Bifunctional Chiral Thiourea Catalysts

The Takemoto s catalyst (9) was extensively employed for the enantioselective addition of arylthiols to a,P-unsaturated carbonyl compounds and P-arylthio ketones were obtained in good ees [90]. Conjugate addition of thioacetic acid to nitroalkene and to enone have been also reported by Wang [91]. 

The bifunctional thiourea catalyst was anchored to the developed polymer and subjected to the Michael and aza Henry reactions [93]. 

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Following work on Michael addition of triazoles to nitro-olefins (discussed in Sect. 2.5), bifunctional chiral thiourea catalysts were used in the addition of triazoles to chalcones [83]. The catalytic system was applicable to enones bearing aromatic groups of varying electronic natures to provide good yields and moderate selectivity. a-Cyanoacetates [84] were also applied in Michael addition to chalcones under similar catalytic conditions (Scheme 33). 

The asymmetric alcoholytic ring opening of 4-substituted-2-phenyl-4,5-dihydro-l,3-oxazin-6-ones proved to be a efficient method for the preparation of enatiomerically pure /3-amino acid derivatives <2005AGE7466>. Treatment of 2,4-diphenyl-4,5-dihydro-l,3-oxazin-6-one 208 in the presence of the bifunctional chiral thiourea catalyst 211 resulted in formation of an enantiomerically enriched mixture of the unchanged oxazinone (iJ)-208 and allyl (4)-3-benzoyl-amino-3-phenylpropanoate 209. The resolved material (iJ)-208 and the product 209 could easily be separated by a selective hydrolytic procedure that converted oxazinone (iJ)-208 quantitatively into the insoluble iV-benzoyl /3-amino acid 210 (Scheme 37). 

Disubstituted thiochroman-4-ols are formed with excellent enantio- and diastereo-selectivity when thiosalicylaldehydes react with an a,P-unsaturated oxazolidinone in the presence of a chiral bifunctional amine-thiourea catalyst. A tandem Michael - aldol process is involved (Scheme 43) <07JA1036>. 

In 2006, Wang and coworkers reported the use of chiral bifunctional amine thiourea catalysts for the Michael reaction between thioacetic acid and different enones, affording products in excellent yields but moderate enantioselectivities (up to 63% ee) [117]. 

Takemoto and colleagues demonstrated that bifunctional ammonium-thiourea catalyst 110, prepared in situ by treatment of a chiral thiourea precatalyst with a strong Br0nsted acid, is also able to effect the same sequential transformation enantioselectively (Scheme 42.40). With ee-values of up to 69%, however, the enantiodiscrimination remained comparatively modest [90]. 

Using the addition of dimethyl malonate to nitro-olefms as the model reaction, Connon et al. [72] in 2(X)5 reported a highly functionahzed Cinchona alkaloid-derived chiral thiourea. Key functional groups were identified to enhance the catalyst s stereodirecting properties. Aside from the advantage of a bifunctional Cinchona alkaloid... 

In 2003, Takemoto and co-workers introduced the first tertiary amrne-function-ahzed thiourea catalyst [129]. This new type of stereoselective thiourea catalyst incorporating both (R,R)-l,2-diaminocyclohexane as the chiral scaffold and the privileged 3,5-bis(trifluoromethyl)phenyl thiourea motif for strong hydrogen-bonding substrate binding, marked the introduction of the concept of bifunctional-... 

The modification of thiourea catalyst 93 through incorporation of the (S,S)-diaminocyclohexane backbone as an additional chirality element and a Schiff base imidazoyl-moiety led to the bifunctional catalyst 94 that, in contrast to 93 in the Strecker reaction (Scheme 6.99), exhibited enantioinduction (83-87% ee) in the nitro-Michael addition of acetone to trons-P-nitrostyrenes. The desired adducts were isolated in moderate yields (46-62%) as depicted in Scheme 6.100) [259]. 

A more simple thiourea catalyst with amino functionality catalyses the asymmetric Michael addition of 1,3-dicarbonyl compound to nitroolefin [29,30]. In the reaction of malonate to nitrostyrene (Table 9.11) the adduct is satisfactorily obtained when A-[3,5-bis(trifluor-omethyl)phenyl]-A -(2-dimethylaminocyclohexyl)thiourea is used as a catalyst (ran 1), whereas the reaction proceeds slowly when the 2-amino group is lacking (ran2). In addition, chiral amine without a thiourea moiety gives a poor yield and enantioselectivity of the product (run 3). These facts clearly show that both thiourea and amino functionalities are necessary for rate acceleration and asymmetric induction, suggesting that the catalyst simultaneously activates substrate and nucleophile as a bifunctional catalyst. 

Using the bifunctional chiral primary amine thiourea catalyst 41 (20 mol%) in CH Clj and in the presence of five equivalents of H O as additive, a highly enanti-oselective direct conjugate addition of a wide range of a,a-unsymmetrically dis-ubstituted aldehydes (only a twofold excess of aldehyde relative to nitroaUcene) to nitroolefins is obtained (see Table 2.1, entry 15, for a representative example) [61], The beneficial role of water is proposed to lie in increasing turnover by eliminating potential catalyst deactivation pathways, and accelerating the final imine hydrolysis. 

The utilization of bifunctional thiourea catalyst containing a chiral secondary amine was first reported by Peng and co-workers [45], The prolinol-derived thiourea catalyst 72 has been successfully appUed to the ATift-selective direct asymmetric... 

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