Isoleucine, chlorination

Much was unknown for the halogenation for unreactive substrates until very recently, when the biosynthesis of the cyclopropyl amino acid side chain of coronatine was elucidated. This intriguing pathway, which involves /-chlorination of an enzyme-bound L-isoleucine followed by chloride displacement by the a-carbon, yields the cyclopropanated precursor... 

With the use of gene clusters of the natural products coronatine and kutznerides, the biosynthetic pathway of coronamic acid has also been elucidated by Walsh and coworkers. From the biosynthetic analyses, a nonheme Fe -dependent halogenase was identified as the chlorinating enzyme that converts L- //a-isoleucine to 7-chloroisoleucine. A second enzyme carries out a dehydrochlorination reaction to yield coronamic acid. The general biosynthetic pathway is shown below (Scheme 7). 

Fig. 4.6 Dependence of the observed second-order rate constant (Ar0bs) upon acidity in the chlorination of amino acids, glycine ( ) and isoleucine (A) T = 298 K. The solid lines correspond to non-linear fitting of the experimental data to Equation 4.12.

Under certain conditions, chlorinated aldimines (SO) which are surprisingly stable can be formed from isoleucine and perhaps other amino acids (Nweke and Scully,... 

Aldehydes from amino acid chlorination, such as 2-methylpropanal (derived from valine), 2- and 3-methylbutanal (derived from leucine and isoleucine, respectively), and phenylacetaldehyde (derived from phenylalanine), have been found to be potent contributors to taste-and-odor problems in the drinking water supply of Edmonton, Alberta. The incidents occur in the spring following snowmelt and concomitant increases in raw water color and TOC (Hrudey et al., 1988). Interestingly, the aldehydes were also formed during monochloramine disinfection. 

Nweke, A. and F. E. Scully, Jr. 1989. Stable N-chloroaldimines and other products of the chlorination of isoleucine in model solutions and in a wastewater. Environ. Sci. Technol. 23, 989-994. 

Sulfonylureas are generally extremely potent inhibitors of ALS [181] the key enzyme within the biosynthesis of branched amino acids such as leucine, isoleucine or valine [181, 182] (for more details see Chapter 2.2). Approximately 57.5% of commercialized sulfonylureas or development products are halogen free. The remaining 42.5% (halogens/subclass a > b) launched so far contain halogen atoms such as fluorine ( 24%), chlorine ( 15%) or iodine ( 3%) (Fig. 35.21). 

Oxidative cyclization of the nitrogen atom onto the C-5-methyl group of isoleucine appears to be a unique biosynthetic transformation. Two reasonable pathways, depicted in Scheme 18 would involve 4-electron oxidation of the distal side-chain methyl group to an aldehyde followed by cyclization and loss of water to produce an iminium species subsequent reduction (or in the case of VM55597, oxidation) furnishes the -methylproline derivative. Alternatively, direct functionalization of the C-5 methyl group, for example, by chlorination and closure can also be envisioned to lead to )3-methylproline a related example of this type of reaction has been observed by Arigoni and Looser [40] in the biosynthesis of victorin C. 

Curiously, one of the first a-ketoglutarate-dependent halogenases to be functionally characterized, CmaB, is involved in the biosynthesis of a nonhalogenated metabolite, the phytotoxin coronatine 29. Experiments with radio-labeled amino acids confirmed that CmaB carries out the chlorination of the y-position of L-a//o-isoleucine bound to the carrier protein CmaD but not CmaA (Scheme 45.10a). 

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