Chiral thiourea-amide

A more thorough investigation encompassing 22 nudeophUic species (118-139) and various HB catalysts (115-117) (Figure 41.13) with the idea of forming a more soluble chiral ion pair unveiled a new catalytic system that combined the readily available chiral thiourea-amide catalyst 116 with 4-di-n-propylaminopyridine (120) and led to improved selectivities at lower catalyst loadings [126]. 

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. 

Et) to 3/-chiral acyclic nitrosoalkenes, such as PhCH(Me)CH=CHNO, generated in situ from the corresponding a-chloro oxime derivatives, for example, PhCH(Me)CH(Cl)CH=N-0-t-butyldimethylsilyl (NOTES), and potassium bis(trimethylsilyl)amide (KHDMS) and BU4NF, have been found to afford exclusively the anti-products.In a similar way, addition of 5-nucleophiles 0 R SH to nitroalkenes R CH=CR NO, generated in situ from cr-halo oximes R CH(X)C(R )=NOH on treatment with NaHC03, can be catalysed by chiral thioureas. The resulting a-sulfenylated oximes R CH(SR )C(R )=NOH were obtained with <82% eeP (J)... 

The Jacobsen group independently focussed on the development of primary amine-functionalized thiourea derivatives and published, in 2006, the thioureas 100-103 incorporating the established tert-leucine (amide) motif (Figure 6.14) and the diaminocyclohexane or diphenylethylenediamine chiral backbone, respectively (Figure 6.31) [262]. The catalyst screening was carried out in the asymmetric Michael addition [149-152] of 2-phenylpropionaldehyde, an a,a-disubstituted aldehyde, to 1-nitrohex-l-ene (at 20mol% loading, DCM, rt, variable equiv. of H2O)... 

Chiral derivatization of the amino group has included the formation of diastereomeric amides, ureas, thioureas and isoindoles, the carboxylic acid group being either protected or left unreacted. Diastereomeric dipeptides have been prepared using a range of N-substituted activated amino acids, e.g. S( — )-N-(trifluoroacetyl)propyl chloride (11), L-leucine-N-carboxyanhydride (45) and t-butoxycarbonyl-L-leucine N-hydroxysuednimide ester (55). (See Section 4.6.2 for reagent structures). 

Kokotos and coworkers investigated the use of prolinamide-based thioureas as bifunctional organocatalysts for the direct aldol reaction. The amide and the thiourea functionalities, tethered by a chiral diamine motif, offered multiple hydrogen bonding sites for electrophile activation, while the pyrrolidine skeleton served to activate the nucleophile via enamine catalysis. Thiourea 61 proved to provide the best catalyst in the presence of 4-nitrobenzoic acid as cocatalyst at low temperature and delivered the anti-aXAoX products in moderate to high yields and in high to excellent... 

Wu and coworkers have developed phosphine-squaramate-catalyzed enantioselective intramolecular Morita-Baylis-HiUman reactions [106]. UtiUzing a chiral squaramate containing tertiary phosphine as catalyst (28), a wide range of (O-formylenones was converted into the cycUc hydroxyl enones in high yield and high enantioselectivity (Scheme 10.28). The reaction afforded low yield and selectivity when the corresponding phosphine-squaramide or phosphine-amide was used as a catalyst The authors noted that the phosphine-squaramate catalyst provided a better enantioselectivity than the phosphine-thiourea analog [107]. 

Eventually, the use of a catalytic amount of chiral amide-thiourea anion-receptor 116 in conjunction of with achiral nucleophUic co-catalyst 120 allowed for the resolution of several l,2-diaryl-l,2-diaminoethanes (Scheme 41.54) with useful levels... 

Chiral proline 3 and thiourea 12 also afforded chiral cyclopropanes in high enantiomeric excess [11, 12]. For example, Takemoto and coworkers reported that efficient MIRC cyclo-propanation occurred with a-cyano-a, 3-unsatiirated amides in the presence of 10 mol% of chiral catalyst 12 (Scheme 1.8). 

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