Amide-forming coupling processe

Sulfite reductases contain siroheme and iron-sulfur centers. Siroheme, also present in some nitrite reductases, is an iron tetrahydroporphyrin of the isobacteriochlorin type with eight carboxylic acid side-chains (Fig. 1). Siroheme isolated from Desulfovibrio species was found to be a monoamide, heptamethyl ester derivative, rather than the usual octamethyl ester derivative, which suggests that in these organisms an amidated form of the siroheme may be the physiologically active prosthetic group [93]. Sulfite reductases are divided into two classes, the assimilatory and the dissimilatory enzymes. The assimilatory sulfite reductases produce sulfide for use in the cell biosynthetic pathways. The dissimilatory enzymes are present in the sulfate-reducing organisms, and reduce sulfite as a respiratory substrate in a process coupled to ATP formation. 

Palladium-catalyzed carbonylation of organic halides to form esters, amides, ketones, and aldehydes (Equation 17.58) has been studied and reviewed extensively. " These reactions are closely related to the palladium-catalyzed cross-coupling processes presented in Chapter 19. However, the addition of CO to ttiese processes generates organic carbonyl compounds, rather than products from direct cross coupling. 

The intermolecular a-arylation of amides with aryl chlorides was unknown until very recently. Fortunately, the work developed by Walsh and coworkers [93] has demystified the theme. Aryl chlorides are generally less reactive than aryl bromides in oxidative additions nonetheless, aryl chlorides are less expensive and more readily accessible when compared with aryl bromides, making their use in cross-coupling reactions highly desirable. Walsh and coworkers reported the first deprotonative cross-coupling process for the intermolecular arylation of amides with aryl chlorides. Buchwald-type [94] precatalysts formed with Kwong s [95] indole-based phosphane ligand effectively catalyzes the... 

A substantial number of bioactive molecules, such as polypeptides, N-acetyl-DL-penicillamine, p-(dipropylsulfamoyl)benzoic acid, and nicotinic acid, contain a carboxylic acid function, and this provides a site for linkage to a polyphosphazene chain. A number of prototype polymers have been synthesized in which pendent amino groups provide coupling sites for the carboxylic acid (34). The amide linkages so formed are potentially bioerodible, but the use of a hydrolytic sensitizing cosubstituent would be expected to accelerate the process. 

Figure 4.3 In aqueous solution, a sulfo-NHS ester can either couple to an amine group to form an amide bond or react with water to hydrolyze back to a carboxylate. Both processes release the sulfo-NHS leaving group.

Carbodiimide coupling to carboxylate-containing QDs usually involves the use of EDC in a single-step or two-step process to form an amide bond. If a one-step reaction is done, the QD is activated with EDC in the presence of an amine-containing molecule, such as a protein. Many protocols use this method, but it can result in protein polymerization in addition to coupling, because proteins contain both carboxylates and amines. A two-step protocol results in better control of the reaction (Figure 9.61). In the first step, EDC is used in the presence of sulfo-NHS to activate the carboxylates on the particles to intermediate sulfo-NHS esters. After a quick separation step to remove excess reactants, the activated QDs are added to the protein solution to be coupled. This then results in amide bond formation without polymerization of the protein in solution. See Chapter 3, Section 1 and Chapter 14, Section 1 for additional information on this process. 

Acyl residues are usually activated by transfer to coenzyme A (2). In coenzyme A (see p. 12), pantetheine is linked to 3 -phos-pho-ADP by a phosphoric acid anhydride bond. Pantetheine consists of three components connected by amide bonds—pantoic acid, alanine, and cysteamine. The latter two components are biogenic amines formed by the decarboxylation of aspartate and cysteine, respectively. The compound formed from pantoic acid and p-alanine (pantothenic acid) has vitamin-like characteristics for humans (see p. 368). Reactions between the thiol group of the cysteamine residue and carboxylic acids give rise to thioesters, such as acetyl CoA. This reaction is strongly endergonic, and it is therefore coupled to exergonic processes. Thioesters represent the activated form of carboxylic adds, because acyl residues of this type have a high chemical potential and are easily transferred to other molecules. This property is often exploited in metabolism. 

In a subsequent paper on the use of the Stille reaction to form biaryls,58 the reaction was carried out under ambient conditions to allow robotic automation of the process. Attachment of the tin species to resin was very straightforward, in that 4-tri-n-butylstannylphenyl acetic acid was linked to Rink amide resin simply using a DIC coupling. Loading of this species was determined by tin elemental analysis and correlated with a quantitative ninhydrin test of free amines remaining on the support (Scheme 24). 

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