CN116789559A - Synthesis method of aspergillin A and analogues thereof - Google Patents
Synthesis method of aspergillin A and analogues thereof Download PDFInfo
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- CN116789559A CN116789559A CN202310516306.1A CN202310516306A CN116789559A CN 116789559 A CN116789559 A CN 116789559A CN 202310516306 A CN202310516306 A CN 202310516306A CN 116789559 A CN116789559 A CN 116789559A
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- FIVPIPIDMRVLAY-UHFFFAOYSA-N aspergillin Natural products C1C2=CC=CC(O)C2N2C1(SS1)C(=O)N(C)C1(CO)C2=O FIVPIPIDMRVLAY-UHFFFAOYSA-N 0.000 title claims abstract description 17
- FIVPIPIDMRVLAY-RBJBARPLSA-N gliotoxin Chemical compound C1C2=CC=C[C@H](O)[C@H]2N2[C@]1(SS1)C(=O)N(C)[C@@]1(CO)C2=O FIVPIPIDMRVLAY-RBJBARPLSA-N 0.000 title claims abstract description 17
- 238000001308 synthesis method Methods 0.000 title claims abstract description 8
- 238000000034 method Methods 0.000 claims abstract description 21
- 241000228212 Aspergillus Species 0.000 claims abstract description 15
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 12
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 11
- RLZXKARDPOFVNB-UHFFFAOYSA-N aziridine-1-carboxylic acid Chemical compound OC(=O)N1CC1 RLZXKARDPOFVNB-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000007142 ring opening reaction Methods 0.000 claims abstract description 5
- 125000006239 protecting group Chemical group 0.000 claims abstract description 4
- 125000003277 amino group Chemical group 0.000 claims abstract description 3
- 230000000269 nucleophilic effect Effects 0.000 claims abstract description 3
- 238000005580 one pot reaction Methods 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 19
- 239000003960 organic solvent Substances 0.000 claims description 16
- 229940125782 compound 2 Drugs 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 13
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 10
- BGXZJSLTGNPDDH-UHFFFAOYSA-N benzenethiol;sodium Chemical compound [Na].SC1=CC=CC=C1 BGXZJSLTGNPDDH-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 229940125898 compound 5 Drugs 0.000 claims description 9
- WPHUUIODWRNJLO-UHFFFAOYSA-N 2-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=CC=C1S(Cl)(=O)=O WPHUUIODWRNJLO-UHFFFAOYSA-N 0.000 claims description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- 229940125904 compound 1 Drugs 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 230000035484 reaction time Effects 0.000 claims description 6
- 229940126214 compound 3 Drugs 0.000 claims description 5
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 5
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- 230000002194 synthesizing effect Effects 0.000 claims description 3
- 238000006561 solvent free reaction Methods 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims 2
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000012512 characterization method Methods 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000007858 starting material Substances 0.000 description 7
- 102000006635 beta-lactamase Human genes 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 4
- 108090000204 Dipeptidase 1 Proteins 0.000 description 3
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 102000020235 metallo-beta-lactamase Human genes 0.000 description 3
- 108060004734 metallo-beta-lactamase Proteins 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- XFTWUNOVBCHBJR-UHFFFAOYSA-N Aspergillomarasmine A Chemical compound OC(=O)C(N)CNC(C(O)=O)CNC(C(O)=O)CC(O)=O XFTWUNOVBCHBJR-UHFFFAOYSA-N 0.000 description 2
- 108020004256 Beta-lactamase Proteins 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 239000003781 beta lactamase inhibitor Substances 0.000 description 2
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000011369 resultant mixture Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 1
- 229940123930 Lactamase inhibitor Drugs 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- FNCGNFXGKHSMKJ-QMMMGPOBSA-N ditert-butyl (2s)-2-aminobutanedioate Chemical compound CC(C)(C)OC(=O)C[C@H](N)C(=O)OC(C)(C)C FNCGNFXGKHSMKJ-QMMMGPOBSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- NBRKLOOSMBRFMH-UHFFFAOYSA-N tert-butyl chloride Chemical compound CC(C)(C)Cl NBRKLOOSMBRFMH-UHFFFAOYSA-N 0.000 description 1
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
- C07D203/02—Preparation by ring-closure
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
The invention provides a synthesis method of aspergillin A and analogues thereof, which adopts a one-pot method to synthesize a large amount of aziridine carboxylic acid ester, then sequentially carries out solvent-free nucleophilic ring-opening reaction on the aziridine carboxylic acid ester, removes protecting groups on amino groups after each ring-opening, and obtains the aspergillin A and analogues thereof. The synthesis process is simple, the condition is mild, the aspergillus A with specific chiral structure and analogues thereof can be selectively synthesized, the yield of the target product is high, and the industrial production is easy to realize.
Description
Technical Field
The invention belongs to the technical field of natural product synthesis, and particularly relates to a synthesis method of aspergillum A and analogues thereof.
Background
In recent years, with the abuse of antibiotics, resistance to antibiotics has become an increasingly serious problem clinically faced worldwide. Bacterial evolution secretes beta-lactamase as its primary cause of drug resistance. Beta-lactamases are classified into serine beta-lactamases and metallo beta-lactamases. Some serine beta-lactamase inhibitors, such as the bartams, have been successfully marketed as pharmaceuticals, but there is currently no safe and effective metallobeta-lactamase inhibitor.
Aspergillum A is proved to be a metal beta-lactamase inhibitor with very good application prospect (A.M.King, S.A.Reid-Yu, W.Wang, et al, aspergillomarasmine A overcomes metallo-beta-lactamase antibiotic resistance, nature,2014,510,503-506.) and has strong inhibition effect on common metal beta-lactamase, thereby being expected to solve the problem of increasingly serious antibiotic resistance caused by the metal beta-lactamase. However, the current chemical synthesis method of the aspergillus A has long steps and low yield, and greatly limits the industrial production of the aspergillus A.
The structures of aspergillin a and its analogues are shown below:
disclosure of Invention
The invention aims to provide a synthesis method of aspergillum A and the like, which has short steps and high yield and is easy to realize industrial production.
In order to achieve the above object of the present invention, the following technical solutions are adopted:
a process for synthesizing aspergillin A and its analogues includes such steps as synthesizing aziridine carboxylate in one pot, sequentially solvent-free nucleophilic ring-opening reaction, removing protecting group from amino group, and removing protecting group.
Preferably, the synthetic route is as follows:
wherein R is 1 ，R 2 Each independently tBu or Bn represents a chiral center.
Preferably, the method specifically comprises the following steps:
(1) Dissolving the compound 1 in an organic solvent, adding o-nitrobenzenesulfonyl chloride, sodium bicarbonate and a small amount of water, and reacting until the compound 1 is basically completely converted; then o-nitrobenzenesulfonyl chloride and sodium hydroxide are sequentially added to react to obtain a compound 2;
(2) Mixing and reacting the compound 2 and the compound 3 to obtain a compound 4;
(3) Dissolving the compound 4 in an organic solvent, adding sodium thiophenol, and reacting to obtain a compound 5;
(4) Mixing and reacting the compound 5 and the compound 2 to obtain a compound 6;
(5) Dissolving the compound 6 in an organic solvent, adding sodium thiophenol, and reacting to obtain a compound 7;
(6) And (3) dissolving the compound 7 in an organic solvent, adding anisole and trifluoromethanesulfonic acid, and reacting to obtain the aspergillus A or the analogue thereof.
Preferably, the reaction temperature in step (1) is 10-40 ℃ and the reaction time is 4-16 hours.
Preferably, the organic solvent in the step (1) is methylene dichloride, and the molar ratio of the o-nitrobenzenesulfonyl chloride to the compound 1 is (1.0-3.0): 1.
Preferably, the reactions in steps (2) and (4) are solvent-free reactions at a temperature of 10-40 ℃ for a period of 1-4 hours.
Preferably, the molar ratio of compound 3 to compound 2 in step (2) is (1.0-1.5): 1; the molar ratio of compound 5 to compound 2 in step (4) is (1.0-1.5): 1.
Preferably, the organic solvent in the step (3) is acetonitrile, the reaction temperature is 10-40 ℃, the reaction time is 0.5-4 hours, and the molar ratio of the sodium thiophenol to the compound 4 is (3.0-5.0): 1.
Preferably, in the step (5), the organic solvent is N, N-dimethylformamide, the reaction temperature is 10-40 ℃, the reaction time is 0.5-4 hours, and the molar ratio of the sodium thiophenol to the compound 6 is (3.0-5.0): 1.
Preferably, in the step (6), the organic solvent is methylene dichloride, the mole ratio of anisole, trifluoromethanesulfonic acid and the compound 7 is (5.0-13.0): 4.0-12.0): 1, the reaction temperature and time are 0.5-2.0 hours at-10-10 ℃, and then 0.5-2.0 hours at 10-40 ℃.
Compared with the prior art, the invention has the following beneficial effects:
(1) The synthesis method of the aspergillus A and the analogue thereof has simple process and mild condition, and can selectively synthesize the aspergillus A and the analogue thereof with specific chiral structures.
(2) The yield of the aspergillus A and the analogue thereof is high.
Drawings
FIG. 1 shows the structure of example 1 of the present invention 1 H nuclear magnetic spectrum.
Detailed Description
The raw materials and equipment used in the invention are all known products and are obtained by purchasing commercial products or the preparation method of reference publications.
Example 1: synthesis of aspergillin a (chiral SSS):
the method comprises the following steps:
(1) To 400mL of methylene chloride and 16mL of water were added, in this order, compound 1 serine tert-butyl hydrochloride (7.9 g,40 mmol), sodium hydrogencarbonate (10.1 g,120 mmol) and o-nitrobenzenesulfonyl chloride (13.3 g,60 mmol), and the mixture was reacted at 25℃for 12 hours. O-nitrobenzenesulfonyl chloride (10.6 g,48 mmol) and sodium hydroxide (9.6 g,240 mmol) were then added in sequence and reacted for 1 hour. After the reaction was completed, anhydrous magnesium sulfate was added to dry, suction filtration was performed, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography to obtain 12.2g of compound 2 (yellowish oily liquid which became a white solid after standing for a long time) in 93% yield.
The structural characterization data for compound 2 are as follows:
1 H NMR(400MHz,CDCl 3 )δ8.26–8.22(m,1H),7.84–7.69(m,3H),3.49(dd,J＝7.1,4.5Hz,1H),3.00(d,J＝7.1Hz,1H),2.71(d,J＝4.4Hz,1H),1.46(s,9H). 13 C NMR(101MHz,CDCl 3 )δ165.54,148.46,134.92,132.60,131.82,131.55,124.74,83.42,38.73,34.09,27.93.
(2) Compound 2 (6.6 g,20 mmol) and compound 3 di-tert-butyl aspartate (5.9 g,24 mols) were mixed and reacted at 25℃for 2 hours without solvent, and the resultant mixture was directly purified by silica gel column chromatography to give 11.1g of compound 4 (yellowish oily liquid which became a white solid after standing for a long time) in 96% yield.
The structural characterization data for compound 4 are as follows:
1 H NMR(400MHz,CDCl 3 )δ8.13–8.01(m,1H),7.93–7.81(m,1H),7.74–7.62(m,2H),6.64(d,J＝8.0Hz,1H),4.16–4.06(m,1H),3.38(dd,J＝6.7,5.5Hz,1H),3.28(dd,J＝12.5,4.2Hz,1H),2.78(dd,J＝12.5,4.4Hz,1H),2.58(dd,J＝16.1,5.5Hz,1H),2.49(dd,J＝16.1,6.8Hz,1H),1.44(s,18H),1.26(s,9H). 13 C NMR(101MHz,CDCl 3 )δ172.59,170.22,169.03,147.91,134.86,133.43,132.75,130.65,125.45,82.72,81.83,81.34,58.87,57.66,50.50,39.49,28.18,28.14,27.83.
(3) Compound 4 (9.2 g,16 mmol) was dissolved in 80mL of acetonitrile, sodium thiophenol (7.4 g,56 mmol) was added, after 30 minutes reaction at 25℃80mL of ethyl acetate and 80mL of water were added, the solution was separated, the aqueous phase was extracted 1 time with 80mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered off with suction, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography to give 5.3g of Compound 5 (yellowish oily liquid) in 85% yield.
The structural characterization data for compound 5 are as follows:
1 H NMR(400MHz,CDCl 3 )δ3.43(dd,J＝7.3,5.7Hz,1H),3.37(dd,J＝7.0,4.1Hz,1H),2.87(dd,J＝11.9,7.0Hz,1H),2.73(dd,J＝11.9,4.2Hz,1H),2.57(dd,J＝15.7,5.7Hz,1H),2.44(dd,J＝15.7,7.3Hz,1H),2.09(s,3H),1.49–1.40(m,27H). 13 C NMR(101MHz,CDCl 3 )δ173.94,172.91,170.26,81.51,81.31,80.99,58.73,55.19,51.30,39.65,28.17,28.15,28.13.
(4) Compound 5 (5.3 g,13.6 mols) and compound 2 (4.3 g,13.2 mols) were mixed and reacted for 2 hours at 25 ℃ without solvent, and the resultant mixture was directly purified by silica gel column chromatography to obtain 7.8g of compound 6 (yellowish oily liquid) in 80% yield.
The structural characterization data for compound 6 are as follows:
1 H NMR(400MHz,CDCl 3 )δ8.08–8.03(m,1H),7.89–7.83(m,1H),7.74–7.64(m,2H),4.10(t,J＝4.6Hz,1H),3.42(t,J＝6.4Hz,1H),3.20–3.08(m,2H),2.86–2.66(m,3H),2.58(dd,J＝16.0,6.4Hz,1H),2.51(dd,J＝15.9,6.5Hz,1H),1.51–1.38(m,27H),1.26(s,9H). 13 C NMR(101MHz,CDCl 3 )δ172.75,172.67,170.27,169.09,147.87,134.81,133.42,132.73,130.56,125.42,82.62,81.68,81.47,80.89,62.31,58.63,57.75,50.25,49.99,39.44,28.15,28.11,28.09,27.80.
(5) Compound 6 (5.4 g,7.5 mmol) was dissolved in 20mL of N, N-dimethylformamide, sodium thiophenol (3.5 g,26.3 mmol) was added, after 30 minutes at 25℃150mL of ethyl acetate and 150mL of water were added, the mixture was separated, the aqueous phase was extracted 1 time with 150mL of ethyl acetate, the organic phases were combined, extracted 5 times with 150mL of water, 150mL of saturated saline solution was extracted 1 time, the organic phase was dried over anhydrous sodium sulfate, suction filtration was performed, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography to give 3.3g of Compound 7 (yellowish oily liquid) in 83% yield.
The structural characterization data for compound 7 are as follows:
1 H NMR(400MHz,CDCl 3 )δ3.41(t,J＝6.5Hz,1H),3.38(dd,J＝7.2,4.5Hz,1H),3.19(dd,J＝7.4,4.9Hz,1H),2.81–2.65(m,4H),2.55(dd,J＝15.8,6.2Hz,1H),2.46(dd,J＝15.8,6.7Hz,1H),2.01(s,4H),1.47–1.34(m,36H). 13 C NMR(101MHz,CDCl 3 )δ174.03,173.18,172.74,170.26,81.41,81.37,81.28,80.90,62.29,58.62,55.43,51.34,50.38,39.56,28.20,28.17,28.14,28.13.
(6) Compound 7 (3.3 g,6.2 mmol) was dissolved in 100mL of dichloromethane, anisole (4.1 mL,37.4 mmol) and trifluoromethanesulfonic acid (2.7 mL,31.2 mmol) were added at 0deg.C, and after 30 minutes the reaction was continued at 25deg.C for 1 hour. Then, an aqueous sodium bicarbonate solution (3.7 g in 100mL of water) was added at 0deg.C and quenched for 1 hour, the solution was separated, the aqueous phase was extracted and washed 3 times with 100mL of dichloromethane, and the aqueous phase was concentrated and purified by ion exchange column chromatography to give 1.1g of compound 8. Aspergilloside A in 57% yield.
Structural characterization data for aspergillin a are as follows:
1 H NMR(600MHz,D 2 O)δ3.89–3.83(m,2H),3.43(dd,J＝9.8,4.2Hz,1H),3.31(dd,J＝12.9,4.3Hz,1H),3.29(dd,J＝13.5,5.8Hz,1H),3.16(dd,J＝12.9,9.8Hz,1H),2.89(dd,J＝13.5,3.9Hz,1H),2.84(dd,J＝17.5,3.7Hz,1H),2.71(dd,J＝17.6,9.4Hz,1H). 13 C NMR(151MHz,D 2 O)δ177.43,177.34,173.26,173.12,59.79,59.30,54.54,47.95,47.06,35.78.
the nuclear magnetic spectrum is shown in figure 1.
Example 2: synthesis of aspergillin a analog (chiral RSS):
the same procedure as in example 1 was used except that the corresponding chiral starting material was changed.
Structural characterization data for the aspergillus a analog (chiral RSS) are as follows:
1 H NMR(600MHz,D 2 O)δ3.82(dd,J＝6.0,4.0Hz,1H),3.79(dd,J＝9.1,3.9Hz,1H),3.41(dd,J＝9.6,4.3Hz,1H),3.24(dd,J＝13.4,6.0Hz,1H),3.27–3.17(m,1H),3.06(dd,J＝12.7,9.6Hz,1H),2.90(dd,J＝13.4,4.0Hz,1H),2.79(dd,J＝17.1,4.0Hz,1H),2.65(dd,J＝17.1,9.1Hz,1H).
example 3: synthesis of aspergillin a analog (chiral SRS):
the same procedure as in example 1 was used except that the corresponding chiral starting material was changed.
Structural characterization data for the aspergillus a analog (chiral SRS) are as follows:
1 H NMR(600MHz,D 2 O)δ3.85(dd,J＝6.1,4.0Hz,1H),3.79(dd,J＝8.9,4.1Hz,1H),3.43(dd,J＝9.4,4.3Hz,1H),3.25(dd,J＝13.3,6.2Hz,1H),3.21(dd,J＝12.7,4.4Hz,1H),3.05(dd,J＝12.7,9.4Hz,1H),2.93(dd,J＝13.3,4.0Hz,1H),2.80(dd,J＝16.9,4.1Hz,1H),2.67(dd,J＝16.9,8.9Hz,1H).
example 4: synthesis of aspergillin a analogue (chiral SSR):
the same procedure as in example 1 was used except that the corresponding chiral starting material was changed.
Structural characterization data for the aspergillus a analog (chiral SSR) are as follows:
1 H NMR(600MHz,D 2 O)δ3.70(dd,J＝7.0,4.1Hz,1H),3.61(dd,J＝8.9,4.4Hz,1H),3.34(dd,J＝9.2,4.4Hz,1H),3.07(dd,J＝13.0,7.0Hz,1H),3.01(dd,J＝12.5,4.4Hz,1H),2.88(dd,J＝13.0,4.1Hz,1H),2.85(dd,J＝12.4,9.2Hz,1H),2.67(dd,J＝16.1,4.4Hz,1H),2.51(dd,J＝16.2,8.9Hz,1H).
example 5: synthesis of aspergillin a analogue (chiral RRS):
the same procedure as in example 1 was used except that the corresponding chiral starting material was changed.
Structural characterization data for the aspergillus a analog (chiral RRS) are as follows:
1 H NMR(600MHz,D 2 O)δ3.90–3.80(m,2H),3.43(dd,J＝9.8,4.4Hz,1H),3.30(ddd,J＝13.8,8.7,5.0Hz,2H),3.16(dd,J＝12.9,9.8Hz,1H),2.92–2.80(m,2H),2.71(dd,J＝17.6,9.2Hz,1H).
example 6: synthesis of aspergillin a analogue (chiral RSR):
the same procedure as in example 1 was used except that the corresponding chiral starting material was changed.
Structural characterization data for the aspergillus a analog (chiral RSR) are as follows:
1 H NMR(600MHz,D 2 O)δ3.69(dd,J＝7.2,4.1Hz,1H),3.62(dd,J＝9.1,4.2Hz,1H),3.34(dd,J＝9.4,4.3Hz,1H),3.07(dd,J＝13.1,7.2Hz,1H),3.03(dd,J＝12.5,4.3Hz,1H),2.89(dd,J＝13.2,4.0Hz,1H),2.88–2.82(m,1H),2.68(dd,J＝16.3,4.2Hz,1H),2.51(dd,J＝16.3,9.1Hz,1H).
example 7: synthesis of aspergillin a analogues (chiral SRR):
the same procedure as in example 1 was used except that the corresponding chiral starting material was changed.
Structural characterization data for the aspergillus a analog (chiral SRR) are as follows:
1 H NMR(600MHz,D 2 O)δ4.23–4.04(m,2H),3.74(dd,J＝8.2,4.4Hz,1H),3.50(dd,J＝8.8,6.2Hz,1H),3.42(dd,J＝13.7,5.4Hz,1H),3.04(dd,J＝13.8,5.8Hz,1H),2.85(dd,J＝13.8,6.2Hz,1H),2.75–2.59(m,2H).
example 8: synthesis of aspergillin a analog (chiral RRR):
the same procedure as in example 1 was used except that the corresponding chiral starting material was changed.
Structural characterization data for the aspergillus a analog (chiral RRR) are as follows:
1 H NMR(600MHz,D 2 O)δ4.49(t,J＝5.1Hz,1H),4.31(t,J＝5.1Hz,1H),4.15(dd,J＝8.5,4.8Hz,1H),3.95(dd,J＝14.9,8.5Hz,1H),3.90–3.80(m,2H),3.75(dd,J＝13.2,5.0Hz,1H),3.12(dd,J＝18.1,5.8Hz,1H),2.98(dd,J＝18.1,4.3Hz,1H)。
Claims (10)
1. a process for synthesizing aspergillin A and its analogues features that the aziridine carboxylate is synthesized by one-pot method, and then the solvent-free nucleophilic ring-opening reaction is sequentially carried out on aziridine carboxylate, and after each ring opening, the protecting group on amino group is removed to obtain aspergillin A and its analogues.
2. The synthesis method according to claim 1, wherein the synthesis route is as follows:
wherein R is 1 ，R 2 Each is independently tBu or Bn.
3. The synthesis method according to claim 2, comprising the steps of:
(1) Dissolving the compound 1 in an organic solvent, adding o-nitrobenzenesulfonyl chloride, sodium bicarbonate and a small amount of water, and reacting until the compound 1 is basically completely converted; then o-nitrobenzenesulfonyl chloride and sodium hydroxide are sequentially added to react to obtain a compound 2;
(2) Mixing and reacting the compound 2 and the compound 3 to obtain a compound 4;
(3) Dissolving the compound 4 in an organic solvent, adding sodium thiophenol, and reacting to obtain a compound 5;
(4) Mixing and reacting the compound 5 and the compound 2 to obtain a compound 6;
(5) Dissolving the compound 6 in an organic solvent, adding sodium thiophenol, and reacting to obtain a compound 7;
(6) And (3) dissolving the compound 7 in an organic solvent, adding anisole and trifluoromethanesulfonic acid, and reacting to obtain the aspergillus A or the analogue thereof.
4. A synthetic method according to claim 3, wherein the reaction temperature in step (1) is 10-40 ℃ and the reaction time is 4-16 hours.
5. The method according to claim 4, wherein the organic solvent in the step (1) is methylene chloride, and the molar ratio of the o-nitrobenzenesulfonyl chloride to the compound 1 is 1.0-3.0.
6. The method according to claim 3, 4 or 5, wherein the reactions in steps (2) and (4) are solvent-free reactions at a temperature of 10 to 40 ℃ for a time of 1 to 4 hours.
7. The method according to claim 6, wherein the molar ratio of compound 3 to compound 2 in step (2) is 1.0 to 1.5:1; the molar ratio of compound 5 to compound 2 in step (4) is (1.0-1.5): 1.
8. The method according to claim 7, wherein the organic solvent in the step (3) is acetonitrile, the reaction temperature is 10-40 ℃, the reaction time is 0.5-4 hours, and the molar ratio of sodium thiophenol to compound 4 is (3.0-5.0): 1.
9. The method according to claim 8, wherein the organic solvent in the step (5) is N, N-dimethylformamide, the reaction temperature is 10-40 ℃, the reaction time is 0.5-4 hours, and the molar ratio of sodium thiophenol to the compound 6 is (3.0-5.0): 1.
10. The synthetic method according to claim 9, wherein the organic solvent in the step (6) is methylene chloride, the mole ratio of anisole, trifluoromethanesulfonic acid and the compound 7 is (5.0-13.0): (4.0-12.0): 1, the reaction temperature and time are 0.5-2.0 hours at-10-10 ℃ and then 0.5-2.0 hours at 10-40 ℃.
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