A-Acylation

In spite of the routine nature of the chemistry involved in N-acylation (Equation (4.2)), Schotten-Baumann acylation requires an acid chloride as reagent, a compound that can react with the carboxy group as well. The mystification that the consequences of this caused at the time (1962) - since dipeptides and oligopeptides were being formed in this way - actually had a constructive outcome, since the mixed anhydride procedure of peptide-bond formation (Chapter 7) was developed by the workers who unravelled the course of events (Equation (4.2)). 

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The tryptophan side-chain can also be introduced using methyl 2-ethoxy-1-nitroacrylate as an clcctrophile[l 7b]. Vinylation occurs at room temperature by addition elimination. Reduction by SnCl2 followed by acylation generates A -acyl-o(, 3-dehydrotryptophans. 

In the case of the aspidosperma structure, the 5-mcmbcrcd C-ring is constructed from the A -acyl substituent. For the kopsine skeleton, an allyl group is installed and used to form the C6-C20 bridge. 

A number of A/-acyl-. A/-alkyl-, and /V-arylamin on apbtbalenol sulfonic acids are used as couplers for a2o dyes. Examples of such intermediates are shown in Table 8. 

Important analogs of aniline include the toluidines, xyUdines, anisidines, phenetidines, and its chloro-, nitro-. A/-acetyl. A/-alkyl. A/-aryl. A/-acyl, and sulfonic acid derivatives. 

Most derivatives of aniline are not obtained from aniline itself, but ate prepared by hydrogenation of their nitroaromatic precursors. The exceptions, for example, /V-a1ky1ani1ines, /V-ary1ani1ines, sulfonated anilines, or the A/-acyl derivatives, can be prepared from aniline and have been discussed. Nitroanilines are usually prepared by ammonolysis of the corresponding chloronitroben2ene. Special isolation methods may be requited for some derivatives if the boiling points are close and separation by distillation is not feasible. Table 6 Hsts some of the derivatives of aniline that are produced commercially. 

This procedure is restricted mainly to aminodicarboxyhc acids or diaminocarboxyhc acids. In the case of neutral amino acids, the amino group or carboxyl group must be protected, eg, by A/-acylation, esterification, or amidation. This protection of the racemic amino acid and deprotection of the separated enantiomers add stages to the overall process. Furthermore, this procedure requires a stoichiometric quantity of the resolving agent, which is then difficult to recover efficiendy. Practical examples of resolution by this method have been pubUshed (50,51). 

Acylation. A/-Acylation and related reactions ate brought about in straightforward ways with acyl chloride or acid anhydride, although the proximity of the carboxyl group may produce other reactions, eg, oxa2olinone formation, under some conditions. 

In these cases, it is better to protect the carboxyl group. Optimized conditions for A/-acetylation have been studied (78). A/-Acylation can be utilized for protecting the amino group in the reaction of amino acids, for example in peptide synthesis. 

Surfa.cta.nts, Ai-Acylglutamates, sodium A/-lauroyl sarcosinate [137-16-6] and A/-acyl-alanine Na salt are used in the cosmetic field as nontoxic surfactants (237). Some of them (eg, A/-acylglutamic acid dibutylamide) are used as oil geUating agents to recover efduent oil in seas and rivers (238). 

The resulting acetyl compound is usually hydrolyzed with aqueous alkaU to give the free amine. Other A/-acyl derivatives may be used, particularly for the less soluble succinyl and phthaloyl products. The use of -nitrobenzenesulfonyl chloride, followed by reduction of the nitro to an amino function, is much more expensive and is rarely used. A/-Acetylsulfanilyl chloride [121 -60-8] is obtained by the chlorosulfonation of acetanilide [103-84-4] which is the basic material for most of the sulfonamides. 

MonoaLkylation using small alkyl groups of the 1-, 2 - and 3 -amines tends to reduce potency somewhat, whereas alkylation of the 3-amino group reduces activity considerably (147). 1-/V-Alkylation, as in the case of 1-A[-acylation, can lead to resistance to some bacterial resistance reactions, eg,... 

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). 

The steric bulk of the three iodine atoms in the 2,4,6-triiodoben2ene system and the amide nature of the 1,3,5-substituents yield rotational isomers of the 5-A/-acyl-substituted 2,4,6-triiodoisophthalamides. Rotational motion in the bonds connecting the side chains and the aromatic ring is restricted. These compounds also exhibit stereoisomerism when chiral carbon atoms are present on side chains. (R,5)-3-Amino-l,2-propanediol is incorporated in the synthesis of iohexol (11) and ioversol (12) and an (3)-2-hydroxypropanoyl group is used in the synthesis of iopamidol (10). Consequendy, the resulting products contain a mixture of stereoisomers, ie, meso-isomers, or an optical isomer. 

Amidosulfonates. Amidosulfonates or A/-acyl-A/-alkyltaurates, are derived from taurine, H2NCH2CH2S02Na, and are effective surfactants and lime soap dispersants (Table 9). Because of high raw material cost, usage is relatively small. Technically, amidosulfonates are of interest because they are stable to hydrolysis, unaffected by hard water, and compatible with soap. They have been used in soap—surfactant toilet-bar formulations. With shorter, acyl groups, they make excellent wetting agents. 

Substitution of penicillins by 6a-methoxy was found to be compatible with an a-acidic side chain in terms of antibacterial activity, but less beneficial when the side chain contained an a-acyl or a-ureido substituent. However, analogues of the ureido penicillin VX-VC-43 (Table 2) containing a 6a-methoxy substituent (10) were found to combine good stabiUty to P-lactamase and relatively high antibacterial activity (37). Following an extensive program to identify other 6a-substituents that would stabilize the acyl and ureido series of penicillins, the 6a-formamido series (11) represented by formidacillin (BRL 36650) (Table 2) was developed (38). 

The main type of hydrolysis reaction is that of halogenoaryl compounds to hydroxyaryl compounds, eg, the aqueous caustic hydrolysis of 0- and /)-chloronitrobenzene derivatives to nitrophenols. Another important reaction is the hydrolysis of A/-acyl derivatives back to the parent arylamine, where the acyl group is frequently used to protect the amine. 

Resolution of Racemic Amines and Amino Acids. Acylases (EC3.5.1.14) are the most commonly used enzymes for the resolution of amino acids. Porcine kidney acylase (PKA) and the fungaly3.spet i//us acylase (AA) are commercially available, inexpensive, and stable. They have broad substrate specificity and hydrolyze a wide spectmm of natural and unnatural A/-acyl amino acids, with exceptionally high enantioselectivity in almost all cases. Moreover, theU enantioselectivity is exceptionally good with most substrates. A general paper on this subject has been pubUshed (106) in which the resolution of over 50 A/-acyl amino acids and analogues is described. Also reported are the stabiUties of the enzymes and the effect of different acyl groups on the rate and selectivity of enzymatic hydrolysis. Some of the substrates that are easily resolved on 10—100 g scale are presented in Figure 4 (106). Lipases are also used for the resolution of A/-acylated amino acids but the rates and optical purities are usually low (107). 

Fig. 4. Examples of enzymatically resolved A/-acyl amino acids.

In the diaziridine field many compounds are known bearing N-YL, A/-alkyl and A-acyl groups, but here no dramatic changes in reactivity are caused by A-substituents. N-Aryldiaziridines are underrepresented. The ring carbon is in the oxidation state of a carbonyl compound or, in the diaziridinones (5) and the diaziridinimines (6) that of carbonic acid. In single cases, diaziridine carbon bears chlorine or fluorine. 

Ring enlargement of A-acyl compounds, generally observed with oxaziridines, is observed only occasionally with diaziridines. Under more forced conditions of acylation with acetic anhydride, oxadiazolines like (139) were obtained (76MIP50800). A 4-nitrobenzoyl derivative rearranged at room temperature (76JOC3229). 

Halogen-free A/-acyl aldimines and N-acyl ketiimnes tautomenze readily to give enamides [J6] In contrast, perfluonnatedyV-acylimines are stable compounds These electron-deficient itnmes not only exhibit high thermal stability but also show umque properties both as electrophiles and as strongly polanzed hetero-1,3-dienes... 

The reaction of tnfluoromethyl-substituted A -acyl umnes toward nucleophiles in many aspects parallels that of the parent polyfluoro ketones Heteronucleophiles and carbon nucleophiles, such as enarmnes [37, 38], enol ethers [38, 39, 40], hydrogen cyanide [34], tnmethylsilylcarbomlnle [2,47], alkynes [42], electron-nch heterocycles [43], 1,3-dicarbonyl compounds [44], organolithium compounds [45, 46, 47, 48], and Gngnard compounds [49,50], readily undergo hydroxyalkylation with hexafluoroace-tone and amidoalkylation with acyl imines denved from hexafluoroacetone... 

Electrophilic aromatic substitution (Section 22.14) Arylamines are very reactive toward electrophilic aromatic substitution. It is customary to protect arylamines as their A/-acyl derivatives before carrying out ring nitration, chlorination, bromination, sulfonation, or Friedel-Crafts reactions. 

FIGURE 18.23 The structure of coeuzytne A. Acyl groups form thioester Uukages with the —SH group of the /3-mercaptoethylamiue moiety. 

Carbamates can be used as protective groups for amino acids to minimize racem-ization in peptide synthesis. Racemization occurs during the base-catalyzed coupling reaction of an A-protected, carboxyl-activated amino acid and takes place in the intermediate oxazolone that forms readily from an A-acyl-protected amino acid (R = alkyl, aryl) ... 

The B SE group was used for intemucleotide protection and is removed with ammonia, also used to remove A -acyl protective groups. Compared with the methylsulfonylethyl group, the B SE group has better solubility properties for solution phase synthesis. ... 

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