Guanidine, enantioselective Michael catalysts

The axially chiral guanidine catalyst (155) (0.4-5 mol%) has been developed to facilitate the highly enantioselective Michael addition of 1,3-dicarbonyl compounds (g to a broad range of conjugated nitroalkenes (<98% ee).211... 

Ye, W., Jiang, Z., Zhao, Y. et a/. (2007) Chiral bicyclic guanidine as a versatile Brdnsted base catalyst for the enantioselective Michael reactions of dithiomalonates and P-keto thioesters. Advanced Synthesis and Catalysis, 349, 2454-2458. 

Surprisingly, there have been only few synthetic studies on polymer-supported asymmetric superbase reagents. Recently, Wannaporn and Ishikawa prepared a new chiral guanidine based polymer catalyst and applied it to the asymmetric Michael addition reaction of iminoacetate with methyl vinyl ketone [39] (Scheme 6.7). Although the catalyst shows only moderate levels of reactivity and enantioselectivity, the result demonstrates the possibility of expanding an exciting field of asymmetric synthesis using polymer-supported chiral superbase catalysts. 

Feng and coworkers reported a highly enantioselective Michael reaction of p-ketoesters and nitro-olefins. Ethyl acetate, the recommended solvent, (Table 23.1), is rarely employed in guanidine catalysed asymmetric reactions. It was found to be optimal for this reaction and 2 to 5 mol% of catalyst gives excellent enantioselectivity and diastereoselectivity. The yields are generally high and a practical application of the reaction was demonstrated with a 2-g-scale synthesis of an intermediate for the synthesis of Ramipril analogues (Scheme 23.8). 

In addition, several organocatalysts other than cinchona alkaloid derivatives have been developed very recently. As an example, a chiral bicyclic guanidine was found by Tan et al. to be an excellent catalyst for enantioselective Michael additions of malonates or ethyl benzoylacetates to cyclopentenone or... 

In 2009, Feng and coworkers developed new guanidine catalysts with an amino amide skeleton [139]. Among the various catalysts tested, guanidine 49 was found to be the most active for the enantioselective Michael reaction of a (i-ketoester with nitroolefins (Scheme 10.46). The conjugate addition products were obtained in high yields and excellent diastereo- and enantioselectivities. The same researchers used bis-guanidine catalysts for the enantioselective inverse-electron-demand hetero-Diels-Alder reaction of chalcones with azlactones (Scheme 10.47) [140] and enantioselective Mannich-type reaction of a-isothiocyanato imide and sulfonyl imines (Scheme 10.48) [141]. 

Terada expanded the phospha-Michael reaction to include diphenyl-phosphites [128]. A novel binaphthol-derived guanidine catalyst promoted the addition in high yields and enantioselectivities (Scheme 73). Functionalizing the external nitrogen with a diphenylmethine moeity enhanced selectivities for a large scope of nitro-olefm derivatives. 

Chiral bicyclic guanidine (221) has been identified as an excellent catalyst for reactions between anthrones (219) and various dienophiles, such as (220). The catalyst can tolerate a range of substituents and substitution patterns, making several anthrone derivatives suitable for this reaction. Both Diels-Alder and Michael adducts were obtained in excellent yields, high regioselectivities, and high enantioselectivities (<99% ee). This is the first case of a highly enantioselective base-catalysed anthrone Diels-Alder reaction.263... 

Modified guanidines 3 efficiently catalyzed the asymmetric Michael addition of a prochiral glycine derivatives with acrylate, acrylonitrile and methyl vinyl ketone under simple and mild conditions. Remarkably, both product formation and enantioselectivity were dramatically improved using solvent-free conditions (Scheme 12) [34]. The addition of alcohols to methyl propiolate was performed using fluorous phosphines such as P[(CH2)2 (CF2)7 CF3]3 and again better yields of 99% have been obtained under solvent-free conditions. Toluene was added to efficiently separate the product from the solid catalyst, which was then reused without loss of activity [35],... 

Guanidines have also been employed as catalysts in Michael reactions with enones and, for example, bicyclic guanidine 86 has been found to perform well in the Michael reaction of different 1,3-dicarbonyl compounds with cyclo-pentenones, providing the final Michael adducts with excellent yields and enantioselectivities (Scheme 4.33). In this case, the authors found that the use of triethylamine as solvent resulted in a dramatic increase in the rate of the reaction, without affecting significantly its stereochemical outcome with respect to the same reaction in toluene, which is the usually chosen solvent when working with this type of catalyst. 

Scheme 4.75 The catalytic enantioselective phospha-Michael reactions using guanidines as catalysts.

Atom economy is used as the first filter to select suitable guanidine-catalysed enantioselective reactions. Most guanidine-catalysed reactions fit well with this criterion for example, Michael reactions and its variants have perfect atom economy when the guanidine catalyst is used as a Bronsted-base catalyst. Subsequently, we apply the E-factor to give a rough guide on waste generation of these selected reactions. 

Tan et al. recently reported that chiral guanidine could be used as catalyst to catalyze the asymmetric Michael addition of malonate to 2-cyclopenten-l-one (Table 9.8). The results suggested that this chiral guanidine was exceptionally suitable for the asymmetric Michael addition of 2-cyclopenten-l-one and malonate. It should be noted that all malonates completely reacted with 2-cyclopenten-l-one to afford the Michael adducts with more than 90% of asymmetric induction. Moreover, basic additives such as achiral amines could greatly accelerate the rate of reaction. When triethylamine was used as the solvent, the reaction rate could be increased up to 1000 times without deteriorating the enantioselectivity. The asymmetric Michael additions of (3-keto ester to 2-cyclopenten-l-one were also investigated (Table 9.8). Excellent yields and enantio-selectivities were obtained within 72 hours. In particular, the asymmetric induction could be increased to more than 90% for ethyl 3-oxo-3-m-tolylpropanoate and ethyl 3-(4-nitrophenyl)-3-oxopropanoate when toluene was used instead of EtsN as the reaction medium. 

The mechanism and origin of enantioselectivity has been evaluated for a bicyclic guanidine-catalyzed phospha-Michael reaction between diphenyl-phosphine oxide and p-nitrostyrene by DFT calculations (Scheme 32). The catalyst was found to be involved in all three steps of the catalytic cycle proposed. 

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