Carbonic acid anhydrides active

In solution-phase peptide synthesis, acylation of amino acids or peptides with N-protected azetidine-2-carboxylic acid is performed via the active esters, e.g. A-hydroxysuccin-imide 100 111-112 or pentachlorophenyl ester, m 117 as well as by the mixed anhydride 101114 or carbodiimide 118 methods. An attempt to prepare the A-carbonic acid anhydride by cycli-zation of A-(chloroformyl)azetidine-2-carboxylic acid with silver oxide in acetone or by addition of triethylamine in situ failed, presumably due to steric hindrance. 111 In SPPS, activation of the Fmoc-protected imino acid by HBTU 119,120 is reported. In solution-phase peptide synthesis, coupling of N-protected amino acids or peptides to C-protected azetidine-2-carboxylic acid or related peptides may be performed by active esters, 100 118 121 mixed anhydrides, 95 or similar methods. It may be worth mentioning that the probability of pip-erazine-2,5-dione formation from azetidine-2-carboxylic acid dipeptides is significantly reduced compared to proline dipeptides. 111 ... 

For efficient peptide bond formation acid halides azides 2,b l and Leuchs anhydridesb l were employed as the first activated species in peptide synthesis. Since then, besides considerable improvements to the azide (see Section 3.1) as well as the V-carboxyanhydride 7 procedure d (sgg Section 3.4.3), the methods have evolved over decades along a few basic principles as outlined in Scheme 2. The symmetrical the mixed carboxylic acid 4,b 5s] and the carbonic acid anhydrides were developed and remain useful despite the... 

Alternative paths for decomposition of the metal carboxylate can lead to ketones, acid anhydrides, esters, acid fluorides (1,11,22,68,77,78), and various coupling products (21,77,78), and aspects of these reactions have been reviewed (1,11). Competition from these routes is often substantial when thermal decomposition is carried out in the absence of a solvent (Section III,D), and their formation is attributable to homolytic pathways (11,21,77,78). Other alternative paths are reductive elimination rather than metal-carbon bond formation [Eq. (36)] (Section III,B) and formation of metal-oxygen rather than metal-carbon bonded compounds [e.g., Eqs. (107) (119) and (108) (120). Reactions (36) and (108) are reversible, and C02 activation (116) is involved in the reverse reactions (48,120). 

Peptide bond formation. The process requires that the derivative (42), a carboxylic acid, should be caused to acylate the free base liberated from the hydrochloride (43). Activation of the carboxyl group is effected by conversion into a type of acid anhydride the mixed carbonic anhydride (44) is used here, and is prepared by reaction of the acid (42) with ethyl chloroformate. 

The reaction under consideration is typified by the formation of saturated carboxylic acids from olefins, carbon monoxide, and water. Other compounds have been used in place of olefins (alkyl halides, alcohols), and besides water, a variety of compounds containing active hydrogen may be employed. Thus, alcohols, thiols, amines, and acids give rise to esters, thio-esters, amides, and acid anhydrides, respectively (15). If the olefin and the active hydrogen are part of the same molecule, three or four atoms apart, cyclizations may occur to produce lactones, lactams, imides, etc. The cyclizations are formally equivalent to carbonylations, however, and will be considered later. 

Although rather scant information concerning the structure of active sites in the above copolymerisation systems is available [183-189], cyclic acid anhydrides can be considered as coordinating to metal species via the carbonyl oxygen atom and reacting by nucleophilic attack of the metal substituent on the carbon atom of the coordinated carbonyl group [190,191], Thus, the oxi-rane/cyclic acid anhydride copolymerisation pathway may be presented schematically as follows [82] ... 

Carboxylic acids can be activated in situ as mixed anhydrides B (Figure 6.14) that are mixed anhydrides of a carboxylic acid and a carbonic acid half ester. As can be seen from Table 6.1, in anhydrides of this type the C=0 double bond of the carboxylic acid moiety is stabilized less by resonance than the C=0 double bond of the carbonic acid moiety. Therefore, a nucleophile chemoselectively reacts with the carboxyl carbon of the carboxylic and not the carbonic acid ester moiety. 

The last of these special examples of SN reactions of heteroatom nucleophiles at the carboxyl carbon of a carboxylic acid derivative is given in Figure 6.21. There, the free carboxyl group of the aspartic acid derivative A is activated according to the in situ procedure of Figure 6.14 as a mixed carbonic acid/carboxylic acid anhydride B that is then treated with N,0-dimethylhydroxyl amine. This reagent is an N nucleophile, which is thus acylated to give the... 

For a carboxylic acid and an amine to form an amide, the carboxylic acid usually must be activated that is, it must be converted to a more reactive functional group. Conversion to an acyl chloride is a common way to accomplish this for normal organic reactions (see Chapter 19). However, acyl chlorides are quite reactive and do not give high enough yields in peptide synthesis because of side reactions. Therefore, milder procedures for forming the amide bond are usually employed. In one method the carboxylic acid is reacted with ethyl chloroformate (a half acyl chloride, half ester of carbonic acid) to produce an anhydride. Treatment of this anhydride with an amine results in the formation of an amide ... 

The amino group in Z-Ala is protected as the nonnucleophilic amide half of a carbamate ester. The carboxyl group can be activated without reacting with the protected amino group. Treatment with ethyl chloroformate converts the carboxyl group to a mixed anhydride of the amino acid and carbonic acid. It is strongly activated toward nucleophilic attack. 

All anhydrides derived from an amino acid, other than a symmetrical anhydride, are mixed anhydrides . However, in the field of peptide chemistry, the term mixed anhydride is commonly used to refer to anhydrides derived from an amino acid and either a carboxylic acid 1 or a carbonic acid 2 (Scheme 1). Other mixed anhydrides will be addressed separately. The use of mixed anhydrides 1 and 2 for peptide synthesis encompasses two distinct reaction steps, as outlined in Scheme 2. The first step is the formation of the mixed anhydride, the activation step, which is the reaction of an amino acid derivative 8 with an acid chloride 9, in the presence of a tertiary amine, in an inert solvent to give the mixed anhydride 10. The second step is the condensation of the mixed anhydride 10 with the amine of an amino acid derivative 11 to give peptide product 12 and the carboxylic acid 13. 

Cyanogen bromide, triazine method, cychc trani-2,3-carbonate reaction, carbonylation, periodate oxidation, epoxide activation Curtis azide rearrangement, coupling reagent method, acid anhydride reaction Schiff base formation reaction... 

Mixed anhydrides of carbonic acid half esters contain an activating carbonyl group with reduced electrophilic character (due to lone pairs of electrons on the vicinal oxygen atom) and are rapidly amidated by amines. The anhydride is formed at low temperature in the presence of tertiary amines (equation 5). 

Isobutyl chloroformate is most frequently applied in peptide chemistryfollowed by ethyl chloto-formate (see Table 1). The advantage of this method is that the mixed anhydride does not have to be isolated, and during work-up only carbonic acid half esters are formed, which decompose to an alcohol and carbon dioxide. Only in the case of sterically hindered amino acids does the opening of the anhydride at the undesired carbonyl occur in considerable amounts. Furthermore, short activation times (30 s) at low temperatures lead to peptides with minimal racemization. With isopropenyl chloroformate the mixed anhydride is prepared at room temperature, and during reaction only acetone and carbon dioxide are formed. 

Activation with sulfonic acid chlorides is more general, rendering amides with the possible participation of symmetric anhydrides after disproportionation. This method has also found use in the synthesis of modem 3-lactam antibiotics. However, in peptide chemistry this activation method leads to unwanted side reactions, like formation of nitriles in the cases of glutamine and asparagine, and racemization. In a convenient one-pot procedure, the carboxylic acids are activated by sulfonyl chlorides under solid-liquid phase transfer conditions using solid potassium carbonate as base and a lipophilic ammonium salt as catalyst. ... 

Acid anhydrides in the presence of basic catalysts can be used instead of acyl chlorides in acylation reactions of thiols.Mixed anhydrides of N-protected amino acids and ethyl carbonate yield the corresponding S-f-butyl thiocarboxylic esters, which are useful reagents for peptide syntheses (equation 22). Acylation of thiols with ketenes (equation 23) is a method of long standing. In many cases the yields are nearly quantitative. Functionalities such as acetamino groups or carbon-carbon double bonds in the thiol are not attacked under the mild reaction conditions and optically active thiol esters are obtained without racemization. 3 ... 

The central feature of this reaction is the transformation of an N-oxide to an iminium ion intermediate. Depending upon the N-oxide stmcture and the acid anhydride or other activating reagent employed, this can occur through loss of an a-hydrogen or through fragmentation of a Ca-carbon bond (equation 2). 

Metabolic Role. Biotin picks up carbon dioxide that has been activated by combining with an ATP-donated phosphate, producing the mixed anhydride of phosphoric and carbonic acids (Fig. 8.42). The biotin enolate receives the carbon dioxide, producing the keto carbon dioxide-releasing coenzyme. 

During the enzymic synthesis of carbamyl phosphate (34), two molecules of ATP are involved for every molecule of (34) that is synthesized. One molecule of ATP reacts with bicarbonate to form a mixed anhydride of orthophosphoric and carbonic acids, while the second molecule of ATP phosphorylates the carbamate once it is formed. The half-life of the mixed anhydride is short (two minutes or less), but it can be trapped chemically, and moreover, 0 is transferred from bicarbonate to orthophosphate during this reaction. P P -Diadenosine 5 -polypentaphosphate is an inhibitor of the enzyme from E. coli, while the equivalent diadenosine pyro- and polyhexa-phosphates are not. It has been suggested that the two molecules of ATP and the bicarbonate bind at the active site of the enzyme as shown in (35). Once the enzyme-bound mixed anhydride has been formed, this reacts with glutamine or ammonia to generate the enzyme-bound carbamate, which is finally phosphorylated by the second molecule of ATP (Scheme 10). 

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