Oxime ethers cyclic—

I.4.I.5.2. Cyclic Oxime Ethers 1.4.1.5.2.1. Substrate-Induced Diastereoselection... 

It should be emphasized that this consideration may be fruitful in explaining the stereoselectivity of other reactions of six-membered cyclic nitronates and oxime ethers (see, e.g., Section 3.5.2.3.). 

Radical cyclization of oximes or oxime ethers having allylic substituents or an aldehyde group to tetrahydropyrrole derivatives was described Thus, Sm -induced 5-exo-trig radical cyclization of oxime ethers containing a formyl group was found to be particularly effective for the preparation of cyclic trans-wimo alcohols. For example, oxime 96 in the system SmE/THF/f-BuOH at 25 °C or —78°C afforded pyrrolidin-3-ols 97 and 98 in a ratio 3 2 or 9 1 (equation 41) . Cyclization of oxime ether 99 in the... 

A new synthetic method of benzofuran was reported (equation 39). The [3,31-sigma-tropic rearrangement of Af-trifluoroacetyl enehydroxylamines 136 obtained in situ by acylation of oxime ethers 135 in the presence of trifluoroacetic anhydride lead to the synthesis of cyclic or acyclic dihydrobenzofurans 138. The effects of base and temperature on the reaction products were studied. A similar pathway to that of Fisher indolization was proposed. The acylimine formed by the [3,3]-sigmatropic rearrangement of the V-trifluoroacetyl enehydroxylamine 136 gave the dihydrobenzofuran 137 by an intramolecular cyclization or the benzofuran 138 after elimination. 

Radical cyclizations are often used in ring formations and are an effective methodology in the synthesis of piperidines. The intramolecular cyclization of an oxime ether, such as 63 onto an aldehyde or ketone gives a new entry into cyclic amino alcohols <99JOC2003, 99H(51)2711>. Similarly, reaction of a terminal acetylene with BujSnH generates a vinyl radical, which will cyclize with an imine moiety to give 3-methylenepiperidine <99TL1515>. The indolizidine alkaloid ipalbidine was prepared by a sulfur-controlled 6-exo-selective radical cyclization of an a/p/ia-phenylthio amide <99H(50)31>. 

In contrast to alkylations of oximes and oxime ethers, geminal dialkylation can be achieved with the cyclic analogs15, e.g., preparation of the 4,4-dimethyl derivative 3. 

An oxidized stage of isohexide nitrates, wherein the remaining hydroxyl group is transformed into the ketone, gives rise to a number of derivatives 161, such as oximes, semicarbazones, acyclic and cyclic acetals, and hydra-zones.154 Among them, 3-amino-2-hydroxypropyl-substituted oxime ethers... 

XII. CYCLIC OXIME ETHERS AS HETEROCYCLIC SYSTEMS WITH... 

Different heterocyclic systems can undergo cleavage reaction that leads to a linear carbon skeleton with functional groups. The easier to get those systems, to modify them and to break them in several ways, the more their diversity. Two systems of cyclic oxime ethers that were studied in this connection are 2-isoxazoline and 1,2-oxazine. The former, which was obtained by 1,3-dipolar cycloaddition of a nitrile oxide, and a substituted double bond114, can be cleaved in several ways, in which the latent functions are revealed. One example in which a,/Lenoximes and enones114 are formed is shown in equation 43. 

Tandem radical addition-aldol-type reaction of a,/3-unsaturated oxime ethers bearing an Oppolzer sultam auxiliary leads to stereoselective incorporation of alkyl groups in the 5- and 3-positions in tetrahydrofurans (Scheme 77) <2005AGE6190>. The observed /ra r,/ra r-stereoselectivity was explained by invoking a cyclic six-membered ring transition state. 

An interesting preparation of 128 involves the cycloaddition of carbon suboxide to the anil of cyclopentanone (129).87 Compound 129 also reacts with monosubstituted malonyl chlorides to give iV-aryl-2-oxo-3-alkyl-4-hydroxy-6,7-dihydro-5ff-1 -pyrindines (131) in fair yields.88 Similarly, the oxime ether of cyclopentanone (132) reacts to give the cyclic hydroxamic acid derivative (133),89 and benzylmalonyl chloride reacts with the A,A-dimethylhydrazone of cyclopentanone (134a) to give 134b in 90% yield.90... 

The in situ generated catalyst from ATBH and trimethyl borate has also been used in the stereoselective reduction of a-oxoketoxime ethers to prepare the corresponding chiral 1,2-amino alcohols. Thus the asymmetric borane reduction of buta-2,3-dione monoxime ether followed by acidic work-up and subsequent reaction with benzyloxycarbonyl chloride affords a 90% yield of 7V-(Z)-3-aminobutan-2-ol with excellent enantioselectivities (eq 5). A trityl group in the oxime ether is required for high enantioselectivity. This method has been successively applied to both cyclic and acyclic a-oxoketoxime ethers. 

Entry 9 in Table 15 illustrates another synthetically useful stereocontrolled reduction of cyclic oxime ethers (isoxazolines) to alicyclic amino alcohols using LAH. The stereoselectivity obtained is further enhanced by the incorporation of a 4a-hydroxy group which, upon reduction, affords almost entirely the erythro isomer (equation High diastereoselectivity in the reductive cleavage of isoxazolines has... 

Reaction with (172) and other aldoximes may require oxime activation, which can be achieved with the addition of 1 equiv. of BF3-OEt2." " Yields in the addition of organometallic reagents to substituted aldoximes are modest and are a function of the isomeric composition of the oxime ethers, as the (Z)-oxime isomers are reported to preferentially react with organolithium reagents (entries 1 and 2, Table 13). ° The reaction has been employed for the preparation of 6-aminoalkyl-substituted pencillins (entry 3, Table 13)."° Cyclic oxime ether additions have also been evaluated (entries 4 and 5, Table 13). ° With the lability of the nitrogen-oxygen bond, addition to S-substituted isoxazolines provides a potential avenue for stereospecific synthesis of substituted 3-aminoalcohols (entry 5, Table 13). 

A similar method for cyclic ketone synthesis via an intramolecular carbonyl ad-dition/elimination strategy has been reported by Kim and Jon, who used acylsul-fides and acylselenides as radical acceptors (Scheme 4-21) [41]. As has previously been observed in the cases of sulfonyl oxime ethers which liberate sulfonyl radicals, thiyl and selenenyl radicals react with ditin to propagate the chain. Generally acylselenides are more efficient substrates than acylsulfides due to the better leaving ability of the phenylseleno group. As shown in the third example in Scheme 4-21, a tandem cyclization leading to a tricyclic ketone has also been effected. 

There has been research in developing semisynthetic EM derivatives to improve efficacy by a variety of chemical modifications. Examples are the addition of an F atom at C-8 and esterifications at C-11. Attempts to eliminate the acid sensitivity by manipulating the C-9 keto function have shown promise. One example is formation of a cyclic ketal with the C-9 keto and the C-ll-OH functions. Another involves the formation of the 9-oxime (with hydroxylamine) and its derivatization with (2-methoxyethoxy)methyl chloride to form the corresponding oxime-ether (Eq. 6.13). The resultant drug, roxithromycin, exhibits pharmacology and antibacterial spectrum similar to EM. 

Oxime EM 11,12-cyclic carbonate (65) (Fig. 12) and its oxime ethers have also been reported [84]. Their antibacterial activities are comparable to 1 and slightly more potent against H. influenzae. The derivatives of 4"-(9-methyl EM A... 

This free-radical acylation approach is extended for the synthesis of a-keto esters and ketones using phenylsulfonyl methoxycarbonyl oxime ether 5 [23] and bis-methanesulfonyl oxime ether 6, respectively (Scheme 6) [24], 5 is more reactive and effective than 2b. For instance, radical reaction of tert-butyl iodide with 5 gave tert-butyl oxime ester in 65% yield, whereas the use of 2b gave the corresponding tert-butyl oxime ether in 15% yield. In free-radical-mediated ketone synthesis via a sequential radical acylation approach, 6 is used as a carbonyl equivalent geminal radical acceptor. This method works well with primary alkyl iodides but somewhat less efficiently with secondary iodides and can be applied to prepare unsymmetrical acyclic ketones as well as cyclic ketones. It is noteworthy that stable allylic and benzylic radicals react smoothly with 6. 

Dimethyl (Z)-a-hydroxyiminobenzylphosphonates undergo fragmentation to benzoni-trile and dimethyl hydrogenphosphate . A four-centred cyclic mechanism was suggested for this reaction (equation 122). The fragmentation of 0-methyl oxime ethers required a much higher temperature and it was found to yield trimethyl phosphate, in addition to benzonitrile . The rate and the ease of this reaction are influenced by the groups attached to the phosphorus. For example, in a-hydroxyiminobenzylphosphonate esterified with the... 

Cyclic 1,2-amino alcohols Intramolecular reductive coupling of carbonyl-tethered oxime ethers with Smij forms the cyclic products even in the absence of HMPA. Only one diastereomer is produced. After water has been added (20-25 equiv), the N-0 bond is cleaved in a subsequent reduction with the excess reagent at room temperature. A previous report indicates the failure of the intermolecular version. 

Cyclic oxime ethers of butyrophenones exhibit neuroleptic... 

The cyclic oxime ether (69) can be selectively lithiated at either the 3-methyl or the 4-methylene position by choosing an appropriate lithium dialkylamide. Scheme 35 illustrates how this provides the basis for a new synthesis of a-methylene ketones. ... 

A number of routes can be envisioned for the preparation of polysubstituted pyrrolidines, and the intramolecular addition of a silyl ketene acetal to an oxime ether has been employed in the synthesis of ABT-627 (4). However, the reductive cyclization of a nitroketone, which could be obtained via the conjugate addition of a ketoester to a nitrostyrene, was viewed as being the most direct, convergent approach to ABT-546. In this approach, the nitro functionality is reduced to generate the cyclic imine, which is then further reduced to the trisubstituted pyrrolidine (Figure 2). As the trans-trans isomer is thermodynamically favored, both it and the cis-cis isomer are usable intermediates. 

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