Amides a-hydroxylation

In an effort to make productive use of the undesired C-13 epimer, 100-/ , a process was developed to convert it into the desired isomer 100. To this end, reaction of the lactone enolate derived from 100-) with phenylselenenyl bromide produces an a-selenated lactone which can subsequently be converted to a,) -unsaturated lactone 148 through oxidative syn elimination (91 % overall yield). Interestingly, when 148 is treated sequentially with lithium bis(trimethylsilyl)amide and methanol, the double bond of the unsaturated lactone is shifted, the lactone ring is cleaved, and ) ,y-unsaturated methyl ester alcohol 149 is formed in 94% yield. In light of the constitution of compound 149, we were hopeful that a hydroxyl-directed hydrogenation52 of the trisubstituted double bond might proceed diastereoselectively in the desired direction In the event, however, hydrogenation of 149 in the presence of [Ir(COD)(py)P(Cy)3](PF6)53 produces an equimolar mixture of C-13 epimers in 80 % yield. Sequential methyl ester saponification and lactonization reactions then furnish a separable 1 1 mixture of lactones 100 and 100-) (72% overall yield from 149). 

Ketones and carboxylic esters can be a hydroxylated by treatment of their enolate forms (prepared by adding the ketone or ester to LDA) with a molybdenum peroxide reagent (MoOs-pyridine-HMPA) in THF-hexane at -70°C. The enolate forms of amides and estersand the enamine derivatives of ketones can similarly be converted to their a hydroxy derivatives by reaction with molecular oxygen. The M0O5 method can also be applied to certain nitriles. Ketones have also been Qc hydroxylated by treating the corresponding silyl enol ethers with /n-chloroperoxy-... 

V-Acetylneuraminic acid is a common group in glycoproteins, and it contains both the amide and carboxyl chromophores. As shown in formula 11, this nine-carbon sugar derivative has an equatorial amido group on C-5 and both a hydroxyl group and a carboxyl group on the anomeric carbon atom. 

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). 

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]. 

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... 

C domains can display functions that deviate from typical amide bond formation. Several C domains are postulated to act as ester synthases, catalyzing ester formation instead of amide formation. NRPS modules containing C domains that display this activity are present in the biosynthetic pathways for the kutznerides, cryptophycins, " cereulide, valinomycin, hectochlorin, and beauvericin. Each of these C domains likely utilizes a PCP-bound a-hydroxyl acceptor in the condensation reaction. Another NRPS C domain that catalyzes ester bond formation is involved in the biosynthesis of the polyketide-derived mycotoxins known as the fiimonisins. Du and coworkers have shown that a recombinant PCP-C didomain of an NRPS involved in the biosynthetic pathway of the fnmonisins can catalyze ester bond formation between hydroxyfumonisins and the A-acetylcysteamine thioester of tricarballylic acid, even though PCP-bound tricarballylic acid is not... 

An enzyme reaction intermediate (Enz—O—C(0)R or Enz—S—C(O)R), formed by a carboxyl group transfer (e.g., from a peptide bond or ester) to a hydroxyl or thiol group of an active-site amino acyl residue of the enzyme. Such intermediates are formed in reactions catalyzed by serine proteases transglutaminase, and formylglyci-namide ribonucleotide amidotransferase . Acyl-enzyme intermediates often can be isolated at low temperatures, low pH, or a combination of both. For acyl-seryl derivatives, deacylation at a pH value of 2 is about 10 -fold slower than at the optimal pH. A primary isotope effect can frequently be observed with a C-labeled substrate. If an amide substrate is used, it is possible that a secondary isotope effect may be observed as welF. See also Active Site Titration Serpins (Inhibitory Mechanism)... 

Removal of the amide function is much easier if the reaction is intramolecular, and —CONEt2 amides (sometimes even —CONPr-i2 amides) may be converted to lactones, lactams and other heterocycles in this way . Addition of an aldehyde or ketone as an electrophile generates a hydroxyl group (in some cases, atroposelectively, as it happens —though this is usually irrelevant to the stereochemistry of the product) which cyclizes to give a lactone via a benzylic cation in acid. This reaction has found wide use in the synthesis of polycyclic aromatics, particularly alkaloids. 

Compounds containing a hydroxyl group (OH) have a strong very broad absorption in the 3,600-2,500 cm region of the spectrum. The most common examples are the alcohols and the carboxylic acids. The combination of a broad 3,600-2,500 cm band with a 1,700 cm peak often indicates a carboxylic acid (or amide — keep reading). 

The isomerization of the (Z)-isomer into the ( )-isomer promoted by the iridium complex explains the lack of stereospecificity of the transformation. O-Alkylated oximes and ketoximes do not react and this fact suggests that the presence of both hydrogen and a hydroxyl group is required for the success of the transformation. The authors proposed that the initial displacement of a chloride ion of the iridium complex by the oxime allows the iridium to remove both the oxygen and the hydride from the initial oxime. Swapping places of both substituents produces the amide. 

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