Hydantoins peptide synthesis

HF, they can be removed by hydrogenolysis. " A method for the masking of terminal amino-groups during peptide synthesis is to convert the C-terminally protected peptide [e.g. (202)] into the corresponding hydantoin derivative (203) using N,AT -carbonyldi-imidazole the reaction occurs without racemization. " A report has appeared on the use of various substituted phenylsulphenyl groups for N -protection of a-amino-acids. ... 

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 ... 

Its use in solution synthesis is limited by the presence of sulfur-containing anoino acid residues as these poison metal catalysts, albeit methods have been proposed that partially overcome this serious drawback (see Section 2.1.1.1.1.1.3.1). This linoitation is also bypassed in cases where the target peptide molecule permits acidolysis with strong acids (HBr/AcOH or HF). As an additional limitation, the saponification of Al -Z-protected peptide esters under drastic conditions, such as those required for longer peptide intermediates, was found to induce decomposition of the Al -Z moiety with generation of N-ternninal hydantoins. ... 

Classical reactions involving nucleophiles such as saponification ("OH as the nucleophile), aminolysis (with amines also ammonia in ammonolysis reactions), transesterification (alkoxides, "OR) and others (hydrazinolysis, hydroxamic acid synthesis, etc.) have been adapted to solid phane and used to obtain, for instance, carboxylic acids, amides and esters. Internal or intramolecular nucleophilic attack has been employed to obtain cyclic products such as lactones, lactams (including cyclic peptides) and a great variety of heterocycles (hydantoins, diketopiperazines, benzodiazepinones, etc.). 

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. 

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... 

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