Nitrones intramolecular cycloadditions

For diastereoselective nitrone intramolecular cycloaddition to conjugated esters, see R. Annunziata, M. Cinquini, F. Cozzi and L. Raimondi, Tetrahedron Lett., 1988, 29, 2881. 

Silyl nitronates. Intramolecular cycloaddition of j3-propargyloxy nitroalkanes is induced by MeySiCl-EtyN. It is a convenient way to dihydrofuraldehydes. Dihy-dropyranaldehydes are obtainable from the homologous nitro ethers. 

The reaction of nitrones with allenes produced three main products an azepine, a pyrrolidinone and an isoxazolidine (Scheme 155) (79JOC4213). The intramolecular cycloaddition of nitrones (529) produced different products depending on the length of n (Scheme 156) (78H(10)257). 

The elegant, enantiospecific synthesis of biotin (1) by Hoffmann-La Roche1 is based on a strategy that takes advantage of the powerful intramolecular nitrone-olefin cycloaddition reaction. Our analysis begins with model studies in which the straightforward conversion of L-cysteine (2) into aldehyde 3 (see Scheme 1) constitutes... 

Intramolecular Silyl Nitronate-Olefin Cycloaddition (ISOC)... 

Lithium perchlorate and lithium triflate in acetonitrile catalyze intramolecular cycloaddition reactions of nitrones of allyloxybenzaldehydes and unsaturated aldehydes.154... 

The Michael addition of allyl alcohols to nitroalkenes followed by intramolecular silyl nitronate olefin cycloaddition (Section 8.2) leads to functionalized tetrahydrofurans (Eq. 4.15).20... 

Reductions of y-nitroketones yield cyclic nitrones, which undergo inter- and intramolecular cycloaddition to various alkenes. The result of addition to acrylonitrile is shown in Eq. 8.42, in which a mixture of regio- and stereoisomers is formed.65... 

Diastereoselective intramolecular cycloaddition of nitrones is useful for constructing nitrogen- containing cyclic structures. The reaction serves as a key step in a number of natural product syntheses.63 Tufarriello and coworkers have used this strategy for preparing cocaine and other alkaloids.74 As a classical example, enantioselective total synthesis of (+)-luciduline is presented in Scheme 8.13, in which a useful feature of the 1,3-dipolar addition of nitrones is nicely illustrated.75... 

Intramolecular cycloadditions of chiral nitrones provide a useful tool for the preparation of bioactive heterocyclic compounds.63 Shing et al. demonstrated that 1,3-dipolar cycloaddition of nitrones derived from 3-0-allyl-hexoses is dependent only on the relative configuration at C-2,3, as shown in Scheme 8.16. Thus 3-0-allyl-D-glucose and -D-altrose (both with threo-configuration at C-2,3) produce oxepanes selectively, whereas 3-O-allyl-D-allose and -D-man-nose (both with erythro-configuration at C-2,3) give tetrahydropyranes selectively.80... 

Hassner and coworkers have developed a one-pot tandem consecutive 1,4-addition intramolecular cycloaddition strategy for the construction of five- and six-membered heterocycles and carbocycles. Because nitroalkenes are good Michael acceptors for carbon, sulfur, oxygen, and nitrogen nucleophiles (see Section 4.1 on the Michael reaction), subsequent intramolecular silyl nitronate cycloaddition (ISOC) or intramolecular nitrile oxide cycloaddition (INOC) provides one-pot synthesis of fused isoxazolines (Scheme 8.26). The ISOC route is generally better than INOC route regarding stereoselectivity and generality. 

The intramolecular cycloaddition of nitrones derived from iV-allyl-2-indolecarbaldehyde was used to an entry to pyrrolo- and pyrido[ 1,2-a]indole skeletons . For instance, the cinnamyl-substituted aldehyde 157 upon treatment with benzylhydroxylamine affords to the nitrone 158, which upon heating in refluxing toluene leads to mainly the cycloadduct 159. 

According to general (or principal) Scheme 2.211a, the enolate group of nitrone (433), generated on treatment with LDA, acts as the dipolarophile on attacking the nitrone group. The bicyclic compound (434) is obtained from a spontaneous intramolecular cycloaddition (Scheme 2.212) (703). 

Regiospecilic intramolecular cycloadditions of nitrones to sulfur-substituted dienes, with 3-sulfolene precursors, has been realized (Scheme 2.217). The stereochemical outcome of these reactions is affected by the structure of the substituent (sulfide or sulfone) in the diene and by the chain length connecting the diene and nitrone (a) and (b) (see Scheme 2.211). The bicyclic products obtained from these reactions have been converted to interesting heterocyclic compounds (709). 

Bicyclopropylidenyl-substituted nitrones (443) and (444) undergo regio- and diastereoselective intramolecular cycloadditions to afford exclusively the... 

In agreement with Schemes 2.211b and 2.211c, intramolecular cycloadditions of nitrones to 5-allyl- (Scheme 2.225) or 5-homoallylproline (Scheme 2.226), are fully regio- and stereoselective. These reactions are the key steps in the synthesis of functionalized azaoxobicyclo[X.3.0] alkane amino acids, mimics of a homoSer-Pro dipeptide (721). 

Cycloaddition of nitrone (508) to allyl alcohol at ambient temperature gave a mixture of four cycloadducts in a 23 5 4 1 ratio (Scheme 2.244). All of the adducts (509) are derived from the regiochemical approach opposite to the intramolecular pathway (Fig. 2.35). Formation of the cycloadduct in the intramolecular cycloaddition reaction is ascribed to a high preference for an endo-syn transition state, due to the constraint imposed by the short, three atom connecting chain (116). The major product in the intermolecular cycloaddition reaction was the exo-anti -(509) adduct (Scheme 2.244 and Fig. 2.35). 

Recently, dipolarophile 1)13 (fumaronitrile) (777) has been used in the synthesis of indolizine lactone (677). Both, intermolecular and intramolecular cycloadditions were studied. Intermolecular 1,3-cycloaddition of nitrone (671) to D13 led to the formation of isoxazolidine (672). Subsequent deprotection and esterification of the obtained alcohol (673) with (674) gave isoxazolidine (675) in 65% yield. Ester (675), when refluxed in xylene for 10 min, after elimination of fumaronitrile by cyclo-reversion, underwent spontaneously intramolecular cycloaddition to give the tricyclic cycloadduct (676) in 84% yield (Scheme 2.291). 

This process was carried out with the use of diastereomerically and enan-tiomerically pure five-membered cyclic nitronates (213). After selective silylation of the hydroxy group and intramolecular cycloaddition, these compounds give enantiomerically pure fused systems, which are similar precursors of enantiomer-ically pure hydroxyamino acids and other polyfunctional compounds possessing potential biological activity. 

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