Method for preparing (S)-camptothecin chiral compound under catalysis of bifunctional spiro catalyst

Abstract

The invention relates to the technical field of catalyst synthesis, in particular to a method for preparing an (S)-camptothecin chiral compound through catalysis of a bifunctional spiro catalyst, and according to the method, a sulfamide bifunctional catalyst is utilized to introduce a chiral center in the early stage of a chiral synthesis route to complete asymmetric synthesis of camptothecin. Compared with other existing chiral synthesis routes, the method is greatly improved, the reaction efficiency is remarkably improved, and the method is simple in process, low in cost and wide in application prospect.

Description

Technical Field

[0001] This invention relates to the field of catalyst synthesis technology, and specifically to a method for preparing (S)-camptothecin chiral compounds by catalysis using a bifunctional spirocyclic catalyst. Background Technology

[0002] Camptothecin (CPT) is a pentacyclic natural alkaloid, first isolated in 1966 by Wani and Wall from the camptotheca tree, native to southern China. This natural alkaloid exhibits significant antitumor activity by binding to topoisomerase I and inhibiting DNA degradation, leading to DNA damage and apoptosis. However, due to its poor solubility and severe toxicity, CPT itself cannot be used as an anticancer drug. With ongoing research into structural modifications, several CPT analogues have been approved by the U.S. Food and Drug Administration (FDA) for cancer treatment, such as topotecan, beloteccan, and irinotecan, showing broad clinical application prospects.

[0003] CPT analogues are mainly synthesized using semi-synthetic strategies, requiring industrial-scale extraction from Camptotheca acuminata. Therefore, developing practical and efficient routes for the total synthesis of CPT has become a research focus. Camptotheca acuminata is a chiral compound, and only (S)-CPT and its analogues can effectively inhibit DNase topoisomerase I, making the asymmetric total synthesis of CPT of great significance. Currently, the synthesis methods for chiral pure CPT are mainly divided into the following four types: (1) chiral resolution, (2) chiral-assisted induction, (3) sharpless asymmetric dihydroxylation, and (4) asymmetric α-hydroxylation. However, the above synthetic methods still have problems such as resolution difficulties. Therefore, developing reaction routes with high enantioselectivity remains the current research focus.

[0004] This study explores the asymmetric synthesis of CPTs based on catalytic asymmetric Mannich reactions and molecular skeleton editing strategies. It reveals that current methods for introducing chiral centers into CPTs are limited, with most relying on induced chiral auxiliary groups, sharpless asymmetric dihydroxylation, or stoichiometric asymmetric α-hydroxylation. Given the importance of asymmetric synthesis in obtaining chiral tertiary alcohols similar to camptothecin (CPTs), further development of highly enantioselective chiral transformations is needed.

[0005] To address the aforementioned technical problems, this invention utilizes a bifunctional spirocyclic catalyst synthesized using an SPD framework to achieve a one-pot Mannich / Acylation / Wittig reaction of indole and acetaldehyde. This introduces chirality in the early stages of camptothecin synthesis, and in subsequent synthesis processes, this chiral center induces the establishment of subsequent chiral centers, thereby achieving the asymmetric synthesis of camptothecin. It also has advantages such as simple process, low cost, and high efficiency. The asymmetric synthesis of (S)-CPT was designed and completed. Summary of the Invention

[0006] The purpose of this invention is to provide a method for preparing (S)-camptothecin chiral compounds catalyzed by a bifunctional spirocyclic catalyst, the method comprising the following steps:

[0007] (1) Preparation of compound 4a by a one-pot, three-step method;

[0008]

[0009] (2) Preparation of compound 5 by oxaDA reaction;

[0010]

[0011] (3) Preparation of compound 6;

[0012]

[0013] (4) Preparation of compounds 8-1 and 8-2;

[0014]

[0015] (5) Preparation of compound 14;

[0016]

[0017]

[0018] Preferably, the catalyst described in step (1) has the following structural formula:

[0019]

[0020] Wherein, R is one or more of H, 1,3,5-triMe, 4-OMe, 2,4-diOMe, 3,5-diCF3, 4-OCF3, and 4-NO2.

[0021] Preferably, the catalyst described in step (1) has the following structural formula:

[0022]

[0023] Where R is 2,4-diOMe.

[0024] Preferably, in the reaction described in step (2), the reaction conditions are mesitylene, reflux or BF. 3· Et2O, 0℃ toRT.

[0025] Preferably, in the reaction described in step (2), R 1 For TMS, the R 2The reaction is carried out under the following conditions: methylbenzene, reflux.

[0026] Preferably, the reaction conditions in step (4) are as follows: Potassium persulfate.

[0027] The beneficial effects of this invention are as follows: This invention provides a method for preparing (S)-camptothecin chiral compounds by catalysis with a bifunctional spirocyclic catalyst. The method utilizes a sulfonamide bifunctional catalyst to introduce a chiral center in the early stage of the chiral synthesis route to complete the asymmetric synthesis of camptothecin. This method is a significant improvement over other existing chiral synthesis routes, with a significant increase in reaction efficiency. Moreover, the process is simple, low in cost, and has broad application prospects. Detailed Implementation

[0028] The present invention will be further described below with reference to specific embodiments. The following embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the present invention, and all such modifications and substitutions should be covered within the scope of the claims of the present invention.

[0029] It should be noted that, unless otherwise specified, the methods used in the following embodiments are all conventional methods.

[0030] Unless otherwise specified, the reagents and consumables used in the following examples are commercially available.

[0031] It should be noted that in this invention, CH3CHO is acetaldehyde, t-BuOK is potassium tert-butoxide, MeOH is methanol, H2O is water, DCM is dichloromethane, Toluene is toluene, Mesitylene is mesitylene, Boc2O is ditert-butyl dicarbonate, DMAP is 4-dimethylaminopyridine, Et3N is triethylamine, THF is tetrahydrofuran, Oxone is potassium persulfate, Na2EDTA is disodium ethylenediaminetetraacetate, and NaHCO3 is... 3 represents sodium bicarbonate, dioxane represents dioxane, TBAI represents tetrabutylammonium iodide, NIS represents N-iodosuccinimide, TBAF represents tetrabutylammonium fluoride, TFA represents trifluoroacetic acid, piperidine represents piperidine, Tf2NPh represents N-phenylbis(trifluoromethanesulfonyl)imide, Pd(AcO)2 represents palladium acetate, DPPF represents 1,1'-bis(diphenylphosphine)ferrocene, HCOOH represents formic acid, and DDQ represents 2,3-dichloro-5,6-dicyano-p-benzoquinone.

[0032] Structurally, camptothecin is composed of five rings: A, B, C, D, and E. Rings A and B are quinoline rings, ring C is a pyrrole ring, ring D is a pyridone ring, and ring E is an α-hydroxy lactone with an sigmoid chiral carbon. The molecular structure is highly unsaturated, with a continuous conjugated system between the five rings. The lactone ring has a chiral tertiary alcohol center.

[0033] Example 1: Preparation of Catalyst

[0034] Taking catalyst cat.5 as an example:

[0035]

[0036] Preparation of compound cat.5:

[0037] (1) Under an argon atmosphere at room temperature, spiroamine S1 (4.06 g, 16.9 mmol, 1.0 equiv) was dissolved in tetrahydrofuran (100 mL). LiHMDS2 5.5 mL (1.0 M tetrahydrofuran, 1.5 equiv) was added to the system at -78 °C. After the system was heated to room temperature for 10 min, it was cooled to -78 °C and PhNTf2 (6.68 g, 18.7 mmol, 1.1 equiv) was added. The system was then gradually heated to room temperature. After the reaction was completed by TLC monitoring, water was added to quench the reaction. The mixture was extracted with EA (3 × 100 mL). The organic phases were combined, washed with saturated brine, dried with Na2SO4, concentrated under reduced pressure, and separated by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1 to 10:1) to obtain compound S2, which was then directly proceeded to the next step.

[0038] (2) At room temperature, compound S2 (1.05 g, 2.8 mmol, 1.0 equiv) was dissolved in a mixed solvent of tetrahydrofuran (20 mL) and methanol (10 mL). Et3N (1.1 mL, 11.2 mmol, 4.0 equiv) and Pd(PPh3)4 (328 mg, 0.28 mmol, 0.1 equiv) were added to the system. CO was bubbled through at 1 atm and replaced three times. After reacting at 60 °C for 24 h, the mixture was filtered through diatomaceous earth and washed with ethyl acetate. The filtrate was evaporated to dryness and separated by silica gel column chromatography (petroleum ether:ethyl acetate = 30:1 to 15:1) to obtain compound S3 (two-step yield 60%-70%). The purity of the first step had a significant impact on the second step; the higher the purity of the first step, the faster the reaction in the second step and the higher the yield.

[0039] (3) Compound S3 (140 mg, 0.5 mmol, 1.0 equiv) was dissolved in methanol (3 mL) and water (3 mL). Lithium hydroxide hydrate (200 mg, 5 mmol, 10.0 equiv) was added, and the system was reacted at 60 °C. After the starting material disappeared, MeOH was removed by pressure vortexing, and water (10 mL) was added. The aqueous phase was extracted twice with DCM (to remove impurities). The aqueous phase was acidified to pH 2-3 with 1 M KHSO4 and extracted five times with DCM (5 × 10 mL). The product was dried over anhydrous Na2SO4 and concentrated under reduced pressure. After separation by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1 to 1:1), a white solid compound S4 was obtained with a yield of 81%.

[0040] (4) Compound S4 (534 mg, 2.0 mmol, 1.0 equiv) was dissolved in anhydrous dichloromethane (20 mL), sulfonamide (2.1 mmol, 1.05 equiv) and DMAP (268 mg, 2.2 mmol, 1.1 equiv) were added, and EDCl (420 mg, 2.2 mmol, 1.1 equiv) was added to the system at 0 °C. The system was heated naturally and reacted overnight. After the starting material disappeared as monitored by TLC, the mixture was diluted with dichloromethane, washed with HCl (0.05 M), washed with water, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound S5.

[0041] (5) Trifluoroacetic acid (2 ml) was slowly added dropwise to a dichloromethane (20 ml) system containing compound S5 at 0 °C. The ice bath was removed and the reaction was kept at a constant temperature. After the starting material disappeared under TLC monitoring, the solvent was removed by pressure vortexing. Saturated sodium bicarbonate was added to the reaction flask until neutral. Silica gel was added and the mixture was evaporated by direct column chromatography (dichloromethane:methanol = 20:1) to obtain compound cat.5. Further recrystallization purification was performed. Characterization is as follows:

[0042] 1 H NMR (600MHz, CD3OD): δ7.87(d,J=9.3Hz,1H),6.74(t,J=2.6Hz,1H),6.63–6.51(m,2H),3.84(d,J=12.7Hz,6H),3.60(dt,J=11.5,7.6Hz,1H),3 .35–3.31(m,1H),2.46(qd,J=8.3,7.5,2.7Hz,2H),2.31–2.16(m,3H),2.12(ddd,J=13.3,9.6,7.6Hz,2H),1.92(ddd,J=12.1,7.5,2.1Hz,1H);

[0043] 13C NMR (101MHz, CD3OD): δ167.6,164.2,158.0,143.1,138.9,131.8,123.0,103.7,98.7,76.7,55.1,54.7,43.7,35.1,33.6,28.3,22.3;

[0044]

[0045] IR(neat)ν3462,2923,2850,1961,1746,1635,1595,1462,1410,1380,1319,1 258,1210,1120,1071,1022,926,837,766,725,675,597,568,532,445,422cm -1 ;

[0046] HRMS(ESI)calcd for [M+H] + C 17 H 23 N2O5S,m / z:367.1322,found:367.1316.

[0047] Example 2: Preparation of chiral compound 4,4a

[0048] 1. Compound 1: Purchase Compound 1 with the following structural formula.

[0049]

[0050] 2. Preparation of compound 2:

[0051]

[0052] Pd(OAc)₂ (0.01 mmol) and xantphos (0.02 mmol) were added to a 10 mL pressure-resistant tube equipped with a rotor. The tube was evacuated and refilled with argon gas, and this process was repeated three times. 2.0 mL of toluene, acetylene (1 mmol), formic acid (1.5 mmol), and N,N'-dicyclohexylcarbodiimide (0.2 mmol) were added. The reaction mixture was heated at 80 °C for 20 hours. After the reaction was complete, the mixture was cooled to room temperature. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give 2-1 (130 mg, 90%) a yellow oily liquid. Characterization is as follows:

[0053] 1H NMR (600MHz, CDCl3): δ11.30 (s, 1H), 7.72–6.90 (m, 1H), 6.24 (d, J = 18.8Hz, 1H), 0.13 (s, 9H);

[0054] 13 C NMR (151MHz, CDCl3): δ173.0, 155.0, 135.2.

[0055] Add 2-1 (0.04 g), 0.3 mmol oxalyl chloride, and a catalytic amount of DMF (4 mol%) to DCM (0.56 mL) at 0 °C. Then heat the reaction mixture to room temperature and stir for approximately 30 minutes. The reaction is considered complete when no more bubbles are produced. The reaction mixture containing 2-1 is then concentrated under vacuum and proceeded directly to the next step.

[0056] 3. Preparation of compound 3:

[0057]

[0058] At room temperature, triphenylphosphine (4 mmol) was added to toluene (20 mL) and stirred. Then, iodopropane (0.43 mL) was added, and the mixture was refluxed at 120 °C for 24 hours. A large amount of white precipitate was produced. After cooling to room temperature, the mixture was filtered, and the white solid was washed with toluene and petroleum ether to obtain 3-1. Characterization is as follows:

[0059] 1 H NMR (600MHz, CDCl3): δ7.87–7.78(m,9H),7.73(dt,J=7.7,3.8Hz,6H),3.71–3.59(m,2H),1.88–1.60(m,2H),1.26(td,J=7.3,1.8Hz,3H).

[0060] 13 C NMR (151MHz, CDCl3): δ135.1,135.1,133.7,133.7,130.6,130.5,118.4,117.9,25.1,24.7,16.6,16.6,15.5,15.4.

[0061] Under argon atmosphere, 3-1 (0.93 g) was dissolved in tetrahydrofuran (7.2 mL), and n-butyllithium (1.1 equiv) was added dropwise at 0 °C. The mixture was stirred at room temperature for three hours, and then the temperature was lowered to 0 °C again. Potassium tert-butoxide (1.1 equiv) and ethyl formate (2.5 equiv) were added sequentially. The mixture was stirred at this temperature for 30 minutes, then quenched with water. The mixture was extracted three times with dichloromethane, and the organic phases were combined, washed three times with saturated brine, dried with Na2SO4, concentrated under reduced pressure, and separated by silica gel column chromatography (dichloromethane:methanol = 50:1 to 10:1) to obtain product 3.

[0062] 4. Preparation of Compound 4

[0063] Compound 4 was prepared from compound 1, acryloyl chloride, and compound 3 using a one-pot, three-step process, as shown in the following flowchart:

[0064]

[0065] (1) Effects of different catalysts and reaction conditions on the synthesis efficiency of compound 4

[0066] The catalysts used in the reaction process are shown below:

[0067]

[0068] Table 1 Screening of conditions for asymmetric catalytic Mannich / Acylation / Wittig one-pot reaction.

[0069]

[0070]

[0071] a. Unless otherwise stated, all reactions were carried out in 0.5 mL of DCE and 0.5 mL of water (items 1-7, 13, 14) or 1 mL of methanol and water (100 equivalents) (items 8-12), with the reaction system containing 1 (0.1 mmol), acetaldehyde (0.3 mmol), catalyst (0.01 mmol), and base (0.05 mmol). After the reaction was complete, the solution was evaporated, and then DCM (1 mL), acryloyl chloride (0.15 mmol), and phosphorus ylide 3 (0.2 mmol) were added sequentially to the reaction system. b. 0.02 mmol of catalyst was used.

[0072] In our previous study, SPD-derived methanesulfonyl-substituted bifunctional organocatalysts (Table 1) yielded α,β-unsaturated enal products with moderate yields and excellent enantioselectivity (91% ee) (item 13). However, achieving such high enantioselectivity requires a high catalyst loading (20 mol%). To reduce catalyst loading, this study explored various N-sulfonylamide catalysts. As shown in Table 1, initial screening revealed that catalyst 5 performed exceptionally well: it yielded enal product 4 in 30% yield and 59% ee via one-pot amidation with Wittig (items 1-7). Subsequent screening of reaction conditions showed that the choice of base played a decisive role in improving reaction efficiency and selectivity (items 8-11). Notably, the use of potassium tert-butoxide (t-BuOK) significantly improved the yield (42%) and enantioselectivity (93%). In all cases, the loading of the N-sulfonylamide catalyst could be reduced to 10 mol% while maintaining enantioselectivity (items 11 and 12). In contrast, reducing the amount of catalyst 1 leads to a decrease in enantioselectivity (ee value drops from 91% to 88%).

[0073]

[0074] At 0 °C, cat.5 (3.7 mg, 0.01 mmol, 0.1 eq.) was dissolved in MeOH (1 mL) and H2O (180 μL, 10 mmol, 100 eq.), followed by the addition of 1 (0.1 mmol, 1.0 eq.), potassium tert-butoxide (3.4 mg, 0.03 mmol, 0.3 eq.), and acetaldehyde (17 μL, 0.3 mmol, 3.0 eq.). The mixture was stirred at this temperature for 3 days until the substrate disappeared as detected by TLC, after which the resulting solution was concentrated under vacuum.

[0075] At -20°C, 1 mL of DCM acyl chloride 2 (0.12 mmol, 1.2 eq.) was added sequentially to the mixture obtained above. The mixture was then brought to room temperature and stirred for 15 minutes, followed by vacuum concentration of the reaction solution.

[0076] The residue was dissolved in toluene (0.5 mL), and 3 (0.07 g, 2.0 eq.) was added to the reaction at room temperature. The mixture was refluxed for 7 hours, and then the system was directly concentrated under vacuum and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 6:1 to 4:1) to give compound 4a (18.7 mg, total yield of 38% in three steps).

[0077] Example 3: Substituent Screening for Diastereomeric Ratios in the Oza-DA Reaction

[0078]

[0079] Table 2 Substituent screening for diastereomeric ratios in the oxa-DA reaction.

[0080] R 2 For H, R 1 When OMe, OEt, STol, and TMS are used respectively, the dr values ​​of this step are all greater than 20:1. However, since OMe, OEt, and STol have poor subsequent leaving properties, we choose TMS as the best option.

[0081]

[0082] A solution of 50 mg of 4a in 10 mL of trimethylbenzene was heated at 170 °C for one week and then cooled to room temperature. The system was purified by silica gel column chromatography (petroleum ether: EtOAc = 6:1) to give amorphous solid substrate 5 (28.6 mg, 73%).

[0083]

[0084] At -5°C, DMAP (0.2 eq.), Et3N (1.5 eq.), and Boc2O (1.2 eq.) were added to a solution of 5 (750 mg, 1.9 mmol) of THF (9.5 mL). The reaction was then continued at this temperature for approximately 1 hour until the starting material disappeared as detected by TLC. The reaction mixture was then quenched with water, extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, and concentrated under vacuum. The reaction mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:1) to give 6 (890 mg, 95%) as an amorphous solid.

[0085] Example 4: Conditional Screening of Dihydroxylated Diastereomer Ratios

[0086]

[0087] Table 3. Screening of dihydroxylated diastereomer ratios

[0088]

[0089] We then systematically studied a series of dihydroxylation and epoxidation reaction conditions (Table 3). Because up to four different configurations could be generated, NMR analysis could not definitively determine the diastereomeric ratio of compound 7; therefore, this compound was further oxidized to the corresponding lactones 8-1 and 8-2. Overall, the stereoselectivity of these transformation reactions was poor (items 1-7). However, it is noteworthy that when using a combination of HCA and oxone (potassium peroxymonosulfate), the diastereoselectivity reached a moderate level (diastereoselectivity 6.6:1, item 8).

[0090]

[0091] At 0 °C, Na₂EDTA (0.06 eq. in H₂O, M = 0.0004) was added to a stirred solution of 1,4-dioxane (3 mL) of 6 (50 mg, 0.1 mmol). Oxone (614 mg, 1 mmol) and NaHCO₃ (130 mg, 1.6 mmol) were then added to the system in portions. The mixture was stirred at this temperature until the starting material disappeared as monitored by TLC (approximately 24 hours). The mixture was then quenched with a saturated aqueous solution of Na₂S₂O₃, and 20 mL of water was added with vigorous stirring. Next, the mixture was extracted with EtOAc, the combined organic phases were washed with brine, dried over anhydrous Na₂SO₄, concentrated under vacuum, and purified by silica gel column chromatography (DCM and petroleum ether: EtOAc = 1:1) to obtain a mixture of 7 (49 mg, 92%) as a colorless liquid. The mixture was then concentrated under vacuum and proceeded directly to the next step.

[0092] At 0 °C, TBAI (55 mg, 0.15 mmol) and NIS (68 mg, 0.3 mmol) were added to a DCM (0.8 mL) solution of 7 (53 mg, 0.1 mmol). The system was then stirred at room temperature until the starting material disappeared as monitored by TLC. The mixture was then quenched with saturated Na₂S₂O₃. Next, the product was extracted with DCM, the combined organic phases were washed with brine, dried over anhydrous Na₂SO₄, concentrated under vacuum, and purified by silica gel column chromatography (petroleum ether: EtOAc = 6:1 to 4:1) to give 8⁻¹ (45.8 mg, 87%) as a colorless liquid and 8⁻² (6 mg, 11%) as a white solid.

[0093]

[0094] TBAF (24 μL, 1M THF solution) was added to a THF (0.1 mL) solution of 8-1 (10 mg, 0.019 mmol) at 0 °C. The mixture was then stirred at this temperature until the starting material disappeared as monitored by TLC. The reaction mixture was then quenched with water. Next, the mixture was extracted with EtOAc, the combined organic phases were washed with brine, dried over anhydrous Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (petroleum ether: EtOAc = 1:1 to 0:1) to give 9 (7.6 mg, 88%) of a colorless liquid.

[0095]

[0096] At 0°C, 0.2 mL of TFA was added to 9 (45 mg, 0.1 mmol) of 1 mL of DCM solution and stirred for 2 hours. The disappearance of the starting material was monitored by TLC. After vacuum concentration, the TFA salt was dissolved in 2 mL of methanol (saturated ammonia solution), stirred for several minutes, and then concentrated under vacuum. The reaction system was purified by silica gel column chromatography (DCM:MeOH = 25:1) to obtain 10 (23.4 mg, 66%), a colorless liquid.

[0097]

[0098] At -78°C, ozone was blown onto the surface of 10 (50 mg, 0.142 mmol) DCM (0.7 mL) for approximately 5 minutes with vigorous stirring until the starting material disappeared as monitored by TLC. Then, argon gas was bubbled under the liquid surface to raise the temperature to 0°C. Hexahydropyridine (8.5 μL, 0.6 eq.) and a catalytic amount of ethanol were added to the system, and the mixture was stirred overnight at this temperature. After the starting material disappeared as monitored by TLC, the system was concentrated under vacuum and purified by silica gel column chromatography (DCM:MeOH = 10:1) to give a mixture of 11 (23.5 mg, 45%) as a white solid.

[0099]

[0100] Compound 11 (10 mg, 0.027 mmol) was dissolved in DCM (2 mL) at room temperature and sonicated for 5 minutes to homogenize the reaction solution. Then, N-phenyl-bis(trifluoromethanesulfonylimide) (15 mg, 0.04 mmol), Et3N (6 μL, 0.04 mmol), and DMAP (2 mg, 0.016 mmol) were added sequentially to the system. After stirring for 0.5 hours, water (1 mL) was added to quench the reaction. Next, the mixture was extracted with DCM, washed with brine, and the combined organic phases were dried over anhydrous Na2SO4. The mixture was concentrated under vacuum and purified by silica gel column chromatography (petroleum ether: EtOAc = 1:1) to give 12 (11 mg, 81%) as a white solid.

[0101]

[0102] Compound 12 (40 mg, 0.08 mmol) was added to 1,4-dioxane (3 mL) at room temperature, followed by palladium acetate (1 mg, 0.006 mmol), 1,1'-bis(diphenylphosphino)ferrocene (1 mg, 0.0024 mmol), Et3N (33 μL, 0.24 mmol), and formic acid (6 μL, 0.16 mmol). The mixture was then reacted at 80 °C for 1 h. The reaction was monitored by TLC until complete. The mixture was then extracted with DCM, washed with brine, dried over anhydrous Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (DCM:MeOH = 25:1) to give 13 (15 mg, 53%) as a white solid.

[0103]

[0104] Compound 13 (20 mg, 0.06 mmol) and DDQ (25 mg, 0.11 mmol) were dissolved in 1,4-dioxane (2 mL) at room temperature, and a catalytic amount of glacial acetic acid was added. The mixture was stirred for 4 hours and monitored by TLC until the reaction was complete. After vacuum concentration, the mixture was subjected to silica gel column chromatography (DCM:MeOH = 30:1) to give 14 (15 mg, 72%) as a white solid.

[0105] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from the spirit or essential characteristics of the invention. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, it is intended that all variations falling within the meaning and scope of equivalents of the claims be included within the present invention.

Claims

1. A process for the preparation of a chiral compound of (S)- camptothecin catalyzed by a bifunctional spirocyclic catalyst, characterized in that, The method comprises the following steps: (1) one-pot three-step method for preparing compound 4a; (2) preparation of compound 5 by oxa DA reaction; (3) preparation of compound 6; (4) preparation of compounds 8-1, 8-2; (5) preparation of compound 14; 2. The method of claim 1, wherein, The structural formula of the catalyst in step (1) is as follows: Wherein, R is one or several of H, 1,3,5-triMe, 4-OMe, 2,4-diOMe, 3,5-diCF3, 4-OCF3, 4-NO2.

3. The method of claim 2, wherein, The structural formula of the catalyst in step (1) is as follows: Wherein, R is 2,4-diOMe.

4. The method of claim 1, wherein, The reaction described in step (2) is carried out under the reaction conditions of mesitylene, reflux or BF 3· Et20, 0 °C to RT.

5. The method of claim 4, wherein, The reaction described in step (2) wherein R 1 is TMS and R 2 is H; and the reaction conditions are mesitylene, reflux.

6. The method of claim 1, wherein, The reaction conditions described in step (4) are Monopersulfate potassium.

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