IV-Acylamino acids

NL Benoiton, YC Lee, FMF Chen. Studies on asymmetric induction associated with the coupling of iV-acylamino acids and /V-ben/.yloxycarbonyldi peptides. Ini J Pent Prot Res 38, 574, 1991. 

TABLE 7.21. iV-ACYLAMINO ACID ESTERS FROM ALCOHOLYSIS OE SATURATED 5(4i7)-OXAZOLONES... 

The favorable effect of the enamide function on asymmetric induction is indicated not only by the result with compound I, but also by later results summarized in Table I, where optical purities in the range of 70 to 80% were generally obtained for various derivatives of alanine, phenylalanine, tyrosine, and 3,4-dihydroxyphenylalanine (DOPA). The Paris group found that the Rh-(-)-DIOP catalyst yielded the unnatural R or d -amino acid derivatives, whereas l-amino acid derivatives could be obtained with a (+)-DIOP catalyst. Since the optical purity of the IV-acylamino acids can often be considerably increased by a single recrystallization (fractionation of pure enantiomer from racemate) and the IV-acetyl group can be removed by acid hydrolysis, this scheme provides an excellent asymmetric synthesis route to several amino acids. 

The use of homochiral complexation agents to separate the fluorine-19 chemical shifts of enantiomers containing fluorine has also been examined. Addition of the supported dipeptide 9 to a solution of the racemic iV-acylamino acid ester 10 in carbon tetrachloride leads to the appearance of two CF3 peaks corresponding to the two enantiomers. The separation is obviously concentration-dependent, but peak separation was sufficient for mixtures of enantiomers to give enantiomeric excesses comparable with those determined by gc analysis55. 

The catalyst for cleavage of peptide deformylase was searched with a library of catalyst candidates synthesized by the Ugi reaction (Scheme 2) (134). In this multicomponent condensation reaction, the mixture of a carboxylic acid, an amine, an aldehyde, and an isocyanide produces an iV-acyl amino acid amide. The catalyst candidates, therefore, are iV-acylamino acid amides containing various polar and nonpolar pendants as well as the Co(III) complex of cyclen. The Co(III) complex of cyclen (135) was chosen as the proteolytic center in view of the results described in Section V.A. Cyclen with three secondary amines protected with ferf-butyloxycarbonyl (t-boc) groups was incorporated in either the carboxyl or the amine component of the Ugi reaction. Later, the t-boc groups were removed and Co(III) ion was inserted to the cyclen portion. 

Similar to the work of Anderson and in continuation of their proline-derived munchnone generation and DMAD trapping (116 117), Laduree and co-workers also used the reaction between the munchnones derived from cyclic IV-acylamino acids 175 and 177 and DMAD to prepare a series of potential new antileukemic agents derived from cycloadducts 176 and 178 (Fig. 4.63). 

Intramolecular 1,3-dipolar cycloadditions represent a powerful synthetic tool. Kato and co-workers were apparently the first to report an intramolecular munchnone-alkyne cycloaddition. Thus munchnones 184, as generated from iV-acylamino acids 183, yield the corresponding benzopyrano[4,3-f ]pyrroles 186 after extrusion of carbon dioxide from adduct 185 (Fig. 4.65). The yields shown are for high-dilution reaction conditions. Under normal conditions of concentration, the yields are stiU about 60%. Interestingly, attempts to divert the intramolecular cycloaddition by the addition of A -phenylmaleimide had no effect on the reaction pathway. 

Clerici and co-workers investigated the behavior of munchnones with isothiazole 1,1-dioxide 241. As shown in Table 4.17, the products 242 are formed in good yields, along with minor amounts of the tautomeric imine (not shown). The azalactones-munchnones were generated from the corresponding iV-acylamino acids and acetic anhydride. 

Most of the enzymatic peptide forming reactions are strictly stereo-specific for L-amino acids so that racemization that often accompanies chemical coupUng of optically active amino acids does not occur. The formation of only the L-amino acid derivative out of a D,L-mixture, in an enzymatic formation e.g. of an anilide from a D,L-Z-amino acid ester and aniUne, makes proteolytic enzymes useful reagents for the resolution of racemic mixtures. This is supplementary to the enzymatic stereospecific deacylation of D,L-iV-acylamino acid mixtures where exclusively the L-derivative will be deacylated. 

The substituted aryl esters prepared and examined as potential acylating agents are too numerous to be described here. They are discussed in a comprehensive review article [24]. Yet, the studies of J. Pless and R.A. Biossonnas [25] should be mentioned even in this brief presentation. Based on an extensive comparison of substituted phenyl esters, they chose the 2,4,5-tri-chlorophenyl esters of iV-acylamino acids as practical acylating agents, a choice fairly well accepted by several laboratories. The powerful pentafluorophenyl esters introduced by J. Kovacs, L. Kisfaludi and M.Q. Ceprini in 1967 [26] has gained importance in recent years through their application in solid phase peptide synthesis. 

FIG. 22 Relationship between biodegradability and acyl chain length of iV-acylamino acids time required for 25% of theoretical decomposition. (From Ref. 103.)... 

FIG. 24 Relationship between the hydrophobicity and the hemohtiactivity (HD ) or denaturation of Cuj-Transfeiine (DD50) of iV-acylamino acids. (From Ref. 49.)... 

Carbonylation Reactions. A three-component palladium-catalyzed amidocarbonylation reaction provides IV-acylamino acids from aromatic and aliphatic aldehydes or acetals with amides under elevated CO pressure (60 bar) in the presence of PdBr2, PPhs, LiBr, an acid additive (typically H2SO4), and iV-methyl-2-pyrrolidone. Mechanistically, the palladium-catalyzed amidocarbonylation reaction is proposed to proceed through the in situ formation of an a-haloamide and Pd(0) species, which can undergo oxidative addition, followed by CO insertion, and lastly hydrolysis of the acyl palladium complex to afford the product and regenerate the catalyst (eq 45). 

An iV-acylamino acid (1) is reacted with thionyl chloride yielding the oxazolone (2), which by treatment with an aroyl chloride gave (3). The latter compound was hydrolysed and decarboxylated to yield (4), which reacted with chlorosulfonic acid-thionyl chloride to give the sulfonyl chloride, and subsequent reaction with ammonia afforded the sulfonamide (5) (Scheme 1). 

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