Catalysts cinchona-thiourea

Dicarbonyl donors are excellent Michael donors in asymmetric conjugate addition to a,p-nnsatnrated ketones. Wang and co-workers [79] applied chiral Cinchona-thiourea catalyst 131 to various carbon donors in the addition to aromatic enones. A diverse array of nucleophiles, mainly 1,3-dicarbonyls proceeded smoothly in the conjugate addition to a,p-unsaturated enone 132 (Scheme 29). 

A practical and highly enantioselective Michael addition of malonates to enones catalysed by bifunctional primary amine-thiourea (5) derived from 1,2-diaminocyclohexane has been reported. The addition of weak acids and elevated temperature improved the efficiency of the Michael reaction. This approach enables the efficient synthesis of 1,5-ketoesters with good yields, excellent enantioselectivities (up to 99% ee), and low loading (0.5-5 mol%) of catalysts. A related bifunctional cinchona-thiourea catalyst has been involved in asymmetric organocatalysed conjugate addition reactions of monoth-iomalonates to nitroolefins. ... 

Papai et al. selected as model reaction the addition of 2,4-pentanedione (acetylacetone) to trans-(R)-mtrostyvQnQ, catalyzed by the bifunctional thiourea catalyst shown in Scheme 6 [46]. The analogous Michael-addition involving dimethyl malonate and nitroethylene as substrates, and a simplified catalyst was calculated at the same level of theory by Liu et al. [47]. Himo et al. performed a density functional study on the related cinchona-thiouTQa catalyzed Henry-reaction between nitromethane and benzaldehyde [48]. 

Modified Cinchona alkaloids catalysts have been developed in the last two decades to enhance further the bifunctional mode of the catalyst. Derivations at the C(9)-OH group, replacement of quinoline C(6 )-OCH3 with a hydroxyl group to enhance hydrogen bonding, syntheses of bis-Cinchona alkaloids, and development of thiourea-derived Cinchona alkaloids are most notable. 

Cinchona alkaloid-derived chiral thiourea catalyst xo... 

Catalyst 3 is proposed to function in a manner similar to the cinchona alkaloid catalysts (1 and 2), with the tertiary amine providing activation for the nucleophilic thiol, which is held in close proximity to the thiourea-bound carbonyl substrate. 

Disubstituted flavanones and chromanones are produced with good enantioselectivity from chalcones activated by an a-fert-butyl ester function through an intramolecular Michael addition catalysed by a chiral thiourea derivative. In situ decarboxylation enhances the ee and yields remain high <07JA3830>. A comprehensive study of the asymmetric cyclisation of 2 -hydroxychalcones to flavanones has refuted the ability of camphorsulfonic acid to achieve enantioselectivity but has shown that cinchona-based catalysts can be effective <07EJO5886>. 

The use of naphthols 145 as the carbon nucleophilic readion component in Friedel-Crafts type Michael addition readions was also reported in 2007 by Chen and coworkers [43], In this system, the pronucleophile is activated by the quinuclidine unit of bifundional cinchona-based thiourea catalysts such as 81a. A range of aryl-and alkyl-substituted nitroalkene derivatives 124 were applicable to this system. The corresponding adducts 146 were obtained with 85-95% ee at low temperature... 

In 2007, Jorgensen and coworkers demonstrated that the bifunctional thiourea-cinchona alkaloid catalysts 81b also promoted the enantioselective addition of oximes 153 as oxygen nucleophiles to nitroolefins 124 giving the adduct 154 in good yield with a high level of enantioselectivity (Scheme 9.52) [45]. The obtained adduct 154 can be converted to the optically active aliphatic nitro- or aminoalcohols. It is believed that the... 

As described above, cinchona-based (thio)ureas have proven to be highly efficient H-bond donor catalysts. In 2008, Rawal and coworkers developed a highly promising new family of cinchona-based H-bond donor catalysts such as 157 by replacing the thiourea moiety of cinchona-based thiourea catalysts with the squaramide unit [47]. The squaramide moiety of 157 is able to form two H-bonds to a reactant due to the more accessible reaction site and fixed syn-orientation of the NH-protons. Using only 0.5 mol% of the cinchonine-derived squaramide catalyst 157, various Michael donors 158 and nitroalkenes 130 were smoothly converted to the desired adducts 159 in excellent yield and ee values (up to 99% ee) (Scheme 9.54). 

For a review on cinchona-derived thiourea catalysts, see Connon, S.J. (2008) Chem. Commun., 2499. 

Thiourea catalyst with a modified cinchona alkaloid unit is applied to intramolecular Michael addition of phenol chiral chromanone is produced in high yield with good... 

Few examples have been reported for the organocatalytic asymmetric conjugate addition of sulfur nucleophiles other than thiols. The reaction of thiocarboxylic acids to cyclohex-2-enones [390] and a,p-nnsatnrated esters [391] was initially studied by Wynberg et al. employing Cinchona alkaloid catalysts with limited success in terms of selectivity (up to 54% ee). Slightly better enantioselectivities have been recently obtained by Wang et al. in the 1,4-addition of thioacetic acid to P-nitrostyrenes (up to 78% ee) [392] and trani-chalcones (up to 65% ee) [393], using Takemoto s thiourea 142 as catalyst (2-10 mol%). 

Later Schaus and co-workers used the cinchona alkaloid-derived thiourea catalyst 60 to catalyze the nucleophilic addition of both nitroalkanes (not shown) and dimethyl malonate to the Al-carbamoyl protected imines 46b, 61a-d to produce the corresponding Mannich adducts 62 in excellent yields and high enantioselectivities (Scheme 5.30) [41], The level of selectivity observed in these reactions is indicative of a catalyst-associated complex with a high degree of coordination. Modelling... 

Scheme 19.24 As mimetric addition of nitromethane to trans-chalcones utilising Cinchona-thiourea 17 as catalyst.

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