酒石酸及衍生物合成

SYNTHESIS OF TARTARIC ACID

AND O-ACYL TARTARIC ACIDS AND ANHYDRIDES

Ludwik Synoradzki*, Pawel Rus´kowski and Urszula Bernas´Laboratory of Technological Processes, Faculty of Chemistry

Warsaw University of Technology

ul. Noakowskiego 3, 00-6 Warsaw, POLAND

e-mail: Ludwik.Synoradzki@ch.pw.edu.pl

INTRODUCTION........................................................................................................................39I. O,O'-Diacyltartaric Acid Anhydrides.....................................................................................43a) By Acylation-Dehydration with Acid Chlorides.................................................................44b) By Acylation-Dehydration with Acid Anhydrides...............................................................45c) By Reaction with Thionyl Chloride .....................................................................................45d) By Dehydration of O,O'-Diacyltartaric Acids ....................................................................46II. O-Acyltartaric Acids................................................................................................................46a) Partial Hydrolysis of O,O'-Diacyltartaric Acids.................................................................49b) Partial Aminolysis of O,O'-Diacyltartaric Acids................................................................49c) Hydrogenolysis of Dibenzyl O-Acyltartrates......................................................................49III.O,O'-Diacyltartaric Acids......................................................................................................50a) Hydrolysis of O,O'-Diacyltartaric Acid Anhydrides...........................................................51b) Hydrolysis without Anhydride Isolation after Tartaric Acid Acylation...............................52c) Synthesis via Tartaric Acid Esters.......................................................................................53d) Synthesis via Tartaric Acid Salts.........................................................................................54e) Resolution of Racemic O,O'-Diacyltartaric Acids..............................................................54IV. SUMMARY.............................................................................................................................56REFERENCES..............................................................................................................................57

©2005 by Organic Preparations and Procedures Inc.37SYNTHESIS OF TARTARIC ACID AND O-ACYL TARTARIC ACIDS AND ANHYDRIDES

TARTARIC ACID AND ITS O-ACYL DERIVATIVES. PART 1.

SYNTHESIS OF TARTARIC ACID

AND O-ACYL TARTARIC ACIDS AND ANHYDRIDESLudwik Synoradzki*, Pawel Rus´kowski and Urszula Bernas´Laboratory of Technological Processes, Faculty of Chemistry

Warsaw University of Technology

ul. Noakowskiego 3, 00-6 Warsaw, POLAND

e-mail: Ludwik.Synoradzki@ch.pw.edu.pl

INTRODUCTION

Tartaric acid (1) and its derivatives and especially acyl derivatives, are very widely used

in organic synthesis. In their monograph,1 Gawron´ski and Gawron´ska distinguish four types ofapplications a) resolution of racemic mixtures,1-5b) ligands (in chiral catalysts),1,6,7c) chiralauxiliaries,1,7,8and d) chiral tetracarbon building blocks.1,5In spite of the considerable practicalimportance of acyl derivatives of 1, reports on the methods of their preparation are scattered andrather scarce. Many of them are very old, in difficult to access journals, and some are even erro-neous. These are often patent information, short reports in Chemical Abstracts, or only notes inexperimental sections. The present review collects and critically evaluates all available informa-tion on the preparation and production of acyltartaric anhydrides and acids, especially of diben-zoyltartaric acid up the year 2004.

Tartaric acid 1occurs in four forms: a pair of optically active enantiomers (+) (L-1), (–)

(D-1) and racemic mixture (rac-1) as well as the symmetric form meso(meso-1). Some physico-chemical properties of tartaric acids are summarized in Table 1.9

L-Tartaric acid is a natural product occurring both in the free form as well as a salt in

many fruits, especially grapes. It is produced as its calcium salt10from potassium hydrogentartrate (cream of tartar) – a by-product of the wine industry. Hence Italian, French, Hungarian,Chinese and Japanese companies belong to the largest tartaric acid producers. Due to the consid-erable, continuously replenished sources and simplicity of preparation, it is one of the cheapestenantiomerically pure organic compounds available. It is also less expensive than the other enan-tiomers obtained synthetically. If the catalog price for 100g of acid L-1is set as 1, the price ofracemic acid is 3, of D-120, and of meso-1270.11Although examples on biotechnological

39´KOWSKI AND BERNAS´SYNORADZKI, RUS

Table 1.mps, Specific Rotation and Solubility of Tartaric Acids9aCommonSystematicStructuremp.NameName(°C)[CAS No.]L-Tartaric (2R,3R)-2,3-168-170ObAciddihydroxy-HOOH(L-1)butane-1,4-OHdioic acidHO[87-69-4]OD-Tartaric(2S,3S)-2,3-168-170Obdihydroxy-AcidHOOH(D-1)butane-1,4-OHHOdioic acidO[147-71-7]meso-(2R,3S)-2,3-140dOTartaric dihydroxy-HOOHAcidbutane-1,4-OH(meso-1)dioic acidHO[147-73-9]OOHOOHOHOOHOHOOOHOH[α]20DSolubility in H2Oa20°C100°C139343+12.0c–12.0c1393430125----D,L-TartaricAcide(rac-1)Dihydroxy-butane-1,4-dioic acid[133-37-9]HO206020.6185a) Grams in 100 mL of water; b)Solubility in other solvents: good in isobutanol (4.6%9b),dioxane,40ethanol (41.1%,9c32.5%,9d21.6%9e), furfural (10.9%9f), glycerol,9amethanol,9gpropanol;9apoor in HOAc (1.4%9b), diethyl ether (0.31%9h); insoluble in chloroform,9adichloroethane,9itrichloroethane9i; c) 20% in water; d) As monohydrate; e) Solubility in othersolvents: HOAc (0.11%9b), isobutanol (0.37%9b), diethyl ether (1.08%9c), ethanol (2.08%,9c3.15%9j).methods to obtain L-1 are given in a monograph,12they do not appear to be of any practicalimportance. L-1has been obtained from the fermentation of panthothenic acid or its salt withGluconobacter suboxydans,13from cis-epoxysuccinic acid (obtained chemically from maleicacid) or its salts as a result of asymmetric hydrolysis in the presence of Acinetobacter, Agrobac-terium, Rhizobium, Pseudomonas,14Nocardia tartaricans(or cis-epoxysuccinate hydroxylaseobtained from N. Tartaricans)15or biocatalyst, e.g. Achromobacter tartarogenesimmobilized ona polymer, e. g.polyacrylamide.16Although the acid D-1is mainly obtained synthetically by separation from the racemic40SYNTHESIS OF TARTARIC ACID AND O-ACYL TARTARIC ACIDS AND ANHYDRIDES

acid (rac-1) with diastereomeric salts with amines, it also occurs in small quantities in the fruitand leaves of the African plant Bauchinia reticulataD. C.17Among other amines used, cinchoni-dine (12%),18(2S)-2-[2-(1'S)-(1'-methyl-1'-phenyl-p-chlorobenzyloxy)ethyl]-1-methylpyrrolidine(48%),19metamphetamine (76-79%)20,21or 2-[L-gluco-L-gulo-heptohexahydroxyhexyl]benz-imidazole (96,5%)22were used for the resolution.The rac-1acid can be obtained by several methods. The catalytic hydroxylation ofmaleic acid is of the greatest practical importance.23The best results were obtained when maleicacid was oxidized with an excess of hydrogen peroxide (1.5:1 mol/mol) in the presence of 0.5%of the tungsten catalysts, in an aqueous medium (70∞C, 12 h). After cooling, very pure rac-1acid crystallized directly from the post-reaction mixture in 80% yield. The filtrate containingmainly unreacted maleic acid, catalyst, and also dissolved rac-1acid was recycled for subse-quent syntheses (Scheme 1).OOHOHOH2O2, 0.5% WO3, KOHaq70ºC, 12 hrac-1Scheme 1The racemization of natural L-1acid in a strongly alkaline medium was the previouslyused method to obtain the rac-1acid.18,24-37Many variants of this process have been described,such as changing the excess of the base (3-13 equivalents per equivalent of rac-1),33,35concentra-tion of acid 1(12-88%),24,27temperature (100-176∞C),24,35reaction time (4 hrs-one week),33,35types of salt used for the resolution of tartrates (Na, Ba, Ca),18,32,35and finally by crystallizationof the racemic sodium hydrogen tartrate (after partial neutralization) and thus purifying it fromthe less soluble mesoderivative.18Despite the simple chemistry, the process is technologicallycomplicated and does not proceed in high yields. The concurrent formation of the meso-1acidduring racemization and the prolonged and arduous crystallization of both sodium and calciumsalts of 1and the tendency of the latter ones often used for the resolution of the rac-1acid, toform super-saturated solutions, may be the two basic reasons for the low yields.33The oxidation of fumaric acid is another method to obtain the rac-1acid. Potassiumperman-ganate was initially used as the oxidant;25,26sodium chlorate (55% rac-sodium tartrate)29or hydrogen peroxide in the presence of a catalytic amount of osmium tetraoxide (99.5% rac-potassium tartrate),30(48% rac-calcium tartrate) have also been used (Scheme 2).34HOOCCOOHH2O2, 0.5% OsO4tBuOH, 0ºC, 48 hrac-1Scheme 2The meso-1acid is formed as a by-product during the racemization of L-1(17%),35whereas it is obtained mainly by the oxidation of maleic acid. Potassium permanganate was41´KOWSKI AND BERNAS´SYNORADZKI, RUS

initially used as the oxidant,25,26and later sodium chlorate in the presence of a catalytic amountof osmium tetraoxide (72% meso-calcium tartrate) has been utilized.29meso-Potassium tartratewas obtained directly after the reaction, and then meso-calcium tartrate was precipitated withcalcium chloride. Milas and Terry reported the highest yield of the meso-1salt (98% of meso-sodiumtartrate) as a result of maleic acid oxidation with sodium chlorate in the presence of OsO4carrying out the process for 7 h at 50∞C (Scheme 3).30OOHOHO1.3 NaClO3, 0.5% OsO450ºC, 7 hmeso-1Scheme 3However, somewhat later Milas and Sussman obtained the meso-1acid in only 30%yield when hydrogen peroxide was used instead of sodium chlorate.34Braun obtained the meso-1acid exclusively when maleic anhydride was oxidized with barium chlorate at room temperatureover a period of two months (91% of mesobarium tartrate) (Scheme 4).32OOO1.5 Ba(ClO3)2, 1% OsO4rt, 2 monthsmeso-1Scheme 4The preparation of meso-1from maleic acid by bromination and hydrolysis38or fromfurfural by oxidation with sodium chlorate in dilute hydrochloric acid in the presence of acatalytic amount of osmium tetraoxide, are of lesser importance. After the addition of calciumchloride, the product was isolated in the form of mesocalcium tartrate (49%), and the oxalic acidformed as by-product remained in solution (Scheme 5).311.5 NaClO3, 0.5% OsO4OCHOrt, 60 daysmeso-1+(COOH)2Scheme 5The anhydride of 1could not be isolated and characterized, probably due to the facilepolymerization resulting from the presence of free hydroxyl groups; its formation is postulated,however, as a reactive intermediate.39,40The report in Chemical Abstracts41of the existence ofacid 1anhydride is an error, since this compound is not mentioned in the referenced paper. Simi-larly, Peynaud,42cited in a monograph,1postulates the formation of an intermolecular ester(lactide), and not of the anhydride of 1, despite the fact that she calls it an anhydride.O-Acylation is a simple and economical method to protect the hydroxy groups of acid1. The acyl group can be readily removed by hydrolysis or basic methanolysis; O-acetyl groupsare particularly easy to deprotect. O-Acylation increases the acidity of the neighboring carboxy42SYNTHESIS OF TARTARIC ACID AND O-ACYL TARTARIC ACIDS AND ANHYDRIDES

group.1,5O,O'-Diacyl acids and their anhydrides, in particular diacetyl or dibenzoyl derivatives,are the most often used. Recently, monoacyltartaric acids have gained increasing importance.I. O,O'-Diacyltartaric Acid AnhydridesDiacyltartaric acid anhydrides (2) are stable compounds (Fig. 1, Table 2), which aremost often used for the resolution of racemic alcohols “viaesters” (also including the kineticmethod),43-47or of amines “via amides”.44,46,48-51They are important intermediates for the prepa-ration of the corresponding acids. They can be obtained by esterification of the hydroxy groupswith acid anhydrides or acid chlorides.2,40,45,52-The methods described differ in the type of theacylating agent used, solvent (toluene, xylene, dioxane, acetone, hexane), reaction conditions,types of crystallization system, mode of precipitation and maceration as well as removal of side-products. Economic aspects and the properties of the carboxylic acid formed as a by-product (ifit is volatile, as in the case of acetic acid, then an acid anhydride as the acylating agent would beused, and a solvent is not necessary) are major factors in the choice of the method used. Due tothe corrosive nature of the medium, resulting from the presence of mineral and carboxylic acids,and the possibility of metal complexation by tartaric acid, the apparatus used must be made ofglass, enamel or special steel. ORCOOORCOOR =a)CH3methylb) Cl3C–trichloromethylc)F3C–trifluoromethyld)C2H5–ethylCl2Oe)CH3CH=CH–propenylf) (CH3)2C=CH–2-methylpropenylg)(CH3)3C–t-butylh)2-chlorophenylCH2–i)phenylj)cyclohexyl–o)2-phenylvinylOHCk)CH3l)3-tolylCH3m)4-tolylbenzylCH2HCn)cyclohexymethylHCHCp)CH3CH3r)H3CCH33,4-dimethylphenylO3,5-dimethylphenyls)2-cyclohexyvinylt)3-coumarinylu)1-naphthylw)1-adamantylFig. 143´KOWSKI AND BERNAS´SYNORADZKI, RUS

a) By Acylation-Dehydration with Acid Chlorides (Method A)This method has been known since 1880, when Anschütz and Pictet obtained diacetyl-L-tartaric (L-2a) diacetyl-D,L-tartaric(rac-2a) and dibenzoyl-L-taratric (L-2i) anhydrides bytreatiment of L-1or rac-1with acid chlorides.52Since that time, this original method was usedroutinely and, only during the last decade of the 20thcentury, have considerable modificationsbeen made to it (Scheme 6, Fig. 1, Table 2).1,2,40,45,52,54,56-61,63,65-69,71,74,75,79-83,87,88OHORCOOOHOHOO +3 RCOClRCOOOO+RCOOH +3 HClHO1Scheme 62The necessity of using 3 equivalents of the acid chloride as the acylating agent for 1stems from the fact that 2 moles are used for the O-acylation of two hydroxy groups, and 1 molefor formation of the anhydride. One equivalent of the corresponding carboxylic acid is formed asa by-product and 3 equivalents of hydrogen chloride evolve. The acylation is usually carried out at 120-170∞C, without solvent, using 3-3.5 equiva-lents of the chloride per 1 equivalent of 1. The carboxylic acid formed as a by-product and unre-acted acyl chloride were extracted into aromatic solvents. In this fashion, a number anhydrideshave been obtained (Fig. 1, Table 2). The basic disadvantage of this procedure is that the reactionmixture becomes thick, solidifies quickly and is difficult to remove from the reaction vessel; thenthe side-product must be extracted from the mixture and the anhydride purified. The procedure to prepare the L-2lanhydride was modified by Kidd2by the introductionof xylene to the reaction system. The use of a solvent allowed the reaction to be performed at alower temperature and prevented solidification of the mixture. Purification of the product alsobecame much easier, since the monocarboxylic acids formed as by-products are more soluble inaromatic solvents than the corresponding anhydrides 2.Since 1983, reactions to obtain anhydrides 2have been prepared in the presence of cata-lysts such as iron oxide,81mineral acids (sulfuric, hydrochloric, nitric, phosphoric), organic acids(p-toluenesulfonic, acetic),82and Lewis acids (AlCl3,83FeCl3,75,83ZnCl2,83BF3•Et2O83). Thesyntheses were carried out in various solvents (acetone, hexane and chloroform,82toluene andxylene,83and dioxane81), the best yields being achieved in toluene. The application of catalystsimproved the safety of the process (the reaction starts at a lower temperature, and thus is lessviolent) and favorably affected the yields obtained. Contamination of the product is a side-effectof using catalysts which are insoluble in the reaction system; this is especially obvious in theformation of color when FeCl3was used. The use of mineral acids, provided the highest yields(>90%) and BF3•Et2O does not cause coloration of the product. The contamination with the cata-lyst is especially important in the case when anhydride 2is the desired final product, and not anintermediate for the preparation of the corresponding acid.44SYNTHESIS OF TARTARIC ACID AND O-ACYL TARTARIC ACIDS AND ANHYDRIDES

b) By Acylation-Dehydration with Acid Anhydrides (Method B)Acylation with acid anhydrides is performed mainly to prepare diacetyl-45,52,53,55,60,62,,70-73,76-78,84-86,dipropionyl-62and trihaloacetyltartaric anhydrides (Table2).40It isnecessary to use 3 equivalents of the anhydride per 1 equivalent of acid 1, 2 equivalents beingused for the O-acylation of the two hydroxy groups of acid 1, and one for cyclization to the anhy-dride 2(Scheme 7).1+ 3 (RCO)2O2+4 RCOOHScheme 7The syntheses were most often carried out without a solvent, taking advantage of thefact that both the anhydrides used for acylation as well as the acids formed as by-products areliquids; there is only one report of the reaction being performed in a solvent (dioxane)40in whichtartaric acid is very soluble and the tartaric anhydrides are not and thus easily precipitate readily.Sulfuric acid,53,55,62,,70,71,78,84-86phosphoric acid62or hydrogen chloride60were used as catalysts.Benzene, toluene, ethanol, diethyl ether were used for the crystallization of anhydrides.The ease of purification of the product in the case of acids of low boiling point is a greatadvantage of this method which was applied for the first time by Wohl and Oesterlin to obtainanhydride (L-2a).53The highest yield (95%) in this procedure was achieved when 3.5 equiva-lents of acetic anhydride containing 3% of hydrogen chloride was used and the reaction wasperformed at 60∞C for 20 h60or when 3.5 equivalents of the anhydride and sulfuric acid as cata-lysts were used at 120∞C with concurrent gentle distillation of the acetic acid generated.55,85c) By Reaction with Thionyl Chloride (Methods C-E)The principal observation of the newest methods to synthesize these anhydrides is thefact that the inclusion of agents such as thionyl chloride, phosphorus pentachloride or trichloride,may cause chlorination of monocarboxylic acids (by-products) only, but not of both the carboxygroups and the secondary hydroxy groups of acid 1; therefore, it is not the source of by-products.83Thus carboxylic acid formed as a by-product during acylation of 1with an acid anhy-dride or chloride, is converted in situto an acid chloride. Moreover, the carboxylic acid 1alonecan be applied for the acylation of 1, as a precursor of the acylating agent, which is the acid chlo-ride (Scheme 8).1 +2 RCOCl+ SOCl21 + (RCO)2O+2 SOCl21 +2 RCOOH+ 3 SOCl22+ SO2+4 HCl (Method C)2+2 SO2+ 4 HCl (Method D)2+3 SO2 +6 HCl (Method E)Scheme 845´KOWSKI AND BERNAS´SYNORADZKI, RUS

The application of a chlorinating agent allowed the amount of the acid chloride (fromover 3 to 2.0-2.4) or anhydride (from over 3.0 to 1-1.2) equivalents per equivalent of acid 1 to bedecreased. The reactions were carried out in aromatic hydrocarbons, with toluene being the best,at 40-200ºC, without catalysts or in the presence of a catalytic amount of AlCl3, FeCl3, ZnCl2orBF3•Et2O. It was stressed that the conversion of the carboxylic acid formed as a by-product toacid chloride, proceeds already below 110ºC.For the reaction with carboxylic acids, the use of 2.2 equivalents of a correspondingacid and 3.5 equivalents of SOCl2per equivalent of 1 is favored. The reaction with aromaticcarboxylic acids has been carried out in the presence of AlCl3, FeCl3, ZnCl2or BF3as catalysts,for 1-3 h at temperatures as high as 170°C.The more efficient use of acylating agents is one great advantage of the methoddescribed, and is especially important in the case of expensive acid chlorides or anhydridesbecause it allows the use of carboxylic acid instead of the corresponding chloride or anhydridefor the acylation of acid 1, as the cheapest and more commonly available source of acyl groups.Thionyl chloride has been used most often, since it produces sulfur dioxide andhydrogen chloride as gaseous by-products, which are easily removable from the reactionmedium, thus making product purification easier;however, on a technical scale it is necessary tohave available the means for the separation and absorption of these gases and their utilization.The use of thionyl chloride requires great caution, since it is an extremely toxic compound whichreacts very vigorously with water.d) By Dehydration of O,O'-Diacyltartaric Acids (Method F)Anhydrides 2may be obtained from corresponding O,O'-diacylacids 4 through dehy-dration by means of such agents as thionyl chloride,60,63acetyl chloride (in benzene)46or aceticanhydride90(Scheme 9, Fig.1, Table 2). This method found application only for anhydride 2isince acid 4jis easily accessible and inexpensive.OPhCOOOHOHPhCOOSOCl2 or AcCl or Ac2O–H2O2i4jOScheme 9II. O-Acyltartaric AcidsMonoacyltartaric acids (3) are not as commonly used as their disubstituted counterparts.However, they are acquiring increasing importance because of the important role, e. g.as a chiralligand in borate complexes (CAB-Chiral Acylborane) used in asymmetric Diels-Alder reac-tions,6,91-94hetero Diels-Alder reactions,95,96aldol condensations97-101and the allylation of 46SYNTHESIS OF TARTARIC ACID AND O-ACYL TARTARIC ACIDS AND ANHYDRIDES

Table 2. Preparation and Properties of O,O'-Diacyltartaric Acid AnhydridesCmpdConf.a2aD2aL2aL2aD2arac2aL2aL2bL2cL2dL2eL2eD2fL2fD2gL2hL2hD2hL2hD2iL2iL2iD2irac2imeso2iL2iL2iL2iD2iL2iL2imeso2jL2kL2kLYieldMethodb(%)93A7673B9585Bf----Bf----Bf63E86D85BB----Bf54A----A91A86A79A54C91Cf54E91Ef9482Af8079A68A-A75A91Cf8083C81Ef92Ef93Df-F7663F80A76C76Emp.(ºC)133-135128-12973133-13470133-134122-123132-134132-134176-17754-55----76-7775-7610679-99167--------165-169--------195-19682194-19618257141-144--------------------192-19588139-14263139.5-141----142-14747[α]20DReferences–.3c80d,e----52, 73e+97.2c,7053, 55, 60, 62, , 70,71, 72d, 76d, 77, 78d,e,84d, 85, 86e, –97.0c84d052-83-83+.6g40d+40,4c40d----62----68----68----68----68+76g74d,e----83----83----83d,e----83----81, 82, 83+153h,7152, 56, 58, 60, 71, 79e, 83-161h66057, 59063----75, 83----83d,e----83d,e----83----83196c,8860, 90d,e046e, 63+35i69----83----83d,e´KOWSKI AND BERNAS´SYNORADZKI, RUS

Table 2. Continued...CmpdConf.aYieldMethodbmp.[α]20DReferences(%)(ºC)2lL7661A204-2052+195h,612, 612lD8487A199.5-200.587–195h,6161, 872lrac----A162-1630672lL91C--------832lrac80C--------832lL92Cf--------832lD91Cf--------832lL90E204-205----83d,e2lrac80E--------832lD92Ef--------832mL80A115.5-116+53i692nL93A111-112.5+40i692oL----A146-148+291h12oD----A158-159–274h542pD90Cf--------832pD90E180-182----832pD90Ef--------832rL60A--------88d2sL58A106-107+66i692tL68A122-125----682tD----A--------682uD80A174----652wL70A220+34.8i74d,ea) Configuration; b) In text; c) In chloroform; d) NMR data; e)IR data; f) With catalyst; g) Inbenzene; h) In acetone; i) In dioxane.aldehydes.102,103The utilization of these complexes allowed to achieve high reaction stereoselec-tivity and yields. Acids 3may be obtained by three methods (Fig. 2, Table 3).ORCOOOHOHHOR =a) CH3–methylb)(CH3)3C–t -butylc)3OH3COOCH3H3COCH3OCH3CH3d)2,6-dimethoxyphenyle)2,6-diisopropoxyphenylFig. 248SYNTHESIS OF TARTARIC ACID AND O-ACYL TARTARIC ACIDS AND ANHYDRIDES

a) Partial Hydrolysis of O,O'-Diacyltartaric Acids (MethodA)Langenbeck described the selective hydrolysis of dibenzoyltartaric acid (4j) in boilingwater for 10 h (45%).104After filtration of the unreacted 4jand of benzoic acid formed as a by-product, water was distilled off and the residue was crystallized from a benzene/ethanol (4:1)mixture. The authors of this review achieved a much lower yield (10%) when performing thisreaction, since multiple crystallizations were required to obtain a pure product (Scheme 10).refOPhCOOOHOHPhCOOOH2Oreflux, 10 hPhCOOOHOHHO+PhCOOH4jOScheme 103cOb) Partial Aminolysis of O,O'-Diacyltartaric Acids (Method B)Bell obtained acid 3cin the reaction of acid 4j at low temperature, with a large excess ofbenzylamine.105The product was isolated in the form of the double benzylamine salt of 3c. Theadvantage of this method is the fact that the double salt formed is insoluble in the reaction systemand thus there is no possibility of aminolysis of the second benzoyl group. On the other hand, adisadvantage is the necessity of using a very large excess of the amine (yield 88%) (Scheme 11).4j10 BnNH23c•2 BnNH2Scheme 11c) Hydrogenolysis of Dibenzyl O-Acyltartrates (Method C)Monoacetyl- (3a) and monopivaloyl- (3b),6monobenzoyl- (3c) and mono(2,6-dimethoxy-benzoyl)- (3d)6,93,94,100and mono(2,6-diisopropoxybenzoyl)tartaric (3e)92,96,97,99,100,103acids were obtained from dibenzyl tartrate (5), after it was converted into a monoacyl derivative.The dibenzyl monoacyltartrate thus obtained was hydrogenolysed on palladium to afford acid 3.(Scheme 12, Fig. 2, Table 3)OOOBnOBnOHOHORCOOHOO1a or bc or d or eOBnOBnH210% Pd/C(100%)35a: BnBr, DBU, DMF, (94%).100b: BnOH, TsOH, toluene 130ºC, 13 h.93c: RCOOH, (CF3COO)2O, benzene or CH2Cl2, rt, 30-60 min, (65%).92,94,96,99,103d: RCOOH, DCC, DMAP, CH2Cl2, rt, 48 h, (86%).100e: RCOCl, Et3N, DMAP, CH2Cl2, 0ºC-reflux, 12-18 h, (78-82%).6,93,97Scheme 1249´KOWSKI AND BERNAS´SYNORADZKI, RUS

Table 3. Preparation and Properties O-Monoacyltartaric AcidsCmpdConf.aYieldbMethodcmp.(%)(ºC)3aL----C----3bL-C----3cL45A202-2033cL88eB155-156e3cmeso-B149-150e3cL70C211-2123c-----C----3dL62C178-1813dD62C173-1763d3d3eLLL8675936592CCC187-188184-186938192[α]20D---------4.4d---------5.76g----–75.1d+72.2d–69.2g–73d,93–28.5d,92References66104105f105f100f,h694f,h94f,h100f,h6, 93f,h92f,h, 96f,h, 99f,h, 103f,h3eL74C----–23.6d100f,h3e--------C--------97a) Configuration; b) for method Cyield was count over for 1; c) In text; d) In ethanol; e) Asdisalt with benzylamine; f) NMR data; g) In methanol; h) IR data. III.O,O'-Diacyltartaric acidsThe oldest use of diacyltartaric acids (4) for the resolution of racemic mixtures ofcompounds of basic character (amines,2-5,106,107aminoacids5,108,109by “diastereomeric salts” orracemic alcohols “by esters”5,110) is still their present application.A two-stage synthesis is the main method of obtaining acids 4. In the first step, thecorresponding anhydride 2is prepared and then it is hydrolyzed to the desired acid. The acyla-tion of the second hydroxy group and cyclization proceed concurrently, and therefore the appli-cation in the reaction of only 2 equivalents of acid chloride does not lead to acid 4, but to amixture of mono- and diacylated acids as well as corresponding anhydrides 2, from which theisolation of acid 4is economically unjustified. Fortunately, the anhydride and ester bonds ofdiacyltartaric anhydrides 2 differ substantially in their tendency toward hydrolysis, the anhydridebond being much easier than the ester; thus under appropriate conditions it is possible to open theanhydride ring without or negligible cleavage of acyloxy groups. Diacetyltartaric acid (4a),,111dibenzoyltartaric acid (4j),56-59,63,66,75,83,104,112-114ditoluoyltartaric acid (4m),2,61,67,75,83,87 dipivaloyl-tartaric acid (4g),74,113chicoric acid (4s)115,116and several others mentioned in Table 4 (Fig. 3)have been obtained in this way.1,54,65,68,69,74,83,113,116-12350SYNTHESIS OF TARTARIC ACID AND O-ACYL TARTARIC ACIDS AND ANHYDRIDES

ORCOOOHOHRCOOR =a)CH3–methyl–= b) CH3CH CHpropenyl c)(CH3)2BrC–1-bromo-1-methylethyld)S2-thienyl4 e)OCl j)=–g)(CH3)3C–h) (CH3)3CCH2– i) f)(CH3)2C CH2-methylpropenylt -butyl2,2-dimethylpropyl3-thienylphenyl2-chlorophenylSCH2–Ok)cyclohexyl l) (CH3)3C(CH2)2– m)3,3-dimethylbutyl n)CH3o)benzylCH3 p)OCH34-tolylCH2–CHHC2-methoxyphenyl4-methoxyphenylCH2–CHH2CHC q)cyclohexylmethyl r)s)OHOHt)CH3CH3u)2-phenylethylCH2-phenylvinyl2-(3,4-dihydroxy-phenyl)vinylO3,4-dimethylphenylHCCHHCOv)2-cyclohexylvinylHCw)3-coumarinylx)1-naphthyly)1-adamantylz)AcOAcOCH2-(3,4-diacetoxyphenyl)-vinylaa)CH3OCOOCH3OCOOab) CH3(CH2)11CH2–myristylac)CH3(CH2)13CH2–palmitylad) CH3(CH2)15CH2–stearyl2-(3,4-dimethoxycarbonyl-oxyphenyl)vinylFig. 3a) Hydrolysis of O,O'-Diacyltartaric Acid Anhydrides (Method A)The hydrolysis of anhydrides 2has been carried out in an acetone and watermixture,74,87or in water, most often at the boiling point of the reaction mixture in 0.5-1 h,83without or with the addition of a solvent immiscible with water,83,112which prevented agglomer-ation of acid 4during crystallization (Scheme 13). Benzene, toluene, xylene and chlorobenzenehave been used as solvents.83Mezei et al.112carried out the hydrolysis of anhydride D-2ito the51´KOWSKI AND BERNAS´SYNORADZKI, RUS

corresponding acid in a mixture of dichloromethane and a small amount of water, under the pres-sure of 0.15-0.5 MPa (87%). ORCOOORCOOOH2ORCOORCOOOHOH2OScheme 134OIn a majority of cases, the acids obtained or their monohydrates formed an oily phase,immiscible with water and easily overcooled, which makes crystallization difficult; the yieldafter crystallization are >90%. On the basis of our own experience,ref.it can be stated that heatingthe anhydride in water at boiling point without solvent, is the best way of carrying out thehydrolysis. An organic solvent causes a decrease in the yield and may additionally cause prob-lems with waste water treatment.b) Hydrolysis without Anhydride Isolation after AcylationThe preparation of acids 4by direct reaction of acid chlorides with acid 1in a 2:1 ratiohas rarely been applied. Rabe119carried out the reaction of anisoyl chloride with L-1(2:1, 120ºC,2 h), followed by the hydrolysis with water at boiling point without isolation of anhydride 2.Drying over sulfuric acid, isolation of anisic acid by crystallization from acetone, and boilingfive-time with benzene was necessary to isolate pure dianisoyltartaric acid 4p from the mixtureof products. The yield was not given, but it was probably not high. According to a Hungarianpatent,75acid 4jcan be obtained using 2 equivalents of benzoyl chloride per equivalent of acid 1in the presence of AlCl3as catalyst; however, this patent raises doubts.Scarpati and Oriente115obtained all the isomers of chicoric acid 4sfrom the reaction ofcarbonylcaffeic acid chloride with 1in a ratio of 1.8 of the chloride to 1(such a small amount ofthe acid chloride was used probably due to its high cost). Acid 4sand its analogs are utilized instudies of the HIV integrase inhibitors. It was found that the enantiomer of natural acid 4sinhibits the HIV integrase in the extracellural enzyme synthesis and increases the immunedefense of cells towards the possibility of HIV virus infection.Carbonylcaffeic acid chloride was heated with tartaric acid under reduced pressure at115-135ºC for 10 min (Scheme 14). After cooling, the resulting white solid was separated andHOOHOOOOHOHO1RCOCl135ºC, 10 minO2CH1. AcOH, reflux, 40 min2. H2O, 50ºCOOR:OOCHScheme 1452HOOH4sSYNTHESIS OF TARTARIC ACID AND O-ACYL TARTARIC ACIDS AND ANHYDRIDES

heated with 80% acetic acid till complete dissolution. The solution was evaporated, and theresidue (anhydride, acid 4s, unreacted acid 1and caffeic acid) was heated with water at 50ºC.The mixture was filtered, and the filtrate was extracted twice with ether. After evaporation ofether, the residue was dissolved in warm water and barium acetate was added, which causedprecipitation of the acid 4sas its barium salt. The salt was acidified with HCl and acid 4swasextracted into ether. The acid obtained after evaporation of ether was crystallized from water.Such a way of obtaining acid 4sis very laborious and moreover, the product is obtained in pooryield (35%). A further disadvantage is the use of diethyl ether and harmful (?) barium salt for thepurification of the product.c) Synthesis via Tartaric Acid Esters (Method B)Zhao and Burke116obtained enantiomers of acid 4sand indirectly tetraacetyl-L-chicoricacid (4z) in a three-stage process starting from 3,4-diacetylcaffeoyl chloride and di-t-butyltartrate at 2.5:1 mol ratio (Scheme 15). Acylation of the tartrate has been carried out in the pres-ence of pyridine in toluene (rt, 12 h). After removal of pyridine and of toluene, the residue wasOHOHOOOtBuOtBuOOOtBuOtBuRCOClPy, toluene, rt, 12 hRCOOTFAA, CH2Cl2rt, 12 hAcOCHCHAcORCOOOHOHRCOORCOOsO4zO4zHCl, acetonereflux, 3 hR:Scheme 15passed through silica gel (EtOAc-hexane 1:1) then crystallized from EtOAc-hexane to give ester6 as a white solid (97%). In the second step, the t-butyl groups were removed with trifluoroaceticacid in dichloromethane (rt, 12 h) to afford acid 4z (96%). The same acid was similarly obtainedby Reinke et al.120starting from tartrate 5; in the last stage, the acetyl groups were hydrolyzedwith 3 M hydrochloric acid, in acetone (reflux, 3 h). After some work-up, evaporation of thesolvent and crystallization from water, acid 4swas obtained (90%), with respect to di-t-butyltartrate (84%). High yields, elimination of the use of ether and of barium salts are advantages ofthis method. Despite the fact that it is a three-stage process, it is simpler than the method used byScarpati and Oriente.Tohma et al.121similarly obtained bis(2-methoxybenzoyl)tartaric acid (4o) from tartrate5and o-anisic acid. In the first step, upon the action of trifluoroacetic acid ester 7is formed,which undergoes hydrogenolysis on palladium to 4o(Scheme 16).53´KOWSKI AND BERNAS´SYNORADZKI, RUS

OOOBnOBn5aRCOORCOOObRCOORCOOOOHOH4o7a) MeOC6H4COOH, (CF3CO)2O, benzene, rt, 1 h; b) H2, Pd, AcOEt, 0.3 MPa, rt, 2 hScheme 16d) Synthesis via Tartaric Acid Salts (Method C)Kolodyn´ska and Wieniawski122performed the acylation of the quinoline salt of acid 1.Dried acid 1(100ºC, vac.), the acid chloride and quinoline were stirred in chloroform at roomtemperature for 22 h. The mixture was then acidified with 6% hydrochloric acid and the organiclayer was washed with water, dried and evaporated to give the product 4aa(25%) which wasrecrystallized from methanol (Scheme 17).1. quinoline, CHCl3, rt, 22 h2. HClaqOCH3OCOO1+RCOCl4aaR:CHCHCH3OCOScheme 17Using the same method, but with pyridine instead of quinoline, Kunitake andOkahata,123obtained dimyristoyltartaric acid (4ab).e) Resolution of Racemic O,O'-Diacyltartaric Acids (Method D)This method is rarely used and may be of practical importance only to obtain of diacylderivatives of acid D-1. Acid D-4mresulted from the resolution of acid rac-4mby means ofcinchonine by the formation of diastereomeric salts.67The enantio-separation of rac-4jis possible in a simple two-step crystallization proce-dure. In fact, a complex of the neutral calcium O,O'-dibenzoyl tartrate with two molecules of 2-methoxyethanol, which exists as a conglomerate, is the key compound. This salt crystallizesreadily (crystallization is practically complete within 15-20 min.) in contrast to the hydrated salt,which crystallizes slowly and can be handled only with difficulty. Acid rac-4jobtained from thehydrolysis of anhydride rac-2i, was dissolved in a mixture of ethanol, water, methoxyethanol andcalcium oxide. After seeding with crystals of L-8complex at 35-45ºC and cooling to 0ºC (15-20min.), crystals of L-8precipitated (Scheme 18).OPhCOOPhCOOOOCaOHOrac-4j+CaOHOO•O+D-4jScheme 1854L-8SYNTHESIS OF TARTARIC ACID AND O-ACYL TARTARIC ACIDS AND ANHYDRIDES

Another portion of 2-methoxyethanol as well asrac-4jcalcium oxide were then addedto the mother liquor and the whole was seeded this time with complex D-8to afford crystalsofD-8respectively. The procedure was repeated five times. The combined fractions of particularcomplexes were hydrolyzed with hydrochloric acid. The corresponding crystals of acids L-4jand D-4j(overall yields 80% and 81%, respectively) precipitated from the aqueous solutions.114Table 4. Preparation and Properties O,O'-Diacyltartaric AcidsCmpdConf.aYieldMethodbmp.(%)(ºC)4aL----A1184bL----A74-7bD----A73-754cD----A----4d4e4f4f4g4h4i4j4jLLLDLLLLrac979561h66h9874----94j9358----AfAfAAAAAAA186-187194-195131-132132-13413574--------88-90j,56138-14056112-113j,57112.5-114and 169-172j,11488-90j,66138-13966208-21288-.5j88-j65-6869----172j,61171-17287188168133-13569187186[a]20D–24.6c,–58d+56.5d–3.95e--------–61.5c+63.7c–24.2e,74–21.1e----–116j,l,56–118.5l,560References, 1116868113120g120g686874g,i, 1131138356, 58, 75k, 104, 11357, 59,1144j4j4j4j4k4l4m4m4m4m4n4o4pDmesoLDLLLDracDLLL9383----93946169----96j,83798775----8069100----AADDAAAAADABA+114l,660–112m+112m–29e,69–24.4e–140l,61+141l,870+140l–31e,69–115.3c–162.8l66, 83, 1126311411469, 1131132, 61, 75, 8361, 87676769, 11312111955´KOWSKI AND BERNAS´SYNORADZKI, RUS

Table 4. Continued...CmpdConf.aYield(%)4qL834rL----4sL----4sD----4srac----4smeso----4sL904sD----4tL9u4v4w4w4x4y4zDLLDDLL----10072----100967498120MethodbAAAAnABBAAAAAAABmp.(ºC)125.5-126166-16754206206206225204-206204-206----[a]20D–26e–207.4e,113–384.2m+384.6m00-333m+340m----References691, 54, 113115115115115116g116g83----–25.511382-85–54e69195-196+150e68195-196–151e681-199j-c/d6527374decomp.–26.1e,7474g,i, 113200-202120–159m,116116g, 120g186-18811aaL25C150-152----1224abrac----C49-5001234acL----A--------1174adL----A28-30118----117, 118a) Configuration; b) In text; c) In acetone; d) In water; e) In dioxane; f) Hydrolysis with 80%AcOH; g) NMR data; h) After twice crystallization with benzene; i) IR data; j) As hydrate; k)After acylation of 1hydrolysis of 2 without isolation; l) In ethanol; m) In methanol; n) Mixingenantiomers and crystallization.IV. SummaryMethods of preparation and basic physical properties of isomers of acid 1as well as ofanhydrides 2and acyl acids 3and 4 have been presented. The compounds obtained have beentabulated according to their molecular formula.The natural acid (+) L-1, formed as a by-product of wine production, is one of thecheapest chiral products of two asymmetric centers. Acid (-) D-1became also a valuable productof industrial importance, due to the discovery of a simple and efficient method to obtain rac-1bycatalytic oxidation of maleic acid in the presence of WO3and effective resolution of the racemateinto both diastereoisomers. Methods to prepare meso-1are not very efficient and it is the mostexpensive compound and is of only laboratory importance.56SYNTHESIS OF TARTARIC ACID AND O-ACYL TARTARIC ACIDS AND ANHYDRIDES

Anhydrides 2are obtained mainly from acid 1and acid chlorides ,or less often from

acid anhydrides. The addition of a chlorinating agent, e. g.SOCl2, is one of the most importantmodifications of the process, because of the resulting considerable decrease in the consumptionof the acylating agent achieved.

The acylation of dibenzyl tartrate followed by catalytic debenzylation with hydrogen in

the presence of palladium is the basic method of obtaining acids 3.

The most important method of obtaining acids 4consists in the hydrolysis of corre-sponding anhydrides; however, the synthesis “viaesters” or “viasalts” with amines, especially inthe case of complicated and expensive substituents, is also of importance.

Acid 1and its diacyl derivatives 2and 4are most often used for the resolution of

racemic mixtures of amines, alcohols and compounds of a basic character. Monoacyl acids 3aregaining increasing importance fulfilling an important role, e. g.as a selective chiral ligand inborate complexes used in asymmetric Diels-Alder reactions, aldol condensations or allylation ofaldehydes. The application of chicoric acid 4sand its derivatives in studies of the HIV virusinhibitors is also interesting.

In summary, although tartaric acid 1and its derivatives 2-4have been known for over

150 years, they are still very attractive compounds which enjoy wide applications in organicchemistry and technology.

Acknowledgments.- This work was financially supported by Warsaw University of Technology(504/G/1021/0441/000). The authors kindly thank Dr. Marek Wlostowski for valuable discus-sions and Ms. Renata Przedpelska for technical assistance.

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