Nitrones, cycloaddition with interaction

Scheeren et al. reported the first enantioselective metal-catalyzed 1,3-dipolar cycloaddition reaction of nitrones with alkenes in 1994 [26]. Their approach involved C,N-diphenylnitrone la and ketene acetals 2, in the presence of the amino acid-derived oxazaborolidinones 3 as the catalyst (Scheme 6.8). This type of boron catalyst has been used successfully for asymmetric Diels-Alder reactions [27, 28]. In this reaction the nitrone is activated, according to the inverse electron-demand, for a 1,3-dipolar cycloaddition with the electron-rich alkene. The reaction is thus controlled by the LUMO inone-HOMOaikene interaction. They found that coordination of the nitrone to the boron Lewis acid strongly accelerated the 1,3-dipolar cycloaddition reaction with ketene acetals. The reactions of la with 2a,b, catalyzed by 20 mol% of oxazaborolidinones such as 3a,b were carried out at -78 °C. In some reactions fair enantioselectivities were induced by the catalysts, thus, 4a was obtained with an optical purity of 74% ee, however, in a low yield. The reaction involving 2b gave the C-3, C-4-cis isomer 4b as the only diastereomer of the product with 62% ee. 

Alkenylboronic esters undergo regio- and stereoselective 1,3-dipolar cycloadditions with nitrones. These reactions lead to boronic ester-substituted isoxazolidines, which can be converted by oxidation with H202 to the corresponding 4-hydroxy derivatives (Eq. 8.48).69 The high selectivity could be the result of a favorable interaction between the boronic ester and the amino group. 

The acyclic precursor is an oc, 3-unsaturated amido aldehyde that was condensed with iV-methylhydroxylamine to generate the nitrone ( )-48, which then underwent a spontaneous cycloaddition with the alkene to afford the 5,5-ring system of the isoxazolidinyl lactam 47. The observed product arises via the ( )-nitrone transition state A [or the (Z)-nitrone equivalent] in which the position of the benzyl group ot to the nitrone effectively controls the two adjacent stereocenters while a third stereocenter is predicted from the alkene geometry. Both transition states maintain the benzyl auxiliary in an equatorial position and thus avoid the unfavorable 1,3-diaxial interaction with the nitrone methyl or oxygen found in transition state B. Semiempirical PM3 calculations confirm the extra stability, predicting exclusive formation of the observed product 47. Related cycloadducts from the intramolecular reaction of nitrones containing ester- rather than amide-tethered alkene functionality are also known (83-85). 

Nitrones can be activated mainly in two different ways for the 1,3-dipolar cycloaddition with alkenes. In the reaction between a nitrone and an electron-dehcient alkene, such as an a,p-unsaturated carbonyl compound (a normal electron-demand reaction), it is primarily controlled by the interaction between HOMOnitrone-LUMOaikene (Scheme 12.64). By coordination of a Lewis acid (LA) catalyst to the a,p-unsaturated carbonyl compound, the LUMOaikene energy decreases and a better interaction with the nitrone can take place (16,17). 

Since then researchers in the field of nitrone cycloaddition seem to have more or less tacitly assumed that secondary interactions play an important role in determining endo/exo selectivity also in the case of N-alkyl and N-arylnitrone cycloaddi-tions.2 However, our experimental endo/exo selectivity studies " for the reactions of cyclic and open-chain nitrones with Z-disubstituted dipolarophiles revealed a clear-cut dominance (77% in benzene) of the endo mode only in one case the reaction of 1-pyrroline-l-oxide with maleonitrile, a reaction where the steric effects... 

According to a qualitative orbital consideration, the vi/i orbital of the ji-system of nitrone can interact with the formal nitrogen nonbonding electron pair of cyclo adducts. The anomeric effect (classic and kinetic) that can become operational in the transition state of cycloaddition can stabilize the transition state. On the other side, the unoccupied x /3 orbital of the jt-system of nitrone through its interaction with the unoccupied o orbital of Cl-O bond can decrease the activation energy, and with that increase the electrophilic character of nitrone (Fig. 8.37). 

A computational study of the [3 + 2] cycloaddition between nitronate 83 and an electron-rich (66) or electron-poor (84) dipolarophile sheds additional light on this issue (Figure 16.6) [120]. In each case, the gap between the HOMOd ie and the LUMOdipoiarophiie is smaller than between the LUMOdipoie and the HOMOdjpoiarophiie- However, the separation between the HOMOdipoie and the LUMOd ian hfle IS Smaller for the electron-poor dipolarophile 84 (4.64 eV) flian for the electron-rich dipolarophile 66 (7.17 eV). This difference suggests that the reaction is governed by normal-electron-demand in both cases, and the major interactions are between the HOMOdipoie and the LUMOdipoiarophiie- This Conclusion is supported by competition experiments in which electron-deficient dipolarophiles react faster than electron-rich vinyl ethers in [3 + 2] cycloadditions with nitronates [55, 101]. 

In the 1,3-dipolar cycloaddition reactions of especially allyl anion type 1,3-dipoles with alkenes the formation of diastereomers has to be considered. In reactions of nitrones with a terminal alkene the nitrone can approach the alkene in an endo or an exo fashion giving rise to two different diastereomers. The nomenclature endo and exo is well known from the Diels-Alder reaction [3]. The endo isomer arises from the reaction in which the nitrogen atom of the dipole points in the same direction as the substituent of the alkene as outlined in Scheme 6.7. However, compared with the Diels-Alder reaction in which the endo transition state is stabilized by secondary 7t-orbital interactions, the actual interaction of the N-nitrone p -orbital with a vicinal p -orbital on the alkene, and thus the stabilization, is small [25]. The endojexo selectivity in the 1,3-dipolar cycloaddition reaction is therefore primarily controlled by the structure of the substrates or by a catalyst. 

The typical 1,3-dipolar cycloaddition reaction of nitrones with alkenes involves a dominant interaction of HOMO (nitrone) and LUMO (alkenes). The inverse-electron demand of the... 

The reaction of nitrostyrene with cyclopentadiene gives the normal Diels-Alder adduct. However, the Lewis acid-catalyzed cycloaddition affords two isomeric nitronates, syn and anti in an 80-to-20 ratio. The major isomer is derived from an endo transition state. The preference of yy/i-fused cycloadducts can be understood by considering secondary orbital interactions (Eq. 8.95).152... 

The interaction of trinitromethide salts with alkenes has also been investigated (174). In aprotic solvents, trinitromethide anions undergo extrusion of a nitro group to produce a dinitrocarbene (Scheme 2.18). In the presence of monsubstituted alkenes a formal [3 + 2] cycloaddition produces a nitronate that then further reacts... 

Nitrones interact with substituted perfluoroolefins by the 1,3-cycloaddition mechanism. For example, with ethyl 2-hydroxypolyfluoroalk-2-enoate they give 5-fluoroalkylisoxazolidine in the form of a mixture of two cis and trans epimers. 

One important nitrone is a cyclic compound that has the structure below and adds to dipolarophiles (essentially any alkene ) to give two five-membered rings fused together. The stereochemistry comes from the best approach with the least steric hindrance, as shown. There is no endo rule in these cycloadditions as there is no conjugating group to interact across space at the back of the dipole or dipolarophile. The product shown here is the more stable exo product. 

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