Acyl activated acids

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. 

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. 

Mocimycin has been chemically converted to aurodox by protection of the 4-hydroxy group at the pyridone moiety as the benzoylformate, followed by /V-methylation and hydrolytic removal of the protective group (1,55). Whereas aurodox esters are active growth promotors in animals, goldinamines that are A/-acylated by acids other than goldinonic acid, such as acetic, benzoic, or arylsulfonic acids, lack useful antimicrobial or growth-promoting activity (1). 

Methylation of 1-hydroxyindoles can be achieved readily by the reaction with diazomethane, Mel, orMc2S04 in the presence of an appropriate base, as described in previous reviews (79MI1, 90AHC105, 91YGK205, 99H1157). Alkylation and acylation also work well with alkyl halides, acyl halides, acid anhydrides, and acids in the presence of acid activators such as DCC and so on. 

Dialkyl phosphites react with acyl halides such as lauroyl chloride to yield surface-active acid esters of acylphosphonic acid [84-87] see Eq. (40). 

Imidazolides can also be activated by N-alkylation with methyl triflate.116 Imidazolides react with alcohols on heating to give esters and react at room temperature with amines to give amides. Imidazolides are particularly appropriate for acylation of acid-sensitive materials. 

Another -activation of amino acids for peptide synthesis is achieved by preparing sulfenamides from sulfenylimidazoles. A sulfenylimidazole is formed in situ from the sulfenyl chloride (prepared from the disulfide and chlorine) and imidazole, which reacts further with an amino acid ester to give a sulfenamide in high yield. Conversion of such sulfenamides with IV-acyl amino acids by means of triphenylphosphine affords dipeptides with racemization of less than 0.5%.[481... 

Bergman described indole C-3 acylation with acid chlorides via 1-indolylzinc chloride in the absence of palladium [108]. Davidsen and co-workers synthesized 86, which is a potent antagonist of platelet activating factor-mediated effects, using this Bergman acylation sequence... 

Owing to steric hindrance, the acylation reaction must be carried out using a large excess (4-10 Eq.) of the activated acid and for an extended period. In some cases, repeat acylation is recommended. Acylation has also been successfully carried out using Fmoc-amino acid fluorides (e.g., Fmoc-Phe-F4, 4Eq. in the presence of DIEA, 1.1 Eq. 18h >98% acylation efficiency). While acylation with unhindered activated carboxylic acids are achieved in >98%, acylation with hindered carboxylic acids generally resulted in ca. 80% efficiencies. 

Co(III)-chelated amino acid ester reactant and/or peptide product (Scheme 1). This basic difficulty was quickly pointed out (5), and has subsequently been examined and commented upon by others (6, 7). Such criticisms are well-founded since epimerization (or racemization) is a common problem, at least to some degree, in all chemical methods of synthesis where acyl-activation is employed. As a result, metal-activation methods have received little attention. However, since 1981 we have refined the Co(III) method such that very fast, clean, couplings can now be carried out using A-[Co(en)2((S)-AAOMe)]3+ reagents, which involve minimal (<2%) epimerization/racemization provided experimental conditions are strictly adhered to. 

Fig. 8.26. The two-step activation of oxazolidin-5-one derivatives of peptides and N-acy/ amino acids (8.190). Hydrolysis (Reaction a) yields an A-(l-hydroxyalkyl) derivative that breaks down to liberate the peptide or A-acyl amino acid (Reaction b) [247] [248],...

Some enzymes are nonfunctional until posttranslationally modified. Examples of these enzymes include the acyl- and carboxyltransferases. While lipoate and phosphopantetheine are necessary for acyl transfer chemistry, tethered biotin is used in carboxyl transfer chemistry. Biotin and lipoate tethering occur under a similar mechanism the natural small molecule is activated with ATP to form biotinyl-AMP or lipoyl-AMP (Scheme 20). A lysine from the target protein then attacks the activated acid and transfers the group to the protein. The phosphopantetheine moiety is transferred using its own enzyme, the phosphopantetheinyltrans-ferase (PPTase). The PPTase uses a nucleophilic hydroxy-containing amino acid, serine, to attach the phosphopantetheinyl (Ppant) arm found in coenzyme A to convert the apo (inactive) carrier protein to its holo (active) form. The reaction is Mg -dependent. 

The natural substrates of lipases are triglycerides and, in an aqueous environment, lipases catalyze their hydrolysis into fatty acids and glycerol. In anhydrous media, lipases can be active in the reverse reaction [19]. In fact, in the acylation step, acids, lactones, (cyclic) carbonates [20, 21], cyclic amides [22, 23], (cyclic) thioesters [24, 25], and cyclic phosphates [26] have been found to act as suitable acyl donors. In the deacylation step, apart from water, lipases also accept alcohols [27], amines [28, 29], and thiols [30] as nucleophiles although the specificity of lipases is lower for amines and thiols than for water and alcohols [31]. 

Synthesis of fatty acids via the malonyl CoA pathway does not proceed beyond palmitic acid (C16 0) and mammary tissue contains an enzyme, thioacylase, capable of releasing the acyl fatty acid from the carrier protein at any stage between C4 and C16. Probable interspecies differences in the activity of thioacylase may account for some of the interspecies differences in milk fatty acid profiles. 

In acylation with acidic ammonium and cesium salts of phosphotungstic acid, direct correlation was found between activity and the number of accessable Br0nsted acid sites.69,70 Moreover, cesium salts were found to be more active, than HY and H-Beta zeolites.70... 

Hydroboration of a variety of alkenes and terminal alkynes with catecholborane in the fluorous solvent perfluoromethylcyclohexane was performed using fluorous analogs of the Wilkinson catalyst.135 136 Recycling of a rhodium-based alkene hydrosilylation catalyst was also successful.137 Activated aromatics and naphthalene showed satisfactory reactivity in Friedel-Crafts acylation with acid anhydrides in the presence of Yb tris(perfluoroalkanesulfonyl)methide catalysts.138... 

Figure 14-1 Coenzyme A, an acyl-activating coenzyme containing the vitamin pantothenic acid.

Activation of amino acids for incorporation into oligopeptides and proteins can occur via two routes of acyl activation. In the first of these an acyl phosphate (or acyl adenylate) is formed and reacts with an amino group to form a peptide linkage (Eq. 13-4). The tripeptide glutathione is formed in two steps of this type (Box 11-B). In the second method of activation aminoacyl... 

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. 

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