CN114957315A - Preparation method of [5.7.6.5] carbocyclic ring framework - Google Patents
Preparation method of [5.7.6.5] carbocyclic ring framework Download PDFInfo
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- 125000002837 carbocyclic group Chemical group 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 34
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 30
- 229940125898 compound 5 Drugs 0.000 claims abstract description 29
- 229940125782 compound 2 Drugs 0.000 claims abstract description 22
- 229940126214 compound 3 Drugs 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 21
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 15
- 229940125904 compound 1 Drugs 0.000 claims abstract description 15
- 229910052710 silicon Inorganic materials 0.000 claims abstract description 15
- 239000010703 silicon Substances 0.000 claims abstract description 15
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims abstract description 13
- 230000001681 protective effect Effects 0.000 claims abstract description 11
- 239000003513 alkali Substances 0.000 claims abstract description 9
- 238000003379 elimination reaction Methods 0.000 claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 6
- 238000006467 substitution reaction Methods 0.000 claims abstract description 5
- CCGKOQOJPYTBIH-UHFFFAOYSA-N ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 123
- 238000006243 chemical reaction Methods 0.000 claims description 80
- 239000002904 solvent Substances 0.000 claims description 50
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 34
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N N,N-Diethylethanamine Substances CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 17
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 17
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 10
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 10
- 230000035484 reaction time Effects 0.000 claims description 10
- 238000005286 illumination Methods 0.000 claims description 8
- WLLIXJBWWFGEHT-UHFFFAOYSA-N [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate Chemical compound CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F WLLIXJBWWFGEHT-UHFFFAOYSA-N 0.000 claims description 7
- 229960001701 chloroform Drugs 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 5
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 5
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 claims description 5
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 5
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 claims description 5
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 claims description 5
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 claims description 5
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 3
- STMPXDBGVJZCEX-UHFFFAOYSA-N triethylsilyl trifluoromethanesulfonate Chemical compound CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F STMPXDBGVJZCEX-UHFFFAOYSA-N 0.000 claims description 3
- 150000008282 halocarbons Chemical class 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 2
- 230000008707 rearrangement Effects 0.000 abstract description 5
- 239000011941 photocatalyst Substances 0.000 abstract description 3
- 230000001678 irradiating effect Effects 0.000 abstract 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 35
- 239000012074 organic phase Substances 0.000 description 35
- 239000007864 aqueous solution Substances 0.000 description 29
- 238000010791 quenching Methods 0.000 description 26
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 25
- 238000001035 drying Methods 0.000 description 25
- 238000001914 filtration Methods 0.000 description 25
- 230000000171 quenching effect Effects 0.000 description 25
- 229920006395 saturated elastomer Polymers 0.000 description 22
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 20
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- 238000001816 cooling Methods 0.000 description 14
- 238000000746 purification Methods 0.000 description 14
- 239000012043 crude product Substances 0.000 description 13
- 238000002390 rotary evaporation Methods 0.000 description 12
- 235000019270 ammonium chloride Nutrition 0.000 description 11
- 238000004440 column chromatography Methods 0.000 description 10
- 239000007788 liquid Substances 0.000 description 8
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 8
- 229910052753 mercury Inorganic materials 0.000 description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 7
- 125000004122 cyclic group Chemical group 0.000 description 6
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 229930014626 natural product Natural products 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000006555 catalytic reaction Methods 0.000 description 3
- 238000010276 construction Methods 0.000 description 3
- -1 cyclic lactone Chemical class 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 230000001590 oxidative effect Effects 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000006462 rearrangement reaction Methods 0.000 description 3
- KEOQZUCOGXIEQR-DPSUQCTMSA-N (1S,3R,4R,6S,8R,10S,13R,14R,16R)-5,5,14-trimethyl-9-methylidenetetracyclo[11.2.1.01,10.04,8]hexadecane-3,4,6,14,16-pentol Chemical compound C[C@@]1(O)C[C@@]23C[C@@H](O)[C@@]4(O)[C@H](C[C@H](O)C4(C)C)C(=C)[C@@H]2CC[C@@H]1[C@H]3O KEOQZUCOGXIEQR-DPSUQCTMSA-N 0.000 description 2
- 238000005698 Diels-Alder reaction Methods 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- FWFSEYBSWVRWGL-UHFFFAOYSA-N cyclohex-2-enone Chemical compound O=C1CCCC=C1 FWFSEYBSWVRWGL-UHFFFAOYSA-N 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 238000007306 functionalization reaction Methods 0.000 description 2
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 2
- 239000010931 gold Substances 0.000 description 2
- 229910052737 gold Inorganic materials 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 235000010265 sodium sulphite Nutrition 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000011925 1,2-addition Methods 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- VUMZHZYKXUYIHM-GLHQSWFFSA-N 2β,3β-epoxy-grayanotpxane-5β,6β,10α,14β,16β-pentol Chemical compound C1[C@@H](O)[C@]2(O)C(C)(C)[C@H]3O[C@H]3[C@H]2[C@](C)(O)[C@@H]2CC[C@H]3[C@](C)(O)C[C@]21[C@@H]3O VUMZHZYKXUYIHM-GLHQSWFFSA-N 0.000 description 1
- 238000006027 Birch reduction reaction Methods 0.000 description 1
- 240000006122 Chenopodium album Species 0.000 description 1
- 235000009344 Chenopodium album Nutrition 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 229930189130 Grayanotoxin Natural products 0.000 description 1
- BWMFRQKICHXLSH-ZZZNUFMVSA-N Grayanotoxin-III Natural products O[C@H]1[C@@H]2[C@@](O)(C)C[C@]31[C@H]([C@](O)(C)[C@H]1[C@](O)([C@H](O)C3)C(C)(C)[C@@H](O)C1)CC2 BWMFRQKICHXLSH-ZZZNUFMVSA-N 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- VUMZHZYKXUYIHM-ZFLTZYTDSA-N Rhodojaponin III Natural products C[C@]1(O)C[C@]23C[C@H](O)[C@]4(O)[C@@H]([C@@H]5O[C@@H]5C4(C)C)[C@](C)(O)[C@H]2CC[C@H]1[C@H]3O VUMZHZYKXUYIHM-ZFLTZYTDSA-N 0.000 description 1
- 108010052164 Sodium Channels Proteins 0.000 description 1
- 102000018674 Sodium Channels Human genes 0.000 description 1
- 238000003477 Sonogashira cross-coupling reaction Methods 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000000035 biogenic effect Effects 0.000 description 1
- 150000001717 carbocyclic compounds Chemical class 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000010523 cascade reaction Methods 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000003009 desulfurizing effect Effects 0.000 description 1
- 150000002009 diols Chemical group 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 125000001699 ent-kaurane group Chemical group 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- BWMFRQKICHXLSH-FIRPSQKQSA-N grayanotoxin iii Chemical compound C1[C@@H](O)[C@]2(O)C(C)(C)[C@@H](O)C[C@H]2[C@](C)(O)[C@@H]2CC[C@H]3[C@](C)(O)C[C@]21[C@@H]3O BWMFRQKICHXLSH-FIRPSQKQSA-N 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 230000000749 insecticidal effect Effects 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000001699 photocatalysis Effects 0.000 description 1
- 238000006046 pinacol coupling reaction Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-N propynoic acid Chemical class OC(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-N 0.000 description 1
- 238000007154 radical cyclization reaction Methods 0.000 description 1
- 229930195000 rhodomollein Natural products 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a [5.7.6.5]]A method for preparing a carbocyclic skeleton, comprising the steps of: (1) to have [6.6.6.5]Taking a compound 1 with a carbocyclic ring skeleton structure as a raw material, and sequentially adding alkali, a silicon-based protective reagent and PhMe 3 N + Br 3 ‑ Reacting to obtain a bromo-compound 2; (2) carrying out elimination reaction on the compound 2 and DBU to obtain an ketene compound 3; (3) sequentially adding alkali, silicon-based protective reagent and PhMe into the solution of the compound 3 3 N + Br 3 ‑ Carrying out substitution reaction to obtain a bromo-compound 4; (4) reacting compound 4 with DBU to eliminate and obtain dienone compound 5; (5) dissolving compound 5 in acetic acid, and irradiating to obtain compound 6 with [5.7.6.5] as the rearrangement product of Lanzhou province]A carbocyclic ring backbone. Compared with the prior art, the method has the advantages of being green, free of photocatalyst, high in atom economy, simple to operate, low in cost, high in universality and the like.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a preparation method of a [5.7.6.5] carbocyclic ring framework.
Background
The [5.7.6.5] carbocyclic skeleton containing [3.2.1] bridge ring is mainly present in the natural products of the quinoveralkane class. Some veralkane natural products have activity in modulating sodium ion channels; the rhodojaponin III and the grayanotoxin III are insecticidal; the compound, piperaristonins N, has very significant analgesic activity.
The group of the problem of the Bulbilk peak in 2019 constructs an 5.7.6.6 carbocyclic ring framework through an [ ODI ] -Diels-Alder reaction, then Ti (III) is reduced to open ring oxygen to generate Beckwith-Down rearrangement to migrate carbonyl groups 1 and 2, so that [2.2.2] bridge rings are rearranged into [3.2.1] bridge rings to complete the construction of the [5.7.6.5] carbocyclic ring framework, and then the complete synthesis of Rhodomolleins XX and XXII is completed through later-stage functionalization, wherein the synthetic route is shown as follows.
In 2019, a Timothy R.Newhouse topic group synthesizes principinol D by adopting a convergent strategy. Construction of [3.2.1] by Nickel-catalyzed alkenylation of the carbonyl alpha position]Bridge rings (D rings); connecting carbon-carbon bonds at 6,7 positions through 1, 2-addition; oxidizing the alcohol at the C3 position into carbonyl to form an enone structure, oxidizing and cutting a double bond at the C10-C20 position to obtain an aldehyde group at the C10 position, and then carrying out SmI 2 The carbon-carbon bond (B ring) at C1-C10 is formed by participating reduction coupling, so that the structure containing [3.2.1]]Of bridged rings [5.7.6.5]A carbocyclic ring backbone. The natural product principinol D is synthesized by post-functionalization, and the synthetic route is shown below.
In 1994, Haruhisa Shirahama project group synthesizes cyclohexenone (C ring) by using Wittig reaction and Diels-Alder reaction, propargyl is introduced, and key intermediate hemiketal is obtained by gold catalysis. By SmI 2 Coupling of reduced carbonyl and alkenyl groups to form [3.2.1]Bridged ring (D ring), and Sm (III) chelate with hydroxyl group at C14 controls the hydroxyl group at C16 to face alpha. 1, 3-migration by nucleophilic cleavage of epoxides and sulphides by carbon negativityMoving, growing the carbon chain at the C1 position and letting the phenylthio group be at the C20 position. SmI 2 Reducing carbonyl and alkenyl at the C5 position to form an A ring, and desulfurizing to obtain a methylene at the C20 position. Construction of carbonyl groups at C5 and C6, hydroxyl group at C3 to Smi by oxidation strategy 2 The participated Pinacol coupling has guiding function to obtain cis-vicinal diol structures of C5 site and C6 site, and the B ring is successfully constructed. And performing later deprotection to obtain a natural product, namely the grayanotoxins III, wherein the synthetic route is shown as follows.
The 2019 giardian et al reported route-improved synthesis of hemiketal intermediates in the Haruhisa Shirahama article. Taking cyclohexenone as a raw material, carrying out 1, 4-addition by using a Grignard reagent, and capturing methyl chloroformate to obtain an addition product of unsaturated double bonds. Nucleophilic substitution propargylates the extended carbon chain by regioselective Mukaiyama water and reaction to give the hydroxyl group at position C10, followed by reaction of the hydroxyl group with the methyl ester to give the 5-membered cyclic lactone. The method adopts a substitution elimination method to construct unsaturated double bonds, stereoselectively reduces carbonyl at C14, and then forms a key intermediate containing a hemiketal structure by gold catalysis, and the synthetic route is shown as follows.
In 2011 Craig M.Williams et al constructed [3.2.1] bridged rings (C/D rings) by Birch reduction, alkylation and free-radical cyclization. The splicing of the A-ring and C/D-ring fragments is accomplished by modification of the A-ring fragment using Sonogashira coupling. Lindlar reduction and Claisen cyclization gave ring B, which resulted in the synthesis of the [5.7.6.5] carbocyclic skeleton of Pierisformaside C, the synthetic route of which is shown below.
However, some of the above methods still remainFoot, constructed using a stepwise looping approach [5.7.6.5]Of ring systems [5.7]Ring systems, which are not highly applicable in compounds with complex chemical environments; using Smi 2 、OsO 4 、Pd(PPh 3 ) 4 And the like, complicate the process.
Disclosure of Invention
The invention aims to provide a preparation method of a novel [5.7.6.5] carbon ring framework.
The purpose of the invention can be realized by the following technical scheme: a method for preparing a [5.7.6.5] carbocyclic skeleton, comprising the steps of:
(1) to have [6.6.6.5]Taking a compound 1 with a carbocyclic ring skeleton structure as a raw material, dissolving the compound 1 in a solvent, sequentially adding alkali and a silicon-based protective reagent into the solution of the compound 1 to obtain a silicon enol ether intermediate, and adding PhMe 3 N + Br 3 - Carrying out substitution reaction to obtain a bromo-compound 2;
(2) dissolving the compound 2 in a solvent, adding DBU, and heating to eliminate to obtain an ketene compound 3;
(3) sequentially adding alkali and silicon-based protective reagent into the solution of the compound 3 to obtain a silicon enol ether intermediate, and then adding PhMe 3 N + Br 3 - Carrying out substitution reaction to obtain a bromo-compound 4;
(4) dissolving the compound 4 in a solvent, adding DBU, and heating to eliminate to obtain a dienone compound 5;
(5) dissolving the compound 5 in acetic acid, and performing a mountain-road-year rearrangement reaction under illumination to obtain a compound 6 with a [5.7.6.5] carbocyclic skeleton.
Preferably, step (5) is carried out by a mountain-road-year rearrangement reaction under irradiation of a mercury lamp.
Preferably, the illumination of step (5) is λ 365 nm.
Preferably, the solvent used in the preparation process comprises one or more of benzene, acetonitrile, ether solvents and halogenated alkane solvents.
Further preferably, the ethereal solvent comprises tetrahydrofuran and 1, 4-dioxane, and the halogenated hydrocarbon solvent comprises dichloromethane, trichloromethane and 1, 2-dichloroethane.
Preferably, the solvent in step (1) comprises dichloromethane, trichloromethane, 1, 2-dichloroethane, acetonitrile, tetrahydrofuran; the alkali comprises TEA, DIPEA, HMDS, py and DMAP; the silicon protecting reagent comprises TMSOTf, TMSCl, TESOTf, TESCl, TBSOTf and TBSCl.
Preferably, the base comprises TEA, DBU, py, DMAP, DIPEA, HMDS.
Preferably, the silicon-based protective reagent comprises TMSOTf, TMSCl, TESOTf, TESCl, TBSOTf, TBSCl.
Preferably, the compound 1, the base, the silicon-based protective reagent and the PhMe in the step (1) 3 N + Br 3 - The molar ratio of (1), (2-6), (1-3), (1-2), the reaction temperature is-10-35 ℃, and the reaction time is 0.5-3 h.
Preferably, the solvent in step (2) comprises tetrahydrofuran, 1, 4-dioxane, benzene; DBU as base.
Preferably, the molar ratio of the compound 2 to the DBU in the step (2) is 1 (2-8), the elimination reaction temperature is 35-65 ℃, and the reaction time is 8-24 h.
Preferably, the compound 3, the base, the silicon-based protective reagent and the PhMe in the step (3) 3 N + Br 3 - The molar ratio of (1), (2-6), (1-3), (1-2), the reaction temperature is-10-35 ℃, and the reaction time is 0.5-3 h.
Preferably, the solvent in step (4) comprises tetrahydrofuran, 1, 4-dioxane, benzene; DBU as base.
Preferably, the molar ratio of the compound 4 to the DBU in the step (4) is 1 (2-8), the elimination reaction temperature is 35-65 ℃, and the reaction time is 8-24 h.
Preferably, the molar concentration of the compound 5 in the step (5) is 0.01mol/L, and the reaction time is 60 min.
Preferably, the preparation method comprises the following steps:
the invention is based on the hypothesis that the biogenic hypothesis of the chenopodium album alkane skeleton (shown in the following) can be obtained by transferring the chemical bond C5-C10 in the ent-kaurane skeleton to the position C1, and the [5.7.6.5] ring system can be obtained by carrying out photocatalytic mountain-year rearrangement on the commonly available [6.6.6.5] ring system.
Compared with the prior art, the invention has the following advantages:
1. the method has the advantages of simple operation condition, mild reaction condition, only light driving, high economic efficiency of the rearrangement reaction atoms in the mountain road year, greenness and no pollution;
2. the invention provides energy through illumination, and is a clean and green method;
3. the invention constructs the dienone by the halogenation reaction and elimination reaction, and avoids using an oxidant oxidation strategy and a metal reagent catalysis method;
4. according to the invention, through the design of the preparation process, the mountain-road-year rearrangement is carried out spontaneously on the light absorption by utilizing the dienone substrate, and the condition is mild and green without using a photocatalyst;
5. the method is green, does not need a photocatalyst, and has high atom economy, simple operation, low cost and higher universality;
6. the invention successfully constructs the [5.7.6.5] ring system containing the high ring tension [3.2.1] bridge ring through the mountain-road annual rearrangement, which shows that the method has great possibility to be applied to complex ring system compounds to construct a [5.7] unit structure and has great application prospect in the pharmaceutical industry production.
Drawings
FIG. 1 is an NMR hydrogen spectrum of compound 5 having a [6.6.6.5] carbocyclic skeleton;
FIG. 2 is an NMR hydrogen spectrum of Compound 6 having a [5.7.6.5] carbocyclic skeleton.
Detailed Description
The invention is described in detail below with reference to the figures and specific embodiments. The following examples are carried out on the premise of the technical scheme of the invention, and detailed embodiments and specific operation processes are given, but the scope of the invention is not limited to the following examples. [6.6.6.5] carbocyclic skeleton compound 7 can be obtained through [ ODI ] - [5+2] cycloaddition/Pinacol type 1, 2-acyl tandem reaction reported by the Buthanfeng topic group, and then compound 1 is obtained through multi-step oxidation state adjustment, wherein the preparation route is shown as follows. Other reagents used in the experiments are commercially available.
Example 1
(1) Compound 1(1.1g) was dissolved in methylene chloride (20mL), TEA (0.84g), TMSOTf (0.92g) were added in that order at 0 ℃ and reacted at that temperature for 15 min; PhMe was added at 0 DEG C 3 N + Br 3 - (1.12g), then moving to room temperature for reaction for 1 h; and quenching the reaction by using a saturated sodium sulfite aqueous solution and a saturated sodium bicarbonate aqueous solution, extracting and separating by using dichloromethane, drying an organic phase by using anhydrous sodium sulfate, filtering, concentrating to remove a solvent, and directly using a crude product of the compound 2 in the next reaction without further purification.
(2) The crude compound 2 was dissolved in tetrahydrofuran (20mL), DBU (1.4g) was added at room temperature, and the reaction was allowed to warm to 50 ℃ for 12 h. Cooling to room temperature, quenching the reaction with saturated aqueous ammonium chloride solution, removing tetrahydrofuran by rotary evaporation under reduced pressure, extracting with dichloromethane, separating, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating to remove the solvent, and purifying with a chromatographic column to obtain compound 3(0.79 g).
(3) Compound 3(0.79g) was dissolved in methylene chloride (15mL), TEA (0.75g), TMSOTf (0.83g) were added in that order at 0 ℃ and reacted at that temperature for 15 min; PhMe was added at 0 deg.C 3 N + Br 3 - (0.84g), then moving to room temperature for reaction for 1 h; quenching reaction with saturated aqueous sodium sulfite solution and saturated aqueous sodium bicarbonate solution, extracting and separating with dichloromethane, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating to remove the solvent, and using the crude product of the compound 4 in the next reaction without further purification.
(4) The crude compound 4 was dissolved in tetrahydrofuran (15mL), DBU (1g) was added at room temperature, and the reaction was allowed to warm to 50 ℃ for 12 h. Cooling to room temperature, quenching the reaction with saturated ammonium chloride aqueous solution, removing tetrahydrofuran by rotary evaporation under reduced pressure, extracting and separating with dichloromethane, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating to remove the solvent, and purifying with a chromatographic column to obtain compound 5(0.6g), wherein the yield of the four-step reaction is 55%.
(5) Compound 5(0.6g) was dissolved in acetic acid at a concentration of 0.01mol/L, reacted under the illumination of mercury lamp (. lamda. times.365 nm) for 60min, quenched with saturated aqueous sodium bicarbonate, extracted with dichloromethane, the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated to remove the solvent, and purified by column chromatography to give compound 6(0.053g, 40% brsm) and recovered to give raw material 5(0.48g, 80%).
As shown in FIGS. 1 to 2, the [6.6.6.5] carbocyclic compound 5 and the [5.7.6.5] carbocyclic skeleton compound 6 having a dienone structure were successfully obtained in example 1.
Example 2
(1) Compound 1(1.1g) was dissolved in methylene chloride (20mL), DMAP (1g) and TMSCl (0.92g) were added in this order at 0 ℃ and reacted at that temperature for 20 min; PhMe was added at 0 DEG C 3 N + Br 3 - (1.17g), then moving to room temperature for reaction for 1 h; and quenching the reaction by using a saturated sodium sulfite aqueous solution and a saturated sodium bicarbonate aqueous solution, extracting and separating by using dichloromethane, drying an organic phase by using anhydrous sodium sulfate, filtering, concentrating to remove a solvent, and directly using a crude product of the compound 2 for the next reaction without further purification.
(2) Compound 2 was dissolved in tetrahydrofuran (20mL), DBU (1.26g) was added at room temperature, and the reaction was allowed to warm to 50 ℃ for 12 h. Cooling to room temperature, quenching the reaction with saturated aqueous ammonium chloride solution, removing tetrahydrofuran by rotary evaporation under reduced pressure, extracting with dichloromethane, separating, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating to remove the solvent, and purifying with a chromatographic column to obtain compound 3(0.7 g).
(3) Compound 3(0.7g) was dissolved in methylene chloride (15mL), and DMAP (0.8g) and TMSCl (0.73g) were added in this order at 0 ℃ to react at that temperature for 20 min; PhMe was added at 0 deg.C 3 N + Br 3 - (0.75g), followed by bringing to room temperatureReacting for 1 h; and quenching the reaction by using a saturated sodium sulfite aqueous solution and a saturated sodium bicarbonate aqueous solution, extracting and separating by using dichloromethane, drying an organic phase by using anhydrous sodium sulfate, filtering, concentrating to remove a solvent, and directly using a crude product of the compound 4 in the next reaction without further purification.
(4) Compound 4 was dissolved in tetrahydrofuran (15mL), DBU (0.8g) was added at room temperature, and the reaction was allowed to warm to 50 ℃ for 12 h. Cooling to room temperature, quenching the reaction with saturated ammonium chloride aqueous solution, carrying out reduced pressure rotary evaporation to remove tetrahydrofuran, extracting and separating with dichloromethane, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating to remove the solvent, and purifying with a chromatographic column to obtain compound 5(0.47g), wherein the yield of the four steps is 43%.
(5) Compound 5(0.47g) was dissolved in acetic acid at a concentration of 0.01mol/L, reacted under irradiation of mercury lamp (. lamda. ═ 365nm) for 60min, the reaction was quenched with saturated aqueous sodium bicarbonate solution, the separated liquid was extracted with dichloromethane, the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated to remove the solvent, and purified by a column chromatography to give compound 6(0.042g, 40% brsm) and recovered to give compound 5(0.376g, 80%).
Example 3
(1) Compound 1(1.1g) was dissolved in chloroform (20mL), DIPEA (1.06g), TESOTF (1.1g) were added in this order at 0 ℃ and reacted at that temperature for 15 min; PhMe was added at 0 DEG C 3 N + Br 3 - (1.17g), then moving to room temperature for reaction for 1 h; quenching reaction by saturated sodium sulfite aqueous solution and saturated sodium bicarbonate aqueous solution, drying the organic phase by anhydrous sodium sulfate, filtering, concentrating to remove the solvent, and directly using the crude product of the compound 2 for the next reaction without further purification.
(2) Compound 2 was dissolved in 1, 4-dioxane (20mL), DBU (1.3g) was added at room temperature, and the reaction was allowed to warm to 65 ℃ for 10 h. After cooling to room temperature, the reaction was quenched with saturated aqueous ammonium chloride, the reaction mixture was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to remove the solvent, and purified by a column chromatography to obtain compound 3(0.73 g).
(3) Compound 3(0.73g) was dissolved in chloroform (15mL), DIPEA (0.89g), TESOTF (0.9g) were added in this order at 0 ℃ and reacted at that temperature for 15 min; PhMe was added at 0 DEG C 3 N + Br 3 - (0.78g), reaction at this temperature for 1 h; and quenching the reaction by using a saturated sodium sulfite aqueous solution and a saturated sodium bicarbonate aqueous solution, extracting and separating by using dichloromethane, drying an organic phase by using anhydrous sodium sulfate, filtering, concentrating to remove a solvent, and directly using a crude product of the compound 4 in the next reaction without further purification.
(4) Compound 4 was dissolved in 1, 4-dioxane (15mL), DBU (0.17g) was added at room temperature, and the reaction was allowed to warm to 65 ℃ for 10 h. After cooling to room temperature, the reaction was quenched with saturated aqueous ammonium chloride, the reaction mixture was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to remove the solvent, and purified by a column chromatography to give compound 5(0.51g) in 47% yield.
(5) Compound 5(0.51g) was dissolved in acetic acid at a concentration of 0.01mol/L, reacted under the illumination of mercury lamp (. lamda. times.365 nm) for 60min, the reaction was quenched with saturated aqueous sodium bicarbonate solution, the separated liquid was extracted with dichloromethane, the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated to remove the solvent, and purified by a column chromatography to give compound 6(0.045g, 40% brsm) and recovered to give raw material 5(0.408g, 80%).
Example 4
(1) Compound 1(1.1g) was dissolved in chloroform (20mL), DIPEA (1.07g) and TESCl (0.62g) were added in this order at 0 ℃ and reacted at that temperature for 20 min; PhMe was added at 0 DEG C 3 N + Br 3 - (1.17g), then moving to room temperature for reaction for 1 h; and quenching the reaction by using a saturated sodium sulfite aqueous solution and a saturated sodium bicarbonate aqueous solution, extracting and separating by using dichloromethane, drying an organic phase by using anhydrous sodium sulfate, filtering, concentrating to remove a solvent, and directly using a crude product of the compound 2 in the next reaction without further purification.
(2) The crude compound 2 was dissolved in 1, 4-dioxane (20mL), DBU (0.26g) was added at room temperature, and the reaction was allowed to warm to 55 ℃ for 12 h. Cooling to room temperature, quenching the reaction with saturated aqueous ammonium chloride solution, extracting the separated solution with dichloromethane, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating to remove the solvent, and purifying with a chromatographic column to obtain compound 3(0.66 g).
(3) Compound 3(0.66g) was dissolved in chloroform (15mL), DIPEA (0.95g) and TESCl (0.47g) were added in this order at 0 ℃ and reacted at that temperature for 20 minutesmin; PhMe was added at 0 DEG C 3 N + Br 3 - (0.71g), then moving to room temperature for reaction for 1 h; and quenching the reaction by using a saturated sodium sulfite aqueous solution and a saturated sodium bicarbonate aqueous solution, extracting and separating by using dichloromethane, drying an organic phase by using anhydrous sodium sulfate, filtering, concentrating to remove a solvent, and directly using a crude product of the compound 4 in the next reaction without further purification.
(4) Compound 4 was dissolved in 1, 4-dioxane (15mL), DBU (0.77g) was added at room temperature, and the reaction was allowed to warm to 55 ℃ for 12 h. Cooling to room temperature, quenching the reaction with saturated aqueous ammonium chloride solution, extracting the separated liquid with dichloromethane, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating to remove the solvent, and purifying with a chromatographic column to obtain compound 5(0.46g) with a yield of 42% in four steps.
(5) Compound 5(0.46g) was dissolved in acetic acid at a concentration of 0.01mol/L, reacted under irradiation of mercury lamp (. lamda. times.365 nm) for 60min, quenched with saturated aqueous sodium bicarbonate, extracted with dichloromethane, the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated to remove the solvent, and purified by column chromatography to give compound 6(0.041g, 40% brsm) and recovered to give compound 5(0.368g, 80%).
Example 5
(1) Compound 1(1.1g) was dissolved in tetrahydrofuran (20mL), HMDS (1.07g), TBSOTf (1.09g) were added in that order at 0 ℃ and reacted at that temperature for 20 min; PhMe was added at 0 DEG C 3 N + Br 3 - (1.17g), then moving to room temperature for reaction for 2 h; quenching reaction by saturated sodium sulfite aqueous solution and saturated sodium bicarbonate aqueous solution, removing tetrahydrofuran by reduced pressure rotary evaporation, extracting and separating by dichloromethane, drying an organic phase by anhydrous sodium sulfate, filtering, concentrating to remove a solvent, and directly using a crude product of the compound 2 in the next reaction without further purification.
(2) Compound 2 was dissolved in 1, 4-dioxane (20mL), DBU (0.26g) was added at room temperature, and the reaction was allowed to warm to 55 ℃ for 10 h. After cooling to room temperature, the reaction was quenched with saturated aqueous ammonium chloride, the reaction mixture was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to remove the solvent, and purified by a column chromatography to obtain compound 3(0.74 g).
(3) Compound 3(0.74g) was dissolved in tetraTo tetrahydrofuran (15mL), HMDS (0.9g) and TBSOTf (0.92g) were added in this order at 0 ℃ and reacted at that temperature for 20 min; PhMe was added at 0 DEG C 3 N + Br 3 - (0.79g), then moving to room temperature for reaction for 2 h; quenching reaction by saturated sodium sulfite aqueous solution and saturated sodium bicarbonate aqueous solution, removing tetrahydrofuran by reduced pressure rotary evaporation, extracting and separating by dichloromethane, drying an organic phase by anhydrous sodium sulfate, filtering, concentrating to remove a solvent, and directly using a crude product of the compound 4 in the next reaction without further purification.
(4) Compound 4 was dissolved in 1, 4-dioxane (15mL), DBU (0.85g) was added at room temperature, and the reaction was allowed to warm to 55 ℃ for 10 h. Cooling to room temperature, quenching the reaction with saturated aqueous ammonium chloride solution, extracting the separated liquid with dichloromethane, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating to remove the solvent, and purifying with a chromatographic column to obtain compound 5(0.52g) with a yield of 48% in four steps.
(5) Compound 5(0.52g) was dissolved in acetic acid at a concentration of 0.01mol/L, reacted under irradiation of mercury lamp (. lamda. times.365 nm) for 60min, quenched with saturated aqueous sodium bicarbonate, extracted with dichloromethane, the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated to remove the solvent, and purified by column chromatography to give compound 6(0.046g, 40% brsm) and recovered to give compound 5(0.416g, 80%).
Example 6
(1) Compound 1(1.1g) was dissolved in acetonitrile (20mL), TEA (0.84g), TBSCl (0.62g) were added sequentially at 0 ℃ and reacted at that temperature for 30 min; PhMe was added at 0 DEG C 3 N + Br 3 - (1.17g) and then moving to room temperature for reaction for 1.5 h; quenching reaction by saturated sodium sulfite aqueous solution and saturated sodium bicarbonate aqueous solution, removing acetonitrile by reduced pressure rotary evaporation, extracting and separating by dichloromethane, drying an organic phase by anhydrous sodium sulfate, filtering, concentrating to remove a solvent, and directly using a crude product of the compound 2 in the next reaction without further purification.
(2) The crude compound 2 was dissolved in benzene (20mL), DBU (1.2g) was added at room temperature, and the reaction was allowed to warm to 60 ℃ for 8 h. Cooling to room temperature, quenching the reaction with saturated ammonium chloride aqueous solution, removing benzene by rotary evaporation under reduced pressure, extracting and separating with dichloromethane, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating to remove the solvent, and purifying with a chromatographic column to obtain compound 3(0.67 g).
(3) Compound 3(0.67g) was dissolved in acetonitrile (15mL), TEA (0.64g), TBSCl (0.47g) were added sequentially at 0 ℃ and reacted at that temperature for 30 min; PhMe was added at 0 DEG C 3 N + Br 3 - (0.71g), reaction at this temperature for 1.5 h; quenching reaction by saturated sodium sulfite aqueous solution and saturated sodium bicarbonate aqueous solution, removing acetonitrile by reduced pressure rotary evaporation, extracting and separating by dichloromethane, drying an organic phase by anhydrous sodium sulfate, filtering, concentrating to remove a solvent, and directly using a crude product of the compound 4 in the next reaction without further purification.
(4) Compound 4 was dissolved in benzene (15mL), DBU (0.75g) was added at room temperature, and the reaction was allowed to warm to 60 ℃ for 8 h. Cooling to room temperature, quenching the reaction with saturated aqueous ammonium chloride solution, removing benzene by reduced pressure rotary evaporation, extracting the separated liquid with dichloromethane, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating to remove the solvent, and purifying with a chromatographic column to obtain compound 5(0.44g) with a yield of 40% in four steps.
(5) Compound 5(0.44g) was dissolved in acetic acid at a concentration of 0.01mol/L, reacted under illumination with mercury lamp (. lamda. times.365 nm) for 60min with saturated aqueous sodium bicarbonate solution to quench the reaction, the separated liquid was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to remove the solvent, and purified by a column chromatography to give compound 6(0.039g, 40% brsm) and recovered to give compound 5(0.352g, 80%).
Example 7
(1) Compound 1(1.1g) was dissolved in 1, 2-dichloroethane (20mL), TEA (0.84g), TBSOTf (1.1g) were added in that order at 0 ℃ and reacted at that temperature for 25 min; PhMe was added at 0 DEG C 3 N + Br 3 - (1.17g), reaction at this temperature for 1.5 h; and quenching the reaction by using a saturated sodium sulfite aqueous solution and a saturated sodium bicarbonate aqueous solution, extracting and separating by using dichloromethane, drying an organic phase by using anhydrous sodium sulfate, filtering, concentrating to remove a solvent, and directly using a crude product of the compound 2 in the next reaction without further purification.
(2) Compound 2 was dissolved in benzene (20mL), DBU (1.18g) was added at room temperature, and the reaction was allowed to warm to 60 ℃ for 8 h. Cooling to room temperature, quenching the reaction with saturated aqueous ammonium chloride solution, removing benzene by rotary evaporation under reduced pressure, extracting the separated liquid with dichloromethane, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating to remove the solvent, and purifying with a chromatographic column to obtain compound 3(0.64 g).
(3) Compound 3(0.64g) was dissolved in 1, 2-dichloroethane (15mL), TEA (0.61g), TBSOTf (0.8g) were added in that order at 0 ℃ and reacted at that temperature for 30 min; PhMe was added at 0 DEG C 3 N + Br 3 - (0.68g), reaction at this temperature for 1.5 h; quenching reaction with saturated aqueous solution of sodium sulfite and saturated aqueous solution of sodium bicarbonate, extracting and separating with dichloromethane, drying organic phase with anhydrous sodium sulfate, filtering, concentrating to remove solvent, and directly using in next reaction without purification.
(4) Compound 4 was dissolved in benzene (15mL), DBU (0.69g) was added at room temperature, and the reaction was allowed to warm to 60 ℃ for 8 h. Cooling to room temperature, quenching the reaction with saturated aqueous ammonium chloride solution, removing benzene by reduced pressure rotary evaporation, extracting the separated liquid with dichloromethane, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating to remove the solvent, and purifying by a chromatographic column to obtain the compound 5(0.39g) with a yield of 36% in four steps.
(5) Compound 5(0.39g) was dissolved in acetic acid at a concentration of 0.01mol/L, reacted under illumination with mercury lamp (. lamda. times.365 nm) for 60min, quenched with saturated aqueous sodium bicarbonate, extracted with dichloromethane, the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated to remove the solvent, and purified by column chromatography to give compound 6(0.035g, 40% brsm) and recovered as compound 5(0.312g, 80%).
The invention provides a preparation method for preparing a [5.7.6.5] carbocyclic skeleton containing a [3.2.1] bridged ring, which is green, high in atom economy, simple to operate, low in cost and few in process steps.
The embodiments described above are described to facilitate an understanding and use of the invention by those skilled in the art. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above embodiments, and those skilled in the art should make improvements and modifications within the scope of the present invention based on the disclosure of the present invention.
Claims (10)
1. A preparation method of a [5.7.6.5] carbocyclic ring framework is characterized by comprising the following steps:
(1) to have [6.6.6.5]Taking a compound 1 with a carbocyclic ring skeleton structure as a raw material, and sequentially adding alkali, a silicon-based protective reagent and PhMe 3 N + Br 3 - Reacting to obtain a bromo-compound 2;
(2) carrying out elimination reaction on the compound 2 and DBU to obtain an ketene compound 3;
(3) sequentially adding alkali, silicon-based protective reagent and PhMe into the solution of the compound 3 3 N + Br 3 - Carrying out substitution reaction to obtain a bromo-compound 4;
(4) reacting compound 4 with DBU to eliminate and obtain dienone compound 5;
(5) dissolving the compound 5 in acetic acid, and obtaining a compound 6 of the retro-rearrangement product under illumination, wherein the compound 6 has a [5.7.6.5] carbocyclic skeleton.
2. The method for preparing [5.7.6.5] carbocycle skeleton according to claim 1, wherein the solvent used in the preparation process comprises one or more of benzene, acetonitrile, ether solvent, and halogenated alkane solvent.
3. The method for preparing [5.7.6.5] carbocyclic ring skeleton according to claim 2, wherein the ethereal solvent comprises tetrahydrofuran and 1, 4-dioxane, and the halogenated hydrocarbon solvent comprises dichloromethane, trichloromethane and 1, 2-dichloroethane.
4. The method of claim 1, wherein the base comprises TEA, DBU, py, DMAP, DIPEA, HMDS.
5. The method of claim 1, wherein said silicon-based protecting reagent comprises TMSOTf, TMSCl, TESOTf, TESCl, TBSOTf, TBSCl.
6. The [5.7.6.5] of claim 1]The preparation method of the carbon ring framework is characterized in that the compound 1, alkali, silicon-based protective reagent and PhMe in the step (1) 3 N + Br 3 - The molar ratio of (1), (2-6), (1-3), (1-2), the reaction temperature is-10-35 ℃, and the reaction time is 0.5-3 h.
7. The method for preparing a [5.7.6.5] carbocyclic ring skeleton according to claim 1, wherein the molar ratio of compound 2 to DBU in step (2) is 1 (2-8), the elimination reaction temperature is 35-65 ℃, and the reaction time is 8-24 h.
8. The [5.7.6.5] of claim 1]The preparation method of the carbon ring framework is characterized in that the compound 3, the alkali, the silicon-based protective reagent and the PhMe in the step (3) 3 N + Br 3 - The molar ratio of (1), (2-6), (1-3), (1-2), the reaction temperature is-10-35 ℃, and the reaction time is 0.5-3 h.
9. The method for preparing a [5.7.6.5] carbocyclic ring skeleton according to claim 1, wherein the molar ratio of compound 4 to DBU in step (4) is 1 (2-8), the elimination reaction temperature is 35-65 ℃, and the reaction time is 8-24 h.
10. The method for preparing [5.7.6.5] carbocyclic skeleton according to claim 1, wherein the molar concentration of compound 5 in step (5) is 0.01mol/L, and the reaction time is 60 min.
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| HIROSHI MAEJIMA ET AL.: "Distinct Sites Regulating Grayanotoxin Binding and Unbinding to D4S6 of Na v 1.4 Sodium Channel as Revealed by Improved Estimation of Toxin Sensitivity", 《THE JOURNAL OF BIOLOGICAL CHEMISTRY》 * |
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