Takemotos Catalyst

The two depicted transition structures yield the product in the (R)-configuration. 

As demonstrated, self-association lowers the concentration of the monomeric catalyst form, resulting in supramolecular structures with diminished or altered reactivity. 

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Spirocyclohexene compounds bearing 1,3-thiazohdinediones were prepared through a double Michael domino reaction of 1,3-thiazolidinedione, malonon-itrile, and aromatic aldehydes and organic amines [104]. Later, in the field of preparing the spirocyclohexene scaffold, a single carbon quaternary stereocenter of a l, 3-spiro-2 -oxocyclohexan-3,4-dihydrocoumarin 202 was constmcted through a domino Michael/acetalization sequence. Following treatment of 2-oxocyclohexanecarbaldehyde 200 with the Takemoto catalyst 3 in the presence of the phenol 201, the reaction was completed in under 30 min (Scheme 7.41) [105]. 

A domino Mannich/aza-Michael reaction was applied to the synthesis of 2,5-cis-configured polysubstituted pyrrolidines from y-malonate-substituted a,P-unsaturated esters with N-protected arylaldimines [117]. In this report, bifunctional thioureas were trialed with the Takemoto catalyst, being the most efficient with respect to yield as well as enantiomeric and diastereomeric excess. In a separate approach, the Garcia-Tellado group approached the pyrrole ring system 234, beginning with a tertiary skipped diyne 233 and a primary amine (Scheme 7.50). 

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)... 

The P-nucleophile (Ph0)2P(0)H has been shown to add to RCH=CHN02 (R = Ar, alkyl) in CH2CI2 at -10 °C in the presence of Takemoto catalyst (163a) to produce nitrophosphonates (Ph0)2P(0)CH(R)CH2N02 with <95% ee. DPT calculations suggest the Re face attack, from which the absolute configuration of the product was inferred. ... 

Yet another variant of the original Takemoto catalyst, namely (384), has been developed for the Michael addition of -aryl-a-ketophosphonates to nitroalkenes RCH=CHN02, which afforded, after aminolysis, the amides (385) with <81% ee and >95 5... 

In 2011, Hong and coworkers reported the synthesis of spirodihydrocoumarins in excellent yields and enantioselectivities [48]. The reaction involved a cascade Michael hemiacetal formation between 2-oxocyclohexanecarbaldehyde (79) and 2-hydroxy nitrostyrenes 80, followed by the oxidation of resulting intermediate. The cascade reaction was efficiently catalyzed by the Takemoto catalyst (XIX) to afford the spirodihydrocoumarins 81 in good yields (51-72%) and excellent enantioselectivities (Scheme 10.28). 

Very recently, Rodriguez and coworkers developed a new methodology for the synthesis of spirocycles. a,p-Unsaturated acylcyanides 95 reacted with p-ketoamides % via a formal [3+3] cyclization process catalyzed by the Takemoto catalyst (XIX) [55]. The reaction rendered highly functionalized azaspiro[4,5]decanones 97 with good yields and stereoselectivities (Scheme 10.34). 

Scheme 6.3 Alternative mechanisms for the activation of a tra i-P-nitrostyrene and acetoacetate anion with the Takemoto catalyst[8]...

Catalysts lacking phosphorus ligands have also been used as catalysts for allylic substitutions. [lr(COD)Cl]2 itself, which contains a 7i-accepting diolefin ligand, catalyzes the alkylation of allylic acetates, but the formation of branched products was only favored when the substitution reaction was performed with branched allylic esters. Takemoto and coworkers later reported the etherification of branched allylic acetates and carbonates with oximes catalyzed by [lr(COD)Cl]2 without added ligand [47]. Finally, as discussed in Sect. 6, Carreira reported kinetic resolutions of branched allylic carbonates from reactions of phenol catalyzed by the combination of [lr(COE)2Cl]2 and a chiral diene ligand [48]. 

Since Curran and Kuo and Schreiner and coworkers reported that urea and thiourea derivatives act like Lewis acid catalysts, several chiral urea and thiourea catalysts have been designed by Jacobsen et al. and Takemoto et al. ... 

Bifunctional catalysts have proven to be very powerful in asymmetric organic transformations [3], It is proposed that these chiral catalysts possess both Brpnsted base and acid character allowing for activation of both electrophile and nucleophile for enantioselective carbon-carbon bond formation [89], Pioneers Jacobsen, Takemoto, Johnston, Li, Wang and Tsogoeva have illustrated the synthetic utility of the bifunctional catalysts in various organic transformations with a class of cyclohexane-diamine derived catalysts (Fig. 6). In general, these catalysts contain a Brpnsted basic tertiary nitrogen, which activates the substrate for asymmetric catalysis, in conjunction with a Brpnsted acid moiety, such as urea or pyridinium proton. 

Takemoto and co-workers reported the use of a similarly structured bifunctional catalyst for the first enantioselective organocatalytic Michael addition of malonitrile to... 

Takemoto and co-workers designed a small hbrary of thiourea cyclohexane-diamine derived catalysts for the Michael reaction of malonates to nitrolefins [15]. The authors observed an interesting trend in catalysis the reaction only proceeded enantioselectively and in decent yields when the catalyst possessed both thiourea... 

Two distinct reaction pathways can be envisioned for the C—C bond formation step of this catalytic process (see Scheme 3.7). According to the mechanism proposed by Takemoto et al. [30], the nitroolefin interacts with the thiourea moiety of complex 3 (Scheme 3.7, route A), forming a ternary complex, wherein both substrates are activated, and C—C bond formation can occur to produce the nitronate form of the adduct Alternatively, the facile interconversion between 3 and 3" may allow an interaction of the nitroolefin with the cationic ammonium group of the protonated catalyst (Scheme 3.7, route B). In both cases, ternary complexes result... 

Takemoto[131] first bifunctional thiourea catalyst asym. addition of malonates to nitrostyrenes (up to 99% yl. 94% ee)... 

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 Takemoto group synthesized a series ofdiaminocyclohexane-based thiourea derivatives (e.g., 12, 40, 57, and 58) for catalysis of the Michael addition [149-152] ofmalonates to trons-j3-nitrostyrenes (Figure 6.18) [129, 207]. In the model, Michael addition of diethyl malonate to trons-]3-nitrostyrene at room temperature and in toluene as the solvent tertiary amine-functionalized thiourea 12 (10mol% loading) was identified to be the most efficient catalyst in terms of catalytic activity (86%... 

Takemoto et al. discovered N-phosphinoyl-protected aldimines as suitable electrophilic substrates for the enantioselective aza-Henry [224] (nitro-Mannich) reaction [72] with nitromethane, when utilizing thiourea 12 (10mol%) as the catalyst in dichloromethane at room temperature [225]. The (S)-favored 1,2-addition of nitromethane to the electron-deficient C=N double bond allowed access to various P-aryl substituted N-phosphinoyl-protected adducts 1-5 in consistently moderate to good yields (72-87%) and moderate enantioselectivities (63-76%) as depicted in Scheme 6.73. Employing nitroethane under unchanged reaction conditions gave adduct 6 as a mixture of diastereomers (dr 73 27) at an ee value of 67% (83% yield) of the major isomer (Scheme 6.73). 

More complex catalysts have not been studied in detail. An exception is the work of Imoto and Takemoto (75) who investigated polymerization rates in benzene using a series of substituted benzoyl peroxides along and with dimethylaniline. They found a rough linear relationship between log () and er, where R and Rjj are rates with the substituted and unsubstituted peroxide and a is the Hammett constant. The overall rate depended on the monomer to the first power and peroxide and amine each to the one-half power. They concluded tentatively that the benzoyl-oxy radical is the initiating species. 

While alkyl halides are typically employed as an electrophile for this transformation, Takemoto developed palladium-catalyzed asymmetric allylic alkylation of 1 using allylic acetates and chiral phase-transfer catalyst 4k, as depicted in Scheme 2.5 [ 2 3 ]. The choice of triphenyl phosphite [(PhO)3P] as an achiral palladium ligand was crucial to achieve high enantioselectivity. 

Takemoto and coworkers extended their palladium-catalyzed asymmetric allylic alkylation strategy using allyl acetate and chiral phase-transfer catalyst to the quaternization of 13 [23b]. A correct choice of the achiral palladium ligand, (PhO P, was again crucial to achieve high enantioselectivity and hence, without chiral phosphine ligand on palladium, the desired allylation product 15 was obtained with 83% ee after hydrolysis of the imine moiety with aqueous citric acid and subsequent benzoylation (Scheme 2.12). 

The best enantioselectivity in the addition of C-nudeophiles to nitroolefins is that achieved by Takemoto et al. using the bifunctional thiourea-amine catalyst 55 (Scheme 4.26) [45]. 

For similar reactions, Takemoto et al. developed a novel organocatalyst 40, which was designed to place both acidic and basic moieties appropriately on the same catalyst scaffold (Scheme 20) [23]. It was proposed the thiourea activated nitroolefins by hydrogen bonding. 

Chen and co-workers later reported the successful asymmetric 1,4-addition of aryl thiols to a,/ -unsaturated cyclic enones and imides using Takemoto s elegantly simple catalyst (3) [43]. This bifunctional amine-thiourea catalyst gives optimal reactivity and reproducibility when used at 10 mol% loading in the presence of freshly dried 4 A molecular sieves (MS). This combination afforded the expected addition products in high yields (90-99%) and moderate to good enantioselectiv-ities (55-85% ee) for a variety of cyclic and acyclic Michael acceptors (Table 6.2). 

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