Stille acylation

Another large successful commercial application of enzymes is in the amino acid industry. Amino acids for food and feed fortification, nutritional supplements, or as feedstock for downstream products can be made by fermentation processes, from protein hydrolysates or by chemical synthesis. While chemical synthesis is cheaper for a number of amino acids,, it often produces a racemic mixture. The racemic mixture is successfully resolved on a commercial scale by acylating the amino acids, then using an aminoacylase to remove the acyl group from the L-amino acid and separating the free L-amino acid from the still acylated-D-amino acid. Ajinamoto and other companies, especially in Japan, make large amounts of amino acids by this process. 

Acyl halides, both aliphatic and aromatic, react with the sodium derivative, but the product depends largely on the solvent used. Thus acetyl chloride reacts with the sodium derivative (E) suspended in ether to give mainly the C-derivative (t) and in pyridine solution to give chiefly the O-derivative (2). These isomeric compounds can be readily distinguished, because the C-derivative (1) can still by enolisation act as a weak acid and is therefore... 

This acylation might still be assumed to proceed via the aminocyclobutanone with subsequent rearrangement, but it was shown (75) that the hydrochloride salt of the aminocyclobutanone (101), prepared by an alternate method, was not rearranged under the reaction conditions. The intermediacy of (101)... 

The treatment of enamines with acid halides which possess no a hydrogens results in the simple acylation of the enamine (7,12,62-67). If the acid halide possesses an a hydrogen, however, ketenes are produced in situ through base-catalyzed elimination of hydrogen chloride from the acid halide. The base catalyst for this reaction may be the enamine itself or some other base introduced into the reaction mixture such as triethylamine. However, if the ketene is produced in situ instead of externally, there still remains the possibility of a side reaction between the acid halide and the enamine other than the production of ketene (67,84). 

Such methyenepyrans afford still another possibility for obtaining new pyrylium salts, namely, electrophilic alkylation or acylation at the exocyclio methylene carbon atom. Thus, 2,6-diphenyl-4-iso-propylidene-4/I-pyran is converted into 2,6-diphenyl-4-i-butyl-pyrylium iodide on refluxing with methyl iodide (see Scheme 3). Unlike the protonation of methylenepyrans, this reaction is no longer... 

Introduction of an additional methyl group on the donor atom of TMM moiety gives a low 33% yield of the perhydroindans (49, X=H2) and (50, X=H2) with substantial production of the diene by-products [24]. However, it is still remarkable that the reaction works at all since the corresponding intermolecular cycloaddition failed. Incorporation of a carbonyl moiety adjacent to the donor carbon atom doubles the yield of the cycloadducts to 66% (Scheme 2.15). This so-called acyl effect works by making the donor carbon of the TMM unit "softer," thus facilitating the initial step of the conjugate addition, as well as inhibiting base-induced side reactions [22]. 

With acyl halides, the corresponding acyl phosphonates are obtained. Furthermore allylic and acetylenic halides, as well as a-halogenated carboxylic esters and dihalides, can be used as starting materials. If substituents R and R are different, a mixture of products may be obtained, because the reaction product RX 5 can further react with phosphite 1 that is still present ... 

It was almost immediately recognised that the deacylated product, 7-aminocephalosporanic add (7-ACA, Figure 6.16), would be of similar importance as was 6-APA in the development of new penidllins. However, 7-ACA, the cephalosporin equivalent of 6-APA, could not be found in fermentations of Cephalosporin acremonium. In Figure 6.15 we have shown that penicillin acylase hydrolyses the acyl residue from natural cephalosporins. Up to a point this is true. These acylases will, however, only work with a limited range of acyl residues. It now seems that nature does not provide for acylases or transacylases that have the capacity to remove or change the D-a-aminoadipyl side chain of cephalosporin C efficiently in a single step. Widespread search for such an enzyme still remains unsuccessful. 

In addition, nonenzymatic acylation of cysteine thiols on proteins incubated in the presence of acyl-CoA has been described, although the biological importance of this process is still unclear. 

Diaryl sulfones can be formed by treatment of aromatic compounds with aryl sulfonyl chlorides and a Friedel-Crafts catalyst. This reaction is analogous to Friedel-Crafts acylation with carboxylic acid halides (11-14). In a better procedure, the aromatic compound is treated with an aryl sulfonic acid and P2O5 in polypho-sphoric acid. Still another method uses an arylsulfonic trifluoromethanesulfonic anhydride (ArS020S02CF3) (generated in situ from ArS02Br and CF3S03Ag) without a catalyst. ... 

The exact mechanism has still not been completely worked out. Opinions have been expressed that it is completely intermolecular, completely intramolecular, and partially inter- and intramolecular. " One way to decide between inter- and intramolecular processes is to run the reaction of the phenolic ester in the presence of another aromatic compound, say, toluene. If some of the toluene is acylated, the reaction must be, at least in part, interraolecular. If the toluene is not acylated, the presumption is that the reaction is intramolecular, though this is not certain, for it may be that the toluene is not attacked because it is less active than the other. A number of such experiments (called crossover experiments) have been carried out sometimes crossover products have been found and sometimes not. As in 11-14, an initial complex (40) is formed between the substrate and the catalyst, so that a catalyst/substrate molar ratio of at least 1 1 is required. 

In another nonelectrolytic process, arylacetic acids are converted to vi c-diaryl compounds 2A1CR2COOH —> ArCR2CR2Ar by treatment with sodium persulfate (Na2S20g) and a catalytic amount of AgNOs." Both of these reactions involve dimerization of free radicals. In still another process, electron-deficient aromatic acyl chlorides are dimerized to biaryls (2 ArCOCl —> ArAr) by treatment with a disilane RsSiSiRs and a palladium catalyst." " ... 

Since the pioneering work of H. J. Bestmann and coworkers in the 1960s, acylation of phosphonium ylides is a well known process for the preparation of P-ox-ophosphonium yhdes. The classical way (a) using acylating agents such as acyl chlorides and in situ transylidation is still useful (Scheme 4) [16,17]. 

Other reactions not described here are formal [3 -i- 2] cycloadditions of a,p-unsaturated acyl-fluorides with allylsilanes [116], or the desymmetrization of meso epoxides [117]. For many of the reactions shown above, the planar chiral Fe-sandwich complexes are the first catalysts allowing for broad substrate scope in combination with high enantioselectivities and yields. Clearly, these milestones in asymmetric Lewis-base catalysis are stimulating the still ongoing design of improved catalysts. 

---