Malic acids, enantiomers

Optically inactive starting materials can give optically active products only if they are treated with an optically active reagent or if the reaction is catalyzed by an optically active substance The best examples are found m biochemical processes Most bio chemical reactions are catalyzed by enzymes Enzymes are chiral and enantiomerically homogeneous they provide an asymmetric environment m which chemical reaction can take place Ordinarily enzyme catalyzed reactions occur with such a high level of stereo selectivity that one enantiomer of a substance is formed exclusively even when the sub strate is achiral The enzyme fumarase for example catalyzes hydration of the double bond of fumaric acid to malic acid m apples and other fruits Only the S enantiomer of malic acid is formed m this reaction... 

The reaction is reversible and its stereochemical requirements are so pronounced that neither the cis isomer of fumaric acid (maleic acid) nor the R enantiomer of malic acid can serve as a substrate for the fumarase catalyzed hydration-dehydration equilibrium... 

Chemical Properties. Because of its chiral center, malic acid is optically active. In 1896, when tartaric acid was first reduced to malic acid, the levorotatory enantiomer, S(—), was confirmed as having the spatial configuration (1) (5,6). The other enantiomer (2) has the R configuration. A detailed discussion of configuration assignment by the sequence rule or the R and S system is available (7). 

The optical activity of malic acid changes with dilution (8). The naturally occurring, levorotatory acid shows a most peculiar behavior in this respect a 34% solution at 20°C is optically inactive. Dilution results in increasing levo rotation, whereas more concentrated solutions show dextro rotation. The effects of dilution are explained by the postulation that an additional form, the epoxide (3), occurs in solution and that the direction of rotation of the normal (open-chain) and epoxide forms is reversed (8). Synthetic (racemic) R,.9-ma1ic acid can be resolved into the two enantiomers by crystallisation of its cinchonine salts. 

Whenever possible, the chemical reactions involved in the fonnation of diastereomers and their- conversion to separate enantiomers are simple acid-base reactions. For example, naturally occurring (5)-(—)-malic acid is often used to resolve fflnines. One such amine that has been resolved in this way is 1-phenylethylarnine. Amines are bases, and malic acid is an acid. Proton transfer from (5)-(—)-malic acid to a racemic mixture of (/ )- and (5)-1-phenylethylarnine gives a mixture of diastereorneric salts. 

Once again, one reaction and only one must be an inversion, but which7" It may also be noticed [illustrated by the use of thionyl chloride on (+)-malic acid and treatment of the product with KOH] that it is possible to convert an optically active compound into its enantiomer." ... 

Hiemstra and co-workers reported the first example of an iodine-promoted allenyl N-acyliminium ion cyclization for the total synthesis of (+)-gelsedine, the enantiomer of the naturally occurring (-)-gelsedine [72], Compound 341 was prepared from (S)-malic acid. When 341 was dissolved in formic acid with a large excess of Nal and heated at 85 °C for 18 h, 343 was found to be the major product isolated in 42% yield. The latter was then successfully converted to (+)-gelsedine in a multi-step manner. Other routes without the allene moiety failed to provide the desired stereoisomer. The successful one-step transformation of 341 to 343 was key to the success of this synthesis. 

The two molecules are enantiomers. If two of four groups attached to the C are identical as in CH3CH2CO2H, the 2 H s are enantiotopic and are attached to a prochiral center. Replacement of one of the H s by OH obviously leads to enantiomers. If there is already one chiral center in the molecule, as in (R)-malic acid... 

The synthesis of 9-(l,4-dihydroxybut-2-oxy)purines commenced with 2-butene-l,4-diol (1004) and via 1005 to 1006, which upon reaction with 1007 gave 1011 and then, upon hydrolysis, the racemic alkoxyamine 1012. The chiral derivatives commenced with the enantiomers of malic acid (1009) through 1010 to 1008, as shown in the scheme. Treatment of 1012 with 996 and further transformations followed almost the same sequence as before to give 1013. 

The direction of enantio-differentiation (the predominant enantiomer R or S, to be produced) is decided by two factors. One factor is the configuration of the chiral structure, that is, if the catalyst modified with (S)-glutamic acid [(S)-Glu-MRNi] produces (R)-MHB from MAA, then (R)-Glu-MRNi produces (S)-MHB (2). The other factor is the nature of X. That is, when the amino acid or hydroxy acid with the same configuration is used as the modifying reagent, the configurations of the predominant products are enantiomers of each other in most cases. For example, (S)-aspartic acid-MRNi produces (R)-MHB and (S)-malic acid-MRNi produces (S)-MHB (19). 

Another example is provided by malic acid, a chiral molecule which also contains a prochiral center (see Eq. 9-74). In this case replacement of the pro-R or pro-S hydrogen atom by another atom or group would yield a pair of diastereoisomers rather than enantiomers. Therefore, these hydrogen atoms are diastereotopic. When L-malic acid is dehydrated by fumarate hydratase (Chapter 13) the hydrogen in the pro-R position is removed but that in the pro-S position is not touched. This can be demonstrated by allowing the dehydration product, fumarate, to be hydrated to malate in 2HzO (Eq. 9-74). The malate formed contains deuterium in the pro-R position. If this malate is now isolated and placed with another portion of enzyme in H20, the deuterium is removed cleanly. The fumarate produced contains no deuterium. 

The more soluble salt must have the opposite configuration at the stereogenic center of 1-phenylethylamine, that is, the S configuration. The malic acid used in the resolution is a single enantiomer, S. In this particular case the more soluble salt is therefore (S)-l-phenylethylammonium (5)-malate. 

Dicarboxyaziridine (4.c) is a potent competitive inhibitor (Ki = 80 nM) of fumarase, an enzyme that catalyzes the hydration of fumaric acid (4.a) to (S)-malic acid (4.b). Rationalize how 4.c might act as a competitive inhibitor of fumarase. Would you expect the enantiomer of the inhibitor to have a higher or lower K- value Explain. [Greenhut, J., Umezawa, H. Rudolph, F. B. Inhibition of Fumarase by 5-2,3-Dicarboxyaziridine../. Biol. Chem. 1985, 260, 6684-6686.]... 

Examples of alkylation of malic esters are listed in Table I, together with those of double alkylation, which can also be achieved, see 2 4 in Scheme 1. Since the (S) and the (R) forms of malic acid are both readily available,18 the enantiomers of all structures shown in Table I can be... 

Note that, although the product is racemic (2R,3R + 2S,3S)-malic acid, in each enantiomer, the protons at C-2 and C-3 are both in the threo relationship. Since the deuteron and OH group are also threo, the material may be described as ( )-threo-[3 -2H]-malic acid. 

Enantiopure p-lactones have been obtained from the reaction of acid chlorides or ketene with aldehydes in the presence of optically active tertiary amines. The reaction of ketene with chloral has been studied in considerable detail (Scheme 2). In the presence of 2 mol % of quinidine at -SO C die p-lac-tone is formed in virtually quantitative chemical and optical yield By proper choice of the catalyst, either enantiomer of the -lactone can be obtained. The transition state picture (4) has been propos for the ketene-chloral addition in the presence of quinidine. Hydrolysis converts the -lactone to malic acid with inversion of configuration (Scheme 2). ... 

If the products of a reaction are capable of existing in more than one stereoisomeric form, the form that is obtained may give information about the mechanism. For example, (+)-malic acid was discovered by Walden to give (—)-chlorosuccinic acid when treated with PCI5 and the (+) enantiomer when treated with SOCI2,... 

Heating the mixture of isomers of 109 with TsOH equilibrates the diastereoisomers so that the required more stable syn (H and Et syn) diastereoisomer of 109 crystallises out. Treating this with (+) malic acid leads to crystals of the natural enantiomer (+)-sy -109. Both the unwanted anti-diastereoisomer and the unwanted enantiomer can be equilibrated again with TsOH. This cannot be enolisation as there are no a-hydrogens and is presumably equilibration by reversible Mannich reaction as 110 lacks either stereogenic centre and so epimerises both ... 

A few hydroxy acids are very cheap. (S)-(+)-Lactic acid 33 occurs in milk, (f )-(-)-malic acid in apples, and both enantiomers of the very important tartaric acid 35 and 36 are reasonably cheap. (+)-Tartaric acid 35 is usually called natural as it occurs in grapes, but (-) -tartaric acid 36 is natural too as it occurs in the West African tree Bankinia reticulata. The other enantiomers of malic and mandelic acids are commercially available and are not that much more expensive. 

The Wittig reaction between the ylid formed from 182 with BuLi and the protected aldehyde 179 does indeed give the Z-alkene 183, a protected version of 175, ready for cyclisation and completion of the synthesis of laurencin. Notice how far apart (1,6-related) are the chiral centres in 183. Making both independently from malic acid ensures that the right diastereoisomer, as well as the right enantiomer, results. 

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