Method for synthesizing Aogacillin spirolactone

Abstract

The invention provides the method for synthesizing the Aogacillin spiro lactone, the synthesis steps are simple and rapid, the reaction conditions are mild, especially aldol condensation and ester exchange are carried out in one pot in the seventh step, a spiro skeleton is effectively constructed, and the total synthesis of (-)-ent-Aogacillin A and (+)-Aogacillin B is smoothly realized.

Description

Technical Field

[0001] The invention relates to the technical field of natural drug synthesis, and in particular to a method for efficiently synthesizing Aogacillins spirolactone. Background Art

[0002] Methicillin-resistant Staphylococcus aureus (MRSA) is a multidrug-resistant pathogen that is resistant to multiple antibiotics, including beta-lactam antibiotics such as methicillin and other penicillins. This bacterium can cause a range of serious infections, from skin and soft tissue infections to more severe conditions such as sepsis, pneumonia, and endocarditis. Therefore, the development of new antimicrobial compounds to combat infections caused by drug-resistant bacteria like MRSA is crucial.

[0003] Aogacillins A and B are two natural products isolated from the culture broth of the fungus Simplicillium sp. FKI-5985. These compounds have been shown to significantly reduce the minimum inhibitory concentration (MIC) of arbekacin (ABK) against MRSA. Specifically, aogacillins A and B reduced the MIC of ABK against MRSA from 256 μg / mL to 8 μg / mL, suggesting their potential as druggable compounds. Structurally, aogacillins are a class of spirocyclic β-carbonyl-δ-lactones with a dense functional group structure, particularly a continuous series of high oxidation states on the δ-lactone ring. They also possess an exocyclic double bond conjugated to the carbonyl group, making them Michael acceptors and susceptible to nucleophilic attack. This poses significant challenges to their chemical synthesis. Since their discovery, no synthetic studies have been reported.

[0004] In recent years, scientists have discovered that Aogacillins can also be used to prepare anti-kidney cancer drugs, anti-breast cancer drugs, drugs for treating renal insufficiency, hypoglycemic drugs and anti-Alzheimer's disease drugs.

[0005] While it is feasible to extract these compounds from natural sources, this approach is often limited by low yields, high costs, and difficulties in large-scale production. Therefore, developing chemical synthesis methods that are simple, cost-effective, and suitable for industrial production is crucial. Chemical synthesis can not only ensure sufficient supply to meet research needs but also ensure the availability of these compounds for subsequent clinical trials and ultimately commercial applications. Summary of the Invention

[0006] In view of the problem that there is currently no method for chemically synthesizing Aogacillins spirolactones, the present invention provides a method for synthesizing (-)-ent-Aogacillin A and (+)-Aogacillin B with simple and rapid synthesis steps, readily available raw materials, mild reaction conditions, and environmental friendliness.

[0007] In order to solve the above technical problems, the present invention provides a method for efficiently synthesizing Aogacillins spirolactone, which comprises:

[0008] In the first step, 2-methylcyclohexanone (±)-1 is reacted with ethyl formate via Claisen condensation to give compound (±)-2;

[0009] In the second step, compound (±)-2 reacts with tetrahydropyrrole through enamination to obtain compound (±)-3;

[0010] In the third step, compound (±)-3 reacts with methylmagnesium chloride through addition elimination reaction to obtain compound (±)-4;

[0011] In the fourth step, compound (±)-4 is subjected to hydrogenation reduction reaction by palladium / carbon to obtain compound (±)-5;

[0012] In the fifth step, compound (±)-5 reacts with isopropenylmagnesium bromide to obtain compound (±)-6;

[0013] Step 6: Compound (±)-6 reacts with diphenyl diselenide through allylic oxidation to obtain compound (±)-7;

[0014] In the seventh step, compound (±)-7 reacts with (2S,5S)-2-(tert-butyl)-5-methyl-1,3-dioxolane-4-one via aldol condensation and transesterification to give compounds 8 and 9;

[0015] In the eighth step, compounds 8 and 9 are oxidized to obtain (-)-ent-Aogacillin A and (+)-Aogacillin B.

[0016] Among them, the first step is further specifically: dissolving the alkaline catalyst, 2-methylcyclohexanone, and ethyl formate in toluene, then adding methanol at 0°C, reacting at room temperature for 24 hours under the action of the alkaline catalyst, and performing post-treatment to form compound (±)-2. The molar ratio of 2-methylcyclohexanone to the alkaline catalyst is 1:2~3.

[0017] The second step is further specified as follows: the compound (±)-2 prepared in the first step is dissolved in toluene, a secondary ammonia reagent is added, and the reaction is preferably carried out at 120° C. for 9 hours. The solvent is removed in vacuo to form a compound (±)-3, and the molar ratio of the compound (±)-2 to the secondary ammonia reagent is preferably 1:1 to 3.

[0018] Among them, the third step is further specifically, dissolving compound (±)-3 in tetrahydrofuran, adding a strong nucleophile and reacting preferably at 0°C for 2h, and post-treating to obtain compound (±)-4, and the molar ratio of the compound (±)-3 and the strong nucleophile is preferably 1:1 to 3.

[0019] Among them, the fourth step is further specifically: dissolving compound (±)-4 in ethyl acetate, adding a catalyst, passing hydrogen, maintaining one atmosphere of pressure, stirring at room temperature for 2 hours, filtering with diatomaceous earth, and concentrating to obtain compound (±)-5, and the molar ratio of compound (±)-4 and catalyst is 1:0.1~0.3.

[0020] Among them, the fifth step is further specifically, dissolving compound (±)-5 in tetrahydrofuran at 0°C, adding a highly active nucleophile and reacting preferably at 0°C for 1 hour, and post-treating to obtain compound (±)-6, wherein the molar ratio of compound (±)-5 and the highly active nucleophile is preferably 1:1 to 3.

[0021] The sixth step is further specifically as follows: under nitrogen protection, compound (±)-6 is dissolved in toluene, diphenyl diselenide and an oxidant are added, preferably stirred at 110° C. for 4 hours, and post-treated to obtain compound (±)-7, wherein the molar ratio of compound (±)-6 to diphenyl diselenide is 1:1 to 3, more preferably 1:2. The molar ratio of compound (±)-6 to the oxidant is 1:2 to 5, more preferably 1:3.

[0022] Among them, the seventh step is further specifically as follows: (2S, 5S)-2-(tert-butyl)-5-methyl-1,3-dioxolane-4-one is dissolved in tetrahydrofuran, lithium diisopropylamide is added and the reaction is carried out at -78°C for 1 hour, compound (±)-7 is added, the temperature is raised to -10°C, and the reaction is carried out for 3 hours, and post-treatment is performed to obtain compounds 8 and 9. The molar ratio of the compound (±)-7 and lithium diisopropylamide is 1:2~3, and the molar ratio of the compound (±)-7 and (2S, 5S)-2-(tert-butyl)-5-methyl-1,3-dioxolane-4-one is 1:2~3.

[0023] In the eighth step, compounds 8 and 9 are dissolved in dimethyl sulfoxide, an oxidant is added, and the mixture is stirred at room temperature for 3 hours, followed by post-treatment to obtain (-)-ent-Aogacillin A and (+)-Aogacillin B, wherein the molar ratio of compounds 8 and 9 to the oxidant is 1:2-4.

[0024] Beneficial effects of the present invention

[0025] The method for synthesizing (-)-ent-Aogacillin A and (+)-Aogacillin B of the present invention has simple and rapid synthesis steps and mild reaction conditions. In particular, in the seventh step, aldol condensation and transesterification are carried out in one pot, a spirocyclic skeleton is effectively constructed, and the total synthesis of (-)-ent-Aogacillin A and (+)-Aogacillin B is smoothly achieved. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 The nuclear magnetic resonance spectrum of (-)-ent-Aogacillin A of the present invention Figure 1 H-NMR;

[0027] Figure 2 This is the nuclear magnetic resonance spectrum of (-)-ent-Aogacillin A of the present invention 13 C-NMR;

[0028] Figure 3 This is the nuclear magnetic resonance spectrum of (+)-Aogacillin B of the present invention 1 H-NMR;

[0029] Figure 4 This is the nuclear magnetic resonance spectrum of (+)-Aogacillin B of the present invention 13 C-NMR;

[0030] Figure 5 This is the nuclear magnetic resonance spectrum of the compound (±)-6 of the present invention 1 H-NMR;

[0031] Figure 6 This is the nuclear magnetic resonance spectrum of the compound (±)-6 of the present invention 13 C-NMR;

[0032] Figure 7 This is the nuclear magnetic resonance spectrum of the compound (±)-7 of the present invention 1 H-NMR;

[0033] Figure 8 This is the nuclear magnetic resonance spectrum of the compound (±)-7 of the present invention 13 C-NMR;

[0034] Figure 9The nuclear magnetic resonance spectra of compounds 8 and 9 of the present invention are 1 H-NMR;

[0035] Figure 10 The nuclear magnetic resonance spectra of compounds 8 and 9 of the present invention are 13 C-NMR;

[0036] Figure 11 The synthetic route of (-)-ent-Aogacillin A and (+)-Aogacillin B is shown in FIG. DETAILED DESCRIPTION

[0037] The specific synthetic routes of (-)-ent-Aogacillin A and (+)-Aogacillin B provided by the present invention are as follows:

[0038]

[0039] Specifically:

[0040] In the first step, 2-methylcyclohexanone (±)-1 is reacted with ethyl formate via Claisen condensation at room temperature for 18-24 hours to obtain compound (±)-2;

[0041] In the second step, compound (±)-2 is subjected to an enamination reaction at 100°C-120°C for 6-12h to obtain compound (±)-3;

[0042] In the third step, compound (±)-3 undergoes an addition elimination reaction at 0°C for 0.5-1h to obtain compound (±)-4;

[0043] In the fourth step, compound (±)-4 is subjected to catalytic hydrogenation reduction reaction at room temperature for 0.5-1 h to obtain compound (±)-5;

[0044] In the fifth step, compound (±)-5 is subjected to an addition reaction at 0°C for 0.5-1h to obtain compound (±)-6;

[0045] Step 6: Compound (±)-6 is oxidized at the allylic position at 90°C-120°C for 4-6 hours to obtain compound (±)-7;

[0046] In the seventh step, compound (±)-7 was subjected to aldol condensation and transesterification reaction at -78°C for 4-6 hours to obtain compounds 8 and 9. The reaction time was 4 hours.

[0047] In the eighth step, compounds 8 and 9 were oxidized to synthesize ent-Aogacillin A and Aogacillin B at room temperature for 2-3 h.

[0048] The first step is further specifically as follows: dissolving the alkaline catalyst, 2-methylcyclohexanone, and ethyl formate in toluene, then adding methanol at 0°C, reacting at room temperature for 24 hours under the action of the alkaline catalyst, and performing post-treatment to form the compound (±)-2, wherein the molar ratio of 2-methylcyclohexanone to the alkaline catalyst is 1:2 to 3, more preferably 1:3, and the reaction time is preferably 24 hours.

[0049] The alkaline catalyst is preferably sodium hydride, sodium methoxide, LDA, potassium tert-butoxide, LiHMDS or NaOH, more preferably sodium hydride.

[0050] The second step is further specified as follows: the compound (±)-2 prepared in the first step is dissolved in toluene, a secondary ammonia reagent is added, and the reaction is preferably carried out at 120°C for 9 hours. The solvent is removed in vacuo to form a compound (±)-3. The molar ratio of the compound (±)-2 to the secondary ammonia reagent is preferably 1:1 to 3, and more preferably 1:2.

[0051] The secondary ammonia reagent is preferably tetrahydropyrrole, dimethylamine, diethylamine or piperidine, and more preferably tetrahydropyrrole.

[0052] The third step is further specifically, dissolving compound (±)-3 in tetrahydrofuran, adding a strong nucleophile and reacting preferably at 0°C for 2h, and post-treating to obtain compound (±)-4, wherein the molar ratio of compound (±)-3 to the strong nucleophile is preferably 1:1 to 3, more preferably 1:2.

[0053] The strong nucleophile is preferably methylmagnesium chloride, methylmagnesium bromide, methylmagnesium iodide or methyllithium, and more preferably methylmagnesium chloride.

[0054] The fourth step is further specifically as follows: dissolving compound (±)-4 in ethyl acetate, adding a catalyst, passing hydrogen, maintaining one atmosphere of pressure, stirring at room temperature for 2 hours, filtering with diatomaceous earth, and concentrating to obtain compound (±)-5. The molar ratio of compound (±)-4 to catalyst is 1:0.1 to 0.3, and more preferably 1:0.2.

[0055] The catalyst is preferably palladium / carbon, palladium hydroxide / carbon, platinum / carbon or Raney nickel, and more preferably a palladium / carbon catalyst.

[0056] The fifth step is further specifically as follows: dissolving compound (±)-5 in tetrahydrofuran at 0°C, adding a highly active nucleophile and reacting preferably at 0°C for 1 hour, and post-treating to obtain compound (±)-6. The molar ratio of compound (±)-5 to the highly active nucleophile is preferably 1:1 to 3, and more preferably 1:2.

[0057] The highly active nucleophilic reagent is preferably isopropenylmagnesium bromide, isopropenylmagnesium chloride or isopropenyllithium, and is more preferably isopropenylmagnesium bromide.

[0058] The sixth step is further specifically as follows: under nitrogen protection, compound (±)-6 is dissolved in toluene, diphenyl diselenide and an oxidant are added, preferably stirred at 110° C. for 4 hours, and post-treated to obtain compound (±)-7, wherein the molar ratio of compound (±)-6 to diphenyl diselenide is 1:1 to 3, more preferably 1:2. The molar ratio of compound (±)-6 to the oxidant is 1:2 to 5, more preferably 1:3.

[0059] The oxidizing agent is preferably 2-iodobenzoic acid, Dess-Martin reagent, PhIO2, PhIO, PhI(O2CCF3)2 or PhI(OAc)2, more preferably PhIO2.

[0060] The seventh step is further specifically as follows: (2S, 5S)-2-(tert-butyl)-5-methyl-1,3-dioxolane-4-one is dissolved in tetrahydrofuran, lithium diisopropylamide is added and the mixture is reacted at -78°C for 1 hour, compound (±)-7 is added, the temperature is raised to -10°C, and the reaction is carried out for 3 hours. Post-treatment is performed to obtain compounds 8 and 9, wherein the molar ratio of the compound (±)-7 to lithium diisopropylamide is 1:2 to 3, more preferably 1:2.5, and the molar ratio of the compound (±)-7 to (2S, 5S)-2-(tert-butyl)-5-methyl-1,3-dioxolane-4-one is 1:2 to 3, more preferably 1:2.2.

[0061] In the eighth step, compounds 8 and 9 are dissolved in dimethyl sulfoxide, an oxidant is added, and stirred at room temperature for 3 hours, followed by post-treatment to obtain (-)-ent-Aogacillin A and (+)-Aogacillin B, wherein the molar ratio of compounds 8 and 9 to the oxidant is 1:2 to 4, more preferably 1:3.

[0062] The oxidizing agent is preferably 2-iodoacetylbenzoic acid, pyridinium chlorochromate or Dess-Martin reagent, and more preferably 2-iodoacetylbenzoic acid.

[0063] The following examples and drawings are used to describe the embodiments of the present invention in detail, so that the implementation process of how the present invention applies technical means to solve technical problems and achieve technical effects can be fully understood and implemented accordingly.

[0064] Figure 11 The specific synthetic routes of (-)-ent-Aogacillin A and (+)-Aogacillin B are shown as follows:

[0065] Example 1 Preparation of Compound (±)-2

[0066] To a 60% NaH solution (6.4 g, 160.5 mmol, NaH stored in mineral oil at a mass ratio of 60%) in toluene (535 mL) were added the compound 2-methylcyclohexanone (6 g, 53.5 mmol) and ethyl formate (27.7 g, 374.5 mmol) in sequence. Methanol (2.1 mL, 53.5 mmol) was then added at 0°C. The mixture was stirred for 24 h, quenched with water, and the aqueous layer was washed with ethyl acetate. The aqueous layer was acidified with hydrochloric acid (1.0 M, 20 mL), the pH adjusted to 1-2, and then extracted with ethyl acetate. The combined organic phases were washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 2-methyl-6-hydroxymethylenecyclohexanone (±)-2 (7.0 g, 93% yield), which was used directly in the next step without further purification.

[0067] 1 H NMR (400MHz, CDCl3): δ14.55 (s, 1H), 8.59 (s, 1H), 2.50-2.39 (m, 1H), 2.35-2.28 (m, 2H), 1.90-1 .80 (m, 1H), 1.80-1.70 (m, 1H), 1.62-1.50 (m, 1H), 1.44-1.32 (m, 1H), 1.19 (d, J=7.2Hz, 3H)ppm. 13 C NMR (100MHz, CDCl3): δ188.51, 187.16, 108.26, 35.76, 29.95, 23.70, 20.92, 17.43ppm.

[0068] Example 2 Preparation of Compound (±)-3

[0069] Tetrahydropyrrole (9.1 g, 128.4 mmol) was added to a toluene solution of compound (±)-2 (9.0 g, 64.2 mmol), and the reaction mixture was heated under reflux at 120°C for 9 h, and then the solvent was removed in vacuo to obtain enamine (±)-3 as a crude product, which was used directly in the next step without further purification.

[0070] Example 3 Preparation of Compound (±)-4

[0071] To a solution of compound 3 in tetrahydrofuran (64 mL), a solution of methylmagnesium chloride in tetrahydrofuran (3.0 M, 2.8 mL, 128.4 mmol) was slowly added, the reaction mixture was stirred at 0°C for 2 h, and then quenched by adding saturated ammonium chloride solution. The organic layer was collected, and the aqueous phase was extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with water (100 mL × 2) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1) to give 2-methyl-6-ethylidenecyclohexanone (±)-4 (4.5 g, two-step yield 51%).

[0072] 1 H NMR (400MHz, CDCl3): δ6.58 (q, J=7.26Hz, 1H), 2.70-2.60 (m, 1H), 2.37-2.22 (m, 2H), 2.05-1 .95(m, 1H), 1.91-1.81(m, 1H), 1.72-1.57(m, 4H), 1.55-1.42(m, 1H), 1.13-1.08(m, 3H)ppm. 13 C NMR (100MHz, CDCl3): δ203.87, 137.48, 133.01, 43.92, 31.88, 26.73, 22.52, 16.12, 13.51 ppm.

[0073] Example 4 Preparation of Compound (±)-5

[0074] To a solution of compound (±)-4 (4.5 g, 32.6 mmol) in ethyl acetate (100 mL) was added palladium on carbon (10 wt %, 0.7 g), which was then flushed three times with hydrogen. Under a H₂ atmosphere, the mixture was stirred at room temperature for 2 h, then filtered through celite, and the filtrate was concentrated under reduced pressure. Silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1) afforded cis-2-methyl-6-ethylcyclohexanone (±)-5 (2.9 g, 64% yield).

[0075] 1 H NMR (400MHz, CDCl3): δ2.45-2.26 (m, 1H), 2.21-2.03 (m, 3H), 1.86-1.64 (m, 3H), 1.33-1.11 (m, 3H), 0.98 (d, J=6.5Hz, 3H), 0.85 (t, J=7.4Hz, 3H); 13 C NMR (100MHz, CDCl3): δ214.42, 52.48, 45.71, 37.53, 34.84, 25.65, 22.20, 14.58, 11.90.

[0076] Example 5 Preparation of Compound (±)-6

[0077] To a 0°C solution of compound (±)-5 (1.3 g, 9.3 mmol) in tetrahydrofuran (10 mL), a solution of isopropenylmagnesium bromide in tetrahydrofuran (1.0 M, 18.6 mL, 18.6 mmol) was slowly added. The reaction mixture was stirred at 0°C for 1 h, then quenched by addition of saturated ammonium chloride solution. The organic layer was collected, and the aqueous layer was extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with water (20 mL × 2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Silica gel column chromatography (petroleum ether / ethyl acetate = 40 / 1) gave 2-methyl-6-ethyl-1-isopropenylcyclohexanol (±)-6 (1.0 g, yield 60%).

[0078] 1 H NMR (400MHz, CDCl3): δ5.01 (s, 1H), 4.91 (s, 1H), 2.55 (s, 4H), 1.78-1.55 (m, 6H), 1.43-1.15 (m, 6H), 0.87-0.78 (m, 4H), 0.74-0.64 (m, 3H)ppm. 13 C NMR (100MHz, CDCl3): δ148.22, 111.14, 79.43, 43.73, 36.63, 29.92, 25.84, 22.29, 19.31, 15.43, 12.49ppm. HRMS (ESI): m / z Calcd.for[C 12 H 23 O, M+H]+: 183.1743; Found: 183.1623.

[0079] Example 6 Preparation of Compound (±)-7

[0080] Under nitrogen protection, PhIO2 (1.1 g, 4.9 mmol) and Ph2Se2 (1.0 g, 3.3 mmol) were added to a toluene (22 mL) solution of compound (±)-6 (300 mg, 1.7 mmol). The reaction mixture was stirred at 110°C for 4 h and then quenched by adding water. The organic layer was collected and the aqueous layer was extracted with ethyl acetate (20 mL×2). The combined organic phases were washed with water (20 mL×2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give compound (±)-7 (250 mg, yield 77%).

[0081] 1H NMR (400MHz, CDCl3): δ9.57 (s, 1H), 6.68 (s, 1H), 6.18 (s, 1H), 1.79-1.65 (m, 2H), 1.55-1.09 (m, 8H), 0.83-0.74 (m, 4H), 0.67-0.61 (m, 3H); 13 C NMR (100MHz, CDCl3): δ193.46, 153.22, 138.08, 42.96, 36.22, 29.65, 25.62, 25.30, 22.84, 15.75, 12.21.

[0082] Example 7 Preparation of Compounds 8 and 9

[0083] To a solution of (R)-lactic acid (3.0 g, 33.3 mmol) and p-valeraldehyde (8.5 mL, 78.3 mmol) in petroleum ether (31.6 mL) were added p-toluenesulfonic acid (78.5 mg, 0.46 mmol) and 1 drop of concentrated sulfuric acid. The mixture was then heated to reflux and separated using a water separator for 7 h until no more water was produced. The organic layer was washed with water (10 mL x 2) and saturated brine (10 mL), respectively, and dried over anhydrous sodium sulfate. The product was concentrated under reduced pressure and dissolved in petroleum ether (30 mL). Recrystallization at -78°C afforded (2S,5S)-2-(tert-butyl)-5-methyl-1,3-dioxolane-4-one (2.9 g, 55% yield).

[0084] To a solution of (2S,5S)-2-(tert-butyl)-5-methyl-1,3-dioxolane-4-one (270 mg, 1.7 mmol) in tetrahydrofuran (3 mL) was added a solution of lithium diisopropylamide in tetrahydrofuran (2.0 M, 1.0 mL, 2.0 mmol). The reaction mixture was stirred at -78°C for 1 h, followed by the addition of a solution of compound (±)-7 (130 mg, 0.66 mmol) in tetrahydrofuran (1 mL). The mixture was heated to -10°C and allowed to react for 3 h. The mixture was then quenched by addition of saturated ammonium chloride solution. The aqueous phase was extracted with ethyl acetate (10 mL x 2). The combined organic phases were washed with water (10 mL x 2) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was separated by silica gel column chromatography (petroleum ether / ethyl acetate volume ratio = 1 / 1) to afford a mixture of compounds 8 and 9 (100 mg, 56% yield).

[0085] 1H NMR (400MHz, CDCl3): δ5.60-5.03 (m, 1H), 5.59-5.11 (m, 1H), 4.24-4.15 (s, 1H), 2.76-2.66 (m, 1H), 2.52-2.4 3(m, 1H), 1.84-1.74(m, 3H), 1.66-1.54(m, 6H), 1.50-1.46(m, 1H), 1.43-1.32(m, 4H), 0.92-0.74(m, 8H)ppm. 13 C NMR (100MHz, CDCl3): δ173.51, 145, 91, 110.61, 109.95, 92.40, 73.87, 73.50, 71.94, 52.35, 49.20, 46 .04, 42.69, 30.14, 25.51, 24.92, 24.15, 23.75, 23.02, 22.76, 16.92, 12.47, 11.92ppm. HRMS (ESI): m / z Calcd.for[C 15 H 24 O4Na, M+Na]+: 291.1567; Found: 291.2729.

[0086] Example 8 Preparation of Compounds (-)-ent-Aogacillin A and (+)-Aogacillin B

[0087] To a solution of compounds 8 and 9 (100 mg, 0.37 mmol) in dimethyl sulfoxide (1 mL) was added 2-iodoacylbenzoic acid (336 mg, 1.2 mmol). The reaction mixture was stirred at room temperature for 3 h, and then water was added. The organic phase was collected and the aqueous phase was extracted with ethyl acetate (10 mL×2). The combined organic phases were washed with water (10 mL×3) and saturated brine (10 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain a mixture of compounds aogacillin B and ent-aogacillin A (45 mg, 46%). Finally, (-)-ent-Aogacillin A (5.8 mg) and (+)-Aogacillin B (4 mg) were successfully separated by liquid chromatography.

[0088] The specific separation method was as follows: 0-35 min: 20% acetonitrile + 80% water, gradually decreasing to 60% acetonitrile + 40% water, at 7 mL / min; 35-42 min: 60% acetonitrile + 40% water, decreasing to 75% acetonitrile + 25% water, with the flow rate gradually decreasing to 5 mL / min; and finally 3 min: 75% acetonitrile + 25% water, at 5 mL / min. 40 mg was injected into six separate injections, and the resulting mixture was combined and freeze-dried to yield pure (-)-ent-Aogacillin A (5.8 mg) and pure (+)-Aogacillin B (4 mg).

[0089] ent-Aogacillin A 1 H NMR (400MHz, CD3OD): δ6.44 (s, 1H), 5.77 (s, 1H), 2.17-2.06 (m, 1H), 1.86-1.77 (m, 2H), 1.65-1.58 (m, 3 H), 1.54 (s, 3H), 1.45-1.34 (m, 2H), 1.29-1.19 (m, 1H), 0.95 (d, J=6.8Hz, 3H), 0.71 (t, J=7.2Hz, 3H)ppm. 13 C NMR (100MHz, CD3OD): δ197.39, 174.92, 145.54, 125.52, 91.64, 77.84, 54.61 , 42.36, 30.70, 27.29, 27.23, 26.18, 23.92, 17.18, 12.31ppm.HRMS (ESI): m / z Calcd.for[C 15 H 22 O4Na, M+Na] + :289.1410; Found:289.1414.

[0090] Aogacillin B 1 H NMR (400MHz, CD3OD): δ6.44 (s, 1H), 5.77 (s, 1H), 1.94-1.87 (m, 1H), 1.87-1.78 (m, 2H), 1.73-1.59 (m, 3 H), 1.54 (s, 5H), 1.56-1.51 (m, 2H), 1.18-1.07 (m, 1H), 0.94 (d, J = 7.4Hz, 3H), 0.71 (t, J = 6.6Hz, 3H) ppm. 13CNMR (100MHz, CD3OD): δ197.63, 174.98, 145.64, 125.14, 91.87, 77.95, 31.46, 27.35, 26.38, 26.20, 24.71, 16.10, 12.30ppm. HRMS (ESI): m / z Calcd.for[C 15 H 22 O4Na, M+Na] + :289.1410; Found:289.1415.

[0091] All of the above are intended to be primary implementations of this intellectual property and do not constitute limitations on other implementations of such new products and / or methods. Those skilled in the art will utilize this important information and modify the above to achieve similar implementations. However, all modifications or adaptations based on this invention to new products are reserved.

[0092] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any other manner. Any person skilled in the art may utilize the above-disclosed technical content to modify or modify the present invention into equivalent embodiments. However, any simple modifications, equivalent variations, and modifications to the above embodiments that do not depart from the technical content of the present invention and are based on the technical essence of the present invention remain within the scope of protection of the present invention.

Claims

1. A method for synthesizing Aogacillins spirolactone, characterized in that: The synthetic route is as follows:

2. The method for synthesizing Aogacillins spirolactones as claimed in claim 1, wherein: The method specifically comprises the following steps: In the first step, compound (±)-5 reacts with isopropenylmagnesium bromide to obtain compound (±)-6; In the second step, compound (±)-6 reacts with diphenyl diselenide through allylic oxidation to obtain compound 7; In the third step, compound (±)-7 reacts with (2S,5S)-2-(tert-butyl)-5-methyl-1,3-dioxolane-4-one through aldol condensation and transesterification to give compounds 8 and 9; In the fourth step, compounds 8 and 9 are oxidized to obtain (-)-ent-Aogacillin A and (+)-Aogacillin B.

3. The method for synthesizing Aogacillins spirolactones as claimed in claim 1, wherein: The first step is further specifically, dissolving compound (±)-5 in tetrahydrofuran at 0°C, adding a highly active nucleophile and reacting preferably at 0°C for 1 hour, and post-treating to obtain compound (±)-6, wherein the molar ratio of compound (±)-5 to the highly active nucleophile is preferably 1:1 to 3.

4. The method for synthesizing Aogacillins spirolactones as claimed in claim 1, wherein: The second step is further specifically as follows: under nitrogen protection, compound (±)-6 is dissolved in toluene, diphenyl diselenide and an oxidant are added, and the mixture is preferably stirred at 110°C for 4 hours, and post-treated to obtain compound (±)-7, wherein the molar ratio of the compound (±)-6 and diphenyl diselenide is 1:1 to 3, and the molar ratio of the compound (±)-6 and the oxidant is 1:2 to 5.

5. The method for synthesizing Aogacillins spirolactones as claimed in claim 1, wherein: The third step is further specifically as follows: (2S,5S)-2-(tert-butyl)-5-methyl-1,3-dioxolane-4-one is dissolved in tetrahydrofuran, lithium diisopropylamide is added and the mixture is reacted at -78°C for 1 hour, compound (±)-7 is added, the temperature is raised to -10°C, and the reaction is carried out for 3 hours. Post-treatment is performed to obtain compounds 8 and 9, wherein the molar ratio of the compound (±)-7 and lithium diisopropylamide is 1:2 to 3, and the molar ratio of the compound (±)-7 and (2S,5S)-2-(tert-butyl)-5-methyl-1,3-dioxolane-4-one is 1:2 to 3.

6. The method for synthesizing Aogacillins spirolactones as claimed in claim 1, wherein: In the fourth step, compounds 8 and 9 are dissolved in dimethyl sulfoxide, an oxidant is added, and the mixture is stirred at room temperature for 3 hours, followed by post-treatment to obtain (-)-ent-Aogacillin A and (+)-Aogacillin B, wherein the molar ratio of compounds 8 and 9 to the oxidant is 1:2-4.

7. An intermediate compound for synthesizing Aogacillins spirolactone prepared by the method according to claim 1 or 2, characterized in that: Its chemical structural formula I is shown below:

8. An intermediate compound for synthesizing Aogacillins spirolactone prepared by the method according to claim 1 or 2, characterized in that: Its chemical structural formula II is shown below:

9. An intermediate compound for synthesizing Aogacillins spirolactone prepared by the method according to claim 1 or 2, characterized in that: Its chemical structural formula III is shown below:

10. An intermediate compound for synthesizing Aogacillins spirolactone prepared by the method according to claim 1 or 2, characterized in that: Its chemical structural formula IV is shown below:

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