Phenylalanine with cyclic peptides

The ring dynamics of the two phenylalanine containing cyclic peptides have been studied in solution, both of these peptides show H and NMR spectra consistent with... 

These data, taken together with mass spectrometric degradation and other spectral evidence (see Table II), clearly favor a seven-membered cyclic peptide formed from anthranilate and phenylalanine as the basic skeleton of cyclopenin (3) and cyclopenol (4). This structure, including the epoxide linkage, was further supported by biosynthetic probing (51,52) (see Section IV,A). 

Inoue s group pioneered studies on the cyclic peptide (diketopiperazine) 7 (Figure 10.9), which is readily available from L-histidine and L-phenylalanine, and used it as a catalyst for the addition of hydrogen cyanide to benzaldehyde with up to 97% (Equation 10.20) [42]. 

Feeding experiments with various possible intermediates have shown that the two N-methyl cyclic peptides cyclopeptine (160) and its dehydroderivative (161) are precursors for cyclopenin and cyclopenol. Further, (160) and (161) could be isolated from the culture and were themselves labelled by radioactive phenylalanine and anthranilic acid. In addition, cyclopeptine (160) was found to be reversibly transformed into dehydrocyclopeptine (161). Negative results with compounds likely to be implicated earlier on the pathway suggested that the formation of cyclopeptine (160) from the precursor amino-acids took place with enzyme-bound intermediates. The pathway established so far is summarized in Scheme 16. 

Volkmer et al. used amphiphilic cyclic peptides based on asparagines and phenylalanine. These peptides favor the formation of calcite crystals. Furthermore, in addition to the normal [10.4] faces, a new set of diamond-shaped [01.2] crystal faces formed, depending on the concentration of the amphiphilic peptides. These additional crystal faces also form in the presence of proteins isolated from sea urchin spicules or sponge spicules [169]. There, similar calcite crystals were formed with [01.1] (/= 1-5) faces [166]. 

N-Silylated peptide esters are acylated by the acid chloride of N-Cbo-glycine to N-acylated peptide bonds [11]. Likewise, acid chlorides, prepared by treatment of carboxylic acids with oxalyl chloride, react with HMDS 2 at 24°C in CH2CI2 to give Me3SiCl 14 and primary amides in 50-92% yield [12]. Free amino acids such as L-phenylalanine or /5-alanine are silylated by Me2SiCl2 48 in pyridine to 0,N-protected and activated cyclic intermediates, which are not isolated but reacted in situ with three equivalents of benzylamine to give, after 16 h and subsequent chro-... 

Cyclic dipeptides, especially when N-alkylated, undergo extremely fast epimerization (79JA1885). For example, cyclo(L-Pro-L-Phe) is rapidly converted to its diastereomer, cyclo(D-Pro-L-Phe) (80% conversion), by treatment with 0.5 N NaOH at 25°C for 15 min. This diastereomer is the one in which the proline residue has epimerized and not the more activated phenylalanine. CNDO/2 calculations seem to provide a rationale for this. It is not yet completely clear why such base-catalyzed epimerizations of piperazinediones are so easy the conformation of the molecule may play a role in this (79MI1). It is also worth noting that even in linear peptides, rm-amides of N-alkyl-amino acids, which consist of s-trans and s-cis rotamers of almost equal energy, are more prone to racemization than the sec-amides, which exist only in the s-trans configuration. Of course, the amide functions of piperazine-2,5-diones are obliged to assume the s-cis conformation. 

The molecular weight of polymyxin B was shown by the method of partial substitution to be 1,150 d 10 per cent. Quantitative amino acid analysis yielded the amino acids a,y-diaminobutyric acid, L-threonine, D-phenylalanine and L-leucine in the molar proportions 6 2 1 1. Because no free a-carboxyl- and no free a-amino groups could be detected, polymyxin Bi had to be of a cyclic nature . Neither pepsin nor trypsin was found to attack the molecule and therefore partial hydrolysis and separation of the fragments was used for the elucidation of the structure. Of the 14 fragments isolated and identified, seven key peptides were necessary for proposing four tentative structures for polymyxin Two were formulated with a ring... 

A groundbreaking study in the field of organocatalysis with peptides was published in 1979 by Oku and Inoue, showing that cyclic dipeptides are valuable catalysts for the asymmetric addition of hydrogen cyanide to benzaldehyde to give the corresponding cyanohydrins (Scheme 5.6) [25]. Synthetic diketopiperazine 13 (cyclo-L-phenylalanine-L-histidine), in which the imidazole group of the histidine residue is catalytically active as a base, afforded (R)-mandelonitrile in 90% ee in only 30 min [26]. 

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