Citramalic acid

Both enantiomers of citramalic acid are commercially available, each selling for approximately 10.00 per gram. Many synthetic methods exist for the preparation of chiral citramalates, but few produce products of acceptable enantiomeric purity. 

Oxidation of the phenyl group to an acid with ruthenium tetroxide followed by esterification with diazomethane furnishes the ( S)-citramalate 1028 with 97.2% ee, 

25-Hydroxyvitamin D3 26,23-lactone (calcidiol lactone, 1045), another metabolite of vitamin D3, has also been synthesized by a coupling methodology applied to steroidal ade- 

The optically active chroman unit (1050) of a-tocopherol (vitamin E) (1051) is constructed by an initial coupling reaction between aldehyde 1032 and the hydroquinone Grignard reagent 

Within the last 10 years, various methods have been employed to synthesize (7 )-citramalate derivatives with acceptable enantiomeric purity. One of the first methods that produced reasonably enriched product was based on a tin(II) enolate chiral auxiliary-induced asymmetric aldol-type reaction. 

---

S. Except for oxido-reductases, transferases, and hydrolases, most ligases (enzymes that catalyze bond formation) are entirely substrate specific. Thus, fumarate hydratase (or fumarase) reversibly and stereospecifically adds water to fumaric acid to produce (S)-( — )-malic acid only (8) (Figure 1), and another enzyme, mesaconase, adds water to mesaconic acid to form (+ )-citramalic acid (9) (Figure 2). Although no extensive studies are available, it appears that neither fumarase nor mesaconase will add water stereospecifically to any other a,(3-unsaturated acid. 

Barker, H. A. Blair, A. H. Biochem. Prep. 1962, 9, 21. See also Hulme, A. C. Biochim. Biophys. Acta 1954, 14, 36, for a suggestion that (- )-citramalic acid occurs in nature. 

Among the compounds commonly determined in research laboratories are diacetyl, 2,3-butandiol, glycerol, citramalic acid, amino acids (especially proline), histamine, ammonia, succinic acid, phosphate, ash, alkalinity of the ash, ethyl, acetate, methyl anthranilate, total volatile esters, higher alcohols (both total and individually) phenolic compounds, etc. An elegant method for determining ethyl esters, capronate, caprylate, caprinate, and laurate using carbon disulfide extraction and GLC has been published (123). 

Bromal (25.0 g 89.1 mmol) and (S)-citramalic acid (11.0 g 74.2 mmol) were cooled to 0°C under inert atmosphere. Sulfuric acid/acetic acid (1/1 25 ml) was added dropwise with stirring. After 2 h the contents were a yellow solution with a white precipitate. The ice bath was removed and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with ice and extracted 4 times with ethyl acetate. The organic layer was back extracted with water and then was dried with MgS04. After filtration, the filtrate was concentrated to an oil. The product was obtained as a white solid after crystallization from toluene/hexanes. Yield 23.2 g (77%) mp 151°C (sublime). 

The cycloaddition of ketene with chloral in the presence of catalytic quantities of quinidine or quinine leads to the oxetanones in high optical and chemical yield (Scheme 26.22). This reaction is practiced on an industrial scale with the chiral building blocks malic and citramalic acids being formed by hydrolysis.492... 

Citramalic acid (= 2- Malus domestica (apple peel) (Rosaceae) Sour (acid) taste... 

Reaction with trichloroacetone is similarly high-yielding and enantioselective giving the p-lactone 172 and after hydrolysis with inversion, (.S )-citramalic acid 173. Again, quinine gives the other enantiomer. 

Citramalic Acid. 2-Hydroxy-2-methylbutanedioic acid 2-methylmalic acid 2-hydroxy-2-methylsuccinic acid a-hydroxypyrotartaric acid trnns-methylbutanedioic add. CjHjO., mol wt 148.11. C 40.54%. H 5.44%. O 54.01%. Enzymatic synthesis Barker. Blair, Biochem. Prepns, 9, 21 (1962). Chemical synthesis Barker, ibid. 25 J. B. Wilkes, R. G. Wall. J. Org. Chem. 45, 247 (1980). Stereoselective synthesis E. G. J. Staring el al. ReC. Trav. Chim. 105, 374 (1986). 

Isobutylmalic acid (18) and (— )-2-benzylmalic acid (19), the constituent acids of cornucervine and phalaenopsine La, respectively, have now been shown to have the / -configuration. This was established by a partial asymmetric synthesis of the enantiomers of these acids and comparison of the c.d. spectra of their molybdate complexes with that of the molybdate complex of (-f )-citramalic acid (20) of known S-configuration. 

In the enolate-forming step, the chiral center inherent to the malic acid is destroyed (205), but in the alkylation step the bulky cr butyl group directs the approach of the incoming electrophile to the opposite face of the enolate, thereby furnishing alkylated derivatives 206 with the same hydroxyl configuration as in the starting malic acid. This process is called selfreproduction of chirality . Acidic hydrolysis of 206 (R=CH3) furnishes (5)-(-h )-citramalic acid (207). For further uses of citramalic acid see Section 3.5. 

S)-Citramalic acid (also shown below as 1029), the a-methyl analog of ( S)-malic acid, has been isolated from a variety of natural sources. It can be produced microbially by incubation of mesaconic acid with an extract from Clostridium tetanomorphum cells [220]. 

S)-Citramalic acid (1029) is readily reduced to triol 1030 with either diborane [222] or borane methylsulfide-trimethylborate [223]. Conversion of 1030 to acetonide 1031 can be accomplished either with acetone in the presence of a catalytic quantity of perchloric acid (73% yield from 1029) [222] or with acetone [224] or 2,2-dimethoxypropane [223] in the presence of copper sulfate (48% yield from 1029). Oxidation of the alcohol with pyridinium chlorochromate furnishes aldehyde 1032 in 72% yield [223]. 

The gastric antisecretory properties of 15-deoxy-l 6-methyl-16-a,iS-hydroxyprostaglandin El methyl ester are associated exclusively with the 16(S) diastereomer 1054. Diol 1053, a key chiral synthon for the synthesis of 1054, is readily prepared from 1031 by conversion of the primary alcohol to a tosylate, displacement of the tosylate by mixed cuprate to give 1052, and then hydrolysis of the acetonide (Scheme 156) [222]. The overall yield of the sequence starting from (5)-citramalic acid is 50.4%. 

---