Lewis base-catalyzed construction of 1,3-dioxolane derivatives from electron-deficient alkenyl oxiranes

Abstract

The invention belongs to the field of pharmaceutical synthesis chemistry, and specifically relates to the construction of 1,3-dioxolane derivatives by Lewis base-catalyzed electrodeficient alkenyl oxirane. The invention discloses a class of 1,3-dioxolane derivatives with novel structures, develops a Lewis base-catalyzed [3+2] cycloaddition reaction between vinyl epoxide and various active carbonyl compounds, and provides an effective strategy for synthesizing dioxolane skeleton derivatives.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical synthesis chemistry, and specifically relates to the construction of 1,3-dioxolane derivatives by using Lewis base to catalyze electricity-deficient alkenyl oxirane. Background Art

[0002] The information disclosed in this background technology section is only intended to increase some understanding of the overall background of the invention, and should not be necessarily regarded as an admission or any form of suggestion that the information constitutes the prior art already known to ordinary technicians in this field.

[0003] The 1,3-dioxolane skeleton is widely present in drug molecules, natural active substances, and organic material molecules, and plays a vital role in life activities. Among the 311 oxygen-containing drug molecules approved by the US FDA, 24 contain a dioxolane skeleton. For example, terconazole is a common antifungal agent; topiramate is a commonly used anticonvulsant drug; guanidine is an orally active post-adrenergic drug; halcinonide is a glucocorticoid used to treat local skin infections; in addition, the oxidized indole spiro-1,3-dioxolane skeleton has been studied to have good antagonistic activity against tuberculosis resistance ( Figure 1 ).

[0004] Vinyl oxirane is an important and widely used organic synthesis reagent. Due to its structure containing two active parts, namely, a conjugated adjacent carbon-carbon double bond and oxirane, its chemical properties are unique and very active. These activities cannot be achieved by a single functional group. Usually, reactions involving alkenyl oxirane are generally carried out under the catalysis of transition metals or Lewis acids. Under the catalysis of transition metals, alkenyl oxirane can be converted into highly active zwitterionic metal-allyl intermediates, which then undergo allylation to form highly allyl compounds or cyclization to form oxygen-containing heterocyclic compounds ( Figure 2 On the other hand, under Lewis acid catalysis, alkenyl oxiranes usually undergo Meinwald rearrangement to generate Lewis acid-stabilized dienolate intermediates, which then participate in addition cascade reactions ( Figure 2 ).

[0005] However, as far as the inventors know, there is no report on the participation of organocatalysis in the ring-opening reaction of vinyl oxide. As the third catalyst, organocatalysis has the advantages of mild reaction conditions, environmental friendliness, and easy recovery. It has become an important field after enzyme catalysis and metal catalysis. Therefore, it is very necessary to develop organocatalytic reactions involving alkenyl oxiranes, which will further expand its scope of application and enhance the diversity of its reactions.

[0006] Although the Lewis base-catalyzed cyclization of organic phosphines and amines has achieved great success, there has been little development in the synthetic methodology for the synthesis of polyoxygen heterocycles. The reason is that a common oxygen-containing active intermediate has not been developed. Lewis base catalysis is an effective strategy for constructing various carbon-carbon or carbon-heteroatom bonds. Through the nucleophilic addition of Lewis base catalysts, electron-deficient acceptor molecules can be smoothly converted into zwitterionic intermediates, which serve as universal all-carbon synthons for subsequent reactions. The acceptors currently used to develop cyclization reactions in this field include olefins, alkynes, allenes, MBH adducts, and activated cyclopropanes (cyclopropenes), which generally provide C synthons. 1) Unsubstituted or γ-substituted allenes and some alkynes can be used as acceptor molecules, often acting as C3 synthons under phosphine catalysis (Lu reaction and variations), and often participating in the reaction as C2 synthons under amine catalysis ( Figure 3 2) Kwon's group found that α-alkyl-substituted allenoates can react with imines as C4 synthons in the presence of organophosphine catalysis to undergo [4+2] cyclization. In addition, they can also participate in cyclization as C2 synthons ( Figure 3 b). 3) Tong Xiaofeng's research group developed a method for β'-OAc substituted allenoic acid esters to form dienylphosphonium intermediates (C4 synthons) under the catalysis of organic phosphine, which then react with dinucleophilic reagents to undergo cyclization reaction ( Figure 3 4) MBH adducts often undergo cyclization reactions as C3 and C1 synthons under the catalysis of organic phosphine and amine ( Figure 3 5) Liang Fushun's research group reported that DABCO activated cyclopropane ring opening participated in cyclization; Academician Aso Akira's research group found that activated cyclopropene can also accept organic phosphine attack to undergo intramolecular cyclization to construct furan ring; Li Yang and Xu Silong's research groups also successively realized nucleophilic catalysis of intramolecular cyclization / rearrangement cyclization of alkylidene cyclopropane and alkenyl cyclopropane ( Figure 3 e); Lu Yixin used bifunctional chiral phosphine to realize the asymmetric [3+2] cyclization reaction of activated alkenyl cyclopropane and imine. Therefore, the development of an oxygen-containing acceptor molecule is of great significance for the construction of oxygen-containing, especially polyoxygen-containing heterocycles catalyzed by organophosphine and amine Lewis bases. Summary of the invention

[0007] The inventors expect that Lewis base catalysis can be applied to the ring-opening cyclization reaction of readily available and highly reactive vinyl epoxides. They designed and synthesized an electron-deficient olefinic oxirane, which is assumed to form an oxygen-containing zwitterionic intermediate under the nucleophilic attack of a Lewis base, and then undergo a cyclization reaction with a carbonyl compound to construct a target polyoxyheterocyclic compound, providing an effective strategy for the synthesis of dioxolane skeleton derivatives ( Figure 4 ).

[0008] Lewis base (LB) catalyzed cyclization has made great achievements in the field of organic synthesis, especially in the construction of functional heterocycles and the synthesis of natural active substances. The acceptors currently used to develop cyclization reactions in this field include olefins, alkynes, allenes, MBH adducts, and activated cyclopropanes (cyclopropenes), which can accept Lewis base attacks to form C2 to C5 pure carbon synthons. If you want to construct an oxygen ring, it can only react with a carbonyl group to construct a monooxygen heterocycle. However, there is little development in the synthetic methodology for synthesizing polyoxygen heterocycles. The reason is that there is a lack of a universal oxygen-containing synthon in this field. Therefore, the development of an oxygen-containing active intermediate is very necessary for the synthesis of polyoxygen heterocycles.

[0009] In view of the shortcomings of the prior art, the present invention develops an unprecedented [3+2] cycloaddition reaction between vinyl epoxides and various active carbonyl compounds catalyzed by oxygen-containing synthons and novel Lewis bases. The reaction conditions are mild, the yield is high, and many compounds can be derived, providing an effective strategy for the synthesis of dioxolane skeleton derivatives.

[0010] The technical solution adopted by the present invention is as follows:

[0011] In the first aspect of the present invention, a 1,3-dioxolane derivative is provided, the structure of which is shown in general formula I:

[0012] Where R 1 Selected from H, Me, Et, i -Pr, Ph, Bn, CO2Me, CO2Et, CO2Bn, 2-XC6H4, 3-XC6H4, 4-XC6H4, 2,3-X2C6H3, 2,4-X2C6H3, 2,5-X2C6H3, 2,6-X2C6H3, 3,4-X2C6H3, 3,5-X2C6H3, 2, 3,4-X3C6H2、2,3,5-X3C6H2、2,3,6-X3C6H2、2,4,6-X3C6H2、3,4,5-X3C6 H2, 3,4,6-X3C6H2, 2,3,4,5-X4C6H1, 2,3,4,6-X4C6H1, 2,3,4,5,6-X5C6;

[0013] R 2 Selected from H, Bn;

[0014] R 3 Selected from Me, Et, Bn;

[0015] R 4 Selected from Me, Bn, 4-FC6H4CO, Ts, Boc, Ac;

[0016] R 5Selected from H, 4-X, 5-X, 6-X, 7-X, 4,5-X2, 4,6-X2, 4,7-X2, 5,6-X2, 5,7-X2, 6,7-X2, 4,5,6-X3, 4,5,7-X3, 4,6,7-X3, 5,6,7-X3, 4,5,6,7-X4;

[0017] Me represents methyl, Et represents ethyl, i -Pr represents isopropyl, Ph represents phenyl, Bn represents benzyl, Ts represents p-toluenesulfonyl, Boc represents tert-butyloxycarbonyl, Ac represents acetyl, and X represents an electron-donating group (alkyl, alkoxy), an electron-withdrawing group (nitro, cyano, sulfonic acid, trihalomethyl), or a halogen atom (fluorine, chlorine, bromine, iodine).

[0018] In a second aspect of the present invention, a method for preparing the 1,3-dioxolane derivative is provided, the method comprising the following steps:

[0019] Under an argon atmosphere, a set amount of alkenyl epoxide, active ketone, Lewis base and inorganic base are mixed, and then a solvent is added, reacted at a set temperature to obtain a reaction mixture, concentrated to dryness, and finally purified to obtain a cycloaddition product, the structure of which is shown in general formula I;

[0020] The structure of the alkenyl epoxide is shown in Formula II:

[0021] Where R 1 Selected from H, Me, Et, i -Pr, Ph, Bn, CO2Me, CO2Et, CO2Bn, 2-XC6H4, 3-XC6H4, 4-XC6H4, 2,3-X2C6H3, 2,4-X2C6H3, 2,5-X2C6H3, 2,6-X2C6H3, 3,4-X2C6H3, 3,5-X2C6H3, 2, 3,4-X3C6H2、2,3,5-X3C6H2、2,3,6-X3C6H2、2,4,6-X3C6H2、3,4,5-X3C6 H2, 3,4,6-X3C6H2, 2,3,4,5-X4C6H1, 2,3,4,6-X4C6H1, 2,3,4,5,6-X5C6;

[0022] R 2 Selected from H, Bn;

[0023] R 3 Selected from Me, Et, Bn.

[0024] The structure of the active ketone is shown in Formula III:

[0025] Where R 4Selected from Me, Bn, 4-FC6H4CO, Ts, Boc, Ac;

[0026] R 5 Selected from H, 4-X, 5-X, 6-X, 7-X, 4,5-X2, 4,6-X2, 4,7-X2, 5,6-X2, 5,7-X2, 6,7-X2, 4,5,6-X3, 4,5,7-X3, 4,6,7-X3, 5,6,7-X3, 4,5,6,7-X4.

[0027] Furthermore, the Lewis base is one or more of DMAP (N,N-dimethylaminopyridine), 1,8-diazabicyclo[5.4.0]undec-7-ene, 4-pyrrolidinylpyridine, 4-piperidinylpyridine, and 4-morpholinopyridine.

[0028] Furthermore, the inorganic base is one or more of potassium carbonate, potassium bicarbonate, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydroxide, cesium carbonate, and cesium fluoride.

[0029] Furthermore, the solvent is one of dichloromethane, toluene, acetone, tetrahydrofuran and acetonitrile.

[0030] Further, the feeding ratio of alkenyl epoxide, active ketone, Lewis base, inorganic base and solvent is (0.1mmol~0.15mmol): (0.1mmol~0.15mmol): (0.02mmol~0.04mmol): (0.05mmol~0.1mmol): (1mL~2mL). Preferably, the feeding ratio of alkenyl epoxide, active ketone, Lewis base, inorganic base and solvent is 0.15mmol: 0.1mmol: 0.02mmol: 0.05mmol: 2mL.

[0031] Further, the reaction conditions are: stirring the reaction at -20°C to 25°C for 36 h to 48 h. Preferably, the reaction temperature is -20°C and the reaction time is 48 h.

[0032] Furthermore, the purification method is flash silica gel column chromatography.

[0033] Furthermore, in the purification method, the eluent is composed of ethyl acetate and petroleum ether. Preferably, the volume ratio of ethyl acetate to petroleum ether is 1:10.

[0034] In the third aspect of the present invention, there is provided the use of the 1,3-dioxolane derivative in the preparation of anticancer drugs.

[0035] Furthermore, the 1,3-dioxolane derivative is used in the preparation of anti-breast cancer drugs.

[0036] Furthermore, the obtained compound was used for its anti-cancer cell proliferation activity in human breast cancer cell MCF-7.

[0037] In the present invention, human breast cancer cells (Michigan Cancer Foundation-7, MCF-7) are selected as the cell line. The cell suspension is counted, and the complete medium is added and diluted to 50,000-70,000 / mL, and 100 μL is inoculated in a 96-well plate per well. The cycloaddition product to be tested is dissolved in DMSO at a concentration of 100 μmol / mL to prepare a mother solution, and then the mother solution is diluted one thousand times with complete medium. A blank group and a control group are set up, and 100 μL of drug-containing medium is added to each well, and then placed in an incubator for incubation for 36 hours. Subsequently, the CCK8 kit is used to measure the absorbance at 450 nm on an ELISA reader to calculate the inhibition rate.

[0038] Compared with the related art known to the inventor, one of the technical solutions of the present invention has the following beneficial effects:

[0039] The present invention provides an unprecedented development of oxygen-containing synthons and a novel Lewis base-catalyzed [3+2] cycloaddition reaction between vinyl epoxides and various active carbonyl compounds, providing an effective strategy for the synthesis of dioxolane skeleton derivatives.

[0040] The compound of the invention has a novel structure, a simple preparation process, many derivatizable compounds, mild reaction conditions, high product yield, and an environmentally friendly catalyst; the synthesized compound has certain anticancer activity. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] The accompanying drawings constituting a part of the present invention are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their description are used to explain the present invention and do not constitute improper limitations on the present invention.

[0042] Figure 1 Common drugs or active substances containing 1,3-dioxolane skeleton.

[0043] Figure 2 Activation methods of vinyl ethylene oxide.

[0044] Figure 3 Nucleophilic phosphines, amine Lewis base catalytic acceptor molecules, reactive intermediates, and cyclization syntheses subtypes.

[0045] Figure 4 Lewis base-catalyzed construction of 1,3-dioxolane derivatives from electron-deficient alkenyl oxiranes.

[0046] Figure 5 Synthetic route of 1,3-dioxolane derivatives.

[0047] Figure 6 The synthetic route of the target [3+2] cycloaddition reaction product 3aa in Example 2.

[0048] Figure 7 The synthetic route of the target [3+2] cycloaddition reaction product in Examples 2 to 7.

[0049] Figure 8 H NMR spectrum of compound 3aa: 1 H NMR (800 MHz, Chloroform- d ) of product3aa.

[0050] Fig. 9 Compound 3aa carbon NMR spectrum: 13 C{ 1 H} NMR (101 MHz, Chloroform- d ) ofproduct 3aa.

[0051] Fig.10 Compound 3ab H NMR spectrum: 1 H NMR (800 MHz, Chloroform- d ) of product3ab.

[0052] Fig.11 Compound 3ab carbon NMR spectrum: 13 C{ 1 H} NMR (201 MHz, Chloroform- d ) ofproduct 3ab.

[0053] Fig.12 Compound 3ac H NMR spectrum: 1 H NMR (800 MHz, Chloroform- d ) of product3ac.

[0054] Fig.13 Compound 3ac carbon NMR spectrum: 13 C{ 1 H} NMR (201 MHz, Chloroform- d ) ofproduct 3ac.

[0055] Fig.14 Compound 3ac NMR fluorine spectrum: 19 F NMR (376 MHz, Chloroform-d ) ofproduct 3ac.

[0056] Fig.15 Compound 3ba H NMR spectrum: 1 H NMR (800 MHz, Chloroform- d ) of product3ba.

[0057] Fig.16 Compound 3ba carbon NMR spectrum: 13 C{ 1 H} NMR (101 MHz, Chloroform- d ) ofproduct 3ba.

[0058] Fig.17 Compound 3ca H NMR spectrum: 1 H NMR (800 MHz, Chloroform- d ) of product3ca.

[0059] Fig.18 Compound 3ca carbon NMR spectrum: 13 C{ 1 H} NMR (101 MHz, Chloroform- d ) ofproduct 3ca.

[0060] Fig.19 Compound 3da H NMR spectrum: 1 H NMR (800 MHz, Chloroform- d ) of product3da ( d.r . = 3 : 2).

[0061] Fig. 20 Compound 3da carbon NMR spectrum: 13 C{ 1 H} NMR (201 MHz, Chloroform- d ) ofproduct 3da.

[0062] Fig.21 Compound 3ad H NMR spectrum: 1 H NMR (800 MHz, Chloroform- d ) of product3ad.

[0063] Fig. 22Compound 3ad carbon NMR spectrum: 13 C{ 1 H} NMR (201 MHz, Chloroform- d ) ofproduct 3ad.

[0064] Fig.23 Compound 3ad NMR fluorine spectrum: 19 F NMR (753 MHz, Chloroform- d ) of product3ad.

[0065] Fig.24 Compound 3ae H NMR spectrum: 1 H NMR (800 MHz, Chloroform- d ) of product3ae.

[0066] Fig.25 Compound 3ae carbon NMR spectrum: 13 C{ 1 H} NMR (201 MHz, Chloroform- d ) ofproduct 3ae.

[0067] Fig.26 Compound 3af H NMR spectrum: 1 H NMR (800 MHz, Chloroform- d ) of product3af.

[0068] Fig. 27 Compound 3af carbon NMR spectrum: 13 C{ 1 H} NMR (201 MHz, Chloroform- d ) ofproduct 3af.

[0069] Fig.28 Compound 3ea H NMR spectrum: 1 H NMR (800 MHz, Chloroform- d ) of product3ea.

[0070] Fig.29 Compound 3ea carbon NMR spectrum: 13 C{ 1 H} NMR (201 MHz, Chloroform- d ) ofproduct 3ea.

[0071] Fig.30 Compound 3ea NMR fluorine spectrum: 19 F NMR (753 MHz, Chloroform- d ) of product3ea.

[0072] Fig.31 Compound 3fa H NMR spectrum: 1 H NMR (800 MHz, Chloroform- d ) of product3fa.

[0073] Fig.32 Compound 3fa carbon NMR spectrum: 13 C{ 1 H} NMR (201 MHz, Chloroform- d ) ofproduct 3fa.

[0074] Fig.33 Compound 3ga H NMR spectrum: 1 H NMR (800 MHz, Chloroform- d ) of product3ga.

[0075] Fig.34 Compound 3ga carbon NMR spectrum: 13 C{ 1 H} NMR (201 MHz, Chloroform- d ) ofproduct 3ga. DETAILED DESCRIPTION

[0076] It should be noted that the following detailed descriptions are exemplary and are intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs.

[0077] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit exemplary embodiments according to the present invention. As used herein, unless the context clearly indicates otherwise, the singular form is also intended to include the plural form. In addition, it should be understood that when the terms "comprising" and / or "including" are used in this specification, it indicates the presence of features, steps, operations and / or combinations thereof.

[0078] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below in conjunction with specific embodiments.

[0079] Example 1 Preparation of the compound of formula I

[0080] Synthesis route such as Figure 5 As shown:

[0081] Under argon atmosphere, 0.15 mmol of alkenyl epoxide 1, 0.1 mmol of active ketone 2, 0.02 mmol of DMAP catalyst and 0.05 mmol of potassium carbonate were weighed and added to a Schlenk tube. 2 mL of dichloromethane was added and stirred at -20 °C for 48 hours to obtain a reaction mixture, which was then concentrated to dryness. The obtained cycloaddition product 3 was purified by flash silica gel column chromatography, and the eluent consisted of ethyl acetate / petroleum ether = 1 / 10.

[0082] Example 2 Synthesis of target [3+2] cycloaddition product 3aa

[0083] Synthesis route such as Figure 6 As shown:

[0084] First, the reaction conditions were optimized using the power-deficient alkenyl oxirane 1a and active ketone 2a as template substrates. Using 0.15 mmol alkenyl oxirane and 0.1 mmol N-methyl isatin, the optimized reaction conditions were obtained by screening factors such as the type of Lewis base, reaction solvent, and additives. That is, under an argon atmosphere, 0.15 mmol alkenyl oxirane 1a and 0.1 mmol active ketone 2a, 0.02 mmol DMAP catalyst, and 0.05 mmol potassium carbonate were weighed and added to a Schlenk tube. 2 mL of dichloromethane was added and stirred at -20 °C for 48 hours. Finally, the target [3+2] cycloaddition reaction product 3aa was obtained with a yield of 97%.

[0085] benzyl

[0086] 2-((3S,4'R)-1-methyl-2-oxo-4'-phenylspiro[indoline-3,2'-[1,3]dioxolan]-4'-yl)acrylate (3aa)

[0087] Prepared according to the above procedure, yield 97% (42.9 mg). White solid, mp = 90 - 91 °C; 1 H NMR (800 MHz, Chloroform- d) δ 7.55 – 7.48 (m, 2H), 7.32 – 7.27 (m, 3H), 7.27 –7.20 (m, 4H), 7.12 (dd, J = 7.3, 2.3 Hz, 2H), 6.82 (td, J = 7.6, 0.9 Hz, 1H),6.68 (d, J = 7.8 Hz, 1H), 6.52 (dd, J = 7.4, 1.3 Hz, 1H), 6.43 (d, J = 1.3Hz, 1H), 6.37 (d, J = 1.3 Hz, 1H), 5.24 (d, J = 9.6 Hz, 1H), 5.05 – 4.97 (m,2H), 4.79 (d, J = 9.6 Hz, 1H), 3.06 (s, 3H); 13 C{ 1 H} NMR (101 MHz, Chloroform- d ) δ 172.6, 165.0, 144.6, 141.8, 141.6, 135.4, 131.6, 128.6, 128.5, 128.3,128.0, 126.3, 126.1, 125.6, 124.2, 123.3, 108.5, 103.3, 85.8, 74.2, 66.7,25.9; HRMS (ESI) calculate for C 27 H 23 NO5Na + [M+Na] + 464.1474, found 464.1476. Figure 8 and Fig. 9 .

[0088] Example 3 Synthesis of target [3+2] cycloaddition product 3ab

[0089] Synthesis route such as Figure 7 As shown:

[0090] Under argon atmosphere, 0.15 mmol of alkenyl oxirane 1a, 0.1 mmol of active ketone 2b, 0.04 mmol of DMAP catalyst and 0.05 mmol of potassium carbonate were weighed into a Schlenk tube. 2 mL of dichloromethane was added and stirred at -20 °C for 48 hours to obtain the target [3+2] cycloaddition product 3ab with a yield of 84%.

[0091] benzyl

[0092] 2-((3S,4'R)-1-benzyl-2-oxo-4'-phenylspiro[indoline-3,2'-[1,3]dioxolan]-4'-yl)acrylate (3ab)

[0093] Prepared according to the above procedure, yield 84% (43.5 mg). White solid, mp = 120 - 121 °C; 1 H NMR (800 MHz, Chloroform- d ) δ 7.55 – 7.51 (m, 2H), 7.33 – 7.26 (m, 3H), 7.26 –7.22 (m, 4H), 7.22 – 7.18 (m, 3H), 7.17 (d, J = 11.0 Hz, 1H), 7.11 (dd, J =6.8, 2.3 Hz, 2H), 7.09 – 7.05 (m, 1H), 6.76 (t, J = 7.6 Hz, 1H), 6.53 (dd, J = 7.8, 3.2 Hz, 2H), 6.45 (t, J = 1.7 Hz, 1H), 6.40 (q, J = 1.4 Hz, 1H), 5.27(dd, J = 9.6, 2.4 Hz, 1H), 5.06 – 4.96 (m, 2H), 4.84 (ddd, J = 9.6, 3.0, 1.7Hz, 1H), 4.78 – 4.70 (m, 2H); 13 C{ 1 H} NMR (201 MHz, Chloroform- d) δ 171.7,164.0, 142.7, 140.6, 140.4, 134.4, 134.2, 130.4, 127.8, 127.51, 127.49,127.2, 127.04, 127.00, 126.7, 126.2, 125.3, 125.1, 124.6, 123.2, 122.3,108.6, 102.3, 84.9, 73.3, 65.7, 42.5; HRMS (ESI) calculate for C 33 H 27 NO5Na + [M+Na] + 540.1787, found 540.1794. Fig.10 and Fig.11 .

[0094] Example 4 Synthesis of target [3+2] cycloaddition product 3ac

[0095] Synthesis route such as Figure 7 As shown:

[0096] Under argon atmosphere, 0.15 mmol of alkenyl oxirane 1a, 0.1 mmol of active ketone 2c, 0.02 mmol of DMAP catalyst and 0.05 mmol of cesium carbonate were weighed into a Schlenk tube. 2 mL of dichloromethane was added and stirred at -20 °C for 48 hours to obtain the target [3+2] cycloaddition product 3ac in 77% yield.

[0097] benzyl

[0098] 2-((3S,4'R)-1-(2-(4-fluorophenyl)-2-oxoethyl)-2-oxo-4'-phenylspiro[indoline-3,2'-[1,3]dioxolan]-4'-yl)acrylate (3ac)

[0099] Prepared according to the above procedure, yield 77% (43.6 mg). White solid, mp = 145 - 146 °C; 1 H NMR (800 MHz, Chloroform- d ) δ 7.99 – 7.92 (m, 2H), 7.56 – 7.49 (m, 2H), 7.32 –7.25 (m, 4H), 7.23 (dd, J= 5.2, 2.0 Hz, 3H), 7.14 (td, J = 7.8, 1.3 Hz, 1H),7.12 – 7.09 (m, 3H), 6.81 (td, J = 7.6, 0.8 Hz, 1H), 6.56 (dd, J = 7.5, 1.3Hz, 1H), 6.53 (d, J = 7.9 Hz, 1H), 6.43 (d, J = 1.4 Hz, 1H), 6.36 (d, J = 1.4Hz, 1H), 5.26 (d, J = 9.6 Hz, 1H), 5.04 (d, J = 12.4 Hz, 1H), 4.99 – 4.93 (m,2H), 4.84 (d, J = 17.1 Hz, 1H), 4.79 (d, J = 9.6 Hz, 1H); 13 C{ 1 H} NMR (201MHz, Chloroform- d ) δ 190.6, 172.8, 166.3 (d, J 1 = 257.0 Hz), 165.0, 143.6,141.6 (d, J 2 = 22.2 Hz), 135.4, 131.6, 131.0 (d, J 3 = 9.5 Hz), 128.6, 128.5,128.3, 128.11, 128.07, 127.7, 127.0, 126.3, 126.1, 125.8, 124.0, 123.7, 116.2(d, J 2 = 21.9 Hz), 109.0, 103.2, 85.9, 74.4, 66.8, 46.0; 19 F NMR (376 MHz,Chloroform- d ) δ -102.88; HRMS (ESI) calculate for C 34 H 26 FNO6Na+ [M+Na] + 586.1642, found 586.1647. Fig.12 , Fig.13 and Fig.14 .

[0100] Example 5 Synthesis of target [3+2] cycloaddition product 3ba

[0101] Synthesis route such as Figure 7 As shown:

[0102] Under argon atmosphere, 0.1 mmol of alkenyl oxirane 1b, 0.15 mmol of active ketone 2a, 0.02 mmol of DMAP catalyst and 0.05 mmol of potassium carbonate were weighed into a Schlenk tube. 2 mL of dichloromethane was added and stirred at -20 °C for 48 hours to obtain the target [3+2] cycloaddition product 3ba in a yield of 72%.

[0103] methyl

[0104] 2-((3S,4'R)-1-methyl-2-oxo-4'-phenylspiro[indoline-3,2'-[1,3]dioxolan]-4'-yl)acrylate (3ba)

[0105] Prepared according to the above procedure, yield 72% (26.3 mg). White solid, mp = 146 -147 °C; 1 H NMR (800 MHz, Chloroform- d ) δ 7.54 (dd, J = 8.4, 1.3 Hz, 2H), 7.31 (dd, J = 8.3,6.9 Hz, 2H), 7.27 (d, J = 7.4 Hz, 1H), 7.22 (td, J = 7.7, 1.3 Hz, 1H), 6.82(td, J = 7.6, 0.9 Hz, 1H), 6.70 – 6.64 (m, 1H), 6.53 (dd, J = 7.3, 1.3 Hz,1H), 6.36 (dd, J = 12.6, 1.3 Hz, 2H), 5.28 (d, J = 9.5 Hz, 1H), 4.78 (d,J =9.6 Hz, 1H), 3.60 (s, 3H), 3.06 (s, 3H); 13 C{ 1 H} NMR (101 MHz, Chloroform- d ) δ171.6, 164.6, 143.6, 140.8, 140.6, 130.6, 127.4, 127.0, 125.2, 124.7, 124.5,123.2, 122.3, 107.5, 102.2, 84.8, 73.1, 50.9, 24.9; HRMS (ESI) calculate forC 21 H 19 NO5Na + [M+Na] + 388.1161, found 388.1149. Fig.15 and Fig.16 .

[0106] Example 6 Synthesis of target [3+2] cycloaddition product 3ca

[0107] Synthesis route such as Figure 7 As shown:

[0108] Under argon atmosphere, 0.15 mmol of alkenyl oxirane 1c, 0.1 mmol of active ketone 2a, 0.02 mmol of DMAP catalyst and 0.05 mmol of potassium carbonate were weighed into a Schlenk tube. 2 mL of dichloromethane was added and stirred at -20 °C for 48 hours to obtain the target [3+2] cycloaddition product 3ca with a yield of 81%.

[0109] ethyl

[0110] 2-((3S,4'R)-1-methyl-2-oxo-4'-phenylspiro[indoline-3,2'-[1,3]dioxolan]-4'-yl)acrylate (3ca)

[0111] Prepared according to the above procedure, yield 81% (30.7 mg), colorless oil. 1 H NMR (800 MHz, Chloroform- d ) δ 7.56 – 7.52 (m, 2H), 7.31 (dd, J= 8.4, 6.9 Hz, 2H), 7.27 –7.25 (m, 1H), 7.22 (td, J = 7.8, 1.3 Hz, 1H), 6.82 (t, J = 7.6 Hz, 1H), 6.68(d, J = 7.8 Hz, 1H), 6.52 (dd, J = 7.4, 1.3 Hz, 1H), 6.38 (d, J = 1.4 Hz,1H), 6.34 (d, J = 1.4 Hz, 1H), 5.28 (d, J = 9.5 Hz, 1H), 4.79 (d, J = 9.5 Hz,1H), 4.04 (ddd, J = 41.5, 10.9, 7.1 Hz, 2H), 3.06 (s, 3H), 1.12 (t, J = 7.1Hz, 3H); 13 C{ 1 H} NMR (101 MHz, Chloroform- d ) δ 171.6, 164.2, 143.6, 140.9,140.8, 130.6, 127.4, 127.0, 125.2, 124.52, 124.49, 123.2, 122.3, 107.4,102.2, 84.8, 73.2, 59.9, 24.9, 13.0; HRMS (ESI) calculate for C 22 H 21 NO5Na + [M+Na] + 402.1317, found 402.1318. Fig.17 and Fig.18 .

[0112] Example 7 Synthesis of target [3+2] cycloaddition product 3da

[0113] Synthesis route such as Figure 7 As shown:

[0114] Under argon atmosphere, 0.15 mmol of alkenyl oxirane 1d, 0.1 mmol of active ketone 2a, 0.02 mmol of DMAP catalyst and 0.05 mmol of potassium carbonate were weighed into a Schlenk tube. 2 mL of dichloromethane was added and stirred at -20 °C for 48 hours to obtain the target [3+2] cycloaddition product 3da with a yield of 88%.

[0115] benzyl

[0116] 2-((3S,5'R)-4'-benzyl-1-methyl-2-oxospiro[indoline-3,2'-[1,3]dioxolan]-5'-yl)acrylate (3da)

[0117] Prepared according to the above procedure, yield 88% (40.1 mg), colorless oil. 1 H NMR (800 MHz, Chloroform- d ) δ 7.36 – 7.22 (m, 6H), 7.20 – 7.02 (m, 6H), 6.96 (dtd, J =17.9, 7.5, 0.9 Hz, 1H), 6.68 (dd, J = 8.1, 4.5 Hz, 1H), 6.51 (d, J = 1.0 Hz,0.6H), 6.44 (d, J = 1.1 Hz, 0.6H), 6.31 (d, J = 1.0 Hz, 0.4H), 5.93 (d, J =1.2 Hz, 0.4H), 5.30 (dd, J = 7.0, 1.0 Hz, 0.4H), 5.22 – 5.17 (m, 1H), 5.18 –5.10 (m, 2H), 4.95 (dd, J = 8.2, 1.1 Hz, 0.6H), 4.79 (ddd, J = 8.4, 7.0, 3.9Hz, 0.6H), 4.51 (ddd, J = 9.4, 7.0, 3.9 Hz, 0.4H), 3.41 (dd, J = 14.4, 9.3Hz, 0.4H), 3.15 (d, J= 4.0 Hz, 0.6H), 3.12 – 3.10 (m, 0.4H), 3.07 (s, 1H), 3.02 (s, 2H), 3.01 – 2.99 (m, 0.6H); 13 C{ 1 H} NMR (201 MHz, Chloroform- d ) δ172.2, 164.6, 163.8, 143.5, 143.4, 137.0, 136.2, 135.8, 135.6 134.6, 134.5,130.62, 130.59, 128.9, 128.8, 128.2, 127.64, 127.61, 127.5, 127.41, 127.35,127.33, 127.26, 127.2, 127.10, 127.10, 126.0, 125.5, 125.3, 124.1, 123.8,123.6, 123.6, HRMS (ESI) calculate for C 28 H 25 NO5Na + [M+Na] + 478.1630, found 478.1636. Fig.19 and Fig. 20 .

[0118] Example 8 Synthesis of target [3+2] cycloaddition product 3ad

[0119] Synthesis route such as Figure 7 As shown:

[0120] Under argon atmosphere, 0.15 mmol of alkenyl oxirane 1a, 0.1 mmol of active ketone 2d, 0.02 mmol of 1,8-diazabicyclo[5.4.0]undec-7-ene catalyst and 0.05 mmol of potassium carbonate were weighed and added to a Schlenk tube. 2 mL of dichloromethane was added and stirred at -20 °C for 48 hours to obtain the target [3+2] cycloaddition product 3ad with a yield of 86%.

[0121] benzyl

[0122] 2-((3S,4'R)-5-fluoro-1-methyl-2-oxo-4'-phenylspiro[indoline-3,2'-[1,3]dioxolan]-4'-yl)acrylate (3ad)

[0123] Prepared according to the above procedure, yield 86% (39.4 mg). White solid, mp = 137 -138 °C; 1 H NMR (800 MHz, Chloroform- d ) δ 7.51 – 7.46 (m, 2H), 7.34 – 7.27 (m, 3H), 7.25 –7.20 (m, 3H), 7.13 – 7.08 (m, 2H), 6.91 (td, J = 8.7, 2.7 Hz, 1H), 6.60 (dd, J = 8.5, 3.8 Hz, 1H), 6.43 (d, J = 1.3 Hz, 1H), 6.36 (d, J = 1.2 Hz, 1H),6.16 (dd, J = 7.4, 2.7 Hz, 1H), 5.25 (d, J = 9.5 Hz, 1H), 5.04 (d, J = 12.4Hz, 1H), 4.97 (d, J = 12.4 Hz, 1H), 4.74 (d, J = 9.6 Hz, 1H), 3.04 (s, 3H); 13 C{ 1 H} NMR (201 MHz, Chloroform- d ) δ 171.4, 163.8, 158.3 (d, J 1 = 242.8 Hz),140.28, 140.27, 139.4 (d, J 4 = 2.1 Hz), 134.3, 127.6, 127.5, 127.2, 127.0,125.2, 125.0, 124.8 (d, J 3 = 7.5 Hz), 116.8 (d, J 2 = 23.7 Hz), 112.6 (d, J2 =25.2 Hz), 108.2 (d, J 3 = 7.9 Hz), 101.9, 85.0, 73.1, 65.7, 25.0; 19 F NMR (753MHz, Chloroform- d ) δ -119.30; HRMS (ESI) calculate for C 27 H 22 FNO5Na + [M+Na] + 482.1380, found 482.1385. Fig.21 , Fig. 22 and Fig.23 .

[0124] Example 9 Synthesis of target [3+2] cycloaddition product 3ae

[0125] Synthesis route such as Figure 7 As shown:

[0126] Under argon atmosphere, 0.15 mmol of alkenyl oxirane 1a, 0.1 mmol of active ketone 2e, 0.02 mmol of DMAP catalyst and 0.05 mmol of sodium bicarbonate were weighed into a Schlenk tube. 2 mL of toluene was added and stirred at -20 °C for 48 hours to obtain the target [3+2] cycloaddition product 3ae with a yield of 82%.

[0127] benzyl

[0128] 2-((3S,4'R)-5-bromo-1-methyl-2-oxo-4'-phenylspiro[indoline-3,2'-[1,3]dioxolan]-4'-yl)acrylate (3ae)

[0129] Prepared according to the above procedure, yield 82% (42.6 mg). White solid, mp = 123 - 124 °C; 1 H NMR (800 MHz, Chloroform- d ) δ 7.51 – 7.47 (m, 2H), 7.35 – 7.28 (m, 4H), 7.26 –7.21 (m, 3H), 7.14 – 7.10 (m, 2H), 6.54 (d, J = 8.3 Hz, 1H), 6.46 (d, J= 2.0Hz, 1H), 6.42 (d, J = 1.3 Hz, 1H), 6.34 (d, J = 1.3 Hz, 1H), 5.25 (d, J = 9.5Hz, 1H), 5.04 (d, J = 12.4 Hz, 1H), 4.98 (d, J = 12.4 Hz, 1H), 4.72 (d, J =9.6 Hz, 1H), 3.03 (s, 3H); 13 C{ 1 H} NMR (201 MHz, Chloroform- d ) δ 170.9, 163.8,142.5, 140.21, 140.16, 134.3, 133.2, 127.9, 127.6, 127.5, 127.30, 127.26,127.0, 125.3, 125.1, 125.0, 114.8, 109.0, 101.7, 85.1, 73.2, 65.7, 25.0; HRMS(ESI) calculate for C 27 H 22 BrNO5Na + [M+Na] + 542.0579, found 542.0583. Fig.24 and Fig.25 .

[0130] Example 10 Synthesis of target [3+2] cycloaddition product 3af

[0131] Synthesis route such as Figure 7 As shown:

[0132] Under argon atmosphere, 0.15 mmol of alkenyl oxirane 1a, 0.1 mmol of active ketone 2f, 0.02 mmol of DMAP catalyst and 0.05 mmol of potassium carbonate were weighed into a Schlenk tube. 1 mL of dichloromethane was added and stirred at 25 °C for 48 hours to obtain the target [3+2] cycloaddition product 3af with a yield of 36%.

[0133] benzyl

[0134] 2-((3S,4'R)-5-iodo-1-methyl-2-oxo-4'-phenylspiro[indoline-3,2'-[1,3]dioxolan]-4'-yl)acrylate (3af)

[0135] Prepared according to the above procedure, yield 36% (20.6 mg). White solid, mp = 121 - 122 °C; 1 H NMR (800 MHz, Chloroform- d ) δ 7.53 – 7.47 (m, 3H), 7.35 – 7.29 (m, 3H), 7.27 –7.20 (m, 3H), 7.15 – 7.09 (m, 2H), 6.58 (d, J = 1.8 Hz, 1H), 6.44 (d, J = 8.2Hz, 1H), 6.42 (d, J = 1.2 Hz, 1H), 6.34 (d, J = 1.3 Hz, 1H), 5.25 (d, J = 9.5Hz, 1H), 5.04 (d, J = 12.4 Hz, 1H), 4.98 (d, J = 12.4 Hz, 1H), 4.69 (d, J =9.6 Hz, 1H), 3.02 (s, 3H); 13 C{ 1 H} NMR (201 MHz, Chloroform- d ) δ 170.7, 163.8,143.2, 140.2, 140.1, 139.1, 134.3, 133.6, 127.54, 127.52, 127.34, 127.26,127.0, 125.4, 125.3, 125.0, 109.5, 101.5, 85.0, 84.6, 73.1, 65.8, 25.0; HRMS(ESI) calculate for C 27 H 22 INO5Na + [M+Na] + 590.0440, found 590.0448. Fig.26 and Fig. 27 .

[0136] Example 11 Synthesis of target [3+2] cycloaddition product 3ea

[0137] Synthesis route such as Figure 7 As shown:

[0138] Under argon atmosphere, 0.15 mmol of alkenyl oxirane 1e, 0.1 mmol of active ketone 2a, 0.02 mmol of DMAP catalyst and 0.1 mmol of potassium carbonate were weighed into a Schlenk tube. 2 mL of dichloromethane was added and stirred at 0 °C for 48 hours to obtain the target [3+2] cycloaddition product 3ea with a yield of 60%.

[0139] benzyl

[0140] 2-((3S,4'R)-4'-(4-fluorophenyl)-1-methyl-2-oxospiro[indoline-3,2'-[1,3]dioxolan]-4'-yl)acrylate (3ea)

[0141] Prepared according to the above procedure, yield 60% (27.6 mg). White solid, mp = 99 - 100 °C; 1 H NMR (800 MHz, Chloroform- d ) δ 7.51 – 7.45 (m, 2H), 7.29 – 7.21 (m, 4H), 7.15 –7.11 (m, 2H), 6.99 – 6.95 (m, 2H), 6.85 (td, J = 7.6, 0.9 Hz, 1H), 6.69 (d, J = 7.8 Hz, 1H), 6.53 (dd, J = 7.5, 1.3 Hz, 1H), 6.42 (d, J = 1.3 Hz, 1H), 6.36(d, J = 1.3 Hz, 1H), 5.19 (d, J = 9.7 Hz, 1H), 5.06 (d, J = 12.3 Hz, 1H),4.99 (d, J = 12.4 Hz, 1H), 4.79 (d, J = 9.6 Hz, 1H), 3.06 (s, 3H); 13 C{1 H} NMR (201 MHz, Chloroform- d ) δ 171.4, 163.9, 161.4 (d, J 1 = 246.8 Hz), 143.6,140.4, 136.7 (d, J 4 = 3.1 Hz), 134.3, 130.7, 127.5, 127.3, 127.2 (d, J 3 = 8.1Hz), 127.1, 125.1, 124.4, 123.0, 122.3, 114.3 (d, J 2 = 21.3 Hz), 107.6,102.3, 84.3, 73.2, 65.8, 24.9; 19 F NMR (753 MHz, Chloroform- d ) δ -114.29; HRMS(ESI) calculate for C 27 H 22 FNO5Na + [M+Na] + 482.1380, found 482.1384. Fig.28 , Fig.29 and Fig.30 .

[0142] Example 12 Synthesis of target [3+2] cycloaddition product 3fa

[0143] Synthesis route such as Figure 7 As shown:

[0144] Under argon atmosphere, 0.15 mmol of alkenyl oxirane 1f, 0.1 mmol of active ketone 2a, 0.02 mmol of DMAP catalyst and 0.05 mmol of potassium carbonate were weighed into a Schlenk tube. 2 mL of dichloromethane was added and stirred at -20 °C for 36 hours. Finally, the target [3+2] cycloaddition product 3fa was obtained with a yield of 73%.

[0145] benzyl

[0146] 2-((3S,4'R)-1-methyl-4'-(3-nitrophenyl)-2-oxospiro[indoline-3,2'-[1,3]dioxolan]-4'-yl)acrylate (3fa)

[0147] Prepared according to the above procedure, yield 73% (35.5 mg), colorless oil. 1 H NMR (800 MHz, Chloroform- d ) δ 8.39 (t, J = 2.1 Hz, 1H), 8.14 – 8.10 (m, 1H), 7.85 (ddd, J =7.8, 1.9, 1.0 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.27 – 7.22 (m, 4H), 7.18 –7.14 (m, 2H), 6.85 (td, J = 7.6, 0.9 Hz, 1H), 6.71 (d, J = 7.8 Hz, 1H), 6.55(dd, J = 7.5, 1.3 Hz, 1H), 6.49 (d, J = 1.0 Hz, 1H), 6.41 (d, J = 1.1 Hz,1H), 5.21 (d, J = 9.9 Hz, 1H), 5.07 – 5.00 (m, 2H), 4.90 (d, J = 9.9 Hz, 1H),3.07 (s, 3H); 13 C{ 1 H} NMR (201 MHz, Chloroform- d ) δ 171.1, 163.7, 147.3,143.7, 143.5, 139.6, 134.1, 131.4, 131.0, 128.4, 127.6, 127.5, 127.2, 126.3,124.1, 122.4, 122.3, 122.0, 120.6, 107.7, 102.5, 83.9, 73.2, 66.0, 24.9; HRMS(ESI) calculate for C 27 H 22 N2O7Na+ [M+Na] + 509.1325, found 509.1314. Fig.31 and Fig.32 .

[0148] Example 13 Synthesis of target [3+2] cycloaddition product 3ga

[0149] Synthesis route such as Figure 7 As shown:

[0150] Under argon atmosphere, 0.15 mmol of alkenyl oxirane 1g, 0.1 mmol of active ketone 2a, 0.02 mmol of DMAP catalyst and 0.05 mmol of potassium carbonate were weighed and added into a Schlenk tube. 2 mL of dichloromethane was added and stirred at -20 °C for 48 hours to finally obtain the target [3+2] cycloaddition product 3ga with a yield of 86%.

[0151] ethyl

[0152] (3S,4'R)-4'-(3-(benzyloxy)-3-oxoprop-1-en-2-yl)-1-methyl-2-oxospiro[indoline-3,2'-[1,3]dioxolane]-4'-carboxylate (3ga)

[0153] Prepared according to the above procedure, yield 86% (37.6 mg), colorless oil. 1 H NMR (800 MHz, Chloroform- d ) δ 7.41 (dd, J = 7.4, 1.3 Hz, 1H), 7.32 – 7.28 (m, 5H), 7.28 –7.25 (m, 1H), 7.02 (td, J = 7.6, 0.9 Hz, 1H), 6.71 (d, J = 7.8 Hz, 1H), 6.46(d, J = 0.9 Hz, 1H), 6.27 (d, J = 0.8 Hz, 1H), 5.14 (s, 2H), 5.02 (d, J = 9.1Hz, 1H), 4.56 (d, J = 9.1 Hz, 1H), 4.12 (q, J= 7.1 Hz, 2H), 3.05 (s, 3H), 1.13 (t, J = 7.1 Hz, 3H); 13 C{ 1 H} NMR (201 MHz, Chloroform- d ) δ 171.0, 168.7,164.0, 143.5, 136.5, 134.3, 131.0, 127.6, 127.4, 127.3, 126.2, 124.8, 122.6,122.4, 107.6, 103.3, 83.4, 73.1, 65.9, 61.1, 24.9, 12.9; HRMS (ESI) calculatefor C 24 H 23 NO7Na + [M+Na] + 460.1372, found 460.1377. Fig.33 and Fig.34 .

[0154] Embodiment 14

[0155] The cell line used was human breast cancer cells (Michigan Cancer Foundation-7, MCF-7). The cell suspension was counted, diluted to 50,000-70,000 / mL with complete culture medium, and inoculated into a 96-well plate at 100 μL per well. The cycloaddition products 3aa, 3ab, 3ac, 3ba, 3ca, 3da, 3ad, 3ae, 3af, 3ea, 3fa, and 3ga to be tested were dissolved in DMSO at a concentration of 100 μmol / mL to prepare a mother solution, and then the mother solution was diluted one thousand times with complete culture medium. A blank group and a control group were set up, 100 μL of drug-containing culture medium was added to each well, and then placed in an incubator for 36 hours. Subsequently, the CCK8 kit was used to measure the absorbance at 450 nm on an ELISA reader to calculate the inhibition rate.

[0156] Inhibition of MCF-7 cell proliferation by cycloaddition products

[0157] Serial number Inhibition rate Serial number Inhibition rate 3aa 59.43% 3ba 2.43% 3ab 32.06% 3ca 64.91% 3ac 13.10% 3da 94.26% 3ad 72.46% 3ea 73.61% 3ae 64.63% 3fa 71.39% 3af 60.00% 3ga 75.61%

[0158] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. Use of 1,3-dioxolane derivatives having the following structural formula in the preparation of anti-breast cancer drugs: In the structural formula, Bn represents benzyl, and Et represents ethyl.

Images