6, 140.5, 131.6, 130.4, 125.6, 123.0, 117.1, 111.3, 104.5, 101.8,99.6, 70.5, 61.7, 60.7, _58.5 , _{58.1 ,} 57.9, 57.4, 55.4 ^, 41.8 540.2343. Large polar isomer: [ α ] ²⁰ _D = +189.3 ( c =0.14, CHCl ₃ ). IR(neat) υ _max 3425, 2954, 2924,2853, 2360, 1635, 1484, 1450, 1417, 1378, 1344, 1234, 1143, 1086, 1048, 997,927, 892, 812, 771 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.65 (s, 1H), 5.87 (d, J = 6.6Hz, 1H), 5.77 (s, 1H), 5.03 (q, J = 6.0 Hz, 2H), 4.24 (d, J = 2.7 Hz, 1H), 4.10 (d, J = 12.0 Hz, 2H), 4.00 (d, J = 12.9 Hz, 1H), 3.79 (dt, J = 12.0, 2.7 Hz, 1H),3.63 (s, 3H), 3.51 (s, 3H), 3.40 (d, J = 8.2 Hz, 1H), 3.36 – 3.32 (m, 1H), 3.17 (d, J = 6.2 Hz, 1H), 3.01 (dd, J = 17.9, 8.3 Hz, 1H), 2.85 (s, 1H), 2.54 (d, J = 17.9 Hz, 8.4 Hz, 1H), 3H), 2.24 (s, 3H), 2.20 (s, 3H), 2.12 (dd, J = 13.8, 2.9 Hz, 1H), 1.80(s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 200.7, 160.0, 157.2, 148.9, 148.3, 137.8,130.9, 130.3, 125.3, 124.3, 116.8, 113.8, 105.2, 100.9, 99.3, 72.4, 60.0,58.4, 57.9, 57.4, 56.8, 56.7, 56.2, 55.3, 41.6, 41.5, 29.9, 25.6, 16.1, 7.3. HRMS (ESI) m/z calcd for C ₂₈ H ₃₃ N ₃ O ₈ [M + H] ⁺ 540.2340, found 540.2345.

0.49 mmol of compound 6 was dissolved in 4.5 mL of anhydrous dichloromethane, and 4.9 mmol of DMAP and 4.5 mmol of TBDPSCl were added to the solution at room temperature and stirred overnight. Water was added to quench the reaction, and the liquids were separated. The aqueous phase was extracted three times with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to obtain compound I-1 with a yield of 94%. ] ²⁰ _D = +81.7 ( c = 1.17, CHCl ₃ ); IR (neat) υ _max 3393, 2930, 2856, 1671,1588, 1460, 1426, 1392, 1339, 1318, 1235, 1155, 1108, 1071, 1047, 1002, 969,930, 907, 825, 774, 739, 705, 613, 504 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 –7.59 (m, 2H), 7.51 – 7.47 (m, 2H), 7.43 – 7.33 7.29 (t, J = 7.3 Hz,2H), 6.65 (s, 1H), 6.46 (s, 1H), 5.82 (s, 1H), 5.17 (d, J = 5.9 Hz, 1H), 5.10(d, J = 5.9 Hz, 1H), 4.39 (d, J = 2.4 Hz, 1H), 4.23 (dd, J = 7.1, 2.8 Hz, 1H), 4.19(d, J = 2.3 Hz, 1H), 3.75 (s, 3H), 3.70 (s, 3H), 3.67 – 3.62 (m, 1H), 3.60 (s,3H), 3.34 – 3.26 (m, 3H), 3H), 2.96 (dd, J = 17.7, 8.0 Hz, 1H), 2.78 (dd, J = 15.1,2.0 Hz, 1H), 2.70 (d, J = 17.7 Hz, 1H), 2.31 (s, 3H), 2.26 (s, 3H), 2.20 (s,3H), 2.10 (dt, J = 19.5, 8.6 Hz, 1H),1.70 (s, 1H). 0.96 (d, J = 6.1 Hz, 9H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 148.6, 148.2, 145.4, 143.7, 135.8, 135.6, 133.5, HRMS (ESI) m/z calcd for C 4 4 H 54 N 3 O 6 Si[M + H] + 740.3776, found 37.84, 26.23, 19.1; m/z calcd for C 4 4 H 54 N 3 O 6 Si[M + H] + 740.3776, found 37.84, 26.23, 19.1; m/z calcd for C 4 4 H 54 N 3 O 6 Si[M + H] + 740.3776, found 37.84, 26.23, 19.1; m/z calcd for C _{4 4} H ₅₄ N ₃ O ₆ Si[M + H] ⁺ 740.3776, found 740.3778.

0.60 mmol of compound I-1 was dissolved in 6.0 mL of anhydrous acetonitrile at room temperature, 0.20 mmol of salcomine was added to the reaction solution, and the reaction solution was stirred at room temperature for 2 h under an oxygen atmosphere, filtered and concentrated. The crude product was purified by column chromatography to obtain compound II-1 with a yield of 87%. ] ²⁰ _D = -11.7 ( c = 1.7, CHCl ₃ ); IR (neat) υ _max 2926, 2855,1737, 1655, 1620, 1462, 1428, 1374, 1337, 1318, 1236, 1157, 1111, 1040, 1000,968, 930, 882, 842, 806, 772, 743, 614, 504 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.54 (dd, J = 7.8, 1.5 Hz, 2H), 7.44 – 7.36 (m, 6H), 7.29 3H), 3.71 (d, J = 1.7 Hz, 1H), 3.59 (s, 3H), 3.54 (d, J = 7.5 Hz, 2H), 3.25 (d, J = 1.6 Hz, 1H), 3.35 (s, 3H), 3.14 (d, J = 7.5 Hz, 2H), 3.24 (d, J = 2.7 Hz, 2H), 3.55 (s, 3H), 3.24 (d, J = 1.6 Hz, 1H), 3.34 (d, J = 8.6 Hz, 1H), 3.19 (m, 2H), 3.23 (dd, J = 17.8, 7.2 Hz, 1H), 3.28 (d, J = 1.8 Hz, 1H), ⁸ , 135.4, 133.0, 132.5, 130.8, 130.3,129.9, 129.8 , 128.2 _, 127.8, 127.8, 125.3, 123.7, 118.1, 99.3, 66.5, 137.4, 136.3, 137.5, 136.4, 136.5, 137.6, 136.7, 136.8, 136.9, 136.8, 136.4, 136.5, 136.8, 136.4, 136.5 HRMS (ESI) m/z calcd for C ₄₄ H ₅₂ N ₃ O ₇ Si [M + H] ⁺ 762.3569, found 762.3565.

Under argon protection, 0.50 mmol of compound II-1 was dissolved in 5.0 mL of tetrahydrofuran. The reaction solution was irradiated under blue light for 2 h at room temperature and concentrated. The crude product was purified by column chromatography to obtain compound B-1 with a yield of 88%. ] ²⁰ _D = +10.1 ( c = 0.77, CHCl ₃ ) ; IR (neat) υ _max 3400, 2928, 2855, 1459, 1432, 1156, 1106,1061, 1046, 1023, 967, 926 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.58 (dd, J = 7.9, 1.3 Hz, 2H), 7.45 – 7.39 (m, 3H), 7.39 – 7.31 (m, 3H), 7.29 (d, J = 7.5 Hz, 2H),6.68 (s, 1H), 5.73 (d, J = 1.4 Hz, 1H), 3.71 (s, 3H) , 3.69 (dd, J = 10.0,2.4 Hz, 1H), 3.27 (m, 3H), 3.12 (dd, J = 14.9 , 2.4 Hz, 1H) , 3.03 (d, J = 17.8, 8.2 Hz, 1H), 3.54 (d, J = 2.6 Hz, 1H), 3.23 (d, J = 2.7 Hz, 1H), 3.12 (d, J = 2.6 Hz, 1H), 3.08 (d, J = 1.7, 8.2 Hz, 1H), 3.50 (d, J = 2.6 Hz, 1H), 3.51 (d, J = 2.6 Hz, 1H), 7.8 (d, J = 17.8 Hz, 1H), 2.26 (s, 3H), 2.09 (s, 3H), 1.91 (dd, J = 14.7, 11.7 Hz, 1H), 0.91 (s, 9H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 149.1, 147.6, 145.5, 144.4, 136.5, 135.8, 135.5, 133.4, 132.8, 131.1, 130.7,129.7, 129.6, 127.7, 127.6, 125.2, 123.4, 118.7, HRMS (ESI) m /z calcd for C ₄ 4 H _{5 2} N ₃ O ₇ Si [M + H] ⁺ 762.3569, found 762.3570.

0.49 mmol of compound B-1 was dissolved in 5 mL of dichloromethane. 0.49 mmol of (PhSeO) ₂ O was added to the reaction solution at -10 ^° C. After reacting at -10 ^° C for 20 min, saturated NaHCO ₃ solution and dichloromethane were added. The liquid was separated, and the aqueous phase was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to obtain compound B'-1 with a yield of 86%. [ α ] ²⁰ _D = + 130.1 ( c = 0.15, CHCl ₃ ); IR(neat) 3500, 2929,1634, 1428, 1377, 1346, 1330, 1232, 1145, 112, 1065, 1054, 1034, 1014, 998,925, 823 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.66 (m, 4H), 7.43 – 7.31 (m, 6H),6.54 (s, 1H), 5.27 (s, 1H), 5.23 (s, 1H), 5.00 (q, J = 6.1 Hz, 2H), 3H), 3.77 (s, 3H), 3.51 (d, J = 7.9 Hz, 1H), 3.57 (d, J = 11.7 Hz, 1H), 3.25 (d, J = 3.0 Hz, 1H), 3.45 (d, J = 2.9 Hz, 1H), 4.35 (dd, J = 11.9, 2.6 Hz, 1H), 4.05 – 3.97 (m, 2H), 3.88 (dd, J = 5.9, 2.5 Hz, 1H), 3.79 (m, 1H), 3.62 (s, 3H), 3.54 (s, 3H), 3.30 (d, J = 7.9 Hz, 1H), 2.90 (dd, J = 17.8, 8.2 Hz, 2H), 2.40 (d, J = 17.7 Hz, 1H), 2.22 (s,3H), 2.18 (s, 3H), 9H ); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 201.1, 160.4, 148.7, 148.1,137.9, 135.7, 133.6, 132.9, 130.6, 130.4, 129.9, 129.8, 127.8, 127.8, 125.2,124.5, 117.4, 113.6, 104.4, 100.4, 99.3, 73.0, 64.5, 59.9, 59.1, 58.8, 57.9,56.9, 56.7, 55.4, 42.7, 41.4, 36.6, 27.0, 25.8, 19.5, 15.9, 7.2. HRMS(ESI-TOF) m/z calcd for C ₄₄ H ₅₂ N ₃ O ₈ Si [M + H] ⁺ 778.3518, found 778.3516.

0.46 mmol of compound 6 was dissolved in 5 mL of anhydrous dichloromethane under an ice-water bath, and 0.56 mmol of compound VI-1, 0.90 mmol EDCI, 0.90 mmol HOBT, 0.90 mmol triethylamine, and 0.05 mmol DMAP were added to the reaction solution in sequence, and the mixture was reacted at room temperature for 1.5 h. Water was added to quench the reaction, and the liquid was separated. The aqueous phase was extracted three times with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to obtain compound III-1 with a yield of 90%. IR (neat) _{υ max} 3428, 2926, 2854, 1714, 1587, 1501, 1458, 1374,1315 , 1264, 1160, 1050, 929, 855, 740 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.74 (d, J =7.5 Hz, 2H), 7.62 (m, 2H), 7.39 (t, J = 7.5 Hz, 2H), 7.33 – 7.28 (m, 2H), 6.61 ₍ s, ^1H ), 6.42 (s, 1H), 5.90 5.9 (d, J = 13.5 Hz, 1H), 4.27 ( t , J =5.0 Hz, 1H), 4.15 (d, J = 2.3 Hz, 1H) , 4.09 (d, J = 2.4 Hz, 1H) , 4.03 – 3.89 (m,3H), 3.74 (s, 3H), 3.69 (s, 3H), 3.57 (d, J = 1.8 Hz, 3H), 3.32 – 3.23 (m, 2H),3.04 – 3.13 ( m, 3H), 9H), 2.91 (m, 3H), 2.79 (td, J = 15.2, 3.4 Hz, 2H), 2.57 – 2.47 (m, 2H), 2.29(s, 3H), 2.19 (s, 3H), 2.15 (s, 3H), 2.03 (m, 1H), 1.45 (s, 9H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 171.0, 155.3, 148.6, 148.3, 145.9, 145.3, 143.7, 141.1, 132.4,130.8, 129.4, 127.7, 127.2, 127.1, 125.2, 9 S [M + H] + 891.594, found 891.594. 3.3.2. 3.4.3. 3.2.3. _3.2.4 . 3.2.3 . _3.4.3 . _3.6.5 . 3.0.3. 3.3.4. _3.8.5 . 3.1.3. 3.2.3. 3.4.3. 3.8.5 ^. 3.0.3.

0.36 mmol of compound III-1 was dissolved in 5 mL of anhydrous acetonitrile at room temperature, 0.18 mmol of Salcomine was added to the reaction solution, and the reaction solution was stirred at room temperature for 1.5 h under an oxygen atmosphere, filtered and concentrated. The crude product was purified by column chromatography to obtain compound IV-1 with a yield of 92%. IR (neat) _{υ max} 3425,2928, 2854, 1718, 1653, 1490, 1450, 1371 , 1338, 1237, 1160, 1048, 1001, 967,923, 742 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.73 (d, _J = 7.5 Hz, ^2H ) , 7.61 (t, J = 7.4 Hz, 2H), 7.38 (t, J = 7.4 Hz, 2H), 7.30 (m, , 2H), 6.58 (s, 1H), 5.12 9 ( m , 2H), 4.96 (d, J = 8.1 Hz, 1H), 4.51 (dd, J = 11.5, 2.8 Hz, 1H), 4.20 (d, J =1.8 Hz, 1H), 4.10 (d, J = 2.4 Hz, 1H), 4.07 (dd, J = 11.6, 3.1 Hz, 1H), 4.02 –3.95 (m, 3H), 3.94 (s, 3H), 3.76 (s, 3H), 3.54 (s, 3H), 3.33 (d, J = 8.2 Hz,1H), 3.09 (m, 2H), 3.03 – 2.88 (m, 3H ), 2.8 9H); 13 C NMR (100 MHz, CDCl ₃ ) δ ^185.7 , 181.3, 170.6,155.7, 154.9, 148.9, 148.4, 145.9, 143.0, 141.1 , 141.0, 134.9, 131.2, 130.5,128.7, 127.7, 34.8, 29.8, 28.35, 25.0, 24.8, 15.9, 8.8; HRMS (ESI) m/z calcd for C ₅₀ H ₅₇ N ₄ O ₁₀ S [M + H] ⁺ 905.3790, found 905.3795.

Under argon protection, 0.17 mmol of compound IV-1 was dissolved in 3.4 mL of anhydrous tetrahydrofuran, and the reaction was carried out under blue light at room temperature for 20 min to obtain a reaction solution containing the intermediate product V-1. After turning off the blue light, the temperature was lowered to -10 ^o C, and 0.17 mmol (PhSeO) ₂ O was added to the reaction solution, and the reaction was carried out at -10 ^o C for 10 min. The reaction was quenched by adding a saturated NaHCO ₃ solution, the liquids were separated, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated, and the crude product was purified by column chromatography to obtain C-1 (a mixture of two isomers) with a yield of 81%.

Less polar isomer: [α] ²⁵ _D = +60.0 ( c = 0.2, CHCl ₃ ); IR (neat) υ _max 3420, 2926,2854,2357, 2328, 1744, 1714, 1645, 1573, 1556, 1506, 1482, 1338, 1232, 1159,1085, 1049, 997, 925, 893, 744 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.74 (d, J = 7.5 Hz,2H), 7.63 (t, J = 6.9 Hz, 2H), 7.38 (t, J = 7.4 Hz, 7.29 (t, J = 7.3 Hz, 2H),6.63 (s, 1H), 5.73 (s, 1H), 5.70 (s, 1H), 5.31 (d, J = 7.2 Hz, 1H), 5.12 – 5.06 (m, 2H), 4.46 (d, J = 6.4 Hz, 1H), 4.23 (m, 1H), 4.15 – 4.09 (m, 1H), 4.09 –3.98 (m, 3H), 3.94 (t, J = 5.9 Hz, 1H), 3.86 (d, J = 2.4 Hz, 1H), 3.84 (s, 2H),3.51 – 3.48 (m, 3H), 3.26 (d, 3H ), 2.97 (dd, J =17.3, 7.1 Hz, 2H), 2.46 (d, J = 18.1 Hz, 1H), 2.41 – 2.33 (m, 2H), 2.29 – 2.25 (m, 3H), 2.24 – 2.17 (m, 3H), 1.87 – 1.80 (m, 2H), 1.77 ( s , 2H), 1.43 (d, J = 5.1 Hz, 9H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 198.6,170.7, 158.2, 155.1, 148.7, 148.6, 145.7,145.6, 142.3, 141.1, 131.3, 129.8,127.7, 127.1, 125.2, 124.9, 122.7, 120.0, 117.3, 108.3, 104.6, 101.6, 99.3,80.4, 70.7, 66.7, 60.9, 60.3, 57.7, 56.9, 56.4, 55.7, 55.3, 53.7, 46.9, 41.5,37.2, 36.9, 35.5, 28.4, 28.2, 25.7, 15.8, 7.5; HRMS (ESI) m/z calcd for C ₅₀ H ₅₇ N ₄ O ₁₁ S [M + H] ⁺ 921.3739, found 921.3780.

More polar isomer: [α] ²⁵ _D = +87.6 (c = 0.5, CHCl ₃ ); IR (neat) υ _max 3417, 3062,2926, 2854, 1747, 1714, 1699, 1651, 1633, 1504, 1494, 1487, 1415, 1344, 1232,1211, 1159, 1085, 1051, 1018, 999, 925, 767, 744 cm ^-1 ; ¹ H NMR (400 MHz, CDCl ₃ )δ 7.74 (d, J = 7.5 Hz, 2H), 7.72 – 7.60 (m, 2H), 7.42 – 7.36 (m, 2H), 7.36 –7.28 (m, 2H), 6.62 – 6.51 (m, 1H), 5.73 (s, 1H), 5.64 (s, 1H), 5.33 (d, J = 8.1 Hz, 1H), 5.01 (q, J = 6.0 Hz,2H), 4.68 (d, J = 12.0 Hz, 1H), 4.52 (d, J = 6.7 Hz,1H), 4.42 – 4.33 (m, 1H), 4.11 (t, J = 6.3 Hz, 1H), 4.06 (dd, J = 11.9, 3.3 Hz,1H), 3.98 (dd, J = 10.2, 2.4 Hz, 1H), 3.92 – 3.87 (m, 1H), 3.73 (dt, J = 15.3,4.4 Hz, 1H), 3.67 – 3.58 (m, 3H), 3.56 (s, 3H), 3.28 (d, J = 7.6 Hz, 1H), 3.20 – 3.11 (m, 2H), 3.00 – 2.80 (m, 4H), 2.38 (d, J = 18.0 Hz, 1H), 2.29 – 2.22 (m,1H), 2.21 (s, 3H), 2.17 (s, 3H), 2.08 (dd, J = 13.9, 2.4 Hz, 1H), 1.78 (s, 3H),1.44 3 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 200.4, 170.9, 160.2, 155.3, 148.7,148.1, 145.6, 141.0, 138.5, 130.7, 130.1, 127.7, 127.1, 125.0, 124.9, 124.8,124.0, 119.9, 116.9, 111.6, 104.8, 101.0, 99.2, 80.3, 72.4, 59.8, 58.2, 57.7,56.6, 56.5, 56.0, 55.1, 53.6, HRMS (ESI) m/z calcd for C ₅₀ H ₅₇ N ₄ O ₁₁ S [M + H] ⁺ 921.3739, found 921.3738.

The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims (3)

1. A method for preparing pentacyclic intermediate compounds A and A' for synthesizing Et-743: It is characterized by comprising the steps of: (a) Compound 8 is subjected to a cyclocoupling reaction with compound 2 to obtain compound 9, wherein the reaction is carried out in the presence of a catalyst AcOH and a molecular sieve, the reaction is carried out at 20-80° C., and the reaction is carried out in a mixed solvent of CH ₂ Cl ₂ :TFE=1-10:1 in v:v: (b) through the aminomethylation reaction of compound 9, compound 10 is obtained: (c) Compound 11 is obtained by oxidation of the primary alcohol of compound 10, and compound 12 is obtained by intramolecular Strecker reaction, wherein the oxidation reaction is carried out in a mixed solvent of CH ₂ Cl ₂ :DMSO=0.5-10:1, the oxidation reaction is carried out in the presence of SO ₃ ·Py and a base, the base is selected from Et ₃ N and DIPEA, the intramolecular Strecker reaction is carried out in a mixed solvent of CH ₂ Cl ₂ :TFA=0.5-10:1, and the intramolecular Strecker reaction is carried out in the presence of TMSCN: (d) Compound 13 is obtained by reacting the protected phenolic hydroxyl group of compound 12: (e) through the deallyl reaction of compound 13, compound 6 is obtained: (f1) Compound 7 is obtained by phenol oxidation reaction of compound 6: (g1) Compound A is obtained by photoreaction of compound 7, wherein the photoreaction is carried out in an inert solvent under irradiation with blue light, and the inert solvent is THF: (h1) Obtaining compound A' by oxidation reaction of compound A: 2. A method for preparing five-ring intermediate compounds B and B' for synthesizing Et-743: Wherein, R is selected from the following groups: TBDPS, TIPS, TBS, TES, TMS; It is characterized by comprising the steps of: Starting from compound 8 and compound 2, compound 6 is obtained through the same five-step reaction as (a), (b), (c), (d) and (e) in claim 1: (f2) Compound 1 is obtained by protecting the primary alcohol silyl group of compound 6: Wherein, R is selected from the following groups: TBDPS, TIPS, TBS, TES, TMS; (g2) Compound II is obtained by phenol oxidation reaction of compound I: Wherein, R is selected from the following groups: TBDPS, TIPS, TBS, TES; (h2) Compound B is obtained by photoreaction of Compound II, wherein the photoreaction is carried out in an inert solvent under irradiation with blue light, and the inert solvent is THF: Wherein, R is selected from the following groups: TBDPS, TIPS, TBS, TES, TMS; (i2) through the oxidation reaction of compound B, to obtain compound B': Wherein, R is selected from the following groups: TBDPS, TIPS, TBS, TES, TMS. 3. A method for preparing a five-ring intermediate compound C for synthesizing Et-743: Wherein, R' is selected from the following groups: Boc, Alloc, Troc, Cbz; It is characterized by comprising the steps of: Starting from compound 8 and compound 2, compound 6 is obtained through the same five steps (a), (b), (c), (d) and (e) as in claim 1: (f3) Compound III is obtained by esterification reaction of compound 6 and compound VI: Wherein, R' is selected from the following groups: Boc, Alloc, Troc, Cbz; (g3) Compound IV is obtained by phenol oxidation reaction of compound III: Wherein, R' is selected from the following groups: Boc, Alloc, Troc, Cbz; (h3) Compound V is obtained by photoreaction of compound IV, wherein the photoreaction is carried out in an inert solvent under irradiation with blue light, and the inert solvent is THF: Wherein, R' is selected from the following groups: Boc, Alloc, Troc, Cbz; (i3) Compound C is obtained by oxidation reaction of compound V: Wherein, R' is selected from the following groups: Boc, Alloc, Troc, Cbz; (j3) Optionally, in the steps (h3) and (i3), the illumination reaction and the oxidation reaction are combined into a one-pot operation, and compound IV is sequentially irradiated with blue light and oxidized with (PhSeO) ₂ O to directly obtain compound C in one pot.