Nitrone cycloaddition asymmetric

Monodentate dipolarophiles such as acrolein, methacrolein, and a-bromoacrolein could be successfully utilized in the l ,J -DBFOX/Ph-transition metal complex-catalyzed asymmetric nitrone cycloadditions [76]. The reactions of N-benzylideneani-line N-oxide with acrolein in the presence of the nickel(II) aqua complex R,R-DBF0X/Ph-Ni(C104)2 3H20 (10mol%) and MS 4 A produced a mixture of two regioisomers (5-formyl/4-formyl regioisomers ca 3 1). However, enantio-... 

Nitronates show a similar reactivity to that of nitrones, and nitrones are one of 1,3-dipoles that have been successfully developed to catalyzed asymmetric versions, as discussed in the section on nitrones (Section 8.2.1). However, asymmetric nitronate cycloadditions catalyzed chiral metal catalysts have not been reported. Kanemasa and coworkers have demonstrated that nitronate cycloaddition is catalyzed by Lewis acids (Eq. 8.93).146 This may open a new way to asymmetric nitronate cycloaddition catalyzed by chiral catalysts. 

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. 

Whereas it is easy to foresee expanded application of nitronate cycloadditions in synthesis, important challenges still remain. For example, the potential of these reactions would benefit from the development of catalysts to accelerate the process. Moreover, asymmetric catalysis has only recently been successful in dipolar cycloaddition chemistry and would have a great impact here. Another important avenue would be the invention of new tandem processes that allow for the creation of nitronates from different precursors in the presence of dipolarophiles. 

The magnesium ion-mediated nitrone cycloaddition methodology can be successfully applied to the asymmetric reactions of a chiral cyclic nitrone of the lactone type (Scheme 11.51) (169). Although (/ )-2(/f)-oxo-5-phenyl-5,6-dihydro-1,4-oxazine A-oxide is an ( )-nitrone, all of its reactions are highly diastereose-lective, producing isoxazolidine 5-alcohol cycloadducts. The chelated transition... 

Chiral crotonates derived from S-citroncllol, l-(—)-menthol, and S-solketol undergo 1,3-dipolar cycloaddition with cyclic and acyclic nitrones.66 Asymmetric 1,3-dipolar cycloaddition of optically active hifluoromethylated a, /l-unsaturated aiyl sulfones (43) with nitrones yield the corresponding isoxazolidmes (44) and (45) with high regio- and... 

MacMillan s imidazolidinone salts, used successfully in the organocatalysed Diels-Alder reaction (see Section 8.1) also function as effective catalysts in the asymmetric nitrone cycloaddition with simple monodentate dipolarophiles. Thus acrolein (8.63) and crotonaldehyde (8.99) both react with acyclic C-aryl, N-benzyl nitrones and C-aryl N-alkyl nitrones such as (8.198) with high ees ranging from 90 to 99% in the presence of the perchlorate salt of imidazolidinone (8.91). 

Elements of Stereocontrol in [4+2] Cycloadditions of Nitroalkenes The ability to constmct enantio-merically enriched nitronates through asymmetric [4 + 2] cycloadditions of nitroalkenes would be of great value for organic synthesis. Unfortunately, no example of catalysis by a Lewis acid let alone a chiral Lewis acid has been reported. However, a single example of the use of a stoichiometric amount of a chiral Lewis acid is on record, although with less than ideal results [92]. 

White, J.D. and Hansen, J.D. (2002) Asymmetric synthesis of epicylindrospermopsin nia intra-molecular nitrone cycloaddition. Assignment of absolute configuration./. Am. Chem. Soc., 124, 4950-4951. 

The fact that dipolar cycloaddition reactions lead to the rapid assembly of a variety of heterocycles spurred considerable interest in the development of asymmetric processes controlled by chiral auxdiaries [23, 30, 34). Early investigations in this area showcased the use of menthyl [68] and phenethyl [23, 69] derivatives as chiral auxiliaries in nitrone cycloadditions. A notable example of the latter was reported by Baldwin (Scheme 18.13) [70], The cycloaddition reaction of 59 was observed to proceed with high induction to afford 60 in 70% yield (dr= 16 1). This adduct served as a key intermediate in synthetic studies directed towards the antitumor and antiviral alkaloid pretazet-tine (61). 

Vasella reported a convenient, mannose-derived auxiliary for asymmetric nitrone cycloaddition reactions [71], The requisite auxiliary is prepared from mannose, acetone, and N-hydroxyl amine hydrochloride to give 62... 

Cationic complexes of rran.s-chelating tridentate ligand, (/ ,/ )-4,6-dibenzo-furandiyl-2,2 -bis(4-phenyloxazoline), with transition metal(II) perchlorates as effective catalysts for asymmetric cycloaddition of nitrones 98YGK368. 

Asymmetric cycloaddition of functionalized alkenes to nitrile oxides and nitrones 98YGK11. 

Application in organic synthesis of optically active isoxazolidones obtained by asymmetric cycloaddition of nitrones with allenes 97T403. 

Asymmetric bias generated by protected vicinal diol controller and its application to asymmetric nitrone-olefin cycloaddition reactions 98YGK86. 

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. 

The above described approach was extended to include the 1,3-dipolar cycloaddition reaction of nitrones with allyl alcohol (Scheme 6.35) [78]. The zinc catalyst which is used in a stoichiometric amount is generated from allyl alcohol 45, Et2Zn, (R,J )-diisopropyltartrate (DIPT) and EtZnCl. Addition of the nitrone 52a leads to primarily tmns-53a which is obtained in a moderate yield, however, with high ee of up to 95%. Application of 52b as the nitrone in the reaction leads to higher yields of 53b (47-68%), high trans selectivities and up to 93% ee. Compared to other metal-catalyzed asymmetric 1,3-dipolar cycloaddition reactions of... 

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