Pantolactone

Currentiy (ca 1997) pantothenic acid is produced mainly by chemical methods. Initial efforts ia this area are summari2ed ia Reference 14. Several groups are actively involved ia developing syntheses of pantothenic acid or its precursor, (R)-pantolactone (9) by microbial methods. 

R)-Calcium pantothenate (3) is prepared by condensing (R)-pantolactone (9) with P-alanine (10) in the presence of base, followed by treatment of the sodium salt (11) with calcium hydroxide. 

An alternative procedure for the preparation of (R)-calcium pantothenate (3) is to condense (R)-pantolactone (9) with the preformed calcium salt (12) of p-alaniue (15). 

Similaily, panthenol (4) and pantyl ethei (5) aie prepared by condensing 3-aminopropanol (13) and 3-ethoxypropylamine (14) with (R)-pantolactone (16,17). 

Racemic pantolactone is prepared easily by reacting isobutyraldehyde (15) with formaldehyde ia the presence of a base to yield the iatermediate hydroxyaldehyde (16). Hydrogen cyanide addition affords the hydroxy cyanohydria (17). Acid-cataly2ed hydrolysis and cyclization of the cyanohydria (17) gives (R,3)-pantolactone (18) ia 90% yield (18). 

R)-Pantolactone (9) is prepared ia either of two ways by resolution of the (R,5)-pantolactone mixture (18), or by stereoselective reduction of ketopantolactone (19) by chemical or microbial methods (19). 

Ketopantolactone (19) is conveniently prepared by oxidation of (R,5)-pantolactone (18). Various oxidising agents have been patented for the oxidation of pantolactone, such as MnO ( 1)> DMSO—AC2O (32), and hypohahtes (33). An improved yield of ketopantolactone (19) via electrolytic oxidation of pantolactone with an aqueous solution containing an alkaH metal salt was reported (34). Ketopantolactone (19) has been prepared in good yield via cyclocondensation of the 2-keto-3-methylbutyrate (20) with formaldehyde (35). 

Asymmetric hydrogenation of ketopantolactone (19) in the presence of chiral dirhodium complexes gave (R)-pantolactone (9) in high yield and excellent selectivity (36) (Table 2). 

In a novel approach, enantiomerically enriched (R)-pantolactone (9) is obtained in a enzymatic two-step process starting from racemic pantolactone. 

In a first step, JS ocardia asteroides selectively oxidizes only (3)-pantolactone to ketopantolactone (19), whereas the (R)-pantolactone remains unaffected (47). The accumulated ketopantolactone is stereospecificaHy reduced to (R)-pantolactone in a second step with Candidaparapsilosis (product concentration 72 g/L, 90% molar yield and 100% ee) (48). Racemic pantolactone can also be converted to (R)-pantolactone by one single microbe, ie, Jiodococcus erythropolis by enantioselective oxidation to (3)-pantolactone and subsequent stereospecific reduction in 90% yield and 94% ee (product concentration 18 g/L) (40). 

Although not of industrial importance, several asymmetric syntheses of (R)-pantolactone (9) have been developed. Stereoselective abstraction of the j Z-proton of the achiral 1,3-propanediol derivative (23) by j -butyUthium-(-)-sparteine, followed by carboxylation and hydrolysis, results in (R)-pantolactone in 80% yield and 95% ee (53). 

R)-Pantolactone is also prepared in a sequence involving Claisen rearrangement of the chiral glycolate (24), although with poor enantioselectivity... 

By employing Sharpless epoxidation as a key step, a multistep chemical synthesis of (E)-pantolactone has also been reported (55). 

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). 

Despite the progress made in the stereoselective synthesis of (R)-pantothenic acid since the mid-1980s, the commercial chemical synthesis still involves resolution of racemic pantolactone. Recent (ca 1997) synthetic efforts have been directed toward developing a method for enantioselective synthesis of (R)-pantolactone by either chemical or microbial reduction of ketopantolactone. Microbial reduction of ketopantolactone is a promising area for future research. 

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. 

The cyclic a-hydroxylactone, pantolactone, has been used extensively as a chiral auxiliary in D-A reactions.84 Reactions involving TiCl4 and SnCl4 occur through chelated TSs.85... 

Entry 6 uses a chiral auxiliary derived from pyroglutamic acid. Entry 7 is an example of the use of pantolactone as a chiral auxiliary to form a prostaglandin precursor. 

Figure 4.6 Classical kinetic resolution with subsequent reracemization of unconverted enantiomer Synthesis of pantoic acid from pantolactone applying a stirred-tank reactor, extraction module and racemization step...

D-Pantolactone and L-pantolactone are used as chiral intermediates in chemical synthesis, whereas pantoic acid is used as a vitamin B2 complex. All can be obtained from racemic mixtures by consecutive enzymatic hydrolysis and extraction. Subsequently, the desired hydrolysed enantiomer is lactonized, extracted and crystallized (Figure 4.6). The nondesired enantiomer is reracemized and recycled into the plug-flow reactor [33,34]. Herewith, a conversion of 90-95% is reached, meaning that the resolution of racemic mixtures is an alternative to a possible chiral synthesis. The applied y-lactonase from Fusarium oxysporum in the form of resting whole cells immobilized in calcium alginate beads retains more than 90% of its initial activity even after 180 days of continuous use. The biotransformation yielding D-pantolactone in a fixed-bed reactor skips several steps here that are necessary in the chemical resolution. Hence, the illustrated process carried out by Fuji Chemical Industries Co., Ltd is an elegant way for resolution of racemic mixtures. 

Among ketoesters, tremendous efforts have been devoted to the hydrogenation of dihydro-4,4-dimethyl-2,3-furandione (KPL), not only as a model reaction but also because the product R(-)-pantolactone is a key intermediate in the synthesis of vitamin B5 and coenzyme A (Scheme 33.1). 

By employing chiral proton sources for the protonation of the intermediate samarium species 184/185, highly enantioenriched allenes were accessible in some cases [98]. Thus, in the reaction of propargylic phosphate 198, (R,Rj- 1,2-diphenyl-1,2-ethandiol (200) and (R)-pantolactone (201) were found to give the highest selec-tivities, affording allene 199 with up to 95% ee (Scheme 2.61). 

The enantioselective synthesis of an allenic ester using chiral proton sources was performed by dynamic kinetic protonation of racemic allenylsamarium(III) species 237 and 238, which were derived from propargylic phosphate 236 by the metalation (Scheme 4.61) [97]. Protonation with (R,R)-(+)-hydrobcnzoin and R-(-)-pantolactone provided an allenic ester 239 with high enantiomeric purity. The selective protonation with (R,R)-(+)-hydrobenzoin giving R-(-)-allcnic ester 239 is in agreement with the... 

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