Amino acid ester chelates

Amino acid esters act as chelates to Co111 for example, the /3-alanine isopropyl ester is known as both a chelate and as an /V-bonded monodentate,983 and the mechanism of hydrolysis of the ester, which is activated by coordination, to yield chelated /3-alanine has been closely examined. 

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. 

Rate Constants (km0, kon) for Intermolecular Hydrolysis of Some Free and Co(III)-Chelated Amino Acid Esters at 25°C, I = 1.0 M... 

Typical syntheses of Co(III)-amino acid, amino acid ester, and dipeptide ester chelates are described below. The NMR spectra of the isolated products were in accord with expectation. The procedures given here are generally applicable, except for that given for [Co(en)2((iS)-GluOBzl)]I2. If this method is used to coordinate amino acids that are only partially soluble in Me2SO, more forcing conditions (extended reaction times, 1-5 h, 50-60°C) may be required. Dipeptide ester complexes are not always as amenable as [Co(en)2 (Val-GlyOEt)]I3 to crystallization from water. 

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. 

These chelates are structurally similar to that postulated above for the metal ion-catalyzed hydrolysis of oj-amino esters the position of the protons in the transition state is different, but this is a completely arbitrary distinction. A further distinction is that the metal ion is facilitating attack in this instance not by a polarization of the substrate molecule, but rather by the positioning and fixation of the hydroxide ion at the reaction site. It is not clear which of these two representations—for the amino acid esters involving polarization or for the carboxylate esters involving fixation of the hydroxide ion—is the correct interpretation. It is conceivable that both are correct. A similar explanation will account for the large effect of calcium ions on the alkaline hydro ysis of acetylcitric and benzoyl-citric acids (53). 

Reaction 3, the intramolecular counterpart of reaction 2, has been observed for amino acid esters,156 amides157 and nitriles,158 where five- and six-membered chelate rings can be formed. In the case of the aminoacetonitrile complex (37) a rate enhancement of ca. 1011 occurs at pH 7, and this may be compared with an acceleration of ca. 106 for the reaction 1 analogue.159 For reaction 3, AH values become of considerable significance. 

The rapid aminolysis of cobalt(llI)-chelated glycine esters in aprotic solvents (Scheme 10 N4 = (en)2 or trien, R = Me, Et, R = H, CHR"C02Et) could be of value in peptide synthesis. The cobalt atom acts as both an N-protecting and an activating group. The synthesis of the chelated amino acid esters has presented some difficulties.207 A recent paper208 describes the use of methyl trifluoromethanesulfonate for the alkylation of chelated amino acids using dry trimethyl phosphate... 

The metal-accelerated hydrolysis of amino acid esters or amides comprises one of the best investigated types of metal-mediated reaction (Fig. 3-7). One of the reasons for this is the involvement of chelating ligands, which allows chemical characterisation of intermediates and products in favourable cases, and allows detailed mechanistic studies to be made. The reactions have obvious biological relevance and may provide good working models for the role of metals in metalloproteins. 

In the case of inert cobalt(m) complexes it is possible to isolate the chelated products of the reaction. Let us return to the hydrolysis of the complex cations [Co(en)2(H2NCH2C02R)Cl]2+ (3.1), which contain a monodentate iV-bonded amino acid ester, that we encountered in Fig. 3-8. The chelate effect would be expected to favour the conversion of this to the chelated didentate AO-bonded ligand. However, the cobalt(iu) centre is kinetically inert and the chloride ligand is non-labile. When silver(i)... 

Figure 3-9. The stepwise hydrolysis of an amino acid ester. The labilisation of the chloride by interaction with silver(i) is a crucial prerequisite to the formation of the reactive chelated AO-bonded ligand.

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 3-11. The reaction of a chelated amino acid ester with an amine, R NH2, to yield an amino acid amide complex.

There are a number of useful synthetic applications of these reactions of chelated amino acid esters (Fig. 3-12). For example, if the attacking nucleophile is not a simple amine, but is another amino acid ester or an O-protected amino acid, then peptide or polypeptide esters are formed in excellent yields. This may be developed into a general methodology for the metal-directed assembly (and, in the reverse reaction, the hydrolysis) of polypeptides. 

We saw in Chapter 3 that the hydrolysis of chelated amino acid esters and amides was dramatically accelerated by the nucleophilic attack of external hydroxide ion or water and that cobalt(m) complexes provided an ideal framework for the mechanistic study of these reactions. Some of the earlier studies were concerned with the reactions of the cations [Co(en)2Cl(H2NCH2C02R)]2+, which contained a monodentate amino acid ester. In many respects these proved to be an unfortunate choice in that a number of mechanisms for their hydrolysis may be envisaged. The first involved attack by external hydroxide upon the monodentate A-bonded ester (Fig. 5-62). This process is little accelerated by co-ordination in a monodentate manner. 

Figure 5-64. The five co-ordinate intermediate is rapidly trapped by chelation to the amino acid ester.

An aromatic Claisen rearrangement has been used as a key step in a total synthesis of racemic heliannuols C and E.18 A formal synthesis of (-)-perhydrohistrionicotoxin has used Claisen rearrangement of an amino acid ester enolate as the key step, in which almost total chirality transfer was observed from (S, )-oct-3-en-2-ol in the sense predicted by a chair-shaped transition state with chelation control of enolate geometry.19 Treatment of 1-(cyclohex-l-enyl)-6-methoxy-2-propargylindanol derivatives with base... 

The enhanced reactivity of chelated amino acid esters towards attack by other nucleophiles has been used to advantage in the sequential synthesis of small peptides equation (4l).225 Formation of the amide bond takes only seconds to minutes at room temperature in DMSO as solvent, and the peptide can be easily recovered by reducing the metal to the Co" state. Recent studies have shown that the A and A diastereoisomeric reactants are selective in their couplings to (2 ) and (S) amino acid esters and that mutarotation at the asymmetric centre of the chelated ester reactant varies from 0-6%.226 Isied and coworkers have described the use of the Co(NH3)3+ as a C-terminal protecting group for the sequential synthesis of peptides (equation 42).227 This procedure has advantages over other methods in some cases. 

Metal chelating amino acid derivatives of cellulose were recently obtained via modification of cellulose with 2,4-toluenediisocyanate, followed by treatment with amino acid ester derivatives [58,59]. Diisocyanates are able to crosslink cellulose chains and/or to yield reactive cellulose isocyanate, depending on the reaction conditions. Sato and his coworkers [60] examined the optimum conditions for the reaction between cellulose and 2,4-toluenediisocyanate and succeeded in introducing 0.30 mol of free isocyanate group per glucose unit. Cellulose isocyanate was further converted into isothiocyanate [61]. This derivative has also been synthesized by condensation of cellulose with 2,4-diisocyanototoluene, followed by hydrolysis and thiophosgene treatment [61]. 

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