Other Readily Racemized Substrates

Kellogg, Feringa and co-workers have achieved successful dynamic kinetic resolution reactions using cyclic hemiacetals as substrates[13, 14l The enzyme-catalyzed acetylation of 6-hydroxypyranone shown in Fig. 9-6 has been achieved with reasonable enantioselectivity with essentially complete conversion. The racemisation of the hemiacetal is presumed to proceed via reversible ring-opening of the pyranone1 1. The rate of reaction was found to greatly increase when the enzyme, lipase PS (Pseudomonas sp.) was immobilized on Hyflo Super Cell (HSC). 

The related dynamic resolutions of the furanone and pyrrolinone substrates were achieved with higher selectivities (Fig. 9-7) U). Again, these substrates underwent spontaneous racemization under the reaction conditions. Appropriate choice of enzyme afforded a good example of an essentially perfect dynamic kinetic resolution process in the case of the esterification of the hydroxypyrrolinone substrate. 

Rayner and co-workers have demonstrated that hemithioacetals can be racemized on exposure to silica1151. In a typical experiment, an aldehyde and a thiol are combined to give a hemithioacetal. In the presence of silica, the enzyme-catalyzed acetylation proceeds under dynamic resolution conditions, as shown in Fig. 9-8. 

Representative products obtained using this procedure are given in Fig. 9-9. The acetylated products are inert to racemization under the reaction conditions. 

An interesting example of dynamic kinetic resolution of an alcohol has been reported by Taniguchi and Ogasawara[16]. The a-hydroxy ketone in Fig. 9-10 under- 

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The SnI reactions do not proceed at bridgehead carbons in [2.2.1] bicyclic systems (p. 397) because planar carbocations cannot form at these carbons. However, carbanions not stabilized by resonance are probably not planar SeI reactions should readily occur with this type of substrate. This is the case. Indeed, the question of carbanion stracture is intimately tied into the problem of the stereochemistry of the SeI reaction. If a carbanion is planar, racemization should occur. If it is pyramidal and can hold its structure, the result should be retention of configuration. On the other hand, even a pyramidal carbanion will give racemization if it cannot hold its structure, that is, if there is pyramidal inversion as with amines (p. 129). Unfortunately, the only carbanions that can be studied easily are those stabilized by resonance, which makes them planar, as expected (p. 233). For simple alkyl carbanions, the main approach to determining structure has been to study the stereochemistry of SeI reactions rather than the other way around. What is found is almost always racemization. Whether this is caused by planar carbanions or by oscillating pyramidal carbanions is not known. In either case, racemization occurs whenever a carbanion is completely free or is symmetrically solvated. 

Although this is a resolution approach, racemic epoxides are readily available, and other than the catalysts, the substrate and water are the only materials present. The method can be made more amenable to scale up by the use of oligomer catalysts.113... 

Several multi-ton industrial processes still use enzymatic resolution, often with lipases that tolerate different substrates. BASF, for example, makes a range of chiral amines by acylating racemic amines with proprietary esters. Only one enantiomer is acylated to an amide, which can be readily separated from the unreacted amine. Many fine chemicals producers also employ acylases and amidases to resolve chiral amino acids on a large scale. l-Acylases, for example, can resolve acyl d,l-amino acids by producing the I-amino acids and leaving the N-acyl-l-amino acid untouched after separation, the latter can be racemized and returned to the reaction. d-Acylase forms the alternative product. Likewise, DSM and others have an amidase process that works on the same principle d,l-amino acid amides are selectively hydrolyzed, and the remaining d-amino acid amide can be either racemized or chemically hydrolyzed. 

On the other hand, the racemization of amines is more difficult compared to that of alcohols. Several metal systems based on palladium (Pd), Ru, nickel (Ni), cobalt (Co), and Ir have been employed as the racemization catalysts. Pd-based catalysts include Pd/C, Pd/BaSO, and Pd/A10(0H). They are readily available but require higher temperatures for satisfactory racemization. So they should be coupled with thermostable enzymes such as Novozym 435 for the successful DKR. A possible mechanism for the Pd-catalyzed racemization of amine is described in Scheme 5.5. The racemization occurs via reversible dehydrogenation/hydrogena-tion steps including an imine intermediate. The imine intermediate can react with starting material to afford a secondary amine as the byproduct. The deamination of substrate and byproduct are also possible at elevated temperature. In case the... 

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