Nitroalkanes, asymmetric conjugate addition

Yamaguchi and coworkers have found that proline rubidium salts catalyze the asymmetric Michael addition of nitroalkanes to prochiral acceptors. When (25)-L-prolines are used, acyclic ( )-enones give (S)-adducts. Cyclic (Z)-enones give (R)-adducts predominantly (Eq. 4.139).203 Recently, Hanessianhas reported that L-proline (3 7% mol equiv) and 2,5-dimethylpiperazine are more effective to induce catalytic asymmetric conjugate addition of nitroalkanes to cycloal-kanones.204... 

The Cu(I)-catalysed asymmetric conjugate addition of dialkyl zinc reagents to 3-nitrocoumarins 45 gives high yields of 3,4-dihydrocoumarins in a pH-dependent diastereoisomeric ratio. Subsequent decarboxylation gives optically active p-aryl nitroalkanes... 

Table 5.10 Asymmetric conjugate addition of nitroalkanes to alkylidenemalonates under phase-transfer conditions.

As an extension of this research, Maruoka and coworkers succeeded in the catalytic asymmetric conjugate addition of nitroalkanes to cyclic a,[S-unsaturated ketones under phase-transfer conditions (Scheme 5.40) [39]. Here, the use of 3,5-bis(3,4,5-trifluorophenyl)phenyl-substituted catalyst (S,S)-lj is crucial for obtaining the high enantioselectivity. 

Pyrrolidin-2-yltetrazole has been found to be a versatile organocatalyst for the asymmetric conjugate addition of nitroalkanes to enones.45 Using this catalyst, this transformation requires short reaction times, tolerates a broad substrate scope, and possibly proceeds via generation of an iminium species. 

The first examples of catalytic asymmetric conjugate addition of alkylzinc reagents to trisubstituted nitroalkenes, such as PhC(Me)=CHN02, leading to the formation of nitroalkanes bearing a quaternary carbon stereogenic centre, have been reported. Reactions are promoted by the readily available amino acid-based phosphine (211)... 

Halland N, Hazell RG, Jprgensen KA (2002) Organocatalytic asymmetric conjugate addition of nitroalkanes to alpha,beta-unsaturated enones using novel imidazoline catalysts. J Qrg Chem 67 8331-8338... 

The direct asymmetric conjugate addition of simple aldehydes to electrophiles is crucial in organic reactions. Barbas et al. developed the first example of a highly stereoselective direct Michael reaction that involved adding unmodified aldehydes to nitro-olefins. After various p3Trolidine-diamines were screened, (S)-2-(morpholinomethyl)pyrrolidine Ic was determined to be the ideal catalyst for obtaining satisfactory stereoselectivity in the reaction. These reactions afforded various 2,3-disubstituted y-formyl nitroalkanes with satisfactory yields and moderate to good enantioselectivity (Scheme 9.12). ... 

In 2009, Bernadi and Adamo designed 4-nitro-5-sttyrylisoxazole (66) as a novel Michael acceptor. The asymmetric conjugate addition of nitroalkanes to 66 in the presence of cinchonidine-derived PTC catalyst 8o afforded the addition adduct 67 with high enantioselectivity (97% enantiomeric excess). The 4-nitroisoxazole eore serves as an activator of the conjugated alkene and is readily derivatised to pharmaceutically valuable compounds, such as y-nitroesters and y-amino acids (Scheme 16.20). " ... 

Silyl nitronates, the preactivated nucleophiles of nitroalkanes, are also applicable in the asymmetric conjugated addition reaction with a,(S-unsaturated aldehydes, ketones, and nitroalkenes. Maruoka and co-workers [115] found that AT-spiro... 

A dihydroquinidine-derived chiral thiourea (DHQD-30), which demonstrated significantly better stereocontrol than other cinchona alkaloids, was utilized in the aza-Henry reaction with nitroalkanes and aldimines by Schaus and coworkers (Scheme 13.8) [26]. The utility of the nitroethane pronucleophile conveniently offers a tertiary stereogenic center in the P-nitroamine product 32. The methodology is also conveniently applicable to novel a,P-unsaturated aliphatic imines 29, which are difficult substrates in asymmetric conjugate addition reactions. Similar reaction conditions can be appHed towards to the use of dimethyl malonates as pronucleophiles that generate adducts in high enantioselectivity, which then convert smoothly into P-amino esters under the Nef conditions. 

Baschieri A, Bemardi L, Ricci A, Suresh S, Adamo MFA. Catalytic asymmetric conjugate addition of nitroalkanes to 4-nitro-5-st5Tylisoxazoles. Angew. Chem. Int. Ed. 2009 48(49) 9342-9345. 

Michael-aldol reaction as an alternative to the Morita-Baylis-Hillman reaction 14 recent results in conjugate addition of nitroalkanes to electron-poor alkenes 15 asymmetric cyclopropanation of chiral (l-phosphoryl)vinyl sulfoxides 16 synthetic methodology using tertiary phosphines as nucleophilic catalysts in combination with allenoates or 2-alkynoates 17 recent advances in the transition metal-catalysed asymmetric hydrosilylation of ketones, imines, and electrophilic C=C bonds 18 Michael additions catalysed by transition metals and lanthanide species 19 recent progress in asymmetric organocatalysis, including the aldol reaction, Mannich reaction, Michael addition, cycloadditions, allylation, epoxidation, and phase-transfer catalysis 20 and nucleophilic phosphine organocatalysis.21... 

In 2004, the tra s-4-amino-L-proline derived di-, tri- and tetrapeptides 13a-c were studied in the group of Tsogoeva for asymmetric 1,4-conjugate addition reactions. The addition of different nitroalkanes to cyclic a,p-unsaturated ketones in the presence of achiral tra s-2,5-dimethylpiperazine (14) of Hanessian as a stoichiometric additive and peptides 13a-c at only 2 mol% loading were investigated. Two 4-trans-amino-proline residues (catalyst 13a) were shown to be sufficient to eatalyse the conjugate addition reactions with up to 88% enantiomeric excess and up to 100% yield (Scheme 13.11). 

Use of proline as a catalyst has become an important methodology in the catalytic asymmetric addition of stabilized carbanions to conjugated carbonyl compounds. Hannessian employed L-proline (S)-l in the addition of nitroalkanes to enones (Scheme 1) [5]. In the presence of 3-7 mol % of (S)-l and an excess of trans-2,5-dimethylpiperazine in chloroform, comparable or higher enantiose-lectivities were attained compared to the Yamaguchi s method using L-proline... 

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