Mixed carbonic anhydrides

FIGURE 23.4 A mechanism for the pyruvate carboxylase reaction. Bicarbonate must be activated for attack by the pyruvate carbanion. This activation is driven by ATP and involves formation of a carbonylphosphate intermediate —a mixed anhydride of carbonic and phosphoric acids. (Carbonylphosphate and car-boxyphosphate are synonyms.)... 

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. 

The mixed carbonic anhydride procedure8-7 has been useful in the preparation of amide linkages and thiol esters. Mixed carbonic anhydrides have successfully acylated, under very mild conditions, the carb-anions derived from diethyl ethylmalonate and diethylcadmium.8 The latter gives as a product the corresponding ketone. Mixed anhydrides derived from acetic and acetylsalicylic acids give results similar to those described here.8... 

GW Anderson, JE Zimmerman, FM Callahan. A reinvestigation of the mixed carbonic anhydride method of peptide synthesis. J Am Chem Soc 89, 5012, 1967. 

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

J Meienhofer. The mixed carbonic anhydride method of peptide synthesis, in E Gross, J Meienhofer, eds. The Peptides Analysis, Synthesis, Biology, Academic, New York, 1979, Vol 1, pp 263-314. 

FIGURE 2.27 More on additives. In a carbodiimide-mediated reaction between acid 1 and amine 2, addition of HOObt can lead to the side reaction of aminolysis at the carbonyl of the activating moiety of ester 3, generating addition product 4. Addition of HOBt to a mixed-anhydride reaction containing unconsumed chloroformate generates mixed carbonate 5, leading to production of urethane 6. 

There is a claim that HOBt suppresses undesired aminolysis at the carbonate carbonyl of a mixed anhydride (Figure 2.25, path F). It is rarely used for this purpose, but if it is, it must be added only after the chloroformate has been consumed otherwise, mixed carbonate 5 is formed, and it depletes the amino-containing component by acylating it, giving stable urethane 6 (Figure 2.27).2 UI 3477... 

FIGURE 7.12 Preparation of activated esters of A-alkoxycarbonylamino acids by reaction of the hydroxy compound with a mixed anhydride (path A), obtained by leaving the three reagents (NMM = A-methylmorpholine) in CH2C12 at 23°C for 2 minutes.35 Mixed carbonate that is formed (path B) is readily eliminated by crystallization of the ester. 

The alternative method for making activated esters is base-catalyzed transesterification. Fmoc-amino acids are esterified in excellent yields by reaction with pentafluorophenyl trifluoroacetate at 40°C in the presence of pyridine (Figure 7.13). A mixed anhydride is formed initially, and the anhydride is then attacked by the pentafluorophenoxy anion that is generated by the pyridine. Succinimido, chlorophe-nyl, and nitrophenyl esters were made by this method when it was introduced decades ago. A unique variant of this approach is the use of mixed carbonates that contain an isopropenyl group [Cf C CfyO-COjR]. These react with hydroxy compounds in the presence of triethylamine or 4-dimethylaminopyridine (see Section 4.19) to give the esters and acetone.30 35... 

Bis alkanoyl amino-2,4,6-triiodobenzyl esters Nanoparticulate diagnostic diatrizoxy ester Nanoparticulate diagnostic mixed carbonic anhydrides... 

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. 

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. 

Azotomycin is anticancer antibiotic produced by Streptomyces ambofaciens. Total sythesis of it from y-benzyl-N-tert-butyloxycarbonyl-L-glutamic acid (y-OBzi-N-Boc-L-Glu) has been accomplished in nine steps. The mixed carbonic anhydride method was chosen for peptide bond formation. Commerically available y-OBzi-N-Boc-L-Glu was esterified with ethereal diazomethane, deprotected with trifluoroacetic acid-methylene chloride (1 1), and converted to hydrochloride y-benzyl-L-glutamic acid a-methyl ester (y-OBzi-L-Glu-a-OMe HCI) by treatment with dry hydrogen chloride in ethyl ether, MP 129°-135°C (dec.) [a]D25= + 13.3° (CHCI3). 

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. 

Mixed carbonic anhydrides are a form of activated esters that can react with amines to form amides. The addition-elimination mechanism, illustrated below using arrow pushing, involves addition of an amine followed by an elimination step driven by the release of carbon dioxide. 

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. 

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). 

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... 

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