CN113912524A - Polypeptide compound containing sulfamide and synthesis method thereof - Google Patents

Polypeptide compound containing sulfamide and synthesis method thereof Download PDF

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CN113912524A
CN113912524A CN202111254112.6A CN202111254112A CN113912524A CN 113912524 A CN113912524 A CN 113912524A CN 202111254112 A CN202111254112 A CN 202111254112A CN 113912524 A CN113912524 A CN 113912524A
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glycine
derivatives
ester hydrochloride
methyl ester
phenylalanine
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CN113912524B (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
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C325/00—Thioaldehydes; Thioketones; Thioquinones; Oxides thereof
    • C07C325/02—Thioketones; Oxides thereof
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    • 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
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    • 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 sulfamide as shown in formulas 3 and 4 and a synthesis method thereof, amino aldehyde, inorganic sulfur and amino acid are used as reaction raw materials and react in a solvent under the action of a catalyst and an additive to obtain a series of polypeptide compounds containing sulfamide. According to the invention, through catalysis conditions, an inorganic sulfur reagent is used as a sulfur source, a polypeptide compound containing the thioamide is constructed by a one-pot method, and the chirality is maintained, so that the defects of phosphorus-sulfur reagents represented by Lawson reagents in the prior art are avoided; dipeptide, tripeptide, tetrapeptide and peptide-drug coupling compounds can be successfully obtained by the synthesis strategy developed by the invention, and the peptide-drug coupling compounds have great potential in the future drug development field.

Description

Polypeptide compound containing sulfamide 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 sulfamide and a synthesis method thereof.
Background
The polypeptide compounds containing the sulfur amides are very important compounds, and in recent years, people find that the metabolic stability and the biological activity of the polypeptide can be further improved if the amido bonds on the polypeptide are subjected to sulfo treatment, so that the development of a method for synthesizing the polypeptide compounds containing the amides, which is efficient, environment-friendly and economical in steps, is particularly important.
The preparation method of the sulfur amide-containing polypeptide compound is mainly characterized in that the sulfur-oxygen substitution is directly carried out by a phosphorus-sulfur reagent represented by a Lawson reagent. However, this preparation method uses phosphorus-sulfur reagents, which make it impossible to selectively substitute oxygen and sulfur, and such reagents have a foul odor and generate a large amount of phosphorus-oxygen polymer after the reaction is completed. Therefore, the development of a synthetic method of the sulfur amide-containing polypeptide compound which is environment-friendly and has application potential is of great significance.
Disclosure of Invention
In order to solve the defects in the prior art, the invention aims to provide a method for efficiently constructing a polypeptide compound containing sulfamide by directly utilizing amino aldehyde and amino acid in multiple components by a three-component coupling method under a catalytic condition. The synthesis method is simple, the raw materials are cheap and easy to obtain, the substrate universality is wide, and the yield (33% -92%) is better. The polypeptide compound containing the sulfamide provided by the invention can be applied to the preparation of dipeptide, tripeptide, tetrapeptide and peptide-drug coupling compounds.
The invention provides a synthesis method of a polypeptide compound containing sulfamide, which comprises the steps of taking amino aldehyde, an 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 the sulfamide, and keeping chirality; the reaction process is shown as the following reaction formula (I):
Figure BDA0003323300600000011
wherein the content of the first and second substances,
R1hydrogen, alkyl, benzyl and tetrahydropyrrole;
r is carbobenzoxy, fluorenylmethyloxycarbonyl, allyloxycarbonyl, tert-butyloxycarbonyl, alkyl and the like;
R2hydrogen, alkyl, benzyl, etc.;
R3alkyl and benzyl.
Preferably, the first and second electrodes are formed of a metal,
R1hydrogen, methyl, isobutyl, benzyl and tetrahydropyrrolyl;
r is carbobenzoxy, fluorenylmethyloxycarbonyl, allyloxycarbonyl, tert-butyloxycarbonyl, alkyl and the like;
R2hydrogen, methyl, isopropyl, isobutyl, benzyl, etc.;
R3methyl, benzyl and tert-butyl.
Further preferably, 1, 1' is selected from the group consisting of phenylaminoaldehyde, alaninaldehyde, prolinaldehyde, leuminaldehyde, glycinal, a propanglycinal derivative, a phenylpropanoic-glycinal derivative, a glycinal-phenylaminoaldehyde derivative, an ibuprofen-glycinal derivative, a naproxen-glycinal derivative and an isoethanic acid-glycinal derivative;
further preferably, 2, 2' is selected from 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 phenylalanine-leucine methyl ester hydrochloride.
In the present invention, 1,1 'represents formula (1) or formula (1'); 2,2 'represents formula (2) or formula (2'); 3 and 4 are represented by formula (3) and formula (4).
In the invention, the reaction temperature is 25-100 ℃; preferably 50 deg.c.
In the invention, the reaction time is 1-12 hours; preferably, it is 10 hours.
In the present invention, 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 the like; preferably, tetrahydrofuran.
In the invention, the dosage of the solvent is 0.5-5 mL by taking the dosage of the amino aldehyde as a reference.
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 sulfur.
In the invention, the catalyst is a copper catalyst and is selected from one or more of cuprous iodide, cuprous bromide, cuprous chloride, copper hexachlorophosphate, copper tetracyanoferrate, copper chloride, copper bromide, copper fluoride, copper acetate, copper bis (acetylacetonate), copper trifluoroacetate, copper oxide and copper sulfate; preferably, copper chloride.
In the invention, the additive is selected from one or more of potassium carbonate, sodium carbonate, dipotassium hydrogen carbonate, potassium dihydrogen phosphate, sodium bicarbonate, dodecyl mercaptan, p-methyl benzenethiol, 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, the inorganic sulfur reagent, the amino acid, the catalyst and the additive is 1: (1-5): (1-5): (0.01-0.4): (0.5-5); preferably, 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, the 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 imine and copper are coordinated and complexed to form a five-membered ring intermediate a, and imine is activated and isomerization (intermediates B and C) is avoided to keep the chirality of a substrate. Elemental sulfur is ring opened by the action of sodium sulfide to give a nucleophilic sulfur species S, which is then added to an imine to give intermediate D and ligand-exchanged intermediate E. Next, intermediate F is obtained by the 1,2-H migration process of intermediate D. Finally, cleavage of the S-S bond in the intermediate F provides the thioamide containing polypeptide compound 3 a.
Figure BDA0003323300600000031
Wherein the group PG mentioned in the reaction formula (II) has the same meaning as R in the formula (I).
In one particular embodiment: the reaction process is shown in the following reaction formula (I').
Figure BDA0003323300600000032
Wherein R is1、R2、R3And R is as defined for formula (I), i.e., R1Hydrogen, alkyl, benzyl and tetrahydropyrrole; r is carbobenzoxy, fluorenylmethyloxycarbonyl, allyloxycarbonyl, tert-butyloxycarbonyl, alkyl and the like; r2Hydrogen, alkyl, benzyl, etc.; r3Alkyl and 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),
Figure BDA0003323300600000041
wherein R is1、R2、R3And R is as defined for formula (I), i.e., R1Hydrogen, alkyl, benzyl and tetrahydropyrrole; r is carbobenzoxy, fluorenylmethyloxycarbonyl, allyloxycarbonyl, tert-butyloxycarbonyl, alkyl and the like; r2Hydrogen, alkyl, benzyl, etc.; r3Alkyl and benzyl.
Preferably, R1Hydrogen, methyl, isobutyl, benzyl, tetrahydropyrrole; r is carbobenzoxy, fluorenylmethyloxycarbonyl, allyloxycarbonyl, tert-butyloxycarbonyl or alkyl; r2Hydrogen, methyl, isopropyl, isobutyl, benzyl; r3Methyl, benzyl and tert-butyl.
Further preferably, the compound of formula 3,4 is:
phenylalanine-glycine derivatives, alanine-glycine derivatives, leucine-glycine derivatives, prolineglycine derivatives, glycine-alanine derivatives, glycine-valine derivatives, glycine-leucine derivatives, glycine-phenylalanine derivatives, glycine-methionine derivatives, glycine-serine derivatives, glycine-tyrosine derivatives, glycine-tryptophan derivatives, glycine-glutamic acid derivatives, glycine-lysine derivatives, alanine-glycine-leucine derivatives, alanine-glycine derivatives, phenylalanine-glycine derivatives, glycine-leucine derivatives, glycine-phenylalanine-leucine derivatives, phenylalanine-glycine derivatives, glycine-arginine derivatives, glycine-tyrosine derivatives, glycine-tryptophan derivatives, glycine-lysine derivatives, glycine-arginine derivatives, glycine-serine derivatives, glycine-tyrosine derivatives, glycine-alanine derivatives, glycine-lysine derivatives, glycine-arginine derivatives, glycine-serine derivatives, glycine-arginine derivatives, glycine-glycine derivatives, glycine-lysine derivatives, glycine-lysine derivatives, and the like, A phenylalanine-glycine-valine derivative, a phenylalanine-glycine-leucine derivative, a phenylalanine-glycine-phenylalanine derivative, an ibuprofen-glycine-alanine derivative, an ibuprofen-glycine-leucine derivative, a naproxen-glycine-alanine derivative, an isoxolone-glycine-leucine derivative, and an isoxolone-glycine-methionine derivative.
The invention also provides application of the thioamide-containing polypeptide compound shown in the formula (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, an inorganic sulfur reagent and amino acid as reaction raw materials, and constructs the polypeptides containing the thioamide in a one-pot method under the action of a catalyst and an additive, so that the defect of synthesizing the polypeptides containing the thioamide by using the traditional phosphorus-sulfur reagent is overcome. Preferably, the invention innovatively provides a method for efficiently constructing the polypeptide compound containing the thioamide by directly using inorganic sulfur reagents with multiple components through a one-pot method under the catalysis of metal copper. The synthesis method is simple, the raw materials are cheap and easy to obtain, the substrate universality is wide, and the yield (33% -92%) is better. Dipeptide, tripeptide, tetrapeptide and peptide-drug coupling compounds can be successfully obtained by the synthesis strategy developed by the invention, and the compound has great potential in the future drug development field.
Detailed Description
The present invention will be described in further detail with reference to the following specific examples. The procedures, conditions, experimental methods and the like for carrying out the present invention are general knowledge and common general knowledge in the art except for the contents specifically mentioned below, and the present invention is not particularly limited.
In the examples 1 to 59 of the present invention, the reaction temperature was 50 ℃.
Example 1
Synthesis of compound 3 a:
Figure BDA0003323300600000051
preparation of Compound 3a to a reaction tube under an air atmosphere was added aminoaldehyde 1a (28.3mg,0.1mmol), S8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S.9H2O (28.8mg,0.12mmol), glycine methyl ester hydrochloride (25.0mg,0.2mmol) and the redistilled solvent THF (1mL) were reacted at 50 ℃ for 10 hours. After the reaction is finished, extracting, concentrating, and performing column chromatography (V)PE/VEA2/1) to yield 33.2mg of 3a as a colorless oil (PE/EA 2:1, R)f0.5), the yield was 86%.1H NMR(400MHz,CDCl3)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).13C NMR(101MHz,CDCl3)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 C20H22N2O4S386.1300, Found 386.1297. ee: 92%, HPLC assay parameters (Daicel chiralpak AD, n-hexane/isopropanol 70/30, flow rate 1.0mL/min, column oven temperature 30 ℃, wavelength 254nm) tR 13.997min (main), tR 8.703min (secondary).
Example 2
Synthesis of compound 3 b:
Figure BDA0003323300600000052
preparation of Compound 3b amino aldehyde 1b (24.9mg,0.1mmol), S was added to a reaction tube under air atmosphere8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S·9H2O (28.8mg,0.12mmol), glycine methyl ester hydrochloride (25.0mg,0.2mmol) and the redistilled solvent THF (1mL) were reacted at 50 ℃ for 10 hours. After the reaction is finished, extracting, concentrating, and performing column chromatography (V)PE/VEA5/1) to give 29.2mg of 3b as a colourless oil (PE/EA: 5:1, R)f0.5), the yield was 83%.1H NMR(400MHz,CDCl3)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).13C NMR(101MHz,CDCl3)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 C17H24N2O4NaS 375.1349, Found 375.1346. ee: 85%, HPLC detection parameters (Daicel chiralpak AD, n-hexane/isopropanol 85/15, flow rate 1.0mL/min, column oven temperature 30 ℃, wavelength 254nm) tR 7.890min (main), tAnd R is 7.107min (secondary).
Example 3
Synthesis of compound 3 c:
Figure BDA0003323300600000061
preparation of Compound 3c amino aldehyde 1c (23.3mg,0.1mmol), S was added to a reaction tube under air atmosphere8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S·9H2O (28.8mg,0.12mmol), glycine methyl ester hydrochloride (25.0mg,0.2mmol) and the redistilled solvent THF (1mL) were reacted at 50 ℃ for 10 hours. After the reaction is finished, extracting, concentrating, and performing column chromatography (V)PE/VEA5/1) to give 28.2mg of colorless oil 3c (PE/EA 5:1, R)f0.5), yield was 84%.1H NMR(400MHz,CDCl3)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).13C NMR(101MHz,CDCl3)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 C16H21N2O4S337.1217 with Found 337.1208 ee value 83%. the HPLC assay parameters (Daicel chiralpak AD, n-hexane/isopropanol 85/15, flow rate 1.0mL/min, column oven temperature 30 ℃, wavelength 254nm) tR 12.737min (primary), tR 10.183min (secondary).
Example 4
Synthesis of compound 3 d:
Figure BDA0003323300600000071
preparation of Compound 3d amino aldehyde 1d (37.1mg,0.1mmol), S was added to a reaction tube under air atmosphere8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S·9H2O (28.8mg,0.12mmol), glycine methyl ester hydrochloride (25.0mg,0.2mmol) and the redistilled solvent THF (1mL) were reacted at 50 ℃ for 10 hours. After the reaction is finished, extracting, concentrating, and performing column chromatography (V)PE/VEA3/1) to yield 38.3mg of 3d as a colorless oil (PE/EA: 5:1, R)f0.3), the yield was 81%.1H NMR(400MHz,CDCl3)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).13C NMR(101MHz,CDCl3)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 C27H27N2O4S475.1686 with a Found 475.1680 ee value of 82%. detection parameters for HPLC (Daicel chiralpak ID, n-hexane/isopropanol 70/30, flow rate 1.0mL/min, column oven temperature 30 ℃, wavelength 254nm) tR 11.607min (primary), tR 8.890min (secondary).
Example 5
Synthesis of compound 3 e:
Figure BDA0003323300600000072
preparation of Compound 3e amino aldehyde 1a (28.3mg,0.1mmol), S was added to a reaction tube under air atmosphere8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S·9H2O (28.8mg,0.12mmol), glycine benzyl ester hydrochloride (40.2mg,0.2mmol) and the redistilled solvent THF (1mL) were reacted at 50 ℃ for 10 hours. After the reaction is finished, extracting, concentrating, and performing column chromatography (V)PE/VEA3/1) to give 31.4mg of 3e as a colourless oil (PE/EA: 3:1, R)f0.5), yield was 68%.1H NMR(400MHz,CDCl3)1H NMR(400MHz,CDCl3)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).13C NMR(101MHz,CDCl3)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 C26H27N2O4S463.1686, Found 463.1677.ee value 78%. detection parameters for HPLC (Daicel chiralpak AD, n-hexane/isopropanol 70/30, flow rate 1.0mL/min, column oven temperature 30 ℃, wavelength 254nm) tR 14.343min (main), tR 11.760min (secondary).
Example 6
Synthesis of compound 3 f:
Figure BDA0003323300600000081
preparation of Compound 3f amino aldehyde 1a (28.3mg,0.1mmol), S was added to a reaction tube under air atmosphere8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S·9H2O (28.8mg,0.12mmol), glycine tert-butyl ester hydrochloride (33.2mg,0.2mmol) and the redistilled solvent THF (1mL) were reacted at 50 ℃ for 10 hours. After the reaction is finished, extracting, concentrating, and performing column chromatography (V)PE/VEA5/1) to yield 35.5mg of colorless oil 3f (PE/EA 5:1, R)f0.5), the yield was 83%.1H NMR(400MHz,CDCl3)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).13C NMR(101MHz,CDCl3)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 C23H28N2O4NaS 451.1662, Found 451.1652.ee value 59%. detection parameters for HPLC (Daicel chiralpak AD, n-hexane/isopropanol 70/30, flow rate 1.0mL/min, column oven temperature 30 ℃, wavelength 59 ℃254nm) tR 11.397min (primary) and tR 10.430min (secondary).
Example 7
Synthesis of Compound 3 g:
Figure BDA0003323300600000082
Figure BDA0003323300600000091
preparation of 3g of Compound 1g (20.7mg,0.1mmol) of aminoaldehyde and S were added to a reaction tube under an air atmosphere8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S·9H2O (28.8mg,0.12mmol), glycine methyl ester hydrochloride (25.0mg,0.2mmol) and the redistilled solvent THF (1mL) were reacted at 50 ℃ for 10 hours. After the reaction is finished, extracting, concentrating, and performing column chromatography (V)PE/VEA3/1) to yield 27.6mg of colorless oil (PE/EA 2:1, R)f0.5), the yield was 89%.1H NMR(400MHz,CDCl3)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).13C NMR(101MHz,CDCl3)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 C14H18N2O4S310.0987, Found 310.0993 ee 91%. HPLC assay parameters (Daicel chiralpak ID, n-hexane/isopropanol 85/15, flow rate 1.0mL/min, column oven temperature 30 ℃, wavelength 254nm) tR 17.737min (primary), tR 25.600min (secondary).
Example 8
Synthesis of compound 3 h:
Figure BDA0003323300600000092
preparation of Compound 3h in air atmosphereNext, amino aldehyde (24.9mg,0.1mmol), S was added to the reaction tube for 1h8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S·9H2O (28.8mg,0.12mmol), glycine methyl ester hydrochloride (25.0mg,0.2mmol) and the redistilled solvent THF (1mL) were reacted at 50 ℃ for 10 hours. After the reaction is finished, extracting, concentrating, and performing column chromatography (V)PE/VEA3/1) to give 27.6mg of colorless oil 3h (PE/EA: 2:1, R)f0.5), the yield was 87%.1H NMR(400MHz,CDCl3)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).13C NMR(101MHz,CDCl3)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 C17H24N2O4S352.1457, Found 352.1451.ee value 94%. HPLC assay parameters (Daicel chiralpak ID, n-hexane/isopropanol 85/15, flow rate 1.0mL/min, column oven temperature 30 ℃, wavelength 254nm) tR 14.113min (main), tR 11.100min (secondary).
Example 9
Synthesis of compound 3 i:
Figure BDA0003323300600000101
preparation of Compound 3i amino aldehyde 1i (23.3mg,0.1mmol), S was added to a reaction tube under air atmosphere8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S·9H2O (28.8mg,0.12mmol), glycine methyl ester hydrochloride (25.0mg,0.2mmol) and the redistilled solvent THF (1mL) were reacted at 50 ℃ for 10 hours. After the reaction is finished, extracting, concentrating, and performing column chromatography (V)PE/VEA2/1) to give 30.1mg of 3i as a colourless oil (PE/EA: 2:1, R)f0.5), the yield was 92%.1H NMR(400MHz,CDCl3～50:50mixture 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).13C NMR(101MHz,CDCl3)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 C16H20N2O4S336.1144, Found 336.1138.ee value 96%. HPLC assay parameters (Daicel chiralpak ID, n-hexane/isopropanol 70/30, flow rate 1.0mL/min, column oven temperature 30 ℃, wavelength 254nm) tR 14.387min (major), tR 9.560min (minor).
Example 10
Synthesis of compound 3 j:
Figure BDA0003323300600000102
preparation of Compound 3j by charging aminoaldehyde 1j 19.3mg,0.1mmol), S into a reaction tube under an air atmosphere8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S·9H2O (28.8mg,0.12mmol), alanine methyl ester hydrochloride (27.8mg,0.2mmol) and the redistilled solvent THF (1mL) were reacted at 50 ℃ for 10 hours. After the reaction is finished, extracting, concentrating, and performing column chromatography (V)PE/VEA3/1) to yield 26.7mg of 3j (PE/EA 3:1, R) as a colorless oilf0.5), the yield was 86%.1H NMR(400MHz,CDCl3)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).13C NMR(101MHz,CDCl3)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 C14H18N2O4S310.0987, Found 310.0989.ee value is>99% detection parameters of HPLC (Daicel chiralpak ID, n-hexane/isopropanol 85/15, flow rate 1.0mL/min, column oven temperature 30 ℃, wavelength 254nm) tR 21.283min (primary) and tR 31.990min (secondary).
Example 11
Synthesis of compound 3 k:
Figure BDA0003323300600000111
preparation of Compound 3k amino aldehyde 1j 19.3mg,0.1mmol), S was added to a reaction tube under air atmosphere8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S·9H2O (28.8mg,0.12mmol), valine methyl ester hydrochloride (33.4mg,0.2mmol) and the redistilled solvent THF (1mL) were reacted at 50 ℃ for 10 hours. After the reaction is finished, extracting, concentrating, and performing column chromatography (V)PE/VEA3/1) to give 25.3mg of colorless oil 3k (PE/EA: 3:1, R)f0.5), the yield was 75%.1H NMR(400MHz,CDCl3)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).13C NMR(101MHz,CDCl3)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 C14H18N2O4S310.0987, Found 310.0989.ee value is>HPLC assay parameters (Daicel chiralpak ID, n-hexane/isopropanol 85/15, flow rate 1.0mL/min, column oven temperature 30 ℃, wavelength 254nm) tR 13.703min (primary), tR 20.480min (secondary).
Example 12
Synthesis of compound 3 l:
Figure BDA0003323300600000121
preparation of Compound 3l amino aldehyde 1j 19.3mg,0.1mmol), S was added to a reaction tube under an air atmosphere8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S·9H2O (28.8mg,0.12mmol), leucine methyl ester hydrochloride (36.2 mg)0.2mmol) and the redistilled solvent THF (1mL) at 50 ℃ for 10 hours. After the reaction is finished, extracting, concentrating, and performing column chromatography (V)PE/VEA3/1) to give 21.8mg of 3l as a colourless oil (PE/EA: 3:1, R)f0.5), the yield was 62%.1H NMR(400MHz,CDCl3)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).13C NMR(101MHz,CDCl3)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 C17H24N2O4S352.1457, Found 352.1461.ee value>HPLC assay parameters (Daicel chiralpak ID, n-hexane/isopropanol 85/15, flow rate 1.0mL/min, column oven temperature 30 ℃, wavelength 254nm) tR 10.463min (primary), tR 14.463min (secondary).
Example 13
Synthesis of compound 3 m:
Figure BDA0003323300600000122
preparation of Compound 3m by charging aminoaldehyde 1j 19.3mg,0.1mmol), S into a reaction tube under an air atmosphere8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S·9H2O (28.8mg,0.12mmol), phenylalanine methyl ester hydrochloride (43.1mg,0.2mmol) and the redistilled solvent THF (1mL) were reacted at 50 ℃ for 10 hours. After the reaction is finished, extracting, concentrating, and performing column chromatography (V)PE/VEA3/1) to give 22.8mg of colorless oil 3m (PE/EA: 3:1, R)f0.5), the yield was 59%.1H NMR(400MHz,CDCl3)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).13C NMR(101MHz,CDCl3)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 C20H22N2O4S386.1300 with Found 386.1305.ee value of>HPLC assay parameters (Daicel chiralpak ID, n-hexane/isopropanol 85/15, flow rate 1.0mL/min, column oven temperature 30 ℃, wavelength 254nm) tR 13.340min (primary), tR 11.830min (secondary).
Example 14
Synthesis of compound 3 n:
Figure BDA0003323300600000131
preparation of Compound 3n by charging aminoaldehyde 1j 19.3mg,0.1mmol), S into a reaction tube under an air atmosphere8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S·9H2O (28.8mg,0.12mmol), methionine methyl ester hydrochloride (32.8mg,0.2mmol) and the redistilled solvent THF (1mL) were reacted at 50 ℃ for 10 hours. After the reaction is finished, extracting, concentrating, and performing column chromatography (V)PE/VEA3/1) to yield 27.0mg of colorless oil 3n (PE/EA 3:1, R)f0.5), the yield was 73%.1H NMR(400MHz,CDCl3)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).13C NMR(101MHz,CDCl3)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 C16H22N2O4S2370.1021, Found 370.1023.ee value of>HPLC assay parameters (Daicel chiralpak ID, n-hexane/isopropanol 85/15, flow rate 1.0mL/min, column oven temperature 30 ℃, wavelength 254nm) tR 13.930min (primary), tR 12.077min (secondary).
Example 15
Synthesis of compound 3 o:
Figure BDA0003323300600000132
preparation of Compound 3o by charging aminoaldehyde 1j 19.3mg,0.1mmol), S into a reaction tube under air atmosphere8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S·9H2O (28.8mg,0.12mmol), serine methyl ester hydrochloride (31.0mg,0.2mmol) and the redistilled solvent THF (1mL) were reacted at 50 ℃ for 10 hours. After the reaction is finished, extracting, concentrating, and performing column chromatography (V)PE/VEA3/1) to give 24.1mg of colorless oil 3o (PE/EA: 3:1, R)f0.5), the yield was 74%.1H NMR(400MHz,CDCl3)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).13C NMR(101MHz,CDCl3)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 C14H18N2O5S326.0936, Found 326.0931.ee value is>HPLC assay parameters (Daicel chiralpak AD, n-hexane/isopropanol 80/20, flow rate 1.0mL/min, column oven temperature 30 ℃, wavelength 254nm) tR 14.540min (primary), tR 11.637min (secondary).
Example 16
Synthesis of compound 3 p:
Figure BDA0003323300600000141
preparation of Compound 3p in air atmosphere, amino aldehyde 1j 19.3mg,0.1mmol), S was added to a reaction tube8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S·9H2O (28.8mg,0.12mmol), tyrosine methyl ester hydrochloride (46.2mg,0.2mmol) and the redistilled solvent THF (1mL) were reacted at 50 ℃ for 10 hours. After the reaction is finished, extracting, concentrating, and performing column chromatography (V)PE/VEA22.9mg of 3P (P) as a colorless oil were isolated as 1/1E/EA＝1:1,Rf0.5), the yield was 57%.1H NMR(400MHz,CDCl3)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).13C NMR(101MHz,CDCl3)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 C20H23N2O5S403.1322, Found 403.13141.ee value is>HPLC assay parameters (Daicel chiralpak ID, n-hexane/isopropanol 70/30, flow rate 1.0mL/min, column oven temperature 30 ℃, wavelength 254nm) tR 10.030min (primary), tR 17.653min (secondary).
Example 17
Synthesis of compound 3 q:
Figure BDA0003323300600000151
preparation of Compound 3q in air atmosphere, amino aldehyde 1j 19.3mg,0.1mmol), S was added to a reaction tube8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S·9H2O (28.8mg,0.12mmol), tryptophan methyl ester hydrochloride (20.8mg,0.2mmol) and the redistilled solvent THF (1mL) were reacted at 50 ℃ for 10 hours. After the reaction is finished, extracting, concentrating, and performing column chromatography (V)PE/VEA3/1) to give 31.9mg of colorless oil 3q (PE/EA: 3:1, R)f0.5), the yield was 75%.1H NMR(400MHz,CDCl3)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).13C NMR(101MHz,CDCl3)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 C22H23N3O4An S425.1409 Found 425.1412. ee value of>HPLC assay parameters (Daicel chiralpak ID, n-hexane/isopropanol 70/30, flow rate 1.0mL/min, column oven temperature 30 ℃, wavelength 254nm) tR 15.163min (primary), tR 31.783min (secondary).
Example 18
Synthesis of compound 3 r:
Figure BDA0003323300600000152
preparation of Compound 3r by charging aminoaldehyde 1j 19.3mg,0.1mmol), S into a reaction tube under an air atmosphere8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S·9H2O (28.8mg,0.12mmol), glutamic acid dimethyl ester hydrochloride (42.2mg,0.2mmol) and the redistilled solvent THF (1mL) were reacted at 50 ℃ for 10 hours. After the reaction is finished, extracting, concentrating, and performing column chromatography (V)PE/VEA3/1) to give 30.2mg of colorless oil 3R (PE/EA: 3:1, R)f0.5), the yield was 79%.1H NMR(400MHz,CDCl3)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).13C NMR(101MHz,CDCl3)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 C17H22N2O6S382.1199, Found 382.1194.ee value is>HPLC assay parameters (Daicel chiralpak AD, n-hexane/isopropanol 85/15, flow rate 1.0mL/min, column oven temperature 30 ℃, wavelength 254nm) tR 17.493min (primary), tR 18.710min (secondary).
Example 19
Synthesis of compound 3 s:
Figure BDA0003323300600000161
preparation of Compound 3S amino aldehyde 1j (19.3mg,0.1mmol), S was added to a reaction tube under an air atmosphere8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S.9H2O (28.8mg,0.12mmol), N6 (tert-butylcarbonyl) -L-lysine methyl ester hydrochloride (32.2mg,0.2mmol) and the redistilled solvent THF (1mL) were reacted at 50 ℃ for 10 hours. After the reaction is finished, extracting, concentrating, and performing column chromatography (V)PE/VEA3/1) to give 32.2mg of colorless oil 3s (PE/EA: 3:1, R)f0.5), the yield was 69%.1H NMR(400MHz,CDCl3)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).13C NMR(101MHz,CDCl3)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 C22H33N3O6S467.2090, Found 467.2083.ee value is>HPLC assay parameters (Daicel chiralpak ID, n-hexane/isopropanol 70/30, flow rate 1.0mL/min, column oven temperature 30 ℃, wavelength 254nm) tR 12.937min (primary), tR 25.547min (secondary).
Example 20
Synthesis of compound 4 a:
Figure BDA0003323300600000171
preparation of Compound 4a to a reaction tube in an air atmosphere was added aminoaldehyde 1 a' (26.4mg,0.1mmol), S8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S·9H2O (28.8mg,0.12mmol), alanine methyl ester hydrochloride (27.9mg,0.2mmol) and redistilled solutionThe reagent THF (1mL) was reacted at 50 ℃ for 10 hours. After the reaction is finished, extracting, concentrating, and performing column chromatography (V)PE/VEA3/1) to give 21.3mg of colorless oil 4a (PE/EA: 3:1, R)f0.5), the yield was 56%.1H NMR(400MHz,CDCl3)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).13C NMR(101MHz,CDCl3)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 C17H23N3O5S381.1358, Found 381.1351.ee value is>HPLC assay parameters (Daicel chiralpak AD, n-hexane/isopropanol 85/15, flow rate 1.0mL/min, column oven temperature 30 ℃, wavelength 254nm) tR 13.037min (primary), tR 15.133min (secondary).
Example 21
Synthesis of compound 4 b:
Figure BDA0003323300600000172
preparation of Compound 4b amino aldehyde 1 a' (26.4mg,0.1mmol), S was added to a reaction tube under air atmosphere8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S.9H2O (28.8mg,0.12mmol), leucine methyl ester hydrochloride (36.2mg,0.2mmol) and the redistilled solvent THF (1mL) were reacted at 50 ℃ for 10 hours. After the reaction is finished, extracting, concentrating, and performing column chromatography (V)PE/VEA3/1) to give 23.3mg of 4b as a colourless oil (PE/EA: 3:1, R)f0.5), yield was 55%.1H NMR(400MHz,CDCl3)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).13C NMR(101MHz,CDCl3)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 C20H29N3O5S423.1828, Found 423.1826.ee value is>HPLC assay parameters (Daicel chiralpak AD, n-hexane/isopropanol 90/10, flow rate 1.0mL/min, column oven temperature 30 ℃, wavelength 254nm) tR 15.177min (primary), tR 11.400min (secondary).
Example 22
Synthesis of compound 4 c:
Figure BDA0003323300600000181
preparation of Compound 4c amino aldehyde 1 a' (26.4mg,0.1mmol), S was added to a reaction tube under air atmosphere8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S·9H2O (28.8mg,0.12mmol), methionine methyl ester hydrochloride (26.4mg,0.2mmol) and the redistilled solvent THF (1mL) were reacted at 50 ℃ for 10 hours. After the reaction is finished, extracting, concentrating, and performing column chromatography (V)PE/VEA3/1) to give 16.7mg of colorless oil 4c (PE/EA 3:1, R)f0.5), the yield was 38%.1H NMR(400MHz,CDCl3)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).13C NMR(101MHz,CDCl3)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 C19H27N3O5S2441.1392 Found 441.1386.ee value is>HPLC assay parameters (Daicel chiralpak AD, n-hexane/isopropanol 85/15, flow rate 1.0mL/min, column oven temperature 30 ℃, wavelength 254nm) tR 13.587min (primary), tR 19.503min (secondary).
Example 23
Synthesis of compound 4 d:
Figure BDA0003323300600000191
preparation of Compound 4d amino aldehyde 1 d' (34.0mg,0.1mmol), S was added to a reaction tube under an air atmosphere8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S.9H2O (28.8mg,0.12mmol), phenylalanine methyl ester hydrochloride (26.4mg,0.2mmol) and the redistilled solvent THF (1mL) were reacted at 50 ℃ for 10 hours. After the reaction is finished, extracting, concentrating, and performing column chromatography (V)PE/VEA3/1) to give 30.6mg of 4d as a colourless oil (PE/EA: 3:1, R)f0.5), the yield was 67%.1H NMR(300MHz,CDCl3)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).13C NMR(101MHz,CDCl3)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 C23H27N3O5S457.1671, Found 457.1677.ee value is>HPLC assay parameters (Daicel chiralpak OJ, n-hexane/isopropanol 80/20, flow rate 1.0mL/min, column oven temperature 30 ℃, wavelength 254nm) tR 26.443min (primary), tR 20.930min (secondary).
Example 24
Synthesis of compound 4 e:
Figure BDA0003323300600000192
preparation of Compound 4e amino aldehyde 1 d' (34.0mg,0.1mmol), S was added to a reaction tube under an air atmosphere8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S.9H2O (28.8mg,0.12mmol), b leucine methyl ester hydrochloride (26.4mg,0.2mmol) and the redistilled solvent THF (1mL) were reacted at 50 ℃ for 10 hours. After the reaction is finished, extracting, concentrating, and performing column chromatography (V)PE/VEA3/1) to give 28.9mg of 4e as a colourless oil (PE/EA: 3:1, R)f0.5), the yield was 58%.1H NMR(400MHz,CDCl3)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)..13C NMR(101MHz,CDCl3)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 C26H33N3NaO5S522.2039, Found 522.2059.ee value is>HPLC assay parameters (Daicel chiralpak AD, n-hexane/isopropanol 90/10, flow rate 1.0mL/min, column oven temperature 30 ℃, wavelength 254nm) tR 21.530min (primary), tR 18.090min (secondary).
Example 25
Synthesis of compound 4 f:
Figure BDA0003323300600000201
preparation of Compound 4f amino aldehyde 1 j' (19.3mg,0.1mmol), S was added to a reaction tube under an air atmosphere8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S.9H2O (28.8mg,0.12mmol), 2 f' (77.8mg,0.2mmol) and the redistilled solvent THF (1mL) were reacted at 50 ℃ for 10 hours. After the reaction is finished, extracting, concentrating, and performing column chromatography (V)PE/VEA3/1) to give 16.5mg of colorless oil 4f (PE/EA 3:1, R)f0.5), the yield was 33%.1H NMR(400MHz,CDCl3)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).13C NMR(101MHz,CDCl3)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 C26H33N3O5S499.2141, Found 499.2138 ee 98%. HPLC assay parameters (Daicel chiralpak AD, n-hexane/isopropanol 85/15, flow rate 1.0mL/min, column oven temperature 30 ℃, wavelength 254nm) tR 19.247min (main), tR 12.813min (secondary).
Example 26
Synthesis of Compound 4 g:
Figure BDA0003323300600000211
preparation of 4g Compound 4g aminoaldehyde 1a (28.3mg,0.1mmol), S was added to a reaction tube under air atmosphere8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S.9H2O (28.8mg,0.12mmol), 2 g' (36.4mg,0.2mmol) and the redistilled solvent THF (1mL) were reacted at 50 ℃ for 10 hours. After the reaction is finished, extracting, concentrating, and performing column chromatography (V)PE/VEA3/1) to give 29.2mg of colorless oil 4g (PE/EA: 3:1, R)f0.5), the yield was 66%.1H NMR(400MHz,CDCl3)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).13C NMR(101MHz,CDCl3)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 C22H25N3O5S443.1515 with a Found 443.1519 ee value of 80%. the detection parameters for HPLC (Daicel chiralpak AD, n-hexane/isopropanol 85/15, flow rate 1.0mL/min, column oven temperature 30 ℃, wavelength 254nm) tR 21.227min (main), tR 35.833min (secondary).
Example 27
Synthesis of compound 4 h:
Figure BDA0003323300600000212
preparation of Compound 4h by charging aminoaldehyde 1 d' (34.0mg,0.1mmol), S into a reaction tube under air atmosphere8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S.9H2O (28.8mg,0.12mmol), 2 h' (44.8mg,0.2mmol) and the redistilled solvent THF (1mL) were reacted at 50 ℃ for 10 hours. After the reaction is finished, extracting, concentrating, and performing column chromatography (V)PE/VEA3/1) to give 26.5mg of colorless oil 4g (PE/EA: 3:1, R)f0.5), yield was 49%.1H NMR(400MHz,CDCl3)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).13C NMR(101MHz,CDCl3)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 C27H34N4O6S 542.2199,Found 542.2184.
Example 28
Synthesis of compound 4 i:
Figure BDA0003323300600000221
preparation of Compound 4i by charging the reaction tube under an air atmosphereAmino aldehyde 1 d' (34.0mg,0.1mmol), S8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S.9H2O (28.8mg,0.12mmol), 2 i' (47.6mg,0.2mmol) and the redistilled solvent THF (1mL) were reacted at 50 ℃ for 10 hours. After the reaction is finished, extracting, concentrating, and performing column chromatography (V)PE/VEA3/1) to give 4g (PE/EA: 3:1, R) as a colorless oil (28.3 mg)f0.5), the yield was 51%.1H NMR(400MHz,CDCl3)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).13C NMR(101MHz,CDCl3)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 C28H36N4O6S 556.2356,Found 556.2363.
Example 29
Synthesis of compound 4 j:
Figure BDA0003323300600000222
preparation of Compound 4j amino aldehyde 1 d' (34.0mg,0.1mmol), S was added to a reaction tube under an air atmosphere8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S.9H2O (28.8mg,0.12mmol), 2 j' (54.4mg,0.2mmol) and the redistilled solvent THF (1mL) were reacted at 50 ℃ for 10 hours. After the reaction is finished, extracting, concentrating, and performing column chromatography (V)PE/VEA3/1) to give 26.0mg of colorless oil 4g (PE/EA: 3:1, R)f0.5), the yield was 61%.1H 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).13C 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 C31H34N4O6SNa 613.2097,Found 613.2075.
Example 30
Synthesis of compound 4 k:
Figure BDA0003323300600000231
preparation of Compound 4k amino aldehyde 1 k' (24.7mg,0.1mmol), S was added to a reaction tube under air atmosphere8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S.9H2O (28.8mg,0.12mmol), alanine methyl ester hydrochloride (27.8mg,0.2mmol) and the redistilled solvent THF (1mL) were reacted at 50 ℃ for 10 hours. After the reaction is finished, extracting, concentrating, and performing column chromatography (V)PE/VEA3/1) to yield 22.2mg of 4k as a colorless oil (PE/EA 3:1, R)f0.5), the yield was 61%.1H NMR(400MHz,CDCl3)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).13C NMR(101MHz,CDCl3)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 C19H28N2O3S364.1821, Found 364.1819 ee 97%, HPLC assay parameters (Daicel chiralpak ID, n-hexane/isopropanol 85/15, flow rate 1.0mL/min, column oven temperature 30 ℃, wavelength 254nm) tR 9.627min (main), tR 12.937min (secondary).
Example 31
Synthesis of Compound 4 l:
Figure BDA0003323300600000241
preparation of Compound 4l amino aldehyde 1 k' (24.7mg,0.1mmol), S was added to a reaction tube under an air atmosphere8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S·9H2O (28.8mg,0.12mmol), leucine methyl ester hydrochloride (36.2mg,0.2mmol) and the redistilled solvent THF (1mL) were reacted at 50 ℃ for 10 hours. After the reaction is finished, extracting, concentrating, and performing column chromatography (V)PE/VEA3/1) to give 21.1mg of 4l as a colourless oil (PE/EA: 3:1, R)f0.5), the yield was 52%.1H NMR(400MHz,CDCl3)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).13C NMR(101MHz,CDCl3)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 C22H34N2O3S406.2290, Found 406.2283.ee value is>HPLC assay parameters (Daicel chiralpak ID, n-hexane/isopropanol 95/05, flow rate 1.0mL/min, column oven temperature 30 ℃, wavelength 254nm) tR 10.317min (primary), tR 7.620min (secondary).
Example 32
Synthesis of compound 4 m:
Figure BDA0003323300600000242
preparation of Compound 4m amino aldehyde 1 m' (27.1mg,0.1mmol), S was added to a reaction tube under an air atmosphere8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S.9H2O (28.8mg,0.12mmol), alanine methyl ester hydrochloride (27.8mg,0.2mmol) and the redistilled solvent THF (1mL) were reacted at 50 ℃ for 10 hours. After the reaction is finished, extracting, concentrating, and performing column chromatography (V)PE/VEA3/1) to give 28.7mg of colorless oil 4m (PE/EA: 3:1, R)f0.5), the yield was 74%.1H NMR(400MHz,CDCl3)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).13C NMR(101MHz,CDCl3)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 C20H24N2O4S388.1457, Found 388.1451.ee value is>HPLC assay parameters (Daicel chiralpak AD, n-hexane/isopropanol 85/15, flow rate 1.0mL/min, column oven temperature 30 ℃, wavelength 254nm) tR 15.093min (primary), tR 12.697min (secondary).
Example 33
Synthesis of compound 4 n:
Figure BDA0003323300600000251
preparation of Compound 4n amino aldehyde 1 n' (30.9mg,0.1mmol), S was added to a reaction tube under an air atmosphere8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S.9H2O (27.8mg,0.12mmol), alanine methyl ester hydrochloride (27.8mg,0.2mmol) and the redistilled solvent THF (1mL) were reacted at 50 ℃ for 10 hours. After the reaction is finished, extracting, concentrating, and performing column chromatography (V)PE/VEA3/1) to yield 22.1mg of 4n as a colorless oil (PE/EA 3:1, R)f0.5), the yield was 52%.1H NMR(400MHz,CDCl3)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).13CNMR(101MHz,CDCl3)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 C22H22N2O5S426.1249, Found 426.1246.ee value is>HPLC assay parameters (Daicel chiralpak AD, n-hexane/isopropanol 70/30, flow rate 1.0mL/min, column oven temperature 30 ℃, wavelength 254nm) tR 13.893min (primary), tR 16.260min (secondary).
Example 34
Synthesis of compound 4 o:
Figure BDA0003323300600000261
preparation of Compound 4o amino aldehyde 1 n' (30.9mg,0.1mmol), S was added to a reaction tube under an air atmosphere8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S.9H2O (27.8mg,0.12mmol), leucine methyl ester hydrochloride (36.2mg,0.2mmol) and the redistilled solvent THF (1mL) were reacted at 50 ℃ for 10 hours. After the reaction is finished, extracting, concentrating, and performing column chromatography (V)PE/VEA3/1) to give 16.4mg of colorless oil 4o (PE/EA: 3:1, R)f0.5), the yield was 35%.1H NMR(400MHz,CDCl3)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).13C NMR(101MHz,CDCl3)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 C25H28N2O5S468.1719, Found 468.1705.ee value>HPLC assay parameters (Daicel chiralpak AD, n-hexane/isopropanol 85/15, flow rate 1.0mL/min, column oven temperature 30 ℃, wavelength 254nm) tR 25.727min (primary), tR 20.853min (secondary).
Example 35
Synthesis of compound 4 p:
Figure BDA0003323300600000271
preparation of Compound 4p in an air atmosphere, aminoaldehyde 1 n' (30.9mg,0.1mmol), S was added to a reaction tube8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S.9H2O (27.8mg,0.12mmol), methionine methyl ester hydrochloride (39.9mg,0.2mmol) and the redistilled solvent THF (1mL) were reacted at 50 ℃ for 10 hours. After the reaction is finished, extracting, concentrating, and performing column chromatography (V)PE/VEA3/1) to give 23.3mg of 4p as a colourless oil (PE/EA: 3:1, R)f0.5), the yield was 48%.1H NMR(400MHz,CDCl3)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).13C NMR(101MHz,CDCl3)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 C24H26N2O5S2486.1283, Found 486.1277.ee value is>HP LC assay parameters (Daicel chiralpak AD, n-hexane/isopropanol 70/30, flow rate 1.0mL/min, column oven temperature 30 ℃, wavelength 254nm) 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 may occur to those skilled in the art may be incorporated into the invention without departing from the spirit and scope of the inventive concept, which is set forth in the following claims.

Claims (10)

1. A method for synthesizing a sulfamide-containing polypeptide compound, comprising the steps of: in a solvent, taking amino aldehyde, an inorganic sulfur reagent and amino acid as reaction raw materials, and reacting under the action of a catalyst and an additive to obtain a polypeptide compound containing sulfamide, wherein the reaction process is shown as the following reaction formula (I):
Figure FDA0003323300590000011
wherein the content of the first and second substances,
R1hydrogen, alkyl, benzyl, tetrahydropyrrole;
r is carbobenzoxy, fluorenylmethyloxycarbonyl, allyloxycarbonyl, tert-butyloxycarbonyl or alkyl;
R2hydrogen, alkyl, benzyl;
R3alkyl and benzyl.
2. The method of synthesis according to claim 1,
R1hydrogen, methyl, isobutyl, benzyl, tetrahydropyrrole;
r is carbobenzoxy, fluorenylmethyloxycarbonyl, allyloxycarbonyl, tert-butyloxycarbonyl or alkyl;
R2hydrogen, methyl, isopropyl, isobutyl, benzyl;
R3methyl, benzyl and tert-butyl.
3. The method of synthesis according to claim 1,
the 1, 1' is selected from any one or more of phenylalanine, alanine, proline, leucine, glycinal, alanine-glycinal derivatives, phenylalanine-glycinal derivatives, glycine-phenylalanine derivatives, ibuprofen-glycinal derivatives, naproxen-glycinal derivatives and esoximic acid-glycinal derivatives;
the 2, 2' is selected from any one or more 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-butyloxycarbonyl 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 phenylalanine-leucine methyl ester hydrochloride.
4. The method of synthesis according to claim 1, wherein the reaction temperature is 25-100 ℃; the reaction time is 1-12 hours.
5. The method of synthesis of claim 1, wherein the inorganic sulfur reagent is a reactive sulfur source selected from one or more of elemental sulfur, sodium sulfide nonahydrate, potassium sulfide, sodium hydrosulfide, sodium sulfite, potassium thioacetate, and bis (trimethylsilicon sulfide); and/or the catalyst is a copper catalyst and is selected from one or more of cuprous iodide, cuprous bromide, cuprous chloride, copper hexachlorophosphate, copper hexachlorocyanate, copper chloride, copper bromide, copper fluoride, copper acetate, copper bis (acetylacetonate), copper trifluoroacetate, copper oxide and copper sulfate; and/or the additive is selected from one or more of potassium carbonate, sodium carbonate, dipotassium hydrogen carbonate, potassium dihydrogen phosphate, sodium bicarbonate, dodecyl mercaptan, p-methyl benzenethiol, potassium sulfide, sodium sulfide nonahydrate, tetrabutylammonium chloride, tetrabutylammonium iodide and tetrabutylammonium fluoride.
6. The synthetic method of claim 1 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 dosage of the solvent is 0.5-10 mL by taking the dosage of the amino aldehyde as a reference.
7. The method of synthesis according to claim 1, wherein the molar ratio of the aminoaldehyde, the inorganic sulfur reagent, the amino acid, the catalyst, and the additive is 1: (1-5): (1-5): (0.01-0.4): (0.5-5).
8. A sulfamide-containing polypeptide compound obtained by the synthesis method according to any one of claims 1 to 7.
9. A polypeptide compound containing sulfamide is characterized in that the structure of the compound is shown as the following formulas 3 and 4,
Figure FDA0003323300590000021
wherein R is1Hydrogen, alkyl, benzyl and tetrahydropyrrole; r is carbobenzoxy, fluorenylmethyloxycarbonyl, allyloxycarbonyl, tert-butyloxycarbonyl and alkyl; r2Hydrogen, alkyl, benzyl; r3Alkyl and benzyl.
10. The sulfur amide-containing polypeptide compound of claim 9, which comprises:
phenylalanine-glycine derivatives, alanine-glycine derivatives, leucine-glycine derivatives, prolineglycine derivatives, glycine-alanine derivatives, glycine-valine derivatives, glycine-leucine derivatives, glycine-phenylalanine derivatives, glycine-methionine derivatives, glycine-serine derivatives, glycine-tyrosine derivatives, glycine-tryptophan derivatives, glycine-glutamic acid derivatives, glycine-lysine derivatives, alanine-glycine-leucine derivatives, alanine-glycine derivatives, phenylalanine-glycine derivatives, glycine-leucine derivatives, glycine-phenylalanine-leucine derivatives, phenylalanine-glycine derivatives, glycine-arginine derivatives, glycine-tyrosine derivatives, glycine-tryptophan derivatives, glycine-lysine derivatives, glycine-arginine derivatives, glycine-serine derivatives, glycine-tyrosine derivatives, glycine-alanine derivatives, glycine-lysine derivatives, glycine-arginine derivatives, glycine-serine derivatives, glycine-arginine derivatives, glycine-glycine derivatives, glycine-lysine derivatives, glycine-lysine derivatives, and the like, A phenylalanine-glycine-valine derivative, a phenylalanine-glycine-leucine derivative, a phenylalanine-glycine-phenylalanine derivative, an ibuprofen-glycine-alanine derivative, an ibuprofen-glycine-leucine derivative, a naproxen-glycine-alanine derivative, an isoxolone-glycine-leucine derivative, and an isoxolone-glycine-methionine derivative.
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Citations (2)

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CN105294601A (en) * 2015-10-29 2016-02-03 华东师范大学 Thioamide compound and compounding method thereof
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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

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