Amide labilizing effect

The conclusion regarding the site of protonation of phosphin-amides has been reached rather indirectly, from the effect of protonation on coupling across the P—N bond. Phosphinamides [128] are very labile in acid solution (Haake and Koizumi, 1970),... 

Convertible isocyanide reagent 66 allows a mild and chemoselective in situ post-Ugi activation of the isonitrile bom amide with simultaneous deprotection of the nucleophilic amine, that is, liberation and activation of two Ugi-reactive groups, if desired also under subsequent lactam formation [33]. Another recently introduced convertible isocyanide, l-isocyano-2-(2,2-dimethoxyethyl)-benzene 73, was shown effective by Rhoden et al. In the course of this short sequence, a hydrolytically labile W-acylindole 78 is formed, which is displaced intramolecularly by the amine portion of the former Boc-protected amino acid 75 (Scheme 13). 

Bodor and Brewster (1983) first used the term CDS, in describing the use of dihydropyridine ester- (or amide)-linked prodrugs such as 27 (X-OH is the parent) which can partition readily into the CNS, there to be oxidized to pyridinium salts (28), which are effectively trapped in the biophase because of their extreme polarity, and which then undergo enzymic or chemical hydrolysis of the now very labile ester link to release active drug. 

The rates of hydrolysis of amino acid esters or amides are often accelerated a million times or so by the addition of simple metal salts. Salts of nickel(n), copper(n), zinc(n) and cobalt(m) have proved to be particularly effective for this. The last ion is non-labile and reactions are sufficiently slow to allow both detailed mechanistic studies and the isolation of intermediates, whereas in the case of the other ions ligand exchange processes are sufficiently rapid that numerous solution species are often present. Over the past thirty years the interactions of metal ions with amino acid derivatives have been investigated intensively, and the interested reader is referred to the suggestions for further reading at the end of the book for more comprehensive treatments of this interesting and important area. 

The most effective, and commercially applied, method to produce polylactide is via the ring-opening polymerization of lactide. This process is initiated by metal complexes and proposed to occur via a coordination-insertion mechanism, as illustrated in Fig. 2. The most common initiators for this polymerization are Lewis acidic metal alkoxide or amide complexes. Key initiator criteria are sufficient Lewis acidity to enable binding and activation of the lactide unit and a labile metal alkoxide (or amide) bond so as to enable efficient insertion. 

Perhexiline Analogs. Perhexiline is a Ca + channel blocker that is effective in the treatment of angina pectoris, the most common symptom of chronic ischemic heart disease, but is of limited use because of side effects such as hepatotoxicity, weight loss, and peripheral neuropathy. Given that these undesirable effects are related to the slow metabolism and accumulation of perhexiline, soft analogs may represent a conceivable alternative. A class of analogs with an amide moiety inserted as a possible enzymatically labile cen-... 

The addition of lithium salts can alter the melting, flow behavior, and mechanical properties of aliphatic polyamides (1-4). These effects have been attributed to the formation of a labile network resulting from the salt interacting with the amide group of the polymer. Subsequent work using polycaprolactam lithium chloride demonstrated a direct binding of the lithium ions to the carbonyl oxygen (5). 

The structure-activity relationships of p-aminophenol derivatives have been widely studied. Based on the comparative toxicity of acetanilide and acetaminophen, aminophenols are less toxic than the corresponding aniline derivatives, although p-aminophenol itself is too toxic for therapeutic purposes. Etherification of the phenolic function with methyl or propyl groups produces derivatives with greater side effects than with ethyl groups. Substituents on the nitrogen atom that reduce basicity reduce activity unless that substituent is metabolically labile (e.g., acetyl). Amides derived from aromatic acids (e.g., N-phenylbenzamide) are less active or inactive. 

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