Amino acids esters, metal complexes

Boehm et al.100 have synthesised and studied a series of half-sandwich rhodium (III) and iridium (III) complexes, derivatives of salicylaldehyde and L-amino acid esters. The diastereoselectivity has shown strong dependence on the type of metal as well as amino acid residue. The labile configuration of the metal atoms was suggested because of changes in the diastereomers ratio with increasing temperature. Fast epimerisation at the metal atom was suggested for some S-phenylalanine complexes. 

The other direction concerns the use of immobilized transition metal catalysts in the synthesis of libraries of organic compounds of interest in therapeutic drug discovery. One such strategy uses immobilized catalysts (e.g., scandium complexes), leading to efficient library syntheses of quinolines, amino ketones, and amino acid esters.72,73... 

Metal-ion catalysis has been extensively reviewed (Martell, 1968 Bender, 1971). It appears that metal ions will not affect ester hydrolysis reactions unless there is a second co-ordination site in the molecule in addition to the carbonyl group. Hence, hydrolysis of the usual types of esters is not catadysed by metal ions, but hydrolysis of amino-acid esters is subject to catalysis, presumably by polarization of the carbonyl group (KroU, 1952). Cobalt (II), copper (II), and manganese (II) ions promote hydrolysis of glycine ethyl ester at pH 7-3-7-9 and 25°, conditions under which it is otherwise quite stable (Kroll, 1952). The rate constants have maximum values when the ratio of metal ion to ester concentration is unity. Consequently, the most active species is a 1 1 complex. The rate constant increases with the ability of the metal ion to complex with 2unines. The scheme of equation (30) was postulated. The rate of hydrolysis of glycine ethyl... 

On the basis of this evidence it was postulated that a 1 to 1 complex is formed between the metal ion and the amino acid ester, in which the metal ion chelates with the amino group and the carbonyl oxygen of the ester, and that this chelate is attacked by hydroxide ion to give the products of reaction through the intermediate formation of a tetrahedral addition compound. 

It is well over 40 years since Pfeiffer discovered that certain reactions of a-amino acid esters, in particular, ester exchange, racemization and oxygenation, are effected very readily when their Schiff bases with salicylaldehyde are complexed to a transition metal ion (most notably Cu11). The Schiff bases result from a condensation reaction between a reactive carbonyl group and the amino group of the amino acids. Snell and his co-workers43 were also one of the first to point out that similar reactions also occurred if pyridoxal was used instead of salicylaldehyde, and that there is a close analogy with pyridoxal phosphate-promoted enzymic reactions of a-amino acid metabolism. Since then much work has been due on these and other similar systems and their reactivities. 

The ability of metal ions to catalyze the hydrolysis of peptide bonds has been known for 50 years, while the catalytic effect on the hydrolysis of amino acid esters was highlighted in the 1950s. As Hay and Morris point out in their review,76 the major problem with the kinetically labile systems is determining the nature of the reactive complex in solution. Such problems generally do not arise in the more inert systems and consequently reactions involving Co111 have been the more popular for study. 

It has been known for many years that the rate of hydrolysis of a-amino acid esters is enhanced by a variety of metal ions such as copper(II), nickel(II), magnesium(H), manganese(II), cobalt(II) and zinc(II).338 Early studies showed that glycine ester hydrolysis can be promoted by a tridentate copper(II) complex coupled by coordination of the amino group and hydrolysis by external hydroxide ion (Scheme 88).339 Also, bis(salicylaldehyde)copper(II) promotes terminal hydrolysis of the tripeptide glycylglycylglycine (equation 73).340 In this case the iV-terminal dipeptide fragment... 

An interesting correlation has been observed53 between the formation constant XCuL of the metal complex and its catalytic activity in a mixed ligand with an amino acid ester. Large values of XCUL (equation 13) lead to lower base hydrolysis rates in the ternary complex. The Lewis... 

A number of studies have been carried out on the ligand reactivities of the metal complexes of Schiff bases derived from amino acid esters and carbonyl compounds. Ester exchange reactions were first reported by Pfeiffer et a/.492 and extended by other investigators.493 496... 

Figure 3-8. The hydrolysis of a kinetically inert complex containing a monodentate amino acid ester co-ordinated through nitrogen. The only effect of the metal is a long-range polarisation which slightly increases the electrophilic character of the carbonyl carbon atom.

The ability of a metal ion to increase the rate of hydrolysis of a peptide has enormous implications in biology, and many studies have centred upon the interactions and reactions of metal complexes with proteins. However, hydrolysis is not the only reaction of this type which may be activated by chelation to a metal ion, and chelated esters are prone to attack by any reasonably strong nucleophile. For example, amides are readily prepared upon reaction of a co-ordinated amino acid ester with a nucleophilic amine (Fig. 3-11). In this case, the product is usually, but not always, the neutral chelated amide rather than a depro-tonated species. 

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

Metal rf-inline complexes with various transition metals [1-10] and lanthanides [11,12] are well known in the literature. Early transition metal if-imine complexes have attracted attention as a-amino carbanion equivalents. Zirconium rf-imine complexes, or zirconaaziridines (the names describe different resonance structures), are readily accessible and have been applied in organic synthesis in view of the umpolung [13] of their carbons whereas imines readily react with nucleophiles, zirconaaziridines undergo the insertion of electrophilic reagents. Accessible compounds include heterocycles and nitrogen-containing products such as allylic amines, diamines, amino alcohols, amino amides, amino am-idines, and amino acid esters. Asymmetric syntheses of allylic amines and a-amino acid esters have even been carried out. The mechanism of such transformations has implications not only for imine complexes, but also for the related aldehyde and ketone complexes [14-16]. The synthesis and properties of zirconaaziridines and their applications toward organic transformations will be discussed in this chapter. 

The rate of hydrolysis of peptides by cobalt(III) complexes is 10" times faster than hydrolysis with no metal present. " Unlike the hydrolysis of amino acid esters, where the rate of hydrolysis is dependent on how the ester is bonded to the cobalt(III) complex, peptides are hydrolyzed equally if they are bound to the cobalt(III) complex in a monodentate fashion (throngh the carbonyl oxygen) or in a bidentate fashion (throngh the amino nitrogen and carbonyl oxygen). 

Originally devised as a method for the conversion of amino acids or amino acid esters to aldehydes. The Akabori reaction has been modihed for use in the determination of C-terminal amino acids by performing the reaction in the presence of hydrazine and for the production of derivatives useful for mass spectrometric identihcation. See Ambach, E. and Beck, W., Metal-complexes with biologically important ligands. 35. Nickel, cobalt, palladium, and platinum complexes with Schiff-bases of... 

Amino acid esters, amides, and peptides can be hydrolyzed in basic solution, and the addition of many different metal ions speeds the reactions. Labile complexes of Cu(II), Co(ll), Ni(II), Mn(II), Ca(II), and Mg(II), as well as other metal ions, promote the reactions. Whether the mechanism is through bidentate coordination of the a-amino group and the carbonyl, or only through the amine, is uncertain, but seems to depend on the... 

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