DKR of Hydantoins

Scheme 5.4 DKR of hydantoins under weak basic conditions.

Another approach for the synthesis of enantiopure amino acids or amino alcohols is the enantioselective enzyme-catalyzed hydrolysis of hydantoins. As discussed above, hydantoins are very easily racemized in weak alkaline solutions via keto enol tautomerism. Sugai et al. have reported the DKR of the hydantoin prepared from DL-phenylalanine. DKR took place smoothly by the use of D-hydantoinase at a pH of 9 employing a borate buffer (Figure 4.17) [42]. 

Racemic hydantoins result from the reaction of carbonyl compounds with potassium cyanide and ammonium carbonate or the reaction of the corresponding cyanohydrins with ammonium carbonate (Bucherer-Bergs reaction). Hydantoins racemize readily under basic conditions or in the presence of hydantoin racemase, thus allowing DKR (Figure 6.43). Hydantoinases (EC 3.5.2.2), either isolated enzymes or whole microorganisms, catalyze the hydrolysis of five-substituted... 

Enzymatic racemisation is an attractive option in DKR because the reactions catalysed by enzymes are performed under mild conditions. The Degussa group have recently described their successful commercialization of two DKR-based processes that employ racemases, namely (i) the DKR of 5-substituted hydantoins using whole cells coexpressing a L-carbamoylase, a hydantoin racemase and a hydantoinase and (ii) the DKR of N-acetyl amino acids using an acylase in combination with an N-acetyl amino acid racemase from Amycolatopsis orientalis. 

Approaches to the synthesis of the non-proteinogenic amino acid tert-leucine were made possible through the DKR of 5-tert-butyl-hydantoin. The hydantoin racemised in situ and was opened enantioselectively using (R)-hydantoinase. Decarbamoylation then yielded the expected (i )-tert-leucine, as shown in Scheme 3.39. 

For successful DKR two reactions an in situ racemization (krac) and kinetic resolution [k(R) k(S)] must be carefully chosen. The detailed description of all parameters can be found in the literature [26], but in all cases, the racemization reaction must be much faster than the kinetic resolution. It is also important to note that both reactions must proceed under identical conditions. This methodology is highly attractive because the enantiomeric excess of the product is often higher than in the original kinetic resolution. Moreover, the work-up of the reaction is simpler since in an ideal case only the desired enantiomeric product is present in the reaction mixture. This concept is used for preparation of many important classes of organic compounds like natural and nonnatural a-amino acids, a-substituted nitriles and esters, cyanohydrins, 5-alkyl hydantoins, and thiazoUn-5-ones. 

In many cases, the racemization of a substrate required for DKR is difficult As an example, the production of optically pure cc-amino acids, which are used as intermediates for pharmaceuticals, cosmetics, and as chiral synfhons in organic chemistry [31], may be discussed. One of the important methods of the synthesis of amino acids is the hydrolysis of the appropriate hydantoins. Racemic 5-substituted hydantoins 15 are easily available from aldehydes using a commonly known synthetic procedure (Scheme 5.10) [32]. In the next step, they are enantioselectively hydrolyzed by d- or L-specific hydantoinase and the resulting N-carbamoyl amino acids 16 are hydrolyzed to optically pure a-amino acid 17 by other enzymes, namely, L- or D-specific carbamoylase. This process was introduced in the 1970s for the production of L-amino acids 17 [33]. For many substrates, the racemization process is too slow and in order to increase its rate enzymes called racemases are used. In processes the three enzymes, racemase, hydantoinase, and carbamoylase, can be used simultaneously this enables the production of a-amino acids without isolation of intermediates and increases the yield and productivity. Unfortunately, the commercial application of this process is limited because it is based on L-selective hydantoin-hydrolyzing enzymes [34, 35]. For production of D-amino acid the enzymes of opposite stereoselectivity are required. A recent study indicates that the inversion of enantioselectivity of hydantoinase, the key enzyme in the... 

The antipode, (R)-tert-leucine (47), was synthesized using DKR with an enantioselective (R)-hydantoinase. Here the racemic 5-tert-butyl-hydantoin (48), which racemizes in situ at a pH >8, produces the V-carbamoyl-(/0-/erMeucinc (49) in >99% yield through the action of the (II)-hydantoinase. Decarbamoylation of intermediate 49 produced enantiomerically pure 47 in 85.5%... 

A new route to (R)-4-benzyloxazolidinone was developed starting from phenylalanine, using the o-hydantoinase-catalysed enantioselective hydrolysis of 5-benzyl-hydantoin under the DKR conditions, as shown in Scheme 3.41. ... 

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