Peptides epimerization

It is likely that the madurastatins are biosynthesized on a nonribosomal peptide synthetase, from salicylic acid as the starter acid. L-Serine is probably the precursor to the aziridine moiety, with epimerization occurring on the enzyme-bound amino acid as found for other nonribosomal peptides, with aziridine formation occurring at a late stage. Compounds 120 and 123 could therefore be biosynthetic precursors to 119 and 122, respectively. 

Parr method 995 Pauling s electronegativities 561 Penicillin sulphoxides epimerization of 750 synthesis of 246 Peptides 854, 864-866... 

Although these Boc derivatives underwent methylation with poor selectivity (compared to 3-amino-N-benzoyl butanoates [106] and Z-protected methyl 4-phen-yl-3-aminobutanoate [107]), epimers were succesfully separated by preparative HPLC or by flash chromatography. However, saponification of the methyl ester caused partial epimerization of the a-stereocenter and a two-step (epimerization free) procedure involving titanate-mediated transesterification to the corresponding benzyl esters and hydrogenation was used instead to recover the required Boc-y9 -amino acids in enantiomerically pure form [104, 105]. N-Boc-protected amino acids 19 and 20 for incorporation into water-soluble /9-peptides were pre-... 

The synthesis of aldehydes and ketoamides was performed on solid phase as well as in solution (Scheme 2.2). A semicarbazone linker (6) was employed for the assembly of the aldehydes on solid phase whereas the corresponding aminoalcohol was coupled in solution to the tripeptide and oxidized to the aldehyde, which produced epimeric mixtures [137]. For the synthesis of the ketoamides, hydroxyester THP resins were used as solid support ((7), Scheme 2.2) [138]. In solution the peptide bond was formed using an aminohydroxycarboxylic acid building block [138, 147]. Oxidation of the free hydroxyl group yielded the final inhibitors ((8), Scheme 2.2). 

Co(III)-chelated amino acid ester reactant and/or peptide product (Scheme 1). This basic difficulty was quickly pointed out (5), and has subsequently been examined and commented upon by others (6, 7). Such criticisms are well-founded since epimerization (or racemization) is a common problem, at least to some degree, in all chemical methods of synthesis where acyl-activation is employed. As a result, metal-activation methods have received little attention. However, since 1981 we have refined the Co(III) method such that very fast, clean, couplings can now be carried out using A-[Co(en)2((S)-AAOMe)]3+ reagents, which involve minimal (<2%) epimerization/racemization provided experimental conditions are strictly adhered to. 

FIGURE 2.20 Intermediates and their fate in benzotriazol-l-yl-oxyphosphonium salt-mediated reactions. Indirect evidence (Figure 2.21) is not compatible with the tenet that the precursor of the peptide is the benzotriazolyl ester (path C). The evidence indicates that the peptide originates from the acyloxyphosphonium cation (path B). Conversion of this intermediate into the oxazolone (path E) can account for the epimerization that occurs during segment couphngs. 

FORMING REACTIONS TO THE COUPLING OF N-PROTECTED PEPTIDES IS DICTATED BY THE REQUIREMENT TO AVOID EPIMERIZATION 5(4H)-OXAZOLONES FROM ACTIVATED PEPTIDES... 

NL Benoiton, Y Lee, B Liberek, R Steinauer, FMF Chen. High-performance liquid chromatography of epimeric TV-protected peptide acids and esters for assessing race-mization. Ini J Pept Prot Res 31, 581, 1988. 

C Griehl, A Kolbe, S Merkel. Quantitative description of epimerization pathways using the carbodiimide method in the synthesis of peptides. J Chem Soc Perkin Trans 2 2525, 1996. 

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