Oxime moieties, addition

Compound 26 containing an oxime moiety saw an increase in rat bioavailability and AUC of two-fold and approximately four-fold, respectively, when compared to azithromycin [82]. Other cores not depicted here but that can be incorporated into the series include telithromycin-type carbamates, additional oxime variants, as well as any of the common 14- and 15-membered macrolides. 

The key step in the total synthesis of e/ir-lycoricidine, recently accomplished by Keck and Wager [55] consisted of the thiy] radical addition to a triple bond of a suitable precursor followed by cyclization onto a pendant oxime moiety, as shown in Scheme 7. Then the alkoxyaminyl radical abstracts hydrogen from PhSH, when R=C02Me, or attacks intramolecularly the carbonyl moiety, when R = CHO. Following the former strategy, the target compound was obtained after two other transformations and in an overall yield of 11.1 % starting from lyxo.se, in 14 steps. 

The first organocatalytic oxo-Michael addition to enals was reported by Jot-gensen in 2007 [65], Jorgensen used as a suitable nucleophile benzaldehyde oxime, which reacts with enals with catalysis by 28. The resulting product, reduced directly to the alcohol due its UabiUty, was obtained in excellent yields and enan-tioselectivities (Scheme 33.20). The oxime moiety can easily be cleaved to afford the 1,3-diols without loss of enantiomeric purity. However, aromatic enals turned out to be unreactive in this transformation. 

An enzyme being complementary to a nitrile hydratase, which catalyzes water addition to a nitrile, is an aldoxime dehydratase as a biocatalyst being capable to eliminate water from an oxime moiety, thus leading to the formation of a nitrile. Such aldoxime dehydratases are also synthetically useful as demonstrated by the Asano group who applied an aldoxime dehydratase from a Bacillus sp., for example, for the dehydration of Z-phenylacetaldoxime to produce phenylacetonitrile [37-41], For this substrate, the overexpressed aldoxime dehydratase showed a high activity of 14000U/1 of fermentation culture of a developed recombinant E. coli strain [3 . In addition, numerous other transformations of aromatic and aliphatic aldehydes have been reported [37 1],... 

Reaction of 0-arylmethyl alkynyl oxime ethers with Cu(OTf)2 has been reported to give 4-arylmethylisoxazoles via the sequential intramolecular addition of the oxime moiety to the alkyne with subsequent 1,3-migration of the arylmethyl group (Scheme 102). " ... 

Oxime carbamates have high polarity and solubility in water and are relatively chemically and thermally unstable. They are relatively stable in weakly acidic to neutral media (pH 4-6) but unstable in strongly acidic and basic media. Rapid hydrolysis occurs in strongly basic aqueous solutions (pH > 9) to form the parent oxime/alcohol and methylamine, which is enhanced at elevated temperature. Additionally, oxime carbamates are, generally, stable in most organic solvents and readily soluble in acetone, methanol, acetonitrile, and ethyl acetate, with the exception of aliphatic hydrocarbons. Furthermore, most oxime carbamates contain an active -alkyl (methyl) moiety that can be easily oxidized to form the corresponding sulfoxide or sulfone metabolites. 

The scheme required to prepare the potent tri-fluoro corticoid cormethasone acetate (292) illustrates the synthetic complexities involved in some of this work. Sequential acetylation of the pregnenolone derivative 278 with first acetic anhydride in pyridine and then acetic anhydride in the presence of tosic acid affords diacetate 279. Reaction of that intermediate with nitrosyl fluoride results initially in addition of the reagent to the 5,6-olefin moiety to afford the fluoro oxime reaction with a second mole of reagent at nitrogen gives the nitroimine derivative 280 passage over alumina serves to hydrolyze the imine function to the corresponding 6-ketone (281). 

It is assumed that, after the initial formation of the oxime 2-634, a Michael addition occurs to give 2-635 with formation of a nitrone moiety which then can undergo a 1,3-dipolar cycloaddition to give 2-636. 

An exceptionally high influence of the C-substituent at the C=N bond on the cyclization direction has been observed (89KGS927) in a large series of derivatives 80. In the solid state and in solution in several solvents, these compounds exist solely as the isomer 80B. Independently of the mutual disposition of the oxime and hydrazone moieties—i.e., for either X = NCOR, Y = O or for X = O, Y = NCOR and for X = Y = NCOPh—the intramolecular cyclization proceeds only along the path involving nucleophilic XH or YH group addition to the more reactive and less hindered aldoxime or aldohydrazone C=N bond. However, in the gas phase, the presence of small amounts of the isomers 80A and 80B was detected. 

The quinoline formation from 2,4-dinitrophenyl oximes suggested to us the possibility of generating radical intermediates and prompted us to study the synthesis of cyclic imines by iminyl radical addition to an internal olefinic moiety as shown in Scheme 44. 

Miyabe et al. developed a tandem addition/cycUzation reaction featuring an unprecedented addition of alkoxycarbonyl-stabihzed radicals on oxime ethers [117], and leading to the diastereoselective formation of /1-amino-y-lactone derivatives [118,119]. The reaction proceeds smoothly in the absence of toxic tin hydride and heavy metals via a route involving a triethylborane-mediated iodine atom-transfer process (Scheme 37). Decisive points for the success of this reaction are (1) the differentiation of the two electrophilic radical acceptors (the acrylate and the aldoxime ether moieties) towards the nucleophilic alkyl radical and (2) the high reactivity of triethylborane as a trapping reagent toward a key intermediate aminyl radical 125. The presence of the bulky substituent R proved to be important not only for the... 

The chiral moiety of the nitrone can also be located at the carbon atom. Yokoyama et al. [50] used this approach in the asymmetric synthesis of spiro isoxazohdines (Scheme 10.21). The ribose-derived nitrone 62 is obtained from the corresponding oxime by Michael addition to methyl acrylate. With a second equivalent of methyl acrylate, the sugar nitrone 62 gave a single cycloadduct 63, which was converted into the corresponding pyrrolidine by reduction. 

Many synthetic pyrethroids with excellent insecticidal activity have been discovered through modification of the acid and alcohol moieties of the natural pyrethrins. However, replacement of the pyrethroid ester linkage with an alternative linkage usually leads to compounds of diminished biological activity(D. One exception to this trend of lower activity is the class of compounds wherein the oxime linkage is introduced in place of the ester linkage in the fenvalerate series. Additionally, only the E-isomer of the alkyl aryl oxime ethers is reported to be insecticidal< 2-4). 

When oxime benzoates, prepared by benzoylation of dialkyl 1-hydroxyiminophosphonates in the presence of Py, are submitted to the action of tin hydrides under radical conditions, the weakness of the N-0 bond is responsible for the fast formation of the reactive iminyl radical. In the example displayed in Scheme 7.71, the intermediate iminyl radical undergoes cyclization faster than the P-scission to nitrile to give a cyclic aminophosphonale. "- The reaction has also been explored with dialkyl l-benzoyloxyimino-2,2-dimethyl-3,4-pentadienylphosphonate and BujSnH/AIBN in refluxing cyclohexane. In this case, the iminyl radical generated by stannyl radical addition on the benzoyl moiety leads to the sole formation of phosphonylated dihydropyridine in quantitative yield. ... 

The oxyacetic acid residue of the monoxacetams is bioisosteric with the sulfate moiety of the monosulfactams. In addition, the presence of the carboxylate moiety provided opportunity for the preparation of esters that could act as orally absorbed prodrugs. Based on structure-activity relationships, SQ 82,291 (45) [90898-90-1]y C12H15N506S, the nonacidic methoxime side chain of which was necessary to maintain oral absorption of the prodrugs, was prepared. SQ 82,291 has a high, specific affinity for the PBP-3 transpeptidase of gram-negative bacteria. However, it lacks the isobutyric acid moiety of aztreonam (17) on the oxime residue and whereas the activity of SQ 82,291 vs the Enterobacteriaceae was maintained, antipseudomonal activity was significandy diminished (37). 

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