Amino-thioureas

The enantioselective Michael reaction of malonates to nitroolefins catalysed by bifunctional amino-thioureas has recently been reported by Take-moto [161]. Excellent ee (75-93%) were obtained with diethylmalonate after solvent optimisation, toluene being the best solvent both for the activity and for the selectivity. Substituted malonates were then reacted with various nitroolefins under the same conditions. Excellent enantioselectivities were observed (Scheme 45). 

This bifunctionnal amino-thiourea organocatalyst led to high selectivity because it was activating both the nitrone and the malonate, in its enol form, due to the acidic hydrogen atoms of the thiourea. Thus, the amino-thiourea catalyst promoted the Michael reaction of malonates to various nitroolefins... 

PreUminary studies on the racemic reaction of protected imines with ni-tromethane showed that the thiourea and the amine mutually weakened their reactivities. However, the bifunctional amino-thiourea led to good results. Enantioselectivity of the adduct depended on the protecting group, P(0)Ph2 affording the best results (76% ee). Then, other aromatic imines substrates were successfully phosphorylated with good to high enantioselec-tivities (63-76% ee). 

Development of amino thiourea catalysts as an artificial enzymes and their application to catalytic enantioselective synthesis of natural products and medical supplies 06Y1139. 

Figure 2.6 Some amino-thiourea bifunctional catalysts for the MBH reaction.

A new catalyst incorporating chiral thiourea and nucleophilic Lewis base showed efficiency in the asymmetric BH reactions. The use of a binaphthyl-based amino-thiourea catalyst 63 synthesized by Wang et al. [ 114] resulted in good yields and enantioselectivities in the reaction of cyclohexenone and aldehydes. Another amino-thiourea 12 was demonstrated as an efficient bifunctional catalyst for the enantio-selective aza-BH reaction of (3-methyl-nitrostyrene and iV-tosyl-aldimines, affording P-nitro-y-enamines in modest to excellent enantioselectivities and diastereoselec-tivities (Scheme 9.32). It was found that no reaction occurred in the absence of the methyl group of nitroalkene [115]. A similar phophine-thiourea catalyst 64 was reported in 2008 by Wu and co-workers [116] and turned out to be efficient in the asymmetric BH reaction of MVK and aldehydes, providing fast reaction rate, good yields, and excellent enantioselectivities (87-94% ee). More recently, aL-threonine-derived phosphine-thiourea catalyst 65 was readily synthesized by Lu and coworkers [117] and applied in the enantioselective BH reaction of aryl aldehyde with methyl acrylate. 

The synthesis of six-membered all-carbon rings have been extensively studied in the literature, mainly because of their importance as constituents in natural products and biologically relevant compounds. The first example of an enantioselective organocatalytic domino reaction with nitroalkenes to furnish cyclohexanes was disclosed by Takemoto and co-workers [38] in 2004. In this work, a domino Michael addition of 7,8-unsaturated-(3-ketoesters (58) to nitroalkenes (28) catalyzed by a bifunctional amino-thiourea (Takemoto s catalyst, XVIII) and 1,1,3,3-tetramethylguanidine (TMG) was reported with excellent results and diastereoselectivities (up to 71% yield, up to >99% ee) and was recently applied to the synthesis of (-)-epibatidine. 

Increasing the steric hindrance at the C4-position is a general strategy for realizing complete y-selectivity in the addition of azlactone enolates. In fact, rert-leucine-derived azlactone reacted with iV-aryl maleimides predominantly at the C2-position with excellent diastereo- and enantiocontrol by use of amino thiourea 20 as a bifunctional catalyst (Scheme 16) [32],... 

Selective a-addition of C4-substituted azlactones was observed in the Michael addition-[1,2]-sulfone rearrangement sequence, which proceeded with moderate to good enantioselectivity (Scheme 20) [37]. Although 5% of the y-addition product was detected in the reaction with triethylamine as a base, the use of bifunctional amino-thiourea 20 was pivotal for achieving complete site-selectivity and high enantioselectivity. 

Complete a-selectivity was observed in the isosteviol-derived amino-thiourea 24-catalyzed conjugate addition-aromatization reaction of azlactone with a,-P-unsaturated pyrazolones (Scheme 22) [39]. Although generally good to excellent chemical yield and stereoselectivity were obtained with C2-aryl azlactones, the reaction failed with C2-alkyl azlactone (Ar = u, = Pr) even at room temper-... 

The iminium activation strategy with the trifunctional chiral primary amine 28, which was used in the y-selective conjugate addition of y-butenolides (Scheme 28), also proved highly effective for promoting reaction with the y-butyrolactam (Scheme 32, first line) [52]. Although various chiral diamines, amino thioureas, and amino sulfonamides were evaluated during the optimization study, none of these catalysts gave rise to impressive levels of diastereoselectivity. Eventually, a bulky acid additive, such as the protected tryptophan derivative (V-Boc-L-Trp-OH),... 

Takemoto Y, Miyabe H (2007) The Amino Thiourea-Catalyzed Asymmetric Nucleophilic Reactions. Chimia 61 269... 

A cooperative participation of the amido group via hydrogen bonding in the Michael addition of /S-ketoamides to a,-unsaturated carbonyl derivatives, catalysed by amino-thioureas, has been recognized as an important factor to attain high enantioselectivities in the construction of quaternary stereocentres (<98% Takemoto catalyst (163a) (g)... 

Addition of naphthoquinone (178) to jS,y-unsaturated esters R CH=CHC0C02R, catalysed by the rrani-indane amino-thiourea (182), produced (183) as a result of the subsequent hemiketalization (<98% ee) An analogous addition of 0 4-hydroxycoumarin to a-enones, catalysed by the amino-thioiuea (184), afforded the warfarin-type adducts in <95% As a variation of the same theme, the 0... 

Ma and collaborators devised the first hydrogen-bond-directed enanti-oselective decarboxylative Mannich reaction of P-ketoacids with ketimines, employing saccharide-based amino-thiourea catalysts, and applied this method to the synthesis of anti-HIV drug DPC 083 (Scheme 49) (13AG(I)3869). 

Zuend, S. J. Jacobsen, E. N. Cooperative Catalysis by Tertiary Amino-Thioureas Mechanism and Basis for Enantioselectivity of Ketone Cyanosilylation. J. Am. Chem. Soc. 2007,129,15872-15883. 

Interestingly, when the nucleophiles were replaced by a-nitro ketones 194 under the promotion of tertiary amino thioureas, the Michael-haniketalization products would undergo further acyl transfer reaction to afford 5-nitro-2-acyloxy-pen-2-enoates 195, as described independently by Gao et al. [77a] and Lu et al. [77b] (Schane 2.52). 

Bis[[(3-hydroxy-5-hydroxymethyl-2-methyl-4-pyridyl)methylene]amino]thiourea, see B-00376... 

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