CN112250684A - Dimeric tryptamine compound and preparation method thereof - Google Patents

Dimeric tryptamine compound and preparation method thereof Download PDF

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CN112250684A
CN112250684A CN202011144383.1A CN202011144383A CN112250684A CN 112250684 A CN112250684 A CN 112250684A CN 202011144383 A CN202011144383 A CN 202011144383A CN 112250684 A CN112250684 A CN 112250684A
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dimeric
compound
tryptamine
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methyl
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谢卫青
魏宏博
陈固洲
雷盼
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Northwest A&F University
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    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D487/04—Ortho-condensed systems
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    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
    • B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
    • B01J31/181—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine
    • B01J31/184—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine mixed aromatic/aliphatic ring systems, e.g. indoline
    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
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    • B01J31/22—Organic complexes
    • B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
    • B01J31/2208—Oxygen, e.g. acetylacetonates
    • B01J31/2217—At least one oxygen and one nitrogen atom present as complexing atoms in an at least bidentate or bridging ligand
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
    • B01J2531/0213—Complexes without C-metal linkages
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    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/30—Complexes comprising metals of Group III (IIIA or IIIB) as the central metal
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    • C07B2200/07—Optical isomers
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    • Y02P20/00—Technologies relating to chemical industry
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Abstract

The invention belongs to the technical field of drug synthesis, and particularly discloses a plurality of dimeric tryptamine compounds with chemical structures shown in formula (I), and a substituent R1、R3Represents hydrogen, alkyl, alkoxy, halogen; r2Represents hydrogen, alkyl, benzyl, allyl, isopentenyl; r4Represents alkyl, azide, methyl aminocarbonate, tert-butyl aminocarbonate, allyl aminocarbonate, phthalimide, o-nitrobenzenesulfonamide; r5Representing carbonate and sulfonyl protecting groups. The invention also provides a synthesis method of the compound, which adopts substrates of 3-bromooxoindole and substituted tryptamine derivatives to carry out asymmetric dearomatization reaction under the action of a chiral catalyst to construct continuous chiral quaternary carbon C3a-C3 a' bonds in the dimeric tryptamine compound. The invention adopts the synthesis method to prepare various dimeric tryptamine compounds for the first time, and has the advantages of high yield, high enantioselectivity, high diastereoselectivity and easiness inSeparation and the like.

Description

Dimeric tryptamine compound and preparation method thereof
Technical Field
The invention belongs to the technical field of drug synthesis, relates to a synthetic method of a dimeric tryptamine compound, and particularly relates to a novel synthetic route of the dimeric tryptamine compound, and a plurality of dimeric tryptamine compounds with novel structures are prepared based on the synthetic route.
Background
As a very important structural unit, hexahydropyrrole indole is widely present in natural products with biological activity. Representative compounds having such structural units are meso-chimonanthine (NP-1), (+) -helicanthine (NP-2), (-) -chimonanthidine (NP-3). The alkaloid which has representative significance in oligomeric hexahydropyrrole indole type natural products has a special structure and wide medicinal value and biological activity, such as antibacterial, antiviral and analgesic effects.
How to efficiently synthesize compounds having such structures is one of the hot issues that the skilled person is interested in. It is noteworthy that in these dimeric or oligomeric molecular structures, there is a single carbon-carbon bond of C3a-C3 a'. The carbon-carbon single bond not only has poor stability, but also has larger steric hindrance effect, so that the structure with continuous all-carbon quaternary carbon is more difficult to construct. At present, no method for efficiently constructing carbon-carbon single bonds through indirect routes is available, especially in the aspect of asymmetric synthesis. In order to search for a new preparation method of the hexahydropyrrole indole compound, synthesize more compounds with novel structures, and search for higher-activity molecules applicable to the field of biological medicines, the search for a new synthesis path of the compounds has important practical significance.
Figure BDA0002739213930000011
Disclosure of Invention
The invention aims to provide a new synthetic route of the dimeric tryptamine compound and prepare a plurality of dimeric tryptamine compounds with novel structures based on the synthetic route.
In order to achieve the purpose, the invention adopts a metal-containing Ni (II) or scandium (II) catalyst, 3-bromine oxidized indole (compound A) and substituted tryptamine derivative (compound B) are used as substrates to carry out asymmetric dearomatization reaction, so as to construct continuous chiral quaternary carbon C3a-C3 a' bonds of the dimeric tryptamine compound C, and the structural formula of the target compound is confirmed by using analytical techniques such as HR-MS, NMR, X-ray and the like.
Specifically, the invention provides a method for preparing dimeric tryptamine compounds, which adopts substrate compounds A and B to carry out asymmetric dearomatization reaction under the action of a chiral catalyst to construct continuous chiral quaternary carbon C3a-C3 a' bonds of the dimeric tryptamine compounds C, and the preparation route is as follows:
Figure BDA0002739213930000021
wherein, the substituent R1、R3Represents hydrogen, alkyl, alkoxy, halogen; r2Represents hydrogen, alkyl, benzyl, allyl, isopentenyl; r4Represents alkyl, azide, methyl aminocarbonate, tert-butyl aminocarbonate, allyl aminocarbonate, phthalimide, o-nitrobenzenesulfonamide; r5Representing carbonate and sulfonyl protecting groups.
Preferably, the chiral catalyst is obtained by the complexation reaction of a divalent metal salt of Ni or Sc and a chiral ligand in an ester solvent;
the chiral ligand is a compound L1-L10
Figure BDA0002739213930000022
Any one of them.
Preferably, the method for preparing the dimeric tryptamine compound is that NiCl is selected as the metal salt2、NiBr2、NiI2、Ni(OAc)2、Ni(acac)2、Ni(BF4)2·6H2O、Ni(ClO4)2、Ni(OTf)2Or Sc (OTf)3Any one of the above.
Preferably, the molar ratio of the metal salt to the chiral ligand is (1-1.2): 1.
Preferably, the mole ratio of the compound A to the chiral catalyst is 10: 1.
Preferably, in the preparation method of the dimeric tryptamine compound, the mass volume ratio of the compound A to the ester solvent is 1: 100. The ester solvent of the present invention may be a conventional solvent such as ethyl acetate, but the present invention does not specifically limit or specify the selection of the ester solvent, and any ester solvent that can obtain the dimer amine compound of the present invention may be used as the solvent suitable for the present invention.
As the optimization of the preparation method of the dimeric tryptamine compound, the asymmetric dearomatization reaction temperature is 20-30 ℃, and the stirring reaction time is 8-20 h.
As the optimization of the preparation method of the dimeric tryptamine compound, the substituent R5Selecting any one of methoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, trichloroethoxycarbonyl, methylsulfonyl, p-toluenesulfonyl and o-nitrobenzenesulfonyl.
The invention also provides a dimeric tryptamine compound which is prepared by the method. The dimeric tryptamine compounds have the chemical structure of the dimeric tryptamine compound C, i.e.
Figure BDA0002739213930000031
Wherein the content of the first and second substances,
substituent R1Represents hydrogen, methyl, methoxy, halogen;
substituent R2Represents hydrogen, methyl, benzyl, allyl, isopentenyl;
substituent R3Represents hydrogen, methyl, halogen;
substituent R4Represents methyl, azide, methyl aminocarbonate, tert-butyl aminocarbonate, allyl aminocarbonate, phthalimide, o-nitrobenzenesulfonamide;
substituent R5Represents methoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, trichloroethoxycarbonyl, methylsulfonyl or p-tolueneSulfonyl, o-nitrobenzenesulfonyl.
In order to describe the structure of the dimeric tryptamine compounds in detail, the present invention defines the terms in the context.
The term "allyl" shall mean a monovalent radical derived from propylene by removal of a hydrogen atom from carbon atom number 3, and "isopentenyl" shall mean a monovalent radical derived from propylene by removal of a hydrogen atom from carbon atom number 4. "alkyl" can be divided into "straight chain alkyl" and "branched chain alkyl". The term includes the primary, secondary and tertiary alkyl sub-classes, such as methyl, tertiary butyl, and in particular, the term "alkane" refers to a saturated hydrocarbon compound containing only carbon and hydrogen.
The term "benzyl" shall mean a monovalent group derived from toluene by the removal of one hydrogen atom from the methyl group.
The term "alkoxy" refers to a monovalent group derived from an alcohol by removal of the hydrogen. For example, methanol is derived as "methoxy", allyl alcohol is derived as "allyloxy", tert-butyl alcohol is derived as "tert-butoxy" and benzyl alcohol is derived as "benzyloxy".
The term "halogen" shall denote fluorine, chlorine, bromine or iodine.
The invention confirms the chemical structural formulas of various target compounds by utilizing analysis technologies such as HR-MS, NMR, X-ray and the like. The invention uses compounds 1-29 to express 29 kinds of dimeric tryptamine compounds with different chemical structures, which specifically comprise:
Figure BDA0002739213930000041
compound 1, substituent R1Is 4-methyl, R2Is hydrogen, R3Is hydrogen, R4Is azido, R5Is a methoxycarbonyl group;
compound 2, substituent R1Is 6-methyl, R2Is hydrogen, R3Is hydrogen, R4Is azido, R5Is a methoxycarbonyl group;
compound 3, substituent R1Is 7-methyl, R2Is hydrogen, R3Is hydrogen, R4Is azido, R5Is a methoxycarbonyl group;
compound 4, substituent R1Is 5-methoxy, R2Is hydrogen, R3Is hydrogen, R4Is azido, R5Is a methoxycarbonyl group;
compound 5, substituent R1Is 6-fluoro, R2Is hydrogen, R3Is hydrogen, R4Is azido, R5Is a methoxycarbonyl group;
compound 6, substituent R1Is 5-chloro, R2Is hydrogen, R3Is hydrogen, R4Is azido, R5Is a methoxycarbonyl group;
compound 7, substituent R1Is 4-bromo, R2Is hydrogen, R3Is hydrogen, R4Is azido, R5Is a methoxycarbonyl group;
compound 8, substituent R1Is 6-bromo, R2Is hydrogen, R3Is hydrogen, R4Is azido, R5Is a methoxycarbonyl group;
compound 9, substituent R1Is hydrogen, R2Is hydrogen, R3Is hydrogen, R4Is N-phthalamide, R5Is a methoxycarbonyl group;
compound 10, substituent R1Is hydrogen, R2Is hydrogen, R3Is hydrogen, R4Is (triisopropylsilyl) oxy, R5Is a methoxycarbonyl group;
compound 11, substituent R1Is hydrogen, R2Is hydrogen, R3Is hydrogen, R4Aminocarbonic acid methyl ester, R5Is a methoxycarbonyl group;
compound 12, substituent R1Is hydrogen, R2Is allyl, R3Is hydrogen, R4Is azido, R5Is a methoxycarbonyl group;
compound 13, substituent R1Is hydrogen, R2Is isopentenyl, R3Is hydrogen, R4Is azido, R5Is a methoxycarbonyl group;
compound 14, substituent R1Is hydrogen, R2Is methyl, R3Is hydrogen, R4Is azido, R5Is methoxycarbonyl；
Compound 15, substituent R1Is hydrogen, R2Is benzyl, R3Is hydrogen, R4Is azido, R5Is a methoxycarbonyl group;
compound 16, substituent R1Is 5-chloro, R2Is allyl, R3Is 5-chloro, R4Is methyl aminocarbonate, R5Is a methoxycarbonyl group;
compound 17, substituent R1Is hydrogen, R2Is allyl, R3Is 5-chloro, R4Is N-o-nitrobenzenesulfonamido, R5Is a methoxycarbonyl group;
compound 18, substituent R1Is hydrogen, R2Is hydrogen, R3Is 5-bromo, R4Is azido, R5Is a methoxycarbonyl group;
compound 19, substituent R1Is hydrogen, R2Is hydrogen, R3Is 6-chloro, R4Is azido, R5Is a methoxycarbonyl group;
compound 20, substituent R1Is hydrogen, R2Is hydrogen, R3Is 5-bromo, 6-methyl, R4Is azido, R5Is a methoxycarbonyl group;
compound 21, substituent R1Is hydrogen, R2Is hydrogen, R3Is 6-methyl, R4Is azido, R5Is a methoxycarbonyl group;
compound 22, substituent R1Is hydrogen, R2Is hydrogen, R3Is 5-bromo, R4Is methyl aminocarbonate, R5Is a methoxycarbonyl group;
compound 23, substituent R1Is hydrogen, R2Is hydrogen, R3Is hydrogen, R4Is azido, R5Is a methoxycarbonyl group;
compound 24, substituent R1Is hydrogen, R2Is hydrogen, R3Is hydrogen, R4Is azido, R5Is benzyloxycarbonyl;
compound 25, substituent R1Is hydrogen, R2Is hydrogen, R3Is hydrogen, R4Is azide，R5Is an allyloxycarbonyl group;
compound 26, substituent R1Is hydrogen, R2Is hydrogen, R3Is hydrogen, R4Is azido, R5Is p-toluenesulfonyl;
compound 27, substituent R1Is hydrogen, R2Is hydrogen, R3Is hydrogen, R4Is azido, R5Is methylsulfonyl;
compound 28, substituent R1Is hydrogen, R2Is hydrogen, R3Is hydrogen, R4Is azido, R5Is o-nitrobenzenesulfonyl;
compound 29, substituent R1Is hydrogen, R2Is hydrogen, R3Is hydrogen, R4Is azido, R5Is trichloroethoxycarbonyl.
Compared with the prior art, the dimeric tryptamine compound and the preparation method thereof have at least the following advantages or beneficial effects:
(1) the invention carries out asymmetric dearomatization reaction under the action of chiral catalyst to construct continuous chiral quaternary carbon C3a-C3 a' bonds of the dimeric tryptamine compound C, has the characteristics of high enantioselectivity, high yield, high conversion number and the like, and most substrates obtain more than 99% of conversion rate and more than 90% of ee value under the condition of one percent of catalyst.
(2) The synthetic route provided by the invention is also successfully applied to the synthesis of the compounds for the first time, is novel, has high yield and high enantioselectivity and diastereoselectivity, is easy to separate, and is an optimal route for preparing the compounds.
(3) The solvent and the reagent used in the synthetic method are common organic chemical reagents, and can be recycled, so that the cost is reduced; the used instruments and equipment do not have conditions of ultrahigh temperature, ultralow temperature, ultrahigh pressure or other complicated conditions which are difficult to realize, and the experimental process is not special, and toxic and harmful reagents are used, so that the industrial production of products is facilitated.
(4) The invention successfully applies the synthetic route for the first time to prepare a plurality of common structure dimeric tryptamine compounds, such as compounds 1-29, which have novel structures, are novel compounds, have the possibility of being developed as the precondition of drug synthesis and have potential physiological activity.
Detailed Description
The invention is further described in the following examples, which are not intended to limit the scope of the invention in any way as indicated by the claims.
This example provides methods for the synthesis of the dimeric tryptamine compounds, as well as structural identification data for a portion of the target compounds.
1. Synthesis of target Compounds 1-29
The substrates of the synthetic route provided by the embodiment are compounds a and B, the catalysts are chiral catalysts, the compounds a and B are subjected to asymmetric dearomatization reaction under the action of the chiral catalysts, and the continuous chiral quaternary carbon C3a-C3 a' bonds of the dimeric tryptamine compound C are constructed, and the preparation route is as follows:
Figure BDA0002739213930000071
the chiral catalyst is obtained by the complexation reaction of Ni or Sc metal salt and a chiral ligand in an ester solvent. The metal salt is NiCl2、NiBr2、NiI2、Ni(OAc)2、Ni(acac)2、Ni(BF4)2·6H2O、Ni(ClO4)2、Ni(OTf)2Or Sc (OTf)3Any one of the above.
The chiral ligand is any one of compounds L1-L10.
Figure BDA0002739213930000072
Adding a substrate B (0.1mmol), a metal salt (0.01mmol), a chiral ligand (0.01mmol) and a molecular sieve (20mg) into a dry reaction tube at room temperature, adding a solvent ethyl acetate (2ml), stirring at room temperature for 30 minutes, then adding diisopropylethylamine (2.0mmol), dissolving a substrate A (0.2mmol) into ethyl acetate (1ml), adding into the system, stirring at room temperature, detecting the reaction by TLC, using a developing agent of petroleum ether-ethyl acetate (V/V ═ 2:1), adding a silica gel rotary drying solvent after the reaction is completed (about 8-20h), and performing column chromatography, wherein a mobile phase of petroleum ether-ethyl acetate (V/V ═ 8:1) to obtain corresponding products 1-29.
2. Spectral data of partial compounds
This example employs a spectroscopic analysis technique (1HNMR、13C NMR and ESI-HRMS) to carry out structural characterization on the dimeric tryptamine compound, and nuclear magnetic resonance spectrogram data of 17 representative compounds are shown below.
methyl(8aR)-3a-((S)-3-(2-azidoethyl)-2-oxoindolin-3-yl)-6-methyl-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (2)
White solid, yield 93%; the ee value was 91%.1HNMR(500MHz,Acetone-d6):δ9.53(s 1H),7.20(q,J＝7.3Hz,1H),7.10-6.92(m,1H),6.90(d,J＝7.7Hz,1H),6.79(dt,J＝14.7,7.6Hz,1H),6.63-6.35(m,2H),6.33(s,1H),5.46(s,1H),5.38(s,1H),3.75-3.64(m,1H),3.63(s,1H),3.59(s,2H),3.22(tdd,J＝14.2,9.9,7.0Hz,1H),3.03-2.76(m,4H),2.58-2.42(m,2H),2.23(s,1H),2.21(s,2H)；13C NMR(126MHz,Acetone-d6)δ178.09,151.45,142.23,138.86,129.15,129.08,128.34,128.32,125.24,124.49,124.42,124.28,121.47,118.51,118.46,109.79,109.59,109.43,77.77,76.96,62.39,61.19,54.02,53.87,51.62,51.52,47.48,44.83,44.69,31.33,20.80,20.78；HRMS-ESI calcd.for[M+H]+433.1983,found 433.1988。
methyl(8aR)-3a-((S)-3-(2-azidoethyl)-2-oxoindolin-3-yl)-5-methoxy-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (4)
A white solid; the yield was 65% and the ee value was 95%; 1H NMR (500MHz, CDCl3): δ 8.51(s,1H),7.23(t, J ═ 7.7Hz,0.46H),6.94(t, J ═ 7.7Hz,0.66H),6.90-6.84(m,2H),6.76-6.71(m,1H),6.46(d, J ═ 8.5Hz,1H),6.31-6.30(m,1H),5.30(s,1H),4.60(s,1H),3.74(s,3H),3.74-3.68(m,1H),3.67(s,3H),3.27-3.12(m,1H),3.06-2.95(m,2H),2.91-2.82(m,1H),2.52-2.49(m,1H), 2.46-2.26 (m,1H), 2.26-2.26H); 13C NMR (126MHz, CDCl3) delta 178.84,178.79,155.13,153.46,153.35,144.73,141.24,141.02,129.51,128.86,128.74,128.69,128.51,124.49,122.41,122.31,115.20,114.84,111.16,111.04,109.95,109.92,78.38,63.10,61.89,55.99,55.82,54.36,54.07,52.63,52.34,47.46,44.93,31.52, 31.44; HRMS-ESI calcd.for [ M + H ] +449.1932, found 449.1933.
methyl(8aR)-3a-((S)-3-(2-azidoethyl)-2-oxoindolin-3-yl)-6-fluoro-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (5)
A white solid; the yield was 92% and the ee value was 62%;1H NMR(500MHz,Chloroform-d):δ8.56(s,1H),7.23(t,J＝7.7Hz,1H),6.98-6.93(m,1H),6.91-6.85(m,2H),6.46(t,J＝8.8Hz,1H),6.27(bs,1H),6.19(dd,J＝9.6,2.3Hz,1H),5.26(s,1H),5.10(s,1H),3.75(s,1H),3.75(s,1H),3.73-3.70(m,1H),3.66(s,2H),3.30-3.15(m,1H),3.06-2.94(m,2H),2.93-2.81(m,1H),2.57-2.46(m,1H),2.42-2.37(m,1H),2.25-2.14(m,1H)；13C NMR(126MHz,Acetone)δ177.9,165.3,163.3,154.5,153.8,153.2,153.1,153.0,142.4,142.3,128.9,128.9,128.5,125.7,125.6,124.4,123.8,121.6,109.6,103.4,103.2,96.0,95.8,95.7,95.5,77.9,77.1,62.0,60.8,54.0,53.9,51.7,51.6,47.5,44.7,44.6,31.1.HRMS-ESI calcd.for[M+H]+437.1732,found437.1733。
methyl(8aR)-3a-((S)-3-(2-azidoethyl)-2-oxoindolin-3-yl)-5-chloro-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (6)
a white solid; the yield was 78% and the ee value was 80%.1H NMR(500MHz,Acetone-d6):δ9.55(s,1H),7.24(q,J＝7.4Hz,1H),7.03(ddd,J＝14.2,8.3,2.2Hz,1H),6.92(d,J＝7.9Hz,1H),6.91-6.81(m,2H),6.72(s,1H),6.48(d,J＝8.4Hz,1H),5.74(s,1H),5.48(s,1H),3.74-3.66(m,1H),3.63(s,1H),3.59(s,2H),3.11(td,J＝12.0,8.0Hz,1H),2.96-2.91(m,3H),2.51(ddt,J＝13.2,8.5,4.3Hz,1H),2.43(dt,J＝13.4,7.9Hz,1H),2.22(td,J＝12.7,5.8Hz,1H).13C NMR(126MHz,Acetone-d6)δ177.84,154.53,153.94,150.25,142.46,130.09,128.85,128.69,124.88,124.73,124.44,121.66,121.49,109.80,109.67,109.57,77.75,76.94,62.91,61.71,54.01,53.87,51.75,51.64,47.49,44.68,44.57,30.95,30.90；HRMS-ESI calcd.for[M+H]+453.1436,found453.1439.
methyl(8aR)-3a-((S)-3-(2-azidoethyl)-2-oxoindolin-3-yl)-6-bromo-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (8)
White solid, yield 80%, ee value 90%.1H NMR(500MHz,CDCl3):δ8.48(s,1H),7.20(t,J＝7.7Hz,1H),6.85(t,J＝6.8Hz,3H),6.74(dt,J＝10.5,4.5Hz,1H),6.59(d,J＝1.4Hz,1H),6.30(s,1H),5.23(s,1H),5.04(s,1H),3.71(s,1H),3.68-3.64(m,1H),3.61(s,2H),3.19-3.12(m,1H),2.99-2.91m,2H),2.89-2.76(m,1H),2.51-2.39(m,1H),2.37-2.30(m,1H),2.19-2.10(m,1H)；13C NMR(126MHz,CDCl3)δ178.62,155.11,152.02,140.86,128.89,128.20,126.92,125.84,124.34,123.37,122.54,121.27,112.72,109.98,62.34,61.05,53.87,52.45,47.41,44.99,31.40；HRMS-ESI calcd.for[M+H]+497.0936,found497.0931。
2-(((2-((3S)-3-((8aR)-1-(methoxycarbonyl)-2,3,8,8a-tetrahydropyrrolo[2,3-b]indol-3a(1H)-yl)-2-oxoindolin-3-yl)ethyl)-l2-azaneyl)carbonyl)benzoic acid (9)
A white solid; the yield was 76%, ee value was1H NMR(500MHz,Acetone-d6):δ9.55(s,1H),7.76(dt,J＝7.0,3.5Hz,2H),7.74-7.67(m,2H),7.05(dq,J＝16.3,7.7Hz,3H),6.85(d,J＝7.7Hz,1H),6.71-6.54(m,2H),6.48(d,J＝7.8Hz,1H).,6.28(bs,1H),5.49(s,1H),5.28(s,1H),3.77-3.62(m,1H),3.61(s,1H),3.57(s,2H),3.50-3.40(m,1H),3.35-3.21(m,2H),,2.96(s,1H)2.91-2.83(m,1H),2.81-2.75(m,1H),2.6--2.57(m,1H),2.25-2.19(m,1H)；13C NMR(126MHz,Acetone-d6)δ151.24,142.10,133.86,132.14,129.36,129.30,129.07,128.06,128.03,124.79,124.68,124.27,122.65,121.35,117.61,109.52,109.01,108.80,77.61,76.80,62.74,61.55,54.24,54.10,51.66,51.55,44.94,44.79,33.92,30.03。
methyl(8aR)-3a-((S)-3-(2-((methoxycarbonyl)amino)ethyl)-2-oxoindolin-3-yl)-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (11)
White solid, yield 60%, ee 93%.1H NMR(500MHz,Acetone-d6):δ9.53(d,J＝15.5Hz,1H),7.18(q,J＝7.2Hz,1H),7.06(dt,J＝11.5,7.4Hz,2H),6.89(d,J＝7.7Hz,1H),6.77(dt,J＝14.8,7.7Hz,1H),6.65(dt,J＝18.3,7.6Hz,1H),6.42(d,J＝7.9Hz,1H),6.08(t,J＝5.9Hz,1H),5.45(s,1H),5.29(s,1H),3.73-3.65(m,1H),3.62(s,1H),3.60(s,2H),3.51(s,3H),3.32-3.24(m,1H),3.00-2.94(m,1H),2.92-2.87(m,1H),2.86-2.76(m,1H),2.60-2.57(m,1H),2.50-2.47(m,1H),2.41-2.35(m,1H),2.25-2.19(m,1H)；13C NMR(126MHz,Acetone-d6)δ156.54,151.25,129.66,129.03,128.23,128.16,124.72,124.62,124.38,121.46,117.52,117.49,109.32,108.98,108.77,77.56,76.79,62.56,61.39,54.23,54.11,51.64,51.53,50.92,44.87,44.71,36.88,32.40；HRMS-ESI calcd.for[M+H]+451.1975,found 451.1976。
methyl(8aR)-8-allyl-3a-((S)-3-(2-azidoethyl)-2-oxoindolin-3-yl)-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (12)
White solid, 93% yield, ee value 95%.1H NMR(500MHz,CDCl3):δ8.25(s,1H),7.23-7.08(m,2H),6.85(dd,J＝13.2,7.8Hz,2H),6.75(ds,1H),6.67(ds,1H),6.23(d,J＝8.1Hz,1H),5.98(ds,1H),5.24(ds,1H),5.11(s,1H),4.98-4.75(m,2H),3.84(dd,J＝11.0,7.9Hz,1H),3.67(s,1H),3.66(s,2H),3.63-3.55(m,1H),3.25(bs,1H),3.02-2.94(m,2H),2.84-2.76(m,1H),2.53-2.33(m,2H),2.14-2.10(m,1H)；13C NMR(126MHz,CDCl3)δ178.14,151.43,134.39,129.66,128.71,127.83,124.56,122.50,122.40,116.81,115.47,115.06,109.85,106.47,81.98,81.84,62.32,61.16,54.60,54.30,52.52,47.44,31.56；HRMS-ESI calcd.for[M+H]+459.2133,found 459.2139。
methyl(8aR)-3a-((S)-3-(2-azidoethyl)-2-oxoindolin-3-yl)-8-(3-methylbut-2-en-1-yl)-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (13)
Yield of white solid 93%, ee 95%.1H NMR(500MHz,CDCl3)δ8.15(s,1H),7.29–7.19(m,1H),7.17-7.12(m,1H),6.89(dd,J＝12.9,7.7Hz,2H),6.79(t,J＝7.4Hz,1H),6.70(s,1H),6.21(dd,J＝11.3,7.8Hz,1H),6.00(s,1H),5.27(s,1H),4.45–4.21(m,1H),3.88(dd,J＝10.9,7.9Hz,1H),3.73(s,1H),3.70(s,2H),3.68-3.49(m,2H),3.38–3.17(m,1H),3.06–2.97(m,2H),2.91–2.72(m,1H),2.58–2.34(m,2H),2.16–2.13(m,1H),1.63–1.59(m,6H)；13C NMR(126MHz,CDCl3)δ178.02,151.48,132.93,129.65,128.82,128.67,124.72,124.42,122.48,122.37,122.07,121.48,116.65,116.40,109.62,106.15,82.07,81.70,62.22,61.04,54.22,52.46,47.44,45.13,43.71,31.60,25.64,17.90；HRMS-ESI calcd.for[M+H]+487.2452,found 487.2445。
(8aR)-3a-((S)-3-(2-azidoethyl)-2-oxoindolin-3-yl)-8-methyl-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (14)
White solid, 91% yield, ee value 95%.1H NMR(500MHz,CDCl3):δ8.46(s,1H),7.28-7.09(m,2H),6.90(t,J＝6.5Hz,2H),6.81(t,J＝7.8Hz,1H),6.70(ds,1H),6.64-6.48(m,1H),6.29(d,J＝7.9Hz,1H),6.07(ds,1H),5.15(s,1H),3.84(dd,J＝10.8,7.9Hz,1H),3.77(s,1H),3.70(s,2H),3.27-3.21(m,1H),3.05-2.93(m,2H),2.90-2.81(m,1H),2.75-2.35(m,5H),2.18-2.14(m,1H)；13C NMR(126MHz,CDCl3)δ178.64,178.37,155.56,152.63,140.74,129.82,128.88,128.74,127.89,124.49,124.34,124.05,122.38,122.17,117.11,109.94,109.84,107.02,83.25,82.50,62.49,61.37,54.45,52.54,52.46,47.52,45.08,33.53,33.31,31.15；HRMS-ESI calcd.for[M+H]+433.1983,found 433.1969。
(8aR)-3a-((S)-3-(2-azidoethyl)-2-oxoindolin-3-yl)-8-benzyl-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (15)
White solid, yield 92%, ee 93%.1H NMR(500MHz,Acetone-d6):δ9.55(s,1H),7.32(t,J＝7.7Hz,1H),7.28-7.11(m,3H),7.11-6.70(m,6H),6.63(ds,1H),6.34(ds,1H),6.10(d,7.8Hz,1H),5.68(ds,1H),4.50-4.00(m,2H),3.94(t,J＝9.3Hz,1H),3.60(s,1H),3.31(s,2H),3.06-2.82(m,4H),2.61-2.56(m,1H),2.55-2.43(m,1H),2.22-2.20(m 1H)；13C NMR(126MHz,Acetone-d6)δ177.86,142.40,129.29,129.15,128.65,128.18,126.35,126.25,125.91,124.59,124.38,121.65,117.22,116.98,109.78,106.28,82.87,82.58,54.28,51.83,51.39,49.69,47.45,44.86；HRMS-ESI calcd.for[M+H]+509.2296,found 509.2296。
(3S)-3-((8aR)-8-allyl-1-((4-nitrophenyl)sulfonyl)-2,3,8,8a-tetrahydropyrrolo[2,3-b]indol-3a(1H)-yl)-3-(2-azidoethyl)indolin-2-one (16)
White solid, yield 85%, ee value 89%.1HNMR(500MHz,CDCl3)δ8.41(d,J＝8.8Hz,2H),8.17(s,1H),8.06(d,J＝8.6Hz,2H),7.26(t,J＝7.6Hz,1H),7.18(t,J＝7.0Hz,1H),6.94(d,J＝7.7Hz,1H),6.87-6.82(m,1H),6.72(s,1H),6.34(d,J＝7.9Hz,1H),6.03(s,1H),5.35(s,1H),5.11(s,1H),4.93(d,J＝10.6Hz,2H),3.86-3.73(m,1H),3.73-3.57(m,2H),3.11-3.05(m,1H),3.02-2.84(m,2H),2.84-2.71(m,1H),2.42-2.23(m,2H),2.16-2.13(m,1H)；13C NMR(126MHz,CDCl3)δ150.78,145.66,140.59,133.49,130.0,129.02,128.56,126.75,124.60,124.50,124.26,122.74,117.63,116.52,110.09,107.06,84.93,62.36,53.97,47.73,47.45,47.2,31.69；HRMS-ESI calcd.for[M+H]+586.1867,found 586.1846。
methyl(8aR)-3a-((S)-3-(2-azidoethyl)-5-bromo-2-oxoindolin-3-yl)-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (18)
White solid, yield 70%, ee value 90%. 1H NMR (500MHz, Acetone-d6): δ 9.74(s,1H),7.34(ddd, J ═ 7.8,4.8,2.0Hz,1H),7.31-7.23(m,1H),7.14(q, J ═ 8.3Hz,1H),6.87(d, J ═ 8.3Hz,1H),6.76(dt, J ═ 14.3,7.4Hz,1H),6.50(dd, J ═ 36.7,7.8Hz,1H),6.12(s,1H),5.62(s,1H),5.13(s,1H),3.75-3.66(m,1H),3.62(s,1H),3.60(s,2H),3.32(dtd, J ═ 9.8, 19.8, 1H),3.75-3.66(m,1H),3.62(s,1H),3.60(s,2H),3.32(dtd, J ═ 9, 8, 11.8, 1H), 3.95 (1H), 2.35H), 2.26, 2.9, 1H), 2.35 (ddd, 1H);13C NMR(126MHz,Acetone-d6)δ177.63,151.19,141.29,131.31,131.25,131.05,129.47,127.64,127.50,124.64,124.59,117.78,113.79,110.99,109.28,109.02,77.62,76.85,62.53,61.38,54.28,54.16,51.61,47.36,45.13,44.94,31.41；HRMS-ESI calcd.for[M+H]+497.0931,found 497.0935。
methyl (8aR) -3a- ((S) -3- (2-azidoethyl) -6-chloro-2-oxoindolin-3-yl) -3,3a,8,8 a-tetrahydrorrolo [2,3-b ] indole-1(2H) -carboxylate (19). white solid, yield 92%, ee value 60%.
1H NMR(500MHz,CDCl3):δ8.86(s,1H),7.21-7.15(m,2H),6.92(d,J＝12.4Hz,1H),6.82(m,1H),6.74(d,J＝8.0Hz,1H),6.50(d,J＝7.8Hz,1H),6.06-5.84(m,1H),5.09(s,1H),4.72(s,1H),3.70(d,J＝39.5Hz,4H),3.37-3.16(m,1H),3.07-3.00(m,1H),2.98-2.92(m,1H),2.91-2.82(m,1H),2.59-2.53(m,1H),2.46-2.41(m,1H),2.29-2.25(s,1H)；13C NMR(126MHz,CDCl3)δ178.98,155.17,150.65,141.83,134.32,129.85,127.44,125.31,124.57,122.32,118.65,110.46,110.05,61.34,53.74,52.39,47.32,45.18,31.61；HRMS-ESI calcd.for[M+H]+453.1436,found 453.1439。
methyl(8aR)-3a-((S)-3-(2-azidoethyl)-5-bromo-6-methyl-2-oxoindolin-3-yl)-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (20)
White solid, yield 81% and ee 80%.1H NMR(500MHz,Acetone-d6):δ9.63(s,1H),7.23(d,J＝32.9Hz,1H),7.12(q,J＝8.1Hz,1H),6.75(dd,J＝13.9,7.9Hz,1H),6.47(dd,J＝38.3,8.0Hz,1H),6.15(d,J＝27.0Hz,1H),5.46(s,1H),5.09(s,1H),3.67(dt,J＝17.8,9.3Hz,1H),3.60(s,1H),3.58(s,2H),3.37-3.15(m,1H),3.00-2.79(m,4H),2.49(tt,J＝11.0,4.5Hz,2H),2.30(s,3H)；13C NMR(126MHz,Acetone-d6)δ177.82,151.28,141.63,137.52,129.39,128.53,128.24,124.64,117.77,117.73,116.21,111.63,109.22,108.95,77.67,76.90,62.52,61.37,54.04,53.92,51.61,51.53,47.36,45.11,44.92,31.46,22.41；HRMS-ESI calcd.for[M+H]+433.1983,found 433.1988。
methyl(8aR)-3a-((S)-3-(2-azidoethyl)-2-oxoindolin-3-yl)-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1(2H)-carboxylate (23)
White solid, yield 85%, ee value 97%.1H NMR(500MHz,CDCl3):δ8.29(s,1H),7.25-6.98(m,3H),6.84(t,J＝8.2Hz,1.6H),6.75(m,1.5H),6.45(d,J＝7.9Hz,1H),6.05(s,1H),5.15(s,1H),4.82(s,1H),3.69(s,1H),3.68-3.63(m,1H),3.62(s,2H),3.29-3.22(m,1H),3.02-2.90(m,2H),2.87-2.75(m,1H),2.53-2.47(m,1H),2.44-2.37(m,1H),2.24-2.19(m,1H)；13C NMR(126MHz,CDCl3)δ178.78,155.17,140.89,129.65,128.76,124.69,124.50,122.41,122.34,118.59,109.95,109.76,77.74,76.81,61.43,53.97,52.59,52.33,47.46,45.22,45.13,31.62；HRMS-ESI calcd.for[M+H]+419.1826,found 419.1831。
(3S)-3-(2-azidoethyl)-3-((8aR)-1-((4-nitrophenyl)sulfonyl)-2,3,8,8a-tetrahydropyrrolo[2,3-b]indol-3a(1H)-yl)indolin-2-one (28)
White solid, 91% yield, ee 93%.1HNMR(500MHz,CDCl3):δ8.36(d,J＝8.3Hz,2H),8.13(s,1H),8.05(d,J＝8.3Hz,2H),7.27(t,J＝7.7Hz,1H),7.13(d,J＝7.7Hz,1H),6.89(d,J＝7.4Hz,2.38H),6.77(s,1.43H),6.47(d,J＝7.6Hz,1H),6.28(m,1H),5.51(s,1H),4.54(s,1H),3.64(t,J＝8.8Hz,1H),3.13(s,1H),3.06-2.78(m,3H),2.53-2.31(m,2H),2.25(m,1H)；13C NMR(126MHz,CDCl3)δ178.45,149.98,145.36,140.68,129.98,129.09,128.57,127.62,124.36,124.21,122.65,119.81,110.76,110.10,80.06,63.22,54.22,47.32,46.85,31.43；HRMS-ESI calcd.for[M+H]+546.1554,found 546.1554。
The crystal structure of compound 28 is as follows.
Figure BDA0002739213930000131
The present invention has been further described with reference to the examples, but the present invention is not limited to the above-described embodiments, and various changes can be made without departing from the spirit of the present invention within the knowledge of those skilled in the art.

Claims (10)

1. The method for preparing the dimeric tryptamine compound is characterized in that the compound A and the compound B are subjected to asymmetric dearomatization reaction under the action of a chiral catalyst to construct a continuous chiral quaternary carbon C3a-C3 a' bond of the dimeric tryptamine compound C, and the preparation route is as follows:
Figure FDA0002739213920000011
wherein, the substituent R1、R3Represents hydrogen, alkyl, alkoxy, halogen; r2Represents hydrogen, alkyl, benzyl, allyl, isopentenyl; r4Represents alkyl, azide, methyl aminocarbonate, tert-butyl aminocarbonate, allyl aminocarbonate, phthalimide, o-nitrobenzenesulfonamide; r5Representing carbonate and sulfonyl protecting groups.
2. The method for preparing the dimeric tryptamine compound according to claim 1, wherein the chiral catalyst is obtained by a complexation reaction of a metal salt of Ni or Sc and a chiral ligand in an ester solvent;
the chiral ligand is a compound L1-L10
Figure FDA0002739213920000012
Any one of them.
3. The method of claim 2, wherein the metal salt is NiCl2、NiBr2、NiI2、Ni(OAc)2、Ni(acac)2、Ni(BF4)2·6H2O、Ni(ClO4)2、Ni(OTf)2Or Sc (OTf)3Any one of the above.
4. The method for preparing the dimeric tryptamine compound according to claim 2, wherein the molar ratio of the metal salt to the chiral ligand is (1-1.2): 1.
5. The method for preparing the dimeric tryptamine compound according to claim 2, wherein the molar ratio of the compound a to the chiral catalyst is 10: 1.
6. The method for preparing the dimeric tryptamine compound according to claim 2, wherein the mass-to-volume ratio of the compound a to the ester solvent is 1: 100.
7. The method for preparing dimeric tryptamine compound according to claim 1, wherein the asymmetric dearomatization reaction temperature is 20-30 ℃ and the stirring reaction time is 8-20 h.
8. The method of claim 1, wherein the substituent R is selected from the group consisting of5Selecting any one of methoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, trichloroethoxycarbonyl, methylsulfonyl, p-toluenesulfonyl and o-nitrobenzenesulfonyl.
9. A dimeric tryptamine compound produced by the method of any one of claims 1-7.
10. The dimeric tryptamine compound of claim 9, having the chemical structure of dimeric tryptamine compound C, wherein,
substituent R1Represents hydrogen, methyl, methoxy, halogen;
substituent R2Represents hydrogen, methyl, benzyl, allyl, isopentenyl;
substituent R3Represents hydrogen, methyl, halogen;
substituent R4Represents methyl, azide, methyl aminocarbonate, tert-butyl aminocarbonate, allyl aminocarbonate, phthalimide, o-nitrobenzenesulfonamide;
substituent R5Represents methoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, trichloroethoxycarbonyl, methylsulfonyl, p-toluenesulfonyl or o-nitrobenzenesulfonyl.
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