Carbon-nitrogen bond formation activation

Lipases are the enzymes for which a number of examples of a promiscuous activity have been reported. Thus, in addition to their original activity comprising hydrolysis of lipids and, generally, catalysis of the hydrolysis or formation of carboxylic esters [107], lipases have been found to catalyze not only the carbon-nitrogen bond hydrolysis/formation (in this case, acting as proteases) but also the carbon-carbon bond-forming reactions. The first example of a lipase-catalyzed Michael addition to 2-(trifluoromethyl)propenoic acid was described as early as in 1986 [108]. Michael addition of secondary amines to acrylonitrile is up to 100-fold faster in the presence of various preparations of the hpase from Candida antariica (CAL-B) than in the absence of a biocatalyst (Scheme 5.20) [109]. 

The active site for this reaction lies in a domain formed by the aminoterminal third of CPS. This domain forms a structure, called an ATP-grasp fold, that surrounds ATP and holds it in an orientation suitable for nucleophilic attack at the Y phosphoryl group. Proteins containing ATP-grasp folds catalyze the formation of carbon-nitrogen bonds through acyl-phosphate intermediates and are widely used in nucleotide biosynthesis. In the final step catalyzed by carbamoyl phosphate synthetase, carbamic acid is phosphorylated by another molecule of ATP to form carbamoyl phosphate. 

In a number of cases, the addition of lithium reagents to ketone mono- and di-tosylhydrazones can be improved by the inclusion of Cu which activates the carbon-nitrogen bond toward nucleophilic addition. However, the formation of complex product mixtures with many ketone tosylhydrawnes limits its synthetic utility. ... 

It is well known that alkyl azides also behave as 1,3-dipoles in intramolecular thermal cycloaddition reactions. The formation of two carbon-nitrogen bonds leads to triazolines, which are usually not stable. They decompose after the loss of nitrogen to aziridines, diazo compounds, and heterocyclic imines. There are a limited number of examples reported in which the triazoline was isolated [15]. The dipolar cycloaddition methodology has been extremely useful for the synthesis of many natural products with interesting biological activities [16], In recent years, the cycloaddition approach has allowed many successful syntheses of complex molecules which would be difficult to obtain by different routes. For instance, Cha and co-workers developed a general approach to functionalized indolizidine and pyrrolizidine alkaloids such as (-i-)-crotanecine [17] and (-)-slaframine [18]. The key step of the enantioselective synthesis of (-)-swainsonine (41), starting from 36, involves the construction of the bicyclic imine 38 by an intramolecular 1,3-dipolar cycloaddition of an azide derived from tosylate 36, as shown in Scheme 6 [ 19). 

Tandem catalysis [1-10], which involves several catalytic cycles within the same medium to produce a desired product, is becoming increasingly important for the economic and environmental acceptability of the process. Copper salts are efficient catalysts in various transformations, including formation of carbon-carbon and carbon-nitrogen bonds [11-14], The author postulated they could play key parts in construction of complex nitrogen heterocycles with important biological activities through formation of multiple bonds [15-23]. 

Carboxylases which utilize bicarbonate as the CO2 donor require ATP to provide energy for the formation of the new carbon-nitrogen bond, while in the case of transcarboxylases and decarboxylases, car-boxyl-biotinyl enzyme formation occurs by a transcarboxylation pathway not requiring ATP. In the latter instance, either a malonyl-CoA derivative or a beta-keto acid serving as a carboxyl donor provide the active CO2. 

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