Pantolactone synthesis

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

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. 

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). 

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... 

Hansen and colleagues177 used (+)-pantolactone as a chiral auxiliary to achieve asymmetric induction in the first step toward their synthesis of d.v-perhydroisoq uinol inc 278. The titanium tetrachloride catalyzed reaction between 1,3-cyclohexadiene (275) and chiral acrylate 276 proceeded with high diastereofacial selectivity to give 277 (94% de) in 75% yield (equation 77). 

Silanes can react with acceptor-substituted carbene complexes to yield products resulting from Si-H bond insertion [695,1168-1171]. This reaction has not, however, been extensively used in organic synthesis. Transition metal-catalyzed decomposition of the 2-diazo-2-phenylacetic ester of pantolactone (3-hydroxy-4,4-dimethyltetrahydro-2-furanone) in the presence of dimethyl(phenyl)silane leads to the a-silylester with 80% de (67% yield [991]). Similarly, vinyldiazoacetic esters of pantolactone react with silanes in the presence of rhodium(II) acetate to yield a-silylesters with up to 70% de [956]. 

The reaction of vinylcarbenoids with vinyl ethers can lead to other types of [3 + 2] cycloadditions. The symmetric synthesis of 2,3-dihydrofurans is readily achieved by reaction of rhodium-stabilized vinylcarbenoids with vinyl ethers (Scheme 14.17) [107]. In this case, (J )-pantolactone is used as a chiral auxihary. The initial cyclopropanation proceeds with high asymmetric induction upon deprotection of the silyl enol ether 146, ring expansion occurs to furnish the dihydrofuran 147, with no significant epi-merization during the ring-expansion process. 

Substrates include benzyl (2 g) and cinnamyl (2.7 g) alcohols to acids cyclopentanol (1 g), benzhydrol (3.9 g), benzoin (4 g), pantolactone (2.6 g) to ketones (RuCy TCCA/( Bu N)Br/aq. Kj(C03)/CH3CN) (Fig. 2.14) [25] [[2-[2-hydroxypropyl) amino]-l,2-dioxoethyl]amino]acetic acid ethyl ester (6.21 kg) to [(l,2-dioxo-2-oxopropyl)amino]ethyl)amino] acetic acid ethyl ester, part of the industrial-scale synthesis of thrombin inhibitor (RuCyaq. Na(BrOj)/CH3CN) [166] (H-)-dihydroc-holesterol (8 g) to cholest-3-one (RuO /aq. K(10 )/(BTEAC)/CHCl3) [308] ... 

Pantothenic acid is produced commerdally by synthesis involving the condensation of d-pantolactone with salt of -alanine. Some of the dietary supplement forms include caldum pantothenate, dexpanthenol, and panthenol. 

Fig. 8. Possible routes for the synthesis of D-pantothenic acid through the enzymatic transformation. PL, pantolactone KPL, ketopantolactone KPA, ketopantoic acid d-PA, D-pantoic acid KPaOEt, ethyl 2 -ketopantothenate KPaCN, 2 -ketopantothenonitrile D-PaOEt, ethyl D-pan-tothenate D-PaCN, D-pantothenonitrile...

Effenberger F, Eichhom J et al (1995) Enzyme catalyzed addition of hydrocyanic acid to substituted pivalaldehydes - a novel synthesis of (/J)-pantolactone. Tetrahedron Asymmetry 6 271-282... 

Pantolactone, dihydro-3-hydroxy-4//-dimethyl-2(3//)-furanone (103) which is an important starting material of the synthesis of pantothenic acid, was also easily resolved by complexation with 10a. When a solution of 10a (5.5 g, 9.93 mmol) and rac-103 (2.6 g, 20 mmol) in 1 1 benzene-hexane (20 ml) was kept at room temperature for 1 h, a 1 1 complex of 10a and (.S)-(-)- 03 was obtained, after two recrystallizations from 1 1 benzene-hexane, as colorless needles (2.05 g), which upon heating in vacuo gave (S)-(-)-103 of 99% ee (0.39 g, 30%).40 In order to clarify the mechanism of the precise chiral recognition between 10a and (S)-(-)-103, their inclusion complex crystal was studied by X-ray analysis40 and by AFM technique.41... 

Replacing the benzyl carbamate in 65 with a chiral carbamate derived from (R)-pantolactone generates diaster-eomeric molybdenum 1,2-dihydropyridine complexes 76 and 77, which are easily separable by crystallization <20000L3909>. Once separated, these chiral complexes 76 and 77 are easily converted to the more reactive methyl carbamate molybdenum 1,2-dihydropyridine complexes 78 and 79, respectively, and allow the synthesis of enantio-pure 2,6-disubstituted tetrahydropyridines (Scheme 21). 

Chiral Pool Reagent. (7 )-Pantolactone has been used as a source of chiral fragments for synthesis. Applications include use in the syntheses of the elfamycins (eq 12) and the bryostatins (eq IS). It has also been used to prepare potentially useful chiral epoxide synthons possessing a quaternary gem-dimethyl carbon. ... 

Control of the stereochemistry of the Diels-Alder reaction by means of a chiral center in the substrate is a versatile means of synthesizing cychc systems stereoselec-tively [347]. For preparation of ring systems with multi-stereogenic centers, in particular, the diastereoselective Diels-Alder reaction is, apparently, one of the most dependable methods. The cyclization of optically active substrates has enabled asymmetric synthesis. Equation (147) shows a simple and very efficient asymmetric Diels-Alder reaction, starting from commercially available pantolactone [364,365], in which one chlorine atom sticking out in front efficiently blocks one side of the enone plane. A fumarate with two chiral auxiliaries afforded virtually complete stereocontrol in a titanium-promoted Diels-Alder reaction to give an optically active cyclohexane derivative (Eq. 148) [366,367]. A variety of diastereoselective Diels-Alder reactions mediated by a titanium salt are summarized in Table 13. 

A novel enantioselective synthesis of an antagonist of the NMDA receptor, c/s-perhydroisoquinoline LY235959, was achieved in 13% overall yield and 17 steps from (R)-pantolactone in the laboratory of M.M. Hansen. The phosphoric acid portion of the target was introduced by a high-yielding Arbuzov reaction. 

Asymmetric reduction of ketopantoyl lactone is an effective biomimetic route to R-(- )-pantolactone, an intermediate in the synthesis of the important d-( + )-pantothenic acid (a component of vitamins B and of coenzyme A) ... 

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). 

Figure 19 17. Synthesis of D-pantolactone (Fuji Chemical Industries).

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). 

Figure 19-18. Comparison of chemical and biocatalytic route for the enantioselective synthesis of pantolactone.

Chiral ( >2-cyanocinnamates 16 bearing ethyl (.S i-lactate and (7 )-pantolactone as the chiral auxiliary are very efficient dienophiles in the asymmetric Dicls-Alder reaction with cyclopentadiene, opening up a route to the synthesis of cycloaliphatic atnino acids96. 

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