Cinchona polymeric

Janda, Bolm and Zhang generated soluble polymer-bound catalysts for the asymmetric dihydroxylation by attaching cinchona alkaloid derivatives to polyethylene glycol monomethyl ether (MeO-PEG) [84—87]. Since these polymeric catalysts like (24) are soluble in many common solvents they are often as effective as their small homogenous counterparts. Janda et al. prepared catalyst (24) in which two dihydroquinidine (DHQD) units were linked together by phthalazine and finally were attached to MeO-PEG via one of the bicyclic ring system moieties (Scheme... 

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]. 

Preliminary mechanistic studies show no polymerization of the unsaturated aldehydes under Cinchona alkaloid catalysis, thereby indicating that the chiral tertiary amine catalyst does not act as a nucleophilic promoter, similar to Baylis-Hilhnan type reactions (Scheme 1). Rather, the quinuclidine nitrogen acts in a Brpnsted basic deprotonation-activation of various cychc and acyclic 1,3-dicarbonyl donors. The conjugate addition of the 1,3-dicarbonyl donors to a,(3-unsaturated aldehydes generated substrates with aU-carbon quaternary centers in excellent yields and stereoselectivities (Scheme 2) Utility of these aU-carbon quaternary adducts was demonstrated in the seven-step synthesis of (H-)-tanikolide 14, an antifungal metabolite. 

A polymeric cinchona alkaloid-derived ligand 44 was prepared and used to catalyze the asymmetric dihydroxylation of olefins (see the diagram below).66 Both aliphatic and aromatic olefins afforded diols with good enantioselectivities. 

The first example of the use of a polymer-bound cinchona alkaloid in the AD was described in 1990 by Sharpless [48,49], The polymer was readily obtained by radical co-polymerization of 9-(p-chlorobenzoyl)quinidine acrylate with acrylonitrile. First applications in dihydroxylations of frans-stilbene using NMO as co-oxidant yielded products with enantioselectivities in the range of 85 -93 % ee. It is interesting that a repetitive use of the polymer was possible without great loss of reactivity, indicating that the metal was retained in the polymeric array. 

The development of polymeric cinchona-derived PTCs was triggered by the group of Jew and Park in 2001 [8]. The group paid particular attention to the fact that the cinchona alkaloids have demonstrated great utility in the Sharpless asymmetric dihydroxylation. Especially, it was noted that the significant improvements in both stereoselectivity and scope of the asymmetric dihydroxylation were achieved when the dimeric ligands of two independent cinchona alkaloid units attached to heterocyclic spacers were used, such as (DHQ)2-PHAL or (DHQD)2-PYR (Figure 4.4) [9]. 

Polymeric Cinchona-PTCs with Other Linkers... 

Figure 4.8 Polymeric cinchona-PTCs with other linkers.

Asymmetric Epoxidation with Polymeric Cinchona-PTCs 63... 

Petri, A., Pini, D. and Salvadori, P. Heterogeneous enantioselective dihydroxylation of aliphatic olefins - A comparison between different polymeric cinchona alkaloid derivatives, Tetrahedron Lett., 1995, 36, 1549-1552. 

To remove the feedback regulation mechanism and to avoid product degradation various adsorbents have been used for the in situ separation of plant cell cultures as shown in Table 1. In situ removal with polymeric adsorbents stimulated anthraquinone production more than the adsorbent-free control in Cinchona ledgeriana cells [35]. It was found that nonionic polymeric resins such as Amberlite XAD-2 and XAD-4 without specific functional groups are suitable for the adsorption of plant metabolite [36]. The use of the natural polymeric resin XAD-4 for the recovery of indole alkaloids showed that this resin could concentrate the alkaloids ajmalicine by two orders of magnitude over solvent extraction [37] but the adsorption by this resin proved to be relatively nonspecific. A more specific selectivity would be beneficial because plant cells produce a large number of biosynthetically related products and the purification of a several chemically similar solutes mixture is difficult [16]. 

Figure 1. Nucleophile catalysis by polymeric cinchona-alkaloids.

Quinine-acrylonitrile copolymer. Cinchona alkaloids can be copolymerized with another vinyl monomer such as acrylonitrile with AIBN as initiator. The highest yield of polymer in the case of quinine is obtained when the quinine/acrylonitrile ratio is 1 20. This method was used to obtain a polymeric form of the alkaloid in which the crucial part of the molecule for asymmetric reactions—the amino alcohol unit—is free. The polymers are stable, light yellow solids, soluble in polar aprotic solvents (DMF and DMSO), but insoluble in common organic solvents. 

To explore the possibility of recycling alkaloid-Os04 complexes, several polymer-bound alkaloid derivatives have been used for heterogeneous catalytic asymmetric dihydroxylations. As chiral ligands, polymerized cinchona alkaloids or copolymers of quinine derivatives with acrylonitrile or styrene were studied [46]. In general, lower select vities and decreased rates were observed. 

From the systematic investigation of the Park and Jew group, several highly efficient and practical polymeric cinchona PTCs were developed (Scheme 6.6). Interestingly, polymeric catalysts with a specific direction of attachment between aromatic linkers (e.g., benzene or naphthalene) and each cinchona unit were found to be effective in the asymmetric alkylation of 4b. The phenyl-based polymeric PTCs with the meta-relationship between cinchona units such as 14, 15, and 18 showed their high catalytic efficiencies. Furthermore, the 2,7-dimethylnaphthalene moiety as in 16 and 17 was ultimately found to be the ideal spacer for dimeric cinchona PTC for this asymmetric alkylation. For example, with 5 mol% of 16, the benzylation of 4b was completed within a short reaction time of 30 min at 0 ° C, affording (S)-5a in 95% yield with 97% ee. Almost optically pure (>99% ee) (S)-5a was obtained at lower reaction temperature (—40 °C) with 16, and moreover, even with a smaller quantity (1 mol%), its high catalytic efficiency in terms of both reactivity and enantioselectivity was well conserved. 

Pioneering attempts at using cinchona alkaloids as a platform for chiral stationary phase preparation have been reported as early as in the mid-1950s by Grubhofer and Schleith [52]. The chiral anion exchange polymeric materials were prepared by immobilization of quinine (and other cinchona alkaloids) via the 9-hydroxyl group or quinuclidine nitrogen to a polymer support. However, this resulted in very low selectivities of these phases toward racemic mandelic acid as a test analyte. Results of the early studies have been reviewed in detail by Davankov [53]. 

Cinchona alkaloids are by far the chiral fragments most used for the challenge of achieving chiral PTC using insoluble supports. For this purpose, one of the nitrogen atoms of 71, usually the aliphatic one, is quaternized, either by using this atom to anchor the polymeric backbone (92, Scheme 10.17) or by its appropriate... 

The power of column-like reactors for continuous flow processes lies in the possibility to sequentially link them up in order to carry out multistep syntheses in solution in one run (see also Schemes 1 and 2). Lectka and coworkers utilized conventional fritted and jacketed columns for this purpose. These columns were filled with conventional functionalized polymeric beads [47]. The continuous flow was forced by gravity. En route to / -lactams polymer beads functionalized with the Schwesinger base 17, a cinchona alkaloid derivative 18 as a chiral catalyst, and a primary amine 19 were sequentially employed. They first guaranteed the generation of phenyl ketene from phenyl... 

Although very low levels of alkaloids are produced by the Cinchona cell cultures, they are capable of producing considerable amounts of anth-raquinones, particuleu-ly after elicitation with fungal elicitors. The anth-raquinones are thought to act as phytoalexins in this plant genus (575). Anthraquinone production could be stimulated by adding polymeric adsorbents like Amberlite XAD-7 to the medium. A production rate of 20 mg/liter/day could be obtained in this way (576). 

Other approaches to immobilization have included the use of macroporous resins and functionalized silica solids that contain residual vinyl groups which can be dihydroxylated as a means of anchoring the transition metal to the solid support the resulting osmium(VI) complexes are then reoxidized in situ. The AD reaction has also been investigated with polymeric versions of Sharpless chiral cinchona based ligands. ... 

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