CN110218203A - The synthetic method of 8 substitution -3,4,7,8- tetrahydro -2H- oxo octyl- 2- ketone octatomic rings - Google Patents
The synthetic method of 8 substitution -3,4,7,8- tetrahydro -2H- oxo octyl- 2- ketone octatomic rings Download PDFInfo
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- 238000010189 synthetic method Methods 0.000 title claims description 8
- 238000006467 substitution reaction Methods 0.000 title description 2
- -1 allyl alcohol compound Chemical class 0.000 claims abstract description 75
- 238000006243 chemical reaction Methods 0.000 claims abstract description 41
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000002904 solvent Substances 0.000 claims abstract description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims abstract description 8
- KFJMFIWWEMGNQI-UHFFFAOYSA-N 2-tert-butylsulfonylacetic acid Chemical compound CC(C)(C)S(=O)(=O)CC(O)=O KFJMFIWWEMGNQI-UHFFFAOYSA-N 0.000 claims abstract description 7
- MJGFBOZCAJSGQW-UHFFFAOYSA-N mercury sodium Chemical compound [Na].[Hg] MJGFBOZCAJSGQW-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229910001023 sodium amalgam Inorganic materials 0.000 claims abstract description 6
- SPJQDMKTFSPPLO-UHFFFAOYSA-N 2-tert-butylsulfonyl-2-methylpropane Chemical group CC(C)(C)S(=O)(=O)C(C)(C)C SPJQDMKTFSPPLO-UHFFFAOYSA-N 0.000 claims abstract description 5
- 150000001299 aldehydes Chemical class 0.000 claims abstract description 5
- 150000001336 alkenes Chemical class 0.000 claims abstract description 5
- XXROGKLTLUQVRX-UHFFFAOYSA-N hydroxymethylethylene Natural products OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 claims abstract description 5
- 150000002576 ketones Chemical class 0.000 claims abstract description 5
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000005686 cross metathesis reaction Methods 0.000 claims abstract description 4
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims abstract description 4
- 239000011986 second-generation catalyst Substances 0.000 claims abstract description 4
- 238000003747 Grignard reaction Methods 0.000 claims abstract description 3
- FCDPQMAOJARMTG-UHFFFAOYSA-M benzylidene-[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichlororuthenium;tricyclohexylphosphanium Chemical compound C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1.CC1=CC(C)=CC(C)=C1N(CCN1C=2C(=CC(C)=CC=2C)C)C1=[Ru](Cl)(Cl)=CC1=CC=CC=C1 FCDPQMAOJARMTG-UHFFFAOYSA-M 0.000 claims abstract description 3
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- 150000004808 allyl alcohols Chemical class 0.000 claims description 4
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- AQTUHJABKZECGA-UHFFFAOYSA-N hept-1-en-4-ol Chemical compound CCCC(O)CC=C AQTUHJABKZECGA-UHFFFAOYSA-N 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical class CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 12
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- 238000007273 lactonization reaction Methods 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 229930014626 natural product Natural products 0.000 description 5
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
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- MWYYLZRWWNBROW-UHFFFAOYSA-N 6-epiophiobolin A Natural products CC1CC(C=C(C)C)OC11C2CC=C(C=O)C(C(=O)CC3(C)O)C3CC2(C)CC1 MWYYLZRWWNBROW-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- HPVHSSYMRJUBHG-UHFFFAOYSA-N Ophiobolin A Natural products CC1CC(OC12CCC3(C)CC4C(C=C(CC23)C=O)C(=O)CC4(C)O)C=C(C)C HPVHSSYMRJUBHG-UHFFFAOYSA-N 0.000 description 2
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- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 2
- 229910000510 noble metal Inorganic materials 0.000 description 2
- MWYYLZRWWNBROW-BDZRSQQBSA-N ophiobolin A Chemical compound C[C@H]1C[C@H](C=C(C)C)O[C@]11[C@@H]2C\C=C(C=O)/[C@@H](C(=O)C[C@@]3(C)O)[C@@H]3C[C@@]2(C)CC1 MWYYLZRWWNBROW-BDZRSQQBSA-N 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- ZHZCYWWNFQUZOR-RXMQYKEDSA-N (2r)-pent-4-en-2-ol Chemical compound C[C@@H](O)CC=C ZHZCYWWNFQUZOR-RXMQYKEDSA-N 0.000 description 1
- ZRPFJAPZDXQHSM-UHFFFAOYSA-L 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazole;dichloro-[(2-propan-2-yloxyphenyl)methylidene]ruthenium Chemical compound CC(C)OC1=CC=CC=C1C=[Ru](Cl)(Cl)=C1N(C=2C(=CC(C)=CC=2C)C)CCN1C1=C(C)C=C(C)C=C1C ZRPFJAPZDXQHSM-UHFFFAOYSA-L 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- YTEFAALYDTWTLB-UHFFFAOYSA-N 2-(benzenesulfonyl)acetic acid Chemical compound OC(=O)CS(=O)(=O)C1=CC=CC=C1 YTEFAALYDTWTLB-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- ZSPTYLOMNJNZNG-UHFFFAOYSA-N 3-Buten-1-ol Chemical compound OCCC=C ZSPTYLOMNJNZNG-UHFFFAOYSA-N 0.000 description 1
- ZNPHYMBSDNDCCM-UHFFFAOYSA-N 3-ethylhex-5-en-3-ol Chemical compound CCC(O)(CC)CC=C ZNPHYMBSDNDCCM-UHFFFAOYSA-N 0.000 description 1
- 241000186361 Actinobacteria <class> Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 102000003915 DNA Topoisomerases Human genes 0.000 description 1
- 108090000323 DNA Topoisomerases Proteins 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
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- 239000007818 Grignard reagent Substances 0.000 description 1
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- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 240000002044 Rhizophora apiculata Species 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 241001587868 Streptomyces marinus Species 0.000 description 1
- YNCYZSBUDLGGQA-ARJAWSKDSA-N [(z)-4-methoxycarbonyloxybut-2-enyl] methyl carbonate Chemical compound COC(=O)OC\C=C/COC(=O)OC YNCYZSBUDLGGQA-ARJAWSKDSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 238000005865 alkene metathesis reaction Methods 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
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- 230000005494 condensation Effects 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- ZHZCYWWNFQUZOR-UHFFFAOYSA-N pent-4-en-2-ol Chemical compound CC(O)CC=C ZHZCYWWNFQUZOR-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000011426 transformation method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
- C07D313/16—Eight-membered rings
- C07D313/18—Eight-membered rings not condensed with other rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Epoxy Compounds (AREA)
Abstract
本发明公开了8位取代‑3，4，7，8‑四氢‑2H‑氧代辛‑2‑酮八元环的合成方法，首先是醛或酮发生格氏反应得到烯丙醇类化合物；再与2‑(叔丁基磺酰基)乙酸发生缩合反应，得到叔丁砜基乙酸烯丙酯类化合物；之后在Grubbs第二代催化剂的作用下发生烯烃交叉复分解反应，得到甲氧羰基叔丁砜乙酸酯类化合物；接着在催化剂醋酸钯和配体三苯基膦的作用下，以无水N，N‑二甲基甲酰胺作溶剂，发生分子内反应，得到3‑叔丁砜基8位取代‑3，4，7，8‑四氢‑2H‑氧代辛‑2‑酮八元环内酯化合物；最后在钠汞齐和醋酸反应液中，并用乙醇做溶剂条件下，脱去叔丁砜基，得到8位取代‑3，4，7，8‑四氢‑2H‑氧代辛‑2‑酮八元环内酯化合物。该方法产率高，分子内钯催化合成各类取代的八元环内酯时，反应浓度无需非常稀的溶液，工艺条件简单，具有普适性。The invention discloses a synthesis method of an 8-position substituted-3,4,7,8-tetrahydro-2H-oxooct-2-one eight-membered ring. Firstly, an aldehyde or a ketone undergoes a Grignard reaction to obtain an allyl alcohol compound Condensation reaction occurs with 2-(tert-butylsulfonyl) acetic acid again to obtain allyl tert-butylsulfone-acetate compound; afterward, under the effect of Grubbs second-generation catalyst, olefin cross-metathesis reaction occurs to obtain methoxycarbonyl tert-butylsulfone Acetate compound; then under the action of catalyst palladium acetate and ligand triphenylphosphine, with anhydrous N, N-dimethylformamide as solvent, intramolecular reaction occurs to obtain 3-tert-butylsulfone group 8-substituted- 3,4,7,8-tetrahydro-2H-oxooct-2-ketone eight-membered cyclic lactone compound; finally in the reaction solution of sodium amalgam and acetic acid, and use ethanol as the solvent, remove the tert-butylsulfone group, Obtain 8-substituted-3,4,7,8-tetrahydro-2H-oxooct-2-one eight-membered ring lactone compound. The method has high yield, and when intramolecular palladium catalyzes the synthesis of various substituted eight-membered ring lactones, the reaction concentration does not need a very dilute solution, and the process conditions are simple and universal.
Description
技术领域technical field
本发明涉及八元环骨架化合物的制备方法，特别涉及8位取代-3，4，7，8-四氢-2H-氧代辛-2-酮八元环的合成方法。The invention relates to a preparation method of an eight-membered ring skeleton compound, in particular to a synthesis method of an 8-substituted-3,4,7,8-tetrahydro-2H-oxooct-2-one eight-membered ring.
背景技术Background technique
八元环骨架化合物广泛存在于海洋微生物和植物中，绝大多数提取得到的八元环化合物具有一定的药理活性。据研究发现，从海洋海洋链霉菌提取出的八元环骨架天然产物对多种癌细胞具有一定的细胞毒性。此外，海红树土壤的海洋放线菌中提取的八元环天然产物对人体DNA拓扑异构酶具有生物活性。随着各种二倍半萜类化合物蛇孢菌素被提取出来，科学家发现八元环天然产物ophiobolin A对黑色素瘤、胶质细胞瘤、直肠癌细胞具有一定的细胞毒性，也可作CaM抑制剂用于杀菌除虫等防治研究。近年来，人类越来越关注对人体健康安全有益的天然产物，因此含八元环骨架的化合物成为科研工作者的研究热点。Eight-membered ring skeleton compounds widely exist in marine microorganisms and plants, and most of the extracted eight-membered ring compounds have certain pharmacological activities. According to the research, the natural product with eight-membered ring skeleton extracted from marine Streptomyces marina has certain cytotoxicity to various cancer cells. In addition, eight-membered ring natural products extracted from marine actinomycetes from sea mangrove soils are biologically active against human DNA topoisomerase. With the extraction of various sesquiterpenoids, ophiobolin A, scientists discovered that the eight-membered ring natural product ophiobolin A has certain cytotoxicity to melanoma, glioma, and colorectal cancer cells, and can also be used as a CaM inhibitor The agent is used for control research such as sterilization and insecticide. In recent years, humans have paid more and more attention to natural products that are safe and beneficial to human health, so compounds containing eight-membered ring skeletons have become a research hotspot for researchers.
现有技术中含有顺式双键八元环内酯化合物的合成方法有如下：In the prior art, the synthetic method of the eight-membered cyclic lactone compound containing cis-type double bonds is as follows:
1、内酯化反应：内酯化反应是一类较为常见的有机化学反应，是羟基跟同一分子的羧酸集团在缩合试剂的作用下发生脱水反应并生成八元环内酯的反应。八元环的内酯化反应，在所有的内酯化反应中是最慢的，比六元环的内酯化反应要慢20000倍(JACS，1977，99，2591)，并且反应的浓度要求很低，一般情况在0.001M左右。并且，合成目标产物的过程中还会伴有分子间内酯化反应的副产物。在此反应中，需要制备含有顺式双键的底物，通常下，此底物的制备需要多步反应，并且比较困难。内酯化反应式如下：1. Lactonization reaction: Lactonization reaction is a relatively common organic chemical reaction. It is a reaction in which a hydroxyl group and a carboxylic acid group of the same molecule undergo a dehydration reaction under the action of a condensation reagent to generate an eight-membered ring lactone. The lactonization reaction of the eight-membered ring is the slowest of all lactonization reactions, 20,000 times slower than the lactonization reaction of the six-membered ring (JACS, 1977, 99, 2591), and the concentration of the reaction requires Very low, generally around 0.001M. Moreover, the process of synthesizing the target product will also be accompanied by by-products of the intermolecular lactonization reaction. In this reaction, it is necessary to prepare a substrate containing a cis double bond. Usually, the preparation of this substrate requires multi-step reactions and is relatively difficult. The lactonization reaction formula is as follows:
2、关环复分解反应(RCM)：烯烃复分解反应，是指在含有贵金属的烯烃交叉偶联催化剂催化下碳碳双键或碳碳叁键切断并重组的有机化学反应过程，是目前比较常用的一种碳骨架改造手段。可以利用目标产物中的两个双键，从而使用Hoveyda-Grubbs第二代催化剂进行关环复分解反应来得到产物。但是该反应在合成含有顺式双键8元环化合物的时候有重大缺陷，在没有导向基团或者并环的存在下，是不能得到高于20％的收率的，这主要是由于八元环的高度环张力所导致的，同时还有有如下等缺点：容易产生大量的16元环二聚物或者多聚体；而且需要在高稀浓度(10-3M-10-5M)下反应；并且贵金属，如钌，铑等，非常困难的从产物中完全除去。关环复分解反应的反应式如下：2. Ring-closing metathesis reaction (RCM): Olefin metathesis reaction refers to the organic chemical reaction process in which carbon-carbon double bonds or carbon-carbon triple bonds are cut and recombined under the catalysis of olefin cross-coupling catalysts containing noble metals. It is currently more commonly used A carbon skeleton transformation method. The two double bonds in the target product can be utilized to obtain the product by ring-closing metathesis reaction using Hoveyda-Grubbs second-generation catalyst. However, this reaction has a major defect in the synthesis of 8-membered ring compounds containing cis-type double bonds. In the absence of directing groups or the presence of rings, it is impossible to obtain a yield higher than 20%, which is mainly due to the eight-membered ring compound. Due to the high ring tension of the ring, there are also the following disadvantages: it is easy to produce a large number of 16-membered ring dimers or polymers; and it needs to be reacted at a high dilute concentration (10-3M-10-5M); And noble metals, such as ruthenium, rhodium, etc., are very difficult to completely remove from the product. The reaction formula of the ring-closing metathesis reaction is as follows:
发明内容Contents of the invention
发明目的：本发明目的是提供一种产率高、普适性广、反应条件简单的8位取代-3，4，7，8-四氢-2H-氧代辛-2-酮八元环的合成方法。Purpose of the invention: The purpose of the invention is to provide an 8-substituted-3,4,7,8-tetrahydro-2H-oxooct-2-one eight-membered ring with high yield, wide applicability and simple reaction conditions synthetic method.
技术方案：本发明提供8位取代-3，4，7，8-四氢-2H-氧代辛-2-酮八元环的合成方法，包括如下步骤：Technical solution: The present invention provides a synthesis method of 8-substituted-3,4,7,8-tetrahydro-2H-oxooctan-2-one eight-membered ring, comprising the following steps:
(1)醛或酮发生格氏反应得到烯丙醇类化合物；(1) Grignard reaction of aldehyde or ketone to obtain allyl alcohol compound;
(2)将烯丙醇类化合物与2-(叔丁基磺酰基)乙酸发生缩合反应，得到叔丁砜基乙酸烯丙酯类化合物；(2) Condensing allyl alcohol compounds with 2-(tert-butylsulfonyl)acetic acid to obtain allyl tert-butylsulfone acetate compounds;
(3)叔丁砜基乙酸烯丙酯类化合物在Grubbs第二代催化剂的作用下发生烯烃交叉复分解反应，得到甲氧羰基叔丁砜乙酸酯类化合物；(3) Allyl tert-butylsulfone-acetate compounds undergo olefin cross-metathesis reactions under the action of Grubbs second-generation catalysts to obtain methoxycarbonyl tert-butylsulfone acetate compounds;
(4)甲氧羰基叔丁砜乙酸酯类化合物在催化剂醋酸钯和配体三苯基膦的作用下，以无水N，N-二甲基甲酰胺作溶剂，发生分子内反应，得到3-叔丁砜基8位取代-3，4，7，8-四氢-2H-氧代辛-2-酮八元环内酯化合物；(4) methoxycarbonyl tert-butyl sulfone acetate compound is under the effect of catalyzer palladium acetate and ligand triphenylphosphine, with anhydrous N, N-dimethylformamide is made solvent, intramolecular reaction takes place, obtains 3 -3,4,7,8-tetrahydro-2H-oxooct-2-one eight-membered ring lactone compound substituted by the 8-position of tert-butylsulfone group;
(5)3-叔丁砜基8位取代-3，4，7，8-四氢-2H-氧代辛-2-酮八元环内酯化合物在钠汞齐和醋酸反应液中，并用乙醇做溶剂条件下，脱去叔丁砜基，得到8位取代-3，4，7，8-四氢-2H-氧代辛-2-酮八元环内酯化合物。所述8位取代-3，4，7，8-四氢-2H-氧代辛-2-酮八元环内酯化合物结构式如下：(5) 3-tert-butylsulfone group 8-substituted-3,4,7,8-tetrahydro-2H-oxooct-2-one eight-membered ring lactone compound in sodium amalgam and acetic acid reaction solution, and made with ethanol Under the solvent condition, the tert-butylsulfone group is removed to obtain the 8-substituted-3,4,7,8-tetrahydro-2H-oxooct-2-one eight-membered ring lactone compound. The structural formula of the 8-substituted-3,4,7,8-tetrahydro-2H-oxooct-2-one eight-membered ring lactone compound is as follows:
进一步地，所述步骤(1)中丙醇类化合物为1-苯基-3-烯-1-醇、2-甲基己-5-烯-3-醇、庚-1-烯-4-醇或2，2-二甲基己-5-烯-3-醇。所述步骤(2)中叔丁砜基乙酸烯丙酯类化合物为丁-3-烯-1-基2-(叔丁基磺酰基)乙酸酯、1-苯基-3-烯-1-基-2-(叔丁基磺酰基)乙酸酯、2-(叔丁基磺酰基)乙酸戊-4-烯-2-基酯、2-甲基己-5-烯-3-基2-(叔丁基磺酰基)乙酸酯、2-(叔丁基磺酰基)乙酸庚-1-烯-4-基、2，2-二甲基己-5-烯-3-基2-(叔丁基磺酰基)乙酸酯或3-乙基己-5-烯-3-基2-(叔丁基磺酰基)乙酸酯。所述步骤(3)中甲氧羰基叔丁砜乙酸酯类化合物为5-((甲氧基羰基)氧基)戊-3-烯-1-基2-(叔丁基磺酰基)乙酸酯、5-((甲氧基羰基)氧基)-1-苯基戊-3-烯-1-基2-(叔丁基磺酰基)乙酸酯、6-((甲氧基羰基)氧基)己-4-烯-2-基-2-(叔丁基磺酰基)乙酸酯、7-((甲氧基羰基)氧基)-2-甲基庚-5-烯-3-yl2-(叔丁基磺酰基)乙酸甲酯、8-((甲氧基羰基)氧基)辛-6-烯-4-基2-(叔丁基磺酰基)乙酸酯、7-((甲氧基羰基)氧基)-2，2-二甲基庚-5-烯-3-基-2-(叔丁基磺酰基)乙酸酯或3-乙基-7-((甲氧基羰基)氧基)庚-5-烯-3-基2-(叔丁基磺酰基)乙酸酯。所述步骤(4)中3-叔丁砜基8位取代-3，4，7，8-四氢-2H-氧代辛-2-酮八元环内酯化合物为(Z)-3-(叔丁基磺酰基)-8-甲基-3，4，7，8-四氢-2H-环氧辛英-2-酮、(Z)-3-(叔丁基磺酰基)-8-丙基-3，4，7，8-四氢-2H-环氧辛英-2-酮、(Z)-3-(叔丁基磺酰基)-8-异丙基-3，4，7，8-四氢-2H-环氧辛英-2-酮、(Z)-8-(叔丁基)-3-(叔丁基磺酰基)-3，4，7，8-四氢-2H-环氧辛英-2-酮、(Z)-3-(叔丁基磺酰基)-8-苯基-3，4，7，8-四氢-2H-环氧辛英-2-酮或(Z)-3-(叔丁基磺酰基)-8，8-二乙基-3，4，7，8-四氢-2H-环氧辛英-2-酮。所述步骤(5)中8位取代-3，4，7，8-四氢-2H-氧代辛-2-酮八元环内酯化合物为(R，Z)-8-甲基-3，4，7，8-四氢-2H-环氧辛英-2-酮。所述步骤(5)中钠汞齐和醋酸当量比为1：2。Further, the propanol compound in the step (1) is 1-phenyl-3-en-1-ol, 2-methylhex-5-en-3-ol, hept-1-en-4- alcohol or 2,2-dimethylhex-5-en-3-ol. In the step (2), allyl tert-butylsulfone acetate compounds are but-3-en-1-yl 2-(tert-butylsulfonyl) acetate, 1-phenyl-3-en-1-yl -2-(tert-butylsulfonyl)acetate, 2-(tert-butylsulfonyl)acetate pent-4-en-2-yl ester, 2-methylhex-5-en-3-yl 2- (tert-butylsulfonyl) acetate, 2-(tert-butylsulfonyl) acetate hept-1-en-4-yl, 2,2-dimethylhex-5-en-3-yl 2-( tert-butylsulfonyl) acetate or 3-ethylhex-5-en-3-yl 2-(tert-butylsulfonyl) acetate. In the step (3), the methoxycarbonyl tert-butylsulfone acetate compound is 5-((methoxycarbonyl)oxy)pent-3-en-1-yl 2-(tert-butylsulfonyl)acetic acid Esters, 5-((methoxycarbonyl)oxy)-1-phenylpent-3-en-1-yl 2-(tert-butylsulfonyl)acetate, 6-((methoxycarbonyl) Oxy)hex-4-en-2-yl-2-(tert-butylsulfonyl)acetate, 7-((methoxycarbonyl)oxy)-2-methylhept-5-ene-3 -yl2-(tert-butylsulfonyl)methyl acetate, 8-((methoxycarbonyl)oxy)oct-6-en-4-yl 2-(tert-butylsulfonyl)acetate, 7- ((Methoxycarbonyl)oxy)-2,2-dimethylhept-5-en-3-yl-2-(tert-butylsulfonyl)acetate or 3-ethyl-7-(( Methoxycarbonyl)oxy)hept-5-en-3-yl 2-(tert-butylsulfonyl)acetate. In the step (4), the 3-tert-butylsulfone group 8-substituted-3,4,7,8-tetrahydro-2H-oxooct-2-one eight-membered ring lactone compound is (Z)-3-(tert- Butylsulfonyl)-8-methyl-3,4,7,8-tetrahydro-2H-epoxyoctin-2-one, (Z)-3-(tert-butylsulfonyl)-8-propane Base-3,4,7,8-tetrahydro-2H-epoxyoctine-2-one, (Z)-3-(tert-butylsulfonyl)-8-isopropyl-3,4,7, 8-tetrahydro-2H-epoxyoctine-2-one, (Z)-8-(tert-butyl)-3-(tert-butylsulfonyl)-3,4,7,8-tetrahydro-2H -Epoxyoctine-2-one, (Z)-3-(tert-butylsulfonyl)-8-phenyl-3,4,7,8-tetrahydro-2H-epoxyoctine-2-one Or (Z)-3-(tert-butylsulfonyl)-8,8-diethyl-3,4,7,8-tetrahydro-2H-epoxyoctin-2-one. In the step (5), the 8-substituted-3,4,7,8-tetrahydro-2H-oxooctan-2-one eight-membered ring lactone compound is (R, Z)-8-methyl-3 , 4,7,8-tetrahydro-2H-epoxyoctin-2-one. In the step (5), the equivalent ratio of sodium amalgam to acetic acid is 1:2.
有益效果：本发明步骤(4)中用分子内钯催化合成各类取代的八元环内酯时，反应浓度无需非常稀的溶液，这与传统的内酯化反应和关环复分解反应要求极稀的浓度形成鲜明对比，工艺条件简单；本方法普适性较广，可以适用于不同取代基八元环内酯的制备，如甲基、苯基、异丙基、正丙基、叔丁基、二乙基等取代的八元环内酯产物；本方法易操作，催化量的催化剂催化底物发生分子内反应即可得到不同取代的八元环内酯；本方法在脱出叔丁砜基时，配比非常关键，保证了反应的顺利进行。Beneficial effect: when using intramolecular palladium in the step (4) of the present invention to catalyze the synthesis of various types of substituted eight-membered ring lactones, the reaction concentration does not need a very dilute solution, which is extremely different from the requirements of traditional lactonization reactions and ring-closing metathesis reactions. The dilute concentrations are in sharp contrast, and the process conditions are simple; this method has wide applicability, and can be applied to the preparation of eight-membered ring lactones with different substituents, such as methyl, phenyl, isopropyl, n-propyl, tert-butyl The eight-membered ring lactone product substituted by base, diethyl, etc.; this method is easy to operate, and the catalytic amount of the catalyst can catalyze the intramolecular reaction of the substrate to obtain the eight-membered ring lactone with different substitutions; , the ratio is very critical to ensure the smooth progress of the reaction.
具体实施方式Detailed ways
一、合成烯丙醇类化合物，操作工艺流程如下：1. Synthetic allyl alcohol compounds, the operating process is as follows:
氩气状态下，向干燥的圆底烧瓶中加入各类醛或酮(1.0eq.)，将其溶于无水乙醚(1mL/mmol)溶剂中，依据醛酮空间位阻等特性控制温度在0-25℃，抽取新鲜制得的格氏试剂(3.0eq.)缓慢滴加到烧瓶中。加料完毕，室温搅拌15h。反应结束，饱和氯化铵溶液淬灭至溶液透明，乙酸乙酯和饱和食盐水萃取，有机层用无水硫酸钠干燥，过滤旋蒸，柱层析离，分别得到相应的烯丙醇类化合物。Under argon gas, add various aldehydes or ketones (1.0eq.) to a dry round bottom flask, dissolve them in anhydrous ether (1mL/mmol) solvent, and control the temperature according to the steric hindrance of aldehydes and ketones. 0-25°C, extract the freshly prepared Grignard reagent (3.0eq.) and slowly drop it into the flask. After addition, stir at room temperature for 15h. After the reaction was completed, the saturated ammonium chloride solution was quenched until the solution was transparent, extracted with ethyl acetate and saturated brine, the organic layer was dried with anhydrous sodium sulfate, filtered and rotary evaporated, and separated by column chromatography to obtain the corresponding allyl alcohol compounds .
本步骤反应式如下：This step reaction formula is as follows:
化合物核磁谱图：Compound NMR spectrum:
1-苯基-3-烯-1-醇：62％，1H NMR(400MHz，CDCl3)δ7.39-7.26(m，5H)，5.81(m，1H)，5.20-5.12(m，2H)，4.76-4.71(m，1H)，2.58-2.43(m，2H)。1-Phenyl-3-en-1-ol: 62%, 1 H NMR (400MHz, CDCl 3 ) δ7.39-7.26(m, 5H), 5.81(m, 1H), 5.20-5.12(m, 2H ), 4.76-4.71 (m, 1H), 2.58-2.43 (m, 2H).
2-甲基己-5-烯-3-醇：37％，1H NMR(600MHz，CDCl3)δ5.96-5.74(m，1H)，5.24-5.02(m，2H)，3.43-3.39(m，1H)，2.37-2.29(m，1H)，2.17-2.10(m，1H)，1.73-1.67(m，1H)，0.96(d，J＝7.3Hz，3H)，0.95(d，J＝7.3Hz，3H)。2-Methylhex-5-en-3-ol: 37%, 1 H NMR (600 MHz, CDCl 3 ) δ 5.96-5.74 (m, 1H), 5.24-5.02 (m, 2H), 3.43-3.39 ( m, 1H), 2.37-2.29(m, 1H), 2.17-2.10(m, 1H), 1.73-1.67(m, 1H), 0.96(d, J=7.3Hz, 3H), 0.95(d, J= 7.3Hz, 3H).
庚-1-烯-4-醇：42％，1H NMR(600MHz，CDCl3)δ5.87-5.79(m，1H)，5.16-5.11(m，2H)，3.71-3.61(m，1H)，2.33-2.27(m，1H)，2.18-2.11(m，1H)，1.52-1.42(m，3H)，1.42-1.34(m，1H)，0.94(t，J＝7.0Hz，3H)Hept-1-en-4-ol: 42%, 1 H NMR (600MHz, CDCl 3 ) δ5.87-5.79 (m, 1H), 5.16-5.11 (m, 2H), 3.71-3.61 (m, 1H) , 2.33-2.27(m, 1H), 2.18-2.11(m, 1H), 1.52-1.42(m, 3H), 1.42-1.34(m, 1H), 0.94(t, J=7.0Hz, 3H)
2，2-二甲基己-5-烯-3-醇：48％，1H NMR(600MHz，CDCl3)δ5.88(dddd，J＝16.9，10.3，8.5，5.7Hz，1H)，5.19-5.13(m，2H)，3.27(ddd，J＝10.6，3.5，2.2Hz，1H)，2.41-2.35(m，1H)，2.05-1.96(m，1H)，1.64(d，J＝3.5Hz，1H)，0.94(s，9H)。2,2-Dimethylhex-5-en-3-ol: 48%, 1 H NMR (600MHz, CDCl 3 ) δ5.88 (dddd, J=16.9, 10.3, 8.5, 5.7Hz, 1H), 5.19 -5.13(m, 2H), 3.27(ddd, J=10.6, 3.5, 2.2Hz, 1H), 2.41-2.35(m, 1H), 2.05-1.96(m, 1H), 1.64(d, J=3.5Hz , 1H), 0.94(s, 9H).
二、合成叔丁砜基乙酸烯丙酯类化合物，操作工艺流程如下：Two, synthetic tert-butyl sulfone group allyl acetate compound, the operating process is as follows:
氩气状态下，向干燥的圆底烧瓶中加入底物3-丁烯-1-醇(300mg，4.16mmol，1.0eq.)，将其溶于5mL四氢呋喃溶剂中，然后加入2-(叔丁基磺酰基)乙酸(1.50g，8.32mmol，2.0eq.)，搅拌5min后，将圆底烧瓶置于冰浴条件下，缓慢加入溶于5mL四氢呋喃溶液的二环己基碳二亚胺(3.12g，16.64mmol，4.0eq.)。加料完毕，室温反应15h。反应结束，旋蒸，除去溶剂四氢呋喃，柱层析分离，得到858mg化合物2.31，收率为88％。Under argon, the substrate 3-buten-1-ol (300 mg, 4.16 mmol, 1.0 eq.) was added to a dry round bottom flask, dissolved in 5 mL of THF solvent, and then 2-(tert-butyl Sulfonyl)acetic acid (1.50g, 8.32mmol, 2.0eq.), after stirring for 5min, the round bottom flask was placed in ice bath, and dicyclohexylcarbodiimide (3.12g , 16.64mmol, 4.0eq.). After the addition was complete, the reaction was carried out at room temperature for 15 hours. After the reaction was completed, rotary evaporation was performed to remove the solvent tetrahydrofuran and separated by column chromatography to obtain 858 mg of compound 2.31 with a yield of 88%.
根据上述步骤，4-戊烯-2-醇，3-乙基己-5-烯-3-醇和不同取代基的烯丙醇与2-(叔丁基磺酰基)乙酸进行反应，分别得到相应的叔丁砜基乙酸烯丙酯类化合物。According to the above steps, 4-penten-2-ol, 3-ethylhex-5-en-3-ol and allyl alcohol of different substituents react with 2-(tert-butylsulfonyl) acetic acid to obtain the corresponding Allyl tert-butylsulfone acetate compounds.
本步骤反应式如下：This step reaction formula is as follows:
化合物核磁谱图：Compound NMR spectrum:
丁-3-烯-1-基2-(叔丁基磺酰基)乙酸酯：88％，1H NMR(400MHz，CDCl3)δ5.78(ddt，J＝17.0，10.2，6.7Hz，1H)，5.15-5.05(m，2H)，4.25(t，J＝6.8Hz，2H)，3.94(s，2H)，2.43(q，J＝6.8Hz，2H)，1.44(s，9H)。But-3-en-1-yl 2-(tert-butylsulfonyl)acetate: 88%, 1 H NMR (400MHz, CDCl 3 ) δ5.78 (ddt, J=17.0, 10.2, 6.7Hz, 1H ), 5.15-5.05(m, 2H), 4.25(t, J=6.8Hz, 2H), 3.94(s, 2H), 2.43(q, J=6.8Hz, 2H), 1.44(s, 9H).
1-苯基-3-烯-1-基-2-(叔丁基磺酰基)乙酸酯：97％，1HNMR(400MHz，CDCl3)δ7.39-7.24(m，5H)，5.86-5.80(m，1H)，5.77-5.65(m，1H)，5.12-5.01(m，2H)，3.94(s，2H)，2.79-2.70(m，1H)，2.65-2.56(m，1H)，1.39(s，9H)。1-phenyl-3-en-1-yl-2-(tert-butylsulfonyl)acetate: 97%, 1 HNMR (400MHz, CDCl 3 ) δ7.39-7.24 (m, 5H), 5.86- 5.80(m, 1H), 5.77-5.65(m, 1H), 5.12-5.01(m, 2H), 3.94(s, 2H), 2.79-2.70(m, 1H), 2.65-2.56(m, 1H), 1.39(s, 9H).
2-(叔丁基磺酰基)乙酸戊-4-烯-2-基酯：92％，1H NMR(600MHz，CDCl3)δ5.83-5.68(m，1H)，5.13-5.01(m，3H)，3.92(s，2H)，2.45-2.27(m，2H)，1.44(s，9H)，1.28(d，J＝6.3Hz，3H)。Pent-4-en-2-yl 2-(tert-butylsulfonyl)acetate: 92%, 1 H NMR (600 MHz, CDCl 3 ) δ5.83-5.68 (m, 1H), 5.13-5.01 (m, 3H), 3.92(s, 2H), 2.45-2.27(m, 2H), 1.44(s, 9H), 1.28(d, J=6.3Hz, 3H).
2-甲基己-5-烯-3-基2-(叔丁基磺酰基)乙酸酯：54％，1H NMR(400MHz，CDCl3)δ5.80-5.65(m，1H)，5.12-4.98(m，2H)，4.85(q，J＝6.0，5.4Hz，1H)，3.92(s，2H)，2.34(t，J＝6.9Hz，2H)，1.96-1.83(m，1H)，1.44(s，9H)，0.94(d，J＝1.9Hz 3H)，0.93(d，J＝2.0Hz，3H)。2-Methylhex-5-en-3-yl 2-(tert-butylsulfonyl)acetate: 54%, 1 H NMR (400MHz, CDCl 3 ) δ5.80-5.65 (m, 1H), 5.12 -4.98(m, 2H), 4.85(q, J=6.0, 5.4Hz, 1H), 3.92(s, 2H), 2.34(t, J=6.9Hz, 2H), 1.96-1.83(m, 1H), 1.44 (s, 9H), 0.94 (d, J=1.9Hz 3H), 0.93 (d, J=2.0Hz, 3H).
2-(叔丁基磺酰基)乙酸庚-1-烯-4-基：66％，1H NMR(600MHz，CDCl3)δ5.79(ddt，J＝17.2，10.2，7.1Hz，1H)，5.13-5.06(m，2H)，5.06-5.00(m，1H)，3.94(s，2H)，2.41-2.34(m，2H)，1.66-1.61(m，1H)，1.59-1.53(m，1H)，1.46(s，9H)，1.43-1.40(m，1H)，1.39-1.32(m，1H)，0.92(t，J＝7.4Hz，3H)。2-(tert-butylsulfonyl)acetate hept-1-en-4-yl: 66%, 1 H NMR (600 MHz, CDCl 3 ) δ5.79 (ddt, J=17.2, 10.2, 7.1 Hz, 1H), 5.13-5.06(m, 2H), 5.06-5.00(m, 1H), 3.94(s, 2H), 2.41-2.34(m, 2H), 1.66-1.61(m, 1H), 1.59-1.53(m, 1H ), 1.46 (s, 9H), 1.43-1.40 (m, 1H), 1.39-1.32 (m, 1H), 0.92 (t, J=7.4Hz, 3H).
2，2-二甲基己-5-烯-3-基2-(叔丁基磺酰基)乙酸酯：52％，1H NMR(400MHz，CDCl3)δ5.79-5.66(m，1H)，5.00(dd，J＝21.2，13.6Hz，2H)，4.87-4.81(m，1H)，3.96-3.83(m，2H)，2.42-2.33(m，1H)，2.29-2.13(m，1H)，1.42(s，9H)，0.93(s，9H)。2,2-Dimethylhex-5-en-3-yl 2-(tert-butylsulfonyl)acetate: 52%, 1 H NMR (400MHz, CDCl 3 ) δ5.79-5.66 (m, 1H ), 5.00(dd, J=21.2, 13.6Hz, 2H), 4.87-4.81(m, 1H), 3.96-3.83(m, 2H), 2.42-2.33(m, 1H), 2.29-2.13(m, 1H ), 1.42(s, 9H), 0.93(s, 9H).
3-乙基己-5-烯-3-基2-(叔丁基磺酰基)乙酸酯：44％，1H NMR(400MHz，CDCl3)δ5.75(dq，J＝16.9，7.4Hz，1H)，5.09(d，J＝6.3Hz，1H)，5.07(d，J＝10.6Hz，1H)，3.85(s，2H)，2.60(d，J＝7.2Hz，2H)，1.85(q，J＝7.5Hz，4H)，1.42(s，9H)，0.87(t，J＝7.5Hz，6H)。3-Ethylhex-5-en-3-yl 2-(tert-butylsulfonyl)acetate: 44%, 1 H NMR (400MHz, CDCl 3 ) δ5.75 (dq, J=16.9, 7.4Hz , 1H), 5.09(d, J=6.3Hz, 1H), 5.07(d, J=10.6Hz, 1H), 3.85(s, 2H), 2.60(d, J=7.2Hz, 2H), 1.85(q , J=7.5Hz, 4H), 1.42(s, 9H), 0.87(t, J=7.5Hz, 6H).
三、合成甲氧羰基叔丁砜乙酸酯类化合物，操作工艺流程如下：3. Synthesis of methoxycarbonyl tert-butylsulfone acetate compounds, the operation process is as follows:
氩气状态下，向干燥的圆底烧瓶中加入丁-3-烯-1-基2-(叔丁基磺酰基)乙酸酯(500mg，2.13mmol，1.0eq.)，将其溶于130mL甲苯溶液中，将(Z)-丁-2-烯-1，4-二基二甲基双(碳酸酯)(871mg，4.27mmol，2.0eq.)加入到圆底烧瓶中。搅拌2min后，向反应液中加入Grubbs 2催化剂(46mg，0.05mmol，2.5％eq.)，溶液迅速变为锈红色。加料完毕，氩气保护下110℃回流15h。反应结束，溶液变为红棕色，旋蒸，除去溶剂甲苯，柱层析分离，得到537mg棕色油状物5-((甲氧基羰基)氧基)戊-3-烯-1-基2-(叔丁基磺酰基)乙酸酯，收率为78％。Under argon, to a dry round bottom flask was added but-3-en-1-yl 2-(tert-butylsulfonyl)acetate (500 mg, 2.13 mmol, 1.0 eq.), dissolved in 130 mL In toluene solution, (Z)-but-2-ene-1,4-diyldimethylbis(carbonate) (871 mg, 4.27 mmol, 2.0 eq.) was added into a round bottom flask. After stirring for 2 min, Grubbs 2 catalyst (46 mg, 0.05 mmol, 2.5% eq.) was added to the reaction solution, and the solution quickly turned rust red. After the addition was complete, the mixture was refluxed at 110° C. for 15 h under the protection of argon. Reaction finishes, and solution turns reddish-brown, and rotary steaming removes solvent toluene, and column chromatography separates, and obtains 537mg brown oily matter 5-((methoxycarbonyl) oxygen group) pent-3-en-1-yl 2-( tert-Butylsulfonyl) acetate, the yield was 78%.
根据上述步骤，各种叔丁砜基乙酸烯丙酯类化合物分别与(Z)-丁-2-烯-1，4-二基二甲基双(碳酸酯)进行烯烃交叉复分解反应，分别得到相应的甲氧羰基叔丁砜乙酸酯类化合物。According to the above steps, various allyl tert-butylsulfone acetate compounds are respectively carried out with (Z)-but-2-ene-1,4-diyl dimethyl bis(carbonate) for olefin cross-metathesis reaction to obtain corresponding Methoxycarbonyl tert-butylsulfone acetate compounds.
本步骤反应式如下：This step reaction formula is as follows:
化合物核磁谱图：Compound NMR spectrum:
5-((甲氧基羰基)氧基)戊-3-烯-1-基2-(叔丁基磺酰基)乙酸酯：78％，E/Z＝15～1，E-isomer：1H NMR(400MHz，CDCl3)δ5.77(dt，J＝13.3，6.5Hz，1H)，5.68(dt，J＝15.9，6.2Hz，1H)，4.55(d，J＝5.9Hz，2H)，4.24(t，J＝6.7Hz，2H)，3.93(s，2H)，3.75(s，3H)，2.44(q，J＝6.8Hz，2H)，1.43(s，9H)；Z-isomer(diagnostic peaks only)：1H NMR(400MHz，CDCl3)δ4.66(d，J＝5.2Hz，2H)，4.31(t，J＝6.5Hz，2H)。5-((methoxycarbonyl)oxy)pent-3-en-1-yl 2-(tert-butylsulfonyl)acetate: 78%, E/Z=15～1, E-isomer: 1 H NMR (400MHz, CDCl3) δ5.77 (dt, J=13.3, 6.5Hz, 1H), 5.68 (dt, J=15.9, 6.2Hz, 1H), 4.55 (d, J=5.9Hz, 2H), 4.24 (t, J=6.7Hz, 2H), 3.93(s, 2H), 3.75(s, 3H), 2.44(q, J=6.8Hz, 2H), 1.43(s, 9H); Z-isomer(diagnostic peaks only): 1 H NMR (400MHz, CDCl 3 ) δ 4.66 (d, J=5.2Hz, 2H), 4.31 (t, J=6.5Hz, 2H).
5-((甲氧基羰基)氧基)-1-苯基戊-3-烯-1-基2-(叔丁基磺酰基)乙酸酯：E-isomer：1H NMR(400MHz，CDCl 3)δ7.39-7.25(m，5H)，5.83(t，J＝6.8Hz，1H)，5.77-5.60(m，2H)，4.52(d，J＝5.6Hz，2H)，3.94(s，2H)，3.75(s，3H)，2.78-2.68(m，1H)，2.66-2.56(m，1H)，1.38(s，9H)；Z-isomer(diagnostic peaks only)：1H NMR(400MHz，CDCl 3)δ4.55(d，J＝5.4Hz，2H)。5-((Methoxycarbonyl)oxy)-1-phenylpent-3-en-1-yl 2-(tert-butylsulfonyl)acetate: E-isomer: 1 H NMR (400 MHz, CDCl 3) δ7.39-7.25(m, 5H), 5.83(t, J=6.8Hz, 1H), 5.77-5.60(m, 2H), 4.52(d, J=5.6Hz, 2H), 3.94(s, 2H), 3.75(s, 3H), 2.78-2.68(m, 1H), 2.66-2.56(m, 1H), 1.38(s, 9H); Z-isomer(diagnostic peaks only): 1H NMR (400MHz, CDCl 3) δ4.55 (d, J=5.4Hz, 2H).
6-((甲氧基羰基)氧基)己-4-烯-2-基-2-(叔丁基磺酰基)乙酸酯：55％，E/Z＝6∶1，E-isomer：1H NMR(400MHz，CDCl3)δ5.71(dt，J＝14.3，6.9Hz，1H)，5.66-5.55(m，1H)，5.04-4.93(m，1H).，4.50(d，J＝6.1Hz，2H)，3.87(s，2H)，3.70(s，3H)，2.39-2.24(m，2H)，1.38(s，9H)，1.21(d，J＝6.4Hz，3H)；Z-isomer(diagnostic peaks only)：1H NMR(400MHz，CDCl3)δ4.61(d，J＝4.5Hz，2H)，3.92(s，2H)，3.75(s，3H)。6-((methoxycarbonyl)oxy)hex-4-en-2-yl-2-(tert-butylsulfonyl)acetate: 55%, E/Z=6:1, E-isomer: 1 H NMR (400MHz, CDCl 3 ) δ5.71(dt, J=14.3, 6.9Hz, 1H), 5.66-5.55(m, 1H), 5.04-4.93(m, 1H)., 4.50(d, J= 6.1Hz, 2H), 3.87(s, 2H), 3.70(s, 3H), 2.39-2.24(m, 2H), 1.38(s, 9H), 1.21(d, J=6.4Hz, 3H); Z- isomer (diagnostic peaks only): 1 H NMR (400 MHz, CDCl3) δ 4.61 (d, J=4.5 Hz, 2H), 3.92 (s, 2H), 3.75 (s, 3H).
7-((甲氧基羰基)氧基)-2-甲基庚-5-烯-3-yl2-(叔丁基磺酰基)乙酸甲酯：82％，E/Z＝6∶1，E-isomer：1H NMR(400MHz，CDCl3)δ5.74(dt，J＝14.4，7.0Hz，1H)，5.69-5.57(m，1H)，4.87-4.79(m，1H)，4.52(d，J＝6.8Hz，2H)，3.92(s，2H)，3.74(s，3H)，2.39-2.31(m，2H)，1.93-1.81(m，1H)，1.43(s，9H)，0.93(d，J＝2.7Hz，5H)，0.92(d，J＝2.6Hz，5H)；Z-isomer(diagnostic peaks only)：1H NMR(400MHz，CDCl3)δ4.65(d，J＝5.0Hz，2H)。7-((methoxycarbonyl)oxy)-2-methylhept-5-ene-3-yl 2-(tert-butylsulfonyl)acetic acid methyl ester: 82%, E/Z=6:1, E -isomer: 1 H NMR (400MHz, CDCl 3 ) δ 5.74 (dt, J=14.4, 7.0Hz, 1H), 5.69-5.57(m, 1H), 4.87-4.79(m, 1H), 4.52(d, J=6.8Hz, 2H), 3.92(s, 2H), 3.74(s, 3H), 2.39-2.31(m, 2H), 1.93-1.81(m, 1H), 1.43(s, 9H), 0.93(d , J=2.7Hz, 5H), 0.92 (d, J=2.6Hz, 5H); Z-isomer (diagnostic peaks only): 1 H NMR (400MHz, CDCl 3 ) δ4.65 (d, J=5.0Hz, 2H).
8-((甲氧基羰基)氧基)辛-6-烯-4-基2-(叔丁基磺酰基)乙酸酯：87％，E/Z＝5∶1，E-isomer：1H NMR(400MHz，CDCl3)δ5.76(dd，J＝14.3，7.0Hz，1H)，5.65(dd，J＝14.7，7.1Hz，1H)，5.07-4.94(m，1H)，4.55(d，J＝6.1Hz，2H)，3.96-3.90(m，2H)，3.76(s，3H)，2.43-2.30(m，2H)，1.67-1.49(m，2H)，1.44(s，9H)，1.30-1.20(m，2H)，0.89(t，J＝7.3Hz，3H)；Z-isomer(diagnostic peaks only)：1H NMR(400MHz，CDCl3)δ4.66(d，J＝5.2Hz，2H)8-((methoxycarbonyl)oxy)oct-6-en-4-yl 2-(tert-butylsulfonyl)acetate: 87%, E/Z=5:1, E-isomer: 1 H NMR (400MHz, CDCl 3 ) δ5.76(dd, J=14.3, 7.0Hz, 1H), 5.65(dd, J=14.7, 7.1Hz, 1H), 5.07-4.94(m, 1H), 4.55(d , J=6.1Hz, 2H), 3.96-3.90(m, 2H), 3.76(s, 3H), 2.43-2.30(m, 2H), 1.67-1.49(m, 2H), 1.44(s, 9H), 1.30-1.20 (m, 2H), 0.89 (t, J=7.3Hz, 3H); Z-isomer (diagnostic peaks only): 1 H NMR (400MHz, CDCl 3 ) δ4.66 (d, J=5.2Hz, 2H)
7-((甲氧基羰基)氧基)-2，2-二甲基庚-5-烯-3-基-2-(叔丁基磺酰基)乙酸酯：80％，E/Z＝6∶1，E-isomer：1H NMR(400MHz，CDCl3)δ5.80-5.68(m，1H)，5.66-5.56(m，1H)，4.88-4.82(m，1H)，4.58-4.45(m，2H)，4.00-3.87(m，2H)，3.75(s，3H)，2.44-2.34(m，1H)，2.32-2.20(m，1H)，1.44(s，9H)，0.95(s，9H)；Z-isomer(diagnostic peaks only)：1H NMR(400MHz，CDCl3)δ4.68-4.65(m，2H)。7-((methoxycarbonyl)oxy)-2,2-dimethylhept-5-en-3-yl-2-(tert-butylsulfonyl)acetate: 80%, E/Z= 6:1, E-isomer: 1 H NMR (400 MHz, CDCl 3 ) δ5.80-5.68 (m, 1H), 5.66-5.56 (m, 1H), 4.88-4.82 (m, 1H), 4.58-4.45 ( m, 2H), 4.00-3.87(m, 2H), 3.75(s, 3H), 2.44-2.34(m, 1H), 2.32-2.20(m, 1H), 1.44(s, 9H), 0.95(s, 9H); Z-isomer (diagnostic peaks only): 1 H NMR (400 MHz, CDCl3) δ 4.68-4.65 (m, 2H).
3-乙基-7-((甲氧基羰基)氧基)庚-5-烯-3-基2-(叔丁基磺酰基)乙酸酯：77％，E/Z＝6∶1，E-isomer：1H NMR(400MHz，CDCl3)δ5.82-5.72(m，1H)，5.71-5.60(m，1H)，4.57(d，J＝6.2Hz，2H)，3.86(s，2H)，3.76(s，3H)，2.63(d，J＝7.2Hz，2H)，1.85(q，J＝7.4，6.9Hz，4H)，1.43(s，9H)，0.87(t，J＝7.5Hz，6H)；Z-isomer(diagnostic peaks only)：1H NMR(400MHz，CDCl3)δ4.67(d，J＝5.4Hz，2H)，3.87(s，2H)，2.68(d，J＝5.7Hz，2H)。3-Ethyl-7-((methoxycarbonyl)oxy)hept-5-en-3-yl 2-(tert-butylsulfonyl)acetate: 77%, E/Z=6:1, E-isomer: 1 H NMR (400MHz, CDCl 3 ) δ5.82-5.72(m, 1H), 5.71-5.60(m, 1H), 4.57(d, J=6.2Hz, 2H), 3.86(s, 2H ), 3.76(s, 3H), 2.63(d, J=7.2Hz, 2H), 1.85(q, J=7.4, 6.9Hz, 4H), 1.43(s, 9H), 0.87(t, J=7.5Hz , 6H); Z-isomer(diagnostic peaks only): 1 H NMR (400MHz, CDCl 3 ) δ4.67(d, J=5.4Hz, 2H), 3.87(s, 2H), 2.68(d, J=5.7 Hz, 2H).
四、合成8位取代-3-叔丁砜基-3，4，7，8-四氢-2H-氧代辛-2-酮八元环，操作工艺流程如下：4. Synthesis of 8-substituted-3-tert-butylsulfone-3,4,7,8-tetrahydro-2H-oxooctan-2-one eight-membered ring, the operating process is as follows:
氩气状态下，向干燥的封管中加入Pd(OAc)2(0.1eq.)，PPh 3(0.4eq.)，将其溶于无水N，N-二甲基甲酰胺(20mL/mmol)中，完全溶解后，将叔丁基磺酰基乙酸酯类化合物(1.0eq.)加入到反应液中。根据反应条件，最后确定是否加入氢化钠(0.1eq.)。加料完毕，保持90℃，50℃或室温反应15h。反应结束，用乙酸乙酯和饱和食盐水萃取，有机层用无水硫酸钠干燥，过滤旋蒸，柱层析分离，得到不同取代基的八元环化合物。Under argon atmosphere, add Pd(OAc)2(0.1eq.), PPh3(0.4eq.) into the dry sealed tube, dissolve it in anhydrous N,N-dimethylformamide (20mL/mmol ), after completely dissolving, tert-butylsulfonyl acetate compound (1.0eq.) was added to the reaction solution. Depending on the reaction conditions, it was finally determined whether to add sodium hydride (0.1 eq.). After the addition is complete, keep at 90°C, 50°C or room temperature for 15h. After the reaction was completed, it was extracted with ethyl acetate and saturated brine, and the organic layer was dried with anhydrous sodium sulfate, filtered, rotary evaporated, and separated by column chromatography to obtain eight-membered ring compounds with different substituents.
本步骤反应式如下：This step reaction formula is as follows:
化合物核磁谱图：Compound NMR spectrum:
(Z)-3-(叔丁基磺酰基)-8-甲基-3，4，7，8-四氢-2H-环氧辛英-2-酮：1H NMR(600MHz，CDCl3)δ5.94-5.88(m，1H)，5.72-5.65(m，1H)，4.91-4.84(m，1H)，3.99(dd，J＝12.4，4.1Hz，1H)，3.37-3.30(m，1H)，2.61-2.52(m，2H)，2.11(ddd，J＝14.1，8.4，1.4Hz，1H)，1.45(s，9H)，1.42(d，J＝6.3Hz，3H)。(Z)-3-(tert-butylsulfonyl)-8-methyl-3,4,7,8-tetrahydro-2H-epoxyoctin-2-one: 1 H NMR (600MHz, CDCl 3 ) δ5.94-5.88(m, 1H), 5.72-5.65(m, 1H), 4.91-4.84(m, 1H), 3.99(dd, J=12.4, 4.1Hz, 1H), 3.37-3.30(m, 1H ), 2.61-2.52 (m, 2H), 2.11 (ddd, J=14.1, 8.4, 1.4Hz, 1H), 1.45 (s, 9H), 1.42 (d, J=6.3Hz, 3H).
(Z)-3-(叔丁基磺酰基)-8-丙基-3，4，7，8-四氢-2H-环氧辛英-2-酮：1H NMR(400MHz，CDCl3)δ5.94-5.85(m，1H)，5.72-5.63(m，1H)，4.75-4.67(m，1H)，3.98(dd，J＝12.4，4.2Hz，1H)，3.33(q，J＝11.8Hz，1H)，2.62-2.51(m，2H)，2.09(dd，J＝14.0，8.5Hz，1H)，1.83-1.73(m，1H)，1.59-1.49(m，2H)，1.44(s，9H)，1.42-1.35(m，1H).0.93(t，J＝7.3Hz，3H)。(Z)-3-(tert-butylsulfonyl)-8-propyl-3,4,7,8-tetrahydro-2H-epoxyoctin-2-one: 1 H NMR (400MHz, CDCl 3 ) δ5.94-5.85(m, 1H), 5.72-5.63(m, 1H), 4.75-4.67(m, 1H), 3.98(dd, J=12.4, 4.2Hz, 1H), 3.33(q, J=11.8 Hz, 1H), 2.62-2.51(m, 2H), 2.09(dd, J=14.0, 8.5Hz, 1H), 1.83-1.73(m, 1H), 1.59-1.49(m, 2H), 1.44(s, 9H), 1.42-1.35 (m, 1H). 0.93 (t, J=7.3Hz, 3H).
(Z)-3-(叔丁基磺酰基)-8-异丙基-3，4，7，8-四氢-2H-环氧辛英-2-酮：1H NMR(400MHz，CDCl3)δ5.89(q，J＝8.2Hz，1H)，5.66(q，J＝9.3Hz，1H)，4.48-4.39(m，1H)，4.00-3.94(m，1H)，3.32(q，J＝10.6Hz，1H)，2.60-2.48(m，2H)，2.19-2.09(m，1H)，1.98-1.85(m，1H)，1.44(s，9H)，0.98(d，J＝5.3Hz，3H)，0.97(d，J＝5.7Hz，3H)。(Z)-3-(tert-butylsulfonyl)-8-isopropyl-3,4,7,8-tetrahydro-2H-epoxyoctin-2-one: 1 H NMR (400MHz, CDCl 3 )δ5.89(q, J=8.2Hz, 1H), 5.66(q, J=9.3Hz, 1H), 4.48-4.39(m, 1H), 4.00-3.94(m, 1H), 3.32(q, J =10.6Hz, 1H), 2.60-2.48(m, 2H), 2.19-2.09(m, 1H), 1.98-1.85(m, 1H), 1.44(s, 9H), 0.98(d, J=5.3Hz, 3H), 0.97 (d, J = 5.7 Hz, 3H).
(Z)-8-(叔丁基)-3-(叔丁基磺酰基)-3，4，7，8-四氢-2H-环氧辛英-2-酮：1H NMR(400MHz，CDCl3)δ5.90(q，J＝8.5Hz，1H)，5.67(q，J＝9.6Hz，1H)，4.40-4.34(m，1H)，4.00-3.93(m，1H)，3.32(q，J＝11.8，11.4Hz，1H)，2.61-2.49(m，2H)，2.17-2.08(m，1H)，1.44(s，9H)，0.98(s，9H)。(Z)-8-(tert-butyl)-3-(tert-butylsulfonyl)-3,4,7,8-tetrahydro-2H-epoxyoctin-2-one: 1 H NMR (400MHz, CDCl 3 ) δ5.90(q, J=8.5Hz, 1H), 5.67(q, J=9.6Hz, 1H), 4.40-4.34(m, 1H), 4.00-3.93(m, 1H), 3.32(q , J=11.8, 11.4Hz, 1H), 2.61-2.49(m, 2H), 2.17-2.08(m, 1H), 1.44(s, 9H), 0.98(s, 9H).
(Z)-3-(叔丁基磺酰基)-8-苯基-3，4，7，8-四氢-2H-环氧辛英-2-酮：1H NMR(400MHz，CDCl3)δ7.45-7.29(m，5H)，6.07-5.97(m，1H)，5.84-5.70(m，2H)，4.15-4.04(m，1H)，3.49(q，J＝11.0Hz，1H)，2.90-2.78(m，1H)，2.69-2.60(m，1H)，2.38-2.30(m，1H)，1.45(s，9H)。(Z)-3-(tert-butylsulfonyl)-8-phenyl-3,4,7,8-tetrahydro-2H-epoxyoctin-2-one: 1 H NMR (400MHz, CDCl 3 ) δ7.45-7.29(m, 5H), 6.07-5.97(m, 1H), 5.84-5.70(m, 2H), 4.15-4.04(m, 1H), 3.49(q, J=11.0Hz, 1H), 2.90-2.78 (m, 1H), 2.69-2.60 (m, 1H), 2.38-2.30 (m, 1H), 1.45 (s, 9H).
(Z)-3-(叔丁基磺酰基)-8，8-二乙基-3，4，7，8-四氢-2H-环氧辛英-2-酮：1H NMR(400MHz，CDCl3)δ5.93-5.84(m，1H)，5.83-5.75(m，1H)，3.97(dd，J＝12.2，4.4Hz，1H)，3.33-3.20(m，1H)，2.74(dd，J＝13.8，8.0Hz，1H)，2.56-2.69(m，1H)，2.20-2.07(m，2H)，1.80-1.68(m，3H)，1.43(s，9H)，0.94(dt，J＝17.9，7.4Hz，6H)。(Z)-3-(tert-butylsulfonyl)-8,8-diethyl-3,4,7,8-tetrahydro-2H-epoxyoctin-2-one: 1 H NMR (400MHz, CDCl 3 ) δ5.93-5.84 (m, 1H), 5.83-5.75 (m, 1H), 3.97 (dd, J=12.2, 4.4Hz, 1H), 3.33-3.20 (m, 1H), 2.74 (dd, J=13.8, 8.0Hz, 1H), 2.56-2.69(m, 1H), 2.20-2.07(m, 2H), 1.80-1.68(m, 3H), 1.43(s, 9H), 0.94(dt, J= 17.9, 7.4Hz, 6H).
五、合成天然产物(-)-Cephalosporolide D骨架结构(R，Z)-8-甲基-3，4，7，8-四氢-2H-环氧辛英-2-酮，操作工艺流程如下：5. The synthetic natural product (-)-Cephalosporolide D skeleton structure (R, Z)-8-methyl-3,4,7,8-tetrahydro-2H-epoxyoctine-2-one, the operation process is as follows :
氩气状态下，向干燥的圆底烧瓶中加入底物(R)-戊-4-烯-2-醇(1.00g，11.60mmol，1.0eq.)和2-(苯基磺酰基)乙酸(5.81g，29.00mmol，2.5eq.)，将其溶于250mL二氯甲烷中，再将1-羟基苯并三唑(4.71g，34.80mmol，2.0eq.)，4-二甲氨基吡啶(284mg，2.32mmol，0.2eq.)，1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(6.68g，34.80mmol，3.0eq.)和三乙胺(4.70g，46.40mmol，4.0eq.)依次加入反应液中。加料完毕，室温反应15h。反应结束，二氯甲烷和饱和食盐水萃取，有机层用无水硫酸钠干燥，过滤旋蒸，柱层析分离，得到(R)-Pent-4-en-2-基-2-(苯磺酰基)乙酸酯2.40g，收率为77％。The substrate (R)-pent-4-en-2-ol (1.00 g, 11.60 mmol, 1.0 eq.) and 2-(phenylsulfonyl)acetic acid ( 5.81g, 29.00mmol, 2.5eq.), it was dissolved in 250mL of dichloromethane, and then 1-hydroxybenzotriazole (4.71g, 34.80mmol, 2.0eq.), 4-dimethylaminopyridine (284mg , 2.32mmol, 0.2eq.), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.68g, 34.80mmol, 3.0eq.) and triethylamine (4.70 g, 46.40mmol, 4.0eq.) were added to the reaction solution in turn. After the addition was complete, the reaction was carried out at room temperature for 15 hours. After the reaction was completed, dichloromethane and saturated brine were extracted, the organic layer was dried over anhydrous sodium sulfate, filtered and rotary evaporated, and separated by column chromatography to obtain (R)-Pent-4-en-2-yl-2-(benzenesulfonate Acyl) acetate 2.40g, the yield is 77%.
(R)-戊-4-烯-2-基-2-(苯磺酰基)乙酸酯：1H NMR(400MHz，CDCl3)δ7.90(d，J＝7.1Hz，2H)，7.64(dd，J＝9.1，4.9Hz，1H)，7.54(t，J＝7.3Hz，2H)，5.58(ddd，J＝12.2，9.6，6.5Hz，1H)，5.05-4.93(m，2H)，4.95-4.81(m，1H)，4.07(s，2H)，2.28-2.13(m，2H)，1.10(d，J＝6.3Hz，3H)。(R)-pent-4-en-2-yl-2-(benzenesulfonyl)acetate: 1 H NMR (400MHz, CDCl 3 ) δ7.90 (d, J=7.1Hz, 2H), 7.64( dd, J=9.1, 4.9Hz, 1H), 7.54(t, J=7.3Hz, 2H), 5.58(ddd, J=12.2, 9.6, 6.5Hz, 1H), 5.05-4.93(m, 2H), 4.95 -4.81 (m, 1H), 4.07 (s, 2H), 2.28-2.13 (m, 2H), 1.10 (d, J=6.3Hz, 3H).
氩气状态下，向干燥的圆底烧瓶中加入(R)-Pent-4-en-2-基-2-(苯磺酰基)乙酸酯(800mg，2.98mmol，1.0eq.)，将其溶于140mL甲苯溶液中，将(Z)-2-烯-1，4-二基二甲基双(碳酸酯)(1.52g，7.45mmol，2.5eq.)加入到圆底烧瓶中。搅拌2min后，向反应液中加入Grubbs 2催化剂(63mg，0.07mmol，2.5％eq.)，溶液迅速变为锈红色。加料完毕，氩气保护下110℃回流15h。反应结束，溶液变为红棕色，旋蒸，除去溶剂甲苯，柱层析分离，得到754mg(R)-6-((甲氧基羰基)氧基)己-4-烯-2-基-2-(苯基磺酰基)乙酸酯，收率为71％。Under argon atmosphere, (R)-Pent-4-en-2-yl-2-(benzenesulfonyl) acetate (800mg, 2.98mmol, 1.0eq.) was added to a dry round bottom flask, and it was Dissolved in 140 mL of toluene solution, (Z)-2-ene-1,4-diyldimethylbis(carbonate) (1.52 g, 7.45 mmol, 2.5 eq.) was added to a round bottom flask. After stirring for 2 min, Grubbs 2 catalyst (63 mg, 0.07 mmol, 2.5% eq.) was added to the reaction solution, and the solution quickly turned rust red. After the addition was complete, the mixture was refluxed at 110° C. for 15 h under the protection of argon. After the reaction was completed, the solution turned reddish-brown. Rotary evaporation removed the solvent toluene and separated by column chromatography to obtain 754 mg of (R)-6-((methoxycarbonyl)oxy)hex-4-en-2-yl-2 -(phenylsulfonyl)acetate, yield 71%.
(R)-6-((甲氧基羰基)氧基)己-4-烯-2-基-2-(苯基磺酰基)乙酸酯：E/Z＝5∶1，E-isomer：1H NMR(400MHz，CDCl3)δ7.91(d，J＝7.7Hz，2H)，7.66(t，J＝7.4Hz，1H)，7.55(t，J＝7.5Hz，2H)，5.66-5.52(m，2H)，4.89(q，J＝6.6Hz，1H)，4.52(d，J＝4.7Hz，2H)，4.08(s，2H)，3.74(s，3H)，2.29-2.18(m，2H)，1.12(d，J＝6.3Hz，3H)；Z-isomer(diagnostic peaksonly)：1H NMR(400MHz，CDCl3)δ4.58(d，J＝7.5Hz，2H)。(R)-6-((methoxycarbonyl)oxy)hex-4-en-2-yl-2-(phenylsulfonyl)acetate: E/Z=5:1, E-isomer: 1H NMR (400MHz, CDCl 3 ) δ7.91(d, J=7.7Hz, 2H), 7.66(t, J=7.4Hz, 1H), 7.55(t, J=7.5Hz, 2H), 5.66-5.52( m, 2H), 4.89(q, J=6.6Hz, 1H), 4.52(d, J=4.7Hz, 2H), 4.08(s, 2H), 3.74(s, 3H), 2.29-2.18(m, 2H ), 1.12 (d, J=6.3Hz, 3H); Z-isomer (diagnostic peaks only): 1 H NMR (400MHz, CDCl 3 ) δ4.58 (d, J=7.5Hz, 2H).
氩气状态下，向干燥的封管中加入Pd(OAc)2(50mg，0.23mmol，0.1eq.)，PPh3(236mg，0.90mmol，0.4eq.)，将其溶于5mL无水N，N-二甲基甲酰胺中，将底物5.49(800mg，2.24mmol，1.0eq.)加入到反应液中。加料完毕，保持90℃反应15h。反应结束，乙酸乙酯和饱和食盐水萃取，有机层用无水硫酸钠干燥，过滤旋蒸，柱层析分离，得到390mg八元环混合物，收率为62％。Under argon, to a dry sealed tube was added Pd(OAc) 2 (50 mg, 0.23 mmol, 0.1 eq.), PPh 3 (236 mg, 0.90 mmol, 0.4 eq.), dissolved in 5 mL of anhydrous N, In N-dimethylformamide, the substrate 5.49 (800 mg, 2.24 mmol, 1.0 eq.) was added to the reaction solution. After the addition was complete, the reaction was maintained at 90°C for 15h. After the reaction was completed, ethyl acetate and saturated brine were extracted, the organic layer was dried over anhydrous sodium sulfate, filtered and rotary evaporated, and separated by column chromatography to obtain 390 mg of the eight-membered ring mixture with a yield of 62%.
(8R，Z)-8-甲基-3-(苯基磺酰基)-3，4，7，8-四氢-2H-环氧辛英-2-酮：1H NMR(400MHz，CDCl3)δ7.90(d，J＝7.4Hz，2H)，7.67(t，J＝7.2Hz，1H)，7.55(t，J＝7.6Hz，2H)，5.80(q，J＝8.6Hz，1H)，5.62(q，J＝9.7Hz，1H)，4.82-4.69(m，1H)，3.96(d，J＝12.3Hz，1H)，3.13(q，J＝11.3Hz，1H)，2.54-2.45(m，1H)，2.44-2.33(m，1H)，2.02(dd，J＝14.0，8.3Hz，1H)，1.30(d，J＝5.9Hz，3H)。(8R, Z)-8-methyl-3-(phenylsulfonyl)-3,4,7,8-tetrahydro-2H-epoxyoctin-2-one: 1H NMR (400MHz, CDCl 3 ) δ7.90(d, J=7.4Hz, 2H), 7.67(t, J=7.2Hz, 1H), 7.55(t, J=7.6Hz, 2H), 5.80(q, J=8.6Hz, 1H), 5.62(q, J=9.7Hz, 1H), 4.82-4.69(m, 1H), 3.96(d, J=12.3Hz, 1H), 3.13(q, J=11.3Hz, 1H), 2.54-2.45(m , 1H), 2.44-2.33 (m, 1H), 2.02 (dd, J=14.0, 8.3Hz, 1H), 1.30 (d, J=5.9Hz, 3H).
氩气状态下，向干燥的圆底烧瓶中加入八元环内酯化合物(1.0eq.)，将其溶于乙醇中，将乙酸(10.0eq.)和钠汞齐(5.0eq.)依次加至反应液中。加料完毕，室温搅拌6h。反应结束，饱和氯化铵淬灭，乙酸乙酯和饱和碳酸氢钠萃取，有机层用无水硫酸钠干燥，过滤旋蒸，柱层析分离，得到脱磺酰基化合物。Under argon atmosphere, add eight-membered ring lactone compound (1.0eq.) to a dry round bottom flask, dissolve it in ethanol, add acetic acid (10.0eq.) and sodium amalgam (5.0eq.) in sequence into the reaction solution. After addition, stir at room temperature for 6h. After the reaction was completed, quenched with saturated ammonium chloride, extracted with ethyl acetate and saturated sodium bicarbonate, dried the organic layer with anhydrous sodium sulfate, filtered and rotary evaporated, and separated by column chromatography to obtain the desulfonyl compound.
(R，Z)-8-甲基-3，4，7，8-四氢-2H-环氧辛英-2-酮：1HNMR(400MHz，CDCl3)δ5.82-5.68(m，2H)，4.77-4.68(m，1H)，2.89-2.75(m，1H)，2.73-2.65(m，1H)，2.48-2.35(m，1H)，2.34-2.23(m，1H)，2.14-2.00(m，2H)，1.30(d，J＝6.3Hz，3H)。(R, Z)-8-methyl-3,4,7,8-tetrahydro-2H-epoxyoctin-2-one: 1 HNMR (400MHz, CDCl 3 ) δ5.82-5.68 (m, 2H ), 4.77-4.68(m, 1H), 2.89-2.75(m, 1H), 2.73-2.65(m, 1H), 2.48-2.35(m, 1H), 2.34-2.23(m, 1H), 2.14-2.00 (m, 2H), 1.30 (d, J=6.3Hz, 3H).
本步骤反应式如下：This step reaction formula is as follows:
Claims (7)
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Application publication date: 20190910 |