Pantolactone enantioselective hydrolysis

The enantioselective hydrolysis of pantolactone into (R)-pantoic acid and (S)-pantolactone (Fig. 8.21), in the presence of (R)-pantolactone hydrolase from Fu-sarium oxysporum [110b], offers a better alternative. An alginate-entrapped... 

Pantenoic acid is used as a vitamine B2 complex, d- and L-pantolactone are used as chiral intermediates in chemical synthesis. The enantioselective hydrolysis is carried out in the aqueous phase with a substrate concentration of 2.69 M = 350 g L 1 (Fig. 19-17). For the synthesis whole cells are immobilized in calcium alginate beads and used in a fixed bed reactor. The immobilized cells retain more than 90 % of their initial activity after 180 days of continuous use. At the end of the reaction l-pantolactone is extracted and reracemized to d,L-pantolactone, which is recycled to the reactor. The D-pantenoic acid is chemically lactonized to D-pantolactone and extracted. By applying cells from Brevibacterium protophormia the L-lactone is available. The biotransformation eliminates several steps that are necessary in the chemical resolution process (Fig. 19-18). 

Enantioselective addition of hydrogen cyanide to hydroxypivaldehyde (25), catalyzed by (lf)-oxynittilase, afforded (R)-cyanohydrin (26) in good optical yield. Acid-catalyzed hydrolysis followed by cyclization resulted in (R)-pantolactone in 98% ee and 95% yield after one recrystallization (56). 

The highly ordered cyclic TS of the D-A reaction permits design of diastereo-or enantioselective reactions. (See Section 2.4 of Part A to review the principles of diastereoselectivity and enantioselectivity.) One way to achieve this is to install a chiral auxiliary.80 The cycloaddition proceeds to give two diastereomeric products that can be separated and purified. Because of the lower temperature required and the greater stereoselectivity observed in Lewis acid-catalyzed reactions, the best diastereoselectivity is observed in catalyzed reactions. Several chiral auxiliaries that are capable of high levels of diastereoselectivity have been developed. Chiral esters and amides of acrylic acid are particularly useful because the auxiliary can be recovered by hydrolysis of the purified adduct to give the enantiomerically pure carboxylic acid. Early examples involved acryloyl esters of chiral alcohols, including lactates and mandelates. Esters of the lactone of 2,4-dihydroxy-3,3-dimethylbutanoic acid (pantolactone) have also proven useful. 

Availability. Although commercially available via the degradation of pantothenic acid, (i )-pantolactone is also conveniently prepared by enantioselective reduction of its corresponding keto lactone employing homogeneous catalysis," " or by microbial methods. The (5)-enantiomer has been prepared by inversion of the natural product in 90% yield and 97% ee via triflate activation, acetate displacement, and Lithium Hydroxide hydrolysis. The enantiomers were also prepared by resolution of the race-mate with (R)- and (5)-phenethylamine. A gas chromatographic method exists for ee determination. ... 

While the reactions ofketenes with enantiopure alcohols usually give modest selectivities [769], the use of (ethyl lactate (isopropyl lactate (/ )-2.1 (R = Me, R = i-Pr) or (R)-pantolactone 1.16 as proton donors has allowed the highly enantioselective formation of 2-arylpropionic esters. A mild hydrolysis (AcOH/HCl or LiOH) leads to the corresponding adds, which are anti-inflammatory drugs [554,923] (Figure 4.8). This method has been extended by Durst and Koh [861, 999] to the synthesis of enantioenriched a-halogenated esters, which are precursors of aminoacids (Figure 4.8). 

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