Hydantoins 3-amino- from

In a modification of the original method. Read (60) replaced a-amino acids with a-amino nitriles. This reaction is sometimes known as Strecker hydantoin synthesis, the term referring to the reaction employed for the synthesis of the a-amino nitrile from an aldehyde or ketone. The cycli2ation intermediate (18) has been isolated in some cases (61), and is involved in a pH-controUed equiUbrium with the corresponding ureide. 

The other most important synthetic utility of the Bucherer-Bergs reaction is the preparation of amino acids from the hydrolysis of hydantoins. When carbonyl 1 was symmetrical, the Henze modification gave hydantoin 2, which was then hydrolyzed to the... 

Figure 2.13 Reactions and enzymes involved in the production of L-amino acids from racemic hydantoins by the three-enzyme hydantoinase process [55],...

Scheme 5.10 Enzyme-catalyzed synthesis of a-amino acids from hydantoins.

Gross, C., Syldatk, C. and Wagner, F. (1987) Screening method for micro-organisms producing L-amino acids from D,L-5-monosubstituted hydantoins. Biotechn. Techniques, I, 85-90. 

URECH HYDANTOIN SYNTHESIS. Formation of hydantoins from o -amino acids by treatment with potassium cyanate in a aqueous solution and heating of the salt of the intermediate hydantoic acid with 25% hydrochloric acid. 

Thus, provided all necessary biocatalysts are or were available, either d- or i-amino acids can be synthesized. Straightforward synthesis of most racemic 5-monosub-stituted hydantoins from inexpensive and often readily available starting materials through the following reactions provides another advantage for the process (Syldatk, 1999) ... 

C. Gross, C. Syldatk, and F. Wagner, Screening method for microorganisms produdng L-amino adds from DL-5-monosubstituted hydantoins, Biotechnol. Technol. 1987, 1, 85-90. 

Hydantoinases and decarbamoylases have been applied for the production of optically active amino acids from DL-5-monosubstituted hydantoins. A variety of enzymes have been reported elsewhere. Runser et al. [33] reported the occurrence of D-hydantoinase without dihydropyrimidinase activity. Watabe et al. [34] reported that an ATP-dependent hydantoin-hydrolyzing enzyme is involved in the L-amino acid production from DL-5-monosubstituted hydantoin by Pseudomonas sp. NS671. This enzyme shows no stereospecificity. Hydan-toinase showing no stereospecificity and not requiring ATP was also reported [35]. Recently, hydantoin-racemizing enzymes were found [36,37], These enzymes make it possible to totally convert racemic substrates, which only slowly racemize under reaction conditions, to a single stereoisomer. The combinations of these hydantoin-transforming enzymes provide a variety of processes for optically active amino acid production (Fig. 4). 

Syldatk, C., Muller, R., Siemann, M., Krohn, K., Wagner, F. Microbial and Enzymatic Production of D-Amino Acids from DL-5-Monosubstituted Hydantoins. In Biocatalytic Production of Amino Acids and Derivatives, Rozzell, J. D., Wagner, F. Eds., Carl Hanser Verlag Munich, 1992, p. 75. 

Figure 12.14 Initial reaction rate for the production of different optically pure D-amino acids from 5-monosubstituted hydantoins using systems 1 and 2. TRP, D-tryptophan TYR, D-tyrosine pH PC, D-p-hydroxyphenyl glycine VAL, D-valine ...

The development of this multienzymatic system for the production of D-amino acids from any D,L-5-monosubstituted hydantoin allows the hydantoinase process to produce not only two amino acids, such as D-phenylglycine and D-p-hydroxy-phenylglycine (as explained at the beginning of the chapter), but also many non-natural D-amino acids that could be components of potential pharmaceuticals. 

The use of a whole cell allows for a required enzyme cofactor to be regenerated. In other cases, it allows for several enzymes to work in parallel and to perform many complex transformations. An example is provided by the synthesis of D-amino acids from hydantoins (Fig. 3). The carbomylase drives the reaction to completion as carbon dioxide and ammonia are evolved. The same approach has been used with the l-versions of the enzymes to synthesize L-amino acids (14, 42, 55). 

All microorganisms producing D-aminoacylases commonly produce L-aminoacy-lases as well. Therefore, to reach high optical purity of the D-amino acids produced from the respective N-acetyl-D,L-amino acids, the D-aminoacylases have to be separated from the L-aminoacylases (Table 12.3-13). However, this is a disadvantage in view of an industrial application since additional purification steps lead to more expensive enzymes and thus add costs to the whole production process. This is one of several reasons why it is widely accepted today that the production of D-amino acids by enzyme-catalyzed hydrolysis of D,L-hydantoins seems to be more promising than the D-aminoacylase route via N-acetyl-D,L-amino acids. The enzyme-catalyzed synthesis of D-amino acids from the respective D,L-hydantoins is described in Chapter 12.4. 

Nishida et al. 46, Syldatk et al. 47, 48, Yamashiro et al. 49, 50, and Yokozeki et al. 51-53 found new L-5-arylalkylhydantoinases and a N-carbamoyl-L-amino acid amidohydrolases (L-N-carbamoylase), which are involved in the L-selective cleavage of 5-arylalkylhydantoins and could be most favorably induced by D,L-5-indolylme-thylhydantoin or its N-3-methylated derivative17. The natural functions of these enzymes are not yet known, while one of the associated N-carbamoyl-L-amino acid amidohydrolases (L-N-carbamoylase) was also shown by Syldatk et al. to be reactive on N-formyl-L-amino acids[54]. In this strain both, hydantoinase and L-N-carbamoylase were shown to occur in combination with a hydantoin racemase 7, 55, 56. Resting cells were used for the industrial production of L-amino adds from d,l-5-monosubstituted hydantoin derivatives as shown in Fig. 12.4-2 57. ... 

Figure 17-15. Enzymatic synthesis of d- or L-amino acids from 5-substituted D,L-hydantoins through N-carbamoyl-D- or L-amino acids.

Yamashiro, A., Kubota, K. Yokoseki, K., Mechanism of stereospecific production of L-amino acids from the corresponding 5-substituted hydantoins by Bacillus brevis. Agric. Biol. Chem., 52 (1988) 2857-2863. 

Reproduced from Konnert L, Reneaud B, de Figueiredo RM, Campagne J-M, Lamaty F, Martinez J, et al. Mechanochemical preparation of hydantoins from amino esters application to the synthesis of the antiepileptic drug phenytoin. J Org Chem 2014 79 10132-42, copyright (2014), with permission from American Chemical Society. 

Mass spectrometry has been suggested for the identification of phenylthio-hydantoins produced during the classical and automated sequencing process and a combined gas-liquid chromatography-mass spectrometry technique for amino-acids from oligopeptide hydrolysates has been discussed. "... 

Figure 7.2 Reaction scheme for production (a) a-D-amino acids from 5-monosubstituted hydantoins and (b) p-amino acids from 5-dihydrouracils. HYD, hydantoinase/dihydropyrimi-dinase a-DCAR, D-N-a-carbamoylase NCpAA, N-carbamoyl-p-alanine amidohydrolase.

Mass spectral fragmentation patterns of alkyl and phenyl hydantoins have been investigated by means of labeling techniques (28—30), and similar studies have also been carried out for thiohydantoins (31,32). In all cases, breakdown of the hydantoin ring occurs by a-ftssion at C-4 with concomitant loss of carbon monoxide and an isocyanate molecule. In the case of aryl derivatives, the ease of formation of Ar—NCO is related to the electronic properties of the aryl ring substituents (33). Mass spectrometry has been used for identification of the phenylthiohydantoin derivatives formed from amino acids during peptide sequence determination by the Edman method (34). 

Synthesis from OC-Amino Acids and Related Compounds. Addition of cyanates, isocyanates, and uiea derivatives to a-amino acids yields hydantoin piecuisois. This method is called the Read synthesis (2), and can be considered as the reverse of hydantoin hydrolysis. Thus the reaction of a-amino acids with alkaline cyanates affords hydantoic acids, which cyclize to hydantoins in an acidic medium. 

Amino acid synthesis from aldehydes and hydantoin (Bergmann), synthesis of serine derivatives (Erlenmeyer) or of y-hydroxyaminoacids (Plochl)... 

---