Cinchona nitrogen

A third variation on this theme was recently reported by Hodge (48), who alkylated the cinchona alkaloids on the quinuclidine nitrogen using the well-known chloromethylated cross-linked polystyrenes. Optical yields were low (10 to 30%) and no significant conclusions were drawn. 

Asymmetric dihydroxylation can be achieved using osmium tetroxide in conjunction with a chiral nitrogen ligand. " The very successful Sharpless procedure uses the natural cinchona alkaloids dihydroquinine (DHQ) and its diastereomer dihy-droquinidine (DHQD), as exemplified in the epoxidation of imni-stilbene... 

Since the cinchona alkaloid-derived selectors do possess two basic sites, the qui-nuclidine and quinoline nitrogens with the former being more basic, ion-pairs of 1 1 or 2 1 stoichiometry could be formed. To shed light on this issue, the binding stoichiometry was investigated by Maier et al. [92] and Czerwenka et al. [93]... 

The notable mode of stereoselectivity of Cinchona alkaloids is presented by its psendoenantiomeric pairs which can be employed to generate either enantiomer of chiral prodnct. Key moieties that are central to Cinchona alkaloids are the quinuclidine nitrogen and the adjacent C(9)-OH (the N-C(8)-C(9)-OH moiety) (Fig. 2). In psendoentiomeric alkaloids in the natural open conformation, the torsion angle N-C(8)-C(9)-0 are opposite in sign Q and CD are (-), and thereby induce selectivity for one enantiomer, whereas QD and C are (-I-) and afford the other enantiomer [28, 29],... 

The focus of this review is to discuss the role of Cinchona alkaloids as Brpnsted bases in organocatalytic asymmetric reactions. Cinchona alkaloids are Lewis basic when the quinuclidine nitrogen initiates a nucleophilic attack to the substrate in asymmetric reactions such as the Baylis-Hillman (Fig. 3), P-lactone synthesis, asymmetric a-halogenation, alkylations, carbocyanation of ketones, and Diels-Alder reactions 30-39] (Fig. 4). 

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. 

Concerns over toxicity have also been raised for the Cinchona alkaloids, which have been described as dangerous to handle and highly toxic by Federsel [59], who recommended linkage to a solid support as a means of preventing toxic effects. At the present time, there is no indication of what effect the many substituents that have been linked to the quinudidine nitrogen in Cinchona alkaloids could have on toxicity and, until this problem is solved, they will be viewed with caution by industry. 

Cinchona alkaloids, naturally ubiquitous /3-hydroxy tertiary-amines, are characterized by a basic quinuclidine nitrogen surrounded by a highly asymmetric environment (12). Wynberg discovered that such alkaloids effect highly enantioselective hetero-[2 -I- 2] addition of ketene and chloral to produce /3-lactones, as shown in Scheme 4 (13). The reaction occurs catalytically in quantitative yield in toluene at — 50°C. Quinidine and quinine afford the antipodal products by leading, after hydrolysis, to (S)- and (/ )-malic acid, respectively. The presence of a /3-hydroxyl group in the catalyst amines is not crucial. The reaction appears to occur... 

Carbon-Nitrogen Bonds. Several groups have studied the synthesis of optically active a-amino acids from inexpensive and readily available a-haloesters by displacement with phthalimide in the presence of chiral cinchona catalysts [1 le,24h,24i,47e,60d,77]. Early studies, with chiral, non-racemic starting material, showed that this reaction occurs with partial... 

Moreover, bulk MIP was prepared [56] exhibiting diastereoselectivity for cinchona alkaloids. In the presence of MIP in solution, the cinchonidine fluorescence emission was hypsochromically shifted with the increase of the cinchonide concentration. That is, maximum of the fluorescence emission was at 390 nm in the absence of cinchonidine whereas it was at 360 nm at higher concentrations of cinchonidine. When cinchonidine was examined in the absence of MIP or in the presence of NIP, there was no spectral shift or this shift was negligibly small. This shift has been explained on the basis of protonation of the nitrogen atoms present in the cinchonidine structure. 

It is generally considered that a quaternary ammonium salt derived from cinchona alkaloids has an imaginary tetrahedron composed of four carbon atoms adjacent to the bridgehead nitrogen. As shown in Figure 4.2, in order to serve as an efficient... 

Dehmlow and coworkers [17] compared the efficiency of monodeazadnchona alkaloid derivatives 14a-c in the enantioselective epoxidation of naphthoquinone 50 with that of cinchona alkaloid-derived chiral phase-transfer catalysts 15a-c (Table 7.7) (for comparison of the alkylation reaction, see Table 7.1). Interestingly, the non-natural cinchona alkaloid analogues 14a-c afforded better results than natural cinchona alkaloids 15a-c. The deazacinchonine derivatives 14a,b produced epoxidation product 51 in higher enantioselectivity than the related cinchona alkaloids 15a,b. Of note, catalyst 14c, which possessed a bulky 9-anthracenylmethyl substituent on the quaternary nitrogen, afforded the highest enantioselectivity (84% ee). 

Several families of efficient chiral phase transfer catalysts are now available for use in asymmetric synthesis. To date, the highest enantiomeric excesses (>95% ee) are obtained using salts derived from cinchona alkaloids with a 9-anthracenylmethyl substituent on the bridgehead nitrogen (e.g. lb, 2b). These catalysts will be used to improve the enantiose-lectivity of existing asymmetric PTC reactions and will be exploited in other anion-mediated processes both in the laboratory and industrially. 

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