CN103360358A - 15-oxospiramilactone derivatives, and preparation method and applications thereof - Google Patents

15-oxospiramilactone derivatives, and preparation method and applications thereof Download PDF

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CN103360358A
CN103360358A CN2013103001162A CN201310300116A CN103360358A CN 103360358 A CN103360358 A CN 103360358A CN 2013103001162 A CN2013103001162 A CN 2013103001162A CN 201310300116 A CN201310300116 A CN 201310300116A CN 103360358 A CN103360358 A CN 103360358A
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compound
preparation
nmr
cdcl
oxospiramilactone
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CN103360358B (en
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郝小江
晏晨
刘海洋
何红平
李林
何小丽
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Kunming Institute of Botany of CAS
Key Laboratory of Natural Product Chemistry of Guizhou Academy of Sciences
Shanghai Institute of Nutrition and Health of CAS
Center for Excellence in Molecular Cell Science of CAS
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Shanghai Institutes for Biological Sciences SIBS of CAS
Kunming Institute of Botany of CAS
Key Laboratory of Natural Product Chemistry of Guizhou Academy of Sciences
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Abstract

The invention provides various type derivatives of 15-oxospiramilactone, a pharmaceutical composition by taking the derivatives as an active component, a preparation method of the derivatives, and applications in preparation of antitumor drugs. During research on antitumor natural products, it is discovered that 15-oxospiramilactone possesses activities of resisting multiple tumor cell strains, and most of the derivatives are stronger than the primer 15-oxospiramilactone in activity. The above compounds are subjected to a test of inhibiting activity of Wnt signaling pathway and a test of inhibiting activity of various tumor cell strains, and it is discovered that antineoplastic activity of the above compounds is positively correlated to the activity of inhibiting Wnt signaling pathway.

Description

15-oxospiramilactone derivative and its preparation method and application
Technical field:
The invention belongs to technical field of pharmaceuticals, specifically, relate to diterpene salicylate 15-oxospiramilactone (S-3) derivative, its preparation method, the pharmaceutical composition take this compounds as activeconstituents, with and in the application of preparation in the antitumor drug.
Background technology:
Although the tumour science has been made significant headway, up to now, cancer is still the most serious in the world public health problem.Worldwide, estimate new cancer number will by 2008 1,270 ten thousand, rise to more than 2,000 ten thousand of the year two thousand thirty, tumour has become the No.1 killer of human health." poor cancer " sickness rate is high, and " rich cancer " also increases rapidly, and China is in the period from developing country's distribution to developed country's distribution transition.Cause the reason of China cancer patients rejuvenation to have environmental pollution, bad life style and stress excessive etc.Meanwhile, another surging factor of " cancer feelings " is the quick aging of population.At present, the cancer therapy means of clinical application comprise operation, radiation and chemotherapy, although these means have some curative effects, bring the huge human body and spiritual misery owing to its larger toxic side effect to the patient.A major issue that affects simultaneously chemotherapy effect is the resistance that has occured cell toxicity medicament, some cancer cells are to a kind of antitumour drug deposits yields resistance, simultaneously other non-similar drugs also being developed immunity to drugs, is to cause the failed major cause of tumour chemotherapy (chemotherapy).The antitumor drug of many natural origins such as alkaloid anticarcinogen (colchicine, vinealeucoblastine(VLB), harringtonine and taxol etc.), anthracycline antitumor antibiotic (Zorubicin and daunorubicin), MDR all very easily occurs in epipodophyllotoxin class (Vp-16 and VM-26) and synthetic drug (mitoxantrone and the pyridine of amine benzene bifurcation).Newfound medicine such as taxol and the leukemic STI-571 of the chronic graininess for the treatment of are just to be used for clinical just the discovery resistance is arranged, and this makes problem more serious.Yet signal transduction pathway exists greatest differences between normal cell and tumour cell, and this otherness is just in time given the new Historic Opportunities for th e Development of antitumor drug of characteristics such as having targeting, potent low toxicity.So far, now in the technology there are no the report of 15-oxospiramilactone of the present invention (S-3) derivative.
Summary of the invention:
The purpose of this invention is to provide a kind of 15-oxospiramilactone (S-3) derivative with structure formula I, (II), its preparation method, the pharmaceutical composition take this compounds as activeconstituents, with and in the application of preparation in the antitumor drug.
The objective of the invention is to realize by following technological method:
15-oxospiramilactone (S-3) derivative of following structural formula (I), (II):
Figure BDA00003525815000021
Wherein: R in the structure formula I 1, R 6For-OH or=O, R 2For-H or=O or=CH 2Or-Cl or-Br or-SCH 3Or-CH 2OH or-CH 2N (CH 3) 2Or-CH 2N (CH 2) 4O or-CH 2OCOCH 3Or-CH 2OSO 2CH 3, R 3For-H or R 2With R 3Between be two keys; X 1, X 3For-CH 2Or-CH or carbonyl; X 2For Sauerstoffatom or nitrogen-atoms or-SO 2;
Work as X 1During for CH, R 5For-OCH 3Or R 1With R 5Form oxo bridge;
Work as X 2During for nitrogen-atoms, R 4For-H or-CH 2CH 2OH or-CH 2CH 2OTBDMS or R 4, R 5, X 1, X 2Form oxazole ring or R 4, X 2, X 3Form the oxazole ring.
In the structure formula II, R 1, R 5For-OH, or=O; R 2For-H or=O or=CH 2Or-CH 2OH or-CH 2N (CH 2) 4O or-CH 2OCOCH 3Or-CH 2OSO 2CH 3R 3, R 4For-0H or-COCH 3Or-COCH 2Cl or-CON (CH 2) 4O or-Ms or-CH 2CN or 2-Thenoyl; X 1For-CH 2Or-CO.
Particularly, 15-oxospiramilactone of the present invention (S-3) derivative is:
Figure BDA00003525815000022
Figure BDA00003525815000031
The present invention provides a kind of pharmaceutical composition with anti-tumor activity simultaneously, and it comprises one or more above-mentioned 15-oxospiramilactone derivatives and the pharmaceutically acceptable auxiliary material for the treatment of significant quantity.
The preparation method of above-claimed cpd of the present invention comprises the steps:
(1) compound 1-9,25,26 preparation method:
Figure BDA00003525815000041
(2) preparation method of compound 10:
Figure BDA00003525815000042
(3) preparation method of compound 11-13:
Figure BDA00003525815000043
(4) preparation method of compound 14-20:
Figure BDA00003525815000051
(5) preparation method of compound 21:
Figure BDA00003525815000052
(6) compound 22,27 preparation method:
Figure BDA00003525815000053
(7) preparation method of compound 23,24,28-36:
Figure BDA00003525815000061
(8) preparation method of compound 37-41:
Figure BDA00003525815000062
(9) compound 42,43,44 syntheti c route:
(10) compound 45,46,47,48,49 preparation method:
(11) preparation method of compound 50-55:
Figure BDA00003525815000081
(12) preparation method of compound 56-58:
Figure BDA00003525815000082
The application of compound in the preparation antitumor drug that the present invention is above-mentioned.
The application of compound in preparation Wnt signal pathway inhibitor medicine that the present invention is above-mentioned.
When the compounds of this invention is used as medicine, can directly use, perhaps use with the form of pharmaceutical composition.This pharmaceutical composition contains 0.1-99.5%, is preferably the compounds of this invention of 0.5-90%, and all the other are acceptable on the pharmacology, pharmaceutically acceptable carrier and/or the vehicle of and inertia nontoxic to humans and animals.
Described pharmaceutical carrier or vehicle are one or more solids, semisolid and liquid diluent, filler and pharmaceutical preparation assistant agent.Pharmaceutical composition of the present invention is used with the form of per weight dose.The method that the composition of phenanthridines analog derivative of the present invention adopts pharmacy and field of food to generally acknowledge is prepared into various formulations, such as liquid preparation (injection, suspensoid, emulsion, solution, syrup etc.), solid preparation (tablet, capsule, granule, electuary etc.), spray, aerosol etc.Medicine of the present invention can resist antineoplastic treatment through route of administration such as injection (intravenous injection, intravenous drip, intramuscular injection, abdominal injection, subcutaneous injection) and oral, sublingual administration, mucous membrane dialysis.
Studies show that of the present invention's early stage: the 15-oxospiramilactone (S-3) that comes from the pink blossom Ramulus et Folium Spiraeae Salicifolia has brand-new mechanism of action, the apoptosis that S-3 induces non-Bax/Bak to rely on, the high expression level that S-3 induces pro apoptotic protein Bim is specifically found in further investigation, itself and Bcl-2 have an effect in the plastosome level, cause that the Bcl-2 conformational change is converted to short apoptosis function by anti-apoptosis, thereby the release of activating cells pigment C causes the dependent apoptosis of the non-Bax/Bak of cell, and this is the new mechanism of cell death inducing; Find that S-3 is optionally inhibitor of tumour cell Wnt signal path, suppress the expression of Wnt downstream target gene by the interaction that weakens β-catenin and TCF4; Cause cell cycle arrest in the G2/M phase by suppressing the downstream expression of target gene; SW480 transplants experiment of nude mouse and shows that the S-3 of low dosage can suppress the growth of tumour.The present invention on this basis, to the large intestine of S-3 and colon tumor strain, Normocellular cytotoxic activity, and the early stage Fast Evaluation of ADME/T done analysis, finds that S-3 has " first pass effect ", it eliminates the transformation period is 0.43 hour, the hydrolysate anti-tumor activity completely dissolve of lactonic ring.For its defective that becomes the property of medicine, it is carried out structure of modification and composition optimizes,, seek the more rational antineoplastic compound of patent medicine and be very important as foundation with the inhibition activity of Wnt signal path, the cytotoxic activity of different tumor lines etc.
Embodiment:
The below further specifies essentiality content of the present invention with embodiments of the invention, but does not limit the present invention with this.
Embodiment 1:
The preparation of the compounds of this invention:
(1) compound 1-9,25,26 syntheti c route are:
Figure BDA00003525815000101
The preparation method:
Compound 1: get the dry compound 15-oxospiramilactone (S-3) (2.00g, 6.06mmol) that comes from the pink blossom Ramulus et Folium Spiraeae Salicifolia, at N 2Protection is lower to dry methylene chloride 5ml dissolving; with oxalyl chloride (7.28mmol; 692ul) be injected in the long-neck low-temp reaction bottle of the methylene dichloride that the 5ml drying is housed in nitrogen protection; place-78 ℃ to stir 20 minutes; then slowly drip DMSO(14.56mmol; 1032ul is among the in5ml DCM) solution, after dripping in 5 minutes; low temperature stirred 30 minutes; dichloromethane solution with compound S-3 slowly is added drop-wise in the reaction flask again, after stirring 1 hour under-78 ℃ of stirrings, under rapid stirring; slowly drip triethylamine (14.56mmol; 2020ul), add the rear normal temperature that naturally is warming up to, pour in the water of 20ml; extracting and demixing; water layer continues to use the 20ml dichloromethane extraction, combined dichloromethane, saturated common salt water washing; anhydrous sodium sulfate drying; resistates obtains compound 1, colourless powder 1888.2mg, yield: 95.0% through silica gel column chromatography after concentrated.
Compound 2: weigh up compound 1(1.0mmol, 328mg), Paraformaldehyde 96 (5mmol, 150mg), Bu 4NI (0.2mmol, 73.8mg), in the dry round-bottomed flask of Anhydrous potassium carbonate (2.0mmol, 276mg) as for 50ml, N 2Protection is lower; with dry toluene 15ml dissolution sample; reaction mixture, is cooled to room temperature and adds 20ml water after TLC point plate determines that raw material disappears as for 50 ℃ of lower stirrings 24 hours; with ethyl acetate extraction (2 * 20ml); organic layer is used the saturated common salt water washing in succession, and anhydrous sodium sulfate drying is concentrated that resistates obtains compound 2 through silica gel column chromatography; colourless powder 204mg, yield: 60%.
Compound 3: weighing Paraformaldehyde 96 (5mmol, 150mg) is suspended in the dry toluene solution of 10ml, N 2Protection is lower; injection morpholine (5mmol, 436ul) is at 40 ℃ of lower 1h that stir; after the solution becomes clarification; be down to stirring at room, inject successively compound 1(1mmol, 328mg) toluene solution 5ml; AcOH(1.0mmol; 60ul), stirring at room 3 hours, TLC shows that raw material disappears; stopped reaction; add the dilution of 20ml saturated sodium bicarbonate, with ethyl acetate (2 * 20ml) extractions, water, saturated common salt water washing; anhydrous sodium sulfate drying; silica gel column chromatography obtains compound 3, colourless powder 320mg, yield: 75%.
Compound 4: weighing Paraformaldehyde 96 (5mmol, 150mg), dimethylamine hydrochloride (5mmol, 407.7mg) are suspended in the dry toluene solution of 10ml successively, N 2Protection is lower, at 40 ℃ of lower 1h that stir, after the solution becomes clarification; be down to stirring at room, inject successively compound 1(1mmol, 328mg) toluene solution 5ml; AcOH(1.0mmol, 60ul), stirring at room 1 hour; TLC shows that raw material disappears, and stopped reaction adds the dilution of 20ml saturated sodium bicarbonate; with ethyl acetate (2 * 20ml) extractions, water, saturated common salt water washing, anhydrous sodium sulfate drying; silica gel column chromatography obtains compound 4, colourless powder 366mg, yield: 95%.
Compound 5,6: take by weighing compound 1(1mmol, 328mg), with the dry DMSO dissolving of 10ml, N 2Lower NCS(1.1mmol, the 147mg of adding of protection), under room temperature, stir 1h; the TCL demonstration is not reacted, and heats 45 ℃ of lower 3h of stirring, and TLC point plate finds that raw material disappears; stopped reaction is cooled to room temperature and adds the dilution of 20ml water, with ethyl acetate (2 * 20ml) extractions; water, saturated common salt water washing, anhydrous sodium sulfate drying, silica gel column chromatography obtain compound 5; colourless powder 164.7mg, yield 46%, compound 6; colorless oil 149.6mg, yield: 40%.
Compound 7: take by weighing compound 1(1mmol, 328mg), with the dry DMSO dissolving of 10ml, N 2Lower NBS(1.1mmol, the 196mg of adding of protection), under room temperature, stir 1h; the TCL demonstration is not reacted, and heats 45 ℃ of lower 3h of stirring, and TLC point plate finds that raw material disappears; stopped reaction; be cooled to room temperature and add the dilution of 20ml water, with ethyl acetate (2 * 20ml) extractions, water, saturated common salt water washing; anhydrous sodium sulfate drying; silica gel column chromatography obtains compound 7, red-brown powder 374mg, yield: 92%.
Compound 8: take by weighing compound 1(1mmol, 328mg) dissolves N with the dry toluene of 5ml 2Lower NCS(1.1mmol, the 146.8mg of adding of protection), ionic liquid [(BMIM) PF 4] 1ml, stirring at room 1h, raw material disappears, and stops to stir adding the dilution of 20m water, and (anhydrous sodium sulfate drying, silica gel column chromatography obtain compound 8, colourless powder 50mg, yield: 13.8% for 2 * 20ml) extractions, water, saturated common salt water washing with ethyl acetate.
Compound 9: get compound S-3(1.0mmol, 330mg) be dissolved in toluene: in dimethyl sulfoxide (DMSO)=2:110ml solution, N 2The lower 2-iodoxy phenylformic acid (IBX, 3.0mmol, 840mg) that adds of protection; in 70 ℃ of lower stirrings 30 hours, raw material is cooled to room temperature after disappearing; ethyl acetate dilution with 100ml; use successively saturated sodium bicarbonate solution, water, saturated common salt water washing; anhydrous sodium sulfate drying; concentrated that resistates obtains compound 9 through silica gel column chromatography, colourless powder 97.8mg, yield: 30%.
Compound 25,26: get compound 1(330mg, 1.0mmol) be dissolved in the methanol solution of 10ml, added morpholine (1.5eq, 1.5mmol) stirring at room 10 hours, after raw material disappears, stopped reaction, concentrating under reduced pressure gets resistates, gets compound 25(187mg, yield through silica gel column chromatography: 45%, 26(179mg, yield; 43%).
(2) preparation of compound 10:
Figure BDA00003525815000121
Compound 10: with oxalyl chloride (1.0mmol, 95ul) at N 2Protection is made a bet and is injected in the dry long-neck reaction flask; miscible with the dry DCM of 5ml; place-78 ℃ of lower stirrings; slowly drip DMSO (2.0mmol; 142ul in2ml DCM); stir 30min, slowly dripping S-1(332mg, 1.0mmol in2ml DCM); behind-78 ℃ of lower stirring 30min; naturally rise to room temperature after dripping triethylamine (2.0mmol, 278ul), add water 20ml dilution; extract with methylene dichloride (2*20ml); the saturated common salt water washing, anhydrous sodium sulfate drying obtains compound S-3(165mg) through silica gel column chromatography; with compound M-1(165mg); compound M-1 is prepared compound 10 by the method similar to preparing compound 2, colourless powder 162.4mg, two step yield: 47.5%.
(3) preparation of compound 11-13:
Figure BDA00003525815000131
The preparation method:
With compound S-1(3.0g, 9.04mmol) be dissolved among the analytically pure acetone 250ml N 2Protection is lower stirs, and adds the tosic acid (monohydrate) of (1.81mmol, 343.5mg), at room temperature stirs 24 hours, and continuous adularescent solid washes out in the reaction process, after raw material reaction is complete, and stopped reaction.Cross filter solid, sherwood oil: acetone=20:1 solution, washing leaching cake, mother liquor continues the solution weight crystallization with sherwood oil-acetone=1:1, air-dry, combining solid obtains midbody compound M-2(3.30g, yield 97%).The M-2 of drying is dissolved in the dry 250mlTHF solution N 2Protection; place ice bath to stir, slowly add Lithium Aluminium Hydride (10.5mmol, 400mg); stir after 20 minutes; placed on 45 ℃ of oil bath pans heated and stirred 3 hours, and after TLC shows that raw material disappears, reaction flask was placed in the ice bath again stirs; the sodium hydroxide solution 200ml that slowly adds 2N; in ice bath, stirred 10 minutes suction filtration, ethyl acetate washing leaching cake; the filtrate layering; water layer partly continues to use ethyl acetate extraction 2 times, and combined ethyl acetate is used the saturated common salt water washing; anhydrous sodium sulfate drying; concentrated solvent gets midbody compound M-3, colourless powder 3.33g, yield: 100%.Get compound M-3(376.0mg, 1.0mmol) be dissolved in the DCM solution of 10ml drying, at room temperature slowly add PDC(1.0mmol, 376mg), room temperature rapid stirring 5 hours is after TLC point board raw material disappears, reactant is poured in the frozen water, layering, water layer is used the 20ml dichloromethane extraction again, merge organic layer, the saturated common salt water washing, anhydrous sodium sulfate drying, concentrated, obtain midbody compound M-4(336mg, yield through silica gel column chromatography: 90%).With compound M-4(224mg, 0.60mmol) be dissolved in the analytical pure methyl alcohol of 10ml, drip 2NHCl(3ml), 35 ℃ of lower stirrings 24 hours, after raw material disappears, stop to stir, be spin-dried for methyl alcohol under the decompression, thin up, ethyl acetate extraction is used saturated sodium bicarbonate solution, saturated common salt water washing in succession, anhydrous sodium sulfate drying, silica gel column chromatography obtains midbody compound M-5, colorless oil 198mg, yield: 95%.
Compound 11: get compound M-5(50mg, 0.144mmol) is dissolved in the dry methylene chloride of 10ml minute 3 batches of freshly prepd activated manganese dioxides of adding, every batch of Manganse Dioxide amount is (0.288mmol, 25mg), and be 10 hours pitch time, after raw material disappears substantially, stop to stir, filter Manganse Dioxide, with methylene dichloride repetitive scrubbing Manganse Dioxide, concentrated methylene dichloride gets grey oily matter, obtain compound 11, colorless oil 28mg, yield: 56.2% through silica gel column chromatography.
Compound 12: with oxalyl chloride (1.28mmol, 110ul) at N 2Protection is made a bet and is injected in the dry long-neck reaction flask; miscible with the dry DCM of 5ml; place-78 ℃ of lower stirrings; slowly drip DMSO(2.56mmol, 182ul in2ml DCM), stir 30min; slowly dripping M-5(148mg; 0.425mmol in2ml DCM), behind-78 ℃ of lower stirring 30min, drip triethylamine (2.56mmol; naturally rise to room temperature 369ul); add water 10ml dilution, with methylene dichloride (2 * 10ml) extractions, saturated common salt water washing; anhydrous sodium sulfate drying; obtain compound 12, colourless powder 146mg, yield: 100% through silica gel column chromatography.
Compound 13: weigh up compound 12(0.29mmol, 100mg), Paraformaldehyde 96 (1.45mmol, 44mg), Bu4NI(0.06mmol, 21mg), in the dry round-bottomed flask of Anhydrous potassium carbonate (0.58mmol, 80mg) as for 25ml, N 2Protection is lower; in dry toluene 10ml dissolution sample; reaction mixture, is cooled to room temperature and adds 10ml water after TLC point plate determines that raw material disappears as for 50 ℃ of lower stirrings 24 hours; with ethyl acetate extraction (2 * 15ml); organic layer is used the saturated common salt water washing in succession, and anhydrous sodium sulfate drying is concentrated that resistates obtains compound 13 through silica gel column chromatography; colourless powder 56.7mg, yield: 55%.
(4) syntheti c route of compound 14-20:
Figure BDA00003525815000151
The preparation method:
With compound M-3(376.0mg, 1.0mmol) be dissolved among the THF of 10ml drying N 2Protection is lower; add triphenyl phosphorus (1.1mmol; 288mg); slowly drip diisopropyl azodiformate (1.1mmol, 222mg are diluted in the dry THF of 2ml); stirring at normal temperature 30 minutes; after TLC point plate determines that raw material disappears, add the dilute hydrochloric acid (5ml) of 2N 35 ℃ of lower stirrings 24 hours, after TLC tracks to acetonylidene and all takes off; the thin up reaction solution; use ethyl acetate extraction, saturated common salt water washing, anhydrous sodium sulfate drying; concentrated; resistates obtains compound M-6, colorless oil 318mg, yield: 100% through silica gel column chromatography.
Compound 14,18 preparation obtain by the method similar to compound 10; Simultaneously compound 15,20 preparation are by obtaining to compound 12,13 similar methods.
Compound 16,17,20 preparation: the round bottom reaction flask with 25ml takes by weighing compound 15(100mg, 0.318mmol successively), salt of wormwood (0.636mmol, 87.8mg), Paraformaldehyde 96 (1.59mmol, 47.7mg), N 2Protection is lower, with the toluene dissolution sample of 10ml drying, stirs 24 hours under the room temperature, TLC follows the tracks of, after raw material disappears, stop to stir, add the dilution of 10ml water, with ethyl acetate (2 * 15ml), organic layer saturated common salt water washing, anhydrous sodium sulfate drying, concentrated that resistates obtains compound 16 through silica gel column chromatography, colourless powder 82mg, yield: 75%; The compound 16(50mg, the 0.15mmol that in succession take by weighing), DMAP (5mg) in the round bottom reaction flask of 10ml, N 2Injector to inject pyridine (0.18mmol, 15ul) is used in the lower methylene dichloride dissolving with the 5ml drying of protection in succession, Methanesulfonyl chloride (0.18mmol, 14ul) at room temperature stirred 3 hours, TLC point plate is followed the tracks of, and after raw material disappears, stops to stir, add the dilution of 10ml water, and methylene dichloride (2 * 15ml), organic layer saturated common salt water washing, anhydrous sodium sulfate drying, concentrated that resistates obtains compound 17 through silica gel column chromatography, colorless oil 62mg, yield: 98%; In the round bottom reaction flask of 15ml, take by weighing compound 17(50mg, 0.118mmol), N 2Protection is lower, dissolves with the dry tetrahydrofuran of 5ml, adds DBU(0.236mmol, 35ul), stirring at room 24 hours, TLC detects and finds that raw material disappears, direct concentrating under reduced pressure, the compound of silica gel column chromatography gets compound 20, colourless powder 27mg, yield: 70%.
Compound 19: with compound M-6(1.0mmol, 318mg) being dissolved in 20ml analyzes in the acetone, slowly drip the Jones reagent(2.2mmol of new configuration under the ice bath, 0.84ml) rapid stirring 30 minutes, after finding that raw material disappears, add Virahol (5ml) stopped reaction, the concentrated acetone that removes, thin up, with ethyl acetate extraction 2 times, the saturated common salt water washing, anhydrous sodium sulfate drying, concentrated, resistates obtains compound through silica gel column chromatography and obtains compound 15(72mg, yield: 20.7%), compound M-8(45mg, yield: 13.6%), compound M-8 (BMIM) PF4 ionic liquid suspendible of 5ml, in succession add morpholine (0.136mmol, 12ul), acetic acid (0.136mmol, 9ul), Paraformaldehyde 96 (0.68mmol, 20mg), stir 10h at 70 ℃, after raw material disappears, react with saturated sodium bicarbonate solution 10ml cancellation, ethyl acetate (2 * 20ml) extractions, organic layer is used saturated common salt water washing, anhydrous sodium sulfate drying in succession, concentrated that resistates obtains compound 19(32mg through silica gel column chromatography, yield: 70%).
(5) syntheti c route of compound 21:
Figure BDA00003525815000161
The preparation method:
Compound 21: in the round-bottomed flask of 25ml, take by weighing compound M-4(112mg, 0.3mmol) is dissolved in the methylene dichloride of 10ml N 2Protection is lower to add DMAP (5mg), pyridine (1.0mmol, 80.6ul), Ac successively 2O(0.45mmol, 42.5ul), room temperature is stirred 3h, after raw material disappears, concentrated resistates with 10ml dissolve with methanol resistates, adds 2N HCl(5ml) 35 ℃ of lower stirrings 24 hours, TLC point plate is found, raw material disappears, and produces new point, the concentrated methyl alcohol that removes, add ethyl acetate extraction 2 times, in succession use saturated sodium bicarbonate solution, saturated common salt water washing ethyl acetate layer, anhydrous sodium sulfate drying, concentrated that resistates obtains compound M-10 through silica gel column chromatography, compound M-10 obtains compound 21(79mg through a Swern oxidation, two step yield 95%).
(6) compound 22,27 syntheti c route:
Figure BDA00003525815000171
The preparation method:
Compound 22,27: with compound S-1(500mg, 1.50mmol) place the round bottom reaction flask of 250ml, with 100ml analytical pure dissolve with methanol sample, add the KOH of (7.5mmol, 420mg), stir, heat back and heat up in a steamer 24 hours, after raw material disappears, stopped reaction, thin up, concentrating under reduced pressure removes methyl alcohol, with the dilute hydrochloric acid furnishing neutral solution of 2N, uses ethyl acetate extraction 2 times, the saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure obtain intermediate M-11 crude product 550mg, get dry crude product compound M-11(100mg, 0.28mmol) be dissolved in N is housed in the dry DCM round bottom of the 50ml reaction flask 2Protection is lower, adds new system MnO in batches 2(1.42mmol, 123.5mg), stirring at normal temperature 72 hours after raw material no longer changes, is filtered Manganse Dioxide, and concentrated, resistates obtains compound 27, colourless powder 30mg, yield: 30.2% through silica gel column chromatography.Get dry crude product compound M-11(200mg, 0.56mmol) be dissolved in the round bottom reaction flask that 50ml analytical pure acetone is housed, place under the ice bath, slowly drip Jones reagent (2.52mmol, 0.96ml), under ice bath, stirring after 30 minutes, TLC point plate finds that raw material disappears, react with Virahol (5ml) cancellation, concentrate and remove acetone, thin up is used ethyl acetate extraction 2 times, the saturated common salt water washing, anhydrous sodium sulfate drying, concentrated, resistates obtains compound through silica gel column chromatography and obtains compound 22, colourless powder 80mg, yield: 40.8%.
(7) syntheti c route of compound 23,24,28-36:
Figure BDA00003525815000181
The preparation method:
With compound M-3(376.0mg, 1.0mmol) be dissolved in the methylene dichloride of 10ml drying, place 0 ℃, N 2Lower thionyl chloride (the 1.1mmol that slowly is injected into of gas protection; 80ul); after adding; rose to stirring at room 30 minutes; raw material disappears; add the shrend reaction of going out; be spin-dried for DCM; add 10ml THF dissolution sample, add again the dilute hydrochloric acid 5ml of 2N, 35 ℃ of lower stirrings 24 hours; after acetonylidene is all taken off; stop to stir, add ethyl acetate extraction 2 times, in succession use saturated sodium bicarbonate solution; saturated common salt water washing ethyl acetate layer; anhydrous sodium sulfate drying; concentrated that resistates obtains midbody compound M-12 through silica gel column chromatography, oxidation obtains compound 23 to compound M-12 through Manganse Dioxide, and M-12 has prepared compound 24 with preparation compound 13 similar methods simultaneously.
In the round bottom reaction flask of 50ml, with compound M-3(752.0mg, 2.0mmol), DMAP (10mg) is dissolved in the methylene dichloride of 15ml drying, places 0 ℃, N 2Lower pyridine (the 6.0mmol that slowly is injected into successively of gas protection; 484ul); diacetyl oxide (6.0mmol; 567ul); after adding, rose to stirring at room 24 hours, after TLC shows that raw material disappears; add the 20ml shrend reaction of going out; with methylene dichloride (2 * 20ml) extractions, saturated common salt water washing dichloromethane layer, anhydrous sodium sulfate drying; concentrate to get resistates; with 15ml THF dissolution sample, add again the dilute hydrochloric acid 8ml of 2N, 35 ℃ of lower stirrings 24 hours; after acetonylidene is all taken off; stop to stir, add ethyl acetate extraction 2 times, in succession use saturated sodium bicarbonate solution; saturated common salt water washing ethyl acetate layer; anhydrous sodium sulfate drying; concentrated that resistates obtains midbody compound M-13, colorless oil 773mg, yield: 92% through silica gel column chromatography.
Compound 28,30: take by weighing compound M-13(150mg, 0.36mmol) be dissolved in the dry methylene dichloride, add freshly prepd Manganse Dioxide (2.16mmol, 188mg) in batches, stirring at room 72 hours, after raw material disappears substantially, filter Manganse Dioxide, with methylene dichloride repetitive scrubbing Manganse Dioxide, filtrate concentrates to get resistates, obtain compound 30, colorless oil 113mg, yield: 75% through silica gel column chromatography.Get compound 30(80mg, 0.19mmol) be dissolved in the analytically pure tetrahydrofuran (THF), the HCl(5ml that adds 2N) stirring at room is 24 hours, after raw material disappears, add the dilution of 10ml water, with ethyl acetate (2 * 20ml) extracting twice, ethyl acetate layer is used saturated sodium bicarbonate, water, saturated common salt water washing in succession, anhydrous sodium sulfate drying is concentrated that resistates obtains compound 28, colourless powder 38mg, yield: 60% through silica gel column chromatography.
Compound 31,32,33,34,36 prepares through the method similar to front 15,16,17,20 preparation; Compound 31 obtains compound 29 through hydrochloric acid hydrolysis, and method is identical with compound 30 preparation compounds 28; Compound 35 prepares with compound 3 similar methods.
(8) syntheti c route of compound 37-41:
The preparation method:
Compound 37,38,40 similar with 30,31 preparation method; Compound 39,41 preparation methods are similar with the preparation of compound 19.
(9) compound 42,43,44 syntheti c route:
The preparation method:
Compound 42,43: compound M-3(376.0mg, 1.0mmol) places the round bottom reaction flask of 25ml, N 2The lower THF dissolving with the 10ml drying of protection is stirred under ice bath, slowly adds 60%NaH(3.0mmol, 120mg), stirred 20 minutes, slowly inject 4-morpholine carbonyl chloride (3.0mmol, 351ul), rose to stirring at room 3 hours, and do not react, heated up in a steamer next time 12 hours at 40 ℃ again, after raw material disappears, add water 10ml cancellation reaction, ethyl acetate equal-volume extraction 2 times, combined ethyl acetate layer, the saturated common salt water washing, anhydrous sodium sulfate drying concentrates to get resistates, obtains intermediate M-17 and M-18 through silica gel column chromatography, be all the oily compound thing, M-17(269mg wherein, yield: 55%), M-18(171mg, yield: 35%), then M-17 and M-18 pass through another hydroxymethyl sulfonylation again and take off acetonylidene, and polite oxidation obtains respectively compound 42(colorless oil 230mg, two step yield: 44%); Compound 43(colorless oil 143mg, two step yield: 27%).
Compound 44: weighing compound M-3(376.0mg, 1.0mmol) in the round bottom reaction flask of 25ml, N 2The lower DMF dissolving with the 10ml drying of protection, under ice bath, stir, slowly add 60%NaH(3.0mmol, 120mg), stirred 20 minutes, slowly inject bromoacetonitrile (3.0mmol, 209ul) under ice bath, stirred 2 hours, TLC detects and finds that raw material disappears, and stops to stir, and adds shrend and goes out, the ethyl acetate extraction layering that adds 50ml, the water continuous washing of each usefulness 20ml 3 times, saturated common salt water washing, anhydrous sodium sulfate drying, concentrate to get resistates, obtain intermediate M-16, colorless oil 311mg, yield 75% through silica gel column chromatography; Then M-16 is dissolved in the methylene dichloride of 10ml drying, adds DMAP (5mg), N 2The lower pyridine (2.0mmol, 161ul), thiophene-2-formyl chloride (2.0mmol, 215ul) of adding successively of protection; heated up in a steamer next time 12 hours at 40 ℃, raw material takes off acetonylidene through one after disappearing again; polite oxidation obtains compound 44, colorless oil 264mg, two step yield: 55%.
(10) compound 45,46,47,48,49 syntheti c route:
Figure BDA00003525815000211
The preparation method:
Compound 47,48 preparation method and compound 37,38 preparation methods are similar, similar to the preparation method of compound 19 from compound 48 preparation compounds 45,46,49 preparation method, wherein the yield of compound 49 is 55%, and the yield of compound 45 is 20%, and the yield of compound 46 is 10%.
(11) syntheti c route of compound 50-55:
Figure BDA00003525815000221
The preparation method:
Compound 51-54: take by weighing compound spiramine C/D(1.0g, 2.80mmol), analytical pure dissolve with methanol with 100ml, slowly add sodium borohydride (5.0mmol under the room temperature in batches, 189.5mg), add rear stirring 30min, after raw material disappears, slowly drip acetone under the ice bath to no longer emitting till the bubble, add the dilution of 50ml water, concentrating under reduced pressure removes methyl alcohol, with ethyl acetate (2 * 100ml) extractions, washing, the saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure reclaims solvent and gets not purified directly next step reaction of resistates, the resistates of drying is dissolved among the dry DMF of 20ml N 2Protection adds TERT-BUTYL DIMETHYL CHLORO SILANE (TBDMSCl, 2.50mmol, 376.7mg) successively under ice bath; imidazoles (imidazole, 2.50mmol, 170mg); stirring at room 2h after raw material disappears, adds water (50ml) dilution; with ethyl acetate (2 * 100ml) extractions; successively water, saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure get resistates and obtain midbody compound M-22(950mg through silica gel column chromatography; 2.0mmol, two step yield: 71.4%).With oxalyl chloride (2.0mmol, 190ul) at N 2Protection is made a bet and is injected in the dry long-neck reaction flask; miscible with the dry DCM of 10ml; place-78 ℃ of lower stirrings; slowly drip DMSO (4.0mmol, 283.6ul in2ml DCM), stir 30min; slowly dripping M-22(950mg; 2.0mmol, in5ml DCM), behind-78 ℃ of lower stirring 30min; drip triethylamine (4.0mmol; 554.9ul) naturally rise to room temperature, add water 20ml dilution, with methylene dichloride (2 * 20ml) extractions; the saturated common salt water washing; anhydrous sodium sulfate drying concentrates to get paste (927mg, yield: 98%).Getting paste (460mg, 0.97mmol) carries out silica gel column chromatography and obtains compound M-23(220mg, 0.46mmol) and M-24(215mg, 0.45mmol).With M-23(220mg, 0.46mmol), Paraformaldehyde 96 (69mg, 2.3mmol), Bu 4NI (34mg, 0.09mmol), in the dry round-bottomed flask of dry salt of wormwood (127mg, 92mmol) as for 50ml, N 2Protection is lower, in dry toluene 10ml dissolution sample, reaction mixture is as for 50 ℃ of lower stirrings 12 hours, after TLC point plate determines that raw material disappears, be cooled to room temperature and add entry 20ml, (2 * 20ml), organic layer is used the saturated common salt water washing in succession with ethyl acetate extraction, anhydrous sodium sulfate drying concentrates to get resistates; The resistates that drying is good dissolves with dry THF10ml, N 2Hemostasis TBAF (0.55mmol, 550ul are stirred in protection; 1M TBAF in THF); stirring at room 2h after raw material disappears, adds the dilution of 20ml water; extract with ethyl acetate (2*20ml); the saturated common salt water washing, anhydrous sodium sulfate drying, concentrated that resistates obtains compound 51(colorless oil through silica gel column chromatography; 85mg, yield: 49.8%).M-24(215mmol, 0.45mmol) get compound 50(colorless oil, 105mg, 65% with the TBAF deprotection).The again polite oxidation of mixture (467mg) (swern oxidation) of getting M-23 and M-24 obtains M-25 (420mg, 0.89mmol), gets M-25 (100mg; 0.21mmol); get compound 52(colorless oil, 55mg, yield: 73%) with the TBAF deprotection.Get M-25 (320mg, 0.68mmol), Paraformaldehyde 96 (102mg, 3.4mmol), Bu 4NI (50.2mg, 0.136mmol), in the dry round-bottomed flask of dry salt of wormwood (188mg, 1.36mmol) as for 50ml, N 2Protection is lower; in dry toluene 10ml dissolution sample, reaction mixture is as for 50 ℃ of lower stirrings 12 hours, after TLC point plate determines that raw material disappears; be cooled to room temperature and add entry 20ml; (2 * 20ml), organic layer is used saturated common salt water washing, anhydrous sodium sulfate drying in succession with ethyl acetate extraction; concentrate to get resistates; obtain compound 53(colorless oil, 147.7mg, yield: 45%) through silica gel column chromatography.Get compound 53(100mg, 0.207mmol) get compound through the TBAF deprotection and obtain compound 54(colorless oil, 49mg, yield: 65%).
Compound 55: take by weighing in the methylene dichloride that compound spiramine C/D (100mg, 0.28mmol) is dissolved in 30ml, add freshly prepd Manganse Dioxide (0.28mmol under the room temperature in batches, 0.56mmol 0.56mmol), be 10h pitch time, 10h, 10h after raw material disappears substantially, filters Manganse Dioxide, use the methylene dichloride repetitive scrubbing, merging filtrate, concentrated resistates gets compound 55(69.6mg, productive rate through silica gel column chromatography: 70%).
(12) syntheti c route of compound 56-58:
The preparation method:
Compound 56: take by weighing in the analytically pure acetone that compound spiramine C/D (100mg, 0.28mmol) is dissolved in 30ml, add freshly prepd Manganse Dioxide (0.56mmol in batches, 0.56mmol, 0.56mmol, 0.56mmol, 0.56mmol), stir 72h under the room temperature, after raw material disappears substantially, filter Manganse Dioxide, use the acetone repetitive scrubbing, merging filtrate, concentrated resistates is through the compound 48(31.6mg of silica gel column chromatography, productive rate: 30%).
Compound 57,58: take by weighing compound spiramine C/D(500mg, 1.4mmol) be dissolved in the analytical pure methyl alcohol of 50ml, add sodium borohydride (2.8mmol in batches, 105.8mg), stir 30min under the room temperature, after disappearing, raw material adds the acetone termination reaction, add the dilution of 30ml water, concentrating under reduced pressure removes methyl alcohol, with ethyl acetate (2 * 100ml) extractions, washing, the saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure gets resistates without being further purified directly next step reaction, dried residue (454mg, 1.26mmol) is dissolved in the methyl alcohol of 25ml, adds K 3Fe (CN) 6The aqueous solution (1.24g, 3.78mmo in10ml H 2O), add the aqueous solution (in the 750mg KOH solution 5ml water) of KOH, flow heated water 4h after raw material disappears, filters again, and the resistates of concentrating under reduced pressure gets compound M-26(180mg through silica gel column chromatography, two step yields: 35.8%).Compound M-26 is dissolved in the analytically pure acetone, adds Manganse Dioxide (880mg, 10.1mmol) in batches, stirring at room 72h after raw material disappears substantially, stops to stir, filter Manganse Dioxide, with acetone repetitive scrubbing Manganse Dioxide, merging filtrate, concentrate to get resistates, compound 57(59.8mg through silica gel column chromatography, 32%), compound 58(33mg, 18%).
The spectral data of above-claimed cpd is as follows:
Compound (1): 1H-NMR (400MHz, CDCl 3) δ: 6.05 (1H, d, J=1.2Hz), 5.34 (1H, d, J=1.2Hz), 4.24 (1H, dd, J=2.4,12.4Hz), (4.16 1H, d, J=12.4Hz), 2.86-2.91 (2H, m), (2.78 1H, dd, J=6.0,18.0Hz), 2.05-2.32 (5H, m), 1.66-1.95 (7H, m), 1.48-1.50 (1H, m), (1.25-1.38 2H, m), 0.91 (3H, s). 13C-NMR (100MHz, CDCl 3) δ: 206.2,195.9,173.2,146.6,119.4,76.0,57.5,45.8,44.9,44.8,40.4,38.2,36.6,35.9,33.1,27.2,25.9,24.3,22.8,20.1.HR-EI-MS m/z328.1673[M] +(C 20H 24N 2O 4, calcd328.1675).
Compound (2): 1H-NMR (400MHz, CDCl 3) δ: 5.98 (1H, s), 5.93 (1H, s), 5.34 (1H, s), (5.26 1H, s), 3.93 (2H, s), 2.83 (1H, d, J=3.2Hz), 2.68 (1H, t, J=11.2Hz), 2.52 (1H, d, J=1.2Hz), 2.16-2.22 (3H, m), 2.01-2.08 (1H, m), 1.87-1.97 (2H, m), 1.54-1.82 (5H, m), 1.35 (1H, ddd, J=4.4,12.4,16.8Hz), 0.94 (3H, s). 13C-NMR (100MHz, CDCl 3) δ: 202.3,195.7,173.3,146.2,144.8,125.8,119.9,75.4,57.8,53.5,44.7,42.5,39.5,36.3,36.2,35.0,27.3,25.9,24.3,20.9,20.8.HR-EI-MS m/z340.1682[M] +(C 21H 24O 4, calcd340.1675).
Compound (3): 1H-NMR (400MHz, CDCl 3) δ: 6.02 (1H, s), 5.37 (1H, s), 4.17 (1H, d, J=12.0Hz), 4.02 (1H, d, J=12.0Hz), 3.71 (4H, t, J=4.4Hz), 2.85 (1H, d, J=2.4Hz), 2.66-2.75 (3H, m), 2.53 (4H, brs), 2.10-2.53 (5H, m), (1.89-2.01 2H, m), 1.62-1.82 (3H, m), 1.53-1.60 (3H, m), 1.31-1.35 (1H, m), 0.92 (3H, s). 13C-NMR (100MHz, CDCl 3) δ: 208.2,197.0,173.0,146.6,119.7,75.5,68.8 (2CH 2-morpholine), 63.5,58.2,53.6 (2CH 2-morpholine), 52.5,47.4,44.6,42.5,40.4,37.1,36.3,34.4,27.6,26.0,22.5,22.3,20.6.HR-EI-MS m/z427.2366[M] +(C 25H 33NO 5, calcd427.2359).
Compound (4): 1H-NMR (400MHz, CDCl 3) δ: 6.04 (1H, d, J=1.6Hz), 5.39 (1H, d, J=1.6Hz), 4.22 (1H, dd, J=2.4,12.0Hz), 4.04 (1H, dd, J=1.6,12.0Hz), 2.40-2.90 (6H, m), (2.38 6H, s), 1.25-2.29 (13H, m), 0.91 (3H, s) .HR-EI-MS m/z385.2266[M] +(C 23H 31NO 4, calcd385.2253).
Compound (5): 1H-NMR (400MHz, CDCl 3) δ: 6.10 (1H, s), 5.47 (1H, s), (4.16 1H, d, J=12.0Hz), 4.06 (1H, d, J=12.0Hz), 3.88 (1H, m), (3.61 1H, m), 2.88 (1H, m), (2.81 1H, m), 2.63-2.69 (2H, m), 2.34 (1H, t, J=10.0,10.0Hz), 2.20-2.28 (2H, m), 1.92-2.12 (3H, m), (1.49-1.84 6H, m), 1.34-1.42 (1H, m), 0.90 (3H, s). 13C-NMR (100MHz, CDCl 3) δ: 210.4,198.8,172.7,145.8,121.1,75.2,65.9,58.2,52.6,48.5,44.0,42.2,40.1,36.4,35.9,33.6,27.1,25.9,22.2,21.7,20.2.HR-EI-MS m/z358.1791[M] +(C 21H 26O 5, calcd358.1980).
Compound (6): 1H-NMR (400MHz, CDCl 3) δ: 6.04 (1H, d, J=1.6Hz), 5.36 (1H, d, J=1.6Hz), 4.22 (1H, dd, J=2.0,12.0Hz), (4.09 1H, dd, J=1.2,12.0Hz), (3.08 1H, d, J=4.8Hz), 2.86 (1H, m), 2.67 (1H, m), 2.50 (1H, t, J=10.0,10.0Hz), 2.21-2.29 (2H, m), 2.17 (3H, s), 1.90-2.11 (3H, m), 1.68-1.84 (2H, m), 1.53-1.67 (4H, m), 1.30-1.38 (1H, ddd, J=4.4,11.0,15.2Hz), 1.02 (3H, s). 13C-NMR (100MHz, CDCl 3) δ: 200.4,197.1,172.8,146.6,119.5,75.5,57.4,54.8,48.9,44.5,44.0,40.3,40.2,36.8,34.0,27.6,25.8,23.6,22.2,20.5,16.2.HR-EI-MS m/z374.1536[M] +(C 21H 26O 4S, calcd374.1552).
Compound (7): 1H-NMR (400MHz, CDCl 3) δ: 6.11 (1H, d, J=1.2Hz), 5.42 (1H, d, J=1.2Hz), (4.20 1H, d, J=4.8Hz), 4.19 (1H, d, J=1.6Hz), 4.10 (1H, dd, J=1.6,12.4Hz), (2.90 1H, d, J=3.2Hz), 2.67 (1H, m), (2.56 1H, m), 2.50 (1H, m), 2.21-2.29 (2H, m), 1.41-2.10 (9H, m), 1.12 (3H, s). 13C-NMR (100MHz, CDCl 3) δ: 199.8,194.8,172.1,145.7,120.3,75.3,59.1,58.4,45.0,43.3,41.0,40.3,36.9,36.0,34.1,27.5,25.8,23.3,22.4,20.2.HR-EI-MS m/z406.0786[M] +(C 20H 23O 4Br, calcd406.0780).
Compound (8): 1H-NMR (400MHz, CDCl 3) δ: 6.10 (1H, d, J=1.2Hz), 5.42 (1H, d, J=1.2Hz), 4.09-4.16 (3H, m), 2.89 (1H, s), (2.67 1H, t, J=11.6Hz), 2.54 (1H, t, J=9.6Hz), 2.22-2.99 (3H, m), 1.92-2.13 (3H, m), (1.81-1.85 2H, m), 1.59-1.70 (4H, m), 1.42 (1H, m), 1.25 (1H, m), 1.08 (1H, s). 13C-NMR (100MHz, CDCl 3) δ: 199.9,194.9,172.1,146.0,120.4,75.6,58.9,58.8,54.6,44.5,41.3,40.3,37.0,36.2,33.9,27.5,25.9,23.2,22.5,20.3.HR-EI-MS m/z362.1287[M] +(C 20H 23O 4Cl, calcd362.1285).
Compound (9): 1H-NMR (400MHz, CDCl 3) δ: 6.13 (1H, s), 6.02 (1H, d, J=1.6Hz), (5.31 1H, d, J=1.6Hz), 4.27 (1H, d, J=10.8Hz), 3.83 (1H, dd, J=2.4,10.8Hz), (3.26 1H, m), 2.88 (1H, t, J=2.8Hz), (2.49-2.54 2H, m), 2.17 (1H, m), 1.70-1.96 (7H, m), 1.56 (1H, m), 1.18 (3H, s). 13C-NMR (100MHz, CDCl 3) δ: 196.9,195.6,171.5,159.8,147.3,123.4,118.4,79.8,54.9,47.6,42.5,38.9,38.8 (C tAnd C s), 35.8,25.5,24.5,23.4,21.8,19.5.HR-EI-MS m/z326.1512[M] +(C 20H 22O 4, calcd326.1518).
Compound (10): 1H-NMR (400MHz, CDCl 3) δ: 5.89 (1H, s), 5.43 (1H, s), (5.10 1H, brs), 4.08 (1H, d, J=11.6Hz), 4.00 (1H, d, J=11.6Hz), (3.95 1H, s), 2.70 (1H, s), (2.64 1H, t, J=10.8Hz), 2.51 (1H, brs), 2.47 (1H, brs), 2.46 (1H, d, J=13.2Hz), 2.17 (2H, s), 2.05-2.13 (1H, m), (1.56-1.83 8H, m), 1.32-1.38 (1H, m), 1.03 (3H, s). 13C-NMR (100MHz, CDCl 3) δ: 208.5,173.4,151.2,144.1,125.8,112.6,75.3,74.8,53.0,44.1,40.2,36.6,35.5,27.8,25.1,24.3,20.8,17.0.HR-EI-MS m/z342.1839[M] +(C 21H 26O 4, calcd342.1831).
Compound (11): 1H-NMR (400MHz, CDCl 3) δ: 5.96 (1H, d, J=1.6Hz), 5.25 (1H, d, J=1.6Hz), (5.11 1H, s), 4.18 (1H, dd, J=4.8, J=12.0Hz), (3.66 1H, dd, J=2.4, J=11.2Hz), 3.55 (1H, dd, J=1.2, J=11.2Hz), 3.49 (3H, s), (2.73 1H, brs), 2.64-2.72 (2H, m), 1.18-1.94 (14H, m), 0.78 (1H, m), 0.75 (3H, s). 13C-NMR (100MHz, CDCl 3) δ: 204.5,147.2,117.5,103.7,71.3,70.5,55.9,50.5,49.0,43.6,41.9,40.7,35.8,34.2,33.0,27.1,24.9,24.1,23.1,21.9,18.7.HR-EI-MS m/z346.2122[M] +(C 21H 30O 4, calcd346.2144).
Compound (12): 1H-NMR (400MHz, CDCl 3) δ: 6.02 (1H, d, J=1.6Hz), 5.32 (1H, d, J=1.6Hz), (4.40 1H, s), 3.45 (2H, m), 3.42 (3H, s), 2.77 (1H, brs), 2.48-2.64 (2H, m), (2.16-2.40 4H, m), 1.96 (1H, t, J=10.4Hz), (1.63-1.88 6H, m), 1.51-1.54 (1H, m), 1.41-1.43 (1H, m), 0.97 (1H, m), 0.66 (3H, s). 13C-NMR (100MHz, CDCl 3) δ: 209.9,196.7,146.5,119.3,102.7,70.4,57.7,55.5,47.9,45.7,40.4,39.7,37.5,35.7,33.6,31.2,27.2,26.8,23.5,21.6,21.4.HR-EI-MS m/z344.1998[M] +(C 21H 28O 4, calcd344.1988).
Compound (13): 1H-NMR (400MHz, CDCl 3) δ: 5.99 (1H, d, J=1.2Hz), 5.98 (1H, dd, J=1.2,2.4Hz), 5.33 (1H, dd, J=1.2,2.4Hz), 5.32 (1H, d, J=1.2Hz), 4.39 (1H, d, J=1.2Hz), 3.46 (1H, dd, J=1.8,11.2Hz), 3.43 (3H, s), 3.27 (1H, dd, J=1.8,11.2Hz), 2.78 (1H, d, J=3.0Hz), 2.33-2.45 (4H, m), (2.15 1H, t, J=10.4Hz), 1.94 (1H, t, J=10.4Hz), 1.52-1.88 (7H, m), (1.07 1H, m), 0.84 (3H, s). 13C-NMR (100MHz, CDCl 3) δ: 203.3,196.3,146.6,145.5,126.2,119.3,103.3,71.6,57.0,55.2,54.8,44.2,41.0,39.2,35.9,35.5,30.6,27.4,26.6,24.0,22.7,21.3.HR-EI-MS m/z356.1985[M] +(C 22H 28O 4, calcd356.1988).
Compound (14): 1H-NMR (400MHz, CDCl 3) δ: 6.00 (1H, d, J=1.6Hz), 5.29 (1H, d, J=1.6Hz), 4.13 (1H, dddd, J=2.8,5.2,11.6,12.8Hz), (4.07 1H, dd, J=2.8,11.6Hz), (3.87 1H, d, 11.6Hz), 3.54 (1H, dd, J=2.8,11.6Hz), 3.47 (1H, d, 11.6Hz), 2.77 (1H, brs), (2.64 1H, d, J=3.2Hz), 2.33-2.41 (1H, m), 1.97-2.17 (2H, m), 0.78-1.83 (13H, m), 0.73 (3H, s). 13C-NMR (100MHz, CDCl 3) δ: 203.8,146.3,118.5,73.0,70.5,67.5,50.0,47.3,42.2,40.8,39.3,38.3,35.8,33.0,27.3,25.1,24.6,23.4,22.2,18.7.HR-EI-MSm/z316.2043[M] +(C 20H 28O 3, calcd316.2038).
Compound (15): 1H-NMR (400MHz, CDCl 3) δ: 6.04 (1H, s), 5.33 (1H, s), 3.90 (1H, d, J=11.2Hz), 3.76 (1H, dd, J=2.4,11.2Hz), 3.45 (2H, s), 2.82 (1H, d, J=2.4Hz), 2.58 (1H, d, J=9.2Hz), 2.38-2.46 (1H, m), 2.08-2.18 (2H, m), 1.39-1.98 (11H, m), (1.14-1.23 1H, m), 0.66 (3H, s). 13C-NMR (100MHz, CDCl 3) δ: 208.6,195.6,145.8,119.6,71.7,66.9,56.9,45.6,45.0,40.4,37.4,37.2,36.9,35.5,33.3,26.9,26.1,25.1,22.3,21.8.HR-EI-MS m/z314.1889[M] +(C 20H 26O 3, calcd314.1882).
Compound (16): 1H-NMR (400MHz, CDCl 3) δ: 6.07 (1H, d, J=0.8Hz), 5.41 (1H, d, J=0.8Hz), 3.82-3.89 (2H, m), (3.55 1H, m), 3.52 (1H, d, J=10.8Hz), 3.29-3.36 (2H, m), 2.85 (1H, brs), 2.67-2.71 (2H, m), 2.36-2.47 (2H, m), 2.02-2.13 (2H, m), (1.93-1.99 1H, m), 1.70-1.80 (3H, m), 1.56-1.63 (2H, m), (1.44-1.52 3H, m), 1.25-1.30 (1H, m), 0.70 (3H, s). 13C-NMR (100MHz, CDCl 3) δ: 212.2,198.8,145.6,120.7,72.8,68.9,66.1,57.6,52.2,49.3,43.7,40.6,37.4,35.8,35.6,34.2,26.8,25.8,24.1,21.8,21.6.HR-EI-MS m/z344.1989[M] +(C 21H 28O 4, calcd344.1988).
Compound (17): 1H-NMR (400MHz, CDCl 3) δ: 6.00 (1H, s), 5.34 (1H, s), (4.32 1H, dd, J=3.6, J=9.6Hz), (4.25 1H, dd, J=5.6, J=9.6Hz), (3.91 1H, d, J=11.2Hz), 3.49 (1H, d, J=12.0Hz), 3.30-3.37 (2H, m), (3.12 3H, s), 2.77-2.82 (2H, m), (2.34-2.45 2H, m), 2.04-2.17 (2H, m), 1.96-1.97 (1H, m), (1.46-1.81 8H, m), 1.25-1.31 (1H, m), 0.73 (3H, s). 13C-NMR (100MHz, CDCl 3) δ: 209.0,195.6,145.8,119.7,72.5,72.0,68.8,57.8,48.5,47.5,42.8,40.6,37.3,36.9,35.8,35.5,34.3,26.6,26.1,25.3,22.1,21.6.HR-EI-MSm/z422.1759[M] +(C 22H 30O 6S, calcd422.1763).
Compound (18): 1H-NMR (400MHz, CDCl 3) δ: 5.94 (1H, s), 5.46 (1H, s), 5.08 (2H, s), 3.93 (1H, s), 3.91 (1H, d, J=12.0Hz), 3.58 (1H, dd, J=2.8, J=12.0Hz), (3.44 1H, d, J=11.2Hz), 3.25 (1H, dd, J=2.8, J=11.2Hz), 2.34-2.49 (4H, m), 2.03 (1H, m), 1.21-2.06 (11H, m), 0.86 (3H, s). 13C-NMR (100MHz, CDCl 3) δ: 209.4,150.0,144.8,126.8,113.1,74.5,73.7,69.6,53.2,48.6,44.9,41.6,36.7,35.7,35.3,35.2,26.6,25.6,24.4,21.8,20.3.HR-EI-MS m/z328.2040[M] +(C 21H 28O 3, calcd328.2038).
Compound (19): 1H-NMR (400MHz, CDCl 3) δ: 5.98 (1H, s), 5.35 (1H, s), (3.97 1H, d, J=12.0Hz), 3.53 (1H, dd, J=2.8, J=12.0Hz), 3.43 (1H, dd, J=1.2, J=11.6Hz), 3.14 (1H, dd, J=3.2, J=11.6Hz), 3.12 (1H, d, J=6.0Hz), 2.87 (1H, d, J=6.0Hz), 2.42-2.57 (2H, m), 2.41 (1H, brs), 2.07-2.18 (3H, m), 1.52-1.99 (9H, m), 1.53 (1H, m), 1.34-1.36 (1H, m), 0.83 (3H, s). 13C-NMR (100MHz, CDCl 3) δ: 203.8,201.1,145.1,126.9,73.9,68.9,60.3,58.0,53.2,52.8,43.1,41.0,37.2,35.4,34.1,24.5,24.3,24.1,23.4,21.7.HR-EI-MS m/z342.1840[M] +(C 21H 28O 4, calcd342.1831).
Compound (20): 1H-NMR (400MHz, CDCl 3) δ: 5.99 (2H, s), 5.35 (1H, s), 5.33 (1H, s), (3.93 1H, d, J=11.6Hz), 3.53 (1H, dd, J=2.4,11.6Hz), 3.42 (1H, d, J=11.6Hz), (3.13 1H, dd, J=2.4,11.6Hz), 2.83 (1H, d, J=2.4Hz), 2.41-2.50 (3H, m), 1.47-2.06 (10H, m), 1.25-1.34 (1H, m), 0.83 (3H, s). 13C-NMR (100MHz, CDCl 3) δ: 202.7,195.8,145.9,145.7,126.4,119.3,73.9,69.2,57.0,53.2,44.0,41.1,37.1,35.7,35.5,35.4,26.8,26.1,24.3,23.7,21.7.HR-EI-MS m/z326.1879[M] +(C 21H 26O 3, calcd326.1882).
Compound (21): 1H-NMR (400MHz, CDCl 3) δ: 5.93 (1H, d, J=1.6Hz), 5.25 (1H, d, J=2.0Hz), (5.24 1H, d, J=1.6Hz), 4.12 (1H, d, J=5.2Hz), (3.86 1H, dd, J=3.2,11.6Hz), 3.30 (1H, dd, J=1.6,11.6Hz), 2.81 (1H, m), (2.25-2.35 2H, m), 2.02-2.08 (1H, m), 1.48-1.91 (10H, m), 1.17-1.27 (3H, m), 0.69 (3H, s). 13C-NMR (100MHz, CDCl 3) δ: 200.7,148.0,117.4,96.3,68.9,66.1,49.1,43.7,43.4,40.3,36.7,34.7,33.7,29.6,27.3,24.5,24.1,23.5,22.5,20.8.HR-EI-MS m/z314.1882[M] +(C 20H 26O 3, calcd314.1882).
Compound (22): 1H-NMR (400MHz, CDCl 3) δ: 6.08 (1H, s), 5.39 (1H, s), 2.71-2.91 (3H, m), 2.41-2.22 (1H, m), 2.23 (1H, t, J=9.6Hz), 1.47-2.13 (12H, m), 1.30 (3H, s). 13C-NMR (100MHz, CDCl 3) δ: 203.5,194.9,170.5,169.8,146.1,120.2,57.2,45.8,45.5,44.8,44.0,39.1,37.3,35.7,35.4,26.8,25.9,24.9,21.7,19.9.HR-EI-MS m/z342.1456[M] +(C 20H 22O 5, calcd342.1467).
Compound (23): 1H-NMR (400MHz, CDCl 3) δ: 6.00 (1H, d, J=1.6Hz), 5.29 (1H, d, J=1.6Hz), 4.81 (1H, d, J=14.0Hz), 4.16 (1H, dd, J=6.4,12.4Hz), 4.02 (1H, d, J=12.4Hz), 3.95 (1H, d, J=14.0Hz), 3.61 (1H, brs), 2.82 (1H, m), 2.74 (1H, d, J=2.0Hz), 2.18-2.26 (3H, m), (1.71-1.86 6H, m), 1.66 (1H, d, J=14.0Hz), 1.43-1.55 (3H, m), 1.35 (1H, ddd, J=4.0,14.4Hz), 1.79 (1H, d, J=12.0Hz), 0.85-0.91 (4H, m). 13C-NMR (100MHz, CDCl 3) δ: 204.8,146.7,117.9,77.2,71.2,58.2,51.3,50.4,46.0,38.8,38.5,36.1,35.4,30.9,28.7,28.1,25.3,25.0,19.1,15.5.HR-EI-MS m/z380.1651[M] +(C 20H 28O 5S, calcd380.1657).
Compound (24): 1H-NMR (500MHz, CDCl 3) δ: 6.14 (1H, d, J=2.4Hz), 6.04 (1H, d, J=1.2Hz), 5.80 (1H, d, J=2.4Hz), 5.36 (1H, d, J=1.2Hz), 4.86 (1H, d, J=13.6Hz), (4.02 1H, brs), 3.87 (1H, d, J=13.6Hz), (2.87 1H, m), 2.65 (1H, m), (2.22-2.36 2H, m), 1.15-2.14 (15H, m). 13C-NMR (125MHz, CDCl 3) δ: 198.7,195.5,146.3,146.1,124.2,119.7,66.4,57.7,56.2,54.5,45.2,38.5,37.9,35.8,32.5,31.7,29.2,27.3,26.9,22.4,18.1.HR-EI-MS m/z390.1512[M] +(C 21H 26O 5S, calcd390.1501).
Compound (25): 1H-NMR (400MHz, CDCl 3) δ: 4.26 (1H, dd, J=2.0,11.6Hz), (4.09 1H, d, J=11.6Hz), 4.03 (1H, dd, J=4.4,11.6Hz), 3.69 (4H, m), 3.17-3.21 (1H, m), 2.87 (1H, m), 2.67 (1H, dd, J=4.4,12.4Hz), 2.49-2.52 (3H, m), 2.43-2.46 (1H, d, 12.4Hz), 2.31-2.38 (4H, m), (2.21-2.24 1H, d, 13.2Hz), (1.98-2.05 1H, m), 1.15-1.80 (12H, m), 0.95 (3H, s). 13C-NMR (100MHz, CDCl 3) δ: 220.7,174.0,76.3,69.8,66.8,56.9,53.5,50.8,49.8,46.9,45.9,43.3,40.5,37.3,32.7,29.4,27.3,27.2,23.5,20.2,18.4,17.3.HR-EI-MS m/z417.2514[M] +(C 24H 35NO 5, calcd417.2515).
Compound (26): 1H-NMR (400MHz, CDCl 3) δ: 4.25 (1H, d, J=11.6Hz), 4.03-4.10 (2H, m), 3.69-3.74 (4H, m), 3.00-3.03 (1H, m), 2.59-3.61 (4H, m), 2.36-2.43 (4H, m), 2.17-2.27 (3H, m), (1.98-2.01 1H, m), 1.13-1.82 (12H, m), 0.94 (3H, s). 13C-NMR (100MHz, CDCl 3) δ: 220.1,174.0,76.4,69.6,66.9,56.9,53.5,51.0,49.7,47.1,45.9,44.2,40.6,37.6,32.8,29.2,27.3,24.0,23.5,21.2,20.2,16.4.HR-EI-MS m/z417.2532[M] +(C 24H 35NO 5, calcd417.2515).
Compound (27): 1H-NMR (400MHz, CD 3OD) δ: 5.89 (1H, d, J=3.2Hz), 5.26 (1H, d, J=3.2Hz), 4.10 (1H, dd, J=4.8,12.0Hz), 3.49 (1H, d, J=11.6Hz), 3.41 (1H, d, J=11.6Hz), (2.73 1H, brs), 2.14-2.57 (3H, m), 1.97-2.03 (1H, m), (1.42-1.90 10H, m), 1.21-1.28 (1H, m), 0.99 (3H, s), (0.97 1H, m), 0.80 (1H, td, J=3.6,12.8Hz). 13C-NMR (100MHz, CD 3OD) δ: 203.7,179.1,149.0,117.9,71.5,65.3,53.9,51.7,50.3,46.7,39.7,36.5,30.7,29.4,28.0,27.3,26.5,24.2,20.8,17.2.HR-EI-MS m/z348.1937[M] +(C 20H 28O 5, calcd348.1937).
Compound (28): 1H-NMR (400MHz, CD 3OD) δ: 5.90 (1H, d, J=1.6Hz), 5.26 (1H, d, J=1.6Hz), 4.05 (1H, dd, J=4.8,12.0Hz), 3.97 (1H, d, J=12.4Hz), 3.91 (1H, d, J=12.4Hz), (3.72 1H, d, J=11.2Hz), 3.57 (1H, d, J=11.2Hz), 2.75 (1H, brs), (2.06-2.12 4H, m), 1.66-1.92 (8H, m), (1.53-1.63 1H, m), 1.28-1.41 (2H, m), (0.95-1.06 3H, m), 0.99 (3H, s), 0.70 (1H, m). 13C-NMR (100MHz, CD 3OD) δ: 204.1,149.3,117.5,71.6,65.9,62.3,54.4,51.6,43.9,39.2,37.3,37.2,36.4,29.0,28.0,27.8,26.5,20.5,19.0.HR-EI-MSm/z334.2146[M] +(C 20H 30O 4, calcd334.2144).
Compound (29): 1H-NMR (400MHz, CDCl 3) δ: 6.04 (1H, s), 5.34 (1H, s), (4.30 1H, d, J=12.8Hz), 4.22 (1H, d, J=12.8Hz), 3.60 (1H, d, J=11.2Hz), 3.56 (1H, d, J=11.2Hz), (2.83 1H, brs), 2.58-2.77 (2H, m), (2.28 1H, t, J=11.2Hz), (2.02-2.13 2H, m), 2.00 (3H, s), 1.52-1.93 (11H, m), (1.25 1H, brs), 1.00-1.07 (2H, m), 0.96 (3H, s). 13C-NMR (100MHz, CDCl 3) δ: 208.4,196.5,170.5,146.2,119.5,64.1,64.0,58.1,51.8,48.4,38.7,38.4,38.1,35.6,33.6,27.1,26.3,25.7,23.5,20.9,18.0.HR-EI-MSm/z374.2082[M] +(C 22H 30O 5, calcd374.2093).
Compound (30): 1H-NMR (400MHz, CDCl 3) δ: 5.98 (1H, d, J=1.2Hz), 5.28 (1H, d, J=1.2Hz), (4.59 1H, d, J=13.2Hz), 4.25 (1H, d, J=13.2Hz), (4.10 1H, m), 3.99 (1H, d, J=11.2Hz), 2.79 (1H, s), 2.48 (1H, s), 2.13 (3H, s), (2.06 3H, s), 1.43-1.97 (15H, m), 1.12-1.16 (1H, m), 1.03 (3H, s), 0.82 (1H, m). 13C-NMR (100MHz, CDCl 3) δ: 203.8,171.1,170.8,146.7,118.2,71.2,66.8,63.3,53.0,50.5,46.8,41.5,36.5,36.4,35.6,35.3,28.0,27.5,25.6,25.0,21.1,20.9,19.5,18.0.HR-EI-MS m/z418.2341[M] +(C 24H 34O 6, calcd418.2355).
Compound (31): 1H-NMR (400MHz, CDCl 3) δ: 6.05 (1H, d, J=0.8Hz), 5.35 (1H, d, J=0.8Hz), 4.34 (1H, d, J=12.8Hz), 4.17 (1H, d, J=12.8Hz), (4.06 1H, d, J=11.2Hz), 3.99 (1H, d, J=11.2Hz), 2.85 (1H, brs), (2.66 1H, s), 2.63 (1H, s), (2.28 1H, m), 2.07-2.13 (1H, m), (2.05 3H, s), 2.02 (3H, s), (1.57-1.93 10H, m), 1.03-1.09 (2H, m), 0.93 (3H, s). 13C-NMR (100MHz, CDCl 3) δ: 207.6,196.1,170.6,170.1,146.0,119.3,64.9,63.6,57.8,51.5,48.0,38.5,38.1,36.6,36.0,35.4,33.3,26.8,26.1,25.7,23.2,20.6 (2CH 3), 17.8.HR-EI-MS m/z416.2220[M] +(C 24H 32O 6, calcd416.2199).
Compound (32): 1H-NMR (400MHz, CDCl 3) δ: 5.99 (1H, d, J=1.2Hz), 5.35 (1H, d, J=1.2Hz), 4.19 (1H, d, J=13.2Hz), 3.98 (1H, d, J=13.2Hz), 3.93 (1H, d, J=11.6Hz), (3.87 1H, d, J=11.6Hz), 3.83 (1H, d, J=4.0Hz), 3.47 (1H, m), (2.81 2H, m), 2.69 (1H, m), (2.12-2.26 2H, m), 1.98 (3H, s), (1.94 3H, s), 1.75-1.86 (1H, m), (1.69-1.73 2H, m), 1.43-1.63 (7H, m), (0.99-1.10 1H, m), 0.93 (3H, s). 13C-NMR (100MHz, CDCl 3) δ: 208.9,199.1,170.8,170.4,145.8,120.7,65.8,65.6,63.3,57.4,54.0,53.6,44.9,38.5,37.8,36.6,35.6,32.9,27.1,26.6,26.4,22.5,20.8,20.7,17.8.HR-EI-MS m/z446.2305[M] +(C 25H 34O 7, calcd446.2305).
Compound (33): 1H-NMR (400MHz, CDCl 3) δ: 5.98 (1H, s), 5.33 (1H, s), 4.31 (1H, dd, J=3.2,11.2Hz), 4.29 (1H, d, J=13.6Hz), 4.11 (1H, d, J=8.0Hz), 4.08 (1H, d, J=13.6Hz), (4.06 1H, d, J=8.0Hz), 3.99 (2H, d, J=3.6Hz), 3.10 (1H, m), (2.84 1H, brs), 2.29-2.30 (2H, m), (2.05 3H, s), 2.04 (3H, s), (2.00 3H, s), 1.48-1.96 (9H, m), (1.09-1.25 2H, m), 1.04 (3H, s). 13C-NMR (100MHz, CDCl 3) δ: 206.7,195.9,170.9,170.8,170.5,146.6,119.0,66.3,65.8,63.4,57.6,53.9,49.5,44.7,38.5,38.9,36.8,35.7,33.3,27.1,26.7,26.5,23.3,20.8 (3CH 3), 17.9.HR-EI-MS m/z488.2397[M] +(C 27H 36O 8, calcd488.2410).
Compound (34): 1H-NMR (400MHz, CDCl 3) δ: 5.94 (1H, s), 5.31 (1H, s), 4.43 (1H, dd, J=6.0,10.0Hz), 4.27 (1H, dd, J=2.4,10.0Hz), 4.23 (1H, d, J=13.2Hz), 4.06 (1H, d, J=13.2Hz), 3.99 (1H, d, J=11.6Hz), (3.92 1H, d, J=11.6Hz), 3.07 (3H, s), 3.01 (1H, m), 2.80 (1H, brs), 2.13-2.27 (2H, m), 2.02 (3H, s), 1.95 (3H, s), 1.70-1.91 (2H, m), 1.58-1.68 (6H, m), 1.46 (1H, t, J=12.0Hz), 1.07-1.21 (2H, m), (1.01 3H, s), 0.82 (1H, m). 13C-NMR (100MHz, CDCl 3) δ: 206.7,196.0,170.8,170.3,146.3,119.5,71.9,65.8,63.6,57.9,52.3,49.7,44.2,38.3,38.1,36.8 (3CH 3), 35.6,33.0,27.1,26.6,26.5,23.6,20.8,20.7,17.8.HR-EI-MS m/z524.2072[M] +(C 26H 36O 9S, calcd524.2080).
Compound (35): 1H-NMR (400MHz, CDCl 3) δ: 5.92 (1H, d, J=1.2Hz), 5.26 (1H, d, J=1.2Hz), 4.22 (1H, d, J=13.2Hz), 3.97 (1H, d, J=11.2Hz), (3.92 1H, d, J=13.2Hz), 3.87 (1H, d, J=11.2Hz), 3.64-3.71 (4H, m), (2.77-2.85 1H, m), 2.57 (1H, brs), (2.05-2.53 9H, m), 1.99 (3H, s), (1.96 3H, s), 1.45-1.83 (9H, m), (1.39 1H, d, J=7.6Hz), 1.00-1.19 (1H, m), 0.98 (3H, s). 13C-NMR (100MHz, CDCl 3) δ: 205.1,197.3,170.8,170.5,146.5,118.9,66.8 (2CH 2-morpholine), and 65.9,63.1,62.5,57.6,57.1,53.0 (2CH 2-morpholine), 47.7,45.5,38.7,38.1,36.9,35.7,33.2,26.9,26.7,26.6,22.9,20.8,20.7,17.8.HR-EI-MS m/z515.2879[M] +(C 29H 41NO 7, calcd515.2833).
Compound (36): 1H-NMR (400MHz, CDCl 3) δ: 6.51 (1H, t, J=3.6Hz), 6.05 (1H, s), (5.82 1H, t, J=3.6Hz), 5.34 (1H, s), (4.38 1H, d, J=11.2Hz), 4.30 (1H, d, J=12.8Hz), 4.16 (1H, d, J=11.2Hz), 4.14 (1H, d, J=12.8Hz), (2.84 1H, s), 2.52 (1H, s), (2.22 1H, m), 2.13 (1H, m), (2.06 3H, s), 2.01 (3H, s), (1.51-1.96 8H, m), 1.21 (3H, s), (1.11 2H, m), 0.87 (1H, m). 13C-NMR (100MHz, CDCl 3) δ: 197.2,195.8,171.0,170.3,146.1,142.5,125.1,119.6,63.6,63.5,57.4,57.0,47.8,39.6,38.5,37.6,35.7,33.3,28.1,27.2,24.7,20.8,20.7,17.7.HR-EI-MS m/z428.2202[M] +(C 25H 32O 6, calcd428.2199)
Compound (37): 1H-NMR (400MHz, CDCl 3) δ: 5.98 (1H, d, J=1.2Hz), 5.30 (1H, d, J=1.2Hz), 4.56 (1H, d, J=11.2Hz), 4.24 (1H, d, J=11.2Hz), (4.22 1H, d, J=13.2Hz), 4.20 (1H, d, J=13.2Hz), 4.07 (1H, d, J=12.0Hz), 3.13 (3H, s), 3.04 (3H, s), 2.8 (1H, s), 2.60 (1H, s), 2.08 (1H, d, J=13.6Hz), (2.00 1H, dd, J=4.8,13.6Hz), (1.65-1.84 6H, m), 1.58-1.65 (1H, m), (1.38-1.49 3H, m), 1.12-1.23 (1H, m), (1.09 3H, s), 0.84-0.92 (1H, m). 13C-NMR (100MHz, CDCl 3) δ: 202.9,146.2,118.6,72.3,70.6,67.8,52.3,50.1,46.7,41.5,37.4,36.6,36.9,35.7,35.3,34.7,27.9,27.0,25.6,24.8,19.2,17.9.HR-EI-MSm/z490.1703[M] +(C 22H 34O 8S 2, calcd490.1695).
Compound (38): 1H-NMR (400MHz, CDCl 3) δ: 6.05 (1H, s), 5.39 (1H, s), 4.80 (1H, d, J=11.2Hz), 4.33 (1H, d, J=11.2Hz), 4.30 (1H, d, J=10.0Hz), (4.15 1H, d, J=10.0Hz), 3.06 (3H, s), 3.04 (3H, s), 2.89 (1H, brs), 2.66 (1H, dd, J=9.6,9.6Hz), 2.51 (1H, dd, J=11.6,11.6Hz), 2.31 (1H, t, J=12.4,14.0Hz), 2.17 (1H, t, J=8.8,10.4Hz), 1.86-2.06 (5H, m), 1.76-1.80 (1H, d, J=13.6Hz), 1.60-1.71 (4H, m), (1.08-1.20 2H, m), 1.03 (3H, s). 13C-NMR (100MHz, CDCl 3) δ: 207.3,195.9,145.8,119.9,71.6,65.8,57.9,51.1,47.9,38.8,38.5,37.9,37.1,36.6,35.3,35.2,32.8,26.7,26.1,25.5,23.3,17.5.HR-EI-MS m/z488.1512[M] +(C 22H 32O 8, calcd488.1539).
Compound (39): 1H-NMR (400MHz, CDCl 3) δ: 6.48 (1H, d, J=2.8Hz), 6.06 (1H, d, J=1.2Hz), 5.79 (1H, d, J=2.8Hz), 5.38 (1H, d, J=2.8Hz), (4.43 1H, d, J=10.4Hz), 4.41 (1H, d, J=10.8Hz), 4.33 (1H, d, J=10.4Hz), 4.27 (1H, d, J=10.8Hz), (3.05 3H, s), 2.98 (3H, s), (2.88 1H, s), 2.66 (1H, t, J=2.8Hz), 2.33 (1H, m), 2.12-2.20 (1H, m), 2.02-2.08 (2H, m), 1.89-1.94 (3H, m), 1.63-1.74 (5H, m), 1.35 (3H, s), 1.13-1.25 (1H, m). 13C-NMR (100MHz, CDCl 3) δ: 197.2,195.5,145.8,142.5,125.2,120.1,70.0,65.9,56.9,47.4,39.8,38.0,37.8,37.5,37.0,35.5,32.8,28.3,26.9,24.5,17.7.HR-EI-MS m/z500.1541[M] +(C 23H 32O 8S 2, calcd500.1539).
Compound (40): 1H-NMR (400MHz, CDCl 3) δ: 6.06 (1H, d, J=1.2Hz), 5.36 (1H, d, J=1.2Hz), 4.52 (1H, d, J=12.8Hz), 4.20-4.26 (3H, m), 3.97-4.10 (5H, m), 2.86 (1H, s), 2.57-2.70 (2H, m), 2.10-2.31 (2H, m), 1.61-1.98 (8H, m), (1.08-1.25 3H, m), 1.07 (3H, s). 13C-NMR (100MHz, CDCl 3) δ: 207.6,196.1,167.3,167.0,145.9,119.9,66.9,65.4,58.0,51.6,48.3,40.7,40.5,38.6,38.5,37.0,36.0,35.5,33.3,26.9,26.3,25.9,23.6,17.9.HR-EI-MS m/z484.1423[M] +(C 24H 30O 6Cl 2, calcd484.1419).
Compound (41): 1H-NMR (400MHz, CDCl 3) δ: 6.53 (1H, d, J=2.4Hz), 6.06 (1H, s), 5.82 (1H, d, J=2.4Hz), 5.36 (1H, s), 4.48 (1H, m), (4.33 1H, d, J=11.2Hz), 4.21 (1H, d, J=13.2Hz), (4.10 2H, s), 4.04 (2H, s), 2.86 (1H, s), (2.57 1H, s), 2.12-2.30 (2H, m), 1.55-1.93 (10H, m), 1.25 (3H, s), 1.12-1.22 (2H, m). 13C-NMR (100MHz, CDCl 3) δ: 197.2,195.6167.4,166.8,145.9,142.1,125.8,119.8,65.4,65.1,57.3,57.0,47.7,40.7,40.5,39.9,38.2,37.7,35.6,32.9,28.0,27.1,27.0,24.8,17.7.HR-EI-MS m/z496.1422[M] +(C 25H 30O 6Cl 2, calcd496.1419).
Compound (42): 1H-NMR (400MHz, CDCl 3) δ: 6.05 (1H, s), 5.36 (1H, s), (4.39 1H, d, J=12.8Hz), 4.32 (1H, d, J=12.8Hz), 4.20 (1H, d, J=9.6Hz), 4.06 (1H, d, J=9.6Hz), (3.68 4H, brs), 3.50 (1H, brs), (3.46 1H, brs), 3.30 (2H, brs), (3.01 3H, s), 2.85 (1H, brs), (2.70 1H, dd, J=8.8,20.0Hz), (2.46 1H, dd, J=12.0,20.0Hz), (2.22 1H, t, J=12.0Hz), 2.10 (1H, t, J=10.0Hz), 1.59-1.99 (10H, m), (1.05-1.17 2H, m), 1.01 (3H, s). 13C-NMR (100MHz, CDCl 3) δ: 207.6,195.9,154.6,145.8,119.8,70.6,66.4,64.8,57.9,51.1,48.0,38.5,38.3,36.8,35.5,35.4,33.6,26.9,26.3,25.5,23.5,17.8.HR-EI-MS m/z523.2231[M] +(C 26H 37NO 8S, calcd523.2240).
Compound (43): 1H-NMR (400MHz, CDCl 3) δ: 6.03 (1H, s), 5.34 (1H, s), 4.49 (1H, d, J=11.2Hz), 4.29 (1H, d, J=11.2Hz), (4.19 1H, d, J=10.8Hz), 4.05 (1H, d, J=10.8Hz), 3.64 (4H, brs), 3.43 (4H, brs), (3.07 3H, s), 2.83 (1H, brs), 2.65 (1H, dd, J=8.8,20.0Hz), 2.48 (1H, dd, J=12.4,19.6Hz), 2.26 (1H, t, J=13.2Hz), 2.07-2.15 (2H, m), (1.81-1.94 6H, m), 1.59-1.70 (4H, m), (1.04-1.11 2H, m), 0.94 (3H, s). 13C-NMR (100MHz, CDCl 3) δ: 207.4,196.1,155.1,145.9,119.7,66.8,66.1,58.0,51.4,48.3,39.2,38.2,37.6,37.0,35.8,35.5,33.1,26.8,26.4,26.2,23.6,17.7.HR-EI-MS m/z523.2245[M] +(C 26H 37NO 8S, calcd523.2240).
Compound (44): 1H-NMR (400MHz, CDCl 3) δ: 7.80 (1H, dd, J=1.2,3.6Hz), 7.59 (1H, dd, J=1.2,4.8Hz), 7.12 (1H, dd, J=3.6,4.8Hz), 6.05 (1H, d, J=1.2Hz), (5.35 1H, d, J=1.2Hz), 4.39 (1H, d, J=11.6Hz), 4.34 (1H, d, J=16.0Hz), 4.18 (1H, d, J=16.0Hz), 4.15 (1H, d, J=11.6Hz), (4.06 1H, d, J=10.8Hz), 3.69 (1H, d, J=10.8Hz), 2.86 (1H, brs), (2.65 2H, m), 2.27 (1H, m), (2.03-2.11 2H, m), 1.84-1.92 (4H, m), (1.57-1.73 5H, m), 1.08-1.19 (1H, m), (1.00-1.08 1H, m), 1.06 (3H, s). 13C-NMR (100MHz, CDCl 3) δ: 207.8,196.4,162.2,146.1,133.3,133.2,132.6,127.8,119.5,114.7,71.5,66.2,57.9,56.2,51.5,48.1,39.4,38.6,36.9,36.1,35.6,33.7,26.9,26.5,26.0,24.0,18.1.HR-EI-MS m/z481.1932[M] +(C 27H 31NO 5S, calcd481.1923).
Compound (45): 1H-NMR (400MHz, CDCl 3) δ: 7.80 (1H, d, J=3.2Hz), 7.57 (1H, d, J=4.4Hz), 7.12 (1H, m), 6.06 (1H, s), (5.36 1H, s), 4.20-4.38 (4H, m), 2.85 (1H, s), 2.66-2.81 (2H, m), 2.29 (1H, m), (2.12 1H, m), 1.99 (3H, s), 1.57-1.97 (10H, m), 1.06-1.25 (2H, m), 1.04 (3H, s). 13C-NMR (100MHz, CDCl 3) δ: 207.6,196.3,170.4,162.0,146.1,133.3 (C dAnd C s), 132.5,127.8,119.6,70.8,65.9,63.8,58.0,51.7,48.3,38.8,38.3,37.2,36.4,35.6,33.6,27.0,26.3,25.9,23.4,20.8,17.9.HR-EI-MS m/z484.1923[M] +(C 27H 32O 6S, calcd484.1920).
Compound (46): 1H-NMR (400MHz, CDCl 3) δ: 7.81 (1H, dd, J=1.2,3.6Hz), 7.57 (1H, dd, J=1.2,5.2Hz), 7.21 (1H, m), (6.54 1H, d, J=2.4Hz), 6.06 (1H, d, J=1.2Hz), 5.90 (1H, d, J=2.4Hz), 5.34 (1H, d, J=1.2Hz), 4.59 (1H, dd, J=1.2,11.6Hz), 4.90 (1H, d, J=1.2Hz), 4.32 (1H, d, J=12.8Hz), 4.21 (1H, d, J=12.8Hz), 2.85 (1H, d, J=3.2Hz), (2.58 1H, m), 2.23-2.31 (1H, m), (2.14-2.19 1H, m), 2.02 (3H, s), (1.70-2.03 8H, m), 1.54-1.59 (1H, m), (1.31 3H, s), 1.10-1.30 (2H, m). 13C-NMR (100MHz, CDCl 3) δ: 197.1,195.8,170.3,162.2,146.1,142.6,133.5 (C dAnd C s), 132.5,127.8,125.2,119.6,64.2,63.4,57.4,56.9,47.8,39.6,38.5,38.1,35.6,33.4,28.1,27.2,27.1,24.7,20.7,17.8.HR-EI-MSm/z496.1918[M] +(C 28H 32O 6S, calcd496.1920).
Compound (47): 1H-NMR (500MHz, CDCl 3) δ: 7.87 (1H, d, J=3.8Hz), 7.79 (1H, d, J=3.8Hz), 7.56 (2H, m), 7.11 (2H, m), (6.00 1H, s), 5.29 (1H, s), (4.98 1H, d, J=12.9Hz), 4.51 (1H, d, J=11.4Hz), 4.49 (1H, d, J=13.2Hz), 4.38 (1H, d, J=11.4Hz), (4.17 2H, m), 2.81 (1H, brs), (2.46 1H, brs), 2.10-2.15 (2H, m), (1.48-1.99 11H, m), 1.15-1.25 (1H, m), (1.58 3H, s), 0.88-0.91 (1H, m). 13C-NMR (125MHz, CDCl 3) δ: 203.7,162.1,146.7,133.8,133.7,133.4,133.3,132.7,132.3,128.0,127.8,71.4,67.7,64.0,53.1,50.6,46.8,42.2,36.9,35.7,35.3,28.1,27.8,26.1,25.0,19.6,18.2.HR-EI-MS m/z554.1970[M] +(C 30H 34O 6S 2, calcd554.1797).
Compound (48): 1H-NMR (400MHz, CDCl 3) δ: 7.67-7.70 (2H, m), 7.50-7.53 (2H, m), 7.02-7.06 (2H, m), (6.06 1H, d, J=1.6Hz), 5.35 (1H, d, J=1.6Hz), 4.61 (2H, d, J=3.2Hz), 4.37 (1H, d, J=11.2Hz), 4.25 (1H, d, J=11.2Hz), (2.78-2.94 3H, m), 2.12-2.28 (2H, m), 1.61-2.03 (11H, m), 1.10-1.28 (1H, m), 1.06 (3H, s). 13C-NMR (100MHz, CDCl 3) δ: 207.5,195.8,161.6,161.5,145.9,133.7,133.0, (C dAnd C s), 132.9,132.1,132.0,127.8,127.4,119.3,66.3,64.2,57.8,51.2,48.1,38.5,38.4,36.8,36.6,35.4,33.7,26.7,26.3,26.0,23.8,17.8.HR-EI-MS m/z552.1655[M] +(C 30H 32O 6S 2, calcd552.1640).
Compound (49): 1H-NMR (400MHz, CDCl 3) δ: 7.75-7.80 (2H, m), 7.55-7.60 (2H, m), 7.09-7.13 (2H, m), 6.70 (1H, d, J=2.8Hz), (6.07 1H, d, J=1.6Hz), 6.00 (1H, d, J=2.8Hz), 5.35 (1H, d, J=1.6Hz), 4.74 (1H, d, J=11.6Hz), (4.60 1H, d, J=12.8Hz), 4.49 (1H, d, J=11.6Hz), 4.40 (1H, d, J=12.8Hz), 2.86 (1H, m), 2.60 (1H, t, J=2.8Hz), 1.56-2.28 (12H, m), (1.30 3H, s), 1.14-1.25 (1H, m). 13C-NMR (100MHz, CDCl 3) δ: 196.8,195.8,162.0,161.7,146.2,141.3,134.2,133.5,133.4,133.1,132.6,132.5,128.1,127.8,126.4,119.6,64.2,63.8,57.4,57.1,47.9,40.4,38.8,38.0,35.7,33.4,27.7,27.2,27.0,25.2,17.6.HR-EI-MS m/z564.1643[M] +(C 31H 32O 6S 2, calcd564.1640).
Compound (50): 1H-NMR (400MHz, CDCl 3) δ: 6.00 (1H, d, J=1.6Hz), 5.30 (1H, d, J=1.6Hz), 4.14 (1H, dd, J=4.4, J=12.4Hz), 3.65 (2H, t, J=4.8Hz), 2.80 (1H, s), 2.64 (1H, d, J=11.2Hz), 2.37-256 (4H, m), (2.22 1H, d, J=11.2Hz), 2.13 (2H, m), 1.90-1.95 (2H, m), 1.54-1.80 (9H, m), 1.39-1.44 (2H, m), 1.25 (1H, s), 1.14-1.17 (1H, s), 1.03 (1H, m), 0.84 (3H, s). 13C-NMR (100MHz, CDCl 3) δ: 203.8,146.4,118.5,70.6,60.7,59.9,57.8,53.5,50.2,47.8,43.0,40.8,39.5,39.2,35.8,33.5,27.5,26.3,25.3,24.6,23.0,18.8.HR-EI-MS m/z359.2452[M] +(C 22H 33NO 3, calcd359.2460).
Compound (51): 1H-NMR (400MHz, CDCl 3) δ: δ: 5.90 (1H, s), 5.45 (1H, s), 5.08 (2H, s), (3.92 1H, s), 3.61 (2H, t, J=5.6Hz), 2.86 (1H, d, J=11.6Hz), 2.67 (1H, s), 2.32-2.53 (7H, m), 2.11-2.14 (2H, dd, J=2.8, J=11.2Hz), (1.90-1.98 2H, m), 1.50-1.73 (7H, m), 1.33-1.43 (2H, m), 1.24-1.26 (1H, m), 0.96 (3H, s). 13C-NMR (100MHz, CDCl 3) δ: 209.4,150.2,145.1,126.4,113.0,74.6,60.9,60.3,57.8,56.5,53.7,48.8,45.6,41.6,37.4,35.8,35.7,35.5,27.3,26.5,25.7,22.4,20.5.HR-EI-MS m/z371.2460[M] +(C 23H 33NO 3, calcd371.2460).
Compound (52): 1H-NMR (400MHz, CDCl 3) δ: 6.03 (1H, d, J=2.0Hz), 5.32 (1H, d, J=2.0Hz), 3.63 (2H, m), 2.82 (2H, m), (2.38-2.53 5H, m), 2.30 (1H, dd, J=2.4,10.8Hz), 2.11-2.18 (2H, m), 1.89-2.03 (3H, m), (1.51-1.82 7H, m), 1.37-1.46 (1H, m), 1.15-1.25 (2H, m), 0.82-0.90 (1H, m), 0.73 (3H, s). 13C-NMR (100MHz, CDCl 3) δ: 209.6,196.1,146.3,119.8,60.7,59.1,58.3,57.6,53.6,46.6,46.0,40.9,38.4,37.6,37.4,36.0,34.1,27.3,26.4,25.4,25.3,23.0.HR-EI-MS m/z357.2301[M] +(C 22H 31NO 3, calcd357.2304).
Compound (53): 1H-NMR (400MHz, CDCl 3) δ: 5.98 (1H, d, J=1.6Hz), 5.93 (1H, t, J=2.0Hz), (5.31 1H, t, J=2.0Hz), 5.30 (1H, d, J=1.6Hz), (3.67 2H, t, J=6.0Hz), 2.96 (1H, d, J=11.2Hz), (2.81-2.87 2H, m), 2.40 (1H, d, J=11.2Hz), (2.29 1H, m), 2.27 (2H, t, J=6.0Hz), (1.22-2.10 12H, m), 0.92 (2H, m), 0.90 (12H 4Me, s), 0.05 (6H 2Si-Me, s). 13C-NMR (100MHz, CDCl 3) δ: 203.1,196.1,146.4,146.2,125.5,118.9,62.0,61.5,60.8,57.2,56.7,53.9,44.7,41.7,38.0,36.1,35.9 (2C, 1d, 1s), 27.3,26.9,26.1,25.8 (3CH 3), 23.8,21.7,18.2 ,-5.3 (2Si-CH 3) .HR-EI-MS m/z483.3155[M] +(C 29H 45O 3Si, calcd483.3169)
Compound (54): 1H-NMR (400MHz, CDCl 3) δ: 6.00 (1H, s), 5.96 (1H, s), 5.35 (1H, s), 5.32 (1H, s), 3.60 (2H, m), 2.87 (2H, m), 1.25-2.29 (20H, m), 0.93 (3H, s). 13C-NMR (100MHz, CDCl 3) δ: 203.5,196.3,146.4,146.3,126.3,119.7,61.1,60.3,57.9,57.2,56.2,53.8,44.7,41.2,38.1,35.9 (2C), 35.7,27.4,26.9,26.1,23.9,22.5.HR-EI-MS m/z369.2301[M] +(C 23H 31NO 3, calcd369.2304)
Compound (55): 1H-NMR (400MHz, CDCl 3) δ: 5.91 (1H, s), 5.21 (1H, s), 4.67 (1H, s), (4.20 1H, s), 3.95 (1H, d, J=5.2Hz), (3.92 1H, s), 3.68-3.98 (2H, m), 3.46-3.50 (1H, m), 3.22-3.27 (1H, m), 3.04-3.07 (1H, m), (2.79-2.81 1H, m), 2.26-2.49 (2H, m), 1.96-2.13 (1H, m), 1.01-1.90 (11H, m), 1.06 (3H, s). 13C-NMR (100MHz, CDCl 3) δ: 200.8,148.2/148.1,117.3/117.1,95.1/91.1,85.7/83.5,67.8/67.4,64.9/63.1,51.0,49.2/49.1,47.4,45.5/44.3,43.1/43.0,36.8/36.7,35.7/35.4,35.3/35.1,29.9,29.8/29.6,27.4,24.5/24.0,23.5/23.3,22.8/22.7,20.6/20.3.HR-EI-MS m/z355.2137[M] +(C 22H 29NO 3, calcd355.2147).
Compound (56): 1H-NMR (400MHz, CDCl 3) δ: 6.03 (1H, d, J=1.6Hz), 5.34 (1H, d, J=1.6Hz), 5.09 (1H, s), (4.15-4.21 2H, m), 3.86-3.98 (2H, m), (3.24-3.32 1H, m), 2.81 (1H, s), (2.48 1H, d, J=3.6Hz), 2.33-2.37 (1H, m), 2.19-2.25 (1H, m), 2.17 (1H, s), 1.99-2.13 (1H, m), 1.77-1.87 (3H, m), 1.63-1.77 (2H, m), (1.25-1.54 6H, m), 1.22 (3H, s), 0.82-0.89 (1H, m). 13C-NMR (100MHz, CDCl 3) δ: 202.9,173.1,146.2,119.1,88.9,70.1,64.8,50.9,49.7,42.6,42.2,41.4,40.8,40.2,35.7,33.8,28.4,26.4,25.3,22.3,20.7,18.9.HR-EI-MS m/z371.2107[M] +(C 22H 29NO 4, calcd371.2097).
Compound (57): 1H-NMR (400MHz, CDCl 3) δ: 5.95 (1H, d, J=1.6Hz), 5.28 (1H, d, J=1.6Hz), 4.92 (1H, d, J=2.4Hz), 3.99 (1H, d, J=3.6Hz), (3.91-3.91 1H, m), 3.81-3.87 (1H, m), (3.76-3.80 1H, m), 3.65-3.72 (1H, m), (3.21-3.28 1H, m), 2.82 (1H, m), (2.27-2.36 1H, m), 2.11-2.15 (1H, m), (1.97-2.03 1H, m), 1.83-1.92 (2H, m), (1.74-1.79 2H, m), 1.28-1.67 (9H, m), 1.16 (3H, s). 13C-NMR (100MHz, CDCl 3) δ: 199.9,175.5,147.6,117.9,86.6,67.6,61.8,51.8,48.5,46.5,44.5,44.4,39.4,36.5,33.9,29.5,27.1,26.4,24.7,23.3,21.0,19.7.HR-EI-MS m/z371.2094[M] +(C 22H 29NO 4, calcd371.2097).
Compound (58): 1H-NMR (400MHz, CDCl 3) δ: 6.47 (1H, s), 5.95 (1H, d, J=1.6Hz), 5.26 (1H, d, J=1.6Hz), (4.88 1H, m), 3.93 (1H, m), (2.83 1H, m), 2.27-2.36 (1H, m), (2.11-2.17 1H, m), 1.97-2.04 (1H, m), (1.17-1.91 13H, m), 1.14 (3H, s). 13C-NMR (100MHz, CDCl 3) δ: 200.3,177.2,147.8,117.8,80.5,67.2,48.7,46.9,44.6,44.2,39.6,36.6,33.7,29.5,27.3,26.5,24.8,23.4,20.7,20.0.HR-EI-MS m/z327.1841[M] +(C 22H 29NO 4, calcd327.1834)+.
Embodiment 2:
The compounds of this invention is to the restraining effect of various tumor cell lines:
(1) experimental technique
1. inoculating cell: be made into the individual cells suspension with the nutrient solution (DMEM or RMPI1640) that contains 10% foetal calf serum, be inoculated into 96 orifice plates with every hole 5000-10000 cell, every pore volume 100 μ l, attached cell shifts to an earlier date 12 hours inoculation culture.
2. add testing compound solution (fixed concentration 40 μ M primary dcreening operations are suppressed near 50% compound in this concentration to growth of tumour cell and establish 5 concentration and enter gradient and sieve again), every hole final volume 200 μ l, every kind of processing is all established 3 and is answered holes.
3. colour developing: cultivate after 48 hours for 37 degrees centigrade, every hole adds MTT solution 20 μ l.Continued to hatch 4 hours, and stopped cultivating, inhale and abandon culture supernatant in the hole, every hole adds the SDS solution (10%) of 200 μ l, and night incubation (37 ℃ of temperature) is fully melted crystallisate.
4. colorimetric: select the 595nm wavelength, enzyme-linked immunosorbent assay instrument (Bio-Rad680) reads each hole absorbance value, and the record result is take concentration as X-coordinate, cell survival rate is that ordinate zou is drawn cell growth curve, uses the IC of two-point method (Reed and Muench method) computerized compound 50Value [8]
(2) the selection result:
Tumor cytotoxic activity (the IC of table 1 15-oxospiramilactone (S-3) derivative 50, μ M)
Compound HL-60 SMMC-7721 A-549 MCF-7 SW-480
1 4.56 4.72 3.16 4.61 3.74
2 2.02 0.72 0.59 0.96 0.66
3 4.43 3.53 2.80 3.55 7.77
4 3.41 0.71 0.83 1.18 1.03
5 3.85 2.48 2.44 3.94 2.80
6 4.69 2.41 3.14 4.83 3.71
7 3.86 0.83 0.73 1.51 1.21
8 3.82 1.96 3.03 2.63 2.38
9 0.80 0.80 0.91 1.44 1.21
10 5.56 12.02 4.77 3.09 11.44
11 4.20 1.87 3.17 5.04 4.19
12 1.46 0.51 0.67 1.57 2.20
13 0.51 0.15 0.20 0.24 0.39
14 4.87 4.92 3.25 4.00 6.33
15 4.90 4.62 2.97 2.85 2.37
16 1.94 1.90 0.77 1.44 1.53
17 3.45 3.12 2.22 2.02 1.58
18 3.60 4.44 6.11 8.86 5.43
19 >40 >40 >40 >40 >40
20 1.31 1.79 0.76 1.71 0.62
21 16.97 10.88 13.69 18.53 24.59
22 28.77 34.76 17.46 21.53 20.73
23 1.58 0.90 2.18 2.24 2.09
24 0.68 0.16 0.58 0.78 0.59
25 3.78 5.97 3.64 4.12 8.01
26 5.28 13.14 4.04 5.96 7.69
27 >40 >40 >40 >40 >40
28 4.28 4.48 4.28 8.07 4.42
29 - - - - -
30 4.74 7.83 3.49 4.82 9.89
31 3.38 3.91 2.95 3.38 3.74
32 5.03 6.13 3.04 2.93 3.94
33 6.33 15.44 11.10 15.13 12.88
34 6.50 13.99 10.97 12.81 15.51
35 6.30 10.83 4.69 4.23 6.57
36 1.21 0.75 0.64 0.65 0.78
37 1.37 0.93 1.86 1.55 1.85
38 3.97 0.77 2.89 2.36 2.57
39 0.51 0.26 0.56 0.53 0.15
40 0.79 0.24 0.55 0.56 0.22
41 0.54 0.19 0.41 0.32 0.14
42 4.18 3.95 4.21 3.31 2.94
43 2.70 2.18 2.32 2.05 3.37
44 0.62 1.06 1.17 0.65 0.80
45 0.71 0.57 0.80 0.89 0.76
46 0.24 0.13 0.14 0.15 0.10
47 - - - - -
48 0.61 0.57 0.70 0.67 0.59
49 0.29 0.22 0.35 0.33 0.16
50 7.95 11.16 9.92 16.57 14.41
51 4.82 1.48 3.04 6.98 9.84
52 14.32 15.19 9.24 15.70 11.82
53 1.39 2.63 1.55 2.90 2.78
54 6.61 11.52 6.50 3.57 2.81
55 1.95 1.18 2.93 5.22 2.38
Embodiment 3:
The compounds of this invention is to the restraining effect of Wnt signal path reporter gene Top-flash:
(1) experimental technique:
1) cell cultures and conditioned medium preparation:
The HEK293T cell DMEM(Invitrogen that contains 10% foetal calf serum) cultivate, 37 ℃, CO 2Concentration 5%.Go down to posterity every other day.Density is 70～80% when keeping going down to posterity.The L cell strain of stably excreting mouse Wnt3a albumen (CRL-2647 is available from U.S. ATCC cell bank) and contrast strain (CRL-2648 is available from U.S. ATCC cell bank) maintain the DMEM that contains 50ug/ml G418 and 10% foetal calf serum, and 37 ℃, CO 2Concentration is under 5% the condition.It is changed liquid (DMEM that contains 10% foetal calf serum) at Growth of Cells when about 70% density, cultured continuously was collected nutrient solution and centrifugal after four days, stayed supernatant, obtained the Wnt conditioned medium.After titration, liquid nitrogen flash freezer ,-80 ℃ of prolonged preservation, it is stable to keep tiring.
2) cell transfecting:
Cell is pressed every dish 2.0～2.5 * 10 6The density kind of individual cell enters 48 porose discs, transfection after 20 hours.The used plasmid transfection reagent of transfection calculates take the consumption in the every hole of 48 porose discs: the plasmid total amount is as the 125ng/ hole; Plasmid at first adds the middle mixing of training liquid (25 μ L/ hole) of serum-free, then adds PLUS reagent (Invitrogen) according to 0.5 μ L/ hole and mixes, and leaves standstill 15 minutes; According to the amount in 0.5 μ L/ hole with Lipofectamine(Invitrogen) liposome adds mixing in the serum-free DMEM training liquid (25 μ L/ hole), the mixing solutions with above-mentioned plasmid and PLUS mixes again, leaves standstill 15 minutes; Cell is changed to serum-free DMEM training liquid (100 μ L/ hole), is added dropwise to the packing mixt of final plasmid, PLUS and Lipofectamine in the cell, hatch after 3 hours the substratum that contains 10% foetal calf serum with 200 μ L/ holes and stop transfection and react.
3) the Wnt reporter gene is surveyed and is lived and IC 50Calculate:
Will be for detection of the HEK293T cell of reporter gene activity by 2) shown in method carry out transfection.The Wnt reporter gene activity detects: each plasmid amount of transfection is: 5ng/ hole TOP-flash and 5ng/ hole are as interior target GFP plasmid, with lacZ polishing 125ng/ hole.After transfection, add the contrast culture liquid that contains DMSO in 18 hours and contain different concns (DMSO, 2.5 μ M, 5 μ M, 10 μ M, 15 μ M, 20 μ M, 30 μ M; IC50 is then used instead DMSO, 5 μ M, 15 μ M, 30 μ M, 40 μ M, 50 μ M, 60 μ M greater than the small molecules of 30 μ M) micromolecular Wnt3a conditioned medium processed 6 hours, with Boehringer Mannheim Luci-ferase Assay Kit lysing cell (200 μ L/ hole).Respectively get 50 μ L and enter 96 orifice plates, with photofluorometer FL600(BIO-TEK Inc.Winooski, VT) intensity of GFP albumen in the survey cell pyrolysis liquid, interior mark as cell transfecting efficient, then the substrate that adds 10 μ L luciferases to every hole, with Micro Lumate Plus(Perkin Elmer Inc.Wellesley, MA) luminometer measures uciferase activity.Be the active numerical value of interior mark correction luciferase with GFP intensity at last, be the Wnt reporter gene activity.
IC 50Calculate (to calculate IC50 to the Wnt signal path as example): will not contain or contain the measured reporter gene activity deduction background (the conditioned medium treatment group gained that only contains DMSO is active) of the micromolecular Wnt3a conditioned medium of different concns treatment group, the numerical value of gained is defined as Wnt and induces or add remaining reporter gene activity behind the small molecules.All residual activities of reporter gene activity homogenization so that Wnt induces obtain the relative residual activity.Make point and line chart in conjunction with small molecules concentration again, with the method match amount effect curve based on four parameter l ogistic, corresponding small molecules concentration is this small molecules to the IC of Wnt signal path when the relative residual activity is 0.5 50
(2) the selection result:
Table 2 15-oxospiramilactone (S-3) derivative suppresses the activity (IC of Wnt signal reporter gene Top-flash 50, μ M)
Compound Inhibitory Compound Inhibitory
S-3 18.35±1.82 7 16.46±1.16
1 12.05±1.88 8 20.06±1.32
6 19.75±1.34 ? ?
Table 3 15-oxospiramilactone (S-3) derivative suppresses the activity (IC of Wnt signal reporter gene Top-flash 50, μ M)
Compound Inhibitory Compound Inhibitory
S-3 18.73±0.58 27 >60(0)
11 27.35±0.98 30 9.98±1.00
12 17.56±1.90 31 16.89±1.89
14 21.71±0.63 37 12.59±1.04
15 9.12±0.21 38 42.99±5.35
21 18.05±2.67 40 10.36±0.57
22 >60(15%) 45 8.39±0.63
23 >60(20%) 48 7.83±0.70
Table 4 15-oxospiramilactone (S-3) derivative suppresses the activity (IC of Wnt signal reporter gene Top-flash 50, μ M)
Compound Inhibitory Compound Inhibitory
S-3 17.97±0.28 25 >60(33%)
2 4.09±0.07 26 >60(21%)
3 8.56±1.15 32 46.93±1.26
4 9.54±1.34 33 >60(10%)
5 6.89±0.27 34 58.22±1.18
9 11.05±0.63 35 56.04±0.92
10 8.27±1.24 36 7.30±0.22
13 6.72±1.11 39 11.18±1.54
19 >60(24%) 41 7.2±0.71
20 7.10±0.70 46 4.92±0.69
24 12.85±0.13 49 7.68±0.19
Table 5 15-oxospiramilactone (S-3) derivative suppresses the activity (IC of Wnt signal reporter gene Top-flash 50, μ M)
Compound Inhibitory Compound Inhibitory
S-3 22.49±0.56 54 17.04±1.28
50 >60(0) 55 >60(35%)
51 8.34±0.90 56 28.67±0.97
52 49.35±1.42 57 >60(26%)
53 31.93±0.21 58 60.63±3.09
Table 6 15-oxospiramilactone (S-3) derivative suppresses the activity (IC of Wnt signal reporter gene Top-flash 50, μ M)
Compound Inhibitory Compound Inhibitory
S-3 13.9100±2.0100 29 44.8350±3.3450
16 15.4150±1.5050 42 43.7800±3.0500
17 19.8000±1.0400 43 32.3000±3.0100
18 12.0600±1.2500 44 12.1400±1.2500
28 27.7400±2.8000 ? ?
Studies show that of the present invention's early stage: the 15-oxospiramilactone (S-3) that comes from the pink blossom Ramulus et Folium Spiraeae Salicifolia has brand-new mechanism of action, the apoptosis that S-3 induces non-Bax/Bak to rely on, the high expression level that S-3 induces pro apoptotic protein Bim is specifically found in further investigation, itself and Bcl-2 have an effect in the plastosome level, cause that the Bcl-2 conformational change is converted to short apoptosis function by anti-apoptosis, thereby the release of activating cells pigment C causes the dependent apoptosis of the non-Bax/Bak of cell, and this is the new mechanism of cell death inducing; Find that S-3 is optionally inhibitor of tumour cell Wnt signal path, suppress the expression of Wnt downstream target gene by the interaction that weakens β-catenin and TCF4; Cause cell cycle arrest in the G2/M phase by suppressing the downstream expression of target gene; SW480 transplants experiment of nude mouse and shows that the S-3 of low dosage can suppress the growth of tumour.The present invention on this basis, to the large intestine of S-3 and colon tumor strain, Normocellular cytotoxic activity, and the early stage Fast Evaluation of ADME/T done analysis, finds that S-3 has " first pass effect ", it eliminates the transformation period is 0.43 hour, the hydrolysate anti-tumor activity completely dissolve of lactonic ring.For its defective that becomes the property of medicine, it is carried out structure of modification and composition optimizes,, seek the more rational antineoplastic compound of patent medicine and be very important as foundation with the inhibition activity of Wnt signal path, the cytotoxic activity of different tumor lines etc.
Embodiment 4:
Any compound of tablet: embodiment 1 gained 10mg, lactose 180mg, starch 55mg, Magnesium Stearate 5mg
The preparation method: compound, lactose and starch are mixed, and water is evenly moistening, moistening mixture is sieved and drying, after sieve, adds Magnesium Stearate, then with the mixture compressing tablet, and every heavy 250mg, compounds content is 10mg.
Embodiment 5:
Any compound of ampulla: embodiment 1 gained 2mg, sodium-chlor 10mg;
Preparation method: compound and sodium-chlor are dissolved in an amount of water for injection, filter gained filtrate, in the ampoule of under aseptic condition, packing into.
Embodiment 6:
Any compound of capsule: embodiment 1 gained 10mg, lactose 187mg, Magnesium Stearate 3mg
The preparation method: compound is mixed with auxiliary agent, sieve, evenly mix, the mixture that obtains is packed in the hard gelatin capsule, each capsule weight 200mg, activeconstituents is 10mg.

Claims (6)

1. following structural formula is led to 15-oxospiramilactone (S-3) derivative shown in formula I, (II),
Wherein: R in the logical formula I of structural formula 1, R 6For-OH or=O, R 2For-H or=O or=CH 2Or-Cl or-Br or-SCH 3Or-CH 2OH or-CH 2N (CH 3) 2Or-CH 2N (CH 2) 4O or-CH 2OCOCH 3Or-CH 2OSO 2CH 3, R 3For-H or R 2With R 3Between be two keys; X 1, X 3For-CH 2Or-CH or carbonyl; X 2For Sauerstoffatom or nitrogen-atoms or-SO 2
Work as X 1During for CH, R 5For-OCH 3Or R 1With R 5Form oxo bridge;
Work as X 2During for nitrogen-atoms, R 4For-H or-CH 2CH 2OH or-CH 2CH 2OTBDMS or R 4, R 5, X 1, X 2Xing Cheng oxazole ring or R 4, X 2, X 3Xing Cheng oxazole ring.
In the logical formula II of structural formula, R 1, R 5For-OH, or=O; R 2For-H or=O or=CH 2Or-CH 2OH or-CH 2N (CH 2) 4O or-CH 2OCOCH 3Or-CH 2OSO 2CH 3R 3, R 4For-OH or-COCH 3Or-COCH 2Cl or-CON (CH 2) 4O or-Ms or-CH 2CN or 2-Thenoyl; X 1For-CH 2Or-CO.
2. according to the 15-oxospiramilactone shown in the claim 1 (S-3) derivative, it is:
Figure FDA00003525814900021
3. the pharmaceutical composition with anti-tumor activity is characterized in that, comprises one or more claims 1 for the treatment of significant quantity or 2 related 15-oxospiramilactone derivative and pharmaceutically acceptable auxiliary material in each.
4. the preparation method of compound shown in the claim 1 or 2 comprises the steps:
(1) compound 1-9,25,26 preparation method:
Figure FDA00003525814900031
(2) preparation method of compound 10:
Figure FDA00003525814900032
(3) preparation method of compound 11-13:
Figure FDA00003525814900033
(4) preparation method of compound 14-20:
Figure FDA00003525814900041
(5) preparation method of compound 21:
Figure FDA00003525814900042
(6) compound 22,27 preparation method:
Figure FDA00003525814900043
(7) preparation method of compound 23,24,28-36:
Figure FDA00003525814900051
(8) preparation method of compound 37-41:
Figure FDA00003525814900052
(9) compound 42,43,44 syntheti c route:
(10) compound 45,46,47,48,49 preparation method:
Figure FDA00003525814900062
(11) preparation method of compound 50-55:
Figure FDA00003525814900071
(12) preparation method of compound 56-58:
Figure FDA00003525814900072
5. the application of compound shown in the claim 1 or 2 in the preparation antitumor drug.
6. the application of compound shown in the claim 1 or 2 in preparation Wnt signal pathway inhibitor medicine.
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