Enantioselectivity nitrone cycloadditions

Accordingly, cyclic nitronates can be a useful synthetic equivalent of functionalized nitrile oxides, while reaction examples are quite limited. Thus, 2-isoxazoline N-oxide and 5,6-dihydro-4H-l,2-oxazine N-oxide, as five- and six-membered cyclic nitronates, were generated in-situ by dehydroiodination of 3-iodo-l-nitropropane and 4-iodo-l-nitrobutane with triethylamine and trapped with monosubstituted alkenes to give 5-substituted 3-(2-hydroxyethyl)isoxazolines and 2-phenylperhydro-l,2-oxazino[2,3-fe]isoxazole, respectively (Scheme 7.26) [72b]. Upon treatment with a catalytic amount of trifluoroacetic acid, the perhydro-l,2-oxazino[2,3-fe]isoxazole was quantitatively converted into the corresponding 2-isoxazoline. Since a method for catalyzed enantioselective nitrone cycloadditions was established and cyclic nitronates should behave like cyclic nitrones in reactivity, there would be a good chance to attain catalyzed enantioselective formation of 2-isoxazolines via nitronate cycloadditions. 

Evans and coworkers reported Ce(IV)-PyBOX catalyzed highly enantioselective nitrone cycloaddition by employing a,P-unsaturated 2-acyl imidazoles. Five mole percent of Ce(OTf)4/Ph-PyBOX promoted the reaction under mild conditions (0°C, EtOAc), giving products in up to 99% yield, 97% ee, and endojcxo =... 

Catalytic enantioselective nitrone cycloadditions were first published in 1994, by Scheeren [84] and by Jorgensen [85, 86]. Jorgensen reported that the TADDOL-derived titanium catalyst 92 [87] promoted the cycloaddition re-... 

In the nitrone cycloaddition reactions catalyzed by the l ,J -DBFOX/Ph transition metal complexes also, the diastereo- and enantioselectivities were found to depend upon the presence of MS 4 A [71]. Thus, both the selectivities were much lowered in the iron(II) or nickel(II) complex-catalyzed reactions without MS 4 A,... 

Bis(oxazoline)-type complexes, which have been found useful for asymmetric aldol reactions, Diels-Alder, and hetero Diels-Alder reactions can also be used for inducing 1,3-dipolar reactions. Chiral nickel complex 180, which can be prepared by reacting equimolar amounts of Ni(C10)4 6H20 and the corresponding (J ,J )-4,6-dibenzofurandiyl-2,2 -bis(4-phenyloxazoline) (DBFOX/Ph) in dichloromethane, can be used for highly endo-selective and enantioselective asymmetric nitrone cycloaddition. The presence of 4 A molecular sieves is essential to attain high selectivities.88 In the absence of molecular sieves, both the diastereoselectivity and enantioselectivity will be lower. Representative results are shown in Scheme 5-55. 

The number of investigations on the enantioselective dipolar cycloaddition of nitronates is still rather limited. In the case of simple alkyl nitronates, the facial selectivity is controlled solely by the steric environment about the two faces of the chiral unit. For example, the reaction of steroid dipolarophile 270 proceeds with the nitronate approaching the Re face of the alkene (Eq. 2.23) (234). The facial selectivity is controlled by the C(19) methyl group, which blocks the Si face of the dipolarophile. Similarly, exposure of 279 to ethyl acrylate at 40 °C for 24 h, provides a single nitroso acetal (Scheme 2.21) (242). The facial selectivity is presumed to arise from steric shielding by the menthol group, however the full stereostructure has not been established. 

Nitrones are the most widely studied of the 1,3-dipoles in the field of catalyzed enantioselective 1,3-dipolar cycloaddition reactions. Effective catalysis using a variety of chiral Lewis acid catalysts has been reported for the nitrone cycloaddition... 

A polymer-supported version of catalyst 1 was also used in the nitrone cycloaddition, with promising results [58]. The enantioselectivity of the reaction was usually comparable to what has been observed in solution, although catalyst recycling was accompanied by substantial decrease in chemical yield. 

R,R)-4,6-Dibenzofiirandiyl-2,2 -bis(4-phenyloxazoline), DBFOX/Ph (5), is a novel tridentate bisoxazoline ligand developed by Kanemasa and coworkers that has been successfully used as a chiral Lewis acid in enantioselective Diels-Alder-reactions, nitrone cycloadditions and conjugate additions of radicals and thiols to 3-(2-alkenoyl)-2-oxazolidinones. Representative examples for cycloadditions using the Ni(C104)2-6H20 derived complex are shown below. 

Nitrone cycloaddition reactions promoted by dichlorotitanium TADDOLate can be improved by using A(-(2-alkenyl)succinimides as the dipolarophiles. Regioselective and enantioselective formation of cyclopentenecarboxylic esters is observed using 8 to catalyze the [3+2]cycloaddition of 2,3-butadienoates with electron-deficient alkenes. ... 

The Ti(IV) TADDOL catalyst D leads to moderate to high enantioselectivity in nitrone cycloaddition with iV-acyloxazolidinones. ... 

Kanemasa e t al. had found that Ni( 11) and F e (11) chiral complexes derived from 4,6-dibenzofurandiyl-2,2 -bis(4-phenyloxazoline)-Ph ligand act as chiral Lewis acids to make isoxazolidines through nitrone cycloadditions reactions. Strong binding of nitrones to catalysts is a serious problem in the Lewis acid catalyzed nitrone cycloadditions, and therefore, bidentate dipolarophile such as 3-(2-alkenoyl)-2-oxazolidinones have been mostly used to protect the tight coordination of acceptors to the catalysts. Recently, they reported that Ni(II), Zn(II), Mg(II), and Co(II) complexes with (R,R)-DBFOX-Ph ligand catalyzed enantioselective nitrone reactions to a variety of... 

Cu(OTf)2/(49) was also reported to be efficient for exo selective nitrone cycloadditions to a-substituted and a,P-disubstituted dipolarophiles (323) (Scheme 17.71) [102]. In this report, the use of a,P-disubstituted acrylimides proved critical to providing the enhanced reactivity necessary for cycloadditions with a,P-disubstituted substrates. The isoxazolidine cycloadducts (324) and (325) are isolated in moderate to good chemical yields with high enantioselectivity and good to excellent exo endo ratios. 

Kobayashi has documented that chiral Yb complexes are also effective catalysts for nitrone cycloadditions (Scheme 18.19) [88]. In the presence of the putative ytterbium complex 98, derived from (S)-BINOL and chiral amine 99, the endo-isoxazolidine 100 was obtained in 96% ee. The chiral amine additive proved crucial for the observation of high enantioselectivity. Subsequently, the product 100 was readily converted into -lactam 101. 

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. 

In an analogous study by Meske, the impact of various oxazaborolidinone catalysts for the 1,3-dipolar cycloaddition reactions between acyclic nitrones and vinyl ethers was studied [31]. Both the diastereo- and the enantioselectivities obtained in this work were low. The highest enantioselectivity was obtained by the application of 100 mol% of the tert-butyl-substituted oxazaborolidinone catalyst 3d [27, 32] in the 1,3-dipolar cycloaddition reaction between nitrone la and ethyl vinyl ether 8a giving endo-9a and exo-9a in 42% and 27% isolated yield, respectively, with up to 20% ee for endo-9a as the best result (Scheme 6.10). 

A model for the mechanism of the highly enantioselective AlMe-BINOL-cata-lyzed 1,3-dipolar cycloaddition reaction was proposed as illustrated in Scheme 6.13. In the first step nitrone la coordinates to the catalyst 11b to form intermediate 12. In intermediate 13, which is proposed to account for the absolute stereoselectivity of this reaction, it is apparent that one of the faces of the nitrone, the si face, is shielded by the ligand whereas the re face remains available... 

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