Michael additions of cyclic ketones

Pyrrolidine-based diamine (136) and triamine derivatives that incorporate the secondary diamine motif have been developed as additional organocatalysts for the highly diastereoselective and enantioselective Michael addition of cyclic ketones to... 

Scheme 2.50 Michael addition of cyclic ketones to the chalcone derivative 49, catalyzed by 38.

General Procedure for the Michael Addition of Cyclic Ketones to Nitroalkenes [27] (p. 80)... 

FIGURE 23 Organocatalyzed asymmetric Michael addition of cyclic ketones and nitroalkenes (SS). (For a color version of this figure, the reader is referred to the Web version of this chapter.)... 

Very recently, Lu and coworkers successfully applied aminocatalysis via the enamine intermediate to the Michael addition of cyclic ketones to vinyl sulfones 181 [56]. In the presence of the cinchonidine-derived primary amine salt 179, the Michael reactions between vinyl sulfones 181 and cyclic ketones 180 proceeded smoothly, affording the desired adduct 182 in very high yield and with excellent enantioselectivity (up to 97% ee) (Scheme 9.63). They also successfully applied this methodology to the synthesis of sodium cyclamate. However, this protocol gave poor yields and ee values for acyclic ketones. 

In 2013 Chen et al. reported the direct organocatalytic Michael addition of cyclic ketones to l,l-bis(phenylsulfonyl)ethylene using the camphor-derived pyrrolidine 25." The desired Michael adducts were obtained in high chemical yields and very good stereoselectivities (Scheme 11.21). 

In 2011, the group of Chen reported the application of proline-based reduced dipeptides in the asymmetric Michael addition of cyclic ketones to tra s-p-nitrostyrenes. Comparative studies revealed that the presence of the carbonyl moiety at the N-terminal L-proline unit results in a lower enantioselectivity compared to the corresponding amine analogues. Thus, a series of reduced dipeptides was tested on the above-mentioned Michael addition unveiling reduced dipeptide 17, derived from L-proline and L-phenylalanine, as the optimal catalyst generating the desired products in... 

Scheme 19.65 Application of catalyst 57 to the asymmetric Michael addition of cyclic ketones to aromatic nitroalkenes.

In 2006, Wang and co-workers [53] developed a highly enantioselective organo-catalytic Michael addition of cyclic ketones to chalcones. In the presence of (5)-pyrrolidinesulfonamide 6, the reaction proceeded smoothly under mild conditions to afford a variety of synthetically useful 1,5-diketone compounds in high... 

In the course of synthesising enantioenriched y-keto gem-bisphosphonates having anti-arthritic and anti-inflammatory activities, Barros and Phillips have finalised organocatalytic asymmetric Michael additions of cyclic ketones to vinyl gem-bisphosphonates. The reactions were performed in the presence of (iS)-( + )-l-(2-pyrrolidininylmethyl)pyrrolidine as an organocatalyst and benzoic acid as an additive, leading to the expected Michael products in high yields, excellent diastereoselectivities (> 98% de) combined with enantioselectivities... 

On the other hand, several cinchona alkaloid-derived primary amines have been successfully investigated as organocatalysts for asymmetric Michael additions of ketones to Michael acceptors. As an example, Lu et al. have described the first Michael addition of cyclic ketones to vinyl sulfone catalysed by a catalyst of this type, providing an easy access to chiral a-alkylated carbonyl compounds with high yields and enantioselectivities of up to 96% ee, albeit with moderate diastereoselectivities (<72% de), as shown in Scheme 1.21. This novel methodology was apphed to the synthesis of sodium cyclamate, an important compound in the artificial sweeteners industry. 

Scheme 1.21 Michael additions of cyclic ketones to vinyl sulfone catalysed by cinchona alkaloid-derived primary amine.

The Michael addition of cyclic ketones to l,3-diene-l,l-dicarboxylates ArCH= CHCH=CH(C02R)2> catalysed by the proline-derived salt (252), has been reported to proceed in a 1,4- (rather than 1,6-) manner with 45-80% ee and <83 17 drP More successful was the proline thioether (253), which under solvent-free conditions was able to catalyse the 1,4-addition of ketones R CH2COR to monohaloalkenes ArCH=C(X)CH=CHN02 with up to >99% ee and >99 1 dr ... 

The net effect of the Stork reaction is the Michael addition of a ketone to an cn/3-unsaturated carbonyl compound. For example, cyclohexanone reacts with the. cyclic amine pyrrolidine to yield an enamine further reaction with an enone such as 3-buten-2-one yields a Michael adduct and aqueous hydrolysis completes the sequence to provide a 1,5-diketone (Figure 23.8). 

Lavallee, J.-F. Berthiaume, G. Deslongchamps, P. Grein, F. Intramolecular Michael addition of cyclic P-keto esters onto conjugated acetylenic ketones. Tetrahedron Lett. 1986, 27, 5455-5458. 

The Michael addition of cyclic a-nitro ketones to acrolein or methyl vinyl ketone followed by reduction of the carbonyl group and treatment with base results in the ring expansion (Eq. 

Table 5.8. Michael additions to cyclic ketones and lactones via their secondary enamines. The yields listed are for the overall conversion of the ketone educt into the diketone or keto ester product.

Cedronolactone E (42) isolated from Simaba cedran possesses a unique pentacyclic structure [24]. The structural similarity between cedronolactone C (30) may suggest a biogenetic relation between the former and the latter (Scheme 2). The cleavage of hemiketal at C-ll produces the cyclic ketone intermediate (30a), which via Michael addition of the ketone oxygen atom to C-4 from the si face produces (42) [24],... 

The asymmetric Michael addition of nonstabilised ketone enolates has proved difficult, with most success achieved using 1,3-dicarbonyls as donors. However, Shibasaki and coworkers have achieved high ees in the addition of a-hydroxyketones with both aromatic Michael acceptors such as (11.32) and also cyclic enones and alkyl vinyl ketones, using bifiinctional zinc catalysts prepared from linked BINOL (11.33). These catalysts are also effective in the asymmetric aldol reaction (see Section 7.1) and incorporate two zinc atoms, one of which activates the acceptor carbonyl group and the other forms a zinc enolate with the donor. In addition, catalysts of this type have been used to good effect in the addition of P-ketoesters to cyclic enones. 

S.2.2.3. a, -Unsaturated Sulfones, Malononitriles, and Maleimides as Acceptors, Base on their previous achievements on the asymmetric Michael addition of aldehydes [24], Lu and co-workers [55] developed the first enantiose-lective conjugate addition of cyclic ketones to vinyl sulfone catalyzed by a primary amine 57 (Scheme 5.28). Various cyclic ketones could be applied, affording the corresponding adducts in good yields and with high to excellent enantioselectivities. However, linear ketones were not suitable substrates for this catalytic system. Performing the desulfonylation procedure on a-substituted ketones and in combination... 

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