Sulfa-Michael reactions activation

Most reports on organocatalytic sulfa-Michael reactions are based on Br0nsted base catalysis, in order to activate pro-nucleophiles containing a S H or a Se—H bond. The early works, appeared in the lates 1970s, featured natural cinchona alkaloids 1-4 as basic catalysts (Figure 14.1). In their seminal works, Wynberg and co-workers employed less than 1 mol% of quinine 1 as chiral catalyst for the conjugated addition of arenethiols to 2-cyclohexen-l-ones. The enantiocontrol was unsatisfactory with benzyhnercaptan [6]. The quasi-enantiomeric catalyst quinidine 2 furnished the... 

Although there are two distinctive approaches to enan-tioselective sulfa-Michael reactions—nucleophilic activation of thiols and electrophilic activation of alkenes—the recent emergence of bifunctional catalysts has greatly improved our understanding in the wider perspective of origin of asymmetric induction. A comprehensive review of asymmetric sulfa-Michael reactions by Ender and co-work-ers appeared in 2007 that covered the advances in this field from 1970s to 2005. " The reader is advised to refer this review article for a historical overview. The goal of this section, thus, is to focus on a few selected stereoselectivity issues in the asymmetric sulfa-Michael reactions and to document new advances made from 2005 to the present time. 

Organocatalysis Continuing efforts to harness the cooperative activity of bifunctional organocatalysts have led to the examinations of chiral calix[4]arenes containing amino phenol stractures and chiral per-6-amino-P-cyclodextrin in the asymmetric sulfa-Michael reactions to cyclic and acylic enones.The preliminary results indicated that further structural modification would be required to allow more efficient asymmetric catalyst systems. 

In a completely different context, an A-protected version of the amino acid cysteine has been found to be an excellent promoter for the intramolecular Rauhut-Currier reaction (Scheme 6.20)," in which an enolizable enone played the role of the Michael acceptor, adding to another a,p-unsaturated ketone moiety in already present at the substrate structure. The mechanism of the reaction involved the activation of the enone which has to play the role of the donor by the catalyst via sulfa-Michael addition through the mercapto functionality of the A-protected cysteine derivative. The formed enolate... 

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]. 

Whereas secondary amines are suitable catalysts for activation of a,(3-unsaturated aldehydes, more difficulties are usually encountered with sterically demanding substrates, such as a,(5-unsaturated ketones. Primary amines can be useful catalysts in such cases. Yoshida et al. [52] reported an amino acid-catalyzed sulfa-Michael addition of arylmethyl mercaptans to cyclic enones. The proposed mechanism invokes the formation of an imine intermediate. However, even with the best screened catalyst, 5-trityl L-cysteine, the reaction proceeded with modest levels of enantioselectivity (8-58% ee). 

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