R -Malic Acid

D-Malic acid (885), the unnatural form with the (R)-configuration, has found its way into the arsenal of the organic chemist as a way of complementing the chemistry of L-malic acid. 

It is not the purpose of this section to reiterate chemical transformations discussed previously in this chapter, since it is quite obvious that virtually all the chemistry associated with L-malic acid can be applied to D-malic acid in order to produce compounds with the opposite configuration. Here we focus instead on the use of D-malic acid in the synthesis of medicinal agents and natural products. 

Many of the basic manipulations of D-malic acid and the various derivatives that will be used as starting materials in this section have already been described in detail in terms of the corresponding L-malic acid derivatives. The reader should refer to relevant portions of the chapter for more detailed discussion of their preparation. 

Since D-malic acid is rarer than its L-counterpart, it is also less readily available and consequently significantly more expensive to purchase. Currently the cost of D-malic acid is approximately 30 times that of L-malic acid. When cost is a factor in planning an asymmetric synthesis it may be more advantageous for the chemist to prepare D-malic acid instead of buying it. Numerous methods exist for obtaining D-malic acid. 

The most obvious approach is the resolution of DL-malic acid. This is readily accomplished by forming salts of the racemic acid with (7 )-( -f )-l-phenylethylamine. After filtration of the (i )-( + )-amine salt of L-malic acid, the filtrate is neutralized and the resulting enriched D-malic acid is exposed to ( S)-( — )-phenylethylamine to precipitate the (S)-( — )-amine salt of D-malic acid. Freeing the acid from the amine affords essentially pure D-malic acid (885) in 13% yield [195]. Although the yield is rather low, this resolution can be performed on a large scale, and when one considers that the cost of DL-malic acid is about 60 times less than that of D-malic acid the process is acceptable. 

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Thus, enantiomerically pure (S)35- or (R)36-acetoxysuccinimide derivatives of type 1, easily prepared from (S)- or (R)-malic acid, are diastereoselectively reduced with sodium borohydride in methanol at lower temperature to yield 85 % of an 11 1 mixture of diastereomeric hy-droxylactams of type 2, from which the enantiomerically pure chiral /V-acyliminium ions 3 are generated. 

The cycloaddition of aldehydes and ketones with ketene under the influence of quinine or quinidine produce chiral 2-oxetanones [46,47]. Solvolytic cleavage of the oxetanone, derived from chloral, and further solvolysis of the trichloromethyl group leads to (5)- and (R)-malic acids with a 98% ee [46] (the chirality of the product depends on the configuration of the catalyst at C-8 and, unlike other alkaloid-induced reactions, it is apparently independent of the presence of the hydroxyl group). No attempts have been made to catalyse the reaction with chiral ammonium salts. 

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... 

Fig. 23. Effect of cation used for the adjustment of modifying pH on EDAs of MRNis (O) modified with (R.R)-TA, pH 5.0, 0 C ( ) modified with (R,R)-TA, pH 5.0, 100 C ( ) modified with (R)-malic acid, pH 5.0,0 C. Reaction conditions MAA (neat), 60 C, 90 kg/cm2.

A study of the photochemical reactivity of salts of the amino ketone (44) with enantiomerically pure carboxylates has been reported. The irradiations involved the crystalline materials using A, > 290 nm and the reactions are fairly selective which is proposed to be the result of hindered motion within the crystalline environment. Some of the many results, using (S)-(—)-malic acid, R-(+)-malic acid and (2R,3R)-(+)-tartaric acid, are shown in Scheme 1. The principal reaction in all of the examples is a Norrish Type II hydrogen abstraction and the formation of a 1,4-biradical. This leads mainly to the cis-cyclobutanol (45) by bond formation or the keto alkene (46) by fission within the biradical. A very minor path for the malate example is cyclization to the trn 5-cyclobutanol (47). A detailed examination of the photochemical behaviour of a series of large ring diketones (48) has been carried out. Irradiation in both the solid phase and solution were compared. Norrish Type II reactivity dominates and affords two cyclobutanols (49), (50) and a ring-opened product (51) via the conventional 1,4-biradical. Only the diketone (48a) is unreactive... 

The enantiomer of (+)-(R)-malic acid occurs in many fruits and is called "anple acid." Draw a three-dimensional structure of apple acid. What is its sign of rotation What is its absolute configuration ... 

The 2 4-2 cycloaddition of ketene to chloral in toluene at —50 °C in the presence of 4 mol% of cinchonine results in the formation of j -lactone 886 in high yield with 84% ee. Recrystallization from methylcyclohexane furnishes optically pure (R)-lactone. Mild acid hydrolysis of the lactone to the trichloromethyl hydroxy acid 887 followed by careful basic hydrolysis gives optically pure (R)-malic acid (885) in 79% overall yield [196]. 

Naturally occurring (R,R)-tartaric acid (888), currently about 150 times less expensive than (R)-malic acid, is an ideal precursor, because the correct absolute configuration at C-2 is... 

R)-Malic acid can be selectively protected as a dioxolanone (904). Treatment of 904 with excess methyl magnesium iodide affords lactone 905 as the result of a completely regiose-lective reaction of Grignard reagent with the dioxolanone carbonyl followed by lactonization (Scheme 133) [201]. Reduction of the lactone with lithium aluminum hydride gives triol 906, which is converted to iodoacetonide 907 (OH OTs I). This intermediate is used to supply the chiral side chain for the steroid 24,25-dihydroxycholecalciferol. 

The C-17 to C-22 subunit of ionomycin (937) is synthesized by regioselective fragmentation of an appropriately substituted tetrahydrofuran (935), which is readily accessible from (R)-malic acid (Scheme 137) [205]. Alkylation of the dianion of diethyl (7 )-malate (897) with methyl iodide provides anti-929 in 69% yield with 10 1 stereoselectivity. Reduction of the esters, acetal formation, oxidation of the primary alcohol of 930 to an aldehyde, and Wittig olefination furnishes a,j -unsaturated ester 931. 

Copyrigjtit O 20CG Witey-VCH Vetfe GmbH Co. KGaA ISBNs 3-527-29093-1 (Hmrdbadc) 3-527-60085-X (Electronic) 3 4 (R).Malic Acid... 

A strange method of preparation of optically active compounds without any chiral inductors was described using an electrochemical cell with electrodes of special asymmetric configuration made of barium titanate Reduction of fumaric acid resulted in (R)-(+)-malic acid with an ee of 17%, or... 

Poly(R-malic acid) was recently foimd in living systems and is thus a synthetic polymer that is also a true biopolymer. ... 

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