Chiral thiourea-based catalyst

Jprgensen s group has very recaitly d onstrated the usefulness of o,P-unsaturated acyl phosphonates as hydrogen-bond acceptors in the enantioselective Hiedel-Crafts reaction with indoles [341]. Since the acyl phosphonate moiety is a powerful ester and amide surrogate, this reaction is an interesting approach towards the synthesis of optically active p-(3-indolyl)esters and amides as represented in Scheme 2.119 for selected examples. The reaction is catalyzed by chiral thiourea-based catalyst ent-191 that activates the nucleophile and the electrophile through hydrogen-bond interactions. 

Chiral phosphoric acid analogs as catalysts in the F-C alkylation reaction of indoles with a,(l-unsaturated aromatic enones were also devised [53]. p,y-Unsaturated a-ketoesters were also used as electrophiles in organocatalyzed F-C alkylations of indoles and 2-naphthols. With indoles, chiral acidic N-triflylphos-phoramide was successfully employed (Scheme 35.4) [28], whereas in the presence of 2-naphthols a thiourea-based catalyst showed better capacity to mediate a sequential F-C/cycUzation process, giving naphthopyran scaffolds in moderate yields and selectivities (up to 90% ee) [54]. Recently, a,P-unsaturated acyl phos-phonates were effectively used as hydrogen bond acceptors for F-C alkylations of indole derivatives in the presence of thiourea catalyst ent-19 [55]. 

Systematic investigations of the catalyst structure-enantioselectivity profile in the Mannich reaction [72] led to significantly simplified thiourea catalyst 76 lacking both the Schiff base unit and the chiral diaminocyclohexane backbone (figure 6.14 Scheme 6.88). Yet, catalyst 76 displayed comparable catalytic activity (99% conv.) and enantioselectivity (94% ee) to the Schiff base catalyst 48 in the asymmetric Mannich reaction of N-Boc-protected aldimines (Schemes 6.49 and 6.88) [245]. This confirmed the enantioinductive function of the amino acid-thiourea side chain unit, which also appeared responsible for high enantioselectivities obtained with catalysts 72, 73, and 74, respectively, in the cyanosilylation of ketones (Schemes 6.84 and 6.85) [240, 242]. 

Catalysts similar to 24 were also developed by the Tsogoeva group (Scheme 2.42) [28], with the best results being obtained with chiral naphthylamine-based thiourea catalysts having free NH2 functions in the side chains (e.g., 25). This led to syn products with cyclic ketones (Scheme 2.43), whereas acyclic ketones afforded the anti product (Scheme 2.42). 

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 first primary amine-thioureas as effective bifunctional organocatalysts were reported in 2006. Tsogoeva and Wei synthesised a thiourea based on (l5,25)-diphenylethylene-l,2-diamine and a chiral arylethyl moiety, for the Michael reaction between aliphatic ketones and aromatic nitro-olefins (Scheme 19.36). Utilising catalyst 29 (15 mol%) and acetone as the Michael donor, the Michael products were obtained in high yields (84-99%) and enantioselectivities (90-91% enantiomeric excess). When cyclohexanone 31 was employed, product 33 was obtained in high yields (82 and 89%, respectively), good diastereoselectivity (up to 83 17 symanti) and excellent enantioselectivity (96 and 98% enantiomeric excess, respectively). 

In the next few years, the use of isobutyraldehyde as the nucleophile in conjugate additions to aromatic nitroalkenes received a lot of attention. He and coworkers reported a chiral thiourea that could efficiently catalyse this transformation, while Chen and coworkers employed a catalyst combining the 1,2-diaminocyclohexane moiety with the privileged Cinchona alkaloid scaffold. A more sustainable protocol was provided by Ma and coworkers, where catalyst 40, based on a beyerane skeleton, was found to promote the same transformation both in organic solvents (up to 92% yield and 98%... 

Some bifunctional hydrogen-bond donor/Brpnsted base catalysts are shown in Figures 2.39 and 2.40. They comprise chiral amino alcohols and amino phenols, chiral amine-thiourea derivatives, and chiral guanidines, among others. In the absence of detailed experimental NMR or kinetic studies [179], most of our... 

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