Cinchona alkaloid thiourea

Some bifunctional 6 -OH Cinchona alkaloid derivatives catalyse the enantioselective hydroxyalkylation of indoles by aldehydes and a-keto esters.44 Indole, for example, can react with ethyl glyoxylate to give mainly (39) in 93% ee. The enan- tioselective reaction of indoles with iV-sulfonyl aldimines [e.g. (40)] is catalysed by the Cu(OTf)2 complex of (S)-benzylbisoxazoline (37b) to form 3-indolylmethanamine derivatives, in up to 96% ee [e.g. (41a)] 45 Some 9-thiourea Cinchona alkaloids have been found to catalyse the formation of 3-indolylmethanamines [e.g. (41b)] from indoles and /V-PhS02-phenyli mines in 90% ee.46 Aryl- and alkyl-imines also give enantioselective reactions. 

However, when the dienophile was replaced with unsaturated nitrile, 1 j (or lk) was proved to be ineffective. Other bifunctional catalysts, 9-thiourea cinchona alkaloids 11 and lm [21], which were prepared from 9-amino-9-deoxyepiquinidine and 9-amino-... 

This challenging problem was addressed by Deng and coworkers [51] by the use of 9-thiourea cinchona alkaloids as acid-base bifunctional catalysts. As shown in Scheme 10.30, the enantioselective aza-Friedel-Crafts reaction proceeded through a network of hydrogen bonding interactions between indoles 145 and A-Ts aldimines 149... 

SCHEME 10.30 Enantiodivergent aza-Friedel-Crafts reaction of indoles with imines catalyzed by bifunctional 9-thiourea cinchona alkaloids. 

In 2007, Jorgensen and coworkers demonstrated that the bifunctional thiourea-cinchona alkaloid catalysts 81b also promoted the enantioselective addition of oximes 153 as oxygen nucleophiles to nitroolefins 124 giving the adduct 154 in good yield with a high level of enantioselectivity (Scheme 9.52) [45]. The obtained adduct 154 can be converted to the optically active aliphatic nitro- or aminoalcohols. It is believed that the... 

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.)...

Amere, M. Lasne, M. C. Rouden, J. Highly Enantioselective Decarboxylative Protonation of a-Aminomalonates Mediated by Thiourea Cinchona Alkaloid Derivatives Access to Both Enantiomers of Cyclic and Acyclic a-Aminoacids. Org. Lett. 2007, 9, 2621. 

Amere M, Lasne MC, Rouden J. Highly enantioselective decarboxylative protonation of a-aminomalonates mediated by thiourea cinchona alkaloid derivatives access to both enantiomers of cyclic and acyclic a-aminoacids. Org. Lett. 2007 9 2621-2624. 

A further important advance was also achieved by Rouden et al. [17] who developed the use of thiourea cinchona alkaloids 33-34 in the enantioselective decarboxylative protonation of a-aminomalonates (Scheme 3.12). The basic idea in using these bifunctional catalysts was to take advantage of the good hydrogen-bond donor properties of the thiourea moiety to promote further interactions between the chiral proton source and the prochiral enolate intermediate. Bifunctional catalyst 33 in quinidine series turned out to be especially efficient with a large range of substrates... 

Modified Cinchona alkaloids catalysts have been developed in the last two decades to enhance further the bifunctional mode of the catalyst. Derivations at the C(9)-OH group, replacement of quinoline C(6 )-OCH3 with a hydroxyl group to enhance hydrogen bonding, syntheses of bis-Cinchona alkaloids, and development of thiourea-derived Cinchona alkaloids are most notable. 

Novel asymmetric conjugate-type reactions have been accomplished with Cinchona alkaloid-derived chiral thioureas, including less traditional reactions such as asymmetric decarboxylation [71]. In the following discussion, asymmetric reactions involving nitro-olefms, aldehydes and enones, and imines will be highlighted (Fig. 5). 

Using the addition of dimethyl malonate to nitro-olefms as the model reaction, Connon et al. [72] in 2(X)5 reported a highly functionahzed Cinchona alkaloid-derived chiral thiourea. Key functional groups were identified to enhance the catalyst s stereodirecting properties. Aside from the advantage of a bifunctional Cinchona alkaloid... 

Cinchona alkaloid-derived chiral thiourea catalyst xo... 

The aza-Henry reaction of imines to nitroalkanes promoted by modified Cinchona alkaloids has been investigated by several groups. Optically active p-nitroamine products are versatile functional building blocks. In 2005 and 2006, several reports regarding use of chiral thioureas emerged, using nitroalkanes in the aza-Henry reaction to various imines. 

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 Chen group early in 2005 constituted the novel class of thiourea-function-ahzed cinchona alkaloids with the first reported synthesis and application of thioureas 116 (8R, 9S) and 117 (8R, 9R) prepared from cinchonidine and cinchonine in over 60% yield, respectively (Scheme 6.112) [273]. In the Michael addition of thiophenol to an a,(5-unsaturated imide, the thioureas 116 and 117 displayed only poor stereoinduction (at rt 116 7% ee 117 17% ee), but high catalytic activity (99% yield/2h) (Scheme 6.112). 

Scheme 6.112 Michael addition of thiophenol to an a,p-unsaturated imide catalyzed by cinchonidine-derived thiourea 116 and cinchonine-derived thiourea 117, the first representatives of this class of bifunctional hydrogen-bonding cinchona alkaloid-thioureas.

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... 

Figure 6.39 Cinchona alkaloid-thioureas prepared from quinine (121), dihydroquinine (122), C9-epi-quinine (123), and quinidine (124) catalytic efficiency evaluated in the Michael addition of nitromethane to tram-chalcone 1,3-diphenyl-propenone at 10mol% loading and rt.

C9-epi-122 98% conv. (99% ee) after 30h, respectively (Figure 6.40). This structure-efficiency relationship supported the results already published by the Soos group for quinine- and quinidine-derived thioureas (Figure 6.39) [278]. C9-epimeric catalysts were found to be remarkably more efficient in terms of rate acceleration and stereoinduction than the analogs of natural cinchona alkaloid stereochemistry. This trend was also observed for the corresponding (thio)ureas derived from DHQD as shown by the experimental results in Figure 6.40 [279]. 

Scheme 6.146 Representative adducts obtained from the asymmetric Henry reaction between nitromethane and (hetero)aromatic aldehydes under bifunctional catalysis of C6 -thiourea-functionalized cinchona alkaloid 131.

The Cinchona alkaloid-derived thiourea (112), has been developed as an organocat-alyst for conjugate addition of a wide range of nucleophilic enol species to enones. The reaction is characterized by high enantioselectivities and mild reaction condition.160... 

Cinchona alkaloids and their derivatives have been reported to catalyse the Michael addition of (V-heterocycles, such as benztriazole, to nitroalkenes in moderate to high enantioselectivities (<94% ee) 15 The thiourea derivative (149) catalysed Michael addition of thioacetic acid to a range of frafts-/f-nitrostyrenes to afford RCH(SAc)- CH2NO2 (<70% ee) 16 The thiourea derivative (149) and its congeners have been identified as efficient organocatalysts for the Michael addition of a-substituted cyano-acetates RCH(CN)C02Et to vinyl sulfones CH2=C(R)S02Ph (72-96% ee) 17 ... 

Michael addition of nitromethane to chalcones can be catalysed by cinchona alkaloid-derived chiral bifunctional thiourea (142) (0.5-10 mol%) to give the corresponding products at 25-100 °C in high chemical yields and high enantioselectivity ... 

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