Quinine-squaramide

Briere and coworkers reported an original approaeh to 3-isoxazoline carboiylate derivatives (Seheme 15.28). In a one-pot oxa-Miehael-eyelo-condensation reaction, catalysed by quinine-squaramide Q-SQ 1, IV-proteeted hydrojylamine reacted with unsaturated a-ketoesters to form a eyelie intermediate that by treatment with TFA provided deproteeted 3-isoxazolines. 

The rather complex BINOL-quinine-squaramide (393) has been reported as an optimal catalyst for the Michael addition / -dicarbonyls to nitroalkenes, attaining <99%... 

Subsequently, several groups have studied related squaramide-catalyzed enantioselective Michael addition of 1,3-dicarbonyl compounds to nitroalkenes. High enantioselectivities have been achieved using pyrrolidine-cinchonine-squaramide catalyst 14 [81], quinine-squaramide catalyst 15 [82, 83], and Cs-symmetrical cinchonine-squaramide catalyst 16 (Figure 10.4) [84]. Notably, the reaction time... 

The addition of diphenyl phosphite to ketimines derived from isatin was attempted using several Cinchona derived organocatalysts. The best results were achieved with a quinine-derived bifunctional squaramide (Q-SQ 1),... 

Chalchones were recently also used as substrates for addition of indolines catalysed by quinine-derived squaramides and for addition of pyrazole catalysed by 9-epi-QA in combination with l-hydro)y-2-naphthoic acid additive. 

The addition of thioacetic acid to tra 5-chalcones furnished only moderate enantioselectivity (33-65% ee with Takemoto s catalyst 11) [33]. Better results were obtained by the Chen group, with various thiols employing quinine-derived squaramide 13 [34]. It is worth noting that, in this case, substituted benzyl thiols, furfuryl thiol, and aliphatic thiols were better donors than thiophenol (Scheme 14.6). 

An enantioselective sulfa-Michael addition of thiols to a,y3-unsaturated A-acylated oxazolidinones, catalysed the quinine-derived squaramide (134), has been reported to afford the corresponding products with <99% ee °... 

Squaramides offer yet another variant of the bis-NH proton donor with different geometry compared to thioureas and their congeners. Thus, the quinine-derived squaramide (238b) can catalyse Michael addition of -dicarbonyls to ArCH=CHN02. Here, brine has been found to provide remarkable rate acceleration and a higher level of stereoselectivity (>98% ee) over organic solvents, presumably because of the hydrophobic hydration effect. ... 

Squaramide (244) with two quinine-derived units has been developed as a catalyst (2mol%) for Michael addition of nitroalkanes RCH2NO2 (R=Me, Et) to R CH=CHN02 (R = aryl, alkyl, heteroaryl), which occurs in CH2CI2 at —20 °C with <95 5 dr and 97% ee ... 

H-pyrane] derivatives in the presence of isatins, malononitrile, and acetylacetone/ethyl 3-oxobutanoate [103]. Yan and coworkers showed in 2012 that chiral tertiary amine-thiourea (158) derived from quinine can catalyze a three-component reaction between isatins 118, malononitrile (119), and a-phenyl-isocyanoacetate (217) (Scheme 2.75) [104]. The process affords dihydropyrryl-spirooxindoles 218 and involves an initial Knoevenagel condensation of 118 and 119 followed by the nucleophilic anion attack of 217 (see the key transition state intermediate on Scheme 2.75). Final intramolecular cyclo-addition affords the expected compounds where H bond interactions are supposed to direct the attack of isocyanate anion and, consequently, contfol the enantioselectivity. One year later, Xu s group used a bifunctional cinchona-based squaramide to catalyze multicomponent cascade reaction to synthesize spiro[pyrrolidin-3,2 -oxindoles] via 1,3-proton shift and [3h-2]... 

A Michael addition of a-substituted isocyanoacetates ArCH(NC)C02R A-aryl maleimides, catalysed by the cyclohexane-1,2-diamine-derived squaramide (293), afforded adducts (294) with <91% ee and >20 1 dr. Enantiomers of (293) (with <94% ee) were obtained in the same reaction catalysed by the quinine-derived squaramide (283b).252... 

In a similar way, spirooxindole tetrahydroquinolines (301) were prepared in 94% ee and >25 1 dr via the aza-Michael-Michael domino addition of tosylamide (299) to oxindoles (300), catalysed by the quinine-derived squaramide (283c).2 ... 

A one-pot approach to the 0- and A-heterocycles (392) (X = O, NCOPh, NTs) has been developed, starting with the Michael addition of malonate to the o-substituted / -nitrostyrenes (390), catalysed by the quinine-derived squaramide (283c). The... 

The C9 squaramide derivatives of quinine (31) and quinidine have also been prepared and shown to catalyze the addition of nitromethane to chalcones (Scheme 6.40). Catalysts with a 3,5-(CF3)2C,5H3 group attached to the second nitrogen performed slightly better than if a 4-CF3C5H4 or 4-FC5H4 group was present [87]. 

Du and coworkers have developed a stereoselective direct Michael addition of nitroalkanes to nitroalkenes catalyzed by quinine-derived dimeric squaramide 21 [93]. This transformation provided facile access to 1,3-dinitro compounds in high diastereo- and enantioselectivities starting from aryl-substituted nitroalkenes (Scheme 10.18). However, the use of an aliphatic nitroalkene as Michael acceptor resulted in a low yield and diminished enantioselectivity. While nitroethane and 1-nitropropane are excellent substrates, branched 2-nitropropane did not undergo the Michael addition reaction. The authors also noted that slightly reduced dias-... 

Chen and coworkers have developed a bifunctional quinine-derived squaramide-promoted enantioselective alcoholysis of meso-succinic anhydride 36 [116]. Whereas modest enantioselectivity can be obtained in the presence of a catalytic amount of squaramide 22, high enantioselectivity was realized when more than 1 equivalent of squaramide was utQized (Scheme 10.36). The utility of the squaramide-catalyzed desymmetrization was nicely illustrated by carrying out an efficient synthesis of (-f)-biotin from the enantioenriched hemiester 37, which, in turn, was obtained by desymmetrization of 36. 

A chiral quinine-derived squaramide catalysed the highly enantioselective Michael addition of malononitrile to chalcones. The reactions take place at a very low catalyst loading (0.5 mol%) and provide the Michael adducts with high yields and good enan-tioselectivities (up to 96% ee). Chiral bifunctional squaramides have also been used as multiple hydrogen-bond donor-acceptor organocatalysts for the asymmetric Michael addition of nitroolefins to 1,3-dicarbonyl compounds. ... 

In nearly aU cases, catalysts bearing the unnatural C9-epi configuration (e.g. SS, 9S for the quinine derivatives or R,9R for the quinidine-derived catalysts) have turned out to be more enantioselective [2]. A thorough review by Schreiner and Kotke discusses the developments in this area until 2009 [2, 13]. In spite of recent developments in the area, only a handful of X-ray crystal structures of the active catalysts have been reported. The X-ray stracture of a cinchonine-derived (8R, 9R configuration) squaramide catalyst is displayed in Fig. 6.3. 

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