Reaction with carboxylic aids

Pd -catalyzed hydrocarboxylation of aromatic olefins leads directly to the requisite carboxylic acids (cf. Section 2.1.2.2) under mild conditions (Scheme 5). The reaction, with the aid of (5)-BNPPA (21), a chiral hydrogen phosphate, gives regio- and enantioselectively (S)-ibuprofen and (S)-naproxen, but the turnover efficiency as well as the enantioselectivity can still be improved [26]. 

However, if we can design some sophisticated routes to generate carbanion equivalents in the active site of the enzyme, carboxylation reaction might be possible. In fact, acetyl-CoA is carboxylated with the aid of biotin in the biosynthetic pathway of long-chain fatty acids. 

The decarboxylation reaction usually proceeds from the dissociated form of a carboxyl group. As a result, the primary reaction intermediate is more or less a carbanion-like species. In one case, the carbanion is stabilized by the adjacent carbonyl group to form an enolate intermediate as seen in the case of decarboxylation of malonic acid and tropic acid derivatives. In the other case, the anion is stabilized by the aid of the thiazolium ring of TPP. This is the case of transketolases. The formation of carbanion equivalents is essentially important in the synthetic chemistry no matter what methods one takes, i.e., enzymatic or ordinary chemical. They undergo C—C bond-forming reactions with carbonyl compounds as well as a number of reactions with electrophiles, such as protonation, Michael-type addition, substitution with pyrophosphate and halides and so on. In this context,... 

Several pharmaceutical enzymes belong to the group of serine-histidine estero-proteolytic enzymes (serine proteases), which display their catalytic activity with the aid of an especially reactive serine residue, whoso p-hydroxyi group forms a covalent bond with the substrate molecule. This reaction takes place by cooperation with the imidazole base of histidine. The specificity of the enzymes is achieved by the characteristic strocture of their substrate-binding centers, which in these proteases are built according to the same principle. They consist of a hydrophobic slit formed by apolar aide chains of amino acids and a dissociated side chain-located carboxyl group of an aspartic add residue at the bottom. 

Sulphonic acids are usually esterified with diazomethane [121] by methods analogous to those used for the preparation of esters of carboxylic acids (see p. 54). If the reaction starts from the salts, it is necessary to convert them into acids either by direct acidification or with the aid of a cation-exchange resin in the H+ form. 

The reaction of methyl 1/7-azepine-l-carboxylate with A,a-diphenylnitrone yields [2 -I- 3] dipolar cycloaddition products (28) as a mixture of exo- and e /o-isomers <92H(34)497>, the structures of which were assigned with the aid of LAOCOON III simulated NMR spectra. The almost equal distribution of isomers at C5 and the absence of any tra 5-product favors a concerted 1,3-dipolar addition rather than the involvement of a stepwise ionic mechanism, since in a stepwise reaction the conformational flexibility of the azepine ring would allow the second bond to be formed on either face of the azepine ring. 

Sequence distribution and chemical structure of mass-selected macromolecules of macroinitiators derived from selected biopolyesters were accomplished recently with the aid of ESI-Mtechnique. The NMR and ESI-MS evaluation of the chemical structure of macroinitiators obtained by partial depolymerization of natural PHB, PHBV and PHO revealed that due to the elimination reaction they contain olefinic and carboxylic end groups. Based on the ESI-MS" studies of PHBV macroinitiator obtained by partial alkaline depolymerization of natural PHBV (containing 5 mole % of hydroxyvalerate units) the microstructure of this bacterial copolyester was assessed, starting from dimer up to the oligomer containing 22 repeat units. ... 

The synthesis of the second building block [62] for meropenem starts from trans-hydroxyproline. First, the amino acid is protected on both, the amino and the carboxyl group. By reaction with thioacetic acid m a Mitsunobu esterification, the thiol ftmction is introduced, and the carboxyl group is then selectively deprotected with trifluoroacetic add. The dimethylamino-group is introduced with the aid of isopropyl chloroformate, and the thiol acetate is finally hydrolysed with aqueous sodium hydroxide. 

As can be seen from these examples, a great number of exceptional carboxylic acids can be prepared starting from CO2 with the aid of nickel complexes, but up to the present only stoichiometrically. However, if phenyl isocyanate is used which has a structure very analogous to carbon dioxide, a catalytic reaction with ethene occurs in the presence of nickel(0) complexes [17]. When a mixture of phenyl isocyanate, nickelbis(cyclooctadiene) and triphenylphosphine is initially treated with ethene under pressure (3 bar) at -50°C and then heated for 2 d at 60 C, acrylanilide is obtained after protonation in about 180 % yield with respect to nickel(0). This corresponds to 1,8 catalytic cycles (Figure 7). 

Dithioacetals, 1,3-dithianes or 13-dithiolanes are prepared by reaction of the corresponding carbonyl compound in the presence of an acid catalyst (cone. HQ, Lewis acids such as Znh, BFs EtaO, TMS-Cl, etc.) with a thiol or dithiol. Silica gel treated with thionyl chloride was found to be an effective as well as selective catalyst for thioacetalization of aldehydes. Thioacetalization can also be achieved using a (polystyryl)diphenylphosphine-4odine complex as a catalyst Conversion of aldehydes or acetals into 1,3-dithianes is achieved with the aid of organotin thioalkoxides and organotin triflates or with 2,2-di-methyl-2-sila-l,3-dithiane. Direct conversion of carboxylic acids to 1,3-dithianes can be carried out by reaction with 1,3,2-dithiabomenane-dimethyl sulfide and tin(II) chloride or 1,3,2-dithiaborolene with trichloromethyllithium followed by basic hydrolysis. 

To circumvent this uncertainty without use of the caesium salt procedure, hydroxymethyl [87] or aminomethyl functions on the polymer can be reacted with carboxylic partners in an esterification reaction [207] or peptide bond formation with the aid of condensing agents like carbonylbisimidazole [88], dicyclohexylcarbodiimide [89] or others. For this purpose in the author s laboratory the use of symmetric anhydrides [3] of the N-protected amino acids to be attached to the support was found to be most effective [90], especially in the formation of activated esters on the gel phase with phenolic hydroxyl functions [38]. By this procedure, on 0.5% cross-linked polystyrenes, load levels up to 1.5 millimoles/g of the support are reached. 

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