CN1072676C - Method for synthesizing hexasaccharide and heptasaccharide used as plant immunological system activator using trisaccharid ortho-ester as key intermediate - Google Patents
Method for synthesizing hexasaccharide and heptasaccharide used as plant immunological system activator using trisaccharid ortho-ester as key intermediate Download PDFInfo
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Abstract
The present invention relates to a method for synthesizing hexasaccharide and heptasaccharide used as a plant immunological system activator using a trisaccharid ortho ester as a key intermediate, which has the technical scheme that bromo acyl glucose is used as a glycosyl donor; 1, 2-O-ethylidene protected glucose, methyl glucoside of glucose or allyl glycoside of glucose, and a methanol ortho ester of glucose or an allyl alcohol ortho ester are used as a glycosyl acceptor; 2 mol of the donor and 1 mol of the acceptor are dissolved in methylene chloride, and a trisaccharide ortho ester is firstly obtained under the action of 2 mol of silver salt and 2 mol of organic alkali; then, a trisaccharide donor of glucose is produced by the rearrangement of a saccharide ortho ester; a trisaccharide acceptor of glucose with 6-bit dissociated hydroxide radicals is made in the similar method; the trisaccharide donor and the trisaccharide acceptor are coupled, and thus, hexasaccharide and heptasaccharide of glucose which can be used as a plant immunological system activator for agricultural chemicals can be obtained.
Description
The invention relates to bioactive, plant immunization activator, particularly related to the synthetic method that can be used as plant immunization system activating agent six sugar agricultural chemicals, that with the trisaccharide ortho-esters be key intermediate and seven sugar.
Oligosaccharides can be [the J.K.Sharp that U.S. Albersheim found in 84 years as the activator (Elicitor) of plant immunization system, B.Valent, P.Albersheim, J.Biol.Chem., 1984,259,11312.], in bean, the oligosaccharides activator can increase the metabolism of hydrocinnamyl enzyme, and the biosynthesizing of plant protecting chemical (Phytoalexin) in this enzyme energy catalysis bean.The oligosaccharides activator is that a class can be at the molecule of the special metabolism of DNA transcriptional level adjusted, genetic expression.Grape seven sugar that β on the mycelia body wall of fungal pathogen Pmg (Phytophthora megasperma f.sp.glycinea) connects are found first oligosaccharides activator, and 10ng (1 * 10
-8The gram) be applied to 1 the gram plant tissue can produce enough plant protecting chemicals, up to now it be found in the plant protecting chemical activator most effective.Because 1 → 3 β, the dextran that 1 → 6 β connects is present in a lot of pathogenic fungies, so the oligosaccharides activator uses as agricultural chemicals and can suppress multiple microorganism.Research also show, though the effect of oligosaccharides activator at first in soybean, find, it can be applicable to multiple higher plant [S.Aldington, S.C.Fry, Adv.Bol Res., 1992,19,1-101.].But because the mycelia body wall of Pmg only accounts for mycelial 3%, after the part acidolysis, the actual activated oligosaccharides that can access seldom, for example by the mycelia body walls of 10 grams after the part acidolysis, separating, seven sugar of activity the highest (1800 units/microgram) only have 0.1 milligram, and separating step is loaded down with trivial details, need to carry out the separation of high performance liquid chromatography with the stationary phase of costliness, only can not prepare in a large number as research.Later studies show that [J.J.Cheong, M.G.Hahn, Plant Cell, 1991,3,127-147.], six sugar of the few glucose unit of reducing end have the function that is similar to seven sugar.
This important discovery has caused organic chemist's great interest, and the study on the synthesis of oligosaccharides activator has all successively been carried out in several famous laboratories, as the Lindberg[J.K.Sharp of Sweden, P.Albersheim, B.Lindberg, J.Biol.Chem., 1984,259,11341.], the Ogawa[N.Hong of Japan, T.Ogawa, Tetrahedron Lett., 1990,31,3179.], the Nicolaou[K.C.Nicolaou of the U.S., N.Winssinger, J.Pastor, F.Derosse, J.Am.Chem.Soc., 1997,119,449.] all successively reported the synthetic of oligosaccharides activator, but because used reagent costliness, reactions steps is various, only can be used for structure, the checking research of activity relationship, be difficult to batch preparations, do not see the production report of the oligosaccharides activator of using as agricultural chemicals abroad as yet.
We also delivered recently the synthesis of oligose activator a kind of new, effective means [king is Kong Fanzuo Tetrahedron Lett., 1998,39,1937.], to compare with the method for having delivered, this is effective, the simplest method up to now, but, still have suitable distance apart from producing in batches.
The objective of the invention is to adopt brand-new thinking, our invention in the past, be on the basis of key intermediate synthesis of oligose [Chinese patent application number 97125788.4] with the ortho ester of sugar, method is simplified greatly, provide a kind of step simple, save time, the labour-saving, can be used as that agricultural chemicals is used, be plant immunization system activating agent six sugar of key intermediate and the synthetic method of seven sugar with the trisaccharide ortho-esters.
The object of the present invention is achieved like this: with the simplest bromo acyl group sugar is glycosyl donor, with 1, the glucose 2 of 2-O-ethylideneization, glucose methyl glucoside 3, allyl group glycosides 4 are glycosyl acceptor, under alkaline condition and silver catalyst agent effect, one step obtained the ortho ester 5,6 or 7 of trisaccharide, and the ortho ester of this trisaccharide is reset under the katalysis of TMSOTF, with 1 activation, obtain three saccharide donors 15 or 16 of glucose again; With synthetic 6 of similar method is three saccharide acceptors 40,42,43,44,45,46 of the glucose of free hydroxyl group, with three saccharide donors and three saccharide acceptor couplings, promptly obtains required six sugar.With 1 activation of three saccharide acceptors,, promptly make tetrose acceptor 56 with a glucose molecule coupling; With three saccharide donors and the coupling of tetrose acceptor, promptly obtain required seven sugar 57.The sugar of its label representative is shown in the structural formula of back.
Synthetic method of the present invention is: (1) is glycosyl donor with 2 moles bromo ethanoyl glucose 1, with 1 mole 1, the glucose 2 of 2-O-ethidine protection, the methyl glucoside 3 of glucose, the allyl group glycosides 4 of glucose, the methyl alcohol ortho ester 8 of glucose or the vinyl carbinol ortho ester of glucose 9 are glycosyl acceptor, be dissolved in glycosyl donor and glycosyl acceptor in the methylene dichloride respectively, then with the two mixing, add 2 moles silver salt and 2 moles organic bases, stirring, reaction is 2-4 hour under the room temperature, prepares the ortho ester 5 of trisaccharide respectively, the ortho ester 6 of trisaccharide, the ortho ester 7 of trisaccharide, the ortho ester 10 of trisaccharide or the ortho ester 11 of trisaccharide;
Or be that the glucose bromo-derivative 17 of chloracetyl is a glycosyl donor with six, 1, the glucose 2 of 2-O-ethidine protection, the methyl glucoside 3 of glucose, allyl group glycosides 4, the methyl alcohol ortho ester 8 of glucose or vinyl carbinol ortho ester 9 are glycosyl acceptor, its mol ratio is 1: 1, be dissolved in the methylene dichloride respectively, then with the two mixing, the silver salt and the organic bases of mol ratios such as adding, room temperature, stir reaction down 2-4 hour, at first prepare the ortho ester 18 of disaccharide, the ortho ester 23 of disaccharide, the ortho ester 24 of disaccharide, the ortho ester 31 of disaccharide or the ortho ester 32 of disaccharide, be glycosyl donor with bromo ethanoyl glucose 1 then, the ortho ester 18 of disaccharide, the ortho ester 23 of disaccharide, the ortho ester 24 of disaccharide, the ortho ester 31 of disaccharide or the ortho ester of disaccharide 32 are glycosyl acceptor, its mol ratio is 1: 1, under silver salt that waits mol ratio and organic bases effect, room temperature, stir reaction down 2-4 hour, obtain the ortho ester 19 of trisaccharide, the ortho ester 25 of trisaccharide, the ortho ester 26 of trisaccharide, the ortho ester 33 of trisaccharide or the ortho ester 34 of trisaccharide;
Or be glycosyl donor with bromo ethanoyl glucose 1,1, the glucose 2 of 2-O-ethidine protection, the methyl glucoside 3 of glucose, allyl group glycosides 4, the methyl alcohol ortho ester 8 of glucose or vinyl carbinol ortho ester 9 are glycosyl acceptor, its mol ratio is 1: 1, be dissolved in the methylene dichloride respectively, then with the two mixing, the silver salt and the organic bases of mol ratios such as adding, room temperature, stir reaction down 2-4 hour, at first prepare the ortho ester 20 of disaccharide, the ortho ester 27 of disaccharide, the ortho ester 28 of disaccharide, the ortho ester 35 of disaccharide or the ortho ester 36 of disaccharide, be glycosyl donor with bromobenzene formyl radical glucose 21 then, the ortho ester 20 of disaccharide, the ortho ester 27 of disaccharide, the ortho ester 28 of disaccharide, the ortho ester 35 of disaccharide or the ortho ester of disaccharide 36 are glycosyl acceptor, its mol ratio 1: 1, under silver salt that waits mol ratio and organic bases effect, room temperature, stir reaction down 2-4 hour, obtain the ortho ester 22 of trisaccharide, the ortho ester 29 of trisaccharide, the ortho ester 30 of trisaccharide, the ortho ester 37 of trisaccharide or the ortho ester 38 of trisaccharide;
(2) with the ortho ester 5 of trisaccharide; the ortho ester 6 of trisaccharide; the ortho ester 7 of trisaccharide; the ortho ester 10 of trisaccharide or the ortho ester 11 of trisaccharide; with diacetyl oxide in pyridine after the acetylize; be dissolved in the methylene dichloride; trimethyl silicane fluoroform sulphonate (TMSOTF) thorough mixing with catalytic amount; stirring; reaction is 2-6 hour under the room temperature; carry out the rearrangement of hepatin acid ester; remove ethidine with ordinary method through acid hydrolysis again; or allyl group; or methyl; acetylize; bromination, or remove ethidine through acid hydrolysis; or allyl group; or methyl; acetylize; selectivity is taken off an ethanoyl; use DBU-CCl
3CN gets Schmidt reagent, prepares three saccharide donors 15 or three saccharide donors 16 of glucose;
In the formula: a-acetylize b-TMSOTF resets the c-acid hydrolysis, acetylize d-bromination e-selectivity is taken off 1 ethanoyl, used DBU-CCl
3CN gets Schmidt reagent
(3) trisaccharide ortho-esters 19, trisaccharide ortho-esters 25, trisaccharide ortho-esters 26, trisaccharide ortho-esters 33 or trisaccharide ortho-esters 34 are earlier through diacetyl oxide acetylize in pyridine; Trisaccharide ortho-esters 22, trisaccharide ortho-esters 29, trisaccharide ortho-esters 30, trisaccharide ortho-esters 37 or trisaccharide ortho-esters 38 are earlier through benzoylation; Then with trimethyl silicane fluoroform sulphonate (TMSOTF) thorough mixing of catalytic amount, reaction is 2-6 hour under stirring, room temperature, carry out the rearrangement of hepatin acid ester, through 6 deacetylations of selectivity, prepare three saccharide acceptors 40, three saccharide acceptors 42 of the glucose β 1 → 6, the β 1 → 3 that contain ethidine, and methyl glucoside three saccharide acceptors 43, allyl group glycosides three saccharide acceptors 44, methyl glucoside three saccharide acceptors 45 or allyl group glycosides three saccharide acceptors 46;
A-acetylize d-benzoylation b-TMSOTF resets e-TMSOTF and resets 6 dechlorination acetyl of c-selectivity f-selectivity deacetylation
(4) will wait three saccharide donors 15 or three saccharide donors 16 of mol ratio, with three saccharide acceptors 40, three saccharide acceptors 42, three saccharide acceptors 43, three saccharide acceptors 44, three saccharide acceptors 45 or three saccharide acceptors 46, be dissolved in the methylene dichloride, under the silver catalyst that waits mol ratio, carry out coupling, again acetylize; Or be dissolved in the methylene dichloride, under silver salt that waits mol ratio and organic bases effect, obtain ortho ester earlier; with the trimethyl silicane three fluoro sulfonate thorough mixing of catalytic amount, reset, more again through benzoylation; reaction solution is aftertreatment according to a conventional method, obtains six sugar, 47 or six sugar 48 of 1,2 protection.
In the formula: the agent of a-silver catalyst, methylene dichloride b-acetylize c-methylene dichloride, silver catalyst agent, 2,4-lutidine d-methylene dichloride, TMSOTFe-Benzoyl chloride, pyridine
Or with ordinary method with six sugar 47, or the acyl group of six sugar 48 removes, obtain 1,6 sugar 49 of 2 forkizations, or with ordinary method with six sugar 47, or 1,2 ethidine of six sugar 48 respectively in the aqueous solution, methyl alcohol, vinyl carbinol acidolysis remove, can obtain free six sugar 50, the methyl glucoside 51 of six sugar or the allyl group glycosides 52 of six sugar;
In the formula; Acidolysis in the acidolysis e-vinyl carbinol solution in the a-aqueous acid medium hydrolysis b-acetylize c-catalysis deacylated tRNA base d-methanol solution
(5) will being converted into the Schmidt reagent 54 of bromo-derivative 53 or trisaccharide after the acidolysis of trisaccharide receptor 39 (GPR 39), is acidylate methyl glucoside 55 couplings of free hydroxyl group with 6 again, obtains tetrose acceptor 56 through 6 dechlorination acetyl of selectivity;
In the formula: a-acid hydrolysis b-acetylize c-bromo d-selectivity is taken off 1 acetyl, uses CCl
3CN system Schmidt reagent e-methylene dichloride, silver trifluoromethanesulfonate f-sulphur is urinated again with tetrose acceptor 56 and three saccharide donors 15 or 16 couplings of three saccharide donors, obtains seven sugar 57;
At last, acetylizad seven sugar 57 are used the ordinary method deprotection, obtain seven sugared activator 58;
Reducing end is that seven sugar of allyl group or other alkyl prepare with identical method; Described silver salt is a silver trifluoromethanesulfonate, silver suboxide, silver carbonate, silver perchlorate; Described organic bases is 2,4-lutidine, 2,6-lutidine.
Adopting method of the present invention, can be raw material with cheap, bromo acyl group sugar that is easy to get and the sugar of not protecting, and by synthetic plant immunization system activating agent six sugar and seven sugar of simple steps, these six sugar and seven sugar can be as high effect nontoxic, non-harmful environment friendly agriculturals.
Below in conjunction with embodiment the present invention is described in detail.
The preparation of embodiment 1 trisaccharide ortho-esters donor 5:
Bromo acetyl glucosamine 1 (822 milligrams, 2 mmoles) is dissolved in 20 milliliters of methylene dichloride, gets solution A, 1,2-O-ethidine glucose 2 (206 milligrams, 1 mmole) is dissolved in 10 milliliters of methylene dichloride, solution B, with B mix with A solution C, in C, add 2, the 4-lutidine, (0.23 milliliter, 2 mmoles), under agitation add (512 milligrams of silver trifluoromethanesulfonates, 2 mmoles), after two hours, thin-layer chromatographic analysis shows to react to be finished at room temperature reaction.Reaction solution is diluted with 10 milliliters of methylene dichloride, wash solution with water, aqueous phase discarded, organic phase is drained under vacuum, the hepatin acid ester crude product that contains free hydroxyl group that obtains is refining with silica gel column chromatography, as leacheate drip washing, collects respective components with ethyl acetate/petroleum ether (1/2), obtain the pure hepatin acid ester that contains free hydroxyl group 5, productive rate: 85%.
The preparation of embodiment 2 trisaccharide ortho-esters donors 7:
Bromo acetyl glucosamine 1 (822 milligrams, 2 mmoles) is dissolved in 20 milliliters of methylene dichloride, gets solution A, glucose allyl group glycosides 4 (220 milligrams, 1 mmole) is dissolved in 10 milliliters of dimethyl formamides, gets solution B, with B mix with A solution C, in C, add 2, the 4-lutidine, (0.23 milliliter, 2 mmoles), under agitation add silver suboxide (464 milligrams, 2 mmoles), after four hours, thin-layer chromatographic analysis shows to react to be finished at room temperature reaction.Reaction solution is diluted with 10 milliliters of methylene dichloride, wash solution with water, aqueous phase discarded, organic phase is drained under vacuum, the hepatin acid ester crude product that contains free hydroxyl group that obtains is refining with silica gel column chromatography, as leacheate drip washing, collects respective components with ethyl acetate/petroleum ether (1/2), obtain the pure hepatin acid ester that contains free hydroxyl group 7, productive rate: 65%.
The preparation of embodiment 3 trisaccharide ortho-esters donors 10:
Bromo acetyl glucosamine 1 (822 milligrams, 2 mmoles) is dissolved in 20 milliliters of methylene dichloride, gets solution A, glucose methyl alcohol ortho ester 8 (236 milligrams, 1 mmole) is dissolved in 10 milliliters of methylene dichloride, gets solution B, with B mix with A solution C, in C, add 2, the 4-lutidine, (0.23 milliliter, 2 mmoles), under agitation add silver suboxide (464 milligrams, 2 mmoles), after two hours, thin-layer chromatographic analysis shows to react to be finished at room temperature reaction.Reaction solution is diluted with 10 milliliters of methylene dichloride, wash solution with water, aqueous phase discarded, organic phase is drained under vacuum, the hepatin acid ester crude product that obtains is refining with silica gel column chromatography, as leacheate drip washing, collects respective components with ethyl acetate/petroleum ether (1/2), obtain the pure hepatin acid ester that contains free hydroxyl group 10, productive rate: 45%.Quantitatively acetylize according to a conventional method obtains the ortho ester of full acetylated sugar.
The preparation of embodiment 4 three saccharide donors 15 (by trisaccharide ortho-esters donor 5):
With trisaccharide ortho-esters donor 5 quantitatively acetylize according to a conventional method; obtain the ortho ester of full acetylated sugar; its (2 mmole) is dissolved in 10 milliliters of methylene dichloride; add TMSOTf (38 μ L; 0.2 mmole); in nitrogen protection; reset under room temperature, the stirring; finish after 2 hours, reaction solution ordinary method aftertreatment, crude product is refining with silica gel column chromatography; with ethyl acetate/petroleum ether (1/2) as leacheate drip washing; collect respective components, obtain the oligosaccharide compound 12 that the inventive method is prepared, productive rate: 52%.Oligosaccharide compound 12 is dissolved in 15 milliliters of mixed solvents of being made up of by 4: 1 volume ratios 80% acetate and 1N hydrochloric acid; reflux; use the tlc analysis detection reaction; afterreaction was finished in 5 hours; reaction solution under reduced pressure concentrated drain; get soup compound; productive rate: 64%; with this soup compound with the quantitative acetylize of ordinary method; obtain full acetylated trisaccharide, it is dissolved in 10 milliliters of methylene dichloride, add hydrogen bromide-acetic acid solution of 30%; hydrogen bromide is 5: 1 with the mol ratio of sugar, and reaction is at room temperature carried out finishing after 2 hours.Carry out aftertreatment according to a conventional method, refining with silica gel column chromatography, obtain bromo-derivative 15, productive rate: 62%
The preparation of embodiment 5 three saccharide donors 16 (by trisaccharide ortho-esters donor 7):
With trisaccharide ortho-esters donor 7 quantitatively acetylize according to a conventional method, obtain the ortho ester of full acetylated sugar, it is prepared oligosaccharide compound 14 by the method for preparing oligosaccharide compound 12, productive rate: 55%.It is dissolved in the solution of trifluoroacetic acid in methylene dichloride that concentration is 1N; reaction is 6 hours under the room temperature; reaction solution ordinary method aftertreatment; refining with silica gel column chromatography then; productive rate: 60%, the product after refining with the quantitative acetylize of ordinary method, is taken off 1 acetyl with full acetylated trisaccharide with the hydrazine acetate selectivity; productive rate: 90%, again with CCl
3The CN reaction obtains three saccharide donors 16, productive rate: 85%
The preparation of embodiment 6 three saccharide donors 16 (by trisaccharide ortho-esters 11):
With trisaccharide ortho-esters 11 quantitatively acetylize according to a conventional method; obtain the ortho ester of full acetylated sugar; its (2 mmole) is dissolved in 10 milliliters of methylene dichloride; add TMSOTf (38 μ L; 0.2 mmole); in nitrogen protection; reset under room temperature, the stirring; finish after 2 hours, reaction solution ordinary method aftertreatment, crude product is refining with silica gel column chromatography; with ethyl acetate/petroleum ether (1/2) as leacheate drip washing; collect respective components, obtain the oligosaccharide compound 14 that the inventive method is prepared, productive rate: 42%.Undertaken by the method described in the example 5 by oligosaccharide compound 14 preparations three saccharide donors 16.
7 six of embodiment are the preparation of the trisaccharide ortho-esters of chloracetyl;
With 2,3,4-three-O-acetyl-6-O-chloro acetyl-α-D-glucopyanosyl bromine 17 (446 milligrams, 1 mmole), is dissolved in 10 milliliters of methylene dichloride, gets solution A, with 1,2-O-ethidine glucose 2 (206 milligrams, 1 mmole) is dissolved in 10 milliliters of methylene dichloride, solution B, with B mix with A solution C, in C, add 2, the 4-lutidine, (0.115 milliliter, 1 mmole), under agitation add (256 milligrams of silver trifluoromethanesulfonates, 1 mmole), after two hours, thin-layer chromatographic analysis shows to react to be finished at room temperature reaction, in this reaction solution, add 10 milliliters and contain (411 milligrams of bromo acetyl glucosamines 1,1 mmole) dichloromethane solution adds 2 again, the 4-lutidine, (0.115 milliliter, 1 mmole), silver trifluoromethanesulfonate (256 milligrams, 1 mmole), in room temperature, stir down and react after two hours, reaction is finished.Identical with described in the preparation of trisaccharide ortho-esters 5 of the aftertreatment of reaction solution, product refining obtains containing the trisaccharide ortho-esters 19 of 6 chloracetyls, productive rate: 42% (two-step reaction totally).
Embodiment 8 has the preparation of the trisaccharide ortho-esters 22 of benzoyl:
With 2,3,4,6-four-O-acetyl-α-D-glucopyanosyl bromine 1 (411 milligrams, 1 mmole) is dissolved in 10 milliliters of methylene dichloride, solution A, with 1,2-O-ethidine glucose 2 (206 milligrams, 1 mmole) be dissolved in 10 milliliters of methylene dichloride, solution B, with B mix with A solution C, in C, add 2,4-lutidine, (0.115 milliliter, 1 mmole), under agitation add silver trifluoromethanesulfonate (256 milligrams, 1 mmole), at room temperature reaction after two hours, thin-layer chromatographic analysis shows to react to be finished, in this reaction solution, add 2,3,4,6-four-O-benzoyl-α-D-glucopyanosyl bromine 21 (659 milligrams, 1 mmole) solution in 10 milliliters of methylene dichloride adds 2 again, the 4-lutidine, (0.115 milliliter, 1 mmole), silver trifluoromethanesulfonate (256 milligrams, 1 mmole), in room temperature, stir down and react after two hours, reaction is finished.Identical with described in the preparation of trisaccharide ortho-esters 5 of the aftertreatment of reaction solution, product refining obtains containing the trisaccharide ortho-esters 22 of benzoyl, productive rate: 45% (two-step reaction totally).
Embodiment 9 has the trisaccharide ortho-esters 25 of 6 chloracetyls or has the preparation of the trisaccharide ortho-esters 26 of 6 chloracetyls (by the methyl glucoside 3 of glucose or the allyl group glycosides 4 of glucose):
With glucose bromo-derivative 17 is glycosyl donor (1 mmole); etc. the methyl glucoside 3 of the glucose of mol ratio or the allyl group glycosides 4 of glucose is glycosyl acceptor; donor is dissolved in 10 milliliters of methylene dichloride; acceptor is dissolved in 10 milliliters of dimethyl formamides; mix 2 of mol ratios such as back adding and donor; the 4-lutidine; (0.115 milliliter; 1 mmole); (256 milligrams of silver trifluoromethanesulfonates; 1 mmole); at first make the ortho ester 23 of disaccharides or the ortho ester 24 of disaccharides; method described in the use-case 5 makes the ortho ester 23 of disaccharides or the ortho ester 24 and 1 reaction of bromo ethanoyl glucose of disaccharides then, obtains the trisaccharide ortho-esters 25 of 6 chloracetyls or the trisaccharide ortho-esters 26 of 6 chloracetyls.
Embodiment 10 has the preparation (by glucose methyl alcohol ortho ester 8 or glucose vinyl carbinol ortho ester 9) of the trisaccharide ortho-esters 33 or the trisaccharide ortho-esters 34 of 6 chloracetyls:
With glucose bromo-derivative 17 is glycosyl donor (1 mmole); glucose methyl alcohol ortho ester 8 or glucose vinyl carbinol ortho ester 9 etc. mol ratio are glycosyl acceptor; donor is dissolved in 10 milliliters of methylene dichloride; acceptor is dissolved in 10 milliliters of dimethyl formamides; mix 2 of mol ratios such as back adding and donor; the 4-lutidine; (0.115 milliliter; 1 mmole); (256 milligrams of silver trifluoromethanesulfonates; 1 mmole); at first make the ortho ester 31 of disaccharides or the ortho ester 32 of disaccharides; then in the use-case 5 method, make the ortho ester 32 and 1 reaction of bromo ethanoyl glucose of the ortho ester 31 of disaccharides or disaccharides, obtain having the trisaccharide ortho-esters 33 or the trisaccharide ortho-esters 34 of 6 chloracetyls.
Embodiment 11 has the preparation of the trisaccharide ortho-esters 29 of benzoyl or trisaccharide ortho-esters 30 (by grape
The methyl glucoside 3 of sugar or the allyl group glycosides 4 of glucose)
With bromo ethanoyl glucose 1 is glycosyl donor; etc. the methyl glucoside 3 of the glucose of mol ratio or the allyl group glycosides 4 of glucose is glycosyl acceptor; at first prepare two hepatin acid esters 27 or two hepatin acid esters 28 by the method described in the example 9; method described in the use-case 8 then; make two hepatin acid esters 27 or two hepatin acid esters 28 and 21 reactions of bromobenzene formyl radical glucose, the trisaccharide ortho-esters 30 that obtains having the trisaccharide ortho-esters 29 of benzoyl or have benzoyl.
Embodiment 12 has the preparation of the trisaccharide ortho-esters 37 or the trisaccharide ortho-esters 38 of benzoyl.(by grape
Sugar methyl alcohol ortho ester 8 or glucose vinyl carbinol ortho ester 9):
With bromo ethanoyl glucose 1 is glycosyl donor; glucose methyl alcohol ortho ester 8 or glucose vinyl carbinol ortho ester 9 etc. mol ratio are glycosyl acceptor; at first prepare two hepatin acid esters 35 or two hepatin acid esters 36 by the method described in the example 11; method described in the use-case 8 then; make two hepatin acid esters 35 or two hepatin acid esters 36 and 21 reactions of bromobenzene formyl radical glucose, obtain having the trisaccharide ortho-esters 37 or the trisaccharide ortho-esters 38 of benzoyl.
The preparation of embodiment 13 3 saccharide acceptors 40:
With trisaccharide ortho-esters 19 quantitatively acetylize according to a conventional method, then by the method for stating in the example 3, under the effect of TMSOTF, reset, obtain trisaccharide 39, be reagent with sulphur urine, optionally take off 6 chloracetyl, obtain three saccharide acceptors 40.
The preparation of embodiment 14 3 saccharide acceptors 42:
With trisaccharide ortho-esters 22 according to a conventional method; quantitative benzoylation; then by the method described in the example 3; under the effect of TMSOTF, reset; obtain trisaccharide 41, it is dissolved in 15 milliliters of dichloromethane solutions that contain 1 mmole Acetyl Chloride 98Min., reacted 8 hours; use the ordinary method aftertreatment, behind silica gel column chromatography, obtain not three saccharide acceptors 42 of acetyl-containing.
The preparation of embodiment 15 3 saccharide acceptors 43 or three saccharide acceptors 44:
Method by described in the example 13 through acetylize, rearrangement, obtains three saccharide acceptors 43 by trisaccharide ortho-esters 25 or trisaccharide ortho-esters 33, obtains three saccharide acceptors 44 by trisaccharide ortho-esters 26 or trisaccharide ortho-esters 34.
The preparation of embodiment 16 3 saccharide acceptors 45 or three saccharide acceptors 46:
Method by described in the example 14 through benzoylation, rearrangement, obtains three saccharide acceptors 45 by trisaccharide ortho-esters 29 or trisaccharide ortho-esters 37, obtains three saccharide acceptors 46 by trisaccharide ortho-esters 30 or trisaccharide ortho-esters 38.
Embodiment 17 can be used as the preparation of activator six sugar of the plant immunization system that agricultural chemicals uses:
Three saccharide donors 15 or three saccharide donors 16 (1 mmole) and three saccharide acceptors 40 (1 mmole) are dissolved in 20 milliliters of exsiccant methylene dichloride; the silver trifluoromethanesulfonate (256 milligrams) that mol ratio such as in this solution, adds; be reflected under room temperature, the stirring and carry out; finish after 2 hours; reaction solution is aftertreatment according to a conventional method; after silicagel column is refining, obtain 6 sugar 47 of 1,2 full acetylated protection.Productive rate 68%-75%.
Also can by example 5 described conditions, obtain the ortho ester of 6 sugar earlier, under the TMSOTF effect, reset then, obtain 6 sugar 48 of 1,2 protection of ethanoyl and benzoylization by three saccharide donors 15 or three saccharide donors 16 and 42 reactions of three saccharide acceptors.Two step accumulative total productive rates 42%.
6 sugar 47 or 6 sugar 48 (1 mmole) are dissolved in 10 milliliters of anhydrous methanols, add 10 milligrams of sodium methylates, stirred 10 minutes down, behind the decompressing and extracting solvent, obtain 6 sugar 49 of 1,2 protection quantitatively at 50 ℃.
6 sugar, 47 or 6 sugar 48 are removed 1,2 ethidine by the method described in the example 3, and deacetylation promptly obtains free 6 sugared activator 50 again.
6 sugar 47 or 6 sugar 48 (1 mmole) are dissolved in 10 milliliters of methanol solutions (0.2N) that contain dry hydrogen chloride, and reaction was at room temperature carried out 6 hours, and reaction solution is under reduced pressure drained, and was dissolved in 5 ml methanol, with negatively charged ion (OH again
-Type) drains under the decompression of in the exchange resin and back, be dissolved in again in 10 ml methanol, take off ethanoyl, with Zeo-karb (H with the sodium methylate of catalytic amount
+Type) methyl glucoside 51 that obtains 6 sugar is drained in the decompression of neutralization back down.
6 sugar 47 or 6 sugar 48 (1 mmole) are dissolved in 10 milliliters of vinyl carbinol solution (0.2N) that contain dry hydrogen chloride, and reaction conditions is identical with the methyl glucoside 51 for preparing 6 sugar, obtains the allyl group glycosides 52 of 6 sugar at last.
The preparation of embodiment 18 tetrose acceptors 56:
With 6 chloroacetylations, 1; the trisaccharide 39 of 2 ethidines protection; the Schmidt reagent 54 for preparing trisaccharide bromo-derivative 53 or trisaccharide by the condition of preparation three saccharide donors 15 or three saccharide donors 16 in the example 3; make the Schmidt reagent 54 and 55 couplings of monose acceptor of trisaccharide bromo-derivative 53 or trisaccharide; optionally taking off 6 chloracetyl, promptly get tetrose acceptor 56 with sulphur urine.
Embodiment 19 can be used as the preparation of activator seven sugar 58 of the plant immunization system that agricultural chemicals uses:
With three saccharide donors 15 or three saccharide donors 16 and 56 couplings of tetrose acceptor, promptly obtain seven full acetylated sugar 57, take off acetyl through catalysis and promptly obtain seven sugar 58.
Claims (1)
1. one kind is plant immunization system activating agent six sugar of key intermediate and the synthetic method of seven sugar with the trisaccharide ortho-esters, it is characterized in that:
(1) be glycosyl donor with 2 moles bromo ethanoyl glucose 1, with 1 mole 1, the glucose 2 of 2-O-ethidine protection, the methyl glucoside 3 of glucose, the allyl group glycosides 4 of glucose, the methyl alcohol ortho ester 8 of glucose or the vinyl carbinol ortho ester of glucose 9 are glycosyl acceptor, be dissolved in glycosyl donor and glycosyl acceptor in the methylene dichloride respectively, then with the two mixing, add 2 moles silver salt and 2 moles organic bases, stirring, reaction is 2-4 hour under the room temperature, prepares the ortho ester 5 of trisaccharide respectively, the ortho ester 6 of trisaccharide, the ortho ester 7 of trisaccharide, the ortho ester 10 of trisaccharide or the ortho ester 11 of trisaccharide;
Or be that the glucose bromo-derivative 17 of chloracetyl is a glycosyl donor with six, 1, the glucose 2 of 2-O-ethidine protection, the methyl glucoside 3 of glucose, allyl group glycosides 4, the methyl alcohol ortho ester 8 of glucose or vinyl carbinol ortho ester 9 are glycosyl acceptor, its mol ratio is 1: 1, be dissolved in the methylene dichloride respectively, then with the two mixing, the silver salt and the organic bases of mol ratios such as adding, room temperature, stir reaction down 2-4 hour, at first prepare the ortho ester 18 of disaccharide, the ortho ester 23 of disaccharide, the ortho ester 24 of disaccharide, the ortho ester 31 of disaccharide or the ortho ester 32 of disaccharide, be glycosyl donor with bromo ethanoyl glucose 1 then, the ortho ester 18 of disaccharide, the ortho ester 23 of disaccharide, the ortho ester 24 of disaccharide, the ortho ester 31 of disaccharide or the ortho ester of disaccharide 32 are glycosyl acceptor, its mol ratio is 1: 1, under silver salt that waits mol ratio and organic bases effect, room temperature, stir reaction down 2-4 hour, obtain the ortho ester 19 of trisaccharide, the ortho ester 25 of trisaccharide, the ortho ester 26 of trisaccharide, the ortho ester 33 of trisaccharide or the ortho ester 34 of trisaccharide;
Or be glycosyl donor with bromo ethanoyl glucose 1,1, the glucose 2 of 2-O-ethidine protection, the methyl glucoside 3 of glucose, allyl group glycosides 4, the methyl alcohol ortho ester 8 of glucose or vinyl carbinol ortho ester 9 are glycosyl acceptor, its mol ratio is 1: 1, be dissolved in the methylene dichloride respectively, then with the two mixing, the silver salt and the organic bases of mol ratios such as adding, room temperature, stir reaction down 2-4 hour, at first prepare the ortho ester 20 of disaccharide, the ortho ester 27 of disaccharide, the ortho ester 28 of disaccharide, the ortho ester 35 of disaccharide or the ortho ester 36 of disaccharide, be glycosyl donor with bromobenzene formyl radical glucose 21 then, the ortho ester 20 of disaccharide, the ortho ester 27 of disaccharide, the ortho ester 28 of disaccharide, the ortho ester 35 of disaccharide or the ortho ester of disaccharide 36 are glycosyl acceptor, its mol ratio 1: 1, under silver salt that waits mol ratio and organic bases effect, room temperature, stir reaction down 2-4 hour, obtain the ortho ester 22 of trisaccharide, the ortho ester 29 of trisaccharide, the ortho ester 30 of trisaccharide, the ortho ester 37 of trisaccharide or the ortho ester 38 of trisaccharide;
(2) with the ortho ester 5 of trisaccharide; the ortho ester 6 of trisaccharide; the ortho ester 7 of trisaccharide; the ortho ester 10 of trisaccharide or the ortho ester 11 of trisaccharide; with diacetyl oxide in pyridine after the acetylize; be dissolved in the methylene dichloride; trimethyl silicane fluoroform sulphonate (TMSOTF) thorough mixing with catalytic amount; stirring; reaction is 2-6 hour under the room temperature; carry out the rearrangement of hepatin acid ester; remove ethidine with ordinary method through acid hydrolysis again; or allyl group; or methyl; acetylize; bromination, or remove ethidine through acid hydrolysis; or allyl group; or methyl; acetylize; selectivity is taken off an ethanoyl; use DBU-CCl
3CN gets Schmidt reagent, prepares three saccharide donors 15 or three saccharide donors 16 of glucose;
In the formula: a-acetylize b-TMSOTF resets the c-acid hydrolysis, acetylize d-bromination e-selectivity is taken off 1 ethanoyl, used DBU-CCl
3CN gets Schmidt reagent
(3) trisaccharide ortho-esters 19, trisaccharide ortho-esters 25, trisaccharide ortho-esters 26, trisaccharide ortho-esters 33 or trisaccharide ortho-esters 34 are earlier through diacetyl oxide acetylize in pyridine; Trisaccharide ortho-esters 22, trisaccharide ortho-esters 29, trisaccharide ortho-esters 30, trisaccharide ortho-esters 37 or trisaccharide ortho-esters 38 are earlier through benzoylation; Then with trimethyl silicane fluoroform sulphonate (TMSOTF) thorough mixing of catalytic amount, reaction is 2-6 hour under stirring, room temperature, carry out the rearrangement of hepatin acid ester, through 6 deacetylations of selectivity, prepare three saccharide acceptors 40, three saccharide acceptors 42 of the glucose β 1 → 6, the β 1 → 3 that contain ethidine, and methyl glucoside three saccharide acceptors 43, allyl group glycosides three saccharide acceptors 44, methyl glucoside three saccharide acceptors 45 or allyl group glycosides three saccharide acceptors 46;
A-acetylize d-benzoylation b-TMSOTF resets e-TMSOTF and resets 6 dechlorination acetyl of c-selectivity f-selectivity deacetylation
(4) will wait three saccharide donors 15 or three saccharide donors 16 of mol ratio, with three saccharide acceptors 40, three saccharide acceptors 42, three saccharide acceptors 43, three saccharide acceptors 44, three saccharide acceptors 45 or three saccharide acceptors 46, be dissolved in the methylene dichloride, under the silver catalyst that waits mol ratio, carry out coupling, again acetylize; Or be dissolved in the methylene dichloride, under silver salt that waits mol ratio and organic bases effect, obtain ortho ester earlier, with the trimethyl silicane three fluoro sulfonate thorough mixing of catalytic amount, reset, more again through benzoylation, reaction solution is aftertreatment according to a conventional method, obtains six sugar, 47 or six sugar 48 of 1,2 protection;
In the formula: the agent of a-silver catalyst, methylene dichloride b-acetylize c-methylene dichloride, silver catalyst agent, 2,4-lutidine d-methylene dichloride, TMSOTFe-Benzoyl chloride, pyridine
Or with ordinary method with six sugar 47, or the acyl group of six sugar 48 removes, obtain 1,6 sugar 49 of 2 ethylideneizations, or with ordinary method with six sugar 47, or 1,2 ethidine of six sugar 48 respectively in the aqueous solution, methyl alcohol, vinyl carbinol acidolysis remove, can obtain free six sugar 50, the methyl glucoside 51 of six sugar or the allyl group glycosides 52 of six sugar;
In the formula: acidolysis in the acidolysis e-vinyl carbinol solution in the a-aqueous acid medium hydrolysis b-acetylize c-catalysis deacylated tRNA base d-methanol solution
(5) will being converted into the Schmidt reagent 54 of bromo-derivative 53 or trisaccharide after the acidolysis of trisaccharide receptor 39 (GPR 39), is acidylate methyl glucoside 55 couplings of free hydroxyl group with 6 again, obtains tetrose acceptor 56 through 6 dechlorination acetyl of selectivity;
In the formula: a-acid hydrolysis b-acetylize c-bromo d-selectivity is taken off 1 acetyl, uses CCl
3CN system Schmidt reagent e-methylene dichloride, silver trifluoromethanesulfonate f-sulphur is urinated again with tetrose acceptor 56 and three saccharide donors 15 or 16 couplings of three saccharide donors, obtains seven sugar 57;
At last, acetylizad seven sugar 57 are used the ordinary method deprotection, obtain seven sugared activator 58;
Described silver salt is a silver trifluoromethanesulfonate; Described organic bases is 2,4-lutidine or 2,6-lutidine.
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| CN98103241A CN1072676C (en) | 1998-07-17 | 1998-07-17 | Method for synthesizing hexasaccharide and heptasaccharide used as plant immunological system activator using trisaccharid ortho-ester as key intermediate |
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| CN98103241A CN1072676C (en) | 1998-07-17 | 1998-07-17 | Method for synthesizing hexasaccharide and heptasaccharide used as plant immunological system activator using trisaccharid ortho-ester as key intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108892740A (en) * | 2018-06-19 | 2018-11-27 | 朱玉亮 | A kind of synthetic method of 3,6 branching glucohexaoses |
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| CN1136223C (en) * | 1999-09-30 | 2004-01-28 | 中国科学院生态环境研究中心 | Simple synthesis of hexa-saccharide as plant self defence system activating agent |
| CN1394867A (en) | 2001-07-06 | 2003-02-05 | 中国科学院生态环境研究中心 | Medicinal oligose and its preparation method and medicine composition containing said oligose |
| CN114409817A (en) * | 2022-01-24 | 2022-04-29 | 艾立斯特(合肥)生物科技有限公司 | Heptasaccharide synthesis method of lentinan core fragment beta- (1 → 6) branched chain beta- (1 → 3) main chain |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH04134091A (en) * | 1990-09-25 | 1992-05-07 | Towa Kasei Kogyo Kk | Production of trehalose isomer |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH04134091A (en) * | 1990-09-25 | 1992-05-07 | Towa Kasei Kogyo Kk | Production of trehalose isomer |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108892740A (en) * | 2018-06-19 | 2018-11-27 | 朱玉亮 | A kind of synthetic method of 3,6 branching glucohexaoses |
| CN108892740B (en) * | 2018-06-19 | 2022-01-25 | 艾立斯特(合肥)生物科技有限公司 | Synthesis method of 3, 6-branched glucan hexaose |
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