Hydantoin, 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 ... 

The use of the Fmoc-protected 4-nitrophenyl carbamate building blocks and resins with acid-labile linkers allows synthesis of the final products with C-terminal carboxylic acid or amide groups (Fig. 6). Unfortunately, Fmoc solid-phase synthesis of oligourea peptidomimetics with C-terminal carboxylic acid also leads to formation of corresponding hydantoin byproducts (53-56) (Fig. 7). In this case hydantoin formation arises as a result of an acid-catalyzed intramolecular cyclizafion reaction. It has been reported that the ratio of desired oligourea pepfidomimetic acid product and hydantoin byproduct is approximately 2 1 (53). However, these two compounds are in principle separable by preparative HPLC. 

Since an important feature of Biicherer-Bergs hydantoin formation is that the process can only work for a-aminonitriles without substituent on the amino group, it follows that one compound of the equilibrium mixture formed from an aldehyde, ammonia, and cyanide is selectively reacted through an irreversible process leaving N-alkylated aminonitriles or imino-dinitriles unreacted. However, the difficulty with this process is that CAAs and hydantoins are poorly reactive towards hydrolysis and need long periods of time to be converted into free AAs. But, CAAs may also have per se a prebi-otic importance in activation pathways towards polypeptides (see Sect. 3.3.7). CAAs can also be synthesized by reaction of free amino acids with cyanic acid/cyanate (a likely prebiotic compound [50]). In the presence of a steady-state concentration of either cyanate or urea in aqueous medium, CAAs are at equilibrium with A A [51]. 

This group was developed by Wieland et al., based on a previous observation that 3-ni-trophenyl phosphates were photolabileJ l Like the benzyloxycarbonyl-based groups, the 3-nitrophenyloxycarbonyl group is cleaved by a photoinduced solvolysis, liberating CO2 in the process. Photodeprotection of 3-nitrophenyloxycarbonyl amino acids has been found to be efficient. However, peptides suffer from some degree of hydantoin formation during the photolysis which lowers the yield. 

F-HPLC to give 17 crude individual products 70-syn/anti and 71. These crude products were not isomerically pure. Removal of the fluorous tag and hydantoin formation was achieved by treatment of the individual amides 70-syn/anti and 71 with diisopropylethyl-amine (DIPEA) under microwave conditions. The cyclative cleavage reactions of 10-syn and 10-anti provided the same products 72. Normal-phase HPLC purification gave 11 of 12 possible final products 72 and 73. 

Figure 12.4-11 gives a survey of the substrates accepted by the different dihy-dropyrimidinase or D-hydantoinase preparations The differences between the en-zyme preparations from mammalian and microbial sources are discussed in more detail in reference13, but D-hydantoinases or dihydropyrimidinases, respectively, seem to have the following in common (i) a wide substrate specificity, (ii) metal dependence and (iii) that they are strictly D-specific. Preferably, cyclic amides are hydrolyzed at pH values around 8.5. Furthermore, most of the enzymes are also described to be able to catalyze the hydantoin formation the optimal pH of this reaction is neutral or weakly acidic. 

Limal et al. [33] reported the synthesis of the carbaza-peptide (56) (in 40% overall yield after HPLC purification) by coupling A -Boc or A -Fmoc iV -alkyl-propylenediamine derivatives (57) on solid-supported amines activated with triphosgene or GDI (Fig. 8). Reaction with triphosgene was found to be faster than with GDI and hydantoin formation was kept at a low level (<3%) when no tertiary base (DIEA) was added during the coupling procedure. 

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. 

Solid-supported isoxazoles were obtained from resin-bound alkynes and nitrile oxides generated in situ from nitroalkanes and isocyanate (Scheme 11.50). The isoxazoles were cleaved from the resin via hydantoin formation upon heating and 18 diverse products were obtained in high purities. 

A related method was applied to the synthesis of 18 isoxazolothiohydantoins (Scheme 11.51)/ Hydantoin formation was also applied to the release of proline derivatives that were obtained from the intramolecular cycloadditions of resin-bound azomethine ylides and alkenes. ... 

Hydantoin formation 10 12 was shown to proceed via partial hydrolysis of the cyano group to the amide 11 as precursor of the cycUzation via ester functionality. 

Path D Hydantoin formation. In certain circumstances hydantoins can be formed from P-tosyloxy-N-benzyloxycarbonylamino acid amides in basic media (273). This reaction can probably be avoided by choice of less drastic conditions. 

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