Proline-based catalysts Michael addition

The organocatalytic asymmetric Michael addition of 2,2-dimethyl-l,3-dioxan-5-one (143) to various nitroalkenes (144), using a number of proline-based catalysts, afforded... 

Nal chiral amines such as DBU, ° (S)-2-[bis(3,5-dimethylphenyl)methyl]pyrrolidine, C2-symmetric (2S,55)-2,5-diphenylpyrrolidine, (-)-quinine, and proline polymer catalysts such as antibody 38C2" and polymer-anchored chiral catalysts and solid base catalysts such as MgO and Mg-Al-O-r-Bu hydrotalcite. Furthermore, the solvent-free Michael addition has been established by application of CeCb 7H20-NaI as catalyst or microwave irradiation of reactants on BiCb or Cdh, EuCb, CeCb 5H20, and alumina surfaces. It is interesting that the thermal treatment or microwave irradiation of 1,5-ketodiesters or 1,5-diketones in DMSO in the presence of NaX (X = Cl, Br, I) results in the retro-Michael addition. ... 

Nevertheless, as was pointed out before, a straightforward solution to the rather limited substrate scope of the reaction with regard to the ketone reagent and also a good way to overcome the lack of reactivity of ketones toward enamine activation has been the use of primary amines as organocatalysts. In fact, literature examples indicate that primary amines are much more active catalysts for the Michael addition of both cyclic and acyclic ketones to nitroalkenes compared to the same reaction using a secondary amine catalyst like most of the proline-based derivatives already presented before. 

In 2011, the group of Chen reported the application of proline-based reduced dipeptides in the asymmetric Michael addition of cyclic ketones to tra s-p-nitrostyrenes. Comparative studies revealed that the presence of the carbonyl moiety at the N-terminal L-proline unit results in a lower enantioselectivity compared to the corresponding amine analogues. Thus, a series of reduced dipeptides was tested on the above-mentioned Michael addition unveiling reduced dipeptide 17, derived from L-proline and L-phenylalanine, as the optimal catalyst generating the desired products in... 

Whereas short peptides, containing N-terminal proline, were introduced in 2003 as catalysts for Michael addition, there were no reports at that time on asymmetric catalysts based on N-terminal primary amino peptides. 

Organocatalytic asymmetric reaction between 1,4-cyclohexanedione and nitroalkenes afford bicyclo-[3.2.1]octane derivatives containing four contiguous stereogenic centers (Scheme 6.41). The product formation involves a domino Michael-Henry process using a proline-based bifunctional catalyst. The reaction gives good selectivity and yield in THF, and 4-nitrobenzoic acid is the most effective additive for this transformation [46]. 

As a novel type of proline-based secondary amine, Du devised the chiral binaphthyl bis-sulfonamide 19 and demonstrated that it could act as an efficient catalyst for the asymmetric Michael addition of cyclohexanone to nitrostyrene, giving rise to the corresponding y-nitroketone derivative with high levels of diastereo- and enantioselectivity (Scheme 7.32) [56]. 

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