CN117069781A - Visible light-promoted O-H insertion reaction of DNA encoding diazo compound - Google Patents

Visible light-promoted O-H insertion reaction of DNA encoding diazo compound Download PDF

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CN117069781A
CN117069781A CN202310957138.XA CN202310957138A CN117069781A CN 117069781 A CN117069781 A CN 117069781A CN 202310957138 A CN202310957138 A CN 202310957138A CN 117069781 A CN117069781 A CN 117069781A
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compound
light
dna coding
heteroaryl
dna
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张学景
苏小灿
鄢明
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Sun Yat Sen University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • C07H21/04—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with deoxyribosyl as saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02B—CLIMATE CHANGE MITIGATION TECHNOLOGIES RELATED TO BUILDINGS, e.g. HOUSING, HOUSE APPLIANCES OR RELATED END-USER APPLICATIONS
    • Y02B20/00—Energy efficient lighting technologies, e.g. halogen lamps or gas discharge lamps

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Abstract

The invention provides a visible light-promoted O-H insertion reaction of a DNA coding diazo compound, which is used for preparing the DNA coding ether and ester compounds, and belongs to the technical field of DNA coding compound libraries. The invention adopts DNA coding diazo compound as raw material, and adds hydroxyl-containing compound including alcohol, phenol and carboxylic acid into organic solvent, and completes O-H insertion reaction under the promotion of light with a certain wavelength to synthesize DNA coding compound. The method for synthesizing the ether and ester compounds by using the DNA promoted by visible light has the advantages of no participation of transition metal photocatalyst, mild condition, convenient operation, good substrate universality and high product yield, and is suitable for constructing a DNA coding compound library. The reaction can conveniently introduce bioactive compounds such as natural products and medicines, greatly expands the structural diversity and drug properties of DNA coding compounds, provides theory and material basis for constructing DNA coding bioactive compound libraries and later structural screening, and has important application prospect.

Description

Visible light-promoted O-H insertion reaction of DNA encoding diazo compound
Technical Field
The invention belongs to the technical field of DNA coding compound libraries, and particularly relates to a visible light-promoted O-H insertion reaction of a DNA coding diazo compound.
Background
DNA-encoded library (DEL) technology is one of the forefront technologies in the current field of new drug discovery. The technology aims at the defect that a large number of compounds synthesized by combinatorial chemistry cannot determine the structure of an active compound in the screening process of new drugs, and utilizes the encodability and detectability of DNA (deoxyribonucleic acid) to enable each compound to be connected with a specific DNA segment at the molecular level to record the related information of the structure of the compound. By the method, a large number of compounds can be stored together at the same time, each compound can be identified, and hardware conditions required by traditional compound storage are greatly reduced. The DEL technology has the advantages of extremely large compound quantity, high structural coverage rate, short screening period, small storage space, low operation cost and the like. The concept of DNA-encoded compound libraries has been proposed to make great progress in both library strategies and new drug screening, but the development of DNA-compatible chemical approaches remains a bottleneck limiting the technology. The DNA must exist stably in the water phase, is sensitive to pH, temperature, metal ions, redox reagents and the like, and has extremely low concentration of DNA encoding raw materials, so that the DNA compatible chemical reaction type is insufficient and the coverage rate of the compound structure is low.
In 2019, the professor Baran and Dawson developed a class of organic phase DNA coding compound construction methods based on a resin reversible adsorption (reversible adsorption to solid support, RASS) strategy, and developed a series of DNA compatible solid phase synthesis methods based on the method, which solve the problem that DNA cannot be stably present in an organic solvent (J.Am.chem.Soc.2019, 141, 9998; angew.chem.int.ed.2020, 59, 7377). The photocatalytic free radical reaction has the characteristics of extremely mild conditions and high reactivity at low concentration, and has wider application in the construction of DNA coding compound libraries in recent years. Such reactions require a metal photocatalyst or an organic photocatalyst to convert electrons to completion, and metal residues may affect DNA recovery and screening results of DNA encoding compound libraries. Therefore, the development condition is milder, and the photochemical conversion DNA compatible reaction without participation of transition metal has important research significance.
Carbenes are an important synthetic intermediate with rich and varied chemical convertibility. The X-H bond insertion reaction of carbenes (x=c, N, O, S, si, etc.), cyclopropanation reaction, maillard formation reaction, wolff rearrangement reaction, buchner reaction, etc. have been widely used in the field of organic synthesis and pharmaceutical chemistry (chem.rev.2015, 115, 9981; chem.rev.2017, 117, 13810). At present, conversion of carbenes is generally required to be carried out in the presence of transition metal catalysts. Such conversion reactions tend to cause metal residue problems, greatly limiting the application of such reactions. The diazo compound can remove nitrogen and decompose into free carbene under the irradiation of heating or high-energy ultraviolet light, but the high-energy ultraviolet light and the high heat bring unnecessary side reactions. In recent years, a visible light-promoted carbene conversion reaction has been developed (chem. Soc. Rev.2020, 49, 6833), and the carbene conversion reaction does not need to additionally add a transition metal catalyst and a transition metal photocatalyst, has extremely mild reaction conditions, and can greatly expand the chemical space of a DNA coding compound library when being applied to the construction of DEL.
The invention provides a light-promoted O-H insertion reaction of a DNA coding diazo compound, which is used for preparing the DNA coding ether and ester compounds, and belongs to the technical field of DNA coding compound libraries. The invention adopts DNA coding diazo compound as raw material, adds hydroxyl compound such as alcohol, phenol and carboxylic acid into organic solvent, completes O-H insertion reaction under the promotion of light with a certain wavelength to synthesize DNA coding compound. The light-promoted DNA coding diazo compound O-H insertion reaction provided by the invention has the advantages of no participation of transition metal photocatalyst, mild condition, convenient operation, good substrate universality and high product yield, and is suitable for construction of a DNA coding compound library. The reaction can conveniently introduce bioactive compounds such as natural products and medicines, greatly expands the structural diversity and drug properties of DNA coding compounds, provides theory and material basis for constructing DNA coding bioactive compound libraries and later structural screening, and has important application prospect.
Disclosure of Invention
The invention aims to provide a method for synthesizing a DNA coding compound shown in a formula (I) by using visible light, which is characterized by comprising the following steps:
1) Immobilizing the DNA coding diazo compound with the structure of formula (II) on resin, and washing with an organic solvent;
2) Adding the DNA coded diazo compound with the solid-supported structure shown in the formula (II) and the compound containing hydroxyl with the structure shown in the formula (III) into an organic solvent, reacting for a certain time at a certain temperature under the irradiation of light with a certain wavelength, removing the reaction solvent after the reaction is finished, and washing for a plurality of times;
3) Adding eluent to elute the DNA coding compound with the structure of formula (I), precipitating and centrifuging the product to obtain the DNA coding ether or ester compound with the structure of formula (I).
Wherein:
the DNA is a double-stranded nucleotide sequence obtained by polymerizing an artificially modified/unmodified nucleotide monomer;
the DNA coding diazo compound (formula (II)) is obtained by connecting an amine compound containing a DNA sequence with an aryl diazo compound containing active ester through an amide bond; wherein R is 1 ，R 2 The group is selected from any one or a combination of a plurality of H, alkyl, heteroatom-containing cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkenyl, carbonyl, ester group, sulfonyl and sulfonate group; wherein aryl and heteroaryl are selected from phenyl, biphenyl, naphthyl, indolyl, furyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyridyl, pyrimidinyl, quinolinyl, diazinyl, triazinyl; the substituted aryl or heteroaryl can be monosubstituted aryl or heteroaryl, or polysubstituted aryl or heteroaryl, and the substituent is selected from methyl, ethyl and C 3 ～C 6 Alkyl, C 3 ～C 6 Cycloalkyl, fluoro, chloro, bromo, iodo, nitro, trifluoromethyl, cyano, ester, amide, methoxy, phenyl; alkyl is methyl, ethyl, benzyl, C 3 ～C 18 Straight chain alkyl, C 3 ～C 18 Branched alkyl, C 3 ～C 8 Cycloalkyl of (c); cycloalkyl radicals containing hetero atoms as C 3 ～C 8 Cycloalkyl containing hetero atoms, wherein the hetero atoms may be nitrogen, oxygen, sulfur, selenium, silicon, boron and phosphorus, and may contain one hetero atom or may contain a plurality of hetero atoms; r is R 1 ，R 2 The groups can be the same or different, can be two independent substituents, and can be cyclic;
the compound shown in the formula (III) is a compound containing hydroxyl, can be an alcohol compound or a phenol compound, can be a carboxylic acid compound, can be aliphatic carboxylic acid or aromatic carboxylic acid, and comprises a natural product containing hydroxyl and a drug molecule; the R3 group of the compound shown in the formula (III) is selected from alkyl and C 3 ～C 8 Heteroatom-containing cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl-substituted acyl, aryl-substituted acyl; wherein alkyl is methyl, ethyl, benzyl, C 3 ～C 18 Straight chain alkyl, C 3 ～C 18 Branched alkyl, C 3 ～C 8 Cycloalkyl of (c); c (C) 3 ～C 8 The heteroatom in the heteroatom-containing cycloalkyl group may be nitrogen, oxygen, sulfur, selenium, silicon, boron, and phosphorus; aryl and heteroaryl are selected from phenyl, biphenyl, naphthyl, indolyl, furyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyridyl, pyrimidinyl, quinolinyl, diazinyl, triazinyl; the substituted aryl or heteroaryl can be mono-substituted aryl or heteroaryl or poly-substituted aryl or heteroaryl, and the substituent is selected from methyl, ethyl and C 3 ～C 6 Alkyl, C 3 ～C 6 Cycloalkyl, fluoro, chloro, bromo, iodo, nitro, trifluoromethyl, cyano, ester, amide, methoxy, phenyl.
The organic solvent is one or two of N-methylpyrrolidone, acetonitrile, benzene, toluene, xylene, mesitylene, chlorobenzene, fluorobenzene, pyridine, dichloromethane, dichloroethane, chloroform, acetone, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, diethyl ether, propylene oxide, isopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, 1, 4-dioxane, anisole and water; preferably, the reaction solvent is one or a mixture of two of dichloromethane, dichloroethane, benzene, chlorobenzene and fluorobenzene.
The molar concentration of the compound of the formula (III) is 0.5M, 1.0M, 1.5M and 2.0M; preferably, the molar concentration of the compound is 1.5M.
The light with a certain wavelength is as follows: CFL light, white light, 365nm light, 390nm light, 427nm light, 455nm light, 530nm light; preferably, the light source is 455nm light.
The reaction temperature is room temperature, 20 ℃, 30 ℃, 40 ℃, 60 ℃, 80 ℃, preferably room temperature.
Reaction time the reaction time is 1 hour, 3 hours, 5 hours, 9 hours, 18 hours, preferably the reaction time is 5 hours.
Detailed Description
The invention is further illustrated below with reference to examples, which are not intended to limit the invention.
Example 1
Step 1: synthesis of DNA encoding diazo Compound (II-a)
2, 5-Dioxopyrrolidin-1-yl 4- (1-diazonium-2-methoxy-2-oxoethyl) benzoate (15.9 mg, 50. Mu. Mol) was dissolved in DMA (200. Mu.L), TEA (7.0. Mu.L, 50. Mu. Mol) was added, and the resulting mixed solution was added to a solution of DNA-NH2 (500 nmol) mixed with borax buffer solution (625 mM, pH 9.5, 200. Mu.L) and reacted at room temperature for 3 hours. Ethanol (1.5 mL) and NaCl solution (5M, 0.4 mL) were added to precipitate the DNA encoding diazonium compound (II-a) after the reaction, and the structure of the compound was determined by LC-MS, with a yield of 91%.
Step 2: O-H insertion reaction of DNA encoding diazo Compound (II-a) with phenol (III-a)
DNA encoding diazo compound (II-a, 10 nmol) is immobilized on resin, firstly washed three times by DMA, then washed three times by fluorobenzene, fluorobenzene (0.2 mL) and phenol (III-a, 1.5M) are respectively added, the mixture is irradiated by a 455nm light source and reacted for 5 hours at room temperature, after the reaction is finished, the reaction solvent is removed, washing is carried out for many times, finally eluent (0.25 mL) is added for eluting, then NaCl solution (5M, 0.025 mL) and ethanol (1.5 mL) are added, precipitation and centrifugation are carried out, and the DNA encoding ether compound (I-a) is obtained, and the yield is 91%.
Example 2
By the same method as in example 1, the light source in the reaction of step 2 was replaced with 365nm light source instead of 455nm light source, to obtain DNA encoded ether compound (I-a) in 36% yield.
Example 3
By adopting the same method as in example 1, toluene was used as a reaction solvent in the reaction of step 2 instead of fluorobenzene to obtain a DNA encoded ether compound (I-a) in a yield of 47%.
Example 4
By the same method as in example 1, in the reaction of step 2, III-b was used as a starting material instead of phenol III-a to obtain a DNA encoded ether product (I-b) in 80% yield.
Example 5
By the same method as in example 1, in the reaction of step 2, III-c was used as a starting material instead of phenol III-a to obtain a DNA encoded ether product (I-c) in a yield of 65%.
Example 6
By the same method as in example 1, in the reaction of step 2, III-d was used as a starting material instead of phenol III-a to obtain a DNA encoded ether product (I-d) in a yield of 74%.
Example 7
By the same method as in example 1, in the reaction of step 2, III-e was used as a starting material instead of phenol III-a to obtain a DNA encoded ester product (I-e) in 54% yield.
Example 8
By the same method as in example 1, in the reaction of step 2, III-f was used as a starting material instead of phenol III-a, to obtain a DNA encoded ester product (I-f) in a yield of 66%.
Example 9
By the same method as in example 1, in the reaction of step 2, III-g was used as a starting material instead of phenol III-a to obtain a DNA encoded ester product (I-g) in 73% yield.
Example 10
By the same method as in example 1, in the reaction of step 2, III-h was used as a raw material instead of phenol III-a to obtain a DNA encoded ester product (I-h) in 53% yield.
The specific structural formula of the DNA-head piece related by the invention is as follows:

Claims (6)

1. a method for synthesizing a DNA coding compound shown in a formula (I) promoted by visible light is characterized in that:
1) Immobilizing the DNA coding diazo compound with the structure of formula (II) on resin, and washing with an organic solvent;
2) Adding the DNA coded diazo compound with the solid-supported structure shown in the formula (II) and the compound containing hydroxyl with the structure shown in the formula (III) into an organic solvent, reacting for a certain time at a certain temperature under the irradiation of light with a certain wavelength, removing the reaction solvent after the reaction is finished, and washing for a plurality of times;
3) Adding eluent to elute the DNA coding compound with the structure of formula (I), precipitating and centrifuging the product to obtain the DNA coding ether or ester compound with the structure of formula (I).
Wherein:
the DNA is a double-stranded nucleotide sequence obtained by polymerizing an artificially modified/unmodified nucleotide monomer;
the DNA coding diazo compound (formula (II)) is obtained by connecting an amine compound containing a DNA sequence with an aryl diazo compound containing active ester through an amide bond; wherein R is 1 ，R 2 The group is selected from any one or a combination of a plurality of H, alkyl, heteroatom-containing cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkenyl, carbonyl, ester group, sulfonyl and sulfonate group; wherein aryl and heteroaryl are selected from phenyl, biphenyl, naphthyl, indolyl, furyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyridyl, pyrimidinyl, quinolinyl, diazinyl, triazinyl; the substituted aryl or heteroaryl can be mono-substituted aryl or heteroaryl or poly-substituted aryl or heteroaryl, and the substituent is selected from methyl, ethyl and C 3 ～C 6 Alkyl, C 3 ～C 6 Cycloalkyl, fluoro, chloro, bromo, iodo, nitro, trifluoromethyl, cyano, ester, amide, methoxy, phenyl; alkyl is methyl, ethyl, benzyl, C 3 ～C 18 Straight chain alkyl, C 3 ～C 18 Branched alkyl, C 3 ～C 8 Cycloalkyl of (c); containingHeteroatom cycloalkyl is C 3 ～C 8 Cycloalkyl containing hetero atoms, wherein the hetero atoms may be nitrogen, oxygen, sulfur, selenium, silicon, boron and phosphorus, and may contain one hetero atom or may contain a plurality of hetero atoms; r is R 1 ，R 2 The groups can be the same or different, can be two independent substituents, and can be cyclic;
the compound shown in the formula (III) is a compound containing hydroxyl, can be an alcohol compound or a phenolic compound, can be carboxylic acid, can be aliphatic carboxylic acid or aromatic carboxylic acid, and comprises a natural product containing hydroxyl and a drug molecule; r of the Compound of formula (III) 3 The radicals being selected from alkyl, C 3 ～C 8 Heteroatom-containing cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl-substituted acyl, aryl-substituted acyl; wherein alkyl is methyl, ethyl, benzyl, C 3 ～C 18 Straight chain alkyl, C 3 ～C 18 Branched alkyl, C 3 ～C 8 Cycloalkyl of (c); c (C) 3 ～C 8 The heteroatom in the heteroatom-containing cycloalkyl group may be nitrogen, oxygen, sulfur, selenium, silicon, boron, and phosphorus; aryl and heteroaryl are selected from phenyl, biphenyl, naphthyl, indolyl, furyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyridyl, pyrimidinyl, quinolinyl, diazinyl, triazinyl; the substituted aryl or heteroaryl can be mono-substituted aryl or heteroaryl or poly-substituted aryl or heteroaryl, and the substituent is selected from methyl, ethyl and C 3 ～C 6 Alkyl, C 3 ～C 6 Cycloalkyl, fluoro, chloro, bromo, iodo, nitro, trifluoromethyl, cyano, ester, amide, methoxy, phenyl;
the organic solvent is one or two of N-methylpyrrolidone, acetonitrile, benzene, toluene, xylene, mesitylene, chlorobenzene, fluorobenzene, pyridine, dichloromethane, dichloroethane, chloroform, acetone, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, diethyl ether, propylene oxide, isopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, 1, 4-dioxane, anisole and water; preferably, the reaction solvent is one or a mixture of two of dichloromethane, dichloroethane, benzene, chlorobenzene and fluorobenzene;
the molar concentration of the compound of the formula (III) is 0.5M, 1.0M, 1.5M and 2.0M;
the light with a certain wavelength is as follows: CFL light, white light, 365nm light, 390nm light, 427nm light, 455nm light, 530nm light;
the reaction temperature is room temperature, 20 ℃, 30 ℃, 40 ℃, 60 ℃ and 80 ℃, preferably room temperature;
the reaction time is 1 hour, 3 hours, 5 hours, 9 hours and 18 hours.
2. The method according to claim 1, wherein the reaction solvent is one or a mixture of dichloromethane, dichloroethane, benzene, chlorobenzene and fluorobenzene.
3. The method of claim 1, wherein the molar concentration of the compound is 1.5M.
4. The method of claim 1, wherein the light source is 455nm light.
5. The method of claim 1, wherein the reaction temperature is room temperature.
6. The method of claim 1, wherein the reaction time is preferably 5 hours.
CN202310957138.XA 2023-07-24 2023-07-24 Visible light-promoted O-H insertion reaction of DNA encoding diazo compound Pending CN117069781A (en)

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