Malic acid Isomerism

Colourless prisms m.p. 130 C. Manufactured by treating maleic anhydride with water. It is converted to the anhydride by heating at By prolonged heating at 150 "C or by heating with water under pressure at 200 C, it is converted to the isomeric (trans) fumaric acid. Reduced by hydrogen to succinic acid. Oxidized by alkaline solutions of potassium permanganate to mesotartaric acid. When heated with solutions of sodium hydroxide at 100 C, sodium( )-malate is formed. Used in the preparation of ( )-malic acid and in some polymer formulations. 

The enantiomerically pure indolizidine (—)-422 has been synthesized starting from L-malic acid diethyl ester 407. The hydroxyl function of L-malic acid diethyl ester 407 has been protected as dihydropyranyl ether 408 with 2/7-dihydropyran and Amberlyst 15 in pentane at room temperature. The diethyl ester 408 was then reduced with lithium aluminium hydride in diethyl ether under reflux and the newly generated hydroxyl functions then protected with mesyl chloride in the presence of triethylamine in dichloromethane at 0°C. This was converted into newly protected pyrroline nitrone 409 in 44% overall yield through a well-established method (Scheme 90). The regio-isomeric 5-pyrroline-iV-oxide 410 formed in 4% overall yield was easily separated by column chromatography <20000L2475>. 

Maleic isomerization, 20 99-100 Maleic resins, 20 100 Maleimide method, for covalent ligand immobilization, 6 396t Maleimide terminated monomers, 20 273 Malic acid, 72 45 uses for, 75 512 ([Pg.547]

The reverse of these reactions viz., the conversion of maleic and fumaric acids, by the addition of hydrogen bromide, into mono-brom succinic acid by the addition of two bromine atoms, into di-brom succinic acid and also by the addition of two hydrogen atoms, into succinic acid itself all show these same relations of maleic and fumaric acids to succinic acid and its bromine substitution products and establish the constitution of these isomeric di-basic unsaturated acids as given. The two acids may also be prepared from malic acid which is, in fact, the chief method by which they are prepared. This reaction will be considered later when malic acid itself is studied. 

Stereo Isomerism of Malic Acid.—On examination of the formula of malic acid it will be seen that one of the carbons is asymmetric i.e.j it has united to it four different elements or groups, viz., (—H), (—OH), (—COOH), and (—CH2—COOH). We should, therefore, expect to find that malic acid is optically active and that it exists in the three forms of dextroj levo, and inactive. This is in accordance with the facts. The formulas for the three stereo-isomeric forms of malic acid may be written as follows, corresponding exactly to those for lactic acid. 

The study of malic acid in connection with its stereo-isomerism, together with the similar study of the related acids, lactic, tartaric, maleic and fumaric has been of the greatest importance in establishing our ideas of stereo-isomerism. 

Isomerism of Tartaric Acid.—Examination of the formula for tartaric acid, which, by the facts given above, has its constitution fully established as symmetrical di-hydroxy succinic acid, shows the interesting fact that there are present two asymmetric carbon atomsy and that each of these has linked to it the same set of four different groups. We should, therefore, expect to find tartaric acid existing in the dextrOy the levo and the inactive forms. The stereo-chemical formulas similar to those of lactic and malic acids we may write as follows. 

Catalysts also exhibit selectivity in their initial binding to reactants. Enzymes are well known for their ability to bind selectively to only one member of a pair of stereoisomers. The bound stereoisomer will undergo reaction, and the remaining isomer is inert to the reaction conditions. For example, the enantioselective addition of water to fumaric acid (the E isomer), which yields (.S )-malic acid (equation 9.7), is catalyzed by an enzyme called fumarase. Isomeric maleic acid (the Z isomer) fails to react in the presence of fumarase. 

We carried out another synthesis of (2R,6S,8R)-8Sr, as shown in Figure 4.37, by employing (.S )-malic acid as the starting material.67 In this synthesis, the enantiomeric purity of the intermediate C was rigorously proved to be 100% ee as checked by the H-NMR analysis of its a-methoxy-a-trifluoromethylphenylacetate (MTPA ester). Subsequently, C was converted to (2R,6.S ,8R)-88, whose rotation value was [a]o23 +60.1 (pentane). As a byproduct of this synthetic study, (2R,6R,8.S )-2,8-dimclhyl-l,7-dioxaspiro[5.5]undecane (F ) was synthesized from D, which was obtained by isomerization of E. This isomerization was made possible by the fact that the crystalline 3,5-dinitrobenzoate of D precipitated, while that of E remained oily. 

Isomerization takes place in an aqueous solution at 100°C, in the presence of ammonium bromide and ammonium persulfate, or hydrochloric acid, or even thiourea. Pure fumaric acid is obtained by cooling the reaction medium, centrifugal drying, washing, and drying of the crystals obtained. Fumaric acid is used in the manufacture of polyester resins, adhesives and food additives (malic acid obtained by the hydration of fumaric add). 

The antineoplastic agent (— )-aplysistatin (998), isolated from the sea hare, is synthesized from (7 )-malic acid via butyrolactone 987 by a biomimetic brominative cyclization of the homogeranyl-alkylated lactone 996 (Scheme 147) [215]. The cyclization occurs in poor yield, and affords a 19 81 mixture of isomeric dihydroaplysistatins (997), the desired isomer being the minor component. The mixture is converted to (— )-aplysistatin (998) and ( + )-12-epiaplysistatin (999) by phenylselenation of the lactone enolates followed by oxidative elimination of phenylselenic acid. The mixture (12 88) is separated by HPLC to give the pure compounds. 

Activation of thioamides to thioimidates with alkylation is also applied to the synthesis of amidines. Dijkink et al. [28] applied this method to the synthesis of chiral bicyclic amidines from (5)-malic acid as a key step. However, the amidine was found to be unstable due to isomerization of the imine double bond followed by ehmination of the silyloxy group (Scheme 3.15). 

FEMA 2655 INS296 E296 Synonyms Apple acid Butanedioic acid, hydroxy- Deoxytetraric acid Hydroxybutanedioic acid 1-Hydroxy-1,2-ethanedicarboxylic acid Hydroxysuccinic acid a-Hydroxysuccinic acid Malic acid (INCI) Succinic acid, hydroxy-Empirical C4H6O5 Formula COOHCH2CH(OH)COOH Properties Wh. or colorless cryst. powd. or gran., strongly acid taste dl, I, and d isomeric forms very sol. in water, alcohol si. sol. in ether m.w. 134.09 dens. 1.595 (20/40 C, d or I), 1.601 (dl) m.p. 100 C (d or I), 128 C (dl) b.p. 140 C (dec.)... 

In 1817, the dry distillation of malic acid by Braconnet and independently by Vauquelin led to the discovery of two isomeric acids, that is, maleic acid (the c -form) and fumaric acid (the tran -form) (Meek, 1975). Fumaric acid is a naturally occurring acid that is, it is found in plants that belong to the genus Fumaria (e.g., Fumaria officinalis), a common European herb and a climbing annual plant, hence its name. Fumaric acid (2-butenedioic acid tra i-l,2-ethylenedicarboxylic acid, H02CCH=CHC02H) is a symmetric, unsaturated dicarboxylic acid. 

Malic acid is known in two active isomeric forms the naturally occurring isomer has the L-(-)-configuration. This dibasic acid as a member of the TCA cycle is formed by hydration of fumaric acid catalyzed by fumarase. In the glyoxylate... 

All four diastereomeric 2-acetamido-2,4-dideoxy-D-hexopyranoses have been synthesized from the (5)-malic acid derived four-carbon aldehyde (37) (Scheme 11) as potential inhibitors of A/-acetylneuraminic acid synthase. The intermediates involved in the synthesis of the v-arabino-isomer (38) are shown in Scheme 11. The two vinyl Grignard addition reactions provided separable equimolar mixtures of C-3 epimers the analogous reactions applied to these yielded the three other isomeric amino-sugars. iV-Acyl-derivative (40) of L-daunosamine has been synthesized from the C-4-carboxy-branched intermediate (39), obtained by a stereoselective enolate-imine condensation (Scheme 12). The C-4-epimeric L-acosamine derivative was obtained by a similar sequence when compound (39) was first epimerized at C-4 (LiOH-HjO-MeOH). ... 

This optical activity can be observed with many RR-related compounds. Thus, ->amino acids (with the exeption of glycine) can exist in two optically active isomers. Many hydroxy acids (- lactic acid, - tartaric acid, malic acid) are also active, and optical isomerism is frequently observed in saccharide chemistry. 

Adrenal Conical Hormones. The adrenal gland is made up of two parts, the medulla and the cortex, each of which secretes characteristic hormones. The hormones of the adrenal medulla art- the catecholamines, epinephrine adrenalin and norepinephrine (noradrenalint. which are closely related chemically, dil lning only in that epinephrine has an added methyl group. See Table I. In fact, animal experiments have established a metabolic pathway lor Ihe biosynthesis of both compounds Irom Ihe ammo acid pheny lal.inine. which involves enzy malic oxidation and decarboxylation reactions It is also to he noted ihui the isomeric form of norepinephrine is most important the natural D-lonn (which incidentally, is levorntatory) has many times die uciiviiy of die synthetic isomer. Epinephrine has a pronounced action upon the circulatory system, increasing both blood... 

One of the first functionalized substrates subjected to the asymmetric P-H addition promoted by metal complexes were phosphine-functionalized alkenols, viz., 3-diphenylphosphinobut-3-en-l-ol and 2-diphenylphosphinoprop-2-en-l-ol (Scheme 7) [54]. The target was the diphosphine ProPhos which had previously been prepared by tedious organic manipulations extending to 14 steps from a chiral pool consisting of malic and L-ascorbic acid [55, 56]. The hydrophosphination reaction employing (/ )- was carried out as shown in scheme 7 and showed excellent selectivity in the case of 3-diphenylphosphinobut-3-en-l-ol (four isomeric products in the ratio 2 18 1 4) and moderate selectivity in the case of 2-diphenyl-phosphino prop-2-en-l-ol (1 2 5 8). Isomer 12a was the major product in the case of 3-diphenylphosphinobut-3-en-l-ol (n = 1), and for 2-diphenylphosphinoprop-2-en-l-ol (n = 2), 11a and 11b co-crystallized out. The two analogous substrates gave products that differ in the chirality at the newly formed carbon center. 

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