Heterocycles, enzymatic oxidation

D. Model Studies on Enzymatic Oxidation of Heterocycles and Aromatic... 

FIGURE 4.12 A modified condensation domain facilitates the cyclization of serine or cysteine residues to the corresponding oxazoline or thiazoline. These heterocycles may remain untouched for the remainder of the biosynthesis or they may undergo enzymatic oxidation to the thiazole as in epothilone D or undergo enzymatic reduction to the thiazolidine as in yersiniabactin. 

For the direct hydroxylation of N-heterocycles a microbial oxidation is most suitable. Lonza developed a process to produce 6-hydroxynicotinic acid on a 10 tonnes scale [5]. The enzymatic production is carried out in two-steps. Firstly, Achromobacter xylosoxydans LK1 biomass is produced, which possesses a highly... 

Oxidation of chroman-4-one and its thio analogue with Mn(OAc)3 gives the 3-acetates and subsequent basic hydrolysis yields the 3-hydroxychroman-4-one. Enzymatic hydrolysis of the 0-heterocycle using Amano PS lipase in a phosphate buffer selectively cleaved the (+)-isomer <03TA1489>. Enol ethers derived from chroman-4-one are converted into the 3-hydroxy-chromanone with high enantioselectivity, optimal with the pentyl ether, using a modified Sharpless asymmetric dihydroxylation reaction <03JOC8088>. 

The majority of heterocyclic compounds are formed through thermal interactions of reducing sugars and amino acids, known as the Halliard reaction. Other thermal reactions such as hydrolytic and pyrolytic degradation of food components (e.g. sugars, amino acids, vitamins) and the oxidation of lipids also contribute to the formation of heterocyclic compounds responsible for the complex flavor of many foodstuffs. Heterocyclic compounds may also be formed enzymatically in vegetables (tomatoes, bell peppers, aspara-... 

Naturally occurring oxazoles are derived from enzymatic post-translational modifications of peptide-based precursors <1999NPR249>. The oxygen functionality on the side chain of A -acylated serines (R = H) and threonines (R = Me) 307 is capable of undergoing heterocyclization onto the preceding carbonyl group to create five-membered saturated heterocycles 308 (Scheme 86). Dehydration followed by two-electron oxidation results in aromatic oxazoles 309. 

The thiazole ring is synthesized biochemically by enzymatic post-translational modifications of cysteine-containing peptides. Heterocyclization between cysteine side-chains and neighboring carbonyl groups produces dihydrohetero-aromatic thiazolines as initial products followed by a two-electron redox reaction yielding either thiazole or thiazo-lidine rings (Scheme 104). All three oxidation states are seen in natural products. 

The use of biological methods has a small, but significant niche in synthetic heterocyclic chemistry, being used both on a research scale and for fine-chemicals production. The processes may use isolated enzymes or whole microorganisms, the main reactions being oxidations of a heterocyclic nucleus or of side-chains, but other reaction types are also used, for example enzymatic catalysis has been used to ribosylate purines and related bases by reaction with a 7-aUcylated nucleoside.""... 

Heterocydes are common motifs in natural products, which may occur as single, tandem, and multiple moieties within a given molecule (Scheme 8.5) [35-37]. These motifs often provide molecular interaction with nudeotide and protein targets. In the biosynthesis of NRPs, an oxazoline was usually formed from a dipeptide containing serine in the second position upon dehydration (Scheme 8.5) [38]. The syntheses of a thiazoline from cysteine and a 2-methyloxazoline from threonine follow a similar mechanism. These heterocycles can be further custom-made to provide thiazolidines/oxazolidines upon reduction or thiazoles/oxazoles upon oxidation. Enzymatic heterocyclization can be portable, as demonstrated in the synthesis of novel chiral heterocyclic carboxylic adds by hybrid enzymes [39]. 

Complex mixtures are produced by non-enzymatic browning reactions between thermally oxidized lipids and amines, amino acids and proteins (see Chapter 11.B.4). Interactions between aldehydes, epoxides, hydroxy ketones, and dicarbonyls with proteins cause browning that has been related with losses of lysine, histidine, and methionine. Schiff base formation results in polymerization to form brown macromolecules. Interactions between epoxyalkenals formed at elevated temperatures and reactive groups of proteins produce protein pyrroles polymers and volatile heterocyclic compounds. Much of the published research in this complex chemical area was based on model systems. More stmctural information is needed however with real foods subjected to frying conditions. 

Kynurenine Metaholism. Kynurenine may be metabolized in five ways acetylation to iV -acetylkynurenine,i decarboxylation to kynuramine, oxidation to 3-hydroxykynurenine, cyclization to a quinoline derivative, and cleavage to yield anthranilic acid." The oxidation, cyclization, and cleavage reactions are components of major pathways of tryptophan metabolism. Ommochrome is composed of a series of heterocyclic condensed ring systems that have been shown to be derived from tryptophan via kynurenine. The individual steps in the enzymatic formation of the pigments have not separated. ... 

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