The rational design of modified Cinchona alkaloid catalysts. Application to a new asymmetric synthesis of chiral chromanes

Abstract

Abstract-A new asymmetric synthesis of 2-substituted chiral chromanes has been achieved. The key step is the intramolecular conjugate addition of a phenolic nucleophile on a a,b-unsaturated ester catalyzed by Cinchona alkaloids. The high ee's obtained with cinchonine and its derivatives have been rationalized by ab initio quantum chemistry calculations of transition state structures. Ó 2004 Elsevier Ltd. All rights reserved.Functionalized chromanes possess potentially useful biological properties.1 In the scope of a research program, we developed earlier the synthesis of 2,6-disubstituted-chromanes from 6-substituted chromanones 2 ( Fig. 1).Although high overall yields of racemic material were obtained, this approach suffered from the need to perform an optical resolution in the last step of the synthesis.In order to improve the productivity of the process without having to develop a new route, we sought to utilize a chiral base in the Wittig-oxa-Michael step (Fig. 2). The results of those efforts are reported herein. Initially very low enantioselectivities (ca. 28% ee with cinchonine) were obtained in a tandem process by heating a mixture of lactol 1, phosphorane, and cinchonine to 80-100°C. In this temperature range, we observed that the phosphorane alone was able to catalyze the cyclization thus competing with the chiral catalyst. Therefore, we modified the procedure and performed the reaction sequentially: (i) the Wittig step was carried out at ambient temperature (ii) the remaining phosphorane and the triphenylphosphine oxide by-product were removed by silica gel treatment, and (iii) the chiral

Recent applications of Cinchona alkaloids and their derivatives as catalysts in metal-free asymmetric synthesis

“…141 Functionalised chromanes possess potentially useful biological properties. 142 High enantioselectivities were observed with cinchonine and its derivatives 246aed.…”

Asymmetric organocatalytic synthesis of six-membered oxygenated heterocycles

“…31a,32 Merschaert et al have also used cinchona alkaloid derivatives as catalysts in the first asymmetric 6-exo-trig oxa-Michael addition reaction of a phenolic nucleophile on an a,b-unsaturated ester for the synthesis of 2-substituted chromanes. 33 Among the readily available cinchona alkaloids, the best results were obtained using cinchonine (10 mol %) as catalyst (27 in Fig. 3).…”

“…After a broad screening of these modified catalysts, 28 was found to give the highest enantioselectivities for both Z (80% ee) and E (52% ee) isomers, although with a slight decrease in conversion. 33 The highly enantioselective cyclization of 2 0 -hydroxychalcones to flavanones catalyzed by the enzyme chalcone isomerise, is a well-known step in the biosynthesis of flavonoids. It cannot, however, be reproduced enantioselectively so far using asymmetric organocatalysis.…”

Acid-catalyzed intramolecular oxa-Michael addition reactions under solvent-free and microwave irradiation conditions

“…9 Various catalysts have been reported for intermolecular oxa-Michael additions, such as pro-azaphosphatranes of ionic liquid as solvent for toluenesulfonic acid-catalyzed oxa-Michael addition has also been reported. 22 For intramolecular oxa-Michael addition, cinchona alkaloids, 23 thiourea derivatives, 24 quinine, 25 guanidine, 26 30,31 have been utilized as the catalysts. It was reported that the intramolecular oxa-Michael addition of (E)-1-aryl-4-hydroxy-4-methylpent-1-en-3-ones in the presence of TsOH should be carried out by refluxing in dichloroethane for 24 h, while the products were hard to purify due to the impurities.…”