Biosynthesis halogenation

Halogenated phenols, particularly 2-bromo-, 2,4-dibromo-, and 2,4,6-tribromophenol, have been identified in automotive emissions and are the products of thermal reactions involving the dibromoethane fuel additive (Muller and Buser 1986). It could therefore no longer be assumed that such compounds are exclusively the products of biosynthesis by marine algae. 

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... 

Galonic, P.D., Vaillancourt, FH. and Walsh, C.T. (2006) Halogenation of unactivated carbon centers in natural product biosynthesis trichlorination of leucine during barbamide biosynthesis. Journal of the American Chemical Society, 128, 3900-3901. 

In order to synthesize biologically relevant phosphonylimidazole 73, bromoimidazole 72 was derived from radical-initiated bromination of methyl l-p-methoxybenzyl-2-thiomethyl-5-imidazolylcarboxylate (71) [56]. The thiomethyl group served to block the C(2) position, which would otherwise undergo preferential halogenation under these conditions. As expected, a variety of Arbusov-Michaelis reaction conditions failed even under forcing conditions. On the other hand, Pd-catalyzed phosphorylation of 72 with diethyl phosphite led to methyl-4-diethylphosphonyl-l-p-methoxybenzyl-2-thiomethyl-5-imidazolylcarboxylate (73). After further manipulations, the desired phosphonic acid-linked aminoimidazoles, which resembled intermediates formed during purine biosynthesis, were accessed. 

Nature utilizes the shikimate pathway for the biosynthesis of amino acids with aryl side chains. These nonprotein amino acids are often synthesized through intermediates found in the shikimate pathway. In many cases, L-a-amino acids are functionalized at different sites to yield nonprotein amino acids. These modifications include oxidation, hydroxylation, halogenation, methylation, and thiolation. In addition to these modifications, nature also utilizes modified biosynthetic pathways to produce compounds that are structurally more complex. When analyzing the structures of these nonprotein amino acids, one can generally identify the structural similarities to one of the L-a-amino acids with aromatic side chains. 

Much was unknown about the halogenation for unreactive substrates until very recently, when the biosynthesis of the cyclopropyl amino acid side-chain of coro-... 

Certain structural indications of thromboxane A2 biosynthesis inhibition and hence potential therapeutic utility in arterial thrombosis prompted the synthesis of the pyridine prostanoid 544 (Scheme 165) (83TL3291). Brief metalation of 42 followed by DMF quench afforded aldehyde 541, which upon Homer-Emmons chain extension, reduction, and protection gave 542. Having served as a DMG, the bromo function was subjected to metal-halogen exchange, transmetalation (CuCN), and condensation with an iodo allene to furnish the 3,4-disubstituted pyridine 543. The latter was transformed into two derivatives 544 (with and without double bond), which were shown to be effective inhibitors of thromboxane A2. 

Other enzymes capable of halogenation processes include a bacterial esterase from Pseudomonas fluorescens (2316), acid phosphatases from the bacteria Shigella flexneri and Salmonella enterica ser. typhimurium (2317), a lactonohydrolase from Acinetobacter calcoaceticus F46 (2318), and hydroperoxide halolyse from the marine diatom Stephanopyxis turris (2319). The biosynthesis of the ubiquitous methyl halides seems to involve methyl transferase enzymes, which have been isolated and purified in the plant Brassica oleracea (S -adenosyl-L-methionine ... 

The biosynthesis of organohalogens has seen enormous interest since the first survey, and several examples are mentioned earlier in the present review. Space does not allow for full coverage of this topic, but some additional examples are presented here. The reader is also directed to general reviews on the biosynthesis of marine natural products, many of which contain halogen (2398-2401), terrestrial fungal (basidiomycetes) metabolites (2402), and halogenated alkaloids (2403). 

Urhahn T, Ballschmiter K (1998) Chemistry of the Biosynthesis of Halogenated Methanes Cl-Organohalogens as Pre-Industrial Chemical Stressors in the Environment Chemosphere 37 1017... 

Polzin JJ, Rorrer GL, Cheney DP (2003) Metabolic Flux Analysis of Halogenated Monoterpene Biosynthesis in Microplantlets of the Macrophytic Red Alga Ochtodes secundiramea. Biomol Eng 20 205... 

Piraee M, White RL, Vining LC (2004) Biosynthesis of the Dichloroacetyl Component of Chloramphenicol in Streptomyces venezuelae ISP5230 Genes Required for Halogenation. Microbiology 150 85... 

Galonic DP, Vaillancourt FH, Walsh CT (2006) Halogenation of Unactivated Carbon Centers in Natural Product Biosynthesis Trichlorination of Leucine During Barbamide Biosynthesis. J Am Chem Soc 128 3900... 

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