Pantolactone, addition

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). 

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 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],... 

The enzyme catalyzing the reduction of ketopantolactone to D-pantolactone was isolated in a crystalline form from the cells of Candida parapsilosis and characterized in some detail [106] (see Tables 4 and 5). It is a novel NADPH-dependent carbonyl reductase with a molecular mass of about 40,000. In addition to the reduction of ketopantolactone, the enzyme catalyzes those of a variety of cyclic diketones, including derivatives of ketopantolactone, isatin, camphorquinone and so on, to give the corresponding (R)-alcohols [106, 107], The enzyme was termed conjugated polyketone reductase , since the enzyme catalyzes only the reduction of conjugated polyketones as follows. 

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... 

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. ... 

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). ... 

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. 

Prompted by the X-ray studies of the acryloyl lactate-TiCU complex (380a), commercially available pantolactone was chosen as an auxiliary aiming to facilitate entropically the formation of a seven-mem-bered titanium chelate (385). Indeed, using 0.1-0.75 mol equiv. of TiCU the acrylate and crotonate of (/ )-pantolactone (384) underwent smooth addition of cyclopentadiene, butadiene and isoprene to give adducts (386) and (387) in ratios of >93 <7 (Scheme 94, Table 24, entries a-d). Opposite product ratios were obtained using dienophiles (388) derived from (S)-pantolactone (entiy e) or (390) derived from the more readily available A -methyl-2-hydroxysuccinimide (entries f, g). The major products were purified by crystallization and saponified without epimerization (LiOH, THF/water, r.t.) to furnish the corresponding carboxylic acids. 

The simple homochiral adduct from Diels-Alder cycloaddition of (/ )-pantolactone acrylate ester with cyclopentaidiene was hydrolyzed and converted to the methyl ketone in 89% yield through addition of 3... 

Additives (cosolvents) which serve as ligands have great influence on the reducing power of Smlj. Allylic and propargylic derivatives are reduced via it-allylpalladium species, and the proton source has important effects on the generation of allenes or alkynes. Chiral allenic esters are obtained when pantolactone delivers a proton to racemic organosamarium species derived from 4-phosphato-2-alkynoic esters. ... 

Diels-Alder reactions with Oppolzer s chiral sultam Diels-Alder reactions with pantolactone as chiral auxiliary Chiral auxiliaries attached to the diene Improved Oxazolidinones SuperQuats Asymmetric Michael (Conjugate) Additions... 

About 6,0001 of the animal feed additive calcium-D-pantothenate are produced annually via D-pantolactone (d-112) (Scheme 35, left side).D-Pantolactone itself is an important chiral intermediate for chemical synthesis and a chiral resolution agent for optically pure amines. Optically pure d-112 is for instance produced by Fuji Chemical Industries by using the D-specific 1,4-lactone hydroxy-acylhydrolase from Fusarium oxysporum [100-102], an enzyme that catalyzes the stereospecific hydrolysis of various kinds of lactones. Treatment of mc-112 leads to an exclusive hydrolysis of d-112 the hydroxy acid d-113 can be easily separated from the remaining lactone l-1 12 and is subsequently chemically con-... 

Contrary to the Fuji process, BASF described the characterization and cloning of an L-specific pantolactone hydrolase from Agrobacterium tumefa-ciens [103,104]. This enzyme exclusively opens up the undesired lactone l-1 12, providing a more direct route to d-1 12 (Scheme 35, right side). In addition, this new process is expected to be much more robust toward the competing spontaneous chemical hydrolysis, which could theoretically cause a diminished optical yield in the Fuji process. The enzymatic resolution of d/l-112 in repeated batches with membrane filtration techniques provided d-1 12 in 50% yield and with 90-95% ee. By immobilization onto Eupergit C it was possible to obtain a stable biocatalyst which was easy to use in repeated batch reactions. 

Formation of cyclic acetals was also observed in the MBH reaction of aliphatic aldehydes with pantolactone acrylate 28. The more stable cis isomers 29 are formed predominantly, and mixed products 30 can be isolated by sequential addition of two different aldehydes (Scheme 1.14). However, benzaldehyde failed to give the cyclic adduct on reaction with the pantolactone ester under the same conditions electronic effects rather than steric hindrance... 

The conversion of (R)-pantolactone (78) into the corresponding free sugar derivative (79) which has been used as starting material for the addition of 2-lithio-l,3-dithiane to afrord pentose products (80) and (81) has been described. ... 

---