CN115448824A - Synthetic method of natural product ustisal A - Google Patents
Synthetic method of natural product ustisal A Download PDFInfo
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- CN115448824A CN115448824A CN202210972058.7A CN202210972058A CN115448824A CN 115448824 A CN115448824 A CN 115448824A CN 202210972058 A CN202210972058 A CN 202210972058A CN 115448824 A CN115448824 A CN 115448824A
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- ustisal
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- 229930014626 natural product Natural products 0.000 title claims abstract description 22
- 238000010189 synthetic method Methods 0.000 title claims description 6
- 238000000034 method Methods 0.000 claims abstract description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 8
- 239000001301 oxygen Substances 0.000 claims abstract description 8
- 238000006722 reduction reaction Methods 0.000 claims abstract description 8
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 5
- 150000001336 alkenes Chemical class 0.000 claims abstract description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 4
- 238000010523 cascade reaction Methods 0.000 claims abstract description 4
- 230000033444 hydroxylation Effects 0.000 claims abstract description 4
- 238000005805 hydroxylation reaction Methods 0.000 claims abstract description 4
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 75
- 150000001875 compounds Chemical class 0.000 claims description 43
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 22
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 21
- 229940125782 compound 2 Drugs 0.000 claims description 21
- 238000003756 stirring Methods 0.000 claims description 19
- 229940125898 compound 5 Drugs 0.000 claims description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 17
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 229940126214 compound 3 Drugs 0.000 claims description 15
- 239000012074 organic phase Substances 0.000 claims description 15
- YSHOWEKUVWPFNR-UHFFFAOYSA-N burgess reagent Chemical compound CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC YSHOWEKUVWPFNR-UHFFFAOYSA-N 0.000 claims description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 239000012043 crude product Substances 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 11
- 229940125904 compound 1 Drugs 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 8
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 8
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 7
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 claims description 7
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 7
- 239000012279 sodium borohydride Substances 0.000 claims description 7
- AYEKOFBPNLCAJY-UHFFFAOYSA-O thiamine pyrophosphate Chemical compound CC1=C(CCOP(O)(=O)OP(O)(O)=O)SC=[N+]1CC1=CN=C(C)N=C1N AYEKOFBPNLCAJY-UHFFFAOYSA-O 0.000 claims description 7
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 5
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims description 3
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 3
- IMKJGXCIJJXALX-SHUKQUCYSA-N Norambreinolide Chemical compound CC([C@@H]1CC2)(C)CCC[C@]1(C)[C@@H]1[C@]2(C)OC(=O)C1 IMKJGXCIJJXALX-SHUKQUCYSA-N 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 230000018044 dehydration Effects 0.000 claims description 3
- IMKJGXCIJJXALX-UHFFFAOYSA-N ent-Norambreinolide Natural products C1CC2C(C)(C)CCCC2(C)C2C1(C)OC(=O)C2 IMKJGXCIJJXALX-UHFFFAOYSA-N 0.000 claims description 3
- 229940096995 sclareolide Drugs 0.000 claims description 3
- 239000007858 starting material Substances 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims 8
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 7
- 229930004725 sesquiterpene Natural products 0.000 abstract description 4
- 238000001308 synthesis method Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract 2
- 238000009776 industrial production Methods 0.000 abstract 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 abstract 1
- 229920001223 polyethylene glycol Polymers 0.000 abstract 1
- -1 sesquiterpene alditol Chemical class 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 238000005481 NMR spectroscopy Methods 0.000 description 13
- 238000002360 preparation method Methods 0.000 description 6
- 239000003480 eluent Substances 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 4
- 230000003115 biocidal effect Effects 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 150000004354 sesquiterpene derivatives Chemical class 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241000238631 Hexapoda Species 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- 108010059993 Vancomycin Proteins 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 244000052769 pathogen Species 0.000 description 2
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 2
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 2
- 229960003165 vancomycin Drugs 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 108010013198 Daptomycin Proteins 0.000 description 1
- ZNZYKNKBJPZETN-WELNAUFTSA-N Dialdehyde 11678 Chemical compound N1C2=CC=CC=C2C2=C1[C@H](C[C@H](/C(=C/O)C(=O)OC)[C@@H](C=C)C=O)NCC2 ZNZYKNKBJPZETN-WELNAUFTSA-N 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000206602 Eukaryota Species 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 241000233855 Orchidaceae Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 241000228143 Penicillium Species 0.000 description 1
- 241000243142 Porifera Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 1
- 229960003022 amoxicillin Drugs 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 230000001887 anti-feedant effect Effects 0.000 description 1
- 230000001315 anti-hyperlipaemic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- HZZVJAQRINQKSD-PBFISZAISA-N clavulanic acid Chemical compound OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 HZZVJAQRINQKSD-PBFISZAISA-N 0.000 description 1
- 229960003324 clavulanic acid Drugs 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 231100000409 cytocidal Toxicity 0.000 description 1
- 230000000445 cytocidal effect Effects 0.000 description 1
- DOAKLVKFURWEDJ-QCMAZARJSA-N daptomycin Chemical compound C([C@H]1C(=O)O[C@H](C)[C@@H](C(NCC(=O)N[C@@H](CCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@H](CO)C(=O)N[C@H](C(=O)N1)[C@H](C)CC(O)=O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](CC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)CCCCCCCCC)C(=O)C1=CC=CC=C1N DOAKLVKFURWEDJ-QCMAZARJSA-N 0.000 description 1
- 229960005484 daptomycin Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
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- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 238000007146 photocatalysis Methods 0.000 description 1
- 230000001699 photocatalysis Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 238000011277 treatment modality Methods 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/65—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups
- C07C45/66—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups by dehydration
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/14—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of a —CHO group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
- C07C45/57—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom
- C07C45/60—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom in six-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/64—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of functional groups containing oxygen only in singly bound form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/02—1,2-Dioxanes; Hydrogenated 1,2-dioxanes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/14—All rings being cycloaliphatic
- C07C2602/26—All rings being cycloaliphatic the ring system containing ten carbon atoms
- C07C2602/28—Hydrogenated naphthalenes
-
- 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
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention relates to a synthetic route of a natural product, ustisal A, and belongs to the field of chemical synthesis. The synthesis method takes sesquiterpene alditol as a raw material, and sequentially carries out regioselective dehydration reaction, olefin isomerization-ortho-position hydroxylation tandem reaction, dehydration reaction, carbonyl reduction reaction, cyclization reaction with oxygen [4+2] and peroxy bond reduction reaction, thereby realizing the synthesis of the natural product, ustusal A. The method has the characteristics of easily obtained raw materials, simple operation, good repeatability, suitability for industrial production and the like.
Description
Technical Field
The invention relates to a synthetic method of a natural product, ustisal A.
Background
It is well known that penicillin, cephalosporin, pleuroperitoxin and fosidic acid have been key factors in combating bacterial infections in the past century and have contributed to the prolongation of human life. Despite the tremendous success of antibiotic discovery in the 50 and 60 th century, a later antibiotic era has emerged due to the increase in antibiotic resistance. Pathogens such as vancomycin-resistant enterococci, multidrug-resistant enterococci, staphylococcus aureus, etc. are listed as serious threats by the united states centers for disease control and prevention, and may compromise health care systems (j. Nat. Prod. 2021, 84, 37-45) and may turn into more dangerous chemically resistant pathogens due to their limited defenses. Combination therapies directed against multiple bacterial pathways or enhancing drug activity are currently being used, such as amoxicillin in combination with clavulanic acid to treat beta-lactamase-producing staphylococcus aureus, although there is some controversy, the use of vancomycin in combination with beta-lactam or daptomycin as the last treatment modality. Finding synergistic compounds may increase the chance of resistance against drug resistance and thus the ability to combat infectious diseases (nat. Rev. Microbiol. 2015, 13, 42).
Aspergillus pyroxylum is capable of producing terpenoids, including drimeric sesquiterpenes, which are biologically active. Complementary alkane-type sesquiterpenes are a large class of natural products with bicyclic skeletons. They are mainly found in eukaryotes such as plants, orchids, penicillium, sponges and fungi. Such natural products have diverse biological activities including bactericidal, anti-inflammatory, cytocidal, anti-diabetic, anti-hyperlipidemic. In addition, the known drimenon dialdehyde can be used as a antifeedant of insects and thus as an alternative insect insecticide, and the natural product, ustisal A, is used as one of drimenon type sesquiterpenes, so that the yield is low, the synthesis steps are complex, a metal catalytic reaction is needed, and the environment is seriously damaged.
Disclosure of Invention
The invention aims to solve the defects of the prior art and provide a method which has simple and rapid synthesis steps and high yield in each step. The synthesis method of the natural product, the usual A, has the advantages of no metal catalytic reaction in the reaction process, mild experimental conditions and environmental friendliness.
The technical scheme adopted by the invention for solving the technical problem is as follows:
a synthetic method of a natural product, ustisal A, is characterized by comprising the following synthetic steps:
a) Compound 1
By regioselective dehydration to give Compound 2
；
b) The compound 2 is subjected to alkene isomerization-ortho-position hydroxylation tandem reaction to obtain a compound 3
；
c) The compound 3 is dehydrated to obtain a compound 4
；
d) The compound 4 is subjected to carbonyl reduction reaction to obtain a compound 5
；
e) Compound 5 through [4+2] with oxygen]Cyclization reaction to give compound 6
；
f) The compound 6 has a peroxide bond reduction reaction, and realizes the natural product ustisal A
The synthesis of (2).
In the step a, the compound 1 is prepared by taking sclareolide as a starting material.
The step a is specifically as follows: dissolving the compound 1 in dichloromethane, reacting at 0 ℃ for 2 hours under the action of stannic chloride, and dehydrating to form a compound 2, wherein the molar ratio of the compound 1 to the stannic chloride is 1 to 1-2.
The step b is specifically as follows: dissolving the compound 2 in dichloromethane, adding m-chloroperoxybenzoic acid, stirring at room temperature for 1 h, adding a sodium bicarbonate aqueous solution, extracting with dichloromethane for 3 times, combining organic phases, drying with anhydrous sodium sulfate, concentrating a solvent to obtain a crude product, dissolving the crude product in diethyl ether, adding tetrahydropyrrole, and stirring at room temperature for 1 h to obtain a compound 3. Wherein the molar ratio of the compound 2 to m-chloroperoxybenzoic acid is 1.2 to 2, and the ratio of the compound 2 to tetrahydropyrrole is 1:1.5 to 3.
The step c specifically comprises the following steps: dissolving the compound 3 in toluene, adding Burgess reagent, and reacting at 120 ℃ for 2 h to obtain a compound 4, wherein the molar ratio of the compound IV to the Burgess reagent is 1 to 3-5.
The step d is specifically as follows: dissolving a compound 4 in ethanol, adding sodium borohydride, stirring at room temperature for 1 h, then adding a saturated ammonium chloride solution, extracting with chloroform for 3 times, combining organic phases, drying with anhydrous sodium sulfate, and concentrating to obtain a compound 5, wherein the molar ratio of the compound 4 to the sodium borohydride is 1 to 1.2.
The step e is specifically as follows: dissolving the compound 5 in dichloromethane, adding TPP, and introducing oxygen under the irradiation of a 150W halogen lamp to obtain a compound 6, wherein the molar ratio of the compound 5 to the TPP is 1.
The step f is specifically as follows: dissolving a compound 6 in dichloromethane, adding DMP, stirring for 1 h at room temperature, adding sodium bicarbonate to enable the solution to be extracted by dichloromethane for 3 times, combining organic phases, drying the organic phases with anhydrous sodium sulfate, concentrating to obtain a crude product, adding thiourea into methanol, and stirring for 2 h to obtain the ustusal A, wherein the molar ratio of the compound 6 to the DMP is 1.
The invention adopts the steps, so the synthesis steps are simple and quick, and each step has high yieldThe rate, metal catalytic reaction is not used in the reaction process, the experimental conditions are mild, and the method is environment-friendly, wherein the main step is photocatalysis [4+2]]Obtaining an oxidation intermediate, subjecting the obtained compound to nuclear magnetic resonance spectroscopy (c) 1 H-NMR and 13 C-NMR), the structure is correct.
Drawings
FIG. 1 is a diagram of a particular synthesis scheme of the present invention.
Detailed Description
The invention is further described below with reference to the accompanying drawings:
as shown in the attached drawings, the technical scheme adopted by the invention for solving the technical problem is as follows:
a synthetic method of a natural product, ustisal A, is characterized by comprising the following synthetic steps:
a) Compound 1
By regioselective dehydration to give Compound 2
；
b) The compound 2 is subjected to alkene isomerization-ortho-position hydroxylation tandem reaction to obtain a compound 3
；
c) The compound 3 is dehydrated to obtain a compound 4
；
d) The compound 4 is subjected to carbonyl reduction reaction to obtain a compound 5
；
e) Compound 5 through [4+2] with oxygen]Cyclization reaction to obtain compound 6
；
f) The compound 6 is subjected to peroxide bond reduction reaction, and a natural product, ustusal A, is realized
The synthesis of (2).
In the step a, the compound 1 is prepared by taking sclareolide as a starting material.
The step a specifically comprises the following steps: dissolving the compound 1 in dichloromethane, and reacting for 2 h under the action of stannic chloride at 0 ℃ to dehydrate to form a compound 2, wherein the molar ratio of the compound 1 to the stannic chloride is 1 to 1-2.
The step b is specifically as follows: dissolving the compound 2 in dichloromethane, adding m-chloroperoxybenzoic acid, stirring at room temperature for 1 h, adding a sodium bicarbonate aqueous solution, extracting with dichloromethane for 3 times, combining organic phases, drying with anhydrous sodium sulfate, concentrating a solvent to obtain a crude product, dissolving the crude product in diethyl ether, adding tetrahydropyrrole, and stirring at room temperature for 1 h to obtain a compound 3. Wherein the molar ratio of the compound 2 to m-chloroperoxybenzoic acid is 1.2 to 2, and the ratio of the compound 2 to tetrahydropyrrole is 1:1.5 to 3.
The step c is specifically as follows: dissolving the compound 3 in toluene, adding Burgess reagent, and reacting at 120 ℃ for 2 h to obtain a compound 4, wherein the molar ratio of the compound IV to the Burgess reagent is 1 to 3-5.
The step d is specifically as follows: dissolving a compound 4 in ethanol, adding sodium borohydride, stirring at room temperature for 1 h, then adding a saturated ammonium chloride solution, extracting with chloroform for 3 times, combining organic phases, drying with anhydrous sodium sulfate, and concentrating to obtain a compound 5, wherein the molar ratio of the compound 4 to the sodium borohydride is 1 to 1.2.
The step e is specifically as follows: dissolving the compound 5 in dichloromethane, adding TPP, and introducing oxygen under the irradiation of a 150W halogen lamp to obtain a compound 6, wherein the molar ratio of the compound 5 to the TPP is 1:0.05 to 0.1.
The step f is specifically as follows: dissolving a compound 6 in dichloromethane, adding DMP, stirring for 1 h at room temperature, adding sodium bicarbonate to enable the solution to be extracted by dichloromethane for 3 times, combining organic phases, drying the organic phases with anhydrous sodium sulfate, concentrating to obtain a crude product, adding thiourea into methanol, and stirring for 2 h to obtain the ustusal A, wherein the molar ratio of the compound 6 to the DMP is 1.
Example 1
1.1 Preparation of Compound 2
4.5 g of compound 1 was dissolved in 20 mL of dichloromethane, added to a 50 mL round bottom flask, placed at 0 ℃ under nitrogen protection, added with 1.5 mL of tin tetrachloride, stirred at this temperature for 2 h, poured into saturated ammonium chloride solution and extracted 3 times with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, the solvent was concentrated and separated by a chromatography column (eluent petroleum ether: ethyl acetate = 50) to give compound 2 (4.1 g) in 93% yield as a colorless liquid. 1 H NMR (400 MHz, CDCl 3 ) δ(ppm): 9.67 (d, J = 5.1 Hz, 1H), 5.71–5.36 (m, 1H), 2.57 (ddd, J = 3.9, 2.5, 1.3 Hz, 1H), 2.13 – 2.01 (m, 1H), 2.01 – 1.88 (m, 1H), 1.69 – 1.61 (m, 1H), 1.60 (dd, J = 2.7, 1.4 Hz, 3H), 1.56 – 1.49 (m, 1H), 1.45 – 1.42 (m, 1H), 1.41 (q, J = 2.8 Hz, 1H), 1.34 – 1.09 (m, 4H), 1.05 (d, J = 0.7 Hz, 3H), 0.90 (s, 3H), 0.86 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ (ppm): 206.62, 127.75, 125.43, 67.55, 49.02, 41.96, 40.32, 36.97, 33.26, 32.99, 23.62, 22.04, 21.57, 18.24, 15.67。
Example 2
1.2 Preparation of Compound 3
Dissolving 4.1 g of compound 2 in 20 mL of dichloromethane, adding 3.8 g of m-chloroperoxybenzoic acid, stirring at room temperature for 1 h, pouring a saturated sodium bicarbonate solution, extracting with dichloromethane for 3 times, combining organic phases, drying with anhydrous sodium sulfate, concentrating the solvent, and then adding sodium bicarbonate solutionThe crude product was obtained without purification. The crude product obtained is dissolved in 20 mL of diethyl ether, 1.5 mL of tetrahydropyrrole are added and the mixture is stirred at room temperature for 1 h. Condensation gave crude product 3 which was isolated by column chromatography (eluent petroleum ether: ethyl acetate = 10) to give compound 3 (3.5 g) in 82% yield as a colorless oily liquid. 1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 10.06 (s, 1H), 4.03 (dd, J = 4.6, 1.4 Hz, 1H), 2.60 – 2.29 (m, 1H), 2.12 (s, 3H), 1.86–1.53 (m, 3H), 1.52–1.35 (m, 2H), 1.23 (s, 2H), 1.14 (s, 3H), 1.03 – 0.96 (m, 1H), 0.90 (s, 3H), 0.85 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ(ppm):194.27, 193.97, 151.66, 148.55, 144.99, 144.61, 77.32, 77.00, 76.68, 73.52, 70.38, 65.78, 53.38, 49.01, 45.72, 41.28, 41.04, 38.39, 38.36, 35.96, 35.76, 33.15, 33.07, 32.83, 32.77, 28.84, 28.09, 21.54, 21.53, 20.32, 18.73, 18.71, 18.60, 16.78, 14.29。
Example 3
1.3 Preparation of Compound 4
3.5 g of compound 3 was dissolved in 15 mL of toluene, 3.7 g of Burgess reagent was added, the reaction was carried out at 120 ℃ for 2 h, the toluene was removed after cooling to room temperature, and the mixture was separated by column chromatography (eluent petroleum ether: ethyl acetate =50: 1) to obtain compound 4 (3.1 g) with a yield of 89%. 1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 10.07 (s, 1H), 6.22 (d, J = 3.1 Hz, 1H), 6.01 (dd, J = 9.5, 3.1 Hz, 1H), 2.72 – 2.41 (m, 1H), 2.12 (s, 3H), 2.01 (t, J = 3.2 Hz, 1H), 1.69–1.40 (m, 4H), 1.29–1.11 (m, 3H), 0.99 (s, 3H), 0.97 (s, 3H), 0.93 (s, 3H), 0.90–0.84 (m, 1H). 13 C NMR (101 MHz, CDCl 3 ) δ(ppm): 192.21, 145.93, 141.05, 137.63, 130.25, 52.70, 40.73, 39.05, 35.07, 32.85, 32.55, 22.64, 18.69, 17.57, 15.83。
Example 4
1.4 Preparation of Compound 5
Dissolving 3.1 g of compound 4 in 15 mL of ethanol, adding 0.5 g of sodium borohydride, stirring for 1 h, pouring into a saturated ammonium chloride solution, extracting with ethyl acetate for 3 times, combining organic layers, drying with anhydrous sodium sulfate, and concentrating the solvent to obtain 3.0 g of compound 5, wherein the yield is 96%. 1 H NMR (400 MHz, CDCl 3 ) δ(ppm): 5.89 (dd, J = 9.5, 2.7 Hz, 1H), 5.84 (dd, J = 9.6, 2.4 Hz, 1H), 4.29 – 4.12 (m, 2H), 2.02 (t, J = 2.5 Hz, 1H), 1.92 – 1.86 (m, 1H), 1.83 (s, 3H), 1.72 – 1.49 (m, 6H), 1.49 – 1.42 (m, 2H), 1.29 – 1.15 (m, 3H), 0.97 (s, 3H), 0.94 (s, 3H), 0.91 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ (ppm): 141.79, 129.56, 129.35, 129.27, 58.02, 52.99, 41.00, 38.19, 35.23, 32.95, 32.49, 22.75, 18.89, 17.49, 16.49。
Example 5
1.5 Preparation of Compound 6
After 1.5 g of compound 5 was dissolved in dichloromethane, 10 mg of TPP was added, oxygen was introduced, and irradiation with 150W halogen lamp was performed for 2 h, the solvent was concentrated, and separation by column chromatography (eluent petroleum ether: ethyl acetate = 10) was performed to obtain 0.96 g of compound 6, the yield of which was 58%. 1 H NMR (400 MHz, CDCl 3 ) δ (ppm): 6.33 (d, J = 6.0 Hz, 1H), 4.53 (d, J = 5.9 Hz, 1H), 3.95 (d, J = 13.1 Hz, 1H), 3.76 (d, J = 13.0 Hz, 1H), 2.08 (s, 2H), 1.85 (dd, J = 12.4, 7.1 Hz, 2H), 1.73 – 1.63 (m, 3H), 1.57 (dt, J = 13.2, 6.2 Hz, 3H), 1.37 – 1.27 (m, 1H), 1.23 (dt, J = 11.7, 5.5 Hz, 4H), 1.05 (d, J = 1.4 Hz, 3H), 0.98 (s, 3H), 0.81 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ(ppm): 142.43, 126.14, 88.66, 73.00, 58.68, 52.53, 43.48, 39.12, 32.45, 32.03, 30.55, 24.20, 21.01, 19.42, 18.76.
Example 6
1.6 Preparation of compound ustusal A
0.55 g of compound 6 is dissolved in 10 mL of dichloromethane, 1.2 g of DMP is added, stirring is carried out at room temperature for 1 h, sodium bicarbonate solution is poured and extracted 3 times with dichloromethane, the combined organic phases are dried over anhydrous sodium sulfate, the solvent is concentrated and then dissolved in 10 mL of methanol, 0.24 g of thiourea is added, stirring is carried out at room temperature for 2 h, the solvent is concentrated and separated by column chromatography (eluent petroleum ether: ethyl acetate = 10) to give the compound ustusal a,0.41 g, yield 80%. 1 H NMR (400 MHz, DMSO-d 6 ) δ(ppm): 9.70 (s, 1H), 5.55 (s, 1H), 5.20 (s, 1H), 4.45 (d, J = 7.4 Hz, 1H), 4.02 (d, J = 7.1 Hz, 1H), 1.98 (s, 1H), 1.65 (d, J = 10.2 Hz, 2H), 1.49 (s, 4H), 1.22 (s, 4H), 1.10 (s, 3H), 1.04 (s, 3H), 1.01 (s, 3H). 13 C NMR (101 MHz, DMSO-d 6 )) δ (ppm): 207.16, 134.15, 130.13, 82.08, 66.96, 47.36, 43.17, 42.75, 36.54, 33.88, 32.91, 22.78, 18.48, 18.17, 17.87。
Claims (8)
1. A synthetic method of a natural product, ustisal A, is characterized by comprising the following synthetic steps:
a) Compound 1
By regioselective dehydration to give Compound 2
；
b) The compound 2 is subjected to alkene isomerization-ortho-position hydroxylation tandem reaction to obtain a compound 3
；
c) The compound 3 is dehydrated to obtain a compound 4
；
d) The compound 4 is subjected to carbonyl reduction reaction to obtain a compound 5
；
e) Compound 5 through [4+2] with oxygen]Cyclization reaction to obtain compound 6
；
f) The compound 6 has a peroxide bond reduction reaction, and realizes the natural product ustisal A
And (4) synthesizing.
2. The method for synthesizing a natural product, ustusal a, according to claim 1, wherein compound 1 in step a is prepared by using sclareolide as a starting material to form compound 1.
3. The method for synthesizing a natural product, ustusal a, according to claim 1, wherein the step a specifically comprises: dissolving the compound 1 in dichloromethane, and reacting for 2 h under the action of stannic chloride at 0 ℃ to dehydrate to form a compound 2, wherein the molar ratio of the compound 1 to the stannic chloride is 1 to 1-2.
4. The method for synthesizing a natural product, ustisal A, according to claim 1, wherein the step b is specifically: dissolving a compound 2 in dichloromethane, adding m-chloroperoxybenzoic acid, stirring at room temperature for 1 h, adding a sodium bicarbonate aqueous solution, extracting with dichloromethane for 3 times, combining organic phases, drying with anhydrous sodium sulfate, concentrating a solvent to obtain a crude product, dissolving in diethyl ether, adding tetrahydropyrrole, stirring at room temperature for 1 h to obtain a compound 3, wherein the molar ratio of the compound 2 to the m-chloroperoxybenzoic acid is 1.2 to 2, and the ratio of the compound 2 to the tetrahydropyrrole is 1.5 to 3.
5. The method for synthesizing a natural product, ustisal A, according to claim 1, wherein the step c is specifically: dissolving the compound 3 in toluene, adding Burgess reagent, and reacting at 120 ℃ for 2 h to obtain a compound 4, wherein the molar ratio of the compound IV to the Burgess reagent is 1 to 3-5.
6. The method for synthesizing a natural product, ustisal a, according to claim 1, wherein the step d is specifically: dissolving a compound 4 in ethanol, adding sodium borohydride, stirring at room temperature for 1 h, then adding a saturated ammonium chloride solution, extracting with chloroform for 3 times, combining organic phases, drying with anhydrous sodium sulfate, and concentrating to obtain a compound 5, wherein the molar ratio of the compound 4 to the sodium borohydride is 1-1.2.
7. The method for synthesizing a natural product, ustisal A, according to claim 1, wherein the step e is specifically: dissolving the compound 5 in dichloromethane, adding TPP, and introducing oxygen under the irradiation of a 150W halogen lamp to obtain a compound 6, wherein the molar ratio of the compound 5 to the TPP is 1.
8. The method for synthesizing a natural product, ustisal A, according to claim 1, wherein the step f is specifically: dissolving a compound 6 in dichloromethane, adding DMP, stirring for 1 h at room temperature, adding sodium bicarbonate to enable the solution to be extracted by dichloromethane for 3 times, combining organic phases, drying the organic phases with anhydrous sodium sulfate, concentrating to obtain a crude product, adding thiourea into methanol, and stirring for 2 h to obtain the ustusal A, wherein the molar ratio of the compound 6 to the DMP is 1.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JPH01258647A (en) * | 1988-04-07 | 1989-10-16 | Yoshinori Asakawa | Novel drimane-type sesquiterpene carboxylic acid derivative |
| CN103755568A (en) * | 2013-12-10 | 2014-04-30 | 江西科技师范大学 | Method for stereoselective synthesis of IeodomycinA and B |
| US20200331953A1 (en) * | 2018-01-03 | 2020-10-22 | Council Of Scientific And Industrial Research | Artemisinic acid glycoconjugate compounds, process for preparation and use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH01258647A (en) * | 1988-04-07 | 1989-10-16 | Yoshinori Asakawa | Novel drimane-type sesquiterpene carboxylic acid derivative |
| CN103755568A (en) * | 2013-12-10 | 2014-04-30 | 江西科技师范大学 | Method for stereoselective synthesis of IeodomycinA and B |
| US20200331953A1 (en) * | 2018-01-03 | 2020-10-22 | Council Of Scientific And Industrial Research | Artemisinic acid glycoconjugate compounds, process for preparation and use thereof |
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