Sulfa-Michael addition

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... 

Optically active sulfur containing compounds play a very important role in biochemistry as well as synthetic chemistry. The asymmetric conjugate addition of sulphur nucleophiles, or sulfa-Michael addition [379], provides a direct and versatile approach toward optically active sulfur compounds. This strategy is particularly valuable, since enantioselective nucleophilic additions to a C-S double bond, unlike those to carbonyls and imines, are not synthetically feasible. 

Very recently two comprehensive review articles dealing with organocatalytic carbon-sulfur bond-forming reactions and asymmetric sulfa-Michael additions have been published. Historically, the first catalytic enantio-selective sulfenylations of conjugated enones in the presence of Cinchona alkaloids were published in 1977 by Pracejus where acrylamides and... 

The possibilities of enantioselective sulfa-Michael additions using amino derivatives of Cinchona alkaloids are also demonstrated through tandem (cascade, domino) reactions, thus allowing the formation of multiple stereocentres with up to 99% ee. In comparison to Cfnc/zona-thiourea derivatives, natural Cinchona alkaloids or their ethers gave lower... 

FIGURE 14.1. Natural cinchona alkaloids used in the Brpnsted base-catalyzed sulfa-Michael addition. 

Natural cinchona alkaloids were reported to promote the sulfa-Michael addition to different electron-poor alkenes as well. Catalysts 1 and 2 were employed by Pracejus et al. [11] in the moderately enantioselective additions (up to 54% ee) of benzylmercaptan to a-phthalimidomethacrylate. The same bases were found to promote the asymmetric addition of benzylmercaptan and tritylmercaptan to nitro-alkenes. Similar results were later reported with thioglycolic acid as the nucleophile [12]. Low enantioselectivities were obtained in the process catalyzed by different alkaloids such as bmcine, strychnine, and A-methyl ephedrine [11]. Catalyst 4 was successfully employed in the sulfa-Michael addition of thiophenol to maleic acid... 

FIGURE 14.2. Ternary transition state proposed for the cinchona alkaloid-catalyzed sulfa-Michael addition. 

Several derivatives of cinchona alkaloids 1—4 were prepared and used in the asymmetric sulfa-Michael addition. The first highly efficient method, based on the catalyst (DHQD)2PYR 5, was presented by the Deng group in 2002 [18]. Especially high ees were observed in the conjugated addition of 2-thionaphthol to several six-to nine-membered cyclic enones at low temperature (Scheme 14.3). Although 2-cyclopentenone reacted with moderate enantioselectivity (41% ee), the ee was increased dramatically with 4,4-dimethyl-2-cyclopentenone (92% ee). 

Different chiral organic bases proved to be suitable for catalytic sulfa-Michael addition. Mukaiyama and coauthors reported the asymmetric addition of arenethiols to cycloalkenones catalyzed by the p-hydroxyprolinamine 8 (Figure 14.3) [25]. While the results are interesting with cyclohexenones (up to 88% ee), unsatisfactory ees were obtained with smaller and larger cyclic enones. The authors emphasized the... 

FIGURE 14.3. Different aminoalcohol catalysts employed in the sulfa-Michael additions. 

As anticipated by the work of Wynberg [7], the presence of a protic group in the catalyst s structure, capable of activating and orienting the electrophile, had a positive impact on the enantioselectivity of the conjugate additions. On this basis, several Brpnsted acid/Brpnsted basic bifunctional catalysts has been applied in the sulfa-Michael addition. A list of them is reported in Figure 14.4. 

SCHEME 14.6. Sulfa-Michael addition to tra/M-chalcones catalyzed by squaramide 13. 

SCHEME 14.7. Sulfa-Michael addition to a,p-imsaturated JV-acyloxazolidin-2-ones catalyzed by thiourea 14. 

FIGURE 14.5. Bifunctional mode of activation in the sulfa-Michael additions to a,(3-unsaturated imides and nitroalkenes catalyzed by aminothioureas. 

SCHEME 14.12. Conjugate sulfa-Michael addition to a-substituted (3-nitroacrylates promoted by thiourea 12 and further transformation into a-thio-p -amino acids. 

SCHEME 14.13. Sulfa-Michael addition to (Z)-4,4,4-trifluorocrotonates promoted by 16 as the key step in the formal synthesis of a potent inhibitor of MMP-3. 

SCHEME 14.14. Sulfa-Michael addition to a. -unsaturated aldehydes promoted by O-protected diarylprolinol 17a, and related sulfa-Michael-amination cascade process. 

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). 

FIGURE 14.6. Chiral aminocatalysts and co-catalysts used in the sulfa-Michael additions to a,p-unsaturated ketones and hindered a,p-unsaturated aldehydes. 

SCHEME 14.18. Sulfa-Michael addition to acyclic enones catalyzed by the salt 20. 

SCHEME 14.20. Syn- or a tt-selective sulfa-Michael addition to a,p-disubstituted enones. 

Scheme 3 1,4-Selective sulfa-Michael addition to 1,6-keto ester...

During study of the chiral thiourea 12-catalyzed sulfa-Michael addition of aliphatic thiols to nitroolefins, benzylic mercaptans were subjected to the reaction with nitrodienes (Scheme 8) [17]. Exclusive formation of 1,4-adducts was observed in moderate to good chemical yield with moderate to fair enantioselectivity. 

Scheme 9 1,6-Selective sulfa-Michael addition via vinylogous iminium activation...

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 °... 

Using a chiral primary amine salt derived from 9-amino-(9-deoxy)-e/>i-hydroquinine, Melchiorre et al. achieved an organocatalytic asymmetric protocol for the highly enantioselective sulfa-Michael addition, which was applicable to a large variety of a,p-unsaturated ketones. The highest enantioselectivities of up to 96% ee combined with high yields were obtained with benzyl mercaptan as a nucleophile, as shown in Scheme 1.69. 

In 2009, Enders and Hoffman explored the reactivity of a,(3-unsaturated sulfonates and aromatic thiols in sulfa-Michael additions. When the reactions were catalysed by a chiral bifunctional thiourea derived from quinine, the sulfa-Michael adducts were formed in moderate enantioseleetivities of up to 64% ee, albeit with generally good yields, as shown in Seheme 1.70. 

In addition, Shimizu et al. have applied novel multifunetional inherently chiral calix[4]arene to the sulfa-Michael addition of thiols to cyclohexenone. The expected Michael adducts were obtained in generally excellent yields (18-99%) but with low enantioselectivities (<25% ee). The reaction system was also applied to other cyclic and acyclic enones, providing the corresponding products with a comparable degree of enantioselectivity to that obtained with cyclohexenone. 

Since then, and inspired by this pioneering report, several groups have developed organocatalytic cascade reactions starting with a sulfa-Michael addition [68, 69]. 

Later, Melchiorre s group employed a similar catalyst system in the P-hydroxylation of (x,P-unsaturated ketones 79 (Scheme 43.17) [28], aziridination of enones (Scheme 43.18) [29], and sulfa-Michael addition of a,p-unsaturated ketones (Scheme 43.19) [30]. High chemical yields and excellent enantioselectivities for various chiral products were obtained, which proved the use of chiral co-catalysts to be necessary for optimal enantioselection. 

Scheme 43.19 Asymmetric sulfa-Michael addition of a,p-unsaturated ketones.

An organocatalytic triple cascade reaction, followed by an intramolecular sulfa-Michael addition to produce bicyclic rings with six consecutive stereocenters, was also realized [46]. 

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