P-Hydroxyisobutyric acid

Enantioenriched P-hydroxyisobutyric acid 57 was synthesized using EDP catalyzed by cinchona alkaloids [36], Under the best conditions, with a stoichiometric amount of dnchonidine 26, P-hydroxyisobutyric ester 57 was obtained in low ee and moderate yield (Scheme 7.28). No enantioselectivity was observed when using 10 mol% of base. 

Leon R, Prazeres DMF, Fernandes P, Molinari F, Cabral JMS. A multiphasic hollow fiber reactor for the whole-ceU bioconversion of 2-methyl-1,3-propanediol to (R)-P-hydroxyisobutyric acid. Biotechnol Prog 2001 17 468-473. 

In an attempt to develop a straightforward stereoselective access to P-hydroxyisobutyric acid derivatives, both acadanically and industrially important chiral synthons, Kim et al. [13] investigated the enantioselective decarboxylative... 

Microbial hydroxylation of a methyl group has the potential to be stereoselective in cases where the substrate possesses enantiotopic CH3 substituents. A classic example of such a process is the conversion of isobutyric acid to P-hydroxyisobutyric acid (Fig. 4), where the use of Candida rugosa IFO 0750 leads to formation of the D-(—) (R) isomer [9], and the L-(+) (S) product is obtained from oxidation using Bullera alba IFO 1030 [10]. Similar stereoselectivity is also observed in the oxidation of homologous acids and hydrocarbons by Rhodococcus species [11], and in the oxidation of cumene (1) to (jR)-2-phenylpropionic acid (2) by Pseudomonas oleovorans NRRL B-3429 (Fig. 5) [12]. 

In this section, we review the chemical and biochemical preparation methods that have been reported for optically active 3-hydroxycarboxylic acids, especially P-hydroxybut5nic acid (HBA), p-hydroxyisobutyric acid (HIBA), and 3-hydroxyvaleric acid (HYA), wWch are most versatile for organic syntheses. 

The groups of Masamune [4] and Evans [5] reported the synthesis of optically active p-hydroxycarboxylic acids by means of stereoselective chiral aldol condensation via boron enolates. (S)- and (i )-p-Hydroxyisobutyric acid of high optical purity (98% e.e.) were obtained by means of Masamune s method. However, these methods do not seem favorable for industrial production of p-hydroxycarboxylic acids because these reactions need equal amounts of the chiral starting material for the synthesis of optically active p-hydroxycar-boxylic acids (Scheme 2). 

Methylmalonic acid semialdehyde ethyl ester was reduced by baker s yeast and T. brockii to give (/ )-P-hydroxyisobutyric acid ethyl ester, but the optical purity was not very good (60% e.e. and 72% e.e., respectively [15] (Scheme 5). 

This transformation has been used widely to prepare optically active p-hydroxycarboxylic acids. This process takes place in two stages in initial dehydrogenation to the a,p-unsat-urated carboxylic acid and subsequent hydration. These steps utilize the enzymes of the P-oxidation pathway of lipid cataboUsm, and so the P-hydroxy acids produced are generally of the natural S) form. Both saturated carboxylic acids and their a,P unsaturated counterparts have been used as raw materials. For example, P-hydroxypropionic acid (HPA) has been prepared from acrylic acid through a process mediated by Fusarium [17], and Pseduomonas putida has been used to prepare (5)-P-hydroxyisobutyric acid from isobutyric acid [18]. The preparation of C -C (5)-P-hydroxycarboxylic acids from the corresponding tran -a,p-unsaturated carboxylic acids by microbial hydration catalyzed by resting cells of Mucor sp. has also been reported [19] (Scheme 7). 

At the beginning of this study, we planned the establishment of a new economical synthesis process for captopril, as described later. We speculated that ( )-P-hydroxyisobutyric acid was favorable as a starting material for our planned new process. Previous studies on the stereochemistry of the production of P-hydroxyisobutyric acid from isobutyric acid by R putida demonstrated the production of the (5) form. Thus, the authors began this study with a search for microorganisms that could metabolize isobutyric acid to (/ )-P-hydrox-yisobutyric acid. 

The use of C. rugosa to produce (/ )-p-hydroxyisobutyric acid from isobutyric acid, although novel, was not yet efficient enough to be adopted on an industrial scale. The conversion never exceeded 50% and the byproduct, p-hydroxypropionic acid, was present at a concentration of about 10% of that of (/ )-p-hydroxyisobutyric acid. It is probable that P-hydroxypropionic acid is produced from (i )-p-hydroxyisobutyric acid via propionic acid by this microorganism, through the valine catabolic pathway. It seemed reasonable. 

Table 2 (/ )-p-Hydroxyisobutyric Acid Production by Mutants Unable to Assimilate Propionic Acid ... 

This methodology could be applied for the production of the (S) forms of p-hydroxycar-boxylic acids, and (5)-P-hydroxyisobutyric acid and (5)-3-hydroxybut5nric acid could be produced in high yields using mutants of Trichosporon aculeatum and Endomyces tetra-sperma, respectively. 

Chiral Building Blocks Derived from (S)- and (R)-p-Hydroxyisobutyric Acids... 

Sometimes the hydroxy and carboxy groups of p-hydroxyisobutyric acid are simultaneously protected by the same protective group and the resultant protected p-hydrox-yisobutyrate esters are similarly reduced to monoprotected diols. 

In Scheme 10 are shown the above-mentioned typical transformations of p-hydrox-yisobutyric acid, and in Fig. 4 are listed useful chiral building blocks derived from (S)-and (/ )-P-hydroxyisobutyric acids. 

Figure 4 Chiral building blocks derived from (5)- and (i ).p-hydroxyisobutyric acids.

Syntheses Starting from (S)-p-Hydroxyisobutyric Acid and Its Derivatives... 

S)-P-Hydroxyisobutyric acid and its esters serve as bifunctional building blocks for the S3mthesis of a wide variety of chiral compounds of biological origin. 

The intermediates for 1 -methylcarbapenems have also been synthesized using methyl (5)-P-hydroxyisobutyrate as a starting material (Fig. 8) [82-84]. In these syntheses, the ip-methyl moieties of the target molecules come from the corresponding parts of the (S)-P-hydroxyisobutyric acid derivatives. 

Compared with (5)-p-hydroxyisobutyric acid, the corresponding (R) enantiomer has been less used for the synthesis of chiral biologically active compounds. Thus, we can find several examples of the use of (i )-P-hydroxyisobutyric acid for the synthesis of angiotensin-converting enzyme (ACE) inhibitors [140-106], pheromones [107-109], and an immunosuppressive agent [110]. 

Among the ACE inhibitors, captopril (Fig. 9) is the most famous and Kaneka has developed an effective synthetic process for captopril involving (/ )-P-hydroxyisobutyric acid [104]. In this synthesis, (5)-3-acetylthio-2-methylpropanoic acid, a key intermediate for captopril, is prepared from (/ )-P-hydroxyisobutyric acid on a plant scale. 

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