Cyclic dipeptides, synthesis

The variety of prebiotic organic reactions seems to be almost unlimited. Strasdeit et al. (2002) from the University of Hohenheim (Germany) reported the synthesis of zinc and calcium complexes of the amino acids valine and isovaline. They assume that these could have had a certain significance on the mineral-rich primeval Earth on heating to 593 K under nitrogen, valine was converted to the corresponding cyclic dipeptide. 

Once it is part of a cyclic dipeptide, the prolyl residue becomes susceptible to enantiomerization by base (see Section 7.22). The implication of the tendency of dipeptide esters to form piperazine-2,5-diones is that their amino groups cannot be left unprotonated for any length of time. The problem arises during neutralization after acidolysis of a Boc-dipeptide ester and after removal of an Fmoc group from an Fmoc-dipeptide ester by piperidine or other secondary amine. The problem is so severe with proline that a synthesis involving deprotection of Fmoc-Lys(Z)-Pro-OBzl produced only the cyclic dipeptide and no linear tripeptide. The problem surfaces in solid-phase synthesis after incorporation of the second residue of a chain that is bound to the support by a benzyl-ester type linkage. There is also the added difficulty that hydroxymethyl groups are liberated, and they can be the source of other side reactions. 

An important contribution was recently made by Inoue and co-workers (35) (eq. [4]). Using the chiral cyclic dipeptide cyclo(L-Phe-L-His) these authors obtained a better than 90% e.e. in the reaction of benzaldehyde with cyanide ion. The preparation of the enantiomeric unnatural dipeptide obviously poses far fewer problems than the synthesis of an enantiomeric enzyme. It appears that, at least in principle, optically pure cyanohydrins of the desired configuration are accessible via catalysis by chiral amines or amides. 

DKPs are simple and easy to obtain and are quite common by-products of synthetic, spontaneous, and biological formation pathways. DKP formation has been well documented as side reactions of solid-phase and solution-phase peptide synthesis. In addition, DKPs have been shown to be decomposition products of various peptides, proteins, and other commercial pharmaceuticals. Cyclic dipeptides were found to be present in solutions of human growth hormone, bradykinin, histerlin, and solutions of agents within the classes of penicillins and cephalosporins. " DKPs are also enzymatically synthesized in several protists and in members of the plant kingdom. Hydrolysates of proteins and polypeptides often contain these compounds and they are commonly isolated from yeasts, lichens, and fungi. ... 

Excellent reviews covering the enantioselective synthesis of non-proteinogenic amino acids via metallated his-lactim ethers of cyclic dipeptides (2,5-diketopiperazines) (187) have been compiled by Schollkopf188). 

In the last decades, cyanohydrins have become versatile chiral building blocks, not only for laboratory synthesis, but also for a range of pharmaceuticals and agrochemicals. Several methods for the enantioselective preparation of these compounds have been published [1, 2]. The most important synthetic approaches are catalysis by oxynitrilases, also termed hydroxynitrile lyases (HNLs), wording used in this chapter, [3] and by transition metal complexes [4], whereas the relevance of cyclic dipeptides as catalysts is decreasing [2]. 

Scheme 2. Asymmetric Strecker synthesis with cyclic dipeptide 2 (Lipton and co-workers).

Fig. 6.15. Carboxylic acid activation with DCC. [1,3] means the intramolecular substitution of the oxygen atom 01 by the N atom "3" via a cyclic four-membered tetrahedral intermediate. From the point of view of the heteroatoms, this SN reaction corresponds to a migration of the acyl group R-C=0 from the oxygen to the nitrogen. (Examples for amino acid activations in the form of the pentafluorophenyl ester C or the benzotriazolyl ester D are given in Figure 6.32 (oligopeptide synthesis) and Figure 6.31 (dipeptide synthesis), respectively.

The application of 3-amino-2//-azirines as amino acid equivalents and their use in the synthesis of cyclic dipeptides presumably includes ring enlargement steps [14]. The formation of 12- or 15-membered cyclodepsipeptides from open chain precursors possibly includes ring enlargement steps [3] [15]. 

Iyer, M. S., Gigstad, K. M., Namdev, N. D., Lipton, M. Asymmetric catalysis of the Strecker amino acid synthesis by a cyclic dipeptide. Amino Acids 1996, 11, 259-268. 

The non-equivalence of enantiomers through the spontaneous breaking of mirror-symmetry in nature is amplified by asymmetric autocatalytic reaction [34], e.g. Frank s spontaneous asymmetric synthesis [35, 36] (Fig. 7-8). Alberts and Wyn-berg have reported in enantioselective autoinduction that chiral lithium alkoxide products may be involved in the reaction to increase the enantioselectivity (Eq. (7.9)) [37]. The product % ee however does not exceed the level of catalyst % ee. In asymmetric hydrocyanation catalyzed by cyclic dipeptides, the (Si-cyanohydrin product complexes with the cyclic peptide to increase the enantioselectivity in the (S)-cyanohydrin product, the reaction going up to 95.8% ee (Eq. (7.10)) [38]. In the presence of achiral amine, (/ )-l-phenylpropan-l-ol catalyzed carbonyl-addition reaction of diethylzinc has been reported to show lower % ee than that of the catalyst employed [39]. 

Hydrocyanation of other functional groups such as aldehydes and imines have also been carried out. An industrial process for the synthesis of the pyrethroid insecticide ASANA depends on a cyclic dipeptide-mediated addition of HCN to... 

Keywords a-Cyanoliydrin, a-Aminonitrile, Hydrogen cyanide. Acetone cyanohydrin, TMSCN, Lewis acid. Cyclic dipeptide. Peptide-metal complex, Strecker synthesis... 

Lipton and co-workers employed the cyclic dipeptide 13 (Figure 10.13) bearing a guanidinium moiety as a catalyst in the Strecker synthesis in 1996. Corresponding a-aminonitriles were obtained with high enantioselectivities (Equation 10.27). 

In the last decade, optically pure cyanohydrins (a-hydroxynitriles) have become a versatile source for the synthesis of a variety of chiral building blocks. Diverse methods for the enantioselective synthesis of cyanohydrins have been published and reviewed111. Besides enzyme catalyzed methods, hydrocyanation or silylcyanation of aldehydes or ketones controlled by chiral metal complexes or cyclic dipeptides, as well as diastereoselective hydrocyanation of chiral carbonyl compounds, have been applied with moderate success. 

Chemoenzymatic synthesis. Enzymatic prenylation of indole will probably soon become practical in a chemical sense with general availability of indole prenyl-transferases. N-ferf-Prenylation of L-tryptophan (18) was possible employing the cyclic dipeptide prenyltransferase CdpNPT from Aspergillus fumigatus affording N-ferf-prenyltryptophan 19 (38%, Scheme 5) [41]. A prenyl transferase from Aspergillus oryzae catalysed the simultaneous N-ferf-prenylation and 7-prenylation of the diketopiperazine cyclo-L-Trp-L-Trp [43]. 

Synthesis of Peptides from -Amino Alcohols 25 Table 1.13 Synthesis of cyclic dipeptides from p-amino alcohols. ... 

Moreover, besides the above mechanism of production, some authors (Strom et al, 2002) hypothesized the direct synthesis of cyclic dipeptides by LAB, similarly to other bacteria. While this hypothesis has not been further addressed for LAB, recent research (Wyatt et al., 2010 Zimmermann Fischbach, 2010) pointed out that... 

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