CN113666935A - Chiral indolopyrrole alkaloid and preparation method thereof - Google Patents

Chiral indolopyrrole alkaloid and preparation method thereof Download PDF

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CN113666935A
CN113666935A CN202111038713.3A CN202111038713A CN113666935A CN 113666935 A CN113666935 A CN 113666935A CN 202111038713 A CN202111038713 A CN 202111038713A CN 113666935 A CN113666935 A CN 113666935A
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chiral
indolopyrrole
alkaloid
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丁同梅
王冠军
张书宇
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Shanghai Jiaotong University
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract

The invention relates to a chiral indolopyrrole alkaloid and a preparation method thereof, pyrazolone imine and aromatic amine derivatives are dissolved in a solvent, and 3+2 serial cyclization reaction is carried out under the action of a chiral phosphoric acid catalyst to prepare the chiral indolopyrrole alkaloid. Compared with the prior art, the method avoids the use of a metal catalyst, can realize the synthesis of the chiral indolopyrrole alkaloid with high yield and high enantioselectivity, provides a possible potential strategy for treating tumors, and has better application prospect and certain practical application value.

Description

Chiral indolopyrrole alkaloid and preparation method thereof
Technical Field
The invention belongs to the technical field of organic chemistry, and particularly relates to chiral indolopyrrole alkaloid and a preparation method thereof.
Background
The indolopyrrole alkaloid has attracted much attention in the fields of pharmaceutical chemistry and organic chemistry, and among them, the indolopyrrole compound containing different types of substituent at C-3 position of indole has been studied most extensively in its chemical structure and biological activity. The pharmacological actions of many compounds are well understood and utilized, including muscle relaxants, potassium channel blockers and anti-cancer activities.
Among the structural types of indole alkaloids, alkaloids containing a 3 alpha-amino-hexahydropyrrolo [2,3-b ] indole structure are important. Because the molecular structure has C-3 aza quaternary carbon and two adjacent chiral centers at C-2, the chemical synthesis is very difficult, which makes the construction and expansion of the molecular skeleton very difficult, thereby greatly restricting the research and utilization of the biological function and pharmacy of the compound. In the construction of alkaloids containing 3 α -amino-hexahydropyrrolo [2,3-b ] indole structures, the nucleophilicity at the C-3 position of the indole ring is often utilized, the indole ring is functionalized on the basis of the existing indole ring, the construction of the aza quaternary carbon center is realized through an electrophilic cyclization process, which limits the diversity of the substrate range, and the synthesis of multifunctional indole frameworks is difficult (angelw.chem., int.ed.2011,50,2716; angelw.chem., int.ed.2014,53,5600). Whereas synthetic strategies that achieve indole ring systems by carbon-hydrogen bond activation often require the addition of metal catalysts (ACS cat.2016, 6,4690).
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide the chiral indolopyrrole alkaloid with participation of an organic catalyst, wide substrate applicability, high yield and controllable enantioselectivity and the preparation method thereof.
The purpose of the invention can be realized by the following technical scheme:
a preparation method of chiral indolopyrrole alkaloid is characterized in that pyrazolone imine and an aromatic amine compound are dissolved in a solvent, and 3+2 serial cyclization reaction is carried out under the action of a chiral phosphoric acid catalyst to prepare the chiral indolopyrrole alkaloid.
The synthetic route is as follows:
Figure BDA0003248395890000021
the catalyst comprises:
Figure BDA0003248395890000022
r is selected from H or substituted aryl.
Preferably, the chiral phosphoric acid catalyst is:
Figure BDA0003248395890000023
the pyrazolone imine has a chemical structural formula as follows:
Figure BDA0003248395890000024
the chemical structural formula of the aromatic amine compound is as follows:
Figure BDA0003248395890000025
the chemical structural formula of the prepared chiral indolopyrrole compound is as follows:
Figure BDA0003248395890000031
wherein R is1Is selected from aryl; r2Selected from alkyl groups; r3Is selected from aryl; r4Selected from alkyl, branched alkyl, heteroatom, halogen or aryl.
The solvent comprises one or more of dichloromethane, toluene, chloroform or tetrahydrofuran, and the solvent is preferably dichloromethane and chloroform.
The molar ratio of the chiral phosphoric acid catalyst to the pyrazolone imine to the arylamine compound is 0.02-0.2:1.0: 1.0-1.5.
The concentration of the pyrazolone imine in the solvent is 0.02-0.2 mol/L.
The reaction temperature is controlled to be-20-0 ℃ and the reaction time is 12-18 h.
The design idea of the method is that an aromatic amine compound (such as diphenylamine) and pyrazolone imine and a chiral phosphoric acid catalyst form a hydrogen bond to achieve the effect of activating a substrate, the electron cloud density on a nitrogen atom is reduced due to the conjugated effect of a nitrogen lone electron pair and phenyl, the nucleophilicity of nitrogen is further weakened, the reaction activity of an ortho position is enhanced due to the electron-donating induction effect of nitrogen, and pi-pi stacking interaction exists between a phenyl substituent on the nitrogen atom and an ortho aromatic ring system of the chiral phosphoric acid catalyst, so that the enantioselectivity of the Friedel-Crafts reaction in the first step is well controlled under the synergistic effect. Then, under the action of phosphoric acid protonic acid, nitrogen attacks an imine structure in a pyrazolone ring, and the whole catalytic cycle is completed.
Compared with the prior art, the invention has the following characteristics:
1) the invention adopts the organic micromolecule catalyst, does not need the participation of a metal catalyst, is beneficial to the subsequent separation and purification and simplifies the derivation step;
2) the reaction condition is relatively simple, the dosage of the catalyst is small, the chemical yield is high, the enantioselectivity is good, and a new thought is provided for the synthesis of the chiral indole pyrrole alkaloid;
3) the synthesized indolopyrrole ring system is a basic structural unit of various natural products and drug molecules, so that a drug molecule library of the compound is enriched.
Detailed Description
The present invention will be described in detail with reference to specific examples. The following examples will assist those skilled in the art in further understanding the invention, but are not intended to limit the invention in any way. It should be noted that variations and modifications can be made by persons skilled in the art without departing from the spirit of the invention. All falling within the scope of the present invention.
In the present embodiment, the hydrogen nuclear magnetic resonance spectrum (1H NMR) of the compound was determined by Bruker AVANCE III HD 400 or Bruker AVANCE III HD 500; mass spectra (ESI-MS) were determined from Waters ACQUITYTM UPLC & Q-TOF MS Premier; all reagents used were commercially available reagents.
The synthesis method can prepare the indolopyrrole compound shown as follows:
Figure BDA0003248395890000041
example 1:
preparation of Compound 1
Figure BDA0003248395890000051
Adding 0.10mmol of diphenylamine S1-1, 0.11mmol of pyrazolone imine S2, 0.001mmol of chiral phosphoric acid catalyst CPA I, 50mg of molecular sieve and 1.0mL of chloroform into a reaction bottle, reacting for 12 hours at 0 ℃, and separating by a silica gel column after the reaction is finished to obtain a white solid 1 with the yield of 92%.
Example 2:
preparation of Compound 2
Figure BDA0003248395890000052
Adding 0.10mmol of 4-phenyl diphenylamine S1-2, 0.11mmol of pyrazolone imine S2, 0.001mmol of chiral phosphoric acid catalyst CPA I, 50mg of molecular sieve and 1.0mL of chloroform into a reaction bottle, reacting for 12 hours at 0 ℃, and after the reaction is finished, separating by a silica gel column to obtain a yellow solid 2 with the yield of 90%.
The compounds 3-15 were prepared from the corresponding anilines and pyrazolone imines according to the methods described above.
Example 3:
preparation of Compound 16
Figure BDA0003248395890000053
0.10mmol of N-phenyl 2-naphthylamine S1-16, 0.11mmol of pyrazolone imine S2, 0.001mmol of chiral phosphoric acid catalyst CPA II and 1.0mL of DCM are added into a reaction bottle to react for 12h at the temperature of minus 20 ℃, and after the reaction is finished, white solid 16 is obtained by silica gel column separation, and the yield is 98%.
The compounds 17-25 are prepared from the corresponding naphthylamine and pyrazolone imine according to the method.
Figure BDA0003248395890000061
min.1H NMR(500MHz,acetone-d6):δ8.02(d,J＝10.0Hz,2H)7.58(d,J＝10.0Hz,2H),7.49-7.45(m,3H),7.39-7.30(m,3H),7.21(s,1H),7.13-7.07(m,2H),6.75(t,J＝10.0Hz,1H),6.44(d,J＝10.0Hz,1H),5.70(s,1H),1.43(s,9H),1.40(s,3H).13C NMR(126MHz,DMSO-d6):δ169.43,157.17,148.62,140.76,140.49,130.81,130.00,129.40,128.09,127.09,125.96,124.65,124.54,119.30,118.71,108.05,89.52,80.61,72.55,28.41,17.63.HRMS(ESI):m/z calculated for C27H28N4O3[M+H+]457.2234,found 457.2233.
Figure BDA0003248395890000062
hexane/i-PrOH＝80:20,1.0mL/min,254nm):tR(minor)＝6.1min,tR(major)＝8.7min.1H NMR(400MHz,acetone-d6):δ8.09(s,1H)7.88(d,J＝8.0Hz,2H),7.49-7.47(m,6H),7.28-7.25(m,1H),7.20(s,1H),7.12(t,J＝8.0Hz,1H),6.90(d,J＝4.0Hz,1H),6.33(d,J＝8.0Hz 1H),6.15(s,1H),2.23(s,3H),1.41(s,9H),1.22(s,3H).13C NMR(100MHz,acetone-d6):δ168.30,156.37,147.81,139.98,137.34,133.27,129.96,129.19,129.04,127.32,126.27,125.17,123.82,118.45,117.98,107.17,88.73,79.75,71.70,27.58,19.98,16.80.HRMS(ESI):m/zcalculated for C28H30N4O3[M+H+]471.2391found 471.2388.
Figure BDA0003248395890000063
min,tR(minor)＝4.9min.1H NMR(400MHz,acetone-d6):δ8.05(d,J＝8.0Hz,2H),7.61(d,J＝8.0Hz,2H),7.52-7.48(m,2H),7.42-7.34(m,4H),7.18-7.12(m,2H),6.35(dd,J1＝4.0Hz,J2＝8.0Hz,1H),6.00(d,J＝4.0Hz,1H),5.70(s,1H),3.68(s,3H),1.46(s,9H),1.42(s,3H).13C NMR(126MHz,DMSO-d6):δ168.23,155.93,152.39,140.92,140.50,138.99,129.20,128.65,125.59,125.38,124.41,123.93,117.82,115.56,111.58,107.65,88.27,79.43,71.44,55.61,28.03,17.08.HRMS(ESI):m/z calculated for C28H30N4O4[M+H+]487.2340,found 487.2334.
Figure BDA0003248395890000071
min,tR(major)＝8.8min.1H NMR(500MHz,acetone-d6):δ8.02(d,J＝10.0Hz,2H)7.88(s,1H),7.57-7.47(m,5H),7.39-7.34(m,4H),7.13-7.10(m,1H),6.40(d,J＝10.0Hz,1H),5.73(s,1H),1.44(s,12H),1.32(s,12H).13C NMR(126MHz,acetone-d6):δ169.46,157.24,151.29,140.46,140.06,138.18,132.54,130.12,129.42,128.51,127.56,124.68,124.08,118.67,107.22,89.56,84.01,80.55,72.31,28.41,25.22,25.18,17.79.HRMS(ESI):m/z calculated for C33H39BN4O5[M+H+]583.3086,found 583.3084.
Figure BDA0003248395890000072
min,tR(minor)＝4.3min.1H NMR(500MHz,acetone-d6):δ8.02(d,J＝5.0Hz,2H)7.57-7.45(m,5H),7.39-7.36(m,2H),7.33-7.30(m,2H),7.14-7.10(m,2H),6.41(d,J＝10.0Hz,1H),5.73(s,1H),2.42(s,3H)1.44(s,9H),1.41(s,3H).13CNMR(126MHz,acetone-d6):δ169.16,157.13,147.35,140.51,140.36,132.38,130.03,129.41,127.98,127.37,127.19,126.83,125.50,124.74,118.71,108.62,89.80,80.72,72.42,28.39,18.50,17.58.HRMS(ESI):m/z calculated forC28H30N4O3S[M+H+]503.2111,found 503.2107.
Figure BDA0003248395890000073
min,tR(minor)＝6.0min.1H NMR(400MHz,acetone-d6):δ8.02(d,J＝8.0Hz,2H)7.58(d,J＝8.0Hz,2H),7.47(t,J＝8.0Hz,2H),7.39-7.31(m,4H),7.15-7.09(m,2H),6.32(dd,J1＝4.0Hz,J2＝8.0Hz,1H),5.97(d,J＝4.0Hz,1H),5.67(s,1H),3.65(s,3H),1.34(s,9H),1.39(s,3H).13C NMR(126MHz,acetone-d6):δ169.83,163.03,157.22,150.02,140.62,130.07,129.43,128.35,127.23,126.64,124.60,118.67,116.89,104.65,94.63,89.67,80.56,72.08,55.52,28.43,17.72.HRMS(ESI):m/z calculated for C28H30N4O4[M+H+]487.2340,found487.2334.
Figure BDA0003248395890000074
hexane/i-PrOH＝80:20,1.0 mL/min,254 nm):,tR(major)＝5.6min,tR(minor)＝8.3min.1H NMR(400MHz,acetone-d6):δ8.03(d,J＝8.0Hz,2H),7.58(d,J＝8.0Hz,2H),7.48(m,2H)7.40-7.32(m,4H),7.18-7.10(m,2H),6.58(d,J＝8.0Hz,1H),6.28(s,1H),5.69(s,1H),2.18(s,3H),1.44(s,9H),1.39(s,3H).13C NMR(126MHz,acetone-d6):δ169.65,157.18,148.83,140.88,140.83,140.57,129.98,129.38,128.27,127.04,125.68,124.58,121.85,120.13,118.66,108.71,89.56,80.55,72.36,28.40,21.73,17.63.HRMS(ESI):m/z calculated for C28H30N4O3[M+H+]471.2391,found 471.2385.
Figure BDA0003248395890000081
90:10,1.0mL/min,254 nm):tR(minor)＝9.3min tR(major)＝13.7min.1H NMR(500MHz,acetone-d6):δ8.01(d,J＝10.0Hz,2H)7.58(d,J＝10.0Hz,2H),7.46-7.43(m,2H),7.37-7.34(m,2H),7.30-7.27(m,1H),7.22(s,1H),7.15(s,1H),7.11-7.08(m,1H),6.31(s,1H),5.66(s,1H),2.17(s,3H),2.09(s,3H),1.43(s,9H),1.36(s,3H).13C NMR(126MHz,acetone-d6):δ169.71,157.13,146.77,141.37,140.59,139.05,129.89,129.34,127.67,127.09,126.83,126.62,124.51,122.01,118.62,109.70,89.51,80.49,72.50,28.39,20.26,19.22,17.53.HRMS(ESI):m/zcalculated for C29H32N4O3[M+H+]485.2547,found 485.2542.
Figure BDA0003248395890000082
80:20,1.0 mL/min,254 nm):tR(minor)＝8.4min,tR(major)＝6.8min.1H NMR(400MHz,acetone-d6):δ7.94(d,J＝8.0Hz,2H),7.72(d,J＝8.0Hz,2H),7.46-7.42(m,4H),7.34(t,J＝8.0Hz,2H),7.25(t,J＝8.0Hz,1H),7.09(t,J＝8.0Hz,2H),6.73(t,J＝8.0Hz,1H),6.60(d,J＝8.0Hz,1H),5.69(s,1H),1.96(q,J＝8.0Hz,2H),1.44(s,9H),0.98(t,J＝8.0Hz,3H).13C NMR(100MHz,acetone-d6):δ168.80,156.38,148.03,139.75,139.32,129.70,128.84,128.36,125.72,125.21,124.54,124.19,123.68,118.06,117.74,106.31,90.07,79.60,71.39,27.40,24.74,6.79.HRMS(ESI):m/z calculated for C28H31N4O3[M+H+]471.2391,found471.2389.
Figure BDA0003248395890000083
min,tR(major)＝6.3min.1H NMR(400MHz,acetone-d6):δ7.89(d,J＝8.0Hz,2H),7.57(d,J＝8.0Hz,2H),7.48-7.45(m,3H),7.33-7.30(m,1H),7.20-7.17(m,3H),7.09(t,J＝8.0Hz,1H),6.74(t,J＝8.0Hz,1H),6.43(d,J＝8.0Hz,1H),5.66(s,1H),2.29(s,3H),1.43(s,9H),1.38(s,3H).13C NMR(100MHz,acetone-d6):δ168.10,156.17,147.61,139.78,137.14,133.07,129.76,128.99,128.84,127.12,126.07,124.97,123.62,118.37,118.25,117.78,106.97,88.53,79.55,71.50,27.38,19.78,16.60.HRMS(ESI):m/z calculated for C28H31N4O3[M+H+]471.2391,found 471.2396.
Figure BDA0003248395890000091
8.03(d,J＝8.0Hz,2H),7.55-7.54(m,2H),7.49-7.45(m,3H),7.49-7.38(m,2H),7.34-7.30(m,1H),7.26(s,1H),7.12-7.08(m,1H),6.75(t,J＝8.0Hz,1H),6.42(d,J＝8.0Hz,1H),5.76(s,1H),1.43(s,9H),1.39(s,3H).13C NMR(100MHz,acetone-d6):δ168.72,156.25,147.73,139.72,138.28,129.94,129.07,128.39,128.07,127.22,126.21,125.01,123.37,119.16,118.40,107.13,88.58,79.73,71.53,27.39,16.64.HRMS(ESI):m/z calculated for C27H28ClN4O3[M+H+]491.1844,found 491.1843.
Figure BDA0003248395890000092
min,tR(major)＝8.2min.1H NMR(400MHz,acetone-d6):δ7.92(d,J＝8.0Hz,2H),7.58(d,J＝8.0Hz,2H),7.31(t,J＝8.0Hz,1H),7.18(s,1H),7.09(t,J＝8.0Hz,1H),6.94(d,J＝8.0Hz,2H),6.74(t,J＝8.0Hz,1H),6.44(d,J＝8.0Hz,1H),5.65(s,1H),3.77(s,3H),1.44(s,9H),1.38(s,3H).13C NMR(100MHz,acetone-d6):δ167.66,156.13,147.54,139.82,132.82,129.70,128.97,127.03,126.02,124.94,123.67,119.51,118.24,113.48,106.99,88.53,79.52,71.37,54.61,27.38,16.62.HRMS(ESI):m/z calculated for C28H31N4O4[M+H+]487.2340,found487.2346.
Figure BDA0003248395890000093
(s,J＝1H)7.90(d,J＝5.0Hz,2H),7.40-7.50(m,7H),7.13-7.10(m,1H),6.88(d,J＝10Hz,1H),6.25(d,J＝10Hz,1H),6.06(s,1H),2.32(s,3H),2.23(s,3H),1.41(s,9H),1.21(s,3H).13C NMR(126MHz,DMSO-d6):δ168.59,156.06,145.37,139.18,137.33,135.16,130.25,129.86,128.74,126.71,126.46,126.20,123.95,117.87,106.59,88.13,79.33,71.39,28.15,20.75,20.44,17.21.HRMS(ESI):m/z calculated for C29H32N4O3[M+H+]485.2547,found 485.2547.
Figure BDA0003248395890000094
8.02(d,J＝8.0Hz,2H),7.43-7.09(m,7H),7.00(d,J＝4.0Hz,2H),6.70-6.68(m,1H),6.28(d,J＝8.0Hz,1H),5.60(s,1H),3.83(s,3H),3.74(s,3H),1.43(s,9H),1.33(s,3H).13C NMR(126MHz,acetone-d6):δ169.03,162.22,158.39,156.32,149.93,139.77,131.72,129.58,128.53,125.58,123.65,117.71,115.61,114.33,103.20,93.14,88.76,79.64,71.13,54.81,54.60,27.54,16.67.HRMS(ESI):m/zcalculated for C29H32N4O5[M+H+]517.2445,found 517.2446.
Figure BDA0003248395890000101
(d,J＝8.0Hz,2H),7.68-7.54(m,5H),7.39(t,J＝8.0Hz,3H),7.26(dd,J1＝4.0Hz,J2＝8.0Hz,1H),7.14(t,J＝8.0Hz,1H),6.46(d,J＝8.0Hz,1H),5.85(s,1H),1.44(s,12H).13C NMR(126MHz,acetone-d6):δ16877,157.09,147.29,140.20,139.62,133.54,133.27,129.82,129.49,128.97,124.95,120.13,118.77,110.10,109.85,89.88,80.88,72.26,28.35,17.59.HRMS(ESI):m/z calculated forC27H26Br2N4O3[M+H+]615.0424,found 615.0421.
Figure BDA0003248395890000102
7.59-7.56(m,2H),7.47(d,J＝5.0Hz,1H),7.38-7.35(m,2H),7.26-7.21(m,3H),7.13-7.08(m,2H),6.77-6.74(m,1H),6.38(d,J＝5.0Hz,1H),5.70(s,1H),1.44(s,9H),1.41(s,3H).13C NMR(126MHz,acetone-d6):δ169.37,162.69,160.75,157.14,148.66,140.40,136.72(d,J＝2.5Hz),130.87,130.40(d,J＝8.8Hz),129.39,125.93,124.66,124.40,119.37,118.63,116.77,116.59,107.71,89.46,80.62,72.47,28.37,17.50.HRMS(ESI):m/z calculated for C27H27FN4O3[M+H+]475.2140,found 475.2142.
Figure BDA0003248395890000103
(s,1H),7.85(d,J＝8.0Hz,2H),7.49(s,4H),7.38(t,J＝8.0Hz,2H),7.21(s,1H),7.12(t,J＝8.0Hz,1H),6.38(d,J＝8.0Hz,1H),6.20(s,1H),2.24(s,3H),1.41(s,9H),1.23(s,3H).13C NMR(126MHz,DMSO-d6):δ168.29,155.94,144.26,139.17,138.94,130.24,129.46,129.29,128.68,127.50,127.29,126.26,123.97,123.86,117.84,107.02,87.96,79.33,71.29,28.06,20.38,17.27.HRMS(ESI):m/zcalculated for C28H29ClN4O3[M+H+]505.2001,found 505.2001.
Figure BDA0003248395890000111
6.27(d,J＝8.0Hz,1H),5.83(s,1H),5.60(s,1H),3.84(s,3H),3.63(s,3H),1.42(s,9H),1.37(s,3H).13C NMR(126MHz,acetone-d6):δ169.92,163.11,159.28,157.21,150.82,140.66,132.61,130.47,129.42,126.47,124.54,118.60,116.50,115.22,104.09,94.03,89.65,80.53,72.02,55.70,55.49,28.43,17.56.HRMS(ESI):m/z calculated for C29H32N4O5[M+H+]517.2445,found 517.2445.
Figure BDA0003248395890000112
11.8min.1H NMR(400MHz,acetone-d6):δ8.58(d,J＝8.0Hz,2H),8.00(d,J＝8.0Hz,2H),7.73(dd,J1＝8.0Hz,J2＝20Hz,2H),7.62-7.60(m,2H),7.53-7.44(m,3H),7.38-7.33(m,3H),7.24-7.20(m,1H),7.09(t,J＝8.0Hz,1H),6.84(d,J＝8.0Hz,1H),5.73(s,1H),1.49(s,9H),1.46(s,3H).13C NMR(126MHz,acetone-d6):δ169.33,156.66,147.78,140.67,140.58,132.26,132.07,130.16,129.42,129.35,128.15,127.35,127.28,124.82,124.60,122.86,118.78,113.76,111.74,89.81,80.51,74.46,28.47,18.07.HRMS(ESI):m/z calculated for C31H30N4O3[M+H+]507.2391,found 507.2391.
Figure BDA0003248395890000113
＝13.0min.1H NMR(400MHz,acetone-d6):δ8.58(d,J＝10.0Hz,1H),8.01(d,J＝10.0Hz,2H),7.67(dd,J1＝10.0Hz,J2＝25Hz,2H),7.41-7.39(m,7H),7.37-7.34(m,2H),7.09(t,J＝10.0Hz,1H),6.83(d,J＝10.0Hz,1H),5.71(s,1H),2.39(s,3H),1.50(s,3H),1.46(9H).13C NMR(126MHz,DMSO-d6):δ168.21,155.63,146.38,139.41,139.16,138.68,131.12,129.24,128.57,128.43,127.05,126.34,124.03,123.76,121.79,117.79,112.86,110.68,88.12,79.12,73.20,28.11,21.12,17.80.HRMS(ESI):m/z calculated for C32H32N4O3[M+H+]521.2547,found 521.2547.
Figure BDA0003248395890000114
10.0min.1H NMR(500MHz,acetone-d6):δ8.65-8.62(m,1H),8.00(d,J＝10.0Hz,2H),7.69-7.59(m,3H),7.53-7.45(m,3H),7.38-7.34(m,4H),7.10(t,J＝10.0Hz,1H),6.89(d,J＝10.0Hz,1H),5.77(s,1H),1.48(s,9H),1.46(s,3H).13CNMR(126MHz,DMSO-d6):δ168.07,158.58,156.67,155.62,145.73,139.51,139.06,129.47,129.03(J＝7.56Hz),128.60,128.24,126.56,117.88,116.50(J＝25.2Hz),113.48,111.84,111.39(J＝20.16Hz),88.19,79.19,73.17,28.09,17.76.HRMS(ESI):m/z calculated for C31H29FN4O3[M+H+]525.2296,found 525.2296.
Figure BDA0003248395890000121
10.6min.1H NMR(400MHz,acetone-d6):δ8.56(d,J＝8.0Hz,1H),8.00(d,J＝8.0Hz,2H),7.69-7.51(m,7H),7.38-7.33(m,3H),7.09(t,J＝8.0Hz,1H),6.89-6.81(m,2H),5.87(d,J＝20.0Hz,1H),5.74(s,1H),5.23(d,J＝12.0Hz,1H),1.49(s,3H),1.46(s,9H).13C NMR(126MHz,acetone-d6):δ169.80,157.19,148.49,141.05,138.42,130.69,129.88,128.72,128.53,127.87,119.30,114.64,113.28,112.46,90.32,81.32,74.85,28.98,18.61.HRMS(ESI):m/z calculated forC33H32N4O3[M+H+]533.2547,found 533.2545.
Figure BDA0003248395890000122
min.1H NMR(400MHz,acetone-d6):δ8.70(d,J＝8.0Hz,1H),8.04-8.02(m,3H),7.85-7.76(m,4H),7.63-7.61(m,2H),7.54-7.33(m,10H),7.10(t,J＝8.0Hz,1H),6.87(d,J＝8.0Hz,1H),5.77(s,1H),1.51(s,3H),1.46(s,9H)13C NMR(126MHz,acetone-d6):δ169.35,156.73,141.84,140.61,132.58,130.49,130.20,129.71,129.39,128.17,127.74,127.57,127.36,127.06,118.79,113.77,112.16,89.89,80.63,74.44,28.49,18.13.HRMS(ESI):m/z calculated for C37H34N4O3[M+H+]583.2704,found 583.2701.
Figure BDA0003248395890000123
min.1HNMR(400MHz,acetone-d6):δ8.57(d,J＝8.0Hz,1H),7.86(d,J＝8.0Hz,2H),7.70(dd,J1＝8.0Hz,J2＝20.0Hz,2H),7.59(d,J＝8.0Hz,2H),7.52-7.42(m,3H),7.35(t,J＝8.0Hz,1H),7.22-7.14(m,3H),6.83(d,J＝12.0Hz,1H),5.68(s,1H),2.27(s,3H),1.47(s,3H),1.44(s,9H).13C NMR(126MHz,acetone-d6):δ169.32,156.61,147.07,140.88,140.59,132.02,131.30,130.46,130.35,130.08,129.52,129.32,128.29,127.97,127.08,124.75,124.55,118.74,113.85,111.74,89.75,80.46,74.45,28.45,21.36,18.03.HRMS(ESI):m/zcalculated for C32H33N4O3[M+H+]521.2547,found 521.2540.
Figure BDA0003248395890000131
8.01(d,J＝10.0Hz,2H),7.70(dd,J1＝10.0Hz,J2＝25.0Hz,2H),7.47-7.31(m,7H),7.22-7.19(m,2H),7.09(t,J＝10.0Hz,1H),7.08(d,J＝10.0Hz,1H),5.69(s,1H),2.40(s,3H),1.48(s,3H),1.46(s,9H).13C NMR(126MHz,acetone-d6):δ169.54,156.82,148.27,140.77,137.99,137.21,132.42,132.21,130.87,130.20,129.57,129.49,128.50,127.47,124.90,124.71,122.85,118.90,89.97,80.63,74.57,28.62,21.26,18.16.HRMS(ESI):m/z calculated for C32H32N4O3[M+H+]521.2547,found 521.2547.
Figure BDA0003248395890000132
7.39-7.36(m,2H),7.25-7.11(m,2H),6.83(d,J＝10.0Hz,1H),6.35(s,1H),1.46(s,9H),1.37(s,3H).13C NMR(126MHz,DMSO-d6):δ168.02,156.48,155.64,154.52,145.54,139.00,136.86(J＝5.04Hz),130.99,128.95,128.62(J＝10.08Hz),126.50,123.89,122.21,119.89,117.77,117.59,113.48,110.43,88.07,79.24,73.17,28.10,17.82.HRMS(ESI):m/z calculated for C31H28FN4O3[M+H+]559.1907,found 559.1905.
Figure BDA0003248395890000133
2H),7.47-7.45(m,3H),7.35-7.33(m,2H),7.07(t,J＝10.0Hz,1H),7.06-7.04(m,3H),6.71(d,J＝10.0Hz,1H),5.66(s,1H),3.85(s,3H),1.48(s,12H).13C NMR(126MHz,acetone-d6):δ169.55,159.47,156.81,148.65,140.74,132.91,132.37,132.22,130.39,130.05,129.54,129.46,127.42,124.77,124.64,122.68,118.82,115.44,113.15,119.49,89.99,80.61,74.48,55.84,28.59,18.08.HRMS(ESI):m/zcalculated for C32H32N4O3[M+H+]537.2496,found 537.2498.
Figure BDA0003248395890000134
16.9min 1H NMR(400MHz,acetone-d6):δ8.53(d,J＝8.0Hz,1H),7.91(d,J＝8.0Hz,2H),7.72-7.66(m,4H),7.49-7.41(m,3H),7.33-7.28(m,3H),7.21-7.17(m,3H),7.06(t,J＝8.0Hz,1H),6.95(d,J＝12.0Hz,1H),5.68(s,1H),2.12-1.98(m,2H),1.46(s,9H),1.07(t,J＝8.0Hz).13C NMR(100MHz,acetone-d6):δ168.71,155.83,147.40,139.51,139.33,131.02,128.98,128.36,128.31,126.23,125.58,123.91,123.60,121.69,117.71,113.23,110.20,90.18,79.50,73.32,27.46,25.16,6.87.HRMS(ESI):m/z calculated for C32H33N4O3[M+H+]521.2547,found521.2545.
Figure BDA0003248395890000141
14.7min,tR(major)＝18.0min.1H NMR(400MHz,acetone-d6):δ8.57(d,J＝8.0Hz,1H),7.89(d,J＝8.0Hz,2H),7.70(dd,J1＝8.0Hz,J2＝20.0Hz,2H),7.61-7.59(m,2H),7.52-7.42(m,3H),7.37-7.32(m,1H),7.22-7.18(m,1H),6.92-6.88(m,2H),6.83(d,J＝12.0Hz,1H),5.67(s,1H),3.75(s,3H),1.47(s,3H),1.44(s,9H).13C NMR(100MHz,acetone-d6):δ167.74,156.23,146.81,139.82,133.03,131.38,131.05,129.26,129.23,128.49,127.21,126.40,126.31,123.94,121.92,119.70,113.56,113.06,110.84,88.90,79.53,73.39,54.73,27.55,17.14.HRMS(ESI):m/z calculated for C33H33N4O4[M+H+]537.2496,found537.2499.
Figure BDA0003248395890000142
8.57(d,J＝10.0Hz,1H),8.01(d,J＝10.0Hz,2H),7.70(dd,J1＝8.0Hz,J2＝20.0Hz,2H),7.60-7.57(m,2H),7.53-7.44(m,3H),7.38-7.35(m,3H),7.24-7.20(m,1H),6.82(d,J＝8.0Hz,1H),5.80(s,1H),1.49(s,3H),1.45(s,9H).13C NMR(100MHz,acetone-d6):δ168.51,155.70,146.82,139.58,138.33,131.19,129.18,128.44,128.30,127.96,127.20,126.39,126.36,123.74,121.90,119.15,112.52,110.75,88.83,79.60,73.39,27.43.HRMS(ESI):m/z calculated for C31H30ClN4O3[M+H+]541.2001,found 541.2006.
The embodiments described above are intended to facilitate the understanding and use of the invention by those skilled in the art. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above embodiments, and those skilled in the art should make improvements and modifications within the scope of the present invention based on the disclosure of the present invention.

Claims (10)

1. A preparation method of chiral indolopyrrole alkaloid is characterized in that pyrazolone imine and an aromatic amine compound are dissolved in a solvent and are subjected to series reaction under the action of a chiral phosphoric acid catalyst to prepare the chiral indolopyrrole alkaloid.
2. The method for preparing chiral indolopyrrole alkaloid according to claim 1, wherein the chiral phosphoric acid catalyst comprises:
Figure FDA0003248395880000011
wherein R is selected from H or substituted aryl.
3. The method for preparing chiral indolopyrrole alkaloid according to claim 1, wherein the chiral phosphoric acid catalyst is:
Figure FDA0003248395880000012
4. the method for preparing chiral indolopyrrole alkaloids according to claim 1, wherein the pyrazolone imine has a chemical formula:
Figure FDA0003248395880000013
the chemical structural formula of the aromatic amine compound is as follows:
Figure FDA0003248395880000014
the chemical structural formula of the prepared chiral indole and pyrrole alkaloid is as follows:
Figure FDA0003248395880000021
wherein:
R1is selected from aryl;
R2selected from alkyl groups;
R3is selected from aryl;
R4selected from alkyl, branched alkyl, heteroatoms or halogens.
5. The method for preparing chiral indolopyrrole compounds according to claim 1, wherein the solvent comprises one or more of dichloromethane, toluene, chloroform or tetrahydrofuran.
6. The chiral indolopyrrole compound and the preparation method thereof according to claim 1 or 5, wherein the solvent is preferably dichloromethane or chloroform.
7. The method for preparing chiral indolopyrrole compounds according to claim 1, wherein the molar ratio of the chiral phosphoric acid catalyst, pyrazolone imine and aromatic amine compound is 0.02-0.2:1.0: 1.0-1.5.
8. The chiral indolopyrrole compound and the preparation method thereof according to claim 1, wherein the concentration of pyrazolone imine in the solvent is 0.02-0.2 mol/L.
9. The preparation method of the chiral indolopyrrole compound according to claim 1, wherein the temperature of the series reaction is controlled to be-20-0 ℃ and the time is 12-18 h.
10. A chiral indolopyrrole alkaloid, which is prepared by the preparation method of any one of claims 1-9, and has a chemical structural formula as follows:
Figure FDA0003248395880000022
wherein:
R1is selected from aryl;
R2selected from alkyl groups;
R3is selected from aryl;
R4selected from alkyl, branched alkyl, heteroatoms or halogens.
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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104926818A (en) * 2015-06-23 2015-09-23 河南师范大学 Method for synthesizing pyrazolo-[5, 1-alpha]isoindole compounds
CN105198888A (en) * 2015-10-01 2015-12-30 湘潭大学 2,3a-disubstituted-3H-pyrazole[1,5-a]indole-4(3aH)-ketone, derivative and synthetic method of 2,3a-disubstituted-3H-pyrazole[1,5-a]indole-4(3aH)-ketone and derivative
CN107868087A (en) * 2017-09-18 2018-04-03 浙江大学 A kind of method for preparing pyrrolo-indole analog derivative
CN109053736A (en) * 2018-08-08 2018-12-21 青岛科技大学 A kind of preparation method of pyrrolo- [1,2- α] indoles -3- 01 derivatives
CN110156796A (en) * 2019-06-11 2019-08-23 贵州大学 Isoxazole splices double loop coil Oxoindole compounds of 3,3 '-thio pyrrolinones and preparation method and application
CN110878099A (en) * 2019-11-25 2020-03-13 五邑大学 Preparation method of pyrrole [1,2, α ] indole alkaloid derivative
CN111269235A (en) * 2020-03-03 2020-06-12 安徽师范大学 Cyclopyrazolone derivative and preparation method thereof
CN111471047A (en) * 2020-05-21 2020-07-31 河南师范大学 Method for selectively synthesizing pyrazolo [1,2-a ] pyrazolone or 2-acyl indole compounds

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104926818A (en) * 2015-06-23 2015-09-23 河南师范大学 Method for synthesizing pyrazolo-[5, 1-alpha]isoindole compounds
CN105198888A (en) * 2015-10-01 2015-12-30 湘潭大学 2,3a-disubstituted-3H-pyrazole[1,5-a]indole-4(3aH)-ketone, derivative and synthetic method of 2,3a-disubstituted-3H-pyrazole[1,5-a]indole-4(3aH)-ketone and derivative
CN107868087A (en) * 2017-09-18 2018-04-03 浙江大学 A kind of method for preparing pyrrolo-indole analog derivative
CN109053736A (en) * 2018-08-08 2018-12-21 青岛科技大学 A kind of preparation method of pyrrolo- [1,2- α] indoles -3- 01 derivatives
CN110156796A (en) * 2019-06-11 2019-08-23 贵州大学 Isoxazole splices double loop coil Oxoindole compounds of 3,3 '-thio pyrrolinones and preparation method and application
CN110878099A (en) * 2019-11-25 2020-03-13 五邑大学 Preparation method of pyrrole [1,2, α ] indole alkaloid derivative
CN111269235A (en) * 2020-03-03 2020-06-12 安徽师范大学 Cyclopyrazolone derivative and preparation method thereof
CN111471047A (en) * 2020-05-21 2020-07-31 河南师范大学 Method for selectively synthesizing pyrazolo [1,2-a ] pyrazolone or 2-acyl indole compounds

Non-Patent Citations (17)

* Cited by examiner, † Cited by third party
Title
ALBERTO MARTÍNEZ,: "Versatile Access to Chiral Indolines by Catalytic Asymmetric Fischer Indolization", 《ANGEWANDTE CHEMIE INTERNATIONAL EDITION》 *
ANNA J. KOCHANOWSKA-KARAMYAN: "Marine Indole Alkaloids: Potential New Drug Leads for the Control of Depression and Anxiety", 《CHEMICAL REVIEWS》 *
CHANG GUO: "Core-Structure-Oriented Asymmetric Organocatalytic Substitution of 3-Hydroxyoxindoles: Application in the Enantioselective Total Synthesis of (+)-Folicanthine", 《ANGEWANDTE CHEMIE INTERNATIONAL EDITION》 *
CHUAN LIU: "Enantioselective Synthesis of 3a-Amino-Pyrroloindolines by Copper-Catalyzed Direct Asymmetric Dearomative Amination of Tryptamines", 《ANGEWANDTE CHEMIE INTERNATIONAL EDITION》 *
DOUGLAS A. HORTON: "The Combinatorial Synthesis of Bicyclic Privileged Structures or Privileged Substructures", 《CHEMICAL REVIEWS》 *
ERIK STEMPEL: "Cyclohepta[b]indoles: A Privileged Structure Motif in Natural Products and Drug Design", 《ACCOUNTS OF CHEMICAL RESEARCH》 *
GUY R. HUMPHREY: "Practical Methodologies for the Synthesis of Indoles.", 《CHEMICAL REVIEWS》 *
HOSEA M. NELSON: "Chiral Anion Phase Transfer of Aryldiazonium Cations: An Enantioselective Synthesis of C3-Diazenated Pyrroloindolines", 《ANGEWANDTE CHEMIE INTERNATIONAL EDITION》 *
JIN SONG: "Recent progress in organocatalytic asymmetric total syntheses of complex indole alkaloids", 《NATIONAL SCIENCE REVIEW》 *
JOSÉ BARLUENGA: "Modular Synthesis of Indoles from Imines and o-Dihaloarenes or o-Chlorosulfonates by a Pd-Catalyzed Cascade Process", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 *
KLEMENT FOO: "Total Synthesis Guided Structure Elucidation of (+)-Psychotetramine", 《ANGEWANDTE CHEMIE INTERNATIONAL EDITION》 *
QI LI: "Enantioselective and diastereoselective azo-coupling/iminium-cyclizations: a unified strategy for the total syntheses of (−)-psychotriasine and (+)-pestalazine B", 《CHEMICAL SCIENCE》 *
SHENCI LU: "Transition-Metal-Free Decarboxylative Propargylic Substitution/Cyclization with either Azolium Enolates or Acyl Anions", 《ANGEWANDTE CHEMIE INTERNATIONAL EDITION》 *
STEFFEN MÜLLER,: "The Catalytic Asymmetric Fischer Indolization", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 *
WANGQING KONG: "Palladium-Catalyzed Enantioselective Domino Heck/Intermolecular C–H Bond Functionalization: Development and Application to the Synthesis of (+)-Esermethole.", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 *
ZHIXIONG RUAN: "Nickel-Catalyzed C-H Alkynylation of Anilines: Expedient Access to Functionalized Indoles and Purine Nucleobases", 《ACS CATALYSIS》 *
ZHUANGZHI SHI: "Indoles from Simple Anilines and Alkynes: Palladium-Catalyzed C-H Activation Using Dioxygen as the Oxidant", 《ANGEWANDTE CHEMIE INTERNATIONAL EDITION》 *

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Application publication date: 20211119

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