CN113912524B - Polypeptide compound containing sulfur amide and synthesis method thereof - Google Patents

Polypeptide compound containing sulfur amide and synthesis method thereof Download PDF

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CN113912524B
CN113912524B CN202111254112.6A CN202111254112A CN113912524B CN 113912524 B CN113912524 B CN 113912524B CN 202111254112 A CN202111254112 A CN 202111254112A CN 113912524 B CN113912524 B CN 113912524B
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ester hydrochloride
reaction
methyl ester
sulfur
mmol
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CN113912524A (en
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姜雪峰
廖燕燕
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East China Normal University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/38—Amides of thiocarboxylic acids
    • C07C327/40—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C327/44—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/545—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C325/00—Thioaldehydes; Thioketones; Thioquinones; Oxides thereof
    • C07C325/02—Thioketones; Oxides thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/38—Amides of thiocarboxylic acids
    • C07C327/40—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C327/42—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • C07D313/02—Seven-membered rings
    • C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D313/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D313/12—[b,e]-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala

Abstract

The invention discloses a polypeptide compound containing sulfur amide as shown in formulas 3 and 4 and a synthesis method thereof, wherein amino aldehyde, inorganic sulfur and amino acid are used as reaction raw materials, and a series of polypeptide compounds containing sulfur amide are obtained by reaction in a solvent under the action of a catalyst and an additive. According to the invention, an inorganic sulfur reagent is used as a sulfur source under a catalytic condition, a polypeptide compound containing the sulfur amide is constructed by a one-pot method, and the chirality is maintained, so that the defect of a traditional phosphorus sulfur reagent represented by Lawson reagent is avoided; the dipeptide, tripeptide, tetrapeptide and peptide-drug coupling compounds can be successfully obtained through the synthetic strategy developed by the invention, and have great potential in the future drug development field.

Description

Polypeptide compound containing sulfur amide and synthesis method thereof
Technical Field
The invention belongs to the technical field of synthesis and application of organic compounds, and relates to a polypeptide compound containing sulfur amide and a synthesis method thereof.
Background
The polypeptide compound containing the amide is a very important compound, and in recent years, it has been found that if the amide bond on the polypeptide is thio, the metabolic stability and the biological activity of the polypeptide can be further improved, so that the development of a method for synthesizing the polypeptide compound containing the amide with high efficiency, environmental protection and step economy is very important.
The preparation method of the polypeptide compound containing the sulfur amide is mainly characterized in that the polypeptide compound is prepared by directly carrying out oxygen-sulfur substitution by a phosphorus-sulfur reagent represented by a Lawson reagent. However, this preparation method uses phosphorus-sulfur reagent, which makes it impossible to selectively select replacement of oxygen-sulfur, and such reagent has bad smell and generates a large amount of phosphorus-oxygen polymer after the reaction is completed. Therefore, the development of a synthetic method of the polypeptide compound containing the sulfur amide, which is environment-friendly and has application potential, has important significance.
Disclosure of Invention
In order to solve the defects existing in the prior art, the invention aims to provide a method for efficiently constructing a polypeptide compound containing sulfur amide by directly using amino aldehyde and amino acid multicomponent under the catalysis condition by utilizing a three-component coupling method. The synthesis method is simple, the raw materials are cheap and easy to obtain, the universality of the substrate is wide, and the yield (33% -92%) is good. The polypeptide compound containing the sulfur amide provided by the invention can be applied to the preparation of dipeptide, tripeptide, tetrapeptide and peptide-drug coupling compounds.
The invention provides a method for synthesizing polypeptide compound containing sulfur amide, which comprises the steps of taking amino aldehyde, inorganic sulfur reagent and amino acid as reaction raw materials in a solvent, reacting under the action of a catalyst and an additive to obtain the polypeptide compound containing sulfur amide, wherein the chirality is maintained; the reaction process is shown in the following reaction formula (I):
wherein,
R 1 hydrogen, alkyl, benzyl and tetrahydropyrrolyl;
r is carbobenzoxy, fluorenylmethoxycarbonyl, allyloxycarbonyl, tert-butyloxycarbonyl, alkyl, etc.;
R 2 hydrogen, alkyl, benzyl, etc.;
R 3 is alkyl or benzyl.
Preferably, the method comprises the steps of,
R 1 hydrogen, methyl, isobutyl, benzyl and tetrahydropyrrolyl;
r is carbobenzoxy, fluorenylmethoxycarbonyl, allyloxycarbonyl, tert-butyloxycarbonyl, alkyl, etc.;
R 2 hydrogen, methyl, isopropyl, isobutyl, benzyl, etc.;
R 3 methyl, benzyl and tert-butyl.
Further preferably, 1' is selected from the group consisting of phenylalaninol, alaninol, prolyl, leucinal, glyceraldehyde, alanyl-glyceraldehyde derivatives, phenylpropan-glyceraldehyde derivatives, glycerol-phenylalaninol derivatives, ibuprofen-glyceraldehyde derivatives, naproxen-glyceraldehyde derivatives and exec acid-glyceraldehyde derivatives;
further preferably, 2' is selected from the group consisting of glycine methyl ester hydrochloride, glycine benzyl ester hydrochloride, glycine t-butyl ester hydrochloride, alanine methyl ester hydrochloride, valine methyl ester hydrochloride, leucine methyl ester hydrochloride, phenylalanine methyl ester hydrochloride, methionine methyl ester hydrochloride, serine methyl ester hydrochloride, tryptophan methyl ester hydrochloride, glutamic acid dimethyl ester hydrochloride, N6-t-butoxycarbonyl lysine methyl ester hydrochloride, glycine valine methyl ester hydrochloride, glycine leucine methyl ester hydrochloride, glycine alanine methyl ester hydrochloride and phenylalanine methyl ester hydrochloride.
In the present invention, 1 'represents formula (1) or formula (1'); 2,2 'represents formula (2), formula (2'); 3 and 4 are represented by the formulas (3) and (4).
In the invention, the temperature of the reaction is 25-100 ℃; preferably 50 ℃.
In the invention, the reaction time is 1-12 hours; preferably 10 hours.
In the invention, the solvent is selected from one or more of acetonitrile, toluene, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, tetrahydrofuran, 1, 4-dioxane, 1, 2-dichloroethane, N-methylpyrrolidone, ethyl acetate, chloroform, ethanol, isopropanol and the like; preferably tetrahydrofuran.
In the invention, the dosage of the solvent is 0.5-5 mL based on the dosage of the amino aldehyde.
In the invention, the inorganic sulfur reagent is a reaction sulfur source and is selected from one or more of elemental sulfur, sodium sulfide nonahydrate, potassium sulfide, sodium hydrosulfide, sodium sulfite, potassium thioacetate and bis (trimethyl silicon sulfide); preferably elemental sulphur.
In the invention, the catalyst is a copper catalyst and is selected from one or more of cuprous iodide, cuprous bromide, cuprous chloride, tetraethyl cyanogen hexafluorophosphate, cupric chloride, cupric bromide, cupric fluoride, cupric acetate, copper bis (acetylacetonate), copper trifluoroacetate, cupric oxide and cupric sulfate; preferably copper chloride.
In the invention, the additive is selected from one or more of potassium carbonate, sodium carbonate, dipotassium bicarbonate, potassium dihydrogen phosphate, sodium bicarbonate, dodecyl mercaptan, p-methyl benzene mercaptan, potassium sulfide, sodium sulfide nonahydrate, tetrabutylammonium chloride, tetrabutylammonium iodide and tetrabutylammonium fluoride; preferably sodium sulfide nonahydrate.
In the invention, the molar ratio of the amino aldehyde to the inorganic sulfur reagent to the amino acid to the catalyst to the additive is 1: (1-5): (1-5): (0.01-0.4): (0.5-5); preferably, it is 1:2:2:0.15:1.2.
in the present invention, the reaction is preferably carried out under air.
In the invention, when amino aldehyde, elemental sulfur and amino acid are used as reaction raw materials, under the action of a catalyst and an additive, a reaction mechanism is shown as a reaction formula (II), firstly, the amino aldehyde and the amino acid are condensed and dehydrated to generate an imine intermediate A, wherein the imine is in coordination complexing with copper to form a five-membered ring intermediate a, and the imine is activated and isomerization (intermediates B and C) is avoided so as to maintain the chirality of a substrate. The elemental sulfur is subjected to ring opening under the action of sodium sulfide to obtain a plurality of nucleophilic sulfur species S, and then imine is added to obtain an intermediate D and an intermediate E for ligand exchange. Next, intermediate F is obtained by the 1,2-H migration process of intermediate D. Finally, cleavage of the S-S bond in intermediate F provides thioamide-containing polypeptide compound 3a.
Wherein the radicals PG mentioned in the formula (II) have the same meaning as R in the formula (I).
In one particular embodiment: the reaction process is shown in the following reaction formula (I').
Wherein R is 1 、R 2 、R 3 And R is as defined for formula (I), i.e. R 1 Hydrogen, alkyl, benzyl and tetrahydropyrrolyl; r is carbobenzoxy, fluorenylmethoxycarbonyl, allyloxycarbonyl, tert-butyloxycarbonyl, alkyl, etc.; r is R 2 Hydrogen, alkyl, benzyl, etc.; r is R 3 Is alkyl or benzyl.
The invention also provides the polypeptide compound containing the thioamide, which is obtained by the synthesis method.
The invention also provides a polypeptide compound containing thioamide as shown in the formula (3, 4),
wherein R is 1 、R 2 、R 3 And R is as defined for formula (I), i.e. R 1 Hydrogen, alkyl, benzyl and tetrahydropyrrolyl; r is carbobenzoxy, fluorenylmethoxycarbonyl, allyloxycarbonyl, tert-butyloxycarbonyl, alkyl, etc.; r is R 2 Hydrogen, alkyl, benzyl, etc.; r is R 3 Is alkyl or benzyl.
Preferably, R 1 Is hydrogen, methyl, isobutyl, benzyl, tetrahydropyrrole; r is carbobenzoxy, fluorenylmethoxycarbonyl, allyloxycarbonyl, tert-butyloxycarbonyl, alkyl; r is R 2 Is hydrogen, methyl, isopropyl, isobutyl, benzyl; r is R 3 Methyl, benzyl, tert-butyl.
Further preferably, the compounds of formula 3,4 are:
the derivatives of phenylpropyl-glycine, of propylglycine, of leu-glycine, of prolyl-glycine, of glycine-alanine, of glycine-valine, of glycine-leucine, of glycine-phenylalanine, of glycine-methionine, of serine, of tyrosine, of tryptophan, of glutamic acid, of glycine-lysine, of glycine-alanine, of propylglycine-leucine, of propylglycine-methionine, of phenylpropyl-glycine, of glycine-leucine, of phenylpropyl-glycine, of glycine-valine, of phenylpropyl-glycine-leucine, of glycine-phenylalanine, of ibuprofen-glycine-alanine, of ibuprofen-glycine-leucine, of naproxen-glycine-alanine, of epothilone-alanine, of glycine-alanine, of epoxic acid-glycine-methionine.
The invention also provides application of the polypeptide compound containing the thioamide shown in the formulas (3, 4) in preparation of dipeptide, tripeptide, tetrapeptide and peptide-drug coupling compounds.
The beneficial effects of the invention include: the invention innovatively provides a synthesis method, which adopts amino aldehyde, inorganic sulfur reagent and amino acid as reaction raw materials, and under the action of a catalyst and an additive, the polypeptide containing thioamide is constructed by a one-pot method, so that the defect of synthesizing the polypeptide containing thioamide by the traditional phosphorus sulfur reagent is overcome. Preferably, the invention innovatively provides a method for constructing the polypeptide compound containing the thioamide in a multi-component and efficient way by using an inorganic sulfur reagent through one-pot method under the catalysis of metallic copper. The synthesis method is simple, the raw materials are cheap and easy to obtain, the universality of the substrate is wide, and the yield (33% -92%) is good. The dipeptide, tripeptide, tetrapeptide and peptide-drug coupling compounds can be successfully obtained through the synthetic strategy developed by the invention, and the method has great potential in the future drug development field.
Detailed Description
The present invention will be further described in detail with reference to the following specific examples. The procedures, conditions, experimental methods, etc. for carrying out the present invention are common knowledge and common knowledge in the art, except for the following specific references, and the present invention is not particularly limited.
In examples 1 to 59 of the present invention, the reaction temperature was 50 ℃.
Example 1
Synthesis of compound 3 a:
preparation of Compound 3a amino aldehyde 1a (28.3 mg,0.1 mmol), S was added to a reaction tube under an air atmosphere 8 (6.4mg,0.2mmol)，CuCl 2 (2.0mg,0.015mmol)，Na 2 S.9H 2 O (28.8 mg,0.12 mmol), glycine methyl ester hydrochloride (25.0 mg,0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50℃for 10 hours. After the reaction, the extract was concentrated, and purified by column chromatography (V PE /V EA 33.2mg of 3a (PE/ea=2:1, r) isolated as a colourless oil (2/1) f =0.5), yield was 86%. 1 H NMR(400MHz,CDCl 3 )δ8.44(s,1H),7.24-7.05(m,10H),5.79(d,J＝8.3Hz,1H),4.92(d,J＝7.2Hz,2H),4.78(d,J＝7.0Hz,1H),4.18-4.02(m,2H),3.59(s,3H),3.11-2.87(m,2H). 13 C NMR(101MHz,CDCl 3 )δ204.2,168.6,155.9,136.4,136.2,129.3,128.6,128.6,128.2,127.9,127.0,67.1,62.1,52.6,46.8,42.2.IR(neat)3278,2971,1741,1699,1506,1265,1213,698cm -1 .HRMS(EI)m/z:Calcd for C 20 H 22 N 2 O 4 S386.1300,Found 386.1297.ee value 92%, HPLC detection parameter (Daicel Chirapak AD, n-hexane/isopropanol=70/30, flow rate=1.0 mL/min, column oven temperature 30 ℃, wavelength 254 nm) tr= 13.997min (primary), tr= 8.703min (secondary).
Example 2
Synthesis of compound 3 b:
preparation of Compound 3b amino aldehyde 1b (24.9 mg,0.1 mmol), S was added to a reaction tube under an air atmosphere 8 (6.4mg,0.2mmol)，CuCl 2 (2.0mg,0.015mmol)，Na 2 S·9H 2 O (28.8 mg,0.12 mmol), glycine methyl ester hydrochloride (25.0 mg,0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50℃for 10 hours. After the reaction, the extract was concentrated, and purified by column chromatography (V PE /V EA 29.2mg of 3b (PE/EA=5:1, R) isolated as a colourless oil (5/1) f =0.5), yield was 83%. 1 H NMR(400MHz,CDCl 3 )δ8.22(s,1H),7.23-7.10(m,5H),5.30(s,1H),4.59-4.64(q,J＝14.2,7.0Hz,1H),4.13-4.26(m,3.8Hz,2H),3.66(s,3H),3.17-2.94(m,2H),1.31(s,9H). 13 C NMR(101MHz,CDCl 3 )δ204.1,168.6,155.3,136.6,129.2,128.6,127.0,80.5,62.4,52.5,46.7,42.0,28.2.IR(neat)3271,2978,2360,1747,1685,1496,1365,1211,727cm - 1 .HRMS(ESI)m/z:[M+Na] + Calcd for C 17 H 24 N 2 O 4 NaS 375.1349,Found 375.1346.ee value 85%, HPLC detection parameters (Daicel Chirapak AD, n-hexane/isopropanol=85/15, flow rate=1.0 mL/min, column oven temperature 30 ℃, wavelength 254 nm) tr= 7.890min (primary), tr= 7.107min (secondary).
Example 3
Synthesis of Compound 3 c:
preparation of Compound 3c amino aldehyde 1c (23.3 mg,0.1 mmol), S was added to a reaction tube under an air atmosphere 8 (6.4mg,0.2mmol)，CuCl 2 (2.0mg,0.015mmol)，Na 2 S·9H 2 O (28.8 mg,0.12 mmol), glycine methyl ester hydrochloride (25.0 mg,0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50℃for 10 hours. After the reaction, the extract was concentrated, and purified by column chromatography (V PE /V EA 28.2mg of 3c (PE/EA=5:1, R) was isolated as a colourless oil (5/1) f =0.5), yield was 84%. 1 H NMR(400MHz,CDCl 3 )δ8.20(s,1H),7.34-7.04(m,5H),5.81-5.64(m,2H),5.14(dd,J＝25.5,13.8Hz,2H),4.70(q,J＝14.6,7.2Hz,1H),4.43(d,J＝4.6Hz,2H),4.18(q,J＝41.7,18.7Hz,2H),3.65(s,3H),3.06(d,J＝5.0Hz,2H). 13 C NMR(101MHz,CDCl 3 )δ203.8,168.6,155.7,136.4,132.4,129.2,128.6,127.8,117.8,66.0,62.4,52.6,46.8,42.1.IR(neat)3277,2953,1743,1697,1508,1211,1180,749cm -1 .HRMS(ESI)m/z:[M+H] + Calcd for C 16 H 21 N 2 O 4 S337.1217,Found 337.1208.ee value is 83%. HPLC detection parameters (Daicel Chirapak AD, n-hexane/isopropanol=85/15, flow rate=1.0 mL/min, column oven temperature 30 ℃, wavelength 254 nm) tr= 12.737min (primary), tr= 10.183min (secondary).
Example 4
Synthesis of Compound 3 d:
preparation of Compound 3d amino aldehyde 1d (37.1 mg,0.1 mmol), S was added to a reaction tube under an air atmosphere 8 (6.4mg,0.2mmol)，CuCl 2 (2.0mg,0.015mmol)，Na 2 S·9H 2 O (28.8 mg,0.12 mmol), glycine methyl ester hydrochloride (25.0 mg,0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50℃for 10 hours. After the reaction, the extract was concentrated, and purified by column chromatography (V PE /V EA =3/1) 38.3mg of 3d (PE/ea=5:1, r) isolated as colourless oil f =0.3), yield was 81%. 1 H NMR(400MHz,CDCl 3 )δ8.08(s,1H),7.67(d,J＝7.5Hz,2H),7.44(t,J＝8.3Hz,2H),7.31(t,J＝7.3Hz,2H),7.10-7.23(m,J＝23.3,14.0,7.0Hz,7H),5.67(s,1H),4.69(s,1H),4.07-4.31(m,5H),3.60(d,J＝7.3Hz,3H),3.07(d,J＝4.6Hz,2H). 13 C NMR(101MHz,CDCl 3 )δ203.6,168.5,155.8,143.8,143.7,141.3,136.3,129.2,128.7,127.8,127.2,127.1,125.1,120.0,67.3,62.4,52.6,47.1,46.8,42.1.IR(neat)3277,2949,2360,1739,1697,1517,1446,1215,700cm -1 .HRMS(ESI)m/z:[M+H] + Calcd for C 27 H 27 N 2 O 4 S475.1686,Found 475.1680.ee value is 82%HPLC detection parameters (Daicel Chirapak ID, n-hexane/isopropanol=70/30, flow rate=1.0 mL/min, column oven temperature 30 ℃, wavelength 254 nm) tr= 11.607min (primary), tr= 8.890min (secondary).
Example 5
Synthesis of compound 3 e:
preparation of Compound 3e amino aldehyde 1a (28.3 mg,0.1 mmol), S was added to a reaction tube under an air atmosphere 8 (6.4mg,0.2mmol)，CuCl 2 (2.0mg,0.015mmol)，Na 2 S·9H 2 O (28.8 mg,0.12 mmol), benzyl glycinate hydrochloride (40.2 mg,0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50℃for 10 hours. After the reaction, the extract was concentrated, and purified by column chromatography (V PE /V EA 31.4mg of 3e (PE/ea=3:1, r) isolated as a colourless oil (3/ea=3:1) f =0.5), yield was 68%. 1 H NMR(400MHz,CDCl 3 ) 1 H NMR(400MHz,CDCl 3 )δ8.16(s,1H),7.40-6.98(m,16H),5.65(d,J＝6.7Hz,1H),5.08-4.85(m,4H),4.76-4.63(m,1H),4.26-3.98(m,2H),3.03(s,2H). 13 C NMR(101MHz,CDCl 3 )δ203.7,168.0,155.8,136.4,136.1,134.9,129.2,129.2,128.7,128.5,128.4,128.2,127.9,127.8,127.1,67.5,67.1,62.5,47.0,42.2.IR(neat)3277,2360,1739,1697,1508,1259,1190,751cm -1 .HRMS(ESI)m/z:[M+H] + Calcd for C 26 H 27 N 2 O 4 S463.1686,Found 463.1677.ee value is 78%. HPLC detection parameters (Daicel Chirapak AD, n-hexane/isopropanol=70/30, flow rate=1.0 mL/min, column oven temperature 30 ℃, wavelength 254 nm) tr= 14.343min (primary), tr= 11.760min (secondary).
Example 6
Synthesis of compound 3 f:
compounds of formula (I)3f preparation by adding aminoaldehyde 1a (28.3 mg,0.1 mmol), S to a reaction tube under an air atmosphere 8 (6.4mg,0.2mmol)，CuCl 2 (2.0mg,0.015mmol)，Na 2 S·9H 2 O (28.8 mg,0.12 mmol), glycine tert-butyl ester hydrochloride (33.2 mg,0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50℃for 10 hours. After the reaction, the extract was concentrated, and purified by column chromatography (V PE /V EA =5/1) 35.5mg of 3f (PE/ea=5:1, r) was isolated as a colourless oil f =0.5), yield was 83%. 1 H NMR(400MHz,CDCl 3 )δ8.01(d,J＝33.3Hz,1H),7.27-7.08(m,10H),5.66(s,1H),5.03-4.92(m,2H),4.67(d,J＝7.3Hz,1H),4.01(m,J＝19.1,4.3Hz,2H),3.06(d,J＝6.2Hz,2H),1.36(s,9H). 13 C NMR(101MHz,CDCl 3 )δ202.8,167.2,155.7,136.5,136.2,129.2,129.1,128.7,128.6,128.5,128.1,127.9,127.9,127.1,127.0,83.0,67.1,62.6,47.7,42.2,28.0.IR(neat)3271,2360,1739,1695,1521,1274,1157,763cm -1 .HRMS(ESI)m/z:[M+Na] + Calcd for C 23 H 28 N 2 O 4 NaS 451.1662,Found 451.1652.ee value 59% HPLC detection parameter (Daicel Chirapak AD, n-hexane/isopropanol=70/30, flow rate=1.0 mL/min, column oven temperature 30 ℃, wavelength 254 nm) tr= 11.397min (primary), tr= 10.430min (secondary).
Example 7
Synthesis of Compound 3 g:
preparation of Compound 3g in an air atmosphere, 1g (20.7 mg,0.1 mmol) of aminoaldehyde, S 8 (6.4mg,0.2mmol)，CuCl 2 (2.0mg,0.015mmol)，Na 2 S·9H 2 O (28.8 mg,0.12 mmol), glycine methyl ester hydrochloride (25.0 mg,0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50℃for 10 hours. After the reaction is finished, extractingConcentrating, and subjecting to column chromatography (V PE /V EA =3/1) to give 27.6mg of 3g (PE/ea=2:1, r) as colourless oil f =0.5), the yield was 89%. 1 H NMR(400MHz,CDCl 3 )δ8.87(s,1H),7.32(s,5H),5.88(d,J＝6.4Hz,1H),5.20-5.00(m,2H),4.82-4.58(m,1H),4.15-4.48(m,2H),3.75(s,3H),1.47(d,J＝6.8Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ206.2,169.0,155.9,136.1,128.6,128.2,127.9,67.1,56.3,52.7,46.8,22.3.IR(neat)3241,2961,1739,1697,1514,1213,1047,696cm -1 .HRMS(EI)m/z:Calcd for C 14 H 18 N 2 O 4 S310.0987,Found 310.0993.ee is 91%, HPLC detection parameters (Daicel Chirapak ID, n-hexane/isopropanol=85/15, flow rate=1.0 mL/min, column oven temperature 30 ℃, wavelength 254 nm) tr= 17.737min (primary), tr= 25.600min (secondary).
Example 8
Synthesis of Compound 3 h:
preparation of Compound 3h by adding aminoaldehyde (24.9 mg,0.1 mmol) S to a reaction tube under an air atmosphere 8 (6.4mg,0.2mmol)，CuCl 2 (2.0mg,0.015mmol)，Na 2 S·9H 2 O (28.8 mg,0.12 mmol), glycine methyl ester hydrochloride (25.0 mg,0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50℃for 10 hours. After the reaction, the extract was concentrated, and purified by column chromatography (V PE /V EA 27.6mg of isolated 3h (PE/ea=2:1, r) as colourless oil are isolated =3/1 f =0.5), yield was 87%. 1 H NMR(400MHz,CDCl 3 )δ8.88(s,1H),7.24(s,5H),5.59(d,J＝6.1Hz,1H),5.01(q,J＝12.4Hz,2H),4.58(d,J＝6.4Hz,1H),4.33(d,J＝5.0Hz,1H),4.20–4.06(m,1H),3.67(s,3H),1.60(s,3H),0.85(t,J＝5.0Hz,6H). 13 C NMR(101MHz,CDCl 3 )δ206.6,168.9,156.3,136.1,128.6,128.2,127.9,67.1,59.3,52.6,46.7,45.0,24.8,22.9,22.1.IR(neat)3277,2955,1743,1697,1512,1452,1241,696cm -1 .HRMS(EI)m/z:Calcd for C 17 H 24 N 2 O 4 S352.1457,Found 352.1451.ee value 94% HPLC detection parameter (Daicel Chirapak ID, n-hexane/isopropanol=85/15, flow rate=1.0 mL/min, column oven temperature 30 ℃, wavelength 254 nm) tr= 14.113min (primary), tr= 11.100min (secondary).
Example 9
Synthesis of compound 3 i:
preparation of Compound 3i amino aldehyde 1i (23.3 mg,0.1 mmol), S was added to a reaction tube under an air atmosphere 8 (6.4mg,0.2mmol)，CuCl 2 (2.0mg,0.015mmol)，Na 2 S·9H 2 O (28.8 mg,0.12 mmol), glycine methyl ester hydrochloride (25.0 mg,0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50℃for 10 hours. After the reaction, the extract was concentrated, and purified by column chromatography (V PE /V EA =2/1) to give 30.1mg of 3i (PE/ea=2:1, r) as colourless oil f =0.5), yield 92%. 1 H NMR(400MHz,CDCl 3 ～50:50mixture of rotamers A and B)δ8.80(s,0.5H),8.26(s,0.5H),7.37-7.11(m,5H),5.16-4.91(m,2H),4.72(s,1H),4.36-4.30(dd,J＝18.2,5.0Hz,1.5H),4.07(d,J＝17.3Hz,0.5H),3.66(s,3H),3.59–3.37(m,2H),2.23(d,J＝63.8Hz,2H),1.84(dd,J＝34.4,29.3Hz,2H). 13 C NMR(101MHz,CDCl 3 )δ204.5,168.9,156.2,155.2,136.3,128.5,128.1,127.8,68.5,67.3,52.6,48.0,47.6,46.9,46.4,34.7,32.7,24.1,23.4.IR(neat)3273,2953,1747,1690,1523,1408,1350,734cm -1 .HRMS(EI)m/z:Calcd for C 16 H 20 N 2 O 4 S336.1144,Found 336.1138.ee value is 96%. HPLC detection parameters (Daicel Chirapak ID, n-hexane/isopropanol=70/30, flow rate=1.0 mL/min, column oven temperature 30 ℃, wavelength 254 nm) tr= 14.387min (primary), tr= 9.560min (secondary).
Example 10
Synthesis of compound 3 j:
preparation of Compound 3j by adding aminoaldehyde 1j 19.3mg,0.1mmol) S to a reaction tube under an air atmosphere 8 (6.4mg,0.2mmol)，CuCl 2 (2.0mg,0.015mmol)，Na 2 S·9H 2 O (28.8 mg,0.12 mmol), alanine methyl ester hydrochloride (27.8 mg,0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50℃for 10 hours. After the reaction, the extract was concentrated, and purified by column chromatography (V PE /V EA 26.7mg of 3j (PE/EA=3:1, R) isolated as a colourless oil f =0.5), yield was 86%. 1 H NMR(400MHz,CDCl 3 )δ8.54(s,1H),7.28(s,5H),5.66(s,1H),5.20–4.88(m,3H),4.25–4.03(m,2H),3.69(s,3H),1.42(d,J＝6.0Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ199.3,172.4,156.8,136.0,128.6,128.3,128.1,67.5,53.3,52.8,52.1,16.9.IR(neat)3238,2953,1703,1523,1452,1417,1220,701cm -1 .HRMS(EI)m/z:Calcd for C 14 H 18 N 2 O 4 S310.0987,Found 310.0989.ee value is>99%. HPLC detection parameters (Daicel Chirapak ID, n-hexane/isopropanol=85/15, flow rate=1.0 mL/min, column oven temperature 30 ℃, wavelength 254 nm) tR= 21.283min (primary), tR= 31.990min (secondary).
Example 11
Synthesis of compound 3 k:
preparation of Compound 3k by adding aminoaldehyde 1j 19.3mg,0.1mmol) S to a reaction tube under an air atmosphere 8 (6.4mg,0.2mmol)，CuCl 2 (2.0mg,0.015mmol)，Na 2 S·9H 2 O (28.8 mg,0.12 mmol), valine methyl ester hydrochloride (33.4 mg,0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50℃for 10 hours. After the reaction, the extract was concentrated, and purified by column chromatography (V PE /V EA =3/1) 25.3mg of 3k (PE/ea=3:1, r) isolated as colourless oil f =0.5), yield was 75%. 1 H NMR(400MHz,CDCl 3 )δ8.54(s,1H),7.28(s,5H),5.66(s,1H),5.20–4.88(m,3H),4.25–4.03(m,2H),3.69(s,3H),1.42(d,J＝6.0Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ199.3,172.4,156.8,136.0,128.6,128.3,128.1,67.5,53.3,52.8,52.1,16.9.IR(neat)3238,2953,1703,1523,1452,1417,1220,701cm -1 .HRMS(EI)m/z:Calcd for C 14 H 18 N 2 O 4 S310.0987,Found 310.0989.ee value is>99%. HPLC detection parameters (Daicel Chirapak ID, n-hexane/isopropanol=85/15, flow rate=1.0 mL/min, column oven temperature 30 ℃, wavelength 254 nm) tR= 13.703min (primary), tR= 20.480min (secondary).
Example 12
Synthesis of Compound 3 l:
preparation of Compound 3l amino aldehyde 1j 19.3mg,0.1mmol) S was added to a reaction tube under an air atmosphere 8 (6.4mg,0.2mmol)，CuCl 2 (2.0mg,0.015mmol)，Na 2 S·9H 2 O (28.8 mg,0.12 mmol), leucine methyl ester hydrochloride (36.2 mg,0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50℃for 10 hours. After the reaction, the extract was concentrated, and purified by column chromatography (V PE /V EA 21.8mg of 3l (PE/EA=3:1, R) are isolated as colourless oil (3/1) f =0.5), yield was 62%. 1 H NMR(400MHz,CDCl 3 )δ8.39(s,1H),7.28(dd,J＝7.4,2.7Hz,6H),5.59(s,1H),5.07(s,3H),4.24-4.11(m,2H),3.67(s,3H),1.76–1.48(m,3H),0.86(t,J＝7.0Hz,6H). 13 C NMR(101MHz,CDCl 3 )δ199.9,172.1,157.0,135.9,128.6,128.4,128.2,67.5,56.4,52.6,52.2,40.5,25.0,22.6,22.3.IR(neat)3259,2954,1703,1527,1238,1172,1041,736cm -1 .HRMS(EI)m/z:Calcd for C 17 H 24 N 2 O 4 S352.1457,Found 352.1461.ee value is>99%. HPLC detection parameters (Daicel Chirapak ID, n-hexane/isopropanol=85/15, flow rate=1.0 mL/min, column oven temperature 30 ℃, wavelength 254 nm) tR= 10.463min (primary), tR= 14.463min (secondary).
Example 13
Synthesis of Compound 3 m:
preparation of Compound 3m by adding aminoaldehyde 1j 19.3mg,0.1mmol) S to a reaction tube under an air atmosphere 8 (6.4mg,0.2mmol)，CuCl 2 (2.0mg,0.015mmol)，Na 2 S·9H 2 O (28.8 mg,0.12 mmol), phenylalanine methyl ester hydrochloride (43.1 mg,0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50℃for 10 hours. After the reaction, the extract was concentrated, and purified by column chromatography (V PE /V EA 22.8mg of 3m (PE/EA=3:1, R) isolated as a colourless oil (3/1) f =0.5), yield was 59%. 1 H NMR(400MHz,CDCl 3 )δ8.38(s,1H),7.27(d,J＝11.1Hz,5H),7.16(d,J＝7.7Hz,3H),6.99(d,J＝6.1Hz,2H),5.56(s,1H),5.30(dd,J＝12.8,5.8Hz,1H),5.02(s,2H),4.20-4.04(m,2H),3.64(s,3H),3.32–3.22(m,1H),3.10(dd,J＝13.9,5.2Hz,1H). 13 C NMR(101MHz,CDCl 3 )δ199.5,170.9,156.8,135.9,135.3,129.3,128.7,128.6,128.4,128.2,127.4,67.4,58.3,52.6,52.1,36.3.IR(neat)3298,2951,1705,1496,1215,1176,1028,705cm - 1 .HRMS(EI)m/z:Calcd for C 20 H 22 N 2 O 4 S386.1300,Found 386.1305.ee value is>99%. HPLC detection parameters (Daicel Chirapak ID, n-hexane/isopropanol=85/15, flow rate=1.0 mL/min, column oven temperature 30 ℃, wavelength 254 nm) tR= 13.340min (primary), tR= 11.830min (secondary).
Example 14
Synthesis of compound 3 n:
preparation of Compound 3n by adding aminoaldehyde 1j 19.3mg,0.1mmol) S to a reaction tube under an air atmosphere 8 (6.4mg,0.2mmol)，CuCl 2 (2.0mg,0.015mmol)，Na 2 S·9H 2 O (28.8 mg,0.12 mmol), methionine methyl ester hydrochloride (32.8 mg,0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50℃for 10 hours. After the reaction, the extract was concentrated, and purified by column chromatography (V PE /V EA =3/1) to give 27.0mg of 3n (PE/ea=3:1, r) as colourless oil f =0.5), the yield was 73%. 1 H NMR(400MHz,CDCl 3 )δ8.79(s,1H),7.28(s,5H),5.71(s,1H),5.18(d,J＝6.4Hz,1H),5.06(s,2H),4.25-4.12(m,2H),3.69(s,3H),2.42(d,J＝6.6Hz,2H),2.30–2.17(m,1H),2.13–2.02(m,1H),1.98(s,3H). 13 C NMR(101MHz,CDCl 3 )δ199.9,171.3,156.9,135.9,128.6,128.4,128.1,67.5,56.9,52.8,52.1,30.5,29.8,15.5.IR(neat)3305,2916,1703,1517,1435,1211,1174,703cm -1 .HRMS(EI)m/z:Calcd for C 16 H 22 N 2 O 4 S 2 370.1021,Found 370.1023.ee value is>99%. HPLC detection parameters (Daicel Chirapak ID, n-hexane/isopropanol=85/15, flow rate=1.0 mL/min, column oven temperature 30 ℃, wavelength 254 nm) tR= 13.930min (primary), tR= 12.077min (secondary).
Example 15
Synthesis of Compound 3 o:
preparation of Compound 3o by adding aminoaldehyde 1j 19.3mg,0.1mmol) S to a reaction tube under an air atmosphere 8 (6.4mg,0.2mmol)，CuCl 2 (2.0mg,0.015mmol)，Na 2 S·9H 2 O (28.8 mg,0.12 mmol), serine methyl ester hydrochloride (31.0 mg,0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50℃for 10 hours. After the reaction, the extract was concentrated, and purified by column chromatography (V PE /V EA 24.1mg of 3o (PE/ea=3:1, r) isolated as a colourless oil (3/ea=3:1) f =0.5), yield was 74%. 1 H NMR(400MHz,CDCl 3 )δ8.80(s,1H),7.26(s,5H),5.85(s,1H),5.18–5.13(m,1H),5.04(s,2H),4.16(d,J＝5.8Hz,2H),4.06–3.91(m,2H),3.70(s,3H),3.25(s,1H). 13 C NMR(101MHz,CDCl 3 )δ200.2,170.2,157.1,135.9,128.6,128.4,128.1,67.5,61.5,59.7,53.0,51.7.IR(neat)3338,2953,1701,1517,1223,1168,1043,696cm -1 .HRMS(EI)m/z:Calcd for C 14 H 18 N 2 O 5 S326.0936,Found 326.0931.ee value is>99%. HPLC detection parameters (Daicel Chirapak AD, n-hexane/isopropanol=80/20, flow rate=1.0 mL/min, column oven temperature 30 ℃, wavelength 254 nm) tR= 14.540min (primary), tR= 11.637min (secondary).
Example 16
Synthesis of compound 3 p:
preparation of Compound 3p by adding aminoaldehyde 1j 19.3mg,0.1mmol) S to a reaction tube under an air atmosphere 8 (6.4mg,0.2mmol)，CuCl 2 (2.0mg,0.015mmol)，Na 2 S·9H 2 O (28.8 mg,0.12 mmol), tyrosine methyl ester hydrochloride (46.2 mg,0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50℃for 10 hours. After the reaction, the extract was concentrated, and purified by column chromatography (V PE /V EA 22.9mg of 3p (PE/EA=1:1, R) isolated as a colourless oil (1/1) f =0.5), yield 57%. 1 H NMR(400MHz,CDCl 3 )δ8.33(s,1H),7.26(s,5H),6.79(s,2H),6.59(d,J＝7.9Hz,2H),5.64(s,1H),5.25(d,J＝4.9Hz,1H),5.03(s,2H),4.21-3.97(m,2H),3.66(d,J＝12.7Hz,3H),3.17(s,1H),3.02(dd,J＝13.9,4.5Hz,1H). 13 C NMR(101MHz,CDCl 3 )δ199.4,171.2,156.9,155.3,135.9,130.4,128.6,128.4,128.2,126.7,115.7,67.6,58.4,52.7,51.9,35.4.IR(neat)3327,2953,2360,1699,1519,1436,1225,1172,741cm -1 .HRMS(ESI)m/z:[M+H] + Calcd for C 20 H 23 N 2 O 5 S403.1322,Found 403.13141.ee value is>99%. The detection parameters of HPLC (Daicel Chirapak ID, n-hexane/isopropanol=70/30, flow rate=1.0 mL/min, column oven temperature 30 ℃, wavelength 254 nm) tr= 10.030min (primary), tr=17.653 min (secondary).
Example 17
Synthesis of compound 3 q:
preparation of Compound 3q by adding aminoaldehyde 1j 19.3mg,0.1mmol) S to a reaction tube under an air atmosphere 8 (6.4mg,0.2mmol)，CuCl 2 (2.0mg,0.015mmol)，Na 2 S·9H 2 O (28.8 mg,0.12 mmol), tryptophan methyl ester hydrochloride (20.8 mg,0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50℃for 10 hours. After the reaction, the extract was concentrated, and purified by column chromatography (V PE /V EA 31.9mg of 3q (PE/ea=3:1, r) isolated as a colourless oil (3/1) f =0.5), yield was 75%. 1 H NMR(400MHz,CDCl 3 )δ8.30(s,1H),7.91(d,J＝45.9Hz,1H),7.37(d,J＝7.8Hz,1H),7.23(dd,J＝35.4,14.8Hz,1H),7.06(dd,J＝11.1,3.9Hz,1H),6.99(t,J＝7.4Hz,1H),6.76(s,1H),5.35(d,J＝28.4Hz,1H),4.96(dd,J＝29.3,11.7Hz,1H),4.12–3.97(m,1H),3.59(s,1H),3.42(t,J＝10.3Hz,1H),3.29(dd,J＝14.9,4.7Hz,1H). 13 C NMR(101MHz,CDCl 3 )δ199.3,171.2,156.6,136.1,128.6,128.3,128.1,127.4,123.2,122.3,119.7,118.3,111.4,109.0,67.3,57.9,52.6,52.0,26.1.IR(neat)3291,2981,1716,1521,1230,1176,1085,696cm -1 .HRMS(EI)m/z:Calcd for C 22 H 23 N 3 O 4 S425.1409,Found 425.1412 ee value is>99%. HPLC detection parameters (Daicel Chirapak ID, n-hexane/isopropanol=70/30, flow rate=1.0 mL/min, column oven temperature 30 ℃, wavelength 254 nm) tR= 15.163min (primary), tR= 31.783min (secondary).
Example 18
Synthesis of compound 3 r:
preparation of Compound 3r by adding aminoaldehyde 1j 19.3mg,0.1mmol) S to a reaction tube under an air atmosphere 8 (6.4mg,0.2mmol)，CuCl 2 (2.0mg,0.015mmol)，Na 2 S·9H 2 O(28.8mg,0.12 mmol), dimethyl glutamate hydrochloride (42.2 mg,0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50℃for 10 hours. After the reaction, the extract was concentrated, and purified by column chromatography (V PE /V EA =3/1) to give 30.2mg of 3r (PE/ea=3:1, r) as colourless oil f =0.5), yield was 79%. 1 H NMR(400MHz,CDCl 3 )δ8.76(s,1H),7.29-7.24(m,5H),5.62(s,1H),5.10–5.05(m,1H),4.24–4.13(m,1H),3.68(s,1H),3.58(s,1H),2.37–2.23(m,1H),2.09(dd,J＝13.9,6.6Hz,1H). 13 C NMR(101MHz,CDCl 3 )δ200.3,173.3,171.0,156.8,136.0,128.6,128.3,128.1,67.4,57.0,52.7,52.1,52.0,29.9,26.0.IR(neat)3291,2923,1705,1521,1213,1174,1041,698cm -1 .HRMS(EI)m/z:Calcd for C 17 H 22 N 2 O 6 S382.1199,Found 382.1194.ee value is>99%. HPLC detection parameters (Daicel Chirapak AD, n-hexane/isopropanol=85/15, flow rate=1.0 mL/min, column oven temperature 30 ℃, wavelength 254 nm) tR= 17.493min (primary), tR= 18.710min (secondary).
Example 19
Synthesis of Compound 3 s:
preparation of Compound 3S by charging aminoaldehyde 1j (19.3 mg,0.1 mmol), S into a reaction tube under an air atmosphere 8 (6.4mg,0.2mmol)，CuCl 2 (2.0mg,0.015mmol)，Na 2 S . 9H 2 O (28.8 mg,0.12 mmol), N6 (t-butylcarbonyl) -L-lysine methyl ester hydrochloride (32.2 mg,0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50℃for 10 hours. After the reaction, the extract was concentrated, and purified by column chromatography (V PE /V EA =3/1) to give 32.2mg of 3s (PE/ea=3:1, r) as colourless oil f =0.5), yield was 69%. 1 H NMR(400MHz,CDCl 3 )δ8.48(d,J＝108.7Hz,1H),7.29–7.24(m,1H),5.80(t,J＝10.0Hz,1H),5.07(d,J＝3.3Hz,1H),5.04(q,J＝6.4Hz,1H),4.61(s,1H),4.17(t,J＝5.1Hz,1H),3.67(d,J＝4.7Hz,1H),2.99(d,J＝5.4Hz,1H),1.93(d,J＝5.5Hz,1H),1.81-1.72(m,1H),1.39–1.34(m,1H),1.27–1.17(m,1H). 13 C NMR(101MHz,CDCl 3 )δ199.8,171.6,156.9,156.2,136.0,128.5,128.3,128.1,79.3,67.4,57.4,52.6,52.1,40.0,30.5,30.2,29.6,28.4,22.2.IR(neat)3281,2923,1697,1521,1244,1167,1039,705cm -1 .HRMS(EI)m/z:Calcd for C 22 H 33 N 3 O 6 S467.2090,Found 467.2083.ee value is>99%. HPLC detection parameters (Daicel Chirapak ID, n-hexane/isopropanol=70/30, flow rate=1.0 mL/min, column oven temperature 30 ℃, wavelength 254 nm) tR= 12.937min (primary), tR= 25.547min (secondary).
Example 20
Synthesis of compound 4 a:
preparation of Compound 4a amino aldehyde 1a' (26.4 mg,0.1 mmol), S was added to a reaction tube under an air atmosphere 8 (6.4mg,0.2mmol)，CuCl 2 (2.0mg,0.015mmol)，Na 2 S·9H 2 O (28.8 mg,0.12 mmol), alanine methyl ester hydrochloride (27.9 mg,0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50℃for 10 hours. After the reaction, the extract was concentrated, and purified by column chromatography (V PE /V EA 21.3mg of 4a (PE/EA=3:1, R) isolated as a colourless oil (3/1) f =0.5), yield was 56%. 1 H NMR(400MHz,CDCl 3 )δ8.85(d,J＝6.6Hz,1H),7.26(d,J＝1.6Hz,6H),5.53(d,J＝5.1Hz,1H),5.15–4.82(m,3H),4.34(dd,J＝16.9,4.9Hz,1H),4.21-4.14(m,J＝13.5,6.6Hz,2H),3.65(s,3H),1.43(d,J＝7.2Hz,3H),1.33(d,J＝7.1Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ199.0,173.2,172.3,156.2,136.0,128.6,128.3,128.0,67.2,53.6,52.6,51.0,50.1,18.1,16.8.IR(neat)3286,2953,1697,1521,1226,1174,1035,737cm -1 .HRMS(EI)m/z:Calcd for C 17 H 23 N 3 O 5 S381.1358,Found 381.1351.ee value is>99%. HPLC detection parameters (Daicel Chirapak AD, n-hexane/isopropanol=85/15, flow rate=1.0 mL/min, column oven temperature 30 ℃, wavelength 254 nm) tr= 13.037min (mainly) Tr= 15.133min (minor).
Example 21
Synthesis of Compound 4 b:
preparation of Compound 4b amino aldehyde 1a' (26.4 mg,0.1 mmol), S was added to a reaction tube under an air atmosphere 8 (6.4mg,0.2mmol)，CuCl 2 (2.0mg,0.015mmol)，Na 2 S . 9H 2 O (28.8 mg,0.12 mmol), leucine methyl ester hydrochloride (36.2 mg,0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50℃for 10 hours. After the reaction, the extract was concentrated, and purified by column chromatography (V PE /V EA =3/1) to give 23.3mg of 4b (PE/ea=3:1, r) as colourless oil f =0.5), the yield was 55%. 1 H NMR(400MHz,CDCl 3 )δ8.83(d,J＝7.1Hz,1H),7.39–7.22(m,6H),5.51(d,J＝6.0Hz,1H),5.05(dd,J＝21.9,9.9Hz,3H),4.42–4.29(m,1H),4.24–4.12(m,2H),3.63(s,3H),2.12–1.83(m,1H),1.72-1.56(m,3H),1.33(d,J＝7.1Hz,3H),0.86(dd,J＝7.9,6.6Hz,6H). 13 C NMR(101MHz,CDCl 3 )δ199.5,173.2,172.1,156.2,136.0,128.6,128.3,128.1,67.2,56.6,52.5,50.9,50.2,40.3,25.0,22.6,22.2,18.1.IR(neat)3273,2971,1697,1533,1242,1172,1026,696cm -1 .HRMS(EI)m/z:Calcd for C 20 H 29 N 3 O 5 S423.1828,Found 423.1826.ee value is>99%. HPLC detection parameters (Daicel Chirapak AD, n-hexane/isopropanol=90/10, flow rate=1.0 mL/min, column oven temperature 30 ℃, wavelength 254 nm) tR= 15.177min (primary), tR= 11.400min (secondary).
Example 22
Synthesis of Compound 4 c:
preparation of Compound 4c amino aldehyde 1a' (26.4 mg,0.1 mmol), S was added to a reaction tube under an air atmosphere 8 (6.4mg,0.2mmol)，CuCl 2 (2.0mg,0.015mmol)，Na 2 S·9H 2 O (28.8 mg,0.12 mmol), methionine methyl ester hydrochloride (26.4 mg,0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50℃for 10 hours. After the reaction, the extract was concentrated, and purified by column chromatography (V PE /V EA =3/1) to give 16.7mg of 4c (PE/ea=3:1, r) as colourless oil f =0.5), yield was 38%. 1 H NMR(400MHz,CDCl 3 )δ8.95(d,J＝7.0Hz,1H),7.27(s,6H),5.49(d,J＝5.5Hz,1H),5.20(d,J＝5.7Hz,1H),5.03(q,J＝12.1Hz,2H),4.44–4.29(m,1H),4.24–4.10(m,2H),3.66(s,3H),2.45(t,J＝7.4Hz,2H),2.20(dd,J＝22.6,17.1Hz,2H),2.00(s,3H),1.34(d,J＝7.1Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ199.6,173.2,171.2,156.3,136.0,128.6,128.3,128.1,67.3,57.0,52.7,51.0,50.3,30.4,30.0,18.0,15.5.IR(neat)3329,2980,1693,1512,1223,1176,1026,748cm -1 .HRMS(EI)m/z:Calcd for C 19 H 27 N 3 O 5 S 2 441.1392,Found 441.1386.ee value is>99%. HPLC detection parameters (Daicel Chirapak AD, n-hexane/isopropanol=85/15, flow rate=1.0 mL/min, column oven temperature 30 ℃, wavelength 254 nm) tR= 13.587min (primary), tR= 19.503min (secondary).
Example 23
Synthesis of Compound 4 d:
preparation of Compound 4d by charging aminoaldehyde 1d' (34.0 mg,0.1 mmol), S into a reaction tube under an air atmosphere 8 (6.4mg,0.2mmol)，CuCl 2 (2.0mg,0.015mmol)，Na 2 S . 9H 2 O (28.8 mg,0.12 mmol), b alanine methyl ester hydrochloride (26.4 mg,0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50℃for 10 hours. After the reaction, the extract was concentrated, and purified by column chromatography (V PE /V EA =3/1) to give 30.6mg of 4d (PE/ea=3:1, r) as colourless oil f =0.5), the yield was 67%. 1 H NMR(300MHz,CDCl 3 )δ8.85(d,J＝5.9Hz,1H),7.39–7.24(m,4H),7.02(s,3H),5.45(d,J＝6.6Hz,1H),5.07(s,2H),4.40(d,J＝6.4Hz,1H),4.16(dd,J＝16.7,4.1Hz,1H),3.74(s,2H),3.17(dd,J＝13.8,6.4Hz,1H),3.08(d,J＝7.6Hz,1H),1.52(d,J＝7.1Hz,2H). 13 C NMR(101MHz,CDCl 3 )δ198.7,172.2,171.8,156.3,136.0,135.9,129.2,128.8,128.6,128.3,128.0,127.2,67.3,56.8,53.6,52.6,50.3,37.8,16.8.IR(neat)3273,3021,1739,1654,1525,1263,1197,701cm -1 .HRMS(EI)m/z:Calcd for C 23 H 27 N 3 O 5 S457.1671,Found 457.1677.ee value is>99%. HPLC detection parameters (Daicel Chirapak OJ, n-hexane/isopropanol=80/20, flow rate=1.0 mL/min, column oven temperature 30 ℃, wavelength 254 nm) tR= 26.443min (primary), tR= 20.930min (secondary).
Example 24
Synthesis of compound 4 e:
preparation of Compound 4e amino aldehyde 1d' (34.0 mg,0.1 mmol), S was added to a reaction tube under an air atmosphere 8 (6.4mg,0.2mmol)，CuCl 2 (2.0mg,0.015mmol)，Na 2 S . 9H 2 O (28.8 mg,0.12 mmol), b-leucine methyl ester hydrochloride (26.4 mg,0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50℃for 10 hours. After the reaction, the extract was concentrated, and purified by column chromatography (V PE /V EA 28.9mg of 4e (PE/EA=3:1, R) was isolated as a colourless oil (3/1) f =0.5), yield 58%. 1 H NMR(400MHz,CDCl 3 )δ8.72(s,1H),7.27-7.20(m,8H),7.08-7.06(m,2H),5.36(s,1H),5.07(q,J＝7.2Hz,1H),4.98(s,1H),4.39-4.27(m,J＝14.1,7.0Hz,2H),4.07-4.02(m,1H),3.68-3.63(s,1H),3.11-3.06(m,1H),2.98-2.93(m,J＝13.6,7.8Hz,1H),1.71(dd,J＝13.3,6.4Hz,2H),1.66-1.57(m,J＝13.4,6.7Hz,1H),0.87(dd,J＝8.4,6.5Hz,6H).. 13 C NMR(101MHz,CDCl 3 )δ199.2,172.1,171.8,156.2,136.1,135.8,129.1,128.8,128.6,128.3,128.1,127.2,67.3,56.6,52.4,50.4,40.3,37.7,25.0,22.6,22.2.IR(neat)3291,2953,1745,1660,1521,1230,1028,748cm -1 .HRMS(ESI)m/z:[M+Na] + Calcd for C 26 H 33 N 3 NaO 5 S522.2039,Found 522.2059.ee value is>99%. HPLC detection parameters (Daicel Chirapak AD, n-hexane/isopropanol=90/10, flow rate=1.0 mL/min, column oven temperature 30 ℃, wavelength 254 nm) tR= 21.530min (primary), tR= 18.090min (secondary).
Example 25
Synthesis of Compound 4 f:
preparation of Compound 4f amino aldehyde 1j' (19.3 mg,0.1 mmol), S was added to a reaction tube under an air atmosphere 8 (6.4mg,0.2mmol)，CuCl 2 (2.0mg,0.015mmol)，Na 2 S . 9H 2 O (28.8 mg,0.12 mmol), 2f' (77.8 mg,0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50℃for 10 hours. After the reaction, the extract was concentrated, and purified by column chromatography (V PE /V EA =3/1) to give 16.5mg of 4f (PE/ea=3:1, r) as colourless oil f =0.5), the yield was 33%. 1 H NMR(400MHz,CDCl 3 )δ8.64(s,1H),7.43-7.15(m,10H),6.04(s,1H),5.56(s,1H),5.13(dd,J＝13.1,7.6Hz,1H),5.02(d,J＝4.4Hz,2H),4.49-4.39(m,1H),4.20-4.07(m,2H),3.66-3.59(m,3H),3.24(dd,J＝13.6,4.9Hz,1H),3.01(dd,J＝13.3,8.0Hz,1H),1.51-1.33(m,3H),0.78(d,J＝5.4Hz,6H). 13 C NMR(101MHz,CDCl 3 )δ199.1,172.5,169.3,156.7,135.9,129.4,128.8,128.6,128.6,128.3,128.2,127.3,67.5,59.4,52.4,51.1,41.2,37.0,29.7,24.7,22.7,21.9.IR(neat)3298,2951,1716,1533,1456,1226,1107,696cm -1 .HRMS(EI)m/z:Calcd for C 26 H 33 N 3 O 5 S499.2141,Found 499.2138.ee value is 98%. HPLC detection parameters (Daicel Chirapak AD, n-hexane/isopropanol=85/15, flow rate=1.0 mL/min, column oven temperature 30 ℃, wavelength 254 nm) tr= 19.247min (primary), tr= 12.813min (secondary).
Example 26
Synthesis of Compound 4 g:
preparation of Compound 4g in an air atmosphere, amino aldehyde 1a (28.3 mg,0.1 mmol), S was added to a reaction tube 8 (6.4mg,0.2mmol)，CuCl 2 (2.0mg,0.015mmol)，Na 2 S . 9H 2 O (28.8 mg,0.12 mmol), 2g' (36.4 mg,0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50℃for 10 hours. After the reaction, the extract was concentrated, and purified by column chromatography (V PE /V EA 29.2mg of 4g (PE/EA=3:1, R) are isolated as colourless oil (=3/1) f =0.5), the yield was 66%. 1 H NMR(400MHz,CDCl 3 )δ8.65(s,1H),7.19(dtt,J＝17.7,10.9,5.3Hz,10H),6.65(s,1H),5.70(d,J＝7.2Hz,1H),4.95(q,J＝12.3Hz,2H),4.71(q,J＝7.2Hz,1H),4.25-4.08(m,J＝21.8,17.0,4.8Hz,2H),3.95–3.81(m,2H),3.64(s,3H),3.14-2.99(m,J＝20.5,13.4,7.5Hz,2H). 13 C NMR(101MHz,CDCl 3 )δ204.1,170.1,167.4,156.0,136.2,136.0,129.2,128.7,128.6,128.2,127.9,127.2,67.2,62.7,52.6,48.2,41.8,41.2.IR(neat)3311,2954,1695,1519,1242,1220,1028,738cm -1 .HRMS(EI)m/z:Calcd for C 22 H 25 N 3 O 5 S443.1515,Found 443.1519.ee value is 80%. HPLC detection parameters (Daicel Chirapak AD, n-hexane/isopropanol=85/15, flow rate=1.0 mL/min, column oven temperature 30 ℃, wavelength 254 nm) tr= 21.227min (primary), tr= 35.833min (secondary).
Example 27
Synthesis of Compound 4 h:
preparation of Compound 4h by charging aminoaldehyde 1d' (34.0 mg,0.1 mmol), S into a reaction tube under an air atmosphere 8 (6.4mg,0.2mmol)，CuCl 2 (2.0mg,0.015mmol)，Na 2 S . 9H 2 O (28.8 mg,0.12 mmol), 2h' (44.8 mg,0.2 mmol) and redistilled solvent THF (1 mL) at 50The reaction was carried out at a temperature of 10 hours. After the reaction, the extract was concentrated, and purified by column chromatography (V PE /V EA 26.5mg of 4g (PE/EA=3:1, R) are isolated as colourless oil (3/1) f =0.5), yield was 49%. 1 H NMR(400MHz,CDCl 3 )δ8.99(s,1H),7.33–7.04(m,12H),6.80(d,J＝8.7Hz,1H),5.76(d,J＝6.9Hz,1H),5.05–4.84(m,2H),4.48–4.04(m,5H),3.62(d,J＝23.4Hz,3H),3.09-2.89(m,2H),2.12-2.04(m,1H),0.83(t,J＝6.8Hz,6H). 13 C NMR(101MHz,CDCl 3 )δ199.5,172.3,172.3,167.4,156.6,136.2,136.0,129.2,128.7,128.5,128.2,128.0,127.1,67.3,57.5,56.7,52.3,50.3,48.5,37.9,31.1,19.0,17.9.IR(neat)3305,2956,1666,1525,1263,1151,737,698cm -1 .HRMS(EI)m/z:Calcd for C 27 H 34 N 4 O 6 S 542.2199,Found 542.2184.
Example 28
Synthesis of Compound 4 i:
preparation of Compound 4i by charging aminoaldehyde 1d' (34.0 mg,0.1 mmol), S into a reaction tube under an air atmosphere 8 (6.4mg,0.2mmol)，CuCl 2 (2.0mg,0.015mmol)，Na 2 S . 9H 2 O (28.8 mg,0.12 mmol), 2i' (47.6 mg,0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50℃for 10 hours. After the reaction, the extract was concentrated, and purified by column chromatography (V PE /V EA 28.3mg of 4g (PE/EA=3:1, R) are isolated as colourless oil (=3/1) f =0.5), yield was 51%. 1 H NMR(400MHz,CDCl 3 )δ8.87(s,1H),7.33–7.07(m,12H),6.64(d,J＝7.9Hz,1H),5.59(d,J＝5.6Hz,1H),5.06–4.91(m,2H),4.52(dd,J＝14.3,8.1Hz,1H),4.39–4.04(m,4H),3.60(s,3H),3.16–2.87(m,2H),1.70–1.41(m,3H),1.21(d,J＝19.1Hz,1H),0.84(t,J＝6.6Hz,6H). 13 C NMR(101MHz,CDCl 3 )δ199.6,173.3,172.3,167.3,156.7,136.1,135.9,129.2,128.8,128.8,128.6,128.3,128.1,127.2,67.4,56.8,52.4,51.0,50.6,48.3,41.1,37.8,24.8,22.8,21.7.IR(neat)3282,2964,1666,1516,1263,1213,1147,701cm -1 .HRMS(EI)m/z:Calcd for C 28 H 36 N 4 O 6 S 556.2356,Found 556.2363.
Example 29
Synthesis of compound 4 j:
preparation of Compound 4j by adding aminoaldehyde 1d' (34.0 mg,0.1 mmol), S to a reaction tube under an air atmosphere 8 (6.4mg,0.2mmol)，CuCl 2 (2.0mg,0.015mmol)，Na 2 S . 9H 2 O (28.8 mg,0.12 mmol), 2j' (54.4 mg,0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50℃for 10 hours. After the reaction, the extract was concentrated, and purified by column chromatography (V PE /V EA 26.0mg of 4g (PE/EA=3:1, R) are isolated as colourless oil (3:1) f =0.5), yield was 61%. 1 H NMR(400MHz,DMSO)δ9.71(t,J＝5.1Hz,1H),8.56(d,J＝7.0Hz,1H),7.58(t,J＝15.8Hz,1H),7.34–7.21(m,1H),4.98–4.91(m,1H),4.54–4.48(m,1H),4.31–4.15(m,1H),4.07(dd,J＝17.0,5.6Hz,1H),3.58(s,1H),3.12(dd,J＝13.9,3.9Hz,1H),3.04(dd,J＝13.8,5.7Hz,1H),2.93(dd,J＝13.7,8.8Hz,1H),2.77(dd,J＝13.7,10.8Hz,1H). 13 C NMR(101MHz,DMSO)δ200.6,172.4,172.1,167.4,156.5,138.6,137.4,137.4,129.6,129.5,128.7,128.5,128.2,128.0,127.1,126.7,65.8,56.7,54.2,52.3,49.7,47.8,37.6,37.2.IR(neat)3310,2951,1728,1660,1498,1213,1028,738cm -1 .HRMS(ESI)m/z:[M+Na] + Calcd for C 31 H 34 N 4 O 6 SNa 613.2097,Found 613.2075.
Example 30
Synthesis of Compound 4 k:
preparation of Compound 4k by charging aminoaldehyde 1k' (24.7 mg,0.1 mmol), S into a reaction tube under an air atmosphere 8 (6.4mg,0.2mmol)，CuCl 2 (2.0mg,0.015mmol)，Na 2 S . 9H 2 O (28.8 mg,0.12 mmol), alanine methyl ester hydrochloride (27.8 mg,0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50℃for 10 hours. After the reaction, the extract was concentrated, and purified by column chromatography (V PE /V EA 22.2mg of 4k (PE/EA=3:1, R) are isolated as colourless oil (=3/1) f =0.5), yield was 61%. 1 H NMR(400MHz,CDCl 3 )δ8.92(s,1H),7.14(d,J＝8.0Hz,2H),7.05(d,J＝8.0Hz,2H),6.58(s,1H),4.96-4.89(m,1H),4.23–4.10(m,2H),3.69(s,3H),3.56(q,J＝7.2Hz,1H),2.38(d,J＝7.2Hz,2H),1.81-1.74(m,J＝13.5,6.8Hz,2H),1.47(d,J＝7.2Hz,3H),1.40–1.35(m,3H),0.82(d,J＝6.6Hz,6H). 13 C NMR(101MHz,CDCl 3 )δ199.3,175.6,172.0,141.0,137.7,129.7,127.4,53.5,52.6,50.4,46.5,45.0,30.2,22.4,18.2,16.8.IR(neat)3253,2967,1734,1653,1541,1417,1201,1174cm -1 .HRMS(EI)m/z:Calcd for C 19 H 28 N 2 O 3 S364.1821,Found 364.1819.ee value is 97% HPLC detection parameter (Daicel Chirapak ID, n-hexane/isopropanol=85/15, flow rate=1.0 mL/min, column oven temperature 30 ℃, wavelength 254 nm) tr= 9.627min (primary), tr= 12.937min (secondary).
Example 31
Synthesis of Compound 4 l:
preparation of Compound 4l in an air atmosphere, amino aldehyde 1k' (24.7 mg,0.1 mmol), S was added to a reaction tube 8 (6.4mg,0.2mmol)，CuCl 2 (2.0mg,0.015mmol)，Na 2 S·9H 2 O (28.8 mg,0.12 mmol), leucine methyl ester hydrochloride (36.2 mg,0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50℃for 10 hours. After the reaction, the extract was concentrated, and purified by column chromatography (V PE /V EA 21.1mg of 4l (PE/EA=3:1, R) are isolated as colourless oil (3:1) f =0.5), yield was 52%. 1 H NMR(400MHz,CDCl 3 )δ8.86(s,1H),7.14(s,2H),7.05(d,J＝8.1Hz,2H),6.50(s,1H),4.99-4.94(m,J＝8.0,6.0Hz,1H),4.29–4.05(m,2H),3.67(s,3H),3.55(q,J＝7.2Hz,1H),2.38(d,J＝7.2Hz,2H),1.83-1.69(m,1H),1.71-1.64(m,2H),1.61–1.51(m,1H),1.47(d,J＝7.2Hz,3H),0.87-0.82(m,12H). 13 C NMR(101MHz,CDCl 3 )δ200.0,175.9,171.8,141.1,137.6,129.8,127.4,56.6,52.4,50.9,46.5,45.0,40.4,30.2,25.0,22.6,22.4,22.1,18.3.IR(neat)3261,2953,1651,1503,1415,1205,1132,748cm -1 .HRMS(EI)m/z:Calcd for C 22 H 34 N 2 O 3 S406.2290,Found 406.2283.ee value is>99%. HPLC detection parameters (Daicel Chirapak ID, n-hexane/isopropanol=95/05, flow rate=1.0 mL/min, column oven temperature 30 ℃, wavelength 254 nm) tR= 10.317min (primary), tR= 7.620min (secondary).
Example 32
Synthesis of Compound 4 m:
preparation of Compound 4m by charging aminoaldehyde 1m' (27.1 mg,0.1 mmol), S into a reaction tube under an air atmosphere 8 (6.4mg,0.2mmol)，CuCl 2 (2.0mg,0.015mmol)，Na 2 S . 9H 2 O (28.8 mg,0.12 mmol), alanine methyl ester hydrochloride (27.8 mg,0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50℃for 10 hours. After the reaction, the extract was concentrated, and purified by column chromatography (V PE /V EA 28.7mg of 4m (PE/EA=3:1, R) isolated as a colourless oil f =0.5), yield was 74%. 1 H NMR(400MHz,CDCl 3 )δ8.86(s,1H),7.62(dd,J＝8.0,6.7Hz,3H),7.31(dd,J＝8.5,1.6Hz,1H),7.10–7.00(m,2H),6.64(s,1H),4.90(t,J＝7.1Hz,1H),4.22–4.07(m,2H),3.83(s,3H),3.74–3.63(m,4H),1.54(d,J＝7.1Hz,3H),1.33(d,J＝7.2Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ199.3,175.5,172.1,157.8,135.7,133.9,129.3,129.0,127.7,126.2,126.1,119.2,105.6,55.3,53.5,52.6,50.5,46.8,18.3,16.8.IR(neat)3271,2937,1734,1653,1503,1237,1028,732cm -1 .HRMS(EI)m/z:Calcd for C 20 H 24 N 2 O 4 S388.1457,Found 388.1451.ee value is>99%. HPLC detection parameters (Daicel Chirapak AD, n-hexane/isopropanol=85/15, flow rate=1.0 mL/min, column oven temperature 30 ℃, wavelength 254 nm) tR= 15.093min (primary), tR= 12.697min (secondary).
Example 33
Synthesis of compound 4 n:
preparation of Compound 4n by adding aminoaldehyde 1n' (30.9 mg,0.1 mmol), S to a reaction tube under an air atmosphere 8 (6.4mg,0.2mmol)，CuCl 2 (2.0mg,0.015mmol)，Na 2 S . 9H 2 O (27.8 mg,0.12 mmol), alanine methyl ester hydrochloride (27.8 mg,0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50℃for 10 hours. After the reaction, the extract was concentrated, and purified by column chromatography (V PE /V EA 22.1mg of 4n (PE/EA=3:1, R) was isolated as a colourless oil (=3/1) f =0.5), yield was 52%. 1 H NMR(400MHz,CDCl 3 )δ8.81(d,J＝6.4Hz,1H),8.05(d,J＝2.3Hz,1H),7.80(dd,J＝7.7,1.1Hz,1H),7.51-7.47(m,1H),7.44–7.35(m,2H),7.31(s,1H),6.98(d,J＝8.4Hz,1H),6.77(s,1H),5.12(s,2H),4.95-4.88(m,1H),4.25-4.13(m,2H),3.67(s,3H),3.58(s,2H),1.39(d,J＝7.2Hz,3H). 13 CNMR(101MHz,CDCl 3 )δ199.1,190.8,172.1,171.8,160.7,140.4,136.4,135.5,132.9,132.6,129.5,129.3,128.1,127.9,125.3,121.6,73.7,53.6,52.7,50.4,42.3,16.8.IR(neat)3298,2951,1734,1647,1541,1303,1120,732cm -1 .HRMS(EI)m/z:Calcd for C 22 H 22 N 2 O 5 S426.1249,Found 426.1246.ee value is>99%. HPLC detection parameters (Daicel Chirapak AD, n-hexane/isopropanol=70/30, flow rate=1.0 mL/min, column oven temperature 30 ℃, wavelength 254 nm) tR= 13.893min (primary), tR= 16.260min (secondary).
Example 34
Synthesis of Compound 4 o:
preparation of Compound 4o by charging aminoaldehyde 1n' (30.9 mg,0.1 mmol), S into a reaction tube under an air atmosphere 8 (6.4mg,0.2mmol)，CuCl 2 (2.0mg,0.015mmol)，Na 2 S . 9H 2 O (27.8 mg,0.12 mmol), leucine methyl ester hydrochloride (36.2 mg,0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50℃for 10 hours. After the reaction, the extract was concentrated, and purified by column chromatography (V PE /V EA =3/1) to give 16.4mg of 4o (PE/ea=3:1, r) as colourless oil f =0.5), yield was 35%. 1 H NMR(400MHz,CDCl 3 )δ8.91(d,J＝7.4Hz,1H),8.05(d,J＝2.3Hz,1H),7.80(d,J＝7.6Hz,1H),7.49(t,J＝7.4Hz,1H),7.43–7.33(m,2H),7.29(d,J＝7.4Hz,1H),7.01–6.84(m,2H),5.11(s,2H),4.99-4.94(m,1H),4.30–4.12(m,2H),3.64(s,3H),3.57(s,2H),1.68–1.47(m,3H),0.81(t,J＝5.8Hz,6H). 13 C NMR(101MHz,CDCl 3 )δ199.7,190.8,171.9,171.8,160.7,140.4,136.4,135.5,132.9,132.6,129.5,129.3,128.1,128.1,127.9,125.3,121.6,73.6,56.7,52.4,50.4,50.4,42.3,40.3,25.0,22.6,22.1.IR(neat)3293,2954,1734,1647,1411,1205,1174,721cm -1 .HRMS(EI)m/z:Calcd for C 25 H 28 N 2 O 5 S468.1719,Found 468.1705.ee value is>99%. HPLC detection parameters (Daicel Chirapak AD, n-hexane/isopropanol=85/15, flow rate=1.0 mL/min, column oven temperature 30 ℃, wavelength 254 nm) tR= 25.727min (primary), tR= 20.853min (secondary).
Example 35
Synthesis of Compound 4 p:
preparation of Compound 4p by charging aminoaldehyde 1n' (30.9 mg,0.1 mmol), S into a reaction tube under an air atmosphere 8 (6.4mg,0.2mmol)，CuCl 2 (2.0mg,0.015mmol)，Na 2 S . 9H 2 O (27.8 mg,0.12 mmol), methionine methyl ester hydrochloride(39.9 mg,0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50℃for 10 hours. After the reaction, the extract was concentrated, and purified by column chromatography (V PE /V EA =3/1) to give 23.3mg of 4p (PE/ea=3:1, r) as colourless oil f =0.5), yield was 48%. 1 H NMR(400MHz,CDCl 3 )δ9.06(d,J＝7.3Hz,1H),8.05(d,J＝2.3Hz,1H),7.80(dd,J＝7.7,1.1Hz,1H),7.51-7.47(m,1H),7.41-7.36(m,2H),7.30(s,1H),6.98(d,J＝8.4Hz,1H),6.90(s,1H),5.16–5.06(m,3H),4.33–4.13(m,2H),3.66(s,3H),3.58(s,2H),2.39(t,J＝7.4Hz,2H),2.19-2.13(m,1H),2.06–1.94(m,4H). 13 C NMR(101MHz,CDCl 3 )δ199.7,190.8,171.8,171.0,160.7,140.3,136.4,135.5,132.9,132.6,129.5,129.3,128.1,127.9,125.3,121.6,73.6,57.1,52.7,50.4,42.3,30.3,29.9,15.5.IR(neat)3246,2916,1737,1643,1487,1284,1176,732cm -1 .HRMS(EI)m/z:Calcd for C 24 H 26 N 2 O 5 S 2 486.1283,Found 486.1277.ee value is>99% the detection parameters of HP LC (Daicel Chirapak AD, n-hexane/isopropanol=70/30, flow rate=1.0 mL/min, column oven temperature 30 ℃, wavelength 254 nm) tR= 16.450min (primary), tR= 19.893min (secondary).
The protection of the present invention is not limited to the above embodiments. Variations and advantages that would occur to one skilled in the art are included within the invention without departing from the spirit and scope of the inventive concept, and the scope of the invention is defined by the appended claims.

Claims (6)

1. A method for synthesizing a polypeptide compound containing a sulfur amide, the method comprising the steps of: in a solvent, amino aldehyde, an inorganic sulfur reagent and amino acid are used as reaction raw materials, and under the action of a catalyst and an additive, polypeptide compounds containing sulfur amide are obtained by reaction, wherein the reaction process is shown in a reaction formula (I):
wherein,
R 1 is hydrogen, alkyl, benzyl, tetrahydropyrrole;
r is carbobenzoxy, fluorenylmethoxycarbonyl, allyloxycarbonyl, tert-butyloxycarbonyl, alkyl;
R 2 is hydrogen, alkyl, benzyl;
R 3 is alkyl or benzyl;
the inorganic sulfur reagent is a reaction sulfur source and is selected from elemental sulfur; the catalyst is copper catalyst, and is selected from one or more of cuprous iodide, cuprous bromide, cuprous chloride, tetraethyl cyanogen hexafluorophosphate, cupric chloride, cupric bromide, cupric fluoride, cupric acetate, copper bis (acetylacetonate), cupric trifluoroacetate, cupric oxide and cupric sulfate; the additive is selected from one or more of potassium carbonate, sodium carbonate, monopotassium phosphate, sodium bicarbonate, dodecyl mercaptan, p-methyl benzene mercaptan, potassium sulfide, sodium sulfide nonahydrate, tetrabutylammonium chloride, tetrabutylammonium iodide and tetrabutylammonium fluoride.
2. The synthesis method according to claim 1, wherein,
R 1 is hydrogen, methyl, isobutyl, benzyl, tetrahydropyrrole;
r is carbobenzoxy, fluorenylmethoxycarbonyl, allyloxycarbonyl, tert-butyloxycarbonyl, alkyl;
R 2 is hydrogen, methyl, isopropyl, isobutyl, benzyl;
R 3 methyl, benzyl, tert-butyl.
3. A method for synthesizing a polypeptide compound containing a sulfur amide, the method comprising the steps of: in a solvent, amino aldehyde, an inorganic sulfur reagent and amino acid are used as reaction raw materials, and under the action of a catalyst and an additive, polypeptide compounds containing sulfur amide are obtained by reaction, wherein the reaction process is shown in a reaction formula (I):
the 1,1' is selected from any one of phenylalaninol, alaninol, prolyl, leucinal, glyceraldehyde, propyl-glyceraldehyde, phenylpropyl-glyceraldehyde, glycerol-phenylalaninol, ibuprofen-glyceraldehyde, naproxen-glyceraldehyde and exec acid-glyceraldehyde;
the 2,2' is selected from any one of glycine methyl ester hydrochloride, glycine benzyl ester hydrochloride, glycine tert-butyl ester hydrochloride, alanine methyl ester hydrochloride, valine methyl ester hydrochloride, leucine methyl ester hydrochloride, phenylalanine methyl ester hydrochloride, methionine methyl ester hydrochloride, serine methyl ester hydrochloride, tryptophan methyl ester hydrochloride, glutamic acid dimethyl ester hydrochloride, N6-tert-butoxycarbonyl lysine methyl ester hydrochloride, glycine alanine methyl ester hydrochloride, glycine valine methyl ester hydrochloride, glycine leucine methyl ester hydrochloride, glycine alanine methyl ester hydrochloride and benzene propyl leucine methyl ester hydrochloride;
the inorganic sulfur reagent is a reaction sulfur source and is selected from elemental sulfur; the catalyst is copper catalyst, and is selected from one or more of cuprous iodide, cuprous bromide, cuprous chloride, tetraethyl cyanogen hexafluorophosphate, cupric chloride, cupric bromide, cupric fluoride, cupric acetate, copper bis (acetylacetonate), cupric trifluoroacetate, cupric oxide and cupric sulfate; the additive is selected from one or more of potassium carbonate, sodium carbonate, monopotassium phosphate, sodium bicarbonate, dodecyl mercaptan, p-methyl benzene mercaptan, potassium sulfide, sodium sulfide nonahydrate, tetrabutylammonium chloride, tetrabutylammonium iodide and tetrabutylammonium fluoride.
4. A synthetic method according to claim 1 or 3 wherein the temperature of the reaction is 25-100 ℃; the reaction time is 1-12 hours.
5. A synthetic method according to claim 1 or 3, wherein the solvent is selected from one or more of acetonitrile, toluene, dimethylsulfoxide, N-dimethylformamide, N-dimethylacetamide, tetrahydrofuran, 1, 4-dioxane, 1, 2-dichloroethane, N-methylpyrrolidone, ethyl acetate, chloroform, ethanol, isopropanol; and/or, the solvent is used in an amount of 0.5-10 mL based on the amount of the amino aldehyde.
6. A method according to claim 1 or 3, wherein the molar ratio of the amino aldehyde, the inorganic sulphur reagent, the amino acid, the catalyst, the additive is 1: (1-5): (1-5): (0.01-0.4): (0.5-5).
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105294601A (en) * 2015-10-29 2016-02-03 华东师范大学 Thioamide compound and compounding method thereof
CN108484461A (en) * 2018-04-02 2018-09-04 江西师范大学 The thioamides preparation method and its application in thio Peptide systhesis that alkynyl amide mediates

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105294601A (en) * 2015-10-29 2016-02-03 华东师范大学 Thioamide compound and compounding method thereof
CN108484461A (en) * 2018-04-02 2018-09-04 江西师范大学 The thioamides preparation method and its application in thio Peptide systhesis that alkynyl amide mediates

Non-Patent Citations (1)

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Title
Yanyan Liao，等.Construction of Thioamide Peptide via Sulfur-Involved Amino Acids/ Amino Aldehydes Coupling.Org. Lett..2021,第23卷8862−8866. *

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