R -Pantolactone

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.  

Diels-Alder Reactions. (i )-Pantolactone is one of the most effective chiral auxiliaries for preparative scale Diels-Alder additions of simple enoate esters in the presence of Lewis acids (eq 1).  

Endo-exo selectivity typically ranges from 20 1 to 45 1 with a maximum of 97.5 2.5 diastereoselection. Prepara-tively convenient reaction conditions are employed (CH2CI2, CH2Cl2/cyclohexane temp, approx. 0°C ca. 0.3 M concentration and 0.1-1.0 molar equiv of Lewis acid). Products are typically crystalline and brought to high optical purity by recrystallization. Epimerization-free hydrolysis is effected with LiOH in THF/water. This procedure has been successfully applied in a nine-step synthesis of cyclosarkomycin in 17% overall yield (eq 2), and to syntheses of the sandalwood fragrances.  

The cyclohexane unit of the C(30) stereocenter of the C(18)-C(35) segment of FK-506 was established in excellent yield and de employing the same concept (eq 3).  

A list of General Abbreviations appears on the front Endpapers 

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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). 

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). 

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... 

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. 

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... 

I 74 Rhodium (ll)-Stabilized Carbenoids Containing Both Donor and Acceptor Substituents Tab. 14.2 Asymmetric cyclopropanation using (R)-pantolactone as the chiral auxiliary. 

R)-(—)-Pantolactone (22), a key intermediate for the preparation of the vitamin pantothenic acid, has been obtained with high stereoselectivity (e.e. = 87 %) by the asymmetric hydrogenation of the corresponding ketopantotyllactone in the presence of a rhodium complex of BPPM (13) 54). 

Stereosectivity is a broad term. The stereoselectivity in cyclopropanation which has been discussed in the above subsection, in fact, can also be referred to as diastereoselectivity. In this section, for convenience, the description of diastereoselectivity will be reserved for selectivity in cyclopropanation of diazo compounds or alkenes that are bound to a chiral auxiliary. Chiral diazoesters or chiral Ar-(diazoacetyl)oxazolidinone have been applied in metal catalysed cyclopropanation. However, these chiral diazo precursors and styrene yield cyclopropane products whose diastereomeric excess are less than 15% (equation 129)183,184. The use of several a-hydroxy esters as chiral auxiliaries for asymmetric inter-molecular cyclopropanation with rhodium(II)-stabilized vinylcarbenoids have been reported by Davies and coworkers. With (R)-pantolactone as the chiral auxiliary, cyclopropanation of diazoester 144 with a range of alkenes provided c yield with diastereomeric excess at levels of 90% (equation 130)1... 

The Sorghum (S)-oxynitrilase exclusively catalyzes the addition of hydrocyanic acid to aromatic aldehydes with high enantioselectivity, but not to aliphatic aldehydes or ketones [519, 526], In contrast, the Hevea (S)-oxynitrilase was also found to convert aliphatic and a,/ -unsaturated substrates with medium to high selectivity [509, 527]. The stereocomplementary almond (R)-oxynitrilase likewise has a very broad substrate tolerance and accepts both aromatic, aliphatic, and a,/ -unsaturated aldehydes [520, 521, 523, 528, 529] as well as methyl ketones [530] with high enantiomeric excess (Table 9). It is interesting to note that this enzyme will also tolerate sterically hindered substrates such as pivalaldehyde and suitable derivatives 164 which are effective precursors for (R)-pantolactone 165 [531],... 

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). 

Asymmetric hydrogenation of > C—O. This bisphosphine is the most effective ligand for asymmetric hydrogenation of ketopantolactone (2) to provide R-(- )-pantolactone (3). ... 

The reaction of (R)-pantolactone with calcium 3-aminopropionate (synthesized from acrylonitrile, see Fig. 8.20) affords calcium pantothenate [111]. 

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... 

Related Reagents. a,(3-Butenolide 7-Butyrolactone R)-Pantolactone p-Propiolactone 2-Trimethylsilyloxyfuran p-Vinyl-a,p-buten olide. 

Use as a Chiral Auxiliary. (5)-Ethyl lactate has been used as a chiral auxiliary in a variety of simple Diels-Alder reactions. As the fumaric acid diester, the de employing cyclopentadiene can almost be completely reversed by addition of Titanium(IV) Chloride (eq 8). In general, superior de values are achieved using (R)-Pantolactone in this context, and also for base-mediated addition to ketenes. ... 

Ketene Additions. Reaction of the ketene derived from ibuprofen (Ar=p-isobutylphenyl) with (R)-pantolactone in the presence of simple tertiary amine bases in apolar solvents yielded >99% de favoring the (R,R)-ester (eq 9). The reaction is first order in each component and possesses a pronounced deuterium isotope effect knlko 4). The ketene from naproxen (Ar=2-(6-methoxynaphthyl)) affords a de of 80% under similar conditions. 

Miscellaneous Applications. Only one attempt to use (R)-pantolactone as an enantioselective protonating agent for enolates has been reported. A series of structurally diverse chiral alcohols afforded modest ee s with (R)-pantolactone affording the largest ee noted for the series. The complexities of attempting a proto-nation of this sort in the presence of base and under exchanging conditions are discussed. Finally, the lactone has been used to resolve chiral acids by crystallization and chromatographic techniques applied to the (R)-pantolactone-derived esters. - ... 

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