Stereoselectivity chiral dipolarophiles

Nitrones derived from cyclic acetals of D-erythrose (479) and (689) and of D-threose (480) and (690), reacted with N -phenylmaleimide D15a to afford the corresponding diastereomeric isoxazolidines (691-706) (Scheme 2.295). The stereoselectivity is dependent on the substituents in the nitrone. In the case of nitrones (479) and (689) the cycloaddition is exo-selective. It was observed that microwave irradiation decreased the reaction times of the cycloadditions dramatically. For example, for nitrone (689) and dipolarophile D15a the reaction time decreased from 11 h to 8 min and for nitrone (690) and D15a it decreased from 3 h to 10 min. Moreover, microwave irradiation reversed the ratio of erythro-frans/erythro-r/.v adducts from 63 37 to 39 55, see compound (689). Cycloadditions of the chiral maleimides D15b and D15c are less stereoselective (817). 

The reaction of tetrahydropyridine 7/-oxide (93) (n = 1) with a chiral sulfinyl maleimide dipolarophile (166) has been reported (Scheme 1.36), but afforded the major product 167 with only modest stereoselectivity, despite the use of a... 

A second strategy to control facial selectivity involves the use of chiral sultams and lactams as auxiliaries for the dipolarophile (120-123). Cycloaddition of 132 with a variety of substituted nitronates provides up to 9 1 selectivity of the major diastereomer (Table 2.38). However, substitution at the a-position of the dipolarophile leads to a reduction in stereoselectivity (entry 5). Assuming an s-cis conformation of the dipolarophile, it is proposed that the major isomer arises from an endo approach of the nitronate to the Re face of the dipolarophile (Fig. 2.13). This is supported by X-ray crystallographic analysis of one of the cycloadducts, which resides in a conformation similar to the proposed transition state. However, this analysis assumes that the silyl nitronate is only reacting through the... 

Another approach to obtain pure enantiomers of isoxazolines involves the use of chiral acrolein aminals, formed with A.A -substituted diaminodiphenylethanes (194). Thus, with this chiral imidazolidinyl auxiliary in the p-position, and with unsaturated esters serving as the dipolarophile, benzonitrile oxide afforded only one regioisomeric cycloadduct with good stereoselectivity (194) (Scheme 6.40). When the analogous A,A -dimethyl auxiliary was chosen, excellent stereoselectivity was accompanied by poor regioselectivity (194). 

The silver acetate-promoted 1,3-dipolar cycloaddition of nitrilimines with 3(/f )-pheny]-4(A )-cinnamoyl-2-azetidinone produced the major adduct, 4-(4,5-dihydro- (g) pyrazol-5-yl)carbonyl-2-azetidinones, with high stereoselectivity.70 The 1,3-dipolar cycloadditions of substituted 2,7-dime(liyl-3-thioxo-3,4,5,6-ici.rahydro-2//- 1,2,41 triazepin-5-one with iV-aryl-C-ethoxycarbonylnitrilimines are highly chemoselective, where the sulfur atom of the dipolarophile interacts with the carbon atom of the dipole.71 The enantioselective 1,3-dipolar cycloaddition of nitrile imines with electron deficient acceptors produces dihydropyrazoles in the presence of 10 mol% of chiral Lewis acid catalyst.72... 

There have been only a few reports of reactions of this type including cycloaddition of dienes 157 with the powerful dienophile 4-phenyl-l,2,4-triazoline-3,5-dione <1996J(P1)2297> and stereoselective cycloaddition of the chiral nitrone 158 with a variety of dipolarophiles <2000JOC7000>. A rare example of intramolecular hetero-Diels-Alder reaction involving a 4-methylene-l,3-oxathiolan-5-one 3 -oxide is provided by the cycloaddition reaction of 159 to give 160 (Equation 42) <1998EJ02733>. 

Azomethine ylides are very important 1,3-dipoles, and they are usually used to react with alkenes leading to the formation of the highly substituted pyrrolidine derivatives [17]. A novel and practical process for the 1,3-dipolar cycloaddition of azomethine ylides with alkenes had been reported by j0rgensen and coworkers [18]. They proposed that a dipol-chiral base ion pair would be generated between a-imino ester-metal complex and a cinchona alkaloid, and subsequent cycloaddition with dipolarophile would take place in a stereoselective manner (Scheme 10.13). 

The reactions of diazoalkanes 9.21 with alkenes lead to pyrazolines 9.22, which are thermally transformed into cyclopropanes. Similar transformations occur during thermal reactions of diazoesters. The use of diazoesters of chiral alcohols did not give useful results, so chiral residues have been introduced on the olefin dipolarophile. Meyers and coworkers [327] carried out the reaction of diazomethane 9.21 (R = R = H) and diazopropane 9.21 (R = R = Me) with chiral lactams 1.92 (R = i-Pr or ferf-Bu, R = Me). These 1,3-dipolar cycloadditions are regioselective, but only CH2N2 leads to an interesting stereoselectivity (Figure 9.9). Morever, when the RM substituent of lactam 1.92 is H, the reaction is no longer stereoselective. 

De Lange and Feringa [137, 203] have performed the cycloadditions of CH2N2 and ethyl diazoacetate to chiral lactone 1.31, derived from menthol. A high stereoselectivity is only observed with ethyl diazoacetate. The reaction occurs on the least hindered face of the dipolarophile, and 2-pyrazoline 9.23 is obtained (Figure 9.9). 

Oxazoline 7V-oxides are nitrile oxide equivalents that cycloadd to electron-poor dipolarophiles such as crotonates. Langlois and coworkers [346] introduced chirality into these reagents. While regio- and stereoselective cycloadditions were observed, the dural auxiliaries have not yet been removed. 

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