Cinchona alkaloid catalysts Michael addition

After this study, the employment of ammonium salts derived from Cinchona alkaloid catalysts, such as [4-(trifluoromethyl)benzyl]cinchoninium bromide (60), for the PTC conjugate addition of 2-afkyUndanones to methyl vinyl ketone was carried out in a two phase toluene/50% aqueous NaOH system yielding higher enantioselec-tivities (up to 80% ee) of the corresponding Michael adduct which is a key intermediate in drug synthesis (Scheme 2.33) [102]. 

Zhao reported the organocatalytic asymmetric synthesis of fluorinated flavanone derivatives by a tandem intramolecular oxa-Michael addition/ electrophilic fluorination and among various Cinchona alkaloid catalysts screened, the best results were obtained using cupreidine substituted with (4-CF3)-benzyl at the 9-0 position. ... 

The hybrid thiourea-cinchona alkaloid catalyst 14 proved to be effective in a stereoselective Michael addition reaction between a,p-unsaturated y-butyrolactam 11 and chalcone 12 (Scheme 3.22). The following mechanistic study addressed the issue of the origin of sfereoselecfion. 

Scheme 3.22 Michael addition reaction catalyzed by hybrid thiourea-cinchona alkaloid catalyst 14. (Data from Zhu, J.-L. et al, /. Org. Chem., 77, 9813-9825, 2012.)...

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). 

The asymmetric conjugate additions with thiol nucleophiles was further expanded to 2-mercaptobenzaldehydes [98]. Wang had previously developed a domino Michael-aldol reaction promoted by Cinchona alkaloids, and now illustrated the utihty of cyclohexane-diamine bifunctionalized catalysts for the domino... 

Wang and co-workers reported a novel class of organocatalysts for the asymmetric Michael addition of 2,4-pentandiones to nitro-olefms [131]. A screen of catalyst types showed that the binaphthol-derived amine thiourea promoted the enantiose-lective addition in high yield and selectivity, unlike the cyclohexane-diamine catalysts and Cinchona alkaloids (Scheme 77, Table 5). 

The Soos group, in 2005, prepared the first thiourea derivatives from the cinchona alkaloids quinine QN (8S, 9R-121), dihydroquinidine DHQD (8S, 9S-122), C9-epi-QN (8S, 9P-123), and quinidine QD (SR, 9R-124) via an experimentally simple one-step protocol with epimerization at the C9-position of the alkaloid starting material (Figure 6.39) [278]. The catalytic efficiency of these new thiourea derivatives and also of unmodified QN and C9-epi-QN was evaluated in the enan-tioselective Michael addition [149-152] of nitromethane to the simple model chal-cone 1,3-diphenyl-propenone resulting in adduct 1 in Scheme 6.119. After 99h reaction time at 25 °C in toluene and at 10 mol% catalyst loading QN turned out to be a poor catalyst (4% yield/42% ee (S)-adduct) and C9-epi-QN even failed to accelerate the screening reaction. In contrast, the C9-modified cinchona alkaloid... 

Recently, chiral phase-transfer-catalyzed asymmetric Michael addition has received much attention, and excellent enantioselectivity (up to 99% ee) has been reported using cinchona alkaloid-derived chiral phase-transfer catalysts [40]. Among noncinchona alkaloid-derived chiral phase-transfer catalysts Shibasaki s tartrate derived C2-symmetrical two-center catalyst provided a Michael adduct with up to 82% ee [41]. 

Michael additions of C-nudeophiles such as the indanone 1 have been the subject of numerous further studies For example, the reaction between the indanone 1 and methyl vinyl ketone was effected by a solid-phase-bound quinine derivative in 85% yield and with remarkable 87% ee by d Angelo, Cave et al. [5], Co-polymers of cinchona alkaloids with acrylonitrile effected the same transformation Kobaya-shi and Iwai [6a] achieved 92% yield and 42% ee and Oda et al. [6b] achieved almost quantitative yield and up to 65% ee. Similarly, partially resolved 2-(hydroxy-methyl)quinudidine was found to catalyze the reaction between 1 and acrolein and a-isopropyl acrolein with induction of asymmetry, but no enantiomeric excesses were determined [7]. As shown in Scheme 4.4, the indanone 7 could be added to MVK with up to 80% ee under phase-transfer conditions, by use of the Cinchona-derived PT-catalysts 9a and 9b, affording the Michael-product 8 or enf-8, respectively [8]. The adducts 8 or ent-8 were intermediates in the stereoselective Robinson anellation of a cydohexenone ring to the indanone 7 [8],... 

Modified cinchona alkaloids 18 and 19, derived from quinine and quinidine, respectively, were utilized by Deng and co-workers for the catalytic asymmetric Michael additions of malonates to nitroolefins [49]. These catalysts effectively promoted the conjugate additions of methylmalonate to a variety of aromatic (90-99% yield 96-98% ee), heteroaromatic (97-99% yield 96-98% ee) and aliphatic (71-86% yield 94% ee) -substituted nitroolefins (Table 6.7). As the two alkaloids... 

Further reports on asymmetric synthesis in the presence of Cinchona alkaloids have been made.142 " For example, hydrogenation of methyl pyruvate with a platinum-alumina catalyst containing quinine gives (+)-(/ )-methyl lactate in 87% optical yield.1426 Asymmetric induction with optical yields up to 36 and 26% has been observed in the Michael addition of thiols and nitro-alkanes to ct/ -unsaturated ketones in the presence of quaternary salts derived from the Cinchona alkaloids.142"... 

Despite the importance of the Michael addition in organic synthesis, the tandem conjugate addition/enantioselective protonation has been little explored [14] and only a few publications have involved cinchona alkaloids as bifunctional catalysts B for controlling the configuration of the chiral carbon created during protonation (Scheme 7.9). 

Quite recently, the use of natural cinchona alkaloids as catalysts for the intramolecular oxo-Michael addition of o-tigloylphenol (3), furnishing chiral ris-2,3-dimethyl-4-chromanone 4, which is a valuable intermediate for the synthesis of the anti-HIV-1 active coumarins, (+ )-calanolide A (5a), and (+ )-inophyllum B (5b), was reexamined by Ishikawa and coworkers (Scheme 9.2) [2], The parent cinchona alkaloids,... 

For the asymmetric synthesis of the 2-substituted chromane 7 via the intramolecular Michael addition reaction of 6, Merschaert et al. also employed natural cinchona alkaloids such as HCD as catalysts (Scheme 9.3) [3]. Here again, the 9-0 functionalization and dehydroxylation of the natural alkaloid showed a large negative effect, indicating that the presence of the 9-OH group is needed to achieve both good kinetics and enantioselectivity. Moreover, C3 modifications of this parent alkaloid did not lead to any significant improvement in the results in terms of the enantioselectivity and catalytic activity. 

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. 

Sharpless bis-cinchona alkaloids such as [DHQD]2PYR (163a) have proved to serve as highly efficient catalysts for the asymmetric vinylogous Michael addition of the electron-deficient vinyl malonitriles 164 as the nucleophilic species to nitroole-fins 124 [50], This process exhibited exclusive y-regioselectivity and high diastereo-and enantioselectivity. Only the anti-products 165 were observed in all reactions (Scheme 9.57). Of note, 1-tetralone did not react with nitroolefins under these... 

Natural cinchona alkaloids were recently examined as catalysts for Michael addition reactions. In the presence of a natural cinchona alkaloid such as cinchonine (CN), 2-hydroxy-l,4-naphthoquinone 168 as the nucleophilic component was added... 

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). 

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