Michael-aldol reaction, -prolinol

The domino Michael/aldol reaction of 3-halogeno-l,2-diones (273) (X = Cl, F) to a,fi-unsaturated aldehydes RCH=CHCH=0 (R = aryl, heteroaryl), catalysed by the prolinol derivatives (256), has been developed as a method for the construction of cyclopen- tanones (274) with four contiguous stereogenic centres (<94% ee, >20 1 dr)P ... 

Hong and co-workers entirely exploited the ability of amine catalysts to promote cascade reactions by different mechanisms. They applied a one-pot oxa Michael-Michael-Michael-aldol reaction for the synthesis of conicol, a marine terpenoid isolated from Aplidium conicum (Scheme 11.32). Using diphenyl prolinol silyl ether 12,... 

Chiral tetrahydrothiophenes are compounds displaying important biological activities. They were obtained also through an enantioselective domino sulfa-Michael-Michael process of a,(3-unsaturated aldehydes with ethyl 4-mercapto-2-butenoate [47]. While catalyst 17a turned out to be ineffective, the diarylprolinol silyl ether 17b afforded cyclic products with high to excellent enantio- and diastereoselectivity (Scheme 14.16a). A closely related sulfa-Michael aldol process was developed by using 3-mercapto a-carbonyl esters as reaction partners. The best stereoselectivity and yield were obtained with diaryl prolinol 17c in the presence of small amounts of H2O (Scheme 14.16b) [48]. 

A BINAP-derived bifunctional thiophosphoramide gives >98% del>99% ee in Michael addition of cyclohexanones to both aryl- and alkyl-substituted nitroolefins. Imidazolylmethyl ketones undergo one-pot Michael-aldol cascade reactions with Q ,/3-unsaturated aldehydes in DCM at 20 °C using the simple organocatalyst, prolinol... 

When nitrostyrenes and dimethylmalonate were reacted with a,p-un-saturated aldehydes in the presence of a combination of chiral diphenyl-prolinol triethylsilyl ether and a chiral cinchona alkaloid catalyst through a three-component reaction, Xu et al. showed that they afforded, according to a Michael-Michael-aldol domino reaction, the corresponding chiral functionalised cyclohexanes in moderate to good yields, good to excellent enantioselectivities of up to >99% ee, albeit moderate diastereoselectivities... 

In addition to pyrrolidine-based structure, prolme-based catalysts were also investigated. Two examples of supported prolinamide-based catalysts for the Michael reaction are 86 and 87 (Figure 24.29). Prolinamide-bridged silsesquioxane 86 was prepared from a bis-sUylated prolinamide by sol-gel methodology and used in water. This catalytic material was also used in aldol reactions [108]. The prolyl-prolinol catalyst 87 was anchored to a polystyrene backbone and used in a dichloromethane/water mixture [22a]. 

Detailed mechanistic studies of this reaction have been undertaken hy several teams. Michael addition of the simplest enolisahle aldehyde, acetaldehyde, poses a significant challenge due to high auto-aldol reactivity of acetaldehyde. List and coworkers used prolinol silyl ether eatalysts to promote enantioselective Michael addition of acetaldehyde to nitroalkenes.The key to successful accomplishment of this transformation was slow addition of acetaldehyde via a syringe pump. 

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