Cupreidine

Cupreines and cupreidines are pseudoenantiomers of Cinchona alkaloids with the replacement of quinoline C(6 )-OCH3 with an OH-group. The result is availability of an additional hydrogen-bonding moiety. 

The nitroaldol reaction, particularly involving ketones has been relatively unexplored in the field of asymmetric organocatalysis. Employing cupreines and cupreidines as catalysts, Deng [63] presented an enantioselective nitroaldol reaction of a-ketoesters... 

The Deng group identified QN-derived thiourea 121 and QD -derived thiourea 124 to be also efficient promoters of enantio- and diastereoselective Diels-Alder reactions between the 2-pyrone diene 3-hydroxypyran-2-one and the dienophiles fumaronitrile, maleonitrile as well as acrylonitrile, while various C9-hydroxy acylated and alkylated (dihydro)cupreines and (dihydro)cupreidines failed for the same reactions under identical conditions (e.g., 97% yield, 15% ee, 64 36 endoxxo) [289], Catalysts 121 and 124 (5mol% loading), however, produced the corresponding Diels-Alder adducts 1-3 with synthetically useful enantioselectivities (85-... 

Column pBondapak C18 (300x4 mm ID), mobile phase 2.5% aqueous acetic acid - acetonitrile (88 12), flow rate 1.8 ml/min, fluorescence detector (excitation 340 nm, emission 418 nm). Peaks 1, 3-hydroxyquinidine 2, cupreidine(=desmethylquinidine) 3, quinidine 4, cinchonidine (internal standard) 5, dihydroquinidine 6, 2 -quinidinone. (reproduced with permission from ref. 21, by courtesy of the C.V. Mosby Company). 

Fig. 5.3. Separation of quinidine and its metabolites Column Partisi1 PXS 5/25 0DS (250x4.6 mm ID) with guard column, mobile phase acetonitrile - 1 M sodium dihydrogen phosphate -1 M sodium perchlorate - 85% phosphoric acid - water (11 2 1 1 85), flow rate 1.5 ml/min, detection UV 254 nm. Peaks 1, 3-hydroxyquinidine 2, cupreidine (=desmethylquinidine) 3, quinidine 4, quinine 5, dihydroquinidine. (Reproduced with permission from ref. 74, by courtesy of Raven Press)...

Figure 13.2 Structural features of cinchona alkaloid molecules (QN, quinine QD, quinidine CN, cinchonine CD, cinchonidine CPN, cupreine CPD, cupreidine).

Cupreines and cupreidines as bifunctional cinchona organocatalysts 06AG (E)7496. 

In the case of using 1,3-diketones as nucleophiles, catalysts 142 [238], 152 [240], 153 [240], 156 [244], 157 [245], 160 [248], 162 [250], 163 [251], and 165 [253] are able to promote the addition to aromatic nitroolefins with high yields and enantiose-lectivities. Among them, it is worthy to mention BlNAM-derived catalyst 156 and squarimide-cupreidine catalyst 162, that afford very good selectivities under very low catalyst loadings (1 and 0.5 mol%, respectively). As depicted in Fig. 2.18, squa-... 

Other activated methylene-containing nucleophiles that have been successfully used in the conjugate addition to nitrooleflns are a-nitroesters [240], a-cyanoesters [240], a-isocyanoesters [259], 2-hydroxy-1,4-naphthoquinones [260], 3-substituted oxindoles [261], and anthrone [262]. For instance, cupreidine-derived catalysts 151 and 152 (see Fig. 2.15) afford very good yields, diastereo- and enantioselectivities... 

Acrylic acid derivatives as well as a,p-unsaturated nitriles, imides, phosphonates, and sulfones have been also studied as Michael acceptors for activated methylenes. Dixon et al. have demonstrated the efficacy of bifunctional cupreidine 125 (Fig. 2.12)... 

Since the scope of the reaction with respect to the electrophile vras limited to trifluoropyruvate, in 2006 Deng and coworkers searched for a more efficient catalyst for the Friedel-Crafts hydro)grallgrlation of indoles. O-Phenanthiyl cupreidine and cupreine derivatives PHNO-CPD and PHNO-CPN were identified as optimal structures, allowing the use of aiyl and allgmyl pyruvates, glyoxalate and (electron-poor) benzaldehydes in this reaction (Scheme 14.18). ... 

Scheme 14.30 Enantioselective Diels-Alder reactions of 2-pyrones, exemplified with (dihydro)cupreidine catalysts, and proposed IS transition state structure.

In a sulfa-Michael reaction of a,p-unsaturated ketones catalysed by the salt derived from 9-amino-9-deoxy-epz -dihydroquinine (9-e/ f-DHQA) and n-N-Boc-phenylglycine, the best results (96% ee) were obtained using fert-bulyl-thiol. ° A similar catalyst, 9-amino-9-deo y-epz-cupreidine (9-epf-CPDA) allowed a diastereodivergent reaction, where selectivity towards both product diastereomers was possible using the same catalyst by changing the acidic additive and reaction conditions (Scheme 15.31). 

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. ... 

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