Domino organocatalytic asymmetric reactions

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]. 

An impressive organocatalytic asymmetric two-component domino Michael/ aldol reaction has been recently published by Jorgensen and coworkers (Scheme 2.23) [38]. 

Recently, a first example of an organocatalytic asymmetric domino Knoevenagel/ Diels-Alder reaction was reported by Barbas and coworkers (Scheme 2.182) [409]. Spiro[5,5]undecane-l,5,9-triones of type 2-818/2-819 were obtained from comma-daily available 4-substituted-3-butene-2-ones 2-813, aldehydes 2-814, and Mel-drum s acid (2-801) in the presence of 20 mol% of the amino acid 2-815 with 80-95% ee and diastereoselectivity of dr> 12 1. 

Optically active 4-alkoxycarbonyl-3-hydroxycyclohexanones (formed in highly enantio- and diastereoselective organocatalytic asymmetric domino Michael aldol reaction of / -keto esters and a,/ -unsaturated ketones) are transformed into corresponding chiral oxepanones under the action of urea-hydrogen peroxide and trifluoroacetic anhydride <2004AGE1272>. 

The risk of a pandemic caused by influenza viruses such as the avian H5N1 virus has recently raised the profile of the anti-influenza neuraminidase inhihitor (—)-oseltamivir (163). Several novel synthetic methods to access the natural product have been proposed [62]. An outstanding approach is the enantioselective total synthesis reported by Hayashi and coworkers [63], in which the natural product was obtained after two one-pot sequences, featuring a domino reaction, in 60% overall yield (Scheme 14.24). Utilizing a-alkoxyaldehyde 155 and nitroalkene 156, the first sequence commenced with an organocatalytic asymmetric Michael... 

Combinations of enamine-iminium ion activations together with other organo-catalytic activations in asymmetric organocatalytic domino and multicomponent reactions have been developed to achieve the enantioselective consecutive formation of two or more bonds in a stereoselective fashion. 

Another important set of bi-component reactions involving C-N and C-C bond formation is based on the Pictet-Spengler reaction, consisting in the cycUzation of electron-rich aromatic moieties onto iminium intermediates. This weU-known sequence constitutes an important domino transformation used for the synthesis of bioactive polyheterocycles. Its organocatalytic asymmetric version was pioneered by Jacobsen and revisited by List, who developed two complementary highly enantioselective accesses to tetrahydro- 3-carbolines from tryptamine-derived imines (Scheme 16.33). Thus, Taylor and Jacobsen [64] reported an enantiomerically pure thiourea-catalyzed cyclization of an acyl iminium intermediate, whereas List and co-workers [65] described the cyclization of an iminium diester intermediate in the presence of a chiral phosphoric acid catalyst. Recently, this methodology has been applied to the synthesis of chiral pyrrolopiperazines [66]. 

Carlone A, Cabrera S, Marigo M et al (2007) A new approach for an organocatalytic multi-component domino asymmetric reaction. Angew Chem Int Ed 46 1101—1104... 

SCHEME 2 7 Organocatalytic asymmetric triple domino reaction of nitromethane (153). 

A. Carlone, S. Cabrera, M. Marigo, K. A. Jprgensen, Angew. Chem. Int. Ed. 2007, 46, 1101-1104. A new approach for an organocatalytic multicomponent domino asymmetric reaction. 

D. Enders, M. Jeanty, J. Bats, Synlett 2009, 3175-3178. Organocatalytic asymmetric triple domino reactions of nitro-methane with a,P-unsaturated aldehydes. 

D. Enders, C. Wang, M. Mukanova, A. Greb, Chem. Commun. 2010, 46, 2447-2449. Organocatalytic asymmetric synthesis of polyfunctionalized 3-(cyclohexenyhnethyl)-indoles via a quadruple domino Friedel-Crafts-type/Michael/Michaehaldol condensation reaction. 

D. B. Ramachary, N. S. Chowdari, C. F. Barhas IB, Angew. Chem. Int. Ed. Engl. 2003, 42, 4233 237. Organocatalytic asymmetric domino Knoevenagel/Diels-Alder reactions a hioorganic approach to the diastereospecific and enanti-oselective construction of highly suhstituted spiro[5,5] undecane-1,5,9-triones. 

Tsakos, M., Elsegood, M. R. J., Kokotos, C. G. (2013). Organocatalytic asymmetric domino Michael-Henry reaction for the synthesis of substituted bicyclo[3.2.1]octan-2-ones. Chemical Communications, 49, 2219-2221. 

Enders, D., Joie, C., Deckers, K. (2013). Organocatalytic asymmetric synthesis of tetracyclic pyridocarbazole derivatives by using a Diels-Alder/aza-Michael/Aldol condensation Domino reaction. Chemistry - A European Journal, 19, 10818-10821. 

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