CN103275133A - Synthetic method of beta-D-oligomannuronate or glucoside - Google Patents

Synthetic method of beta-D-oligomannuronate or glucoside Download PDF

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CN103275133A
CN103275133A CN2013102324369A CN201310232436A CN103275133A CN 103275133 A CN103275133 A CN 103275133A CN 2013102324369 A CN2013102324369 A CN 2013102324369A CN 201310232436 A CN201310232436 A CN 201310232436A CN 103275133 A CN103275133 A CN 103275133A
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methyl
synthetic method
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CN103275133B (en
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李明
王鹏
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Ocean University of China
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Ocean University of China
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Abstract

The invention relates to a method for synthesizing beta-oligosaccharide or glucoside 3 stereoselectively by D-mannuronic acid o-alkynyl benzoate 1, wherein R1-R5 adopts one of C1-C6 alkyl, C3-C6 naphthenic base, silicon substrate and acyl-substituted methyl; and R6OH adopts one of acyl, silicon substrate or alkyl protected monohydroxy or polyhydroxy-sugar, simple alcohol or phenol, steroid sapogenin, steroid saponin, triterpenoid sapogenin or triterpenoid saponin. The synthetic method has the advantages as follows: (1) catalytic amount of an organic gold compound is used as an accelerator for a reaction; (2) the reaction conditions are mild (0-30 DEG C), and the operation is simple and convenient; and (3) the reaction yield is high, and the stereoselectivity is good.

Description

The synthetic method of beta-D-mannuronic acid oligosaccharide or glucosides
Technical field
The invention belongs to the organic synthesis field, relate to a kind of method by synthetic its β-oligosaccharides of the adjacent alkynyl benzoic ether of D-mannuronic acid stereoselectivity or glucosides.
Technical background
The natural product that contains β-mannuronic acid unit extensively exists extremely important biological activity.Beta-D-mannuronic acid oligosaccharide not only have promote plant root growth, antibacterial, promote effect such as people's keratinocyte growth, and can with Toll sample acceptor 2 and 4 combinations, and show immunoregulatory effect.Derive from the Sulfated mannuronic acid oligosaccharide JG of algin 3Not only can be as the heparinase inhibitor, suppress in vitro and in vivo tumor-blood-vessel growth and transfer (Cancer Res.2006,66,8779-8787), and can be combined with tubulin, make cancer cells stop at G 2/ M the stage causes its apoptosis, thereby suppresses the growth of tumour cell.Therefore, JG 3Might as a novel carcinostatic agent (Cancer Biol.Ther.2010,10,89-98).Yet the structure of beta-D-mannuronic acid glycosidic link is one of challenging task of tool; this is because the beta-D-mannuronic acid glycosidic link is 1; (2-OH is in axial bond to the glycosidic link of 2 cis; different bit substituent is in equatorial bond); when making up such glycosidic link; except not having the protecting group of participation of neighboring group function in 2 uses of glycosyl donor, also must overcome different head position effect and the nucleophile of kinetics and be in upright C-2 substituent sterically hindered.The D-mannuronic acid sulphur glycosides of van der Marel group development is the most effective direct method (J.Am.Chem.Soc.2006 of current its β-glycosidic link of structure to body, 128,13066), but this method needs the promotor of equivalent to activating in advance to body, severe reaction conditions and complex operation, wayward.Therefore, development D-mannuronic acid novel, efficient, simple to operation has important science and using value for body β-glucosides technology.
Summary of the invention
The purpose of this invention is to provide a kind of method of being given synthetic its β-oligosaccharides of body stereoselectivity or glucosides by the D-mannuronic acid efficient, simple to operation.
The present invention is as follows to the reaction formula that system is equipped with its β-oligosaccharides or glucosides by the D-mannuronic acid:
Figure BDA00003334397000011
Concrete synthesis step is as follows:
In solvent and dewatering agent in the presence of, be promotor with LAuCl and AgX, the adjacent alkynyl benzoic ether 1 of Compound D-mannuronic acid and compound R 6OH2 obtains compound beta-D-mannuronic acid oligosaccharide or glucosides 3 in-100-100 ℃ of reaction 0.5-72 hour; Wherein, compound 1 is (1.0-5.0) with the mol ratio of compound 2: 1.0; Compound 1 is 1.0:(0.1-0.3 with the mol ratio of LAuCl); Compound 1 is 1.0:(0.1-0.9 with the mol ratio of AgX); Compound 1 is 1.0:(3.0-10.0 with the mass ratio of dewatering agent);
Wavy line represents that the adjacent alkynyl benzoic ether 1 of D-mannuronic acid is α-or beta configuration in the reaction formula; R 1-R 5Be C 1-C 6Alkyl, C 3-C 6A kind of in the methyl of cycloalkyl, silica-based, acyl group, replacement; R 6OH is monohydroxy or poly-hydroxy sugar, simple alcohol or phenol, steroid sapogenin, steroidal saponin, triterpenoid sapogenin or the triterpenoid saponin of acyl group or silica-based or alkyl protection.
Work as R 6When OH was the monohydroxy of acyl group or the protection of silica-based or alkyl or poly-hydroxy sugar, compound 3 was oligosaccharides;
Work as R 6When OH was simple alcohol or phenol, compound 3 was glucosides;
Work as R 6When OH was steroid sapogenin, steroidal saponin, triterpenoid sapogenin or triterpenoid saponin, compound 3 was glucosides.
Wherein,
The methyl of described replacement is methoxyl methyl (MOM), benzyloxymethyl (BOM), benzyl (Bn), a kind of in methoxybenzyl (PMB), 2-naphthyl methyl (NAP), 2-methoxy (ethoxy) methyl (MEM), 2-(trimethyl silicon based) ethoxymethyl (SEM); Preferably benzyl (Bn), to methoxybenzyl (PMB) or 2-naphthyl methyl (NAP).
Described silica-based be methyl, ethyl, sec.-propyl, the tertiary butyl, phenyl etc. constitute three replace silica-based; Preferably triethyl silica-based (TES) or tertiary butyl dimethyl silica-based (TBS) or diethyl sec.-propyl silica-based (DEIPS).
Described acyl group is C 2-C 6Straight or branched aliphatic acyl radical or C 6-C 10Aromaticacyl radical; Preferably ethanoyl (Ac), chloracetyl (ClAc), pivaloyl group, 4-carbonyl pentanoyl (Lev), 2-chloro-2-methyl-propionyl, benzoyl, adjacent azido-methyl benzoyl or 2-(2-nitrophenyl)-ethanoyl; Most preferably ethanoyl (Ac), chloracetyl (ClAc) or 4-carbonyl pentanoyl (Lev).
Described sugar is Glucopyranose (Glcp), galactopyranose (Galp), mannopyranose (Manp), mannopyranose (Manp), mannopyranose (Manp), mannopyranose (Manp), xylopyranose (Xylp), pyrans glucosamine (GlcNACp), pyrans rhamnosyl (Rhap), pyrans rhamnosyl (Rhap), pyrans/furans pectinose (Araf/p), pyrans/furans pectinose (Araf/p), pyrans/furans pectinose (Araf/p), pyrans/furans pectinose (Araf/p), pyrans Fucose (Fucp), Glucopyranose aldehydic acid (GlcAp), the polymerization degree of galactopyranose aldehydic acid monose such as (GalAp) and composition thereof is linearity or the branched oligosaccharides of 2-8.
Described steroid sapogenin is diosgenin, refined nurse sapogenin, for accusing a kind of in sapogenin, NSC 232021, hecogenin, new hecogenin, Chinaroot Greenbier Rhizome sapogenin, timosaponin unit, botogenin, Neobotogenin, different chiapagenin, cholesterol, the Stigmasterol.
Described steroidal saponin is to be made up of above-mentioned steroid sapogenin and monose and oligosaccharides.
Described triterpenoid sapogenin is a kind of in Oleanolic Acid, ursolic acid, glycyrrhetinic acid, betulinic acid, the betulin.
Described triterpenoid saponin is to be made up of above-mentioned triterpenoid sapogenin and monose or oligosaccharides.
Described simple alcohol is C 3-C 10Alkyl or cyclic alkyl alcohols.
Described phenol is C 6-C 12Single phenol or polyphenolic compound.
Described solvent is C 1-C 6Single halo or many halogenated alkanes, 1,4 – dioxane, ether, acetonitrile, 2,2,2 – trimethylacetonitriles, tetrahydrofuran (THF), N, N – dimethyl formamide, N, a kind of in N – N,N-DIMETHYLACETAMIDE, hexamethylphosphoramide, N-methylpyrrolidin-2-ketone, toluene, phenylfluoroform, the Nitromethane 99Min. or their mixture.
Described dewatering agent is
Figure BDA00003334397000031
A kind of in molecular sieve or AW-300 molecular sieve or anhydrous sodium sulphate, anhydrous calciumsulphate, anhydrous cupric sulfate, the anhydrous magnesium sulfate or their mixture.
Described L is the trivalent phosphine compound of methyl, ethyl, sec.-propyl, the tertiary butyl, phenyl, p-methoxyphenyl formation.
Described X is trifluoromethanesulfonic acid root (TfO -), perchlorate (ClO 4 -), tetrafluoroborate (BF 4 -), four (phenyl-pentafluoride base) borate [B (C 6F 5) 4 -), hexafluoroantimonic anion (SbF 6 -), two (fluoroform sulphonyl) imines negative ion (Tf 2N -) in a kind of.
Method of the present invention is recommended under the protection of inert gas carries out, as argon gas, nitrogen etc.
The present invention has reaction conditions gentleness (0-30 ℃), advantage easy and simple to handle, that reaction yield is high, stereoselectivity is good.
Description of drawings
Fig. 1 is by the adjacent alkynyl benzoic ether 1 of D-mannuronic acid and compound 2(2a-2o) synthetic its β of reaction-glucosides product 3(3a-3o) reaction equation and structure iron thereof.
Embodiment
Below in conjunction with accompanying drawing, and synthetic as specific embodiment with compound 3a-3o, the present invention is described in detail, but the invention is not restricted to following content.
Embodiment 1-9: compound 3a, 3b, 3c, 3e, 3f, 3g, 3i, 3j, 3k's is synthetic
Under the argon shield, in reaction flask, add fresh activation AW-300 or
Figure BDA00003334397000032
One (1.0mol) and AgB (C among molecular sieve (3g/mmol), the adjacent alkynyl benzoic ether of D-mannuronic acid 1 (1.2-1.5mol), monose or alcohol or phenol 2a, 2b, 2c, 2e, 2f, 2g, 2i, 2j, the 2k 6F 5) 4(0.1mol), then inject the new anhydrous CH of steaming 2Cl 2(2mL), behind 0 ℃ of stirring 30min, add again (4-MeOPh) 3PAuCl (0.1mol) and AgB (C 6F 5) 4(0.1mol), continue stirring after 0.5-24 hour the TLC detection reaction finishes.With triethylamine cancellation reaction and filtration, filtrate is through concentrating under reduced pressure, and column chromatography obtains compound 3a, 3b, 3c, 3e, 3f, 3g, 3i, 3j, 3k respectively.
Embodiment 10-12: compound 3h, 3l, 3n's is synthetic
Similar with embodiment 1-9 step, with Ph 3PAuCl (0.1mol) and AgB (C 6F 5) 4(0.1mol) be promotor, the adjacent alkynyl benzoic ether 1 of D-mannuronic acid respectively with steroid sapogenin 2h, 2l, 2n in a reaction obtain 3h, 3l, 3n.
Embodiment 13-15: compound 3d, 3m, 3o's is synthetic
Similar with embodiment 1-9 step, with Me 3PAuCl (0.1mol) and AgB (C 6F 5) 4(0.1mol) be promotor, the adjacent alkynyl benzoic ether 1 of D-mannuronic acid respectively with triterpenoid sapogenin 2d, 2m, triterpenoid saponin 2o in a reaction obtain 3d, 3m, 3o.
The data of compound 3a-3o are as follows:
Compound 3a data:
Productive rate: 85%;
[α] D 20-134.0(c2.33,CHCl 3)；
1H?NMR(600MHz,CDCl 3)δ7.43(d,J=6.6Hz,2H),7.37(d,J=7.7Hz,2H),7.35-7.29(m,6H),7.26(m,4H),7.14(d,J=8.3Hz,2H),5.65(s,1H),5.50(t,J=9.9Hz,1H),4.93(d,J=13.2Hz,2H),4.80(d,J=12.1Hz,1H),4.50(d,J=12.7Hz,1H),4.38(d,J=12.1Hz,1H),4.30(d,J=5.5Hz,1H),4.17-4.11(m,2H),3.94(d,J=2.8Hz,1H),3.79(d,J=9.8Hz,1H),3.75(dd,J=9.9,7.7Hz,1H),3.70(s,3H),3.51(dd,J=9.9,3.3Hz,1H),2.71(t,J=7.1Hz,2H),2.54(td,J=6.7,4.5Hz,2H),2.34(s,3H),2.16(s,3H),1.47(s,3H),1.34(s,3H),1.30(d,J=6.2Hz,3H);
13C?NMR(150MHz,CDCl 3)δ206.3,171.6,167.9,138.5,138.1,137.9,132.6,130.0,129.5,128.5,128.4,128.2,127.8,127.7,127.6,109.7,99.6,84.1,78.7,78.4,78.0,77.4,77.2,76.9,76.8,74.2,73.8,73.5,71.6,69.2,65.9,52.6,37.9,29.9,29.8,27.9,27.8,26.6,21.2,17.5;
HRMS(MALDI)calcd?for?C 42H 50O 12Na:801.2915;Found:801.2938。
The data of compound 3b:
Productive rate: 96%;
[α] D 20-109.4(c0.49CHCl 3); 1H?NMR(600MHz,CDCl 3)δ7.46(d,J=7.1Hz,2H),7.32-7.28(m,4H),7.28-7.24(m,3H),7.19(d,J=7.1Hz,2H),5.59(d,J=4.9Hz,1H),5.49(t,J=9.4Hz,1H),4.99(d,J=12.7Hz,1H),4.87(d,J=12.7Hz,1H),4.60(dd,J=8.2,2.8Hz,1H),4.51(s,1H),4.43(d,J=12.6Hz,1H),4.34(dd,J=4.9,2.7Hz,1H),4.26(d,J=12.1Hz,1H),4.21(m,2H),4.11(d,J=8.8Hz,1H),3.99(d,J=2.8Hz,1H),3.82(d,J=9.7Hz,1H),3.72(s,3H),3.60(dd,J=8.3,11.0Hz,1H),3.42(dd,J=9.4,2.8Hz,1H),2.71(t,J=6.8Hz,2H),2.54(m,2H),2.16(s,3H),1.49(s,3H),1.44(s,3H),1.34(s,3H),1.32(s,3H)；
13C?NMR(150MHz,CDCl 3)δ206.3,171.7,168.0,138.4,137.8,128.7,128.5,128.3,127.8,127.7,127.6,109.6,108.9,102.4,96.5,77.9,77.4,77.2,77.0,73.8,73.7,72.4,71.7,71.2,70.9,70.6,70.3,69.2,68.2,52.8,37.9,30.0,28.0,26.2,26.1,25.2,24.5；
HRMS(MALDI)calcd?for?C 38H 48O 14Na:751.2936;Found:751.2958。
The data of compound 3c:
Productive rate: 76%;
[α] D 20=7.1(c2.14,CHCl 3); 1H?NMR(600MHz,CDCl 3)δ8.06(d,J=6.0Hz,2H),7.60(t,J=7.4Hz,1H),7.48(m,4H),7.35(m,3H),7.24(m,2H),7.10(m,5H),7.03(m,2H),5.58(s,1H),5.38(t,J=9.8Hz,1H),5.19(dd,J=9.6,3.8Hz,1H),5.06(d,J=3.8Hz,1H),4.74(d,J=12.3Hz,1H),4.63(s,1H),4.46(d,J=12.4Hz,1H),4.35(t,J=9.2Hz,1H),4.31(dd,J=10.0,4.4Hz,1H),4.09(d,J=12.2Hz,1H),4.00(d,J=12.2Hz,1H),3.90(dd,J=9.8,4.3Hz,1H),3.84(dt,J=14.6,9.6Hz,2H),3.69(d,J=9.8Hz,1H),3.64(d,J=2.7Hz,1H),3.60(s,3H),3.39(s,3H),3.24(dd,J=9.7,2.8Hz,1H),2.66(t,J=6.9Hz,2H),2.49(m,2H),2.13(s,3H)；
13C?NMR(150MHz,CDCl 3)δ206.3,171.5,167.8,165.5,138.3,137.8,137.3,133.7,129.8,129.4,128.9,128.7,128.3,128.3,127.9,127.6,127.3,127.2,126.2,102.7,101.3,97.7,80.1,78.4,78.4,77.4,77.2,77.0,74.4,73.6,73.3,71.1,68.9,68.7,62.6,55.5,52.6,37.8,29.9,27.9；
HRMS(MALDI)calcd?for?C 47H 50O 15Na:877.3042;Found:877.3066。
The data of compound 3d:
Productive rate: 87%;
[α] D 20=20.9(c1.29,CHCl 3); 1H?NMR(600MHz,CDCl 3)δ7.43-7.41(m,2H),7.39-7.30(m,7H),7.29-7.27(m,1H),7.25-7.20(m,5H),5.52(m,2H),5.20(d,J=12.2Hz,1H),5.09(d,J=12.2Hz,1H),5.02(d,J=12.9Hz,1H),4.82(d,J=12.9Hz,1H),4.43(t,J=6.1Hz,2H),4.32(d,J=12.3Hz,1H),3.91(d,J=3.0Hz,1H),3.82(d,J=9.8Hz,1H),3.72(s,3H),3.44(dd,J=9.8,2.9Hz,1H),3.11-3.06(m,1H),2.78(m,1H),2.72-2.68(m,2H),2.54(td,J=6.8,1.6Hz,2H),2.29(s,1H),2.15-2.13(m,1H),2.04-1.08(m,34H),0.90(dd,J=19.7,13.2Hz,9H),0.71(d,J=19.8Hz,5H)；
13C?NMR(150MHz,CDCl 3)δ206.4,200.1,176.3,171.6,168.9,168.2,138.7,138.0,136.3,128.8,128.7,128.5,128.4,128.3,127.8,127.6,127.5,104.5,91.1,79.0,77.4,77.2,77.0,73.9,73.8,73.5,71.6,69.2,66.4,61.9,55.4,52.8,48.3,45.5,44.1,43.3,41.2,39.4,39.4,38.0,37.8,36.9,32.9,31.9,31.3,30.0,28.6,28.4,28.05,26.6,25.9,23.5,18.8,17.6,16.8,16.5；
ESI-MS:m/z1051.3[M+Na];HRMS-(MALDI)calcd?for?C 63H 80O 12Na:1051.5542;Found:1051.5572。
The data of compound 3e:
Productive rate: 78%;
[α] D 20=-21.1(c0.24,CHCl 3);
1H?NMR(600MHz,CDCl 3)δ7.48(dd,J=7.6,1.8Hz,2H),7.46-7.44(m,2H),7.36-7.27(m,11H),7.25(s,1H),7.24-7.15(m,9H),5.63(s,1H),5.61(d,J=1.1Hz,1H),5.44(t,J=9.5Hz,1H),4.94(d,J=12.2Hz,1H),4.72(d,J=12.2Hz,1H),4.71(d,J=12.2Hz,1H),4.50(d,J=12.6Hz,1H),4.49-4.44(m,2H),4.39(d,J=12.6Hz,1H),4.29(m,1H),4.26-4.21(m,2H),4.09(s,1H),4.06(dd,J=3.1,1.3Hz,1H),3.89(t,J=10.1Hz,1H),3.74(d,J=2.9Hz,1H),3.70(s,3H),3.43(d,J=9.5Hz,1H),3.20(dd,J=9.5,2.9Hz,1H),2.72(t,J=6.8Hz,2H),2.58-2.53(m,2H),2.17(s,3H)；
13C?NMR(150MHz,CDCl 3)δ206.5,171.6,167.9,138.7,138.1,137.51,137.3,133.8,132.1,129.4,129.0,128.8,128.7,128.5,128.4,128.2,128.1,128.0,127.9,127.6,127.3,126.3,101.9,97.8,85.9,77.9,77.6,77.4,77.2,77.0,75.7,74.1,73.9,73.6,72.7,72.0,71.3,69.0,68.6,65.6,52.7,38.0,30.0,28.0；
HRMS(MALDI)calcd?for?C 52H 54O 13NaS:941.3177;Found:941.3206。
The data of compound 3f:
Productive rate: 93% (60% β+33% α);
[α] D 20=-34.5(c1.60,CHCl 3)；
1H?NMR(600MHz,CDCl 3)δ7.49(d,J=7.2Hz,2H),7.34(d,J=7.4Hz,2H),7.28(m,7H),7.02(d,J=7.3Hz,2H),6.99(m,1H),5.54(t,J=9.8Hz,1H),5.10(d,J=12.5Hz,1H),4.97(d,J=12.5Hz,1H),4.67(s,1H),4.55(d,J=12.2Hz,1H),4.48(d,J=12.2Hz,1H),4.14(d,J=2.7Hz,1H),3.71(s,1H),3.69(s,3H),3.51(dd,J=9.8,2.9Hz,1H),2.70(d,J=6.7Hz,2H),2.55(m,2H),2.28(s,6H),2.16(s,3H)；
13C?NMR(150MHz,CDCl 3)δ206.4,171.7,167.9,154.0,138.6,137.9,131.8,129.0,128.6,128.4,128.3,128.0,127.8,127.6,125.0,113.1,102.9,78.8,77.4,77.2,77.0,74.4,73.8,73.5,72.0,69.0,52.7,37.9,30.0,28.0,17.3；
ESI-MS:m/z613.0[M+Na];629.0[M+K];HRMS-(MALDI)calcd?for?C 34H 38O 9Na:613.2408;Found:613.2417。
The data of compound 3g:
Productive rate: 89%;
[α] D 20=-79.9(c0.42,CHCl 3)；
1H?NMR(600MHz,CDCl 3)δ7.48(d,J=7.2Hz,2H),7.31(m,7H),7.25(d,J=7.4Hz,2H),5.54(t,J=9.7Hz,1H),5.02(d,J=12.7Hz,1H),4.90(d,J=12.7Hz,1H),4.57(s,1H),4.50(d,J=12.3Hz,1H),4.37(d,J=12.3Hz,1H),3.86(m,2H),3.74(m,4H),3.49(dd,J=9.7,2.7Hz,1H),2.73(t,J=6.7Hz,2H),2.57(m,2H),2.19(s,3H),1.95(m,1H),1.84-1.70(m,3H),1.54(m,2H),1.31(m,5H)；
13C?NMR(150MHz,CDCl 3)δ206.3,171.5,168.1,138.5,137.9,128.6,128.4,128.1,127.7,127.5,127.4,99.4,78.6,77.3,77.1,76.9,73.8,73.7,73.4,71.4,69.3,52.6,37.8,33.2,31.3,29.9,27.9,25.7,23.7,23.6；
ESI-MS:m/z591.0[M+Na];HRMS-(MALDI)calcd?for?C 32H 40O 9Na:591.2565;Found:591.2572。
The data of compound 3h:
Productive rate: 80%;
[α] D 20-115.4(c0.17,CHCl 3)；
1H?NMR(600MHz,CDCl 3)δ7.44(d,J=6.6Hz,2H),7.32-7.25(m,6H),7.21(d,J=7.1Hz,2H),5.50(t,J=9.9Hz,1H),5.32(d,J=5.5Hz,1H),4.95(d,J=12.7Hz,1H),4.84(d,J=12.7Hz,1H),4.51(s,1H),4.46(d,J=12.7Hz,1H),4.41(q,1H),4.33(d,J=12.6Hz,1H),3.81(m,2H),3.55(m,2H),3.45(m,2H),3.37(t,J=11.0Hz,1H),2.71(t,J=6.6Hz,2H),2.25(m,2H),2.16(s,3H),2.01-1.05(m,19H),1.01(s,3H),0.97(d,J=7.1Hz,3H),0.78(t,J=2.8Hz,6H)；
13C?NMR(150MHz,CDCl 3)δ206.3,171.6,168.2,140.6,138.6,137.9,128.7,128.5,128.2,127.8,127.6,121.9,109.4,99.6,80.9,78.8,78.6,77.4,77.2,77.0,74.0,73.8,73.6,71.6,69.4,67.0,62.2,56.6,52.7,50.2,41.7,40.4,39.9,38.8,38.0,37.3,37.0,32.2,32.0,31.6,31.5,30.4,30.0,29.6,28.9,28.0,20.9,19.6,17.3,16.4,14.6；
HRMS(MALDI)calcd?for?C 53H 70O 11Na:905.4810;Found:905.4835。
The data of compound 3i:
Productive rate: 49%;
[α] D 2014.6(c0.49CHCl 3); 1H?NMR(600MHz,CDCl 3)δ7.80(m,3H),7.80(d,J=8.2Hz,1H),7.50-7.40(m,5H),7.36(d,J=6.6Hz,2H),7.34-7.20(m,22H),5.57(d,J=2.8Hz,1H),5.42(t,J=9.4Hz,1H),4.91(d,J=12.7Hz,1H),4.75(s,2H),4.71(d,J=12.1Hz,1H),4.64(d,J=12.1Hz,1H),4.60(dd,J=7.1,11.9Hz,2H),4.26(s,1H),4.45(d,J=12.7Hz,1H),4.36(dd,J=4.4,12.1Hz,2H),4.28-4.20(m,2H),3.99(m,1H),3.93(t,J=2.7Hz,1H),3.70(m,2H),3.64(m,1H),3.50(d,J=9.9Hz,1H),3.48(s,3H),3.23(dd,J=2.8,9.9Hz,1H),2.66(t,J=7.1Hz,2H),2.49(m,2H),2.14(s,3H)；
13C?NMR(150MHz,CDCl 3)δ206.4,171.6,167.9,138.6,138.5,138.0,136.3,134.5,133.4,133.0,131.6,129.1,128.5,128.4,128.2,128.1,128.0,127.9,127.8,127.7,127.6,127.5,126.5,126.2,126.1,125.9,101.4,85.8,78.8,77.7,77.4,77.2,77.0,76.3,74.6,74.2,73.4,72.6,72.3,72.1,71.9,69.4,69.1,52.48,37.9,30.0,28.0；
HRMS(MALDI)calcd?for?C 63H 64O 13NaS:1083.3960;Found:1083.3980。
The data of compound 3j:
Productive rate: 88%;
[α] D 20=-55.4(c2.41CHCl 3); 1H?NMR(600MHz,CDCl 3)δ7.48(d,J=7.1Hz,2H),7.34(t,J=7.3Hz,2H),7.32-7.24(m,7H),5.52(t,J=9.8Hz,1H),5.02(d,J=12.8Hz,1H),4.93(d,J=12.8Hz,1H),4.72(s,1H),4.49(d,J=12.3Hz,1H),4.36(d,J=12.3Hz,1H),3.85(d,J=9.8Hz,1H),3.78(d,J=2.9Hz,1H),3.72(s,3H),3.50(dd,J=9.7,2.9Hz,1H),2.73(t,J=6.8Hz,2H),2.56(td,J=6.7,3.4Hz,2H),2.18(s,6H),1.87(d,J=11.3Hz,3H),1.79(d,J=11.3Hz,3H),1.64(m,8H)；
13C?NMR(150MHz,CDCl 3)δ206.3,171.6,168.2,138.6,138.0,128.7,128.4,128.1,127.7,127.5,127.4,94.6,79.0,77.4,77.2,77.0,75.6,74.2,73.8,73.5,71.5,69.2,52.6,42.4,37.9,36.3,30.7,29.9,29.8,28.0；
HRMS(MALDI)calcd?for?C 36H 44O 9Na:643.2878;Found:643.2886。
The data of compound 3k:
Productive rate: 29%;
[α] D 20=-26.0(c0.58CHCl 3); 1H?NMR(600MHz,CDCl 3)δ7.38-7.30(m,12H),7.27(m,16H),7.07(d,J=7.9Hz,3H),5.47(t,J=9.6Hz,1H),5.18(d,J=11.4Hz,1H),5.03–5.00(m,1H),4.98(d,J=10.8Hz,1H),4.82(d,J=12.2Hz,1H),4.80-4.76(m,3H),4.62-4.58(m,2H),4.48(d,J=12.3Hz,1H),4.43(d,J=12.2Hz,1H),4.38(d,J=12.0Hz,1H),3.99(m,1H),3.74(m,4H),3.64(d,J=9.6Hz,1H),3.60–3.55(m,2H),3.54(s,3H),3.30(dd,J=9.6,2.6Hz,1H),2.71(t,J=6.7Hz,2H),2.56(m,2H),2.18(s,3H)；
13C?NMR(126MHz,CDCl 3)δ206.3,171.6,167.7,157.3,139.1,138.4,138.1,137.9,129.5,128.5,128.4,128.3,128.2,128.1,128.0,127.8,127.8,127.7,127.4,127.1,122.7,116.9,110.0,101.6,101.0,82.7,81.5,78.6,78.0,77.3,77.0,76.8,75.1,74.6,74.5,74.1,73.5,73.4,71.9,69.0,68.7,52.5,37.8,29.9,27.9；
ESI-MS:m/z1017.5[M+Na];HRMS(MALDI)calcd?for?C 59H 62O 14Na:1017.4032;Found:1017.4061。
The data of compound 3l:
Productive rate: 71%;
[α] D 20=-53.4(c1.02,CHCl 3); 1H?NMR(600MHz,CDCl 3)δ7.45(d,J=7.0Hz,2H),7.34-7.21(m,10H),5.50(t,J=9.7Hz,1H),5.33(d,J=5.0Hz,1H),5.15(dd,J=15.1,8.7Hz,1H),5.02(dd,J=15.1,8.7Hz,1H),4.97(d,J=12.7Hz,1H),4.86(d,J=12.7Hz,1H),4.55(s,1H),4.47(d,J=12.3Hz,1H),4.35(d,J=12.3Hz,1H),3.85(m,2H),3.71(s,3H),3.59-3.52(m,1H),3.47(dd,J=9.7,2.9Hz,1H),2.70(t,J=6.7Hz,2H),2.54(dd,J=12.4,6.6Hz,2H),2.25(dd,J=18.8,7.9Hz,2H),2.16(s,3H),2.08-1.94(m,4H),1.85(dd,J=10.1,3.3Hz,1H),1.68(ddd,J=36.3,18.4,9.7Hz,2H),1.59(s,7H),1.54-0.88(m,25H),0.84(d,J=6.3Hz,2H),0.81-0.76(m,5H),0.70(s,3H)；
13C?NMR(150MHz,CDCl 3)δ206.4,171.7,168.2,140.6,138.6,138.4,138.0,129.4,128.7,128.5,128.2,127.8,127.7,127.6,122.2,99.6,79.0,78.6,77.4,77.2,77.0,74.0,73.8,73.6,71.6,69.4,57.0,56.1,52.8,51.4,50.3,42.4,40.6,39.8,38.8,38.0,37.3,36.9,32.1,32.0,30.0,29.6,29.1,28.0,25.6,24.5,21.4,21.2,21.2,19.5,19.1,12.4,12.2；
ESI-MS:m/z903.6[M+Na];HRMS(MALDI)calcd?for?C 55H 76O 9Na:903.5382;Found:903.5391。
The data of compound 3m:
Productive rate: 96%;
[α] D 20=-21.9(c1.49,CHCl 3)；
1H?NMR(600MHz,CDCl 3)δ7.44-7.21(m,15H),5.49(t,J=9.9Hz,1H),5.28(t,J=3.3Hz,1H),5.10(d,J=12.7Hz,1H),5.05(d,J=12.7Hz,1H),5.00(d,J=12.7Hz,1H),4.80(d,J=12.7Hz,1H),4.44(s,1H),4.43(d,J=12.1Hz,1H),4.30(d,J=12.6Hz,1H),3.91(d,J=2.8Hz,1H),3.84(s,1H),3.80(d,J=9.9Hz,1H),3.43(dd,J=2.8,9.8Hz,1H),3.06(dd,J=4.4,11.6Hz,1H),2.89(dd,J=4.4,11.7Hz,1H),2.69(m,2H),2.53(m,2H),2.15(s,3H),2.00-1.10(m,20H),1.10(s,3H),1.04(d,J=13.7Hz,1H),0.91(d,J=2.9Hz,6H),0.89(s,6H),0.86(s,3H),0.70(d,J=10.4Hz,1H),0.60(s,3H)；
13C?NMR(150MHz,CDCl 3)δ206.3,177.5,171.6,168.1,143.7,138.6,137.9,136.5,135.7,135.6,128.5,128.4,128.4,128.2,128.1,128.1,128.0,127.7,127.50,127.4,122.7,114.9,114.8,104.5,91.3,78.9,77.4,77.2,77.0,73.9,73.6,73.4,71.5,69.2,66.0,55.6,55.5,52.7,47.7,46.8,45.9,41.7,41.4,39.4,39.0,38.6,37.9,36.8,33.9,33.2,32.8,32.4,30.8,29.9,28.5,28.0,27.7,25.9,25.8,23.7,23.5,23.1,18.4,16.9,16.8,15.4；
ESI-MS:m/z1037.4[M+Na];HRMS(MALDI)calcd?for?C 63H 82O 11Na:1037.5749;Found:1037.5758。
The data of compound 3n:
Productive rate: 66%;
[α] D 20=-62.9(c2.28,CHCl 3)；
1H?NMR(600MHz,CDCl 3)δ7.47(d,J=7.0Hz,2H),7.36-7.24(m,9H),5.53(t,J=9.7Hz,1H),5.39-5.31(m,1H),4.99(d,J=12.7Hz,1H),4.88(d,J=12.7Hz,1H),4.57(s,1H),4.50(d,J=12.3Hz,1H),4.38(d,J=12.3Hz,1H),3.85(m,2H),3.74(s,3H),3.62–3.55(m,1H),3.49(dd,J=9.7,2.8Hz,1H),2.73(t,J=6.8Hz,2H),2.57(dt,J=11.9,5.8Hz,2H),2.34-2.22(m,2H),2.18(s,3H),2.06-1.96(m,3H),1.90-1.82(m,2H),1.71-1.05(m,22H),1.05-1.00(m,5H),0.94(d,J=6.5Hz,3H),0.89(dd,J=6.6,2.6Hz,6H),0.70(s,3H)；
13C?NMR(150MHz,CDCl 3)δ206.3,171.6,168.2,140.6,138.6,137.9,128.7,128.5,128.2,127.8,127.6,127.5,122.2,99.6,78.9,78.6,77.4,77.2,76.9,73.9,73.8,73.6,71.6,69.4,56.8,56.3,52.7,50.3,42.4,39.9,39.6,38.8,37.9,37.3,36.9,36.3,35.9,32.1,32.0,30.0,29.6,28.4,28.1,28.0,24.4,23.9,22.9,22.7,21.2,19.5,18.8,12.0.ESI-MS:m/z877.5[M+Na];893.5[M+K];HRMS(MALDI)calcd?for?C 53H 74O 9Na:877.5225;Found:877.5244。
The data of compound 3o:
Productive rate: 61%;
[α] D 20=+15.4(c0.59,CHCl 3)；
1H?NMR(600MHz,CDCl 3)δ7.40(d,J=7.1Hz,2H),7.37(m,3H),7.33(d,J=7.4Hz,3H),7.32-7.29(m,7H),7.27(s,1H),7.25(m,4H),5.50(t,J=9.6Hz,1H),5.31(t,J=3.2Hz,1H),5.22(s,1H),5.12(d,J=12.6Hz,1H),5.07(d,J=12.6Hz,1H),4.83(d,J=12.4Hz,1H),4.75(d,J=12.4Hz,1H),4.72-4.61(m,5H),4.51(d,J=12.3Hz,1H),4.38(dd,J=15.3,9.2Hz,2H),4.34(d,J=5.5Hz,1H),4.09(s,1H),3.87(d,J=2.6Hz,1H),3.81(d,J=9.6Hz,1H),3.64(s,3H),3.59(s,4H),3.47(dd,J=9.6,2.8Hz,1H),3.36(d,J=8.6Hz,1H),2.93(dd,J=13.7,3.8Hz,1H),2.72(t,J=6.7Hz,2H),2.60-2.53(m,2H),2.18(s,3H),2.00(td,J=13.4,3.8Hz,1H),1.89-1.85(m,2H),1.14(s,3H),1.06(d,J=11.2Hz,4H),0.92(d,J=8.8Hz,9H),0.83(s,3H),0.78(s,1H),0.64(s,3H)；
13C?NMR(126MHz,CDCl 3)δ206.2,177.5,171.6,170.0,167.7,143.7,138.5,138.2,137.7,136.4,128.4,128.2,128.2,128.1,128.0,127.9,127.7,127.7,127.6,127.5,127.4,122.5,95.1,83.5,78.1,77.3,77.1,76.8,75.7,73.9,73.5,73.0,72.3,71.6,69.0,65.9,55.5,52.6,52.2,47.5,46.7,45.8,41.7,41.4,39.3,38.2,38.1,37.8,36.9,33.9,33.1,32.7,32.4,30.7,29.9,28.4,27.9,27.6,25.9,23.7,23.4,23.1,22.2,18.3,16.9,16.6,15.4;
ESI-MS:m/z1407.8[M+Na];HRMS-(MALDI)calcd?for?C 84H 104O 17Na:1407.7166;Found:1407.7201。

Claims (9)

1. the synthetic method of a beta-D-mannuronic acid oligosaccharide or glucosides is characterized in that its reaction expression is as follows:
Figure FDA00003334396900011
Concrete synthesis step is as follows:
In solvent and dewatering agent in the presence of, be promotor with LAuCl and AgX, the adjacent alkynyl benzoic ether (1) of Compound D-mannuronic acid and compound R 6OH(2) in-100-100 ℃ of reaction 0.5-72 hour, obtain compound beta-D-mannuronic acid oligosaccharide or glucosides (3); Wherein, compound (1) is (1.0-5.0) with the mol ratio of compound (2): 1.0; Compound (1) is 1.0:(0.1-0.3 with the mol ratio of LAuCl); Compound (1) is 1.0:(0.1-0.9 with the mol ratio of AgX); Compound (1) is 1.0:(3.0-10.0 with the mass ratio of dewatering agent);
R in the reaction formula 1-R 5Be C 1-C 6Alkyl, C 3-C 6A kind of in the methyl of cycloalkyl, silica-based, acyl group, replacement; R 6OH is monohydroxy or poly-hydroxy sugar, simple alcohol or phenol, steroid sapogenin, steroidal saponin, triterpenoid sapogenin or the triterpenoid saponin of acyl group or silica-based or alkyl protection.
2. synthetic method as claimed in claim 1, the methyl that it is characterized in that described replacement be methoxyl methyl, benzyloxymethyl, benzyl, a kind of in methoxybenzyl, 2-naphthyl methyl, 2-methoxy (ethoxy) methyl, 2-(trimethyl silicon based) ethoxymethyl.
3. synthetic method as claimed in claim 1 is characterized in that describedly silica-basedly three replacing silica-basedly for what methyl, ethyl, sec.-propyl, the tertiary butyl, phenyl constituted, and preferably the diethyl sec.-propyl is silica-based, triethyl is silica-based or trimethyl silicon based.
4. synthetic method as claimed in claim 1 is characterized in that described acyl group is C 2-C 6Straight or branched aliphatic acyl radical or C 6-C 10Aromaticacyl radical; A kind of in ethanoyl, chloracetyl, pivaloyl group, 4-carbonyl pentanoyl, 2-chloro-2-methyl-propionyl, benzoyl, adjacent azido-methyl benzoyl, 2-(2-the nitrophenyl)-ethanoyl preferably.
5. synthetic method as claimed in claim 1 is characterized in that described solvent is C 1-C 6Single halo or many halogenated alkanes, 1,4 – dioxane, ether, acetonitrile, 2,2,2 – trimethylacetonitriles, tetrahydrofuran (THF), N, N – dimethyl formamide, N, a kind of in N – N,N-DIMETHYLACETAMIDE, hexamethylphosphoramide, N-methylpyrrolidin-2-ketone, toluene, phenylfluoroform, the Nitromethane 99Min. or their mixture.
6. synthetic method as claimed in claim 1, the mol ratio that it is characterized in that described LAuCl and AgX promotor is 1:1-1:3.
7. synthetic method as claimed in claim 1, described dewatering agent is
Figure FDA00003334396900012
A kind of in molecular sieve or AW-300 molecular sieve or anhydrous sodium sulphate, anhydrous calciumsulphate, anhydrous cupric sulfate, the anhydrous magnesium sulfate or their mixture.
8. as claim 1 or 6 described synthetic methods, it is characterized in that described L is the trivalent phosphine compound of methyl, ethyl, sec.-propyl, the tertiary butyl, phenyl, p-methoxyphenyl composition.
9. as claim 1 or 6 described synthetic methods, it is characterized in that described X is a kind of in trifluoromethanesulfonic acid root, perchlorate, tetrafluoroborate, four (phenyl-pentafluoride base) borate, hexafluoroantimonic anion, two (fluoroform sulphonyl) the imines negative ion.
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