Synthesis method and application of chiral tetrahydropyridine compound

Abstract

The synthesis method comprises the following steps: adding alkenyl iodine-alpha, beta unsaturated olefine aldehyde compounds, pivalic acid, hydrazine hydrate, (S)-4-tert-butyl-2-[2-(diphenylphosphino) phenyl]-2-oxazoline and palladium acetate into an organic solvent, heating under an air condition for reaction, after the reaction is completed, filtering, washing and drying to obtain the chiral tetrahydropyridine derivative. And carrying out post-treatment to obtain the chiral tetrahydropyridine compound. According to the method, under the acidic condition, aldehyde and hydrazine hydrate are subjected to one-pot in-situ generation of hydrazone, chiral tetrahydropyridine is prepared with high enantioselectivity under a Pd (0) / chiral PHOX ligand catalytic system, the conversion efficiency is high, and the step economy is good; meanwhile, the synthesis method is simple to operate, high in reaction yield and wide in substrate universality; the product can be applied to the field of total synthesis to synthesize bioactive molecules.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing chiral tetrahydropyridine compounds. Background Art

[0002] The Heck reaction is a famous reaction in the field of organic synthetic chemistry. It was awarded the Nobel Prize in Chemistry in 2010 and is considered to be the cornerstone of efficient synthesis of organic molecules. This reaction plays a huge role in the synthesis of medicines, natural products, pesticides, daily chemicals, functional materials, etc. In recent years, researchers' interest in the Heck reaction has continued to grow, and the most important developments have focused on exploring its asymmetric catalysis and developing various coupling reagents to achieve the formation of carbon-carbon bonds and carbon-hetero bonds.

[0003] Since the Heck reaction was widely studied, its asymmetric transformation has received widespread attention. However, since the Heck reaction tends to generate olefin products through β-H elimination, it is difficult to construct new chiral centers in the products, making the asymmetric version difficult to achieve. It was not until 1989 that Overman and Shibasaki made groundbreaking breakthroughs. The former first realized the asymmetric intramolecular Heck reaction in the presence of (R,R)-DIOP ligand to successfully construct a chiral quaternary carbon center. The latter used the chiral (R)-BINAP ligand to successfully transform the prochiral olefin iodide substrate into decalin containing two chiral centers. Although the catalytic systems developed by both did not achieve high enantioselective asymmetric control, they provided experience for future research. Since then, the asymmetric Heck reaction has developed rapidly and has been widely used in the total synthesis of complex natural products and drugs.

[0004]

[0005] Comparison of the mechanism of the reduction Heck reaction and the Heck reaction in formula 1

[0006] The properties of the traditional Mizoroki-Heck reaction vary slightly depending on the reaction conditions; however, the general mechanism is shown in (Equation 1, right): The mechanism cycle starts with C(sp 2 )-X (X = Br, Cl, I, OTf, etc.) bond to zero-valent palladium species, followed by migration insertion to obtain a divalent alkyl palladium intermediate, Pd IIThe intermediate undergoes rapid β-H elimination to obtain a functionalized olefin product, which is then regenerated by HX reductive elimination. In contrast, the reductive Heck reaction follows a similar mechanism (Formula 1, left), except that after the divalent alkyl palladium species is obtained through migration insertion, it does not undergo a β-H elimination process, but instead undergoes ligand exchange in the presence of a hydrogen source (most commonly formate) to form a palladium hydrogen complex, which is easily reductively eliminated to form a new CC bond.

[0007] Compared with the more well-developed Heck reaction, the research on the reductive Heck reaction is relatively immature. A major focus of realizing the reductive Heck reaction is how to avoid the competitive β-H elimination process. Therefore, it is particularly important to choose a suitable reducing agent, that is, a hydrogen source. Therefore, in recent years, the research on the reductive Heck reaction has mainly focused on the development and use of various reducing agents and the exploration of asymmetric catalytic systems. The types of reducing agents mainly include formates, alcohols, amines and water.

[0008] Since the pioneering work of Cacchi's group in 1983, the reductive Heck reaction has been widely used in the synthesis of complex organic compounds. In 2011, the de Vries and Minnaard groups reported the reductive Heck and competitive reactions of Heck catalyzed by Pd-NHC (azacarbene), respectively. Mechanistic studies have shown that tributylamine can not only act as a hydrogen source in this transformation, but also coordinate with divalent alkyl palladium species, greatly inhibiting the β-H elimination process to a certain extent. In 2015, Jia Yixia's group at Zhejiang University of Technology cleverly used asymmetric catalytic reductive Heck reaction to achieve dearomatization of indole. The reaction uses palladium acetate as a metal catalyst, (R)-BINAP as a chiral ligand, sodium formate (HCOONa) as a reductant-hydrogen source, and methanol MeOH as a reaction solvent. Under the optimal reaction conditions of 100°C, the substrate has a high universality. In 2017, Zhu Jieping's group achieved an intramolecular asymmetric reductive Heck reaction in the form of 5-exo. In this transformation, the authors used a mixture of diboron reagent and water as a hydride source for the first time, which is different from the previous type of hydrogen source and provides a new idea for the development of new reductive Heck reactions. A chiral oxazoline bisphosphorus ligand was developed, and aryl trifluoromethanesulfonate was used as a coupling reagent to obtain indole products with high yield and enantioselectivity (70-94% ee). It is worth noting that deuterated labeled compounds can be obtained by using D2O as a hydrogen source in the reaction, so that deuterated chiral oxidized indoles can be easily synthesized.

[0009] All of the above reactions require the addition of an additional hydrogen source to achieve an asymmetric reduction Heck reaction. In addition, the asymmetric reduction Heck reaction of α,β-unsaturated compounds has been less studied. Based on this background, this paper reports an intramolecular reduction Heck reaction of olefin iodide-α,β-unsaturated olefin hydrazone. The hydrazine hydrate used in this strategy not only serves as a reaction substrate to react with aldehydes in situ to generate hydrazones, but also serves as a hydrogen source to efficiently achieve highly enantioselective asymmetric catalysis. This method is easy to operate, has a wide substrate universality and excellent functional group compatibility, and provides a simple and efficient synthetic route for the synthesis of chiral tetrahydropyridine derivatives with diverse structures. Summary of the invention

[0010] The present invention provides a method for synthesizing chiral tetrahydropyridine compounds, which has wide substrate universality and high reaction yield. Importantly, in order to prove the practicability of the method, we successfully applied the method to the synthesis of a key intermediate for preparing the alkaloid (±)-Eburnamonine.

[0011] A method for synthesizing a chiral tetrahydropyridine compound comprises the following steps: adding an iodine-α,β-unsaturated olefinic aldehyde compound, pivalic acid, hydrazine hydrate, (S)-4-tert-butyl-2-[2-(diphenylphosphino)phenyl]-2-oxazoline and palladium acetate to an organic solvent, heating under air conditions for reaction, and after the reaction is complete, post-processing to obtain the chiral tetrahydropyridine compound;

[0012] The structure of the alkenyl iodide-α,β-unsaturated alkenal compound is shown in formula (II):

[0013]

[0014] The structure of the hydrazine hydrate is shown in formula (III):

[0015] NH2NH2·H2O (III)

[0016] The structure of the chiral tetrahydropyridine compound is shown in formula (I):

[0017]

[0018] In formula (I) to (II), R 1 is selected from aryl;

[0019] Preferably, the chiral tetrahydropyridine compound is one of the compounds represented by formula (I-1) to formula (I-12):

[0020]

[0021]

[0022] Preferably, the organic solvent is dimethyl sulfoxide (DMSO).

[0023] Preferably, all additives are pivalic acid, the reaction temperature is 60° C., and the reaction time is 6 hours in an air atmosphere.

[0024] Preferably, the chiral tetrahydropyridine compound I-12 can be further used as a key intermediate for synthesizing alkaloids (anthraquinone).

[0025] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0026] (1) The present invention synthesizes chiral tetrahydropyridine compounds in one pot with high chemical selectivity and high enantioselectivity by using easily prepared aldehydes and hydrazine hydrate raw materials, with high conversion efficiency and good step economy;

[0027] (2) The synthesis method of the present invention is simple to operate, has a high reaction yield, excellent enantioselectivity, and has good substrate universality and functional group compatibility.

[0028] (3) The product obtained by the present invention has good practicality and can be used as a key intermediate for synthesizing natural active molecules. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 The hydrogen spectrum, carbon spectrum and high performance liquid chromatography spectrum of the compound obtained in Example 1;

[0030] Figure 2 The hydrogen spectrum, carbon spectrum and high performance liquid chromatography spectrum of the compound obtained in Example 2;

[0031] Figure 3 The hydrogen spectrum, carbon spectrum and high performance liquid chromatography spectrum of the compound obtained in Example 12;

[0032] Figure 4 The hydrogen spectrum and carbon spectrum of the compound obtained in Example 13;

[0033] Figure 5 The hydrogen spectrum and carbon spectrum of the compound obtained in Example 14;

[0034] The hydrogen spectrum was tested on a 400MHz nuclear magnetic resonance instrument. The carbon spectrum was tested on a 100MHz nuclear magnetic resonance instrument. The test conditions were all room temperature with tetramethylsilane as the internal standard and the sample was dissolved in deuterated chloroform. The high-performance liquid chromatography was analyzed on a Shimadzu LC-20AT equipped with a variable wavelength UV-Vis detector SPD-20A and a Daicel Chiralpak chiral column. DETAILED DESCRIPTION

[0035] The present invention is further described below in conjunction with specific embodiments, and the following specific embodiments are all optimal implementation modes of the present invention.

[0036] Examples 1 to 12

[0037] According to the raw material ratio in Table 1, iodo-α,β-unsaturated olefinic aldehyde (0.2 mmol), palladium acetate catalyst (0.02 mmol), (S)-4-tert-butyl-2-[2-(diphenylphosphino)phenyl]-2-oxazoline (S,S)- S BuPHOX) (0.04mmol), hydrazine hydrate (0.8mmol), pivalic acid (4mmol) and 3mL of organic solvent dimethyl sulfoxide were mixed and stirred evenly. After the reaction was completed according to the reaction conditions in Table 2, the mixture was cooled, filtered, mixed with silica gel, and purified by column chromatography to obtain the corresponding chiral tetrahydropyridine compound (I). Due to the large polarity of the hydrazone product and the presence of cis-trans configuration, it is difficult to separate it via HPLC chiral column.

[0038] Therefore, we carried out the reaction of alkenyl iodide-α,β-unsaturated enal II to generate tetrahydropyridine product 2, and then obtained the acetal reaction product I after post-treatment reaction and measured the ee value. The specific steps are as follows: the crude hydrazone product 2 was dissolved in 1.0mL THF and transferred to another 25mL Schlenk tube. Then 2.0mL ethylene glycol and concentrated sulfuric acid (60uL) were added to the solution in sequence. The test tube was stirred in an oil bath at 40℃ for 0.5 hours. The mixture was washed with water and brine, extracted with EtOAc (2×20mL), and the organic phase was dried over anhydrous Na2SO4. After removing the solvent under reduced pressure, the residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=5 / 1) to obtain ethylene glycol acetal I. The ee value of product 2 was determined by chiral HPLC.

[0039] The reaction process is shown below:

[0040]

[0041] Table 1 Raw material ratios of Examples 1 to 12

[0042]

[0043] Table 2 Reaction conditions and reaction results of Examples 1 to 12

[0044]

[0045] In Table 1 and Table 2, T is the reaction temperature, t is the reaction time, [1,3]dioxole-Ph is 1,2-methylenedioxyphenyl, and Butanen is n-butyl.

[0046] Example 13

[0047]

[0048] In a dry 25mL Schlenk tube, compound I-12 (0.4mmol, 140.6mg) was dissolved in ethyl acetate (3.0mL), and PtO2 (0.08mmol, 18.2mg) was added. The reaction mixture was stirred overnight at room temperature under H2 atmosphere (using a balloon). The catalyst was then filtered using a silica gel plug and washed with EA (10mL). The organic solvent was removed under reduced pressure, and the crude reaction mixture was purified by silica gel chromatography (petroleum ether / ethyl acetate=6 / 1) to obtain 3,3-disubstituted piperidine derivatives 13 (140.0mg) in a 99% yield.

[0049] Embodiment 14

[0050] Compound 10 (0.2 mmol, 70.7 mg) was added to a dry 25 mL Schlenk tube. After rinsing the test tube with three alternating vacuum and N2 purge cycles, anhydrous THF (0.2 mL) was added via a syringe. Then, freshly prepared naphthalene-sodium (1 M in THF) (4.0 equiv) was added dropwise to the above solution at -78 °C. The reaction mixture was stirred at -78 °C for 10 minutes and then quenched with MeOH. The solution was allowed to reach room temperature, water and 2 M HCl were added, and the solution was washed twice with Et2O. The aqueous solution was basified with 2 M NaOH and extracted three times with CH2Cl2. The solvent was dried over Na2SO4 and evaporated to give a crude product which was used in the next step without further purification. The crude product was dissolved in CH2Cl2 (2 mL), triethylamine (0.6 mmol, 60.7 mg) was added at 0 °C, and then benzyl chloroformate (0.2 mmol, 34.1 mg) was slowly added. After 30 minutes, the reaction mixture was slowly warmed to room temperature and stirred for 1 hour. After completion, the solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=8 / 1) to obtain the desired product 14 with a yield of 40% (26.7 mg). It is a key intermediate for the preparation of alkaloid-Eburnamonine.

[0051] The structural confirmation data of some compounds prepared in Examples 1 to 14 are as follows:

[0052]

[0053] (S)-3-((1,3-dioxolan-2-yl)methyl)-3-methyl-5-phenyl-1-tosyl-1,2,3,6-tetrahydropyridine(I-1):Colorless oil.[α]D 20 =-32.9°(c=1.2,CHCl3).96%ee(determined by HPLC:Chiralpak ODH Column,5 / 95i-PrOH / hexane,1.0mL / min,254nm;TR=17.847min(major),24.959min(minor)). 1 H NMR(400MHz,CDCl3)δ7.64(d,J=8.4Hz,2H),7.27-7.18(m,7H),5.87(s,1H),4.89(t,J=4.8Hz,1H),3.92-3.83(m,2H),3.79-3.71(m,4H),3.01(d,J=11.6,Hz,1H),2.86(d,J=11.2Hz,1H),2.35(s,3H),1.85(dd,J=14.0,4.8Hz,1H),1.74(dd,J=14.0,5.2Hz,1H),1.15(s,3H). 13 C NMR(100MHz,CDCl3)δ143.6,138.4,133.2,131.6,131.5,129.8,128.5,127.8,127.7,125.4,102.4,64.7,53.3,46.4,43.3,35.2,24.9,21.6.

[0054]

[0055] (S)-3-((1,3-dioxolan-2-yl)methyl)-5-(4-methoxyphenyl)-3-methyl-1-tosyl-1,2,3,6-tetrahydropyridine(I-2):Colorless oil.[α]D20=-26.8°(c=1.0,CHCl3).94%ee(determined by HPLC:Chiralpak ODH Column,10 / 90i-PrOH / hexane,1.0mL / min,254nm;TR=14.344min(major),17.870min(minor)).1H NMR(400MHz,CDCl3)δ7.72(d,J=8.0Hz,2H),7.33(d,J=8.0Hz,2H),7.22(d,J=8.8Hz,2H),6.84(d,J=8.8Hz,2H),5.85(s,1H),4.95(t,J=5.2Hz,1H),3.99–3.75(m,9H),3.07(d,J=11.6Hz,1H),2.92(d,J=11.6Hz,1H),2.42(s,3H),1.91(dd,J=14.2,4.8Hz,1H),1.80(dd,J=14.2,5.2Hz,1H),1.21(s,3H).13C NMR(100MHz,CDCl3)δ159.3,143.6,133.3,130.9,130.1,129.7,127.7,126.5,113.9,102.4,64.7,55.3,53.3,46.4,43.4,35.2,24.9.

[0056]

[0057] (S)-3-((1,3-dioxolan-2-yl)methyl)-5-(benzo[d][1,3]dioxol-5-yl)-3-methyl-1-tosyl-1,2,3,6-tetrahydropyridine(I-3):White solid(mp93–94oC).[α]D20=-46.8°(c=1.0,CHCl3).95%ee(determined by HPLC:Chiralpak ODH Column,10 / 90i-PrOH / hexane,1.0mL / min,254nm;TR=17.575min(major),23.436min(minor)).1H NMR(400MHz,CDCl3)δ7.71(d,J=8.2Hz,2H),7.33(d,J=8.2Hz,2H),6.79(s,1H),6.74(d,J=1.6Hz,2H),5.94(s,2H),5.83(t,J=1.6Hz,1H),4.94(t,J=5.2Hz,1H),3.99–3.92(m,2H),3.84–3.70(m,4H),3.05(d,J=11.2Hz,1H),2.90(d,J=11.2Hz,1H),2.43(s,3H),1.90(dd,J=14.2,4.8Hz,1H),1.79(dd,J=14.2,5.2Hz,1H),1.20(s,3H).13C NMR(100MHz,CDCl3)δ147.9,147.3,143.6,133.2,132.7,131.0,130.8,129.8,127.7,118.9,108.2,106.1,102.4,101.2,64.7,53.3,46.5,43.4,35.2,24.9,21.6.

[0058]

[0059] (S)-3-((1,3-dioxolan-2-yl)methyl)-3-methyl-5-(p-tolyl)-1-tosyl-1,2,3,6-tetrahydropyridine(I-4):Yellowoil.[α]D20=-21.9°(c=1.2,CHCl3).96%ee(determined by HPLC:Chiralpak ODH Column,5 / 95 i-PrOH / hexane,1.0mL / min,254nm;TR=14.044min(major),18.873min(minor)).1H NMR(400MHz,CDCl3)δ7.72(d,J=8.4Hz,2H),7.33(d,J=8.4Hz,2H),7.18(d,J=8.4Hz,2H),7.12(d,J=8.4Hz,2H),5.90(s,1H),4.96(t,J=4.8Hz,1H),3.99–3.92(m,2H),3.89–3.77(m,4H),3.08(d,J=11.2Hz,1H),2.92(d,J=11.2Hz,1H),2.43(s,3H),2.33(s,3H),1.91(dd,J=14.2,4.8Hz,1H),1.80(dd,J=14.2,4.8Hz,1H),1.22(s,3H).13C NMR(100MHz,CDCl3)δ143.6,137.6,135.5,133.3,131.4,130.8,129.7,129.2,127.7,125.3,102.4,64.6,53.3,46.4,43.4,35.2,24.9,21.5,21.1.

[0060]

[0061] (S)-3-((1,3-dioxolan-2-yl)methyl)-5-(4-(tert-butyl)phenyl)-3-methyl-1-tosyl-1,2,3,6-tetrahydropyridine(I-5):Yellowoil.[α]D20=-42.4°(c=1.2,CHCl3).90%ee(determined by HPLC:Chiralpak ODH Column,7 / 93 i-PrOH / hexane,1.0mL / min,254nm;TR=15.976min(major),21.687min(minor)).1H NMR(400MHz,CDCl3)δ7.71(d,J=8.0Hz,2H),7.35–7.32(m,4H),7.25–7.23(m,2H),5.92(d,J=1.6Hz,1H),4.96(t,J=5.2Hz,1H),3.99–3.90(m,2H),3.86–3.78(m,4H),3.08(d,J=11.2Hz,1H),2.92(d,J=11.2Hz,1H),2.42(s,3H),1.92(dd,J=14.2,4.8Hz,1H),1.82(dd,J=14.2,4.8Hz,1H),1.30(s,9H),1.22(s,3H).13C NMR(100MHz,CDCl3)δ150.9,143.6,135.5,133.2,131.3,131.0,129.7,127.7,125.4,125.1,102.4,64.7(2C),53.3,46.4,43.3,35.2,34.5,33.27,24.9,21.6.HRMS(ESI)m / z:[M+H]+calcd for C27H36NO4S+:470.2360;found:470.2359.

[0062]

[0063] (S)-3-((1,3-dioxolan-2-yl)methyl)-3-methyl-5-(o-tolyl)-1-tosyl-1,2,3,6-tetrahydropyridine(I-6):Colorless oil.[α]D20=-14.8°(c=0.8,CHCl3).97%ee(determined by HPLC:Chiralpak ODH Column,5 / 95 i-PrOH / hexane,1.0mL / min,254nm;TR=13.596min(major),18.527min(minor)).1H NMR(400MHz,CDCl3)δ7.67(d,J=8.4Hz,2H),7.32(d,J=8.4Hz,2H),7.21–7.11(m,3H),7.02(d,J=7.2Hz,1H),5.48(t,J=2.0Hz,1H),4.98(t,J=5.2Hz,1H),3.99–3.78(m,4H),3.63–3.54(m,2H),3.14(d,J=11.6Hz,1H),2.95(d,J=11.6Hz,1H),2.43(s,3H),2.23(s,3H),1.92(dd,J=14.0,4.8Hz,1H),1.82(dd,J=14.0,5.2Hz,1H),1.23(s,3H).13C NMR(100MHz,CDCl3)δ143.6,139.2,135.7,133.3,132.8,130.3,129.7,128.8,127.7(2C),125.7,102.4,64.7,64.6,53.4,48.1,43.3,35.1,24.8,21.6,19.6.

[0064]

[0065] (S)-3-((1,3-dioxolan-2-yl)methyl)-5-(4-fluorophenyl)-3-methyl-1-tosyl-1,2,3,6-tetrahydropyridine(I-7):Yellow oil.[α]D20=-36.0°(c=1.0,CHCl3).93%ee(determined by HPLC:Chiralpak ODH Column,10 / 90 i-PrOH / hexane,1.0mL / min,254nm;TR=10.300min(major),12.393min(minor)).1H NMR(400MHz,CDCl3)δ7.64(d,J=8.0Hz,2H),7.27(d,J=8.0Hz,2H),7.21–7.16(m,2H),6.95–6.89(m,2H),5.81(t,J=1.6Hz,1H),4.88(t,J=5.2Hz,1H),3.92–3.85(m,2H),3.80–3.66(m,4H),3.00(d,J=11.2Hz,1H),2.85(d,J=11.2Hz,1H),2.36(s,3H),1.84(dd,J=14.4,4.8Hz,1H),1.73(dd,J=14.4,5.2Hz,1H),1.15(s,3H).13C NMR(100MHz,CDCl3)δ162.4(d,JC-F=246.0Hz),143.7,134.5(d,JC-F=3.0Hz),133.2,131.7,130.6,129.8,127.7,127.1(d,JC-F=8.0Hz),115.4(d,JC-F=21.0Hz),102.3,64.7,53.2,46.4,43.3,35.2,24.8,21.6.

[0066]

[0067] (S)-3-((1,3-dioxolan-2-yl)methyl)-5-(4-chlorophenyl)-3-methyl-1-tosyl-1,2,3,6-tetrahydropyridine(I-8):Colorlessoil.[α]D20=-38.6°(c=1.0,CHCl3).95%ee(determined by HPLC:Chiralpak ODH Column,10 / 90i-PrOH / hexane,1.0mL / min,254nm;TR=18.875min(major),28.227min(minor)).1H NMR(400MHz,CDCl3)δ7.65(d,J=8.0Hz,2H),7.27(d,J=8.0Hz,2H),7.22–7.19(m,2H),7.16–7.13(m,2H),5.87(s,1H),4.88(t,J=5.2Hz,1H),3.92–3.67(m,6H),3.00(d,J=11.2Hz,1H),2.86(d,J=11.2Hz,1H),2.36(s,3H),1.84(dd,J=14.4,4.8Hz,1H),1.73(dd,J=14.4,5.2Hz,1H),1.15(s,3H).13CNMR(100MHz,CDCl3)δ143.7,136.8,133.6,133.2,132.3,130.5,129.8,128.7,127.7,126.7,102.3,64.7,53.2,46.2,43.3,35.3,24.8,21.6.

[0068]

[0069] (S)-3-((1,3-dioxolan-2-yl)methyl)-3-methyl-5-(m-tolyl)-1-tosyl-1,2,3,6-tetrahydropyridine(I-9):Yellow oil.[α]D20=-22.4°(c=1.0,CHCl3).95%ee(determined by HPLC:Chiralpak ODH Column,5 / 95 i-PrOH / hexane,1.0mL / min,254nm;TR=13.944min(major),19.177min(minor)).1H NMR(400MHz,CDCl3)δ7.72(d,J=8.4Hz,2H),7.34(d,J=8.0Hz,2H),7.20(t,J=7.6Hz,1H),7.08(d,J=8.0Hz,3H),5.91(t,J=1.6Hz,1H),4.96(t,J=5.2Hz,1H),3.99–3.92(m,2H),3.89–3.78(m,4H),3.08(d,J=11.6Hz,1H),2.92(d,J=11.6Hz,1H),2.43(s,3H),2.34(s,3H),1.92(dd,J=14.4,4.8Hz,1H),1.81(dd,J=14.4,5.2Hz,1H),1.22(s,3H).13C NMR(100MHz,CDCl3)δ143.6,138.4,138.1,133.2,131.7,131.5,129.7,128.6,128.4,127.7,126.2,122.6,102.4,64.7(2C),53.3,46.4,43.3,35.2,24.9,21.6,21.5.

[0070]

[0071] (S)-3-((1,3-dioxolan-2-yl)methyl)-5-(3-methoxyphenyl)-3-methyl-1-tosyl-1,2,3,6-tetrahydropyridine(I-10):Colorlessoil.[α]D20=-25.8°(c=1.0,CHCl3).96%ee(determined by HPLC:Chiralpak ODH Column,5 / 95 i-PrOH / hexane,1.0mL / min,254nm;TR=16.442min(major),21.083min(minor)).1H NMR(400MHz,CDCl3)δ7.71(d,J=8.2Hz,2H),7.33(d,J=8.0Hz,2H),7.25–7.21(m,1H),6.89–6.80(m,3H),5.94(t,J=1.6Hz,1H),4.96(t,J=5.2Hz,1H),3.99–3.92(m,2H),3.88–3.76(m,7H),3.08(d,J=11.6Hz,1H),2.93(d,J=11.6Hz,1H),2.43(s,3H),1.92(dd,J=14.4,4.8Hz,1H),1.81(dd,J=14.4,5.3Hz,1H),1.22(s,3H).13C NMR(100MHz,CDCl3)δ159.7,143.6,130.0,133.3,131.9,131.4,129.8,129.5,127.7,118.0,112.8,111.7,102.4,64.7,55.3,53.3,46.4,43.3,35.2,24.8,21.5.

[0072]

[0073] (S)-3-((1,3-dioxolan-2-yl)methyl)-5-butyl-3-methyl-1-tosyl-1,2,3,6-tetrahydropyridine(I-11):Colorless oil.[α]D20=+13.8°(c=0.9,CHCl3).97%ee(determined by HPLC:Chiralpak ODH Column,5 / 95 i-PrOH / hexane,1.0mL / min,254nm;TR=9.040min(major),10.890min(minor)).1H NMR(400MHz,CDCl3)δ7.67(d,J=8.0Hz,2H),7.32(d,J=8.0Hz,2H),5.28(s,1H),4.89(t,J=5.2Hz,1H),3.97–3.90(m,2H),3.83–3.76(m,2H),3.39–3.31(m,2H),2.97(d,J=11.2Hz,1H),2.79(d,J=11.2Hz,1H),2.43(s,3H),1.90(t,J=7.2Hz,2H),1.79(dd,J=14.4,5.2Hz,1H),1.68(dd,J=14.4,5.2Hz,1H),1.36–1.22(m,4H),1.10(s,3H),0.86(t,J=7.2Hz,3H).13C NMR(100MHz,CDCl3)δ143.4,133.4,132.2,129.6,128.5,127.7,102.5,64.6(2C),53.5,47.2,43.3,34.6,34.2,29.8,24.9,22.3,26.55,13.9.

[0074]

[0075] (S)-3-((1,3-dioxolan-2-yl)methyl)-3-ethyl-1-tosyl-1,2,3,6-tetrahydropyridine(I-12):Colorless oil.[α]D20=+42.0°(c=1.0,CHCl3).90%ee(determined by HPLC:Chiralpak AYH Column,10 / 90 i-PrOH / hexane,1.0mL / min,254nm;TR=39.091min(major),48.618min(minor)).1H NMR(400MHz,CDCl3)δ7.64(d,J=8.0Hz,2H),7.30(d,J=8.0Hz,2H),5.63–5.54(m,2H),4.83(t,J=5.2Hz,1H),3.95–3.85(m,2H),3.81–3.72(m,2H),3.54(dt,J=15.6,2.0Hz,1H),3.38(dt,J=15.6,2.0Hz,1H),3.01(d,J=11.6Hz,1H),2.89(d,J=11.6Hz,1H),2.40(s,3H),1.81–1.70(m,2H),1.66–1.47(m,2H),0.84(t,J=7.2Hz,3H).13C NMR(100MHz,CDCl3)δ143.5,133.5,133.2,129.7,127.7,121.3,102.3,64.7,64.6,51.2,44.8,40.1,37.7,30.2,21.6,8.1.

[0076]

[0077] (R)-3-((1,3-dioxolan-2-yl)methyl)-3-ethyl-1-tosylpiperidine(13):colorless oil.[α]D20=+42.2°(c=1.8,CHCl3).1H NMR(400MHz,CDCl3)δ7.54(d,J=8.0Hz,2H),7.24(d,J=8.4Hz,2H),4.82(t,J=4.8Hz,1H),3.88–3.80(m,2H),3.77–3.69(m,2H),2.95–2.90(m,1H),2.74–2.70(m,2H),2.60(d,J=11.2Hz,1H),2.35(s,3H),1.62–1.57(m,4H),1.47–1.41(m,2H),1.25–1.17(m,2H),0.76(t,J=7.6Hz,3H).13C NMR(100MHz,CDCl3)δ143.2,133.3,129.6,127.6,102.0,77.4,64.6,64.5,54.8,46.8,38.3,34.7,33.1,27.4,21.5,20.9,7.4.

[0078]

[0079] benzyl(R)-3-((1,3-dioxolan-2-yl)methyl)-3-ethylpiperidine-1-carboxylate(14):colorless oil.[α]D20=+30.2°(c=1.2,CHCl3).1H NMR(400MHz,CDCl3)δ7.36–7.30(m,5H),5.15–5.08(m,2H),4.91–4.87(m,1H),3.93–3.76(m,4H),3.54–3.49(m,1H),3.36–3.28(m,2H),3.20(d,J=13.6Hz,1H),1.75–1.42(m,8H),0.85–0.80(m,3H).13C NMR(100MHz,CDCl3)δ155.7,137.0,128.4,127.9,127.8,102.2,67.0,64.7,64.5,52.8,44.5,38.3,34.8,33.7,27.2,7.5。

Claims

1. A method for synthesizing a chiral tetrahydropyridine compound, characterized in that: The method comprises the following steps: adding an iodine-α,β-unsaturated olefinic aldehyde compound, pivalic acid, hydrazine hydrate, (S)-4-tert-butyl-2-[2-(diphenylphosphino)phenyl]-2-oxazoline and a palladium catalyst into an organic solvent, heating in air to react, and after the reaction is complete, post-treating to obtain the chiral tetrahydropyridine compound; The structure of the alkenyl iodide-α,β-unsaturated alkenal compound is shown in formula (II): The structure of the hydrazine hydrate is shown in formula (III): NH2NH2·H2O(III) The structure of the chiral tetrahydropyridine compound is shown in formula (I): In formula (I) to (II), R 1 , R 2 Independently selected from H, aryl or alkyl.

2. The method for synthesizing chiral tetrahydropyridine compounds according to claim 1, characterized in that: R 1 is H, substituted or unsubstituted phenyl, or C1-C4 alkyl, wherein the substituent on the phenyl is selected from C1-C4 alkoxy, C1-C4 alkyl, and halogen; R 2 It is H or C1~C4 alkyl.

3. The method for synthesizing chiral tetrahydropyridine compounds according to claim 1, characterized in that: The chiral tetrahydropyridine compound is one of the compounds represented by formula (I-1) to formula (I-12):

4. The method for synthesizing chiral tetrahydropyridine compounds according to claim 1, characterized in that: The organic solvent is dimethyl sulfoxide.

5. The method for synthesizing chiral tetrahydropyridine compounds according to claim 1, characterized in that: The palladium catalyst is palladium acetate.

6. The method for synthesizing chiral tetrahydropyridine compounds according to claim 1, characterized in that: The reaction temperature is 50 to 70° C., and the reaction time is 5 to 10 hours under air atmosphere.

7. The method for synthesizing chiral tetrahydropyridine compounds according to claim 1, characterized in that: The post-treatment comprises: reacting with ethylene glycol in tetrahydrofuran in the presence of sulfuric acid.

8. An application of the method for synthesizing a chiral tetrahydropyridine compound as claimed in any one of claims 1 to 7, characterized in that: The chiral tetrahydropyridine compound I-12 is further used in the synthesis of biologically active molecules; The bioactive molecule is the alkaloid-codonin or its key intermediate.

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