Peptide bonds enhanced reactivity

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. 

To form catalytically productive enzyme/substrate complexes, many peptide bond cis-trans isomerases essentially require the location of the reactive bond of the substrate in the context of secondary binding sites or a specific spatial organization of the polypeptide chain thus creating features of stereo- and regiospecifi-city [19,20]. As in the case of many endoproteases, PPIases can utilize an extended array of catalytic subsites to enhance catalytic efficiency and substrate specificity. These properties precondition peptide bond cis-trans isomerases toward a complex reaction pattern. Consequently, biochemical investigations have led to the elucidation of three distinct molecular mechanisms that might be operative either in isolation or collectively in the cellular action of both prototypical and multidomain peptide bond cis-trans isomerases ... 

The efforts of D.A. Buckingham, in Duneden, to exploit the enhanced reactivity of peptides in Co-III complexes for rate enhancement in the hydrolysis of their esters and in the formation of a new peptide bonds brought interesting and potentially useful results. At Massey University the research of W.S. Hancock and his associates has led in the last decade to the design of new, selectively removable blocking groups. 

The aliphatic side chains in alanine and leucine have no major influence but branching at the ) -carbon atom in valine and isoleucine can enhance racemization because the combination of electron release and steric hindrance results in reduced coupling rates. The ensuing increase in the life-time of the reactive intermediate provides an extended opportunity for proton abstraction by base. It is obvious from these examples that the effect of individual side chains, the influence of various methods of coupling and the conditions of the peptide bond forming reaction (solvents, concentration, temperature, additives) must be studied in well designed experiments. Several model systems have been proposed for this purpose. 

After metal ions interact with specific peptide side chain functional groups, they act as a Lewis acid to enhance the reactivity of proximal peptide bonds through coordination and polarization of carbonyl groups [49]. Meanwhile, metal ions can also increase the concentration of nucleophilic hydroxide ions by forming metal hydroxides (M-OH). In this way, peptide bond cleavage can be facilitated at specific residues bearing high affinity with metal ions. 

The haloacetophenone type of polymer reacted with N-protected amino acids and peptides — as already known from esterifications with the monomer reagent in conventional syntheses [74] — under milder conditions but in better loading yield compared to chloromethylated polystyrene, resulting in enhanced reactivity of the peptide phenacyl ester bond on polymer towards nucleophilic cleavage reagents [74—76]. (For further details on peptide cleavage, see Sect. 3.5.)... 

We recently reported a novel enzyme model for the synthesis of peptides by using the multi-functionalized chiral 18-crown-6 derivatives [3]. The new hosts have achieved the assembly of plural guests by covalent bonds formed through non-covalent complexes between the host and the guest, and then enhanced the bond formation between the bound guests. This enzyme model has mimicked the general concept of enzyme catalysis, in which the reactive enzyme-substrate covalent intermediate (E/v aSi) is formed from the noncovalent complex (E Si), and then reacts with the second substrate (S2) to give the product (Sj—S2) as shown in Equation (1) [4]. 

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