Carbonic acid anhydrides urethans

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...

CO2 must be activated in order to add to biotin. Nature uses ATP and presumably produces carboxyphosphate, the mixed anhydride of phosphoric and carbonic acids. In model reactions chloromethylformiate and 2-imidazolone were used. Saponification of die urethane gave the anion of iV-carboxy-2-imida-zolone, which decarboxylated again. Attempts to use the evolving carbon dioxide in the carboxylation of carbanions failed, even if it was bound to the imidazolone. 

In order to keep side reactions at a minimum alkyl-carbonic acid mixed anhydrides are prepared and used for acylation in the cold. Nevertheless, both reactions require a very short time. The byproducts of coupling, CO2 and an alcohol (R OH), do not interfere with the isolation of the desired peptide. These features readily explain the popularity of the approach, but the principal advantage of alkylcarbonic acid mixed anhydrides lies in the fact that they give rise to only small amounts of the undesired second acylation product, a urethane ... 

Extensive use of mixed anhydrides of carbonic acids has been made in peptide synthesis. Polymer-based mixed carbonic anhydrides prepared by Shambhu and Digenis (1974) and Martin et al. (1978a) gave exclusively the amide of benzoic acid with aliphatic amines [Eq. (4)], but with aniline, some polymeric urethane was also formed. 

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. 

In fact, recent work indicates that less urethane is formed by aminolysis of an activated peptide than by aminolysis of an activated /V-al ko x y carbon y I am ino acid. Such results are consistent with the postulate that the intermediate undergoing aminolysis during the mixed anhydride reaction of a segment is the 2,4-dialkyl-5(4//)-oxazolonc, a tenet that is indicated by the high rate at which the activated peptide is converted to the oxazolone.10 13... 

Triethylamine (7) is a strong, hindered base originally employed for mixed-anhydride reactions. However, it reduces the rate of anhydride formation if the solvent is dichloromethane or chloroform (see Section 7.3) and promotes disproportionation of the anhydride under conditions in which /V-mcthylmorpholinc does not (see Section 7.5). It causes enantiomerization of urethane-protected amino-acid /V-carboxyanhydrides and reaction between two molecules with release of carbon dioxide (see Section 7.14). It is also used in the synthesis of Atosiban (see Section 8.9). There is no reaction for which it is recommended as superior to other tertiary amines, except possibly for coupling employing BOP-C1 (see Section 8.14). 

The chemical modification of poly (vinyl chloroformate) and its copolymers has been also studied. Treatment of such polymers with amines, alcohols and phenols affords the corresponding poly (vinyl urethanes) and poly (vinyl carbonates) (Ref. 138, 139). Poly (mixed anhydrides) have been also prepared by chemical modification of poly (vinyl chloroformate) by carboxylic acids under various conditions (Ref. 140, 141, 142). 

Alder route, was converted into the urethan (25) by a series of unexceptional steps. Arndt-Eistert homologation of (25) provided the carboxylic acid (26) which, upon treatment with acetic anhydride, readily gave the lactam (27). Introduction of a one-carbon unit into the aromatic ring was achieved with chloromethyl methyl ether, and further reductive and hydrolytic modification afforded the amino-alcohol (28). Osmium tetroxide oxidation of (28) yielded the stereoisomeric triols (29) (20%) and (30) (22%) which were separated and oxidized to ( + )-clivonine (31) and (+ )-clividine (32), respectively. 

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