Cyclic amides, hydroxylation

Both 2-hydroxy- and 3-hydroxypyridine are hydroxylated to 2,5-dihydroxypyridine by strains of Achromobacter sp. (Houghton and Cain 1972). These metabolites are probably, however, formed by different reactions whereas 3-hydroxypyridine behaves as a true pyridine, addition of H2O across the Cg Nj bond would produce the 2,5-dihydroxy compound 2-hydroxypyridine is a cyclic amide and hydroxylation apparently occurs at the diagonal position. The degradation of 4-hydroxypyridine is also initiated by hydroxylation and is followed by dioxygenation before ring fission (Figure 10.12) (Watson et al. 1974). 

Heterocyclic compounds carrying potential hydroxyl groups are cyclic amides or vinylogs of amides. There is much physical evidence that acyclic amides exist almost entirely in the oxo form (for references see reference 6), and the apparent contradiction that ultraviolet spectral data appeared to favor the imidol formulation has now been explained on steric grounds. The value of pKr is estimated to be about 7 on the basis of pK measurements for acyclic amides. Extensive evidence, summarized in the following sections, shows that for a- and y-hydroxy heterocyclic compounds, the cyclic amide form usually predominates by a substantial factor, often ca. 10 . 

Cyclic structures can form as a result of side reactions. One of the most common examples is the formation of diketopiperazines during the coupling of the third amino acid onto the peptide chain (Fig. 7). Intramolecular amide bond formation gives rise to a cyclic dipeptide of a six-membered ring structure, causing losses to the sequence and regeneration of the hydroxyl sites on the resin. The nucleophilic group on the resin can lead to fiuther unwanted reactions [14]. 

Other functional groups which have a heteroatom rather than a hydroxyl group capable of directing the hydrogenation include alkoxyl, alkoxycarbonyl, carboxylate, amide, carbamate, and sulfoxide. The alkoxy unit efficiently coordinates to cationic iridium or rhodium complexes, and high diastereoselectivity is induced in the reactions of cyclic substrates (Table 21.3, entries 11-13) [25, 28]. An acetal affords much lower selectivity than the corresponding unsaturated ketone (Table 21.3, entries 14 and 15) [25]. 

This area has received much less attention in the literature than the reactivity of conjugated systems. As noted in CHEC-II(1996) <1996CHEC-II(8)345>, most of the examples studied contain one or two oxo groups in the six-membered ring and are cyclic amide tautomers of the corresponding hydroxyl compounds. 

Commercially available hyperbranched polymer, a poly(ester-amide) is currently being marketed by DSM under the product name Hybrane [13] (Figure 8.2). It is also a hydroxyl-functionalized product, but contains both amide and ester linkages. The synthesis is accomplished in two steps cyclic anhydrides are reacted with diisopropanolamine to give an amide-intermediate, possessing two hydroxyl groups and one carboxylic acid. The subsequent polymerization takes places via an oxazolinium intermediate which results in the formation of a... 

We observed that cyclic esters (lactones) may be formed when the carboxyl electrophile and hydroxyl nucleophile are in the same molecule (see Section 7.9.1). Similarly, cyclic amides are produced when carboxyl and amine groups are in the same molecule, and are again most favoured when this results in the generation of strain-free five- or six-membered rings. Cyclic esters are termed lactones, whereas cyclic amides are in turn called lactams. The nomenclature of lactams is similar... 

Furthermore, the incorporation of d-amino acids or other unusual (often hydroxylated) amino adds, the N-methylation of amide functionalities or the usage of cyclic peptides and depsipeptides limits these problems to a certain extent. 

Beauveria suffiirescens (ATCC7159) Fungi imperfect 1 la-Hydroxylation of steroids, hydroxylation of cyclic and acyclic amides, tricyclic terpenes and aromatics... 

The presence of an amine or amide group in cyclic substrates greatly fiicilitates the hydroxylation by Beauveria sulfurescens. Numerous mono-, di- and tri-cyclic amides and saturated nitrogen heterocycles have been stuped and a rational basis for the position at vriiich the hydroxy group is inttoduced into the substrate molecule has been put forward however, yet more work is required to define all the factors controlling the selectivi of hydroxylation. Neverdieless useful regio-, stereo- and in some cases... 

Thus the active site of the hydroxylating enzyme ipears insensitive to the relative position of the amide group. This has also been observed for bicyclic ainides, for example both exo and endo isomers of the amide (34) are hydroxylated to the exo-alcohol (35) with the same regio- and stereo-selectivity (equation 10). Further, the hydroxylation can also be insensitive to the position of the carbonyl group. For example, bi-, tri- and tetra-cyclic amides, and the equivalent lactams, of which the amide (36a) and lactam (36b) are representative cases respectively, are both hydroxylated at the same position (Scheme 8a). 7 ... 

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