Pyrrolidine-sulfonamide

Hydroxyaldehydes, with an intervening quaternary centre, have been synthesized enantioselectively by direct aldol reactions of oqa-dialkylaldehydes with aromatic aldehydes, using a chiral bifunctional pyrrolidine sulfonamide organocatalyst.118... 

Organocatalyst (56), a pyrrolidine sulfonamide derived from L-proline, catalyses the direct Michael addition of aldehydes to nitrostyrene with high ee and de, apparently exploiting its bifunctional (acid-base) nature.220 ... 

The bifunctional pyrrolidine sulfonamide catalyst, 38, having basic pyrrolidine nitrogen and Bronsted acidic sulfonamide function, mediates the addition of aldehydes to nitrostyrenes in high yield and selectivity (Scheme 2.47) [34]. Alkyl-substituted nitroolefins afford, however, product in low yield and in low selectivity. 

Wang W, Wang J, Li H (2005) Direct, highly enantioselective pyrrolidine sulfonamide catalyzed Michael addition of aldehydes to nitrostyrenes. Angew Chem Int Ed Engl 44 1369-1371... 

Use of fluorous pyrrolidine sulfonamides 5 for enantioselective aldol reactions and Michael additions are shown in Fignre 1.4. The aldol reaction of cyclohexanone and 4-nitrobenzaldehyde under 10 mol% of the catalyst gave product 6 in 90% yield with a 70% ee and a 2 1 syn/anti ratio. The catalyst can be recovered by F-SPE and reused up to 6 times without significant loss of catalytic activity. 

FIGURE 1.4 Fluorous pyrrolidine sulfonamide-catalyzed Michael addition and aldol reaction. 

The rational design of the catalyst may also address, in addition to performance optimization, recyclability issues. For this reason the fiuorous pyrrolidine sulfonamide 8 was investigated. The hydrophobicity imparted by the fiuorous chain makes 8 an ideal catalyst for heterogeneous aqueous protocols (Scheme 1.4). Both aldehydes and ketones serve as donor units. The catalyst is separated by treating the crude reaction mixture with fiuorous silica gel all the... 

A particularly difficult situation arises when combining in the same reaction the use of these rather unreactive acceptors such as enones with the incorporation of ketones as Michael donors in which the formation of the intermediate enamine by condensation with the amine catalyst is much more difficult. For this reason, the organocatalytic Michael addition of ketones to enones still remains rather unexplored. An example has been outlined in Scheme 2.22, in which it has been shown that pyrrolidine-sulfonamide 3a could catalyze the Michael reaction between cyclic ketones and enones with remarkably good results, although the reaction scope was exclusively studied for the case of cyclic six-membered ring ketones as nucleophiles and 1,4-diaryl substituted enones as electrophiles. In this system the authors also pointed toward a mechanism involving exclusively enamine-type activation of the nucleophile, with no contribution of any intermediate iminium species which could eventually activate the electrophile. Surprisingly, the use of primary amines as catalysts in this transformation has not been already considered. 

Scheme 9.20 Pyrrolidine-sulfonamide 3a-catalysed Michael reactions.

Wang et al. further used pyrrolidine-sulfonamide 3a to develop a highly enantioselective Michael reaction of cyclic ketones to a,p-unsaturated ketones (chalcones). The synthetically useful 1,5-dicarbonyl compounds were obtained in good yields and with high stereoselectivities (>40 1 dr, up to 97% ee). The most satisfactory results were achieved for six-membered cyclic ketones, whereas cyclopentanone appeared to be a more challenging substrate for this reaction (Scheme 9.26). A possible transition-state model was presented to rationalise the stereochemical outcome in which hydrogen-bond formation between the NH in 3a and the carbonyl group of chalcone caused the increase in reactivity. 

Scheme 9.26 Pyrrolidine-sulfonamide 3a-mediated Michael addition to chalcones.

Scheme 9.27 Pyrrolidine-sulfonamide 3a-catalysed asymmetric Michael addition of a-substituted nitro-olefins.

Wang and coworkers reported that pyrrolidine-sulfonamide 3a is an excellent catalyst for the Mannich reaction of ketones with an a-imino ester. The Mannich reaction of various ketones with AT-PMP-protected a-imido ethyl glyoxylate was completed within 2 h at ambient temperature in the presence of catalyst 3a (10 mol%). The desired Mannich adducts were obtained in high chemical yields and with high stereoselectivities (Scheme 9.38). 

Scheme 9.38 Pyrrolidine-sulfonamide (3a)-catalysed Mannich reaction of ketones with a-imino ester.

Hydroxy ketones can be synthesized via the pyrrolidine sulfonamide- and prolinamide-catalyzed direct aldol reaction of methyl-aryl ketones with aromatic aldehydes [51]. Modest enantioselectivities were obtained for all donors and acceptors studied. Yields are strongly affected by the nature of the substrates (Chart 3.2). These ketones react also with acetals and hemiacetals of ttichloro- or trifluoroacetaldehyde in the presence of prohne-derived tetrazol to provide the desired aldols [28c, 52]. 

Diamine catalyst 10, which gives excellent results in the reaction of isobutyr-aldehyde with aromatic aldehydes, affords only moderate diastereoselectivity when used with aliphatic aldehyde donors [119]. Even C2-symmetric catalysts fail to give significant improvements [34c, 139]. Wang reported that the use of fluorous (5)-pyrrolidine sulfonamide 97 in such reactions give better diastereoselectivity and can easily be recovered by simple fluorous solid-phase extraction (Scheme 3.22) [122, 123]. 

For the six-membered-ring cyclic ketones, many effective organocatalysts [36] have been developed in the past decade (as shown in Scheme 5.17 for selected examples). These catalysts proved to be effective for a broad range of aryl nitroalkenes, and some of the reactions could be conducted using alcohol or even water as solvent. Interestingly, alkyl nitroalkene was also suitable electrophile when 29 [36b] was used as the catalyst. On the other hand, the lluorous (S)-pyrrolidine sulfonamide 30 [36c] and functionalized chiral ionic liguids 31 [36d] were reusable. 

In the same context, Wang et al. reported similar highly enantioselective reactions performed in water by using another proline-derived sulfonamide, such as fluorous (5)-pyrrolidine sulfonamide. A notable feature of this simple... 

With regard to the asymmetric a-amination of carbonyl compounds using pyrrolidine sulfonamides as catalysts, only references are given here [220, 221]. 

A slightly different approach is represented by the use of the fluorous (S)-pyrrolidine sulfonamide catalysts 55 (Figure 24.18) [78]. The installation of the... 

Wang J, Li H, Lou B, Zu L, Guo H, Wang W. Enantio- and diastereoselective Michael addition reactions of unmodified aldehydes and ketones with nitroolefins catalyzed by a pyrrolidine sulfonamide. Chem. Eur. J. 2006 12(16) 4321-4332. 

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