Immobilization cinchona derivatives

Other functionalized supports that are able to serve in the asymmetric dihydroxylation of alkenes were reported by the groups of Sharpless (catalyst 25) [88], Sal-vadori (catalyst 26) [89-91] and Cmdden (catalyst 27) (Scheme 4.13) [92]. Commonly, the oxidations were carried out using K3Fe(CN)g as secondary oxidant in acetone/water or tert-butyl alcohol/water as solvents. For reasons of comparison, the dihydroxylation of trons-stilbene is depicted in Scheme 4.13. The polymeric catalysts could be reused but had to be regenerated after each experiment by treatment with small amounts of osmium tetroxide. A systematic study on the role of the polymeric support and the influence of the alkoxy or aryloxy group in the C-9 position of the immobilized cinchona alkaloids was conducted by Salvadori and coworkers [89-91]. Co-polymerization of a dihydroquinidine phthalazine derivative with hydroxyethylmethacrylate and ethylene glycol dimethacrylate afforded a functionalized polymer (26) with better swelling properties in polar solvents and hence improved performance in the dihydroxylation process [90]. 

A series of (1-lactams (64) have been synthesized through the use of an immobilized cinchona alkaloid catalyst. This is postulated to proceed via the cycloaddition of an imine, and a ketene formed in situ through deprotonation of an acid chloride (Scheme 4.81). Different system configurations were described in the paper however, a column filled with a 5 1 mixture of solid K2C03 and immobilized-quinine derivative 65 cooled to —45 °C was found to be the most practical. The solution of the acid chloride and imine was dripped through the column and then directed... 

A few years ago Cahard reported a series of studies on the use of immobilized cinchona alkaloid derivatives in asymmetric reactions with phase-transfer catalysts [17[. Two types of polymer-supported ammonium salts of cinchona alkaloids (types A and B in Scheme 8.4) were prepared from PS, and their activity was evaluated. The enantioselectivity was found to depend heavily on the alkaloid immobilized, with the type B catalysts usually giving better results than the type A catalysts. By performing the reaction in toluene at -50 °C in the presence of an excess of solid cesium hydroxide and 0.1 mol equiv of catalyst 10, benzylation of the tert-butyl glycinate-derived benzophenone imine afforded the expected (S)-product in 67% yield with 94% ee, a value very close to that observed with the nonsupported catalyst. (Scheme 8.4, Equation b) Unfortunately-and again, inexplicably-the pseudoenantiomer of 10 proved to be much less stereoselective, affording the R)-product in only 23% ee. No mention of catalyst recycling was reported [18]. 

Radical addition of thiol or thiol-modified support to the vinyl group gives the respective thioether linkage 34 and represents one of the most convenient ways to immobilize Cinchona alkaloids [163, 172]. There are also few examples of platinum-catalyzed hydrosilylation of Cinchona alkaloids toward 11-silyl-substituted derivatives 35 with the use of monomeric silanes or polysiloxane polymers [173-175]. De Vries reported rhodium-catalyzed hydroformylation of the four main members of Cinchona alkaloids carried out on a hundred gram scale. Under optimized condition, linear aldehydes 36 were selectively obtained with the yield over 80% [176]. 

The first silica-supported CSP with a cinchona alkaloid-derived chromatographic ligand was described by Rosini et al. [20]. The native cinchona alkaloids quinine and quinidine were immobilized via a spacer at the vinyl group of the quinuclidine ring. A number of distinct cinchona alkaloid-based CSPs were subsequently developed by various groups, including derivatives with free C9-hydroxyl group [17,21-27] or esterified C9-hydroxyl [28,29]. All of these CSPs suffered from low enantiose-lectivities, narrow application spectra, and partly limited stability (e.g., acetylated phases). 

It is also worthwhile to outline at this place the immobilization procedure that was used for the preparation of type I CSPs A bifunctional linker with a terminal isocyanate on one side and a triethoxysilyl group on the other end (3-isocyanatopropyl triethoxysilane) was reacted with the native cinchona alkaloids quinine and quinidine and subsequently the resultant carbamate derivative in a second step with silica [30], Remaining silanols have been capped with silane reagents, yet, are less detrimental for acidic solutes because of the repulsive nature of such electrostatic interactions. CSPs prepared in such a way lack the hydrophobic basic layer of the thiol-silica-based CSPs mentioned earlier, which may be advantageous for the separation of certain analytes. 

A copolymerization approach of 0-9-[2-(methacryloyloxy)ethylcarbamoyl] cinchonine and cinchonidine with methacryl-modified aminopropylsilica particles was utilized by Lee et al. [71] for the immobilization of the cinchona alkaloid-derived selectors onto silica gel. The CSPs synthesized by this copolymerization procedure exhibited merely a moderate enantiomer separation capability and only toward a few racemates (probably because they were based on less stereodifferentiating cinchonine and cinchonidine). Moreover, the chromatographic efficiencies of these polymer-type CSPs were also disappointing. 

While this manuscript was under preparation, a considerable number of examples of sohd-phase-attached catalysts appeared in the literature which is a clear indication for the dynamic character of this field. These include catalysts based on palladium [131, 132], nickel [133] and rhodium [134] as well applications in hydrogenations including transfer hydrogenations [135, 136] and oxidations [137]. In addition various articles have appeared that are dedicated to immobilized chiral h-gands for asymmetric synthesis such as chiral binol [138], salen [139], and bisoxa-zoline [140] cinchona alkaloid derived [141] complexes. 

Catalytic asymmetric alkylations of 28 have also been carried out with polymer-bound glycine substrates [43], or in the presence of polymer-supported cinchona alkaloid-derived ammonium salts as immobilized chiral phase-transfer catalysts [44], both of which feature their practical advantages especially for large-scale synthesis. 

To reduce the cost of the AD process immobilization of the chiral Cinchona alkaloid-derived ligands has attracted attention, too. Several approaches to address this problem have been reported [51]. The chiral ligand has been attached to solid supports comprising organic polymers or modified silica. After comple-... 

In an attempt to develop a PEG-supported version of a chiral phase-transfer catalyst the Cinchona alkaloid-derived ammonium salt 15 used by Corey and Lygo in the stereoselective alkylation of amino acid precursors was immobilized on a modified PEG similar to that used in the case of 13. The behaviour of the catalyst obtained 16, however, fell short of the expectations (Danelli et al. 2003). Indeed, while this catalyst (10 mol%) showed good catalytic activity promoting the benzy-lation of the benzophenone imine derived from tert-butyl glycinate in 92% yield (solid CsOH, DCM, -78 to 23 °C, 22 h), the observed ee was only 30%. Even if this was increased to 64% by maintaining the reac-... 

Danelli T, Annunziata R, Benagha M, Cinquini M, Cozzi F, Tocco G (2003) Immobilization of catalysts derived from Cinchona alkaloids on modified polyethylene glycol). Tetrahedron Asymmetry 14 461—467... 

---