Acrolein 1,3-dipolar cycloaddition

The Lewis acid-catalyzed 1,3-dipolar cycloaddition reaction of nitrones to a,/ -un-saturated carbonyl compound in the presence of Lewis acids has been investigated by Tanaka et al. [31]. Ab-initio calculations were performed in a model reaction of the simple nitrone 18 reacting with acrolein 1 to give the two cycloadducts 19 and 20 (Scheme 8.7). 

Dipolarophiles D5. Electron-deficient alkenes based on acrolein and its analogs are widely used as dipolarophiles. To carry out asymmetrical 1,3-dipolar cycloadditions between various nitrones and acrolein, the bis-titanium catalyst (543) (Fig. 2.37) was used as the chiral Lewis acid (Table 2.22) (754a). 

Table 2.22 Asymmetric 1,3-dipolar cycloadditions of nitrones with acrolein"...

Chiral alkenes derived from ot,p-unsaturated aldehydes have also been applied in asymmetric 1,3-dipolar cycloadditions (142). Soucy et al. (142) used (—)-8-(benzylamino)menthol (94) and acrolein for the exclusive formation of 95 having an equatorial C(2) vinyl group (Scheme 12.31). The 1,3-dipolar cycloaddition of acetonitrile oxide with 95 gave 96 with a selectivity of > 90% de. 

BINOL-catalysed enantioselective 1,3-dipolar cycloaddition between a-substituted acroleins and alkyl diazoacetates yielded chiral 2-pyrazolines with 95% ee. This methodology has been used to synthesise manzacidin A.86... 

The PEG-supported imidazolidinone 19 (Scheme 7) was later used in 1,3-dipolar cycloadditions (Puglisi et al. 2004). By reacting A-benzyl-C-phenylnitrone with acrolein, it was shown that the outcome of the reaction was strongly dependent on the nature of the acid employed to generate the catalyst, and that only the use of HBF4 as in the case of 19 allowed reproducible results to be obtained. Under the best reaction conditions (20 mol% of catalyst, DCM, -20 °C, 120 h) the product was obtained in 71% yield as a 85 15 trans/cis mixture of isomers, thetrans isomer having 87% ee (equation b, Scheme 7). 

The first enantioselective organocatalytic 1,3-dipolar cycloaddition of acyclic nitrones with acrolein and crotonal-dehyde has been reported <2000JA9874>. In particular, the reversible formation of iminium ions from a,/3-unsatu-rated aldehydes and the enantiopure imidazolidinone 535 provided ( A-4-formylisoxazolidines in high yields and ees (Equation 86). A polymer-supported version of catalyst 535 was also prepared <2004EJ0567>. The catalytic performance of various chiral pyrrolidinium salts in the cycloaddition of 1-cycloalkene-l-carboxaldehydes was also evaluated <2003EJO2782>. 

Very recently, Maruoka reported an alternative catalytic asymmetric [3 + 2] cycloaddition reaction between various nitrones and acrolein catalyzed by the x-oxo-type chiral bis-Ti(IV) oxide, giving rise to the corresponding isoxazolidine derivatives in good yields and high enantioselectivities [177]. This type of titanium Lewis acid has also been used in enantioselective 1,3-dipolar cycloaddition of diazoacetates to various substituted acroleins, affording 2-pyrazolines with a chiral quarternary carbon center (Scheme 14.78) [178]. The products obtained with these methodologies have been applied to the synthesis of natural product and biologically important molecules. 

Kano, T., Hashimoto, T., Maruoka, K. (2006). Enantioselective 1,3-dipolar cycloaddition reaction between diazoacetates and a-substituted acroleins total synthesis of manzacidin A. Journal of the American Chemical Society, 128, 2174-2175. 

In 2005, Maruoka and coworkers reported asymmetric 1,3-dipolar cycloaddition reaction of nitrones and acrolein catalyzed by (12) (Scheme 1.19) [24c]. 

Subsequently, Maruoka group developed an enantioselective 1,3-dipolar cycloaddition reaction between diazoacetates and a-substituted acroleins (Scheme 1.20) [24d]. The reactions of 1.5 equivalent of ethyl or tert-butyl diazoacetate and various a-substituted acrolein derivatives afford chiral 2-pyrazolines with high... 

For the diazoacetates, Mamoka and coworkers reported on the chiral titanium BINOLate-catalyzed highly enantioselective 1,3-dipolar cycloaddition reactions between diazoacetates and monodentate a-substituted acroleins, which give 2-pyrazolines with an asymmetric tetrasubstituted carbon center in 2006 (Table 7.6) [23], The titanium BINOLates, such as (5)-BlNOL/Ti(OPr )4 (2 1 molar ratio) complex (TB-b) and bis (5)-binaphthoxy)(isopropoxy)titanium oxide (TB-c), showed good results in terms of yields and enantiose-lectivities compared with simple (5)-BINOL/Ti(OPr )4 (1 1 molar ratio) complex (TB-a). The synthetic utility of the present reaction was further demonstrated by the total synthesis of a bromopyrrole alkaloid manzacidin A (Scheme 7.13), which was isolated firom the Okinawan sponge Hymeniacidon sp. [24],... 

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