Bucherer-Bergs synthesis, amino acids

Monosubshtuted hydantoins are a-amino acids cyclically protected at both the carboxyl- and the a-amino group. They can be easily prepared from an aldehyde and isocyanate or by the Bucherer-Bergs synthesis and similar methods. Indeed, the hydantoin synthesis is also a prachcal method for the preparahon of the racemic amino acid. Enzymes belonging to the dihydro-pyrimidinase family hydrolyze hydantoins to the carbamoyl amino acid. The latter can be hydrolyzed in turn to the amino acid by a second enzyme, a carbamoylase. Both enzymes can discriminate between enantiomers and, if their action is cooperative, either the L- or the D-amino acid can be obtained (Scheme 13.10) [36]. What makes the system of special interest is that the proton in the 5-position of the hydantoin ring (it will become the a-hydrogen in the a-amino acid) is considerably more acidic than conventional protons in amino acid esters or amides and much more acidic than the amino acid itself. Thus, the hydantoin can be often racemized in situ at slightly basic pH where the enzymes are stiU stable and active. If these condihons are met. 

Synthesis from Aldehydes and Ketones. Treatment of aldehydes and ketones with potassium cyanide and ammonium carbonate gives hydantoias ia a oae-pot procedure (Bucherer-Bergs reactioa) that proceeds through a complex mechanism (69). Some derivatives, like oximes, semicarbazones, thiosemicarbazones, and others, are also suitable startiag materials. The Bucherer-Bergs and Read hydantoia syntheses give epimeric products when appHed to cycloalkanones, which is of importance ia the stereoselective syathesis of amino acids (69,70). 

In summary, the Bucherer-Bergs reaction converts aldehydes or ketones to the corresponding hydantoins. It is often carried out by treating the carbonyl compounds with potassium cyanide and ammonium carbonate in 50% aqueous ethanol. The resulting hydantoins, often of pharmacological importance, may also serve as the intermediates for amino acid synthesis. 

Several hydrolytic enzymes other than esterases have been applied for synthetic purposes. One important subject is the chemoenzymatic preparation of amino acids. An industrial method for the synthesis of unnatural d- or L-amino acids employs the enzymatic hydrolysis of hydantoins, prepared by Bucherer-Bergs condensation using either D- or L-hydantoinase (cf Section 3.2.1.4) [33]. Another efficient method of preparing natural and unnatural amino acids is the two-step synthesis which features a Pd-catalyzed amidocarbonylation (eq. (2) cf Section 2.1.2.4) to afford racemic A-acyl amino acids followed by enantioselective hydrolysis using various acylases [34]. 

Since the discovery of hydantoin in 1861, when Baeyer isolated it in his uric acid studies, that system has been an important precursor of a-amino acids owing to its lability toward alkali, especially for those acids that are difficult to prepare by other methods.300 Furthermore, the stereochemical courses of the Bucherer-Bergs and Read methods of synthesis for hydantoins (Section II,E), permit the preparation of epimeric amino acids.301-305 Some of these amino acids have been tested as possible tumor growth inhibitors,306,307 as metabolism-resistant amino acid analogues for transport system studies,72,308... 

The Strecker [1] and Bucherer-Bergs [2] reactions are the most important strategies and powerful tools for the synthesis of a-amino acids from a carbonyl compound and cyanide. The classical first approach uses ammonium hydroxide and potassium cyanide to obtain the corresponding aminonitrile compound 1, whereas the second one is a four-component condensation between an aldehyde or ketone derivative reacting with potassium cyanide and ammonium carbonate as source of ammonia and carbon dioxide affording hydan-toin componnds 2 [3], In both cases, final hydrolysis would deliver the corresponding o,a-disubstituted a-amino acid derivatives 3 (Scheme 10.1) [4],... 

Although the Bucherer-Bergs reaction is mainly employed for the synthesis of a-amino acids, the synthesis of interesting hydantoins can be also addressed (Fig. 10.1) [17]. Curiously, hydantoins were initially observed as undesired by-products in the synthesis of peptides [18]. However, nowadays, this motif displays many important biological and pharmacological properties and is commonly used in drug discovery research lines [4a,b, 19]. These features have... 

The Bucherer-Bergs methodology has been successfully applied on the synthesis of diverse amino acid derivatives, some of them conformationally constrained as represented in Figure 10.3. 

An interesting and useful example of synthesis of a-amino acids has been recently reported by Wuts and coworkers, describing a scalable process to prepare the INOS inhibitor PHA-399733 42 using the Bucherer-Bergs hydantoin synthesis as key step to introduce the amino acid function present in the final skeleton (Scheme 10.11) [41]. The methodology was applicable to the isolation of 39.9 kg (75% yield) of the racemic hydantoin 41, and the desired enantiomer was then opened in basic conditions giving the corresponding amino acid moiety. 

The Bucherer-Bergs reaction was also employed to install the masked amino acid functionality present in the diester intermediate 45, key for the synthesis of methionine amide 46 (LY2140023) (Scheme 10.12) [42],... 

Synthesis.—Optimum conditions have been systematically worked out for the preparation of the spiro-4-thiohydantoin (217) from cyclohexanone hydrolysis of (217) leads to the corresponding a-amino-acid. " This overall Bucherer-Bergs reaction is a useful alternative to the classical Strecker synthesis and hopefully the optimum conditions found will be applicable to other ketones. Hydrolysis of 5-substituted hydantoins can be effected enzymatically, giving optically active a-amino-acids of varying purity. ... 

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