Cinchona alkaloids enantioselective Michael addition, base

Enantioselective Michael addition of thiols to enones is a useful reaction for the synthesis of sex pheromones [26] and terpenes [27]. For example, enantioselective Michael additions of thiols to 2-cyclohexenone (64) and maleic acid esters in the presence of chiral bases such as cinchona alkaloids [28, 29] and optically active amino alcohols [30, 31] have been reported. It has also been found that the enantioselective Michael addition reaction proceeds efficiently in an inclusion crystal... 

A particularly elegant example of the build/couple/pair strategy combined with reagent-based skeletal diversity construction can be found in the solution-phase work carried out by Comer et al. (Scheme A.l) Their strategy involved the synthesis of a number of substituted p-nitrostyrenes and alkylated 1,3-dicarbonyls in the build phase that were then coupled by enantioselective Michael addition of the dicarbonyls to the p-ni-trostyrenes using a cinchona alkaloid-derived organocatalyst to give densely functionalized molecules such as 27 and 28. 

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... 

Several examples exist of the application of chiral natural N-compounds in base-catalyzed reactions. Thus, L-proline and cinchona alkaloids have been applied [35] in enantioselective aldol condensations and Michael addition. Techniques are available to heterogenize natural N-bases, such as ephedrine, by covalent binding to mesoporous ordered silica materials [36]. 

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). 

Kumar and coworkers described the Michael addition of thiophenol 13 to 2-phenylacrylates 19 using a catalytic amount of cinchona alkaloids [16]. Among the four natural alkaloids, quinine 20 and quinidine 3 afforded the best results with opposite enantioselectivity (Scheme 7.11). Methyl or isopropyl ester substrates 19a and 19b gave comparable selectivities whereas more sterically demanding esters (e.g., tBu or CH(iPr)2) gave lower optical inductions. Based on the previous considerations and a computational analysis, the authors suggested a transition state... 

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. 

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. 

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 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). 

---