Activated acid derivatives

In synthetic target molecules esters, lactones, amides, and lactams are the most common carboxylic acid derivatives. In order to synthesize them from carboxylic acids one has generally to produce an activated acid derivative, and an enormous variety of activating reagents is known, mostly developed for peptide syntheses (M. Bodanszky, 1976). In actual syntheses of complex esters and amides, however, only a small selection of these remedies is used, and we shall mention only generally applicable methods. The classic means of activating carboxyl groups arc the acyl azide method of Curtius and the acyl chloride method of Emil Fischer. 

First the protected oligopeptide is coupled with polymer-bound nitrophenol by DCC. N"-Deblocking leads then to simultaneous cycliiation and detachment of the product from the polymer (M. Fridkin, 1965). Recent work indicates that high dilution in liquid-phase cycli-zation is only necessary, if the cyclization reaction is sterically hindered. Working at low temperatures and moderate dilution with moderately activated acid derivatives is the method of choice for the formation of macrocyclic lactams (R.F. Nutt, 1980). 

Under natural conditions various strains of Penicillium fungi produce either penicillin G or free 6-aminopenicillanic add ( = 6-APA). The techniques used to prepare analogues such as the ones given above have been (i) fermentation in the presence of an excess of appropriate adds which may be incorporated as side-chain (ii) chemical acylation of 6-APA with activated acid derivatives. 

Pyrazinamide is a structural analogue of isoniazid and is converted to the active acid derivative intracellularly by a nicotinamidase. Pyrazinamide resistance has been linked to reduced levels of nicotinamidase but the genetic determinants of resistance have not been fully elucidated. 

A common procedure in C-C-bond formation is the aldol addition of enolates derived from carboxylic acid derivatives with aldehydes to provide the anion of the [5-hydroxy carboxylic acid derivative. If one starts with an activated acid derivative, the formation of a [Mac lone can follow. This procedure has been used by the group of Taylor [137] for the first synthesis of the l-oxo-2-oxa-5-azaspiro[3.4]octane framework. Schick and coworkers have utilized the method for their assembly of key intermediates for the preparation of enzyme inhibitors of the tetrahydrolipstatin and tetrahydroesterastin type [138]. Romo and coworkers used a Mukaiyama aldol/lac-tonization sequence as a concise and direct route to 3-lactones of type 2-253, starting from different aldehydes 2-251 and readily available thiopyridylsilylketenes 2-252 (Scheme 2.60) [139]. 

The method outlined here competes well with the method developed earlier by Danheiser, et al.618 Its superiority is based on the fact that phenyl ester enolates give almost the same results as the S-phenyl thiolester enolates. However, handling the malodorous benzenethiol for the preparation of the active acid derivative and during workup of the p-lactone can be avoided. In addition, phenol is much cheaper than benzenethiol. The method is well suited for the preparation of p-lactones from symmetrical and unsymmetrical ketones. In addition to 3,3-dimethyM-oxaspiro[3.5]nonan-2-one, ( )-3-ethyl-1-oxaspiro[3.5]nonan-2-one and (3R, 4R )- and (3R, 4S )-4-isopropyl-4-methyl-3-octyl-2-oxetanone were prepared by this procedure in high yields (Notes 11 and 12). In the case of unsymmetrical ketones the less sterically crowded diasteroisomer is formed preferentially. With aldehydes as the carbonyl component the yields are unsatisfactory, because of the competitive formation of 1,3-dioxan-4-ones.6... 

Recently, treatment of the esters or amides of l-methylpyridinium-3,5-dicarboxylic acid salts with an alkanethiol and TEA in methylene chloride was found to give a mixture of dihydropyridines (Scheme 77) (80CC1147). These yellow adducts are particularly useful as thiolate transfer agents. Excellent yields of thioesters, for example (133), are formed by the reaction of the adducts with activated acid derivatives. 

The chemistry of the thiazoles does, of course, bear some similarity to that of the oxazoles. Metallated thiazoles and thiazole derivatives have found use, for example, both as carbonyl equivalents and masked acetaldehyde enolates. Additionally, as will be exemplified below, thiazole derivatives have served as catalysts for benzoin-type condensations, and they have provided access to a unique class of activated acid derivatives. 

Activated acid derivatives are easily prepared by condensation of a carboxylic acid with thiazolidine-2-thione (608) in the presence of DCC or alternatively, by reaction of an acid... 

Tritylamines can serve as both linkers and protective groups for aliphatic amines because, unlike benzhydrylamines, they do not usually undergo acylation when treated with activated acid derivatives. Tritylation of aliphatic amines is readily accomplished by adding excess amine to a support-bound trityl chloride. Illustrative cleavage reactions are listed in Table 3.21. 

The reactivity of uronium- (and phosphonium-) based coupling reagents is mainly determined by the type of activated acid derivative formed during activation (see Figure 13.2). Unlike phosphonium salts, uronium salts can react with amines to yield guanidines [84]. This side reaction can interfere with amide formation if more uronium salt than carboxylic acid is used. Illustrative examples of the use of uronium salts are listed in Table 13.6. 

The esterification of support-bound carboxylic acids has not been investigated as thoroughly as the esterification of support-bound alcohols. Resin-bound activated acid derivatives that are well suited to the preparation of esters include O-acylisoureas (formed from acids and carbodiimides), acyl halides [23,226-228], and mixed anhydrides (Table 13.15). A-Acylurea formation does not compete with esterifications as efficiently as it does with the formation of amides from support-bound acids. Esters can also be prepared from carboxylic acids on insoluble supports by acid-catalyzed esterification [152,229]. Alternatively, support-bound carboxylic acids can be esteri-fied by O-alkylation, either with primary or secondary aliphatic alcohols under Mitsu-nobu conditions or with reactive alkyl halides or sulfonates (Table 13.15). 

Like acid chlorides, anhydrides are activated acid derivatives, and they are often used for the same types of acylations. Anhydrides are not as reactive as acid chlorides, and they are occasionally found in nature. For example, cantharidin is a toxic ingredient of Spanish fly, which is used as a vesicant ( causing burning and blistering ) to destroy warts on the skin. 

Cleavage of an ester by ammonia (or an amine) to give an amide and an alcohol, (p. 1003) (carboxylic acid anhydride) An activated acid derivative formed from two acid molecules with loss of a molecule of water. A mixed anhydride is an anhydride derived from two different acid molecules, (p. 986)... 

Acyl palladium species react like activated acid derivatives... 

Carbodiimides, in particular dicyclohexylcarbodiimide, have been applied in many syntheses where dehydration had to be performed under mild conditions. It is therefore no surprise that this reagent was also introduced for the synthesis of acid anhydrides from carboxylic acids." " In order to avoid N-acylation the reactions are carried out at low temperature. First 0-acylisoureas are formed, which then react further with free acid to the acid anhydride (equation 34). The reaction has been exploited in particular for the preparation of peptides." )V-alkoxycarbonyl-protected amino acids can be transformed in high yield to the corresponding anhydrides, which themselves are activated acid derivatives and may be converted to peptides. As in many other examples polymer-bound carbodiimides may prove superior sometimes, as the isolation of the products is facilitated. Easy preparation of acid anhydrides is possible in this way." ... 

Diclofop-methyl is a herbicide which, upon entry into the plant, undergoes minimal acropetal and basipetal transport (8). In our experiments transport to the roots or to the leaves of [14C] diclofop-methyl applied to the axils of two-leaved susceptible and resistant Lolium plants does not appear to differ. No data are presently available as to whether proplastids or chloroplasts from the two biotypes exhibit differential permeability to diclofop-methyl or to the active acid derivative diclofop. Similarly, there is no evidence for a differential capacity to convert diclofop-methyl to diclofop nor differential sequestration of the ester or the acid in some secondary compartment such as the vacuole or within membranes. 

Terminal carboxyl groups in monolayers can also be activated by treatment with carbodiimides such as dicyclohexylcarbodiimide (DCC) or l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) 59). Alternatively, conversion to a mixed anhydride can be effected by reaction of a carboxyl-terminated film with ethyl chloroformate 49). Exposure of the surface to gaseous SOCI2 has been reported to produce carboxyl chloride groups 48,60). These activated acid derivatives then react smoothly with alcohols or amines to form esters or amides (Scheme 2). 

The propagation step is very rapid when aminolysis takes place at the carbonyl groups of the activated acid derivative (like acyllactam or an acid chloride). It is slower, however, if it involves an amide group... 

Activated acid derivatives, e. g., acid halogenides or anhydrides, are used as acylating agents ... 

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