Anhydrides mixed carboxylic-carbonic

MnClj. The chloromanganese reagents can be used in THF, a more satisfactory solvent for the synthesis of ketones from mixed carbonic-carboxylic anhydrides (prepared by the reaction of carboxylic acids with ethyl chloroformate). 

Anderson, G.W. Zimmermann, J. G. Callahan, E M., Racemization Control in the Synthesis of Peptides by the Mixed Carbonic-Carboxylic Anhydride MethodPJ.Am. Chem. Soc. 1966, 88, 1338. 

A resin with mixed carbonic-carboxylic anhydride function has been prepared and used as acylating reagent [144], Thus, the supported chloroformate 140 was obtained by reaction of hydroxymethylated polystyrene with phosgene in benzene (Scheme 7.43). Further treatment with benzoic acid in the presence of triethyl-amine in benzene gave rise to the supported mixed anhydride 141. This polymer has been used in the benzoylation of several amines, although variable amounts of benzoic acid from attack to the internal carbonyl were obtained when using aromatic amines. 

The polymer-bound mixed carbonic carboxylic anhydrides have re-... 

Tessler, M.M. and Rutenberg, M.W. (1972) Process for Reacting Ungelatinized Starch with a Mixed Carbonic -Carboxylic Anhydride of a Polycarboxylic Acid, U.S. Patent 3,699,095... 

JR Vaughan, RL Osato. The preparation of peptides using mixed carbonic-carboxylic acid anhydrides. J Am Chem Soc 74, 676, 1952. 

Attempts to synthesize C-terminal peptide aldehydes using other reductive techniques are less successful. 24"29 The reduction of a-amino acid esters with sodium amalgam and lithium aluminum hydride reduction of tosylated a-aminoacyldimethylpyrazoles resulted in poor yields. 26,29 The Rosemond reduction of TV-phthaloyl amino acid chlorides is inconvenient because the aldehyde is sensitive to hydrazine hydrate that is used to remove the phthaloyl group. 27 28 jV -Z-Protected a-aminoacylimidazoles, which are reduced to the corresponding aldehydes using lithium aluminum hydride, are extremely moisture sensitive and readily decomposed. 25 The catalytic reduction of mixed carbonic/carboxylic acid anhydrides, prepared from acylated a-amino acids, leads to poor reproducibility and low yields. 24 The major problems associated with these techniques are overreduction, racemization, and poor yields. 

Scheme 1 Mixed Carboxylic Acid Anhydrides 1, Mixed Carbonic Acid Anhydrides 2, Symmetrical Anhydrides 3, Al-Carboxyanhydrides 4, iV-Thiocarboxyanhydrides 5, Al-Substituted iV-Carboxyanhydrides 6, and Urethane-Protected Al-Carboxyanhydrides 7...

Then the 7,8-diaminononanoate (7,8-diaminopelargonic acid) (Scheme 12.93) is converted to the bisamide dethiobiotin (an imidazolidone) by carboxylation with carbon dioxide (CO2) in the presence of ATP in a reaction requiring magnesium (Mg+ ) and catalyzed by dethiobiotin synthase (EC 6.3.3.3). The well-known reversible reaction of amines with carbon dioxide (CO2) and an X-ray crystal structure showing the 8-amino group as a mixed carbonic phosphate anhydride has lent support to this picture (PDB la82). Finally, in the presence of biotin synthase (EC 2.8.1.6), an enzyme that appears to be used only once in each synthesis, reaction occurs with 2 equivalents (but almost certainly one at a time) of SAM and sulfur to produce biotin, 2 equivalents of methionine (Met, M), and 2 equivalents of 5 -deoxyadenosine. 

The synthesis of key intermediate 12, in optically active form, commences with the resolution of racemic trans-2,3-epoxybutyric acid (27), a substance readily obtained by epoxidation of crotonic acid (26) (see Scheme 5). Treatment of racemic 27 with enantio-merically pure (S)-(-)-1 -a-napthylethylamine affords a 1 1 mixture of diastereomeric ammonium salts which can be resolved by recrystallization from absolute ethanol. Acidification of the resolved diastereomeric ammonium salts with methanesulfonic acid and extraction furnishes both epoxy acid enantiomers in eantiomerically pure form. Because the optical rotation and absolute configuration of one of the antipodes was known, the identity of enantiomerically pure epoxy acid, (+)-27, with the absolute configuration required for a synthesis of erythronolide B, could be confirmed. Sequential treatment of (+)-27 with ethyl chloroformate, excess sodium boro-hydride, and 2-methoxypropene with a trace of phosphorous oxychloride affords protected intermediate 28 in an overall yield of 76%. The action of ethyl chloroformate on carboxylic acid (+)-27 affords a mixed carbonic anhydride which is subsequently reduced by sodium borohydride to a primary alcohol. Protection of the primary hydroxyl group in the form of a mixed ketal is achieved easily with 2-methoxypropene and a catalytic amount of phosphorous oxychloride. 

FMF Chen, M Slebioda, NL Benoiton. Mixed carboxylic-carbonic acid anhydrides of acylamino acids and peptides as a convenient source of 2,4-dialky 1 -5(AH)-oxazo-lones. Int J Pept Prot Res 31, 339, 1988. 

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 ... 

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. 

All other carboxylic acid derivatives in Table 6.1, in which the leaving group is bound to the carboxyl carbon through an O atom, are increasingly better acylating agents than carboxylic acid alkyl esters (entry 3) in the order carboxylic acid phenyl ester (entry 4) < acyl isourea (entry 7) < mixed carboxylic acid/carbonic acid anhydride (entry 8) < carboxylic acid anhydride (entry 9) < mixed carboxylic acid anhydride (entry 10). 

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... 

Next, the carboxylate anion participates in an addition-elimination reaction with isobutyl chloroformate. Elimination of a chloride anion results in formation of intermediate A. These reactions are generally facilitated by the introduction of an amine base such as triethylamine (not shown in this problem). The mechanism is illustrated below using arrow pushing, and the illustrated product belongs to a class of compounds known as mixed carbonic anhydrides. 

In the studies of the synthesis of the ansamycin antibiotic rifamycin S (13S), Corey and Clark [76] found numerous attempts to effect the lactam closure of the linear precursor 132 to 134 uniformly unsuccessful under a variety of experimental conditions, e.g. via activated ester with imidazole and mixed benzoic anhydride. The crux of the problem was associated with the quinone system which so deactivates the amino group to prevent its attachment to mildly activated carboxylic derivatives. Cyclization was achieved after conversion of the quinone system to the hydroquinone system. Thus, as shown in Scheme 45, treatment of 132 with 10 equiv of isobutyl chloroformate and 1 eqtuv of triethylamine at 23 °C produced the corresponding mixed carbonic anhydride in 95% yield. The quinone C=C bond was reduced by hydrogenation with Lindlar catalyst at low temperature. A cold solution of the hydroquinone was added over 2 h to THF at 50 °C and stirred for an additional 12 h at the same temperature. Oxidation with aqueous potassium ferricyanide afforded the cyclic product 134 in 80% yield. Kishi and coworkers [73] gained a similar result by using mixed ethyl carbonic anhydride. 

Mixed pivalic anhydride 18 (42) is an example of selective mixed carboxylic anhydride. Selective aminolysis could be caused by the steric hindrance of the fert-butyl group. A mixed carbonic anhydride strategy has also been smdied to... 

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... 

Although mixed anhydrides are often generated and used in condensation reactions in situ, mixed anhydrides 1 derived from carboxylic acids (Scheme 1) are frequently sufficiently stable for isolation and storage if required.f 1 Mixed carbonic anhydrides 2 (Scheme 1) are generally considered too unstable at room temperature for isolation. 

Tilak et described the use of excess mixed carbonic anhydrides to force condensation reactions to completion followed by the destruction of the excess mixed anhydride via the addition of aqueous potassium hydrogencarbonate. Hydrolysis of the nnixed anhydride was rapid and the resulting protected dipeptide could be extracted into ethyl acetate in a high state of purity, leaving the excess amino acid derivative and the salts in the aqueous phase. Without further purification the protected dipeptide was N -deprotected and reacted with the next mixed anhydride, and the process repeated until the desired peptide was obtained. Beyerman et al. substantially expanded the scope of this procedure and named it the REMA method for peptide synthesis (Repetitive Excess Mixed Anhydride).P°1 These reaction conditions provide an excellent method to ensure complete reaction of the amine component as well as rapid reaction rates and minimal side products. However, care must be taken to ensure that the excess carboxylic acid component is soluble in sodium hydrogencarbonate solution, e.g. when Z-Asp(OBzl)-OH is the acid component, it is extracted into the ethyl acetate as the sodium salt along with the product. With the due precautions the yields of small peptides are so high that the method could be applied without purification of the intermediate products, that is, in a repetitive way. 

Where acid chlorides are difficult to obtain, Weinstock s method of using mixed carboxylic-carbonic acid anhydrides can be helpful. The acid to be converted into its azide is treated with ethyl chlorofor-mate and base, the ethyl carbonate moiety is then displaced by azide ion. The method has been used in the penicillin field . It is not general, however when the alkanoyl part of the mixed anhydride is sterically hindered, the azide ion displaces it instead of the carbonate moiety, and ethyl azidoformate is produced Cyclic anhydrides can be opened by azide ion, to give the salts of omega-azidocarbonyl acids, such as Na+ "OOCCHaCHaCONa . 

Cellulose can be esterifled with almost any organic acid [81,82,84], Whereas this is possible in principle with both alkyl chlorides and carboxylic anhydrides, commercial practice has focused on the anhydride option. Although many esters have been described in the literature, industrially manufactured organic esters are prepared only with aliphatic fatty acids with between 2 and 4 carbon atoms in length (i. e., acetates to butyrates, CA to CB). Exceptions are some mixed esters with phthalic acid, which are used for enteric coatings in pharmaceutical applications and a novel carboxymethyl cellulose acetate butyrate (CMCAB), which is used in water-borne coatings applications [81,84],... 

More recently, a similar synthetic strategy was utilized to prepare the Dolastatin 15 via acylation of Meldrum s ester (156). In this work, isopropenyl chloroformate was found to give the best results of several mixed carbonic anhydrides derived from the required starting carboxylic acid when used in the presence of 5 molar equivalents of DMAP. Dolastatin proved to exhibit promising remarkable anticancer properties. 

The course of the decomposition of the mixed anhydrides [Scheme 44] which leads to the formation of expected esters (path A) or to a mixture of symmetrical carbonates and anhydrides (path B) strongly depends on the structures of the chloroformate and the carboxylic acid but also on the choice of the catalyst.. Because selective production of esters if of great interest, we have studied the thermal instability of the mixed anhydrides and developed a new efficient and selective esterification reaction with chloroformates using a silica supported guanidinium catalyst (Ref. 39). This method will be discussed in vol. 2 section 4-4. 

The reagent promotes the coupling in high yields of acylamino acids with amino acid esters in benzene, ethanol, or THF at room temperature. No racemization was detected in the supersensitive Young test, and Bz-Leu-Gly-OEt, an 33.5°, was synthesized in 95% yield. Activation of the carboxyl group involves the transient formation of a mixed carbonic anhydride.3... 

Illustrating the versatility of C-cyanoglycoside nitrile derivatives, Myers, et ai.,15 formed a diazoketone from the peracetylated C-cyanoglucoside shown. The reaction sequence, illustrated in Scheme 2.2.20, involved the initial hydrolysis of the nitrile to the corresponding primary amide. Subsequent hydrolysis afforded the carboxylic acid. On conversion of the acid to a mixed carbonic anhydride followed by treatment with diazomethane, the desired diazoketone was obtained. 

Y-carboxylic acid (74) by approaches involving either acyl chlorides (oxalyl chloride route) or mixed carbonic anhydrides (isobutyl chloroformate route) (Scheme 120). An alternative route to (73) involves selective attack at the Y-carbonyl of anhydride (71) with diazomethane however the DON precursor (72) could not be prepared using this method. 

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