Cinchona alkaloid-based catalysts Michael addition

The Jorgensen group also applied the parent cinchona alkaloids as catalysts to the aza-Michael addition of hydrazones 8 to cyclic enones 9 [4] and the asymmetric deconjugative Michael reaction of alkylidene cyanoacetates 10 with acrolein (11) [5], However, only a moderate level of enantioselectivity was obtained in both reactions (Scheme 9.4). Of note, for the deconjugative Michael reaction, the delocalized allylic anion 12 could be generated via the deprotonation of 10 by the cinchona base and might attack the electrophilic enal at either the a- or the y-position. However, in this study, only the a-adducts were produced. 

In the same year, Connon and coworkers [63] reported that the chiral bifunctional cinchona alkaloid-based thiouea 81a is also able to catalyze the addition of dimethyl chloromalonate 196 to nitroolefins 124, leading to the Michael adduct that cyclizes to form the cyclopropane 197 in the presence of DBU. Almost single diastereomeric nitrocyclopropanes (>98% de) were obtained in good yields. However, the enantios-electivity obtained with this type of catalyst was poor (<47% ee) (Scheme 9.69). 

Asymmetric Michael addition of optically active perhydro-l,4-oxazepin-5,7-diones, and of thioglycollic acid in the presence of a cinchona alkaloid as catalyst, to a-nitro-olefins yields y-nitrocarboxylic acids and 2-nitrothio ethers, respectively, with reasonable enantiomeric excess. Allylsilanes add to a-nitro-olefins in the presence of aluminium chloride to give unsaturated nitronic acids, which are further transformed in a Nef-type reaction to give y,5-enones (Scheme 36).Nitro-compounds are also converted into the corresponding carbonyl compounds upon treatment with base and MoOs pyHMPA, a new modified Nef reaction. 

The same year, jOTgensen and coworkers reported an enantioselective aza-Michael addition to enones using hydrazones as nucleophiles and cinchona alkaloids as catalyst [104]. This base-catalyzed reaction renders the final aminated products in good yields but only moderate enantioselectivities (up to 77% ee). 

Catalytic enantioselective nucleophilic addition of nitroalkanes to electron-deficient alke-nes is a challenging area in organic synthesis. The use of cinchona alkaloids as chiral catalysts has been studied for many years. Asymmetric induction in the Michael addition of nitroalkanes to enones has been carried out with various chiral bases. Wynberg and coworkers have used various alkaloids and their derivatives, but the enantiomeric excess (ee) is generally low (up to 20%).199 The Michael addition of methyl vinyl ketone to 2-nitrocycloalkanes catalyzed by the cinchona alkaloid cinchonine affords adducts in high yields in up to 60% ee (Eq. 4.137).200... 

The majority of the Michael-type conjugate additions are promoted by amine-based catalysts and proceed via an enamine or iminium intermediate species. Subsequently, Jprgensen et al. [43] explored the aza-Michael addition of hydra-zones to cyclic enones catalyzed by Cinchona alkaloids. Although the reaction proceeds under pyrrolidine catalysis via iminium activation of the enone, and also with NEtj via hydrazone activation, both methods do not confer enantioselectivity to the reaction. Under a Cinchona alkaloid screen, quinine 3 was identified as an effective aza-Michael catalyst to give 92% yield and 1 3.5 er (Scheme 4). 

In the presence of cinchona derivatives as catalysts, peroxides or hypochlorites as Michael donors react with electron-deficient olefins to give epoxides via conjugate addition-intramolecular cyclization sequence reactions. Two complementary methodologies have been developed for the asymmetric epoxidation of electron-poor olefins, in which either cinchona-based phase-transfer catalysts or 9-amino-9(deoxy)-epi-dnchona alkaloids are used as organocatalysts. Mechanistically, in these two... 

Wynberg and co-workers reported the first example of a chiral quaternary ammonium fluoride-catalyzed Michael addition of nitromethane to chalcone [48], Although the enantioselectivity in the initial report was modest, a range of chiral phase-transfer catalysts, in particular based on cinchona alkaloids, were reported. 

Based on Pracejus s previous work with cinchona alkaloids, Bergson and Langstrom developed the Michael addition of p-ketoesters to acrolein catalyzed by 2-(hydroxymethyl)quinuclidine.Soon after, Wynberg developed severalorganocatalytic reactions using cinchona alkaloids as chiral Lewis base/nucleophilic catalysts [14]. 

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... 

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... 

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). 

The present situation with regard to non-supported catalysts has been admirably reviewed recently, with Wynberg s excellent articlebeing particularly informative. To date virtually all the work has employed quarternary ammonium salts based either on ephedrine [l] and its relatives or the cinchona alkaloids, notably quinine [II], as the active chiral catalyst. Some confusion still remains in the literature concerning the effectiveness of these catalystsi. However, the results of a number of Michael additions seem to be genuine and have been reproduced in more than one laboratory. For example, a chemical yield of100% in the addition of the cyclohexanone derivative, [III], to methyl... 

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