Dipeptides metal complexes

Only a limited number of examples are known of applications of thietanes in organic synthesis. Prominent among these examples would be electrophilic ring opening reactions leading to polyfunctional sulfur compounds (33)-(37), utilization of 3-thietanones (55) and metal complexes (87) derived therefrom as oxyallyl zwitterion equivalents in cycloaddition reactions, synthesis of dipeptide (63) with a /3-thiolactone, Raney nickel desulfurization of thietanes (e.g. 120 cf. Table 7) as a route to gem-dimethyl compounds, and desulfurization of thietanes (e.g. 17) in the synthesis of cyclopropanes (also see Table 7). 

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]. 

The development of chiral peptide-based metal catalysts has also been studied. The group of Gilbertson has synthesized several phosphine-modified amino adds and incorporated two of them into short peptide sequences.[45J,71 They demonstrated the formation of several metal complexes, in particular Rh complexes, and reported their structure as well as their ability to catalyze enantioselectively certain hydrogenation reactions.[481 While the enantioselectivities observed are modest so far, optimization through combinatorial synthesis will probably lead to useful catalysts. The synthesis of the sulfide protected form of both Fmoc- and Boc-dicyclohexylphosphinoserine 49 and -diphenylphosphinoserine 50 has been reported, in addition to diphenylphosphino-L-proline 51 (Scheme 14).[49 To show their compatibility with solid-phase peptide synthesis, they were incorporated into hydrophobic peptides, such as dodecapeptide 53, using the standard Fmoc protocol (Scheme 15).[451 For better results, the phosphine-modified amino acid 50 was coupled as a Fmoc-protected dipeptide 56, rather than the usual Fmoc derivative 52.[471 As an illustrative example, the synthesis of diphe-nylphosphinoserine 52 is depicted in Scheme 16J45 ... 

Stereoselectivity in the metal complexes of amino acids and dipeptides has been reviewed by Pettit and Hefford,87 and will not be discussed further here. 

Figure 3-12. The reaction of a chelated amino acid ester with another amino acid ester to give a metal complex of a dipeptide.

Table 3. Stability constants of metal-complexes with some diastereoisomeric dipeptides...

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

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. 

Stereoselectivity in the Metal Complexes of Amino Acids and Dipeptides... 

Rolfer, N.C. Oomens, J. Dunbar, R.C. Alkali metal complexes of the dipeptides RheAla and AlaPhe IRMRD spectroscopy. Chemphyschem. 2008, 9, 579-589. 

Severin etal recently pnblished another successful array for differentiating peptides by employing three commercially available metal complexes (27-29). One complex contained rhodium, one ruthenium, and one palladium. In the presence of six selected fluorophores, these constituents formed a collection of differential sensors. The receptors were able to differentiate 10 dipeptides at a 50 pM concentration (the closed symbols in Figure 9) and 2 dipeptides at 20 pM concentration (the open symbols in Figure 9). The authors found that peptides containing histidine and methionine residues were best discriminated, most likely because these residues displaced a larger fraction of... 

Figure 22 An example of sensing array for the analysis of dipeptides, which was described by Severin, by employing different metallic complexes of know dyes.

A cross-reactive sensor array based on luminescence changes has been reported by Severin and coworkers [74]. In this case no synthetic modifications were operated, but the sensing elements were created by mixing some metal complexes with fluorescent dyes. The complex formation between metal ions, such as Rh, Ru or Pd, quenches the dye fluorescence the peptide competes with the dye for metal ion complexation, removing it from the complex. The fluorescence turn on is the signal of the peptide interaction. The activation of fluorescence is also an indication of the equilibrium reported in Fig. 24 and it is the basis of the peptides discrimination. The sensor array was able to differentiate between several dipeptides at 20-50 X 10 M concentration higher oligopeptides, such as bradykinin and kallidin were also discriminated and the system was also able to differentiate between two dipeptides, carnosine and homocamosine, in a more complex environment such as human serum. 

Polfer NC, Oomens J, Dunbar RC. Alkali metal complexes of the dipeptides PheAla and AlaPhe IRMPD spectroscopy. ChemPhysChem. 2008 9 579 89. 

Two phenoxyl radical complexes [Cu (2 )N03] and [Zn (2 )N03] oxidize benzyl alcohol to benzaldehyde and have been studied as models for the enzyme galactose oxidase (GO). GO contains a dipeptide unit (3) in which a tyrosine residue is covalently bound to an adjacent cysteine residue and which is similar to (2), the tyrosyl radical in (3) also being bound to the Cu centre (see Figure 1). Second-order kinetics were observed with respect to [Zn°(2 )N03]+ and there was no evidence of redox reaction at the zinc site, suggesting that a dimeric form of the complex is active however, the reaction of [Cu H2 )N03]+ with benzyl alcohol is first order in the metal complex and [Cu (2H)]+ is identified as a product, suggesting a formal 2e /2H+ mechanism in which the monomeric form coordinates the alcohol in the manner believed to operate for G0. 2... 

Emil Fischer s result involving cyanide additions to carbohydrates had demonstrated the power of diastereoselective synthesis early as the 1890s (Equation 1) [4, 34,162]. The corresponding enantioselective formation of cyanohydrins has been the subject of immense efforts. It has long been appreciated that optically active cyanohydrins are synthetically useful intermediates that can be elaborated into a number of chiral building blocks, such as hydroxy acids. In general, there are three main classes of catalysts for the preparation of chiral cyanohydrins enzymes, cyclic dipeptides, and transition metal complexes [163-166]. 

Numerous investigations concerning the synthesis of optically active cyanohydrins by using chiral metal complexes, cyclic dipeptides, and lipases as catalysts have been published [5,7]. However, due to the easy access of R) and (5)-HNLs and the high optical and chemical yields obtained, HNL-catalyzed preparations of optically active cyanohydrins are superior to other methods. 

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