CN1152038C - Simple synthesis of D-and L-deoxyribose - Google Patents

Simple synthesis of D-and L-deoxyribose Download PDF

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CN1152038C
CN1152038C CNB011320680A CN01132068A CN1152038C CN 1152038 C CN1152038 C CN 1152038C CN B011320680 A CNB011320680 A CN B011320680A CN 01132068 A CN01132068 A CN 01132068A CN 1152038 C CN1152038 C CN 1152038C
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ribodesose
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胡守刚
吴毓林
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Shanghai Institute of Organic Chemistry of CAS
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    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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Abstract

The present invention relates to a novel, simple and efficient synthesis method for D-deoxyribose and L-deoxyribose. The method comprises the following steps: firstly, cheap and available D-homopropargyl alcohol or L-homopropargyl alcohol is used for protecting hydroxyl groups, a Lindlar catalyst is used for carrying out selective hydrogenation, and oxidation is further carried out by ozone; finally, products can be obtained by protective group elimination and cyclisation according to the fact that different substituting groups can react with acids, or firstly react with the acids and then react with alkalis, or firstly react with the acids and then react with a reducing agent, or react with Lewis acids.

Description

The synthetic method of D-and L-ribodesose
Technical field
The invention provides the novel synthesis of a kind of simple and direct D-efficiently and L-ribodesose.
Background technology
The D-ribodesose is the essentially consist unit of DNA, is a crucial basic material in modern biotechnology, and price is comparatively expensive.The L-ribodesose then is the sugar of non-natural, it has been recognized that now L-ribodesose analogue and derivative have important pharmacological properties, as antiviral, anti-tumor activity etc., and its toxicity significantly reduces, and obtained numerous application in the research of current many nucleic acid drugs and synthetic work.Its source of past is by very complicated synthesizing, thereby price is expensive especially.Therefore, developing a kind of simple and direct D-efficiently and L-ribodesose synthetic method, is highly significant.
The synthetic method of D-ribodesose (D-Deoxyribose) has many pieces of bibliographical informations.People [C.De Micheli such as C.De Micheli; Tetrahetron Lett.; 27 (38); 4647-4650; 1986] utilize the compound (1) of acetonylidene protection and the bromine second eyeball oxide compound that produces to take place 1 then and there; 3-dipole cycloaddition reaction gets beta-hydroxy esters through two-step reaction afterwards again, removes acetonylidene and then cyclisation and obtains the D-ribodesose.Its limitation is: Br-CNO will produce immediate response, operational requirement strictness then and there; Uneconomical; Reaction is difficult for enlarging.Shown in reaction formula 1.
Reaction formula 1:
Masahiro Murakamt has reported [Masahiro Murakamt, Chem.Lett., 241-244,1982] another kind of synthetic method is utilized following reaction formula 2 asymmetric aldehyde Aldol reactions, generates beta-hydroxy esters equally, obtain the D-ribodesose: this method productive rate is lower, and used boron and mercury compound, uneconomically also can cause environmental pollution, limited in industrial purposes.
Reaction formula 2:
The synthetic of L-ribodesose is the research field of a hot topic always, its synthetic situation that many pieces of bibliographical informations arranged.When synthetic L-ribodesose, the method that adopts is to be chirality unit with other sugar that is easy to get usually, again through being converted into the L-ribodesose, finishes complete synthesis to it.At this, just list and provide representational a few example.
The synthetic great majority of L-ribodesose adopt sugar as chirality unit method, and another something in common of these synthetic is: the formation of 2-position (C-2) deoxidation is the synthetic committed step, and the method that is adopted is to use the hydroperoxyl radical reduction method basically.
1999, people such as Zhang (Zhang, W.J.; Ramasamy, K.S.; Averett, D.R.NucleosidesNucleotides.1999,18,2357.) reported the synthetic method that is converted into L-ribodesose (4) from L-arabinose (2).The committed step that they adopt is, 2 hydroxyls of L-arabinose are made thiosulfonates (3), uses Ph again 2SiH reagent reduction thiosulfonates just can obtain L-ribodesose derivative (4).Reaction formula 3 is as follows:
Reaction formula 3:
People (Jung, M.E. such as Michael E Jung; Xu, Y.Tetrahedron Lett.1997,38,4199.) (2)s were synthesized L-ribodesose (6) from L-arabinose.Its important step is: change hydroxyl on the anomeric carbon of L-arabinose into bromide (5), use Bu again 3SnH/AIBN reduction, free radical are reset and are obtained L-ribodesose (reaction formula 4).Meanwhile, they are also from symmetrical molecule diene alcohol 7 (Jung, M.E.; Nichols, C.J.Tetrahedron Lett.1998,39,4615.), finished the structure of L-ribodesose chirality by asymmetric Sharpless epoxidation reaction, transform the derivative 8 that obtains the L-ribodesose by several steps again; Although they do not have highly selective to obtain L-ribodesose 6, provide a kind of method (reaction formula 5) that can be for reference for the achirality unit of L-ribodesose synthetic after all.
Reaction formula 4
Reaction formula 5
Because above-mentioned D-/L-ribodesose synthetic route also has various shortcoming, as the production that is not easy for medium-scale amount or even industrialization; Adopt the method for hydroperoxyl radical reduction thiosulfonates, the big and very difficult amount expansion of toxicity with reactant.Therefore seek a kind of suitability for industrialized and environment amenable method, be still the problem that needs exploration.
Summary of the invention
The present invention provides the novel synthesis of a kind of simple and direct D-efficiently and L-ribodesose.
In the inventive method, synthetic starting raw material C-2 position is a methylene radical, and is not connected with oxygen, has then avoided the problem of C-2 position deoxidation fully.Therefore; designed such synthetic route: can set out by D-that is easy to get and L-glyceraldehyde acetonide; through asymmetric propargylization; can obtain compound 9 (Wen-lian WuJ.Org.chem.3257-3259.1995) and 10 (Hu Jian Sichuan University calendar year 2001 Ph D dissertation); selective hydration and ethylene linkage oxidation again; get final product D-and L-ribodesose that high yield is protected, through going to obtain D-and L-ribodesose after the protection quantitatively.Particular content is as follows:
Knownly protect again through acetone from N.F,USP MANNITOL cheap and easy to get, the sodium periodate oxidation fracture can get the D-glyceraldehyde acetonide, carries out the propargyl reaction of highly selective again with zinc powder, propargyl bromide, and the total recovery with 63% obtains the high propargyl alcohol intermediate of D-(9).Perhaps from the L-xitix, through the acetonylidene protection, hydrogen peroxide oxidation ruptures; the lead tetraacetate oxidation; can get the L-glyceraldehyde acetonide, then carry out the propargyl reaction of highly selective with zinc powder, propargyl bromide, the total recovery with 49.2% obtains the high propargyl alcohol intermediate of L-(10).
Figure C0113206800091
The present invention protects hydroxyl from compound 9 (the high propargyl alcohol of D-) or 10 (the high propargyl alcohols of L-).Under the organic solvent existence condition, the organic compound or the NaH that contain lone-pair electron on compound 9 or 10, dihydropyrane or RZ, the nitrogen-atoms react, mol ratio is followed successively by 1: 1-5: 0-100, add on the nitrogen-atoms and contain the organic compound of lone-pair electron reacting favourable, recommend mol ratio to be followed successively by 1: 1.2-2.5: 1-10, temperature of reaction is-78 ℃ and extremely refluxes that the reaction times is 0.5h-50h, generates compound 11 or 12.R=R 2R 3R 4Si, PhCH 2, PhCO, PhCOO, CH 3CO, CH 3COO, CH 3OCH 2Or PhCH 2OCH 2, Z=X, CF 3SO 3, PhCO, CH 3CO or OCH 3, R 2, R 3Or R 4=C 1～6Alkyl, as methyl, ethyl, sec.-propyl, the tertiary butyl, phenyl etc., X=halogen.R can be: tertiary butyl dimethyl-silicon (TBS), tetrahydropyrans (THP), trimethyl silicane (TMS), triethyl silicon (TES); triisopropyl silicon (TIPS), tert-butyl diphenyl silicon (TBDPS), methoxymethyl ether (MOM); benzoyl (Bz), benzyl (Bn), ethanoyl (Ac) etc.RZ can be tertiary butyl dimethyl chloride or fluoroform sulfo group silane (TBSCl or TBSOTf), dihydropyrane, trimethylammonium chlorine or fluoroform sulfo group silane (TMSCl or TMSOTf), triethyl chlorine or fluoroform sulfo group silane (TESCl or TESOTf), triisopropyl chlorine or fluoroform sulfo group silane (TIPSCl or TIPSOTf), tertiary butyl hexichol chlorine or fluoroform sulfo group silane (TBDPSCl or TBDPSOTf), chlorine methoxymethyl ether, Benzoyl chloride, benzyl chlorine, benzyl bromine, Acetyl Chloride 98Min. or acetic anhydride.
X is a halogen.
The organic compound that contains lone-pair electron among the present invention on the above-mentioned nitrogen-atoms can be R 2 5NH or R 3 6N, pyridine, imidazoles, bipyridine, 2,6-lutidine, 4-N, N-lutidine etc., R 5Or R 6=C 1～16Alkyl, as dihexylamine, quadrol, diisopropylamine, Trimethylamine 99, triethylamine, trioctylamine, three (12) amine, triphenylamine, butyl benzylamine etc.
Reaction solvent can be chloroform, dioxane, N, dinethylformamide (DMF), tetrahydrofuran (THF) (THF), CH 2Cl 2, ether (Ether), acetonitrile (CH 3CN) etc.,
Figure C0113206800101
Compound 11 or 12 can carry out selective hydration, generates compound 13 and 14.In organic solvent, in the presence of hydrogen, adding known lindlar catalyst (Lindlar catalyst) in the compound 11 or 12 (Zbigniew Pakulski, Tetrahedron, 53,2653-2660), obtain compound 13 or 14.The weight ratio of lindlar catalyst is the 0.1%-100% of substrate, compound 11 or 12 and the mol ratio of hydrogen be 1: 1～100.Adopt more hydrogen to not influence of reaction.To reflux temperature, react 10min-50h in room temperature, reaction solvent can be ethanol (EtOH), methyl alcohol (MeOH), ethyl acetate (EtOAc), CH 2Cl 2, THF, CHCl 3, CH 3CN etc., lindlar catalyst: Pd/BaSO 4/ lead acetate or Pd/CaCO 3/ lead acetate, wherein containing Pd is 5～20% of catalyst weight.
Figure C0113206800102
In organic solvent, compound 13 or 14 usefulness ozone carry out oxidation, and then add the reductive agent dimethyl sulphide, with the yield acquisition compound 15 and 16 of 70%-80%.The mol ratio of compound 13 or 14, ozone, dimethyl sulphide is 1: 1～1000: 1～1000, adopts more ozone to not influence of reaction.Temperature of reaction be-78 ℃ to room temperature, the reaction times is 1h-48h.Reaction solvent can be EtOH, MeOH, EtOAc, CH 2Cl 2, CH 3CN etc.
Figure C0113206800111
At last compound 15 or 16 is removed protecting group and cyclisation, can distinguish quantitative acquisition D-(17) or L-(18) ribodesose.This reaction can be finished respectively by a step or two steps:
1, R=R in compound 15 or 16 2R 3R 4Si, CH 3OCH 2, PhCH 2OCH 2Or during THP trtrahydropyranyl, R wherein 2, R 3Or R 4As previously mentioned.In the presence of solvent and acid, compound 15 or 16 generates compound 17 or 18.Compound 15 or 16 and the mol ratio of acid be 1: 1～100, adopt more acid to not influence of reaction.Temperature of reaction can be that room temperature extremely refluxes, and the reaction times is 1h-48h.Described solvent can be water or organic solvent.
2, in compound 15 or 16, R=CH 3When CO or PhCO, in the presence of solvent and acid, compound 15 or 16 generates R=CH 3The compound 19 or 20 of CO or PhCO.Compound 15 or 16 and the mol ratio of acid be 1: 1～100, adopt more acid to not influence of reaction.Temperature of reaction can be that room temperature extremely refluxes, and the reaction times is 1h-48h.Described solvent can be water or organic solvent.
R=CH 3The compound 19 of CO or PhCO or 20 generates compound 17 or 18 in the presence of solvent and alkali, above-claimed cpd 19 or 20 and the mol ratio of alkali be 1: 1～100, temperature of reaction can be room temperature to refluxing, the reaction times is 1h-48h.。Described alkali is salt of wormwood (K 2CO 3), ammonia (NH 3), hydrazine, potassium cyanide (KCN), triethylamine (Et 3N), sec.-propyl ethamine ( iPr 2EtN), potassium hydroxide (KOH), sodium methylate etc.Described solvent can be water or organic solvent.
Above-mentioned compound 19 or 20 structural formula are as follows:
3, in compound 15 or 16, R=PhCH 2The time, in the presence of solvent and acid, compound 15 or 16 generates R=PhCH 2Compound 19 or 20.Compound 15 or 16 and the mol ratio of acid be 1: 1～100, adopt more acid to not influence of reaction.Temperature of reaction can be that room temperature extremely refluxes, and the reaction times is 1h-48h.Described solvent can be water or organic solvent.
R=PhCH 2Compound 19 or 20, in the presence of solvent and reductive agent or Louis acid-respons obtain compound 17 or 18.Temperature of reaction can be-70 ℃ to reflux temperature, the reaction times is 1h-48h.The mol ratio of compound 19 or 20, reductive agent or Louis acid is 1: 1～100.The acid of described Louis is Iodotrimethylsilane, tin tetrachloride, iron trichloride or boron trichloride etc.Described reductive agent is: the reductive agent of (1) hydrogen, cyclohexadiene, formic acid or ammonium formiate and 5～20%Pd/C, Raney-Ni or Rh-Al 2O 3Catalyzer, the weight ratio of reductive agent and catalyzer is followed successively by 1: 0.01～5.(2) monovalence metal or liquefied ammonia.Described monovalence metal can be Li, Na or K.Above-mentioned acid can be mineral acid, organic acid, acid organic salt or acidic ion exchange resin.Wherein mineral acid can be a sulfuric acid, and hydrochloric acid, hydrofluoric acid etc., organic acid can be trifluoracetic acid (TFA), CH 3COOH, HCOOH etc., acid organic salt such as tosic acid pyridinium salt (PPTA), acidic ion exchange resin etc., organic solvent can be EtOH, MeOH, CH 2Cl 2, THF, CHCl 3, H 2O, EtOAc, CH 3CN, CCl 4, etc.
D-of the present invention and L-ribodesose novel synthesis, not only raw material reagent cheap and easy to get is cheap, and synthetic route is simple and direct, and reaction conditions is gentle, easy to operate, and productive rate is higher.From N.F,USP MANNITOL, through the reaction of 7 steps, the total recovery with 43.5% obtains the D-ribodesose; From the L-xitix, through the reaction of 8 steps, the total recovery with 35.4% obtains the L-ribodesose.In view of above advantage, present method has the actual application prospect of suitability for industrialized production.
Specific implementation method
To help further to understand the present invention by following embodiment, but not limit content of the present invention.
The specific rotation light value is measured by Perkin-Elmer 241 MC polarimeters among the embodiment; Infrared spectra is by Perkin-Elmer 983 or Digilab FTIR determination of infrared spectroscopy; Nucleus magnetic resonance is by EM-360A, EM-390, and Bruker AM-300 or Bruker AMX-600 nuclear magnetic resonance spectrometer are measured; Mass spectrum is measured by HP5890A or VG QUATTRO type mass spectrograph.
The reagent purifying is with reference to Purfication of Laboratory Chemicals; D.D.Perrin; W.L.F.Armarego; D.R.Perrin Eds.Pergamon Press:Oxford, 1980.Rapid column chromatography carries out on silica gel H (10-40 μ).TLC adopts ammonium molybdate aqueous sulfuric acid and the colour developing of 10% sulfuric acid methyl alcohol.
Synthesizing of embodiment 1 D-ribodesose
From N.F,USP MANNITOL cheap and easy to get, through the acetonylidene protection, the sodium periodate oxidation fracture can get the D-glyceraldehyde acetonide, carries out the propargyl reaction of highly selective again with zinc powder, propargyl bromide, and the total recovery with 63% obtains the high propargyl alcohol intermediate 9 of D-.
1 hydroxyl protection
The high propargyl alcohol compound of 1.13g (6.6mmol) (9) is dissolved in THF or the dry DMF (2mL), and adding TBSCl (1.35g, 8.84mmol) with imidazoles 1.35g (18.35mmol), stirring at room 20 hours.Ether 100mL dilution is also extracted, and uses distilled water (10mL * 2), saturated nacl aqueous solution (10mL) washing respectively, anhydrous Na 2SO 4Dry.Filter, concentrate, column chromatography purification gets the product 11-11.82g of R=TBS, productive rate 97.3%. 1H-NMR(300MHZ，CDCl 3)：δ0.11(3H，s)，0.14(3H，s)，0.85(9H，s)，1.30(3H，s)，1.36(3H，s)，1.92(1H，dd，J 1＝2.17，J 1＝5.22)，2.4-2.6(2H，m)，3.72-3.80(1H，，m)，3.80-3.87(1H，m)，3.96-4.04(1H，m)，4.10-4.18((1H，m).
2 alkynes selective hydrations
3.0g (10.6mmol) substrate (11-1) is dissolved in the 60mL anhydrous methanol, adds Lindlar catalyzer 400mg, quinoline 300 μ l, room temperature normal pressure hydrogenation 1 hour, the TLC demonstration reacts completely.With being covered with the diatomaceous sand core funnel suction filtration of one deck, concentrate column chromatography (PE: EA=40: 1).Get the product 13-1 2.75g of R=TBS, productive rate 91.3%.
IR(KBr)：3080，2987，1643cm -1.
EI-MS(E/Z，％)：271(M +-15，13.65)，245(12.48)，229(10.22)，185(40.13).
The ozonize of 3 ethylene linkages
Figure C0113206800141
1.17g (4mmol) substrate (13-1) is dissolved in anhydrous methanol-CH 2Cl 2(5: 1,60mL) in ,-78 ℃ feed down O 3After system became basket, the TLC demonstration reacted completely, and uses N 2The O that catches up with most system to retain 3-78 ℃ drip 10mL (135mmol) Me down 2S drip to finish stirs 15min ,-20 ℃ of following stirring reactions 1 hour, and 0 ℃ of following stirring reaction 1 hour, stirring reaction is 1 hour under the room temperature.＜25 ℃ of concentrating under reduced pressure, column chromatography (PE: EA=40: 1), get the product 15-1 998mg of R=TBS, productive rate 78%.
[α] 20 D：+7.62
IR(KBr)：2989，2860，1729，1473cm -1.
EI-MS(E/Z，％)：289(M ++1，11.06)，247(31.49)，229(11.85)，189(43.86)，75(100). 1H-NMR(300MHZ，CDCl 3)：0.22(3H，s)，0.26(3H，s)，0.92(9H，s)，1.38(3H，s)，1.40(3H，s)，2.71(2H，m)，3.82-3.90(1H，m)，4.08-4.17(2H，m)，9.86(3H，s).
4 synthetic D-ribodesoses
Figure C0113206800142
Be dissolved under 450mg (0.16mmol) substrate (15-1) stirred 1MHCl-THF (1.5: 1.5,3mL) in, room temperature reaction spends the night.The TLC demonstration reacts completely.Saturated NaHOO 3Aqueous solution neutralization, 40 ℃ of left and right sides concentrating under reduced pressure, dehydrated alcohol (5mL * 3) band water.The dry method upper prop, eluent anhydrous methanol-CH 2Cl 2(1: 10) gets product 17 210mg, quantitative yield.
1H-NMR(300MHZ，CDCl 3)：δ1.62-2.41(2H，m)，3.45-4.41(4H，m)，4.72(0.29H，dd，J 1＝3.02Hz，J 2＝6.87Hz)，5.17(0.48H，dd，J 1＝3.30Hz，J 2＝4.39Hz)，5.45(0.13H，dd，J 1＝5.21Hz，J 2＝2.19Hz)，5.52(0.12H，t，J＝4.40Hz).
Synthesizing of embodiment 2 D-ribodesoses
The high propargyl alcohol compound of 8mmol (9) is dissolved in anhydrous THF of 5mL or anhydrous CH 2Cl 2(3mL), add PhCOCl (10mmol) and triethylamine (18mmol), stirring at room 23 hours.After reaction finishes, add saturated aqueous ammonium chloride, 100mL dichloromethane extraction, saturated nacl aqueous solution (10mL) washing, anhydrous Na 2SO 4Dry.Filter, concentrate, column chromatography purification gets the product 11-2. productive rate 98.9% of R=PhCO.
20.6mmol substrate (11-2) is dissolved in the 60mL anhydrous methanol, adds Lindlar catalyzer 600mg, quinoline 400 μ l, room temperature normal pressure hydrogenation 4 hours, the TLC demonstration reacts completely.With being covered with the diatomaceous sand core funnel suction filtration of one deck, concentrate column chromatography (PE: EA=40: 1).Purifying gets the product 13-2 of R=PhCO, productive rate 99.%
(13-2) is dissolved in anhydrous methanol-CH with the 8mmol substrate 2Cl 2(5: 1,80mL) in ,-78 ℃ feed down O 3After system became basket, the TLC demonstration reacted completely, and uses N 2The O that catches up with most system to retain 3-78 ℃ drip 25mL (135mmol) Me down 2S drip to finish stirs 15min ,-20 ℃ of following stirring reactions 1 hour, and 0 ℃ of following stirring reaction 1 hour, stirring reaction is 4 hours under the room temperature.＜25 ℃ of concentrating under reduced pressure, (PE: EA=40: 1), purifying gets the product 15-2 of R=PhCO, productive rate 82% to column chromatography.
Be dissolved under 0.3mmol substrate (15-2) stirred trifluoroacetic acid and water (1: 1,3mL) in, room temperature reaction spends the night.The TLC demonstration reacts completely.Saturated NaHCO 3Aqueous solution neutralization, 40 ℃ of left and right sides concentrating under reduced pressure, dehydrated alcohol (5mL * 3) band water.The dry method upper prop, eluent anhydrous methanol-CH 2Cl 2(1: 20), the product 19-1 of R=PhCO, quantitative yield.
With being dissolved in the 5mL anhydrous methylene chloride under 0.35mmol substrate (19-1) stirring, add sodium methylate (0.6mmol), room temperature reaction spends the night.The TLC demonstration reacts completely.Saturated NaCl aqueous solution cancellation reaction, 40 ℃ of left and right sides concentrating under reduced pressure, dehydrated alcohol (5mL * 3) band water.The dry method upper prop, eluent anhydrous methanol-CH 2Cl 2(1: 10) gets product 17, quantitative yield.
Synthesizing of embodiment 3 L-ribodesoses:
From the L-xitix, through the acetonylidene protection, the hydrogen peroxide oxidation fracture; the lead tetraacetate oxidation; can get the L-glyceraldehyde acetonide, then carry out the propargyl reaction of highly selective with zinc powder, propargyl bromide, the total recovery with 49.2% obtains high propargyl alcohol intermediate 10.
1 hydroxyl protection
Figure C0113206800161
The high propargyl alcohol compound of 2.88g (16.9mmol) (10) is dissolved in the dry DMF (4mL), add TBSCl (3.19g, 20.9mmol) and imidazoles (3.00g, 44.4mmol), stirring at room 36 hours.The ether dilution is also extracted, water, saturated nacl aqueous solution washing respectively, anhydrous Na 2SO 4Dry.Filter, concentrate, column chromatography purification gets the product 12-1 4.12g of R=TBS, productive rate 86.7%.
IR(KBr)：3315，2988，2932，1462cm -1.
EI-MS(E/Z，％)：269(M +-15，13.2)，227(6.54)，209(13.88)，183(25.04)，169(96.59)，73(100). 1H-NMR(300MHZ，CDCl 3)：0.10(3H，s)，0.13(3H，s)，0.84(9H，s)，1.27(3H，s)1.35(3H，s)，1.94(1H，dd，J 1＝2.25，J 2＝5.52)，2.37-2.41(2H，m)，3.65-3.85(2H，m)，3.87-3.96(2H，m).
2 alkynes selective hydrations
Figure C0113206800162
12-1 is dissolved in the 35mL anhydrous methanol with 0.65g (2.3mmol) substrate, adds Lindlar catalyzer 160mg, quinoline 100 μ l, and room temperature normal pressure hydrogenation 1 hour, the TLC demonstration reacts completely.With being covered with the diatomaceous sand core funnel suction filtration of one deck, concentrate column chromatography (PE: EA=40: 1).Get the product 14-10.655g of R=TBS, quantitative yield
IR(KBr)：3080，2987，2232，1643cm -1.
EI-MS(E/Z，％)：271(M +-15，4.62)，227(3.99)，185(34.76)，171(50.60)，73(100). 1H-NMR(300MHZ，CDCl 3)：δ0.15(6H，s)，δ0.84(9H，s)，1.32(3H，s)，1.38(3H，s)，2.28(2H，t，J 1＝6.04)，3.70-3.82(2H，m)，3.90-4.02(2H，m)，5.08(2H，m)，5.85(1H，dd，J 1＝10.17Hz，J 1＝17.03Hz).
The ozonize of 3 ethylene linkages
Figure C0113206800171
14-1 is dissolved in anhydrous methanol-CH with 256mg (0.88mmol) substrate 2Cl 2(5: 1,60mL) in ,-78 ℃ feed down O 3After system became basket, the TLC demonstration reacted completely, and uses N 2The O that catches up with most system to retain 3-78 ℃ drip 2.2mL (30mmol) Me down 2S drip to finish stirs 15min ,-20 ℃ of following stirring reactions 1 hour, and 0 ℃ of following stirring reaction 1 hour, stirring reaction is 1 hour under the room temperature.＜25 ℃ of concentrating under reduced pressure, column chromatography (PE: EA=40: 1), get the product 16-1213mg of R=TBS, productive rate 83%.
IR(KBr)：2988，2860，1728cm -1.
EI-MS(E/Z，％)：273(M +-15，8.37)，231(8.29)，213(8.59)，173(100).
1H-NMR(300MHZ，CDCl 3)：δ0.30(3H，s)，036(3H，s)，0.82(9H，s)，1.32(3H，s)，1.39(3H，s)，2.64(2H，m)，3.78-3.85(1H，m)，4.00-4.12(3H，m)，9.82(1H，s).
4 synthetic L-ribodesoses
Be dissolved under 800mg (1.6mmol) substrate (16-1) stirred 1MHCl-THF (2.5: 2.5,5mL) in, room temperature reaction spends the night.The TLC demonstration reacts completely.Saturated NaHCO 3Aqueous solution neutralization, 40 ℃ of left and right sides concentrating under reduced pressure, dehydrated alcohol (5mL * 3) band water.The dry method upper prop, eluent anhydrous methanol-CH 2Cl 2(1: 10) gets product 18 380mg, quantitative yield.
1H-NMR(300MHZ，CDCl 3)：δ1.66-2.45(2H，m)，3.44-4.43(4H，m)，4.76(0.31H，dd，J 1＝3.09Hz)，J 2＝6.78Hz)，5.20(0.52H，dd，J 1＝3.34Hz，J 2＝4.34Hz)，5.40(0.11H，dd，J 1＝5.18Hz，J 2＝2.24Hz)，5.49(0.08H，t，J＝4.35Hz).
Synthesizing of embodiment 4 L-ribodesoses:
1 hydroxyl protection
N 2Protection down, with NaH (40mmol) join THF and DMF (1: 1,15mL) in the mixing solutions, under 0 ℃, slowly drip the THF5mL solution of the high propargyl alcohol compound of substrate (20mmol) (10), stirring at room 3 hours.Shang adds benzyl bromine (40mmol) Xia 0 ℃ again.Stirring at room 20 hours adds the less water cancellation.Ether extraction.Organic phase is washed with saturated nacl aqueous solution, anhydrous Na 2SO 4Dry.Filter, concentrate, column chromatography purification gets R=PhCH 2Product 12-2 4.12g, productive rate 88%.
2 alkynes selective hydrations
32mmol substrate 12-2 is dissolved in the 35mL anhydrous methanol, adds Lindlar catalyzer 260mg, quinoline 150 μ l, room temperature normal pressure hydrogenation 1 hour, the TLC demonstration reacts completely.With being covered with the diatomaceous sand core funnel suction filtration of one deck, concentrate column chromatography (PE: EA=40: 1).Get R=PhCH 2Product 14-2, quantitative yield.
The ozonize of 3 ethylene linkages
14-2 is dissolved in anhydrous methanol-CH with the 2.4mmol substrate 2Cl 2(5: 1,60mL) in ,-78 ℃ feed down O 3After system became basket, the TLC demonstration reacted completely, and uses N 2The O that catches up with most system to retain 3-78 ℃ drip 8.6mLMe down 2S drip to finish stirs 15min ,-20 ℃ of following stirring reactions 1 hour, and 0 ℃ of following stirring reaction 1 hour, stirring reaction is 1 hour under the room temperature.＜25 ℃ of concentrating under reduced pressure, column chromatography (PE: EA=40: 1), get R=PhCH 2Product 16-2, productive rate 80%.
4 synthetic L-ribodesoses
To be dissolved in 3mLH under 2.3mmol substrate (16-2) stirring 2O adds Dowex50-W (H +) 1g, room temperature reaction spends the night, and the TLC demonstration reacts completely.The filtering resin, 40 ℃ of left and right sides concentrating under reduced pressure, dehydrated alcohol thick (5mL * 3) band water.The dry method upper prop, eluent anhydrous methanol-CH 2CL 2(1: 20) gets product R=PhCH 220-1, quantitative yield.
Substrate 20-1 2.9mmol adds the 15mL dehydrated alcohol, 500mgPd/C (10%), and the normal temperature pressure hydration, the TLC demonstration reacts completely.The sand core funnel suction filtration concentrates column chromatography, anhydrous methanol-CH 2Cl 2(1: 10).Get product 18, quantitative yield.

Claims (10)

1, the synthetic method of a kind of D-and L-ribodesose, the structural formula of D-and L-ribodesose is as follows:
Figure C0113206800021
Or
Figure C0113206800022
It is characterized in that by following building-up reactions:
(1), under the organic solvent existence condition, the high propargyl alcohol of D- Or the high propargyl alcohol of L-
Figure C0113206800024
The organic compound or the NaH that contain lone-pair electron on dihydropyrane or RZ, the nitrogen-atoms react, and mol ratio is followed successively by 1: 1-5: 0-100, and, temperature of reaction is-78 ℃ and extremely refluxes that the reaction times is 0.5h-50h, generates compound 11 or 12, wherein R=R 2R 3R 4Si, PhCH 2, PhCO, PhCOO, CH 3CO, CH 3COO, CH 3OCH 2Or PhCH 2OCH 2, Z=X, CF 3SO 3, PhCO, CH 3CO or OCH 3, R 2, R 3Or R 4=C 1～6Alkyl; X is a halogen;
(2), in organic solvent, in the presence of hydrogen, add known lindlar catalyst in the compound 11 or 12, its weight ratio is the 0.1%-100% of substrate, compound 11 or 12 and the mol ratio of hydrogen be 1: 1～100.To reflux temperature, reaction 10min-50h obtains compound 13 or 14 in room temperature, and described lindlar catalyst is Pd/BaSO 4/ lead acetate or Pd/CaCO 3/ lead acetate, wherein containing Pd is 5～20% of catalyst weight;
(3), in organic solvent, compound 13 or 14 usefulness ozone carry out oxidation, and then add the reductive agent dimethyl sulphide, obtain compound 15 and 16, the mol ratio of compound 13 or 14, ozone and dimethyl sulphide is 1: 1～1000: 1～1000, temperature of reaction be-78 ℃ to room temperature, the reaction times is 1h-48h;
(4), compound 15 or 16 is removed protecting group and cyclisation, can distinguish quantitative acquisition D-(17) or L-(18) ribodesose, this reaction can be finished respectively by following step:
R=R in compound 15 or 16 2R 3R 4Si, CH 3OCH 2, PhCH 2OCH 2Or during THP trtrahydropyranyl, R wherein 2, R 3Or R 4As previously mentioned, in the presence of solvent and acid, compound 15 or 16 generates compounds 17 or 18, compound 15 or 16 with the mol ratio of acid be 1: 1～100, temperature of reaction is extremely backflow of room temperature, the reaction times is 1h-48h, described solvent is water or organic solvent;
In compound 15 or 16, R=CH 3CO or PhCO, in the presence of solvent and acid, compound 15 or 16 generates compounds 19 or 20, compound 15 or 16 with the mol ratio of acid be 1: 1～100, temperature of reaction is extremely backflow of room temperature, the reaction times is 1h-48h, described solvent is water or organic solvent;
Above-mentioned compound 19 or 20, in the presence of solvent and alkali, generate compound 17 or 18, compound 19 or 20 and the mol ratio of alkali be 1: 1～100, temperature of reaction is that room temperature is to refluxing, reaction times is 1h-48h, described alkali is salt of wormwood, ammonia, hydrazine, potassium cyanide, triethylamine, diisopropylethylamine, sodium methylate or potassium hydroxide, and described solvent can be water or organic solvent;
In compound 15 or 16, R=PhCH 2The time, in the presence of solvent and acid, compound 15 or 16 generates R=PhCH 2Compound 19 or 20, compound 15 or 16 and the mol ratio of acid be 1: 1～100, temperature of reaction is a room temperature to refluxing, the reaction times is 1h-48h, described solvent is water or organic solvent;
R=PhCH 2Compound 19 or 20, in the presence of solvent, obtain compound 17 or 18 with reductive agent or Louis acid-respons, temperature of reaction be-70 ℃ to reflux temperature, reaction times is 1h-48h, the mol ratio of compound 19 or 20, reductive agent or Louis acid is 1: 1～100, described Lewis acid is Iodotrimethylsilane, tin tetrachloride, iron trichloride or boron trichloride, and described reductive agent is 1), reductive agent and 10%Pd/C, Raney-Ni or the Rh-Al of hydrogen, cyclohexadiene, formic acid or ammonium formiate 2O 3Catalyzer, the weight ratio of reductive agent and catalyzer is followed successively by 1: 0.01～5,2), monovalence metal or liquefied ammonia; Described monovalence metal can be Li, Na or K;
The structural formula of above-mentioned compound 11～20 is as follows:
Figure C0113206800031
Figure C0113206800041
Or
Figure C0113206800043
2, the synthetic method of a kind of D-as claimed in claim 1 and L-ribodesose is characterized in that R is a tertiary butyl dimethyl-silicon, tetrahydropyrans; trimethyl silicane, triethyl silicon, triisopropyl silicon, tert-butyl diphenyl silicon; methoxymethyl ether, benzoyl, benzyl or ethanoyl.
3, the synthetic method of a kind of D-as claimed in claim 1 and L-ribodesose, it is characterized in that RZ is tertiary butyl dimethyl chloride or fluoroform sulfo group silane, dihydropyrane, trimethylammonium chlorine or fluoroform sulfo group silane, triethyl chlorine or fluoroform sulfo group silane, triisopropyl chlorine or fluoroform sulfo group silane, tertiary butyl hexichol chlorine or fluoroform sulfo group silane, chlorine methoxymethyl ether, Benzoyl chloride, benzyl chlorine, benzyl bromine, Acetyl Chloride 98Min. or acetic anhydride.
4, the synthetic method of a kind of D-as claimed in claim 1 and L-ribodesose, the organic compound that it is characterized in that containing on the described nitrogen-atoms lone-pair electron is R 5 2NH or R 6 3N, pyridine, imidazoles, bipyridine, R 5Or R 6=C 1～16Alkyl.
5, the synthetic method of a kind of D-as claimed in claim 1 and L-ribodesose is characterized in that the organic compound or the NaH mol ratio that contain lone-pair electron on the high propargyl alcohol of described D-or the high propargyl alcohol of L-, dihydropyrane or RZ, the nitrogen-atoms are followed successively by 1: 1.2-2.5: 1-10.
6, the synthetic method of a kind of D-as claimed in claim 1 and L-ribodesose, it is characterized in that reacting the acid described in 4 is mineral acid, organic acid, acid organic salt or acidic ion exchange resin.
7, the synthetic method of a kind of D-as claimed in claim 6 and L-ribodesose is characterized in that described mineral acid is a sulfuric acid, hydrochloric acid or hydrofluoric acid, and described organic acid is a trifluoracetic acid, CH 3COOH or HCOOH.
8, the synthetic method of a kind of D-as claimed in claim 1 and L-ribodesose is characterized in that organic solvent is chloroform, dioxane, N in the described reaction 1, dinethylformamide, tetrahydrofuran (THF), CH 2Cl 2, ether, acetonitrile.
9, the synthetic method of a kind of D-as claimed in claim 1 and L-ribodesose is characterized in that organic solvent is an ethanol in the described reaction 2, methyl alcohol, ethyl acetate, CH 2Cl 2, THF, CHCl 3, CH 3CN.
10, the synthetic method of a kind of D-as claimed in claim 1 and L-ribodesose is characterized in that organic solvent is EtOH in the described reaction 3, MeOH, EtOAc, CH 2Cl 2Or CH 3CN.
CNB011320680A 2001-10-30 2001-10-30 Simple synthesis of D-and L-deoxyribose Expired - Fee Related CN1152038C (en)

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