3-position polysubstituted chiral oxindole derivative as well as synthesis method and application thereof

Abstract

The invention discloses a 3-position polysubstituted chiral oxindole derivative as well as a synthesis method and application thereof. According to the synthesis method of the 3-position polysubstituted chiral oxoindole derivative, organic alcohol, isatin diazo and allyl carbonate are used as raw materials, chiral phosphoric acid is used as a chiral inducer, an organic reagent is used as a solvent, and the chiral oxoindole derivative is obtained through a one-step reaction under the catalysis of palladium-rhodium bimetal. The raw materials are cheap, easy to obtain, safe and non-toxic, the reaction conditions of the synthesis method are mild, the operation is simple and safe, and the synthesized 3-position polysubstituted chiral oxindole derivative can be widely applied to the fields of organic synthesis and drug research and development.

Description

Technical Field

[0001] This invention relates to the fields of synthetic pharmaceuticals and chemicals, and in particular to the synthesis, properties and applications of a palladium-rhodium bimetallic synergistic catalytic method for the synthesis of chiral indole with multiple substitutions at the 3-position. Background Technology

[0002] Chiral oxidized indoles with multiple substitutions at the 3-position are widely found in natural products and have broad applications in drug development. For example, Convolutamydine A, a brominated chiral oxidized indole alkaloid isolated from marine organisms, exhibits good bioactivity against various tumor cell lines (such as human colon cancer cells HCT-116 and breast cancer cells MCF-7) and shows great potential for the treatment of type 2 diabetes. Chiral drug molecules, neuroprotection, are frequently explored for potential treatment of neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. Another example is Horsfiline, a chiral oxidized indole alkaloid isolated from the Malaysian medicinal plant Horsfieldia superba, which possesses good analgesic activity. Clearly, the efficient construction of chiral oxidized indoles with multiple substitutions at the 3-position has always been a research hotspot in biomedical development. However, the current synthesis and development of 3-position multi-substituted chiral indole oxides suffers from limitations such as substrate-limited reactions and unsatisfactory chiral catalytic effects, which cannot meet the needs of the rapidly developing biopharmaceutical industry. Therefore, the synthesis of novel chiral indole oxide molecules and the development of corresponding synthetic strategies are of great theoretical and practical significance.

[0003] . Summary of the Invention

[0004] To address the shortcomings of existing technologies, this invention proposes a chiral oxidized indole derivative with multiple substitutions at the 3-position and its synthesis method.

[0005] The described synthetic method uses inexpensive, readily available, non-toxic, and harmless raw materials as substrates. Through a three-system synergistic catalytic mode of bimetallic catalysis and chiral phosphoric acid induction, it achieves highly efficient one-step synthesis of chiral indole derivatives with multiple substitutions at the 3-position. This method has advantages such as simple operation, mild conditions, and good substrate versatility.

[0006] Furthermore, natural products (S)-perillyl alcohol or testosterone can be used as reaction substrates in the synthesis method of this invention, synthesizing chiral oxidized indole derivatives with 3-position polysubstituted natural product molecules, demonstrating the practical application value of this invention.

[0007] The technical solution adopted in the invention:

[0008] A chiral oxidized indole derivative with multiple substitutions at the 3-position has the structure shown in formula (4):

[0009] (4)

[0010] Wherein, R is benzyl, naphthylmethyl, C3-C7 substituted alkyl, or allyl;

[0011] Ar 1 It is a phenyl, a methyl-substituted phenyl, a methoxy-substituted phenyl, or a halogen-substituted phenyl;

[0012] Ar 2 It can be phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, halogen-substituted phenyl, benzofuranyl, or indoleyl.

[0013] Preferably, R is 1-naphthylmethyl, 2-naphthylmethyl, isopropyl, n-butyl, tert-butyl, cyclopentyl, or cyclohexyl.

[0014] Ar 1 It is 4-methylphenyl, 6-methylphenyl, 5-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 5-chlorophenyl, or 5-bromophenyl;

[0015] Ar 2 It is 3-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 2-benzofuranyl, 3-N-p-toluenesulfonylindolyl.

[0016] This invention also proposes a method for synthesizing a 3-position polysubstituted chiral oxidindole derivative as shown in formula (4). Using organic alcohol, indigo diazo, and allyl carbonate as raw materials, under palladium-rhodium bimetallic catalysis, with chiral phosphoric acid as a chiral inducer and organic reagent as a solvent, a one-step reaction yields the 3-position polysubstituted chiral oxidindole derivative as shown in formula (4). The reaction process is shown in reaction formula (I):

[0017]

[0018] Reaction formula (I)

[0019] In formula (4) and reaction formula (I), R is benzyl, naphthylmethyl, C3-C7 substituted alkyl, or allyl.

[0020] The specific steps of the method for synthesizing the 3-position multi-substituted chiral oxidized indole derivatives of the present invention are as follows:

[0021] A palladium catalyst, a phosphine ligand, a 4Å molecular sieve, and chiral phosphoric acid were dissolved in an organic solvent under a dry argon atmosphere, and the resulting mixture was stirred thoroughly at room temperature. Then, allyl carbonate 3 and a rhodium catalyst were added, respectively. After stirring at room temperature, solutions of indigo diazo compound 1 and organic alcohol 2 dissolved in their respective organic solvents were slowly added via a syringe pump over 2 hours. After the addition was complete, the reaction mixture was stirred under these conditions until the diazo compound was completely consumed, yielding the 3-position multi-substituted chiral indole oxydeoxygenate derivative shown in formula (4).

[0022] In this invention, the molar ratio of the raw materials is palladium catalyst: phosphine ligand: chiral phosphoric acid: allyl carbonate: rhodium catalyst: indigo diazo compound: organic alcohol = (0.03-0.05): (0.06-0.1): (0.08-0.12): (1.0): (0.01): (1.5-2.0): (1.5-2.0); preferably, it is 0.04:0.08:0.1:1.0:0.01:1.5:1.5.

[0023] In this invention, the solvent for the reaction is either toluene or xylene; preferably, it is xylene.

[0024] In this invention, the reaction time is 8-12 hours; preferably, it is 10 hours.

[0025] The present invention further includes a separation and purification step after preparing the α-amino-substituted amide derivative.

[0026] The separation and purification process involves column chromatography using a mixed solution of ethyl acetate and petroleum ether at a volume ratio of 1:(20~100).

[0027] This invention also incorporates natural products (S)-perillyl alcohol or testosterone into the synthetic method, which can successfully yield chiral oxidized indole derivatives with multiple substitutions at the 3-position.

[0028]

[0029] The chemical mechanism involved in the synthesis method of this invention is as follows: In the presence of chiral phosphoric acid (CPA), Pd-I reacts with CPA through a highly exothermic process to generate the Pd-II species—a complex of the chiral phosphate anion and the cationic allyl palladium—while releasing methanol and carbon dioxide. Simultaneously, the bis-rhodium catalyst Rh2(esp)2 promotes the decomposition of the diazo compound to generate metal carbene I, which then reacts with benzyl alcohol to form the rhodium-complexed oxonium ylide intermediate II. This intermediate is subsequently converted into the more stable rhodium-complexed enol species III. These two active intermediates (the divalent palladium intermediate and the enol intermediate III) undergo a cross-trapping reaction to form the trivalent palladium species, which ultimately generates the three-component product 4a via the transition state TS1, while simultaneously releasing the Rh2(esp)2 catalyst for recycling. Chiral phosphoric acid (CPA) plays a crucial role in this catalytic cycle, promoting the enantioselective generation of the product by constructing an asymmetric environment. Specifically, CPA interacts with the palladium species to form a complex (Pd-II) containing the chiral phosphate anion. The chiral phosphate anion in Pd-II interacts with the positively charged allyl palladium via electrostatic interactions and forms hydrogen bonds with enol intermediate III. These interactions help stabilize the transition state (TS1) and guide the enol intermediate to attack the allyl carbon atom in a specific orientation, thereby generating the target enantiomer.

[0030]

[0031] Beneficial effects of the invention:

[0032] 1. This invention discloses a method for synthesizing 3-position multi-substituted chiral oxidized indole derivatives. The method uses organic alcohols, indigo diazo, and allyl carbonate as raw materials, and employs a palladium-rhodium bimetallic catalytic system with chiral phosphoric acid as a chiral inducer to efficiently prepare the target product through a one-step, multi-component reaction in an organic solvent. This synthetic strategy, with its significant advantages of high stereoselectivity and high atom economy, aligns with the current trend of atom-economical chemistry and has broad application prospects in the field of drug synthesis.

[0033] 2. The 3-position multi-substituted chiral oxidized indole derivatives and their synthesis methods involved in this invention have the characteristics of safe and non-toxic substrates, strong reaction universality, and convenient and efficient operation. The target product can be constructed in high yield through a one-step reaction, which effectively simplifies the synthetic route of multi-substituted chiral oxidized indole skeletons.

[0034] 3. The 3-position multi-substituted chiral oxidized indole derivatives and their corresponding synthetic methods of the present invention also have the advantages of inexpensive and readily available raw materials, mild reaction conditions, and safe and simple operation. The obtained products can be widely used in the fields of organic synthesis and drug development, providing a new material basis and technical support for the creation of related active molecules. Attached Figure Description

[0035] Figure 1 The image shown is the NMR spectrum of a multisubstituted chiral oxyindole derivative from Example 1 of the present invention. 1 H NMR ( Figure 1 A) 13 C NMR ( Figure 1 B) Spectra and racemic high-performance liquid chromatography (HPLC) Figure 1 C) and chirality ( Figure 1 D) Spectrum.

[0036] Figure 2 The image shown is the NMR spectrum of a multisubstituted chiral oxyindole derivative from Example 2 of the present invention. 1 H NMR ( Figure 2 A) 13 C NMR ( Figure 2 B) Spectra and racemic high-performance liquid chromatography (HPLC) Figure 2 C) and chirality ( Figure 2 D) Spectrum.

[0037] Figure 3 The image shown is the NMR spectrum of a multisubstituted chiral oxyindole derivative from Example 3 of the present invention. 1 H NMR ( Figure 3 A) 13 C NMR ( Figure 3 B) Spectra and racemic high-performance liquid chromatography (HPLC) Figure 3 C) and chirality ( Figure 3 D) Spectrum.

[0038] Figure 4 The image shown is the NMR spectrum of a multisubstituted chiral oxyindole derivative from Example 4 of the present invention. 1 H NMR ( Figure 4 A) 13 C NMR ( Figure 4 B) Spectra and racemic high-performance liquid chromatography (HPLC) Figure 4 C) and chirality ( Figure 4 D) Spectrum.

[0039] Figure 5 The image shown is the NMR spectrum of a multisubstituted chiral oxyindole derivative from Example 5 of the present invention. 1 H NMR ( Figure 5 A) 13 C NMR ( Figure 5 B) Spectra and racemic high-performance liquid chromatography (HPLC) Figure 5 C) and chirality ( Figure 5 D) Spectrum.

[0040] Figure 6 The image shown is the NMR spectrum of a multisubstituted chiral oxyindole derivative from Example 6 of the present invention. 1H NMR ( Figure 6 A) 13 C NMR ( Figure 6 B) Spectra and racemic high-performance liquid chromatography (HPLC) Figure 6 C) and chirality ( Figure 6 D) Spectrum.

[0041] Figure 7 The image shown is the NMR spectrum of a multisubstituted chiral oxyindole derivative from Example 7 of the present invention. 1 H NMR ( Figure 7 A) 13 C NMR ( Figure 7 B) Atlas.

[0042] Figure 8 The image shown is the NMR spectrum of a multisubstituted chiral oxyindole derivative from Example 8 of the present invention. 1 H NMR ( Figure 8 A) 13 C NMR ( Figure 8 B) Atlas. Detailed Implementation

[0043] To make the technical concept and advantages of the invention clearer, the technical solution of the present invention will be further described in detail below with reference to the accompanying drawings. It should be understood that the following embodiments are merely preferred embodiments for explaining and illustrating the present invention, and should not be considered as, nor constitute a limitation on, the scope of patent protection claimed by the present invention.

[0044] Example 1:

[0045] (4-1)

[0046] In a 10 mL Schlenk tube equipped with a stir bar, palladium catalyst (10.0 mol%), phosphine ligand (8.0 mol%), and 4 Å molecular sieve (100 mg) were added and dissolved in xylene (1.0 mL) under a dry argon atmosphere. The resulting mixture was stirred at room temperature for half an hour, followed by the addition of chiral phosphoric acid (10.0 mol%) and stirring for another 5 minutes. Next, phenylallyl carbonate 3a (0.2 mmol, 1.0 equivalent) and rhodium catalyst were added, respectively. Then, a xylene solution (1.5 mL) of N-methylindorubin diazo compound 1a (0.3 mmol, 1.5 equivalent) and benzyl alcohol 2a (0.3 mmol, 1.5 equivalent) was slowly added dropwise over 2 hours using a syringe pump while maintaining stirring at room temperature. After the addition was complete, the reaction mixture was stirred under the same conditions until the diazo compound was completely consumed (as monitored by thin-layer chromatography). The solvent was removed under reduced pressure to give the crude product, the structure of which is shown in formula (4-1). Finally, the mixture was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1 / 100~1 / 20) to obtain the pure product. The yield was 93%, 90% ee.

[0047] Nuclear magnetic resonance 1 H NMR, 13 C NMR and HPLC chromatograms are as follows: Figure 1 As shown: 1 H NMR (500 MHz, CDCl3) δ 7.39 – 7.08 (m, 13H), 6.83 (d, J = 7.7 Hz,1H), 6.33 (d, J = 15.8 Hz, 1H), 6.03 –5.92 (m, 1H), 4.24 (d, J = 10.6 Hz,1H), 4.10 (d, J = 10.6 Hz, 1H), 3.16 (s, 3H), 3.05 – 2.97 (m, 1H), 2.80 –2.72 (m, 1H).

[0048] 13 C NMR (125 MHz, CDCl3) δ 175.7, 143.9, 137.6, 137.3, 134.6, 129.9,128.5, 128.3, 128.0, 127.8, 127.3, 127.1, 126.2, 124.8, 123.0, 122.4, 108.4,82.5, 67.8, 41.4, 26.2.

[0049] HPLC: (Chiral OD-H, λ= 254 nm, hexane / 2-propanol = 20 / 1, Flow rate =1.0 mL / min), t minor = 18.70 min, t major = 30.14 min.

[0050] Example 2

[0051] (4-2)

[0052] In a 10 mL Schlenk tube equipped with a stir bar, palladium catalyst (10.0 mol%), phosphine ligand (8.0 mol%), and 4 Å molecular sieve (100 mg) were added and dissolved in xylene (1.0 mL) under a dry argon atmosphere. The resulting mixture was stirred at room temperature for half an hour, followed by the addition of chiral phosphoric acid (10.0 mol%) and stirring for another 5 minutes. Next, allyl carbonate 3a (0.2 mmol, 1.0 equivalent) and rhodium catalyst were added, respectively. Then, a xylene solution (1.5 mL) of 6-chloro-N-methylindoindioxin diazo compound 1b (0.3 mmol, 1.5 equivalent) and benzyl alcohol 2a (0.3 mmol, 1.5 equivalent) was slowly added dropwise over 2 hours using a syringe pump while maintaining stirring at room temperature. After the addition was complete, the reaction mixture was stirred under the same conditions until the diazo compound was completely consumed (as monitored by thin-layer chromatography). The solvent was removed under reduced pressure to give the crude product, the structure of which is shown in formula (4-2). Finally, the mixture was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1 / 100~1 / 20) to obtain the pure product. The yield was 90%, 91% ee.

[0053] Nuclear magnetic resonance 1 H NMR, 13 C NMR and HPLC chromatograms are as follows: Figure 2 As shown: 1 H NMR (500 MHz, CDCl3) δ 7.32 – 7.17 (m, 11H), 7.11 – 7.05 (m, 1H), 6.86 – 6.82 (m, 1H), 6.34 (d, J = 15.8 Hz, 1H), 5.98 –5.95 (m, 1H), 4.23 (d,J = 10.6 Hz, 1H), 4.09 (d,J = 10.5 Hz, 1H), 3.15 (s, 3H), 3.03 – 2.96 (m,1H), 2.77 – 2.69 (m, 1H).

[0054] 13 C NMR (125 MHz, CDCl3) δ 175.6, 145.0, 137.3, 137.1, 135.7, 134.9,128.5, 128.3, 128.0, 127.8, 127.4, 126.2, 125.8, 125.4, 122.8, 121.9, 109.2,82.1, 67.9, 41.2, 26.2.

[0055] HPLC: (Chiral OD-H, λ= 254 nm, hexane / 2-propanol = 9 / 1, Flow rate =1.0 mL / min), t minor = 9.04 min, t major = 10.46 min.

[0056] Example 3

[0057] (4-3)

[0058] In a 10 mL Schlenk tube equipped with a stir bar, palladium catalyst (10.0 mol%), phosphine ligand (8.0 mol%), and 4 Å molecular sieve (100 mg) were added and dissolved in xylene (1.0 mL) under a dry argon atmosphere. The resulting mixture was stirred at room temperature for half an hour, followed by the addition of chiral phosphoric acid (10.0 mol%) and stirring for another 5 minutes. Next, p-methoxyphenyl allyl carbonate 3b (0.2 mmol, 1.0 equivalent) and rhodium catalyst were added, respectively. Then, a xylene solution (1.5 mL) of N-methylindorubin diazo compound 1a (0.3 mmol, 1.5 equivalent) and benzyl alcohol 2a (0.3 mmol, 1.5 equivalent) was slowly added dropwise over 2 hours using a syringe pump while maintaining stirring at room temperature. After the addition was complete, the reaction mixture was stirred under the same conditions until the diazo compound was completely consumed (as monitored by thin-layer chromatography). The solvent was removed under reduced pressure to give the crude product, the structure of which is shown in formula (4-3). Finally, the mixture was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1 / 100~1 / 20) to obtain the pure product. The yield was 89%, 90% ee.

[0059] Nuclear magnetic resonance 1 H NMR, 13 C NMR and HPLC chromatograms are as follows: Figure 3 As shown: 11H NMR (500 MHz, CDCl3) δ 7.40 – 7.32 (m, 2H), 7.32 – 7.21 (m, 5H), 7.16 – 7.08 (m, 3H), 6.86 – 6.76 (m, 3H), 6.27 (d, J = 15.8 Hz, 1H), 5.86 – 5.76 (m, 1H), 4.24 (d, J = 10.6 Hz, 1H), 4.09 (d, J = 10.6 Hz, 1H), 3.77 (s, 3H), 3.17 (s, 3H), 3.03 – 2.95 (m, 1H), 2.78 – 2.70 (m, 1H).

[0060] 13 13C NMR (125 MHz, CDCl3) δ 175.7, 159.0, 143.9, 137.6, 133.9, 130.1, 129.8, 128.2, 128.0, 127.7, 127.3, 127.2, 124.8, 122.9, 120.0, 113.8, 108.3, 82.6, 67.7, 55.3, 41.3, 26.1. HPLC: (Chiral OD-H, λ = 254 nm, hexane / 2-propanol = 9 / 1, Flow rate = 1.0 mL / min), t minor = 9.74 min, t major = 13.17 min.

[0061] Example 4

[0062] (4 - 4)

[0063] In a 10 mL Schlenk tube equipped with a stir bar, palladium catalyst (10.0 mol%), phosphine ligand (8.0 mol%), and 4 Å molecular sieve (100 mg) were added and dissolved in xylene (1.0 mL) under a dry argon atmosphere. The resulting mixture was stirred at room temperature for half an hour, followed by the addition of chiral phosphoric acid (10.0 mol%) and stirring for another 5 minutes. Next, benzofuranyl allyl carbonate 3c (0.2 mmol, 1.0 equivalent) and rhodium catalyst were added, respectively. Then, a xylene solution (1.5 mL) of N-methylindorubin diazo compound 1a (0.3 mmol, 1.5 equivalent) and benzyl alcohol 2a (0.3 mmol, 1.5 equivalent) was slowly added dropwise over 2 hours using a syringe pump while maintaining stirring at room temperature. After the addition was complete, the reaction mixture was stirred under the same conditions until the diazo compound was completely consumed (as monitored by thin-layer chromatography). The solvent was removed under reduced pressure to give the crude product, the structure of which is shown in formula (4-4). Finally, the mixture was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1 / 100~1 / 20) to obtain the pure product. The yield was 85%, 91% ee.

[0064] Nuclear magnetic resonance 1 H NMR, 13 C NMR and HPLC chromatograms are as follows: Figure 4 As shown: 1 H NMR (400 MHz, CDCl3) δ 7.48 – 7.44 (m, 1H), 7.43 – 7.32 (m, 3H), 7.31 – 7.10 (m, 8H), 6.84 (d, J = 7.8 Hz, 1H), 6.43 (s, 1H), 6.33 –6.18 (m,2H), 4.24 (d, J = 10.6 Hz, 1H), 4.10 (d, J = 10.6 Hz, 1H), 3.18 (s, 3H), 3.10– 3.01 (m, 1H), 2.83 – 2.73 (m, 1H).

[0065] 13C NMR (100 MHz, CDCl3) δ 175.6, 154.7, 154.4, 143.8, 137.5, 130.0,128.9, 128.3, 128.0, 127.8, 126.8, 124.84, 124.79, 124.3, 123.1, 122.8,120.8, 110.9, 108.5, 103.9, 82.2, 67.8, 41.3, 26.2.

[0066] HPLC: (Chiral OD-H, λ= 254 nm, hexane / 2-propanol = 9 / 1, Flow rate =1.0 mL / min), t minor = 11.02 min, t major = 15.09 min.

[0067] Example 5

[0068] (4-5)

[0069] In a 10 mL Schlenk tube equipped with a stir bar, palladium catalyst (10.0 mol%), phosphine ligand (8.0 mol%), and 4 Å molecular sieve (100 mg) were added and dissolved in xylene (1.0 mL) under a dry argon atmosphere. The resulting mixture was stirred at room temperature for half an hour, followed by the addition of chiral phosphoric acid (10.0 mol%) and stirring for another 5 minutes. Next, phenylallyl carbonate 3a (0.2 mmol, 1.0 equivalent) and rhodium catalyst were added, respectively. Then, a xylene solution (1.5 mL) of N-methylindorubin diazo compound 1a (0.3 mmol, 1.5 equivalent) and 2-naphthylmethyl alcohol 2b (0.3 mmol, 1.5 equivalent) was slowly added dropwise over 2 hours using a syringe pump while maintaining stirring at room temperature. After the addition was complete, the reaction mixture was stirred under the same conditions until the diazo compound was completely consumed (as monitored by thin-layer chromatography). The solvent was removed under reduced pressure to give the crude product, the structure of which is shown in formulas (4-5). Finally, the mixture was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1 / 100~1 / 20) to obtain the pure product. The yield was 90%, 96% ee.

[0070] Nuclear magnetic resonance 1 H NMR, 13 C NMR and HPLC chromatograms are as follows: Figure 5 As shown: 11H NMR (500 MHz, CDCl3) δ 7.82 – 7.74 (m, 3H), 7.68 (s, 1H), 7.47 –7.40 (m, 4H), 7.39 – 7.34 (m, 1H), 7.25 – 7.16 (m, 5H), 7.15 –7.11 (m, 1H),6.84 (d, J = 7.8 Hz, 1H), 6.36 (d, J = 15.8 Hz, 1H), 6.05 – 5.95 (m, 1H),4.41 (d, J = 10.7 Hz, 1H), 4.27 (d, J = 10.7 Hz, 1H), 3.15 (s, 3H), 3.07 –3.01 (m, 1H), 2.82 –2.75 (m, 1H).

[0071] 13 13C NMR (125 MHz, CDCl3) δ 175.7, 143.9, 137.3, 135.0, 134.6, 133.2,133.0, 129.9, 128.5, 128.0, 127.9, 127.7, 127.3, 127.1, 126.8, 126.22,126.16, 126.0, 125.9, 124.8, 123.0, 122.4, 108.4, 82.5, 68.0, 41.3, 26.1.

[0072] HRMS-ESI: calcd. for C 29 H 25 NO2Na [M + Na] + 442.1778, found 442.1775.

[0073] HPLC: (Chiral OD-H, λ= 254 nm, hexane / 2-propanol = 9 / 1, Flow rate =1.0 mL / min), t major = 11.87 min, t minor = 13.13 min.

[0074] Example 6

[0075] (4 - 6)

[0076] In a 10 mL Schlenk tube equipped with a stir bar, palladium catalyst (10.0 mol%), phosphine ligand (8.0 mol%), and 4 Å molecular sieve (100 mg) were added and dissolved in xylene (1.0 mL) under a dry argon atmosphere. The resulting mixture was stirred at room temperature for half an hour, followed by the addition of chiral phosphoric acid (10.0 mol%) and stirring for another 5 minutes. Next, phenylallyl carbonate 3a (0.2 mmol, 1.0 equivalent) and rhodium catalyst were added, respectively. Then, a xylene solution (1.5 mL) of N-methylindoin diazo compound 1a (0.3 mmol, 1.5 equivalent) and cyclopentanol 2c (0.3 mmol, 1.5 equivalent) was slowly added dropwise over 2 hours using a syringe pump while maintaining stirring at room temperature. After the addition was complete, the reaction mixture was stirred under the same conditions until the diazo compound was completely consumed (as monitored by thin-layer chromatography). The solvent was removed under reduced pressure to give the crude product, the structure of which is shown in formulas (4-6). Finally, the mixture was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1 / 100~1 / 20) to obtain the pure product. The yield was 93%, 92% ee.

[0077] Nuclear magnetic resonance 1 H NMR, 13 C NMR and HPLC chromatograms are as follows: Figure 6 As shown: 1 H NMR (500 MHz, CDCl3) δ 7.35 – 7.28 (m, 2H), 7.26 – 7.13 (m, 5H), 7.11 – 7.04 (m, 1H), 6.80 (d, J = 8.0 Hz, 1H), 6.28 (d, J = 15.8 Hz, 1H),5.97 –5.85 (m, 1H), 3.64 (p, J = 5.8 Hz, 1H), 3.16 (s, 3H), 2.94 – 2.86 (m,1H), 2.70 – 2.60 (m, 1H), 1.72 – 1.55 (m, 4H), 1.53 – 1.40 (m, 2H), 1.40 –1.24 (m, 2H).

[0078] 13C NMR (125 MHz, CDCl3) δ 176.8, 143.5, 137.4, 134.3, 129.6, 128.4,128.3, 127.2, 126.2, 125.0, 122.7, 122.6, 108.2, 82.1, 78.6, 41.9, 33.9,33.2, 26.2, 23.3, 23.2.

[0079] HPLC: (Chiral OD-H, λ= 254 nm, hexane / 2-propanol = 9 / 1, Flow rate =1.0 mL / min), t major = 5.16 min, t minor = 6.81 min.

[0080] Example 7

[0081] (4-7)

[0082] In a 10 mL Schlenk tube equipped with a stir bar, palladium catalyst (10.0 mol%), phosphine ligand (8.0 mol%), and 4 Å molecular sieve (100 mg) were added and dissolved in xylene (1.0 mL) under a dry argon atmosphere. The resulting mixture was stirred at room temperature for half an hour, followed by the addition of chiral phosphoric acid (10.0 mol%) and stirring for another 5 minutes. Next, phenylallyl carbonate 3a (0.2 mmol, 1.0 equivalent) and rhodium catalyst were added, respectively. Then, a xylene solution (1.5 mL) of N-methylindorubin diazo compound 1a (0.3 mmol, 1.5 equivalent) and (S)-perillyl alcohol 2d (0.3 mmol, 1.5 equivalent) was slowly added dropwise over 2 hours using a syringe pump while maintaining stirring at room temperature. After the addition was complete, the reaction mixture was stirred under the same conditions until the diazo compound was completely consumed (as monitored by thin-layer chromatography). The solvent was removed under reduced pressure to give the crude product, the structure of which is shown in formula (4-7). Finally, the mixture was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1 / 100~1 / 20) to obtain the pure product. The yield was 92%, > 95:5 dr.

[0083] Nuclear magnetic resonance 1 H NMR, 13 C NMR and HPLC chromatograms are as follows: Figure 7 As shown: 11H NMR (500 MHz, CDCl3) δ 7.35 – 7.29 (m, 2H), 7.27 – 7.15 (m, 5H),7.12 – 7.06 (m, 1H), 6.80 (d, J = 7.9 Hz, 1H), 6.31 (d, J = 15.8 Hz, 1H),6.00 –5.90 (m, 1H), 5.56 (s, 1H), 4.68 (d, J = 11.6 Hz, 2H), 3.59 (d, J =10.5 Hz, 1H), 3.50 (d, J = 10.4 Hz, 1H), 3.16 (s, 3H), 3.01 – 2.91 (m, 1H),2.74 – 2.66 (m, 1H), 2.18 – 2.00 (m, 4H), 1.87 – 1.75 (m, 2H), 1.70 (s, 3H),1.42 – 1.30 (m, 1H).

[0084] 13 1H NMR (CDCl3, 125 MHz) δ 175.8, 149.9, 143.7, 137.3, 134.4, 134.3,129.7, 128.4, 127.34, 127.25, 126.2, 125.0, 124.7, 122.8, 122.5, 108.6,108.2, 82.0, 70.3, 41.5, 40.8, 30.6, 27.4, 26.6, 26.1, 20.8.

[0085] Example 8

[0086] (4 - 8)

[0087] In a 10 mL Schlenk tube equipped with a stir bar, palladium catalyst (10.0 mol%), phosphine ligand (8.0 mol%), and 4 Å molecular sieve (100 mg) were added and dissolved in xylene (1.0 mL) under a dry argon atmosphere. The resulting mixture was stirred at room temperature for half an hour, followed by the addition of chiral phosphoric acid (10.0 mol%) and stirring for another 5 minutes. Next, phenylallyl carbonate 3a (0.2 mmol, 1.0 equivalent) and rhodium catalyst were added, respectively. Then, a xylene solution (1.5 mL) of N-methylindoindizazo compound 1a (0.3 mmol, 1.5 equivalent) and testosterone 2e (0.3 mmol, 1.5 equivalent) was slowly added dropwise over 2 hours using a syringe pump while maintaining stirring at room temperature. After the addition was complete, the reaction mixture was stirred under the same conditions until the diazo compound was completely consumed (as monitored by thin-layer chromatography). The solvent was removed under reduced pressure to give the crude product, the structure of which is shown in formula (4-8). Finally, the mixture was purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1 / 100~1 / 20) to obtain the pure product. The yield was 81%, > 95:5 dr.

[0088] Nuclear magnetic resonance 1 H NMR, 13 C NMR and HPLC chromatograms are as follows: Figure 8 As shown: 1 H NMR (500 MHz, CDCl3) δ 7.34 – 7.14 (m, 7H), 7.08 – 7.02 (m, 1H), 6.79 (d, J = 7.7 Hz, 1H), 6.31 (d, J = 15.9 Hz, 1H), 6.01 – 5.91 (m, 1H),5.68 (s, 1H), 3.16 (s, 3H), 2.96 –2.86 (m, 2H), 2.69 – 2.61 (m, 1H), 2.46 –2.27 (m, 3H), 2.24 – 2.16 (m, 1H), 2.09 – 1.97 (m, 2H), 1.78 – 1.70 (m, 1H),1.69 – 1.55 (m, 1H), 1.58 – 1.26 (m, 7H), 1.17 (s, 3H), 0.90 –0.65 (m, 7H).

[0089] 13C NMR (125 MHz, CDCl3) δ 199.7, 176.3, 171.5, 143.4, 137.4, 134.2,129.6, 128.8, 128.4, 127.2, 126.1, 125.4, 123.8, 122.9, 122.4, 108.1, 85.8,82.1, 54.0, 50.0, 43.0, 41.5, 38.7, 36.5, 35.7, 35.4, 34.0, 32.8, 31.5, 30.0,26.1, 23.6, 20.6, 17.4, 11.5.

[0090] HRMS-ESI: calcd. for C 37 H 43 NO3Na [M + Na] + 572.3135, found 572.3124.

[0091] Example 9

[0092] (4-9)

[0093] The experimental method in this embodiment is basically the same as that in Example 2. The indigo diazo used in this embodiment is 5-methyl-N-methylindigo diazo, and the obtained product is shown in structural formula (4-9). The yield is 91%, 94% ee.

[0094] Example 10

[0095] (4-10)

[0096] The experimental method in this embodiment is basically the same as that in Example 2. The indigo diazo used in this embodiment is 6-bromo-N-methylindigo diazo, and the obtained product is shown in structural formula (4-10). The yield is 94%, 89% ee.

[0097] Example 11

[0098] (4-11)

[0099] The experimental method in this embodiment is basically the same as that in Example 3. The allyl carbonate used in this embodiment is m-methylphenyl allyl carbonate, and the product obtained is shown in structural formula (4-11). The yield is 86%, 92% ee.

[0100] Example 12

[0101] (4-12)

[0102] The experimental method in this embodiment is basically the same as that in Example 4. The allyl carbonate used in this embodiment is 3-N-p-toluenesulfonylindolyl allyl carbonate, and the product obtained is shown in structural formula (4-12). The yield is 83%, 83% ee.

[0103] Example 13

[0104] (4-13)

[0105] The experimental method in this embodiment is basically the same as that in Example 4. The allyl carbonate used in this embodiment is p-fluorophenyl allyl carbonate, and the product obtained is shown in structural formula (4-13). The yield is 90%, 89% ee.

[0106] Example 14

[0107] (4-14)

[0108] The experimental method used in this embodiment is the same as that in Example 8. The allyl carbonate used in this embodiment is p-bromophenyl allyl carbonate, and the product obtained is shown in structural formula (4-14). The yield is 93%, 91% ee.

[0109] Example 15

[0110] (4-15)

[0111] The experimental method used in this embodiment is the same as that in Example 5. The organic alcohol used in this embodiment is isopropanol, and the product obtained is shown in structural formula (4-15). The yield is 88%, 90% ee.

[0112] Example 16

[0113] (4-16)

[0114] The experimental method used in this embodiment is the same as that in Example 6. The organic alcohol used in this embodiment is allyl alcohol, and the product obtained is shown in structural formula (4-16). The yield is 90%, and the ee is 94%.

[0115] Example 17

[0116] (4-17)

[0117] The experimental method used in this embodiment is the same as that in Example 6. The organic alcohol used in this embodiment is trimethylsilylethanol, and the product obtained is shown in structural formula (4-17). The yield is 92%, 94% ee.

[0118] Example 18

[0119] (4-18)

[0120] The experimental method used in this embodiment is the same as that in Example 6. The organic alcohol used in this embodiment is trimethylsilylpropyne alcohol, and the product obtained is shown in structural formula (4-18). The yield is 88%, 93% ee.

[0121] This invention uses organic alcohols, indigo diazo, and allyl carbonate as raw materials, and under palladium-rhodium bimetallic catalysis, with chiral phosphoric acid as a chiral inducer and organic reagents as solvents, to obtain the chiral indole oxidase derivative in a one-step reaction. The raw materials are inexpensive and readily available, safe and non-toxic, the reaction conditions of the synthesis method are mild, and the operation is simple and safe. The synthesized chiral indole oxidase derivative with multiple substitutions at the 3-position can be widely used in organic synthesis and drug development.

Claims

1. A 3 -position polysubstituted chiral oxindole derivative, characterized in that, Its structure is shown in equation (4): （4） Wherein, R is benzyl, naphthylmethyl, C3-C7 substituted alkyl or allyl; Ar 1 It is a phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, or halogen-substituted phenyl; Ar 2 It is a phenyl group, a methyl-substituted phenyl group, a methoxy-substituted phenyl group, a halogen-substituted phenyl group, a benzofuranyl group, or an indoleyl group.

2. The 3-position multi-substituted chiral indole oxide derivative as described in claim 1, characterized in that: R is 1-naphthylmethyl, 2-naphthylmethyl, isopropyl, n-butyl, tert-butyl, cyclopentyl, or cyclohexyl; Ar 1 It is 4-methylphenyl, 6-methylphenyl, 5-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 5-chlorophenyl, or 5-bromophenyl; Ar 2 It is 3-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 2-benzofuranyl or 3-N-p-toluenesulfonylindolyl.

3. A method for synthesizing a 3-position multi-substituted chiral oxyindole derivative as described in claim 1, characterized in that: Using organic alcohols, indigo diazo and allyl carbonate as raw materials, under the catalysis of palladium-rhodium bimetals, with chiral phosphoric acid as chiral inducer and organic reagent as solvent, a three-position multi-substituted chiral oxidindole derivative as shown in formula (4) was obtained through a one-step reaction. The reaction process is shown in reaction formula (I): （I）； Wherein, R is benzyl, naphthylmethyl, C3-C7 substituted alkyl or allyl; Ar 1 is phenyl, methyl-substituted phenyl, methoxy-substituted phenyl or halogen-substituted phenyl; Ar 2 is phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, halogen-substituted phenyl, benzofuranyl or indolyl.

4. The method of synthesis of claim 3, wherein: Includes the following steps: In step S1, the palladium catalyst, phosphine ligand, 4Å molecular sieve and chiral phosphoric acid are dissolved in an organic solvent under a dry argon atmosphere, and the resulting mixture is stirred thoroughly at room temperature. Step S2: Then, allyl carbonate and rhodium catalyst are added separately, and stirring is continued at room temperature. Over 2 hours, solutions of indigo diazo compound and organic alcohol dissolved in the corresponding organic solvents are slowly added via a syringe pump. Step S3: After the addition is completed, the reaction mixture is stirred under these conditions until the diazo compound is completely consumed, and the 3-position multi-substituted chiral oxidized indole derivative shown in formula (4) is obtained.

5. The method of synthesis of claim 4, wherein: The molar ratio of the raw materials is palladium catalyst: phosphine ligand: chiral phosphoric acid: allyl carbonate: rhodium catalyst: indigo diazo compound: organic alcohol = (0.03-0.05): (0.06-0.1): (0.08-0.12): (1.0): (0.01): (1.5-2.0): (1.5-2.0).

6. The method of synthesis of claim 5, wherein, The palladium catalyst is Pd2(dba)3; The phosphine ligand is DPEphos, which has the structural formula: ; The chiral phosphoric acid additive is a spiro skeleton chiral phosphoric acid (CPA), and its structural formula is: ; The rhodium catalyst is Rh2(esp)2.

7. The method of synthesis of claim 3, 4, 5, or 6, wherein: The organic solvent is toluene or xylene, the volume of the organic solvent is related to the concentration of allyl carbonate at 0.1 mol / mL, the amount of 4Å molecular sieve added is related to the organic solvent at 40 mg / mL, the reaction temperature is room temperature, and the reaction time is 8-12 hours.

8. The method of synthesis of claim 3, 4, 5, or 6, wherein: The process includes step S4, the separation and purification process: the mixture is purified by silica gel column chromatography, wherein the separation and purification is performed by column chromatography with a mixed solution of ethyl acetate and petroleum ether in a volume ratio of 1:(20~100).

9. The method of synthesis of claim 3, 4, 5, or 6, wherein: R is 1-naphthylmethyl, 2-naphthylmethyl, isopropyl, n-butyl, tert-butyl, cyclopentyl, or cyclohexyl; Ar 1 It is 4-methylphenyl, 6-methylphenyl, 5-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 5-chlorophenyl, or 5-bromophenyl; Ar 2 It is 3-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 2-benzofuranyl or 3-N-p-toluenesulfonylindolyl.

10. The application of the synthetic method according to any one of claims 3-9, wherein the organic alcohol is replaced with the natural product (S)-perillyl alcohol or testosterone, to prepare a derivative of a 3-position multi-substituted chiral oxidized indole containing (S)-perillyl alcohol or testosterone modification.

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