✍ Scribed by Franz Effenberger; Joachim Eichhorn; Jürgen Roos
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R)-Cyanohydrins (R)-2b-h are obtained in good optical yields by (R)-oxynitrilase catalyzed enantioselective addition of HCN to [~-substituted pivalaldehydes lb-h. Under optimized reaction conditions with highly purified (R)-oxynitrilase, hydroxypivalaldehyde (la) is converted to (R)-2a in satisfactory chemical and optical yields. By acid-catalyzed hydrolysis the cyanohydrins (R)-2a-h cyclize directly to give crude (R)-pantolactone (R)-3 with ee-values of 56-95% which, after recrystallization, go up to L'98 %ee in all cases.
(R)-Pantolactone (R)-3 is the most important starting compound for (R)-pantothenic acid, a constituent of coenzyme A. 3 (R)-3 serves also for the preparation of (R)-panthenol, 4 a bactericide, or (R)-pantotheine 5 which is a growth factor. In the synthesis of natural products, (R)-pantolactone has been widely used as a chiral auxiliary 6 and as a chiral building block. 7
In the last few years great efforts in the development of technical preparations of (R)-pantolactone have been made, since vitamins have great importance as food and feed additives. Numerous synthetic procedures for (R)-(-)-pantolactone have therefore been developed and described in the literature. Since racemic pantolactone is easily accessible in a "one pot reaction" from hydroxypivalaldehyde, sodium cyanide, hydrochloric acid and calcium chloride, 8 general racemate resolution techniques have been applied to obtain enantiome-ricaUy pure (R)-pantolactone. The resolution via diastereomeric salts or amides using quinine, 9 D(-)-galactamine,10 (+)_3_aminornethylpinane,11 and (1R)-3-endo-aminoborueo112 has been applied. 2,4-Dihydroxybutyric acid derived from pantolactone with sodium hydroxide is enantioselectively protonated in the presence of (1S)-(+)-10-carnphorsulfonic acid and the enantioselective hydrolysis of O-acyl hydrolysis of racemic pantolactone by a undergoes spontaneous cyclization to (R)-pantolactone. 13 Besides pantolactones to (R)-pantolactone using lipases or esterases, 14 the specific fungal hydrolase 15 has been reported. Chromatographic resolutions of racemic pantolactone were performed either directly on chiral phases 16 or after formation of diastereomers using optically active acid chlorides or isocyanates. 17 The enantioselectivc hydrogenation of ketopantoyl lactone is a further general route to (R)-(-)-pantolactonc. The catalytic hydrogenation with rhodium or ruthenium complexes containing chiral ligands provides high ¢nantiomeric excesses and excellent chemical yields. 18 An enantioselective hydrogenation with moderate enantiomeric excesses could also be achieved using NADH model compounds. 19 In enzymatic hydrogenations, cells of the genera Rhodotorula and Agrobacterium 20 or of ycasts 21 have been applied. Also microbial oxidation-reduction processes starting from racemic pantolactone lead to the desired (R)-(-)-pantolactone. 22 A very efficient synthesis of
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