Amide hydrolysis metal-mediated

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. 

Introduction of RLi-unreactive silicon substituents has advantages in protection of Ar-C-H and Ar-CH3 sites. Thus taking advantage of the cooperativity of amide and methoxy DMG, metalation-silylation followed by metalation-E+ quench affords, after fluoride-mediated desilylation and amide hydrolysis, a route 1,2,5-substituted benzoic acids, 18 —> 19 (Scheme 5). Lateral metalation, of considerable utility in post-DoM chain extension [19], followed by double silyla-tion and further DoM-E+ quench and the same fluoride and acid treatment steps, furnishes 1,2,3,4-tetrasubstituted aromatic compounds, 20 —> 21 [10, 20],... 

Sayre proposed five possible mechanisms for metal-mediated amide hydrolysis (Fig. 15).91,92 In these proposed pathways, the metal center can be involved in electrophilic carbonyl activation (A), metal hydroxide nucleophile activation (B), and a combined mechanism involving both of these processes (C). Amide hydrolysis may also involve a metal-bound hydroxide or water molecule acting as a general base or general acid (Fig. 15d and e). 

As with amide hydrolysis reactions, extensive mechanistic studies of metal-mediated phosphate monoester hydrolysis reactions have been performed using exchange inert mononuclear Co(III) complexes.9,188-202 To date, only a few zinc complexes that promote phosphate monoester hydrolysis have been reported. A binuclear zinc complex supported by a macrocyclic cryptate ligand (Fig. 36)... 

Metal-mediated reactions involving water are essential to life and catalytic industrial processes [1-3]. In biological systems, metalloenzymes containing various divalent metal ions catalyze the hydrolysis of amide, carboxylic ester and phosphate ester bonds using both mono- and multinuclear active-site structural motifs [4—6], Mononuclear metal centers are also found within the active sites of enzymes that catalyze the hydration, or the addition of water, to CO2 [Zn(II)] and nitriles [Co(III)/Fe(III)j [7-10]. In many of these processes, formation of a metal hydroxide moiety via deprotonation of a metal-coordinated water molecule is a key proposed step in the reaction pathway. Thus, a substantial amount of research over the past several years has been directed at dehneating how the structural and electronic environments of biological metal ions influence the pKa of a metal-bound water molecule. In this regard, studies directed at the preparation, characterization and elucidation of the reactivity of discrete metal aqua and hydroxo complexes have been paramoimt [11-13]. 

Thus, many metal ions catalyze the hydrolysis of esters [7,8], amides [9], and nitriles [10] via electrophilic activation of the C=0 or C=N group. This type of catalysis is characteristic of coordination complexes and is very common in metalloenzyme-mediated processes. Zinc(II), for example, is a key structural component of more than 300 enzymes, in which its primary function is to act as a Lewis acid (see Chapter 4). The mechanism of action of zinc proteases, e.g., thermolysin, involves electrophilic activation of an amide carbonyl group by coordination to zinc(II) in the active site (Figure 4). 

The hydrolysis of amides is also accelerated by transition metal ions, and in the case of cerium(IV)- and cobalt(III)-mediated processes, the hydrolysis of MeCONHMe is associated with the reduction of the metal. The mechanism proposed,involving an amido radical, is shown in Scheme 3. 

In this way, the desired metallated phthalocyanines remained on the solid support, while the unwanted by-products such as the symmetrically substituted B4-type moieties were formed in solution and could easily be discarded. After an acid-mediated cleavage from the resin using a TFA/TIPS/DCM mixture at ambient temperature, the e-amine of the lysine moiety of the metallated phthalocyanine was used for the attachment of suitable oligonucleotides connected with aryl aldehydes or acids (Scheme 8.9). Interestingly, both the reductive amination and the amidation reaction could be dramatically sped up using microwave irradiation, carrying out the reactions at 70-75°C for a mere 30 min. The reductive amination protocol was found to provide a far superior yield, owing to the competitive ester formation and hydrolysis observed in the microwave-assisted amidation protocol. 

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