Racemic hydantoins, formation

Peach et al. developed a general, racemization free, and high yield procedure for the synthesis of O-desyl peptide esters from the poorly nucleophilic benzoin.1261 Employing the cesium salt of the model dipeptide Z-Gly-Phe-OH in acetone the intramolecular hydantoin formation obtained in polar aprotic solvents, such as DMF and DMSO, can be suppressed and a high yield of Z-Gly-Phe-O-desyl with ee >90% can be generated. 261 ... 

A novel reaction of pyroglutamate (6) and an isocyanate promoted by NaH in THF leads to functionalized hydantoins (7) in good yields. The reaction involves the ring closure of intermediate (8) by a nucleophilic attack on the carbonyl of the ester function followed by expulsion of an alkoxide anion resulting in the formation of the bicyclic intermediate (9). The alkoxide anion in turn can open this bicyclic intermediate with formation of anions (10) and (11) leading to the final racemic hydantoins (7) (Scheme 3).8... 

For example, Yu et al. showed that polystyrene-bound peptides could be hydrolyzed in 7 min in a domestic MW oven, a process normally taking 24 h. Furthermore, traditional soHd-phase peptide couplings were achieved in 4 min in 99-100% conversion with no detected racemization. A broad range of solid-phase reactions was found to undergo substantial rate acceleration, including Claisen and Knoeve-nagel condensations, nucleophilic substitutions, sucdnimide and hydantoin formation, and Suzuki coupHngs. 

The authors developed a scalable route for the synthesis of the intermediate core 45 in 12 steps and 0.4% yield and successfully implemented at a pilot plant scale. In this multistep synthesis, racemic hydantoin 43 was obtained after crystallization in 4 1 mixture of diastereomers. Separation of enantiomers by diastereomeric salt formation with (/ )-2-phenylglycerol and further crystallization followed by salt break gave single isomer (-)-44, with the targeted l-glutamic acid configuration. 

A somewhat different scheme is used for the preparation of an all-aliphatic thio-hydantoin. Thus, reaction of racemic leucine (91-1) with allylisothiocyanate (91-2) leads to the thiourea (91-3). Attack of the anion from treatment of that intermediate with a strong base leads to ring closure and the formation of the imidazoline ring. There is thus obtained the anticonvulsant agent albutoin (91-4) [97]. 

Fig. 7.11. Synthesis of racemic methionine by means of the Bucherer modification of the Strecker synthesis. The first step of the reaction does not stop at the stage the step of the a-aminonitrile but yields a hydantoin (B mechanistic details Figure 7.12). The second step—via the anion C of a hydantoin acid—leads to the formation of the anion E of methionine, which can be pro-tonated during workup to yield the uncharged methionine (D).

Attempts to resolve the racemic acid of 3 and its ester through classic resolution failed. In the early stages of development, a process based on SchoUkopf s asymmetric synthesis was developed (see Section 9.3). Large-scale development work was aimed at finding a biocatalytic process to resolve the amino acids. Racemic a,a-disubstituted a-amino esters were synthesized by standard chemistry through alkylation of the Schiff s bases formed from the amino esters (Scheme 9.5), or through formation of hydantoins. ... 

In a similar manner resonance affects greatly the rate of racemization by reducing the energy required for ionization. This point is discussed with reference to a-phenylamino acids and particularly with regard to amide resonance in acylamino acids, peptides, diketopiperazines and hydantoins. The literature on the racemization of proteins by alkali is also reviewed. The racemization which is observed during acylation of amino acids is also discussed, and it is pointed out that apart from oxazolone formation, mixed anhydrides may also occur as intermediates and be partly responsible for the racemization observed. 

---