Synthesis method of polysubstituted cyclopropyl carbonyl compound

Abstract

The invention discloses a synthesis method of a polysubstituted cyclopropyl carbonyl derivative, and belongs to the technical field of organic synthesis and the technical field of medicine synthesis. The method comprises the following steps: (1) taking substituted olefin as a raw material, and obtaining alpha-chlorocyclobutanone through [2 + 2] cycloaddition and reduction reaction; and (2) carrying out rearrangement reaction on the alpha-chlorocyclobutanone and different types of Grignard reagents or organic lithium reagents to obtain the polysubstituted cyclopropyl carbonyl derivative. The synthesis method provided by the invention has the advantages of wide substrate range, good functional group compatibility, mild reaction conditions, no need of preparation of active intermediates or use of expensive transition metal catalysts, simple operation, capability of obtaining various types of cyclopropyl carbonyl compounds, and the like. The practicability of the method is further shown through later-stage functional group modification of complex bioactive molecules and abundant derivatization of polysubstituted cyclopropyl carbonyl products of the complex bioactive molecules.

Description

Technical Field

[0001] This invention relates to the fields of organic synthesis technology and pharmaceutical synthesis technology, and particularly to a method for synthesizing polysubstituted cyclopropyl carbonyl derivatives. Background Technology

[0002] Cyclopropyl groups, as unique and important structural units, are frequently used in drug structure design. Cyclopropane derivatives are also widely found in natural products, drug molecules, and functional materials with significant biological activity. The synthesis and transformation of cyclopropanes and their derivatives is a rapidly developing research area in organic chemistry. Highly reactive cyclopropyl compounds are convenient building blocks for synthesizing various linear, cyclic, and heterocyclic molecules; therefore, effective methods for preparing cyclopropane derivatives with different substitutions are always of paramount importance. However, among the many traditional synthetic methods for cyclopropane compounds, there are two main strategies for de novo synthesis: cyclization / cyclocondensation reaction strategy and the [2+1] strategy using olefins as substrates. The [2+1] strategy using olefins as substrates is generally more universal, especially in the late-stage functionalization of complex molecules. Alternatively, the Kulinkovich reaction can be used to synthesize the corresponding 1-alkylcyclopropanols or 1-alkylcyclopropylamines from carboxylic esters or amides. When using alkenes as substrates, classic methods for constructing cyclopropane skeletons primarily rely on three intermediates: carbenes (free or metal-bound), carbenes (e.g., Simmons-Smith reactions), and ylides (e.g., Corey-Chaykovsky reactions). However, reactions relying on highly reactive intermediates also have significant limitations, such as the use of expensive metal reagents, cumbersome and unstable reagent preparation, limited functional group compatibility, the need for directing groups, and reaction safety. Furthermore, while various types of cyclopropane derivatives are very important in current technologies, there are few reports on the synthesis of polysubstituted cyclopropyl carbonyl derivatives. Therefore, developing a novel synthetic method for polysubstituted cyclopropyl carbonyl derivatives that is universally applicable, has mild reaction conditions, is simple and safe to operate, and is economical is urgent and important. This method could be applied to the structural modification of a wide range of olefin-containing drug molecules, thereby obtaining new active compounds containing cyclopropyl carbonyl structural fragments and providing diverse compounds for drug screening libraries.

[0003] To date, no methods for synthesizing polysubstituted cyclopropyl carbonyl compounds have been reported in the prior art. Summary of the Invention

[0004] To address the shortcomings of existing technologies, the present invention aims to provide a method for synthesizing multi-substituted cyclopropyl carbonyl derivatives. The method provided by this invention offers advantages such as a broad substrate range and good functional group compatibility, mild reaction conditions, no need for preparing active intermediates or using expensive transition metal catalysts, simple operation, and the yield of diverse cyclopropyl carbonyl compounds. Furthermore, the cyclopropane skeleton and exocyclic carbonyl groups of the multi-substituted cyclopropyl carbonyl derivatives of this invention, as shown in Formula I, can undergo multi-directional subsequent derivatization to achieve high-value-added transformations, demonstrating the application value and prospects of this synthetic method and its products in synthetic chemistry and medicinal chemistry.

[0005] To achieve the above-mentioned objectives of the present invention, the present invention provides the following specific solutions:

[0006] This invention provides a method for synthesizing a multi-substituted cyclopropyl carbonyl derivative as shown in Formula I.

[0007]

[0008] Formula I

[0009] In Formula I, R1 is selected from alkyl; R2 is selected from methyl or hydrogen atom; R3 is selected from alkyl; R4 is selected from straight-chain or branched alkyl or cycloalkyl, olefin or branched olefin, phenyl, benzyl or substituted benzene ring, 5 to 6 membered heterocycle or heteroaromatic ring containing N or S heteroatom.

[0010] A method for synthesizing a polysubstituted cyclopropyl carbonyl derivative according to the present invention includes the following steps: (1) using a highly substituted olefin as a raw material, α-chlorocyclobutanone is obtained through [2+2] cycloaddition and reduction reactions; (2) α-chlorocyclobutanone is reacted with different Grignard reagents or organolithium reagents to obtain the polysubstituted cyclopropyl carbonyl derivative. The general reaction formula and process are as follows:

[0011]

[0012] As a preferred embodiment of the above technical solution, in step (1), the reaction solvent in the [2+2] cycloaddition reaction is diethyl ether; the reaction temperature is room temperature; the reaction time is 3~24h; the protective gas is nitrogen or argon; the molar ratio of the highly substituted olefin to zinc powder is 1:4; and the molar ratio of the highly substituted olefin to trichloroacetyl chloride is 1:1.5.

[0013] As a preferred embodiment of the above technical solution, in step (1), the reaction solvent in the reduction reaction is tetrahydrofuran; the reaction temperature is -78℃; the reaction time is 0.5~1h; the protective gas is nitrogen or argon; and the molar ratio of the highly substituted olefin to the prepared 0.1M samarium diiodide tetrahydrofuran solution is 1:3.

[0014] As a preferred embodiment of the above technical solution, in step (2), the reaction solvent is ethylene glycol dimethyl ether; the reaction temperature is -20℃ to 0℃; the reaction time is 2 to 5 hours; the protective gas is nitrogen or argon; and the molar ratio of α-chlorocyclobutanone to commercially available or freshly prepared Grignard reagent and organolithium reagent is 1:1.5.

[0015] The method for synthesizing multi-substituted cyclopropyl carbonyl derivatives is applied in the cyclopropanation modification of complex active molecules and the subsequent derivatization of their products.

[0016] The method for synthesizing a multi-substituted cyclopropyl carbonyl derivative is applied in the cyclopropanation modification of mycophenolic acid and its subsequent derivatization.

[0017] The polysubstituted cyclopropyl carbonyl derivatives P1-P42 and α-chlorocyclobutanone compounds B1-B13, as shown in the following structural formulas, were synthesized by the aforementioned method for synthesizing polysubstituted cyclopropyl carbonyl derivatives:

[0018]

[0019] .

[0020] The application of the multi-substituted cyclopropyl carbonyl derivatives P1-P42 and α-chlorocyclobutanone compounds B1-B13 in the cyclopropanization modification of complex active molecules and their subsequent derivatization.

[0021] The application of the polysubstituted cyclopropyl carbonyl derivatives P1-P42 and α-chlorocyclobutanone compounds B1-B13 in the cyclopropanation modification of mycophenolic acid and its subsequent derivatization.

[0022] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0023] 1. Compared with classical methods, this invention does not require the preparation of active intermediates or the use of expensive transition metal catalysts. It is not only safer, simpler and more convenient to operate, but also has low experimental costs. Moreover, the experimental conditions are mild, with a wide substrate range and good functional group compatibility. It provides a method for the rapid preparation of polysubstituted cyclopropyl carbonyl derivatives from highly substituted olefins.

[0024] 2. This invention uses readily available Grignard reagents or organolithium reagents to synthesize structurally diverse multi-substituted cyclopropyl carbonyl derivatives, which is an effective strategy for obtaining complex molecules with diverse structural types.

[0025] 3. The cyclopropane skeleton and exocyclic carbonyl groups of the multi-substituted cyclopropyl carbonyl derivatives of this invention can be further derivatized in multiple directions to achieve high added value transformation. The practicality of this synthetic method and the potential value and application prospects of the product, namely the multi-substituted cyclopropyl carbonyl derivatives, are demonstrated by the cyclopropanization modification of the active molecule mycophenolic acid and the subsequent derivatization of the product. Attached Figure Description

[0026] Figure 1 This is a schematic diagram of the chemical structure of compound B, α-chlorocyclobutanone.

[0027] Figure 2 This is a schematic diagram of the chemical structure of the polysubstituted cyclopropyl carbonyl derivative P.

[0028] Figure 3 This study focuses on the cyclopropanation modification of the active molecule mycophenolic acid and the subsequent derivatization and diversification of its products.

[0029] Figure 4 The reaction formula is for polysubstituted cyclopropyl carbonyl derivatives. Detailed Implementation

[0030] A method for synthesizing polysubstituted cyclopropyl carbonyl derivatives, comprising the following steps: (1) using a highly substituted olefin A as a starting material, obtaining α-chlorocyclobutanone compound B through [2+2] cycloaddition and reduction reactions; (2) reacting α-chlorocyclobutanone compound B with different Grignard reagents or organolithium reagents to obtain the corresponding polysubstituted cyclopropyl carbonyl derivative P. The general reaction formula and process are as follows:

[0031]

[0032] (1) The general procedure for the synthesis of α-chlorocyclobutanone compound B is as follows:

[0033] Olefin compound A (1.0 equivalent) was dissolved in anhydrous diethyl ether (0.1–0.2 mol / L), zinc powder (3.0–8.0 equivalent) was added, and trichloroacetyl chloride (1.5 equivalent) was dissolved in the remaining quarter-volume of anhydrous diethyl ether and slowly added dropwise to the system, completing the addition within 1 hour. The mixture was stirred vigorously at room temperature for 3–24 hours. After TLC detection of complete reaction, the solid residue was filtered through diatomaceous earth, and the crude product obtained after concentration under reduced pressure required no further purification. The crude product was dissolved in tetrahydrofuran (0.5 M), and a solution of samarium diiodide in tetrahydrofuran (0.1 M, 2–5 equivalents) was added at -78°C. The mixture was stirred for approximately 30 minutes, and after TLC detection of complete reaction, it was quenched with saturated potassium carbonate aqueous solution, extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain the corresponding α-chlorocyclobutanone compound B, or it could be used in the next reaction without further purification.

[0034] (2) The synthesis of polysubstituted cyclopropyl carbonyl derivative P has two operation methods, and the specific implementation methods are as follows:

[0035] Method 1: Dissolve α-chlorocyclobutanone compound B (1.0 equivalent) in ethylene glycol dimethyl ether (0.2 M). Slowly add commercially available or freshly prepared Grignard reagent (1.5 equivalent) or organolithium reagent (1.5 equivalent) dropwise at -20°C. After complete addition, raise the reaction temperature to 0°C and stir for 2-5 hours. After the reaction is complete as detected by TLC, quench with saturated ammonium chloride aqueous solution, extract three times with ethyl acetate, wash with saturated brine, dry with anhydrous sodium sulfate and filter. After concentration under reduced pressure, purify and separate by column chromatography or preparative TLC plate to obtain the corresponding polysubstituted cyclopropyl carbonyl derivative P. The target product is confirmed by NMR spectroscopy and high-resolution mass spectrometry.

[0036] Method 2: Dissolve α-chlorocyclobutanone compound B (1.0 equivalent) in 1,4-dioxane (0.2 M), and slowly add commercially available or freshly prepared Grignard reagent (1.5 equivalent) or organolithium reagent (1.5 equivalent) dropwise at room temperature. After complete addition, stir for 2-5 hours. After the reaction is complete as detected by TLC, quench with saturated ammonium chloride aqueous solution, extract three times with ethyl acetate, wash with saturated brine, dry with anhydrous sodium sulfate and filter. After concentration under reduced pressure, purify and separate by column chromatography or preparative TLC plate to obtain the corresponding polysubstituted cyclopropyl carbonyl derivative P. The target product is confirmed by NMR spectroscopy and high-resolution mass spectrometry.

[0037] It should be noted that in this invention, both methods of synthesizing the polysubstituted cyclopropyl carbonyl derivative P can yield the target product, but the yields of the target product obtained by the two methods are different. Different substrates are suitable for different methods. If a higher yield is required for the preparation of the polysubstituted cyclopropyl carbonyl derivative P, the reaction can be compared and scaled up by referring to the two methods mentioned above.

[0038] The synthesis, reaction formulas, and specific implementation methods of preparative Grignard reagents D and F are as follows:

[0039] 1) Synthesis of preparative Grignard reagent D:

[0040]

[0041] Dissolve the corresponding bromide or iodide C (1.5 mmol, 1.0 equivalent) in tetrahydrofuran (1.5 mL, 1.0 M), and slowly add isopropyl magnesium bromide solution (1.0 M in THF, 1.5 mL, 1.5 mmol, 1.0 equivalent) at -10 °C or -40 °C. After stirring vigorously for several hours, the resulting Grignard reagents D1-D4 can be used directly in the next reaction.

[0042] 2) Synthesis of preparative Grignard reagent F:

[0043]

[0044] Magnesium shavings (73.0 mg, 3.0 mmol, 2.0 equivalent) and tetrahydrofuran solution (1.0 mL) were added to a dry, sealed tube under argon protection. 2-3 drops of 1,2-dibromoethane were added dropwise with stirring at room temperature. The corresponding bromide E (1.5 mmol, 1.0 equivalent) was diluted in tetrahydrofuran (2.0 mL), and 0.5 mL of the diluted solution was slowly added dropwise to the reaction system. The tube was then heated with a hot air gun until the reaction was initiated. After initiation, the remaining 1.5 mL of the diluted solution was slowly added dropwise to the reaction system, followed by vigorous stirring at 50 °C for approximately 1 hour. The reaction system was cooled to room temperature to obtain Grignard reagents F1-F5.

[0045] The synthesis of the preparative organolithium reagent H (0.3 M in THF), including the reaction formula and specific implementation method, is as follows:

[0046]

[0047] The corresponding thiophene compound G (1.5 mmol, 1.0 equivalent) was dissolved in tetrahydrofuran (4.0 mL), and a solution of n-butyllithium (1.6 M in n-hexane, 0.94 mL, 1.5 mmol, 1.0 equivalent) was slowly added dropwise at -78 °C. After the addition was complete, the mixture was stirred vigorously at room temperature for 30 minutes. The resulting organolithium reagents H1 and H2 were then used directly in the next reaction step.

[0048] In this invention, unless otherwise specified, all raw materials are commercially available products well known to those skilled in the art. In the embodiments of this invention, the olefin raw materials A1 and A2 in Examples 1 and 11 are synthesized. Reactions and products already reported in the literature in the synthetic routes will not be repeated; only new reactions and products will be described.

[0049] The present invention will be further described in detail below with reference to the accompanying drawings and embodiments, but the present invention is not limited to the specific embodiments described below. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention.

[0050] Example 1

[0051] The α-chlorocyclobutanone compound B1 prepared in this embodiment has the following structure:

[0052]

[0053] The preparation method and conditions are the general procedures for the synthesis of α-chlorocyclobutanone compound B, as detailed below:

[0054] 1) Synthesis of olefin feedstock A1:

[0055]

[0056] Under nitrogen protection, 3-(2,6,6-trimethylcyclohexyl-2-en-1-yl)prop-1-ol (10.9 g, 60.0 mmol, 1.0 equivalent) was dissolved in DMF (120 mL, 0.5 M). Sodium hydride (60% dispersion in mineral oil, 2.9 g, 72.0 mmol, 1.2 equivalent) was added in small, partial batches at 0 °C, and the mixture was stirred at room temperature for 1 hour after the addition was complete. Subsequently, benzyl bromide (9.3 mL, 78.0 mmol, 1.3 equivalent) was added dropwise to the reaction system at room temperature, and stirring was continued for 12 hours. After the reaction was confirmed to be complete by TLC, it was quenched with saturated ammonium chloride aqueous solution, extracted three times with ethyl acetate, washed four times with pure water, washed once with saturated brine, dried over anhydrous sodium sulfate and filtered. After concentration under reduced pressure, it was purified and separated by silica gel column chromatography (300-400 mesh) (petroleum ether / ethyl acetate = 150:1-50:1, v / v) to give the corresponding olefin compound A1 (colorless oil, yield 93%). f = 0.45 (silica gel, petroleum ether / ethyl acetate = 22:1); 1 H NMR (400 MHz, CDCl3) δ 7.40–7.32 (m, 4H), 7.32–7.25 (m, 1H), 5.30 (s, 1H), 4.51 (s, 2H), 3.46 (t, J = 6.7 Hz, 2H), 1.97 (s, 2H), 1.80–1.62 (m,2H), 1.69 (s, 3H), 1.55–1.31 (m, 4H), 1.18–1.07 (m, 1H), 0.93 (s, 3H), 0.88(s, 3H); 13 C NMR (125 MHz, CDCl3) δ 138.64, 136.49, 128.29, 127.55, 127.40,120.08, 72.82, 70.97, 49.05, 32.52, 31.51, 30.21, 27.55, 27.43, 27.29, 23.50,23.00; HRMS (ESI) m / z: [M+H] + calcd for C 19 H 29 O 273.2213, found 273.2214.

[0057] 2) Synthesis of α-chlorocyclobutanone compound B1:

[0058]

[0059] Under nitrogen protection, olefin compound A1 (8.2 g, 30.0 mmol, 1.0 equivalent) was dissolved in three-quarters of the volume of anhydrous diethyl ether (112.5 mL, 0.2 M). Zinc powder (7.8 g, 120.0 mmol, 4.0 equivalent) was added, followed by trichloroacetyl chloride (5.1 mL, 45.0 mmol, 1.5 equivalent) dissolved in the remaining quarter of the volume of anhydrous diethyl ether (37.5 mL), which was then slowly added dropwise over one hour until complete. The mixture was stirred vigorously at room temperature for 18 hours. After the reaction was confirmed to be complete by TLC, the solid residue was filtered through diatomaceous earth, and the crude product obtained after concentration under reduced pressure required no further purification. The crude reaction product was dissolved in dry tetrahydrofuran (60.0 mL, 0.5 M), and a solution of samarium diiodide in tetrahydrofuran (0.1 M in THF, 900 mL, 90.0 mmol, 3.0 equivalent) was added at -78 °C. The mixture was stirred for about 30 minutes. After the reaction was confirmed to be complete by TLC, it was quenched with saturated potassium carbonate aqueous solution, extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (300-400 mesh) (petroleum ether / ethyl acetate = 100:1-30:1, v / v) to give the corresponding α-chlorocyclobutanone compound B1 (colorless oil, yield 27%). f = 0.33 (silica gel, petroleum ether / ethyl acetate 12:1); 1 H NMR (400 MHz, CDCl3) δ 7.38–7.31 (m, 4H), 7.31–7.25 (m, 1H), 4.54 (d, J = 2.5 Hz, 1H), 4.50 (s, 2H), 3.52–3.37 (m, 2H), 3.02–2.94 (m, 1H),1.99–1.89 (m, 1H), 1.88–1.76 (m, 2H), 1.65 (tt, J = 13.7, 6.7 Hz, 1H), 1.53(s, 3H), 1.54–1.41 (m, 2H), 1.30–1.13 (m, 3H), 0.93 (s, 3H), 0.88 (s, 3H); 13CNMR (100 MHz, CDCl3) δ 200.70, 138.70, 128.32, 127.55, 127.43, 72.70, 71.89,71.23, 59.32, 46.59, 39.35, 37.69, 33.39, 31.71, 30.94, 24.98, 24.93, 20.11,17.05; HRMS (ESI) m / z: [M+Na] + calcd for C 21 H 29 ClO2Na 371.1748, found 371.1739.

[0060] Example 2

[0061] The α-chlorocyclobutanone compound B2 prepared in this embodiment has the following structure:

[0062]

[0063] The preparation method and conditions in this embodiment are the same as in Example 1, and the feed ratio is the same as in Example 1. The corresponding olefin raw material (10.0 mmol, 1.0 equivalent) is added, and the product is purified and separated by silica gel column chromatography (300-400 mesh) (petroleum ether / ethyl acetate = 200:1-50:1, v / v) to obtain the corresponding α-chlorocyclobutanone compound B2 (light yellow oil, yield 41%). f = 0.38 (silica gel, petroleum ether / ethyl acetate 20:1); 1 H NMR (400 MHz, CDCl3) δ 4.68 (d, J = 3.7 Hz, 1H), 3.20 (dd, J = 7.8,3.7 Hz, 1H), 2.30–2.17 (m, 1H), 2.09 (dd, J = 12.6, 5.1 Hz, 1H), 1.87–1.77(m, 1H), 1.77–1.66 (m, 1H), 1.60–1.47 (m, 2H), 1.53 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 207.14, 69.23, 67.20, 46.30, 35.38, 30.79, 26.84, 25.47; HRMS (ESI)m / z: [M−H] − calcd for C8H 10 ClO 157.0426, found 157.0425.

[0064] Example 3

[0065] The α-chlorocyclobutanone compound B3 prepared in this embodiment has the following structure:

[0066]

[0067] The preparation method and conditions in this embodiment are the same as in Example 1, and the feed ratio is the same as in Example 1. The corresponding olefin raw material (10.0 mmol, 1.0 equivalent) is added, and the product is purified and separated by silica gel column chromatography (300-400 mesh) (petroleum ether / ethyl acetate = 200:1-50:1, v / v) to obtain the corresponding α-chlorocyclobutanone compound B3 (light yellow oil, yield 35%). f = 0.36 (silica gel, petroleum ether / ethyl acetate 20:1); 1 H NMR (400 MHz, CDCl3) δ 4.58 (d, J = 2.2 Hz, 1H), 2.92–2.87 (m, 1H), 2.06–1.95 (m, 1H), 1.66–1.49 (m, 3H), 1.45 (s, 3H), 1.42–1.26 (m, 2H), 1.25–1.00 (m, 2H); 13 C NMR (125 MHz, CDCl3) δ 200.20, 69.65, 57.28, 34.39, 30.74,24.62, 22.04, 20.32, 19.93; HRMS (ESI) m / z: [M+COOH] − calcd for C 10 H 14 ClO3217.0637, found 217.0638.

[0068] Example 4

[0069] The α-chlorocyclobutanone compound B4 prepared in this embodiment has the following structure:

[0070]

[0071] The preparation method and conditions in this embodiment are the same as in Example 1, and the feed ratio is the same as in Example 1. The corresponding olefin raw material (3.0 mmol, 1.0 equivalent) is added, and the product is purified and separated by silica gel column chromatography (300-400 mesh) (petroleum ether / ethyl acetate = 100:1-10:1, v / v) to obtain the corresponding α-chlorocyclobutanone compound B4 (white solid, yield 19%).f = 0.35 (silica gel, petroleum ether / ethyl acetate 8:1); mp 104–108°C; 1 H NMR (400 MHz, CDCl3) δ 7.42–7.33(m, 1H), 7.32–7.22 (m, 3H), 5.32 (dd, J = 9.0, 2.8 Hz, 1H), 4.38 (t, J = 8.3Hz, 1H), 4.12–4.02 (m, 1H), 3.38 (d, J = 16.6 Hz, 1H), 3.15 (dd, J = 16.6,9.2 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ 204.05, 143.66, 137.71, 128.42,128.19, 126.86, 125.42, 65.52, 58.85, 44.94, 34.76; HRMS (ESI) m / z: [MH] - calcd for C 11 H8ClO 191.0269, found 191.0265.

[0072] Example 5

[0073] The α-chlorocyclobutanone compound B6 prepared in this embodiment has the following structure:

[0074]

[0075] The preparation method and conditions in this embodiment are the same as in Example 1, and the feed ratio is the same as in Example 1. The corresponding olefin raw material (4.0 mmol, 1.0 equivalent) is added, and the product is purified and separated by silica gel column chromatography (300-400 mesh) (petroleum ether / ethyl acetate = 100:1-30:1, v / v) to obtain the corresponding α-chlorocyclobutanone compound B6 (colorless oil, yield 63%). f = 0.38 (silica gel, petroleum ether / ethyl acetate 20:1); 1H NMR (400 MHz, CDCl3) δ 7.45–7.34 (m, 4H), 7.34–7.27 (m, 1H), 4.95 (d, J = 2.2 Hz, 1H), 3.56–3.48 (m, 1H), 2.35–2.23 (m, 1H), 2.09–1.99 (m, 1H), 1.81–1.66 (m, 3H), 1.60–1.49 (m, 1H), 1.35–1.11 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 199.53, 146.34, 128.62, 127.07, 125.70, 70.47, 55.38, 41.53, 33.17,21.89, 21.13, 19.43; HRMS (ESI) m / z: [M+Na] + calcd for C 14 H 15 ClONa 257.0704,found 257.0705.

[0076] Example 6

[0077] The α-chlorocyclobutanone compound B8 prepared in this embodiment has the following structure:

[0078]

[0079] The preparation method and conditions in this embodiment are the same as in Example 1, and the feed ratio is the same as in Example 1. The corresponding olefin raw material (5.0 mmol, 1.0 equivalent) is added, and the product is purified and separated by silica gel column chromatography (300-400 mesh) (petroleum ether / ethyl acetate = 100:1-25:1, v / v) to obtain the corresponding α-chlorocyclobutanone compound B8 (colorless oil, yield 33%). f = 0.32 (silica gel, petroleum ether / ethyl acetate 12:1); 1H NMR (400 MHz, CDCl3) δ 5.67 (d, J = 1.5 Hz, 1H), 4.56 (d, J = 2.5Hz, 1H), 3.68 (s, 3H), 3.03–2.96 (m, 1H), 2.43–2.25 (m, 2H), 2.17 (s, 3H), 2.00–1.90 (m, 1H), 1.72–1.47 (m, 3H), 1.54 (s, 3H), 1.31–1.13 (m, 3H), 0.94 (s, 3H), 0.89 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 200.21, 167.31, 160.94,114.81, 71.78, 59.21, 50.80, 46.45, 41.82, 39.43, 37.56, 33.51, 31.66, 26.67,24.71, 20.08, 18.96, 16.94; HRMS (ESI) m / z: [M+Na] + calcd for C 18 H 27 ClO3Na349.1540, found 349.1541.

[0080] Example 7

[0081] The α-chlorocyclobutanone compound B9 prepared in this embodiment has the following structure:

[0082]

[0083] The preparation method and conditions in this embodiment are the same as in Example 1, and the feed ratio is the same as in Example 1. The corresponding olefin raw material (1.0 mmol, 1.0 equivalent) is added, and the product is purified and separated by silica gel column chromatography (300-400 mesh) (petroleum ether / ethyl acetate = 100:1-30:1, v / v) to obtain the corresponding α-chlorocyclobutanone compound B9 (white solid, yield 62%).

[0084] [α]20 D = +14.62 (c = 0.264 in MeOH); 1H NMR (400 MHz, CDCl3) δ 7.72–7.61 (m, 4H), 7.45–7.32 (m, 6H), 4.46 (d, J = 2.5 Hz, 1H), 3.86–3.67 (m, 2H), 3.04–2.97 (m, 1H), 2.02–1.93 (m, 1H), 1.79–1.61 (m, 2H), 1.51 (s, 3H), 1.47–1.14 (m, 6H), 1.05 (s, 9H), 0.90–0.85 (m, 1H), 0.82 (s, 3H), 0.78 (s, 3H),0.77 (s, 3H), 0.74–0.67 (m, 1H), 0.57–0.45 (m, 1H); 13 C NMR (125 MHz, CDCl3) δ201.20, 135.62, 135.60, 134.18, 133.98, 129.50, 129.49, 127.56, 127.53,72.00, 64.57, 59.26, 49.88, 48.13, 41.75, 38.94, 38.74, 36.93, 33.07, 32.94,31.03, 26.92, 25.45, 21.38, 19.14, 18.01, 17.75, 14.32; HRMS (ESI) m / z: [M+K] + calcd for C 34 H 47 ClO2SiK 589.2665, found 589.2669.

[0085] Example 8

[0086] The α-chlorocyclobutanone compound B10 prepared in this embodiment has the following structure:

[0087]

[0088] 1) Synthesis of olefin feedstock A2:

[0089]

[0090] Under nitrogen protection, methyl mycophenolate (3.3 g, 10.0 mmol, 1.0 equivalent) was dissolved in DMF (50 mL, 0.2 M). Imidazole (4.7 g, 70.0 mmol, 7.0 equivalent) and 4-dimethylaminopyridine (24.5 mg, 0.2 mmol, 0.02 equivalent) were added at room temperature, followed by dropwise addition of tert-butyldiphenylchlorosilane (7.9 mL, 30.0 mmol, 3.0 equivalent). The mixture was stirred for 48 hours. After the reaction was confirmed to be complete by TLC, it was quenched with saturated ammonium chloride aqueous solution, extracted three times with ethyl acetate, washed four times with pure water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (300-400 mesh) (petroleum ether / ethyl acetate = 30:1-5:1, v / v) to give the corresponding olefin compound A2 (colorless oil, yield 98%). [α]25 D = +29.41 (c = 0.257 in MeOH); 1 H NMR (400 MHz, CDCl3)δ 7.73–7.66 (m, 4H), 7.41–7.28 (m, 6H), 5.02–4.90 (m, 1H), 4.95 (s, 2H), 3.62 (s, 3H), 3.61 (s, 3H), 3.18 (d, J = 6.1 Hz, 2H), 2.36–2.27 (m, 2H), 2.24–2.16 (m, 2H), 2.12 (s, 3H), 1.50 (s, 3H), 1.09 (s, 9H); 13 C NMR (125 MHz, CDCl3) δ 173.74, 168.28, 163.22, 151.56, 145.91,134.97, 133.66, 133.56, 129.39, 127.29, 123.77, 117.84, 111.20, 67.38, 60.55,51.41, 34.28, 32.73, 26.56, 24.25, 20.35, 16.11, 11.29. HRMS (ESI) m / z: [M+Na] + calcd for C 34 H 40 O6SiNa 595.2486, found 595.2494.

[0091] 2) Synthesis of α-chlorocyclobutanone compound B10:

[0092]

[0093] The preparation method and conditions in this embodiment are the same as in Example 1, and the feed ratio is the same as in Example 1. The corresponding olefin raw material A2 (8.0 mmol, 1.0 equivalent) is added, and the corresponding α-chlorocyclobutanone compound B10 (white solid, yield 46%) is purified and separated by silica gel column chromatography (300-400 mesh) (petroleum ether / ethyl acetate = 25:1-4:1, v / v) to obtain the corresponding α-chlorocyclobutanone compound B10 (white solid, yield 46%). 1 H NMR (400MHz, CDCl3) δ 7.66 (d, J = 6.5 Hz, 2H), 7.57 (d, J = 6.5 Hz, 2H), 7.39–7.18(m, 6H), 4.92 (s, 2H), 4.43 (d, J = 2.5 Hz, 1H), 3.57 2.05 (s, 3H), 2.01–1.91 (m, 1H), 1.87–1.75 (m,1H), 1.67–1.57 (m, 1H), 1.04 (s, 9H), 0.66 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ198.80, 173.11, 168.17, 163.00, 151.93, 146.82, 135.48, 135.34, 132.68,129.77, 129.73, 127.55, 127.38, 124.23, 118.29, 112.02, 67.55, 67.39, 61.64,60.53, 51.73, 38.90, 36.38, 29.69, 26.53, 20.64, 20.46, 14.93, 11.15; HRMS(ESI) m / z: [M+Na] + calcd for C 36 H 41 ClO7SiNa 671.2202, found 671.2209.

[0094] Example 9

[0095] The polysubstituted cyclopropyl carbonyl derivative P1 prepared in this embodiment has the following structure:

[0096]

[0097] The preparation method and conditions are general operations for the synthesis of multi-substituted cyclopropyl carbonyl derivatives P. Both operation methods can yield the target product P1. This example describes the operation of method 1 in detail as follows:

[0098] Under nitrogen protection, α-chlorocyclobutanone compound B1 (34.9 mg, 0.1 mmol, 1.0 equivalent) was dissolved in ethylene glycol dimethyl ether (0.50 mL, 0.2 M). Commercially available magnesium methyl bromide (1.0 M in THF, 0.15 mL, 0.15 mmol, 1.5 equivalent) was slowly added dropwise at -20 °C. The reaction temperature was then raised to 0 °C and stirred for 4 hours. After TLC detection of complete reaction, the mixture was quenched with saturated ammonium chloride aqueous solution, extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (300-400 mesh) (petroleum ether / ethyl acetate = 100:1–25:1, v / v) to obtain the corresponding polysubstituted cyclopropyl carbonyl derivative P1 (colorless oil, yield 34%).

[0099] 1 H NMR (400 MHz, CDCl3)δ 7.39–7.08 (m, 5H), 4.48 (s, 2H), 3.49–3.36(m, 2H), 2.20 (s, 3H), 1.90–1.78 (m, 1H), 1.73–1.60 (m, 2H), 1.63 (d, J = 7.9Hz, 1H), 1.55–1.44 (m, 2H), 1.43–1.27 (m, 4H), 1.16 (s, 3H), 1.19–1.05 (m,1H), 0.85 (s, 3H), 0.80 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 207.84, 138.68,128.33, 127.55, 127.45, 72.87, 70.63, 38.74, 37.95, 33.75, 32.97, 32.13,31.22, 29.67, 28.76, 25.06, 22.39, 22.25, 15.45; HRMS (ESI) m / z: [M+H] + calcdfor C 22 H 33 O2 329.2475, found 329.2479.

[0100] Example 10

[0101] The polysubstituted cyclopropyl carbonyl derivative P2 prepared in this embodiment has the following structure:

[0102]

[0103] The preparation method and conditions in this embodiment are the same as in Example 12, and the feed ratio is the same as in Example 12. α-chlorocyclobutanone compound B1 (34.9 mg, 0.1 mmol, 1.0 equivalent) and commercially available ethyl phthalic magnesium bromide (1.0 minTHF, 0.15 mL, 0.15 mmol, 1.5 equivalent) were added. The mixture was purified and separated by silica gel column chromatography (300-400 mesh) (petroleum ether / ethyl acetate = 100:1-25:1, v / v) to obtain the corresponding polysubstituted cyclopropyl carbonyl derivative P2 (colorless oil, yield 35%).

[0104] 1 H NMR (400 MHz, CDCl3) δ 7.35–7.21 (m, 5H), 4.47 (s, 2H), 3.47–3.33(m, 2H), 2.63–2.42 (m, 2H), 1.91–1.79 (m, 1H), 1.72–1.59 (m, 2H), 1.62 (d, J= 7.9 Hz, 1H), 1.58–1.44 (m, 2H), 1.43–1.22 (m, 4H), 1.16 (s, 3H), 1.18–1.08(m, 1H), 1.01 (t, J = 7.3 Hz, 3H), 0.86 (s, 3H), 0.81 (s, 3H); 13 C NMR (125MHz, CDCl3) δ 210.46, 138.69, 128.32, 127.54, 127.44, 72.86, 70.62, 39.23,38.76, 38.50, 37.24, 33.02, 32.05, 30.85, 29.68, 28.67, 25.03, 22.45, 22.26,15.53, 8.02; HRMS (ESI) m / z: [M+H] + calcd for C 23 H 35 O2 343.2632, found343.2631.

[0105] Example 11

[0106] The polysubstituted cyclopropyl carbonyl derivative P3 prepared in this embodiment has the following structure:

[0107]

[0108] The preparation method and conditions in this embodiment are the same as in Example 12, and the feed ratio is the same as in Example 12. α-chlorocyclobutanone compound B1 (34.9 mg, 0.1 mmol, 1.0 equivalent) and commercially available isopropyl magnesium bromide (1.0 M in THF, 0.15 mL, 0.15 mmol, 1.5 equivalent) were added. The mixture was purified and separated by silica gel column chromatography (300-400 mesh) (petroleum ether / ethyl acetate = 100:1-25:1, v / v) to obtain the corresponding polysubstituted cyclopropyl carbonyl derivative P3 (colorless oil, yield 50%).

[0109] 1 H NMR (400 MHz, CDCl3) δ 7.36–7.21 (m, 5H), 4.47 (s, 2H), 3.48–3.33(m, 2H), 2.74–2.62 (m, 1H), 1.82–1.71 (m, 1H), 1.68 (d, J = 8.4 Hz, 1H),1.71–1.61 (m, 2H), 1.61–1.53 (m, 1H), 1.53–1.44 (m, 2H), 1.42–1.33 (m, 2H),1.33–1.22 (m, 1H), 1.16 (s, 3H), 1.15–1.10 (m, 1H), 1.07 (dd, J = 6.9, 5.4Hz, 6H), 0.86 (s, 3H), 0.81 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 213.53,138.72, 128.30, 127.50, 127.40, 72.78, 70.64, 43.47, 38.58, 38.05, 36.26,33.16, 32.51, 31.12, 29.71, 28.79, 25.13, 22.42, 22.30, 18.42, 18.21, 15.58;HRMS (ESI) m / z: [M+H] + calcd for C 24 H 37 O2 357.2788, found 357.2788.

[0110] Example 12

[0111] The polysubstituted cyclopropyl carbonyl derivative P4 prepared in this embodiment has the following structure:

[0112]

[0113] The preparation method and conditions in this embodiment are the same as in Example 12, and the feed ratio is the same as in Example 12. α-chlorocyclobutanone compound B1 (34.9 mg, 0.1 mmol, 1.0 equivalent) and commercially available cyclopropyl magnesium bromide (0.5 minTHF, 0.30 mL, 0.15 mmol, 1.5 equivalent) were added. The mixture was purified and separated by silica gel column chromatography (300-400 mesh) (petroleum ether / ethyl acetate = 100:1-25:1, v / v) to obtain the corresponding polysubstituted cyclopropyl carbonyl derivative P4 (colorless oil, yield 53%).

[0114] 1 H NMR (400 MHz, CDCl3) δ 7.38–7.18 (m, 5H), 4.48 (s, 2H), 3.50–3.35(m, 2H), 2.05 (tt, J = 8.0, 4.6 Hz, 1H), 1.95–1.82 (m, 1H), 1.81 (d, J = 7.9Hz, 1H), 1.78–1.63 (m, 2H), 1.53–1.42 (m, 2H), 1.41–1.25 (m, 4H), 1.20 (s,3H), 1.16–1.07 (m, 1H), 1.02–0.89 (m, 2H), 0.83 (s, 3H), 0.81 (s, 3H), 0.82–0.70 (m, 2H); 13 C NMR (125 MHz, CDCl3) δ 209.44, 138.72, 128.31, 127.52,127.42, 72.82, 70.68, 39.10, 38.79, 38.72, 32.96, 32.01, 31.12, 29.66, 28.65,25.21, 23.32, 22.34, 15.72, 10.27, 10.23; HRMS (ESI) m / z: [M+H] + calcd forC 24 H 35 O2 355.2632, found 355.2633.

[0115] Example 13

[0116] The polysubstituted cyclopropyl carbonyl derivative P5 prepared in this embodiment has the following structure:

[0117]

[0118] The preparation method and conditions in this embodiment are the same as in Example 12, and the feed ratio is the same as in Example 12. α-chlorocyclobutanone compound B1 (34.9 mg, 0.1 mmol, 1.0 equivalent) and commercially available isopropenyl magnesium bromide (0.5 M inTHF, 0.30 mL, 0.15 mmol, 1.5 equivalent) were added. The mixture was purified and separated by silica gel column chromatography (300-400 mesh) (petroleum ether / ethyl acetate = 100:1-25:1, v / v) to obtain the corresponding polysubstituted cyclopropyl carbonyl derivative P5 (colorless oil, yield 25%).

[0119] 1 H NMR (400 MHz, CDCl3)δ 7.37–7.24 (m, 5H), 5.89 (s, 1H), 5.67 (s,1H), 4.46 (s, 2H), 3.43–3.30 (m, 2H), 2.06 (d, J = 8.1 Hz, 1H), 2.01–1.91 (m,1H), 1.86 (s, 3H), 1.82–1.68 (m, 1H), 1.69–1.58 (m, 1H), 1.53–1.45 (m, 1H),1.44–1.31 (m, 2H), 1.23 (s, 3H), 1.31–1.12 (m, 4H), 0.86 (s, 3H), 0.83 (s,3H); 13 C NMR (125 MHz, CDCl3) δ 201.49, 146.85, 138.72, 128.31, 127.52,127.42, 122.93, 72.77, 70.54, 39.57, 38.67, 33.85, 32.99, 31.22, 30.94,29.68, 28.94, 25.24, 22.36, 21.82, 17.99, 15.72; HRMS (ESI) m / z: [M+H] + calcdfor C 24 H 35 O2 355.2632, found 355.2631.

[0120] Example 14

[0121] The polysubstituted cyclopropyl carbonyl derivative P6 prepared in this embodiment has the following structure:

[0122]

[0123] In this embodiment, the preparation method and conditions are as follows: Method 2 in the general operation for the synthesis of polysubstituted cyclopropyl carbonyl derivative P to obtain the target product P6, as detailed below:

[0124] Under nitrogen protection, α-chlorocyclobutanone compound B1 (34.9 mg, 0.1 mmol, 1.0 equivalent) was dissolved in 1,4-dioxane (0.50 mL, 0.2 M). Commercially available cyclopentylmagnesium bromide (2.0 M inTHF, 0.075 mL, 0.15 mmol, 1.5 equivalent) was slowly added dropwise at room temperature. After complete addition, the mixture was stirred at room temperature for 3 hours. After TLC detection of the reaction, the mixture was quenched with saturated ammonium chloride solution, extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (300-400 mesh) (petroleum ether / ethyl acetate = 100:1–50:1, v / v) to obtain the corresponding polysubstituted cyclopropyl carbonyl derivative P6 (colorless oil, yield 15%).

[0125] 1 H NMR (400 MHz, CDCl3)δ 7.38–7.24 (m, 5H), 4.49 (s, 2H), 3.49–3.35(m, 2H), 3.03–2.90 (m, 1H), 1.90–1.73 (m, 5H), 1.73–1.65 (m, 2H), 1.68 (d, J= 8.1 Hz, 1H), 1.65–1.56 (m, 4H), 1.55–1.45 (m, 3H), 1.44–1.24 (m, 3H), 1.18 (s, 3H), 1.16–1.09 (m, 1H), 0.88 (s, 3H), 0.83 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 212.21, 138.74, 128.31, 127.50, 127.41, 72.78, 70.65, 54.41, 38.67,38.15, 37.18, 33.14, 32.47, 31.02, 29.72, 29.12, 28.75, 28.42, 25.99, 25.96,25.14, 22.40, 22.38, 15.63; HRMS (ESI) m / z: [M+H]+ calcd for C 26 H 39 O2 383.2945, found 383.2949.

[0126] Example 15

[0127] The polysubstituted cyclopropyl carbonyl derivative P7 prepared in this embodiment has the following structure:

[0128]

[0129] The preparation method and conditions in this embodiment are the same as in Example 12, and the feed ratio is the same as in Example 12. α-chlorocyclobutanone compound B1 (34.9 mg, 0.1 mmol, 1.0 equivalent) and commercially available cyclohexyl magnesium bromide (1.0 minTHF, 0.15 mL, 0.15 mmol, 1.5 equivalent) were added. The mixture was purified and separated by silica gel column chromatography (300-400 mesh) (petroleum ether / ethyl acetate = 100:1-50:1, v / v) to obtain the corresponding polysubstituted cyclopropyl carbonyl derivative P7 (colorless oil, yield 92%).

[0130] 1 H NMR (400 MHz, CDCl3)δ 7.39–7.24 (m, 5H), 4.49 (s, 2H), 3.50–3.35(m, 2H), 2.48–2.36 (m, 1H), 1.94–1.84 (m, 2H), 1.82–1.73 (m, 3H), 1.69 (d, J= 8.2 Hz, 1H), 1.73–1.55 (m, 4H), 1.56–1.46 (m, 2H), 1.44–1.32 (m, 3H), 1.32–1.23 (m, 4H), 1.17 (s, 3H), 1.23–1.09 (m, 2H), 0.88 (s, 3H), 0.82 (s, 3H); 13 CNMR (125 MHz, CDCl3) δ 212.95, 138.73, 128.28, 127.46, 127.38, 72.74, 70.66,53.69, 38.60, 37.92, 36.40, 33.15, 32.56, 31.10, 29.71, 28.71, 28.42, 25.97,25.88, 25.86, 25.12, 22.41, 22.35, 15.57; HRMS (ESI) m / z: [M+H] +calcd forC 27 H 41 O2 397.3101, found 397.3108.

[0131] Example 16

[0132] The polysubstituted cyclopropyl carbonyl derivative P8 prepared in this embodiment has the following structure:

[0133]

[0134] The preparation method and conditions in this embodiment are the same as in Example 12, and the feed ratio is the same as in Example 12. α-chlorocyclobutanone compound B1 (34.9 mg, 0.1 mmol, 1.0 equivalent) and commercially available benzyl magnesium bromide (1.0 M in THF, 0.15 mL, 0.15 mmol, 1.5 equivalent) were added. The mixture was purified and separated by silica gel column chromatography (300-400 mesh) (petroleum ether / ethyl acetate = 100:1-25:1, v / v) to obtain the corresponding polysubstituted cyclopropyl carbonyl derivative P8 (colorless oil, yield 51%).

[0135] 1 H NMR (400 MHz, CDCl3) δ 7.39–7.31 (m, 4H), 7.31–7.25 (m, 3H), 7.24–7.16 (m, 3H), 4.49 (s, 2H), 3.78 (s, 2H), 3.46–3.32 (m, 2H), 1.87–1.77 (m,1H), 1.72 (d, J = 8.0 Hz, 1H), 1.70–1.61 (m, 1H), 1.58–1.42 (m, 3H), 1.42–1.31 (m, 3H), 1.28–1.18 (m, 1H), 1.14 (s, 3H), 1.16–1.08 (m, 1H), 0.85 (s, 3H), 0.81 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 206.71, 138.75, 134.72, 129.58,128.53, 128.31, 127.49 127.42, 126.71, 72.79, 70.62, 53.40, 38.60, 38.44,37.32, 33.07, 32.99, 32.01, 29.65, 28.74, 24.94, 22.45, 22.30, 15.50; HRMS(ESI) m / z: [M+H]+ calcd for C 28 H 37 O2 405.2788, found 405.2788.

[0136] Example 17

[0137] The polysubstituted cyclopropyl carbonyl derivative P9 prepared in this embodiment has the following structure:

[0138]

[0139] The preparation method and conditions in this embodiment are the same as in Example 12, and the feed ratio is the same as in Example 12. α-chlorocyclobutanone compound B1 (34.9 mg, 0.1 mmol, 1.0 equivalent) and commercially available phenyl magnesium bromide (1.0 M in THF, 0.15 mL, 0.15 mmol, 1.5 equivalent) were added. Thin-layer chromatography (TLC) purification and separation (petroleum ether / ethyl acetate = 25:1, v / v) yielded the corresponding polysubstituted cyclopropyl carbonyl derivative P9 (colorless oil, yield 94%).

[0140] 1 H NMR (400 MHz, CDCl3)δ 7.91 (d, J = 7.0 Hz, 2H), 7.53–7.46 (m, 1H), 7.46–7.39 (m, 2H), 7.37–7.19 (m, 5H), 4.31 (s, 2H), 3.32–3.19 (m, 2H), 2.34(d, J = 8.0 Hz, 1H), 2.14–2.02 (m, 1H), 1.91–1.77 (m, 1H), 1.66–1.46 (m, 4H), 1.47–1.37 (m, 1H), 1.35 (s, 3H), 1.38–1.31 (m, 1H), 1.29–1.11 (m, 2H), 0.89(s, 3H), 0.87 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 199.91, 139.96, 138.69,132.08, 128.37, 128.23, 127.67, 127.46, 127.34, 72.54, 70.36, 39.72, 38.71,35.15, 33.05, 31.99, 31.86, 29.69, 28.84, 25.38, 22.39, 21.82, 15.92; HRMS(ESI) m / z: [M+H]+ calcd for C 27 H 35 O2 391.2632, found 391.2634.

[0141] Example 18

[0142] The polysubstituted cyclopropyl carbonyl derivative P10 prepared in this embodiment has the following structure:

[0143]

[0144] The preparation method and conditions in this embodiment are the same as in Example 12, and the feed ratio is the same as in Example 12. α-chlorocyclobutanone compound B1 (34.9 mg, 0.1 mmol, 1.0 equivalent) and commercially available 4-(N,N-dimethyl)aniline magnesium bromide (1.0 M in THF, 0.15 mL, 0.15 mmol, 1.5 equivalent) were added. Thin-layer chromatography (TLC) purification and separation (petroleum ether / ethyl acetate = 15:1, v / v) yielded the corresponding polysubstituted cyclopropyl carbonyl derivative P10 (colorless oil, yield 31%).

[0145] 1 H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.8 Hz, 2H), 7.30–7.10 (m, 5H), 6.56 (d, J = 8.8 Hz, 2H), 4.19 (d, J = 2.7 Hz, 2H), 3.25–3.12 (m, 2H), 2.93(s, 6H), 2.18 (d, J = 8.1 Hz, 1H), 2.13–2.02 (m, 1H), 1.81–1.70 (m, 1H), 1.60–1.46 (m, 2H), 1.46–1.28 (m, 3H), 1.25 (s, 3H), 1.28–1.19 (m, 1H), 1.19–1.07 (m, 2H), 0.79 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 197.93, 152.80, 138.83,129.83, 128.16, 128.02, 127.42, 127.23, 110.53, 72.38, 70.51, 40.03, 39.98,38.85, 34.27, 32.91, 30.31, 29.86, 29.69, 28.75, 25.42, 22.37, 21.68, 16.13;HRMS (ESI) m / z: [M+H] + calcd for C 29 H 40 NO2 434.3054, found 434.3058.

[0146] Example 19

[0147] The polysubstituted cyclopropyl carbonyl derivative P11 prepared in this embodiment has the following structure:

[0148]

[0149] The preparation method and conditions in this embodiment are the same as in Example 12, and the feed ratio is the same as in Example 12. α-chlorocyclobutanone compound B1 (34.9 mg, 0.1 mmol, 1.0 equivalent) and commercially available 3-fluorophenyl magnesium bromide (1.0 M inTHF, 0.15 mL, 0.15 mmol, 1.5 equivalent) were added. Thin-layer chromatography (TLC) purification and separation (petroleum ether / ethyl acetate = 25:1, v / v) yielded the corresponding polysubstituted cyclopropyl carbonyl derivative P11 (colorless oil, yield 91%).

[0150] 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 7.7 Hz, 1H), 7.62–7.56 (m, 1H), 7.42 (td, J = 8.0, 5.5 Hz, 1H), 7.35–7.18 (m, 6H), 4.35 (s, 2H), 3.29 (t, J =6.3 Hz, 2H), 2.30 (d, J = 7.9 Hz, 1H), 2.12–2.00 (m, 1H), 1.92–1.78 (m, 1H), 1.68–1.49 (m, 4H), 1.49–1.38 (m, 1H), 1.36 (s, 3H), 1.38–1.29 (m, 1H), 1.29–1.11 (m, 2H), 0.91 (s, 3H), 0.89 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 198.36,163.78, 161.81 (d, J = 247.4 Hz), 142.05 (d, J = 6.10 Hz), 138.64, 129.98 (d,J = 7.5 Hz), 128.25, 127.44, 127.37, 123.42 (d, J = 2.8 Hz), 119.04 (d, J =21.4 Hz), 114.41 (d, J = 22.2 Hz), 72.60, 70.30, 39.71, 38.65, 35.25, 33.06,32.67, 32.30, 29.68, 28.87, 25.34, 22.35, 21.85, 15.86; 19 F NMR (471 MHz, CDCl3) δ -112.33; HRMS (ESI) m / z: [M+H] + calcd for C 27 H 34 FO2 409.2537, found409.2541.

[0151] Example 20

[0152] The polysubstituted cyclopropyl carbonyl derivative P12 prepared in this embodiment has the following structure:

[0153]

[0154] The preparation method and conditions in this embodiment are the same as in Example 12, and the feed ratio is the same as in Example 12. α-chlorocyclobutanone compound B1 (34.9 mg, 0.1 mmol, 1.0 equivalent) and commercially available 4-fluorophenyl magnesium bromide (1.0 M inTHF, 0.15 mL, 0.15 mmol, 1.5 equivalent) were added. Thin-layer chromatography (TLC) purification and separation (petroleum ether / ethyl acetate = 25:1, v / v) yielded the corresponding polysubstituted cyclopropyl carbonyl derivative P12 (colorless oil, yield 64%).

[0155] 1 H NMR (400 MHz, CDCl3) δ 7.96–7.87 (m, 2H), 7.36–7.17 (m, 5H), 7.08(t, J = 8.6 Hz, 2H), 4.31 (s, 2H), 3.25 (t, J = 6.8 Hz, 2H), 2.26 (d, J = 8.0Hz, 1H), 2.09–1.97 (m, 1H), 1.89–1.75 (m, 1H), 1.63–1.43 (m, 4H), 1.44–1.34(m, 1H), 1.32 (s, 3H), 1.34–1.25 (m, 1H), 1.25–1.06 (m, 2H), 0.86 (s, 3H), 0.85 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 198.18, 166.18, 164.17 (d, J = 253.0Hz), 138.60, 136.27 (d, J = 3.0 Hz), 130.17 (d, J = 9.1 Hz), 128.26, 127.42,127.38, 115.35 (d, J = 21.8 Hz), 72.62, 70.33, 39.86, 38.67, 34.99, 33.01,31.99, 31.76, 29.67, 28.95, 25.36, 22.34, 21.77, 15.90; 19 F NMR (471 MHz, CDCl3) δ -107.12; HRMS (ESI) m / z: [M+H] + calcd for C 27 H 34 FO2 409.2537, found409.2538.

[0156] Example 21

[0157] The polysubstituted cyclopropyl carbonyl derivative P13 prepared in this embodiment has the following structure:

[0158]

[0159] The preparation method and conditions in this embodiment are the same as in Example 12, and the feed ratio is the same as in Example 12. α-chlorocyclobutanone compound B1 (34.9 mg, 0.1 mmol, 1.0 equivalent) and commercially available 2-methoxyphenyl magnesium bromide (1.0 min THF, 0.15 mL, 0.15 mmol, 1.5 equivalent) were added. Thin-layer chromatography (TLC) purification and separation (petroleum ether / ethyl acetate = 25:1, v / v) yielded the corresponding polysubstituted cyclopropyl carbonyl derivative P13 (colorless oil, yield 23%).

[0160] 1 H NMR (400 MHz, CDCl3) δ 7.57–7.51 (m, 1H), 7.43–7.36 (m, 1H), 7.34–7.22 (m, 5H), 7.02–6.89 (m, 2H), 4.38 (s, 2H), 3.85 (s, 3H), 3.36 (t, J = 6.5Hz, 2H), 2.38 (d, J = 8.0 Hz, 1H), 2.07–1.94 (m, 1H), 1.86–1.62 (m, 3H), 1.52–1.45 (m, 3H), 1.45–1.31 (m, 2H), 1.28 (s, 3H), 1.24–1.14 (m, 1H), 0.91 (s, 3H), 0.87 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 201.83, 157.80, 138.86,132.27, 131.87, 129.62, 128.22, 127.42, 127.29, 120.48, 111.40, 72.58, 70.69,55.36, 39.79, 38.88, 38.71, 33.19, 33.14, 32.61, 29.76, 28.17, 25.30, 22.38,22.10, 15.99; HRMS (ESI) m / z: [M+H] + calcd for C 28 H 37 O3 421.2737, found421.2738.

[0161] Example 22

[0162] The polysubstituted cyclopropyl carbonyl derivative P14 prepared in this embodiment has the following structure:

[0163]

[0164] The preparation method and conditions in this embodiment are the same as in Example 12, and the feed ratio is the same as in Example 12. α-chlorocyclobutanone compound B1 (34.9 mg, 0.1 mmol, 1.0 equivalent) and commercially available 3-methoxyphenyl magnesium bromide (1.0 min THF, 0.15 mL, 0.15 mmol, 1.5 equivalent) were added. Thin-layer chromatography (TLC) purification and separation (petroleum ether / ethyl acetate = 25:1, v / v) yielded the corresponding polysubstituted cyclopropyl carbonyl derivative P14 (colorless oil, yield 81%).

[0165] 1 H NMR (400 MHz, CDCl3)δ 7.51–7.46 (m, 1H), 7.41 (t, J = 2.1 Hz, 1H), 7.36–7.16 (m, 6H), 7.04–7.00 (m, 1H), 4.30 (s, 2H), 3.80 (s, 3H), 3.28–3.23(m, 2H), 2.30 (d, J = 8.0 Hz, 1H), 2.10–1.98 (m, 1H), 1.87–1.76 (m, 1H), 1.66–1.52 (m, 2H), 1.55–1.43 (m, 2H), 1.45–1.32 (m, 1H), 1.32 (s, 3H), 1.35–1.27 (m, 1H), 1.27–1.09 (m, 2H), 0.87 (s, 3H), 0.85 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 199.66, 159.67, 141.34, 138.69, 129.31, 128.22, 127.44, 127.32,120.45, 118.63, 111.82, 72.53, 70.37, 55.34, 39.75, 38.68, 35.26, 33.04,32.13, 31.93, 29.68, 28.86, 25.37, 22.37, 21.79, 15.92; HRMS (ESI) m / z: [M+H] +calcd for C 28 H 37 O3 421.2737, found 421.2732.

[0166] Example 23

[0167] The polysubstituted cyclopropyl carbonyl derivative P15 prepared in this embodiment has the following structure:

[0168]

[0169] The preparation method and conditions in this embodiment are the same as in Example 12, and the feed ratio is the same as in Example 12. α-chlorocyclobutanone compound B1 (34.9 mg, 0.1 mmol, 1.0 equivalent) and commercially available 4-methoxyphenyl magnesium bromide (1.0 min THF, 0.15 mL, 0.15 mmol, 1.5 equivalent) were added. Thin-layer chromatography (TLC) purification and separation (petroleum ether / ethyl acetate = 25:1, v / v) yielded the corresponding polysubstituted cyclopropyl carbonyl derivative P15 (colorless oil, yield 69%).

[0170] 1 H NMR (400 MHz, CDCl3)δ 7.89 (d, J = 8.9 Hz, 2H), 7.31–7.17 (m, 5H), 6.88 (d, J = 8.9 Hz, 2H), 4.27 (s, 2H), 3.79 (s, 3H), 3.30–3.17 (m, 2H), 2.25(d, J = 8.0 Hz, 1H), 2.12–2.04 (m, 1H), 1.88–1.74 (m, 1H), 1.61–1.50 (m, 2H), 1.51–1.33 (m, 3H), 1.31 (s, 3H), 1.29–1.24 (m, 1H), 1.24–1.08 (m, 2H), 0.85(s, 6H); 13 C NMR (125 MHz, CDCl3) δ 198.38, 162.75, 138.70, 132.96, 129.87,128.22, 127.43, 127.31, 113.45, 72.51, 70.40, 55.35, 39.94, 38.76, 34.69,32.96, 31.07, 31.02, 29.68, 28.85, 25.38, 22.34, 21.72, 16.00; HRMS (ESI) m / z: [M+H] +calcd for C 28 H 37 O3 421.2737, found 421.2738.

[0171] Example 24

[0172] The polysubstituted cyclopropyl carbonyl derivative P16 prepared in this embodiment has the following structure:

[0173]

[0174] The preparation method and conditions in this embodiment are the same as in Example 12, and the feed ratio is the same as in Example 12. α-chlorocyclobutanone compound B1 (34.9 mg, 0.1 mmol, 1.0 equivalent) and commercially available 3-methylphenyl magnesium bromide (1.0 M inTHF, 0.15 mL, 0.15 mmol, 1.5 equivalent) were added. Thin-layer chromatography (TLC) purification and separation (petroleum ether / ethyl acetate = 40:1, v / v) yielded the corresponding polysubstituted cyclopropyl carbonyl derivative P16 (colorless oil, yield 68%).

[0175] 1 H NMR (400 MHz, CDCl3)δ 7.71–7.64 (m, 2H), 7.33–7.16 (m, 7H), 4.28(s, 2H), 3.24 (t, J = 6.1 Hz, 2H), 2.35 (s, 3H), 2.30 (d, J = 8.0 Hz, 1H),2.09–1.97 (m, 1H), 1.87–1.73 (m, 1H), 1.64–1.53 (m, 2H), 1.52–1.43 (m, 2H),1.42–1.36 (m, 1H), 1.36–1.30 (m, 1H), 1.31 (s, 3H), 1.26–1.07 (m, 2H), 0.85 (s, 3H), 0.84 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 200.10, 139.97, 138.70,138.06, 132.83, 128.21, 128.17, 127.42, 127.32, 124.96, 72.51, 70.39, 39.67,38.69, 35.11, 33.03, 31.83, 31.80, 29.68, 28.85, 25.38, 22.38, 21.80, 21.38,15.92; HRMS (ESI) m / z: [M+H] + calcd for C 28 H 37 O2 405.2788, found 405.2784.

[0176] Example 25

[0177] The polysubstituted cyclopropyl carbonyl derivative P17 prepared in this embodiment has the following structure:

[0178]

[0179] The preparation method and conditions in this embodiment are the same as in Example 12, and the feed ratio is the same as in Example 12. α-chlorocyclobutanone compound B1 (34.9 mg, 0.1 mmol, 1.0 equivalent) and commercially available 4-methylphenyl magnesium bromide (1.0 M inTHF, 0.15 mL, 0.15 mmol, 1.5 equivalent) were added. Thin-layer chromatography (TLC) purification and separation (petroleum ether / ethyl acetate = 40:1, v / v) yielded the corresponding polysubstituted cyclopropyl carbonyl derivative P17 (colorless oil, yield 77%).

[0180] 1H NMR (400 MHz, CDCl3)δ 7.85 (d, J = 7.8 Hz, 2H), 7.32 (q, J = 8.9Hz, 2H), 7.29–7.19 (m, 5H), 4.32 (s, 2H), 3.29 (t, J = 6.7 Hz, 2H), 2.40 (s,3H), 2.35 (d, J = 8.0 Hz, 1H), 2.18–2.06 (m, 1H), 1.92–1.80 (m, 1H), 1.68–1.59 (m, 2H), 1.54–1.41 (m, 3H), 1.37 (s, 3H), 1.40–1.32 (m, 1H), 1.30–1.13(m, 2H), 0.90(s, 6H); 13 C NMR (125 MHz, CDCl3) δ 199.50, 142.66, 138.70,137.42, 129.02, 128.21, 127.79, 127.42, 127.30, 72.48, 70.37, 39.74, 38.73,34.94, 33.00, 31.55, 31.51, 29.68, 28.77, 25.36, 22.34, 21.80, 21.51, 15.94;HRMS (ESI) m / z: [M+H] + calcd for C 28 H 37 O2 405.2788, found 405.2791.

[0181] Example 26

[0182] The polysubstituted cyclopropyl carbonyl derivative P18 prepared in this embodiment has the following structure:

[0183]

[0184] The preparation method and conditions in this embodiment are the same as in Example 12, and the feed ratio is the same as in Example 12. α-chlorocyclobutanone compound B1 (34.9 mg, 0.1 mmol, 1.0 equivalent) and commercially available 3-chlorophenyl magnesium bromide (0.5 min THF, 0.30 mL, 0.15 mmol, 1.5 equivalent) were added. Thin-layer chromatography (TLC) purification and separation (petroleum ether / ethyl acetate = 40:1, v / v) yielded the corresponding polysubstituted cyclopropyl carbonyl derivative P18 (colorless oil, yield 17%).

[0185] 1 H NMR (400 MHz, CDCl3)δ 7.87 (t, J = 1.9 Hz, 1H), 7.77 (d, J = 7.7Hz, 1H), 7.49–7.42 (m, 1H), 7.40–7.27 (m, 3H), 7.29–7.20 (m, 3H), 4.34 (s,2H), 3.27 (t, J = 6.3 Hz, 2H), 2.27 (d, J = 8.0 Hz, 1H), 2.08–1.96 (m, 1H), 1.90–1.76 (m, 1H), 1.64–1.45 (m, 3H), 1.48–1.35 (m, 1H), 1.34 (s, 3H), 1.36–1.27 (m, 1H), 1.27–1.06 (m, 3H), 0.88 (s, 3H), 0.86 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 198.33, 141.44, 138.65, 134.70, 132.01, 129.71, 128.25, 127.81,127.44, 127.36, 125.79, 72.60, 70.30, 39.69, 38.63, 35.19, 33.06, 32.74,32.38, 29.68, 28.89, 25.34, 22.36, 21.84, 15.86; HRMS (ESI) m / z: [M+H] + calcdfor C 27 H 34 ClO2 425.2242, found 425.2242.

[0186] Example 27

[0187] The polysubstituted cyclopropyl carbonyl derivative P19 prepared in this embodiment has the following structure:

[0188]

[0189] The preparation method and conditions in this embodiment are the same as in Example 12, and the feed ratio is the same as in Example 12. α-chlorocyclobutanone compound B1 (34.9 mg, 0.1 mmol, 1.0 equivalent) and commercially available 4-chlorophenyl magnesium bromide (1.0 M inTHF, 0.15 mL, 0.15 mmol, 1.5 equivalent) were added. Thin-layer chromatography (TLC) purification and separation (petroleum ether / ethyl acetate = 40:1, v / v) yielded the corresponding polysubstituted cyclopropyl carbonyl derivative P19 (colorless oil, yield 74%).

[0190] 1 H NMR (400 MHz, CDCl3)δ 7.85 (d, J = 8.5 Hz, 2H), 7.45–7.38 (m, 2H), 7.35–7.20 (m, 5H), 4.33 (s, 2H), 3.27 (t, J = 6.4 Hz, 2H), 2.28 (d, J = 7.9Hz, 1H), 2.12–2.00 (m, 1H), 1.91–1.77 (m, 1H), 1.66–1.46 (m, 4H), 1.46–1.37(m, 1H), 1.34 (s, 3H), 1.32–1.28 (m, 1H), 1.27–1.09 (m, 2H), 0.88 (s, 3H), 0.87 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 198.51, 138.59, 138.46, 138.19,129.09, 128.65, 128.28, 127.45, 127.39, 72.63, 70.32, 39.78, 38.66, 35.10,33.03, 32.44, 32.07, 29.66, 28.91, 25.34, 22.33, 21.81, 15.87; HRMS (ESI) m / z: [M+H] + calcd for C 27 H 34 ClO2 425.2242, found 425.2242.

[0191] Example 28

[0192] The polysubstituted cyclopropyl carbonyl derivative P20 prepared in this embodiment has the following structure:

[0193]

[0194] The preparation method and conditions in this embodiment are the same as in Example 12, and the feed ratio is the same. α-chlorocyclobutanone compound B1 (34.9 mg, 0.1 mmol, 1.0 equivalent) and commercially available 2,4,6-trimethylphenyl magnesium bromide (1.0 M in THF, 0.15 mL, 0.15 mmol, 1.5 equivalent) were added. Thin-layer chromatography (TLC) purification and separation (petroleum ether / ethyl acetate = 50:1, v / v) yielded the corresponding polysubstituted cyclopropyl carbonyl derivative P20 (colorless oil, yield 41%). f =0.33 (silica gel, petroleum ether / ethyl acetate 22:1); 1 H NMR (400 MHz, CDCl3)δ 7.33–7.14 (m, 5H),6.74 (s, 2H), 4.43 (s, 2H), 3.42 (q, J = 6.3 Hz, 2H), 2.22–2.09 (m, 10H),1.85 (d, J = 8.7 Hz, 1H), 1.81–1.65 (m, 4H), 1.62–1.45 (m, 3H), 1.45–1.32 (m,1H), 1.21–1.11 (m, 1H), 1.09 (s, 3H), 0.90 (s, 3H), 0.80 (s, 3H); 13 C NMR (125MHz, CDCl3) δ 209.52, 142.53, 138.80, 137.75, 132.94, 128.43, 128.29, 127.46,127.37, 72.71, 70.67, 39.65, 38.15, 37.43, 35.92, 33.55, 33.12, 30.00, 29.41,25.22, 22.74, 22.28, 21.00, 19.35, 16.01; HRMS (ESI) m / z: [M+Na] + calcd forC 30 H 40 O2Na 455.2923, found 455.2921.

[0195] Example 29

[0196] The polysubstituted cyclopropyl carbonyl derivative P21 prepared in this embodiment has the following structure:

[0197]

[0198] The preparation method and conditions in this embodiment are the same as in Example 12, and the feed ratio is the same as in Example 12. α-chlorocyclobutanone compound B1 (34.9 mg, 0.1 mmol, 1.0 equivalent) and freshly prepared Grignard reagent D1 (0.5 M in THF, 0.30 mL, 0.15 mmol, 1.5 equivalent) were added. Thin-layer chromatography (TLC) purification and separation (petroleum ether / ethyl acetate = 25:1, v / v) yielded the corresponding polysubstituted cyclopropyl carbonyl derivative P21 (colorless oil, yield 12%).

[0199] 1 H NMR (400 MHz, CDCl3)δ 8.10 (d, J = 8.4 Hz, 2H), 7.94 (d, J = 8.4Hz, 2H), 7.39–7.10 (m, 5H), 4.31 (s, 2H), 3.93 (s, 3H), 3.26 (t, J = 6.3 Hz,2H), 2.35 (d, J = 7.9 Hz, 1H), 2.10–1.99 (m, 1H), 1.91–1.77 (m, 1H), 1.68–1.39 (m, 4H), 1.36 (s, 3H), 1.41–1.29 (m, 1H), 1.29–1.18 (m, 1H), 1.19–1.07(m, 1H), 0.89 (s, 3H), 0.88 (s, 3H); 13 C NMR (150 MHz, CDCl3)δ 199.31, 166.39,143.21, 138.59, 132.93, 129.71, 128.25, 127.53, 127.42, 127.35, 72.61,70.30, 52.36, 39.64, 38.65, 35.62, 33.15, 33.09, 32.63, 29.67, 28.85, 25.35,22.34, 21.88, 15.85; HRMS (ESI) m / z: [M+H] + calcd for C 29 H 37 O4 449.2686, found449.2692.

[0200] Example 30

[0201] The polysubstituted cyclopropyl carbonyl derivative P22 prepared in this embodiment has the following structure:

[0202]

[0203] The preparation method and conditions in this embodiment are the same as in Example 12, and the feed ratio is the same as in Example 12. α-chlorocyclobutanone compound B1 (34.9 mg, 0.1 mmol, 1.0 equivalent) and freshly prepared Grignard reagent D2 (0.5 M in THF, 0.30 mL, 0.15 mmol, 1.5 equivalent) were added. Thin-layer chromatography (TLC) purification and separation (petroleum ether / ethyl acetate = 25:1, v / v) yielded the corresponding polysubstituted cyclopropyl carbonyl derivative P22 (colorless oil, yield 67%).

[0204] 1 H NMR (400 MHz, Acetone-d6)δ 8.60 (s, 1H), 8.27–8.15 (m, 2H), 7.65 (t, J = 7.8 Hz, 1H), 7.34–7.18 (m, 5H), 4.43–4.33 (m, 2H), 4.29 (s, 2H),3.30–3.17 (m, 2H), 2.56 (d, J = 7.9 Hz, 1H), 2.16–2.05 (m, 1H), 1.91–1.77 (m,1H), 1.66–1.43 (m, 5H), 1.40 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H), 1.34–1.27 (m,1H), 1.27–1.17 (m, 1H), 1.13–0.97 (m, 1H), 0.90 (s, 3H), 0.88 (s, 3H); 13 C NMR(150 MHz, Acetone-d6) δ 198.94, 166.20, 140.90, 140.03, 133.50, 132.79,131.79, 129.80, 129.28, 128.94, 128.07, 127.97, 72.92,70.71,61.81,40.76,39.59,35.54,33.62,32.62,32.20,30.13,29.84,25.20,23.08,22.24,16.56,14.55; HRMS (ESI) m / z: [M+H] + calcd for C 30 H 39 O4 463.2843, found 463.2846.

[0205] Example 31

[0206] The polysubstituted cyclopropyl carbonyl derivative P23 prepared in this embodiment has the following structure:

[0207]

[0208] The preparation method and conditions in this embodiment are the same as in Example 12, and the feed ratio is the same as in Example 12. α-chlorocyclobutanone compound B1 (34.9 mg, 0.1 mmol, 1.0 equivalent) and freshly prepared Grignard reagent D3 (0.5 M in THF, 0.30 mL, 0.15 mmol, 1.5 equivalent) were added. Thin-layer chromatography (TLC) purification and separation (petroleum ether / ethyl acetate = 25:1, v / v) yielded the corresponding polysubstituted cyclopropyl carbonyl derivative P23 (colorless oil, yield 46%).

[0209] 1 H NMR (400 MHz, Acetone-d6)δ 8.47 (dd, J = 4.8, 2.0 Hz, 1H), 7.89 (dd, J = 7.6, 2.0 Hz, 1H), 7.46 (dd, J = 7.6, 4.8 Hz, 1H), 7.36–7.28 (m, 4H),7.29–7.22 (m, 1H), 4.46 (s, 2H), 3.52–3.38 (m, 2H), 2.32 (d, J = 7.4 Hz, 1H),1.90–1.71 (m, 5H), 1.72–1.57 (m, 2H), 1.56–1.34 (m, 2H), 1.29 (s, 3H), 1.26–1.18 (m, 1H), 0.93 (s, 3H), 0.89 (s, 3H); 13 C NMR (150 MHz, Acetone-d6)δ200.78, 151.47, 147.31, 140.07, 139.23, 138.56, 129.01, 128.14, 128.03,123.97, 73.11, 70.99, 39.55, 39.20, 39.08, 35.84, 35.43, 33.96, 30.22, 29.77,25.00, 23.12, 22.61, 16.31; HRMS (ESI) m / z: [M+H] + calcd for C 26 H 33ClNO2426.2194, found 426.2202.

[0210] Example 32

[0211] The polysubstituted cyclopropyl carbonyl derivative P24 prepared in this embodiment has the following structure:

[0212]

[0213] The preparation method and conditions in this embodiment are the same as in Example 12, and the feed ratio is the same as in Example 12. α-chlorocyclobutanone compound B1 (34.9 mg, 0.1 mmol, 1.0 equivalent) and freshly prepared Grignard reagent D4 (0.5 M in THF, 0.30 mL, 0.15 mmol, 1.5 equivalent) were added. Thin-layer chromatography (TLC) purification and separation (petroleum ether / ethyl acetate = 25:1, v / v) yielded the corresponding polysubstituted cyclopropyl carbonyl derivative P24 (colorless oil, yield 54%).

[0214] 1 H NMR (400 MHz, CDCl3)δ 7.73 (d, J = 4.0 Hz, 1H), 7.59 (d, J = 4.0Hz, 1H), 7.38–7.21 (m, 5H), 4.40–4.30 (m, 4H), 3.30 (t, J = 6.2 Hz, 2H), 2.22(d, J = 7.9 Hz, 1H), 2.08–1.96 (m, 1H), 1.88–1.75 (m, 1H), 1.69–1.46 (m, 4H), 1.44–1.35 (m, 2H), 1.37 (t, J = 7.1 Hz, 3H), 1.31 (s, 3H), 1.27–1.12 (m, 2H),0.90 (s, 3H), 0.86 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 191.95, 161.88, 151.44,138.65, 138.62, 133.25, 129.77, 128.25, 127.45, 127.36, 72.64, 70.29, 61.63,39.42, 38.61, 35.95, 33.42, 33.10, 33.08, 29.64, 28.57, 25.21, 22.22, 22.11,15.81, 14.23; HRMS (ESI) m / z: [M+H] +calcd for C 28 H 37 O4S 469.2407, found469.2415.

[0215] Example 33

[0216] The polysubstituted cyclopropyl carbonyl derivative P25 prepared in this embodiment has the following structure:

[0217]

[0218] The preparation method and conditions in this embodiment are the same as in Example 12, and the feed ratio is the same as in Example 12. α-chlorocyclobutanone compound B1 (34.9 mg, 0.1 mmol, 1.0 equivalent) and freshly prepared Grignard reagent F1 (0.5 M in THF, 0.30 mL, 0.15 mmol, 1.5 equivalent) were added. Thin-layer chromatography (TLC) purification and separation (petroleum ether / ethyl acetate = 25:1, v / v) yielded the corresponding polysubstituted cyclopropyl carbonyl derivative P25 (colorless oil, yield 60%).

[0219] 1 H NMR (400 MHz, CDCl3)δ 7.35–7.18 (m, 5H), 7.03 (d, J = 2.3 Hz, 2H), 6.56 (t, J = 2.3 Hz, 1H), 4.30 (s, 2H), 3.77 (s, 6H), 3.27 (t, J = 6.5 Hz,2H), 2.26 (d, J = 8.0 Hz, 1H), 2.08–1.96 (m, 1H), 1.87–1.73 (m, 1H), 1.65–1.52 (m, 2H), 1.53–1.44 (m, 2H), 1.44–1.32 (m, 1H), 1.34–1.25 (m, 1H), 1.30(s, 3H), 1.25–1.12 (m, 2H), 0.86 (s, 3H), 0.84 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 199.50, 160.66, 141.98, 138.72, 128.22, 127.44, 127.32, 105.62,104.38, 72.51, 70.39, 55.49, 39.76, 38.66, 35.27, 33.05, 32.25, 32.00, 29.68,28.88, 25.38, 22.36, 21.75, 15.91; HRMS (ESI) m / z: [M+H] + calcd for C 29 H 39 O4451.2843, found 451.2851.

[0220] Example 34

[0221] The polysubstituted cyclopropyl carbonyl derivative P26 prepared in this embodiment has the following structure:

[0222]

[0223] The preparation method and conditions in this embodiment are the same as in Example 12, and the feed ratio is the same as in Example 12. α-chlorocyclobutanone compound B1 (34.9 mg, 0.1 mmol, 1.0 equivalent) and freshly prepared Grignard reagent F2 (0.5 M in THF, 0.30 mL, 0.15 mmol, 1.5 equivalent) were added. Thin-layer chromatography (TLC) purification and separation (petroleum ether / ethyl acetate = 50:1, v / v) yielded the corresponding polysubstituted cyclopropyl carbonyl derivative P26 (colorless oil, yield 69%).

[0224] 1H NMR (400 MHz, CDCl3)δ 7.67 (t, J = 1.7 Hz, 1H), 7.51–7.43 (m, 1H), 7.38–7.18 (m, 6H), 4.37 (s, 2H), 3.30 (t, J = 6.2 Hz, 2H), 2.22 (d, J = 7.9Hz, 1H), 2.06–1.94 (m, 1H), 1.90–1.76 (m, 1H), 1.66–1.47 (m, 4H), 1.46–1.36(m, 1H), 1.34 (s, 3H), 1.36–1.28 (m, 1H), 1.27–1.18 (m, 1H), 1.18–1.09 (m,1H), 0.89 (s, 3H), 0.87 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 196.80 (d, J = 2.1Hz), 163.59, 161.59 (d, J = 251.3 Hz), 142.66 (d, J = 6.5 Hz), 138.59, 135.39(d, J = 9.8 Hz), 128.26, 127.42, 127.38, 123.86 (d, J = 3.2 Hz), 119.56 (d, J= 25.0 Hz), 113.04 (d, J = 22.3 Hz), 72.64, 70.24, 39.62, 38.56, 35.21,33.45, 33.08, 32.89, 29.66, 28.90, 25.30, 22.32, 21.88, 15.80; 19 F NMR (471MHz, CDCl3)δ -109.86; HRMS (ESI) m / z: [M+H] + calcd for C 27 H 33 ClFO2 443.2148, found 443.2151.

[0225] Example 35

[0226] The polysubstituted cyclopropyl carbonyl derivative P27 prepared in this embodiment has the following structure:

[0227]

[0228] The preparation method and conditions in this embodiment are the same as in Example 12, and the feed ratio is the same as in Example 12. α-chlorocyclobutanone compound B1 (34.9 mg, 0.1 mmol, 1.0 equivalent) and freshly prepared Grignard reagent F3 (0.5 M in THF, 0.30 mL, 0.15 mmol, 1.5 equivalent) were added. Thin-layer chromatography (TLC) purification and separation (petroleum ether / ethyl acetate = 50:1, v / v) yielded the corresponding polysubstituted cyclopropyl carbonyl derivative P27 (colorless oil, yield 68%).

[0229] 1 H NMR (400 MHz, CDCl3)δ 7.42–7.37 (m, 2H), 7.36–7.28 (m, 2H), 7.28–7.18 (m, 3H), 6.94 (tt, J = 8.4, 2.3 Hz, 1H), 4.37 (s, 2H), 3.29 (t, J = 6.3Hz, 2H), 2.22 (d, J = 7.9 Hz, 1H), 2.05–1.96 (m, 1H), 1.89–1.78 (m, 1H), 1.64–1.48 (m, 4H), 1.48–1.36 (m, 1H), 1.34 (s, 3H), 1.33–1.28 (m, 1H), 1.27–1.20 (m, 1H), 1.19–1.08 (m, 1H), 0.89 (s, 3H), 0.87 (s, 3H); 13 C NMR (125 MHz, CDCl3)δ 196.83, 163.95, 161.96 (d, J = 250.5Hz), 163.86, 161.87 (d, J =250.5Hz), 142.89 (t, J = 7.3 Hz), 138.59, 128.26, 127.42, 127.39, 110.70–110.50 (m), 107.32 (t, J = 25.4 Hz), 72.65, 70.24, 39.64, 38.57, 35.22,33.38, 33.08, 32.81, 29.66, 28.88, 25.30, 22.31, 21.88, 15.79; 19 F NMR (471MHz, CDCl3) δ -108.58; HRMS (ESI) m / z: [M+H] + calcd for C 27 H33 F2O2 427.2443, found 427.2452.

[0230] Example 36

[0231] The polysubstituted cyclopropyl carbonyl derivative P28 prepared in this embodiment has the following structure:

[0232]

[0233] The preparation method and conditions in this embodiment are the same as in Example 12, and the feed ratio is the same as in Example 12. α-chlorocyclobutanone compound B1 (34.9 mg, 0.1 mmol, 1.0 equivalent) and freshly prepared Grignard reagent F4 (0.5 M in THF, 0.30 mL, 0.15 mmol, 1.5 equivalent) were added. Thin-layer chromatography (TLC) purification and separation (petroleum ether / ethyl acetate = 25:1, v / v) yielded the corresponding polysubstituted cyclopropyl carbonyl derivative P28 (colorless oil, yield 58%).

[0234] 1 H NMR (400 MHz, CDCl3)δ 7.52 (s, 2H), 7.36–7.27 (m, 2H), 7.28–7.18(m, 3H), 7.13 (s, 1H), 4.32 (s, 2H), 3.28 (td, J = 6.6, 1.7 Hz, 2H), 2.34 (s,6H), 2.31 (d, J = 8.0 Hz, 1H), 2.10–2.01 (m, 1H), 1.88–1.78 (m, 1H), 1.68–1.56 (m, 2H), 1.54–1.47 (m, 2H), 1.46–1.39 (m, 1H), 1.40–1.31 (m, 1H), 1.34(s, 3H), 1.29–1.15 (m, 2H), 0.88 (s, 3H), 0.87 (s, 3H); 13 C NMR (125 MHz, CDCl3)δ 200.29, 140.06, 138.73, 137.87, 133.71, 128.21, 127.40, 127.31,125.53, 72.49, 70.43, 39.62, 38.68, 35.07, 33.03, 31.76, 31.66, 29.69, 28.87,25.39, 22.39, 21.79, 21.27, 15.94; HRMS (ESI) m / z: [M+H]+ calcd for C 29 H 39 O2419.2945, found 419.2952.

[0235] Example 37

[0236] The polysubstituted cyclopropyl carbonyl derivative P29 prepared in this embodiment has the following structure:

[0237]

[0238] The preparation method and conditions in this embodiment are the same as in Example 12, and the feed ratio is the same as in Example 12. α-chlorocyclobutanone compound B1 (34.9 mg, 0.1 mmol, 1.0 equivalent) and freshly prepared Grignard reagent F5 (0.5 M in THF, 0.30 mL, 0.15 mmol, 1.5 equivalent) were added. Thin-layer chromatography (TLC) purification and separation (petroleum ether / ethyl acetate = 25:1, v / v) yielded the corresponding polysubstituted cyclopropyl carbonyl derivative P29 (colorless oil, yield 65%).

[0239] 1 H NMR (400 MHz, CDCl3)δ 7.71–7.60 (m, 2H), 7.32–7.24 (m, 2H), 7.25–7.14 (m, 3H), 6.92 (t, J = 8.3 Hz, 1H), 4.29 (d, J = 2.6 Hz, 2H), 3.86 (s,3H), 3.23 (td, J = 6.5, 2.8 Hz, 2H), 2.20 (d, J = 8.0 Hz, 1H), 2.10–1.98 (m,1H), 1.87–1.73 (m, 1H), 1.60–1.49 (m, 2H), 1.49–1.41 (m, 2H), 1.41–1.32 (m,1H), 1.30 (s, 3H), 1.27–1.15 (m, 2H), 1.15–1.06 (m, 1H), 0.84 (s, 3H), 0.83(s, 3H); 13C NMR (125 MHz, CDCl3)δ 197.27 (d, J = 1.9 Hz), 152.86, 150.89 (d,J = 247.3 Hz), 151.06 (d, J = 10.9 Hz), 138.65, 133.15 (d, J = 4.8 Hz),128.24, 127.40, 127.34, 124.80 (d, J = 3.4 Hz), 115.38 (d, J = 19.0 Hz), 112.13 (d, J = 1.8 Hz), 72.57, 70.35, 56.17, 39.91, 38.69, 34.66, 32.98,31.66, 31.49, 29.66, 28.87, 25.34, 22.30, 21.75, 15.92; 19 F NMR (471 MHz, CDCl3) δ -134.71; HRMS (ESI) m / z: [M+H] + calcd for C 28 H 36 FO3 439.2643, found439.2642.

[0240] Example 38

[0241] The polysubstituted cyclopropyl carbonyl derivative P30 prepared in this embodiment has the following structure:

[0242]

[0243] The preparation method and conditions in this embodiment are the same as in Example 12, and the feed ratio is the same as in Example 12. α-chlorocyclobutanone compound B1 (34.9 mg, 0.1 mmol, 1.0 equivalent) and freshly prepared organolithium reagent H1 (0.3 M inTHF, 0.50 mL, 0.15 mmol, 1.5 equivalent) are added. Thin-layer chromatography (TLC) purification and separation (petroleum ether / ethyl acetate = 25:1, v / v) yields the corresponding polysubstituted cyclopropyl carbonyl derivative P30 (colorless oil, yield 21%).

[0244] 1H NMR (400 MHz, CDCl3)δ 7.48 (d, J = 3.7 Hz, 1H), 7.38–7.21 (m, 5H), 6.78–6.72 (m, 1H), 4.35 (s, 2H), 3.31 (t, J = 6.5 Hz, 2H), 2.48 (s, 3H), 2.16(d, J = 8.0 Hz, 1H), 2.11–1.99 (m, 1H), 1.87–1.73 (m, 1H), 1.66–1.52 (m, 2H), 1.53–1.44 (m, 2H), 1.45–1.33 (m, 2H), 1.28 (s, 3H), 1.26–1.14 (m, 2H), 0.88(s, 3H), 0.86 (s, 3H); 13 C NMR (125 MHz, CDCl3)δ 191.80, 148.02, 145.29,138.77, 130.94, 128.23, 127.47, 127.33, 126.55, 72.55, 70.44, 39.35, 38.72,35.09, 33.03, 31.90, 31.47, 29.67, 28.52, 25.23, 22.24, 22.10, 15.94, 15.88;HRMS (ESI) m / z: [M+H] + calcd for C 26 H 35 O2S 411.2352, found 411.2355.

[0245] Example 39

[0246] The polysubstituted cyclopropyl carbonyl derivative P31 prepared in this embodiment has the following structure:

[0247]

[0248] The preparation method and conditions in this embodiment are the same as in Example 12, and the feed ratio is the same as in Example 12. α-chlorocyclobutanone compound B1 (34.9 mg, 0.1 mmol, 1.0 equivalent) and freshly prepared organolithium reagent H2 (0.3 M inTHF, 0.50 mL, 0.15 mmol, 1.5 equivalent) were added. Thin-layer chromatography (TLC) purification and separation (petroleum ether / ethyl acetate = 25:1, v / v) yielded the corresponding polysubstituted cyclopropyl carbonyl derivative P31 (colorless oil, yield 50%).

[0249] 1 H NMR (400 MHz, CDCl3)δ 7.67 (dd, J = 3.8, 1.1 Hz, 1H), 7.54 (dd, J =5.0, 1.1 Hz, 1H), 7.36–7.21 (m, 5H), 7.09 (dd, J = 5.0, 3.8 Hz, 1H), 4.34 (s,2H), 3.29 (t, J = 6.4 Hz, 2H), 2.24 (d, J = 8.0 Hz, 1H), 2.10–1.98 (m, 1H), 1.88–1.74 (m, 1H), 1.65–1.49 (m, 4H), 1.48–1.37 (m, 2H), 1.30 (s, 3H), 1.27–1.15 (m, 2H), 0.89 (s, 3H), 0.86 (s, 3H); 13 C NMR (125 MHz, CDCl3)δ 192.08,147.47, 138.71, 132.22, 130.44, 128.24, 127.93, 127.50, 127.35, 72.58, 70.38,39.38, 38.66, 35.57, 33.06, 32.26, 32.03, 29.66, 28.57, 25.26, 22.26, 22.06,15.88; HRMS (ESI) m / z: [M+H] + calcd for C 25 H 33 O2S 397.2196, found 397.2202.

[0250] Example 40

[0251] The polysubstituted cyclopropyl carbonyl derivative P32 prepared in this embodiment has the following structure:

[0252]

[0253] The preparation method and conditions in this embodiment are the same as in Example 12, and the feed ratio is the same as in Example 12. α-chlorocyclobutanone compound B2 (15.9 mg, 0.1 mmol, 1.0 equivalent) and commercially available phenyl magnesium bromide (1.0 M in THF, 0.15 mL, 0.15 mmol, 1.5 equivalent) were added. Thin-layer chromatography (TLC) purification and separation (petroleum ether / ethyl acetate = 50:1, v / v) yielded the corresponding polysubstituted cyclopropyl carbonyl derivative P32 (colorless oil, yield 64%).

[0254] 1 H NMR (400 MHz, CDCl3)δ 8.02 (d, J = 7.0 Hz, 2H), 7.59–7.50 (m, 1H), 7.46 (dd, J = 8.4, 7.0 Hz, 2H), 1.97–1.90 (m, 2H), 1.89–1.79 (m, 1H), 1.82(d, J = 8.0 Hz, 1H), 1.71–1.49 (m, 3H), 1.45 (s, 3H), 1.04–0.86 (m, 1H); 13 CNMR (125 MHz, CDCl3)δ 199.39, 137.83, 132.83, 128.46, 128.38, 33.98, 33.47,32.59, 32.02, 26.72, 23.47, 22.61; HRMS (ESI) m / z: [M+H] + calcd for C 14 H 17 O201.1274, found 201.1272.

[0255] Example 41

[0256] The polysubstituted cyclopropyl carbonyl derivative P33 prepared in this embodiment has the following structure:

[0257]

[0258] The preparation method and conditions in this embodiment are the same as in Example 12, and the feed ratio is the same as in Example 12. α-chlorocyclobutanone compound B3 (17.3 mg, 0.1 mmol, 1.0 equivalent) and commercially available 4-methoxyphenyl magnesium bromide (1.0 min THF, 0.15 mL, 0.15 mmol, 1.5 equivalent) were added. Thin-layer chromatography (TLC) purification and separation (petroleum ether / ethyl acetate = 50:1, v / v) yielded the corresponding polysubstituted cyclopropyl carbonyl derivative P33 (colorless oil, yield 76%).

[0259] 1H NMR (400 MHz, Acetone-d6)δ 7.97 (d, J = 8.9 Hz, 2H), 7.02 (d, J =8.9 Hz, 2H), 3.88 (s, 3H), 2.10 (d, J = 8.8 Hz, 1H), 1.97–1.78 (m, 2H), 1.76–1.66 (m, 1H), 1.56–1.45 (m, 1H), 1.41–1.30 (m, 2H), 1.32 (s, 3H), 1.30–1.14(m, 3H); 13 C NMR (125 MHz, Acetone-d6)δ 197.95, 164.06, 133.38, 130.89,114.44, 55.85, 34.11, 29.45, 27.33, 26.46, 24.59, 22.08, 22.02, 19.84; HRMS(ESI) m / z: [M+H] + calcd for C 16 H 21 O2 245.1536, found 245.1537.

[0260] Example 42

[0261] The polysubstituted cyclopropyl carbonyl derivative P34 prepared in this embodiment has the following structure:

[0262]

[0263] The preparation method and conditions in this embodiment are the same as in Example 12, and the feed ratio is the same as in Example 12. α-chlorocyclobutanone compound B4 (19.3 mg, 0.1 mmol, 1.0 equivalent) and commercially available cyclohexyl magnesium bromide (1.0 M inTHF, 0.15 mL, 0.15 mmol, 1.5 equivalent) were added. Thin-layer chromatography (TLC) purification and separation (petroleum ether / ethyl acetate = 30:1, v / v) yielded the corresponding polysubstituted cyclopropyl carbonyl derivative P34 (white solid, yield 44%).

[0264] 1H NMR (400 MHz, Acetone-d6)δ 7.30–7.22 (m, 1H), 7.12–7.01 (m, 3H), 3.42 (d, J = 16.9 Hz, 1H), 3.10–2.98 (m, 2H), 2.37–2.25 (m, 2H), 2.24–2.18(m, 1H), 1.85–1.75 (m, 1H), 1.71–1.62 (m, 1H), 1.62–1.51 (m, 2H), 1.49–1.38(m, 1H), 1.31–0.91 (m, 5H); 13 C NMR (125 MHz, Acetone-d6)δ 209.34, 145.77,141.18, 126.91, 126.62, 125.17, 124.92, 52.21, 34.07, 32.85, 29.99, 29.16,28.68, 26.65, 26.38, 26.27, 25.07; HRMS (ESI) m / z: [M+H] + calcd for C 17 H 21 O241.1587, found 241.1589.

[0265] Example 43

[0266] The polysubstituted cyclopropyl carbonyl derivative P35 prepared in this embodiment has the following structure:

[0267]

[0268] The specific preparation methods and conditions in this embodiment are as follows: The first step is to prepare α-chlorocyclobutanone compound B5 as in Example 1, and the second step is to synthesize the polysubstituted cyclopropyl carbonyl derivative P34 as in Example 12. The difference is that the prepared B5 does not need to be purified and is used in the second step reaction to synthesize the polysubstituted cyclopropyl carbonyl derivative P34. The feed ratio is the same as in Example 12. α-chlorocyclobutanone compound B5 (81.8 mg, 0.3 mmol, 1.0 equivalent) and commercially available 4-methoxyphenyl magnesium bromide (1.0 min THF, 0.45 mL, 0.45 mmol, 1.5 equivalent) are added. Thin-layer chromatography (TLC) purification and separation (petroleum ether / ethyl acetate = 20:1, v / v) yields the corresponding polysubstituted cyclopropyl carbonyl derivative P34 (white solid, total yield of the two steps is 13%).

[0269] 1H NMR (400 MHz, CDCl3)δ 7.93 (d, J = 8.9 Hz, 2H), 6.93 (d, J = 8.9Hz, 2H), 3.87 (s, 3H), 2.12 (d, J = 8.1 Hz, 1H), 2.15–2.06 (m, 1H), 1.94 (s,3H), 1.90–1.78 (m, 1H), 1.73–1.62 (m, 1H), 1.62–1.57 (m, 1H), 1.57–1.49 (m,1H), 1.49–1.41 (m, 1H), 1.44 (s, 3H), 1.43 (s, 3H), 1.41–1.36 (m, 1H), 1.38(s, 3H), 1.05–0.89 (m, 1H); 13 C NMR (150 MHz, CDCl3)δ 198.34, 170.60, 162.96,132.68, 130.07, 113.53, 84.81, 55.43, 42.84, 34.41, 28.70, 27.71, 27.28,26.24, 23.43, 22.87, 22.69, 22.55, 20.28; HRMS (ESI) m / z: [M+Na] + calcd forC 21 H 28 O4Na 367.1880, found 367.1884.

[0270] Example 44

[0271] The polysubstituted cyclopropyl carbonyl derivative P36 prepared in this embodiment has the following structure:

[0272]

[0273] The preparation method and conditions in this embodiment are the same as in Example 12, and the feed ratio is the same as in Example 12. α-chlorocyclobutanone compound B6 (23.5 mg, 0.1 mmol, 1.0 equivalent) and commercially available 4-methylphenyl magnesium bromide (1.0 M inTHF, 0.15 mL, 0.15 mmol, 1.5 equivalent) were added. Thin-layer chromatography (TLC) purification and separation (petroleum ether / ethyl acetate = 70:1, v / v) yielded the corresponding polysubstituted cyclopropyl carbonyl derivative P36 (colorless oil, yield 74%).

[0274] 1H NMR (400 MHz, CDCl3)δ 7.84 (d, J = 8.2 Hz, 2H), 7.33–7.22 (m, 4H), 7.21–7.10 (m, 3H), 2.50 (d, J = 8.9 Hz, 1H), 2.34 (s, 3H), 2.21–2.08 (m, 1H),2.05–1.91 (m, 2H), 1.91–1.77 (m, 2H), 1.51–1.25 (m, 4H); 13 C NMR (125 MHz, CDCl3)δ 198.66, 149.22, 143.28, 136.82, 129.18, 128.58, 128.19, 127.30,126.11, 33.91, 33.21, 27.33, 25.76, 21.56, 21.51, 21.15, 19.23; HRMS (ESI) m / z: [M+Na] + calcd for C 21 H 22 ONa 313.1563, found 313.1567.

[0275] Example 45

[0276] The polysubstituted cyclopropyl carbonyl derivative P37 prepared in this embodiment has the following structure:

[0277]

[0278] The specific preparation methods and conditions in this embodiment are as follows: The first step is to prepare α-chlorocyclobutanone compound B7 as in Example 1, and the second step is to synthesize the polysubstituted cyclopropyl carbonyl derivative P37 as in Example 12. The difference is that the prepared B7 does not need to be purified and is used in the second step reaction to synthesize the polysubstituted cyclopropyl carbonyl derivative P37. The feed ratio is the same as in Example 12. α-chlorocyclobutanone compound B7 (34.5 mg, 0.2 mmol, 1.0 equivalent) and commercially available 4-chlorophenyl magnesium bromide (1.0 M inTHF, 0.30 mL, 0.30 mmol, 1.5 equivalent) are added. Thin-layer chromatography (TLC) purification and separation (petroleum ether / ethyl acetate = 50:1, v / v) yields the corresponding polysubstituted cyclopropyl carbonyl derivative P37 (white solid, total yield of the two steps is 15%).

[0279] 1H NMR (400 MHz, CDCl3)δ 7.89 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 8.7Hz, 2H), 2.63 (t, J = 8.1 Hz, 1H), 1.95–1.65 (m, 9H), 1.38–1.21 (m, 3H); 13 CNMR (125 MHz, CDCl3)δ 198.65, 138.51, 138.36, 129.19, 128.59, 32.11, 29.15,28.80, 28.51, 23.13; HRMS (ESI) m / z: [M+H] + calcd for C 15 H 18 ClO 249.1041, found249.1043.

[0280] Example 46

[0281] The polysubstituted cyclopropyl carbonyl derivative P38 prepared in this embodiment has the following structure:

[0282]

[0283] The preparation method and conditions in this embodiment are the same as in Example 12, and the feed ratio is the same as in Example 12. α-chlorocyclobutanone compound B8 (65.4 mg, 0.2 mmol, 1.0 equivalent) and commercially available 3-fluorophenyl magnesium bromide (1.0 M inTHF, 0.30 mL, 0.30 mmol, 1.5 equivalent) were added. Thin-layer chromatography (TLC) purification and separation (petroleum ether / ethyl acetate = 50:1, v / v) yielded the corresponding polysubstituted cyclopropyl carbonyl derivative P38 (colorless oil, yield 73%).

[0284] 1H NMR (400 MHz, CDCl3)δ 7.72–7.67 (m, 1H), 7.62–7.55 (m, 1H), 7.43(td, J = 8.0, 5.6 Hz, 1H), 7.25–7.20 (m, 1H), 5.50 (s, 1H), 3.65 (s, 3H), 2.31 (d, J = 8.0 Hz, 1H), 2.08–2.00 (m, 1H), 2.02 (d, J = 1.3 Hz, 3H), 1.89–1.78 (m, 1H), 1.68–1.54 (m, 5H), 1.53–1.41 (m, 1H), 1.37–1.30 (m, 1H), 1.33(s, 3H), 1.29–1.19 (m, 1H), 0.90 (s, 3H), 0.88 (s, 3H); 13 C NMR (125 MHz, CDCl3)δ 198.16, 167.15, 163.83, 161.87 (d, J = 247.5 Hz), 160.40, 141.87 (d, J = 5.9 Hz), 130.05 (d, J = 7.7 Hz), 123.38 (d, J = 2.9 Hz), 119.23 (d, J =21.4 Hz), 114.60, 114.45 (d, J = 22.3 Hz), 50.76, 40.13, 39.96, 38.63, 34.99,33.13, 32.34, 32.12, 29.63, 25.18, 24.01, 22.03, 18.93, 15.76; 19 F NMR (471MHz, CDCl3) δ -112.15; HRMS (ESI) m / z: [M+Na] + calcd for C 24 H 31 FO3Na 409.2149, found 409.2150.

[0285] Example 47

[0286] The polysubstituted cyclopropyl carbonyl derivative P39 prepared in this embodiment has the following structure:

[0287]

[0288] The preparation method and conditions in this embodiment are the same as in Example 12, and the feed ratio is the same as in Example 12. α-chlorocyclobutanone compound B8 (65.4 mg, 0.2 mmol, 1.0 equivalent) and commercially available 4-methoxyphenyl magnesium bromide (1.0 min THF, 0.30 mL, 0.30 mmol, 1.5 equivalent) were added. Thin-layer chromatography (TLC) purification and separation (petroleum ether / ethyl acetate = 25:1, v / v) yielded the corresponding polysubstituted cyclopropyl carbonyl derivative P39 (white solid, yield 95%).

[0289] 1 H NMR (400 MHz, CDCl3)δ 7.84 (d, J = 8.9 Hz, 2H), 6.86 (d, J = 8.9Hz, 2H), 5.45 (s, 1H), 3.80 (s, 3H), 3.58 (s, 3H), 2.22 (d, J = 8.1 Hz, 1H),2.08–1.96 (m, 2H), 1.94 (d, J = 1.3 Hz, 3H), 1.83–1.69 (m, 1H), 1.61–1.45 (m,3H), 1.44–1.32 (m, 2H), 1.29–1.20 (m, 1H), 1.25 (s, 3H), 1.21–1.10 (m, 1H),0.82 (s, 3H), 0.81 (s, 3H); 13 C NMR (125 MHz, CDCl3)δ 198.23, 167.23, 162.87,160.83, 132.85, 129.85, 114.40, 113.52, 55.42, 50.75, 40.27, 40.26, 38.79,34.42, 33.06, 31.27, 30.56, 29.64, 25.16, 24.15, 22.04, 19.00, 15.87; HRMS(ESI) m / z: [M+Na] + calcd for C 25 H 34 O4Na 421.2349, found 421.2347.

[0290] Example 48

[0291] The polysubstituted cyclopropyl carbonyl derivative P40 prepared in this embodiment has the following structure:

[0292]

[0293] The preparation method and conditions in this embodiment are the same as in Example 12, and the feed ratio is the same as in Example 12. α-chlorocyclobutanone compound B9 (55.1 mg, 0.1 mmol, 1.0 equivalent) and commercially available 3-fluorophenyl magnesium bromide (1.0 M inTHF, 0.15 mL, 0.15 mmol, 1.5 equivalent) were added. Thin-layer chromatography (TLC) purification and separation (petroleum ether / ethyl acetate = 50:1, v / v) yielded the corresponding polysubstituted cyclopropyl carbonyl derivative P40 (colorless oil, yield 65%).

[0294] [α]20 D = +20.24 (c = 0.244 in MeOH); 1 H NMR (400 MHz, CDCl3)δ 7.58–7.52 (m, 2H), 7.48–7.42 (m, 4H), 7.42–7.35 (m, 2H), 7.34–7.30 (m, 2H), 7.30–7.24 (m, 2H), 7.17–7.03 (m, 2H), 3.51 (td, J = 10.2, 4.5 Hz, 1H), 3.12 (td, J= 9.7, 6.4 Hz, 1H), 2.11–2.03 (m, 2H), 1.77–1.67 (m, 2H), 1.55–1.48 (m, 3H),1.49–1.44 (m, 1H), 0.79 (s, 3H); 13CNMR (125 MHz, CDCl3)δ 197.79, 163.65, 161.69 (d, J = 247.4 Hz), 141.55 (d, J= 5.7 Hz), 135.54, 135.42, 134.08, 133.76, 129.81 (d, J = 7.7 Hz), 129.47,129.40, 127.48, 123.38 (d, J = 2.8 Hz), 118.97 (d, J = 21.4 Hz), 114.21 (d, J= 22.1 Hz), 64.43, 49.70, 42.61, 42.12, 38.01, 36.28, 36.12, 33.87, 32.44, 31.92, 29.97, 27.98, 26.79, 26.34, 21.26, 18.99, 18.93, 17.56, 14.63; 19 F NMR(471 MHz, CDCl3) δ -112.34; HRMS (ESI) m / z: [M+Na] + calcd for C 40 H 51 FO2SiNa633.3535, found 633.3540.

[0295] Example 49

[0296] The polysubstituted cyclopropyl carbonyl derivative P41 prepared in this embodiment has the following structure:

[0297]

[0298] The preparation method and conditions in this embodiment are the same as in Example 12, and the feed ratio is the same as in Example 12. α-chlorocyclobutanone compound B9 (55.1 mg, 0.1 mmol, 1.0 equivalent) and commercially available 4-methoxyphenyl magnesium bromide (1.0 min THF, 0.15 mL, 0.15 mmol, 1.5 equivalent) were added. Thin-layer chromatography (TLC) purification and separation (petroleum ether / ethyl acetate = 25:1, v / v) yielded the corresponding polysubstituted cyclopropyl carbonyl derivative P41 (colorless oil, yield 58%).

[0299] [α]20 D = +75.08 (c = 0.191 in MeOH); 1H NMR (400 MHz, CDCl3)δ 7.73–7.67 (m, 2H), 7.58–7.52 (m, 2H), 7.45–7.38 (m, 3H), 7.37–7.31 (m, 3H), 7.28–7.21 (m, 2H), 6.70–6.63 (m, 2H), 3.78 (s, 3H), 3.58–3.49 (m, 1H), 3.07 (td, J= 10.0, 6.2 Hz, 1H), 2.14 (dd, J = 14.6, 6.6 Hz, 1H), 2.08–2.03 (m, 1H),1.77–1.65 (m, 2H), 1.60–1.44 (m, 3H), 1.43–1.36 (m, 2H), 1.35–1.30 (m, 1H), 1.30–1.25 (m, 1H), 1.20 (s, 3H), 1.19–1.11 (m, 1H), 0.93 (s, 9H), 0.87 (s, 3H), 0.86 (s, 3H), 0.80 (s, 3H), 0.78–0.70 (m, 2H); 13 C NMR (125 MHz, CDCl3)δ197.99, 162.63, 135.57, 135.42, 134.28, 133.83, 132.48, 129.78, 129.42,129.37, 127.46, 127.45, 113.33, 64.63, 55.32, 49.72, 43.00, 42.12, 37.99,36.19, 35.56, 33.84, 32.46, 30.27, 28.82, 28.04, 26.83, 26.35, 21.33, 18.99,18.94, 17.59, 14.66; HRMS (ESI) m / z: [M+Na] + calcd for C 41 H 54 O3SiNa 645.3734, found 645.3735.

[0300] Example 50

[0301] The polysubstituted cyclopropyl carbonyl derivative P42 prepared in this embodiment has the following structure:

[0302]

[0303] The preparation method and conditions in this embodiment are the same as in Example 12, and the feed ratio is the same as in Example 12. α-chlorocyclobutanone compound B10 (1.04 g, 1.6 mmol, 1.0 equivalent) and commercially available 3-fluorophenyl magnesium bromide (1.0 M inTHF, 2.4 mL, 2.4 mmol, 1.5 equivalent) were added. The mixture was purified and separated by silica gel column chromatography (300-400 mesh) (petroleum ether / ethyl acetate = 30:1-4:1, v / v) to obtain the corresponding polysubstituted cyclopropyl carbonyl derivative P42 (white solid, yield 92%).

[0304] 1 H NMR (400 MHz, CDCl3)δ 7.71–7.62 (m, 4H), 7.60–7.53 (m, 1H), 7.48–7.42 (m, 1H), 7.41–7.34 (m, 1H), 7.34–7.26 (m, 3H), 7.26–7.16 (m, 4H), 4.93(s, 2H), 3.54 (s, 3H), 3.39 (s, 3H), 2.85 (dd, J = 14.6, 6.2 Hz, 1H), 2.72(dd, J = 14.6, 6.2 Hz, 1H), 2.28 (d, J = 8.6 Hz, 1H), 2.37–2.13 (m, 2H), 2.02(s, 3H), 1.70–1.49 (m, 2H), 1.38–1.30 (m, 1H), 1.08 (s, 3H), 1.05 (s, 9H); 13CNMR (125 MHz, CDCl3)δ 196.79, 173.67, 168.31, 163.96, 161.50 (d, J = 247.1Hz), 163.52, 151.82, 146.13, 142.30 (d, J = 5.9 Hz), 135.08, 135.05, 133.47,133.26, 129.79 (d, J = 7.7 Hz), 129.50, 129.48, 127.76, 127.40, 127.30,123.41 (d, J = 2.9 Hz), 118.87 (d, J = 21.5 Hz), 118.01, 114.45 (d, J = 22.3Hz), 111.41, 67.38, 60.60, 51.52, 38.05, 37.60, 33.39, 32.95, 31.22, 26.52,20.41, 19.37, 11.22, 11.12; 19 F NMR (471 MHz, CDCl3)δ -112.57; HRMS (ESI) m / z:[M+Na] + calcd for C 42 H 45 FO7SiNa 731.2811, found 731.2815.

[0305] Application Example 1

[0306] Under nitrogen protection, the polysubstituted cyclopropyl carbonyl derivative P47 (16.0 mg, 0.023 mmol, 1.0 equivalent) was dissolved in a mixed solvent of methanol and tetrahydrofuran (0.23 mL, 0.1 M, 1:1). Sodium borohydride (1.7 mg, 0.046 mmol, 2.0 equivalent) was added at 0 °C. After the addition was complete, the mixture was stirred at room temperature for 1 hour. After the reaction was confirmed to be complete by TLC, it was quenched with saturated ammonium chloride aqueous solution, extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solution was concentrated under reduced pressure and purified by silica gel column chromatography (300-400 mesh) (petroleum ether / ethyl acetate = 10:1-3:1, v / v) to give compound M1 (white solid, yield 73%).

[0307] 1H NMR (400 MHz, CDCl3)δ 7.78–7.67 (m, 4H), 7.42–7.25 (m, 7H), 7.12–7.02 (m, 2H), 6.95 (td, J = 8.4, 3.2 Hz, 1H), 5.00 (s, 2H), 4.37 (d, J = 9.3Hz, 1H), 3.69 (s, 3H), 3.54 (s, 3H), 3.46 (br s, 1H), 2.89 (dd, J = 14.2, 3.3Hz, 1H), 2.25 (dd, J = 14.2, 7.9 Hz, 1H), 2.15 (s, 3H), 1.99–1.86 (m, 1H),1.80–1.68 (m, 1H), 1.60–1.48 (m, 1H), 1.17–1.04 (m, 1H), 1.12 (s, 9H), 0.95–0.81 (m, 2H), 0.79 (s, 3H); 13 C NMR (125 MHz, CDCl3)δ 173.86, 168.14, 163.47,162.25 (d, J = 245.8 Hz), 161.91, 151.68, 146.60 (d, J = 6.6 Hz), 146.28,135.10, 135.06, 133.20, 129.81 (d, J = 8.1 Hz), 129.68, 129.65, 127.65,127.54, 127.45, 121.60 (d, J = 2.9 Hz), 118.16, 114.18 (d, J = 21.3 Hz),113.07 (d, J = 21.3 Hz), 112.14, 70.11, 67.48, 61.23, 51.46, 37.43, 34.69,30.82, 27.70, 26.58, 22.22, 20.53, 20.31, 13.04, 11.44; 19 F NMR (471 MHz,CDCl3)δ -113.16; HRMS (ESI) m / z: [M+Na] + calcd for C 42 H 47 FO7SiNa 733.2964,found 733.2967.

[0308]

[0309] Application Example 2

[0310] Under nitrogen protection, activated zinc powder (843.0 mg, 12.9 mmol, 24.0 equivalents), lead dichloride (180.0 mg, 0.65 mmol, 1.2 equivalents), and anhydrous tetrahydrofuran (6.0 mL) were added to reaction flask 1. Diiodomethane (0.364 mL, 4.5 mmol, 8.4 equivalents) was slowly added dropwise at 0°C, and the mixture was stirred at this temperature for 30 minutes. During this period, anhydrous zirconium chloride (500 mg, 2.15 mmol, 4.0 equivalents) and tetrahydrofuran (4.0 mL) were added to reaction flask 2. After stirring at room temperature for 20 minutes, the suspension was transferred to reaction flask 1, and stirring was continued at 0°C for 30 minutes until the system turned dark green, yielding the active methyleneizing reagent (0.435 M). The polysubstituted cyclopropyl carbonyl derivative P47 (20.0 mg, 0.028 mmol, 1.0 equivalent) was dissolved in tetrahydrofuran (0.14 mL, 0.2 M). An active methyleneizing reagent (0.435 M, 0.20 mL, 0.084 mmol, 3.0 equivalent) was slowly added dropwise at 0 °C, and the mixture was stirred at this temperature for 1 hour. After the reaction was confirmed to be complete by TLC, the mixture was back-quenched with ice-cold saturated sodium bicarbonate solution, extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (300-400 mesh) (petroleum ether / ethyl acetate = 15:1–4:1, v / v) to give compound M2 (colorless oil, yield 23%).

[0311] 1H NMR (400 MHz, CDCl3)δ 7.63–7.58 (m, 4H), 7.40–7.34 (m, 3H), 7.30–7.25 (m, 3H), 7.21 (td, J = 8.1, 6.1 Hz, 1H), 7.12–7.09 (m, 1H), 7.01–6.97(m, 1H), 6.95–6.90 (m, 1H), 5.42 (br s, 1H), 4.95 (d, J = 6.7 Hz, 2H), 4.92(br s, 1H), 3.59 (s, 3H), 3.53 (s, 3H), 2.32 (dd, J = 14.5, 4.4 Hz, 1H),2.18–2.14 (m, 1H), 2.09 (s, 3H), 2.12–2.07 (m, 1H), 1.98–1.92 (m, 1H), 1.78–1.72 (m, 1H), 1.57–1.53 (m, 1H), 1.48–1.43 (m, 1H), 1.34–1.28 (m, 1H), 1.05(s, 9H), 0.72 (s, 3H); 13 C NMR (125 MHz, CDCl3)δ 174.16, 168.48, 163.33,163.31, 162.10 (d, J = 244.3 Hz), 151.61, 145.77, 144.21 (d, J = 7.3 Hz),141.94, 135.37, 132.83, 132.65, 129.54, 129.52, 129.30 (d, J = 8.1 Hz),127.80, 127.28, 127.26, 121.18 (d, J = 2.9 Hz), 118.05, 116.66, 113.78 (d, J= 21.3 Hz), 112.45 (d, J = 22.0 Hz), 111.58, 67.40, 60.32, 51.48, 37.97,31.33, 30.59, 26.79, 26.54 (overlap), 23.30, 22.49, 20.54, 13.43, 11.18; 19 FNMR (471 MHz, CDCl3)δ -113.93; HRMS (ESI) m / z: [M+Na] + calcd for C 43 H47 FO6SiNa729.3030, found 729.3026.

[0312]

[0313] Application Example 3

[0314]

[0315] Under nitrogen protection, the polysubstituted cyclopropyl carbonyl derivative P47 (195.0 mg, 0.275 mmol, 1.0 equivalent) was dissolved in tetrahydrofuran (1.38 mL, 0.2 M). Tetrabutylammonium fluoride (1.0 M in THF, 1.38 mL, 1.38 mmol, 5.0 equivalent) was added at 0 °C. After the addition was complete, the mixture was stirred overnight at room temperature. After the reaction was confirmed to be complete by TLC, it was quenched with saturated ammonium chloride aqueous solution, extracted five times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (300-400 mesh) (petroleum ether / ethyl acetate = 10:1-3:1, v / v) to give compound M3 (white solid, yield 81%).

[0316] 1 H NMR (400 MHz, CDCl3)δ 7.83 (d, J = 7.9 Hz, 1H), 7.64–7.56 (m, 1H), 7.49–7.39 (m, 1H), 7.28–7.18 (m, 1H), 5.15–5.06 (m, 1H), 5.10 (s, 2H), 3.93(s, 3H), 3.64 (s, 3H), 3.36–3.19 (m, 3H), 2.87 (d, J = 15.9 Hz, 1H), 2.42 (t,J = 8.3 Hz, 2H), 2.11–1.98 (m, 1H), 2.03 (s, 3H), 1.95–1.83 (m, 1H), 1.18 (s, 3H); 13C NMR (125 MHz, CDCl3)δ 198.29, 173.95, 168.68, 163.76, 161.79 (d, J =248.0 Hz), 159.73, 157.44, 147.12, 139.89 (d, J = 5.9 Hz), 130.37 (d, J = 7.7Hz), 124.44 (d, J = 3.2 Hz), 120.10 (d, J = 21.3 Hz), 116.19, 114.95, 114.66(d, J = 22.7 Hz), 102.58, 90.57, 68.94, 59.16, 51.73, 42.36, 40.24, 30.22, 29.05, 28.94, 20.87, 10.95; 19 F NMR (471 MHz, CDCl3)δ -111.89; HRMS (ESI) m / z:[M+Na] + calcd for C 26 H 27 FO7Na 493.1636, found 493.1633.

[0317] Application Example 4

[0318]

[0319] Under nitrogen protection, the polysubstituted cyclopropyl carbonyl derivative P47 (15.0 mg, 0.021 mmol, 1.0 equivalent) was dissolved in hexafluoroisopropanol (0.3 mL, 0.07 M), and trifluoroacetic acid (6.3 μL, 0.084 mmol, 4.0 equivalent) was added dropwise at room temperature. After the addition was complete, the mixture was stirred at 60 °C for 5 hours. After the reaction was confirmed to be complete by TLC, the system was completely cooled and concentrated under reduced pressure. The resulting solution was purified by silica gel column chromatography (300-400 mesh) (petroleum ether / ethyl acetate = 10:1-3:1, v / v) to give compound M4 (white solid, yield 86%).

[0320] 1H NMR (400 MHz, CDCl3)δ 7.72 (d, J = 7.8 Hz, 1H), 7.65–7.61 (m, 1H),7.48–7.43 (m, 1H), 7.31–7.27 (m, 1H), 5.09 (s, 2H), 3.74 (s, 3H), 3.65 (s,3H), 3.24 (dd, J = 17.3, 3.1 Hz, 1H), 3.04 (dd, J = 17.3, 5.6 Hz, 1H), 2.80(dd, J = 17.3, 9.5 Hz, 1H), 2.72–2.64 (m, 2H), 2.64–2.59 (m, 1H), 2.44 (dd, J= 17.3, 8.3 Hz, 1H), 2.16–2.07 (m, 2H), 2.12 (s, 3H), 1.32 (s, 3H); 13 C NMR(125 MHz, CDCl3)δ 196.79, 174.10, 168.81, 163.51, 162.28 (d, J = 248.7 Hz),162.05, 151.55, 147.40, 138.81 (d, J = 5.9 Hz), 130.42 (d, J = 7.3 Hz),123.77, 120.44 (d, J = 21.3 Hz), 115.72, 114.93, 114.82 (d, J = 22.0 Hz),108.70, 78.46, 68.02, 60.21, 51.73, 39.88, 33.41, 33.29, 28.00, 23.80, 20.01,11.06; 19 F NMR (471 MHz, CDCl3)δ -111.43; HRMS (ESI) m / z: [M+Na] + calcd forC 26 H 27 FO7Na 493.1636, found 493.1633.

Claims

1. A method for synthesizing a multi-substituted cyclopropyl carbonyl derivative, characterized in that, The method includes the following steps: (1) Using highly substituted olefins as raw materials, α-chlorocyclobutanone was obtained through [2+2] cycloaddition and reduction reactions; (2) α-Chlorocyclobutanone reacts with different Grignard reagents or organolithium reagents to give polysubstituted cyclopropyl carbonyl derivatives P. The general reaction formula is: In the formula, R1 is selected from alkyl; R2 is selected from methyl or hydrogen atom; R3 is selected from alkyl; R4 is selected from straight-chain or branched alkyl or cycloalkyl, olefin or branched olefin, phenyl, benzyl or substituted benzene ring, five- to six-membered heterocycle or heteroaromatic ring containing N or S heteroatoms.

2. The method for synthesizing a multi-substituted cyclopropyl carbonyl derivative according to claim 1, characterized in that, In step (1), the [2+2] cycloaddition reaction is carried out in diethyl ether as the solvent, with a reaction concentration of 0.05-0.4 M based on the olefin substrate concentration. The reaction reagents are zinc powder and trichloroacetyl chloride, with amounts of 4.0 times and 1.5 times the equivalent of the olefin substrate, respectively. The reaction temperature is room temperature, and the reaction time is 3-24 hours. The protective gas is nitrogen or argon.

3. The method for synthesizing a multi-substituted cyclopropyl carbonyl derivative according to claim 1, characterized in that, In step (1), the reduction reaction is carried out in the following ways: the reaction solvent is tetrahydrofuran, a solution of samarium diiodide in tetrahydrofuran, and the amount used is 2 to 5 times the equivalent of the olefin substrate; the reaction temperature is -78 degrees Celsius; the reaction time is 0.5 to 2.0 hours; and the protective gas is nitrogen or argon.

4. The method for synthesizing a multi-substituted cyclopropyl carbonyl derivative according to claim 1, characterized in that, The reaction solvent in step (2) is one of tetrahydrofuran, ethylene glycol dimethyl ether or dioxane, and the reaction concentration is 0.01~0.5 M based on the α-chlorocyclobutanone substrate reaction concentration; the reaction reagent is Grignard reagent or organolithium reagent, and the amount used is 1~3 times the equivalent of the substrate; the reaction temperature is -30℃~30℃; and the reaction time is 1~24 hours.

5. The method for synthesizing a multi-substituted cyclopropyl carbonyl derivative as described in claim 1, 2, 3, or 4, is applied in the cyclopropanization modification of complex active molecules and the subsequent derivatization of their products.

6. The application of the method for synthesizing a multi-substituted cyclopropyl carbonyl derivative as described in claim 1, 2, 3, or 4 in the cyclopropanation modification of mycophenolic acid and its subsequent derivatization.

7. The polysubstituted cyclopropyl carbonyl derivatives P1-P42 and α-chlorocyclobutanone compounds B1-B13, obtained by the synthetic method of a polysubstituted cyclopropyl carbonyl derivative according to claim 1, 2, 3 or 4, with the following structural formulas: 。 8. The application of the polysubstituted cyclopropyl carbonyl derivatives P1-P42 and α-chlorocyclobutanone compounds B1-B13 as described in claim 7 in the cyclopropanization modification of complex active molecules and their subsequent derivatization.

9. The application of the polysubstituted cyclopropyl carbonyl derivatives P1-P42 and α-chlorocyclobutanone compounds B1-B13 as described in claim 7 in the cyclopropanation modification of mycophenolic acid and its subsequent derivatization.

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