Carboxylic acid derivative formation

The construction of the naturally derived narbomycin and tylosin-aglycones by Masamune and coworkers employ identical methodology for seco-acid formation. In each case, Peterson alkenadon of a functionalized aldehyde (not shown) and the silyl ketones (96 R = SiMes Scheme 36) or (99 Scheme 37) efficiently introduced the required ( )-a,3-unsaturation. Silyl ketone formation is accomplished in each case through cuprate acylation by an activated carboxylic acid derivative. Formation of an acid chloride was not possible in the sensitive tylosin-aglycone intermediate however, selective acylation of the silylcuprate proceeded at the pyridyl thiol ester moiety of (98) and not with the r-butyl thiol ester. In a related investigation, (97), an advanced intermediate for 6-deoxyerythronolide B, was obtained from (95) via addition of lithium diethylcuprate to the acid chloride (84% yield). In all the above cases, no addition was observed at the f-butyl thiol ester. 

In 2000, an efficient three-step procedure for the synthesis of 5-substituted 3-isoxazolols (without formation of undesired 5-isoxazolone byproduct) was published. The method uses an activated carboxylic acid derivative to acylate Meldrum s acid, which is treated with A,0-bis(ten-butoxycarbonyl)hydroxylamine to provide the N,0-di-Boc-protected P-keto hydroxamic acids 14. Cyclization to the corresponding 5-substituted 3-isoxazolols 15 occurs upon treatment with hydrochloric acid in 76-99% yield. 

In 1983, Yamada et al. developed an efficient method for the racemization of amino acids using a catalytic amount of an aliphatic or an aromatic aldehyde [50]. This method has been used in the D KR of amino acids. Figure 4.25 shows the mechanism of the racemization of a carboxylic acid derivative catalyzed by pyridoxal. Racemization takes place through the formation of Schiff-base intermediates. 

By methods analogous to those used for the tetrahedral intermediates related to carboxylic acid derivatives, Guthrie proceeded from the heat of formation of pentaeth-oxyphosphorane to free energies of the P(OEt) (OH)5 species. °° This allowed the calculation of the equilibrium constants for addition of water or hydroxide to simple alkyl esters of phosphoric acid see Table 1.7. 

The kinetics of deuterium isotope exchange between diphenyl phosphine and t-butylthiol have been studied by H n.m.r. spectroscopy.274 A negative temperature coefficient was observed for the reaction of a perf1uoroalky1 phosphite with a fluorinated aldehyde.275 The kinetics for the reaction of alcohols with phosphoryl trichloride bore strong similarities to those of carboxylic acid derivatives.276 An interesting report desribed the solvolysis of ary 1 hydroxymethyl-phosphonates. It was shown that a phosphoryl group does not prevent carbocation formation on an immediately adjacent carbon atom.277... 

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 cyclization of the five-atom component O-acylated amidoximes 204 leads to 1,2,4-oxadiazoles via C-N bond formation as shown in Scheme 30. The requisite O-acylated amidoximes 204 are accessed via the reaction of an amidoxime with an activated carboxylic acid or a carboxylic acid derivative. Often the O-acylated amidoxime 204 is not isolated and the cyclization is either spontaneous or occurs in a one-pot process, and these approaches are dealt with in Section 5.04.9.1.2 as syntheses from a one-atom component and a four-atom component. In this section, only those methods in which the O-acylated amidoxime 204 is isolated and cyclized in a separate step are dealt with. 

The carboxylic acid derivatives li-lm can only be matrix-isolated if the corresponding quinone diazides 2i-2m are irradiated with monochromatic blue light (k = 436 nm).81 91 92 UV or broad-band visible irradiation rapidly results in the decarboxylation of the carbenes. As expected, the IR and UV/vis spectra of the carbenes are very similar to that of la. Oxygen trapping results in the formation of the photolabile carbonyl oxides 7. Thus, the carbenes li-lm were identified both spectroscopically and by their characteristic reaction with molecular oxygen. 

Five- or six-membered saturated cyclic ketones can also react by another pathway that does not involve decarbonylation. In these reactions, the biradical initially formed by a-cleavage undergoes internal disproportionation without loss of carbon monoxide, resulting in the formation of either an unsaturated aldehyde or a ketene. Methanol is usually added to convert the reactive ketene to a stable carboxylic-acid derivative (Scheme 9.2). 

Since the solvent properties of dimethyl sulfoxide are widely different from those of hydrocarbons and halogenated hydrocarbons, it may be difficult to compare the kinetic and thermodynamic data for the C02H group (Table 16) directly with others. However, heating the carboxylic acid (68, X = OH) in toluene affords the sp isomer almost exclusively. Probably, the observed results with the carboxylic acid derive from difficulty in the formation of a hydrogen bond owing to a steric effect, in addition to the nonplanar conformation of the carboxyl group relative to the naphthalene. 

In humans, ca. 10% of the urinary metabolites of epicainide (4.29, Fig. 4.3), an antiarrhythmic agent, is accounted for by the carboxylic acid derivative 4.32. Three distinct pathways are possible for the formation of this metabolite, namely direct hydrolysis of the secondary amide function of epicainide (Fig. 4.3, Pathway a), hydrolysis of the primary amide (4.30) resulting... 

Formally related reactions are observed when anthracene [210] or arylole-fines [211-213] are reduced in the presence of carboxylic acid derivatives such as anhydrides, esters, amides, or nitriles. Under these conditions, mono- or diacylated compounds are obtained. It is interesting to note that the yield of acylated products largely depends on the counterion of the reduced hydrocarbon species. It is especially high when lithium is used, which is supposed to prevent hydrodimerization of the carboxylic acid by ion-pair formation. In contrast to alkylation, acylation is assumed to prefer an Sn2 mechanism. However, it is not clear if the radical anion or the dianion are the reactive species. The addition of nitriles is usually followed by hydrolysis of the resulting ketimines [211-213]. 

Treatment of aldehydes or ketones with acceptor-substituted carbene complexes leads to formation of enol ethers [1271-1274], oxiranes [1048], or 1,3-dioxolanes [989,1275] by O-alkylation of the carbonyl compound. Carboxylic acid derivatives... 

Matsumura and Bousch (1966) isolated carboxy lest erase (s) enzymes from the soil fungus Trichoderma viride und a bacterium Pseudomonas sp., obtained from Ohio soil samples, that were capable of degrading malathion. Compounds identified included diethyl maleate, desmethyl malathion, carboxylesterase products, other hydrolysis products, and unidentified metabolites. The authors found that these microbial populations did not have the capability to oxidize malathion due to the absence of malaoxon. However, the major degradative pathway appeared to be desmethylation and the formation of carboxylic acid derivatives. 

The most significant change in these reactions is the formation of the carbon-nncleophile bond so, in both types of mechanism, the reaction is termed a nucleophilic addition. It should be noted that the polarization in the carbonyl group leads to nucleophilic addition, whereas the lack of polarization in the C=C donble bond of an alkene leads to electrophilic addition reactions (see Chapter 8). Carbonyl groups in carboxylic acid derivatives undergo a similar type of reactivity to nucleophiles, but the... 

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