Patent Application
20200392150
The present invention belongs to the field of chemical pharmaceutical, and relates to a series of diaryl-β-lactam compounds having significant antitumor activity, the preparation method thereof, and the in vitro and in vivo antitumor activity, and the use of such compounds and their pharmaceutically acceptable salts thereof, or the medicinal component comprising the compounds or salts as ingredient in the prevention and treatment of tumor-related diseases.
Cancer is one of the major diseases that threaten human health, of which the mortality rate is second only to cardiovascular and cerebrovascular diseases. It is estimated that there will be 15 million new cases by 2020, and the death toll will reach 10 million. Till now, treatment methods of cancers include surgery, radiation therapy, chemotherapy (drug therapy) and biological therapy, of which chemotherapy is the most common one, i.e., to treat cancer patients with one or more cytotoxic anti-tumor drugs. Although a large number of drugs are currently in clinical use, due to the long-term use of chemotherapy drugs or mutations in tumor cells themselves, many malignant tumors are resistant to chemotherapy drugs, resulting in weakened or disappeared chemotherapy effects. Also, due to the toxicity induced by the absence of selectivity of the traditional anti-tumor drugs, chemotherapy drugs are unable to meet clinical needs. Therefore, the search for new anti-tumor drugs with potent efficacy and low toxicity has always been a research and development hot spot in the medical field as well as an important problem that needs to be solved urgently.
At present, there are nearly 100 anti-tumor drugs approved for marketing, mainly including the following types: (1) anti-tumor drugs acting on DNA: such as alkylating agents, platinum complexes, DNA topoisomerase inhibitors and anti-metabolite anti-tumor drugs; (2) anti-tumor drugs acting on kinases: such as tyrosine kinase inhibitors and serine/threonine kinase inhibitors; (3) anti-tumor drugs acting on microtubules: such as microtubule aggregation inhibitors and microtubule stabilizers. Among them, anti-tumor drugs acting on microtubules are currently the most effective chemotherapeutic drugs for treating prostate cancer, breast cancer, ovarian cancer and other solid tumors, and being one of the hotspots of anti-tumor drug research in recent years.
Many important achievements and progresses have been made in the inhibition of tubulin aggregation inhibitors, especially in the structural modification of Combretastatin. These drugs are effective in inhibiting tumor growth, but the disadvantage is that although many inhibitors have entered clinical trials, there are not many compounds that are approved for marketing due to possessing a certain degree of toxicity. Therefore, the search for novel tubulin aggregation inhibitors and angiogenesis inhibitors with stronger activity and less side effects rem Cancer is one of the major diseases that threaten human health, of which the mortality rate is second only to cardiovascular and cerebrovascular diseases. It is estimated that there will be 15 million new cases by 2020, and the death toll will reach 10 million. Till now, treatment methods of cancers include surgery, radiation therapy, chemotherapy (drug therapy) and biological therapy, of which chemotherapy is the most common one, i.e., to treat cancer patients with one or more cytotoxic anti-tumor drugs. Although a large number of drugs are currently in clinical use, due to the long-term use of chemotherapy drugs or mutations in tumor cells themselves, many malignant tumors are resistant to chemotherapy drugs, resulting in weakened or disappeared chemotherapy effects. Also, due to the toxicity induced by the absence of selectivity of the traditional anti-tumor drugs, chemotherapy drugs are unable to meet clinical needs. Therefore, the search for new anti-tumor drugs with potent efficacy and low toxicity has always been a research and development hot spot in the medical field as well as an important problem that needs to be solved urgently.
At present, there are nearly 100 anti-tumor drugs approved for marketing, mainly including the following types: (1) anti-tumor drugs acting on DNA: such as alkylating agents, platinum complexes, DNA topoisomerase inhibitors and anti-metabolite anti-tumor drugs; (2) anti-tumor drugs acting on kinases: such as tyrosine kinase inhibitors and serine/threonine kinase inhibitors; (3) anti-tumor drugs acting on microtubules: such as microtubule aggregation inhibitors and microtubule stabilizers. Among them, anti-tumor drugs acting on microtubules are currently the most effective chemotherapeutic drugs for treating prostate cancer, breast cancer, ovarian cancer and other solid tumors, and being one of the hotspots of anti-tumor drug research in recent years.
Many important achievements and progresses have been made in the inhibition of tubulin aggregation inhibitors, especially in the structural modification of Combretastatin. These drugs are effective in inhibiting tumor growth, but the disadvantage is that although many inhibitors have entered clinical trials, there are not many compounds that are approved for marketing due to possessing a certain degree of toxicity. Therefore, the search for novel tubulin aggregation inhibitors and angiogenesis inhibitors with stronger activity and less side effects remains a clinically urgent need.
The object of the present invention is to disclose a series of novel diaryl-β-lactam compounds having the structures of formula I, or the pharmaceutical salts thereof.
In the first aspect of the present invention, a series of diaryl-β-lactam compounds of formula I, and the pharmaceutically acceptable salt, hydrate, solvent mixture, or prodrug thereof are provided,
wherein,
R1 is one or more groups located on the ring selected from the group consisting of substituted or unsubstituted C1-C4 alkoxy, C1-C4 alkyl, halogen, amino, hydroxy, carboxyl, substituted or unsubstituted C2-C10 acyloxy, C2-C10 ester group, methoxyformyl, allyloxy, propargyloxy, sulfonyloxy, alkylamino, amido, sulfonamido, or the combinations of 2-3 identical or different groups;
R2 is one or more groups located on the ring selected from the group consisting of substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkyl, halogen, amino, hydroxy, carboxyl, fluorosulfonyloxy, allyloxy, propargyloxy, C1-C4 alkylamino, C2-C10 ester group, substituted or unsubstituted C1-C6 alkyl-hydroxy, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-12 membered heteroaryl, —OTBS, —CH2—R, —OR, —O(C═O)R, —O—(SO2)—R, —O(PO)—R2, —NH(C═O)R, —NH—(SO2)—R;
R3 and R4 are each independently selected from the group consisting of substituted or unsubstituted C1-C6 alkyl, hydrogen, acyloxy, hydroxy, carboxy, cyclopropyl, amino, substituted or unsubstituted C1-C4 alkylamino, sulfonyloxy, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C1-C6 alkyl-hydroxy, substituted or unsubstituted aryl, substituted or unsubstituted morpholinyl, —CH2—R, —OR, —O(C═O)R, —O—(SO2)—R, —O(PO)—R2, —NH(C═O)R, —NH—(SO2)—R;
or R3 and R4 together form ═CHR, —OC(═O)OCH2—, ═O, C3-C6 cycloalkane, C3-C6 heterocyclic ring or substituted or unsubstituted —(CH2)n—, wherein n is selected from 1, 2, 3, 4, 5 or 6;
R5 and R6 are each independently H; or R5 and R6 together form ═CHR, —OC(═O)OCH2—, ═O, or ═S;
wherein R is selected from the group consisting of vinyl, halogen, amino, hydroxy, carboxy, fluorosulfonyloxy, methylsulfonyl (Ms), substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C2-C10 ester group, substituted or unsubstituted C1-C6 alkyl-hydroxy, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-12 membered heteroaryl;
the substitution means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of C1-C4 alkoxy, C1-C4 alkyl, halogen, C2-C10 acyloxy, C2-C10 ester group, hydroxy, cyclopropyl, vinyl, amino, oxy group (═O), morpholinyl, sulfonyloxy, amido, —NO2, —NHBoc, —NHCbz, —NHC(═O)Me, —OBn, —NHBn, —SiMe3, unsubstituted phenyl or pyridyl or substituted by 1 to 3 substituents selected from the group consisting of C1-C4 alkoxy, C1-C4 alkyl, halogen or hydroxy.
In another preferred embodiment, the substituted phenyl means that the benzene ring is substituted with from 1 to 5 substituents selected from the group consisting of nitro group, fluorine atom or methoxy group.
In another preferred embodiment, the compounds have the following structure of formula I-1:
wherein each group is defined as above.
In another preferred embodiment, the compounds have the following structure of formula I-2:
wherein each group is defined as above.
In another preferred embodiment, the compounds have the following structures of formula I-3, I-4, I-5, I-6 or I-7:
wherein each group is defined as above.
In the second aspect of the present invention, the following compounds are provided:
In another preferred embodiment, the compounds is selected from the following:
In the third aspect of the present invention, a use of a pharmaceutical composition according to the first aspect of the present invention for the preparation of a pharmaceutical composition for treating or preventing a disease is provided, wherein the disease is selected from the group consisting of mammalian diseases associated with tubulin aggregation and angiogenesis.
In another preferred embodiment, the mammalian disease associated with microtubule-associated protein aggregation is tumor.
In another preferred embodiment, the tumor is selected from the group consisting of thyroid cancer, head and neck squamous cell carcinoma, cervical cancer, ovarian cancer, breast cancer, colorectal cancer, pancreatic cancer, esophageal cancer, osteosarcoma, kidney cancer, stomach cancer, lung cancer, liver cancer, melanoma, lymphoma, prostate cancer, bladder cancer, glioma, nasopharyngeal carcinoma, neuroendocrine cancer, undifferentiated carcinoma, interstitial sarcoma, choriocarcinoma, malignant mole, malignant teratoma or benign tumor.
In the fourth aspect of the present invention, a pharmaceutical composition is provided. The pharmaceutical composition comprises: (i) a therapeutically effective amount of formula I compound, or the pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, and (ii) a pharmaceutically acceptable carrier.
In the fifth aspect of the present invention, a method for the preparation of the compound of formula I is provided, wherein comprises:
in an inert solvent, compound If provide formula compound Ig;
and optionally:
compound I is prepared with compound Ig.
It should be understood that, in the present invention, each of the technical features specifically described above and below (such as those in the Examples) can be combined with each other, thereby constituting new or preferred technical solutions which need not be specified again herein due to space limitation.
Embodiments for carrying out the invention. Through long time and in-depth study, the inventors have discovered a novel class of diaryl-β-lactam compounds. The compounds possess excellent tubulin aggregation inhibitory activity and thus can be used as angiogenesis inhibitors for the treatment of cancer. The present invention is completed on this basis.
Terms.
In the present invention, unless otherwise indicated, the term “substitution” means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of C1-C4 alkoxy, C1-C4 alkyl, halogen, C2-C10 acyloxy, C2-C10 ester group, hydroxy, cyclopropyl, vinyl, amino, oxy group (═O), morpholinyl, sulfonyloxy, amido, —NO2, —NHBoc, —NHCbz, —NHC(═O)Me, —OBn, —NHBn, —SiMe3, unsubstituted phenyl or pyridyl or substituted by 1 to 3 substituents selected from the group consisting of C1-C4 alkoxy, C1-C4 alkyl, halogen, hydroxy.
The term “C1-C4 alkyl” refers to linear or branched alkyl with 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or similar groups.
The term “C3-C6 cycloalkyl” refers to cycloalkyl with 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, or the like.
The term “C1-C4 alkoxy” refers to a straight or branched chain alkoxy having 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, tert-butoxy, or the like.
The term “halogen” refers to F, Cl, Br and I.
The term “C1-C4 alkylamino” refers to an amino substituted by a C1-C4 alkyl group, for example, a group having “C1-C4 alkyl-NH—” or “(alkyl)2-N-(the total number of carbon atoms is 1-4)”, “—C1-C4 alkylene-NH2”, “alkyl-N-alkylene-(the total number of carbon atoms is 1-12)”, or “(alkyl)2-N-alkylene group-(the total number of carbon atoms is 1-12)”, such as CH3NH—, C2H5NH—, C3H7NH—, (CH3)2N—, —CH2NH2, —C2H5NH2, —C3H7NH2, —C2H4N(CH3)2, or the like. Among them, the definition of the C1-12 alkyl group is as described above.
The term “C2-C10 ester group” refers to a substituent in the form of “linear or branched alkyl/cycloalkyl/aryl/heteroaryl-carbonyl-oxy-” with 1 to 9 carbon atoms, such as ethyl ester group, propyl ester group, butyl ester group, or the like.
The term “C1-C6 amido” refers to a substituent in the form of “linear or branched alkyl/cycloalkyl/aryl/heteroaryl-carbonyl-amino-” with 0 to-5 carbon atoms, such as acetamido, propionamido, butanamido, or the like.
The term “C6-C10 aryl” refers to an aryl with 6 to-10 carbon atoms, such as phenyl, naphthyl, or the like, the aryl can be substituted or unsubstituted.
The term “5-12 membered heteroaryl” refers to a heteroaryl group having 5 to 12 ring atoms, wherein the ring atom includes carbon atoms, and one or more (preferably 1 to 3) heteroatoms selected from O, S and/or N, preferably a 5-8 membered heteroaryl. The heteroaryl may be substituted or unsubstituted.
The term “C3-C6 heterocyclyl” refers to a non-aromatic cyclic group having 3 to 6 carbon atoms and one or more (preferably 1 to 3) heteroatoms selected from O, S and/or N, preferably 5- to 6-membered heterocyclyl. The heterocyclyl may be substituted or unsubstituted.
In the present invention, the term “pharmaceutically acceptable” component refers to a substance which are suitable for applying to humans and/or animals without undue harmful side reactions (such as toxicity, stimulation or allergy), that is to say, a substance having reasonable benefit/risk ratio.
In the present invention, the term “effective amount” refers to an amount in which the therapeutic agents can treat, relieve or prevent the targeted disease or condition, or exhibit detectable treatment or prevention effects. The exact effective amount for a subject will depend on the size and health condition of the subject, the nature and extent of the disorder, and the therapeutic agent and/or therapeutic agent combination selected for administration. Therefore, it is useless to specify an accurate effective amount in advance. However, for a given situation, the effective amount may be determined by routine experimentation, which can be determined by clinicians.
Unless otherwise indicated, all compounds in the invention are intended to include all possible optical isomers, such as single chiral compounds, or mixtures of various chiral compounds (i.e., racemates). In compounds of the present invention, each chiral carbon atom may optionally be in R configuration or S configuration, or the mixture of R configuration and S configuration.
The “pharmaceutically acceptable salt” as described in the present invention may specifically be a salt formed with an inorganic acid such as hydrohalic acid, sulfuric acid, phosphoric acid or nitric acid, or an organic acid such as citric acid, fumaric acid, oxalic acid, malic acid, lactic acid, camphorsulfonic acid, etc.
Another object of the present invention is to provide a use of the above compound or a pharmaceutically acceptable salt thereof and a composition comprising the compound or the salt thereof in the preparation of a medicament for the prevention or treatment of tumor-related diseases. The cancer-related diseases may specifically be (but are not limited to) thyroid cancer, head and neck squamous cell carcinoma, cervical cancer, ovarian cancer, breast cancer, colorectal cancer, pancreatic cancer, esophageal cancer, osteosarcoma, kidney cancer, stomach cancer, lung cancer, liver cancer, melanoma, lymphoma, prostate cancer, bladder cancer, glioma, nasopharyngeal carcinoma, neuroendocrine cancer, undifferentiated carcinoma, interstitial sarcoma, choriocarcinoma, malignant mole, malignant teratoma, etc., and benign tumor. The present invention provides a diaryl-β-lactam compound or a pharmaceutically acceptable salt thereof having significant antitumor effect and demonstrates that they can show a significant inhibitory effect on tumor growth in vitro and in vivo in anti-tumor experiments by regulatory mechanism of inhibiting tumor cell growth by inhibiting tubulin aggregation.
In the present invention, a preferred class of compounds are diaryl-β-lactam compounds having the structure of formula I:
wherein R1 is selected from hydroxy, amino, halogen, alkoxy with 1 to 3 carbon atoms, methoxycarbonyl, allyloxy, propargyloxy, O(CH2)nR2, OCH2COR3, OCOR4, OSO2R5, NHCOR6, NHSO2NH2, wherein R2 is selected from halogen, hydroxy, N,N-dimethylamino, N-morpholinyl, and n=2 or 3, and R3 is selected from alkoxy with 1 to 3 carbon atoms or amino, R4 is selected from alkyl group with 1 to 3 carbon atoms, phenyl, substituted phenyl, pyridyl, cyclopropyl, vinyl, N-morpholinyl, and the substituted phenyl means the position 2, 3 or 4 of the benzene ring is substituted by and only by one nitro group, fluorine atom or methoxy group, and R5 is selected from amino, 4-methylphenyl, N-morpholinyl, 2-(1,3-dioxoisoindol-2-yl)ethyl, 4-acetaminophenyl, benzyl, n-butyl, 3,4-dimethoxyphenyl, R6 is selected from vinyl, 4-nitrophenyl, cyclopropyl.
A more preferred class of compounds are diaryl-β-lactam compounds having the structure of formula II:
wherein R is selected from methoxy, the number is 1 or 2, and may be substituted at the position 3, 4 or 5.
Or the preferred compound is diaryl-β-lactam compounds with following formula III:
wherein R is selected from methyl, trimethylsilyl, phenyl or tert-butylphenyl, and the configuration of the ethylenic bond is Z or E.
Or the preferred compounds are diaryl-β-lactam compounds with following formula IV or V:
wherein R1 is independently selected from the group consisting of methyl, ethyl, hydroxymethyl, hydrogen, alkoxy, acyloxy, hydroxy, halogen, amino, phenylamino, benzylamino, acetylamino, p-toluenesulfonylamino, methanesulfonylamino, benzoylamino, 3-fluoro benzoylamino, mesyloxy, methoxymethyl, N,N-dimethylaminomethyl, 4-hydroxybenzyl, trimethylsilylethyl, ethoxycarbonylmethyl, carboxypropionyloxy, R2 is independently selected from hydroxy, amino, halogen, methoxy, methyl, fluorosulfonyloxy, hydrogen or acyloxy. Wherein the dominant compounds are:
Or the preferred compounds are diaryl-β-lactam compounds with following formula VI:
wherein R1 is selected from hydrogen atom, methyl, acetyl or acryloyl, and R2 is selected from hydrogen atom, benzyl, acyl or acryloyl.
A particularly preferred class of compounds have the structures shown below:
Pharmaceutical composition and administration method. The compounds of the present invention possess outstanding activity of inhibiting microtubulin. Therefore, the compound of the present invention, and the crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and the pharmaceutical composition comprising the compound of the present invention as a main active ingredient can be used for treating, preventing and alleviating diseases related to microtubulin activity or expression, especially diseases related to microtubulin activity and expression. According to the prior art, the compounds of the invention can be used in the treatment of diseases such as cancer, neurodegenerative diseases, malaria, AIDS, gout, diabetes and the like.
The pharmaceutical composition of the invention comprises a safe and effective amount of the compound of the present invention or the pharmaceutically acceptable salts thereof and a pharmaceutically acceptable excipient or carrier. Wherein the “safe and effective amount” means that the amount of compound is sufficient to significantly ameliorate the condition without causing significant side effects. Generally, the pharmaceutical composition contains 1-2000 mg polymorphs of the invention per dose, preferably, 5-200 mg of the compounds of the invention per dose. Preferably, the “one dose” is a capsule or tablet.
“Pharmaceutically acceptable carrier” means one or more compatible solid or liquid fillers, or gelatinous materials which are suitable for human use and should be of sufficient purity and sufficiently low toxicity. “Compatibility” means that each component in the composition can be admixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and the derivatives thereof (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween®), wetting agent (such as sodium dodecyl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
There is no special limitation of administration mode for the compound or pharmaceutical compositions of the present invention, and the representative administration mode includes (but is not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compounds are mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with any of the following components: (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and arabic gum; (c) humectants, such as, glycerol; (d) disintegrating agents such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain composite silicates, and sodium carbonate; (e) dissolution-retarding agents, such as paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or the mixtures thereof. In capsules, tablets and pills, the dosage forms may also contain buffering agent.
The solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared by using coating and shell materials, such as enteric coatings and any other materials known in the art. They can contain an opaque agent. The release of the active compounds or compounds in the compositions can be released in a delayed mode in a given portion of the digestive tract. Examples of the embedding components include polymers and waxes. If necessary, the active compounds may also be in microencapsulated form with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain any conventional inert diluents known in the art such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethyl formamide, as well as oil, in particular, cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or the combination thereof.
Besides these inert diluents, the composition may also contain additives such as wetting agents, emulsifiers, and suspending agent, sweetening agent, flavoring agents and perfume.
In addition to the active compounds, the suspension may contain suspending agent, for example, ethoxylated isooctadecanol, polyoxyethylene sorbitol and sorbitan ester, microcrystalline cellulose, aluminum methoxide and agar, or the combination thereof.
The compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders which can be re-dissolved into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and any suitable mixtures thereof.
The dosage forms for topical administration of compounds of the invention include ointments, powders, patches, propellants, and inhalants. The active ingredients are mixed with physiologically acceptable carriers and any preservatives, buffers, or propellants if necessary, under sterile conditions.
Compounds of the present invention can be administrated alone, or in combination with any other pharmaceutically acceptable compounds.
When the pharmaceutical compositions are used, a safe and effective amount of compound of the present invention is administered to a mammal (such as human) in need of treatment, wherein the dose of administration is a pharmaceutically effective dose. For a person weighed 60 kg, the daily dose is usually 1-2000 mg, preferably 5-500 mg. Of course, the particular dose should also depend on various factors, such as the route of administration, patient healthy status, which are within the skills of an experienced physician.
The main advantages of the present invention include:
(1) A novel class of compounds having tubulin inhibitory activity are provided.
(2) A novel class of compounds having tumor inhibiting activity is provided, wherein the compounds can be used for the preparation of a medicament for the treatment of tumor.
The present invention will be further illustrated below with reference to the specific examples. It should be understood that these examples are only to illustrate the invention but not to limit the scope of the invention. The experimental methods with no specific conditions described in the following examples are generally performed under the conventional conditions, or according to the manufacturer's instructions. Unless indicated otherwise, parts and percentage are calculated by weight. The preparation method of the target compounds of the present invention can be further carried out by using representative compounds preparation process as follows:
The synthetic route of target compound 1 was designed according the reference (Wang, X.; Meng, F.; Wang, Y.; Han, Z.; Chen, Y.-J.; Liu, L.; Wang, Z.; Ding, K. Angew. Chem. Int. Ed. 2012, 124, 9410-9416).
A 100 mL round-bottom flask was charged with 3-hydroxy-4-methoxybenzaldehyde (1a) (1.58 g, 10.4 mmol), DMAP (25 mg, 0.2 mmol), Et3N (2 mL, 14.5 mmol) and anhydrous dichloromethane (50 mmol). The solution was cooled to 0° C. with an ice bath, and TBSC1 (1.88 g, 12.5 mmol, dissolved in 10 mL of dichloromethane) was dropped into the flask. The solution was then warmed to room temperature and stirred for 2 h. 50 mL of saturated aqueous solution of sodium bicarbonate was added into the solution, and the mixture was extracted with dichloromethane (30 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 1b as colorless oil (2.66 g, yield 96%).
A 50 mL round-bottom flask was charged with 1b (2.66 g, 10 mmol), ethyl acrylate (1.00 g, 10 mmol) and DABCO (1.12 g, 10 mmol). The solution was stirred at room temperature for 14 days. The mixture was directly purified by flash column chromatography to give 1c as colorless oil (1.12 g, yield 31%). 1H NMR (400 MHz, CDCl3) δ 6.92 (dd, J=8.3, 2.1 Hz, 1H), 6.85 (d, J=2.1 Hz, 1H), 6.81 (d, J=8.3 Hz, 1H), 6.70-6.76 (m, 1H), 6.31 (s, 1H), 5.77 (d, J=1.1 Hz, 1H), 5.47 (d, J=5.0 Hz, 1H), 4.17 (q, J=7.1 Hz, 2H), 3.79 (s, 3H), 1.24 (t, J=7.1 Hz, 3H), 0.98 (s, 9H), 0.13 (s, 6H); ESI-LRMS m/z (%): 367.2 [M+H]+.
A 250 mL round-bottom flask was charged with compound 1c (1.12 g, 3.1 mmol), triethylamine (0.63 g, 6.2 mmol), DMAP (45 mg, 0.31 mmol) and dichloromethane (20 mL). The solution was cooled to 0° C. by an ice bath, then acetic anhydride (0.63 g, 6.2 mmol) was added dropwise into the flask within 10 min. After stirred for 1 h, 10 mL of saturated aqueous solution of sodium bicarbonate was added into the solution, and the mixture was extracted with dichloromethane (20 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 1d as colorless oil (1.2 g, yield 96%). 1H NMR (400 MHz, CDCl3) δ 6.93 (dd, J=8.3, 2.2 Hz, 1H), 6.84 (d, J=2.2 Hz, 1H), 6.79 (d, J=8.3 Hz, 1H), 6.58 (s, 1H), 6.36 (s, 1H), 5.77 (s, 1H), 4.14 (q, J=7.1 Hz, 2H), 3.78 (s, 3H), 2.09 (s, 3H), 1.21 (t, J=7.1 Hz, 3H), 0.98 (s, 9H), 0.13 (s, 6H); ESI-LRMS m/z (%): 409.2 [M+H]+.
A 50 mL Schlenk flask was charged with 5 mL of dichloromethane and the solvent was deoxygenized with nitrogen bubbling for 15 min. Tris(dibenzylideneacetone)dipalladium (27 mg, 0.029 mmol) and R1 (49 mg, 0.074 mmol) was added into the flask. The resulted purple solution was stirred under nitrogen atmosphere for 10 min at room temperature. Then 3,4,5-trimethoxyaniline (809 mg, 0.62 mmol), K2CO3 (1.0 M aq. solution, 5 mL, 5 mmol) and compound 1d (1.2 g, 2.9 mmol, dissolved in 10 mL of oxygen free dichloromethane) were added under a steam of nitrogen. The solution was stirred for 2 h at room temperature. Water (20 mL) was added into the solution, and the mixture was extracted with dichloromethane (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give if as yellow oil (1.3 g, yield 84%). 1H NMR (400 MHz, CDCl3) δ 6.91 (dd, J=8.3, 2.1 Hz, 1H), 6.83 (d, J=2.1 Hz, 1H), 6.80 (d, J=8.3 Hz, 1H), 6.34 (s, 1H), 5.88 (s, 1H), 5.81 (s, 2H), 5.28 (s, 1H), 4.15 (q, J=7.1 Hz, 2H), 3.78 (s, 3H), 3.76 (s, 6H), 3.74 (s, 3H), 1.22 (t, J=7.1 Hz, 3H), 0.96 (s, 9H), 0.11 (s, 6H).
To a 100 mL Schlenk flask equipped with a cold finger was added if (1.3 g), Sn[N(TMS)2]2 (1.6 g, 3.7 mmol) and anhydrous toluene (20 mL). The mixture was heated to reflux for 4.5 h under nitrogen atmosphere. The solution was cooled and directly purified by flash chromatography to give 1g as colorless oil (1.1 g, yield 92%); [α]D20=+37.3 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.91-6.88 (m, 1H), 6.78-6.76 (m, 2H), 6.52 (s, 2H), 5.72 (s, 1H), 5.20 (s, 1H), 5.06 (s, 1H), 3.71 (s, 3H), 3.68 (s, 3H), 3.64 (s, 6H), 0.86 (t, J=2.8 Hz, 9H), 0.01 (d, J=4.8 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 160.5, 153.1, 151.1, 149.6, 145.2, 134.2, 133.4, 128.4, 120.1, 118.9, 111.8, 110.1, 94.5, 63.2, 60.5, 55.6, 55.1, 25.3, 18.1, −5.01; ESI-LRMS m/z: 486.2 [M+H+].
A 100 mL round-bottom flask was charged with compound 1g (1.1 g, 2.3 mmol) and THF (25 mL). The solution was cooled to 0° C. by an ice bath, then TBAF (888 mg, 3.4 mmol, dissolved in 5 mL THF) was dropped into the flask. After stirred for 15 min at 0° C., 30 mL of water was added into the solution. The mixture was extracted with ethyl acetate (20 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 1 as white solid (597 mg, yield 71%). Mp 115-117° C.; [α]D20=+38.6 (c1.0, CHCl3); 1H NMR (400 MHz, CDCl3): δ 6.93 (d, J=1.7 Hz, 1H), 6.87 (dd, J=8.2, 1.7 Hz, 1H), 6.82 (d, J=8.2 Hz, 1H), 6.58 (s, 2H), 5.79 (s, 1H), 5.26 (s, 1H), 5.13 (s, 1H), 3.84 (s, 3H), 3.73 (s, 3H), 3.71 (s, 6H). 13C NMR (150 MHz, CDCl3): δ 160.3, 152.9, 149.2, 146.5, 145.6, 134.1, 133.2, 128.9, 118.1, 112.3, 110.3, 110.0, 94.31, 63.0, 60.3, 55.5, 55.4. ESI-MS (m/z): 372.1 (M+H+). ESI-HRMS (m/z): calcd for C20H21NO6+[M+H]+ 372.1442; found, 372.1441.
A 50 mL round-bottom flask was charged with 1 (22 mg, 0.059 mmol), K2CO3 (15 mg, 0.108 mmol), MeI (17 mg, 0.12 mmol) and dimethylsulfate (10 mL). The solution was stirred for 3 h. Then 10 mL of water was added into the solution, and the mixture was extracted with ethyl acetate (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 2 as white solid (23 mg, yield 97%); Mp 138-139° C.; [α]D20=+35.6 (c 0.21, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.00 (dd, J=8.2, 1.8 Hz, 1H), 6.86 (d, J=8.2 Hz, 1H), 6.83 (d, J=1.8 Hz, 1H), 6.60 (s, 2H), 5.84 (s, 1H), 5.31 (s, 1H), 5.17 (s, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.76 (s, 3H), 3.73 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 161.3, 153.8, 150.1, 150.0, 149.9, 134.9, 134.2, 129.1, 120.2, 111.4, 111.2, 109.3, 95.1, 64.3, 61.3, 56.3; ESI-LRMS m/z (%): 386.2 [M+H]+; ESI-HRMS m/z (%): Calcd for C21H24NO6 [M+H]+ 386.1598, found 386.1598.
A 50 mL round-bottom flask was charged with 1 (22 mg, 0.059 mmol), K2CO3 (15 mg, 0.108 mmol), EtBr (12 mg, 0.12 mmol) and dimethylsulfate (10 mL). The solution was stirred for 8 h. Then 10 mL of water was added into the solution, and the mixture was extracted with ethyl acetate (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 3 as white solid (23 mg, yield 97%); Mp 92-93° C.; [α]D20=+34.0 (c 0.27, CHCl3). 1H NMR (400 MHz, CDCl3) δ 6.98 (dd, J=8.2, 2.0 Hz, 1H), 6.86 (d, J=8.2 Hz, 1H), 6.83 (d, J=1.9 Hz, 1H), 6.60 (s, 2H), 5.83 (s, 1H), 5.29 (s, 1H), 5.16 (s, 1H), 4.02 (q, J=7.0 Hz, 2H), 3.86 (s, 3H), 3.75 (s, 3H), 3.72 (s, 6H), 1.41 (t, J=7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 161.2, 153.6, 150.0, 149.9, 149.1, 134.8, 134.0, 128.9, 112.0, 111.5, 111.1, 110.6, 94.9, 64.6, 64.2, 61.2, 56.2, 56.1, 14.8; ESI-LRMS m/z (%): 400.2 [M+H]+; ESI-HRMS m/z (%): Calcd for C22H26NO6[M+H]+ 400.1755, found 400.1756.
A 50 mL round-bottom flask was charged with 1 (20 mg, 0.054 mmol), K2CO3 (15 mg, 0.108 mmol), 1-bromopropane (13 mg, 0.108 mmol) and dimethylsulfate (10 mL). The solution was stirred for 7 h. Then 10 mL of water was added into the solution, and the mixture was extracted with ethyl acetate (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 4 as white solid (19 mg, yield 85%); Mp 90-91° C.; [α]D20=+40.0 (c 0.07, CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.98 (dd, J=8.2 Hz, J=1.4 Hz, 1H), 6.86 (d, J=8.2 Hz, 1H), 6.84 (d, J=1.4 Hz, 1H), 6.60 (s, 2H), 5.84 (s, 1H), 5.30 (s, 1H), 5.17 (s, 1H), 3.90 (t, J=6.8 Hz, 2H), 3.86 (s, 3H), 3.76 (s, 3H), 3.73 (s, 6H), 1.87-1.76 (m, 2H), 1.00 (t, J=7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 161.4, 153.8, 150.3, 150.1, 149.5, 134.9, 134.2, 129.0, 120.1, 111.8, 111.1, 110.9, 95.1, 70.8, 64.4, 61.3, 56.3, 22.7, 10.7; ESI-LRMS m/z (%): 436.2 [M+Na]+; ESI-HRMS m/z (%): Calcd for C23H28NO6 [M+H]+ 414.1911, found 414.1912.
A 50 mL round-bottom flask was charged with 1 (20 mg, 0.054 mmol), K2CO3 (37 mg, 0.27 mmol), 2-bromopropane (15 mg, 0.12 mmol) and THF/DMSO (3:1, 1.5 mL). The solution was stirred for 8 h. Then 10 mL of water was added into the solution, and the mixture was extracted with ethyl acetate (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 5 as white solid (21 mg, yield 98%); Mp 146-147° C.; [α]D20=+13.1 (c 0.21, CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.99 (dd, J=8.2, 2.0 Hz, 1H), 6.93-6.85 (m, 2H), 6.61 (s, 2H), 5.84 (t, J=1.7 Hz, 1H), 5.31 (s, 1H), 5.18 (s, 1H), 4.55-4.42 (m, 1H), 3.86 (s, 3H), 3.77 (s, 3H), 3.73 (s, 6H), 1.33 (d, J=6.1 Hz, 3H), 1.28 (d, J=6.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 160.4, 152.9, 150.4, 149.3, 147.2, 134.1, 133.2, 128.0, 119.5, 133.3, 111.4, 110.1, 70.1, 63.3, 60.3, 55.4, 55.3, 21.3, 21.2; ESI-LRMS m/z (%): 436.2 [M+Na]+; ESI-HRMS m/z (%): Calcd for C23H28NO6 [M+H]+ 414.1911, found 414.1916.
A 50 mL round-bottom flask was charged with 1 (20 mg, 0.054 mmol), Cs2CO3 (35 mg, 0.108 mmol), 3-bromoprop-1-ene (13 mg, 0.054 mmol) and dimethylsulfate (2 mL). The solution was stirred for 8 h. Then 10 mL of water was added into the solution, and the mixture was extracted with ethyl acetate (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 6 as white solid (21 mg, yield 98%); M.p. 92-93° C.; [α]D20=+40.0 (c 0.39, CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.99 (dd, J=8.2, 1.2 Hz, 1H), 6.87 (d, J=8.2 Hz, 1H), 6.85 (s, 1H), 6.59 (s, 2H), 6.00 (ddd, J=17.4, 10.5, 5.5 Hz, 1H), 5.83 (s, 1H), 5.33 (d, J=17.4 Hz, 1H), 5.29 (s, 1H), 5.22 (d, J=10.5 Hz, 1H), 5.16 (s, 1H), 4.55 (d, J=5.5 Hz, 2H), 3.87 (s, 3H), 3.76 (s, 3H), 3.73 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 161.0, 153.5, 150.1, 149.8, 148.6, 134.7, 133.8, 132.8, 128.7, 120.1, 118.3, 111.7, 111.5, 110.7, 94.9, 69.9, 64.0, 61.0, 56.1, 56.0; ESI-LRMS m/z (%): 412.2 [M+H]+; ESI-HRMS m/z (%): Calcd for C23H26NO6 [M+H]+ 412.1755, found 412.1756.
A 50 mL round-bottom flask was charged with 1 (20 mg, 0.054 mmol), Cs2CO3 (35 mg, 0.108 mmol), 3-bromoprop-1-yne (13 mg, 0.054 mmol) and dimethylsulfate (2 mL). The solution was stirred for 8 h. Then 10 mL of water was added into the solution, and the mixture was extracted with ethyl acetate (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 7 as white solid (18 mg, yield 85%); M.p. 106-107° C.; [α]D20=+50.5 (c 0.33, CHCl3); 1HNMR (400 MHz, CDCl3) δ 7.04 (d, J=8.2 Hz, 1H), 7.02 (s, 1H), 6.90 (d, J=8.2 Hz, 1H), 6.60 (s, 2H), 5.84 (s, 1H), 5.33 (s, 1H), 5.17 (s, 1H), 4.73 (d, J=2.2 Hz, 2H), 3.87 (s, 3H), 3.76 (s, 3H), 3.73 (s, 6H), 2.34 (t, J=2.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 160.9, 153.5, 150.3, 149.8, 147.2, 134.7, 133.8, 128.7, 121.0, 112.9, 111.9, 110.8, 95.0, 78.0, 76.0, 63.8, 60.96, 56.9, 56.1, 56.0; ESI-LRMS m/z (%): 410.2 [M+H]+; ESI-HRMS m/z (%): Calcd for C23H24NO6 [M+H]+ 410.1598, found 410.1600.
A 50 mL round-bottom flask was charged with 1 (20 mg, 0.054 mmol), K2CO3 (37 mg, 0.27 mmol), 2-chloroethanol (5 mg, 0.12 mmol) and DMSO (1 mL). The solution was stirred for 8 h at 70° C. Then 10 mL of water was added into the solution, and the mixture was extracted with ethyl acetate (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 8 as white solid (12 mg, yield 54%); [α]D20=+22.0 (c 0.25, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.03 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 6.87 (d, J=8.2 Hz, 2H), 6.58 (s, 2H), 5.83 (s, 1H), 5.29 (s, 1H), 5.15 (s, 1H), 4.05 (t, J=4.0 Hz, 2H), 3.92 (t, J=4.0 Hz, 2H), 3.85 (s, 3H), 3.75 (s, 3H), 3.72 (s, 6H), 2.81 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 160.3, 152.9, 149.7, 149.1, 148.2, 134.1, 133.2, 128.4, 120.2, 111.6, 111.1, 110.3, 94.2, 70.7, 63.2, 60.5, 60.3, 55.4, 55.3; ESI-LRMS m/z (%): 416.2 [M+H]+; ESI-HRMS m/z (%): Calcd for C22H26NO7 [M+H]+ 416.1704, found 416.1704.
A 50 mL round-bottom flask was charged with 1 (20 mg, 0.054 mmol), K2CO3 (15 mg, 0.108 mmol), KI (1.5 mg, 0.0081 mmol), 3-bromopropan-1-ol (9 mg, 0.065 mmol) and MeCN (2 mL). The solution was stirred for 8 h at 50° C. Then 10 mL of water was added into the solution, and the mixture was extracted with ethyl acetate (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 9 as white solid (22 mg, yield 95%); [α]D20=+18.7 (c 0.27, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.01 (d, J=8.2 Hz, 1H), 6.91-6.79 (m, 2H), 6.61 (s, 2H), 5.85 (s, 1H), 5.31 (s, 1H), 5.18 (s, 1H), 4.14 (t, J=5.8 Hz, 2H), 3.86-3.84 (m, 5H), 3.77 (s, 3H), 3.74 (s, 6H), 2.59 (brd, 1H), 2.08-2.03 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 160.4, 152.9, 149.4, 149.2, 148.3, 134.1, 133.2, 128.2, 119.8, 110.7, 110.2, 110.1, 94.2, 67.7, 63.3, 60.7, 60.3, 55.5, 55.3, 31.0, 29.1; ESI-LRMS m/z (%): 431.2 [M+H]+; ESI-HRMS m/z (%): Calcd for C23H28NO7 [M+H]+ 430.1860, found 430.1861.
A 50 mL round-bottom flask was charged with 1 (20 mg, 0.054 mmol), K2CO3 (15 mg, 0.108 mmol), 1-bromo-2-chloroethane (31 mg, 0.162 mmol) and 2-butanone (2 mL). The solution was stirred for 14 h at 80° C. Then 10 mL of water was added into the solution, and the mixture was extracted with ethyl acetate (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 10 as light yellow solid (17 mg, yield 73%); M.p. 91-92° C.; [α]D20=+36.4 (c 0.33, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.05 (dd, J=8.2, 1.8 Hz, 1H), 6.90-6.88 (m, 2H), 6.59 (s, 2H), 5.84 (s, 1H), 5.30 (s, 1H), 5.16 (s, 1H), 4.22 (t, J=6.0 Hz, 2H), 3.87 (s, 3H), 3.80 (t, J=6.0 Hz, 2H), 3.76 (s, 3H), 3.73 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 161.2, 153.7, 150.6, 149.9, 148.5, 134.9, 134.0, 129.1, 121.4, 112.7, 112.3, 111.2, 95.0, 69.7, 64.0, 61.2, 56.3, 42.0; ESI-LRMS m/z (%): 434.1 [M+H]+; ESI-HRMS m/z (%): Calcd for C22H25ClNO6 [M+H]+ 434.1365, found 434.1366.
A 50 mL round-bottom flask was charged with 1 (20 mg, 0.054 mmol), K2CO3 (15 mg, 0.108 mmol), 1-bromo-3-chloropropane (34 mg, 0.216 mmol) and acetone (2 mL). The solution was stirred for 8 h at 56° C. Then 10 mL of water was added into the solution, and the mixture was extracted with ethyl acetate (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 11 as white solid (18 mg, yield 77%); M.p. 72-73° C.; [α]D20=+20.1 (c 0.15, CHCl3); 1HNMR (400 MHz, CDCl3) δ 7.01 (d, J=8.2 Hz, 1H), 6.88-6.86 (m, 2H), 6.60 (s, 2H), 5.84 (s, 1H), 5.30 (s, 1H), 5.17 (s, 1H), 4.18-4.01 (m, 2H), 3.85 (s, 3H), 3.76-3.73 (m, 11H), 2.27-2.22 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 161.2, 153.7, 150.3, 150.0, 149.0, 134.8, 134.0, 129.0, 120.6, 112.0, 111.6, 111.1, 95.0, 65.9, 64.1, 61.2, 56.3, 56.2, 41.7, 32.4; ESI-LRMS m/z (%): 449.1 [M+H]+; ESI-HRMS m/z (%): Calcd for C23H27ClNO6 [M+H]+ 448.1521, found 448.1523.
A 50 mL round-bottom flask was charged with 1 (20 mg, 0.054 mmol), Cs2CO3 (35 mg, 0.108 mmol), ethyl 2-bromoacetate (18 mg, 0.108 mmol) and dimethylsulfate (1.5 mL). The solution was stirred for 6 h at 90° C. Then 10 mL of water was added into the solution, and the mixture was extracted with ethyl acetate (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 12 as colorless oil (33 mg, yield 95%); 1H NMR (400 MHz, CDCl3) δ 7.05 (dd, J=8.3, 1.9 Hz, 1H), 6.90 (d, J=8.3 Hz, 1H), 6.81 (d, J=1.9 Hz, 1H), 6.58 (s, 2H), 5.82 (s, 1H), 5.29 (s, 1H), 5.14 (s, 1H), 4.64 (s, 2H), 4.17-4.11 (m, 2H), 3.88 (s, 3H), 3.76 (s, 3H), 3.73 (s, 6H), 1.22 (t, J=7.2 Hz, 3H); ESI-LRMS m/z (%): 458.0 [M+H]+.
A 50 mL round-bottom flask was charged with 1 (20 mg, 0.054 mmol), Cs2CO3 (35 mg, 0.108 mmol), tert-butyl 2-bromoacetate (21 mg, 0.108 mmol) and dimethylsulfate (1.5 mL). The solution was stirred for 5 h. Then 10 mL of water was added into the solution, and the mixture was extracted with ethyl acetate (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 13 as light yellow oil (24 mg, yield 92%); [α]D20=+37.8 (c 0.12, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.03 (d, J=8.2 Hz, 1H), 6.89 (d, J=8.2 Hz, 1H), 6.76 (s, 1H), 6.58 (s, 2H), 5.81 (s, 1H), 5.27 (s, 1H), 5.13 (s, 1H), 4.53 (s, 2H), 3.88 (s, 3H), 3.75 (s, 3H), 3.72 (s, 6H), 1.39 (s, 9H); 13C NMR (150 MHz, CDCl3) δ 160.9, 153.5, 150.2, 149.9, 148.9, 134.8, 133.8, 128.9, 120.4, 111.7, 111.6, 110.7, 94.9, 67.3, 63.9, 60.9, 58.0, 56.1, 55.9, 45.9; ESI-LRMS m/z (%): 486.2 [M+H]+; ESI-HRMS m/z (%): Calcd for C26H31NNaO8 [M+Na]+ 508.1942, found 508.1944.
A 50 mL round-bottom flask was charged with 1 (30 mg, 0.081 mmol), K2CO3 (45 mg, 0.323 mmol), 2-chloro-N,N-dimethylethanamine hydrochloride (14 mg, 0.097 mmol) and MeCN (2 mL). The solution was stirred for 8 h at 80° C. Then 10 mL of water was added into the solution, and the mixture was extracted with ethyl acetate (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 14 as white solid (27 mg, yield 88%); [α]D20=+37.8 (c 0.12, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.03 (d, J=8.2 Hz, 1H), 6.89 (d, J=8.2 Hz, 1H), 6.76 (s, 1H), 6.58 (s, 2H), 5.81 (s, 1H), 5.27 (s, 1H), 5.13 (s, 1H), 4.53 (s, 2H), 3.88 (s, 3H), 3.75 (s, 3H), 3.72 (s, 6H), 1.39 (s, 9H); 13C NMR (150 MHz, CDCl3) δ 160.9, 153.5, 150.2, 149.9, 148.9, 134.8, 133.8, 128.9, 120.4, 111.7, 111.6, 110.7, 94.9, 67.3, 63.9, 60.9, 58.0, 56.1, 55.9, 45.9; ESI-LRMS m/z (%): 486.2 [M+H]+; ESI-HRMS m/z (%): Calcd for C26H31NNaO8 [M+Na]+ 508.1942, found 508.1944.
A 50 mL round-bottom flask was charged with 1 (20 mg, 0.054 mmol), K2CO3 (30 mg, 0.216 mmol), 4-(2-chloroethyl)morpholine hydrochloride (12 mg, 0.065 mmol) and MeCN (2 mL). The solution was stirred for 9 h at 80° C. Then 10 mL of water was added into the solution, and the mixture was extracted with ethyl acetate (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 15 as white solid (23 mg, yield 88%); Mp 86-87° C.; [α]D20=+115.4 (c 0.13, CHCl3); NMR (400 MHz, CDCl3) δ 7.01 (d, J=8.2 Hz, 1H), 6.86 (d, J=8.2 Hz, 1H), 6.84 (d, J=0.9 Hz, 1H), 6.59 (s, 2H), 5.83 (s, 1H), 5.29 (s, 1H), 5.15 (s, 1H), 4.12-3.97 (m, 2H), 3.85 (s, 3H), 3.76 (s, 3H), 3.74-3.67 (m, 10H), 2.78 (t, J=6.0 Hz, 2H), 2.55 (s, 4H); 13C NMR (150 MHz, CDCl3) δ 160.4, 152.9, 149.5, 149.2, 148.3, 134.1, 133.2, 128.3, 119.9, 111.0, 110.4, 110.2, 94.2, 66.2, 66.0, 63.3, 60.3, 56.8, 55.4, 55.3, 53.4; ESI-LRMS m/z (%): 485.2 [M+H]+; ESI-HRMS m/z (%): Calcd for C26H33N2O7 [M+H]+ 485.2282, found 485.2284.
A 50 mL round-bottom flask was charged with 1 (20 mg, 0.054 mmol), K2CO3 (22 mg, 0.162 mmol), KI (1 mg, 0.0054 mmol), 2-chloroacetamide (12 mg, 0.065 mmol) and 2-Butanone (2 mL). The solution was stirred for 9 h at 80° C. Then 10 mL of water was added into the solution, and the mixture was extracted with ethyl acetate (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 16 as colorless oil (22 mg, yield 95%); [α]D20=+20.9 (c 0.29, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.08 (d, J=8.3 Hz, 1H), 6.92-6.90 (m, 3H), 6.57 (s, 2H), 6.02 (s, 1H), 5.84 (s, 1H), 5.30 (s, 1H), 5.15 (s, 1H), 4.48 (s, 2H), 3.87 (s, 3H), 3.76 (s, 3H), 3.74 (s, 6H); 13C NMR (150 MHz, CDCl3) δ 170.5, 160.1, 153.0, 149.7, 149.0, 147.1, 134.2, 133.0, 128.7, 121.2, 113.1, 111.6, 110.3, 94.3, 68.7, 62.8, 60.3, 55.5, 55.3; ESI-LRMS m/z (%): 429.2 [M+H]+; ESI-HRMS m/z (%): Calcd for C22H24NaO7 [M+Na]+ 451.1476, found 451.1476.
A 50 mL round-bottom flask was charged with 1 (20 mg, 0.054 mmol), K2CO3 (15 mg, 0.108 mmol), KI (1.5 mg, 0.0081 mmol), benzyl (3-bromopropyl)carbamate (44 mg, 0.162 mmol) and dimethylsulfate (2 mL). The solution was stirred for 8 h at 55° C. Then 10 mL of water was added into the solution, and the mixture was extracted with ethyl acetate (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 17 as white solid (22 mg, yield 73%); 1HNMR (400 MHz, CDCl3) δ 7.39-7.27 (m, 5H), 7.00 (d, J=8.0 Hz, 1H), 6.83-6.81 (m, 2H), 6.59 (s, 2H), 6.00 (s, 1H), 5.83 (s, 1H), 5.28 (s, 1H), 5.15 (s, 1H), 5.09 (s, 2H), 4.04 (t, J=5.5 Hz, 2H), 3.75 (s, 3H), 3.72 (s, 6H), 3.71 (s, 3H), 3.43 (dd, J=11.2, 5.5 Hz, 2H), 2.03-1.96 (m, 2H); ESI-LRMS m/z (%): 563.2 [M+H]+.
A 50 mL round-bottom flask was charged with 1 (20 mg, 0.054 mmol), Et3N (11 mg, 0.108 mmol), benzoyl chloride (44 mg, 0.162 mmol) and dichloromethane (2 mL). The solution was stirred for 0.5 h at 0° C. Then 10 mL of water was added into the solution, and the mixture was extracted with dichloromethane (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 18 as white solid (23 mg, yield 90%); M.p. 151-152° C.; [α]D20=+22.2 (c 0.34, CHCl3); NMR (400 MHz, CDCl3) δ 8.18 (d, J=7.8 Hz, 2H), 7.66-7.62 (m, 1H), 7.53-7.49 (m, 2H), 7.30 (dd, J=8.4, 2.0 Hz, 1H), 7.24 (d, J=2.0 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H), 6.61 (s, 2H), 5.86 (s, 1H), 5.34 (s, 1H), 5.22 (s, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 3.76 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 164.5, 160.9, 153.6, 151.9, 149.6, 140.5, 134.8, 133.8, 133.7, 130.3, 129.1, 129.0, 128.6, 125.3, 121.9, 113.0, 111.1, 94.9, 63.4, 61.0, 56.1, 56.0; ESI-LRMS m/z (%): 476.2 [M+H]+; ESI-HRMS m/z (%): Calcd for C27H26NO7 [M+H]+ 476.1704, found 476.1705.
A 50 mL round-bottom flask was charged with 1 (20 mg, 0.054 mmol), Et3N (11 mg, 0.108 mmol), 4-nitrobenzoyl chloride (15 mg, 0.081 mmol) and dichloromethane (2 mL). The solution was stirred for 0.5 h. Then 10 mL of water was added into the solution, and the mixture was extracted with dichloromethane (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 19 as light yellow solid (27 mg, yield 96%); M.p. 88-89° C.; [α]D20=+45.2 (c 0.31, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.35 (s, 4H), 7.34 (dd, J=8.5, 2.1 Hz, 1H), 7.24 (d, J=2.1 Hz, 1H), 7.05 (d, J=8.5 Hz, 1H), 6.60 (s, 2H), 5.87 (s, 1H), 5.35 (s, 1H), 5.22 (s, 1H), 3.83 (s, 3H), 3.77 (s, 3H), 3.76 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 162.6, 160.7, 153.6, 151.6, 151.0, 149.6, 140.0, 134.9, 134.5, 133.7, 131.4, 129.2, 125.9, 123.7, 121.4, 113.0, 111.2, 94.9, 63.3, 61.0, 56.2, 56.1; ESI-LRMS m/z (%): 521.1 [M+H]+; ESI-HRMS m/z (%): Calcd for C27H25N2O9 [M+H]+ 521.1555, found 521.1554.
A 50 mL round-bottom flask was charged with 1 (29 mg, 0.078 mmol), pyridine (130 mg, 1.6 mmol), 4-nitrobenzoyl chloride (15 mg, 0.081 mmol) and dichloromethane (1 mL). The solution was stirred for 0.5 h. Then 10 mL of water was added into the solution, and the mixture was extracted with dichloromethane (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 20 as white solid (35 mg, yield 91%); M.p. 185-186° C.; [α]D20=+38.5 (c 0.15, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.22-8.14 (m, 2H), 7.30 (dd, J=8.5, 2.2 Hz, 1H), 7.22 (d, J=2.2 Hz, 1H), 7.19-7.15 (m, 2H), 7.02 (d, J=8.5 Hz, 1H), 6.60 (s, 2H), 5.86 (t, J=1.7 Hz, 1H), 5.34 (s, 1H), 5.21 (s, 1H), 3.81 (s, 3H), 3.77 (s, 3H), 3.75 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 167.6, 165.1, 163.6, 161.0, 153.7, 152.0, 149.7, 140.4, 134.8, 133.9, 133.1, 133.0, 129.1, 125.6, 125.5, 125.4, 122.0, 116.1, 116.0, 113.0, 111.4, 95.0, 63.5, 61.1, 56.3, 56.2; ESI-LRMS m/z (%): 494.2 [M+H]+; ESI-HRMS m/z (%): Calcd for C27H25FNO8 [M+H]+ 494.1610, found 494.1611.
A 50 mL round-bottom flask was charged with 1 (20 mg, 0.054 mmol), Et3N (11 mg, 0.108 mmol), 2-methoxybenzoyl chloride (14 mg, 0.081 mmol) and dichloromethane (1.5 mL). The solution was stirred for 0.5 h. Then 10 mL of water was added into the solution, and the mixture was extracted with dichloromethane (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 21 as colorless oil (23 mg, yield 84%); [α]D20=+22.2 (c 0.11, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.15-8.11 (m, 2H), 7.35-7.32 (m, 1H), 7.28 (dd, J=8.7, 2.0 Hz, 1H), 7.22 (d, J=2.0 Hz, 1H), 7.02-6.95 (m, 3H), 6.91-6.87 (m, 1H), 6.61 (s, 2H), 5.85 (s, 1H), 5.33 (s, 1H), 5.21 (s, 1H), 3.88 (s, 3H), 3.81 (s, 3H), 3.77 (s, 3H), 3.76 (s, 6H); 13C NMR (151 MHz, CDCl3) δ 171.3, 164.2, 164.0, 160.9, 160.3, 153.6, 152.0, 149.6, 140.6, 134.8, 133.8, 132.4, 129.5, 128.9, 128.2, 127.2, 125.2, 122.0, 121.4, 113.9, 113.7, 112.9, 111.1, 94.9, 92.8, 77.3, 77.1, 76.8, 69.9, 66.9, 63.4, 60.9, 56.1, 56.1, 55.5, 55.3, 10.6; ESI-LRMS m/z (%): 506.1 [M+H]+; ESI-HRMS m/z (%): Calcd for C28H27NNaO8 [M+Na]+ 528.1629, found 528.1630.
A 50 mL round-bottom flask was charged with 1 (20 mg, 0.054 mmol), Et3N (17 mg, 0.216 mmol), nicotinoyl chloride hydrochloride (15 mg, 0.081 mmol) and dichloromethane (1.5 mL). The solution was stirred for 0.5 h. Then 10 mL of water was added into the solution, and the mixture was extracted with dichloromethane (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 22 as white solid (16 mg, yield 62%); M.p. 113-114° C.; [α]D20=+44.9 (c 0.35, CHCl3); NMR (400 MHz, CDCl3) δ 9.37 (s, 1H), 8.85 (d, J=4.4 Hz, 1H), 8.43 (d, J=8.0 Hz, 1H), 7.46 (dd, J=8.0, 4.4 Hz, 1H), 7.32 (dd, J=8.4, 1.7 Hz, 1H), 7.24 (d, J=1.7 Hz, 1H), 7.03 (d, J=8.5 Hz, 1H), 6.60 (s, 2H), 5.86 (s, 1H), 5.34 (s, 1H), 5.22 (s, 1H), 3.82 (s, 3H), 3.77 (s, 3H), 3.76 (s, 6H); 13C NMR (150 MHz, CDCl3) δ 163.2, 160.8, 154.0, 153.6, 151.7, 151.5, 149.6, 140.0, 137.7, 134.9, 133.7, 129.1, 125.7, 125.3, 123.5, 121.7, 113.0, 111.2, 94.9, 63.3, 61.0, 56.1; ESI-LRMS m/z (%): 477.2 [M+H]+; ESI-HRMS m/z (%): Calcd for C26H25N2O7 [M+H]+ 477.1656, found 477.1659.
A 50 mL round-bottom flask was charged with 1 (20 mg, 0.054 mmol), pyridine (90 mg, 1.2 mmol), cyclopropanecarbonyl chloride (40 mg, 0.54 mmol) and dichloromethane (1.5 mL). The solution was stirred for 0.5 h. Then 10 mL of water was added into the solution, and the mixture was extracted with dichloromethane (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 23 as white solid (20 mg, yield 84%); M.p. 68-69° C.; [α]D20=+12.4 (c 0.44, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.23 (dd, J=8.4, 2.1 Hz, 1H), 7.11 (d, J=2.1 Hz, 1H), 6.95 (d, J=8.5 Hz, 1H), 6.58 (s, 2H), 5.84 (s, 1H), 5.30 (s, 1H), 5.18 (s, 1H), 3.83 (s, 3H), 3.76 (s, 3H), 3.73 (s, 6H), 1.91-1.78 (m, 1H), 1.20-1.12 (m, 2H), 1.07-0.98 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 161.0, 153.6, 150.0, 149.8, 148.9, 133.8, 128.9, 120.4, 111.4, 110.9, 110.8, 94.9, 68.3, 64.0, 61.3, 61.0, 56.1, 56.0, 31.7; ESI-LRMS m/z (%): 440.2 [M+H]+; ESI-HRMS m/z (%): Calcd for C24H25NNaO7 [M+Na]+ 462.1523, found 462.1526.
A 50 mL round-bottom flask was charged with 1 (20 mg, 0.054 mmol), Et3N (8.2 mg, 0.108 mmol), acryloyl chloride (10 mg, 0.081 mmol) and dichloromethane (1.5 mL). The solution was stirred for 0.5 h. Then 10 mL of water was added into the solution, and the mixture was extracted with dichloromethane (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 24 as white solid (17 mg, yield 74%); M.p. 109-110° C.; [α]D20=+52.1 (c 0.26, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.26 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7.15 (d, J=2.0 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 6.61-6.57 (m, 3H), 6.32 (dd, J=17.6, 10.4 Hz, 1H), 6.02 (d, J=10.4 Hz, 1H), 5.85 (s, 1H), 5.31 (s, 1H), 5.19 (s, 1H), 3.82 (s, 3H), 3.76 (s, 3H), 3.74 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 163.8, 160.8, 153.6, 151.7, 149.6, 140.0, 134.8, 133.8, 132.9, 128.9, 127.4, 125.3, 121.8, 112.9, 111.1, 94.8, 63.3, 61.0, 56.1, 56.0; ESI-LRMS m/z (%): 426.1 [M+H]+; ESI-HRMS m/z (%): Calcd for C23H23NNaO7 [M+Na]+ 448.1367, found 448.1369.
A 50 mL round-bottom flask was charged with 1 (20 mg, 0.054 mmol), pyridine (90 mg, 1.2 mmol), morpholine-4-carbonyl chloride (81 mg, 0.54 mmol)) and dichloromethane (1.5 mL). The solution was stirred for 9 h. Then 10 mL of water was added into the solution, and the mixture was extracted with dichloromethane (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 25 as white solid (20 mg, yield 84%); M.p. 82-83° C.; [α]D20=+30.0 (c 0.16, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.23 (dd, J=8.4, 2.1 Hz, 1H), 7.15 (d, J=2.1 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 6.59 (s, 2H), 5.84 (s, 1H), 5.31 (s, 1H), 5.19 (s, 1H), 3.84 (s, 3H), 3.76 (s, 3H), 3.76 (s, 3H), 3.75-3.73 (m, 10H), 3.67 (s, 2H), 3.54 (s, 2H); 13C NMR (150 MHz, CDCl3) δ 160.2, 153.0, 152.5, 151.5, 149.0, 140.2, 134.1, 133.1, 128.2, 124.3, 121.3, 112.0, 110.5, 94.3, 66.0, 62.8, 60.3, 55.5, 55.4, 44.5, 43.7; ESI-LRMS m/z (%): 485.2 [M+H]+; ESI-HRMS m/z (%): Calcd for C25H28N2NaO8 [M+Na]+ 507.1738, found 507.1739.
A 50 mL schlenk flask was charged with 1 (40 mg, 0.108 mmol), sulfamoyl chloride (62 mg, 0.54 mmol) and anhydrous N,N-dimethylaniline (2.5 mL). The solution was stirred for 4.5 h under nitrogen atmosphere. Then 10 mL of water was added into the solution, and the mixture was extracted with ethyl acetate (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 26 as light yellow solid (46 mg, yield 95%); M.p. 199-200° C.; [α]D20=−14.3 (c 0.10, DMSO); 1H NMR (400 MHz, DMSO) δ 7.98 (d, J=2.2 Hz, 1H), 7.83 (dd, J=8.5, 2.2 Hz, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.12 (s, 2H), 6.23 (t, J=1.7 Hz, 1H), 6.09 (s, 1H), 5.70 (s, 1H), 4.30 (s, 3H), 4.15 (s, 6H), 4.07 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.1, 153.1, 151.8, 149.2, 138.6, 133.9, 132.9, 128.6, 125.9, 122.7, 113.7, 111.6, 94.6, 61.6, 60.0, 55.7, 55.6; ESI-LRMS m/z (%): 451.1 [M+H]+; ESI-HRMS m/z (%): Calcd for C20H26N3O8S [M+NH4]+468.1435, found 468.1435.
A 50 mL round-bottom flask was charged with 1 (20 mg, 0.054 mmol), Et3N (15 mg, 0.162 mmol), 4-methylbenzene-1-sulfonyl chloride (16 mg, 0.081 mmol) and dichloromethane (1.5 mL). The solution was stirred for 0.5 h. Then 10 mL of water was added into the solution, and the mixture was extracted with dichloromethane (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 27 as white solid (27 mg, yield 95%); M.p. 162-163° C.; [α]D20=+53.1 (c 0.16, CHCl3); 1HNMR (400 MHz, CDCl3) δ 7.66 (d, J=8.3 Hz, 2H), 7.30-7.20 (m, 3H), 7.14 (d, J=2.1 Hz, 1H), 6.88 (d, J=8.5 Hz, 1H), 6.56 (s, 2H), 5.84 (t, J=1.5 Hz, 1H), 5.29 (s, 1H), 5.16 (s, 1H), 3.79 (s, 3H), 3.77 (s, 6H), 3.61 (s, 3H), 2.44 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 160.0, 153.0, 151.80, 148.9, 144.7, 138.1, 134.2, 133.0, 132.4, 128.8, 128.3, 127.8, 125.6, 122.2, 112.7, 110.5, 94.2, 62.3, 60.3, 55.5, 55.2, 21.0; ESI-LRMS m/z (%): 548.1 [M+Na]+; ESI-HRMS m/z (%): Calcd for C27H31N2O8S [M+NH4]+ 543.1796, found 543.1794.
A 50 mL round-bottom flask was charged with 1 (20 mg, 0.054 mmol), Et3N (14 mg, 0.162 mmol), 2-(1,3-dioxoisoindolin-2-yl)ethanesulfonyl chloride (16 mg, 0.081 mmol) and dichloromethane (1.5 mL). The solution was stirred for 48 h. Then 10 mL of water was added into the solution, and the mixture was extracted with dichloromethane (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 28 as white (15 mg, yield 46%); M.p. 69-70° C.; [α]D20=+12.1 (c 0.45, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.88-7.85 (m, 2H), 7.76-7.73 (m, 2H), 7.43 (s, 1H), 7.27 (d, J=8.6 Hz, 1H), 7.00 (d, J=8.6 Hz, 1H), 6.55 (s, 2H), 5.85 (s, 1H), 5.31 (s, 1H), 5.19 (s, 1H), 4.34 (t, J=6.9 Hz, 2H), 3.91 (s, 3H), 3.80-3.64 (m, 11H); 13C NMR (150 MHz, CDCl3) δ 166.9, 160.0, 153.0, 151.2, 148.8, 137.4, 134.2, 133.7, 132.9, 131.2, 128.8, 125.6, 123.4, 123.0, 113.0, 110.7, 94.1, 62.2, 60.3, 55.6, 55.5, 48.4, 31.9; ESI-LRMS m/z (%): 609.1 [M+H]+; ESI-HRMS m/z (%): Calcd for C30H28N2NaO10S [M+Na]+ 631.1357, found 631.1357.
A 50 mL round-bottom flask was charged with 1 (20 mg, 0.054 mmol), Et3N (14 mg, 0.162 mmol), morpholine-4-sulfonyl chloride (15 mg, 0.081 mmol) and dichloromethane (1.5 mL). The solution was stirred for 4 days. Then 10 mL of water was added into the solution, and the mixture was extracted with dichloromethane (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 29 as white solid (20 mg, yield 71%); M.p. 134-135° C.; [α]D20=+24.7 (c 0.11, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J=2.0 Hz, 1H), 7.26 (dd, J=8.5, 2.0 Hz, 1H), 6.99 (d, J=8.5 Hz, 1H), 6.57 (s, 2H), 5.86 (t, J=1.6 Hz, 1H), 5.31 (s, 1H), 5.19 (s, 1H), 3.88 (s, 3H), 3.76-3.73 (m, 13H), 3.38 (t, J=4.8 Hz, 4H); 13C NMR (150 MHz, CDCl3) δ 160.0, 153.0, 151.3, 148.9, 138.5, 134.2, 132.9, 128.6, 125.1, 122.1, 113.0, 110.6, 94.2, 65.3, 62.4, 60.3, 55.6, 55.5, 46.3; ESI-LRMS m/z (%): 521.2 [M+H]+; ESI-HRMS m/z (%): Calcd for C24H29N2O9S [M+H]+ 521.1588, found 521.1590.
A 50 mL round-bottom flask was charged with 1 (20 mg, 0.054 mmol), Et3N (15 mg, 0.162 mmol), 4-acetamidobenzene-1-sulfonyl chloride (21 mg, 0.081 mmol) and dichloromethane (1.5 mL). The solution was stirred for 0.5 h. Then 10 mL of water was added into the solution, and the mixture was extracted with dichloromethane (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 30 as light yellow solid (22 mg, yield 72%); M.p. 87-88° C.; [α]D20=+64.6 (c 0.13, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.63 (d, J=8.8 Hz, 2H), 7.55 (d, J=8.8 Hz, 2H), 7.23 (dd, J=8.5, 1.8 Hz, 1H), 6.98 (d, J=1.8 Hz, 1H), 6.89 (d, J=8.5 Hz, 1H), 6.49 (s, 2H), 5.81 (s, 1H), 5.28 (s, 1H), 5.15 (s, 1H), 3.79 (s, 3H), 3.73 (s, 6H), 3.66 (s, 3H), 2.22 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 168.2, 159.9, 153.1, 151.9, 148.6, 142.8, 138.3, 133.9, 133.0, 129.2, 129.0, 128.1, 125.6, 121.2, 118.2, 112.8, 110.6, 94.1, 62.1, 60.4, 55.5, 55.3, 24.1; ESI-LRMS m/z (%): 569.1 [M+H]+; ESI-HRMS m/z (%): Calcd for C28H28N2NaO9S [M+Na]+ 591.1408, found 591.1409.
A 50 mL round-bottom flask was charged with 1 (20 mg, 0.054 mmol), Et3N (15 mg, 0.162 mmol), butane-1-sulfonyl chloride (21 mg, 0.081 mmol) and dichloromethane (1.5 mL). The solution was stirred for 0.5 h. Then 10 mL of water was added into the solution, and the mixture was extracted with dichloromethane (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 31 as white solid (24 mg, yield 82%); M.p. 99-100° C.; [α]D20=+18.6 (c 0.35, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J=2.1 Hz, 1H), 7.27 (dd, J=8.5, 2.1 Hz, 1H), 6.99 (d, J=8.5 Hz, 1H), 6.56 (s, 2H), 5.85 (s, 1H), 5.31 (s, 1H), 5.19 (s, 1H), 3.87 (s, 3H), 3.76 (s, 3H), 3.74 (s, 6H), 3.29 (td, J=6.9, 1.6 Hz, 2H), 2.00-1.92 (m, 2H), 1.54-1.45 (m, 2H), 0.97 (t, J=7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 160.7, 153.6, 151.9, 149.5, 138.2, 134.8, 133.6, 129.4, 126.0, 124.0, 113.6, 111.2, 94.8, 62.9, 61.0, 56.1, 51.6, 29.7, 25.5, 21.5, 13.5; ESI-LRMS m/z (%): 492.2 [M+H]+; ESI-HRMS m/z (%): Calcd for C24H29NNaO8S [M+Na]+ 514.1506, found 514.1508.
A 50 mL round-bottom flask was charged with 1 (20 mg, 0.054 mmol), Et3N (15 mg, 0.162 mmol), phenylmethanesulfonyl chloride (16 mg, 0.081 mmol) and dichloromethane (1.5 mL). The solution was stirred for 8 h. Then 10 mL of water was added into the solution, and the mixture was extracted with dichloromethane (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 32 as white solid (25 mg, yield 88%); M.p. 58-59° C.; [α]D20=−0.7 (c 0.14, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.46-7.36 (m, 5H), 7.26 (dd, J=8.4, 2.0 Hz, 1H), 7.05 (d, J=2.0 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 6.54 (s, 2H), 5.84 (s, 1H), 5.23 (s, 1H), 5.15 (s, 1H), 4.58 (q, J=14.0 Hz, 2H), 3.89 (s, 3H), 3.76 (s, 3H), 3.74 (s, 6H); 13C NMR (150 MHz, CDCl3) δ 160.0, 153.0, 151.4, 148.8, 137.9, 134.2, 132.9, 130.3, 128.7, 128.3, 126.8, 125.5, 122.9, 112.9, 110.6, 94.2, 62.4, 60.3, 57.3, 55.6, 55.5; ESI-LRMS m/z (%): 526.1 [M+H]+; ESI-HRMS m/z (%): Calcd for C27H31N2O8S [M+NH4]+ 543.1796, found 543.1797.
A 50 mL round-bottom flask was charged with 1 (20 mg, 0.054 mmol), Et3N (15 mg, 0.162 mmol), 3,4-dimethoxybenzene-1-sulfonyl chloride (19 mg, 0.081 mmol) and dichloromethane (1.5 mL). The solution was stirred for 8 h. Then 10 mL of water was added into the solution, and the mixture was extracted with dichloromethane (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 33 as white solid (27 mg, yield 87%); M.p. 70-71° C.; 1H NMR (400 MHz, CDCl3) δ 7.30-7.26 (m, 2H), 7.24 (dd, J=8.5, 2.1 Hz, 1H), 7.18 (d, J=2.1 Hz, 1H), 6.87 (d, J=8.5 Hz, 1H), 6.81 (d, J=8.2 Hz, 1H), 6.55 (s, 2H), 5.83 (s, 1H), 5.29 (s, 1H), 5.15 (s, 1H), 3.94 (s, 3H), 3.83 (s, 3H), 3.77 (s, 3H), 3.76 (s, 6H), 3.63 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 159.9, 153.3, 153.0, 151.8, 148.9, 148.4, 138.1, 134.2, 132.9, 128.4, 126.6, 125.5, 122.2, 122.2, 112.7, 110.4, 110.0, 109.5, 94.2, 62.3, 60.3, 55.7, 55.5, 55.3; ESI-LRMS m/z (%): 572.2 [M+H]+; ESI-HRMS m/z (%): Calcd for C28H29NNaO10S [M+Na]+ 594.1404, found 594.1405.
A 50 mL Schlenk flask was charged with 1 (20 mg, 0.054 mmol), EDCI (41 mg, 0.216 mmol), DMAP (3.6 mg, 0.003 mmol), 2-((tert-butoxycarbonyl)amino)acetic acid (38 mg, 0.216 mmol) and dichloromethane (2 mL). The solution was stirred for 8 h. It was directly purified by column chromatography to give 34 as white solid (26 mg, yield 91%); M.p. 88-89° C.; 1H NMR (400 MHz, CDCl3) δ 7.25 (dd, J=8.5, 2.0 Hz, 1H), 7.14 (s, 1H), 6.97 (d, J=8.5 Hz, 1H), 6.57 (s, 2H), 5.84 (t, J=1.4 Hz, 1H), 5.30 (s, 1H), 5.18 (t, J=1.4 Hz, 1H), 5.07 (s, 1H), 4.19 (d, J=5.5 Hz, 2H), 3.81 (s, 3H), 3.76 (s, 3H), 3.73 (s, 6H), 1.45 (s, 9H); ESI-LRMS m/z (%): 551.0 [M+Na]+.
A 50 mL Schlenk flask was charged with 1 (20 mg, 0.054 mmol), EDCI (41 mg, 0.216 mmol), DMAP (3.6 mg, 0.003 mmol), (S)-2-((tert-butoxycarbonyl)amino)propanoic acid (80 mg, 0.432 mmol) and dichloromethane (2 mL). The solution was stirred for 8 h. It was directly purified by column chromatography to give 35 as white solid (25 mg, yield 85%); 1H NMR (400 MHz, CDCl3) δ 7.24 (d, J=8.5 Hz, 1H), 7.14 (s, 1H), 6.95 (d, J=8.5 Hz, 1H), 6.56 (s, 2H), 5.84 (s, 1H), 5.29 (s, 1H), 5.18 (s, 1H), 5.08 (d, J=7.5 Hz, 1H), 4.61-4.49 (m, 1H), 3.80 (s, 3H), 3.75 (s, 3H), 3.72 (s, 3H), 1.55 (d, J=7.2 Hz, 3H), 1.44 (s, 9H); ESI-LRMS m/z (%): 565.1 [M+Na]+.
A 50 mL Schlenk flask was charged with 1 (20 mg, 0.054 mmol), EDCI (41 mg, 0.216 mmol), DMAP (3.6 mg, 0.003 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (94 mg, 0.432 mmol) and dichloromethane (2 mL). The solution was stirred for 8 h. It was directly purified by column chromatography to give 36 as white solid (19 mg, yield 62%); 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J=8.5 Hz, 1H), 7.12 (s, 1H), 6.96 (d, J=8.5 Hz, 1H), 6.57 (s, 2H), 5.85 (s, 1H), 5.30 (s, 1H), 5.18 (s, 1H), 5.06 (d, J=9.0 Hz, 1H), 4.49 (dd, J=9.0, 6.4 Hz, 1H), 3.80 (s, 3H), 3.76 (s, 3H), 3.74 (s, 6H), 2.40-2.30 (m, 1H), 1.45 (s, 9H), 1.08 (d, J=6.8 Hz, 3H), 1.02 (d, J=6.8 Hz, 3H); ESI-LRMS m/z (%): 593.1 [M+Na]+.
A 50 mL round-bottom flask was charged with 1 (80 mg, 0.216 mmol), NaH (10.5 mg, 0.26 mmol, 60% in mineral oil), tetrabenzyl diphosphate (173 mg, 0.32 mmol) and dichloromethane (2 mL). The solution was stirred for 15 min. It was directly purified by column chromatography to give 37 as white solid (120 mg, yield 96%); 1H NMR (400 MHz, CDCl3) δ 7.37-7.23 (m, 11H), 7.15 (dd, J=8.5, 1.0 Hz, 1H), 6.91 (d, J=8.5 Hz, 1H), 6.56 (s, 2H), 5.80 (t, J=1.7 Hz, 1H), 5.23 (s, 1H), 5.18-5.07 (m, 5H), 3.78 (s, 3H), 3.73 (s, 3H), 3.70 (s, 6H); ESI-LRMS m/z (%): 632.2 [M+H]+.
The synthesis of compound 38 was similar to compound 1:
A 50 mL round-bottom flask was charged with 3-fluoro-4-methoxybenzaldehyde (38a) (175 mg, 1.14 mmol), ethyl acrylate (114 mg, 1.14 mmol) and DABCO (128 mg, 1.14 mmol). The solution was stirred at room temperature for 5 days. The mixture was directly purified by flash column chromatography to give 38b as colorless oil (207 mg, yield 71%). 1H NMR (400 MHz, CDCl3) δ 7.13-7.02 (m, 2H), 6.90 (t, J=8.4, 1H), 6.32 (s, 1H), 5.82 (s, 1H), 5.46 (d, J=5.5 Hz, 1H), 4.16 (q, J=7.1 Hz, 2H), 3.86 (s, 3H), 3.17 (d, J=5.6 Hz, 1H), 1.24 (t, J=7.1 Hz, 3H); ESI-LRMS m/z (%): 255.1 [M+H]+.
A 50 mL round-bottom flask was charged with compound 38b (166 mg, 0.65 mmol), triethylamine (132 mg, 1.3 mmol), DMAP (8 mg, 0.065 mmol) and dichloromethane (5 mL). The solution was cooled to 0° C. by an ice bath, then acetic anhydride (133 mg, 1.3 mmol) was added dropwise into the flask within 10 min. After stirred for 10 min, 3 mL of saturated aqueous solution of sodium bicarbonate was added into the solution, and the mixture was extracted with dichloromethane (20 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 38c as colorless oil (164 mg, yield 85%). 1H NMR (400 MHz, CDCl3) δ 7.12-7.07 (m, 2H), 6.91 (t, J=8.6 Hz, 1H), 6.59 (s, 1H), 6.39 (s, 1H), 5.85 (s, 1H), 4.20-4.10 (m, 2H), 3.87 (s, 3H), 2.09 (s, 2H), 1.22 (t, J=7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.3, 164.8, 153.2, 150.8, 147.7, 147.5, 139.4, 130.7, 130.7, 125.3, 124.0, 123.9, 115.5, 115.3, 112.9, 72.3, 61.0, 56.1, 21.1, 14.0; ESI-LRMS m/z (%): 319.1 [M+Na]+; ESI-HRMS m/z (%): Calcd for C15H17FNaO5[M+Na]+ 319.0952, found 319.0954.
A 50 mL Schlenk flask was charged with 5 mL of dichloromethane and the solvent was deoxygenized with nitrogen bubbling for 15 min. Tris(dibenzylideneacetone)dipalladium (4.3 mg, 0.0047 mmol) and R1 (8.5 mg, 0.0118 mmol) was added into the flask. The resulted purple solution was stirred under nitrogen atmosphere for 10 min at room temperature. Then 3,4,5-trimethoxyaniline (134 mg, 1.41 mmol), K2CO3 (1.0 M aq. solution, 1.5 mL, 1.5 mmol) and compound 38c (140 mg, 0.47 mmol, dissolved in 2 mL of oxygen free dichloromethane) were added under a steam of nitrogen. The solution was stirred for 8 h at room temperature. Water (20 mL) was added into the solution, and the mixture was extracted with dichloromethane (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 38d as yellow oil (1.3 g, yield 69%). [α]D20=+63.7 (c 0.16, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.11 (t, J=2.3 Hz, 1H), 7.08 (s, 1H), 6.91 (t, J=8.3 Hz, 1H), 6.38 (s, 1H), 5.92 (s, 1H), 5.81 (s, 1H), 5.31 (s, 1H), 4.21-4.13 (m, 2H), 3.87 (s, 3H), 3.76 (s, 6H), 3.74 (s, 3H), 1.24 (t, J=7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.0, 153.8, 153.5, 151.0, 147.1, 147.0, 143.3, 140.3, 133.6, 133.6, 130.4, 126.1, 123.1, 123.1, 115.1, 114.9, 113.3, 91.1, 61.1, 60.9, 58.5, 56.2, 55.8, 14.0; ESI-LRMS m/z (%): 420.2 [M+H]+; ESI-HRMS m/z (%): Calcd for C22H27FNO6[M+H]+ 420.1817, found 420.1817.
The corresponding racemate can be obtained by replacing R1 with triphenylphosphine (0.005 eq).
To a 100 mL Schlenk flask equipped with a cold finger was added 38d (137 mg, 0.33 mmol), Sn[N(TMS)2]2 (183 mg, 0.40 mmol) and anhydrous toluene (5 mL). The mixture was heated to reflux for 6 h under nitrogen atmosphere. The solution was cooled and directly purified by flash chromatography to give 38 as colorless oil (60 mg, yield 58%); [α]D20=+107.0 (c 0.17, CHCl3), 97% ee [determined by HPLC analysis using a Chiralcel AD-H column; n-Hex/i-PrOH=85:15, 1.0 mL/min, 254 nm; tR (minor)=14.68 min; tR (major)=21.68 min]; 1H NMR (400 MHz, CDCl3) δ 7.15-7.10 (m, 2H), 6.98-6.94 (m, 1H), 6.57 (s, 2H), 5.84 (s, 1H), 5.30 (s, 1H), 5.16 (s, 1H), 3.88 (s, 3H), 3.76 (s, 3H), 3.74 (s, 6H); 13C NMR (150 MHz, CDCl3) δ 160.0, 153.0, 152.9, 151.2, 148.9, 147.6, 147.5, 134.2, 133.0, 128.7, 128.7, 122.3, 122.2, 113.9, 113.8, 113.07, 110.4, 94.2, 62.5, 60.3, 55.7, 55.5; ESI-LRMS m/z (%): 374.1 [M+H]+; ESI-HRMS m/z (%): Calcd for C20H21eNO5 [M+H]+ 374.1398, found 374.1400.
The synthesis of compound 39 was similar to compound 1:
A 50 mL round-bottom flask was charged with 3-chloro-4-methoxybenzaldehyde (39a) (1.15 g, 6.8 mmol), ethyl acrylate (681 mg, 6.8 mmol) and DABCO (763 mg, 6.8 mmol). The solution was stirred at room temperature for 4 days. The mixture was directly purified by flash column chromatography to give 39b as colorless oil (0.7 g, yield 39%). 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J=2.1 Hz, 1H), 7.23 (dd, J=8.5, 2.1 Hz, 1H), 6.89 (d, J=8.5 Hz, 1H), 6.34 (s, 1H), 5.83 (s, 1H), 5.47 (d, J=5.5 Hz, 1H), 4.17 (q, J=7.1 Hz, 2H), 3.88 (s, 3H), 3.10 (d, J=5.6 Hz, 1H), 1.25 (t, J=7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 165.6, 153.9, 141.2, 134.0, 127.9, 125.5, 125.3, 121.7, 111.2, 71.8, 60.4, 55.5, 13.4; ESI-LRMS m/z (%): 293.1 [M+Na]+; ESI-HRMS m/z (%): Calcd for C13H15ClNaO4 [M+Na]+ 293.0551, found 293.0553.
A 50 mL round-bottom flask was charged with compound 39b (700 mg, 2.6 mmol), triethylamine (523 mg, 5.2 mmol), DMAP (32 mg, 0.26 mmol) and dichloromethane (5 mL). The solution was cooled to 0° C. by an ice bath, then acetic anhydride (530 mg, 5.2 mmol) was added dropwise into the flask within 10 min. After stirred for 10 min, 3 mL of saturated aqueous solution of sodium bicarbonate was added into the solution, and the mixture was extracted with dichloromethane (20 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 39c as colorless oil (0.64 g, yield 79%). 41 NMR (400 MHz, CDCl3) δ 7.36 (d, J=2.1 Hz, 1H), 7.27 (dd, J=8.4, 2.0 Hz, 1H), 6.87 (d, J=8.5 Hz, 1H), 6.57 (s, 1H), 6.39 (s, 1H), 5.87 (s, 1H), 4.20-4.08 (m, 2H), 3.87 (s, 3H), 2.09 (s, 3H), 1.22 (t, J=7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 168.8, 164.2, 154.3, 138.8, 130.4, 128.9, 127.1, 124.7, 121.7, 111.1, 71.7, 60.4, 55.5, 20.5, 13.4; ESI-LRMS m/z (%): 335.1 [M+Na]+; ESI-HRMS m/z (%): Calcd for C15H17ClNaO5[M+Na]+ 335.0657, found 335.0659.
A 50 mL Schlenk flask was charged with 5 mL of dichloromethane and the solvent was deoxygenized with nitrogen bubbling for 15 min. Tris(dibenzylideneacetone)dipalladium (4.3 mg, 0.0047 mmol) and R1 (8.5 mg, 0.0118 mmol) was added into the flask. The resulted purple solution was stirred under nitrogen atmosphere for 10 min at room temperature. Then 3,4,5-trimethoxyaniline (176 mg, 0.96 mmol), K2CO3 (1.0 M aq. solution, 2 mL, 2 mmol) and compound 39c (200 mg, 0.64 mmol, dissolved in 2 mL of oxygen free dichloromethane) were added under a steam of nitrogen. The solution was stirred for 4 h at room temperature. Water (20 mL) was added into the solution, and the mixture was extracted with dichloromethane (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 39d as yellow oil (182 mg, yield 65%). [α]D20=+70.5 (c 0.17, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J=2.1 Hz, 1H), 7.24 (dd, J=8.8, 2.1 Hz, 1H), 6.89 (d, J=8.8 Hz, 1H), 6.39 (s, 1H), 5.94 (s, 1H), 5.81 (s, 2H), 5.30 (s, 1H), 4.21-4.13 (m, 2H), 3.89 (s, 3H), 3.77 (s, 6H), 3.75 (s, 3H), 1.24 (t, J=7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 165.5, 153.9, 153.2, 142.7, 139.6, 133.2, 129.8, 128.5, 126.3, 125.6, 122.0, 111.4, 90.5, 60.5, 60.4, 57.8, 55.6, 55.3, 13.5; ESI-LRMS m/z (%): 436.1 [M+H]+; ESI-HRMS m/z (%): Calcd for C22H27ClNO6 [M+H]+ 436.1521, found 436.1523.
The corresponding racemate can be obtained by replacing R1 with triphenylphosphine (0.005eq).
To a 100 mL Schlenk flask equipped with a cold finger was added 39d (182 mg, 0.42 mmol), Sn[N(TMS)2]2 (220 mg, 0.50 mmol) and anhydrous toluene (5 mL). The mixture was heated to reflux for 3 h under nitrogen atmosphere. The solution was cooled and directly purified by flash chromatography to give 39 as white solid (110 mg, yield 68%); Mp 119-120° C.; [α]D20=+35.1 (c 0.29, CHCl3), 97% ee [determined by HPLC analysis using a Chiralcel AD-H column; n-Hex/i-PrOH=80:20, 1.0 mL/min, 254 nm; tR (minor)=10.62 min; tR (major)=13.97 min]. 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=2.0 Hz, 1H), 7.25 (dd, J=8.5, 2.0 Hz, 1H), 6.92 (d, J=8.5 Hz, 1H), 6.56 (s, 2H), 5.83 (s, 1H), 5.28 (s, 1H), 5.16 (s, 1H), 3.88 (s, 3H), 3.75 (s, 3H), 3.73 (s, 6H); 13C NMR (150 MHz, CDCl3) δ 160.1, 154.8, 153.0, 148.8, 134.2, 133.0, 128.9, 128.2, 125.7, 122.6, 111.8, 110.5, 94.2, 62.3, 60.3, 55.6, 55.5; ESI-LRMS m/z (%): 390.1 [M+H]+; ESI-HRMS m/z (%): Calcd for C20H21ClNO5 [M+H]+ 390.1103, found 390.1103.
The synthesis of compound 40 was similar to compound 1:
A 50 mL round-bottom flask was charged with methyl 5-formyl-2-methoxybenzoate (40a) (2.2 g, 11.3 mmol), ethyl acrylate (1.13 g, 11.3 mmol) and DABCO (1.27 g, 11.3 mmol). The solution was stirred at room temperature for 8 days. The mixture was directly purified by flash column chromatography to give 40b as colorless oil (1.6 g, yield 39%). 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J=2.0 Hz, 1H), 7.45 (dd, J=8.6, 2.0 Hz, 1H), 6.91 (d, J=8.6 Hz, 1H), 6.30 (s, 1H), 5.84 (s, 1H), 5.49 (s, 1H), 4.18-4.07 (m, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 1.21 (t, J=7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 165.8, 165.6, 158.1, 141.3, 132.6, 131.2, 129.4, 125.3, 119.24, 111.4, 72.0, 60.4, 55.5, 51.4, 13.4; ESI-LRMS m/z (%): 317.0 [M+Na]+.
A 50 mL round-bottom flask was charged with compound 40b (438 mg, 1.49 mmol), triethylamine (300 mg, 2.98 mmol), DMAP (18 mg, 0.149 mol) and dichloromethane (5 mL). The solution was cooled to 0° C. by an ice bath, then acetic anhydride (304 mg, 2.98 mmol) was added dropwise into the flask within 10 min. After stirred for 10 min, 3 mL of saturated aqueous solution of sodium bicarbonate was added into the solution, and the mixture was extracted with dichloromethane (20 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 40c as colorless oil (0.35 g, yield 70%). 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J=2.4 Hz, 1H), 7.50 (dd, J=8.6, 2.4 Hz, 1H), 7.26 (s, 1H), 6.94 (d, J=8.6 Hz, 1H), 6.62 (s, 1H), 6.40 (s, 1H), 5.89 (s, 1H), 4.14 (dtt, J=10.8, 7.4, 3.7 Hz, 2H), 3.89 (s, 3H), 3.88 (s, 3H), 2.10 (s, 3H), 1.21 (t, J=7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 168.8, 165.7, 164.2, 158.5, 138.9, 132.7, 130.6, 129.1, 124.6, 119.4, 111.3, 71.8, 60.4, 55.5, 51.4, 20.5, 13.4; ESI-LRMS m/z (%): 359.0 [M+Na]+.
A 50 mL Schlenk flask was charged with 5 mL of dichloromethane and the solvent was deoxygenized with nitrogen bubbling for 15 min. Tris(dibenzylideneacetone)dipalladium (9.2 mg, 0.01 mmol) and R1 (18 mg, 0.025 mmol) was added into the flask. The resulted purple solution was stirred under nitrogen atmosphere for 10 min at room temperature. Then 3,4,5-trimethoxyaniline (286 mg, 1.56 mmol), K2CO3 (1.0 M aq. solution, 3 mL, 3 mmol) and compound 40c (350 mg, 1.04 mmol, dissolved in 2 mL of oxygen free dichloromethane) were added under a steam of nitrogen. The solution was stirred for 1 h at room temperature. Water (20 mL) was added into the solution, and the mixture was extracted with dichloromethane (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 40d as yellow oil (280 mg, yield 59%). [α]D20=+65.2 (c 0.34, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.77 (t, J=4.9 Hz, 1H), 7.47 (dd, J=8.6, 2.1 Hz, 1H), 6.92 (d, J=8.6 Hz, 1H), 6.38 (s, 1H), 5.94 (s, 1H), 5.80 (s, 2H), 5.33 (s, 1H), 4.20-4.03 (m, 3H), 3.87 (s, 3H), 3.85 (s, 3H), 3.74 (s, 6H), 3.72 (s, 3H), 1.21 (t, J=7.1 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 165.8, 165.5, 158.0, 153.2, 142.8, 139.8, 131.9, 131.8, 130.0, 129.9, 125.5, 119.6, 111.7, 90.7, 60.4, 60.3, 57.9, 55.5, 55.3, 51.4, 13.4; ESI-LRMS m/z (%): 460.1 [M+H]+.
The corresponding racemate can be obtained by replacing R1 with triphenylphosphine (0.005eq).
To a 100 mL Schlenk flask equipped with a cold finger was added 40d (280 mg, 0.61 mmol), Sn[N(TMS)2]2 (335 mg, 0.73 mmol) and anhydrous toluene (5 mL). The mixture was heated to reflux for 3.5 h under nitrogen atmosphere. The solution was cooled and directly purified by flash chromatography to give 40 as white solid (100 mg, yield 40%); Mp 112-113° C.; [α]D20=+5.5 (c 0.34, CHCl3); 97% ee [determined by HPLC analysis using a Chiralcel AD-H column; n-Hex/i-PrOH=75:25, 1.0 mL/min, 254 nm; tR (minor)=10.18 min; tR (major)=15.93 min]; 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J=2.1 Hz, 1H), 7.51 (dd, J=8.7, 2.1 Hz, 1H), 7.01 (d, J=8.7 Hz, 1H), 6.59 (s, 2H), 5.88 (s, 1H), 5.37 (s, 1H), 5.20 (s, 1H), 3.92 (s, 3H), 3.91 (s, 3H), 3.78 (s, 3H), 3.75 (s, 6H); 13C NMR (150 MHz, CDCl3) δ 166.1, 160.8, 159.6, 153.6, 149.5, 134.8, 133.6, 131.7, 130.8, 128.1, 120.5, 112.9, 111.2, 94.8, 63.1, 61.0, 56.2, 56.1, 52.3; ESI-LRMS m/z (%): 414.0 [M+H]+; ESI-HRMS m/z (%): Calcd for C22H24NO7 [M+H]+ 414.1547, found 414.1550.
The synthesis of compound 41 was similar to compound 1:
A 50 mL round-bottom flask was charged with 4-methoxy-3-nitrobenzaldehyde (41a) (1.38 g, 7.62 mmol), ethyl acrylate (762 mg, 7.62 mmol) and DABCO (55 mg, 7.62 mmol). The solution was stirred at room temperature for 3 days. The mixture was directly purified by flash column chromatography to give 41b as yellow oil (1.9 g, yield 99%). 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J=2.1 Hz, 1H), 7.57 (dd, J=8.7, 2.2 Hz, 1H), 7.07 (d, J=8.7 Hz, 1H), 6.37 (s, 1H), 5.90 (s, 1H), 5.53 (d, J=5.6 Hz, 1H), 4.18 (q, J=7.1 Hz, 2H), 3.95 (s, 3H), 3.43 (d, J=5.6 Hz, 1H), 1.27 (t, J=7.1 Hz, 3H); 13C NMR (100 MHz, DMSO) δ 166.1, 152.5, 141.6, 139.4, 134.3, 132.7, 126.5, 124.1, 113.6, 72.1, 72.0, 61.4, 56.8, 14.2; ESI-LRMS m/z (%): 304.1 [M+Na]+; ESI-HRMS m/z (%): Calcd for C13H19N2O6 [M+NH4]+299.1238, found 299.1238.
A 50 mL round-bottom flask was charged with compound 41b (1.94 g, 6.9 mmol), triethylamine (1.4 g, 13.8 mmol), DMAP (100 mg, 0.69 mmol) and dichloromethane (20 mL). The solution was cooled to 0° C. by an ice bath, then acetic anhydride (1.4 g, 13.8 mmol) was added dropwise into the flask within 5 min. After stirred for 10 min, 3 mL of saturated aqueous solution of sodium bicarbonate was added into the solution, and the mixture was extracted with dichloromethane (20 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 41c as colorless oil (1.7 g, yield 76%). 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J=2.2 Hz, 1H), 7.59 (dd, J=8.7, 2.2 Hz, 1H), 7.05 (d, J=8.7 Hz, 1H), 6.60 (s, 1H), 6.43 (s, 1H), 5.95 (s, 1H), 4.19-4.10 (m, 2H), 3.94 (s, 3H), 2.10 (s, 3H), 1.23 (t, J=7.1 Hz, 3H); ESI-LRMS m/z (%): 346.1 [M+Na]+; ESI-HRMS m/z (%): Calcd for C15H21N2O7 [M+NH4]+341.1343, found 341.1344.
To a solution of 41c (1.7 g, 5.2 mmol) and zinc powder (1.03 g, 16 mmol) in MeOH (20 mL) was slowly added acetic acid (3.2 g, 52 mmol), followed by heating to reflux for 2 h. The reaction mixture was then allowed to cool down to room temperature and filtered. The solvent was removed under reduced pressure and the residue was added to 30 mL of saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (30 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure to get the crude product. The crude product and di-tert-butyl dicarbonate (740 mg, 3.4 mmol) was dissolved in 10 mL of THF. The reaction mixture was heated to reflux for 16 h. The solvent was removed under vacuum and the residue was purified by column chromatography to give 41e as colorless oil (858 mg, yield 40%). 1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.07 (s, 1H), 7.01 (dd, J=8.3, 2.0 Hz, 1H), 6.79 (d, J=8.3 Hz, 1H), 6.62 (s, 1H), 6.39 (s, 1H), 5.85 (s, 1H), 4.20-4.11 (m, 2H), 3.85 (s, 3H), 2.10 (s, 3H), 1.52 (s, 9H), 1.24 (t, J=7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 168.9, 164.5, 151.9, 146.8, 139.2, 129.8, 127.6, 124.9, 121.4, 116.6, 108.9, 72.7, 60.3, 55.1, 27.7, 20.6, 13.4; ESI-LRMS m/z (%): 416.1 [M+Na]+; ESI-HRMS m/z (%): Calcd for C20H31N2O7 [M+NH4]+ 411.2126, found 411.2128.
A 50 mL Schlenk flask was charged with 5 mL of dichloromethane and the solvent was deoxygenized with nitrogen bubbling for 15 min. Tris(dibenzylideneacetone)dipalladium (3.8 mg, 0.0041 mmol) and R1 (7.2 mg, 0.01 mmol) was added into the flask. The resulted purple solution was stirred under nitrogen atmosphere for 10 min at room temperature. Then 3,4,5-trimethoxyaniline (114 mg, 0.62 mmol), K2CO3 (1.0 M aq. solution, 1.5 mL, 1.5 mmol) and compound 41e (163 mg, 0.41 mmol, dissolved in 2 mL of oxygen free dichloromethane) were added under a steam of nitrogen. The solution was stirred for 2 h at room temperature. Water (20 mL) was added into the solution, and the mixture was extracted with dichloromethane (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 41f as yellow oil (173 mg, yield 81%). [α]D20=+56.4 (c 0.15, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.02 (s, 1H), 6.91 (dd, J=8.4, 2.2 Hz, 1H), 6.72 (d, J=8.4 Hz, 1H), 6.30 (s, 1H), 5.89 (s, 1H), 5.75 (s, 2H), 5.27 (s, 1H), 4.16-4.02 (m, 2H), 3.78 (s, 3H), 3.70 (s, 6H), 3.68 (s, 3H), 1.45 (s, 9H), 1.16 (t, J=7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 165.8, 153.1, 152.0, 146.4, 143.0, 140.1, 132.7, 129.7, 127.8, 125.1, 120.6, 116.5, 109.2, 90.6, 79.8, 60.4, 60.1, 58.4, 55.3, 55.1, 27.7, 13.5; ESI-LRMS m/z (%): 517.3 [M+H]+; ESI-HRMS m/z (%): Calcd for C27H37N2O8 [M+H]+ 517.2544, found 517.2544.
The corresponding racemate can be obtained by replacing R1 with triphenylphosphine (0.005eq).
To a 100 mL Schlenk flask equipped with a cold finger was added 41f (146 mg, 0.28 mmol), Sn[N(TMS)2]2 (149 mg, 0.33 mmol) and anhydrous toluene (5 mL). The mixture was heated to reflux for 6 h under nitrogen atmosphere. The solution was cooled and directly purified by flash chromatography to give 40 as yellow oil (37 mg, yield 35%); [α]D20=+50.0 (c 0.14, CHCl3), 97% ee [determined by HPLC analysis using a Chiralcel AD-H column; n-Hex/i-PrOH=80:20, 1.0 mL/min, 254 nm; tR (minor)=19.58 min; tR (major)=17.42 min]; 1H NMR (400 MHz, CDCl3) δ 6.79 (dd, J=8.1, 1.9 Hz, 1H), 6.75 (d, J=8.1 Hz, 1H), 6.71 (d, J=1.9 Hz, 1H), 6.62 (s, 2H), 5.80 (t, J=1.6 Hz, 1H), 5.24 (s, 1H), 5.15 (t, J=1.6 Hz, 1H), 3.84 (s, 3H), 3.76 (s, 3H), 3.74 (s, 6H); 13C NMR (150 MHz, CDCl3) δ 161.1, 153.5, 150.0, 147.8, 136.8, 134.6, 134.0, 129.0, 117.5, 112.5, 110.5, 110.3, 94.9, 64.0, 60.9, 56.1, 55.5; ESI-LRMS m/z (%): 371.1 [M+H]+; ESI-HRMS m/z (%): Calcd for C20H23N2O5 [M+H]+ 371.1601, found 371.1605.
A 50 mL round-bottom flask was charged with 41 (20 mg, 0.054 mmol), Et3N (11 mg, 0.108 mmol), acryloyl chloride (10 mg, 0.081 mmol) and dichloromethane (1.5 mL). The solution was stirred for 0.5 h. Then 10 mL of water was added into the solution, and the mixture was extracted with dichloromethane (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 42 as white solid (16 mg, yield 66%); M.p. 143-144° C.; [α]D20=−96.4 (c 0.11, CHCl3); NMR (400 MHz, CDCl3) δ 8.70 (s, 1H), 7.93 (s, 1H), 7.05 (dd, J=8.5, 1.9 Hz, 1H), 6.87 (d, J=8.5 Hz, 1H), 6.62 (s, 2H), 6.43 (d, J=16.8 Hz, 1H), 6.29 (dd, J=16.8, 10.1 Hz, 1H), 5.83 (s, 1H), 5.79 (d, J=10.1 Hz, 1H), 5.36 (s, 1H), 5.19 (s, 1H), 3.89 (s, 3H), 3.75 (s, 3H), 3.74 (s, 6H); 13C NMR (150 MHz, CDCl3) δ 162.8, 160.3, 152.9, 149.1, 147.4, 133.9, 133.2, 130.6, 128.4, 127.3, 127.2, 121.0, 118.7, 110.2, 110.0, 94.2, 63.1, 60.3, 55.5, 55.3; ESI-LRMS m/z (%): 425.2 [M+H]+; ESI-HRMS m/z (%): Calcd for C23H28N3O6 [M+NH4]+442.1973, found 442.1975.
A 50 mL round-bottom flask was charged with 41 (20 mg, 0.054 mmol), Et3N (11 mg, 0.108 mmol), 4-nitrobenzoyl chloride (15 mg, 0.081 mmol) and dichloromethane (1.5 mL). The solution was stirred for 20 h. Then 10 mL of water was added into the solution, and the mixture was extracted with dichloromethane (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 43 as yellow solid (25 mg, yield 89%); M.p. 234-235° C.; [α]D20=−81.6 (c 0.20, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.70 (s, 1H, NH), 8.61 (s, 1H), 8.36 (d, J=8.7 Hz, 2H), 8.05 (d, J=8.7 Hz, 2H), 7.14 (dd, J=8.4, 1.8 Hz, 1H), 6.94 (d, J=8.4 Hz, 1H), 6.64 (s, 2H), 5.86 (s, 1H), 5.41 (s, 1H), 5.22 (s, 1H), 3.95 (s, 3H), 3.76 (s, 9H); 13C NMR (150 MHz, CDCl3) δ 162.6, 160.3, 152.9, 149.2, 149.1, 147.7, 139.7, 134.1, 133.1, 128.7, 127.6, 126.9, 123.51, 121.9, 118.6, 110.4, 110.1, 94.3, 63.0, 60.3, 55.5; ESI-LRMS m/z (%): 520.2 [M+H]+; ESI-HRMS m/z (%): Calcd for C27H25N3NaO8 [M+Na]+ 542.1534, found 542.1534.
A 50 mL round-bottom flask was charged with 41 (20 mg, 0.054 mmol), sulfamoyl chloride (62 mg, 0.27 mmol) and dichloromethane (2.5 mL). The solution was stirred for 1 h. Then 10 mL of water was added into the solution, and the mixture was extracted with dichloromethane (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 44 as white solid (11 mg, yield 42%); Mp 101-102° C.; [α]D20=−20.3 (c 0.35, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J=1.9 Hz, 1H), 7.12 (dd, J=8.5, 1.9 Hz, 1H), 7.03 (s, 1H, NH), 6.89 (d, J=8.5 Hz, 1H), 6.59 (s, 2H), 5.85 (s, 1H), 5.34 (s, 1H), 5.19 (s, 1H), 4.84 (s, 2H, NH2), 3.86 (s, 3H), 3.75 (m, 9H); 13C NMR (150 MHz, CDCl3) δ 160.3, 152.9, 148.9, 148.7, 134.2, 133.0, 128.7, 126.4, 122.3, 118.4, 110.7, 110.5, 94.5, 62.8, 60.3, 55.6, 55.4; ESI-LRMS m/z (%): 450.1 [M+H]+; ESI-HRMS m/z (%): Calcd for C20H24N3O7S [M+H]+ 450.1329, found 450.1346.
A 50 mL round-bottom flask was charged with 41 (20 mg, 0.054 mmol), Et3N (11 mg, 0.108 mmol), cyclopropanecarbonyl chloride (8.5 mg, 0.081 mmol) and dichloromethane (1.5 mL). The solution was stirred for 0.5 h. Then 10 mL of water was added into the solution, and the mixture was extracted with dichloromethane (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 45 as white solid (11 mg, yield 54%); Mp 181-182° C.; [α]D20=−77.3 (c 0.24, CHCl3); NMR (400 MHz, CDCl3) δ 8.59 (s, 1H, NH), 8.05 (s, 1H), 7.01 (dd, J=8.5, 1.8 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 6.61 (s, 2H), 5.81 (s, 1H), 5.32 (s, 1H), 5.18 (s, 1H), 3.89 (s, 3H), 3.75 (s, 3H), 3.73 (s, 6H), 1.63-1.53 (m, 1H), 1.08 (s, 2H), 0.87 (dd, J=7.6, 3.1 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 171.4, 160.3, 152.9, 149.1, 147.0, 133.9, 133.2, 128.3, 127.7, 120.4, 118.5, 110.2, 109.9, 94.2, 63.1, 60.3, 55.5, 55.2, 15.5, 7.5, 7.4; ESI-LRMS m/z (%): 439.2 [M+H]+; ESI-HRMS m/z (%): Calcd for C24H26N2NaO6 [M+Na]+ 461.1683, found 461.1685.
A 50 mL round-bottom flask was charged with compound 1 (0.25 g, 0.673 mmol), triethylamine (0.13 mL, 0.94 mmol), DMAP (8 mg, 0.067 mmol) and dichloromethane (10 mL). The solution was cooled to 0° C. by an ice bath, then acetic anhydride (0.09 mL, 0.094 mmol) was added dropwise into the flask within 10 min. After stirred for 5 min, 3 mL of saturated aqueous solution of sodium bicarbonate was added into the solution, and the mixture was extracted with dichloromethane (20 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 46 as white solid (0.23 g, yield 83%). Mp 122-123° C. 1H NMR (400 MHz, CDCl3) δ 7.25 (br d, J=8.4 Hz, 1H), 7.10 (br s, 1H), 6.97 (d, J=8.4 Hz, 1H), 6.57 (s, 1H), 5.84 (s, 1H), 5.30 (s, 1H), 5.18 (s, 1H), 3.83 (s, 3H), 3.76 (s, 3H), 3.73 (s, 6H), 2.29 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 168.0, 160.2, 153.0, 151.0, 149.0, 139.6, 134.1, 133.1, 128.3, 124.6, 121.1, 112.2, 110.4, 94.2, 62.7, 60.3, 55.5, 55.4, 20.0; ESI-HRMS (m/z): calcd for C22H23NO7+[M+H]+, 414.1547; found, 414.1546.
A 50 mL round-bottom flask was charged with 1 (0.15 g, 0.4 mmol), K2CO3 (72 mg, 0.5 mmol), BnBr (58 μL, 0.5 mmol) and DMF (5 mL). The solution was stirred for 8 h at 100° C. Then 10 mL of water was added into the solution, and the mixture was extracted with ethyl acetate (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 47 as white solid (146 mg, yield 78%); Mp 133-134° C.; [α]D20=+61.2 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.40-7.23 (m, 5H), 6.98 (dd, J=8.2, 1.6 Hz, 1H), 6.92-6.82 (m, 2H), 6.54 (s, 2H), 5.78 (s, 1H), 5.24 (s, 1H), 5.11 (s, 2H), 5.07 (s, 1H), 3.89 (s, 3H), 3.77 (s, 3H), 3.70 (s, 6H). 13C NMR (150 MHz, CDCl3): δ 160.3, 152.9, 149.7, 149.1, 147.9, 135.9, 134.0, 133.2, 128.1, 127.9, 127.3, 126.7, 119.6, 111.5, 111.2, 110.1, 94.1, 70.4, 63.2, 60.3, 55.4. ESI-MS (m/z): 461.9 (M+H+). ESI-HRMS (m/z): calcd for C27H27NO6+[M+H]+, 462.1911; found, 462.1909.
The synthesis of compound 48 was similar to compound 1:
A 50 mL Schlenk flask was charged with 5 mL of dichloromethane and the solvent was deoxygenized with nitrogen bubbling for 15 min. Tris(dibenzylideneacetone)dipalladium (5.7 mg, 0.0062 mmol) and R1 (11.1 mg, 0.016 mmol) was added into the flask. The resulted purple solution was stirred under nitrogen atmosphere for 10 min at room temperature. Then 3,4-Dimethoxyaniline (142 mg, 0.93 mmol), K2CO3 (1.0 M aq. solution, 3 mL, 3 mmol) and compound 1d (250 mg, 0.62 mmol, dissolved in 2 mL of oxygen free dichloromethane) were added under a steam of nitrogen. The solution was stirred for 1.5 h at room temperature. Water (20 mL) was added into the solution, and the mixture was extracted with dichloromethane (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 48a as yellow oil (220 mg, yield 72%). [α]D20=−5.1 (c 0.26, CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.91 (dd, J=8.3, 1.9 Hz, 1H), 6.84 (d, J=2.0 Hz, 1H), 6.79 (d, J=8.3 Hz, 1H), 6.70 (d, J=8.6 Hz, 1H), 6.33 (s, 1H), 6.22 (d, J=2.5 Hz, 1H), 6.08 (dd, J=8.6, 2.5 Hz, 1H), 5.88 (s, 1H), 5.24 (s, 1H), 4.21-4.08 (m, 2H), 3.88-3.71 (m, 9H), 1.28-1.16 (m, 3H), 0.97 (s, 9H), 0.11 (d, J=9.2 Hz, 6H); 13C NMR (150 MHz, CDCl3) δ 165.8, 149.8, 149.3, 144.4, 141.1, 140.3, 132.8, 124.7, 120.1, 119.6, 112.5, 111.5, 103.8, 99.0, 60.1, 58.5, 56.1, 55.1, 54.9, 25.1, 17.8, 13.5, −5.2; ESI-LRMS m/z (%): 502.2 [M+H]+.
The corresponding racemate can be obtained by replacing R1 with triphenylphosphine (0.005eq).
To a 100 mL Schlenk flask equipped with a cold finger was added 48a (220 mg, 0.44 mmol), Sn[N(TMS)2]2 (231 mg, 0.53 mmol) and anhydrous toluene (5 mL). The mixture was heated to reflux for 4 h under nitrogen atmosphere. The solution was cooled and directly purified by flash chromatography to give 48b as colorless oil (147 mg, yield 74%); [α]D20=+29.9 (c 0.32, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.23 (s, 1H), 6.94 (dd, J=8.2, 1.7 Hz, 1H), 6.82 (d, J=8.4 Hz, 2H), 6.68 (d, J=8.6 Hz, 1H), 6.57 (dd, J=8.6, 2.0 Hz, 1H), 5.78 (s, 1H), 5.25 (s, 1H), 5.11 (s, 1H), 3.86-3.72 (m, 9H), 0.94 (s, 6H), 0.08 (s, 3H), 0.07 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 160.1, 150.8, 149.5, 148.7, 145.2, 144.9, 130.9, 128.2, 119.6, 118.8, 111.7, 110.8, 109.4, 108.0, 101.5, 62.9, 55.5, 55.3, 54.9, 25.0, 17.8, −5.2, −5.3; ESI-LRMS m/z (%): 456.2 [M+H]+.
A 100 mL round-bottom flask was charged with compound 48b (147 mg, 0.26 mmol) and THF (5 mL). The solution was cooled to 0° C. by an ice bath, then TBAF (136 mg, 0.52 mmol, dissolved in 1 mL THF) was dropped into the flask. After stirred for 15 min at 0° C., 30 mL of water was added into the solution. The mixture was extracted with ethyl acetate (20 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 48 as white solid (72 mg, yield 82%); Mp 74-75° C.; [α]D20=+1.9 (c 0.32, CHCl3); 99% ee [determined by HPLC analysis using a Chiralcel AD-H column; n-Hex/i-PrOH=75:25, 1.0 mL/min, 254 nm; tR (minor)=11.78 min; tR (major)=16.22 min]; 1H NMR (400 MHz, CDCl3) δ 7.28 (d, J=2.1 Hz, 1H), 6.94 (d, J=1.7 Hz, 1H), 6.87 (dd, J=8.2, 1.7 Hz, 1H), 6.81 (d, J=8.2 Hz, 1H), 6.67 (d, J=8.6 Hz, 1H), 6.54 (dd, J=8.6, 2.1 Hz, 1H), 5.91 (s, 1H), 5.76 (s, 1H), 5.26 (s, 1H), 5.11 (s, 1H), 3.85 (s, 3H), 3.81 (s, 3H), 3.78 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 160.1, 149.4, 148.8, 146.4, 145.6, 145.2, 130.9, 129.0, 118.0, 112.3, 110.8, 110.3, 109.5, 107.8, 101.6, 62.9, 55.5, 55.4, 55.3; ESI-LRMS m/z (%): 342.1 [M+H]+; ESI-HRMS m/z (%): Calcd for C20H26NO4 [M+H]+ 342.1336, found 342.1339.
The synthesis of compound 49 was similar to compound 1:
A 50 mL Schlenk flask was charged with 5 mL of dichloromethane and the solvent was deoxygenized with nitrogen bubbling for 15 min. Tris(dibenzylideneacetone)dipalladium (5.7 mg, 0.0062 mmol) and R1 (11.1 mg, 0.016 mmol) was added into the flask. The resulted purple solution was stirred under nitrogen atmosphere for 10 min at room temperature. Then 3,5-Dimethoxyaniline (142 mg, 0.93 mmol), K2CO3 (1.0 M aq. solution, 3 mL, 3 mmol) and compound 1d (250 mg, 0.62 mmol, dissolved in 2 mL of oxygen free dichloromethane) were added under a steam of nitrogen. The solution was stirred for 1.5 h at room temperature. Water (20 mL) was added into the solution, and the mixture was extracted with dichloromethane (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 49a as yellow oil (270 mg, yield 88%). [α]D20=+27.7 (c 0.27, CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.89 (dd, J=8.3, 2.1 Hz, 1H), 6.82-6.78 (m, 2H), 6.35 (s, 1H), 5.88 (d, J=2.1 Hz, 2H), 5.77 (d, J=2.1 Hz, 2H), 5.28 (s, 1H), 4.21-4.05 (m, 2H), 3.78 (s, 3H), 3.72 (s, 6H), 1.20 (t, J=7.1 Hz, 3H), 0.97 (s, 9H), 0.12 (s, 6H); 13C NMR (150 MHz, CDCl3) δ 166.2, 161.6, 150.5, 148.7, 145.1, 140.5, 133.2, 125.4, 120.7, 120.3, 112.2, 92.4, 90.1, 60.7, 58.5, 55.5, 55.1, 25.7, 18.5, 14., −4.6; ESI-LRMS m/z (%): 502.2 [M+H]+; ESI-HRMS m/z (%): Calcd for C27H40NO6Si [M+H]+ 502.2619, found 502.2619.
The corresponding racemate can be obtained by replacing R1 with triphenylphosphine (0.005eq).
To a 100 mL Schlenk flask equipped with a cold finger was added 48a (270 mg, 0.54 mmol), Sn[N(TMS)2]2 (284 mg, 0.65 mmol) and anhydrous toluene (5 mL). The mixture was heated to reflux for 6 h under nitrogen atmosphere. The solution was cooled and directly purified by flash chromatography to give 48b as colorless oil (213 mg, yield 76%); [α]D20=+39.5 (c 0.20, CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.94 (dd, J=8.3, 2.1 Hz, 1H), 6.83-6.81 (m, 2H), 6.53 (d, J=2.2 Hz, 2H), 6.16 (t, J=2.2 Hz, 1H), 5.81 (t, J=1.7 Hz, 1H), 5.25 (s, 1H), 5.18-5.10 (m, 1H), 3.79 (s, 3H), 3.70 (s, 6H), 0.94 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 161.2, 161.1, 151.4, 150.1, 145.6, 139.2, 128.8, 120.2, 119.3, 112.3, 110.7, 96.7, 95.8, 63.6, 55.5, 55.3, 25.7, 18.4, −4.7; ESI-LRMS m/z (%): 456.2 [M+H]+; ESI-HRMS m/z (%): Calcd for C25H34NO75Si [M+H]+ 456.2201, found 456.2202.
A 100 mL round-bottom flask was charged with compound 49b (172 mg, 0.38 mmol) and THF (5 mL). The solution was cooled to 0° C. by an ice bath, then TBAF (198 mg, 0.76 mmol, dissolved in 2 mL THF) was dropped into the flask. After stirred for 15 min at 0° C., 30 mL of water was added into the solution. The mixture was extracted with ethyl acetate (20 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 48 as colorless oil (116 mg, yield 90%); [α]D20=+49.6 (c 0.12, CHCl3), 99% ee [determined by HPLC analysis using a Chiralcel AD-H column; n-Hex/i-PrOH=80:20, 1.0 mL/min, 254 nm; tR (minor)=13.41 min; tR (major)=14.97 min]; 1H NMR (400 MHz, CDCl3) δ 6.93 (d, J=2.0 Hz, 1H), 6.87 (dd, J=8.2, 2.0 Hz, 1H), 6.81 (d, J=8.2 Hz, 1H), 6.53 (d, J=2.2 Hz, 2H), 6.15 (t, J=2.2 Hz, 1H), 5.94 (brd, 1H), 5.80 (t, J=1.2 Hz, 1H), 5.25 (s, 1H), 5.13 (s, 1H), 3.84 (s, 3H), 3.70 (s, 6H); 13C NMR (150 MHz, CDCl3) δ 160.6, 160.5, 149.3, 146.5, 145.6, 138.6, 128.9, 118.0, 112.2, 110.4, 110.3, 95.9, 95.2, 63.0, 55.3, 54.7; ESI-LRMS m/z (%): 342.1 [M+H]+; ESI-HRMS m/z (%): Calcd for C19H20NO5 [M+H]+ 342.1336, found 342.1337.
The synthesis of compound 50 was similar to compound 1:
A 50 mL Schlenk flask was charged with 5 mL of dichloromethane and the solvent was deoxygenized with nitrogen bubbling for 15 min. Tris(dibenzylideneacetone)dipalladium (3.8 mg, 0.0042 mmol) and R1 (7.6 mg, 0.0105 mmol) was added into the flask. The resulted purple solution was stirred under nitrogen atmosphere for 10 min at room temperature. Then 2,4-dimethoxyaniline (104 mg, 0.68 mmol), K2CO3 (1.0 M aq. solution, 1.5 mL, 1.5 mmol) and compound 1d (170 mg, 0.42 mmol, dissolved in 2 mL of oxygen free dichloromethane) were added under a steam of nitrogen. The solution was stirred for 1.5 h at room temperature. Water (20 mL) was added into the solution, and the mixture was extracted with dichloromethane (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 50a as yellow oil (180 mg, yield 86%). 1H NMR (400 MHz, CDCl3) δ 6.92 (dd, J=8.3, 2.0 Hz, 1H), 6.84 (d, J=2.0 Hz, 1H), 6.79 (d, J=8.3 Hz, 1H), 6.44 (d, J=2.4 Hz, 1H), 6.41 (d, J=8.5 Hz, 1H), 6.37-6.30 (m, 2H), 5.85 (s, 1H), 5.24 (s, 1H), 4.23-4.05 (m, 2H), 3.79 (s, 3H), 3.78 (s, 3H), 3.74 (s, 3H), 1.23 (q, J=7.5 Hz, 3H), 0.97 (s, 9H), 0.12 (s, 6H); 13C NMR (151 MHz, CDCl3) δ 166.5, 152.1, 150.4, 147.9, 145.0, 141.1, 133.6, 131.2, 129.0, 128.4, 125.1, 120.9, 120.4, 112.1, 111.3, 103.7, 99.1, 60.7, 58.7, 55.8, 55.5, 55.5, 25.7, 18.5, 14.1, −4.6; ESI-LRMS m/z (%): 502.2 [M+H]+.
The corresponding racemate can be obtained by replacing R1 with triphenylphosphine (0.005eq).
To a 100 mL Schlenk flask equipped with a cold finger was added 50a (180 mg), Sn[N(TMS)2]2 (189 mg, 0.43 mmol) and anhydrous toluene (5 mL). The mixture was heated to reflux for 4.5 h under nitrogen atmosphere. The solution was cooled and directly purified by flash chromatography to give 50b as colorless oil (77 mg, yield 47%); 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J=8.7 Hz, 1H), 6.84 (dd, J=8.2, 2.0 Hz, 1H), 6.76-6.73 (m, 2H), 6.47-6.38 (m, 1H), 6.36 (d, J=2.4 Hz, 1H), 5.76 (s, 1H), 5.60 (s, 1H), 5.08 (s, 1H), 3.76-3.73 (m, 6H), 3.67 (s, 3H), 0.94 (s, 9H), 0.09 (t, J=24.3 Hz, 6H); ESI-LRMS m/z (%): 456.2 [M+H]+.
A 100 mL round-bottom flask was charged with compound 50b (55 mg, 0.12 mmol) and THF (5 mL). The solution was cooled to 0° C. by an ice bath, then TBAF (63 mg, 0.24 mmol, dissolved in 1 mL THF) was dropped into the flask. After stirred for 15 min at 0° C., 30 mL of water was added into the solution. The mixture was extracted with ethyl acetate (20 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 50 as brown oil (37 mg, yield 90%); 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J=8.7 Hz, 1H), 6.88 (d, J=2.0 Hz, 1H), 6.79 (dd, J=8.3, 2.0 Hz, 1H), 6.75 (d, J=8.3 Hz, 1H), 6.43 (dd, J=8.7, 2.5 Hz, 1H), 6.36 (d, J=2.5 Hz, 1H), 5.75 (t, J=1.5 Hz, 1H), 5.66 (d, J=8.3 Hz, 1H), 5.62 (s, 1H), 5.08 (s, 1H), 3.83 (s, 3H), 3.74 (s, 3H), 3.69 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 162.3, 158.5, 152.4, 151.4, 146.6, 145.7, 131.0, 124.7, 118.7, 118.4, 113.2, 110.6, 109.4, 104.6, 99.7, 66.3, 55.9, 55.5; ESI-LRMS m/z (%): 342.0 [M+H]+.
The synthesis of compound 51 was similar to compound 1:
A 50 mL Schlenk flask was charged with 5 mL of dichloromethane and the solvent was deoxygenized with nitrogen bubbling for 15 min. Tris(dibenzylideneacetone)dipalladium (3.8 mg, 0.0042 mmol) and R1 (7.56 mg, 0.0105 mmol) was added into the flask. The resulted purple solution was stirred under nitrogen atmosphere for 10 min at room temperature. Then 3-methoxyaniline (84 mg, 0.68 mmol), K2CO3 (1.0 M aq. solution, 1.5 mL, 1.5 mmol) and compound 1d (170 mg, 0.42 mmol, dissolved in 2 mL of oxygen free dichloromethane) were added under a steam of nitrogen. The solution was stirred for 4 h at room temperature. Water (20 mL) was added into the solution, and the mixture was extracted with dichloromethane (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 49a as yellow oil (170 mg, yield 87%). [α]D20=+118.9 (c 0.14, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.07 (t, J=8.1 Hz, 1H), 6.92 (dd, J=8.3, 2.1 Hz, 1H), 6.84-6.80 (m, 2H), 6.36 (s, 1H), 6.30 (dd, J=8.1, 1.8 Hz, 1H), 6.21 (d, J=8.0 Hz, 1H), 6.14 (t, J=2.2 Hz, 1H), 5.90 (s, 1H), 5.30 (s, 1H), 4.18-4.12 (m, 2H), 3.80 (s, 3H), 3.76 (s, 3H), 1.23 (t, J=7.1 Hz, 3H), 0.99 (s, 9H), 0.14 (s, 6H); 13C NMR (150 MHz, CDCl3) δ 165.7, 160.1, 149.9, 147.6, 144.4, 139.9, 132.6, 129.2, 124.7, 120.1, 119.7, 111.5, 105.9, 102.2, 98.9, 60.1, 57.8, 54.9, 54.4, 25.1, 17.8, 13.5, −5.2; ESI-LRMS m/z (%): 472.1 [M+H]+; ESI-HRMS m/z (%): Calcd for C26H38NO5Si [M+H]+472.2514, found 472.2514.
The corresponding racemate can be obtained by replacing R1 with triphenylphosphine (0.005eq).
To a 100 mL Schlenk flask equipped with a cold finger was added 51a (170 mg), Sn[N(TMS)2]2 (190 mg, 0.43 mmol) and anhydrous toluene (5 mL). The mixture was heated to reflux for 4.5 h under nitrogen atmosphere. The solution was cooled and directly purified by flash chromatography to give 51b as colorless oil (106 mg, yield 69%); [α]D20=+36.5 (c 0.12, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.15 (t, J=8.2 Hz, 1H), 7.04 (s, 1H), 6.97 (dd, J=8.3, 1.9 Hz, 1H), 6.86-6.84 (m, 3H), 6.61 (dd, J=8.3, 1.7 Hz, 1H), 5.84 (s, 1H), 5.30 (s, 1H), 5.17 (s, 1H), 3.81 (s, 3H), 3.76 (s, 3H), 0.96 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 160.5, 159.5, 150.8, 149.4, 144.8, 138.1, 129.2, 128.1, 119.6, 118.7, 111.6, 110.1, 109.5, 108.9, 102.4, 62.8, 54.9, 54.6, 25.1, 17.8, −5.3; ESI-LRMS m/z (%): 426.2 [M+H]+; ESI-HRMS m/z (%): Calcd for C24H32NO4Si [M+H]+ 426.2095, found 426.2096.
A 100 mL round-bottom flask was charged with compound 51b (106 mg, 0.25 mmol) and THF (5 mL). The solution was cooled to 0° C. by an ice bath, then TBAF (130 mg, 0.50 mmol, dissolved in 2 mL THF) was dropped into the flask. After stirred for 15 min at 0° C., 30 mL of water was added into the solution. The mixture was extracted with ethyl acetate (20 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 51 as white solid (63 mg, yield 77%); Mp 104-105° C.; [α]D20=+61.0 (c 0.21, CHCl3); 99% ee [determined by HPLC analysis using a Chiralcel AD-H column; n-Hex/i-PrOH=75:25, 1.0 mL/min, 254 nm; tR (minor)=10.45 min; tR (major)=12.04 min]; 1H NMR (400 MHz, CDCl3) δ 7.14 (t, J=8.2 Hz, 1H), 7.04 (s, 1H), 6.95 (d, J=1.9 Hz, 1H), 6.89 (dd, J=8.2, 1.9 Hz, 1H), 6.84 (s, 1H), 6.82 (s, 1H), 6.60 (dd, J=8.2, 1.6 Hz, 1H), 5.82 (s, 1H), 5.73 (brd, 1H), 5.29 (s, 1H), 5.15 (s, 1H), 3.88 (s, 3H), 3.75 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 161.1, 160.1, 145.0, 147.0, 146.2, 138.7, 129.9, 129.6, 118.6, 112.8, 110.9, 110.8, 110.1, 109.5, 103.1, 63.5, 56.0, 55.3; ESI-LRMS m/z (%): 334.1 [M+Na]+; ESI-HRMS m/z (%): Calcd for C18H18NO4 [M+H]+ 312.1230, found 312.1232.
The synthesis of compound 52 was similar to compound 1:
A 50 mL Schlenk flask was charged with 5 mL of dichloromethane and the solvent was deoxygenized with nitrogen bubbling for 15 min. Tris(dibenzylideneacetone)dipalladium (5 mg, 0.0054 mmol) and R1 (10 mg, 0.011 mmol) was added into the flask. The resulted purple solution was stirred under nitrogen atmosphere for 10 min at room temperature. Then 4-methoxyaniline (100 mg, 0.81 mmol), K2CO3 (1.0 M aq. solution, 1.5 mL, 1.5 mmol) and compound 1d (220 mg, 0.54 mmol, dissolved in 2 mL of oxygen free dichloromethane) were added under a steam of nitrogen. The solution was stirred for 1 h at room temperature. Water (20 mL) was added into the solution, and the mixture was extracted with dichloromethane (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 52a as yellow oil (186 mg, yield 73%). [α]D20=−2.3 (c 0.30, CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.91 (dd, J=8.2, 1.8 Hz, 1H), 6.86-6.69 (m, 4H), 6.53 (d, J=8.8 Hz, 2H), 6.33 (s, 1H), 5.88 (s, 1H), 5.22 (s, 1H), 4.23-4.07 (m, 2H), 3.89 (s, 1H), 3.78 (s, 3H), 3.73 (s, 3H), 1.22 (t, J=7.1 Hz, 3H), 0.97 (s, 9H), 0.12 (s, 6H); 13C NMR (150 MHz, CDCl3) δ 167.4, 151.8, 151.5, 144.4, 141.9, 141.4, 127.1, 126.8, 123.6, 121.8, 114.2, 111.2, 60.3, 55.2, 54.8, 41.4, 25.1, 25.0, 17.7, 13.7, −5.4; ESI-LRMS m/z (%): 472.2 [M+H]+; ESI-HRMS m/z (%): Calcd for C26H38NO5Si [M+H]+ 472.2514, found 472.2515.
The corresponding racemate can be obtained by replacing 1e with triphenylphosphine (0.005eq).
To a 100 mL Schlenk flask equipped with a cold finger was added 52a (186 mg), Sn[N(TMS)2]2 (208 mg, 0.47 mmol) and anhydrous toluene (5 mL). The mixture was heated to reflux for 4.5 h under nitrogen atmosphere. The solution was cooled and directly purified by flash chromatography to give 52b as colorless oil (130 mg, yield 77%); [α]D20=+68.0 (c 0.10, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.28 (d, J=9.1 Hz, 2H), 6.93 (dd, J=8.3, 1.8 Hz, 1H), 6.83-6.77 (m, 4H), 5.78 (s, 1H), 5.25 (s, 1H), 5.11 (s, 1H), 3.79 (s, 3H), 3.74 (s, 3H), 0.94 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 160.1, 155.6, 150.8, 149.5, 144.8, 130.5, 128.2, 119.7, 118.8, 117.9, 113.7, 111.6, 109.3, 62.7, 54.8, 25.1, 17.8, −5.2, −5.3; ESI-LRMS m/z (%): 426.2 [M+H]+; ESI-HRMS m/z (%): Calcd for C24H32NO4Si [M+H]+ 426.2095, found 426.2096.
A 100 mL round-bottom flask was charged with compound 52b (100 mg, 0.25 mmol) and THF (5 mL). The solution was cooled to 0° C. by an ice bath, then TBAF (130 mg, 0.5 mmol, dissolved in 1 mL THF) was dropped into the flask. After stirred for 15 min at 0° C., 30 mL of water was added into the solution. The mixture was extracted with ethyl acetate (20 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 52 as white solid (63 mg, yield 86%); Mp 180-181° C.; [α]D20=+113.4 (c 0.10, CHCl3); 97% ee [determined by HPLC analysis using a Chiralcel AD-H column; n-Hex/i-PrOH=75:25, 1.0 mL/min, 254 nm; tR (minor)=15.28 min; tR (major)=19.43 min]; 1H NMR (400 MHz, CDCl3) δ 7.28 (d, J=8.9 Hz, 2H), 6.98-6.74 (m, 5H), 5.81-5.73 (m, 2H), 5.26 (s, 1H), 5.10 (s, 1H), 3.87 (s, 3H), 3.73 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 160.0, 155.6, 149.5, 146.3, 145.5, 130.5, 129.0, 117.9, 117.9, 113.8, 112.3, 110.3, 109.4, 62.7, 55.3, 54.8; ESI-LRMS m/z (%): 334.1 [M+Na]+; ESI-HRMS m/z (%): Calcd for C15H18NO4 [M+H]+ 312.1230, found 312.1231.
A 50 mL Schlenk tube was charged with 1 (40 mg, 0.1 mmol), allyltrimethylsilane (86 μL, 0.5 mmol), Grubb's 2nd generation catalyst (12 mg, 0.01 mmol) and anhydrous toluene (1 mL). The resulting purple solution was stirred under nitrogen atmosphere for 8 h at 80° C. Water (5 mL) was added into the solution, and the mixture was extracted with ethyl acetate (15 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 53 as white solid (24 mg, yield 49%) and 54 as white solid (17 mg, yield 35%).
53: Mp 65-66° C.; [α]D20=+32.7 (c 1.0, CHCl3). 1HNMR (400 MHz, CDCl3) δ 6.96 (d, J=1.7 Hz, 1H), 6.90 (dd, J=8.2, 1.7 Hz, 1H), 6.83 (d, J=8.2 Hz, 1H), 6.59 (s, 2H), 5.72 (br s, 1H), 5.64 (t, J=9.2 Hz, 1H), 5.17 (s, 1H), 3.88 (s, 3H), 3.75 (s, 3H), 3.73 (s, 6H), 2.18-2.01 (m, 2H), 0.05 (s, 9H). 13C NMR (150 MHz, CDCl3) δ 161.8, 152.8, 146.1, 145.5, 137.8, 133.8, 133.4, 130.2, 129.9, 118.0, 112.3, 110.1, 93.7, 76.6, 76.4, 76.2, 62.3, 60.3, 55.3, 21.2, −2.4. ESI-MS (m/z): 458.2 (M+H+).
54: Mp 67-69° C.; [α]D20=−109.1 (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.00 (d, J=1.8 Hz, 1H), 6.94 (d, J=8.2 Hz, 1.8 Hz, 1H), 6.84 (d, J=8.2 Hz, 1H), 6.57 (s, 2H), 6.35 (t, J=8.7 Hz, 1H), 5.74 (s, 1H), 5.23 (s, 1H), 3.89 (s, 3H), 3.75 (s, 3H), 3.73 (s, 6H), 1.53-1.34 (m, 2H), −0.05 (s, 9H); 13C NMR (150 MHz, CDCl3) δ 161.2, 152.8, 146.2, 145.6, 138.3, 133.7, 133.5, 129.4, 126.6, 118.3, 112.6, 110.3, 93.8, 62.4, 60.3, 55.4, 19.5, −2.3; ESI-LRMS m/z (%): 458.2 [M+H]+.
A 100 mL round-bottom flask was charged with compound 53 (8 mg, 0.018 mmol) and THF (1 mL). The solution was cooled to 0° C. by an ice bath, then TBAF (7 mg, 0.026 mmol) was added into the flask. After stirred for 30 min at 0° C., 10 mL of water was added into the solution. The mixture was extracted with ethyl acetate (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 55 as white solid (6 mg, yield 90%); 1H NMR (400 MHz, CDCl3) δ 6.98 (d, J=1.8 Hz, 1H), 6.91 (dd, J=8.2 Hz, 1.8 Hz, 1H), 6.80 (d, J=8.2 Hz, 1H), 6.71 (s, 2H), 5.62 (br s, 1H), 5.64 (q, J=9.2 Hz, 1H), 5.27 (s, 1H), 3.89 (s, 3H), 3.76 (s, 3H), 3.70 (s, 6H), 2.07 (d, J=9.2 Hz, 2H); ESI-LRMS m/z (%): 386.2 [M+H]+.
A 100 mL round-bottom flask was charged with compound 54 (10 mg, 0.022 mmol) and THF (1 mL). The solution was cooled to 0° C. by an ice bath, then TBAF (9 mg, 0.034 mmol) was added into the flask. After stirred for 30 min at 0° C., 10 mL of water was added into the solution. The mixture was extracted with ethyl acetate (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 56 as white solid (8 mg, yield 95%); 1H NMR (400 MHz, CDCl3) 67.01 (d, J=1.8 Hz, 1H), 6.96 (d, J=8.2 Hz, 1.8 Hz, 1H), 6.82 (d, J=8.2 Hz, 1H), 6.57 (s, 2H), 6.45 (q, J=8.7 Hz, 1H), 5.64 (br s, 1H), 5.11 (s, 1H), 3.81 (s, 3H), 3.74 (s, 3H), 3.70 (s, 6H), 2.09 (d, J=8.7 Hz 2H). ESI-LRMS m/z (%): 386.2 [M+H]+.
A 50 mL Schlenk tube was charged with 1 (16 mg, 0.043 mmol), styrene (13 μL, 0.11 mmol), Grubb's 2nd generation catalyst (5 mg, 0.006 mmol) and 1,2-dichloroethane (1 mL). The resulting purple solution was stirred under nitrogen atmosphere for 12 h at 60° C. Water (5 mL) was added into the solution, and the mixture was extracted with dichloromethane (15 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 57 as yellow solid (10 mg, yield 51%); Mp 168-169° C.; [α]D20=+102.3 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.99 (d, J=7.2 Hz, 2H), 7.41-7.31 (m, 3H), 7.02 (d, J=2.0 Hz, 1H), 6.96 (dd, J=8.2, 2.0 Hz, 1H), 6.86 (d, J=8.2 Hz, 1H), 6.68 (s, 2H), 6.29 (s, 1H), 5.70 (s, 1H), 5.28 (s, 1H), 3.89 (s, 3H), 3.78 (s, 3H), 3.76 (s, 6H). 13C NMR (150 MHz, CDCl3): δ 159.7, 152.9, 146.4, 145.6, 139.9, 133.9, 133.5, 133.4, 130.2, 129.5, 129.3, 129.0, 128.0, 118.2, 112.4, 110.3, 94.0, 61.8, 60.4, 55.4. ESI-MS (m/z): 448.1 (M+H+). ESI-HRMS (m/z): calcd for C26H25NO6+[M+H]+, 448.1755; found, 448.1754.
A 50 mL Schlenk tube was charged with 1 (10 mg, 0.027 mmol), 1-(tert-butyl)-4-vinylbenzene (13 μL, 0.081 mmol), Grubb's 2nd generation catalyst (2 mg, 0.003 mmol) and 1,2-dichloroethane (1 mL). The resulting purple solution was stirred under nitrogen atmosphere for 12 h at 60° C. Water (5 mL) was added into the solution, and the mixture was extracted with dichloromethane (15 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 58 as yellow solid (4 mg, yield 30%); Mp 77-78° C.; [α]D20=+131.8 (c 1.0, CHCl3). 1HNMR (400 MHz, CDCl3): δ 7.92 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.01 (d, J=1.9 Hz, 1H), 6.95 (dd, J=8.2, 1.9 Hz, 1H), 6.85 (d, J=8.2 Hz, 1H), 6.68 (s, 2H), 6.28 (s, 1H), 5.68 (s, 1H), 5.27 (s, 1H), 3.89 (s, 3H), 3.77 (s, 3H), 3.76 (s, 6H), 1.31 (s, 9H). 13C NMR (150 MHz, CDCl3): δ 159.9, 152.9, 152.4, 146.4, 145.6, 139.1, 133.8, 133.6, 130.8, 130.0, 129.6, 129.1, 125.0, 118.2, 112.5, 110.3, 94.0, 76.6, 76.4, 76.2, 61.8, 60.4, 55.4, 55.4, 34.2, 30.5. ESI-MS (m/z): 504.2 (M+H+). ESI-HRMS (m/z): calcd for C30H33NO6+Et [M+H]+, 504.2381; found, 504.2376.
A 50 mL round-bottom flask was charged with a mixture of 53 and 54 (38 mg, 0.083 mmol), 10% Pd/C (4 mg) and methanol (1 mL). The solution was stirred for 12 h under H2 atmosphere (1 atm). Pd/C was filtrated, then the solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 59 as white solid (33 mg, yield 87%); Mp 105-107° C.; [α]D20=+62.7 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) δ 6.86-6.82 (m, 2H), 6.77 (d, J=8.2 Hz, 1H), 6.55 (s, 2H), 5.70 (s, 1H), 5.07 (d, J=5.6 Hz, 1H), 3.89 (s, 3H), 3.81-3.68 (m, 10H), 3.46 (dt, J=9.5, 6.0 Hz, 1H), 0.91-0.82 (m, 1H), 0.48 (td, J=14.0, 4.8 Hz, 1H), 0.21 (td, J=14.0, 3.7 Hz, 1H), −0.21 (s, 9H); ESI-LRMS m/z (%): 482.2 [M+Na]+.
A 50 mL Schlenk tube was charged with 1 (20 mg, 0.054 mmol), 4-vinylphenol (41 mg, 0.34 mmol), Grubb's 2nd generation catalyst (5 mg, 0.006 mmol) and anhydrous toluene (1 mL). The resulting purple solution was stirred under nitrogen atmosphere for 12 h at 80° C. Water (5 mL) was added into the solution, and the mixture was extracted with ethyl acetate (15 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 60a as white solid. It was dissolved in methanol (1 mL). 10% Pd/C (4 mg) was added into the solution. The solution was stirred for 12 h under H2 atmosphere (1 atm). Pd/C was filtrated, then the solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 60 as white solid (17 mg, yield 83%); Mp 107-109° C. [α]D20=+16.4 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) δ 6.85-6.70 (m, 5H), 6.65 (d, J=8.4 Hz, 2H), 6.56 (s, 2H), 5.72 (br s, 1H), 5.26 (br s, 1H), 5.07 (d, J=5.6 Hz, 1H), 3.91 (s, 3H), 3.83-3.74 (m, 4H), 3.71 (s, 6H), 2.84 (dd, J=14.8, 7.2 Hz, 1H), 2.44 (dd, J=14.8, 8.5 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 166.9, 153.5, 152.9, 146.0, 145.2, 133.8, 133.1, 129.7, 129.1, 127.0, 118.5, 114.5, 112.9, 110.0, 94.4, 60.3, 57.9, 55.5, 55.4, 55.2, 29.7. ESI-MS (m/z): 464.2 (M−H+).
A 100 mL round-bottom flask was charged with 75 (30 mg, 0.076 mmol), prop-2-yn-1-ol (5 mL, 0.084 mmol), CuSO4.5H2O (1 mg, 0.004 mmol), L-ascorbic acid sodium salt (2.2 mg, 15% mmol), EtOH (0.7 mL) and H2O (0.3 mL). After stirring for 8 h at room temperature, 5 mL of water was added into the solution, and the mixture was extracted with ethyl acetate (5 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was dissolved in 1 mL of EtOH. 10% Pd/C (2 mg) was added into the mixture. The solution was stirred for 12 h under H2 atmosphere (1 atm). Pd/C was filtrated, then the solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 61 as white solid (26 mg, yield 93%); Mp 93-95° C.; [α]D20=−96.9 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.75 (s, 1H), 6.98 (d, J=1.5 Hz, 1H), 6.94 (dd, J=8.1, 1.5 Hz, 1H), 6.89 (d, J=8.1 Hz, 1H), 6.59 (s, 2H), 5.76 (s, 1H), 5.55 (d, J=1.6 Hz, 1H), 5.31 (d, J=1.7 Hz, 1H), 4.85 (s, 2H), 3.92 (s, 3H), 3.79 (s, 3H), 3.74 (s, 6H). 13C NMR (150 MHz, CDCl3): δ 159.0, 153.7, 147.6, 146.7, 135.5, 132.5, 127.6, 121.5, 118.4, 112.0, 111.2, 100.0, 95.7, 72.0, 63.5, 61.0, 56.7, 56.2, 56.1. ESI-MS (m/z): 457.1 (M+H+). ESI-HRMS (m/z): calcd for C22H24N4O7+[M+H]+, 457.1718; found, 457.1718.
A 25 mL Schlenk tube was charged with 1 (16 mg, 0.043 mmol), dimethylamine hydrochloride (11 mg, 0.13 mmol), DBU (19 mL, 0.13 mmol) and MeOH (1 mL). The solution was heated to reflux for 6 h. 10 mL of water was added into the solution, and the mixture was extracted with ethyl acetate (20 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 62 as light yellow solid (13 mg, yield 75%); Mp 79-81° C.; [α]D20=+86.8 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) δ 6.85-6.83 (m, 2H), 6.77 (d, J=7.1 Hz, 1H), 6.55 (s, 2H), 5.12 (d, J=5.8 Hz, 1H), 3.90 (s, 3H), 3.82-3.74 (m, 4H), 3.71 (s, 6H), 2.44 (dd, J=13.3, 6.8 Hz, 1H), 2.25 (dd, J=13.3, 5.8 Hz, 1H), 2.17 (s, 6H); 13C NMR (150 MHz, CDCl3) δ 166.0, 152.8, 146.1, 145.3, 133.8, 133.1, 126.9, 118.4, 112.9, 110.1, 94.3, 60.3, 57.6, 55.4, 55.3, 53.8, 53.0, 44.9. ESI-HRMS (m/z): calcd for C22H28N2O6+[M+H]+, 417.2023; found, 417.2025.
A 25 mL Schlenk tube was charged with 1 (0.5 g, 1.35 mmol), phenylmethanamine (0.18 mL, 1.63 mmol) and MeOH (12 mL). The solution was heated to reflux for 12 h. 10 mL of water was added into the solution, and the mixture was extracted with ethyl acetate (20 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 63 as light yellow solid (0.15g, yield 23%); Mp 75-77° C.; [α]D20=+65.5 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.26-7.16 (m, 4H), 7.05 (d, J=6.6 Hz, 1H), 6.85 (d, J=1.4 Hz, 1H), 6.81-6.76 (m, 2H), 6.53 (s, 2H), 5.10 (d, J=5.6 Hz, 1H), 3.90 (s, 3H), 3.88-3.74 (m, 4H), 3.71 (s, 6H), 3.63 (d, J=13.2 Hz, 1H), 3.48 (d, J=13.2 Hz, 1H), 2.79 (dd, J=12.3, 6.3 Hz, 1H), 2.60 (dd, J=12.3, 9.2 Hz, 1H). 13C NMR (150 MHz, CDCl3): δ 165.7, 152.9, 146.1, 145.4, 138.8, 133.8, 133.0, 127.7, 127.3, 126.6, 126.3, 118.0, 112.4, 110.2, 94.3, 60.3, 56.9, 55.5, 55.3, 54.1, 53.2, 44.0. ESI-MS (m/z): 479.3 (M+H+). ESI-HRMS (m/z): calcd for C27H30N2O6+[M+H]+, 479.2177; found, 479.2175.
A 50 mL round-bottom flask was charged with 72 (23 mg, 0.049 mmol), succinic anhydride (6 mg, 0.059 mmol), DIPEA (15 mL, 0.09 mmol), DMAP (1 mg) and dichloromethane (1 mL). After stirred for 6 h at room temperature, 10 mL of water was added into the solution, and the mixture was extracted with dichloromethane (30 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was dissolved in 1 mL of EtOH. 10% Pd/C (3 mg) was added into the mixture. The solution was stirred for 12 h under H2 atmosphere (1 atm). Pd/C was filtrated, then the solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 64 as white solid (10 mg, yield 45%); Mp 96-98° C.; [α]D20=−10.5 (c1.0, CHCl3). 41 NMR (400 MHz, CDCl3): δ 6.89-6.80 (m, 3H), 6.58 (s, 2H), 5.95 (d, J=4.8 Hz, 1H), 5.25 (d, J=4.8 Hz, 1H), 3.88 (s, 3H), 3.77 (s, 3H), 3.73 (s, 6H), 2.54-2.44 (m, 1H), 2.42-2.35 (m, 2H), 2.29-2.16 (m, 1H). 13C NMR (150 MHz, CDCl3): δ 175.4, 169.9, 161.0, 153.0, 146.5, 145.1, 134.6, 132.3, 124.4, 119.2, 113.4, 110.0, 94.8, 75.6, 60.7, 60.3, 55.5, 55.4, 27.7. ESI-MS (m/z): 476.1 (M+H+). ESI-HRMS (m/z): calcd for C23H25NO10+[M+H]+, 476.1551; found, 476.1561.
A 50 mL round-bottom flask was charged with 72 (15 mg, 0.032 mmol), ethyl 2-bromoacetate (6 μL, 0.05 mmol), NaH (2 mg, 0.05 mmol, 60% in mineral oil), and THF (1 mL). After stirred for 1 h at 0° C., 10 mL of water was added into the solution, and the mixture was extracted with ethyl acetate (30 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was dissolved in 1 mL of EtOH. 10% Pd/C (2 mg) was added into the mixture. The solution was stirred for 24 h under H2 atmosphere (1 atm). Pd/C was filtrated, then the solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 64 as white solid (7 mg, yield 47%); Mp 142-145° C.; [α]D20=+41.6 (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.01 (d, J=1.8 Hz, 1H), 6.93 (dd, J=8.2, 1.8 Hz, 1H), 6.85 (d, J=8.2 Hz, 1H), 6.57 (s, 2H), 5.67 (s, 1H), 5.11 (dd, J=11.4, 5.0 Hz, 2H), 4.14 (d, J=16.5 Hz, 1H), 4.03 (d, J=16.5 Hz, 1H), 3.89 (s, 3H), 3.76 (s, 3H), 3.72 (s, 6H), 1.25 (t, J=7.1 Hz, 6H); 13C NMR (150 MHz, CDCl3) δ 168.6, 163.1, 152.9, 146.3, 145.1, 134.2, 132.5, 125.4, 119.4, 113.7, 109.9, 94.7, 82.0, 66.5, 60.9, 60.4, 60.3, 55.5, 55.3, 29.1, 13.5.
A 5 mL microwave reaction tube was charged with 73 (50 mg, 0.092 mmol), TBAB (59 mg, 0.18 mmol) and DMF (1 mL). The solution was heated to 170° C. with the microwave reaction machine for 3 h. After cooled to room temperature, 10 mL of water was added into the solution, and the mixture was extracted with ethyl acetate (20 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was dissolved in 1 mL of EtOH. 10% Pd/C (3 mg) was added into the mixture. The solution was stirred for 12 h under H2 atmosphere (1 atm). Pd/C was filtrated, then the solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 66 as white solid (10 mg, yield 53%) and 67 as white solid (5 mg, yield 32%).
66: Mp 43-44° C.; [α]D20=−10.7 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ 6.93 (d, J=1.8 Hz, 1H), 6.90 (dd, J=8.2, 1.8 Hz, 1H), 6.86 (d, J=8.2 Hz, 1H), 6.54 (s, 2H), 5.73 (s, 1H), 4.87 (d, J=1.8 Hz, 1H), 4.59 (d, J=1.8 Hz, 1H), 3.91 (s, 3H), 3.76 (s, 3H), 3.72 (s, 6H). 13C NMR (150 MHz, CDCl3): δ 160.7, 153.6, 147.5, 146.5, 135.3, 133.0, 128.1, 118.2, 112.1, 111.1, 95.4, 77.2, 77.0, 76.8, 66.1, 63.2, 60.9, 56.1, 56.1. ESI-MS (m/z): 437.1 (M+H+). ESI-HRMS (m/z): calcd for C19H20BrNO6+H+ [M+H]+, 438.0552; found, 437.0560.
67: Mp 45-46° C.; [α]D20=+49.8 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ 6.96 (d, J=2.1 Hz, 1H), 6.89 (dd, J=8.3, 2.1 Hz, 1H), 6.84 (d, J=8.3 Hz, 1H), 6.55 (s, 2H), 5.67 (s, 1H), 4.87 (dd, J=5.5, 2.6 Hz, 1H), 3.89 (s, 3H), 3.76 (s, 3H), 3.72 (s, 6H), 3.51 (dd, J=15.2, 5.5 Hz, 1H), 2.93 (dd, J=15.2, 2.6 Hz, 1H). 13C NMR (150 MHz, CDCl3): δ 163.9, 152.9, 146.1, 145.7, 133.8, 133.5, 130.7, 117.1, 111.4, 110.3, 94.0, 60.3, 55.43, 55.39, 53.5, 46.4. ESI-MS (m/z): 360.1 (M+H+). ESI-HRMS (m/z): calcd for C19H21NO6+[M+H]+, 360.1442; found, 360.1442.
A 50 mL Schlenk tube was charged with 1 (11 mg, 0.030 mmol) bis(pinacolato)diboron (10 mg, 0.039 mmol), PPh3 (1 mg, 0.038 mmol), t-BuOLi (0.3 mg, 0.037 mmol), CuCl (0.3 mg, 0.03 mmol), MeOH (16 μL, 0.4 mmol) and anhydrous THF (1 mL) were added in. The mixture was stirred under nitrogen atmosphere for 12 h at room temperature. Water (10 mL) was added into the solution, and the mixture was extracted with ethyl acetate (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was dissolved in THF/H2O (1 mL/1 mL). Then NaBO3.4H2O (23 mg, 0.15 mmol) was added into the mixture and the resulting solution was stirred for 12 h at room temperature. Water (10 mL) was added into the solution, and the mixture was extracted with ethyl acetate (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 68 as white solid (7 mg, 61%) and 69 as white solid (4.5 mg, 39%).
68: [α]D20=+101.2 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ 6.94-6.77 (m, 3H), 6.55 (s, 2H), 5.75 (s, 1H), 5.16 (d, J=5.2 Hz, 1H), 3.90 (s, 3H), 3.87-3.61 (m, 12H). 13C NMR (150 MHz, CDCl3): δ 165.2, 153.6, 146.7, 146.1, 134.7, 133.6, 127.1, 118.5, 112.9, 110.9, 95.1, 77.2, 77.0, 76.8, 61.0, 58.2, 57.3, 56.7, 56.2, 56.0. ESI-MS (m/z): 390.1 (M+H+). ESI-HRMS (m/z): calcd for C20H23NO7+H+ [M+H]+, 390.1547; found, 390.1546.
69: [α]D20=+15.7 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ 6.97 (d, J=1.5 Hz, 1H), 6.91 (dd, J=8.3, 1.5 Hz, 1H), 6.84 (d, J=8.3 Hz, 1H), 6.56 (s, 2H), 5.70 (s, 1H), 4.91 (d, J=1.8 Hz, 1H), 4.15 (dd, J=11.9, 4.5 Hz, 1H), 4.00 (dd, J=11.9, 3.3 Hz, 1H), 3.90 (s, 3H), 3.76 (s, 3H), 3.73 (br s, 7H), 3.28 (d, J=2.3 Hz, 1H). 13C NMR (150 MHz, CDCl3): δ 165.2, 153.6, 146.7, 146.1, 134.7, 133.6, 127.1, 118.5, 112.9, 110.9, 95.1, 77.2, 77.0, 76.8, 61.0, 58.2, 57.3, 56.7, 56.2, 56.0. ESI-MS (m/z): 390.1 (M+Hf). ESI-HRMS (m/z): calcd for C20H23NO7+H+ [M+H]+, 390.1547; found, 390.1546.
A 50 mL round-bottom flask was charged with 1 (15 mg, 0.04 mmol), 10% Pd/C (3 mg) and methanol (1 mL). The solution was stirred for 12 h under H2 atmosphere (1 atm). Pd/C was filtrated, then the solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 70 as white solid (15 mg, yield 99%); Mp 64-66° C.; [α]D20=+138.9 (c 1.0, CHCl3). 1HNMR (400 MHz, CDCl3): δ 6.87-6.78 (m, 2H), 6.72 (d, J=8.2 Hz, 1H), 6.56 (s, 2H), 5.71 (br s, 1H), 5.06 (d, J=5.8 Hz, 1H), 3.89 (s, 3H), 3.77 (s, 3H), 3.72 (s, 6H), 3.67-3.58 (m, 1H), 0.91 (d, J=7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 168.7, 153.7, 146.6, 146.0, 134.5, 134.2, 128.1, 118.9, 113.4, 110.8, 95.1, 61.2, 58.6, 56.3, 56.2 49.5, 29.9, 9.8. ESI-MS (m/z): 374.1 (M+H+). ESI-HRMS (m/z): calcd for C20H23NO6+H+ [M+H]+, 374.1589; found, 374.1597.
A 50 mL round-bottom flask was charged with 84 (0.2 g, 0.41 mmol), sodium periodate (0.13 g, 0.62 mmol), MeOH (4 mL) and H2O (1 mL). After stirred for 3 h at room temperature, 10 mL of water was added into the solution, and the mixture was extracted with ethyl acetate (30 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 71 as yellow solid (0.15 g, yield 79%); 1H NMR (400 MHz, CDCl3) δ 7.17 (dd, J=8.5, 2.2 Hz, 1H), 7.04 (d, J=2.2 Hz, 1H), 6.99 (d, J=8.5 Hz, 1H), 6.74 (s, 2H), 5.49 (s, 1H), 3.83 (s, 3H), 3.81 (s, 3H), 3.76 (s, 6H), 2.30 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 209.3, 191.1, 168.8, 160.6, 153.9, 152.4, 140.6, 136.6, 132.6, 125.1, 124.3, 121.7, 113.4, 96.1, 74.7, 61.3, 56.4, 56.3, 20.9. ESI-MS (m/z): 414.1 (M−H+).
A 50 mL round-bottom flask was charged with 71 (0.18 g, 0.39 mmol), sodium borohydride (18 mg, 0.47 mmol) and MeOH (4 mL). After stirred for 1 h at 0° C., 10 mL of water was added into the solution, and the mixture was extracted with ethyl acetate (30 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 72 as white solid (0.35 g, yield 90%); Mp 149-150° C.; [α]D20=+61.8 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.39-7.22 (m, 5H), 6.94-6.88 (m, 2H), 6.82 (s, 1H), 6.52 (s, 2H), 5.14 (s, 2H), 5.12 (d, J=5.5 Hz, 1H), 5.08 (dd, J=8.8, 5.5 Hz, 1H), 3.90 (s, 3H), 3.78 (s, 3H), 3.69 (s, 6H), 2.15 (d, J=8.8 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 166.5, 152.8, 149.5, 147.4, 135.9, 134.3, 132.3, 127.9, 127.4, 126.6, 124.3, 119.1, 112.0, 111.3, 95.0, 85.7, 70.4, 66.9, 61.6, 60.3, 55.42, 55.36. ESI-MS (m/z): 466.1 (M+H+). ESI-HRMS (m/z): calcd for C26H27NO7+[M+H]+, 466.1860; found, 466.1862.
A 50 mL round-bottom flask was charged with 72 (0.2 g, 0.43 mmol), triethylamine (0.09 mL, 0.64 mmol), methanesulfonyl chloride (0.05 mL, 0.64 mmol) and dichloromethane (4 mL). After stirred for 1 h at room temperature, 10 mL of water was added into the solution, and the mixture was extracted with dichloromethane (30 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 73 as white solid (0.2 g, yield 86%); Mp 76-77° C.; [α]D20=+95.3 (c 2.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.36 (d, J=7.7 Hz, 2H), 7.33-7.20 (m, 3H), 6.99-6.84 (m, 3H), 6.47 (s, 2H), 5.76 (d, J=5.0 Hz, 1H), 5.21 (d, J=5.0 Hz, 1H), 5.13 (s, 2H), 3.88 (s, 3H), 3.77 (s, 3H), 3.67 (s, 6H), 2.66 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 160.3, 153.7, 150.8, 148.3, 136.8, 135.5, 132.6, 128.8, 128.2, 127.5, 123.8, 121.5, 113.7, 111.9, 95.4, 79.4, 71.2, 61.7, 61.2, 56.3, 6.2, 38.9. ESI-MS (m/z): 544.1 (M+H+). ESI-HRMS (m/z): calcd for C27H29NO9S+[M+H]+, 544.1636; found, 544.1640.
A 50 mL round-bottom flask was charged with 73 (11 mg, 0.02 mmol), 10% Pd/C (3 mg) and methanol (1 mL). The solution was stirred for 12 h under H2 atmosphere (1 atm). Pd/C was filtrated, then the solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 74 as white solid (9 mg, yield 98%); Mp 188-191° C.; [α]D20=+60.9 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) δ 6.94 (d, J=1.2 Hz, 1H), 6.93-6.84 (m, 2H), 6.56 (s, 2H), 5.80 (d, J=5.1 Hz, 1H), 5.70 (s, 1H), 5.28 (d, J=5.1 Hz, 1H), 3.90 (s, 3H), 3.77 (s, 3H), 3.73 (s, 6H), 2.91 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 159.5, 153.0, 146.8, 145.4, 134.8, 131.8, 123.8, 119.5, 113.3, 110.1, 94.8, 78.6, 76.6, 76.4, 76.2, 60.7, 60.3, 55.5, 55.3, 38.4.
A 50 mL round-bottom flask was charged with 73 (0.5 g, 0.92 mmol), sodium azide (90 mg, 1.38 mmol) and DMF (10 mL). After stirred for 48 h at 100° C., 20 mL of water was added into the solution, and the mixture was extracted with ethyl acetate (30 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered.
The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 75 as yellow oil (0.24 g, yield 53%); [α]D20=−50.4 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.38-7.23 (m, 5H), 6.94-6.88 (m, 2H), 6.80 (br s, 1H), 6.43 (s, 2H), 5.12 (s, 2H), 4.67 (d, J=1.4 Hz, 1H), 4.39 (d, J=1.4 Hz, 1H), 3.89 (s, 3H), 3.76 (s, 3H), 3.65 (s, 6H). 13C NMR (150 MHz, CDCl3): δ 160.7, 152.9, 150.0, 148.1, 135.8, 134.5, 132.2, 127.9, 127.4, 126.8, 126.6, 118.8, 111.5, 111.0, 94.5, 71.7, 70.5, 62.5, 60.3, 55.5, 55.4. ESI-MS (m/z): 491.1 (M+H+). ESI-HRMS (m/z): calcd for C26H26N4O6+[M+H]+, 491.1925; found, 491.1924.
A 50 mL round-bottom flask was charged with 75 (0.23 g, 0.47 mmol), stannous chloride (0.28 g, 1.4 mmol), 9% hydrochloric acid (2 mL) and methanol (8 mL). After stirred for 1 h at 60° C., 10 mL of saturated aqueous solution of sodium bicarbonate was added into the solution, and the mixture was extracted with ethyl acetate (30 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 76 as white solid (0.14 g, yield 64%); Mp 64-65° C.; [α]D20=+7.9 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.39-7.21 (m, 5H), 6.97-6.82 (m, 3H), 6.47 (s, 2H), 5.12 (s, 2H), 4.50 (s, 1H), 3.98 (s, 1H), 3.89 (s, 3H), 3.77 (s, 3H), 3.66 (s, 6H). 13C NMR (150 MHz, CDCl3): δ 167.9, 153.5, 150.1, 148.6, 136.6, 134.6, 133.6, 129.2, 128.5, 128.0, 127.3, 119.2, 112.1, 111.6, 95.0, 71.1, 69.7, 66.8, 60.9, 56.1, 56.0. ESI-MS (m/z): 465.1 (M+H+). ESI-HRMS (m/z): calcd for C26H28N2O6+[M+H]+, 465.2020; found, 465.2035.
A 50 mL round-bottom flask was charged with 76 (29 mg, 0.062 mmol), DIPEA (16 μL, 0.093 mmol), acetic anhydride (8 μL, 0.08 mmol) and dichloromethane (2 mL). After stirred for 1 h at room temperature, 10 mL of saturated aqueous solution of sodium bicarbonate was added into the solution, and the mixture was extracted with dichloromethane (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was dissolved in 1 mL of EtOH. 10% Pd/C (2 mg) was added into the mixture. The solution was stirred for 24 h under H2 atmosphere (1 atm). Pd/C was filtrated, then the solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 77 as white solid (15 mg, yield 58%); Mp 105-107° C.; [α]D20=+19.7 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ 6.93-6.78 (m, 3H), 6.52-6.49 (m, 3H), 5.75 (br s, 1H), 4.83 (br s, 1H), 4.62 (d, J=7.0 Hz, 1H), 3.88 (s, 3H), 3.75 (s, 3H), 3.69 (s, 7H), 2.05 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 169.8, 163.4, 152.8, 146.4, 145.7, 134.1, 132.8, 128.7, 117.6, 111.5, 110.4, 94.6, 65.3, 62.7, 60.3, 55.4, 28.6, 22.2. ESI-MS (m/z): 417.1 (M+H+). ESI-HRMS (m/z): calcd for C21H24N2O7+[M+H]+, 417.1656; found, 417.1656.
A 50 mL round-bottom flask was charged with 76 (32 mg, 0.069 mmol), DIPEA (19 μL, 0.11 mmol), benzoic anhydride (23 mg, 0.1 mmol) and dichloromethane (5 mL). After stirred for 4 h at room temperature, 10 mL of saturated aqueous solution of sodium bicarbonate was added into the solution, and the mixture was extracted with dichloromethane (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was dissolved in 1 mL of EtOH. 10% Pd/C (2 mg) was added into the mixture. The solution was stirred for 24 h under H2 atmosphere (1 atm). Pd/C was filtrated, then the solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 78 as white solid (26 mg, yield 80%); Mp 102-103° C.; [α]D20=−30.0 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.84 (d, J=7.4 Hz, 2H), 7.47-7.41 (m, 3H), 6.97-6.77 (m, 3H), 5.74 (d, J=3.9 Hz, 1H), 4.95 (d, J=1.9 Hz, 1H), 4.82 (dd, J=6.8, 1.9 Hz, 1H), 3.88 (s, 3H), 3.74 (s, 3H), 3.68 (s, 6H). 13C NMR (150 MHz, CDCl3): δ 166.7, 163.4, 153.1, 152.8, 146.4, 145.7, 134.1, 132.8, 132.2, 131.6, 128.8, 128.2, 128.1, 126.6, 126.5, 117.7, 111.6, 110.5, 94.6, 65.7, 62.8, 60.3, 55.4, 55.3, 55.2. ESI-MS (m/z): 479.1 (M+H+). ESI-HRMS (m/z): calcd for C26H26N2O7+[M+H]+, 479.1813; found, 479.1813.
A 50 mL round-bottom flask was charged with 76 (12 mg, 0.026 mmol), DIPEA (5 μL, 0.031 mmol), methanesulfonyl chloride (2 μL, 0.028 mmol) and dichloromethane (1 mL). After stirred for 2 h at room temperature, 10 mL of saturated aqueous solution of sodium bicarbonate was added into the solution, and the mixture was extracted with dichloromethane (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was dissolved in 1 mL of EtOH. 10% Pd/C (2 mg) was added into the mixture. The solution was stirred for 24 h under H2 atmosphere (1 atm). Pd/C was filtrated, then the solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 78 as white solid (15 mg, yield 99%); Mp 87-88° C.; [α]D20=−10.7 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ 6.86-6.83 (m, 3H), 6.36 (s, 2H), 6.03 (d, J=9.2 Hz, 1H), 5.72 (s, 1H), 4.68 (d, J=2.0 Hz, 1H), 4.44 (dd, J=9.2, 2.0 Hz, 1H), 3.89 (s, 3H), 3.76 (s, 3H), 3.68 (s, 6H), 3.14 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 162.3, 152.8, 152.8, 146.6, 145.8, 133.8, 132.4, 127.8, 117.6, 111.3, 110.5, 94.6, 94.5, 67.1, 63.8, 60.4, 55.4, 41.7, 28.6. ESI-MS (m/z): 453.1 (M+H+). ESI-HRMS (m/z): calcd for C20H24N2O8S+H+ [M+H]+, 453.1326; found, 453.1327.
A 50 mL round-bottom flask was charged with 47 (0.93 g, 2 mmol), potassium osmate (10 mg, 0.03 mmol), NMO (0.62 mL, 3 mmol, 50% a.q.), acetone (5 mL) and H2O (0.2 mL). After stirred for 8 h at room temperature, 10 mL of water was added into the solution, and the mixture was extracted with ethyl acetate (30 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 84 as white solid (0.91 g, yield 92%); Mp 123-124° C.; [α]D20=+61.8 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.34-7.21 (m, 5H), 6.90-6.77 (m, 2H), 6.72 (s, 1H), 6.43 (s, 2H), 5.10 (s, 2H), 4.94 (s, 1H), 4.53 (br d, J=30.9 Hz, 1H), 3.88 (s, 3H), 3.77 (s, 3H), 3.63 (s, 6H), 3.53 (dd, J=12.3, 4.3 Hz, 1H), 3.27 (dd, J=12.3, 5.5 Hz, 1H). 13C NMR (150 MHz, CDCl3): δ 166.5, 152.8, 149.5, 147.4, 135.9, 134.3, 132.3, 127.9, 127.4, 126.6, 124.3, 119.1, 112.0, 111.3, 95.0, 85.7, 70.4, 66.9, 61.6, 60.3, 55.4, 55.4. ESI-MS (m/z): 496.1 (M+H+). ESI-HRMS (m/z): calcd for C27H29NO8+H+ [M+H]+, 496.1966; found, 496.1978.
A 50 mL round-bottom flask was charged with 84 (11 mg, 0.022 mmol), 10% Pd/C (3 mg) and methanol (1 mL). The solution was stirred for 12 h under H2 atmosphere (1 atm). Pd/C was filtrated, then the solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 80 as white solid (8 mg, yield 89%); Mp 96-97° C.; [α]D20=+79.7 (c2.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ 6.84-6.82 (m, 2H), 6.76 (br d, J=8.1 Hz, 1H), 6.52 (s, 2H), 5.80 (s, 1H), 5.01 (s, 1H), 4.53 (br s, 1H), 3.89 (s, 3H), 3.82-3.62 (m, 10H), 3.45 (d, J=12.3 Hz, 1H), 2.49 (br s, 1H). 13C NMR (150 MHz, CDCl3): δ 166.6, 152.9, 146.2, 145.4, 134.3, 132.3, 125.2, 117.8, 112.1, 110.3, 95.1, 85.7, 76.6, 76.4, 76.2, 66.8, 61.6, 60.3, 55.5, 55.3. ESI-MS (m/z): 406.1 (M+H+). ESI-HRMS (m/z): calcd for C20H23NO8+[M+H]+, 406.1496; found, 406.1505.
A 50 mL round-bottom flask was charged with 84 (15 mg, 0.03 mmol), dimethylsulfate (15 μL, 0.15 mmol), NaH (3 mg, 0.075 mmol, 60% in mineral oil) and THF (1 mL). After stirred for 1 h at room temperature, 10 mL of water was added into the solution, and the mixture was extracted with ethyl acetate (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was dissolved in 1 mL of EtOH. 10% Pd/C (3 mg) was added into the mixture. The solution was stirred for 24 h under H2 atmosphere (1 atm). Pd/C was filtrated, then the solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 81 as white solid (11 mg, yield 84%); Mp 58-59° C.; [α]D20=+71.0 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ 6.85 (d, J=1.4 Hz, 1H), 6.82 (d, J=8.3 Hz, 1H), 6.77 (dd, J=8.3, 1.4 Hz, 1H), 6.58 (s, 2H), 5.06 (s, 1H), 3.89 (s, 3H), 3.78 (s, 3H), 3.72 (s, 6H), 3.63 (s, 3H), 3.51 (d, J=11.0 Hz, 1H), 3.37 (d, J=11.0 Hz, 1H), 3.03 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 163.7, 152.9, 145.9, 145.0, 134.3, 132.3, 125.7, 118.4, 112.6, 109.8, 95.1, 91.8, 76.6, 76.4, 76.2, 68.8, 63.1, 60.3, 58.7, 55.5, 55.3, 53.1. ESI-MS (m/z): 434.1 (M+H+). ESI-HRMS (m/z): calcd for C22H27NO8+[M+H]+, 434.1809; found, 434.1808.
A 50 mL round-bottom flask was charged with 46 (96 mg, 0.22 mmol), potassium osmate (3 mg, 0.01 mmol), NMO (0.1 mL, 0.48 mmol, 50% a.q.), acetone (5 mL) and H2O (0.2 mL). After stirred for 8 h at room temperature, 10 mL of water was added into the solution, and the mixture was extracted with ethyl acetate (30 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 82 as white solid (93 mg, yield 95%); 1H NMR (400 MHz, CDCl3) δ 7.10 (d, J=8.2 Hz, 1H), 6.98 (s, 1H), 6.95 (d, J=8.2 Hz, 1H), 6.52 (s, 2H), 5.04 (s, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 3.71-3.69 (m, 7H), 3.46 (d, J=12.2 Hz, 1H), 2.28 (s, 3H). ESI-LRMS m/z (%): 470.1 [M+Na]+.
A 50 mL round-bottom flask was charged with 82 (6.5 mg, 0.015 mmol), DMAP (0.5 mg), acetic anhydride (3.5 μL, 0.03 mmol), triethylamine (5 μL, 0.03 mmol) and dichloromethane (5 mL). After stirred for 0.5 h at room temperature, 10 mL of saturated aqueous solution of sodium bicarbonate was added into the solution, and the mixture was extracted with dichloromethane (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 83 as white solid (6 mg, yield 85%); Mp 75-76° C.; [α]D20=+99.3 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.24 (d, J=8.6 Hz, 1H), 7.13 (s, 1H), 6.95 (d, J=8.6 Hz, 1H), 6.54 (s, 2H), 5.29 (s, 1H), 4.31 (d, J=12.7 Hz, 1H), 4.24 (d, J=12.7 Hz, 1H), 3.83 (s, 3H), 3.78 (s, 3H), 3.71 (s, 6H), 2.28 (s, 3H), 2.21 (s, 3H), 1.99 (s, 3H); ESI-LRMS m/z (%): 532.1 [M+H]+.
The synthesis of compound 85 was similar to compound 1:
82.1 The Synthesis of 3-((tert-butyldimethylsilyl)oxy)benzaldehyde (85b)
A 500 mL round-bottom flask was charged with 3-hydroxybenzaldehyde (85a) (16 g, 0.13 mol), DMAP (320 mg, 2.6 mmol), Et3N (23 mL, 0.182 mol) and anhydrous dichloromethane (150 mmol). The solution was cooled to 0° C. with an ice bath, and TBSCl (20 g, 0.156 mol, dissolved in 50 mL of dichloromethane) was dropped into the flask. The solution was then warmed to room temperature and stirred for 2 h. 50 mL of saturated aqueous solution of sodium bicarbonate was added into the solution, and the mixture was extracted with dichloromethane. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 85b as colorless oil (30 g, yield 97%). 1H NMR (400 MHz, CDCl3) δ 9.95 (s, 1H), 7.47 (d, J=7.6 Hz, 1H), 7.40 (t, J=7.6 Hz, 1H), 7.32 (s, 1H), 7.12-7.08 (m, 1H), 0.99 (s, 9H), 0.22 (s, 6H); ESI-LRMS m/z (%): 237.1 [M+H]+.
A 250 mL round-bottom flask was charged with 85b (30 g, 0.114 mol), ethyl acrylate (13.7 g, 0.136 mol) and DABCO (15.3 g, 0.136 mol). The solution was stirred at room temperature for 20 days. The mixture was directly purified by flash column chromatography to give 85c as colorless oil (17 g, yield 27%). 1H NMR (400 MHz, CDCl3) δ 7.11 (t, J=7.8 Hz, 1H), 6.89 (d, J=7.6 Hz, 1H), 6.81 (s, 1H), 6.69 (dd, J=7.8, 2.0 Hz, 1H), 6.24 (s, 1H), 6.24 (s, 1H), 5.79 (s, 1H), 5.42 (d, J=5.2 Hz, 1H), 4.05 (q, J=7.1 Hz, 2H), 3.76 (d, J=5.2 Hz, 1H), 1.14 (t, J=7.1 Hz, 3H), 0.95 (s, 9H), 0.15 (s, 6H); ESI-LRMS m/z (%): 337.2 [M+H]+.
A 250 mL round-bottom flask was charged with compound 85c (16.6 g, 0.049 mol), triethylamine (9.9 g, 0.098 mmol), DMAP (600 mg, 0.0049 mol) and dichloromethane (100 mL). The solution was cooled to 0° C. by an ice bath, then acetic anhydride (10 g, 0.098 mmol) was added dropwise into the flask within 10 min. After stirred for 10 min, 50 mL of saturated aqueous solution of sodium bicarbonate was added into the solution, and the mixture was extracted with dichloromethane. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 85d as colorless oil (8.9 g, yield 47%). 1H NMR (400 MHz, CDCl3) δ 7.17 (t, J=7.9 Hz, 1H), 6.95 (d, J=7.6 Hz, 1H), 6.83 (s, 1H), 6.78-6.73 (m, 1H), 6.62 (s, 1H), 6.37 (s, 1H), 5.77 (s, 1H), 4.14 (q, J=7.1 Hz, 2H), 2.07 (s, 3H), 1.20 (t, J=7.1 Hz, 3H), 0.96 (s, 9H), 0.17 (s, 6H); 13C NMR (150 MHz, CDCl3) δ 182.1, 177.8, 168.5, 152.9, 152.2, 142.3, 142.2, 138.4, 133.4, 132.8, 132.2, 85.7, 73.7, 38.5, 33.9, 33.8, 31.1, 26.9, 8.4; ESI-LRMS m/z (%): 401.2 [M+Na]+; ESI-HRMS m/z (%): Calcd for C20H34NO5Si [M+H]+ 396.2201, found 396.2201.
A 50 mL Schlenk flask was charged with 10 mL of dichloromethane and the solvent was deoxygenized with nitrogen bubbling for 15 min. Tris(dibenzylideneacetone)dipalladium (22 mg, 0.023 mmol) and R1 (44 mg, 0.060 mmol) was added into the flask. The resulted purple solution was stirred under nitrogen atmosphere for 10 min at room temperature. Then 3,4,5-trimethoxyaniline (653 mg, 3.57 mmol), K2CO3 (1.0 M aq. solution, 7.14 mL, 7.14 mmol) and compound 85d (900 mg, 2.38 mmol, dissolved in 10 mL of oxygen free dichloromethane) were added under a steam of nitrogen. The solution was stirred for 8 h at room temperature. Water (20 mL) was added into the solution, and the mixture was extracted with dichloromethane. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 85e as yellow oil (1.12 g, yield 94%). [α]D20=+27.0 (c 0.16, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.19 (t, J=7.9 Hz, 1H), 6.96 (d, J=7.7 Hz, 1H), 6.83 (t, J=2.0 Hz, 1H), 6.75 (dd, J=7.7, 2.0 Hz, 1H), 6.37 (s, 1H), 5.91 (s, 1H), 5.82 (s, 2H), 5.33 (s, 1H), 4.21-4.12 (m, 2H), 3.76 (s, 6H), 3.75 (s, 3H), 1.23 (t, J=7.1 Hz, 3H), 0.95 (d, J=4.9 Hz, 9H), 0.15 (s, 6H); 13C NMR (150 MHz, CDCl3) δ 166.2, 156.0, 153.8, 143.5, 142.1, 140.8, 130.5, 129.7, 126.0, 120.4, 119.4, 119.2, 91.4, 61.1, 60.9, 59.2, 55.9, 25.7, 18.2, 14.1, −4.4; ESI-LRMS m/z (%): 502.2 [M+H]+; ESI-HRMS m/z (%): Calcd for C27H40NO6Si [M+H]+ 502.2620, found 502.2619.
The corresponding racemate can be obtained by replacing R1 with triphenylphosphine (0.005eq).
To a 100 mL Schlenk flask equipped with a cold finger was added 85e (1.1 g, 2.2 mmol), Sn[N(TMS)2]2 (1.5 g, 3.3 mmol) and anhydrous toluene (10 mL). The mixture was heated to reflux for 6 h under nitrogen atmosphere. The solution was cooled and directly purified by flash chromatography to give 85f as colorless oil (753 mg, yield 40%); [α]D20=+44.3 (c 0.24, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.27-7.20 (m, 1H), 6.99 (d, J=7.7 Hz, 1H), 6.83-6.78 (m, 2H), 6.57 (s, 2H), 5.81 (t, J=1.7 Hz, 1H), 5.30 (s, 1H), 5.16-5.15 (m, 1H), 3.75 (s, 3H), 3.71 (s, 6H), 0.91 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 160.7, 156.4, 153.6, 149.6, 138.0, 134.8, 133.7, 130.1, 120.7, 119.8, 118.2, 110.7, 95.0, 63.7, 60.9, 56.0, 25.6, 18.2, −4.4, −4.5; ESI-LRMS m/z (%): 456.1 [M+H]+; ESI-HRMS m/z (%): Calcd for C25H34NO5Si [M+H]+ 456.2201, found 456.2201.
A 100 mL round-bottom flask was charged with compound 85f (753 mg) and THF (5 mL). The solution was cooled to 0° C. by an ice bath, then TBAF (863 mg, 3.3 mmol, dissolved in 10 mL THF) was dropped into the flask. After stirred for 15 min at 0° C., 30 mL of water was added into the solution. The mixture was extracted with ethyl acetate (20 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 85 as yellow solid (489 mg, yield 86%); Mp 150-151° C.; [α]D20=+101.5 (c 0.13, CHCl3), 98% ee [determined by HPLC analysis using a Chiralcel AD-H column; n-Hex/i-PrOH=80:20, 1.0 mL/min, 254 nm; tR (minor)=12.09 min; tR (major)=8.43 min]; 1H NMR (400 MHz, CDCl3) δ 7.59 (s, 1H), 7.22-7.21 (m, 1H), 6.94 (d, J=7.6 Hz, 1H), 6.88-6.86 (m, 2H), 6.56 (s, 2H), 5.73 ((t, J=1.7 Hz, 1H), 5.31 (s, 1H), 5.14 (dd, J=1.7, 1.2 Hz, 1H), 3.74 (s, 3H), 3.66 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 161.4, 157.4, 153.5, 148.7, 137.7, 133.5, 130.3, 119.1, 116.6, 113.0, 111.5, 95.1, 64.1, 60.9, 56.0; ESI-LRMS m/z (%): 342.1 [M+H]+; ESI-HRMS m/z (%): Calcd for C19H20NO5 [M+H]+ 342.1336, found 342.1337.
A 50 mL round-bottom flask was charged with 85 (20 mg, 0.059 mmol), dimethylsulfate (9.6 mg, 0.077 mmol), K2CO3 (9.7 mg, 0.071 mmol) and acetone (3 mL). After stirred for 0.5 h at 60° C., 10 mL of water was added into the solution, and the mixture was extracted with ethyl acetate (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 86 as white solid (20 mg, yield 96%); Mp 122-123° C.; [α]D20=+64.3 (c 0.29, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.30 (t, J=7.7 Hz, 1H), 6.99 (d, J=7.7 Hz, 1H), 6.89 (m, 2H), 6.59 (s, 2H), 5.83 (s, 1H), 5.33 (s, 1H), 5.17 (s, 1H), 3.78 (s, 3H), 3.76 (s, 3H), 3.73 (s, 6H); 13C NMR (150 MHz, CDCl3) δ 160.2, 159.6, 152.9, 148.8, 137.5, 134.1, 133.2, 129.6, 118.6, 113.6, 111.6, 110.3, 94.2, 63.3, 60.3, 55.4, 54.7; ESI-LRMS m/z (%): 356.0 [M+H]+; ESI-HRMS m/z (%): Calcd for C20H22NO5 [M+H]+ 356.1492, found 356.1494.
The synthesis of compound 84 was similar to compound 1:
A 50 mL round-bottom flask was charged with 4-methylbenzaldehyde (84a) (5 g, 0.042 mol), ethyl acrylate (4.17 g, 0.042 mol) and DABCO (4.67 g, 0.042 mol). The solution was stirred at room temperature for 12 days. The mixture was directly purified by flash column chromatography to give 84b as colorless oil (6.7 g, yield 73%). 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J=8.0 Hz, 2H), 7.15 (d, J=8.0 Hz, 2H), 6.32 (s, 1H), 5.83 (s, 1H), 5.52 (d, J=5.4 Hz, 1H), 4.16 (q, J=7.1 Hz, 2H), 3.07 (d, J=5.4 Hz, 1H), 2.33 (s, 3H), 1.24 (t, J=7.1 Hz, 3H); ESI-LRMS m/z (%): 221.1 [M+H]+.
A 50 mL round-bottom flask was charged with compound 84b (2 g, 8.93 mmol), triethylamine (1.8 g, 17.86 mmol), DMAP (108 mg, 0.893 mmol) and dichloromethane (15 mL). The solution was cooled to 0° C. by an ice bath, then acetic anhydride (1.8 g, 17.86 mmol) was added dropwise into the flask within 10 min. After stirred for 10 min, 3 mL of saturated aqueous solution of sodium bicarbonate was added into the solution, and the mixture was extracted with dichloromethane (20 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 84c as colorless oil (1.95 g, yield 83%). 1H NMR (400 MHz, CDCl3) δ 7.28 (d, J=7.9 Hz, 2H), 7.15 (d, J=7.9 Hz, 2H), 6.67 (s, 1H), 6.39 (s, 1H), 5.84 (s, 1H), 4.15 (q, J=6.6 Hz, 2H), 2.33 (s, 3H), 2.09 (s, 3H), 1.22 (t, J=7.1 Hz, 3H); ESI-LRMS m/z (%): 263.1 [M+H]+.
A 50 mL Schlenk flask was charged with 5 mL of dichloromethane and the solvent was deoxygenized with nitrogen bubbling for 15 min. Tris(dibenzylideneacetone)dipalladium (6 mg, 0.0064 mmol) and R1 (12 mg, 0.016 mmol) was added into the flask. The resulted purple solution was stirred under nitrogen atmosphere for 10 min at room temperature. Then 3,4,5-trimethoxyaniline (175 mg, 0.96 mmol), K2CO3 (1.0 M aq. solution, 2 mL, 2 mmol) and compound 84c (167 mg, 0.64 mmol, dissolved in 2 mL of oxygen free dichloromethane) were added under a steam of nitrogen. The solution was stirred for 4 h at room temperature. Water (20 mL) was added into the solution, and the mixture was extracted with dichloromethane (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 84d as yellow oil (127 mg, yield 52%). [α]D20=+88.9 (c 0.10, CHCl3); 1HNMR (400 MHz, CDCl3) δ 7.26 (d, J=7.9 Hz, 2H), 7.14 (d, J=7.9 Hz, 2H), 6.38 (s, 1H), 5.95 (s, 1H), 5.82 (s, 2H), 5.35 (s, 1H), 4.21-4.05 (m, 3H), 3.76 (s, 6H), 3.75 (s, 3H), 2.33 (s, 3H), 1.22 (t, J=7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 166.3, 153.8, 143.6, 140.8, 137.7, 137.5, 130.5, 129.4, 127.3, 125.7, 91.2, 61.1, 60.8, 59.1, 55.9, 21.1, 14.1; ESI-LRMS m/z (%): 386.2 [M+H]+; ESI-HRMS m/z (%): Calcd for C22H28NO5 [M+H]+ 386.1962, found 386.1964.
The corresponding racemate can be obtained by replacing 1e with triphenylphosphine (0.005eq).
To a 100 mL Schlenk flask equipped with a cold finger was added 84d (127 mg, 0.33 mmol), Sn[N(TMS)2]2 (218 mg, 0.50 mmol) and anhydrous toluene (5 mL). The mixture was heated to reflux for 6 h under nitrogen atmosphere. The solution was cooled and directly purified by flash chromatography to give 84 as white solid (101 mg, yield 89%); [α]D20=+87.5 (c 0.12, CHCl3), 97% ee [determined by HPLC analysis using a Chiralcel AD-H column; n-Hex/i-PrOH=85:15, 1.0 mL/min, 254 nm; tR (minor)=9.04 min; tR (major)=11.43 min]; 1H NMR (400 MHz, CDCl3) δ 7.29 (d, J=8.0 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H), 6.58 (s, 2H), 5.83 (t, J=1.7 Hz, 1H), 5.33 (s, 1H), 5.16-5.12 (m, 1H), 3.76 (s, 3H), 3.72 (s, 6H), 2.35 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 160.9, 153.5, 149.9, 138.9, 134.7, 133.8, 133.5, 129.8, 126.8, 110.7, 94.9, 63.9, 60.9, 56.1, 21.2; ESI-LRMS m/z (%): 340.1 [M+H]+; ESI-HRMS m/z (%): Calcd for C20H22NO4 [M+H]+ 340.1543, found 340.1550.
The synthesis of compound 88 was similar to compound 1:
A 50 mL round-bottom flask was charged with methyl 4-isopropylbenzaldehyde (88a) (2 g, 13.5 mmol), ethyl acrylate (1.35 g, 13.5 mmol) and DABCO (1.5 g, 13.5 mmol). The solution was stirred at room temperature for 13 days. The mixture was directly purified by flash column chromatography to give 88b as colorless oil (1.1 g, yield 47%); 1H NMR (400 MHz, CDCl3) δ 7.29 (d, J=8.2 Hz, 2H), 7.20 (d, J=8.2 Hz, 2H), 6.33 (s, 1H), 5.83 (t, J=1.1 Hz, 1H), 5.54 (s, 1H), 4.17 (q, J=7.1 Hz, 2H), 2.99 (s, 1H), 2.89 (dt, J=13.8, 6.9 Hz, 1H), 1.26-1.23 (m, 9H); ESI-LRMS m/z (%): 249.1 [M+H]+.
A 50 mL round-bottom flask was charged with compound 88b (1.1 g, 4.44 mmol), triethylamine (0.9 g, 8.88 mmol), DMAP (54 mg, 0.444 mmol) and dichloromethane (15 mL). The solution was cooled to 0° C. by an ice bath, then acetic anhydride (0.9 g, 8.88 mmol) was added dropwise into the flask within 10 min. After stirred for 10 min, 3 mL of saturated aqueous solution of sodium bicarbonate was added into the solution, and the mixture was extracted with dichloromethane (20 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 88c as colorless oil (0.95 g, yield 74%). 1H NMR (400 MHz, CDCl3) δ 7.28 (d, J=7.9 Hz, 2H), 7.15 (d, J=7.9 Hz, 2H), 6.67 (s, 1H), 6.39 (s, 1H), 5.84 (s, 1H), 4.25-4.00 (m, 2H), 2.33 (s, 3H), 2.09 (s, 3H), 1.22 (t, J=7.1 Hz, 3H); ESI-LRMS m/z (%): 291.1 [M+H]+.
A 50 mL Schlenk flask was charged with 5 mL of dichloromethane and the solvent was deoxygenized with nitrogen bubbling for 15 min. Tris(dibenzylideneacetone)dipalladium (4.7 mg, 0.0052 mmol) and R1 (9.3 mg, 0.0129 mmol) was added into the flask. The resulted purple solution was stirred under nitrogen atmosphere for 10 min at room temperature. Then 3,4,5-trimethoxyaniline (143 mg, 0.78 mmol), K2CO3 (1.0 M aq. solution, 1.5 mL, 1.5 mmol) and compound 88c (150 mg, 0.52 mmol, dissolved in 2 mL of oxygen free dichloromethane) were added under a steam of nitrogen. The solution was stirred for 24 h at room temperature. Water (20 mL) was added into the solution, and the mixture was extracted with dichloromethane (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 88d as yellow oil (210 mg, yield 98%). [α]D20=+67.5 (c 0.17, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.28 (d, J=8.2 Hz, 2H), 7.19 (d, J=8.2 Hz, 2H), 6.38 (s, 1H), 5.97 (s, 1H), 5.82 (s, 2H), 5.35 (s, 1H), 4.19-4.13 (m, 2H), 3.76 (s, 6H), 3.75 (s, 3H), 2.95-2.82 (m, 1H), 1.26-1.19 (m, 9H); 13C NMR (150 MHz, CDCl3) δ 166.4, 153.8, 148.5, 143.6, 140.8, 138.0, 130.4, 127.4, 126.8, 125.6, 91.2, 61.1, 60.8, 59.1, 55.9, 33.8, 24.0, 14.1; ESI-LRMS m/z (%): 414.1 [M+H]+.
The corresponding racemate can be obtained by replacing R1 with triphenylphosphine (0.005eq).
To a 100 mL Schlenk flask equipped with a cold finger was added 88d (110 mg), Sn[N(TMS)2]2 (140 mg, 0.32 mmol) and anhydrous toluene (5 mL). The mixture was heated to reflux for 3.5 h under nitrogen atmosphere. The solution was cooled and directly purified by flash chromatography to give 88 as white solid (21 mg, yield 21%); Mp 99-100° C.; [α]D20=+47.7 (c 0.11, CHCl3); 92% ee [determined by HPLC analysis using a Chiralcel AD-H column; n-Hex/i-PrOH=75:25, 1.0 mL/min, 254 nm; tR (minor)=5.30 min; tR (major)=6.59 min]; 1H NMR (400 MHz, CDCl3) δ 7.32 (d, J=8.2 Hz, 2H), 7.23 (d, J=8.2 Hz, 2H), 6.58 (s, 2H), 5.83 (t, J=1.7 Hz, 1H), 5.34 (s, 1H), 5.19-5.15 (m, 1H), 3.76 (s, 3H), 3.71 (s, 6H), 2.89 (dq, J=13.7, 6.9 Hz, 1H), 1.24 (s, 3H), 1.22 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 161.0, 153.5, 149.9, 149.8, 134.7, 133.9, 133.8, 127.2, 126.9, 110.7, 95.0, 64.0, 60.9, 56.0, 33.9, 23.9; ESI-LRMS m/z (%): 368.2 [M+H]+; ESI-HRMS m/z (%): Calcd for C20H26NO4 [M+H]+ 368.1856, found 368.1859.
A 50 mL round-bottom flask was charged with 80 (21 mg, 0.052 mmol), Et3N (70 μL, 0.52 mmol), acryloyl chloride (42 μL, 0.52 mmol), DMAP (1 mg) and dichloromethane (1 mL). The solution was stirred for 0.5 h. Then 10 mL of water was added into the solution, and the mixture was extracted with dichloromethane (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 89 as white solid (14 mg, yield 48%); Mp 61-63° C.; [α]D20=+84.2 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.28 (d, J=10.4 Hz, 1H), 7.20 (s, 1H), 6.98 (d, J=8.5 Hz, 1H), 6.65-6.51 (m, 4H), 6.43-6.17 (m, 3H), 6.13-5.96 (m, 3H), 5.84 (d, J=10.5 Hz, 1H), 5.38 (s, 1H), 4.42 (s, 2H), 3.83 (s, 3H), 3.79 (s, 3H), 3.73 (s, 6H); 13C NMR (150 MHz, CDCl3) δ 164.5, 164.3, 163.0, 160.7, 153.0, 151.1, 139.2, 134.5, 133.0, 132.3, 132.2, 131.2, 126.9, 126.8, 126.5, 125.2, 123.6, 121.8, 112.0, 94.9, 88.0, 64.1, 60.3, 55.5, 55.4.
A 50 mL round-bottom flask was charged with 76 (17 mg, 0.045 mmol), Et3N (19 μL, 0.13 mmol), acryloyl chloride (11 μL, 0.13 mmol), DMAP (1 mg) and dichloromethane (1 mL). The solution was stirred for 3 h. Then 10 mL of water was added into the solution, and the mixture was extracted with dichloromethane (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 90 as white solid (15 mg, yield 69%); Mp 98-102° C.; [α]D20=−14.0 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.24 (dd, J=8.5, 2.1 Hz, 1H), 7.12 (d, J=2.1 Hz, 1H), 6.99 (d, J=8.5 Hz, 1H), 6.71 (d, J=6.7 Hz, 1H), 6.59 (d, J=17.1 Hz, 1H), 6.51 (s, 2H), 6.40-6.27 (m, 2H), 6.15 (dd, J=17.1, 10.3 Hz, 1H), 6.02 (d, J=10.3 Hz, 1H), 5.72 (d, J=10.3 Hz, 1H), 5.02 (d, J=2.2 Hz, 1H), 4.57 (dd, J=6.8, 2.2 Hz, 1H), 3.82 (s, 3H), 3.76 (s, 3H), 3.70 (s, 6H). 13C NMR (150 MHz, CDCl3) δ 165.8, 163.9, 163.7, 153.5, 151.6, 140.1, 134.8, 133.4, 132.9, 129.4, 128.8, 128.3, 127.4, 124.7, 121.1, 113.1, 95.2, 77.2, 77.02, 76.8, 66.2, 62.5, 60.9, 56.1.
To a 50 mL Schlenk flask was added anhydrous AlCl3 (36 mg, 0.27 mmol), LiAlH4 (10 mg, 0.27 mmol) and anhydrous THF (3 mL). It was stirred at 0° C. for 5 min under nitrogen atmosphere, and then 1 h at room temperature. Compound 1 (10 mg, 0.027 mmol) was added into the flask. The mixture was stirred for 3 h at room temperature. Then 3 mL of saturated aqueous ammonium chloride solution was added into the solution, and the mixture was extracted with ethyl acetate (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 91 as white solid (5 mg, yield 51%); 1H NMR (400 MHz, CDCl3) δ 6.79 (d, J=1.1 Hz 1H), 6.73 (dd, J=8.1, 1.1 Hz, 1H), 6.63 (d, J=8.1 Hz, 1H), 5.94 (s, 2H), 5.19 (s, 1H), 4.92 (s, 1H), 4.73 (s, 1H), 3.89-3.74 (m, 14H). ESI-MS (m/z): 358.2 (M+H+).
A 50 mL round-bottom flask was charged with 82 (18 mg, 0.04 mmol), Et3N (14 μL, 0.1 mmol), oxalyl chloride (5 μL, 0.058 mmol), DMAP (0.5 mg) and dichloromethane (1 mL). The solution was stirred for 3 h. Then 2 mL of saturated aqueous solution of sodium bicarbonate was added into the solution, and the mixture was extracted with dichloromethane (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 92 as white solid (12 mg, yield 63%); Mp 100-102° C.; [α]D20=−3.5 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.09-7.03 (m, 2H), 6.92 (br s, 1H), 6.53 (s, 2H), 5.33 (s, 1H), 4.55 (d, J=9.9 Hz, 1H), 4.05 (d, J=9.9 Hz, 1H), 3.86 (s, 3H), 3.78 (s, 3H), 3.72 (s, 6H), 2.30 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 168.8, 160.4, 153.9, 152.8, 152.7, 141.0, 135.9, 132.1, 123.4, 113.7, 96.0, 90.3, 67.1, 64.5, 61.3, 56.4, 56.3. ESI-MS (m/z): 474.1 (M+H+).
A 50 mL round-bottom flask was charged with 82 (0.25 g, 0.56 mmol), sodium periodate (0.18 g, 0.84 mmol), methanol (4 mL) and H2O (1 mL). The solution was stirred for 3 h. Then 2 mL of water was added into the solution, and the mixture was extracted with ethyl acetate (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 93 as yellow solid (180 mg, yield 80%); 1H NMR (400 MHz, CDCl3) δ 7.17 (dd, J=8.5, 2.2 Hz, 1H), 7.04 (d, J=2.2 Hz, 1H), 6.99 (d, J=8.5 Hz, 1H), 6.74 (s, 2H), 5.49 (s, 1H), 3.83 (s, 3H), 3.81 (s, 3H), 3.76 (s, 6H), 2.30 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 209.3, 191.1, 168.8, 160.6, 153.9, 152.4, 140.6, 136.6, 132.6, 125.1, 124.3, 121.7, 113.4, 96.1, 74.7, 61.3, 56.4, 56.3, 20.9. ESI-MS (m/z): 414.1 (M−H+).
To a 50 mL Schlenk flask was added 93 (10 mg, 0.024 mmol), MeMgCl (3M in THF, 1.2 μL, 0.036 mmol) and anhydrous THF (1 mL). It was stirred at 0° C. for 5 min under nitrogen atmosphere, and then 1 h at room temperature. Then 3 mL of water was added into the solution, and the mixture was extracted with ethyl acetate (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 94 as white solid (6 mg, yield 58%); Mp 140-142° C.; 1H NMR (400 MHz, CDCl3) δ 7.17 (dd, J=8.5, 2.1 Hz, 1H), 7.02-7.00 (m, 2H), 6.59 (s, 2H), 4.90 (s, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.73 (s, 6H), 2.30 (s, 3H), 1.70 (s, 3H).
A 50 mL round-bottom flask was charged with 94 (6 mg, 0.014 mmol), hydrazine hydrate (1.5 μL, 0.03 mmol) and methanol (1 mL). The solution was stirred for 1 h. Then 2 mL of water was added into the solution, and the mixture was extracted with ethyl acetate (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 95 as white solid (5 mg, yield 96%); 1H NMR (400 MHz, CDCl3) δ 6.84 (d, J=1.5 Hz, 1H), 6.83 (d, J=8.3 Hz, 1H), 6.76 (dd, J=8.3, 1.5 Hz, 1H), 6.57 (s, 2H), 5.61 (br s, 1H), 4.78 (s, 1H), 3.89 (s, 3H), 3.78 (s, 3H), 3.72 (s, 6H), 1.69 (s, 3H); ESI-LRMS m/z (%): 390.1 [M+H]+.
A 50 mL round-bottom flask was charged with 1 (20 mg, 0.054 mmol), Et3N (15 μL, 0.108 mmol), 4-methoxybenzoic acid (17 mg, 0.108 mmol), EDCI (21 mg, 0.108 mmol), DMAP (1 mg, 0.008 mmol) and dichloromethane (2 mL). The solution was stirred for 0.5 h. Then 10 mL of water was added into the solution, and the mixture was extracted with dichloromethane (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 96 as colorless oil (25 mg, yield 93%); [α]D20=+31.7 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz) δ: 7.95 (d, J=8.7 Hz, 1H), 7.11-7.05 (m, 3H), 6.84-6.78 (m, 3H), 6.43 (s, 2H), 5.68 (s, 1H), 5.15 (s, 1H), 5.04 (s, 1H), 3.71 (s, 3H), 3.63 (s, 3H), 3.59-3.58 (m, 9H); 13C NMR (CDCl3, 150 MHz) δ: 163.5, 163.3, 160.2, 153.0, 151.3, 149.0, 139.9, 134.1, 133.1, 131.8, 128.3, 124.5, 121.4, 120.8, 113.2, 112.3, 110.4, 94.2, 62.8, 60.3, 55.5, 55.4, 54.9. MS (ESI) m/z (%): 506.1 [M+H]% HRMS (ESI) calcd for C28H27NNaO8 [M+Na]+ 528.1629, found 528.1631.
A 50 mL round-bottom flask was charged with 69 (0.1 g, 0.26 mmol), K2CO3 (53 mg, 0.39 mmol), BnCl (36 mL, 0.31 mmol) and MeCN (5 mL). The mixture was stirred reflux for 12 h. Water (10 mL) was added into the solution, and the mixture was extracted with ethyl acetate (20 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was dissolved in anhydrous THF (5 mL). Then CBr4 (0.26 g, 0.78 mmol) and PPh3 (0.2 g, 0.78 mmol) were added into the mixture and the resulting solution was stirred for 6 h at room temperature. Water (10 mL) was added into the solution, and the mixture was extracted with ethyl acetate (20 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was then dissolved in 2 mL of ethanol, 10% Pd/C (10 mg) and AcONa (0.1 g, 1.3 mmol) were added and the solution was stirred for 12 h under H2 atmosphere (1 atm). Pd/C was filtrated, then the solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 97 as white solid (20 mg, yield 21%); Mp: 54-55° C.; [α]D20=+12.8 (c 0.5, CHCl3). 1HNMR (400 MHz, CDCl3) δ 6.93 (d, J=1.5 Hz, 1H), 6.87 (dd, J=8.3, 1.5 Hz, 1H), 6.83 (d, J=8.3 Hz, 1H), 6.54 (s, 2H), 5.69 (s, 1H), 4.44 (d, J=2.2 Hz, 1H), 3.89 (s, 3H), 3.76 (s, 3H), 3.72 (s, 6H), 3.11 (qd, J=7.3, 2.2 Hz, 1H), 1.45 (d, J=7.3 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 167.7, 152.9, 146.1, 145.6, 133.7, 133.5, 130.5, 117.1, 111.4, 110.3, 94.1, 62.2, 60.3, 55.4, 54.5, 12.4. ESI-MS (m/z): 374.0 (M+H+).
A 50 mL Schlenk flask was charged with 5 mL of dichloromethane and the solvent was deoxygenized with nitrogen bubbling for 15 min. Tris(dibenzylideneacetone)dipalladium (11 mg, 0.012 mmol) and 98a (21 mg, 0.031 mmol) was added into the flask. The resulted purple solution was stirred under nitrogen atmosphere for 10 min at room temperature. Then 3,4,5-trimethoxyaniline (0.34 g, 0.26 mmol), K2CO3 (1.0 M aq. solution, 2.1 mL, 2.1 mmol) and compound 1d (0.5 g, 1.23 mmol, dissolved in 5 mL of oxygen free dichloromethane) were added under a steam of nitrogen. The solution was stirred for 2 h at room temperature. Water (20 mL) was added into the solution, and the mixture was extracted with dichloromethane (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 98b as colorless oil (0.62 g, yield 95%).
To a 50 mL Schlenk flask equipped with a cold finger was wad added 98b (0.62), Sn[N(TMS)2]2 (0.76 g, 1.77 mmol) and anhydrous toluene (20 mL). The mixture was heated to reflux for 8 h under nitrogen atmosphere. The solution was cooled and directly purified by flash chromatography to give 98c as colorless oil (0.52 g, yield 93%).
A 100 mL round-bottom flask was charged with compound 98c (0.52 g, 1.1 mmol) and THF (5 mL). The solution was cooled to 0° C. by an ice bath, then TBAF (0.42 g, 1.6 mmol, dissolved in 5 mL THF) was dropped into the flask. After stirred for 15 min at 0° C., 30 mL of water was added into the solution. The mixture was extracted with ethyl acetate (20 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 98 as colorless oil (0.29 g, yield 73%); [α]D20=−37.9 (c 0.77, CHCl3); 1H NMR (400 MHz, CDCl3): δ 6.93 (d, J=1.7 Hz, 1H), 6.87 (dd, J=8.2, 1.7 Hz, 1H), 6.82 (d, J=8.2 Hz, 1H), 6.58 (s, 2H), 5.79 (s, 1H), 5.26 (s, 1H), 5.13 (s, 1H), 3.84 (s, 3H), 3.73 (s, 3H), 3.71 (s, 6H). 13C NMR (150 MHz, CDCl3): δ 160.3, 152.9, 149.2, 146.5, 145.6, 134.1, 133.2, 128.9, 118.1, 112.3, 110.3, 110.0, 94.31, 63.0, 60.3, 55.5, 55.4. ESI-MS (m/z): 372.1 (M+H+). ESI-HRMS (m/z): calcd for C20H21NO6+[M+H]+, 372.1442; found, 372.1441.
A 50 mL Schlenk tube was charged with 98 (220 mg, 0.6 mmol) bis(pinacolato)diboron (0.2 g, 0.78 mmol), PPh3 (20 mg, 0.076 mmol), t-BuOLi (6 mg, 0.074 mmol), CuCl (6 mg, 0.06 mmol), MeOH (30 μL, 0.74 mmol) and anhydrous THF (3 mL) were added in. The mixture was stirred under nitrogen atmosphere for 12 h at room temperature. Water (10 mL) was added into the solution, and the mixture was extracted with ethyl acetate (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was dissolved in THF/H2O (2 mL/1 mL). Then NaBO3.4H2O (0.46 g, 3 mmol) was added into the mixture and the resulting solution was stirred for 12 h at room temperature. Water (10 mL) was added into the solution, and the mixture was extracted with ethyl acetate (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 99 as colorless oil (48 mg, 21%) and 100 as white solid (95 mg, 41%).
99: [α]D20=−21 (c 1.6, CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.97 (d, J=1.5 Hz, 1H), 6.91 (dd, J=8.2 Hz, 1.5 Hz, 1H), 6.84 (d, J=8.2 Hz, 1H), 6.56 (s, 2H), 5.70 (s, 1H), 4.91 (d, J=1.8 Hz, 1H), 4.15 (dd, J=12.1, 4.5 Hz, 1H), 4.00 (dd, J=12.1, 3.7 Hz, 1H), 3.90 (s, 3H), 3.79-3.75 (m, 4H), 3.73 (s, 6H), 3.28 (br d, J=2.3 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 165.2, 152.8, 146.2, 145.7, 133.9, 133.1, 130.1, 117.3, 111.6, 110.4, 94.3, 61.5, 60.3, 59.8, 58.1, 56.9, 55.4; ESI-HRMS (m/z): calcd for C20H23NO7+[M+H]+, 390.1547; found, 390.1549.
100: Mp 180-181° C.; [α]D20-116.9 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) δ 6.88 (d, J=1.5 Hz, 1H), 6.84 (d, J=8.3 Hz, 1H), 6.79 (dd, J=8.3, 1.5 Hz, 1H), 6.54 (s, 2H), 5.88 (br d, J=20.7 Hz, 1H), 5.15 (d, J=5.3 Hz, 1H), 3.89 (s, 3H), 3.85-3.73 (m, 5H), 3.71 (br s, 7H), 3.61 (dd, J=11.2, 7.9 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 164.8, 152.9, 146.2, 145.5, 134.0, 133.0, 126.5, 117.9, 112.4, 110.3, 94.4, 60.3, 60.0, 57.4, 56.7, 56.1, 55.5, 55.3. ESI-HRMS (m/z): calcd for C20H23NO7+[M+H]+, 390.1547; found, 390.1551.
A 50 mL round-bottom flask was charged with 98 (15 mg, 0.04 mmol), 10% Pd/C (3 mg) and methanol (1 mL). The solution was stirred for 12 h under H2 atmosphere (1 atm). Pd/C was filtrated, then the solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 101 as white solid (13 mg, yield 95%); [α]D20=−112.8 (c 1.64, CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.86-6.77 (m, 2H), 6.72 (d, J=8.3 Hz, 1H), 6.56 (s, 2H), 5.71 (s, 1H), 5.06 (d, J=5.8 Hz, 1H), 3.89 (s, 3H), 3.77 (s, 3H), 3.72 (s, 6H), 3.66-3.59 (m, 1H), 0.91 (d, J=7.6 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 167.9, 152.9, 145.8, 145.2, 133.8, 133.3, 127.3, 118.1, 112.6, 110.0, 94.4, 60.3, 59.8, 57.8, 55.5, 55.3, 48.6, 26.3. ESI-HRMS (m/z): calcd for C20H23NO6+[M+H]+, 374.1589; found, 374.1601.
A 50 mL round-bottom flask was charged with 99 (30 mg, 0.078 mmol), K2CO3 (16 mg, 0.12 mmol), BnCl (10 μL, 0.09 mmol) and MeCN (2 mL). The mixture was stirred reflux for 8 h. Water (10 mL) was added into the solution, and the mixture was extracted with ethyl acetate (20 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was dissolved in anhydrous THF (5 mL). Then CBr4 (77 mg, 0.23 mmol) and PPh3 (61 mg, 0.23 mmol) were added into the mixture and the resulting solution was stirred for 4 h at room temperature. Water (10 mL) was added into the solution, and the mixture was extracted with ethyl acetate (20 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was then dissolved in 2 mL of ethanol, 10% Pd/C (3 mg) and AcONa (19 mg, 0.23 mmol) were added and the solution was stirred for 8 h under H2 atmosphere (1 atm). Pd/C was filtrated, then the solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 102 as white solid (9 mg, yield 32%); Mp: 54-55° C.; [α]D20=−14.5 (c 0.65, CHCl3). 1HNMR (400 MHz, CDCl3) δ 6.93 (d, J=1.5 Hz, 1H), 6.87 (dd, J=8.3, 1.5 Hz, 1H), 6.83 (d, J=8.3 Hz, 1H), 6.54 (s, 2H), 5.69 (s, 1H), 4.44 (d, J=2.2 Hz, 1H), 3.89 (s, 3H), 3.76 (s, 3H), 3.72 (s, 6H), 3.11 (qd, J=7.3, 2.2 Hz, 1H), 1.45 (d, J=7.3 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 167.7, 152.9, 146.1, 145.6, 133.7, 133.5, 130.5, 117.1, 111.4, 110.3, 94.1, 62.2, 60.3, 55.4, 54.5, 12.4. ESI-MS (m/z): 374.0 (M+H+). ESI-HRMS (m/z): calcd for C20H23NO6+[M+H]+, 374.1589; found, 374.1601.
A 50 mL round-bottom flask was charged with 41 (20 mg, 0.05 mmol), 10% Pd/C (3 mg) and methanol (1 mL). The solution was stirred for 12 h under H2 atmosphere (1 atm). Pd/C was filtrated, then the solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 103 as white solid (17 mg, yield 85%); Mp: 75-76° C.; [α]D20=+120.7 (c 1.0, CHCl3). 1HNMR (400 MHz, CDCl3) δ 6.74 (d, J=8.1 Hz, 1H), 6.61-6.52 (m, 4H), 5.01 (d, J=5.8 Hz, 1H), 3.84 (s, 3H), 3.76 (s, 3H), 3.71 (s, 6H), 3.59 (dq, J=7.6, 5.8 Hz, 1H), 0.91 (d, J=7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 168.8, 153.9, 146.5, 146.2, 134.0, 132.2, 128.2, 118.6, 113.5, 110.0, 95.1, 61.3, 58.8, 56.9, 56.4, 49.5, 29.8, 9.7. ESI-MS (m/z): 373.1 (M+H+).
A 50 mL round-bottom flask was charged with 41f (100 mg, 0.19 mmol), (S)—Ir-PHOX (10 mg) and dichloromethane (5 mL). The solution was stirred for 12 h under H2 atmosphere (1 atm). The solvent was removed under reduced pressure. To a 100 mL Schlenk flask equipped with a cold finger was added the above resident, Sn[N(TMS)2]2 (100 mg, 0.33 mmol) and anhydrous toluene (5 mL). The mixture was heated to reflux for 3 h under nitrogen atmosphere. The solution was cooled and directly purified by flash chromatography to give 40 as white solid (46 mg, yield 65%); Mp: 62-64° C.; [α]D20=−19.1 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) δ 6.82 (d, J=8.0 Hz, 1H), 6.65-6.55 (m, 4H), 4.50 (d, J=2.1 Hz, 1H), 3.88 (s, 3H), 3.79 (s, 3H), 3.70 (s, 6H), 3.32 (qd, J=7.1, 2.1 Hz, 1H), 1.41 (d, J=7.1 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 167.8, 152.8, 146.0, 145.6, 133.0, 133.8, 130.3, 117.0, 111.5, 110.4, 94.2, 62.1, 60.5, 55.5, 54.1, 12.3. ESI-MS (m/z): 373.1 (M+H+).
A 50 mL round-bottom flask was charged with compound 1g (390 mg, 0.81 mmol), TMSCH2N2 (1.2 mL, 2 Min hexane, 2.4 mmol) and dichloromethane (5 mL). After stirred for 12 h, 3 mL of water was added into the solution, and the mixture was extracted with dichloromethane (20 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was dissolved in THF (5 mL). TBAF (210 mg, 0.81 mmol) was added into the flask. the resulting solution was stirred for 3 h at room temperature. Water (10 mL) was added into the solution, and the mixture was extracted with ethyl acetate (20 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 105 as white solid (160 mg, yield 53%); Mp: 120-122° C.; [α]D20=+63.2 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) δ 6.92 (dd, J=8.1, 2.0 Hz, 1H), 6.88 (d, J=8.1 Hz, 1H), 6.77 (d, J=2.0 Hz, 1H), 4.72 (s, 1H), 3.85 (s, 3H), 3.76 (s, 3H), 3.68 (s, 6H), 2.15-2.08 (m, 2H), 1.45-1.38 (m, 2H). 13C NMR (150 MHz, CDCl3) δ 167.6, 152.6, 146.2, 145.8, 133.1, 133.8, 130.4, 117.5, 111.0, 110.5, 94.1, 62.2, 60.4, 55.5, 54.0, 22.9, 18.1, 16.3. ESI-MS (m/z): 386.1 (M+H+).
A 50 mL round-bottom flask was charged with 105 (20 mg, 0.05 mmol), 10% Pd/C (3 mg) and methanol (1 mL). The solution was stirred for 12 h under H2 atmosphere (1 atm). Pd/C was filtrated, then the solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 106 as white solid (15 mg, yield 75%); Mp: 85-87° C.; [α]D20=+130.3 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) δ 6.85-6.78 (m, 2H), 6.70 (d, J=8.1 Hz, 1H), 6.60 (s, 2H), 5.01 (d, J=5.7 Hz, 1H), 3.88 (s, 3H), 3.76 (s, 3H), 3.70-3.63 (m, 7H), 1.24-1.20 (m, 1H), 0.87 (d, J=7.5 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 167.6, 152.8, 147.5, 146.4, 133.4, 133.6, 130.1, 117.5, 111.2, 110.4, 94.0, 62.3, 61.4, 55.5, 54.2, 22.7, 19.0, 18.2, 16.6. ESI-MS (m/z): 388.1 (M+H+).
A 50 mL round-bottom flask was charged with 1 (20 mg, 0.054 mmol), triethylamine (11 mg, 0.108 mmol) and anhydrous dichloromethane (1.5 mL). The solution was stirred for 1 h under FSO2F atmosphere (1 atm). Water (10 mL) was added into the solution, and the mixture was extracted with ethyl acetate (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 107 as yellow solid (21 mg, yield 86%); [α]D20=+30.0 (c 0.34, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.39 (br s, 2H), 7.13-7.00 (m, 1H), 6.53 (s, 2H), 5.87 (s, 1H), 5.33 (s, 1H), 5.19 (s, 1H), 3.91 (s, 3H), 3.76 (s, 3H), 3.73 (s, 6H); 13C NMR (CDCl3, 150 MHz) δ: 159.9, 153.1, 151.0, 148.6, 138.3, 134.4, 132.7, 129.0, 127.2, 120.8, 113.6, 110.8, 94.2, 62.0, 60.3, 55.8, 55.4; MS (ESI) m/z (%): 454.1 (M+H)+; HRMS (ESI) calcd for C20H21FNO8S [M+H]+ 454.0966, found 454.0968.
A 50 mL round-bottom flask was charged with 107 (18 mg, 0.04 mmol), 10% Pd/C (3 mg) and methanol (1 mL). The solution was stirred for 12 h under H2 atmosphere (1 atm). Pd/C was filtrated, then the solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 106 as white solid (17 mg, yield 75%); [α]D20=−98.8 (c 1.64, CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.86-6.77 (m, 2H), 6.72 (d, J=8.3 Hz, 1H), 6.56 (s, 2H), 5.71 (s, 1H), 5.06 (d, J=5.8 Hz, 1H), 3.89 (s, 3H), 3.77 (s, 3H), 3.72 (s, 6H), 3.66-3.59 (m, 1H), 0.91 (d, J=7.6 Hz, 3H).
A 50 mL round-bottom flask was charged with 97 (20 mg, 0.054 mmol), triethylamine (11 mg, 0.108 mmol) and anhydrous dichloromethane (1.5 mL). The solution was stirred for 1 h under FSO2F atmosphere (1 atm). Water (10 mL) was added into the solution, and the mixture was extracted with ethyl acetate (10 mL) for 3 times. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give 107 as colorless oil (19 mg, yield 79%); [α]D20=+10.5 (c 0.5, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.15 (d, J=1.8 Hz, 1H), 7.03 (dd, J=8.1, 1.8 Hz, 1H), 6.93 (d, J=8.1 Hz, 1H), 6.55 (s, 2H), 4.48 (d, J=2.1 Hz, 1H), 3.88 (s, 3H), 3.79 (s, 3H), 3.70 (s, 6H), 3.12-3.04 (m, 1H), 1.47 (d, J=7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 168.7, 152.7, 146.5, 145.4, 133.8, 133.7, 130.5, 117.0, 111.5, 110.5, 94.6, 62.4, 60.3, 55.5, 54.4, 12.8. MS (ESI) m/z (%): 456.1 (M+H)+; HRMS (ESI) calcd for C20H23FNO8S [M+H]+ 456.1128, found 456.1125.
Antiproliferative activities on different cell lines.
5000 tumor cells per well were seeded into 96-well plate and allowed to adhere overnight. Cells were treated with various concentrations of tested compounds or DMSO (0.2%, as negative control) for 48 h. Then, the medium along with tested compounds or DMSO was discarded and 200 mL per well MTT containing medium (0.5 mg/mL) was added. After incubation at 37° C. for 4 h, the MTT-containing medium was replaced by DMSO (150 μL per well) to dissolve the formazan crystals. Absorbance of the resulting solution was measured by microplate reader (Biotech ELx800) at 540 nm wavelength. Growth inhibition rates were calculated with the absorbance. Half maximal inhibitory concentration (IC50) of each compound was calculated using GraphPad Prism, version 6.0.
In vitro tubulin polymerization assay Pig brain tubulin was obtained commercially and stored in aliquots at −70° C. In this assay, tubulin protein was incubated with indicated concentrations of compounds 69, 70 and 97, colchicine as positive control, or diluent (0.2% DMSO) as negative control in general tubulin buffer (100 mM PIPES, 1.0 mM MgCl2, 1 mM EGTA, 1 mM GTP and 5% glycerol). The absorbance of wavelength at 340 nm was detected every 1 min for 20 min by Spectra Max 190 spectrophotometer (Molecular Device) at 37° C. The results were indicated as mean values from three independent determinations. As shown in Table 2, 69, 70 and 97 suppressed in vitro tubulin polymerization in a dose-dependent manner, compared to the solvent (DMSO) control with IC50 of 3.5, 1.7 and 1.6 μM, respectively (
Immunoblotting Analysis
After being treated with diluent (0.2% DMSO), tested compound, CA-4 or PTX for 6 h, Hela cells were lysed with microtubulestabilizing buffer, containing 100 mM PIPES, pH 6.8, 1 mM MgCl2, 2 mM EGTA, 0.5% NP-40, 2 M glycerol, 5 μM PTX and protease inhibitors cocktail (Roche), and the lysate was centrifuged at 15,000 rpm for 15 min. Supernatant containing depolymerized tubulin was carefully collected, whereas pellet (polymerized tubulin) was further dissolved in SDS-lysis buffer (Beyotime, China). Equal amounts of supernatant and dissolved pellet were subjected to immunoblotting analysis as described above using atubulin antibody (Proteintech). Cells treated with 69, 70 and 97 showed dramatically reduction of polymerized tubulin (
Immunofluorescent Analysis
After treatment with diluent (0.2% DMSO) or tested compounds at indicated concentrations for 24 h, SKOV-3 cells were fixed with methanol, permeabilized with 0.1% Triton X-100 in PBS and blocked by goat serum. Then the cells were incubated with a-tubulin antibody at 4° C. overnight, followed by incubation with Alexa 488 labeled secondary antibody (Jackson ImmunoResearch) at RT for 1 h. After being stained with DAPI, cells were examined and photographed with a Leica SP5 co-focal fluorescence microscope. The results clearly demonstrated that 69, 70 and 97 strongly inhibit tubulin assembly in cancer cells (
Capillary-Like Tube Formation Assay
60 mL matrigel (Corning) per well was added to 96-well plate and pre-incubated at 37° C. for 1 h for gelation. 3*104 human umbilical veinendothelial cells (HUVECs) in 100 mL medium per well containing indicated concentrations of 69, 70 and 97, CA-4 as positive control, or diluent (0.2% DMSO) as negative control, respectively, were seeded to 96-well plates on the matrigel layer, followed by continual incubation at 37° C. for 12 h to allow capillary-like tube formation. Images were captured with a CCD Sensicam camera mounted on an Olympus inverted microscope. Representative data from three independent experiments were shown. The results shown that compound 69, 70 and 97 almost completely disrupted the capillary-like tube formation (
Matrigel Plug Assay
6 weeks old female Balb/C nude mice were purchased from Shanghai Slac Laboratory Animal Co. Ltd. (Shanghai, China). Matrigel containing 100 ng/mL human recombinant VEGF-A165 (Peprotech, Rocky Hill, N.J.) were mixed with indicated concentrations of 69, 70 and 97, or diluent (0.2% DMSO) as negative control at 4° C. Then, 0.5 mL of the matrigel mixture per mouse was injected subcutaneously into nude mice (n=4) in the dorsal region to generate matrigel plugs. 2 weeks later, the mice were sacrificed and matrigel plugs were recovered. Representative data from three independent experiments were shown. The results demonstrated that 69, 70 and 97 suppressed VEGF induced angiogenesis in vitro (
Colony Formation Assay
1000 MDA-MB-231 cells per well were seeded into 6-well plate at a single cell density and were cultured at 37° C. for 48 h. After being treated with indicated concentrations of 69, 70 and 97, CA-4 as positive control, or diluent (0.2% DMSO) as negative control for 48 h, the agents containing medium was replaced by fresh medium to allow cell growth for additional 7-10 days. Then the cells were fixed with methanol and stained with gentian violet for 30 min.
The number of colonies which consisted of more than 50 cells were counted. The results were indicated as mean values from three independent determinations. The results shown that the colonies formed by MDA-MB-231 cells were dose-dependently reduced by the exposure to 69, 70 and 97 (
Cell Cycle Analysis
2*105 Hela cells per well were seeded into six-well plate and allowed to adhere overnight at 37° C. After treatment with indicated concentrations of 69, 70 and 97, CA-4 as positive control or diluent (0.2% DMSO) as negative control for 24 h, cells were harvested, washed twice with PBS and fixed with 75% ethanol at −20° C. overnight. Then cells were stained with propidium iodide dye (BD Biosciences) for 15 min in dark conditions at room temperature, followed by subjected to flow cytometry (Cytomics FC 500MPL, Beckman Coulter) detection. The results were analyzed by Multicycle AV (for Windows, version 320) software and indicated as mean values from three independent determinations. The results clearly demonstrate that, 69, 70 and 97 significantly induce cellular mitotic arrest in Hela cells (
Cell Cycle Associated Proteins Assay
A. HeLa cells were treated with 69, 70, 97 or DMSO for 24 h. After being harvested, the cells were lysed, and the concentrations of total protein were determined by BCA protein assay kit (Beyotime, China). Protein samples were separated by 8-12% SDS-PAGE then transferred to polyvinylidene fluoride (PVDF) membrane (Millipore). The membrane was blocked with 5% BSA in TBST for 1.5 h, then incubated overnight with specific primary antibodies (Proteintech) at 4° C. After being washed three times by TBST, the membrane was incubated with specific secondary antibodies (Abnova, Taipei, China) at room temperature for 2 h. Finally, chemiluminescent reagents (Millipore) were employed to detect the protein bands.
B. Quantitative PCR assay: HeLa cells were treated with 69, 70 or 97. The expression level of mRNA of target proteins was tested with qPCR kit (Takara).
These results implied that 69, 70 and 97 can significantly induce the expression of p-histone H3, cyclin B1 and BuBR1 (
Cell Apoptosis Analysis
Cell apoptosis was detected using FITC Annexin V Apoptosis Detection Kit (BD Biosciences) according to manufacturer's instructions. Briefly, cells were incubated with indicated concentrations of 69, 70 and 97, CA-4 as positive control or diluent (0.2% DMSO) as negative control for 48 h. Then the cells were harvested, washed twice with PBS, and re-suspended in binding buffer. After being stained with Annexin-V and PI for 15 min in the dark place, cells were subjected to flow cytometry (Cytomics FC 500 MPL, Beckman Coulter) analysis. The results were indicated as mean values from three independent determinations. These results implied that 69, 70 and 97 can significantly induce cellular apoptosis (
Expression level of apoptosis associated proteins
A. Western blotting: After being treated with candidate compound, cells were harvested and lysed. Then, the lysate was isolated by ultracentrifuge and quantified by BCA assay according to the protocol. After being denatured, equivalent protein of each sample was separated by SDSPAGE gel and wet-transferred onto 0.22 μm nitrocellulose membrane. After being blocked by PBS containing 5% skim milk, the membrane was incubated with primary antibody at 4° C. overnight and secondary antibody at room temperature for 2 h and then visualized by enhanced chemiluminescence kit (Thermo Fisher, USA), sequentially.
B. Quantitative PCR assay: HeLa cells were treated with 69, 70 or 97. The expression level of mRNA of target proteins was tested with qPCR kit (Takara).
These results implied that 69, 70 and 97 can significantly induce the expression of Bax, p53 and cleaved-PARP (
KM mice were housed individually in a specific pathogen free facility. Groups of mice (n=10 per group, half male and half female) were injected intraperitoneally once with various dosages of 69 (95, 70, 50, 35, 25 mg/kg), 70 (500, 425, 350, 275, 200 mg/kg), 97 (275, 200, 150, 125 and 100 mg/kg) or vehicle (8.3% cremohorp EL and 8.3% alcohol in PBS) as negative control, respectively. 69, 70 and 97 was dissolved in cremeohore EL and alcohol mixture (1:1, v/v) and further diluted with PBS (1:5, v/v). The death of mice were monitored daily and recorded up to 14 days after injection. The LD50 of 69 was 61.5 mg/kg. The LD50 of 70 was >500 mg/kg. The LD50 of 95 was 136.5 mg/kg (Table 3).
Xenografts Tumor Growth Assay in Nude Mice
6 weeks old female Balb/c nude mice were purchased from Shanghai Slac Laboratory Animal Co. Ltd. (Shanghai, China). 2*106 A2780 cells suspended in 0.2 mL PBS per mouse was injected subcutaneously into the nude mice. When the average tumor volume reached 100 mm3, mice were randomly divided into 4 groups (n=10) and administered intraperitoneally with 7.5 mg/kg compound 69, 12.5 mg/kg compound 70, 4 mg/kg or 8 mg/kg compound 97, 5 mg/kg PTX (Taxol, Bristol-Myers Squibb Company) injection or vehicle control (same as described in acute toxicity assay), respectively. Administration of agents or vehicle, or agents and measurement of tumor volumes with a digital caliper was done once every 2 days. Tumor volumes were calculated as volume=shortest diameter (W)2*longest diameter (L)*0.52. When the average tumor volumes of vehicle treated group reached 2000 mm3 in diameter, the mice were sacrificed and the tumors were isolated and weighed. Visceral organs of the mice as well as solid tumors were further analyzed by H&E staining.
The results confirmed the anti-tumor activities in vivo of 69, 70 and 97 with no significant weight loss observed. Furthermore, H&E staining of tumor sections showed extensive areas of necrosis or cell death in 69, 70 and 97 treated groups, however, none of abnormal areas were observed in the vehicle treatment group, and no detectable abnormalities were observed in liver, kidney and spleen (
All literatures in this patent are cited as references, just as each document is cited separately as a reference. Any modifications, changes and the equivalent forms to this invention shall also be included in the scope of the claims attached to this patent.
| Number | Date | Country | Kind |
|---|---|---|---|
| 201610188876.2 | Mar 2016 | CN | national |
| 201710162725.4 | Mar 2017 | CN | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CN2017/078444 | 3/28/2017 | WO | 00 |
